ENTITYA TYPEA IDA DATABASEA ENTITYB TYPEB IDB DATABASEB EFFECT MECHANISM RESIDUE SEQUENCE TAX_ID CELL_DATA TISSUE_DATA MODULATOR_COMPLEX TARGET_COMPLEX MODIFICATIONA MODASEQ MODIFICATIONB MODBSEQ PMID DIRECT NOTES ANNOTATOR SENTENCE SCORE SIGNOR_ID CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1350 ISRTTSAtPLKDNTQ 9606 10995387 YES llicata Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter. 0.447 SIGNOR-82141 YY1 protein P25490 UNIPROT ATP6V1A protein P38606 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28592880 YES Giorgia We investigated the relationship between transcription factor YY1 and ATP6V1A, and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A. To validate that YY1 transcriptionally regulates ATP6V1A, we discovered that the ATP6V1A core promoter region contains three YY1 binding sites. Moreover, RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression, while YY1 overexpression increased ATP6V1A expression level. 0.326 SIGNOR-260635 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 YES lperfetto The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)ser(191) and ser(216), were identified, whose mutation to alanine reduces er81 activity upon erk-mapk stimulation. 0.293 SIGNOR-92447 IKK-complex complex SIGNOR-C14 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR down-regulates phosphorylation 9606 10195894 YES lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response 0.843 SIGNOR-216373 pazopanib chemical CHEBI:71219 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 YES Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. 0.8 SIGNOR-257734 ICAM3 protein P32942 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates activity binding 8777714 YES lperfetto A novel leukointegrin, alpha d beta 2, binds preferentially to ICAM-3. 0.612 SIGNOR-253371 MYLK protein Q15746 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 YES lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. 0.837 SIGNOR-188797 GSK3B protein P49841 UNIPROT HNRNPD protein Q14103 UNIPROT down-regulates phosphorylation Ser83 DEGHSNSsPRHSEAA 9606 11903055 YES gcesareni In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation. 0.347 SIGNOR-116140 COL6A2 protein P12110 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. 0.7 SIGNOR-254674 MAP3K8 protein P41279 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8131746 YES lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf 0.573 SIGNOR-244892 ESR1 protein P03372 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 NO miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice 0.289 SIGNOR-253470 CEP135 protein Q66GS9 UNIPROT SASS6 protein Q6UVJ0 UNIPROT up-regulates activity binding 9606 23511974 YES miannu In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation. 0.597 SIGNOR-269676 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser215 RRSRAASsQRAEEED 9606 22422861 YES lperfetto Chmp4c functioned in the aurora b-dependent abscission checkpoint to prevent both premature resolution of intercellular chromosome bridges and accumulation of dna damage. Chmp4c engaged the chromosomal passenger complex (cpc) via interaction with borealin, which suggested a model whereby chmp4c inhibits abscission upon phosphorylation by aurora b 0.47 SIGNOR-196728 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu72 EEAREVFeDSDKTNE -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263673 ROS stimulus SIGNOR-ST2 SIGNOR NLRP3 protein Q96P20 UNIPROT up-regulates activity 28531279 NO lperfetto Different mechanisms have been proposed for NLRP3 activation, including potassium efflux, calcium influx, reactive oxygen species (ROS), oxidized mitochondrial DNA, translocation of cardiolipin from the inner mitochondrial membrane, phagosome destabilization, perturbation in cell volume and pore-formation mechanisms driven by the host or bacteria 0.7 SIGNOR-256427 SEPTIN6 protein Q14141 UNIPROT SEPT6/SEPT7 complex SIGNOR-C72 SIGNOR form complex binding 9606 16914550 YES miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. 0.2 SIGNOR-148895 PC protein P11498 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI down-regulates quantity chemical modification 9606 24363178 YES miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) 0.8 SIGNOR-266554 ETV3 protein P41162 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22028473 YES miannu ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation. 0.2 SIGNOR-262780 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser123 EEGFGSSsPVKSPAA 9606 23051732 YES lperfetto However, when both Ser-123 and Ser-139 were modified (2A), although Wee1 was still phosphorylated by Cdk1, treatment with active Cdc14A did not decrease the phosphorylation signal to any significant extent ( xref , lane 5), indicating that Cdc14A dephosphorylates Wee1 at Ser-123 and Ser-139 residues.|Our results indicate that Wee1 is a substrate of Cdc14 phosphatases in human cells and that by reversing specific Cdk1 phosphorylation, the Cdc14A isoform induces Wee1 stability, which in turn directly inhibits Cdk1 activity. 0.545 SIGNOR-276952 CCKBR protein P32239 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.255 SIGNOR-257238 MYC protein P01106 UNIPROT CUL1 protein Q13616 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12835716 YES gcesareni Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2 0.484 SIGNOR-102749 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser364 TRLDRTGsSPTQGIV 9606 15767678 YES gcesareni Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis. 0.332 SIGNOR-134584 Ub:E2 complex SIGNOR-C497 SIGNOR CBL protein P22681 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271100 UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 21311563 YES lperfetto Beclin 1, the mammalian orthologue of yeast Atg6, has a central role in autophagy, a process of programmed cell survival, which is increased during periods of cell stress and extinguished during the cell cycle. It interacts with several cofactors (Atg14L, UVRAG, Bif-1, Rubicon, Ambra1, HMGB1, nPIST, VMP1, SLAM, IP(3)R, PINK and survivin) to regulate the lipid kinase Vps-34 protein and promote formation of Beclin 1-Vps34-Vps15 core complexes 0.86 SIGNOR-171902 GARS1 protein P41250 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 24898252 YES miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 0.8 SIGNOR-270481 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CSNK1D protein P48730 UNIPROT up-regulates binding 9606 12000790 YES lperfetto Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45). 0.536 SIGNOR-227908 DSCAML1 protein Q8TD84 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR down-regulates 9606 30745321 NO miannu The DSCAM/L1 transcriptome data sets also contained a significant number of genes known to regulate synapse formation or function.Increased nuclear DSCAM levels inhibit synapse formation 0.7 SIGNOR-264281 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr754 KIYSGDYyRQGRIAK 9606 8702477 YES gcesareni By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain. 0.2 SIGNOR-42922 FGR protein P09769 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 YES miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. 0.2 SIGNOR-276394 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates activity binding 9606 18923185 YES miannu IL-6 and IL-11 are the only members of the family that signal via the induction of a gp130 homodimer after binding their specific -receptors, IL-6R and IL-11R. When IL-6 binds to the homodimerized IL-6Rα/gp130Rβ, it results in a signaling cascade that is initiated by the autophoshorylation and activation of JAK. 0.918 SIGNOR-255324 HCRT protein O43612 UNIPROT HCRTR1 protein O43613 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9491897 YES gcesareni Identification and initial biological characterization of two orexins as well as their two receptors 0.771 SIGNOR-53667 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR down-regulates 9606 23620016 NO In the current study, addition of ERK inhibitors suppressed IL-6-induced RORgammat expression and promoted TGF-beta-induced Foxp3 expression. 0.7 SIGNOR-254686 SOD3 protein P08294 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI down-regulates quantity chemical modification 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272271 FGFR1 protein P11362 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 9606 12270934 NO lperfetto Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors 0.31 SIGNOR-244865 midostaurin chemical CHEBI:63452 ChEBI PRKCA protein P17252 UNIPROT down-regulates activity chemical inhibition 16969355 YES lperfetto Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases 0.8 SIGNOR-261981 Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 NO miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.7 SIGNOR-270713 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser72 KSERYSSsGSPANSF 9606 BTO:0000093 35513296 YES miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings 0.342 SIGNOR-277906 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1626 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248805 FKBP5 protein Q13451 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression catalytic activity 9606 BTO:0002035 28978117 YES Barakat FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels 0.2 SIGNOR-274973 BTRC protein Q9Y297 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9534 BTO:0004055 10514424 YES miannu Interaction with beta-TrCP is also necessary for ubiquitination of IkappaBbeta upon stimulation of cells, and deletion of the F-box in beta-TrCP abolishes its ability to ubiquitinate IkappaBbeta. Therefore, these results indicate that beta-TrCP plays a critical role in the activation of NF-kappaB by assembling the ubiquitin ligase complex for both phosphorylated IkappaBalpha and IkappaBbeta.β-TrCP recognizes IκBα phosphorylated at Ser-32 and Ser-36 through its WD40 domain, whereas the F-box motif recruits additional proteins including Skp1 and Cullin to form the Skp1-cullin-F-box (SCF) ubiquitin ligase complex 0.798 SIGNOR-272555 GALR2 protein O43603 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-256741 INSR protein P06213 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 11075717 YES Insulin predominantly phosphorylates the Shc Tyr-317 residue. Phosphorylated Shc binds to Grb2 which forms a complex with Sos guanine nucleotide exchange factor for p21ras.  0.709 SIGNOR-251325 EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 14967450 YES lperfetto The egf-r coimmunoprecipitated with p85 alpha 0.81 SIGNOR-121959 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser233 VSSQHRYsTPHAFTF 9534 12801936 YES miannu Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259). 0.499 SIGNOR-250040 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr88 KHLVALYtRDEHFAI -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.32 SIGNOR-251076 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity phosphorylation Tyr305 GEAPSNIyVEVEDEG 9606 18541536 YES miannu Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition. 0.579 SIGNOR-262890 PLK1 protein P53350 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Thr151 RSYSRLEtLGSASTS -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.704 SIGNOR-276122 BIRC2 protein Q13490 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 14960576 YES lperfetto Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria. 0.2 SIGNOR-121877 IRF7 protein Q92985 UNIPROT IFNA1 protein P01562 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16612387 NO gcesareni Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production. 0.564 SIGNOR-146119 SATB1 protein Q01826 UNIPROT AREG protein P15514 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 17343824 NO miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 0.247 SIGNOR-255133 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser673 RVQSKIGsLDNITHV -1 10090741 YES miannu We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. 0.43 SIGNOR-250175 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.2 SIGNOR-249646 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 YES lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | 0.345 SIGNOR-249118 PRKCG protein P05129 UNIPROT PEBP1 protein P30086 UNIPROT up-regulates activity phosphorylation Ser153 RGKFKVAsFRKKYEL 10116 BTO:0003036 12551925 YES lperfetto Here we report that one mechanism involves dissociation of Raf kinase inhibitory protein (RKIP) from Raf-1. Classic and atypical but not novel PKC isoforms phosphorylate RKIP at serine 153 (Ser-153). RKIP Ser-153 phosphorylation by PKC either in vitro or in response to 12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor causes release of RKIP from Raf-1, whereas mutant RKIP (S153V or S153E) remains bound. I 0.382 SIGNOR-249190 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0002524 32989218 YES miannu The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. 0.2 SIGNOR-277801 Ub:E2 complex SIGNOR-C497 SIGNOR RNF146 protein Q9NTX7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271078 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.499 SIGNOR-248301 GART protein P22102 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI down-regulates quantity chemical modification 9606 34283828 YES miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 0.8 SIGNOR-267299 PTEN protein P60484 UNIPROT NR5A1 protein Q13285 UNIPROT down-regulates activity dephosphorylation 9606 27838257 YES miannu The fact that SF-1 and PIP3 is robustly dephosphorylated by PTEN, yet SF-1 and PIP2 is resistant to phosphorylation by p110 PI3-kinases, suggests that nuclear proteins like SF-1 can help decouple PTEN signaling in the nucleus from p110 signaling.|We also showed that PTEN can dephosphorylate the SF-1 and PIP3 product of the IPMK reaction, and that PTEN inhibits SF-1 transcriptional activity. 0.256 SIGNOR-277117 MC4R protein P32245 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257069 GLI3 protein P10071 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002572 16571352 NO lperfetto The basal expression of Gli1, Ptc1, and Hip1 was positively associated with the loss of Gli3 alleles.These findings implicate Gli3 as a repressor of Hh target gene expression. 0.458 SIGNOR-209638 ATM protein Q13315 UNIPROT SP1 protein P08047 UNIPROT unknown phosphorylation Ser101 DLTATQLsQGANGWQ 9606 18619531 YES llicata Thus, phosphorylation of ser-101 on sp1 is a general response to dna damage, dependent on both atm and atr. 0.411 SIGNOR-179435 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 9606 SIGNOR-C3 18722121 YES llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity 0.547 SIGNOR-180458 RBBP7 protein Q16576 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 YES miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. 0.555 SIGNOR-268815 ENY2 protein Q9NPA8 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.591 SIGNOR-269577 USP15 protein Q9Y4E8 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000567 27368102 YES miannu SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors. Dissociation of the RNF26/SQSTM1 complex, promoted by the DUB USP15 (yellow), releases target vesicles for (4) fast transport into the cell periphery. 0.26 SIGNOR-269829 GRIA2 protein P42262 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 NO Luana AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by naïve ones. 0.7 SIGNOR-265796 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1696 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248774 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000675 23616010 UNK lperfetto The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C_ (PKC_) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun 0.2 SIGNOR-236767 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193540 FBH1 protein Q8NFZ0 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding -1 25585578 YES miannu The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64. 0.2 SIGNOR-272452 PIM1 protein P11309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18593906 YES gcesareni We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro. 0.383 SIGNOR-179296 MAP2K2 protein P36507 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 YES gcesareni The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform. 0.2 SIGNOR-179393 SAV1 protein Q9H4B6 UNIPROT STK3 protein Q13188 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0005238 16930133 YES Hippo pathway Gianni Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. 0.834 SIGNOR-261957 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser146 FYKRRGAsDLSSEEG -1 8954982 YES llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. 0.324 SIGNOR-251034 SMARCE1 protein Q969G3 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.798 SIGNOR-270752 RNF144A protein P50876 UNIPROT PRKDC protein P78527 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24979766 YES miannu We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation. 0.567 SIGNOR-272213 F10 protein P00742 UNIPROT Factor Va-Xa complex SIGNOR-C318 SIGNOR form complex binding -1 2026608 YES lperfetto The binding of factor Xa to factor Va in the presence of Ca2+ ions and phospholipid is fundamental for the activation of prothrombin to thrombin. |Regardless of which protein was labeled, a factor Xa-Va complex (s20,w = 9.8) was formed. The interaction is specific and reversible. I 0.775 SIGNOR-263557 Elongator complex complex SIGNOR-C466 SIGNOR TUBA1A protein Q71U36 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 YES miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 0.332 SIGNOR-269717 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM64B protein A6NI03 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271271 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr95 KGYNDDYyEESYFTT 9606 BTO:0000567 BTO:0000887 19789182 YES llicata Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf 0.452 SIGNOR-188316 RNF123 protein Q5XPI4 UNIPROT CBX5 protein P45973 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 23077635 YES miannu In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation. 0.2 SIGNOR-272035 FBN1 protein P35555 UNIPROT MMP1 protein P03956 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16442122 NO Regulation of expression miannu In this study we show that a fibrillin-1 fragment containing a EGFEPG sequence that conforms to a putative GxxPG elastin-binding protein (EBP) consensus sequence upregulates the expression and production of matrix metalloproteinase (MMP)-1 by up to ninefold in a cell culture system. Mutations in the gene for fibrillin-1 cause Marfan syndrome (MFS), a common hereditary disorder of connective tissue 0.346 SIGNOR-251887 CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 16431920 YES fspada These data suggest that c/CEBP beta activates a single unified pathway of adipogenesis involving its stimulation of PPARgamma expression, which then activates C/EBP alpha expression by dislodging HDAC1 from the promoter for degradation in the proteasome 0.728 SIGNOR-143952 maraviroc chemical CHEBI:63608 ChEBI CCL3 protein P10147 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193928 SRC protein P12931 UNIPROT FLOT1 protein O75955 UNIPROT up-regulates activity phosphorylation Tyr149 MGISVVSyTLKDIHD 9606 BTO:0001583 24983503 YES done miannu Taken together, we conclude that mitochondrial c-Src phosphorylates flotillin-1 at Tyr56 and Tyr149, and that these phosphorylations are required for its interaction with CxII and the prevention of ROS production. 0.335 SIGNOR-273804 D-glucopyranose smallmolecule CHEBI:4167 ChEBI AMP smallmolecule CHEBI:456215 ChEBI down-regulates 9606 10409121 NO gcesareni The activation in response to glucose removal appeared to be due to changes in the concentration of the known regulators of the cascade, i.e. Amp and atp, since ampk activation was associated with a large increase in the cellular amp. 0.8 SIGNOR-69249 JNK proteinfamily SIGNOR-PF15 SIGNOR PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation 9606 18553930 YES inferred from 70% family members gcesareni Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells. 0.2 SIGNOR-269981 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203596 ITGB1 protein P05556 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.803 SIGNOR-253174 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser269 GNLLGRNsFEVRVCA 9606 20959462 YES llicata Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity. 0.718 SIGNOR-168745 thromboxane smallmolecule CHEBI:26995 ChEBI TBXA2R protein P21731 UNIPROT up-regulates activity chemical activation 19747485 YES Thromboxane plays an essential role in hemostasis, regulating platelet aggregation and vessel tone. In humans, it signals through the TPalpha and TPbeta isoforms that are transcriptionally regulated by distinct promoters Prm1 and Prm3, respectively. 0.8 SIGNOR-254264 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser285 NHTLAPAsPAPARPR -1 11113134 YES llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  0.355 SIGNOR-250646 PRKACA protein P17612 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 YES gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. 0.429 SIGNOR-97550 PTPRG protein P23470 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.253 SIGNOR-254708 ATP synthase complex SIGNOR-C264 SIGNOR ATP smallmolecule CHEBI:15422 ChEBI up-regulates quantity chemical modification 9606 21874297 YES miannu Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F(1), situated in the mitochondrial matrix, and F(o), located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. 0.8 SIGNOR-261410 CDK1 protein P06493 UNIPROT UBXN2B protein Q14CS0 UNIPROT down-regulates activity phosphorylation Thr59 TVFKSPRtPPQRFYS 23500464 YES lperfetto At mitosis, Cdc2 kinase phosphorylates p47 on Serine-140 and p37 on Serine-56 and Threonine-59, respectively. The phosphorylated p47 and p37 are unable to bind to Golgi membranes, resulting in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively. 0.2 SIGNOR-265041 AKAP11 protein Q9UKA4 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity binding 9606 BTO:0000007 phosphorylation:Thr1136 AKEFAPAtPPSTPHN 26088133 YES lperfetto A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles. 0.373 SIGNOR-264817 ITCH protein Q96J02 UNIPROT TGIF1 protein Q15583 UNIPROT up-regulates activity ubiquitination 9606 20064471 YES miannu Based on these observations, we suggest that a mechanism of protein stabilization might account for the accumulation of TGIF protein in response to TNF-alpha signaling.Next, we used three different approaches to investigate the possibility that Itch could contribute to the ability of TNF-alpha to promote TGIF stabilization.|We also employed the experimental strategy combining the detection of monoubiquitinated and polyubiquitinated TGIF and found that mutation of K259 not only compromised monoubiquitination of TGIF by Itch but also enhanced its polyubiquitination. 0.2 SIGNOR-278817 CDK5 protein Q00535 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT up-regulates activity phosphorylation Ser1124 PPTSPQSsPRKGYTL 9606 25189171 YES miannu Our results demonstrate that the Cdk5-dependent activation of RapGEF2, spatial activation of Rap1 signalling and Rap1-facilitated surface localization of N-cadherin in the upper intermediate zone control neuronal migration and ultimately the architecture of the mammalian cerebral cortex.|This demonstrates that Cdk5 phosphorylates RapGEF2 at Ser1124 in vitro . 0.39 SIGNOR-278258 hsa-mir-494-3p mirna URS0000535FDD_9606 RNAcentral CDH2 protein P19022 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000150 25955111 YES In the present study, significant upregulation of E-cadherin and downregulation of N-cadherin, vimentin and α-SMA were observed in the miR-494 mimic-transfected cells compared to the control cells, indicating suppression of EMT following miR-494 transfection in breast cancer cells. 0.4 SIGNOR-277945 CD79A protein P11912 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 32323266 YES scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. 0.656 SIGNOR-268200 PXN protein P49023 UNIPROT ILK protein Q13418 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11304546 YES gcesareni Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events. 0.799 SIGNOR-106824 MAF protein O75444 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20067416 NO miannu MMP-13 gene expression is regulated primarily at the transcriptional level. In this study, we investigated the role of c-maf in regulating MMP-13 transcription. Using transient transfection system with an c-maf construct, and MMP-13 promoter-luciferase constructs with specific mutations in transcription factor binding sites, we found that c-maf can significantly enhance MMP-13 promoter activity via the AP-1 sitecv 0.252 SIGNOR-254560 AURKB protein Q96GD4 UNIPROT CDCA2 protein Q69YH5 UNIPROT down-regulates activity phosphorylation Ser542 KKINRRKsQETKCTK 9606 BTO:0000567 32938714 YES done miannu This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin. 0.447 SIGNOR-274002 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Ser387 GQDEDAWsPVEMMGK -1 15014043 YES miannu We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. However, when both S2 and S11 were simultaneously mutated to As, the resulting 6His-RCC1S2,11A failed to be phosphorylated, whereas all of the other double mutants were phosphorylated (Fig. 1C). As expected, mutating all four sites to As (the 6His-RCC1S2,11,387A-T274A) also blocked phosphorylation (Fig. 1C). 0.505 SIGNOR-262703 YY1 protein P25490 UNIPROT SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR form complex binding 10090 20887952 YES lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. 0.2 SIGNOR-235580 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1675 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248809 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273051 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR KRT8 protein P05787 UNIPROT unknown phosphorylation 16554440 YES inferred from 70% family members lperfetto Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002). 0.2 SIGNOR-270135 PPP5C protein P53041 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates activity dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 16954377 YES llicata MAK and MRK require dual phosphorylation in a TDY motif catalyzed by an unidentified human threonine kinase and tyrosine autophosphorylation.| Protein phosphatase 5 (PP5) interacts with MRK in a complex and dephosphorylates MRK at T157 in vitro and in situ. 0.2 SIGNOR-248541 VKORC1 protein Q9BQB6 UNIPROT Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity chemical modification 9606 31226734 YES lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form 0.8 SIGNOR-265901 F2RL1 protein P55085 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.334 SIGNOR-257232 PRPF8 protein Q6P2Q9 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.78 SIGNOR-270641 PLK1 protein P53350 UNIPROT SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser138 RPPVLDEsWIREQTT 9606 25482198 YES miannu Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. 0.453 SIGNOR-263098 KLF1 protein Q13351 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002731 9707565 NO Regulation miannu EKLF is an acetylated transcription factor, and that it interacts in vivo with CBP, p300, and P/CAF. However, its interactions with these histone acetyltransferases are not equivalent, as CBP and p300, but not P/CAF, utilize EKLF as a substrate for in vitro acetylation within its trans-activation region. The functional effects of these interactions are that CBP and p300, but not P/CAF, enhance EKLF's transcriptional activation of the beta-globin promoter in erythroid cells. 0.404 SIGNOR-251790 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI HIF1A protein Q16665 UNIPROT up-regulates activity chemical activation 20383689 YES lperfetto HIF prolyl hydroxylase-3 mediates alpha-ketoglutarate-induced apoptosis and tumor suppression|The hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are enzymes that are functionally inactivated in hypoxia, as they use both oxygen and alpha-ketoglutarate as substrates to hydroxylate target prolyl residues. 0.8 SIGNOR-253138 UBE2D2 protein P62837 UNIPROT PDZRN3 protein Q9UPQ7 UNIPROT up-regulates activity binding 9534 BTO:0000298 17576800 YES miannu Our initial tests of various E2s showed that the RING domain of PDZRN3 exhibits ubiquitin ligase activity in the presence of E1 and the UbcH5 family of E2 enzymes (Fig. 3 A). Consistent with this finding, GST pull-down assays showed that PDZRN3 directly interacts with the UbcH5B ubiquitin conjugating enzyme (Fig. 3 B).  0.386 SIGNOR-271663 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2B protein Q8TCG2 UNIPROT down-regulates activity chemical inhibition -1 21704602 YES Luana Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity 0.8 SIGNOR-258316 Ub:E2 complex SIGNOR-C497 SIGNOR RSPRY1 protein Q96DX4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271210 RELA protein Q04206 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 BTO:0000452;BTO:0002625 22223884 YES alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin 0.442 SIGNOR-254527 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.305 SIGNOR-249009 PTGS2 protein P35354 UNIPROT episterol ester smallmolecule CHEBI:52393 ChEBI down-regulates quantity chemical modification 9606 19126760 YES miannu After biosynthesis, 2-AG is partially degraded by postsynaptic COX-2, and partly released to the extracellular space.¬† 0.8 SIGNOR-264270 suprofen chemical CHEBI:9362 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001061 18667313 YES Luana Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2.  0.8 SIGNOR-257808 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 9736715 YES acerquone Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation. 0.778 SIGNOR-252597 DUSP23 protein Q9BVJ7 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser322 NYPFPLTsWPCSFSP 9606 20855292 YES lperfetto DUSP23 prevents GCM1 from ubiquitination and prolongs the half-life of GCM1.|Second, DUSP23 is able to dephosphorylate Ser322 in GCM1 in vitro and in a stable cell line expressing HA-GCM1. 0.465 SIGNOR-276982 PICK1 protein Q9NRD5 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity binding 10116 BTO:0003036 16554470 YES miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. 0.802 SIGNOR-268178 ITGAV protein P06756 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.915 SIGNOR-253205 JAG1 protein P78504 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 10551863 YES Binding Calcium-dependent. gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. 0.643 SIGNOR-269936 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 YES lperfetto Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites 0.923 SIGNOR-235738 RLIM protein Q9NVW2 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27684546 YES miannu This suggests that RLIM negatively regulates the transcriptional activity of c-Myc.|We further showed that RLIM can promote polyubiquitination of c-Myc in cells. 0.37 SIGNOR-278551 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr605 KDLVSCAyQVARGME 9606 12601080 YES lperfetto Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways. 0.2 SIGNOR-98634 MAPK8 protein P45983 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 YES gcesareni Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset. 0.411 SIGNOR-164089 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 10090741 YES lperfetto We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. 0.595 SIGNOR-249315 TGFB1 protein P01137 UNIPROT LPP protein Q93052 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 22886954 NO miannu Tgf-_1-induced lpp expression dependant on rho kinase during differentiation and migration of bone marrow-derived smooth muscle progenitor cells 0.326 SIGNOR-191768 CLK3 protein P49761 UNIPROT USP13 protein Q92995 UNIPROT up-regulates activity phosphorylation Tyr708 EPLTMPGyGGAASAG 9606 BTO:0003911 32453420 YES done miannu CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes. 0.2 SIGNOR-274122 N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide chemical CHEBI:91407 ChEBI JAK1 protein P23458 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191244 YES1 protein P07947 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation 9606 BTO:0002181 26198631 YES miannu YY1 phosphorylation is mediated by Src family kinases. 0.2 SIGNOR-276941 VCB-Cul2 complex SIGNOR-C524 SIGNOR TNFRSF1B protein P20333 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 15899873 YES miannu While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-alpha by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation 0.2 SIGNOR-271545 MAPK1 protein P28482 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 YES gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. 0.733 SIGNOR-90517 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser51 LRPSTSRsLYASSPG -1 2500966 YES miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. 0.309 SIGNOR-250069 KIF5B protein P33176 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 NO miannu The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue. 0.7 SIGNOR-264068 MARCHF9 protein Q86YJ5 UNIPROT VAMP8 protein Q9BV40 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271531 CREBL2 protein O60519 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 21728997 NO Luana Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression. 0.2 SIGNOR-261573 ATM protein Q13315 UNIPROT STK11 protein Q15831 UNIPROT unknown phosphorylation Thr363 IEDDIIYtQDFTVPG 9606 BTO:0000848 12234250 YES llicata We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo. however, phosphorylation of lkb1 at thr-366 may have some role in enabling lkb1 to suppress cell growth 0.572 SIGNOR-92877 KLHL15 protein Q96M94 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0001938 27561354 YES miannu  Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. 0.46 SIGNOR-272411 CFB protein P00751 UNIPROT C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR form complex binding 9606 BTO:0000089 cleavage:Arg259 GPGEQQKrKIVLDPS 26489954 YES complement factor B, b fragment: PRO_0000027547 lperfetto Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over) 0.906 SIGNOR-263486 TRIM17 protein Q9Y577 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001976 22976837 YES miannu Here, we identified Trim17 as a novel E3 ubiquitin-ligase for Mcl-1. Indeed, Trim17 co-immunoprecipitated with Mcl-1. Trim17 ubiquitinated Mcl-1 in vitro. Overexpression of Trim17 decreased the protein level of Mcl-1 in a phosphorylation- and proteasome-dependent manner. Finally, knock down of Trim17 expression reduced both ubiquitination and degradation of Mcl-1 in neurons. 0.445 SIGNOR-272032 PAK4 protein O96013 UNIPROT PACSIN1 protein Q9BY11 UNIPROT up-regulates activity phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 YES miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 0.295 SIGNOR-263023 ARHGEF1 protein Q92888 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.831 SIGNOR-260528 TEAD1 protein P28347 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21527258 NO gcesareni We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. 0.32 SIGNOR-173445 CGAS protein Q8N884 UNIPROT 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI up-regulates quantity chemical modification 23258413 YES lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. 0.8 SIGNOR-276593 CAPN3 protein P20807 UNIPROT GSK3A protein P49840 UNIPROT up-regulates activity cleavage 9606 25969760 YES lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase 0.2 SIGNOR-251606 SPRY4 protein Q9C004 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002058 20501643 NO miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 0.251 SIGNOR-253041 streptozocin chemical CHEBI:9288 ChEBI SLC2A2 protein P11168 UNIPROT down-regulates quantity chemical inhibition 10090 9421374 YES miannu In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells. 0.8 SIGNOR-259314 PCK2 protein Q16822 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 24632615 YES miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. 0.8 SIGNOR-266556 CEP135 protein Q66GS9 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates activity binding 9606 23511974 YES miannu In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation. 0.808 SIGNOR-269677 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. 0.669 SIGNOR-251321 BDKRB2 protein P30411 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257344 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT down-regulates activity phosphorylation Ser711 NPAKEPTsVSENEGI -1 11328814 YES miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity 0.2 SIGNOR-262977 KLHL25 protein Q9H0H3 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0002552 27664236 YES miannu Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells.  0.53 SIGNOR-272334 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257926 H2BC11 protein P06899 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 YES miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. 0.2 SIGNOR-263875 POLR3K protein Q9Y2Y1 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.825 SIGNOR-266135 CIT protein O14578 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF -1 21457715 YES Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. 0.56 SIGNOR-260306 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser645 LNEKARLsYSDKNLI 9606 11959144 YES PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex 0.378 SIGNOR-248638 PTGIR protein P43119 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.401 SIGNOR-257078 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1270 SDLPVPRtPGSGAGE 9606 10995387 YES llicata Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter. 0.447 SIGNOR-82137 EGFR protein P00533 UNIPROT PCNA protein P12004 UNIPROT up-regulates phosphorylation Tyr211 QLTFALRyLNFFTKA 9606 BTO:0000150 17115032 YES lperfetto Here, we show that the chromatin-bound pcna protein is phosphorylated on tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of egf receptor (egfr) in the nucleus. Phosphorylation on tyr 211 by egfr stabilizes chromatin-bound pcna protein and associated functions. 0.341 SIGNOR-150852 glutamic acid smallmolecule CHEBI:18237 ChEBI GRID1 protein Q9ULK0 UNIPROT up-regulates activity chemical activation 9606 27586965 YES miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors 0.8 SIGNOR-264468 RIMS2 protein Q9UQ26 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity binding 9606 BTO:0005822 28642685 YES miannu Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells. 0.348 SIGNOR-264356 Degranulation phenotype SIGNOR-PH92 SIGNOR TNF protein P01375 UNIPROT up-regulates quantity 9606 BTO:0000830 24232182 NO apalma Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6 0.7 SIGNOR-255347 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 22310283 YES gcesareni Thus, our data revealed a novel interplay between pka phosphorylation and tal1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis. 0.2 SIGNOR-195987 nivolumab antibody DB09035 DRUGBANK PDCD1 protein Q15116 UNIPROT down-regulates activity binding 9606 BTO:0001023 26351349 YES miannu Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer. 0.4 SIGNOR-259895 F2R protein P25116 UNIPROT LATS1 protein O95835 UNIPROT down-regulates 9606 BTO:0000007 22972936 NO Here we report that stimulation of protease-activated receptors (PARs) activates YAP/TAZ by decreasing phosphorylation and increasing nuclear localization. milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. 0.2 SIGNOR-192045 Caspase 3 complex complex SIGNOR-C221 SIGNOR Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 NO miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice 0.7 SIGNOR-256475 VRK2 protein Q86Y07 UNIPROT TKT protein P29401 UNIPROT up-regulates activity phosphorylation Thr287 SKKKILAtPPQEDAP 9606 BTO:0001950 37653031 YES miannu Mechanistically, VRK2 promoted Thr287 phosphorylation of TKT and then recruited FBXL6 to promote TKT ubiquitination and activation.  0.2 SIGNOR-277842 NF2 protein P35240 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 33058421 YES miannu The Hippo pathway tumor suppressor Merlin/NF2 is known to be regulated by phosphorylation. Here, the E3 ubiquitin ligase NEDD4L is shown to promote Hippo pathway activation via ubiquitination of Merlin. 0.738 SIGNOR-263663 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR up-regulates 9606 21529719 NO milica In vertebrates, cell density information feeds into the Hpo pathway, which is transmitted, in part, through the Crumbs polarity complex. The Crumbs complex contains Angiomotin (AMOT), a protein that binds YAP/TAZ and SMAD to inhibit their nuclear activity. 0.7 SIGNOR-230700 D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity precursor of 9606 34775382 YES miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. 0.8 SIGNOR-267063 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000574 11739188 YES lperfetto Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology 0.643 SIGNOR-112649 ponatinib chemical CHEBI:78543 ChEBI FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition 9606 23468082 YES miannu Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. 0.8 SIGNOR-259278 naloxone chemical CHEBI:7459 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.8 SIGNOR-258661 PPP5C protein P53041 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity dephosphorylation Ser211 PGKETNEsPWRSDLL 9606 BTO:0000093 19586900 YES Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription. 0.54 SIGNOR-248538 SP3 protein Q02447 UNIPROT LORICRIN protein P23490 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12200429 NO miannu Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. 0.2 SIGNOR-254537 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 SIGNOR-C83 10339564 YES lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. 0.942 SIGNOR-67544 PTPRA protein P18433 UNIPROT PTPRA protein P18433 UNIPROT down-regulates activity dephosphorylation Tyr798 YIDAFSDyANFK 9606 7518772 YES Transient overexpression of c-Src together with RPTP alpha in human embryonic kidney 293 cells increased phosphorylation of Tyr789, suggesting that c-Src may phosphorylate RPTP alpha in vivo. RPTP alpha had autodephosphorylation activity in vitro. When expressed in 293 cells the level of Tyr789 phosphorylation was higher in a non-functional mutant of RPTP alpha than in wild type RPTP alpha, indicating that RPTP alpha may have autodephosphorylation activity in vivo as well.|We show that RPTP alpha, but not a mutant of RPTP alpha with a Tyr-->Phe mutation at position 789, bound to GRB2 in vitro. 0.2 SIGNOR-248439 PINK1 protein Q9BXM7 UNIPROT RHOT1 protein Q8IXI2 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000007 22078885 YES miannu PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C). 0.774 SIGNOR-272728 NLRX1 protein Q86UT6 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity binding 9606 BTO:0000567; BTO:0002181 18200010 YES Giorgia Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Co-immunoprecipitation studies demonstrate that HA–NLRX1 interacts with MAVS but not with other known mitochondrial outer membrane proteins (BCL2 and BCL2L1), indicating specificity of the NLRX1–MAVS interaction. Finally, endogenous NLRX1 associates strongly with endogenous MAVS after immunoprecipitation with two different MAVS antibodies 0.753 SIGNOR-260357 PBXIP1 protein Q96AQ6 UNIPROT PBX2 protein P40425 UNIPROT down-regulates activity binding 9606 BTO:0000007 24488098 YES miannu This protein that we have termed hematopoietic PBX-interacting protein (HPIP) is mainly localized in the cytosol and in small amounts in the nucleus. The region of PBX that interacts with HPIP includes both the homeodomain and immediate N-terminal flanking sequences. Strikingly, electrophoretic mobility shift assays revealed that HPIP inhibits the ability of PBX-HOX heterodimers to bind to target sequences.  0.267 SIGNOR-273667 ITGA5 protein P08648 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.915 SIGNOR-253177 LRRK2 protein Q5S007 UNIPROT CADPS2 protein Q86UW7 UNIPROT up-regulates quantity transcriptional regulation 9606 28647363 NO gianni This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells. 0.292 SIGNOR-268928 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Ser206 ATPPTLSsTVLIVRN 9606 12815053 YES lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 0.54 SIGNOR-102494 XL147 chemical CHEBI:71957 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252659 SAGA complex complex SIGNOR-C465 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269630 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys66 QFETSAAkLKRKYWW 9606 BTO:0000007 23353890 YES miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. 0.329 SIGNOR-272093 SLC12A3 protein P55017 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 YES lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  0.8 SIGNOR-264633 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates binding 9606 BTO:0001130 16597412 YES gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. 0.852 SIGNOR-145677 MAP3K11 protein Q16584 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 10727406 YES gcesareni These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo. 0.624 SIGNOR-75836 CEBPB protein P17676 UNIPROT CREB1 protein P16220-1 UNIPROT up-regulates activity binding 9534 BTO:0000298 12773552 YES miannu We conclude that C/EBP-β can directly bind to the N-terminal Q1 domain of CREB in addition to binding to the leucine zipper domain. The transactivation potential of full-length CREB fused to the DNA-binding domain of Gal4 was increased synergistically by calcium and cGMP, and overexpression of C/EBP-β enhanced the effect, while a dominant negative C/EBP inhibited it 0.561 SIGNOR-263654 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR IDH2 protein P48735 UNIPROT down-regulates quantity by destabilization phosphorylation Thr197 GTFKMVFtPKDGSGV 34929314 YES lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome 0.265 SIGNOR-267622 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.497 SIGNOR-248799 DHX30 protein Q7L2E3 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 NO miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. 0.7 SIGNOR-261228 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr216 KLDSGGFyITSRTQF 9606 BTO:0000150 12753909 YES lperfetto This study establishes that her2/hrg signaling selectively upregulates tyr phosphorylation of c-src at tyr-215 located within the sh2 domain, increases c-src kinase activity 0.2 SIGNOR-236246 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194343 PER2 protein O15055 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates activity binding 9606 BTO:0001939 23836662 YES miannu This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. 0.2 SIGNOR-254148 BIRC2 protein Q13490 UNIPROT PACS2 protein Q86VP3 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 24633224 YES miannu Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay. 0.304 SIGNOR-272851 PPP2CA protein P67775 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT down-regulates activity dephosphorylation Ser9 SFRAARLsMRNRRND 9606 BTO:0000007 20110357 YES done miannu Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity. 0.2 SIGNOR-273794 MAP3K3 protein Q99759 UNIPROT WDR62 protein O43379 UNIPROT up-regulates quantity by stabilization binding 30566428 YES lperfetto Specifically, we demonstrate that MEKK3 interacts with WDR62 to stabilize WDR62 and regulates JNK activity in a synergic way. On the other hand, JNK activity also regulates the phosphorylation of WDR62 at T1053 in a feedback loop which facilities the recruitment of FBW7 degradation of WDR62 0.2 SIGNOR-271714 Immunoglobulin kappa light chain protein P0DOX7 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323265 YES scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. 0.2 SIGNOR-268186 EGFR protein P00533 UNIPROT KCNJ4 protein P48050 UNIPROT up-regulates activity phosphorylation Tyr234 YMTQEGEyLPLDQRD -1 21486282 YES miannu These results demonstrate that the EGF receptor tyrosine kinase up-regulates the K(IR) 2.3 channel via phosphorylation of the Y234 residue of the WT protein.  0.2 SIGNOR-276322 herbimycin chemical CHEBI:5674 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 11782488 YES gcesareni Herbimycin a and pp2, specific inhibitors of src family kinases, both inhibited h2o2-mediated c-src and bmk1 activation. 0.8 SIGNOR-113767 CDK9 protein P50750 UNIPROT ACTL6A protein O96019 UNIPROT up-regulates activity phosphorylation 9606 21699904 YES miannu Collectively, these results suggest that the cdk9 and Cyclin T complex more efficiently phosphorylates Baf53 in vitro. 0.324 SIGNOR-279689 SMARCD3 protein Q6STE5 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.771 SIGNOR-270613 Guanabenz chemical CHEBI:5553 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258911 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr299 HKLGGGQyGEVYVGV -1 34144039 YES miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. 0.303 SIGNOR-277301 BOC protein Q9BWV1 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR form complex binding 10090 21664576 YES lperfetto Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands. 0.528 SIGNOR-209599 Ub:E2 complex SIGNOR-C497 SIGNOR ZSWIM2 protein Q8NEG5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270950 ATM protein Q13315 UNIPROT EXO1 protein Q9UQ84 UNIPROT up-regulates phosphorylation 9606 20019063 YES gcesareni The phosphorylation of exo1 by atm appears to regulate the activity of exo1 following resection, allowing optimal rad51 loading and the completion of hr repair. 0.83 SIGNOR-162304 WDFY3 protein Q8IZQ1 UNIPROT GABARAP protein O95166 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 24668264 YES miannu Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy. 0.663 SIGNOR-266796 MED20 protein Q9H944 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.774 SIGNOR-266679 KCND3 protein Q9UK17 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 10090 24762397 YES miannu Kv4.3 belongs to voltage activated (Kv) K+ channel, mammalian Shal-related family. It is encoded by KCND3 gene and expressed in heart, brain and smooth muscle. Transient outward K+ current (I(to)) plays a crucial role in the early phase of cardiac action potential repolarization. Kv4.3 K(+) channel is an important component of I(to). The function and expression of Kv4.3 K(+) channel decrease in variety of heart diseases, especially in heart hypertrophy/heart failure. 0.8 SIGNOR-265657 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192826 MYC protein P01106 UNIPROT HNRNPA2B1 protein P22626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20010808 YES We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2, 0.357 SIGNOR-268691 PRKG1 protein Q13976 UNIPROT RYR1 protein P21817 UNIPROT unknown phosphorylation Ser2843 KKKTRKIsQSAQTYD -1 8380342 YES lperfetto Automated Edman sequence analysis of the major phosphopeptide obtained from PK-A and PK-G phosphorylation and one phosphopeptide obtained from PK-CaM phosphorylation yielded the sequence KISQTAQTYDPR (residues 2841€“2852) with serine 2843 as phosphorylation site 0.391 SIGNOR-248918 EGLN3 protein Q9H6Z9 UNIPROT PKM protein P14618 UNIPROT up-regulates activity hydroxylation Pro408 LAPITSDpTEATAVG 9606 BTO:0000567 21620138 YES Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. 0.436 SIGNOR-267477 CSNK2A2 protein P19784 UNIPROT STX1A protein Q16623 UNIPROT unknown phosphorylation Ser14 ELRTAKDsDDDDDVA 10116 BTO:0000142 10844023 YES llicata We generated an antibody that specifically recognizes a casein kinase II-mediated phosphorylation on serine-14 of syntaxin 1. In this report we show that this phosphorylation occurs in vivo and is developmentally regulated in the rat brain | Phosphorylated syntaxin is preferentially associated with SNAP-25 and localizes to discrete domains of the axonal plasma membrane that do not colocalize with pools of synaptic vesicles. 0.365 SIGNOR-251043 RPS28 protein P62857 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.901 SIGNOR-262423 TAB3 protein Q8N5C8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14670075 YES lperfetto We have identified a new binding partner of the tgfbeta (transforming growth factor-beta)-activated protein kinase (tak1), termed tab.two distinct tak1 complexes are present in cells. One comprises tak1 complexed with tab1 and tab2, and the other tak1 complexed with tab1 and tab3 (tak1-binding protein-3). Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1. 0.833 SIGNOR-120325 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser359 SALSYLQsPITTSPS 9606 10617468 YES lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. 0.786 SIGNOR-73629 JAG1 protein P78504 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 18660822 YES Binding Calcium-dependent gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. 0.643 SIGNOR-179625 GSK3B protein P49841 UNIPROT MARK2 protein Q7KZI7 UNIPROT down-regulates activity phosphorylation Ser212 KLDTFCGsPPYAAPE -1 18424437 YES miannu MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. 0.349 SIGNOR-276163 LSM-20934 chemical CHEBI:109533 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258850 TAOK3 protein Q9H2K8 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 YES gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2 0.284 SIGNOR-192762 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM58 protein Q8NG06 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270977 DUSP2 protein Q05923 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 YES gcesareni We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively 0.622 SIGNOR-40918 PPP2R2B protein Q00005 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR form complex binding 9606 23454242 YES gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. 0.762 SIGNOR-243507 TRiC complex SIGNOR-C539 SIGNOR CDC20 protein Q12834 UNIPROT up-regulates quantity by stabilization binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.527 SIGNOR-272869 SRC protein P12931 UNIPROT CNKSR1 protein Q969H4 UNIPROT up-regulates activity phosphorylation Tyr26 LDDSLQDyPFEDWQL 26319181 YES lperfetto We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. 0.505 SIGNOR-275919 phenformin chemical CHEBI:8064 ChEBI KCNJ8 protein Q15842 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000783 BTO:0001260 20188727 YES lperfetto Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). 0.8 SIGNOR-262030 MAPKAPK2 protein P49137 UNIPROT LPCAT2 protein Q7L5N7 UNIPROT up-regulates activity phosphorylation Ser34 PMVPRQAsFFPPPVP 10090 BTO:0002601 20663880 YES miannu Mass spectrometry and mutagenesis analyses identified Ser34 of LPCAT2 as the phosphorylation site to enhance the catalytic activities. The experiments using inhibitors and siRNA against MAPK cascades demonstrated that LPCAT2 phosphorylation through LPS-TLR4 signaling may directly depend on MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2). 0.2 SIGNOR-263077 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11201744 YES CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 0.473 SIGNOR-248348 Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT MAS1 protein P04201 UNIPROT up-regulates activity binding 9606 23488800 YES miannu Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). 0.2 SIGNOR-260229 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK10 protein P53779 UNIPROT down-regulates chemical inhibition 9606 15071501 YES gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor. 0.8 SIGNOR-124034 CHRM2 protein P08172 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.509 SIGNOR-256685 ANKRD11 protein Q6UB99 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10090 BTO:0000142 29274743 NO miannu We found that Ankrd11 knockdown disrupted dendrite and spine formation in developing pyramidal neurons. 0.7 SIGNOR-266730 miR-155 mirna URS000062749E_9606 RNAcentral GFI1 protein Q99684 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 24708856 YES miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. 0.4 SIGNOR-255762 A5/b1 integrin complex SIGNOR-C163 SIGNOR DLL1 protein O00548 UNIPROT up-regulates quantity by expression 10090 25786978 NO lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. 0.267 SIGNOR-253286 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.789 SIGNOR-131829 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.541 SIGNOR-81129 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 YES Does not bind to the ERBB1, ERBB2 and ERBB3 receptors gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.695 SIGNOR-26280 PTPN5 protein P54829 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates activity dephosphorylation Tyr1474 GSSNGHVyEKLSSIE 10090 BTO:0004102 20427654 YES lperfetto  These previous results, together with the present findings, indicate that STEP61 dephosphorylates the NR2B subunit at its regulatory tyr1472 site, and dephosphorylation of this site leads to internalization of the NMDAR complex from neuronal surface membranes. 0.548 SIGNOR-265744 ATR protein Q13535 UNIPROT WDHD1 protein O75717 UNIPROT up-regulates activity phosphorylation Thr826 KAAELTAtQVEEEEE 9606 BTO:0001109 26082189 YES miannu And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR. 0.54 SIGNOR-262664 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation 11493009 YES inferred from 70% family members lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. 0.2 SIGNOR-270147 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 30193097 YES miannu √Ǭ†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).√Ǭ† 0.8 SIGNOR-266586 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Thr733 LPPVFSGtPKGSGAG 9606 BTO:0000567 20667468 YES miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. 0.2 SIGNOR-259822 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR5 protein Q9H228 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257580 CDK2 protein P24941 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 YES lperfetto Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown). 0.254 SIGNOR-87101 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. 0.64 SIGNOR-164408 SP3 protein Q02447 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 NO miannu We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. 0.2 SIGNOR-254813 BCL2 protein P10415 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity 9606 BTO:0000567 12624108 NO lperfetto Bcl-2 blocked the release of mitochondrial cytochrome c 0.644 SIGNOR-99063 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser180 PGSGSIYsSPGLYSK 9606 BTO:0000567 35469017 YES miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. 0.2 SIGNOR-276715 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity acetylation 9606 20851880 YES gcesareni These results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300 0.453 SIGNOR-167966 BAG1 protein Q99933 UNIPROT PPP1R15A protein O75807 UNIPROT down-regulates activity 9606 BTO:0000038 12724406 YES lperfetto Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.|BAG-1 negatively modulates GADD34-bound PP1 activity, and the expression of BAG-1 isoforms can also mask GADD34-mediated inhibition of colony formation and suppression of transcription. Our findings suggest that BAG-1 may function to suppress the GADD34-mediated cellular stress response and support a role for BAG-1 in the survival of cells undergoing stress. 0.445 SIGNOR-254117 SLC2A1 protein P11166 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 YES lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] 0.362 SIGNOR-266038 DRD4 protein P21917 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.446 SIGNOR-256846 PRKCA protein P17252 UNIPROT ATP1A1 protein P05023 UNIPROT down-regulates activity phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 YES miannu Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit. 0.33 SIGNOR-262941 CXCL8 protein P10145 UNIPROT CXCR1 protein P25024 UNIPROT up-regulates binding 9606 11350788 YES gcesareni Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades. 0.779 SIGNOR-107920 ZMYND8 protein Q9ULU4 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 YES lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported 0.2 SIGNOR-262040 SLC36A2 protein Q495M3 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity relocalization 9606 12748860 YES lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. 0.8 SIGNOR-264738 HSD3B1 protein P14060 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 2243100 YES lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. 0.8 SIGNOR-268635 SLC6A4 protein P31645 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity relocalization 9606 BTO:0000227 16789923 YES miannu The function of the serotonin transporter (SERT) is to take up and release serotonin (5-hydroxytyptamine (5-HT)) from cells and this function of SERT in the central nervous system (CNS) is well-documented; SERT is the target of selective serotonin reuptake inhibitors used in the treatment of CNS disorders, such as depression. 0.8 SIGNOR-263953 INS protein P01308 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 10090 12530968 NO lperfetto The forkhead transcription factor foxo1 is regulated by insulin via akt-dependent phosphorylation and nuclear exclusion. 0.752 SIGNOR-97392 PD173074 chemical CHEBI:63448 ChEBI FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205725 CKM protein P06732 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265788 HDAC1 protein Q13547 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 11994312 NO To define a mechanism for repression of AR function, we demonstrate that AR activity is specifically down-regulated by the histone deacetylase activity of HDAC1. Furthermore, using both mammalian two-hybrid and immunoprecipitation experiments, we show that AR and HDAC1 interact, suggestive of a direct role for down-regulation of AR activity by HDAC1. In chromatin immunoprecipitation assays, we provide evidence that AR, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, suggesting that acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity. 0.298 SIGNOR-253666 PRKACA protein P17612 UNIPROT GRIK2 protein Q13002 UNIPROT up-regulates activity phosphorylation Ser715 FMSSRRQsVLVKSNE 9606 BTO:0000007 8094892 YES miannu GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. 0.2 SIGNOR-250315 AKT1 protein P31749 UNIPROT ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 YES miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively 0.281 SIGNOR-276193 MELK protein Q14680 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates activity phosphorylation 9606 23404835 YES miannu MELK Activates FOXM1 Transcriptional Activity Leading to Upregulation of Mitotic Gene Expression.|The autoradiogram clearly shows in vitro phosphorylation of FOXM1 by MELK and CDK2 and cyclinA. 0.501 SIGNOR-278412 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 17251915 YES gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. 0.659 SIGNOR-152808 PRKCH protein P24723 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000093 28939105 YES miannu Protein kinase C-eta regulates Mcl-1 level via ERK1. knockdown of PKCη but not PKCα, -δ or -ε caused a significant decrease in ERK (extracellular signal-regulated kinase) phosphorylation. Knockdown of ERK1 but not ERK2 decreased Mcl-1 level, and the decrease in Mcl-1 caused by PKCη knockdown was restored by ERK1 overexpression. These results suggest that PKCη utilizes the ERK signaling pathway to protect against ubiquitin-mediated proteasomal degradation of Mcl-1. 0.505 SIGNOR-261910 NCAPH protein Q15003 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.97 SIGNOR-263906 SLC9A7 protein Q96T83 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265597 MAPK14 protein Q16539 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Thr56 FSSQPGHtPHPAASR 9606 16714293 YES gcesareni Bcl-2 phosphorylation by p38 mapkin this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, ser(87) and thr(56) as the bcl-2 residues phosphorylated by p38 mapk and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of bcl-2 protein. 0.334 SIGNOR-146786 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 27487822 YES miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. 0.8 SIGNOR-266266 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser195 RRSDSLLsFRLDLDL 10090 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262766 SMARCA1 protein P28370 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 YES miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. 0.695 SIGNOR-268818 PRKACA protein P17612 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser490 KSPTRKKsGPFGSRR -1 1406653 YES miannu We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive. 0.31 SIGNOR-250043 PRKACA protein P17612 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates activity phosphorylation 10116 17023420 YES These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine. 0.402 SIGNOR-256111 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr362 SPPAEDVyDVPPPAP 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246409 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding 10090 10712517 YES ggiuliani Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand. 0.63 SIGNOR-255781 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT up-regulates activity binding 9606 BTO:0000776 12324477 YES lperfetto Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated T cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. cd40 binds its ligand cd40l. 0.929 SIGNOR-93432 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000562 17075052 YES gcesareni The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment. 0.2 SIGNOR-150351 FYN protein P06241 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Tyr142 AVVNLINyQDDAELA -1 12640114 YES Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases.  Transfection of these kinases to epithelial cells disrupted the association between both catenins. 0.851 SIGNOR-251162 MAPK3 protein P27361 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Ser623 ALDFQPSsPSPHRKP 9606 15356145 YES lperfetto Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623. 0.616 SIGNOR-128731 SRC protein P12931 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates phosphorylation Tyr307 VTRRTPDyFL 9606 BTO:0000938 23796501 YES llicata We found that ?-Syn gene overexpression in sk-n-sh cells and primary neurons led to pp2a/c phosphorylation at y307, a known target of src kinase, and consequent phosphatase inhibition. 0.43 SIGNOR-202192 DNMBP protein Q6XZF7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.571 SIGNOR-260547 tolazoline chemical CHEBI:28502 ChEBI ADRA2C protein P18825 UNIPROT down-regulates activity chemical inhibition 9606 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258914 FER protein P16591 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Tyr225 PTSSKDNyLGGTSTI 9606 BTO:0001130 23906537 YES lperfetto Fer is required for il-6 mediated ar activation by phosphorylating ar tyrosine 223 and binding via its sh2 domain. 0.259 SIGNOR-194749 SMURF1 protein Q9HCE7 UNIPROT TOM1 protein O60784 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.261 SIGNOR-272679 DTX1 protein Q86Y01 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates binding 9606 11564735 YES gcesareni Through its binding to p300, dtx1 inhibited transcriptional activation by the neural-specific helix-loop-helix-type transcription factor mash1 0.262 SIGNOR-110626 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 YES miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559 0.2 SIGNOR-277799 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 31160049 YES miannu Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-277655 MAPK1 protein P28482 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 YES gcesareni We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity 0.599 SIGNOR-48338 PSMA5 protein P28066 UNIPROT XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization binding -1 19941857 YES 1 miannu We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination. 0.304 SIGNOR-239213 TNFRSF21 protein O75509 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 32454942 NO miannu Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress. 0.7 SIGNOR-263830 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 21808241 YES gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. 0.608 SIGNOR-175797 CRKL protein P46109 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 YES HPK1 phosphorylated CrkL mainly on serine and weakly on threonine gcesareni We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk. 0.586 SIGNOR-63991 LUBAC complex SIGNOR-C527 SIGNOR GLYR1 protein Q49A26 UNIPROT down-regulates quantity by destabilization ubiquitination Lys505 FYLKYIQkDLRLAIA 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 0.2 SIGNOR-272839 PRPF6 protein O94906 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.771 SIGNOR-270625 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. 0.569 SIGNOR-164483 NRG2 protein O14511 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 YES gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.788 SIGNOR-122056 NFIB protein O00712 UNIPROT ETV5 protein P41161 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268880 MAPK8 protein P45983 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0002923 23255093 YES lperfetto Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3, 0.568 SIGNOR-235704 PIM2 protein Q9P1W9 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by stabilization phosphorylation Thr454 RAPIIAVtRNPQTAR 9606 24142698 YES miannu Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis 0.371 SIGNOR-267472 TET1 protein Q8NFU7 UNIPROT SLIT2 protein O94813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27708339 YES irozzo Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. 0.2 SIGNOR-259093 beta-carboline chemical CHEBI:109895 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). 0.8 SIGNOR-263805 HIF1A protein Q16665 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0001033 27476001 NO miannu Our present study reveals that DAB2IP prevents EMT and metastasis of prostate cancer through targeting PROX1 gene transcription and destabilizing HIF1α protein, which provides a new insight into mechanism that DAB2IP regulates EMT and PCa metastasis. 0.7 SIGNOR-254768 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Thr594 LHGKKNStVDCNGVV 9606 22514276 YES miannu A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues. 0.491 SIGNOR-197067 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CLIP1 protein P30622 UNIPROT up-regulates activity phosphorylation Thr287 KIGFPSTtPAKAKAN 19687009 YES lperfetto Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression. 0.485 SIGNOR-275471 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1C protein Q14123 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. 0.8 SIGNOR-253017 SHANK3 protein Q9BYB0 UNIPROT GRIA3 protein P42263 UNIPROT up-regulates quantity binding 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264603 LYN protein P07948 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276186 CDK5 protein Q00535 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates activity phosphorylation Thr873 LLYSEAKtPIKWMAL 10116 BTO:0004102 12824184 YES llicata We demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival.  0.341 SIGNOR-250664 PKA proteinfamily SIGNOR-PF17 SIGNOR MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 20151718 YES inferred from 70% family members miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.2 SIGNOR-270128 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRA protein P01903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 NO Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. 0.414 SIGNOR-254009 DUSP5 protein Q16690 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 15713638 YES fstefani Here we demonstrate that dusp5, an inducible nuclear phosphatase, interacts specifically with erk2 via a kinase interaction motif (kim) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of dusp5 in vivo, as it inactivates erk2 but not jun n-terminal protein kinase or p38 map kinase. 0.781 SIGNOR-134049 PTPRO protein Q16827 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation 9606 20564182 YES miannu Both Lyn and ZAP70 were dephosphorylated by wild-type PTPROt, but not by its catalytic site mutant.|Lyn kinase and ZAP70 are substrates of PTPROt in B-cells: Lyn inactivation by PTPROt sensitizes leukemia cells to VEGF-R inhibitor pazopanib. 0.326 SIGNOR-277144 CASP3 protein P42574 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 25787076 NO miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice. 0.7 SIGNOR-255337 STAT1 protein P42224 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 19041276 YES lperfetto Each STAT1 monomer becomes tyrosine phosphorylated at tyrosine 701 by the JAKs, dissociates from the receptor to form a STAT1-STAT1 homodimer which translocates to the nucleus 0.2 SIGNOR-249495 PRKACA protein P17612 UNIPROT RGS18 protein Q9NS28 UNIPROT up-regulates activity phosphorylation Ser216 PTNLRRRsRSFTCNE 9606 BTO:0000132 24244663 YES done miannu Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216.  0.2 SIGNOR-273786 HSPA1A protein P0DMV8 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 10934467 YES gcesareni Here we show that the documented anti-apoptotic effect of the principal heat-shock protein, hsp70, is mediated through its direct association with the caspase-recruitment domain (card) of apaf-1 and through apoptosome formation 0.432 SIGNOR-80451 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser269 PCNKRKYsLNGRQPP 9606 12351631 YES lperfetto Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3) 0.383 SIGNOR-93535 FBXW10 protein Q5XX13 UNIPROT CBX5 protein P45973 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23431138 YES miannu As expected, the SKP1 and CUL1 proteins, subunits of all F-box-containing E3 ligases, were also present in the immune complexes containing FBXO10 and BCL2. To test for FBXO10-induced ubiquitination of BCL2, 293T cells were transduced with retroviral vectors expressing Flag-tagged FBXO10, MYC-tagged BCL2, and HA-tagged ubiquitin, and cells were treated with the proteasome inhibitor PS-341 to enhance the detection of ubiquitinated proteins.Together, these data suggest that FBXO10 is a component of a ubiquitin ligase that can target BCL2 protein for degradation. 0.2 SIGNOR-271933 CDK6 protein Q00534 UNIPROT CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR form complex binding 8114739 YES lperfetto Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. 0.935 SIGNOR-273028 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 20086174 YES inferred from 70% of family members lperfetto We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. 0.398 SIGNOR-269944 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone chemical CHEBI:91372 ChEBI ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193600 RUNX1 protein Q01196 UNIPROT BAALC protein Q8WXS3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493267 NO miannu We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis. 0.33 SIGNOR-255077 trichostatin A chemical CHEBI:46024 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258010 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser664 QSAFAGFsFVNPKFE 10090 BTO:0000944 11959144 YES PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex 0.3 SIGNOR-248596 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248678 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120224 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 SIGNOR-C17 12058066 YES gcesareni Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. 0.519 SIGNOR-89601 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257980 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates activity phosphorylation Thr50 QLPVLDKtKFLVPDH -1 31857374 YES done miannu LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). 0.2 SIGNOR-273905 DUSP16 protein Q9BY84 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity dephosphorylation 9606 25077541 YES miannu MKP7 represses mTOR function.|These results suggest that MKP7 could directly dephosphorylate pmTOR and pPRAS40 and forming complexes with these two proteins ( xref ). 0.275 SIGNOR-277067 PLK3 protein Q9H4B4 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser576 DDDFQLRsFDQLSPL 9606 BTO:0000567 18519666 YES lperfetto Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation 0.349 SIGNOR-178739 CTNNB1 protein P35222 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates activity binding 10090 BTO:0001086 21295277 YES flangone We provide evidence suggesting that Beta-catenin’s interaction with the pluripotency regulator Oct-4 at least partially underlies its effects on sustaining pluripotency. 0.576 SIGNOR-241981 SMURF1 protein Q9HCE7 UNIPROT RABEP2 protein Q9H5N1 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272690 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp373 PATQCISdGKLNEGH 9606 11741536 YES gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. 0.365 SIGNOR-112792 NME1 protein P15531 UNIPROT CCN2 protein P29279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17671192 NO miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 0.2 SIGNOR-255160 ATF4 protein P18848 UNIPROT GARS1 protein P41250 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269426 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR NUP98 protein P52948 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16036565 NO miannu Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein 0.2 SIGNOR-260870 IKBKB protein O14920 UNIPROT COMT protein P21964 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000100 19291302 NO Regulation of expression miannu TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression. 0.2 SIGNOR-251965 DOT1L protein Q8TEK3 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 NO irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. 0.2 SIGNOR-255880 ATM protein Q13315 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser51 SSDSIGSsQKAHGIL 9606 20730097 YES miannu Exposure to DNA damage further induced ATF1 phosphorylation on Ser-51 by ATM in a manner that required prior phosphorylation of the upstream CK residues. 0.359 SIGNOR-278909 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Thr449 DDIRQNFtQLPLHKN 9606 22123827 YES lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. 0.655 SIGNOR-177813 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000567 9535909 YES lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. 0.607 SIGNOR-249401 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser2 sDHGDVSL 9534 BTO:0000298 11483516 YES llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. 0.291 SIGNOR-250596 KAT2A protein Q92830 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269609 SESN2 protein P58004 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR down-regulates activity binding 10090 BTO:0002572 25457612 YES We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2 0.716 SIGNOR-253560 ATF2 protein P15336 UNIPROT SIRT4 protein Q9Y6E7 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002572 33861966 YES miannu Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). 0.2 SIGNOR-267831 NEDD4L protein Q96PU5 UNIPROT SPHK2 protein Q9NRA0 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 34305532 YES miannu In this study, we found that NEDD4L interacted with SphK2 to ubiquitinate SphK2 protein.|NEDD4L Mediates the Degradation of SphK2 Protein Through the Ubiquitin-Proteasomal Pathway. 0.2 SIGNOR-278660 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.264 SIGNOR-276097 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 8131746 YES lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. 0.789 SIGNOR-244827 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270381 GRIK4 protein Q16099 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264945 CDK1 protein P06493 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates activity phosphorylation Ser251 EVSIRVGsPQPSSSG 9606 BTO:0002181 29229926 YES miannu  During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs. 0.355 SIGNOR-277375 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser76 ISNKDQHsISYTLSR -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.767 SIGNOR-276134 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 22848740 YES When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form. 0.517 SIGNOR-255755 TRAF2 protein Q12933 UNIPROT UBE2N protein P61088 UNIPROT up-regulates activity binding 9606 BTO:0000459 18635759 YES lperfetto Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades. 0.429 SIGNOR-179479 PRKCG protein P05129 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 YES lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. 0.353 SIGNOR-248975 TRIM32 protein Q13049 UNIPROT DTNBP1 protein Q96EV8 UNIPROT down-regulates quantity ubiquitination 9534 BTO:0000298 19349376 YES miannu TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation. 0.538 SIGNOR-265658 FBXO45 protein P0C2W1 UNIPROT Skp1-Pam E3 complex SIGNOR-C537 SIGNOR up-regulates activity binding 9606 BTO:0000007 24992930 YES miannu Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis.Fbxo45 forms an atypical ubiquitin ligase complex that contains Skp1 and the Ring-finger protein PAM (protein-associated with myc) also known as MYCBP2 (myc-binding protein 2). 0.632 SIGNOR-272225 CAPN3 protein P20807 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates activity cleavage 9606 25969760 YES lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain 0.262 SIGNOR-251604 RNF8 protein O76064 UNIPROT UBE2N protein P61088 UNIPROT up-regulates binding 9606 18678647 YES gcesareni The rnf8 ring domain signals ubc13 to sites of damage, which is sufficient for dna damage signal transduction. 0.749 SIGNOR-179823 CNKSR2 protein Q8WXI2 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 14597674 YES gcesareni We show cnk2 interacts with raf. cnk2 interacts with the gef domain of rlf and with both the regulatory and catalytic domains of raf. The raf interaction was also mapped to the carboxyl-terminal half of cnk2. Overexpression of cnk2 results in inhibition of the mapk signaling pathway. 0.767 SIGNOR-119039 MAFA protein Q8NHW3 UNIPROT SLC2A2 protein P11168 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 NO miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. 0.372 SIGNOR-254565 calcium(2+) smallmolecule CHEBI:29108 ChEBI KCNMA1 protein Q12791 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 31152168 YES miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway) 0.8 SIGNOR-269192 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1721 SPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248823 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1021 PNEGDNDyIIPLPDP -1 7545675 YES Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides 0.69 SIGNOR-248417 NEK2 protein P51955 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates phosphorylation Thr307 EKKKPNAtRPVTPPR 9606 10880350 YES miannu Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2 0.489 SIGNOR-78306 CS protein O75390 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity chemical modification 9606 3013232 YES miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. 0.8 SIGNOR-266240 CUL5 protein Q93034 UNIPROT Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR form complex binding 10090 BTO:0000165 19300455 YES miannu Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation.  Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb. 0.931 SIGNOR-271798 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 BTO:0000782 15326477 YES lperfetto P38sapk2 phosphorylates cyclin d3 at thr-283 and targets it for proteasomal degradation 0.2 SIGNOR-128402 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ -1 1527025 YES The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase. 0.2 SIGNOR-251186 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity phosphorylation Thr155 DSTPPPGtRVRAMAI -1 12628923 YES llicata CK2 phosphoryl ates Thr155, which targets p53 to degradation by the Ub system. 0.667 SIGNOR-250968 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI ADCY10 protein Q96PN6 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 31827278 YES miannu In these cells, trafficking of V-ATPase to the plasma membrane has been shown to be mediated by activation of bicarbonate-dependent soluble adenylate cyclase (sAC), which increases cAMP levels, thereby activating protein kinase A (PKA) 0.8 SIGNOR-277762 ADRA2B protein P18089 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.469 SIGNOR-256857 GSK3B protein P49841 UNIPROT NIFK protein Q9BYG3 UNIPROT up-regulates activity phosphorylation Thr234 TVDSQGPtPVCTPTF -1 16244663 YES miannu The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1. 0.2 SIGNOR-262698 DDX3X protein O00571 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 BTO:0001950 17667941 YES miannu DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G. 0.629 SIGNOR-269193 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser49 HKAELQGsDEDEHVR -1 9461343 YES llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  0.307 SIGNOR-251017 PRKDC protein P78527 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser435 LTVLNAFsQAPSTMQ -1 8407951 YES lperfetto  The carboxyl-terminal transcription activation domain was mapped within a 71-amino acid region that contains both DNA-PK phosphorylation sites. Amino acid substitutions that interfered with phosphorylation by DNA-PK at Ser-435/446 in GAL4-SRF fusion proteins were reduced in transactivation potency. From these data we suggest that DNA-PK phosphorylation may modulate SRF activity in vivo. 0.406 SIGNOR-248921 UBE4B protein O95155 UNIPROT ATXN3 protein P54252 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14749733 YES miannu Mammalian E4B (UFD2a), a ubiquitin chain assembly factor (E4), copurified with the polyubiquitylation activity for ataxin-3. E4B interacted with, and thereby mediated polyubiquitylation of, ataxin-3.  Collectively, these data suggest that E4B promotes the degradation of ataxin-3, and that this effect surmounts the stabilization of ataxin-3 conferred by expansion of the polyglutamine tract. 0.579 SIGNOR-271502 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23150757 YES lperfetto Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity 0.968 SIGNOR-199371 SRC protein P12931 UNIPROT GAK protein O14976 UNIPROT up-regulates activity phosphorylation Tyr1149 CTQPRPNyASNFSVI -1 28135906 YES miannu GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149. 0.275 SIGNOR-263198 MAPKAPK5 protein Q8IW41 UNIPROT RHEB protein Q15382 UNIPROT down-regulates activity phosphorylation Ser130 LHMERVIsYEEGKAL 9606 BTO:0000007 21336308 YES miannu Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation.  0.401 SIGNOR-276313 HARS1 protein P12081 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates quantity chemical modification 9606 10430027 YES miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 0.8 SIGNOR-270490 BCL10 protein O95999 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates binding 9606 SIGNOR-C14 18287044 YES gcesareni Here, we show that bcl10 undergoes k63-linked polyubiquitination in response to t cell activation and subsequently binds nemo, the regulatory subunit of ikk. 0.827 SIGNOR-160967 IFNA1 protein P01562 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates quantity by stabilization 9606 22171011 NO 2 miannu IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9. 0.451 SIGNOR-240610 methotrexate chemical CHEBI:44185 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0004254 23581023 YES miannu Methotrexate, a structural analogue of folic acid, is one of the most frequently used chemotherapeutics, especially in haematological malignancies, various solid tumours and also inflammatory disorders. Methotrexate interferes with folate metabolism, mainly by inhibition of dihydrofolate reductase, resulting in the suppression of purine and pyrimidine precursor synthesis. 0.8 SIGNOR-258481 MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000222 21902831 YES lperfetto TAK1 can phosphorylate and activate MAP kinase kinase 3/6 (MKK3/6), and numerous studies have demonstrated a requirement for MKK3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. 0.503 SIGNOR-236093 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM60 protein Q495X7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271161 PCSK2 protein P16519 UNIPROT Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 YES miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. 0.2 SIGNOR-270337 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G3 protein O43432 UNIPROT up-regulates activity stabilization 9606 17581632 YES lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 0.389 SIGNOR-269157 NatC complex SIGNOR-C417 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 NO miannu About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity. 0.7 SIGNOR-267236 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 BTO:0000567 11606413 YES gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. 0.8 SIGNOR-111064 HOXB8 protein P17481 UNIPROT ACTA2 protein P62736 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 15886193 YES Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively 0.2 SIGNOR-261641 CDK1 protein P06493 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser286 TSGGVSEsPSGFSKH 9606 21765472 YES lperfetto Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency 0.411 SIGNOR-175071 S1PR2 protein O95136 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 YES gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. 0.469 SIGNOR-198556 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.91 SIGNOR-252848 PRKCD protein Q05655 UNIPROT CHAT protein P28329 UNIPROT up-regulates quantity phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000930 15381704 YES lperfetto Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity. 0.311 SIGNOR-249272 GBE1 protein Q04446 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI up-regulates quantity chemical modification 9606 26199317 YES miannu Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating Œ±-1,6-glucosidic branches from Œ±-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains 0.8 SIGNOR-267942 RFFL protein Q8WZ73 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18450452 YES miannu We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation. 0.466 SIGNOR-271482 ORC5 protein O43913 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 YES lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA 0.965 SIGNOR-267563 D-fructofuranose 6-phosphate(2-) smallmolecule CHEBI:61527 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 21310273 YES miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans 0.8 SIGNOR-267813 DUSP23 protein Q9BVJ7 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation 9606 27281782 YES miannu In particular, DUSP23 can dephosphorylate and inactivate MAPK3 ( xref ).|In particular, DUSP23 can dephosphorylate and inactivate MAPK3. 0.311 SIGNOR-277103 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser688 RLFVENDsPSDGGTP 9606 BTO:0001938 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104687 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser732 EAINEAIsVKQEVTD 9606 BTO:0002181 34216621 YES miannu  Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction.  0.574 SIGNOR-277323 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 11258706 YES lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.772 SIGNOR-105741 TWIST1 protein Q15672 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 21931630 NO miannu Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2. 0.449 SIGNOR-255593 solifenacin chemical CHEBI:135530 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition -1 21524581 YES Luana The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference 0.8 SIGNOR-258312 TRIP13 protein Q15645 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 32860853 YES lperfetto Mechanistically, TRIP13 enhanced EGFR protein abundance in part by preventing Cbl-mediated ubiquitination and proteasomal degradation. 0.2 SIGNOR-265084 PMPCB protein O75439 UNIPROT PINK1 protein Q9BXM7 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000007 22354088 YES miannu Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. 0.339 SIGNOR-261363 SMO protein Q99835 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 20654717 YES gcesareni This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1 0.267 SIGNOR-167070 OXGR1 protein Q96P68 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257155 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257971 RB1 protein P06400 UNIPROT ITGA10 protein O75578 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24287699 NO lperfetto Integrin α10 expression is pRb-dependent in mouse osteoblasts|pRb-activated expression of integrin α10 mRNA is effectively translated into higher levels of integrin α10 protein as visualized by immunofluorescence 0.2 SIGNOR-253348 MAPK3 protein P27361 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 10197981 YES gcesareni Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus 0.527 SIGNOR-66755 GDNF protein P39905 UNIPROT ID3 protein Q02535 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.2 SIGNOR-252181 CDK5 protein Q00535 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates activity phosphorylation Ser774 SVPAGRRsPTSSPTP -1 12855954 YES llicata Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE.  0.517 SIGNOR-250661 DDX21 protein Q9NR30 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 21703541 YES miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. 0.266 SIGNOR-260192 CNR2 protein P34972 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.466 SIGNOR-256700 IL1RL1 protein Q01638 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 YES miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  0.602 SIGNOR-277705 DGCR8 protein Q8WYQ5 UNIPROT Microprocessor complex complex SIGNOR-C356 SIGNOR form complex binding 9606 BTO:0000552 24581491 YES lperfetto Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA. 0.924 SIGNOR-264849 ARHGAP15 protein Q53QZ3 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.58 SIGNOR-260470 NR5A2 protein O00482 UNIPROT CYP11B1 protein P15538 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002588 11564608 NO miannu The ability of LRH-1 to enhance transcription of the gene encoding human 11 beta- hydroxylase (hCYP11B1) was then examined using the H295R adrenal cell line. LRH-1 co-transfection with hCYP11B1 luciferase promoter constructs caused a 25-fold induction of luciferase activity. Furthermore, co-transfection of a hCYP11B1 reporter construct containing a mutation in the SF-1 binding cis-element abolished the stimulatory effect of both SF-1 and LRH-1. Electrophoretic mobility shift assay (EMSA) demonstrated that LRH-1 could bind to the SF-1 response element. Taken together, our data suggested that LRH-1 is expressed in the adrenal, and can substitute for SF-1 to enhance transcription of genes encoding certain of the steroid-metabolizing enzymes. 0.342 SIGNOR-254880 P2RY10 protein O00398 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256726 PRKACA protein P17612 UNIPROT RASGRF1 protein Q13972 UNIPROT up-regulates phosphorylation Ser927 KEKYRRMsLASAGFP 9606 BTO:0000938 10601308 YES llicata Phosphorylation of serine 916 of ras-grf1 contributes to the activation of exchange factor activity by muscarinic receptors. 0.518 SIGNOR-73202 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity phosphorylation Ser794 QHLRLSTsSGRLLYA 24841198 YES lperfetto SIK2 is known to attenuate insulin signaling by phosphorylating IRS-1/Ser789 0.568 SIGNOR-265745 BRLF1 protein P03209 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 20381110 YES scontino Epstein-Barr Virus BRLF1 Inhibits Transcription of IRF3 and IRF7 and Suppresses Induction of Interferon-β. These results suggest that EBV Rta is capable of regulating the activation of the IFN-β promoter. 0.2 SIGNOR-266646 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT down-regulates activity phosphorylation Ser657 KSSSRQLsESFKSKE 9606 BTO:0000007 15659405 YES llicata CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity. 0.703 SIGNOR-250960 MAPK7 protein Q13164 UNIPROT ETS1 protein P14921 UNIPROT up-regulates phosphorylation Thr38 CADVPLLtPSSKEMM 9606 12048211 YES gcesareni 9-cis retinoid x receptor alpha (rxr alpha) interacted with erk2 but not erk5 in intact cells, whereas ets-1 interacted preferentially with erk5. Increased phosphorylation of rxr alpha and ets-1 was detected in response to 1,25d. Activated erk2 and erk5 specifically phosphorylated rxr alpha and ets-1, respectively.Mutagenesis of ets-1 (t38a) reduced cyp24 promoter activity to levels observed with the dominant-negative mek5(a) and inhibited erk5-directed phosphorylation. Mutated rxr alpha (s260a) inhibited 1,25d-induced cyp24 promoter activity and abolished phosphorylation by activated erk2. 0.421 SIGNOR-88666 CTH protein P32929 UNIPROT hydrosulfide smallmolecule CHEBI:29919 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275819 ARVCF protein O00192 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.423 SIGNOR-252133 NOTCH3 protein Q9UM47 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21743488 NO gcesareni We demonstrate that her2 overexpression in this cellular model of dcis drives transcriptional upregulation of multiple components of the notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising notch3, its cleaved intracellular domain and the transcriptional regulator hes1. 0.61 SIGNOR-174750 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PKM protein P14618 UNIPROT down-regulates activity phosphorylation Ser37 MCRLDIDsPPITARN 9606 28607489 YES miannu We show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity, which was not further affected by pre-incubation with cyclin D3-CDK6 (Extended Data Fig. 3a, b). 0.259 SIGNOR-276454 PFDN6 protein O15212 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 YES miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR95 0.621 SIGNOR-270918 AMPK complex SIGNOR-C15 SIGNOR HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 21892142 YES lperfetto Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). 0.278 SIGNOR-216554 FBXO21 protein O94952 UNIPROT EID1 protein Q9Y6B2 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 26085330 YES miannu SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO) 0.413 SIGNOR-272429 MAPK1 protein P28482 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 18694962 YES Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. 0.2 SIGNOR-179959 NFY complex SIGNOR-C1 SIGNOR ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 NO We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. 0.268 SIGNOR-255746 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258063 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT down-regulates activity dephosphorylation Ser1137 KRLRPEDsFMSVYPM 9606 BTO:0000567 15737063 YES lperfetto Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase 0.737 SIGNOR-275534 HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity 9606 BTO:0001938 24300895 YES Altering the expression of HES1 did not obviously affect GR abundance (Figure 3A). However, genome-wide microarrays revealed that overexpression of HES1 resulted in inhibition of GR-mediated changes in the glucocorticoid regulated transcriptome, as compared to non-overexpressing controls 0.2 SIGNOR-253064 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr740 AVCPQAHyNMYPQNP 9606 11751923 YES llicata Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor. 0.829 SIGNOR-113397 histidine smallmolecule CHEBI:27570 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264762 FYN protein P06241 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates activity phosphorylation Tyr14 VDSEGHLyTVPIREQ 9606 12921535 YES lperfetto Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn.Therefore, 0.72 SIGNOR-118003 PTPRG protein P23470 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity dephosphorylation Tyr694 LAKAVDGyVKPQIKQ -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.265 SIGNOR-254730 HNF1A protein P20823 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 NO miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. 0.281 SIGNOR-254437 SLC9A2 protein Q9UBY0 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265592 LPAR2 protein Q9HBW0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 15856019 YES gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. 0.401 SIGNOR-135837 COMMD5 protein Q9GZQ3 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity 9606 30021164 NO miannu We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling.We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling. However, the dynamics of Rho GTPase activities are highly complex and tightly regulated in order to achieve their specific subcellular localization (Marjoram et al., 2014); thus, the mechanism by which COMMD5 directly or indirectly regulates the activity of RhoA needs to be investigated further. 0.2 SIGNOR-261690 EPHA3 protein P29320 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 BTO:0000938 9632142 YES gcesareni We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation. 0.527 SIGNOR-58139 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation 11493009 YES inferred from 70% family members lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. 0.2 SIGNOR-270021 MTOR protein P42345 UNIPROT LARP6 protein Q9BRS8 UNIPROT up-regulates activity phosphorylation Ser409 GRLNCSTsPEIFRKC 10116 BTO:0002741 28112218 YES done miannu Binding of La ribonucleoprotein domain family, member 6 (LARP6) to collagen mRNAs regulates their translation and is necessary for high type I collagen expression. Here we show that mTORC1 phosphorylates LARP6 on S348 and S409. The S348A/S409A mutant of LARP6 acts as a dominant negative protein in collagen biosynthesis, which retards secretion of type I collagen and causes excessive posttranslational modifications. 0.2 SIGNOR-273678 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Ser423 QMVNGAHsASTLDEA 9606 19393267 YES lperfetto Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1. 0.823 SIGNOR-185580 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-249667 CBL protein P22681 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20332299 YES lperfetto Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface. 0.602 SIGNOR-30794 PTGS2 protein P35354 UNIPROT prostaglandin D2 smallmolecule CHEBI:15555 ChEBI up-regulates chemical modification 9606 11751058 YES gcesareni Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2 0.8 SIGNOR-113282 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0001593 15207708 NO gcesareni Deltex, meltrin beta, ifi-202, and ifi-204 were also upregulated by notchic in the 2b4.11 t cell hybridoma, whereas ifi-d3 was expressed constitutively at relatively high levels and slightly upregulated by notchic, and pre-talfa was not expressed. Deltex, meltrin beta, pre-talfa, ifi-202, and ifi-204 were upregulated by notchic expression in the akr1 dp thymoma cell line, whereas ifi-d3 was not expressed 0.2 SIGNOR-254341 AMPK complex SIGNOR-C15 SIGNOR KPNA2 protein P52292 UNIPROT up-regulates phosphorylation Ser105 QAARKLLsREKQPPI 9606 15342649 YES lperfetto Ampk phosphorylated importin alpha1 on ser(105). Accordingly, expression of importin alpha1 proteins bearing k22r or s105a mutations failed to mediate the nuclear import of hur in intact cells. Our results point to importin alpha1 as a critical downstream target of ampk and key mediator of ampk-triggered hur nuclear import. 0.2 SIGNOR-216449 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000007 14551213 YES lperfetto The hematopoietic-specific Galpha16 protein has recently been shown to mediate receptor-induced activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727. Galpha16QL-induced STAT3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (ERK1), 0.719 SIGNOR-249450 JUN protein P05412 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 NO miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.343 SIGNOR-254876 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr52 DGFIPKNyIEMKPHP 9606 BTO:0000007 20554525 YES lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. 0.2 SIGNOR-246293 WWTR1 protein Q9GZV5 UNIPROT TTF1 protein Q15361 UNIPROT up-regulates binding 9606 BTO:0000763 19010321 YES miannu Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation. 0.313 SIGNOR-182296 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 YES Cbl binds directly to Tyr1045 receptors gcesareni Consistent with a negative role for c-Cbl, here we report that defective Tyr1045 of EGFR, an inducible c-Cbl docking site, enhances the mitogenic response to EGF 0.886 SIGNOR-114701 PIR protein O00625 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity binding 9606 BTO:0003081 33373853 YES miannu In contrast, the depletion of PIR initiates HMGB1-dependent autophagy by binding to BECN1, and subsequently promotes ferroptosis by activating ACSL4.  0.2 SIGNOR-279852 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr360 YSPRSFEdCGGGYTP 9606 9467953 YES Manara Thus, we propose that the phosphorylation of tyrosine 328 and 360 within Bcr by Bcr-Abl will drastically interfere with Bcr's kinase role in either signal transduction or some other cellular mechanism. 0.2 SIGNOR-260828 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. 0.2 SIGNOR-255851 Ub:E2 complex SIGNOR-C497 SIGNOR RNF223 protein E7ERA6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271259 P4HA1 protein P13674 UNIPROT HMGCR protein P04035 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000192 36702290 YES miannu In this study, we found that the prolyl 4-hydroxylase (P4H) subunit P4HA1 protects NPC cells from erastin-induced ferroptosis by activating HMGCS1, a key enzyme in the mevalonate pathway. Our results show that HMGCS1 and HMGCR are regulated by P4HA subunits at the transcriptional level (Fig. S4). 0.2 SIGNOR-279854 HMGCS1 protein Q01581 UNIPROT Ferroptosis phenotype SIGNOR-PH234 SIGNOR down-regulates 9606 BTO:0000192 36702290 NO miannu In this study, we found that the prolyl 4-hydroxylase (P4H) subunit P4HA1 protects NPC cells from erastin-induced ferroptosis by activating HMGCS1, a key enzyme in the mevalonate pathway. 0.7 SIGNOR-279855 N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide chemical CHEBI:94490 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191277 RLN2 protein P04090 UNIPROT RXFP2 protein Q8WXD0 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 YES gcesareni Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway. 0.707 SIGNOR-114585 YAP1 protein P46937 UNIPROT YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR up-regulates 30224758 YES lperfetto The transcription coactivators YAP/TAZ are ideal candidates to mediate cancer-specific transcriptional addictions. In fact, YAP/TAZ are genetically dispensable for homeostasis in many adult tissues9–17 while YAP/TAZ activation is a hallmark of many human malignancies13,17–19. Here we show that tumor transcriptional dependencies in fact overlap with tumor reliance on YAP/TAZ. 0.55 SIGNOR-276572 TWIST2 protein Q8WVJ9 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 19581928 NO miannu we showed aberrant IL-6 production and STAT3 activation in MCF-7 cells that constitutively express Twist, a metastatic regulator and direct transcriptional repressor of E-cadherin. 0.441 SIGNOR-255536 SLBP protein Q14493 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265403 SRC protein P12931 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates activity phosphorylation 9606 19665017 YES miannu Hence, c-Src-dependent phosphorylation of MPP2 could be part of a negative feedback loop within the circuitry that modulates c-Src activity by MPP2. 0.325 SIGNOR-279117 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263778 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 YES Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts 0.827 SIGNOR-141647 RNF8 protein O76064 UNIPROT ACD protein Q96AP0 UNIPROT up-regulates quantity by stabilization polyubiquitination Lys147 QDLDVQKkLYDCLEE 9606 22101936 YES miannu The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres. 0.2 SIGNOR-272722 CASP8 protein Q14790 UNIPROT CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 18073771 YES amattioni Active caspase-8 then proteolytically processes and activates caspase-7 0.741 SIGNOR-159853 PRKACA protein P17612 UNIPROT PTPRR protein Q15256 UNIPROT down-regulates activity phosphorylation Ser339 GLQERRGsNVSLTLD 9534 10601328 YES miannu The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue. treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.‚  0.344 SIGNOR-250038 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT unknown phosphorylation Ser525 NTWGCGNsLRTALIN -1 8477740 YES lperfetto An interphase-specific phosphorylation at Ser525 matching the PKC consensus sequence and of peptides phosphorylated by unknown kinases was determined. 0.362 SIGNOR-248935 NFE2L2 protein Q16236 UNIPROT NQO1 protein Q5RD31 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.NFE2L2-mediated upregulation of NQO1 is implicated in promoting resistance to ferroptosis inducers, such as erastin and sorafenib, in HCC cells 0.487 SIGNOR-279860 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Heme oxygenase 1 (HMOX1, also known as HO-1), an NFE2L2-dependent inducible enzyme, plays a crucial role in the degradation of heme, a pro-oxidant, into three biologically active products: biliverdin, free iron, and carbon monoxide 0.678 SIGNOR-279861 NFE2L2 protein Q16236 UNIPROT Ferritin complex SIGNOR-C563 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. In HCC cells, NFE2L2-mediated upregulation of FTH1 enhances the cellular antioxidant defense by increasing the capacity for iron storage, thereby reducing erastin- or sorafenib-induced ferroptosis 0.299 SIGNOR-279862 NFE2L2 protein Q16236 UNIPROT MT1G protein P13640 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. The expression of MT1G during ferroptosis is regulated by the NFE2L2 signaling pathway. In the context of cancer, particularly HCC, the upregulation of MT1G has been linked to resistance against sorafenib, a kinase inhibitor commonly used in cancer therapy 0.286 SIGNOR-279866 TM4SF1 protein P30408 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 33015133 YES lperfetto TM4SF1 is a partner of DVL2 and positively modulates Wnt/beta-catenin signaling by enhancing DVL2-Axin interaction. 0.2 SIGNOR-272402 NFE2L2 protein Q16236 UNIPROT GSS protein P48637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy 0.31 SIGNOR-279870 AR protein P10275 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24493753 YES miannu In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression. 0.2 SIGNOR-253466 ANAPC7 protein Q9UJX3 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.841 SIGNOR-252007 RORA protein P35398 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15199055 NO Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. 0.2 SIGNOR-254256 FYN protein P06241 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 10090 BTO:0000782 15735648 YES miannu Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323. 0.487 SIGNOR-276031 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation 9606 BTO:0000801 19327116 YES inferred from 70% family members gcesareni Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes. 0.2 SIGNOR-270045 AKT2 protein P31751 UNIPROT PCBP1 protein Q15365 UNIPROT down-regulates activity phosphorylation Ser43 VKRIREEsGARINIS 10090 BTO:0004183 20154680 YES miannu We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs. 0.43 SIGNOR-262625 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D4 protein O60343 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 12637568 YES gcesareni Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt 0.2 SIGNOR-99300 BTG2 protein P78543 UNIPROT HOXB9 protein P17482 UNIPROT up-regulates activity binding 9606 BTO:0000567 10617598 YES miannu The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. 0.684 SIGNOR-220987 ZBP1 protein Q9H171 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity binding 10090 BTO:0002572 32200799 YES gianni ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. 0.636 SIGNOR-266430 SP1 protein P08047 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 NO irozzo In this system, the basal transcription level from the p15Ink4B promoter was increased with increasing levels of Sp1, and Sp1 was required for transcriptional induction by Smads. Finally, inactivation of the Sp1 binding sites in the p15Ink4B promoter decreased the basal transcription level and TGF-β responsiveness. 0.561 SIGNOR-256289 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 YES esanto Autophosphorylated trka binds directly to plc?, Abl, and shc. 0.651 SIGNOR-75405 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT down-regulates activity phosphorylation Ser120 ARLAREKsQDGGELT -1 18480293 YES miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation 0.2 SIGNOR-262684 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.488 SIGNOR-251209 NOTCH1 protein P46531 UNIPROT IL2RA protein P01589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001454 10933396 NO gcesareni Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression. 0.295 SIGNOR-80336 GNG3 protein P63215 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.383 SIGNOR-154258 SHMT1 protein P34896 UNIPROT 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI down-regulates quantity chemical modification 9606 11802770 YES miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. 0.8 SIGNOR-269687 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA4 protein P48058 UNIPROT up-regulates activity chemical activation 9606 30825796 YES miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses 0.8 SIGNOR-264611 VAMP2 protein P63027 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR form complex binding 9606 30267828 YES miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. 0.933 SIGNOR-263966 17beta-estradiol smallmolecule CHEBI:16469 ChEBI MAPK15 protein Q8TD08 UNIPROT up-regulates chemical activation 9606 BTO:0000150 11043579 YES gcesareni Estrogen rapidly activates the mitogen-activated protein kinases, erk-1 and erk-2, via an as yet unknown mechanism. 0.8 SIGNOR-83277 TSPAN7 protein P41732 UNIPROT DRD2 protein P14416 UNIPROT down-regulates quantity binding 9606 BTO:0000007 28223337 YES miannu Tetraspanin-7 (TSPAN7) is expressed to variable degrees in different tissues, with the highest level in the brain, and multiple mutations in TSPAN7 have been implicated in intellectual disability. Our results showed that TSPAN7 was associated with DRD2 and reduced its surface expression by enhancing DRD2 internalization.Finally, TSPAN7 negatively affects DRD2-mediated signaling. 0.252 SIGNOR-265557 HDAC6 protein Q9UBN7 UNIPROT SRSF2 protein Q01130 UNIPROT up-regulates deacetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 YES miannu Our data support a model in which hdac6 has a key role in the maintenance of srsf2 protein level by inhibiting tip60_mediated acetylation and proteasomal degradation. 0.357 SIGNOR-170590 ID3 protein Q02535 UNIPROT TCF4 protein P15884 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C129 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.459 SIGNOR-241379 PCDHA5 protein Q9Y5H7 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265669 Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 NO lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. 0.7 SIGNOR-273456 FBXL5 protein Q9UKA1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 25249620 YES miannu Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation.  0.657 SIGNOR-272461 AMPK complex SIGNOR-C15 SIGNOR PIKFYVE protein Q9Y2I7 UNIPROT up-regulates activity phosphorylation Ser307 PARNRSAsITNLSLD -1 23905686 YES miannu AMPK phosphorylated PIKfyve at Ser307 both in vitro and in intact cells. We propose that PIKfyve activity is required for the stimulation of skeletal muscle glucose uptake by contraction/AMPK activation. PIKfyve is a new AMPK substrate whose phosphorylation at Ser307 could promote PIKfyve translocation to endosomes for PtdIns(3,5)P2 synthesis to facilitate GLUT4 (glucose transporter 4) translocation. 0.2 SIGNOR-263031 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EBNA1 protein P03211 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29659505 YES scontino We found that EBV-encoded Qp-EBNA1 can be upregulated by NF-κB, while EBNA1 protein expression has been shown to negatively regulate NF-κB activation by inhibiting IKKα/β phosphorylation 0.2 SIGNOR-266803 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 9606 12105215 YES lperfetto To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313 0.346 SIGNOR-216686 AKT1 protein P31749 UNIPROT ALYREF protein Q86V81 UNIPROT up-regulates phosphorylation Thr219 GGGTRRGtRGGARGR 9606 18562279 YES llicata Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export. 0.45 SIGNOR-252518 AURKA protein O14965 UNIPROT MCRS1 protein Q96EZ8 UNIPROT up-regulates activity phosphorylation Ser36 AGQKRASsQALGTIP 9606 27192185 YES miannu We conclude that Aurora-A phosphorylates MCRS1 on Ser35/36 specifically during mitosis. 0.316 SIGNOR-278232 DRD1 protein P21728 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.496 SIGNOR-256796 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity chemical activation 9606 17132853 YES miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 0.8 SIGNOR-256190 VEPH1 protein Q14D04 UNIPROT YAP1 protein P46937 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 23989952 NO or inhibits the Hippo pathway to activate Yki lperfetto A double positive-feedback loop between melt and yki, wherein yki acti- vates melt expression, and melt promotes yki 0.2 SIGNOR-202540 EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 11381086 NO miannu Translation initiation is inhibited in cells exposed to different stressful conditions. The phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) plays an important role in this stereotyped response, and is mediated by distinct kinases that are activated by specific stress signals. When phosphorylated on serine 51, eIF2α binds to and inhibits the guanine nucleotide exchange factor, eIF2B. The latter is required for the formation of the eukaryotic translational preinitiation complexes, and its sequestration in an inactive complex with phosphorylated eIF2α inhibits the initiation step of protein synthesis.  0.7 SIGNOR-260625 CCL4 protein P13236 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  0.862 SIGNOR-255116 INTS1 protein Q8N201 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.894 SIGNOR-261468 HRH1 protein P35367 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256778 ERCC2 protein P18074 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 YES lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.869 SIGNOR-269312 HLA-G protein P17693 UNIPROT LILRB1 protein Q8NHL6 UNIPROT up-regulates binding 9606 15718280 YES gcesareni Hla-g binds a limited repertoire of peptides and interacts with the inhibitory leukocyte ig-like receptors lir-1 and lir-2 0.77 SIGNOR-134180 COX6B1 protein P14854 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.755 SIGNOR-267742 PLK1 protein P53350 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT up-regulates activity phosphorylation Ser311 SDALTDDsMSMTDSS 9606 BTO:0001061 26438599 YES miannu Plk1 phosphorylates axin2 at Ser311.  0.486 SIGNOR-277180 CUDC-101 chemical CID:24756910 PUBCHEM EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262254 Integrator complex complex SIGNOR-C265 SIGNOR GADD45B protein O75293 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25675981 NO lperfetto The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes. 0.2 SIGNOR-261478 PPP2R5C protein Q13362 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates binding 9606 16456541 YES gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk 0.418 SIGNOR-144328 PRKDC protein P78527 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates phosphorylation Thr135 GGGSTSDtQEDILDE 9606 11867762 YES lperfetto Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis 0.429 SIGNOR-115331 PAK5 protein Q9P286 UNIPROT DDX5 protein P17844 UNIPROT up-regulates quantity by stabilization phosphorylation Thr69 HPDLARRtAQEVETY 9606 BTO:0000150 34936874 YES lperfetto PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer|The increased expression levels of PAK5 and phospho-DDX5 threonine 69 are associated with metastasis and poor clinical outcomes of patients. PAK5 facilitates the phosphorylation-dependent sumoylation of DDX5 to stabilize DDX5. Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. 0.2 SIGNOR-275658 SCYL1 protein Q96KG9 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates activity relocalization 9606 BTO:0000567 24769208 YES lperfetto Moreover, TEIF closely co-localized with C-NAP1 at the proximal ends of centrioles, and centriolar loading of TEIF stimulated by EGF/Akt could displace C-NAP1, resulting in centrosome splitting. 0.2 SIGNOR-265497 MAPKAPK2 protein P49137 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation 9606 20626350 YES gcesareni Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2 0.582 SIGNOR-166640 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 9890973 YES Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif gcesareni Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. 0.58 SIGNOR-63972 CDH11 protein P55287 UNIPROT CTNNB1 protein P35222 UNIPROT unknown binding 9606 BTO:0000150 10029089 YES miannu Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin 0.653 SIGNOR-64862 USP5 protein P45974 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 26912724 YES miannu  Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1. 0.352 SIGNOR-277210 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR7 protein P34969 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257526 GSK3B protein P49841 UNIPROT CLOCK protein O15516 UNIPROT down-regulates quantity by destabilization phosphorylation Ser427 ALERFDHsPTPSASS 9606 BTO:0002181 19946213 YES miannu We have identified a conserved cluster of serines that include, Ser431, which is a prerequisite phosphorylation site for the generation of BMAL dependent phospho-primed CLOCK and for the potential GSK-3 phosphorylation at Ser427.  0.341 SIGNOR-276270 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser74 ERYSSSGsPANSFHF 9606 BTO:0000093 35513296 YES miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings 0.342 SIGNOR-277907 (2S)-2-[[2-(2,3-dihydro-1H-inden-5-yloxy)-9-[(4-phenylphenyl)methyl]-6-purinyl]amino]-3-phenyl-1-propanol chemical CHEBI:94469 ChEBI ARFGAP3 protein Q9NP61 UNIPROT down-regulates activity chemical inhibition -1 26152429 YES lperfetto Here we present structure-activity relationship (SAR) studies of QS11 analogs in two assays: direct inhibition of enzymatic activity of purified ARFGAP1 protein and cellular activation of the Wnt/β-catenin pathway. The results confirm the direct inhibition of ARFGAP1 by QS11, and also suggest the presence of other potential cellular targets of QS11 0.8 SIGNOR-261980 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 21993628 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-176766 PRKACA protein P17612 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser879 LIDRNQKsDKKPDRE 9606 BTO:0000763 22798526 YES lperfetto We showed that pkc_ phosphorylation of p120 at serine (s)879 in response to thrombin or lipopolysaccharide challenge reduced p120 binding affinity for ve-cadherin and mediated aj disassembly secondary to ve-cadherin internalization 0.2 SIGNOR-198288 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257934 HMGB1 protein P09429 UNIPROT IL2RA protein P01589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 7862168 NO 2 miannu The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells. 0.2 SIGNOR-240113 INHBA protein P08476 UNIPROT ACVR2A protein P27037 UNIPROT up-regulates activity binding 9606 1646080 YES gcesareni A protein of 494 amino acids comprising a ligand-binding extracellular domain, a single membrane-spanning domain, and an intracellular kinase domain with predicted serine/threonine specificity. 125I-activin A binds to transfected COS cells with an affinity of 180 pM and can be competed by activin A, activin B, and inhibin A, but not by transforming growth factor beta 1. 0.814 SIGNOR-235138 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 YES lperfetto Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl. 0.396 SIGNOR-78020 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-119992 CDK8 protein P49336 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15546612 NO gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. 0.2 SIGNOR-130637 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CRBN protein Q96SW2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0005490 30026574 YES miannu We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase.  0.406 SIGNOR-272316 SDCBP protein O00560 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 BTO:0001444 25122212 NO Luana Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation. 0.2 SIGNOR-260753 EPHB2 protein P29323 UNIPROT EPHB2 protein P29323 UNIPROT up-regulates activity phosphorylation Tyr602 IYIDPFTyEDPNEAV -1 10572014 YES Our results demonstrate that autophosphorylation tyrosine 611 in the juxtamembrane region of chicken EphB2 is critical for the association of the Src SH2 domain. 0.2 SIGNOR-251124 NDN protein Q99608 UNIPROT BMI1 protein P35226 UNIPROT down-regulates 9606 BTO:0000007 24392140 NO lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, 0.252 SIGNOR-253384 CIITA protein P33076 UNIPROT HLA-DMA protein P28067 UNIPROT up-regulates quantity by expression transcriptional regulation 9300700 NO The class II transactivator (CIITA) is a highly specific transcription factor that activates only genes known to be involved in the class II MHC processing pathway, including class II MHC, invariant chain, and HLA-DMA/B genes. 0.402 SIGNOR-254004 SPRY4 protein Q9C004 UNIPROT TIMP1 protein P01033 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002058 20501643 NO miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 0.2 SIGNOR-253038 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr218 GDGSDHPyYNSIPSK -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.777 SIGNOR-273913 PRKN protein O60260 UNIPROT DDIT4 protein Q9NX09 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25101677 YES miannu In conclusion, our work in cellular and animal models and in human samples strongly indicates that RTP801 is a substrate of parkin and that RTP801 elevation due to parkin loss of function in both AR-JP and sporadic Parkinson's disease may contribute to neurodegeneration.|We showed that parkin poly-ubiquitinates RTP801, both in vitro and in vivo. 0.2 SIGNOR-278560 NEURL1 protein O76050 UNIPROT CPEB3 protein Q8NE35 UNIPROT up-regulates activity ubiquitination 9606 22153079 YES miannu If Neurl1 interacts and modulates the activity of CPEB3 and increases the translation of GluA1 and GluA2 mRNAs, this effect would be blocked if we abolished the interaction between CPEB3 and Neurl1.|Neurl1 Interacts with and Ubiquitinates a Translational Regulator of GluA1 and GluA2 : the Cytoplasmic Polyadenylation Element Binding Protein 3. 0.47 SIGNOR-278588 apixaban chemical CHEBI:72296 ChEBI F10 protein P00742 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189865 GRM1 protein Q13255 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264347 RNF43 protein Q68DV7 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization ubiquitination Lys816 NFIDENLkAADTDPT 9606 31286874 YES miannu To identify the E-cadherin ubiquitination site, we individually mutated three lysines in its cytoplasmic domain, including K816A, K855A, and K871A, of which E-cad K816A failed to restore E-cadherin ubiquitination (Additional file xref : Figure S3D), indicating that RNF43 ubiquitinated E-cadherin at the cytoplasmic lysine 816.|Together , these results suggest that RNF43 potentially downregulates E-cadherin in lung adenocarcinoma in the context of c-Src activation . 0.267 SIGNOR-278598 KDM1A protein O60341 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 15620353 YES miannu Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. 0.2 SIGNOR-264508 MDM2 protein Q00987 UNIPROT GRK2 protein P25098 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 33806062 YES miannu Our findings show that the signals enabling activity of the GRK2/MST2/Nek2A axis for separation also switches on Mdm2 degradation of GRK2 to ensure accurate centrosome dynamics and proper mitotic spindle functionality.|Our results show now that EGF-induced phosphorylation of GRK2 on S670 is a key event in initiating centrosome separation and also a relevant clue for limiting centrosome separation, as this event simultaneously triggers the Mdm2-dependent ubiquitination and degradation of GRK2 ( xref ). 0.2 SIGNOR-278629 INO80D protein Q53TQ3 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.53 SIGNOR-270843 DYRK1A protein Q13627 UNIPROT PLK2 protein Q9NYY3 UNIPROT up-regulates quantity by stabilization phosphorylation Ser358 VPDFHLSsPAKNFFK 9606 BTO:0000007 37387444 YES miannu  In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability.  0.313 SIGNOR-277791 SMO protein Q99835 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates binding 9606 16885213 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.427 SIGNOR-148493 MC3R protein P41968 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256891 SALL4 protein Q9UJQ4 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19440552 NO miannu Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. 0.403 SIGNOR-255126 CXCL10 protein P02778 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 NO miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection 0.7 SIGNOR-261031 FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 NO miannu The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. 0.427 SIGNOR-252069 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12151396 YES gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. 0.341 SIGNOR-91071 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29236325 NO irozzo We report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT. 0.2 SIGNOR-255699 SRC protein P12931 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates activity phosphorylation Tyr231 LLPLRRGyIGVVNRS 9606 BTO:0000007 9880482 YES lperfetto Src-mediated tyrosine phosphorylation of dynamin is required for beta2-adrenergic receptor internalization and mitogen-activated protein kinase signalingHere we demonstrate that activation of beta2-adrenergic receptors (beta2-ARs) leads to c-Src-mediated tyrosine phosphorylation of dynamin, which is required for receptor internalization. Two tyrosine residues, Tyr231 and Tyr597, are identified as the major phosphorylation sites 0.636 SIGNOR-247124 CREB1 protein P16220 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by expression transcriptional regulation 8355 10775268 NO lperfetto Here we demonstrate that the closely related acetyltransferases p300 and cbp potentiate beta-catenin-mediated activation of the siamois promoter 0.456 SIGNOR-76984 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser396 FTWKRLRsHSRQYVS 9606 15328002 YES gcesareni Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes. 0.2 SIGNOR-128411 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.361 SIGNOR-273164 CREBL2 protein O60519 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 21728997 NO Luana Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression. 0.2 SIGNOR-261574 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser512 PPKSGDRsGYSSPGS 9606 BTO:0000590 9771888 YES lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. 0.738 SIGNOR-249353 CEBPD protein P49716 UNIPROT MSTN protein O14793 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24011072 NO miannu To identify whether p-Stat3 acts through C/EBPŒ¥ to stimulate myostatin, we knocked down C/EBPŒ¥ using siRNA. In this case, the IL-6-induced increase in myostatin expression was blocked when C/EBPŒ¥was suppressed even though p-Stat3 was increased 0.287 SIGNOR-255332 STK16 protein O75716 UNIPROT DRG1 protein Q9Y295 UNIPROT unknown phosphorylation Thr100 AYEFTTLtTVPGVIR -1 18184589 YES Manara It is therefore likely that MPSK1 regulates DRG1 function by either phosphorylation or through competition with other DRG1 binding partners. 0.392 SIGNOR-260806 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Ser106 DNQLTIKsPSKRELA 9606 10339564 YES lperfetto Based on these results, we propose that phosphorylation of hscdc6 by cdks regulates dna replication of at least two steps: first, by promoting initiation of dna replication and, second, through nuclear exclusion preventing dna rereplication. hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106) 0.942 SIGNOR-217272 RPL27A protein P46776 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.859 SIGNOR-262473 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259793 PPARA protein Q07869 UNIPROT AQP3 protein Q92482 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 NO miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. 0.297 SIGNOR-255045 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM13 protein O60858 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271145 DLG3 protein Q92796 UNIPROT NMDA receptor_2B complex SIGNOR-C348 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 YES lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. 0.736 SIGNOR-266007 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 YES gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.2 SIGNOR-163274 HBA1 protein P69905 UNIPROT AHSP protein Q9NZD4 UNIPROT down-regulates activity 9606 2545495 NO Regulation miannu EDRF is rapidly inactivated by hemoglobin and superoxide. 0.774 SIGNOR-251751 IL31 protein Q6EBC2 UNIPROT IL31RA protein Q8NI17 UNIPROT up-regulates binding 9606 15184896 YES gcesareni Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor. 0.647 SIGNOR-125313 AKT proteinfamily SIGNOR-PF24 SIGNOR PHB2 protein Q99623 UNIPROT down-regulates binding 10090 15173318 YES lperfetto Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation 0.2 SIGNOR-234441 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser573 ENSNSCRsSTTTCPE 9606 BTO:0000007 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249302 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.274 SIGNOR-163776 CARS1 protein P49589 UNIPROT cysteine smallmolecule CHEBI:15356 ChEBI down-regulates quantity chemical modification 9606 11347887 YES miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. 0.8 SIGNOR-270470 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273093 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1167 ESAPAESsPSKIMSK 9606 8816480 YES gcesareni In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1 0.634 SIGNOR-43943 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser315 ITATSPAsMVGGKPG 10116 BTO:0000452 11287630 YES lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten 0.766 SIGNOR-106578 PDHX protein O00330 UNIPROT INS protein P01308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001731 12783165 NO miannu In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. 0.288 SIGNOR-254902 FBXW2 protein Q9UKT8 UNIPROT GCM1 protein Q9NP62 UNIPROT down-regulates quantity binding 9606 BTO:0000007 15640526 YES miannu FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system 0.539 SIGNOR-271524 CHRM4 protein P08173 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.371 SIGNOR-256965 EPHA4 protein P54764 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 28686668 YES miannu EphA4 phosphorylates JAK2.|These findings suggest that EphA4 activates not only growth hormone receptor, as shown above, but also JAK2 by direct phosphorylation. 0.281 SIGNOR-279040 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser59 GDSCPHGsPQGPLAP 12818176 YES miannu JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. 0.636 SIGNOR-250134 GNRHR protein P30968 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257177 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr232 GGLPEVAtPESEEAF 9606 BTO:0004971 7816602 YES lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. 0.791 SIGNOR-235877 GPR132 protein Q9UNW8 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257275 MTSS1 protein O43312 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 16280553 YES lperfetto Mim-b binds and activates rac via its irsp53/mim domain 0.2 SIGNOR-141573 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser486 DDEITEAKsGTATPQRS 10116 BTO:0002135 17023420 YES These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine. 0.422 SIGNOR-256110 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 12612081 YES In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin 0.622 SIGNOR-248386 PRKAA2 protein P54646 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Ser177 AKELDQGsLCTSFVG 9606 SIGNOR-C14 21673972 YES lperfetto These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes 0.257 SIGNOR-174401 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 23633519 YES lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. 0.8 SIGNOR-252641 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 YES llicata We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. 0.357 SIGNOR-163537 HIPK2 protein Q9H2X6 UNIPROT HDAC3 protein O15379 UNIPROT down-regulates activity phosphorylation Ser374 KMLNHAPsVQIHDVP 10090 BTO:0002572 34244427 YES miannu Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation. 0.2 SIGNOR-277568 CKB protein P12277 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity relocalization 9606 BTO:0000099 19333390 YES miannu In summary, data presented here strongly suggest that locally generated ATP is an important regulator for actin-based cytoskeletal dynamics involved in cell extension and motility and that CK-B is a controlling enzyme in the compartmentalization of ATP availability. CK-B co-localizes with cortical actin and facilitates spreading of astrocytes 0.292 SIGNOR-265791 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 15456867 YES gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation 0.726 SIGNOR-129585 CDK5 protein Q00535 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000938 BTO:0000887;BTO:0001760;BTO:0000142 15096606 YES gcesareni We report here that the cdk5/p35 complex associates with stat3 and phosphorylates stat3 on the ser-727 residue in vitro and in vivo. Ser phosphorylation of stat3 and transcription of stat3 target genes, such as c-fos and junb, in a cdk5-dependent manner. 0.402 SIGNOR-124325 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 10660534 YES lperfetto Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function 0.727 SIGNOR-74844 RPS6KA4 protein O75676 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 YES lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) msk 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf-kb isoform p65 and stat 1 and 3. 0.274 SIGNOR-217373 FYN protein P06241 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr288 YETADGGyMTLNPRA -1 8756631 YES lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. 0.532 SIGNOR-249336 COL18A1 protein P39060 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates binding 9606 12682293 YES gcesareni The activity of human endostatin is mediated by alpha 5 beta 1 integrin. 0.556 SIGNOR-99871 CEBPD protein P49716 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 NO fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. 0.522 SIGNOR-210007 PRKCZ protein Q05513 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr564 RGTASRStFHGQPRE 9606 15084291 YES lperfetto Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells 0.2 SIGNOR-124221 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates quantity by destabilization phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 YES miannu PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated 0.2 SIGNOR-250077 HNRNPH1 protein P31943 UNIPROT TERF2 protein Q15554 UNIPROT down-regulates quantity post transcriptional regulation 10116 BTO:0001009 27117401 YES miannu During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. 0.334 SIGNOR-266807 IL22RA1 protein Q8N6P7 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 12087100 YES gcesareni Il-22 activates jak1 and tyk2 0.541 SIGNOR-90165 PKA proteinfamily SIGNOR-PF17 SIGNOR ATG16L1 protein Q676U5-2 UNIPROT down-regulates quantity by destabilization phosphorylation Ser268 SRAATRRsVSSFPVP -1 31580256 YES miannu PKA phosphorylates ATG16L1α at Ser268 and ATG16L1β at Ser269, driving phosphorylation-dependent degradation of ATG16L1 protein.  0.2 SIGNOR-277489 TFEB protein P19484 UNIPROT BLOC1S2 protein Q6QNY1 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). 0.2 SIGNOR-276682 AKAP12 protein Q02952 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity relocalization 14657015 YES lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. 0.2 SIGNOR-271837 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser260 TLSPVNHsLDLQPVT 9606 SIGNOR-C8 11027280 YES gcesareni Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions. 0.548 SIGNOR-82974 MC4R protein P32245 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257392 DMTF1 protein Q9Y222 UNIPROT GAS1 protein P54826 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004532 19816943 NO Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  0.2 SIGNOR-261588 PRKAB2 protein O43741 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 YES gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. 0.859 SIGNOR-139167 N protein P59595 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation -1 14623261 YES Luana The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well 0.2 SIGNOR-260726 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Thr) smallmolecule CHEBI:29180 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269497 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR NAMPT protein P43490 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19299583 YES miannu Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1. Transduction of Clock/Bmal1 into mouse embryonic fibroblasts appeared to up-regulate Nampt expression ∼1.6-fold (Fig. 3E). 0.611 SIGNOR-268021 D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 24929114 YES miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. 0.8 SIGNOR-268141 MIB1 protein Q86YT6 UNIPROT JAG1 protein P78504 UNIPROT up-regulates activity ubiquitination 9606 BTO:0001253 18043734 YES lperfetto Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum. 0.692 SIGNOR-159480 PTPRB protein P23467 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 19136612 YES VE-PTP/VEGFR2 complex formation resumes with time, leading to dephosphorylation and deactivation of VEGFR2 (right). B) In VE-PTP-deficient cells, such as after siRNA treatment, VEGFR2 activation (middle) is exaggerated, leading to increased phosphorylation at the Y951 and Y1175 phosphorylation sites 0.454 SIGNOR-248441 MYOD1 protein P15172 UNIPROT SP1 protein P08047 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9148896 YES lperfetto These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport. 0.374 SIGNOR-241765 MC3R protein P41968 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257230 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273078 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1363 TFFTDNSy 9606 BTO:0000394 12881528 YES lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. 0.2 SIGNOR-104092 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 YES lperfetto Recent work found that CyclinE/CDK2 can phosphorylate OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) in vitro|Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2. 0.319 SIGNOR-264436 SIRT5 protein Q9NXA8 UNIPROT HMGCS2 protein P54868 UNIPROT up-regulates activity post translational modification Lys83 YNNVEAGkYTVGLGQ 9606 BTO:0000007 24315375 YES desuccinylation lperfetto We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5 0.343 SIGNOR-267641 PTGFR protein P43088 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257193 PRKCE protein Q02156 UNIPROT PRKCE protein Q02156 UNIPROT down-regulates phosphorylation Ser729 QEEFKGFsYFGEDLM 9606 11964154 YES llicata Protein kinase-inactive mutants of pkcepsilon were not phosphorylated at ser(729) in cells, and phosphorylation of this site leads to dephosphorylation of the activation-loop thr(566) 0.2 SIGNOR-117324 NFKB1 protein P19838 UNIPROT IEX-1L protein O75353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9703517 NO gcesareni Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here. Its transcription induced by tnf was decreased in cells with defective nf-kappab activation, rendering them sensitive to tnf-induced apoptosis, which was abolished by transfection with iex-1l. 0.2 SIGNOR-59539 STK3 protein Q13188 UNIPROT RCC1 protein P18754 UNIPROT up-regulates phosphorylation Ser11 KRIAKRRsPPADAIP 9606 BTO:0000007 19559616 YES miannu MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets. 0.2 SIGNOR-263145 CDK1 protein P06493 UNIPROT ODF2 protein Q5BJF6 UNIPROT up-regulates activity phosphorylation Ser820 YSTFLTSsPIRSRSP 9606 19386263 YES miannu Phosphorylation of hCenexin1 at S796 is critical for the hCenexin1-Plk1 interaction.Here we show that a splice variant of hODF2 called hCenexin1, but not hODF2 itself, efficiently localizes to somatic centrosomes via a variant-specific C-terminal extension and recruits Plk1 through a Cdc2-dependent phospho-S796 motif within the extension. This interaction and Plk1 activity were important for proper recruitment of pericentrin and gamma-tubulin, and, ultimately, for formation of normal bipolar spindles. 0.541 SIGNOR-273584 PBX1 protein P40424 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 15149596 YES Pbx is constitutively bound close to the Myogenin promoter and can recruit MyoD lperfetto These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site 0.41 SIGNOR-124834 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Thr310 GVGSVEQtPRKRLR 9606 BTO:0000150 23421998 YES lperfetto Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination 0.2 SIGNOR-201046 AEBP2 protein Q6ZN18 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 YES lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). 0.867 SIGNOR-241903 APC-c complex SIGNOR-C150 SIGNOR USP37 protein Q86T82 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21596315 YES lperfetto USP37 is ubiquitinated by APCCDH1 in late mitosis and early G1 phase||Inactive USP37 now becomes a substrate for APCCDH1, undergoing K11-linked polyubiquitination and proteasomal degradation. Elimination of USP37 ensures that it does not antagonize APC/C substrate degradation during mitosis. 0.291 SIGNOR-265048 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Thr235 SSSSPPGtPSPADAK 9606 BTO:0000551 19723873 YES gcesareni Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction. 0.2 SIGNOR-238303 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 21502402 YES inferred from 70% family members llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro 0.2 SIGNOR-270122 CHL1 protein O00533 UNIPROT ANK1 protein P16157 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 YES miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. 0.531 SIGNOR-266724 MAPK10 protein P53779 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 YES Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190 0.2 SIGNOR-124009 Normorphine chemical CHEBI:7633 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258823 IFNG protein P01579 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 NO inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. 0.2 SIGNOR-270238 (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester chemical CHEBI:103931 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258463 RBBP6 protein Q7Z6E9 UNIPROT ZBTB38 protein Q8NAP3 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24726359 YES miannu Thus, RBBP6 induces ZBTB38 protein degradation, and this depends on the activity of the proteasome.We next tested whether RBBP6 might directly ubiquitinate ZBTB38.|We show that ZBTB38 is directly ubiquitinated by RBBP6 in human and mouse cells, in a process that is independent of p53 and MDM2, and leads to proteasomal degradation. 0.424 SIGNOR-278594 H4C1 protein P62805 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 YES miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. 0.2 SIGNOR-263877 CSNK2A2 protein P19784 UNIPROT SUZ12 protein Q15022 UNIPROT up-regulates activity phosphorylation Ser583 PQEMEVDsEDEKDPE 9606 BTO:0002181 36351927 YES miannu CK2 is the kinase for the phosphorylation of S583 of SUZ12. 0.2 SIGNOR-277797 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 SVKSPVSsPNNVTLR 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.35 SIGNOR-276110 CAD protein P27708 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267418 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 SIGNOR-C15 21205641 YES gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.503 SIGNOR-170867 AP-2 complex complex SIGNOR-C245 SIGNOR AAK1 protein Q2M2I8 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 YES Giorgia We therefore characterised protein ligands using liquid chromatography tandem mass spectrometry (LC‐MS/MS) and confirmed this using Western blotting to recognise both major and minor bands. Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs 0.655 SIGNOR-260393 OPTN protein Q96CV9 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 NO same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. 0.2 SIGNOR-259880 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity ubiquitination 9534 11295495 YES lperfetto The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. 0.511 SIGNOR-235305 SLC24A2 protein Q9UI40 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264394 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191301 MRTFA protein Q969V6 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 21673106 NO miR-143 and miR-145 target KLF4 gcesareni This result suggests that mrtf-a, but not myocd, is essential for bmp4-dependent induction ofmir-143/145gene transcription. Of the mirnas identified to target klf4, only mir-143 and mir-145 were induced at least 1.5-fold by both bmp4 and tgf- , suggesting that they may be critical for bmp4- and tgf- -mediated reduction of klf4. 0.2 SIGNOR-174261 bremazocine chemical CHEBI:3171 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258778 GATA1 protein P15976 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity relocalization 9606 BTO:0000150 25726523 YES lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 0.549 SIGNOR-275664 TP53 protein P04637 UNIPROT AIFM1 protein O95831 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23506862 YES miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. 0.352 SIGNOR-267462 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser793 PRPSPLPsPQPAPRR 9606 BTO:0000007 17711861 YES miannu  The activation of MLK3 by GSK-3beta occurred via phosphorylation of MLK3 on two amino acid residues, Ser(789) and Ser(793), that are located within the C-terminal regulatory domain of MLK3.  0.336 SIGNOR-276072 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 YES gcesareni These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis. 0.474 SIGNOR-252617 MAPKAPK2 protein P49137 UNIPROT HNRNPA0 protein Q13151 UNIPROT up-regulates activity phosphorylation Ser84 VELKRAVsREDSARP 10090 BTO:0000801 12456657 YES miannu MAPKAP-K2 phosphorylated hnRNP A0 at Ser84 in vitro and this residue became phosphorylated in LPS-stimulated cells. The simplest explanation for these findings is that the phosphorylation of hnRNP A0 at Ser84 by MAPKAP-K2 enhances binding to the AREs of these mRNAs or allows hnRNP A0 to displace another protein(s) from the AREs. 0.532 SIGNOR-262951 GDNF protein P39905 UNIPROT Neural_tissue_regeneration phenotype SIGNOR-PH68 SIGNOR up-regulates 10116 15212950 NO miannu The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. In normal development, GDNF promotes survival of sympathetic, parasympathetic, and spinal motorneurons. It even promotes regeneration of spinal motor neurons after spinal cord injury. 0.7 SIGNOR-252170 FOXO3 protein O43524 UNIPROT FASLG protein P48023 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10102273 NO gcesareni Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene. 0.708 SIGNOR-66035 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu79 EEAREVFeNTERTTE 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263685 QRICH1 protein Q2TAL8 UNIPROT YARS2 protein Q9Y2Z4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269413 PDPK1 protein O15530 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 YES miannu 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. 0.657 SIGNOR-252763 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser45 FHGVAILsPLLNIEK -1 12361598 YES miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) 0.516 SIGNOR-265957 PRKACA protein P17612 UNIPROT RGS14 protein O43566 UNIPROT up-regulates activity phosphorylation Thr495 SATGKRQtCDIEGLV -1 12534294 YES miannu RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP 0.338 SIGNOR-250046 ARID1B protein Q8NFD5 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 YES miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro 0.336 SIGNOR-271437 ITGB2 protein P05107 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.74 SIGNOR-253196 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser389 LKEAEEEsSGGEEED 9606 18649047 YES gcesareni We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2. 0.395 SIGNOR-179542 Microprocessor complex complex SIGNOR-C356 SIGNOR mir-10b mirna URS00004CAC40_9606 RNAcentral up-regulates quantity post transcriptional regulation 34936874 YES lperfetto Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. 0.4 SIGNOR-275661 KEL protein P23276 UNIPROT EDN3 protein P14138 UNIPROT up-regulates activity cleavage Trp117 YCHLDIIwINTPEQT -1 10438732 YES miannu These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles. 0.675 SIGNOR-256354 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARRB2 protein P32121 UNIPROT up-regulates activity phosphorylation Thr276 FCKVYTItPLLSDNR 10090 BTO:0002572 26324936 YES done miannu ERK1/2-dependent βarr2 phosphorylation on S14 and T276 induces CXCR4 intracellular sequestration. 0.2 SIGNOR-274019 SGK3 protein Q96BR1 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser484 KRRKRMSsGTEECGE 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.276 SIGNOR-275767 FCAR protein P24071 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 9606 30766540 NO lperfetto IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages 0.7 SIGNOR-264861 Hexocyclium chemical CHEBI:5707 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258398 FOXO proteinfamily SIGNOR-PF27 SIGNOR Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 18391974 NO Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism. 0.7 SIGNOR-253016 26S Proteasome complex SIGNOR-C307 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates quantity destabilization 10090 BTO:0003569 9233789 YES Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. 0.415 SIGNOR-270947 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 YES PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. 0.308 SIGNOR-248486 NR2F1 protein P10589 UNIPROT PCDH19 protein Q8TAB3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 34215582 YES miannu We demonstrated that high expression of COUP-TFI induces MEC cell fate and protocadherin 19 expression. We next demonstrated that COUP-TFI is able to directly bind to a conserved Sp1/COUP-TFI binding site in the Pcdh19 promoter region by chromatin immunoprecipitation (ChIP) (Fig. 6, E and F). 0.2 SIGNOR-267223 oxymetazoline chemical CHEBI:7862 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 9913 BTO:0000142 9632357 YES miannu Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives. 0.8 SIGNOR-258928 LYN protein P07948 UNIPROT IL5RA protein Q01344 UNIPROT up-regulates activity phosphorylation 9606 29029406 YES miannu Lyn activate and expand IL-5RA intracellular signaling through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex, provoking eosinophils proliferation and exaggerated activation manifested as CEL.|We further delineated that Lyn can induce IL-5RA tyrosine phosphorylation and physically associate with IL-5RA in F/P expressing cells. 0.473 SIGNOR-279059 GSK3B protein P49841 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization phosphorylation Ser17 MVMSLRVsELQVLLG 10090 BTO:0002268 26157031 YES miannu We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting.  0.333 SIGNOR-276923 PRKACA protein P17612 UNIPROT PTBP1 protein P26599 UNIPROT down-regulates activity phosphorylation Ser16 AVGTKRGsDELFSTC 10116 12851456 YES miannu PKA directly phosphorylates PTB on conserved Ser-16, and PKA activation in PC12 cells induces Ser-16 phosphorylation. PTB carrying a Ser-16 to alanine mutation accumulates normally in the nucleus. However, export of this mutant protein from the nucleus is greatly reduced in heterokaryon shuttling assays. Conversely, hyperphosphorylation of PTB by coexpression with the catalytic subunit of PKA results in the accumulation of PTB in the cytoplasm. 0.31 SIGNOR-263149 DYRK1A protein Q13627 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser261 ARSSRPAsPCNKRKY 9606 28235034 YES miannu DYRK1A phosphorylation of NFATc1 and alphaA at S261, S278, S403 and S409 interfered with NFATc1 ubiquitination and ubiquitin-proteasome degradation.|Here, we demonstrated that DYRK1A increased NFATc1 (NFATc1 and alphaA isoform) protein stability, in contrast to the decrease of NFATc2 protein stability by DYRK1A. 0.429 SIGNOR-278279 CDK1 protein P06493 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 YES gcesareni These results suggest that both ERK and Cdk1 directly phosphorylate Nup50 at Ser221 in intact cells|Notably, erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. 0.419 SIGNOR-188061 PRKCA protein P17252 UNIPROT PIP5K1B protein O14986 UNIPROT down-regulates phosphorylation Ser413 PSKKRCNsIAALKAT 9606 23909401 YES lperfetto Collaboration of ampk and pkc to induce phosphorylation of ser413 on pip5k1b resulting in decreased kinase activity and reduced ptdins(4,5)p2 synthesis in response to oxidative stress and energy restriction. we demonstrate that pkc can directly phosphorylate ser413 in vitro 0.2 SIGNOR-194820 LSM-20934 chemical CHEBI:109533 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258727 PRKCA protein P17252 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser790 IHRKTTAsTRKVSLA -1 1377674 YES lperfetto Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC. 0.399 SIGNOR-248851 WNT7A protein O00755 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.768 SIGNOR-253130 TAF1A protein Q15573 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 15970593 YES lperfetto Gene promoters with a TATA box tend to be bound by the SAGA complex which includes TBP, SUPT3H, and GCN5 (Basehoar et al., 2004; Rodríguez-Navarro, 2009). Therefore, it was thought that TATA-containing genes were mainly regulated by the SAGA complex, while TATA-less genes were independently regulated by TFIID (Pugh and Tjian, 1991; Basehoar et al., 2004). However, recent studies in yeast indicate that most genes utilize both TFIID and SAGA, and that the relative contribution of each complex likely depends on the individual context 0.359 SIGNOR-269591 CDK2 protein P24941 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates phosphorylation Ser443 FLGQTPAsPARYSPV 9606 19066288 YES llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1 0.282 SIGNOR-182765 WDR5 protein P61964 UNIPROT HMT complex SIGNOR-C19 SIGNOR form complex binding 9606 17500065 YES lperfetto The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes. 0.892 SIGNOR-154766 PAICS protein P22234 UNIPROT SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity chemical modification 9606 33179964 YES miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). 0.8 SIGNOR-267322 NELFCD protein Q8IXH7 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 YES miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 0.86 SIGNOR-271399 BUB1B protein O60566 UNIPROT MCC complex SIGNOR-C382 SIGNOR form complex binding 9606 BTO:0000567 25092294 YES miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 0.979 SIGNOR-265974 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates activity phosphorylation Tyr466 VFLRCINyVFFPSLK -1 8605876 YES lperfetto We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2. 0.91 SIGNOR-246934 FYN protein P06241 UNIPROT CNN1 protein P51911 UNIPROT down-regulates activity phosphorylation Tyr261 SQRGMTVyGLPRQVY 9534 BTO:0000298 15206927 YES We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin 0.334 SIGNOR-251158 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22575959 YES gcesareni Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6 0.292 SIGNOR-197414 TRAF6 protein Q9Y4K3 UNIPROT MYC protein P01106 UNIPROT down-regulates activity ubiquitination Lys148 K-->C 9606 35045331 YES miannu We posited that TRAF6 ubiquitination of MYC at K148 prevents its acetylation, which results in diminished MYC activity ( xref ). 0.344 SIGNOR-278563 S1PR2 protein O95136 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257289 CDK2 protein P24941 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 14697231 YES gcesareni Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase. 0.296 SIGNOR-120372 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12950161 YES lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitro.catalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases 0.404 SIGNOR-86581 USP7 protein Q93009 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates deubiquitination 9606 16082221 YES gcesareni Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins. 0.769 SIGNOR-139450 GPER1 protein Q99527 UNIPROT hsa-miR-21-5p mirna URS000039ED8D_9606 RNAcentral up-regulates activity post transcriptional regulation 9606 BTO:0000599 25969534 NO Parnian MiR-21 transcription is regulated by DHEA through GPER. 0.4 SIGNOR-279814 peptide antigen smallmolecule CHEBI:166824 ChEBI Class I MHC:Antigen complex SIGNOR-C426 SIGNOR form complex binding 9606 33374673 YES scontino The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). 0.8 SIGNOR-267773 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr134 LKFYDSNtVKQKYLS 9606 BTO:0004828 32483448 YES lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway 0.2 SIGNOR-273111 IKK-complex complex SIGNOR-C14 SIGNOR CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000661 15870263 YES gianni In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits. 0.629 SIGNOR-266435 ASXL2 protein Q76L83 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity binding 9606 21047783 YES miannu ASXL2, which does not bind HP1, promotes differentiation by binding to PPARγ and increasing the level of methylated H3K4, leading to the elevation of PPARγ activity. Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ. 0.2 SIGNOR-260063 H2BC11 protein P06899 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 YES miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.2 SIGNOR-263720 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. 0.8 SIGNOR-267037 PKA proteinfamily SIGNOR-PF17 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 NO miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex 0.7 SIGNOR-264961 STK33 protein Q9BYT3 UNIPROT STK33 protein Q9BYT3 UNIPROT up-regulates activity phosphorylation 18811945 YES lperfetto Our results show that the serine/threonine kinase Stk33 phosphorylates the intermediate filament protein vimentin in vitro specifically in the vimentin head domain. Stk33 undergoes obligatory autophosphorylation, which might be a prerequisite for its kinasing activity. 0.2 SIGNOR-272957 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser109 NKFAAHIsPAQGSPK -1 29945972 YES miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. 0.2 SIGNOR-277881 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1222 PAFDNLYyWDQDPPE 9606 15156151 YES gcesareni Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227 0.2 SIGNOR-124860 VRK1 protein Q99986 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 17938195 YES gcesareni We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis. 0.2 SIGNOR-265371 ULK2 protein Q8IYT8 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser282 QLADLYKsFIKDYPV 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274037 MDM2 protein Q00987 UNIPROT DYRK2 protein Q92630 UNIPROT down-regulates quantity by destabilization ubiquitination 19965871 YES lperfetto Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation.|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. 0.569 SIGNOR-275579 MAPK14 protein Q16539 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 22933625 NO apalma The IL-10-mediated shift in macrophage phenotype in injured muscle may be amplified by activation of mitogen-activated protein kinase (MAPK), especially p38 MAPK, through signaling that is antagonized by MAPK phosphatase-1 (MKP-1). 0.7 SIGNOR-255447 ANXA1 protein P04083 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 27426034 NO miannu Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups 0.402 SIGNOR-261939 MAPK8IP1 protein Q9UQF2 UNIPROT MAP4K2 protein Q12851 UNIPROT down-regulates binding 9606 BTO:0000007 10702297 YES gcesareni DLK mutants were used to demonstrate that a DLK leucine zipper-leucine zipper interaction is necessary for DLK dimerization and to show that DLK dimerization mediated by the leucine zipper domain is prerequisite for DLK activity and subsequent activation of stress-activated protein kinase (SAPK). 0.2 SIGNOR-75385 proline smallmolecule CHEBI:26271 ChEBI ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 25386178 NO apalma Ornithine, via the enzyme OAT, is also a precursor amino acid for the synthesis of proline, which itself is essential for the synthesis of collagen. 0.7 SIGNOR-255550 CDK1 protein P06493 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser428 KVAASPKsPTAALNE 9606 16198290 YES lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. 0.451 SIGNOR-140886 AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 YES lperfetto Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation 0.2 SIGNOR-71480 ZNRF1 protein Q8ND25 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys39 MADELSEkQVYDAHT 9606 BTO:0000007 28593998 YES miannu The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. ZNRF1 mediates CAV1 polyubiquitination at lysine 39 and promote CAV1 degradation to modulate TLR4-mediated immune response. 0.364 SIGNOR-272327 LY294002 chemical CHEBI:65329 ChEBI PIK3R1 protein P27986 UNIPROT down-regulates chemical inhibition 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 YES gcesareni Here we show that inhibition of pi3-k activity by the pharmacological agent ly294002 affects early processes of myoblast differentiation including the transcriptional activation of myogenin. 0.8 SIGNOR-79347 Ub:E2 complex SIGNOR-C497 SIGNOR LNX2 protein Q8N448 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271195 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 YES gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.722 SIGNOR-134545 C5AR1 protein P21730 UNIPROT SELL protein P14151 UNIPROT down-regulates quantity by repression 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.325 SIGNOR-263468 TLN1 protein Q9Y490 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR up-regulates activity binding 9606 BTO:0000132 16418530 YES lperfetto In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation. 0.698 SIGNOR-253358 PP2B proteinfamily SIGNOR-PF18 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18177723 NO inferred from 70% family members lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy 0.2 SIGNOR-269987 MAPK1 protein P28482 UNIPROT GORASP2 protein Q9H8Y8 UNIPROT unknown phosphorylation Thr225 QMAGTPItPLKDGFT 9606 BTO:0000567 11408587 YES lperfetto Furthermore, ERK2 directly phosphorylated GRASP55 on the same residues that generated the MPM2 phospho-epitope.|The obvious next challenge is to demonstrate the precise role of these phosphorylation events. 0.652 SIGNOR-249404 ITGB1 protein P05556 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.69 SIGNOR-253186 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Thr78 FDPPLHStAIYADEE 9606 17081991 YES lperfetto S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions 0.74 SIGNOR-150457 CR2 protein P20023 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity binding 9606 BTO:0000776 31732528 YES scontino Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling. 0.783 SIGNOR-266642 STXBP4 protein Q6ZWJ1 UNIPROT STX4 protein Q12846 UNIPROT up-regulates activity binding 10029 BTO:0000246 15753124 YES miannu Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4. 0.799 SIGNOR-262634 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 NO apalma ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation 0.7 SIGNOR-256216 Androgen deprivation therapy  stimulus SIGNOR-ST31 SIGNOR androgen smallmolecule CHEBI:50113 ChEBI down-regulates activity 9606 BTO:0000584 30312731 YES miannu The androgen receptor (AR), a nuclear receptor that is activated by binding to androgens [1], promotes the development of prostate cancer [2]. Although traditional AR-targeted therapies are initially effective, most tumors progress to hormone-refractory prostate cancer or castration-resistant prostate cancer (CRPC) within a few years [3]. CRPC patients are commonly treated with androgen deprivation therapy (ADT); however, ADT accelerates neuroendocrine (NE) differentiation with an increased anti-apoptotic stimulus that enables tumor resistance to the AR-targeted therapies  0.7 SIGNOR-277993 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser359 SALSYLQsPITTSPS 9606 10617468 YES lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. 0.805 SIGNOR-73621 PRKACA protein P17612 UNIPROT CACNG2 protein Q9Y698 UNIPROT down-regulates activity phosphorylation Thr321 NTANRRTtPV 9534 11805122 YES miannu phosphorylation of stargazin at T321 by PKA inhibits its interaction with PSD-95. 0.431 SIGNOR-250342 Ub:E2 complex SIGNOR-C497 SIGNOR MYCBP2 protein O75592 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271134 ABL1 protein P00519 UNIPROT ATR protein Q13535 UNIPROT up-regulates phosphorylation Tyr310 FPFEAEAyRNIEPVY 9606 20798688 YES lperfetto C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress. 0.598 SIGNOR-167636 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB4 protein P13762 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.2 SIGNOR-254002 F2RL1 protein P55085 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.255 SIGNOR-254842 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser38 QVSSLSEsEESQDSS 9606 20730097 YES lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5 0.2 SIGNOR-167564 2-[2-Amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl]-5-[(4-bromobenzyl)oxy]phenol smallmolecule CID:135651766 PUBCHEM GIPR protein P48546 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257498 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120156 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207296 PIP3 smallmolecule CHEBI:16618 ChEBI mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity chemical activation 9606 26293922 YES gcesareni PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation 0.8 SIGNOR-252430 FZD5 protein Q13467 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 10937998 NO fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) 0.2 SIGNOR-80610 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 10085140 YES gcesareni On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38. 0.793 SIGNOR-65597 AMPK complex SIGNOR-C15 SIGNOR RB1 protein P06400 UNIPROT unknown phosphorylation Ser811 IYISPLKsPYKISEG 9606 19217427 YES lperfetto Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site. 0.2 SIGNOR-216635 NR1H2 protein P55055 UNIPROT BHLHE40 protein O14503 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19032342 NO lperfetto LXRα and LXRβ are potent positive regulators for hepatic Dec1 0.2 SIGNOR-253690 SMAD3 protein P84022 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 NO miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. 0.7 SIGNOR-260432 NAB2 protein Q15742 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 NO miannu Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene. 0.393 SIGNOR-256042 RAP1GAP protein P47736 UNIPROT RAP1A protein P62834 UNIPROT down-regulates activity binding 9606 BTO:0001949 22173489 YES Marta Tosoni Overexpression of Rap1GAP significantly inhibited Rap1 activation, ERK and Akt phosphorylation of HUVECs compared with pcDNA transfection controls 0.837 SIGNOR-278054 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR WBP2 protein Q969T9 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277670 ATAD5 protein Q96QE3 UNIPROT BRD4 protein O60885 UNIPROT up-regulates binding 9606 BTO:0000007 31875566 YES miannu ATAD5 Interacts with BRD4 through a Conserved BET Protein-Binding Domain. BRD4-ATAD5 binds to acetyl-histones in nascent chromatin. BRD4 release from chromatin correlates with PCNA unloading. Disruption of the interaction between BRD4 and acetyl-histones or between BRD4 and ATAD5 reduces the PCNA amount on chromatin. 0.35 SIGNOR-266412 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser152 PTPAKRRsSALWSEM -1 15684429 YES miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. 0.249 SIGNOR-263017 SRF protein P11831 UNIPROT CNN1 protein P51911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 21673106 NO gcesareni In particular, high expression of vsmc-specific genes, such as smooth muscle -actin (sma), calponin1 (cnn), and sm22 (sm22) are associated with the contractile vsmc phenotype. Transcription of contractile genes is regulated by srf through a dna sequence motif known as the carg box (cc(a/t)6gg), which is present in the promoters of vsmc-specific genes. 0.362 SIGNOR-174358 OPTN protein Q96CV9 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 20174559 YES lperfetto Using biochemical experiments we showed that optineurin interacts with the protein kinase TBK1 and the ubiquitin ligase TRAF3. Furthermore, a mutation in optineurin that prevents the interaction with the small protein modifier ubiquitin (D474N) ablated the negative regulatory function of optineurin. 0.788 SIGNOR-262276 SLBP protein Q14493 UNIPROT H2AC21 protein Q8IUE6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265406 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser709 SEEEEEEsDSSETEK -1 21296876 YES miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis 0.2 SIGNOR-276252 SLC9A5 protein Q14940 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265604 GNA11 protein P29992 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9606 27515033 YES scontino TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C. 0.622 SIGNOR-267203 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1001 SKESEHDsDESSDDD 9606 BTO:0000661 10066810 YES llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  0.435 SIGNOR-251032 BAZ2B protein Q9UIF8 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity binding 9606 31999386 YES inferred from 70% of family members miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. 0.2 SIGNOR-269843 HTR7 protein P34969 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257430 NLGN4X protein Q8N0W4 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.767 SIGNOR-264165 MAPKAPK2 protein P49137 UNIPROT BAG2 protein O95816 UNIPROT up-regulates phosphorylation Ser20 GRFCRSSsMADRSSR 9606 BTO:0000567 15271996 YES lperfetto We provided definite evidence that mapkapk2 phosphorylates bag2 at ser 20 in vitro and in vivo. These results demonstrate that bag2 is a novel component of the p38 mapk signaling pathways. 0.366 SIGNOR-126953 TRAF3 protein Q13114 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination 9606 26882989 YES miannu Biological investigations demonstrated that TRAF3 activates TAK1 protein kinase activity via a direct binding to TAK1, then the RING finger of TRAF3 ubiquitinates TAK1, leading to TAK1 phosphorylation and activation.|TRAF3 activates TAK1 through ubiquitination. 0.458 SIGNOR-278787 PRLHR protein P49683 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.306 SIGNOR-256973 CSNK2A2 protein P19784 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser575 AGESLDQsMEEEEEE 9606 BTO:0000567 12591939 YES llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 0.374 SIGNOR-250985 GMIP protein Q9P107 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.443 SIGNOR-260506 CDK6 protein Q00534 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 BTO:0000776;BTO:0000785 16160006 YES gcesareni Phosphorylation on thr-187, by cdk2 leads to protein ubiquitination and proteasomal degradationp27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization. Interestingly, upon reactivation of kshv lytic cycle, v-cyclin-cdk6 phosphorylated p27(kip1) on thr187, which resulted in down-regulation of p27(kip1) protein levels. 0.855 SIGNOR-140405 ERC1 protein Q8IUD2 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates binding 9606 15218148 YES lperfetto Elks likely functions by recruiting ikappabalpha to the ikk complex and thus serves a regulatory function for ikk activation. 0.61 SIGNOR-217448 FZD2 protein Q14332 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 NO fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) 0.2 SIGNOR-80601 ADRA2C protein P18825 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.396 SIGNOR-256978 CDC25A protein P30304 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity dephosphorylation 9606 21670150 YES miannu In this study, we revealed that Cdc25A enhances Foxo1 stability by dephosphorylating Cdk2, and Foxo1 was shown to directly regulate transcription of the metastatic factor MMP1. 0.313 SIGNOR-277139 PRKDC protein P78527 UNIPROT MCC protein P23508 UNIPROT up-regulates activity phosphorylation Ser118 SELRSELsQSQHEVN 9606 BTO:0001109 21779472 YES miannu MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. 0.2 SIGNOR-273530 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1457 HSKSPAYtPQNLDSE 9606 12356758 YES lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase 0.263 SIGNOR-93993 DDX20 protein Q9UHI6 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 YES lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. 0.858 SIGNOR-253117 GRB10 protein Q13322 UNIPROT IGF1R protein P08069 UNIPROT down-regulates binding 9606 21659604 YES gcesareni Grb10 negatively regulates growth factor signaling. It binds the insulinand insulin-like growth factor 1 (igf-1) receptors, and mice without grb10 are larger and exhibit enhanced insulin sensitivity 0.738 SIGNOR-174062 POU5F1 protein Q01860 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.767 SIGNOR-254939 MAPK9 protein P45984 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 YES gcesareni Wstf, a specific component of two chromatin remodeling complexes (swi/snf-type winac and iswi-type wich), was phosphorylated by the stimulation of mapk cascades in vitro and in vivo. Ser-158 residue in the wac (wstf/acf1/cbpq46) domain, located close to the n terminus of wstf, was identified as a major phosphorylation target 0.2 SIGNOR-188168 SOD1 protein P00441 UNIPROT DERL1 protein Q9BUN8 UNIPROT down-regulates activity binding 9606 BTO:0000007 18519638 YES P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) Various proteins involved in ERAD have been identified recently (Meusser et al. 2005). Among them, components of the retro-translocation machinery including ATPase p97, its cofactors Ufd1 and Npl4, and the ER membrane proteins Derlin-1 and VIMP are of key importance to ERAD function |Here we show that SOD1(mut) specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD. 0.456 SIGNOR-262785 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0003076 19426221 YES lperfetto Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner .cd40 binds its ligand cd40l. 0.929 SIGNOR-185660 metformin chemical CHEBI:6801 ChEBI PRKAA2 protein P54646 UNIPROT up-regulates 9606 11602624 NO gcesareni Here we report that metformin activates ampk in hepatocytes. 0.8 SIGNOR-111034 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR leucine smallmolecule CHEBI:25017 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270413 TCL1A protein P56279 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 10983986 YES miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.546 SIGNOR-81683 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1035 IETDKEYyTVKDDRD 10090 11201744 YES CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 0.455 SIGNOR-248356 KIF5B protein P33176 UNIPROT JAKMIP1 protein Q96N16 UNIPROT up-regulates activity relocalization 10090 17532644 YES SARA Marlin-1 is associated with kinesin-I and suggest that the movement of Marlin-1 is mediated by plus end microtubuledependent molecular motors 0.2 SIGNOR-260989 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 21993628 YES gcesareni The action of kit kinase inhibitors, especially imatinib, sunitinib, dasatinib and pkc412, on different primary and secondary mutants is discussed. 0.8 SIGNOR-176760 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization phosphorylation Ser68 RQRLTHLsPEEKALR 9606 BTO:0001109 23277279 YES miannu Phosphorylation of XBP-1u by ERK is critical for the increased interaction of XBP-1u and FoxO1. 0.2 SIGNOR-276438 CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 8891723 YES lperfetto The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. 0.827 SIGNOR-217514 DPF2 protein Q92785 UNIPROT ESRRA protein P11474 UNIPROT down-regulates activity binding 10090 BTO:0000165 25713408 YES 1 miannu DPF2 directly bound to ERRalpha and suppressed the transactivation function of nuclear receptors such as androgen receptor. DPF2 was recruited to ERR target gene promoters in myoblast cells, and knockdown of DPF2 derepressed the level of mRNA expressed by target genes of ERRalpha. These results show that DPF2 acts as a nuclear receptor-selective co-repressor for ERRalpha by associating with both acetylated histone H3 and HDAC1. 0.2 SIGNOR-239539 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270368 tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates quantity precursor of 9606 16429158 YES miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr 0.8 SIGNOR-270523 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation Thr183 ACTNFMMtPYVVTRY -1 11062067 YES MKK7 phosphorylates SAPK2a p38 exclusively at Tyr-182. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. 0.636 SIGNOR-251417 CCND1 protein P24385 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000575 11731443 NO Cyclin D1 regulates mitogen-dependent progression through G1 phase in cultured cells, and its overexpression in malignant cells is thought to contribute to autonomous proliferation in vivo. 0.7 SIGNOR-260014 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr775 QGWVPSNyITPVNSL 9606 16912036 YES Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 0.2 SIGNOR-260811 ATG7 protein O95352 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates activity binding -1 16303767 YES lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme). 0.905 SIGNOR-142002 MAPK12 protein P53778 UNIPROT JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10330170 NO gcesareni Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. 0.385 SIGNOR-67532 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249321 NEK2 protein P51955 UNIPROT NDC80 protein O14777 UNIPROT up-regulates phosphorylation Ser165 LGYPFALsKSSMYTV 9606 12386167 YES lperfetto Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo. 0.593 SIGNOR-94322 LAMC1 protein P11047 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 YES lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. 0.707 SIGNOR-253231 FHL5 protein Q5TD97 UNIPROT CREM protein Q03060 UNIPROT up-regulates activity binding 9606 10086359 YES miannu ACT (for activator of CREM in testis), a LIM-only protein which specifically associates with CREM. ACT is expressed coordinately with CREM in a tissue- and developmentally regulated manner. It strongly stimulates CREM transcriptional activity in yeast and mammalian cells and contains an intrinsic activation function. 0.665 SIGNOR-222111 GALR2 protein O43603 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.289 SIGNOR-257226 PRKCE protein Q02156 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 YES lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. 0.261 SIGNOR-249258 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 SIGNOR-C17 16280325 YES lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. 0.297 SIGNOR-141565 PRKAA2 protein P54646 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 SIGNOR-C15 16959574 YES gcesareni We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels. 0.576 SIGNOR-149388 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition 9606 19567821 YES miannu The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. 0.8 SIGNOR-262225 TGFB1 protein P01137 UNIPROT SLC5A5 protein Q92911 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14623893 NO miannu The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression 0.2 SIGNOR-259912 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 YES fspada Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42). 0.2 SIGNOR-259428 RNF144A protein P50876 UNIPROT PARP1 protein P09874 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29212245 YES miannu As RNF144A is a newly characterized E3 ubiquitin ligase , ], we next investigated whether RNF144A could promote PARP1 ubiquitination.|RNF144A promotes the proteasomal degradation of PARP1. 0.2 SIGNOR-278776 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr246 STGGTPLtPAARISA 9606 BTO:0000007 16682949 YES done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 0.543 SIGNOR-274086 CCR2 protein P41597 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. 0.33 SIGNOR-255117 TFEB protein P19484 UNIPROT NDUFA8 protein P51970 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). 0.2 SIGNOR-276702 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 15996096 YES miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). 0.8 SIGNOR-266538 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18519666 YES inferred from 70% family members lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ 0.2 SIGNOR-270191 EXT1 protein Q16394 UNIPROT BMP4 protein P12644 UNIPROT up-regulates activity 9606 24860992 NO miannu Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern. 0.356 SIGNOR-264018 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr7 yDFKATAD 9606 BTO:0000007 20554525 YES lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. 0.2 SIGNOR-246285 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 16899510 YES Luana Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2. 0.299 SIGNOR-259848 methionine smallmolecule CHEBI:16811 ChEBI Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270402 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser11 NDDIEVEsDEEQPRF 9606 8018564 YES gcesareni Max activity is affected by phosphorylation at two nh2-terminal sites, ser2 and ser11. 0.362 SIGNOR-35768 HECTD3 protein Q5T447 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0004461 28716524 YES miannu HECTD3 binds and ubiquitinates caspase-9.HECTD3 inhibits caspase-9 oligomerization and association with Apaf-1. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK. 0.2 SIGNOR-272329 KDM5B protein Q9UGL1 UNIPROT CBX4 protein O00257 UNIPROT up-regulates activity binding 9606 19336002 YES miannu Our results clearly showed that the PcG protein hPc2 interacted with the N-terminus of JARID1B both in vivo and in vitro. It is interesting that the C-terminus of hPc2 was essential for the interaction and transcriptional co-repression. 0.4 SIGNOR-226447 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 YES MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. 0.9 SIGNOR-175833 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.2 SIGNOR-252085 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249349 PPARG protein P37231 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates quantity by expression transcriptional regulation 18292390 YES lperfetto EMSA, ChIP, and transient transfection assays indicate that PPAR-gamma activates the CXCR2 promoter by binding to a PPAR response element (PPRE). 0.264 SIGNOR-271682 LUBAC complex SIGNOR-C527 SIGNOR GLYR1 protein Q49A26 UNIPROT down-regulates quantity by destabilization ubiquitination Lys495 NILQGNFkPDFYLKY 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 0.2 SIGNOR-272838 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI 2'-deoxycytosine 5'-monophosphate(2-) smallmolecule CHEBI:57566 ChEBI up-regulates quantity precursor of 20637175 YES lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis 0.8 SIGNOR-275810 UBE2C protein O00762 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 19632176 NO miannu The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint. 0.7 SIGNOR-251544 doxorubicin chemical CHEBI:28748 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 19377506 YES An important reason why Top2 has held the interest of researchers studying cancer was the discovery that active anti-cancer drugs, notably etoposide and doxorubicin target Top2 0.8 SIGNOR-261911 CDK5 protein Q00535 UNIPROT HTT protein P42858 UNIPROT up-regulates phosphorylation Ser1199 EQASVPLsPKKGSEA 9606 BTO:0000938 17611284 YES lperfetto Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage. 0.447 SIGNOR-156840 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 7692235 YES gcesareni We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain. 0.604 SIGNOR-32081 TEK protein Q02763 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9534 BTO:0004055 14665640 YES lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.503 SIGNOR-252728 PRKCG protein P05129 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 YES llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. 0.2 SIGNOR-97295 STOML2 protein Q9UJZ1 UNIPROT NDUFV1 protein P49821 UNIPROT up-regulates activity 9606 BTO:0000782 20359165 NO Giorgia We found that SLP-2hi cells had significantly higher activities of NADH dehydrogenase and succinate dehydrogenase (P < 0.05), complexes I and II of the electron transport chain. 0.285 SIGNOR-260382 PIP4K2A protein P48426 UNIPROT 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI down-regulates quantity chemical modification 9606 9367159 YES Gianni The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K 0.8 SIGNOR-268866 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 16403219 YES miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. 0.2 SIGNOR-259423 CEBPB protein P17676 UNIPROT HSD11B1 protein P28845 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19088256 YES lperfetto In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter. 0.284 SIGNOR-268972 MYC protein P01106 UNIPROT PRPS2 protein P11908 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18677108 YES miannu Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. 0.277 SIGNOR-267376 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR TNK1 protein Q13470 UNIPROT down-regulates activity binding 9606 BTO:0000018 34504101 YES miannu We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.Phosphorylation of TNK1 at S502 within the proline rich domain is required for TNK1 binding to 14-3-3.MARKs mediate phosphorylation at S502 and 14-3-3 binding to TNK1, which restrains the movement of TNK1 into heavy membrane-associated clusters. 0.2 SIGNOR-273869 UBE3A protein Q05086 UNIPROT LAMTOR1 protein Q6IAA8 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 30020076 YES Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity 0.2 SIGNOR-256145 MAPK1 protein P28482 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9534 BTO:0004055 16705159 YES 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner 0.511 SIGNOR-236331 LPAR proteinfamily SIGNOR-PF2 SIGNOR PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 YRPKPSSsPVIFAGG 10090 BTO:0000665 17475908 YES miannu All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells. 0.2 SIGNOR-262669 DIABLO protein Q9NR28 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 17546047 YES gcesareni Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release. 0.571 SIGNOR-155364 RFC4 protein P35249 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 YES lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 0.809 SIGNOR-265508 PLK3 protein Q9H4B4 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 18062778 YES llicata The direct phosphorylation of thr(1342) of topoisomerase iialpha by plk3 was demonstrated with an in vitro kinase assay, and overexpression of plk3 induced the phosphorylation of thr(1342) in cellular topoisomerase iialpha. it is possible that plk3 regulates the activity of topoisomerase iia by phosphorylation in a cell-cycle dependent manner. Another possibility is that plk3 regulates the activity of topoisomerase iia when the checkpoint is activated. 0.268 SIGNOR-159596 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 YES lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. 0.649 SIGNOR-252321 N protein P59595 UNIPROT SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18055455 NO miannu In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. 0.2 SIGNOR-260589 PREX2 protein Q70Z35 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.424 SIGNOR-260572 POLR2G protein P62487 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.868 SIGNOR-266165 DOK3 protein Q7L591 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 YES scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. 0.555 SIGNOR-268448 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCA1-B complex complex SIGNOR-C298 SIGNOR form complex binding 25400280 YES lperfetto Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation 0.78 SIGNOR-263217 CSNK2A3 protein Q8NEV1 UNIPROT F8 protein P00451 UNIPROT down-regulates activity phosphorylation Ser1656 GRTERLCsQNPPVLK -1 8427963 YES lperfetto Our findings suggest that phosphorylation of factors Va and VIIIa by a platelet casein kinase II-like kinase may downregulate the activity of the two cofactors.| Recombinant human factor VIII also showed incorporation of radioactivity in the presence of purified casein kinase II at the acidic NH2-terminal portion of factor VIII light chain (residues 1648 through 1689). Based on all the considerations reported above Se1657 is the most likely candidate within this region capable of incorporation of radioactivity 0.2 SIGNOR-263649 LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 YES lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor 0.754 SIGNOR-198755 Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 NO miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.7 SIGNOR-270886 PTPN1 protein P18031 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr397 SVSETDDyAEIIDEE 9534 BTO:0004055 16291744 YES The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK |The dephosphorylation at Tyr-397 in FAK triggered by wild-type alpha-actinin and PTP 1B caused a significant increase in cell migration. 0.346 SIGNOR-248431 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258897 IDH complex SIGNOR-C396 SIGNOR D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI down-regulates quantity chemical modification 9606 28139779 YES miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 0.8 SIGNOR-266251 CDK1 protein P06493 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C17 12676926 YES gcesareni Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. 0.555 SIGNOR-99742 FLT3 protein P36888 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity 10090 14981546 NO Immunoblot analysis indicated an increased level of Foxo3a phosphorylation on residue Thr32, as shown by the appearance of additional slower-migrating phospho-species immediately after induction of FLT3-ITD4 expression 0.309 SIGNOR-261523 calcium(2+) smallmolecule CHEBI:29108 ChEBI CIB2 protein O75838 UNIPROT up-regulates activity chemical activation 9606 35408910 YES miannu Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions. 0.8 SIGNOR-269667 LPAR6 protein P43657 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.352 SIGNOR-257347 EGR1 protein P18146 UNIPROT COL4A2 protein P08572 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 NO Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) 0.2 SIGNOR-251918 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr494 TGTDKLMtGVISPER 9606 16216881 YES lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. 0.2 SIGNOR-141030 MECOM protein Q03112 UNIPROT TEK protein Q02763 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000669 15889140 YES Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  0.2 SIGNOR-266063 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT up-regulates quantity binding 25296192 YES miannu In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. 0.848 SIGNOR-266300 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser726 KKKEKVEs -1 8810272 YES lperfetto Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC. 0.285 SIGNOR-248953 NOX5 protein Q96PH1 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.8 SIGNOR-264725 BTK protein Q06187 UNIPROT DDX41 protein Q9UJV9 UNIPROT up-regulates activity phosphorylation Tyr414 DVIQEVEyVKEEAKM 10090 BTO:0002572 25704810 YES miannu The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. 0.406 SIGNOR-266404 MYC protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 20551174 NO lperfetto In tissue culture, ectopic expression of Myc suppresses the cell cycle arrest that occurs in response to several anti-mitogenic signals such as transforming growth factor β (TGFβ), since Myc represses expression of the cyclin-dependent kinase inhibitors (CKIs) p15ink4b, p21cip1, and p57kip2 via interaction with Miz1 0.765 SIGNOR-267575 PRKACA protein P17612 UNIPROT RARA protein P10276 UNIPROT down-regulates activity phosphorylation Ser219 NSSEQRVsLDIDLWD 9606 20215566 YES miannu  Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity.  0.403 SIGNOR-276281 ARNT protein P27540 UNIPROT CDK2 protein P24941 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 21544813 NO lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC 0.258 SIGNOR-253693 Ub:E2 complex SIGNOR-C497 SIGNOR PRKN protein O60260 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271041 CAMK2A protein Q9UQM7 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates phosphorylation 9606 12536214 YES inferred from family member gcesareni Receptor internalization, altered;intracellular localization 0.656 SIGNOR-270230 OXGR1 protein Q96P68 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257310 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 16403219 YES lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. 0.2 SIGNOR-259421 ARHGAP31 protein Q2M1Z3 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.565 SIGNOR-260489 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr708 NIHLEKKyVRRDSGF 9606 BTO:0001271 15297464 YES lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. 0.2 SIGNOR-127540 AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 YES gcesareni When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. 0.2 SIGNOR-247992 FBXW5 protein Q969U6 UNIPROT SASS6 protein Q6UVJ0 UNIPROT down-regulates quantity by destabilization ubiquitination 21725316 YES lperfetto We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. |expression of the wild-type form of FBXW5 accelerated the degradation of HsSAS-6 to a half-life of less than two hours 0.537 SIGNOR-275478 POT1 protein Q9NUX5 UNIPROT RPA3 protein P35244 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 YES lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA 0.263 SIGNOR-263326 HTR6 protein P50406 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257395 RNF182 protein Q8N6D2 UNIPROT ATP6V0C protein P27449 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002574 18298843 YES miannu The data indicated that RNF182 targeted ATP6V0C for degradation by the ubiquitin-proteosome pathway. 0.466 SIGNOR-271771 IRX3 protein P78415 UNIPROT GJA1 protein P17302 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003324 21825130 YES Luana Irx3 directly represses Cx43 transcription  0.278 SIGNOR-266044 CSNK2B protein P67870 UNIPROT MME protein P08473 UNIPROT unknown phosphorylation Ser6 sQMDITDI 9606 BTO:0003288 8943850 YES llicata Taken together, these data indicate that CD10/NEP is itself phosphorylated by CKII and that CD10/NEP co-associates with additional tyrosine phosphoproteins including lyn. 0.376 SIGNOR-251078 ASXL3 protein Q9C0F0 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity binding 9606 25450400 YES miannu Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. 0.266 SIGNOR-266764 ATM protein Q13315 UNIPROT ABRAXAS1 protein Q6UWZ7 UNIPROT up-regulates activity phosphorylation Ser406 GPGEYSRsPTF 9606 26778126 YES IR-Induced Double Phosphorylation of Abraxas C Terminus S404 and S406 Is ATM Dependent 0.2 SIGNOR-255588 LCK protein P06239 UNIPROT MED28 protein Q9H204 UNIPROT up-regulates phosphorylation Tyr64 ASLVSQDyVNGTDQE 9606 16899217 YES gcesareni Y64 of magicin is phosphorylated by lck creating a sh2-grb2 binding motif 0.44 SIGNOR-148704 SMURF proteinfamily SIGNOR-PF29 SIGNOR SKIL protein P12757 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002181;BTO:0005493 11389444 YES lperfetto Tgf-beta also induces the association of smurf2 with the transcriptional co-repressor snon and we show that smad2 can function to mediate this interaction. This allows smurf2 hect domain to target snon for ubiquitin-mediated degradation by the proteasome. 0.2 SIGNOR-253262 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser472 AGVTRSAsSPRLSSS 9606 20354225 YES gcesareni Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. 0.507 SIGNOR-164751 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 9748228 YES fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 0.2 SIGNOR-210096 CCNY protein Q8ND76 UNIPROT CyclinY/CDK14 complex SIGNOR-C541 SIGNOR form complex binding 19524571 YES lperfetto A novel cyclin, CCNY, was identified as a PFTK1 interacting protein in a yeast two-hybrid screen. The cyclin box in CCNY and the PFTAIRE motif in PFTK1 are both required for the interaction which was confirmed by in vivo and in vitro assays. 0.829 SIGNOR-273004 ULK2 protein Q8IYT8 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Ser364 TRLGVEPsDDDCVSV 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274041 TPO protein P07202 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 28153798 YES scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. 0.8 SIGNOR-267039 Ub:RBR_E3 complex SIGNOR-C520 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 NO miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 0.7 SIGNOR-271384 PINK1 protein Q9BXM7 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates phosphorylation Ser142 VPSPPPAsPRSQYNF 9606 17906618 YES gcesareni Htra2 is phosphorylated on activation of the p38 pathway, occurring in a pink1-dependent mannerwe suggest that pink1-dependent phosphorylation of htra2 might modulate its proteolytic activity, thereby contributing to an increased resistance of cells to mitochondrial stress. 0.608 SIGNOR-158052 XAB2 protein Q9HCS7 UNIPROT RAD23B protein P54727 UNIPROT up-regulates activity 24086043 NO lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.38 SIGNOR-275695 DHX9 protein Q08211 UNIPROT NUP98 protein P52948 UNIPROT up-regulates activity binding 9606 BTO:0000007 28221134 YES miannu Here we report on the identification of the DExH/D-box helicase DHX9 as an intranuclear Nup98 binding partner. Various results, including in vitro assays, show that the FG/GLFG region of Nup98 binds to N- and C-terminal regions of DHX9 in an RNA facilitated manner. Importantly, binding of Nup98 stimulates the ATPase activity of DHX9, and a transcriptional reporter assay suggests Nup98 supports DHX9-stimulated transcription. 0.356 SIGNOR-260954 Ub:E2 complex SIGNOR-C497 SIGNOR CBLL1 protein Q75N03 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271179 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser669 EDDVLSSsSCGSNSD 9606 BTO:0002181 34216621 YES miannu  Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction.  0.574 SIGNOR-277321 SLC12A2 protein P55011 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 26951057 YES miannu As shown in Fig. 2, the intracellular Cl− concentration is regulated mainly by two cation-chloride cotransporters, NKCC1 and KCC2 [32]. NKCC1 imports Cl− whereas KCC2 extrudes intracellular Cl−. 0.8 SIGNOR-264986 SELE protein P16581 UNIPROT ITGAL protein P20701 UNIPROT up-regulates 9606 BTO:0000130 23994464 NO apalma This deceleration is due to the expression of E-selectins on the inflamed endothelium which provides increased number of binding sites for PSGL-1 and also triggers an intermediate-affinity conformational state of the beta2-integrin LFA-1 on neutrophils. 0.406 SIGNOR-255968 EGR1 protein P18146 UNIPROT FCER2 protein P06734 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003076 9300687 NO Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule. In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription. 0.2 SIGNOR-254277 POLR2B protein P30876 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.87 SIGNOR-266162 MAPK15 protein Q8TD08 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 12169099 YES gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation. 0.428 SIGNOR-91375 TP53 protein P04637 UNIPROT BBC3 protein Q9BXH1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 16151013 NO amattioni Nuclear p53 caused expression of puma, which then displaced p53 from bcl-xl, allowing p53 to induce mitochondrial permeabilization. 0.694 SIGNOR-140245 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR APBB1 protein O00213 UNIPROT unknown phosphorylation 9606 14697653 YES inferred from 70% family members lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.2 SIGNOR-270166 CBFB protein Q13951 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 10090 BTO:0002883 11179217 YES The RUNX genes encode the α subunit of the transcription factor PEBP2/CBF. The β subunit consists of the non-RUNX protein PEBP2β. We found that RUNX1/AML1, which is essential for hematopoiesis, is continuously subjected to proteolytic degradation mediated by the ubiquitin–proteasome pathway. When PEBP2β is present, however, the ubiquitylation of RUNX1 is abrogated and this causes a dramatic inhibition of RUNX1 proteolysis. 0.847 SIGNOR-255742 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12950161 YES lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases 0.34 SIGNOR-86680 EGR1 protein P18146 UNIPROT HPSE protein Q9Y251 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001671;BTO:0001345 16007175 YES Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer. 0.37 SIGNOR-254267 PTPRG protein P23470 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity dephosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.277 SIGNOR-254702 AKT proteinfamily SIGNOR-PF24 SIGNOR KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 YES lperfetto Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome. 0.2 SIGNOR-151216 MTA1 protein Q13330 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.819 SIGNOR-263854 SEC61 complex complex SIGNOR-C368 SIGNOR SEC62 protein Q99442 UNIPROT up-regulates activity binding 33925740 YES lperfetto This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game 0.747 SIGNOR-265275 USP28 protein Q96RU2 UNIPROT MYC protein P01106 UNIPROT up-regulates deubiquitination 9606 BTO:0000150 17558397 YES esanto Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc. 0.702 SIGNOR-155590 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 YES gcesareni Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells. 0.458 SIGNOR-112544 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR JUN protein P05412 UNIPROT down-regulates activity sumoylation Lys254 MESQERIkAERKRMR 9606 BTO:0000567 SIGNOR-C154 16055711 YES lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 0.254 SIGNOR-263005 CREB3L1 protein Q96BA8 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 35051932 NO lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|By luciferase assays, we demonstrate that CREB3L1 may be a transcription factor regulating Oxt gene expression. By RNA immunoprecipitation assays and northern blot analysis of Oxt mRNA poly(A) tails, we have found that CAPRIN2 binds Oxt mRNA and regulates its poly(A) tail length.|To investigate transcriptional regulation of the OXT gene by CREB3L1, we performed luciferase assays using a proximal Oxt promoter region transfected in HEK293T cells. The expression of full-length CREB3L1 (CREB3L1FL) and a constitutively active CREB3L1 (CREB3L1CA) significantly increased luciferase activity by 5.4- and 3.2-fold, respectively, compared with controls 0.2 SIGNOR-268555 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 YES miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. 0.347 SIGNOR-250399 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1675 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248773 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT up-regulates activity binding 10090 BTO:0000944 10908331 YES miannu PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. The degree of interaction with the Pax2 C-terminal polypeptides correlates with their transcription transactivation potential and we have therefore designated this factor PTIP for Pax transactivation-domain interacting protein. 0.571 SIGNOR-236965 DIAPH1 protein O60610 UNIPROT CDH4 protein P55283 UNIPROT up-regulates activity 9606 BTO:0000815 22820501 YES lperfetto Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation. 0.2 SIGNOR-253110 CUX2 protein O14529 UNIPROT OGG1 protein O15527 UNIPROT up-regulates activity binding 10090 26221032 YES miannu CUX2 Interacts Directly with OGG1 and Stimulate Its Binding to DNA Containing 8-OxoG 0.2 SIGNOR-263960 S protein P59594 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity 9606 BTO:0000801 17412287 NO lperfetto The ability of S-protein to induce TNF-a 0.2 SIGNOR-260280 C1QC protein P02747 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR form complex binding -1 29449492 YES lperfetto C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1). 0.576 SIGNOR-263389 IRAK1 protein P51617 UNIPROT PELI2 protein Q9HAT8 UNIPROT up-regulates activity phosphorylation 9606 12860405 YES miannu The phosphorylation of Pellino2 by activated IRAK1 and IRAK4 could trigger and modulate the translocation of IRAKs from complex I to complex II. 0.78 SIGNOR-278947 AMP smallmolecule CHEBI:456215 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity precursor of -1 18940592 YES Luana Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. 0.8 SIGNOR-269738 BMPR1A protein P36894 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 10712517 YES gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors 0.496 SIGNOR-75649 MEST protein Q5EB52 UNIPROT LRP6 protein O75581 UNIPROT down-regulates activity 9606 21375506 NO Mest/Peg1 inhibited maturation of LRP6 by controlling the glycosylation of LRP6. Knockdown of Mest/Peg1, which might enhance Wnt signalling, blocked adipogenic differentiation of 3T3-L1 cells 0.2 SIGNOR-255826 MTA2 protein O94776 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.822 SIGNOR-263853 SNRPC protein P09234 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.903 SIGNOR-270679 CDK1 protein P06493 UNIPROT CKAP2 protein Q8WWK9 UNIPROT up-regulates phosphorylation Thr623 FKELKFLtPVRRSRR 9606 SIGNOR-C17 19369249 YES llicata Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis. 0.288 SIGNOR-185317 UBE3A protein Q05086 UNIPROT SIPA1L1 protein O43166 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12036950 YES miannu  the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation. 0.365 SIGNOR-272608 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2W protein Q96B02 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.689 SIGNOR-271340 MAPK1 protein P28482 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 BTO:0000876 14701740 YES lperfetto Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21. 0.353 SIGNOR-120566 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 25610395 YES lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a γ-secretase substrate. γ-Secretase performs the subsequent cleavage at S3, releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 family of DNA binding proteins. 0.677 SIGNOR-209717 SLC16A2 protein P36021 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI down-regulates quantity relocalization 9606 28153798 YES scontino T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland. 0.8 SIGNOR-267139 SBF1 protein O95248 UNIPROT MTMR2 protein Q13614 UNIPROT up-regulates activity binding 9534 BTO:0001538 12668758 YES miannu We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization.  0.634 SIGNOR-269803 NASP protein P49321 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity binding 9606 BTO:0001370 29733298 YES miannu SNASP inhibits TLR4-induced NF-κB activation through TRAF6.Reciprocal immunoprecipitation and Western blot analyses confirmed that endogenous sNASP binds to TRAF6 in human monocyte cell line THP-1 (Figure 1B).Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways. 0.2 SIGNOR-273655 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser193 GWDSPPAsPLQRQPS 9606 10212242 YES lperfetto Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates. 0.667 SIGNOR-67061 CDC14B protein O60729 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser315 LPNNTSSsPQPKKKP 9606 10644693 YES The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification 0.333 SIGNOR-248332 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr992 DGPLGPLyASSNPEY -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 0.2 SIGNOR-106522 GOT2 protein P00505 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 31422819 YES miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-268060 HIF1A protein Q16665 UNIPROT KDM4C protein Q9H3R0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271570 EFNA1 protein P20827 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.822 SIGNOR-52087 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.29 SIGNOR-249252 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 11323411 YES These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro. 0.952 SIGNOR-248675 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser141 SRSNSDEsNFSEKLR 9606 BTO:0000007 16818229 YES miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. 0.772 SIGNOR-276293 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser28 PQPQHTPsPAAPPAA 9606 22878263 YES llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. 0.411 SIGNOR-198725 MAPK12 protein P53778 UNIPROT Satellite_cells_self-renewal phenotype SIGNOR-PH100 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 BTO:0002314 BTO:0001103 29681515 NO apalma [...] we observed a significant diminution in the number of symmetric satellite stem cell (YFP–) divisions in p38 gamma siRNA-treated fibers, suggesting that p38 gamma is required for symmetric stem cell maintenance. Thus, loss of p38gamma greatly skewed the ratio of asymmetric to symmetric satellite stem cell divisions to favor asymmetric divisions and myogenic commitment at the expense of self-renewal 0.7 SIGNOR-255902 LAMA5 protein O15230 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 YES lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. 0.75 SIGNOR-255317 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser60 ETNQNSSsDSEAERR -1 11711551 YES llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 0.379 SIGNOR-251046 FBXW7 protein Q969H0 UNIPROT MED13L protein Q71F56 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 SIGNOR-C135 23322298 YES miannu The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. 0.359 SIGNOR-266688 metformin chemical CHEBI:6801 ChEBI PRKAA1 protein Q13131 UNIPROT up-regulates activity 10116 11602624 NO gcesareni Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin€™s inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation 0.8 SIGNOR-241952 MAML1 protein Q92585 UNIPROT CDK8 protein P49336 UNIPROT up-regulates binding 9606 15546612 YES gcesareni Mastermind recruits cycc:cdk8 to phosphorylate the notch icd and coordinate activation with turnover 0.596 SIGNOR-130715 PLIN3 protein O60664 UNIPROT IGF2R protein P11717 UNIPROT up-regulates activity relocalization 9534 BTO:0004055 9590177 YES lperfetto TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi. 0.724 SIGNOR-253092 Avacopan chemical CID:49841217 PUBCHEM C5AR1 protein P21730 UNIPROT down-regulates activity binding 9606 31734405 YES lperfetto CCX168 (avocapan), a C5aR antagonist, has proven its safety and efficiency in phase I and phase II trials conducted in AAV patients. 0.8 SIGNOR-263473 POMC protein P01189 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11830546 NO miannu The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. the increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor. 0.266 SIGNOR-252377 BLOC1S3 protein Q6QNY0 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 YES lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. 0.714 SIGNOR-265934 FOXO3 protein O43524 UNIPROT RBL2 protein Q08999 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000944 11884591 YES gcesareni Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. 0.291 SIGNOR-238606 testosterone smallmolecule CHEBI:17347 ChEBI SRD5A1 protein P18405 UNIPROT up-regulates activity chemical activation 9606 15861399 YES miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. 0.8 SIGNOR-251532 CIITA protein P33076 UNIPROT IL4 protein P05112 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000782 10946277 NO We identified two domains of CIITA that interact with two distinct domains of CBP/p300 that are also recognized by NF-AT. CIITA mutants that retain the ability to interact with CBP/p300 are sufficient to inhibit NF-AT-mediated IL-4 gene expression 0.406 SIGNOR-254499 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 17891169 YES fspada Hydroxamate derivatives are the most powerful category of hdaci, active on class i and ii hdac,especially on hdac1 and hdac2. In the study reported here, we described the anti-leukaemic properties of itf2357, a recently synthesized, orally active hydroxamate derivative. 0.8 SIGNOR-157857 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 22514276 YES miannu A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues. 0.491 SIGNOR-197058 RPS4Y1 protein P22090 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.2 SIGNOR-262446 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates activity phosphorylation Thr118 TNLGEKLtDEEVDEM -1 26675311 YES miannu Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. 0.423 SIGNOR-266355 GSK3A protein P49840 UNIPROT NIFK protein Q9BYG3 UNIPROT up-regulates activity phosphorylation Thr234 TVDSQGPtPVCTPTF -1 16244663 YES miannu The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1. 0.2 SIGNOR-262697 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2U protein Q5VVX9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.551 SIGNOR-271337 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 YES miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase 0.497 SIGNOR-250321 HMOX1 protein P09601 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000848 17148680 NO irozzo Here we investigated the effects of HO-1 overexpression in murine and human melanoma cells. The most important findings of our study are that 1) overexpression of HO-1 augments the proliferation [.] 0.7 SIGNOR-256295 FGF12 protein P61328 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253424 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation 10090 14981546 YES miannu Phosphorylation of Foxo proteins through FLT3-ITD signaling promotes their translocation from the nucleus into the cytoplasm, which requires the presence of conserved Akt phosphorylation sites in Forkhead transcription factors and PI3K activity. 0.2 SIGNOR-261526 KDM2B protein Q8NHM5 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 NO miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. 0.2 SIGNOR-252246 HES1 protein Q14469 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates activity binding 10090 BTO:0000562 16682003 YES lperfetto Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. 0.685 SIGNOR-209756 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR PBX3 protein P40426 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 NO miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. PBX3, a member of the PBX family of TALE homeobox genes, is upregulated in both NUP98‐HOXA9–transduced adult and cord blood CD34+ cells (Table 3). 0.2 SIGNOR-261504 NLGN2 protein Q8NFZ4 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 YES brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. 0.759 SIGNOR-264193 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 YES amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. 0.2 SIGNOR-253124 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR BECN1 protein Q14457 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 26687681 YES miannu Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1 0.33 SIGNOR-272419 DGC complex SIGNOR-C217 SIGNOR AQP4 protein P55087 UNIPROT up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626543 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.307 SIGNOR-265443 GSK3B protein P49841 UNIPROT KLF6 protein Q99612 UNIPROT up-regulates activity phosphorylation 9606 23085750 YES miannu Functionally, GSK3beta enhanced KLF6 mediated growth suppression, which was abrogated by the KLF6-4A phosphomutant.|These data establish that GSK3\u03b2 directly phosphorylates KLF6, which augments its induction of p21 and resultant growth suppression. 0.2 SIGNOR-279373 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PIN1 protein Q13526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 19151708 NO lperfetto Previously, we have shown that commitment of the C2C12 cells to the osteoblastic lineage occurs around 24h after BMP treatment, when the osteoblast specific transcription factor Cbfa1 and the novel osteoblast related genes Tcf7 and Hey1 become regulated 0.2 SIGNOR-254342 brimonidine chemical CHEBI:3175 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258901 PREX2 protein Q70Z35 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.406 SIGNOR-260570 KIRREL3 protein Q8IZU9 UNIPROT CASK protein O14936 UNIPROT up-regulates activity binding 9606 BTO:0000232 33853164 YES miannu A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia. KIRREL3 is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with CASK gene.  0.459 SIGNOR-269078 MAPK3 protein P27361 UNIPROT NCKIPSD protein Q9NZQ3 UNIPROT up-regulates phosphorylation 9606 14559906 YES gcesareni Spin90 was phosphorylated by erk1, which was, itself, activated by cell adhesion and platelet-derived growth factor. Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck 0.422 SIGNOR-118747 ATR protein Q13535 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates phosphorylation Thr859 WEVGFPStQTCMERG 9606 23273981 YES llicata Characterization of this site using phospho-specific antibodies and mutational analysis reveals that it is phosphorylated by atr and is required for binding of ctip to chromatin and subsequent processive resection. 0.613 SIGNOR-200245 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI TEK protein Q02763 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194349 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates quantity chemical modification 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.8 SIGNOR-270442 MDM4 protein O15151 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination -1 12393902 YES miannu Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.  0.948 SIGNOR-271389 CSNK2A1 protein P68400 UNIPROT ABCF1 protein Q8NE71 UNIPROT unknown phosphorylation Ser109 KKLSVPTsDEEDEVP 9606 17894550 YES gcesareni We demonstrate that abc50 is a phosphoprotein and is phosphorylated at two sites by ck2. These sites, ser-109 and ser-140, lie in the nterminal part of abc50 but are not required for the binding of abc50 to eif2. 0.2 SIGNOR-157933 GLS protein O94925 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 22049910 YES miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. 0.8 SIGNOR-260000 NUMA1 protein Q14980 UNIPROT TUBB2A protein Q13885 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.2 SIGNOR-116936 PRRX1 protein P54821 UNIPROT MAFK protein O60675 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.273 SIGNOR-221932 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 YES lperfetto Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo 0.2 SIGNOR-244765 MAPK12 protein P53778 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 YES lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. 0.2 SIGNOR-114067 SH3RF1 protein Q7Z6J0 UNIPROT HERPUD1 protein Q15011 UNIPROT up-regulates activity ubiquitination 9606 20976103 YES miannu Upon TG induced ER calcium store depletion, POSH promotes Herp lys-63-linked polyubiquitination, which in turn promotes the redistribution of Herp to the ER .|Upon thapsigargin-induced endoplasmic reticulum calcium store depletion, POSH promotes Herp lys-63-linked polyubiquitination, which in turn promotes the redistribution of Herp to the endoplasmic reticulum . 0.325 SIGNOR-278779 PRKCQ protein Q04759 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity phosphorylation Ser111 TPEGRRTsRRKRAKV 9606 29311580 YES miannu Inhibiting PKC-theta also increased the H3K4 demethylase activity of LSD1, indicating that active PKC-theta may prevent LSD1 from demethylating H3K4 and subsequently causing gene repression.|PKC-theta directly phosphorylates LSD1 at serine 111 and regulates its repressive activity and nuclear localization. 0.259 SIGNOR-279104 MEIS1 protein O00470 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001271 19109563 NO irozzo These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell-cycle entry.Flow cytometric analysis of PI-stained nuclei showed that Meis1 knockdown led to a cell-cycle arrest in the G0/G1 phase. 0.7 SIGNOR-255859 CDK4 protein P11802 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR form complex binding 9606 7736585 YES gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, 0.964 SIGNOR-32301 GATA6 protein Q92908 UNIPROT CDX2 protein Q99626 UNIPROT up-regulates quantity by expression 9606 BTO:0000195 24317510 NO lperfetto Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. 0.457 SIGNOR-253155 Skp1-Pam E3 complex SIGNOR-C537 SIGNOR SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.281 SIGNOR-272188 MAPK8 protein P45983 UNIPROT CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser491 GSCCTIMsPGEMEKH 9606 BTO:0000567 21930785 YES miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  0.369 SIGNOR-276360 SMURF1 protein Q9HCE7 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 11278251 YES miannu Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.  0.882 SIGNOR-272941 PLK3 protein Q9H4B4 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000452 11447225 YES lperfetto Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3. 0.705 SIGNOR-109239 sitaxentan chemical CHEBI:135736 ChEBI EDNRA protein P25101 UNIPROT down-regulates activity chemical inhibition -1 9171878 YES miannu Discovery of TBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist.The optimal compound discovered during these studies, 15q (TBC11251), binds competitively to human ETA receptors with a Ki of 0.43 +/- 0.03 nM and an IC50 of 1.4 nM (IC50 for ETB = 9800 nM). This compound inhibits ET-1-induced stimulation of phosphoinositide turnover with a Ki of 0.686 nM and a pA2 of 8.0. 0.8 SIGNOR-258610 CRHR1 protein P34998 UNIPROT Corticotropin protein P01189-PRO_0000024969 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 23504413 NO lperfetto CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). 0.2 SIGNOR-268613 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCNN1B protein P51168 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 YES inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. 0.2 SIGNOR-270163 OGG1 protein O15527 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275715 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr565 KKKTEGTyDLPYWDR -1 23770091 YES done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. 0.351 SIGNOR-273945 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.73 SIGNOR-252758 CASP1 protein P29466 UNIPROT Caspase 1 complex complex SIGNOR-C220 SIGNOR form complex binding cleavage:Asp119 PAPQAVQdNPAMPTS 7721861 YES lperfetto The interleukin-1 beta-converting enzyme is a heterodimeric cysteine protease that is produced as a 45-kDa precursor. The full-length precursor form of the enzyme was expressed in Escherichia coli as insoluble inclusion bodies. Following solubilization and refolding of the 45-kDa protein, autoproteolytic conversion to a heterodimeric form containing 10- and 20-kDa subunits was observed. 0.2 SIGNOR-256386 PRKAA1 protein Q13131 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates activity phosphorylation Ser510 SPVSRTPsLPAVDTS 9606 27256105 YES Luana Mechanically, we found that AMPKα1 directly phosphorylated protein inhibitor of activated STAT-1 (PIAS1), the SUMO E3-ligase of Runx2, at serine 510, to promote its SUMO E3-ligase activity. Finally, mutation of protein inhibitor of activated STAT-1 at serine 510 suppressed m 0.2 SIGNOR-259866 ACTG1 protein P63261 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 28233384 YES lperfetto Here, we report the highest resolution, cryo-EM structures of actin filaments with bound ATP analog β,γ-imidoadenosine 5′-triphosphate (AMPPNP) (3.1 Å) and ADP with inorganic phosphate (ADP-Pi) (3.1 Å) as well as a 3.6-Å resolution structure of the ADP filament. These structures of the three well-characterized nucleotide states of actin monomers and filaments 0.7 SIGNOR-261878 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation 9606 12832467 YES lperfetto Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk 0.759 SIGNOR-102645 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 YES gcesareni These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor. 0.2 SIGNOR-248031 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269351 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 YES Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. 0.2 SIGNOR-269957 MAPK8 protein P45983 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation Ser82 SIMQQCDsPHVVKYY 9606 20028971 YES llicata C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82. 0.268 SIGNOR-162327 AKT proteinfamily SIGNOR-PF24 SIGNOR CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 YES lperfetto These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf 0.2 SIGNOR-137430 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM39 protein Q9HCM9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270969 XBP1 protein P17861-2 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 9606 15598891 NO miannu ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER. 0.7 SIGNOR-260186 SMARCE1 protein Q969G3 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.838 SIGNOR-270704 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 25406093 YES lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. 0.8 SIGNOR-268566 LARP1 protein Q6PKG0 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 BTO:0002181 28650797 YES SARA LARP1-mTORC1 interaction occurs through direct protein-protein contacts. phosphorylated LARP1 facilitates mTORC1-dependent phosphorylation of S6K1 and 4EBP1 on the LARP1-containing mRNPs by scaffolding mTORC1. 0.302 SIGNOR-260993 HTR2B protein P41595 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257228 NPRL3 protein Q12980 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR form complex binding 9606 23723238 YES miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 0.953 SIGNOR-255282 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser141 MASQKRPsQRHGSKY -1 2413024 YES lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 0.49 SIGNOR-248869 ABL1 protein P00519 UNIPROT JUN protein P05412 UNIPROT unknown phosphorylation Tyr170 LHSEPPVyANLSNFN 9606 10637231 YES gcesareni After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl 0.527 SIGNOR-245370 PAK1 protein Q13153 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation 9606 33432150 YES miannu Pak1 phosphorylates NLRP3 and triggers inflammasome activation. 0.2 SIGNOR-278967 fentanyl chemical CHEBI:119915 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258937 RUVBL2 protein Q9Y230 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.698 SIGNOR-270854 SGK1 protein O00141 UNIPROT SLC9A3 protein P48764 UNIPROT up-regulates activity phosphorylation Ser663 TMRKRLEsFKSTKLG 9606 21054167 YES miannu The NHE3 activation by SGK1 is dependent on their combined interaction with NHERF2 and then phosphorylation at S663 of NHE3 by SGK1 ( xref , xref ). 0.433 SIGNOR-279112 PPM1F protein P49593 UNIPROT LATS1 protein O95835 UNIPROT down-regulates activity dephosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 30863499 YES lperfetto POPX2 is capable of dephosphorylating LATS1 at Thr1079 (Figure xref ), which is a residue critical for LATS1 activity.|POPX2 might negatively regulate the activities of MST1 and LATS1 through dephosphorylation.|We found that POPX2 could dephosphorylate LATS1 on Threonine-1079, leading to inactivation of LATS1 kinase. 0.2 SIGNOR-276989 tamsulosin chemical CHEBI:9398 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258471 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273085 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 21576360 YES When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita 0.789 SIGNOR-256247 AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 17522231 NO lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins 0.7 SIGNOR-260704 DYRK1A protein Q13627 UNIPROT LIN52 protein Q52LA3 UNIPROT up-regulates activity phosphorylation Ser28 FEKLDRAsPDLWPEQ 9606 BTO:0001583 21498570 YES miannu Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly. 0.68 SIGNOR-262846 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 YES Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs. milica In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. 0.697 SIGNOR-197651 FFAR2 protein O15552 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.307 SIGNOR-257075 PRPF4B protein Q13523 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr417 ISVDGLStPVVLSPG 9606 BTO:0000142;BTO:0000763 10799319 YES lperfetto Activated hprp4 phosphorylates residue thr-417 on elk-1 resulting in elk-1 activation. 0.2 SIGNOR-77135 Ub:E2 complex SIGNOR-C497 SIGNOR IRF2BP1 protein Q8IU81 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271057 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270375 CHMP4A protein Q9BY43 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.706 SIGNOR-265529 MRPL20 protein Q9BYC9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.736 SIGNOR-262373 FBXO3 protein Q9UK99 UNIPROT FBXL2 protein Q9UKC9 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25721664 YES miannu F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway. 0.55 SIGNOR-272445 RAC1 protein P63000 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 27571105 YES areggio Although there are other activators of PCP, Wnt5a can activate the PCP pathway by forming a complex with Fzd and Ror2 receptors, activating DVL, which in turn activates Rho-family small GTPases, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK) 0.404 SIGNOR-258972 SP1 protein P08047 UNIPROT PON1 protein P27169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 15380450 NO miannu These data suggest that Sp1 acts as a positive regulator of PON1 transcription, and that an interaction between Sp1 and PKC is a key mechanism for the effect of Sp1 on PON1 transcription. 0.268 SIGNOR-255212 TDGF1 protein P13385 UNIPROT NODAL protein Q96S42 UNIPROT up-regulates activity binding 9606 19874624 YES Regulation miannu Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors. 0.659 SIGNOR-251937 PRKN protein O60260 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 0.2 SIGNOR-272749 APOE protein P02649 UNIPROT MAPT protein P10636 UNIPROT up-regulates activity binding 7566652 YES lperfetto Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3. 0.568 SIGNOR-262588 FCN3 protein O75636 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding 9606 BTO:0000392 11907111 YES lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP. 0.671 SIGNOR-263410 nafadotride chemical CHEBI:64191 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). 0.8 SIGNOR-258854 AKT3 protein Q9Y243 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 YES flangone Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. 0.257 SIGNOR-242107 SLC1A7 protein O00341 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 YES miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). 0.8 SIGNOR-264806 GRIN1 protein Q05586 UNIPROT NMDA receptor_2C complex SIGNOR-C349 SIGNOR form complex binding 9606 BTO:0000938 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits 0.611 SIGNOR-264124 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 YES gcesareni Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip. 0.6 SIGNOR-75788 HES1 protein Q14469 UNIPROT RCAN1 protein P53805 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000667 15866158 YES Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism .... Chromatin immunoprecipitation (ChIP) analysis of keratinocytes overexpressing HES-1 showed that this protein can bind to the HES binding sites present in both distal and proximal promoters 0.2 SIGNOR-252026 ULK1 protein O75385 UNIPROT SEC23B protein Q15437 UNIPROT up-regulates quantity by stabilization phosphorylation Ser186 SCEGISKsYVFRGTK 9606 BTO:0000007 30596474 YES lperfetto Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation. 0.2 SIGNOR-265285 STAG1 protein Q8WVM7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1‚ÄìInt14 (Integrator subunits)¬† 0.916 SIGNOR-267729 Ub:E2 complex SIGNOR-C497 SIGNOR RLF protein Q13129 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271079 EMSY protein Q7Z589 UNIPROT CBX1 protein P83916 UNIPROT up-regulates activity binding 9606 BTO:0000567 14651845 YES miannu The binding sites for HP1β and BS69 with EMSY abut each other, and are found directly adjacent to the ENT domain of EMSY. This demonstrates that EMSY has the capacity to contact directly at least two proteins which contain a Royal Family domain. Since this domain is found in proteins with a chromatin connection, we assume that EMSY functions, at least partly, in the regulation of chromatin. 0.2 SIGNOR-263917 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Pro48 RSFLLRNpNDKYEPF -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.42 SIGNOR-263577 CDR2 protein Q01850 UNIPROT CENPE protein Q02224 UNIPROT up-regulates quantity by expression transcriptional regulation 20383333 NO lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology 0.2 SIGNOR-252020 AKT3 protein Q9Y243 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 18476811 YES lperfetto Phosphorylation of argonaute 2 at serine-387 facilitates its localization to processing bodies, akt3-mediated phosphorylation of ago2 is a molecular switch between target mrna cleavage and translational repression activities of ago2 0.423 SIGNOR-178416 LYST protein Q99698 UNIPROT RAB5C protein P51148 UNIPROT down-regulates activity binding 7227 33725482 YES lperfetto Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment 0.2 SIGNOR-266003 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 16543730 YES lperfetto Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3. 0.442 SIGNOR-249167 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 BTO:0000007 18840653 YES We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. 0.565 SIGNOR-248400 COL1A1 protein P02452 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 35267698 YES lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. 0.637 SIGNOR-272346 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000551;BTO:0000527 BTO:0000142 19478061 YES miannu Transfection of wild-type ptprd resulted in the specific dephosphorylation of stat3 at tyrosine 705, a residue that must be phosphorylated for stat3 to be active 0.518 SIGNOR-185933 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.741 SIGNOR-178383 CREB1 protein P16220 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by expression transcriptional regulation 10841026 YES lperfetto Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription. 0.632 SIGNOR-249619 PIK3R1 protein P27986 UNIPROT PI3K complex SIGNOR-C156 SIGNOR form complex binding 9606 19805105 YES miannu Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1). 0.936 SIGNOR-255300 FMR1 protein Q06787 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates quantity post transcriptional regulation 10090 32118033 YES lperfetto These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets. 0.4 SIGNOR-262109 SRC protein P12931 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Tyr107 PHDPHKIyEFVNSGV 9606 35468896 YES miannu Mechanistically, the progesterone-PGR axis activates SRC, which then mediates phosphorylation of IRF3 at Y107.|Taken together, these results suggest that P4 induces PGR-dependent activation of SRC, which promotes virus-triggered activation of IRF3 as well as induction of downstream antiviral genes.In the above experiments, we noticed that SeV-induced phosphorylation of IRF3S386 but not phosphorylation of TBK1S172 (p-TBK1S172, a hallmark for TBK1 activation) was increased by P4 treatment (Fig. 4g) or decreased by knockout of PGR (Fig. 4h). 0.314 SIGNOR-279118 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr426 NEEWYVSyITRPEAE 9606 BTO:0000782 8702662 YES lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function 0.804 SIGNOR-42976 WDR62 protein O43379 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity relocalization 10090 30566428 YES lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis 0.295 SIGNOR-271716 RPL24 protein P83731 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.848 SIGNOR-262475 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr381 EIEACQVyFTYDPYS -1 10214954 YES Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. 0.643 SIGNOR-251375 ELOVL3 protein Q9HB03 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267893 SRC protein P12931 UNIPROT KDR protein P35968 UNIPROT up-regulates activity phosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 19050761 YES miannu In contrast, our analysis showed that over-expression of c-Src significantly enhances the ability of VEGFR-2 to stimulate proliferation of PAE cells and over-expression of dominant negative Src (Src kinase-dead) inhibits the VEGFR-2 driven proliferation of PAE cells (XREF_FIG).|Taken together, the data demonstrate that Src kinases upon activation by VEGFR-2 phosphorylate Y1173 of VEGFR-2 (XREF_FIG). 0.613 SIGNOR-279120 SRC protein P12931 UNIPROT PTK7 protein Q13308 UNIPROT up-regulates activity phosphorylation 9606 24703874 YES miannu Because Ptk7 lacks intrinsic kinase activitiy, we suggest a positive feedback model in which pre-existing active Src phosphorylates PTK7 enabling it to interact with the SH2 domain of additional Src molecules to result in further activation. 0.279 SIGNOR-279123 ATF2 protein P15336 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 22685333 NO Luana ATF2 contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. 0.7 SIGNOR-261324 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI PPP3CC protein P48454 UNIPROT down-regulates chemical inhibition 9606 15276472 YES gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-127245 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 YES gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. 0.91 SIGNOR-252847 TOMM70 protein O94826 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 YES lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. 0.2 SIGNOR-267677 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273056 MRPL30 protein Q8TCC3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.674 SIGNOR-262365 D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity precursor of 9606 34775382 YES miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. 0.8 SIGNOR-267062 SESN3 protein P58005 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR down-regulates activity binding 10090 BTO:0002572 25457612 YES We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2 0.437 SIGNOR-253561 PPP1CC protein P36873 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity dephosphorylation Ser8 MTTEQRRsLQAFQDY 9606 BTO:0000007 23499489 YES lperfetto We identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.|endogenous RIG-I and MDA5 that interacted with PP1 exhibited markedly decreased phosphorylation levels at S8 and S88, respectively  0.2 SIGNOR-264580 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 YES Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels 0.383 SIGNOR-262524 GOT1 protein P17174 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-267505 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 YES Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. 0.358 SIGNOR-248641 entinostat chemical CHEBI:132082 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257962 WWP2 protein O00308 UNIPROT GSC protein P56915 UNIPROT up-regulates activity ubiquitination 9606 21170031 YES miannu These results indicated that Wwp2 augments the transcription activity of Gsc.|We confirmed that Gsc was being mono-ubiquitinated by Wwp2 via in vitro ubiquitination assays that utilized purified Gsc, recombinant Wwp2 and ubiquitin-K0 proteins that resulted in a pattern of Gsc ubiquitination similar to WT ubiquitin (XREF_FIG). 0.311 SIGNOR-278797 CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 YES lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation 0.638 SIGNOR-90397 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Ser273 VAFSEITsPSKRSQP 9606 11931757 YES lperfetto Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. 0.636 SIGNOR-116325 PK proteinfamily SIGNOR-PF80 SIGNOR HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates activity binding 9606 BTO:0000567 21620138 YES inferred from family member PKM2 interacts directly with the HIF-1Œ± subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, 0.389 SIGNOR-270311 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000165 12063245 YES inferred from 70% family members lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 0.2 SIGNOR-270149 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS1 protein O95835 UNIPROT down-regulates 9606 23450633 NO gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. 0.7 SIGNOR-201522 ADRA1D protein P25100 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257191 LAMC2 protein Q13753 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR form complex binding 9211848 YES lperfetto Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2. 0.583 SIGNOR-253237 AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 NO Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. 0.7 SIGNOR-257606 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser99 HFAIAADsEAEQDSW -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.32 SIGNOR-251074 vorinostat chemical CHEBI:45716 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257916 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 YES The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.614 SIGNOR-138957 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine chemical CID:11617559 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258119 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 10116 BTO:0001009 8336722 YES gcesareni The degree of CREB phosphorylation, assessed with antiserum specific for CREB phosphorylated at Ser-133, correlated with the amount of PKA liberated. The time course of phosphorylation closely paralleled the nuclear entry of the catalytic subun 0.58 SIGNOR-166342 TP53 protein P04637 UNIPROT HK2 protein P52789 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 YES miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. 0.412 SIGNOR-267466 RUNX3 protein Q13761 UNIPROT HSPD1 protein P10809 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255086 PAK1 protein Q13153 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser49 EVLVDPRsRRRYVRG 9606 18427546 YES llicata We show here that pak1 is required for cell proliferation, mitotic progression and plk1 activity in hela cells. phosphorylation of plk1 on ser 49 is important for metaphase-associated events. 0.551 SIGNOR-178353 IKBKB protein O14920 UNIPROT PFKFB3 protein Q16875 UNIPROT down-regulates activity phosphorylation Ser269 QGRIGGDsGLSSRGK -1 27585591 YES miannu IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3.We demonstrate that IKKβ directly interacts with and phosphorylates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform 3 (PFKFB3), a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low. 0.29 SIGNOR-277278 MET protein P08581 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity phosphorylation Tyr1510 LVKLQQTyAALNSKA 9606 BTO:0000815 33087447 YES miannu IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. 0.272 SIGNOR-277532 CDK2 protein P24941 UNIPROT NFYA protein P23511 UNIPROT up-regulates activity phosphorylation Ser320 GEGGRFFsPKEKDSP 12857729 YES llicata Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa) 0.44 SIGNOR-250742 naloxone chemical CHEBI:7459 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258941 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser372 PSPEPSMsPKMHRRR -1 12361598 YES miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) 0.516 SIGNOR-265962 PLPPR1 protein Q8TBJ4 UNIPROT RASGEF1A protein Q8N9B8 UNIPROT up-regulates activity binding 9606 BTO:0002036 27058420 YES miannu Oncogenic effects of imbalanced PRG3 are mediated via PRG3-RasGEF1 interaction and Ras activation. PRG3 interacts with RasGEF1 in vivo.We could further show that PRG3 executes the binding to RasGEF1 predominantly via its C-terminal domain (CT) and in the consequence causes Ras activation. 0.2 SIGNOR-261807 SRPK2 protein P78362 UNIPROT LGMN protein Q99538 UNIPROT up-regulates activity phosphorylation Ser226 CYYDEKRsTYLGDWY 10116 BTO:0000938 28826672 YES miannu Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities.  0.2 SIGNOR-273569 EFEMP2 protein O95967 UNIPROT ELN protein P15502 UNIPROT up-regulates activity binding 9606 19570982 YES miannu Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking. 0.558 SIGNOR-252136 ASIP protein P42127 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.511 SIGNOR-268703 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser645 LNEKARLsYSDKNLI 9606 15731106 YES gcesareni Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt. 0.2 SIGNOR-134207 PPP1CC protein P36873 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity dephosphorylation Ser88 EALRRTGsPLAARYM 9606 23499489 YES lperfetto Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation. 0.247 SIGNOR-264579 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 23486913 YES lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation 0.755 SIGNOR-217114 EGR1 protein P18146 UNIPROT COL7A1 protein Q02388 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 NO Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) 0.2 SIGNOR-251920 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. 0.717 SIGNOR-267970 TAF12 protein Q16514 UNIPROT ATF7 protein P17544 UNIPROT up-regulates activity binding 9534 BTO:0004055 15735663 YES miannu We show that overexpression of hsTAF12 potentiates ATF7-induced transcriptional activation through direct interaction with ATF7, suggesting that TAF12 is a functional partner of ATF7. 0.516 SIGNOR-225249 TNF protein P01375 UNIPROT COMT protein P21964 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000099 19291302 NO Regulation of expression miannu COMT gene expression is downregulated by TNFα in primary rat astrocytes at both protein and mRNA levels. 0.29 SIGNOR-251963 RNF167 protein Q9H6Y7 UNIPROT SLC22A18 protein Q96BI1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16314844 YES miannu  Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop. 0.525 SIGNOR-271551 SOSTDC1 protein Q6X4U4 UNIPROT BMP2 protein P12643 UNIPROT down-regulates activity 10090 18032587 NO lperfetto SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7 0.598 SIGNOR-242746 USP21 protein Q9UK80 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000567 28254948 YES done miannu In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING. HSV-1 infection recruited USP21 to STING at late stage by p38-mediated phosphorylation of USP21 at Ser538. I 0.2 SIGNOR-273671 ponatinib chemical CHEBI:78543 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 23430109 YES lperfetto We assessed the in vitro activity of ponatinib against clinically relevant FLT3-ITD mutant isoforms that confer resistance to AC220 or sorafenib. Substitution of the FLT3 "gatekeeper" phenylalanine with leucine (F691L) conferred mild resistance to ponatinib, but substitutions at the FLT3 activation loop (AL) residue D835 conferred a high degree of resistance. 0.8 SIGNOR-261983 D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity precursor of 9606 24929114 YES miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. 0.8 SIGNOR-268143 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 11108261 YES lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. 0.2 SIGNOR-244255 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser89 KQKQPSFsAKKMTEK 9606 BTO:0000567 24781523 YES miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase 0.31 SIGNOR-276383 PTEN protein P60484 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity dephosphorylation Ser97 LRLAEDRsKDPHDPH 9606 32394474 YES lperfetto PTEN can dephosphorylate IRF-3 S97 residue and facilitate its nuclear import for the IFN signaling pathway (7).|PTEN expression directly increases activated IRF-3 nuclear import and subsequent interferon (IFN) synthesis. 0.256 SIGNOR-277025 PRKAA1 protein Q13131 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSSN 10116 11069105 YES AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. AMPK-mediated PFK-2 activation is likely to be involved in the stimulation of heart glycolysis during ischaemia. 0.464 SIGNOR-260012 IRF5 protein Q13568 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000801 22025054 NO lperfetto IRF5 is directly recruited to gene promoters associated with the M1 phenotype (including Il12b), but it represses Il10, probably also by binding to an ISRE in the gene promoter 0.424 SIGNOR-249509 GRIK2 protein Q13002 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264343 SLBP protein Q14493 UNIPROT H2BC13 protein Q99880 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265389 SLC24A5 protein Q71RS6 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264393 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA3 protein P42263 UNIPROT up-regulates activity chemical activation 9606 30825796 YES miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses 0.8 SIGNOR-264610 RXRA protein P19793 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 12771132 YES gcesareni Rxr agonists still inactivated endogenous beta-catenin via rxr alpha. 0.42 SIGNOR-101293 IMP smallmolecule CHEBI:17202 ChEBI 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity precursor of 9606 19480389 YES miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). 0.8 SIGNOR-267333 IL19 protein Q9UHD0 UNIPROT IL20RA protein Q9UHF4 UNIPROT up-regulates binding 9606 BTO:0000848 11564763 YES gcesareni Il-19 signals only through the type i il-20r complex. 0.744 SIGNOR-110671 CDK2 protein P24941 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 SIGNOR-C83 23028682 YES llicata The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program. 0.4 SIGNOR-199020 PTGES protein O14684 UNIPROT prostaglandin E2 smallmolecule CHEBI:15551 ChEBI up-regulates quantity chemical modification 9606 21983014 YES The mPGES-1, one of three PGE2 synthases, is barely basally expressed, but is inducible by different stimuli and frequently co-expressed with COX-2. COX-2, mPGES-1 and PGE2 are enhanced during pain, inflammatory processes and in several cancer cells 0.8 SIGNOR-254263 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 17548358 YES gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. 0.333 SIGNOR-155377 HOXA9 protein P31269 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 17327400 YES Luana Thus Pim1 appears to be a direct transcriptional target of HOXA9 and a mediator of its antiapoptotic and proproliferative effects in early cells.  0.2 SIGNOR-261632 JAK2 protein O60674 UNIPROT BRD4 protein O60885 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr98 KLNLPDYyKIIKTPM 9606 BTO:0002181 34290255 YES miannu JAK2 induces tyrosine phosphorylation of BRD4 at Y97/Y98, resulting in BRD4 stabilization.  0.325 SIGNOR-277312 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000189 17251915 YES gcesareni Gastrin-releasing peptide receptors (grpr) are coupled primarily to galfaq, and are highly expressed in many cancers, including small-cell lung cancer 0.522 SIGNOR-152679 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 YES gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. 0.305 SIGNOR-76100 DPP10 protein Q8N608 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity relocalization 9534 BTO:0000298 15454437 YES Luisa Coexpression of DPP10 changes the subcellular localization of Kv4.2 expressed in COS-7 cells by promoting surface trafficking.DPP10 accelerates Kv4.2 inactivation at high and low voltages 0.534 SIGNOR-269006 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRB2 protein P07550 UNIPROT up-regulates chemical activation 9606 22863277 YES gcesareni In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function. 0.8 SIGNOR-198501 BRD7 protein Q9NPI1 UNIPROT BRD3 protein Q15059 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000192 12600283 NO miannu BRD7 protein could respectively interact with proteins, BRD2 and BRD3, and BRD7 could up-regulate the expression levels of BRD2 and BRD3 genes in mRNA level to some extent. 0.384 SIGNOR-253764 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT2 protein P31751 UNIPROT down-regulates activity chemical inhibition 25309440 YES lperfetto Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway. 0.8 SIGNOR-262011 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr966 QICKGMEyLGTKRYI 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity 0.2 SIGNOR-236290 romidepsin chemical CHEBI:61080 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257990 SMAD6 protein O43541 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 9892110 YES lperfetto SMAD6 functions as a negative regulator of the TGFB and BMP signaling pathways by interacting with other SMADs and/or TBRI. 0.74 SIGNOR-64079 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 10090 BTO:0000944 7518560 YES lperfetto Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that y-1173 and y-992 are major and minor binding sites, respectively, for shc on the egfr. 0.913 SIGNOR-235481 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.275 SIGNOR-163760 PINK1 protein Q9BXM7 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity phosphorylation Ser442 AEEIRRLsVLVDDYQ 9606 34275172 YES miannu If PINK1 is responsible for the degradation of Mfn2, then silencing PINK1 should induce mitochondrial fusion by upregulating Mfn2 expression.|We show that downregulation of Mfn2 is induced by proteasomal degradation triggered by PINK1, which phosphorylates Mfn2 at S442. 0.809 SIGNOR-278208 DDX1 protein Q92499 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity binding 10090 21703541 YES miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. 0.32 SIGNOR-260191 DBP protein Q10586 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8383844 NO miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators 0.2 SIGNOR-253833 PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 YES tpavlidou Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene. 0.389 SIGNOR-252966 epinastine chemical CHEBI:51032 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257779 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 10733900 YES amattioni Crk could bind to both pdgf alpha- and beta-receptors in vivo. 0.646 SIGNOR-75881 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser117 ARKSTRRsIRLPETI 9606 7559487 YES gcesareni To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%. 0.28 SIGNOR-28884 ZNF217 protein O75362 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 YES miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. 0.553 SIGNOR-222118 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 21460634 YES lperfetto mTORC1, which is often referred to as the gatekeeper to autophagy, is a key regulator of the Ulk1-Atg13-FIP200 kinase complex.11,14,25 Under nutrient-rich conditions, active mTORC1 associates with and inactivates the Ulk1-Atg13-FIP200 complex by phosphorylating Ulk1 and Atg13. 0.849 SIGNOR-183903 TALDO1 protein P37837 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI down-regulates quantity chemical modification 9606 19401148 YES miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 0.8 SIGNOR-267089 CENPT protein Q96BT3 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.727 SIGNOR-265204 romidepsin chemical CHEBI:61080 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257996 MT-ND4 protein P03905 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 0.789 SIGNOR-262146 vitamin D smallmolecule CHEBI:27300 ChEBI calcidiol smallmolecule CHEBI:17933 ChEBI up-regulates quantity precursor of 9606 BTO:0000759 30080183 YES lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. 0.8 SIGNOR-270567 GDNF protein P39905 UNIPROT DCX protein O43602 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. 0.345 SIGNOR-252172 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM TEC protein P42680 UNIPROT down-regulates activity chemical inhibition -1 24556163 YES miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 0.8 SIGNOR-262235 EIF3_complex complex SIGNOR-C401 SIGNOR 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity 9606 15703437 NO lperfetto EIF3 and, to some extent, eIF1A have been implicated in preventing reassociation of free 40S and 60S subunits and in dissociation of empty 80S ribosomes 0.431 SIGNOR-269149 CDK5 protein Q00535 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 25730670 YES miannu CDK5 activates DRP1 in BTICs.|To determine if CDK5 could directly phosphorylate DRP1, we performed an in vitro kinase assay with CDK5, its regulatory partner p25 and GST-DRP1 (wild type or S616A mutant) and found that CDK5 directly phosphorylates DRP1 on the S616 site (Fig. 7d). 0.464 SIGNOR-278275 SMARCB1 protein Q12824 UNIPROT CCNA1 protein P78396 UNIPROT down-regulates 9606 12226744 NO miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. 0.336 SIGNOR-92779 PTAFR protein P25105 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.411 SIGNOR-257436 sirolimus chemical CHEBI:9168 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR down-regulates chemical inhibition -1 17350953 YES lperfetto Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kDa FK506- and rapamycin-binding protein (FKBP12, or FKBP) and the FKBP-rapamycin binding (FRB) domain of the mammalian target of rapamycin (mTOR) kinase. The resulting ternary complex has been used to conditionally perturb protein function, and one such method involves perturbation of a protein of interest through its mislocalization. 0.8 SIGNOR-219385 PP121 chemical CHEBI:50915 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206292 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr306 TTRLKEYtIKSHSSL 9606 15611134 YES lperfetto Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311 0.2 SIGNOR-132475 YAP1 protein P46937 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates binding 9606 23431053 YES Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4 gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. 0.927 SIGNOR-201474 VCB-Cul2 complex SIGNOR-C524 SIGNOR USP33 protein Q8TEY7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 11739384 YES miannu  Finally, we demonstrate that VDU1 is able to be ubiquitinated via a pVHL-dependent pathway for proteasomal degradation, and VHL mutations that disrupt the interaction between VDU1 and pVHL abrogate the ubiquitination of VDU1. Our findings indicate that VDU1, a novel ubiquitin-specific processing protease, is a downstream target for ubiquitination and degradation by pVHL E3 ligase. Targeted degradation of VDU1 by pVHL could be crucial for regulating the ubiquitin-proteasome degradation pathway. 0.46 SIGNOR-272623 MAPK3 protein P27361 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 15262992 YES lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. 0.274 SIGNOR-126871 S1PR3 protein Q99500 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.401 SIGNOR-257263 AMPK complex SIGNOR-C15 SIGNOR PRMT6 protein Q96LA8 UNIPROT down-regulates activity binding 30420520 YES lperfetto AMPK induces R388 hypomethylation by disrupting the association between PRMT6 and SIRT7.|Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 0.2 SIGNOR-275889 SOX17 protein Q9H6I2 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10549281 YES gcesareni Two additional sox proteins, xsox17alfa and xsox3 , likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity 0.685 SIGNOR-72006 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser137 QHSSPAVsDSLPSNS 9606 BTO:0000671 12628002 YES lperfetto Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149) 0.702 SIGNOR-99131 AGO2 protein Q9UKV8 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR form complex binding 9606 16142218 YES lperfetto Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer. 0.904 SIGNOR-140220 EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 YES lperfetto p85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. 0.81 SIGNOR-33633 FZD4 protein Q9ULV1 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates activity binding 9606 27096005 YES areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. 0.575 SIGNOR-258961 MAPK1 protein P28482 UNIPROT EPAS1 protein Q99814 UNIPROT up-regulates quantity by stabilization phosphorylation Ser484 SSCSTPNsPEDYYTS 9606 BTO:0006155 35191554 YES miannu The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. 0.25 SIGNOR-277585 JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization binding 10090 12370803 YES irozzo In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.  0.451 SIGNOR-255810 SREBF1 protein P36956 UNIPROT MTTP protein P55157 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11111091 NO miannu SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. 0.414 SIGNOR-252113 SRGAP3 protein O43295 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.564 SIGNOR-260518 Ub:E2 complex SIGNOR-C497 SIGNOR RNF220 protein Q5VTB9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271166 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by stabilization phosphorylation Ser405 QARAHGLsLIPSTGL 9606 BTO:0005451 25605940 YES miannu We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. 0.436 SIGNOR-276477 MYOG protein P15173 UNIPROT Myog/SWI/SNF complex complex SIGNOR-C94 SIGNOR form complex binding 9606 BTO:0001103 17194702 YES miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle 0.483 SIGNOR-151691 FZD4 protein Q9ULV1 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 25902418 YES areggio Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. 0.703 SIGNOR-258967 MAPK1 protein P28482 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 YES miannu Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome 0.604 SIGNOR-74712 MYC protein P01106 UNIPROT miR-23a mirna URS00001CC864_9606 RNAcentral down-regulates quantity by repression transcriptional regulation 9606 19219026 YES Luana Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.  0.4 SIGNOR-268045 TET2 protein Q6N021 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 NO irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. 0.7 SIGNOR-255704 MRPS27 protein Q92552 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.698 SIGNOR-261446 UVRAG protein Q9P2Y5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 9606 18843052 YES lperfetto Although both human atg14 and uvrag interact with beclin 1 and vps34. 0.809 SIGNOR-181554 E2F1 protein Q01094 UNIPROT NOX4 protein Q9NPH5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002195 18554521 NO lperfetto Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F 0.2 SIGNOR-254134 GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 YES Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells 0.2 SIGNOR-254297 COL4A6 protein Q14031 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.444 SIGNOR-253246 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii 0.777 SIGNOR-203592 RUNX1 protein Q01196 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002580 34902205 YES lperfetto RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia. 0.2 SIGNOR-272145 IARS1 protein P41252 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.2 SIGNOR-270354 ZBTB16 protein Q05516 UNIPROT miR-146a mirna URS000075D8A0_9606 RNAcentral down-regulates quantity by repression transcriptional regulation 9606 22327366 YES In endothelial cells. KLF2 binds to the promoter and induces a signi cant upregulation of the miR-143/145 cluster 0.4 SIGNOR-255941 FRZB protein Q92765 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 YES gcesareni We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos, 0.518 SIGNOR-51762 GPR132 protein Q9UNW8 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.405 SIGNOR-257396 HCRTR2 protein O43614 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.448 SIGNOR-257216 PP2B proteinfamily SIGNOR-PF18 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 YES inferred from 70% family members lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. 0.2 SIGNOR-269988 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003858 12734180 NO miannu The suppressive effect of IGF-1 and OP-1 on MMP-13 expression was due in part to down-regulation of the expression of pro-inflammatory cytokines and the activity of their intermediate molecules, including NF-kappaB and AP-1 factors. 0.31 SIGNOR-254800 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 YES gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. 0.636 SIGNOR-181323 USF2 protein Q15853 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001363; BTO:0000142 11058604 NO miannu We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs. 0.27 SIGNOR-254883 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.2 SIGNOR-141424 SMARCA4 protein P51532 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.868 SIGNOR-270738 BARD1 protein Q99728 UNIPROT BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR form complex binding 25400280 YES lperfetto Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks. 0.795 SIGNOR-263223 NFYB protein P25208 UNIPROT PHGDH protein O43175 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18378410 NO miannu Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. 0.2 SIGNOR-255210 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18211802 YES inferred from 70% family members gcesareni Activates rhoa and as a result regulates actin assembly. 0.2 SIGNOR-270138 WNT9B protein O14905 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20093360 YES gcesareni We find that wnt9b binds to a different part of the lrp6 extracellular domain 0.617 SIGNOR-163552 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity phosphorylation Ser128 LVDTASPsPMETSGC 9606 BTO:0000567 11242082 YES lperfetto Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation. 0.922 SIGNOR-105711 NR3C1 protein P04150 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity 10090 11742987 NO gcesareni The MAP kinase p38 is also a target for negative regulation by glucocorticoids 0.509 SIGNOR-251675 PAK1 protein Q13153 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 18775988 YES gcesareni P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339. 0.601 SIGNOR-180808 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 YES gcesareni We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met. 0.5 SIGNOR-181331 6-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine chemical CHEBI:40629 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189347 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000671 18701453 YES lperfetto We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation. 0.364 SIGNOR-236660 ENPP1 protein P22413 UNIPROT Bone_mineralization phenotype SIGNOR-PH69 SIGNOR up-regulates 9606 19049325 NO miannu PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate. 0.7 SIGNOR-252195 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr116 LASELAKtPQKSVSF 9606 SIGNOR-C83 11931757 YES lperfetto We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. 0.755 SIGNOR-116364 PTPN13 protein Q12923 UNIPROT TRIP6 protein Q15654 UNIPROT down-regulates activity dephosphorylation Tyr55 PLPSEQCyQAPGGPE 10090 BTO:0002572 17591779 YES PTPL1/FAP-1 negatively regulates TRIP6 function in lysophosphatidic acid-induced cell migration.|Here we further demonstrate that a switch from c-Src-mediated phosphorylation to PTPL1/Fas-associated phosphatase-1-dependent dephosphorylation serves as an inhibitory feedback control mechanism of TRIP6 function in LPA-induced cell migration. PTPL1 dephosphorylates phosphotyrosine 55 of TRIP6 in vitro and inhibits LPA-induced tyrosine phosphorylation of TRIP6 in cells. 0.434 SIGNOR-248713 TBX5 protein Q99593 UNIPROT MTA2 protein O94776 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20802524 NO miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. 0.2 SIGNOR-255256 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10734067 YES gcesareni Here we show that the direct association between a p53 n-terminal peptide and mdm2 is disrupted by phosphorylation of the peptide on thr(18) but not by phosphorylation at other n-terminal sites, including ser(15) and ser(37). Thr(18) was phosphorylated in vitro by casein kinase (ck1). 0.577 SIGNOR-75889 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 8131746 YES gcesareni Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf 0.573 SIGNOR-36449 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258003 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT down-regulates activity dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9534 BTO:0004055 10993888 YES A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b 0.675 SIGNOR-248429 EGR2 protein P11161 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16054051 YES fspada Ectopic expression of krox20 can transactivate the c/ebpbeta promoter and increase c/ebpbeta gene expression in 3t3-l1 preadipocytes 0.532 SIGNOR-139292 SERPINE1 protein P05121 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 19387897 NO miannu Plasma PAI-1 levels robustly fluctuate in a circadian manner and consequently contribute to hypofibrinolysis during the early morning. The circadian expression of PAI-1 gene is thought to be directly regulated by the circadian clock proteins such as CLOCK and BMAL1/BMAL2 which drive the endogenous biological clock. Plasma PAI-1 levels are increased in the beginning of the active phase in both diurnal humans and in nocturnal rodents, suggesting that the rhythmic PAI-1 expression is commonly indispensable for organisms. 0.7 SIGNOR-267984 NFE2L2 protein Q16236 UNIPROT GSTA1 protein P08263 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24024136 YES irozzo In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs). 0.342 SIGNOR-256278 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr886 GGEQDYDyLNDWGPR 9606 BTO:0000848 16371504 YES lperfetto Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated. 0.398 SIGNOR-143246 SLBP protein Q14493 UNIPROT H3Y2 protein P0DPK5 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265416 IKBKE protein Q14164 UNIPROT PBXIP1 protein Q96AQ6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser147 REEGRCSsSDDDTDV 9606 BTO:0000007 24488098 YES miannu  Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. 0.2 SIGNOR-276618 ATM protein Q13315 UNIPROT RANBP9 protein Q96S59 UNIPROT up-regulates activity phosphorylation 9606 26943034 YES miannu We demonstrate that ATM phosphorylates RanBP9 in response to Ionizing Radiation and mediates its nuclear accumulation. 0.439 SIGNOR-279005 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 BTO:0000551 20966354 YES lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. 0.767 SIGNOR-256170 TRIM27 protein P14373 UNIPROT WASHC1 protein A8K0Z3 UNIPROT up-regulates activity ubiquitination Lys220 DAPLSISkREQLEQQ 9606 23452853 YES miannu Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport. 0.2 SIGNOR-253514 PCSK6 protein P29122 UNIPROT VWF protein P04275 UNIPROT up-regulates activity cleavage 8218226 YES Giorgia Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine 0.293 SIGNOR-260367 PRKCA protein P17252 UNIPROT RPL10 protein P27635 UNIPROT unknown phosphorylation Ser168 GRQKIHIsKKWGFTK -1 9016777 YES lperfetto Moreover, QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun.  0.307 SIGNOR-248958 clotrimazole chemical CHEBI:3764 ChEBI KCNN4 protein O15554 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9730970 YES miannu IK was blocked by the classical inhibitors of the Gardos channel charybdotoxin (IC50 28 nM) and clotrimazole (IC50 153 nM) as well as by nitrendipine (IC50 27 nM), Stichodactyla toxin (IC50 291 nM), margatoxin (IC50 459 nM), miconazole (IC50 785 nM), econazole (IC50 2.4 microM), and cetiedil (IC50 79 microM). Finally, 1-ethyl-2-benzimidazolinone, an opener of the T84 cell IK channel, activated hIK with an EC50 of 74 microM. 0.8 SIGNOR-258832 PRL protein P01236 UNIPROT KRT5 protein P13647 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20103718 NO Regulation miannu PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. 0.264 SIGNOR-251903 GYPB protein P06028 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.37 SIGNOR-266021 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 YES llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.518 SIGNOR-169522 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr293 HRIDGKTyVIKRVKY 9606 BTO:0001282 16373505 YES PKR autophosphorylates on Y101, Y162, and Y293. The introduction of the Y293F mutation causes significant defects in PKR autophosphorylation and eIF2α phosphorylation, providing evidence for a critical function of this phosphorylated residue. 0.2 SIGNOR-251114 PTK2B protein Q14289 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates activity phosphorylation Tyr721 FDLSEQTyDFLGEMR 9606 21357692 YES miannu Pyk2 Induces Tyrosine Phosphorylation of NPHP1 at Tyr-46, Tyr-349, and Tyr-721.|The expression of wild-type Pyk2 enhances the amount of co-precipitating PACS-1 with wild-type NPHP1 compared with the presence of the kinase-dead variant of Pyk2. 0.462 SIGNOR-278273 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 YES lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 0.607 SIGNOR-161694 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT down-regulates activity phosphorylation Tyr530 FTSTEPQyQPGENL 9606 8755732 YES lperfetto Rapid digestion of pp60c-src tyrosine kinase (src TK) in combination with electrospray ionization mass spectrometry enabled the determination of the time course for autophosphorylation of three tyrosine sites (Y338, Y419, and Y530) and a correlation with src TK activity. Here, conditions were identified which promoted essentially complete autophosphorylation of y530. Phosphorylation of y530 was directly correlated to a decrease in tyrosine kinase activity 0.2 SIGNOR-43315 MDH1 protein P40925 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-266285 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 10649448 YES gcesareni We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPδ; C/EBPδ then binds to PPARγ2 promoter and transactivates PPARγ2 gene expression. 0.315 SIGNOR-253061 FGD1 protein P98174 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.715 SIGNOR-260551 N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide chemical CHEBI:91401 ChEBI INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192883 IKBKG protein Q9Y6K9 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 10090 SIGNOR-C14 SIGNOR-C14 19666475 YES lperfetto Proinflammatory NF-kappaB activation requires the IkappaB (inhibitor of NF-kappaB) kinase (IKK) complex that contains two catalytic subunits named IKKalpha and IKKbeta and a regulatory subunit named NF-kappaB essential modulator (NEMO). 0.93 SIGNOR-209762 MCF2L protein O15068 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.75 SIGNOR-260560 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser270 EFRPRSKsQSSSNCS 9606 BTO:0000975;BTO:0001760;BTO:0000142 9312143 YES lperfetto Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites. 0.787 SIGNOR-51216 GABRG2 protein P18507 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.639 SIGNOR-263755 GSK3B protein P49841 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates activity phosphorylation Ser707 EPLCPLPsPPTSDSD 9606 26999213 YES miannu More recently, phosphorylation of S707 and S711 by GSK3beta has been shown to promote complete proteasomal degradation of p100 involving the E3 ligase Fbw7 .|These studies suggest that a pool of p100 is constitutively phosphorylated by GSK3beta at S707 and S711, triggering the Fbw7 mediated ubiquitination and proteasomal degradation of p100 which controls the levels of p100 available for the non canonical pathway. 0.271 SIGNOR-279186 HTR1D protein P28221 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257208 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Thr187 ESSKERNtPRKEDRS -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.285 SIGNOR-273975 SALL4 protein Q9UJQ4 UNIPROT ABCA3 protein Q99758 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21526180 NO miannu we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples 0.281 SIGNOR-255121 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser299 NQVTQRAsRRSDSAS 9606 17603046 YES gcesareni Here, we demonstrate that pkcdelta undergoes in vitro autophosphorylation at three sites within its v3 region (s299, s302, s304), each of which is unique to this pkc isoform and evolutionarily conserved 0.2 SIGNOR-156523 hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral MET protein P08581 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 25965999 YES Parnian These results show that miR-122 directly inhibits c-Met translation by targeting the 3’UTR region. 0.4 SIGNOR-279816 fexofenadine chemical CHEBI:5050 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 19660947 YES Luana  hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7 0.8 SIGNOR-257827 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA12 protein O60330 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265698 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr189 NRYSFYStCSGQKAI -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273493 ELP1 protein O95163 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 YES miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. 0.2 SIGNOR-269708 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG -1 17711846 YES done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). 0.41 SIGNOR-274098 PDGFRB protein P09619 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 19275932 YES miannu Here, we show that PDGFR-beta-phosphorylation of Abl kinases has functional consequences as PDGFR-beta phosphorylates Abl kinases on Y245 and Y412, sites known to be required for activation of Abl kinases. 0.526 SIGNOR-278318 DNMT3A protein Q9Y6K1 UNIPROT TIMP2 protein P16035 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19786833 NO irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. 0.2 SIGNOR-255807 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation Ser44 RLQERRGsNVALMLD 9606 10559944 YES llicata Here we show that cyclic-amp-dependent protein kinase (pka) phosphorylates serine residue 23 in the kim of heptp in vitro and in intact cells. This modification reduces binding of map kinases to the kim, an effect that is prevented by mutation of serine 23 to alanine. 0.362 SIGNOR-72147 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000132 21592956 YES lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. 0.642 SIGNOR-217012 MPHOSPH10 protein O00566 UNIPROT RPS5 protein P46782 UNIPROT up-regulates activity binding -1 28813493 YES miannu Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome. 0.625 SIGNOR-261175 Neuregulin proteinfamily SIGNOR-PF37 SIGNOR ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 YES Does not bind to the ERBB1, ERBB2 and ERBB3 receptors gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.2 SIGNOR-269970 SMURF1 protein Q9HCE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 YES Ubiquitin-mediated proteolysis. gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. 0.769 SIGNOR-195663 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273047 AKAP5 protein P24588 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates activity relocalization 10116 BTO:0004553 20694001 YES Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin 0.262 SIGNOR-261291 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 YES gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase 0.27 SIGNOR-76072 ATAT1 protein Q5SQI0 UNIPROT TUBA8 protein Q9NY65 UNIPROT up-regulates quantity by stabilization acetylation -1 29703898 YES lperfetto Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules 0.244 SIGNOR-272250 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000830 15526160 YES miannu Activation of PI3-kinase by c-Kit has been linked to mitogenesis, differentiation, survival, adhesion, secretion and actin cytoskeletal reorganization. In c-Kit, Y721 has been found to directly interact with PI3-kinase 0.72 SIGNOR-254949 phosphatidylinositol 4-phosphate smallmolecule CHEBI:37530 ChEBI Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 22253445 NO lperfetto Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment. 0.7 SIGNOR-260745 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR TCHP protein Q9BT92 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0004910 25270598 YES miannu We have identified KCTD17 as a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of KCTD17 specifically arrests ciliogenesis at the initial step of axoneme extension through aberrant trichoplein-Aurora-A activity. Thus, CRL3-KCTD17 targets trichoplein to proteolysis to initiate the axoneme extension during ciliogenesis. 0.2 SIGNOR-272465 PPARG protein P37231 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity 9606 23128507 YES PAX8-PPARγ fusion protein miannu The PAX8-PPARγ rearrangement leads to strong induction of the PPARγ protein and the consequent abrogation of the normal PPARγ function. PPARγ overexpression abolishes the PTEN-inhibitory effect on immunoactive AKT, which in turn induces the PI3K signaling pathway. 0.457 SIGNOR-251997 NARS1 protein O43776 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270458 CKM complex complex SIGNOR-C406 SIGNOR CCNH protein P51946 UNIPROT down-regulates activity phosphorylation Ser304 YEDDDYVsKKSKHEE 9606 10993082 YES lperfetto Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity 0.44 SIGNOR-273141 CD38 protein P28907 UNIPROT NADP(+) smallmolecule CHEBI:18009 ChEBI down-regulates quantity chemical modification 9606 18626062 YES miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. 0.8 SIGNOR-264247 hsa-miR-124-5p mirna URS00003AA409_9606 RNAcentral SPHK1 protein Q9NYA1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002392 22450659 YES Parnian The key finding of the present study was that up- regulation of miR-124 could repress SPHK1 expression by directly targeting the 3′-UTR of SPHK1. In addition, we found that over-expressing miR-124 inhibited proliferation and the anchorage independent growth of gastric cancer cells. proliferation and the anchorage-independent grow 0.4 SIGNOR-279810 dehydroepiandrosterone chemical CHEBI:28689 ChEBI hsa-miR-21-5p mirna URS000039ED8D_9606 RNAcentral up-regulates quantity by expression post transcriptional regulation 9606 BTO:0000599 25969534 NO Parnian Together, these data suggest that the rapid DHEA-induced increase in pri-miR-21 and miR-21 is a transcriptional response that requires GPCR signaling, EGFR activation, Src kinase activity, intact PM structure, and MAPK and PI3K activity. 0.4 SIGNOR-279813 hsa-miR-181a-5p mirna URS00003DA300_9606 RNAcentral PRKCD protein Q05655 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002210 24183997 YES Parnian Findings suggest that miR-181a may function as an oncogene and induce chemoresistance in cervical squamous cell carcinoma cells at least in part by down-regulating PRKCD, thus may provide a biomarker for predicting chemosensitivity to cisplatin in patients with cervical squamous cancer. 0.4 SIGNOR-279817 hsa-miR-199a-5p mirna URS0000554A4F_9606 RNAcentral ATG7 protein O95352 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 22713463 YES Parnian We further demonstrated that miR-199a-5p downregulation increased autophagy activation by targeting ATG7. 0.4 SIGNOR-279818 hsa-miR-622 mirna URS000075E944_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000182 30851425 YES Parnian These findings indicated that miR-622 can inhibit CXCR4 expression in CRC by directly targeting the CXCR4 3′-UTR. 0.4 SIGNOR-279819 TBX2 protein Q13207 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 24470334 NO TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells 0.7 SIGNOR-251563 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr750 PAPDELVyQVPQSTQ -1 23770091 YES done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. 0.351 SIGNOR-273944 KIF14 protein Q15058 UNIPROT CIT protein O14578 UNIPROT up-regulates activity binding 9606 16431929 YES miannu We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase. 0.722 SIGNOR-266422 TRIB3 protein Q96RU7 UNIPROT ACACA protein Q13085 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 16794074 YES miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). 0.274 SIGNOR-271600 DRD3 protein P35462 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 YES miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC 0.45 SIGNOR-264994 CHFR protein Q96EP1 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 YES miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. 0.333 SIGNOR-271457 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BW1 protein Q7Z2G1 UNIPROT down-regulates activity monoubiquitination 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271989 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0000971 17936559 YES gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. 0.755 SIGNOR-158324 FGF14 protein Q92915 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253441 MEGF10 protein Q96KG7 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates activity binding 9606 BTO:0000567 17205124 YES miannu ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level. 0.332 SIGNOR-265165 PTPN1 protein P18031 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 23639442 YES lperfetto This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y 1175 , the site involved in activating ERK signaling. 0.419 SIGNOR-277011 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu618 SEVKMDAeFRHDSGY -1 8943232 YES lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261767 CHEK1 protein O14757 UNIPROT FANCE protein Q9HB96 UNIPROT up-regulates phosphorylation Thr346 LGLLRLCtWLLALSP 9606 17296736 YES llicata Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway. 0.715 SIGNOR-153027 BARD1 protein Q99728 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity ubiquitination 9606 25740706 YES miannu As shown in xref , both FOXK2 and BARD1 enhanced the ubiquitination of ER\u03b1, with the extent of ubiquitination being enhanced when both FOXK2 and BARD1 were overexpressed.|These findings suggested that FOXK2 might act as a negative regulator of Estrogen receptor\u03b1, and its association with both Estrogen receptor\u03b1 and BRCA1/BARD1 could lead to the down-regulation of Estrogen receptor\u03b1 transcriptional activity, effectively regulating the function of Estrogen receptor\u03b1. 0.427 SIGNOR-278803 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000007 SIGNOR-C13 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. 0.885 SIGNOR-129935 DUSP3 protein P51452 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation 9606 28759036 YES miannu Deficiency in VHR/DUSP3, a suppressor of focal adhesion kinase, reveals its role in regulating cell adhesion and migration.|In vitro assays proved that recombinant VHR directly dephosphorylated FAK and paxillin. 0.326 SIGNOR-277033 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 16829981 YES gcesareni Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow. 0.573 SIGNOR-147841 HIRA complex 2 complex SIGNOR-C462 SIGNOR H3-3A protein P84243 UNIPROT up-regulates quantity by stabilization binding 9606 30285846 YES miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. 0.2 SIGNOR-269440 MAPK15 protein Q8TD08 UNIPROT ELAVL1 protein Q15717 UNIPROT down-regulates activity phosphorylation 9606 26595526 YES miannu ERK8 phosphorylates HuR to prevent its binding to PDCD4 mRNA A. ERK8 or control siRNA was transfected into HeLa cells for 48 h followed by treatment of cells with 0.5 mM H2O2 or PBS for 1 h. Cells were fixed and immunofluorescence was performed to monitor HuR localization. 0.346 SIGNOR-278314 MECP2 protein P51608 UNIPROT SST protein P61278 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 18511691 YES Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. 0.297 SIGNOR-264676 HECW2 protein Q9P2P5 UNIPROT TP73 protein O15350 UNIPROT up-regulates quantity by stabilization ubiquitination 9534 BTO:0000298 12890487 YES miannu P73 was efficiently ubiquitinated but stabilized in a NEDL2-dependent manner. Accordingly, p73 decayed at faster rates in the absence of NEDL2 than in its presence. Consistent with the NEDL2-mediated stabilization of p73, NEDL2 enhanced the p73-dependent transcriptional activation. Thus, our results suggest that NEDL2 activates the function of p73 by increasing its stability. 0.371 SIGNOR-269457 PKC proteinfamily SIGNOR-PF53 SIGNOR ARHGAP17 protein Q68EM7 UNIPROT down-regulates activity phosphorylation Ser702 LSAPRRYsSSLSPIQ 9606 BTO:0000132 26507661 YES lperfetto Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex. 0.2 SIGNOR-272157 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr383 GETSLMRtLCGTPTY 9606 BTO:0000007 11901158 YES gcesareni Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387 0.2 SIGNOR-116127 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252333 PRKACA protein P17612 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates activity phosphorylation Ser524 GMRGRKSsGFPKSVK -1 15280375 YES lperfetto These results indicate that PKA phosphorylates 5-LO on Ser-523, which inhibits the catalytic activity of 5-LO and reduces cellular LT generation. 0.336 SIGNOR-264410 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser179 KTRAKGPsESSKERN -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.285 SIGNOR-273979 HDLBP protein Q00341 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 33941620 NO miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. 0.7 SIGNOR-266695 NBR1 protein Q14596 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 YES gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. 0.56 SIGNOR-184270 GATA2 protein P23769 UNIPROT Mast-Cell_diff phenotype SIGNOR-PH117 SIGNOR up-regulates activity 10090 BTO:0000830 25801432 NO We have identified GATA2 as an essential transcription factor in differentiation of newly identified common basophil and mast cell progenitors into basophils and mast cells. ll differentiation and maintenance 0.7 SIGNOR-259959 AKT1 protein P31749 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 YES gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. 0.435 SIGNOR-252496 Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 32979938 YES miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). 0.2 SIGNOR-262511 2-deoxy-D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:62877 ChEBI acetaldehyde smallmolecule CHEBI:15343 ChEBI up-regulates quantity precursor of 9606 25229427 YES miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. 0.8 SIGNOR-268076 CDK1 protein P06493 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr287 SAASNTGtPDGPEAP 9606 15125835 YES lperfetto T287 is phosphorylated by cdk1 during mitosis. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis. 0.465 SIGNOR-124642 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2N protein P61088 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.763 SIGNOR-271354 SLC12A6 protein Q9UHW9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 21613606 YES lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  0.8 SIGNOR-264638 HUWE1 protein Q7Z6Z7 UNIPROT POLL protein Q9UGP5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 22203964 YES miannu Identification of Mule as an E3 ubiquitin ligase regulating cellular protein levels of DNA polymerase λ.Here, we show that the E3 ligase Mule mediates the degradation of Pol λ and that the control of Pol λ levels by Mule has functional consequences for the ability of mammalian cells to deal with 8-oxo-G lesions. 0.309 SIGNOR-272920 SREBF1 protein P36956 UNIPROT VLDL_assembly phenotype SIGNOR-PH62 SIGNOR up-regulates 9606 11111091 NO miannu SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. SREBP1 induced the expression of the genes regulating the synthesis of all VLDL lipids 0.7 SIGNOR-252112 UBE2I protein P63279 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11278694 YES miannu  Co-expression of STRA13 and UBC9 led to an increase of the pSTRA13 ubiquitination and subsequent degradation. These data established that UBC9/STRA13 association in cells is of physiological importance, presenting direct proof of UBC9 involvement in the ubiquitin-dependent degradation of pSTRA13. We also checked whether UBC9 is directly involved in pSTRA13 ubiquitination. Taken together, these results strongly suggest that pSTRA13 is targeted for proteolysis by the ubiquitin-dependent proteasome pathway through association with UBC9. 0.327 SIGNOR-272579 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000567 9687510 YES gcesareni Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha 0.614 SIGNOR-59443 ATM protein Q13315 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 YES gcesareni Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair. 0.701 SIGNOR-151441 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 17157788 YES miannu Atm/atr are generally sensors of dna damage, but, together with the checkpoint kinases chk1 and chk2, they also function as response effectors by phosphorylation of key substrates, such as p53, brca1, and nbs1. In particular, p53 phosphorylation leads to protein accumulation and activation, which in turn promotes cell-cycle arrest or apoptosis. 0.843 SIGNOR-151138 phenylalanine smallmolecule CHEBI:28044 ChEBI tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors 0.8 SIGNOR-264172 PRKCA protein P17252 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000017 15647376 YES lperfetto Phosphorylation of ezrin is required for both conformational activation and for signaling to downstream events. The activating c-terminal threonine phosphorylation on t567 was first described to be downstream of the rho pathway (matsui et al., 1998). Additional studies have implicated protein kinase c (pkc)  in the phosphorylation of ezrin t567. 0.546 SIGNOR-133223 MTNR1A protein P48039 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256985 BRCA1 protein P38398 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 19074868 YES gcesareni The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation 0.507 SIGNOR-252458 MAPK1 protein P28482 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 YES lperfetto Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol 0.383 SIGNOR-137171 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT down-regulates phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 YES gcesareni Rin1 also binds to 14-3-3 proteins through a sequence including serine 351. Mutation of this residue abolished the 14-3-3 binding capacity of rin1 and led to more efficient blockade of ras-mediated transformation. The mutant protein, rin1(s351a), showed a shift in localization to the plasma membrane. Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation. 0.402 SIGNOR-113960 PPARGC1A protein Q9UBK2 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.434 SIGNOR-255057 FLI1 protein Q01543 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 NO miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. 0.313 SIGNOR-253921 PLK1 protein P53350 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 27003818 YES miannu An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (Figure 8C).|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation. 0.289 SIGNOR-278191 DMC1 protein Q14565 UNIPROT SYCP3 protein Q8IZU3 UNIPROT up-regulates activity binding 10090 BTO:0001275 SIGNOR-C351 10525529 YES miannu The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. 0.385 SIGNOR-264206 RPS6KB1 protein P23443 UNIPROT TRIB2 protein Q92519 UNIPROT down-regulates quantity by destabilization phosphorylation Ser83 FRAVHLHsGEELVCK 9606 BTO:0002181 24089522 YES miannu Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2. 0.356 SIGNOR-275433 CHEK1 protein O14757 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity phosphorylation Thr539 INFFQDHtKLILCPL 9606 BTO:0000567 37596441 YES miannu  Chk1 directly phosphorylates Plk1 to disturb its interaction with Sgo1.  0.314 SIGNOR-277914 APH1B protein Q8WW43 UNIPROT PSENEN protein Q9NZ42 UNIPROT up-regulates binding 9606 12522139 YES gcesareni Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex. 0.942 SIGNOR-97110 GSK3A protein P49840 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Thr687 PRGMGPGtPAGYGRG 9606 20932480 YES miannu Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion. 0.2 SIGNOR-168382 SLC24A3 protein Q9HC58 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264396 ARHGAP1 protein Q07960 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.905 SIGNOR-260459 VPS4A protein Q9UN37 UNIPROT CHMP2A protein O43633 UNIPROT up-regulates activity cleavage -1 30989108 YES Giorgia Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission. 0.911 SIGNOR-260846 PP1 proteinfamily SIGNOR-PF54 SIGNOR AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 YES lperfetto The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.2 SIGNOR-264660 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 8846784 YES fstefani Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk. 0.508 SIGNOR-44339 NCOA1 protein Q15788 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 9427757 YES miannu Steroid receptor co-activator (src1) is one of a number of transcriptional co-activators that are capable of potentiating the activity of nuclear receptors including the oestrogen receptor (er). 0.845 SIGNOR-54442 OGT protein O15294 UNIPROT PFKL protein P17858 UNIPROT down-regulates activity glycosylation Ser529 CVIPATIsNNVPGTD 9606 BTO:0000007 22923583 YES lperfetto O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway| O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) to serine or threonine residues 0.277 SIGNOR-267585 AXL protein P30530 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 35022267 NO miannu Gas6 and its main receptor AXL are overexpressed in pancreatic cancer and their expression correlates with poor prognosis.Gas6/AXL signalling in cancer cells is associated with tumour cell proliferation, epithelial mesenchymal transition and metastases. 0.7 SIGNOR-277725 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 16308421 YES gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 0.488 SIGNOR-142211 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates binding 9606 14718519 YES gcesareni We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate tbetari. 0.697 SIGNOR-120471 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates activity phosphorylation Ser97 TIAESEDsQESVDSV 9606 15073328 YES lperfetto Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivophosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp) 0.523 SIGNOR-124043 ANXA1 protein P04083 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 27426034 NO miannu Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups 0.333 SIGNOR-261941 KLF4 protein O43474 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 17308127 YES lperfetto Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. 0.561 SIGNOR-270544 MAP3K7 protein O43318 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 21552290 YES miannu TAK1 also phosphorylates and activates MKK6 and MKK7, leading to the activation of p38 and JNK kinase pathways, which may also contribute to disease pathogenesis ( 0.644 SIGNOR-279214 RNF11 protein Q9Y3C5 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity binding 9606 BTO:0000150 19131965 YES lperfetto Rnf11, together with tax1bp1 and itch, is an essential component of an a20 ubiquitin-editing protein complex; rnf11 is required for a20 to interact with and inactivate rip1 to inhibit tnf-mediated nf-_kb activation. 0.554 SIGNOR-183188 SVIP protein Q8NHG7 UNIPROT L3MBTL1 protein Q9Y468 UNIPROT down-regulates activity binding 9606 BTO:0000007 29018219 YES lperfetto In response to DNA damage, VCP/p97, an ATPase which unfolds proteins, removes L3MBTL1 from H4K20me2, creating free H4K20me2 for 53BP1 to bind to (Fig. 3b). 0.2 SIGNOR-262060 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Phe540 FSPMLGEfVSETESR -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain 0.2 SIGNOR-263623 PPP2CA protein P67775 UNIPROT RBL1 protein P28749 UNIPROT up-regulates dephosphorylation 9606 15467457 YES miannu Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation. 0.622 SIGNOR-129749 TFIIE complex SIGNOR-C458 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR up-regulates activity relocalization 9606 31064989 YES lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. 0.737 SIGNOR-269362 PPP3CB protein P16298 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 YES In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. 0.404 SIGNOR-248379 CUL4A protein Q13619 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR form complex binding 9606 22649780 YES gcesareni The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors 0.902 SIGNOR-234793 MAST2 protein Q6P0Q8 UNIPROT SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation 9606 16159897 YES miannu Coexpression of MAST205 inhibits the activity of Na +/H+ exchanger NHE3.|Consistent with these results, we found that MAST205 phosphorylated NHE3 under in vitro conditions. 0.456 SIGNOR-279229 S protein P59594 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity 9606 BTO:0000801 17412287 NO lperfetto The ability of S-protein to induce TNF-a 0.2 SIGNOR-260278 RPS4X protein P62701 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.855 SIGNOR-262447 TFEB protein P19484 UNIPROT NEU1 protein Q99519 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.2 SIGNOR-276544 PAK4 protein O96013 UNIPROT SYNJ1 protein O43426 UNIPROT up-regulates activity phosphorylation -1 22371566 YES miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 0.2 SIGNOR-263024 RPS6KA3 protein P51812 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity 9606 BTO:0000567 20383198 NO lperfetto We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions. 0.2 SIGNOR-252039 ALDH1A3 protein P47895 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI down-regulates quantity chemical modification 9606 21621639 YES lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. 0.8 SIGNOR-265128 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI1 protein P08151 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0000551 19860666 YES gcesareni Gant58 is a gli antagonist that inhibits gli1-induced transcription 0.8 SIGNOR-188863 WNT1 protein P04628 UNIPROT FZD6 protein O60353 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 YES gcesareni Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical bcatenin pathway. 0.691 SIGNOR-198846 SLC30A9 protein Q6PML9 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 11782429 YES lperfetto Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation. 0.2 SIGNOR-113704 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 16308421 YES gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 0.742 SIGNOR-142218 KEAP1 protein Q14145 UNIPROT PGAM5 protein Q96HS1 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0001538 17046835 YES miannu Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Keap1 is a Bric-a-Brac (BTB) 2 -Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. 0.553 SIGNOR-272645 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000938 16923168 YES The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. 0.451 SIGNOR-148974 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.91 SIGNOR-249625 USP9X protein Q93008 UNIPROT EPS15 protein P42566 UNIPROT down-regulates activity deubiquitination 9606 26748853 YES gcesareni We identify the endocytic protein Eps15 as one of the critical substrates of USP9X 0.272 SIGNOR-245052 RASGRF2 protein O14827 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.496 SIGNOR-260574 MARK3 protein P27448 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 35017636 YES miannu In addition, our results showed that MARK3 phosphorylated serine 323 of CDC25B, which is a phosphorylation site of another checkpoint kinase, MAPKAPK2, to induce cytoplasmic translocation of CDC25B .|In addition, our results showed that MARK3 phosphorylated serine 323 of CDC25B, which is a phosphorylation site of another checkpoint kinase, MAPKAPK2, to induce cytoplasmic translocation of CDC25B xref . 0.26 SIGNOR-279223 lofepramine chemical CHEBI:47782 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258882 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp572 PWHSFGAdSVPANTE -1 8943232 YES lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261761 PRKCG protein P05129 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 YES lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. 0.283 SIGNOR-249094 UBE3A protein Q05086 UNIPROT KCNN2 protein Q9H2S1 UNIPROT up-regulates activity ubiquitination 9606 26166566 YES miannu UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. 0.286 SIGNOR-278527 MAPK1 protein P28482 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser68 PSDLSPEsPMLSSPP -1 22577147 YES lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta 0.2 SIGNOR-264895 MARK3 protein P27448 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 35017636 YES miannu In addition, our results showed that MARK3 phosphorylated serine 323 of CDC25B, which is a phosphorylation site of another checkpoint kinase, MAPKAPK2, to induce cytoplasmic translocation of CDC25B xref .|Indeed, MARK3 overexpression augmented the cytoplasmic localization, and reduced the nuclear localization, of CDC25B. 0.26 SIGNOR-279224 ANKRD11 protein Q6UB99 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 YES miannu Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.  0.2 SIGNOR-266737 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Phe43 ATLDPRSfLLRNPND -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.582 SIGNOR-263562 MRPL39 protein Q9NYK5 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.664 SIGNOR-262358 G3BP2 protein Q9UN86 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity relocalization 9606 BTO:0000567 10969074 YES SARA IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm. 0.343 SIGNOR-260985 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.708 SIGNOR-252875 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1096 RYPNDSVyANWMLSP 9606 14711813 YES llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. 0.2 SIGNOR-121149 ITCH protein Q96J02 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 35638972 YES miannu ITCH Ubiquitinates and Down-Regulates Tumor-Surface PD-L1.|The current study supports a model (Fig. 7) in which the E3 ligase ITCH mediates poly-ubiquitination of PD-L1 and down-regulates tumor cell-surface PD-L1 levels (via ubiquitin-directed lysosomal degradation) in MAPKi-adapted melanoma cells and in potentially other biologic contexts such quasi-mesenchymal tumor cell-states that contribute to therapy resistance and metastatic potential. 0.2 SIGNOR-278815 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser183 RARKMEDsKEKNGKK 9606 17540176 YES miannu Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function 0.289 SIGNOR-155349 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates chemical activation 10116 BTO:0003293 8276865 YES milica LPA activates its own G protein-coupled receptor(s) leading to stimulation of phospholipase C and inhibition of adenylate cyclase. 0.8 SIGNOR-37365 FADS6 protein Q8N9I5 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267914 PRKG2 protein Q13237 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates activity phosphorylation Ser1105 LDRKRHNsISEAKMR 10116 11278298 YES lperfetto PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG. 0.524 SIGNOR-249078 KLKB1 protein P03952 UNIPROT KNG1 protein P01042 UNIPROT up-regulates activity cleavage Arg381 GMISLMKrPPGFSPF 9606 BTO:0000131 cleavage:Arg390 CTTKTSTrIVGGTNS 28966616 YES lperfetto Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1). 0.778 SIGNOR-263547 CSNK2A1 protein P68400 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation Ser186 EAGSGAAsSSGEDKE -1 12527891 YES llicata Mass spectrometry analysis demonstrates that at least two serine residues, Ser-186 and Ser-187, are phosphorylated in vivo. | Finally, we demonstrate that phosphorylation of CDC25B by protein kinase CK2 increases the catalytic activity of the phosphatase in vitro as well as in vivo. 0.338 SIGNOR-250836 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr783 EGRNPGFyVEANPMP 9606 9176240 YES gcesareni In contrast, egf-induced tyrosine phosphorylation of plc-gamma 1 was rather small, indicating that tyrosine phosphorylation of plc-gamma 1 is not proportional to changes in plc activity. These results suggest that autophosphorylation of theegfr may induce a conformational change of its kinase domain which enhances its kinase activity with exogenous substrates and may induce association with phospholipase c-gamma by increasing its affinity to a domain containing tyr-771. 0.84 SIGNOR-48872 perfluorohexanesulfonic acid chemical CHEBI:132448 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268766 TBL1X protein O60907 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0000007 20181957 YES miannu TBL1 appears to serve two roles in regulating the activity of β-catenin. Besides the initially identified role of TBL1 in recruiting β-catenin to the SCF(TBL1) complex, it has also been shown to function as a transcriptional co-activator of β-catenin in recruiting it to the promoter site of Wnt target genes. Our results indicated that TBL1 can inhibit the polyubiquitination of β-catenin by Siah-1 in vitro (Fig. 3) and stabilize β-catenin in cells by protecting it from Siah-1-mediated ubiquitination and proteasomal degradation (Fig. 4). 0.658 SIGNOR-271954 MYC protein P01106 UNIPROT CDK6 protein Q00534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 12835716 NO gcesareni The degradation of c-myc protein decreases the expression of the cell cycle regulators cdk4 and cdk6, which reversibly slows down the cell cycle. 0.454 SIGNOR-102737 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269343 EGFR protein P00533 UNIPROT GPRC5A protein Q8NFJ5 UNIPROT down-regulates activity phosphorylation Tyr320 GDTLYAPySTHFQLQ 9606 25311788 YES miannu EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells. 0.387 SIGNOR-278334 MARK3 protein P27448 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates activity phosphorylation Ser406 TRLRRTEsVPSDINN 9606 22206009 YES miannu C-TAK1 phosphorylates KSR1 at S392, forming a 14-3-3 binding site.|In mammalian cells, C-TAK1 has been shown to negatively regulate KSR1 by phosphorylation of Ser392. 0.641 SIGNOR-279225 C1QBP protein Q07021 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR down-regulates activity binding 28018340 YES lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. 0.375 SIGNOR-263401 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000801;BTO:0000876 17658244 YES gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. 0.2 SIGNOR-157081 MYO1C protein O00159 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 YES miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 0.33 SIGNOR-268820 GPC4 protein O75487 UNIPROT WNT3A protein P56704 UNIPROT up-regulates binding 9606 22302992 YES gcesareni Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways 0.35 SIGNOR-195749 KAT6A protein Q92794 UNIPROT CCL3 protein P10147 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 12771199 YES lperfetto We further demonstrate that the histone acetyltransferase, MOZ, can activate the MIP-1a promoter in T-cells and that this activation is largely dependent upon the proximal RUNX site. Moreover, we show that co-expression of MOZ and RUNX1 can activate the MIP-1a promoter. 0.2 SIGNOR-251726 CAMK2A protein Q9UQM7 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Thr140 LRYLKYRtKTRASAT 9606 BTO:0000975 15107581 YES Translocation from Endosome to Lysosome gcesareni As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2). 0.283 SIGNOR-124348 MAPK8 protein P45983 UNIPROT DCX protein O43602 UNIPROT up-regulates activity phosphorylation 9606 28701917 YES miannu In addition, DCX can be phosphorylated by mitogen activated protein kinase 8 (MAPK8 and JNK1) at Thr321, Thr331, and Ser334 sites in humans with corresponding sites at Thr326, Thr336, and Ser339 in mouse. 0.286 SIGNOR-279228 TWIST1 protein Q15672 UNIPROT F2R protein P25116 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255520 MCRIP1 protein C9JLW8 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates activity binding 9606 BTO:0000007 25728771 YES lperfetto CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications. 0.2 SIGNOR-264776 PRKAA1 protein Q13131 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser621 PKINRSAsEPSLHRA 9606 SIGNOR-C15 9091312 YES gcesareni Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259. The catalytic subunit of PKA also phosphorylated Ser621 in vitro, while its overexpression in intact cells resulted in increased phosphorylation of Ser621 and decreased activity of Raf-1. These results suggest that phosphorylation of Ser621 inactivates Raf-1, but do not prove that PKA is responsible for this in vivo. 0.343 SIGNOR-47148 RB1 protein P06400 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates activity binding 9606 8255752 YES amattioni E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery 0.92 SIGNOR-37305 MAPK8 protein P45983 UNIPROT CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser391 LRSAAPSsPGSPRPA 9606 BTO:0000567 21930785 YES miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  0.369 SIGNOR-276361 CFH protein P08603 UNIPROT C3 protein P01024 UNIPROT down-regulates activity binding 9606 19050261 YES miannu As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity) 0.918 SIGNOR-252141 ATF4 protein P18848 UNIPROT AARS1 protein P49588 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269414 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr973 RLGNGVLyASVNPEY -1 8940173 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.581 SIGNOR-247193 ARHGAP21 protein Q5T5U3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.627 SIGNOR-260475 YAP1 protein P46937 UNIPROT GINS1 protein Q14691 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276566 WARS1 protein P23381 UNIPROT tRNA(Trp) smallmolecule CHEBI:29181 ChEBI down-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 0.8 SIGNOR-270509 MSL acetyltransferase complex SIGNOR-C344 SIGNOR Histone H2B proteinfamily SIGNOR-PF68 SIGNOR down-regulates activity monoubiquitination 9606 BTO:0000567 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271978 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-268107 CS protein O75390 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 3013232 YES miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. 0.8 SIGNOR-266549 DOK1 protein Q99704 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.2 SIGNOR-257690 ADNP protein Q9H2P0 UNIPROT CTCF protein P49711 UNIPROT down-regulates activity relocalization 10090 BTO:0001086 SIGNOR-C407 31491387 YES miannu These results argue against the simultaneous binding of CTCF and ADNP to the same genomic loci. Instead, they support a model in which ADNP counteracts stable association of CTCF with DNA at over 15,000 binding sites in the mouse genome. 0.206 SIGNOR-266755 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 YES lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A 0.58 SIGNOR-84256 ACACA protein Q13085 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity chemical modification 9606 20952656 YES miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA 0.8 SIGNOR-267109 AKT1 protein P31749 UNIPROT CBY1 protein Q9Y3M2 UNIPROT up-regulates activity phosphorylation Ser20 TPPRKSAsLSNLHSL 9606 18573912 YES miannu These observations argue that Chibby is a bona fide Akt substrate and that Akt kinase phosphorylates Chibby at the serine 20 residue. 0.57 SIGNOR-279002 CSNK2A1 protein P68400 UNIPROT FOSB protein P53539 UNIPROT up-regulates phosphorylation Ser27 SAESQYLsSVDSFGS 9606 17241283 YES lperfetto Our findings indicate that ck2 activation increases deltafosb's transactivation potential, while ck2 inhibition decreases it. Further, we show that preventing ser27 phosphorylation by mutating the site to ala results in a significant decrease in deltafosb transactivation 0.2 SIGNOR-152403 COL4A2 protein P08572 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.488 SIGNOR-253243 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1068 HKNETMLsPREKIFY 9606 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104667 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 18498746 YES gcesareni Jnk is the physiogically relevant uv-stimulated kinase that phosphorylates bimel on thr-112/jnk-induced bim apoptotic activity 0.689 SIGNOR-178683 PTPRS protein Q13332 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 12018405 YES miannu Similarly, Pestana et al. (89) have reported that overexpression of RPTPsigma in human A431 carcinoma cells partially inhibits EGFR activation, whereas antisense mediated suppression of RPTPsigma expression enhances EGFR activation, substrate phosphorylation, and signalling.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types. 0.43 SIGNOR-277145 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr534 SRTPSLPtPPTREPK 9606 17078951 YES The effect has been demonstrated using P10636-8 lperfetto Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422 0.738 SIGNOR-150364 NF1 protein P21359 UNIPROT ADCY7 protein P51828 UNIPROT up-regulates 9606 BTO:0000938 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.287 SIGNOR-204246 IRAK1 protein P51617 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates activity phosphorylation 9606 15767370 YES miannu These data indicate that IRAK-1, but not IRAK-4, phosphorylates IRF7 in vitro. 0.791 SIGNOR-278235 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser240 RLSSLRAsTSKSESS -1 1985906 YES miannu The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide. 0.31 SIGNOR-250233 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248518 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268587 TRIM72 protein Q6ZMU5 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24344130 YES miannu Because RING disrupted MG53 mutants (C14A and DeltaR) did not induce FAK ubiquitination and degradation, the RING domain was determined to be required for MG53 induced FAK ubiquitination. 0.326 SIGNOR-278648 AMPK complex SIGNOR-C15 SIGNOR PRPS2 protein P11908 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 YES lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. 0.242 SIGNOR-265732 SIRT7 protein Q9NRC8 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKVA 22722849 YES lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 0.2 SIGNOR-275870 VPS33A protein Q96AX1 UNIPROT HOPS tethering complex complex SIGNOR-C549 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.915 SIGNOR-273691 CAMP protein P49913 UNIPROT FPR2 protein P25090 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11015447 YES gcesareni Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1. 0.534 SIGNOR-82701 olanzapine chemical CHEBI:7735 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258508 CSNK2A1 protein P68400 UNIPROT SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr61 ERRPESFtTPEGPKP 9606 phosphorylation:Thr62 RRPESFTtPEGPKPR 18490441 YES lperfetto Phosphorylation of Thr61 is necessary for subsequent phosphorylation of Thr60 by CK2 in vitro. Inhibitors of CK2 also prevent degradation of SLBP at the end of S phase. Thus, phosphorylation of Thr61 by cyclin A/Cdk1 primes phosphorylation of Thr60 by CK2 and is responsible for initiating SLBP degradation. 0.328 SIGNOR-265260 NR3C1 protein P04150 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 YES miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription 0.296 SIGNOR-268051 CEBPG protein P53567 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 15322262 YES lperfetto Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter. 0.2 SIGNOR-268986 CBL protein P22681 UNIPROT LRIG1 protein Q96JA1 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 15282549 YES gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. 0.588 SIGNOR-127289 STK39 protein Q9UEW8 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Ser96 IEDLSQNsITGEHSQ -1 24043619 YES miannu  We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function. 0.57 SIGNOR-276597 Difluprednate chemical CHEBI:31485 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation -1 21182429 YES Luana BMP had the highest K(i) value (8.4 × 10(-8) nmol/L), whereas DFB had the lowest (6.1 × 10(-11) nmol/L). The GCRBA of DFBA was intermediate to these 2 values (7.8 × 10(-10) nmol/L). 0.8 SIGNOR-257886 HDAC7 protein Q8WUI4 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates deacetylation 9606 16207715 YES miannu Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7. 0.256 SIGNOR-140950 GPR183 protein P32249 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.429 SIGNOR-256858 RAB7A protein P51149 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity binding 10116 16306406 YES Sara Endogenous TrkA and Rab7 form a complex. Inhibition of Rab7 potentiates the signaling of TrkA in response to brief stimulations with NGF 0.472 SIGNOR-261305 PRKCE protein Q02156 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates phosphorylation Ser16 NSCPLSLsWGKRHSV 9606 16757566 YES llicata Here we show that tram is transiently phosphorylated by pkcepsilon on serine-16 our study provides a possible target for these molecules in lps signaling. Dag may activate pkc?, Leading to the phosphorylation and activation of tram. 0.574 SIGNOR-146991 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates phosphorylation Thr201 PHHVHPLtPLITYSN 9606 12556497 YES llicata Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. 0.771 SIGNOR-97819 PPP1CA protein P62136 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 YES Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1. 0.2 SIGNOR-248555 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 12670876 YES inferred from 70% family members lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. 0.2 SIGNOR-270088 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 15758953 YES gcesareni Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm 0.855 SIGNOR-134508 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 10090 BTO:0002572 22863277 NO inferred from 70% of family members milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. 0.8 SIGNOR-269868 phenobarbital chemical CHEBI:8069 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0000318 9727070 YES miannu The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C). 0.8 SIGNOR-258830 ADRA1B protein P35368 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257190 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 21808241 YES Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs. gcesareni Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators 0.697 SIGNOR-175787 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000527;BTO:0000017 9890893 YES lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). 0.76 SIGNOR-236416 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-5 protein Q6NXT2 UNIPROT down-regulates activity binding 9606 BTO:0000007 21041484 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.2 SIGNOR-266972 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates activity phosphorylation Ser866 TAEVKEDsAYGSQSV 10090 BTO:0000785 15084608 YES lperfetto Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52. 0.791 SIGNOR-124226 PDGFB protein P01127 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity binding 9606 11331882 YES miannu Pdgf-b activates both pdgfr-alpha and pdgfr-beta 0.717 SIGNOR-107397 HNF4A protein P41235 UNIPROT ABCG5 protein Q9H222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000398 21123766 NO miannu these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α. 0.28 SIGNOR-254457 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 BTO:0000007 15688006 YES Two of these, S909 and T1079, were required for Lats1 activation. milica Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1. 0.619 SIGNOR-132927 PTPN6 protein P29350 UNIPROT SH3BP2 protein P78314 UNIPROT down-regulates activity dephosphorylation Tyr448 GDDSDEDyEKVPLPN 9606 16649996 YES miannu Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling|adaptor protein 3BP2 serves as a binding protein and a physiological substrate of SHP-1. 3BP2 is phosphorylated on tyrosyl residue 448 in response to TCR activation, and the phosphorylation is required for T c 0.569 SIGNOR-277172 MMP25 protein Q9NPA2 UNIPROT MMP2 protein P08253 UNIPROT up-regulates activity cleavage Asn66 GCPKESCnLFVLKDT -1 14583471 YES miannu Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr. 0.376 SIGNOR-256346 FYN protein P06241 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 YES lperfetto Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir. 0.38 SIGNOR-78702 H4C1 protein P62805 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR form complex binding -1 23324462 YES miannu In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro. 0.2 SIGNOR-263701 CSNK1D protein P48730 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser601 SDKESKEsSVEGAEN 9606 BTO:0000150 19339517 YES lperfetto In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1. 0.285 SIGNOR-184946 PKA proteinfamily SIGNOR-PF17 SIGNOR NLRP3 protein Q96P20 UNIPROT down-regulates activity phosphorylation Ser295 HKIVRKPsRILFLMD -1 27548431 YES miannu PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation. 0.2 SIGNOR-277274 PHACTR1 protein Q9C0D0 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates activity binding 9606 BTO:0001949 21939755 YES miannu Phactr-1 was previously identified as protein phosphatase 1 (PP1) α-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process. 0.537 SIGNOR-260062 GSK3A protein P49840 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1695 EAEAVLAtPPKQPIV 9606 BTO:0002181 25897075 YES miannu We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability.  0.387 SIGNOR-276899 CTDSPL2 protein Q05D32 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 20932329 NO Regulation of transcription miannu CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood. 0.2 SIGNOR-251778 KAT2B protein Q92831 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269613 ITGB4 protein P16144 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.77 SIGNOR-253200 BCOR protein Q6W2J9 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 YES miannu BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E. 0.549 SIGNOR-252238 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr654 DIHHIDYyKKTTNGR 10116 BTO:0002809;BTO:0001009 8622701 YES lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses. 0.2 SIGNOR-236199 CDON protein Q4KMG0 UNIPROT SPAG9 protein O60271 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 YES lperfetto In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway. 0.496 SIGNOR-150282 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 15659650 YES lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. 0.779 SIGNOR-217857 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser325 PGAPPPAsKPKLWSL -1 15133517 YES miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. 0.2 SIGNOR-263061 AKT3 protein Q9Y243 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 9812896 YES gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity 0.516 SIGNOR-61565 pictrelisib chemical CHEBI:65326 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 BTO:0000149 21876152 YES gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed 0.8 SIGNOR-176292 N-tert-butyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-phenylpropanamide chemical CHEBI:104131 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258896 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.68 SIGNOR-249361 PIM2 protein Q9P1W9 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser467 LQLYQVDsRTYLLDF 9606 BTO:0001555 31358902 YES miannu Specifically, we found that PIM2 bound to AMPKα1, and directly phosphorylated it on Thr467. Phosphorylation of AMPKα1 by PIM2 led to decreasing AMPKα1 kinase activity, which in turn promoted aerobic glycolysis and tumor growth. 0.2 SIGNOR-277471 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT up-regulates activity phosphorylation Tyr486 SRRIAVEySDSDDDS 9606 17623672 YES WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. 0.58 SIGNOR-259077 miR-495 mirna URS000075C517_9606 RNAcentral Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 19219026 YES Luana Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.  0.4 SIGNOR-268044 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 9606 22182578 YES Luana  Salbutamol is a well-known β2 adrenoceptor (β2AR) partial agonist. | In order to gain insight, we carried out binding and functional assays for BCSDs in HEK-293T cells transfected with the human β2AR (hβ2AR). The transfected hβ2AR showed similar affinity for BCSDs and salbutamol 0.8 SIGNOR-258326 ITGB4 protein P16144 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9428518 YES gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. 0.415 SIGNOR-54530 EEF1A1 protein P68104 UNIPROT Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269502 MRAP2 protein Q96G30 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. 0.505 SIGNOR-252363 STAT5A protein P42229 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 15840840 YES lperfetto PRL enhanced the binding of Stat5a to the OATP1B3 promoter and DNA-protein binding was inhibited in competition assays by excess OATP1B3 and Stat5 consensus oligomers but not by mutant Stat5 oligomers.|PRL and GH induction of Oatp1b2 and OATP1B3 promoter activity required cotransfection of Stat5a and PRLRL or GHR. 0.2 SIGNOR-268990 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1249 HGHVSDAsISLGEPV -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262906 EIF2B2 protein P49770 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.695 SIGNOR-269135 PRKACA protein P17612 UNIPROT PHOX2A protein O14813 UNIPROT down-regulates phosphorylation Ser153 RKQERAAsAKGAAGA 9606 19564421 YES llicata Phox2a becomes phosphorylated by protein kinase a (pka) on ser153, which prevents association of phox2a with dna and terminates p27(kip1) transcription. 0.307 SIGNOR-186462 CACNA1C protein Q13936 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 NO miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). 0.7 SIGNOR-264330 GGCX protein P38435 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 31539109 NO miannu GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05). 0.2 SIGNOR-261231 NANOG protein Q9H9S0 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.442 SIGNOR-253162 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr291 DDQRSMGyDDLDYGM -1 11382764 YES lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 0.922 SIGNOR-246496 LIN7C protein Q9NUP9 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR form complex binding 9606 24366813 YES lperfetto To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a), 0.65 SIGNOR-203491 MAP3K9 protein P80192 UNIPROT MAP3K9 protein P80192 UNIPROT up-regulates activity phosphorylation Thr312 TKMSAAGtYAWMAPE 10029 15610029 YES lperfetto We present here biochemical and biophysical evidence that MLK1 is activated by autophosphorylation in (or near) the activation loop. The activation loops of the MLK family are highly homologous, and so one might predict that the same residues would be key to their activation. Functional data presented here, however, demonstrate that the key residue for activation of MLK1, Thr312, differs from the key residue for activation of MLK3. 0.2 SIGNOR-249388 RAC1 protein P63000 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 YES gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. 0.789 SIGNOR-248236 PKA proteinfamily SIGNOR-PF17 SIGNOR MYOM1 protein P52179 UNIPROT down-regulates activity phosphorylation Ser618 ARLKSRPsAPWTGQI -1 9029142 YES miannu This interaction is regulated by phosphorylation of Ser482 in the linker between myomesin domains My4 and My5. Myomesin phosphorylation at this site by cAMP-dependent kinase and similar or identical activities in muscle extracts block the association with titin. 0.2 SIGNOR-263156 ATF6 protein P18850 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 14973138 YES Luana  Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β.  0.82 SIGNOR-261565 CCT3 protein P49368 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.754 SIGNOR-272864 CLASP2 protein O75122 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity binding 9534 BTO:0004055 19638411 YES lperfetto IQGAP1 is a novel CLASP2-interacting protein| nonphosphorylated CLASP2 on microtubules is allowed to associate with IQGAP1 for the coupling of microtubules to actin filaments at the front of migrating cells. 0.416 SIGNOR-264828 CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000876 BTO:0001103 19436055 NO apalma As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of beta-c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways 0.2 SIGNOR-255586 GARS1 protein P41250 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 24898252 YES miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 0.8 SIGNOR-270480 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Thr698 KSIQATLtPSAMKSS 9606 SIGNOR-C17 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. 0.483 SIGNOR-164499 IL1B protein P01584 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 9606 BTO:0002417 32454942 NO miannu IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS 0.587 SIGNOR-263820 SGK3 protein Q96BR1 UNIPROT PTOV1 protein Q86YD1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 VRAVRSRsWPASPRG 9606 34654719 YES miannu In this study, we find that the understudied serum and glucocorticoid-induced kinase-2 (SGK2) phosphorylates PTOV1 at S36. 0.2 SIGNOR-279283 SLK protein Q9H2G2 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation 9606 19640899 YES miannu The Ste20 like kinase SLK promotes p53 transactivation and apoptosis.|Thus SLK induces p53 phosphorylation and transactivation, which enhances apoptosis after in vitro ischemia-reperfusion injury. 0.256 SIGNOR-279285 PRKCE protein Q02156 UNIPROT NSF protein P46459 UNIPROT up-regulates activity phosphorylation Thr461 NRHIKAStKVEVDME 9606 20962217 YES miannu PKCepsilon phosphorylation enhances the ATPase activity of NSF.|These results indicate that PKC\u03b5 phosphorylates NSF at both S460 and T461 in vitro . 0.234 SIGNOR-278299 TG101209 chemical CHEBI:90304 ChEBI RET protein P07949 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207269 RPS6KA3 protein P51812 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Ser46 TASTGNLsSSFMEEI 9606 29563609 YES miannu These results demonstrate that TRAF6 K63 ubiquitination might be regulated by an RSK2 mediated phosphorylation dependent mechanism and phosphorylation of TRAF6 at Ser46, 47 and 48 enhances its ubiquitin mediated inflammation signaling. 0.273 SIGNOR-278302 MSX1 protein P28360 UNIPROT DLX2 protein Q07687 UNIPROT down-regulates activity binding 10090 BTO:0000944 9111364 YES 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. 0.4 SIGNOR-240929 FGF12 protein P61328 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.309 SIGNOR-253428 RPLP0 protein P05388 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.828 SIGNOR-262451 ARHGAP10 protein A1A4S6 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.667 SIGNOR-260465 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 YES Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. 0.823 SIGNOR-252563 PRKCB protein P05771 UNIPROT ITGB7 protein P26010 UNIPROT unknown phosphorylation Thr783 PLYKSAItTTINPRF 10090 BTO:0001825 12682249 YES lperfetto Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784). 0.434 SIGNOR-249200 ETS1 protein P14921 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates activity binding 9606 BTO:0002181 17213822 YES miannu Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1-mediated transcriptional activation and ETS1 repressed GFI1-mediated transcriptional activation, in a dose-dependent manner. 0.427 SIGNOR-254202 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser729 ASPQSPEsVDLVNEE 9606 18701649 YES gcesareni Such results suggest that during apoptosis, oxidative stress could activate p38 mapk, phosphorylating nhe1 at s726 and s729. 0.57 SIGNOR-180048 Noncanonical PRC1 complex SIGNOR-C151 SIGNOR PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 NO miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. 0.337 SIGNOR-252251 SYT1 protein P21579 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 16679567 YES miannu Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion 0.95 SIGNOR-263975 regorafenib chemical CHEBI:68647 ChEBI TEK protein Q02763 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259213 WDR5 protein P61964 UNIPROT Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR form complex binding 9606 BTO:0000567 12670868 YES miannu Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles. 0.918 SIGNOR-264480 PRKAA1 protein Q13131 UNIPROT PRPS2 protein P11908 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 YES lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. 0.2 SIGNOR-265731 BTRC protein Q9Y297 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates ubiquitination 9606 BTO:0000785 24469040 YES lperfetto _-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs _-trcp-mediated ezh2 degradation. 0.377 SIGNOR-204481 MAPK3 protein P27361 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 YES lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. 0.328 SIGNOR-264441 ULK1 protein O75385 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser472 THRRMVVsMPNLQDI 9606 25925668 YES lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. 0.433 SIGNOR-264730 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269369 pyruvate smallmolecule CHEBI:15361 ChEBI acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity precursor of 9606 29059435 YES miannu The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. 0.8 SIGNOR-266542 FBP1 protein P09467 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates activity binding 9606 30616754 YES lperfetto FBP1, but not FBP2, suppresses HIF-1a activity by directly binding to its inhibitory domain. 0.327 SIGNOR-267590 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 0.607 SIGNOR-161605 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-70428 NLGN2 protein Q8NFZ4 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.824 SIGNOR-264151 PRKCD protein Q05655 UNIPROT G6PD protein P11413 UNIPROT up-regulates phosphorylation Thr236 NIACVILtFKEPFGT 9606 BTO:0001260 20649491 YES lperfetto A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity. 0.2 SIGNOR-167053 PLK1 protein P53350 UNIPROT MAD2L1BP protein Q15013 UNIPROT down-regulates activity phosphorylation Ser102 KHFYRKPsPQAEEML 9606 BTO:0000567 31118282 YES miannu Purified Plk1 bound to p31comet and phosphorylated it, resulting in the suppression of its activity (with TRIP13) to disassemble checkpoint complexes. We conclude that Plk1 phosphorylates p31 on S102 and on five additional sites. The phosphorylation of the additional sites was possibly not detectable in HeLa cell extracts due to the opposing action of protein phosphatases. 0.408 SIGNOR-265970 POLR2J3 protein Q9H1A7 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.691 SIGNOR-266173 FER protein P16591 UNIPROT FER protein P16591 UNIPROT up-regulates activity phosphorylation Tyr714 RQEDGGVySSSGLKQ -1 19159681 YES miannu  Mutation analysis unveiled a tyrosine (Tyr(616)) embedded in the Hsp90 recognition loop, which is required for the kinase activity of Fer. Replacement of this tyrosine by phenylalanine (Y616F) disabled the auto-phosphorylation activity of Fer and abolished its ability to phosphorylate Stat3.  0.2 SIGNOR-276236 E2F1 protein Q01094 UNIPROT DLK1 protein P80370 UNIPROT up-regulates quantity by expression transcriptional regulation 19874716 YES lperfetto Using luciferase reporter assay, ChIP assay and EMSA, we found that the -211/-194 region of the pref-1 promoter is essential for the binding of E2F1 as well as E2F1-dependent transcriptional activation. 0.2 SIGNOR-271684 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser415 HKLDVSRsPPLMVKK 9606 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS‚‚PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573‚‚577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249307 PKC proteinfamily SIGNOR-PF53 SIGNOR SCN2A protein Q99250 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 32599005 YES lperfetto For example, protein kinase A (PKA) and protein kinase C (PKC) have been shown to phosphorylate multiple serine residues on the interdomain I-II and III-IV linkers of Nav1.2, significantly reducing current and increasing firing thresholds 0.2 SIGNOR-275750 MACROD2 protein A1Z1Q3 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI up-regulates quantity chemical modification 9606 32257385 YES miannu MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins 0.8 SIGNOR-269842 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 9047237 YES lperfetto Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient. 0.804 SIGNOR-46859 AMPK complex SIGNOR-C15 SIGNOR ACACA protein Q13085 UNIPROT down-regulates phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000887;BTO:0001103 12015362 YES lperfetto Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed. 0.558 SIGNOR-216655 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 25728771 YES inferred from 70% family members lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation 0.2 SIGNOR-270092 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-267933 tRNA(Ser) smallmolecule CHEBI:29179 ChEBI Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates quantity precursor of 9606 24095058 YES miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis 0.8 SIGNOR-270499 hsa-miR-101-5p mirna URS000017D10B_9606 RNAcentral SPHK1 protein Q9NYA1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000182 26071354 YES Parnian Together, these results indicate that miR-101 exerts its anti-CRC activities probably through down-regulating SphK1. 0.4 SIGNOR-278859 ULK1 protein O75385 UNIPROT ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Ser761 QSIPRSAsYPCAAPR 9606 25266655 YES miannu Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. 0.583 SIGNOR-266366 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI TET2 protein Q6N021 UNIPROT up-regulates activity binding 9606 25699704 YES irozzo A second group of AML patients (15%–33% of all cases) harbor mutations in either the isocitrate dehydrogenase (IDH) 1 or 2 gene (Shih et al., 2012). These enzymes produce α-ketoglutarate (α-KG), which is required for TET activity. 0.8 SIGNOR-255706 TRAF6 protein Q9Y4K3 UNIPROT ECSIT protein Q9BQ95 UNIPROT down-regulates activity ubiquitination 10090 21525932 YES Giorgia Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation 0.79 SIGNOR-260370 ALDH9A1 protein P49189 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 11802770 YES miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 0.8 SIGNOR-269694 SMO protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT up-regulates activity binding 10090 BTO:0002572 16885213 YES lperfetto Using this assay we determined that mouse Smo couples to all members of the Gi family but does not couple to those of other G protein families. 0.427 SIGNOR-148490 PPM1E protein Q8WY54 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 11864573 YES The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. 0.303 SIGNOR-248760 CHEK1 protein O14757 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation Ser273 SMLNKNPsLRPSAIE 9606 19734889 YES lperfetto We demonstrate that chk1 (checkpoint kinase 1) directly activates nek11 by phosphorylating it on ser 273 0.264 SIGNOR-187863 IL17R complex complex SIGNOR-C260 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 10090 BTO:0000944 8777726 NO lperfetto 3T3 cells were preincubated with an IL-17Rspecific antiserum and then assayed for NF-KB activation by HVS13. Preincubation with the IL-1 7R antiserum dramatically decreased the NF-KB activity induced by HVSl3 as compared with cells preincubated with an irrelevant rat antiserum (Figure 5C). This result indicated that the engagement of the IL-17R by its ligands induced NF-KB activity. 0.2 SIGNOR-261338 GP9 protein P14770 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 16293600 YES lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbalpha, disulfide-linked to GPIbbeta, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. 0.694 SIGNOR-261848 AKT1 protein P31749 UNIPROT USP14 protein P54578 UNIPROT up-regulates activity phosphorylation Ser432 THQGRSSsSGHYVSW 9606 26523394 YES lperfetto Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt. 0.424 SIGNOR-265056 PPARG protein P37231 UNIPROT CEBPA protein P49715 UNIPROT up-regulates activity transcriptional regulation 10090 BTO:0002572;BTO:0000011;BTO:0005065 16431920 NO Dislodging hdac1 from the promoter lperfetto These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome 0.653 SIGNOR-235358 CSNK2A1 protein P68400 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser172 GDVDVSDsDDEDDNL 9606 18559419 YES llicata Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation. 0.206 SIGNOR-178943 CDK2 protein P24941 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity phosphorylation Ser163 KSQKLLRsPRKPTRK 12560341 YES llicata  A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.  0.744 SIGNOR-250733 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity dephosphorylation Thr577 AENGLLMtPCYTANF 10090 15206906 YES RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity 0.361 SIGNOR-248323 TTK protein P33981 UNIPROT BUB1 protein O43683 UNIPROT up-regulates activity phosphorylation Thr461 SKVQPSPtVHTKEAL 9606 28072388 YES miannu After Cdk1 phosphorylates Bub1 S459, Mps1 then phosphorylates Bub1 T461 (b). 0.696 SIGNOR-278255 CDK1 protein P06493 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 SIGNOR-C17 16287866 YES gcesareni Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. 0.429 SIGNOR-141621 AMOTL2 protein Q9Y2J4 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 34404733 YES lperfetto Ubiquitinated AMOTL2 then serves as a physical docking site for LATS2, which phosphorylates YAP to promote its cytoplasmic retention and degradation. 0.727 SIGNOR-271875 GABA-A proteinfamily SIGNOR-PF61 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES miannu GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-264988 AKT1 protein P31749 UNIPROT LARP1 protein Q6PKG0 UNIPROT down-regulates activity phosphorylation Ser847 EHRPRTAsISSSPSE 9606 BTO:0002181 28650797 YES SARA LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. 0.288 SIGNOR-260991 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser376 PPAPAYLsSPLALPS 9606 SIGNOR-C14 SIGNOR-C14 12657630 YES IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKK≈í‚⧠mediates IKK≈í‚â• phosphorylation under physiologic signaling conditions. IKK≈í‚â• is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the I≈í‚à´B kinase complex.both Tax and TNF induce phosphorylation of human IKK≈í‚â• at Ser-31, Ser-43, and Ser-376. 0.962 SIGNOR-251286 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2366 MEQGHFAsPDQNSML 9606 17623675 YES lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. 0.466 SIGNOR-156895 ROCK1 protein Q13464 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser72 SSAVRLRsSVPGVRL 9534 BTO:0000298 9565595 YES lperfetto We found that vimentin, the most widely expressed intermediate filament protein, served as an excellent substrate for Rho-associated kinase (Rho-kinase) and that vimentin phosphorylated by Rho-kinase lost its ability to form filaments in vitro. Two amino-terminal sites on vimentin, Ser38 and Ser71, were identified as the major phosphorylation sites for Rho-kinase, and Ser71 was the most favored and unique phosphorylation site for Rho-kinase in vitro.  0.368 SIGNOR-248998 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1303753 YES gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. 0.577 SIGNOR-16243 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 YES gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required 0.594 SIGNOR-38032 HIF1A protein Q16665 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27141364 NO irozzo STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia. Taken together, these findings suggest that EML4-ALK might increase HIF-1α expression under hypoxia by enhancing transcription and inhibiting ubiquitination of HIF-1α, resulting in the stabilization of HIF-1α, consequently contributing to HIF-1α-mediated upregulation of PD-L1 under hypoxia. 0.281 SIGNOR-259092 PABPC1 protein P11940 UNIPROT NFX1 protein Q12986 UNIPROT up-regulates activity binding 9606 BTO:0000009 17267499 YES Simone We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123. 0.344 SIGNOR-261052 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT up-regulates activity phosphorylation Tyr151 KKDGLKFyTDPSYFF 9606 BTO:0000815 17623672 YES WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. 0.58 SIGNOR-262299 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268784 ANK1 protein P16157 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.365 SIGNOR-266013 SYK protein P43405 UNIPROT LRRFIP1 protein Q32MZ4 UNIPROT up-regulates activity phosphorylation 9606 19151749 YES miannu However, this inhibitory activity TRIP can be reversed by the co-expression of Syk, which might inhibit the activity of cytoplasmic TRIP, sequester TRIP from important nucleolar targets or even counter TRIP 's inhibitory effects on TRAF and TNF signaling by regulating the activity of alternative components of the pathway.|Syk induces phosphorylation of TRIP on tyrosine. 0.2 SIGNOR-279297 NANOGP8 protein Q6NSW7 UNIPROT FGFR2 protein P21802 UNIPROT down-regulates quantity by repression transcriptional regulation 10900 BTO:0000667 23839044 NO Luana Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. 0.2 SIGNOR-266090 DRD1 protein P21728 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.57 SIGNOR-256939 PRKACA protein P17612 UNIPROT KCNJ13 protein O60928 UNIPROT up-regulates phosphorylation Ser287 EICQRRTsYLPSEIM 9606 18976636 YES gcesareni Pka activation induced an increase of kir7.1 currents. This effect was absent in mutant kir7.1 channels lacking pka consensus site (287)s 0.2 SIGNOR-181859 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Ser297 GLRYNRLsAIPRSLA 29383184 YES lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. 0.2 SIGNOR-275567 SYK protein P43405 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 26848618 YES miannu The current study indicates that the plasma cell malignancy is also associated with Syk-activated STAT3 directly downstream of reelin-induced integrin \u03b21 engagement and FAK/Src activation (Figure xref ).|The integrin-activated spleen tyrosine kinase (Syk) was shown to promote STAT3 phosphorylation [42, 44]. 0.553 SIGNOR-279298 TBK1 protein Q9UHD2 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates activity phosphorylation 9606 35172162 YES miannu TBK1 also promotes METTL3 activation and m 6 A modification to stabilize IRF3 mRNA .|We here find TBK1, a key kinase of antiviral pathways, phosphorylates the core m 6 A methyltransferase METTL3 at serine 67. 0.2 SIGNOR-279299 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination 9606 16603398 YES amattioni In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein. 0.767 SIGNOR-145036 ACTB protein P60709 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 BTO:0000007 19121306 NO lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. 0.7 SIGNOR-260608 NR3C1 protein P04150 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 10116 18762022 YES The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene 0.446 SIGNOR-253057 tibolone chemical CHEBI:32223 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 19464167 YES Luana In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1). 0.8 SIGNOR-257823 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 11369754 YES gcesareni These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. 0.454 SIGNOR-108260 MYC protein P01106 UNIPROT BRD4 protein O60885 UNIPROT down-regulates activity 9606 32482868 YES lperfetto Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus. 0.563 SIGNOR-262047 HTR7 protein P34969 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.443 SIGNOR-256926 USP39 protein Q53GS9 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.712 SIGNOR-270640 G6PC2 protein Q9NQR9 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266583 GTP smallmolecule CHEBI:15996 ChEBI GNAS protein P63092 UNIPROT up-regulates chemical activation 9606 17095603 YES gcesareni Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis. 0.8 SIGNOR-253071 ENO3 protein P13929 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI down-regulates quantity chemical modification 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266530 TNKS protein O95271 UNIPROT RNF146 protein Q9NTX7 UNIPROT up-regulates activity 9606 BTO:0000007 21478859 NO lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.722 SIGNOR-263338 TRIM13 protein O60858 UNIPROT CD3D protein P04234 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17314412 YES miannu RFP2, a gene frequently lost in various malignancies, encodes a protein with RING finger, B-box, and coiled-coil domains that belongs to the RBCC/TRIM family of proteins.Rfp2 Regulates the Stability of the ERAD Substrate CD3-δ. In summary, these experiments demonstrate that Rfp2 functions as a RING-dependent ERAD E3 ubiquitin ligase and regulates the degradation of the ER substrate, CD3-δ. 0.2 SIGNOR-271644 CBX1 protein P83916 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR form complex binding 10090 BTO:0002896 29795351 YES miannu Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP. 0.359 SIGNOR-266754 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 10116 11018017 YES Phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc. 0.719 SIGNOR-252080 CSNK1A1 protein P48729 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 21179498 YES miannu CKI\u03b1-Dependent Phosphorylation and Degradation of PER1. 0.318 SIGNOR-279700 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 17015476 YES Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. 0.266 SIGNOR-248578 NCOA2 protein Q15596 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity binding 10090 BTO:0000801 29170386 YES Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator. 0.839 SIGNOR-256095 sirolimus chemical CHEBI:9168 ChEBI CD40 protein P25942 UNIPROT down-regulates quantity by repression 9606 18652845 NO miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. 0.8 SIGNOR-255474 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 8162590 YES gcesareni The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. 0.8 SIGNOR-36557 BLK protein P51451 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.647 SIGNOR-268211 RPS6KA2 protein Q15349 UNIPROT L1CAM protein P32004 UNIPROT up-regulates activity phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 YES lperfetto Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152. 0.514 SIGNOR-248949 SYN1 protein P17600 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 YES miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 0.299 SIGNOR-269184 SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 21628332 NO lperfetto SOCS3 attenuates IL-6-induced STAT3 anti-inflammatory effects, as well as IL-4-induced insulin receptor substrate-2/PI3K-mediated gene expression. 0.708 SIGNOR-249567 NKX3-1 protein Q99801 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 16697957 YES miannu NKX3.1 negatively regulates AKT activity in an AR-dependent manner 0.517 SIGNOR-251552 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR IFIH1 protein Q9BYX4 UNIPROT up-regulates 9606 19052324 YES miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. 0.7 SIGNOR-260142 LAMB1 protein P07942 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR form complex binding 10809728 YES lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 0.616 SIGNOR-253227 mepyramine chemical CHEBI:6762 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 YES miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. 0.8 SIGNOR-258748 IKZF2 protein Q9UKS7 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 NO miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 0.2 SIGNOR-255404 MAPK7 protein Q13164 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 33981002 YES miannu Remarkably, the reduction in ERK5 expression correlated with decreased p-FAK(Tyr397) staining, consistent with the requirement of ERK5 for mediating FAK activation in vivo (Fig. 6C).|We confirmed that JWG-045, a novel pharmacological inhibitor of ERK5 exhibiting significantly reduced affinity for BRD4 compared with XMD8-92 (25, 26), did not suppress FAK phosphorylation at Tyr397 in MDA-MB-231 cells (Supplementary Fig. S3B and C). 0.291 SIGNOR-279304 bethanechol chemical CHEBI:3084 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258622 lisuride chemical CHEBI:51164 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258886 LYN protein P07948 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity phosphorylation Tyr448 TILTEVNyEVSNKDD 18086677 YES lperfetto The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. 0.311 SIGNOR-272980 MLLT1 protein Q03111 UNIPROT AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 BTO:0000664 20153263 YES 1 miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. 0.674 SIGNOR-239228 RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR Meiotic_recombination phenotype SIGNOR-PH162 SIGNOR up-regulates 10090 BTO:0000534 21242291 NO miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. 0.7 SIGNOR-264539 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser422 RFHSLPFsLTKMPNT 9606 BTO:0000938 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.547 SIGNOR-204720 PPME1 protein Q9Y570 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates activity demethylation Leu309 RRTPDYFl -1 18394995 YES lperfetto Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. 0.905 SIGNOR-265748 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000149 1706616 YES gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. 0.2 SIGNOR-21203 AKT proteinfamily SIGNOR-PF24 SIGNOR EZH2 protein Q15910 UNIPROT down-regulates activity phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 YES lperfetto Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3 0.2 SIGNOR-244259 KLHL9 protein Q9P2J3 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates activity binding 9606 BTO:0000567 17543862 YES miannu Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis. 0.709 SIGNOR-271658 Ub:E2 complex SIGNOR-C497 SIGNOR PHF7 protein Q9BWX1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271017 KIT protein P10721 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9534 7509796 YES Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells 0.726 SIGNOR-255948 TP53 protein P04637 UNIPROT SLC2A4 protein P14672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 YES miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. 0.336 SIGNOR-267465 PRKRA protein O75569 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR form complex binding 9606 23661684 YES lperfetto Immunoprecipitation and reconstitution experiments in various systems have shown that Dicer associates with proteins in the Argonaute (Ago) family of endonucleases and with specific double-stranded RNA-binding proteins (dsRBPs) (3–7). | In humans, these dsRBPs are protein activator of PKR (PACT) (5) and trans-activation response RNA-binding protein (TRBP) (3,4). 0.768 SIGNOR-255318 GABRA3 protein P34903 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.604 SIGNOR-263756 Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 32699605 YES miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) 0.7 SIGNOR-270936 BLK protein P51451 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.647 SIGNOR-268217 MAPK12/CARM1 complex SIGNOR-C218 SIGNOR SNTB1 protein Q13884 UNIPROT up-regulates activity binding 29681515 YES apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated 0.369 SIGNOR-255978 FANCM protein Q8IYD8 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.936 SIGNOR-263248 DDR1 protein Q08345 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity relocalization 9615 BTO:0000837 16611743 YES lperfetto Overexpression of DDR1a/b increased the interaction of DDR1 with SHP-2 and up-regulated the tyrosine phosphatase activity of SHP-2. 0.374 SIGNOR-272403 ENO2 protein P09104 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI down-regulates quantity chemical modification 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266529 PAK proteinfamily SIGNOR-PF13 SIGNOR NF2 protein P35240 UNIPROT down-regulates phosphorylation 9606 18071304 YES inferred from 70% family members lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, 0.2 SIGNOR-269976 LYPLA2 protein O95372 UNIPROT GAP43 protein P17677 UNIPROT down-regulates quantity by destabilization deacetylation Cys4 cMRRTKQV 9606 BTO:0000567 21152083 YES miannu Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43. 0.476 SIGNOR-266768 PP2B proteinfamily SIGNOR-PF18 SIGNOR JUN protein P05412 UNIPROT up-regulates dephosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000938;BTO:0000017 17215518 YES lperfetto Importantly, pp2b not only dephosphorylates the c-jun at ser-243 but also interacts with c-jun in pma-treated cells. Pma stimulates the association of the pp2b/c-jun/sp1 complex with the promoter. These findings indicate the dephosphorylation of c-jun c terminus is required for the c-jun/sp1 interaction 0.2 SIGNOR-152006 PRKCB protein P05771 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 YES lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. 0.388 SIGNOR-249049 capecitabine chemical CHEBI:31348 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 15866500 YES miannu These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). 0.8 SIGNOR-259354 CSK protein P41240 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Tyr1218 MVSTFEQyQFLYDVI 9606 BTO:0000782 7507203 YES llicata Tyrosine phosphorylation of cd45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase. 0.47 SIGNOR-26785 EEF1A1 protein P68104 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269503 RORA protein P35398 UNIPROT SHH protein Q15465 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 YES miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 0.252 SIGNOR-266846 MKRN2 protein Q9H000 UNIPROT RELA protein Q04206 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28378844 YES miannu MKRN2 promotes p65 ubiquitination and degradation through RING finger domain. 0.342 SIGNOR-278591 HDAC1 protein Q13547 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 17183360 YES lperfetto Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1. 0.543 SIGNOR-217409 CDK1 protein P06493 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Thr85 TRSQQQPtPVTPKKY 9606 18250300 YES lperfetto Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate. 0.355 SIGNOR-160743 MAFA protein Q8NHW3 UNIPROT PC protein P11498 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 NO miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. 0.25 SIGNOR-254561 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser41 SLSESEEsQDSSDSI 9606 20730097 YES lperfetto Although the functional impact of ck-mediated atf1 phosphorylation is still unclear, we found that mutation of ser-36 and ser-41 increased cbp kix domain binding by up to four fold (fig. 2g). This result is consistent with the negative impact of ck-mediated phosphorylation on cbp binding affinity of creb that we previously reported 0.297 SIGNOR-167552 PRKCB protein P05771 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC -1 27784766 YES miannu Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. 0.2 SIGNOR-276460 SMARCB1 protein Q12824 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.819 SIGNOR-270607 AKT1 protein P31749 UNIPROT PIKFYVE protein Q9Y2I7 UNIPROT up-regulates phosphorylation Ser307 PARNRSAsITNLSLD 9606 BTO:0000887 15546921 YES gcesareni Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme. 0.491 SIGNOR-252474 AKT2 protein P31751 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 38402584 NO miannu Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells.  0.307 SIGNOR-277223 AKT proteinfamily SIGNOR-PF24 SIGNOR ALYREF protein Q86V81 UNIPROT up-regulates phosphorylation Thr219 GGGTRRGtRGGARGR 9606 18562279 YES llicata Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export. 0.2 SIGNOR-179054 CSNK2A1 protein P68400 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Thr142 DSVTKLLtDVQLMKG -1 12659875 YES llicata Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2. 0.371 SIGNOR-250898 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763 12193595 YES miannu Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction. 0.721 SIGNOR-91718 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 9204908 YES miannu MTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. 0.926 SIGNOR-250292 SLBP protein Q14493 UNIPROT H2BU1 protein Q8N257 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265388 VX-745 chemical CHEBI:90528 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258310 TRIP11 protein Q15643 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 9256431 YES miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. 0.315 SIGNOR-50421 PTPN11 protein Q06124 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 18482983 YES we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin 0.652 SIGNOR-248670 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser77 YEPEGSAsPTPPYLK 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.2 SIGNOR-248568 SRSF11 protein Q05519 UNIPROT LRP8 protein Q14114 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 10090 31269452 YES miannu We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. 0.2 SIGNOR-269670 CSNK1D protein P48730 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates phosphorylation Ser385 AGNRTANsEDSDEQD 9606 17911614 YES gcesareni In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover. 0.2 SIGNOR-158121 perifosine chemical CHEBI:67272 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 BTO:0001130 14617782 YES Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation gcesareni Perifosine is an alkylphospholipid that targets the pleckstrin homology domain of akt and blocks its membrane translocation, hence preventing akt phosphorylation and activation 0.8 SIGNOR-252629 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 YES llicata Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291. 0.2 SIGNOR-176879 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 29955047 YES lperfetto Collectively, our findings indicate that TC-PTP negatively regulates Flk-1 and JNK signaling via direct dephosphorylation of Flk-1 on its Y1173 residue, which contributes to increased epidermal apoptosis in response to UVB exposure.|Use of a TC-PTP substrate trapping mutant for immunoprecipitation analysis showed that TC-PTP dephosphorylates four different tyrosine residues of Flk-1 -- Y1052, Y1057, Y1212, and Y994 -- in human umbilical vein endothelial cells; however, it did not dephosphorylate the Y1173 residue of Flk-1 38. 0.565 SIGNOR-276962 TP53 protein P04637 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR down-regulates 9606 27692180 NO miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. 0.7 SIGNOR-267467 LRP6 protein O75581 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23209147 YES Gianni The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization. 0.706 SIGNOR-262526 SGK1 protein O00141 UNIPROT NCSTN protein Q92542 UNIPROT down-regulates quantity by destabilization phosphorylation Ser437 FLRARNIsGVVLADH 9606 BTO:0000007 22590650 YES miannu SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation. 0.338 SIGNOR-276415 NR2F2 protein P24468 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14739255 NO gcesareni Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors. 0.352 SIGNOR-121419 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI AR protein P10275 UNIPROT up-regulates chemical activation 9606 15861399 YES miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. 0.8 SIGNOR-251533 NDUFV1 protein P49821 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.863 SIGNOR-262183 FOXP3 protein Q9BZS1 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 24315995 NO alessandro FoxP3, a lineage-specification factor, executes its multiple activities mostly through transcriptional regulation of target genes. We identified an interleukin-10 (IL-10)-producing FoxP3(+) T regulatory cell population that contributes to IL-10-dependent type 2 cytokine bias in breast-cancer patients. Although genetic ablation of FOXP3 inhibited IL10 transcription, genome-wide analysis ruled out its role as a transcription factor for IL10 0.492 SIGNOR-254525 ponatinib chemical CHEBI:78543 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001669 23539538 YES miannu Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells 0.8 SIGNOR-259272 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser325 LTSVSRGsSLKILSK 9606 10521508 YES Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. 0.2 SIGNOR-260899 CDK2 protein P24941 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity phosphorylation Thr416 EANSRCQtPIKMKPN 9606 BTO:0000007 23241245 YES Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1. 0.548 SIGNOR-255656 PTPRB protein P23467 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members gcesareni When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well 0.433 SIGNOR-269931 IL11 protein P20809 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity binding 9606 28232471 YES miannu Because GP130 is known to interact with other ligand-receptor pairs, we measured the expression of additional GP130 signaling partners in both organoids and PSCs in trans-well cultures. Of the GP130 ligands found to be expressed in PSCs, Il6, Il11, and leukemia inhibitory factor (Lif) were the most highly up-regulated in trans-well cultures when compared with PSC monocultures (Fig. 3 C). Both IL-11 and LIF are reported to have roles in cancer progression 0.714 SIGNOR-277689 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser143 PPFPSRDsGRLSPDL 9606 BTO:0000567 21658950 YES miannu Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. 0.2 SIGNOR-263138 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9606 10212258 YES Manara Tyrosine Phosphorylation of Rad51 by ABL1 Enhances the Interaction between Rad51 and Rad52 | our studies of Rad51·Rad52 complex formation in vitro and in vivo suggest that the ATM and ABL1-mediated signaling is likely to promote repair given the biochemical evidence that Rad51 acts in concert with Rad52 in homologous recombination 0.772 SIGNOR-260777 AKT1 protein P31749 UNIPROT CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Thr310 GVGSVEQtPRKRLR 9606 BTO:0000150 23421998 YES lperfetto Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination 0.448 SIGNOR-252536 CYP2R1 protein Q6VVX0 UNIPROT calcidiol smallmolecule CHEBI:17933 ChEBI up-regulates quantity chemical modification 9606 BTO:0000759 30080183 YES lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. 0.8 SIGNOR-270568 DCK protein P27707 UNIPROT 2'-deoxyguanosine 5'-monophosphate(2-) smallmolecule CHEBI:57673 ChEBI up-regulates quantity chemical modification 20637175 YES lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis 0.8 SIGNOR-275809 PRKCE protein Q02156 UNIPROT GABRG2 protein P18507 UNIPROT down-regulates activity phosphorylation Ser366 FVSNRKPsKDKDKKK -1 17875639 YES miannu Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol. 0.233 SIGNOR-263174 LNPK protein Q9C0E8 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 BTO:0000007 32433973 YES miannu We demonstrate that Lunapark interacts with mechanistic target of rapamycin complex-1 (mTORC1), a central cellular regulator that coordinates growth and metabolism with environmental conditions. We show that mTORC1 binds Lunapark specifically at three-way junctions, and lysosomes, where mTORC1 is activated, make contact with three-way junctions where Lunapark resides. 0.2 SIGNOR-272200 SREBF2 protein Q12772 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12923220 YES lperfetto IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells|evidence that IDH1 may regulate lipogenesis in hepatic cells 0.277 SIGNOR-253133 NEDD4L protein Q96PU5 UNIPROT SCN4A protein P35499 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 YES miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 0.279 SIGNOR-253460 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 11108261 YES lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. 0.2 SIGNOR-244247 CERS3 protein Q8IU89 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 YES done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  0.8 SIGNOR-273995 PIMREG protein Q9BSJ6 UNIPROT PICALM protein Q13492 UNIPROT down-regulates relocalization 9606 16491119 YES miannu The cats interaction domain of calm was mapped to aa 221-335 of calm. This domain is contained in the calm/af10 fusion protein. Cats localizes to the nucleus and shows a preference for nucleoli. Expression of cats was able to markedly increase the nuclear localization of calm and of the leukemogenic fusion protein calm/af10. 0.2 SIGNOR-144680 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone chemical CHEBI:91454 ChEBI INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190446 SYCE3 protein A1L190 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 YES miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. 0.666 SIGNOR-264202 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120028 CHEK1 protein O14757 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 25486478 YES miannu Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21(Waf1) on T145 and S146 residues and induces its proteasome-dependent proteolysis. 0.532 SIGNOR-279325 FBLN5 protein Q9UBX5 UNIPROT ELN protein P15502 UNIPROT up-regulates activity binding 9606 18267938 YES miannu The binding of tropoelastin fragments to fibulin-5 was directly proportional to their propensity to coacervate. Furthermore, the addition of fibulin-5 to tropoelastin facilitated coacervation. Taken together, the present study shows that fibulin-5 enhances elastic fiber formation in part by improving the self-association properties of tropoelastin. 0.76 SIGNOR-252137 RORC protein P51449 UNIPROT Th17 phenotype SIGNOR-PH94 SIGNOR up-regulates 9606 16990136 NO MARCO ROSINA Our results demonstrate that RORgt is the transcription factor that directs the differentiation of inflammatory Th17 cells 0.7 SIGNOR-255028 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser645 NLSTNADsQSSSDFE 9606 16874298 YES lperfetto The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo 0.618 SIGNOR-148323 PHF2 protein O75151 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. 0.2 SIGNOR-264519 SAGA complex complex SIGNOR-C465 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR down-regulates 9606 15970593 NO lperfetto Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs).|this observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools. 0.7 SIGNOR-269569 GRIP1 protein Q9Y3R0 UNIPROT KIF5C protein O60282 UNIPROT up-regulates activity binding 9606 BTO:0000142 31757889 YES miannu HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro 0.324 SIGNOR-264061 TP63 protein Q9H3D4 UNIPROT SYNE3 protein Q6ZMZ3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005098 28595999 YES lperfetto Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. 0.2 SIGNOR-263280 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates binding 9606 BTO:0001253 9311920 YES gcesareni Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r, melanocortin receptor subtypes implicated in weight regulation. 0.593 SIGNOR-51067 MKX protein Q8IYA7 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001592 33115953 YES miannu MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). 0.301 SIGNOR-267215 PINK1 protein Q9BXM7 UNIPROT UBA52 protein P62987 UNIPROT up-regulates phosphorylation Ser65 DYNIQKEsTLHLVLR 10090 BTO:0002572 24784582 YES Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. 0.383 SIGNOR-270342 SKA3 protein Q8IX90 UNIPROT SKA complex complex SIGNOR-C364 SIGNOR form complex binding -1 22483620 YES lperfetto We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. 0.919 SIGNOR-265196 IRF3 protein Q14653 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 NO lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. 0.7 SIGNOR-216316 HOXD10 protein P28358 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 YES 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. 0.376 SIGNOR-241226 FYN protein P06241 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation 9606 14707117 YES miannu As shown in XREF_FIG F, Fyn immunoprecipitates from activated T cells induced the tyrosine phosphorylation of WASp, but neither WASpDeltaPro nor WASpY291F mutant proteins were phosphorylated in this assay. 0.562 SIGNOR-279333 MAPK1 protein P28482 UNIPROT PARVA protein Q9NVD7 UNIPROT up-regulates activity phosphorylation Ser4 sPQKSPSV 9606 22955285 YES lperfetto Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7). 0.26 SIGNOR-265760 RPE protein Q96AT9 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI down-regulates quantity chemical modification 9606 34775382 YES miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. 0.8 SIGNOR-267065 DHODH protein Q02127 UNIPROT ubiquinol smallmolecule CHEBI:17976 ChEBI up-regulates quantity chemical modification 9606 30449682 YES miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway 0.8 SIGNOR-267432 TNPO1 protein Q92973 UNIPROT NUP153 protein P49790 UNIPROT up-regulates activity relocalization 29970603 YES lperfetto TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import 0.5 SIGNOR-262100 PLK1 protein P53350 UNIPROT NUMA1 protein Q14980 UNIPROT down-regulates activity phosphorylation 9606 30456393 YES miannu Phosphorylation of NuMA by Plk1 at 1833/34 residue can impact its cortical localization.|These data strongly suggest that Plk1 negatively regulate cortical NuMA localization and that this impact of Plk1 on NuMA is presumably independent of LGN, at least in the anaphase cells. 0.532 SIGNOR-279345 BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 10629050 YES Translocation from Mitochondria to Cytosol amattioni The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease 0.698 SIGNOR-73898 PRKCB protein P05771 UNIPROT TOP2A protein P11388 UNIPROT up-regulates activity phosphorylation Ser29 EDAKKRLsVERIYQK 9606 BTO:0000567 12569090 YES lperfetto Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides. 0.359 SIGNOR-249195 ABL1 protein P00519 UNIPROT EPHB2 protein P29323 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 11494128 YES lperfetto Two-hybrid screens identified regions of abl and arg that bind to the ephb2 and epha4 receptors, suggesting a novel signaling connection involving the two kinase families.The connection between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 causes tyrosine phosphorylation of Abl and Arg, and vice versa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activate endogenous EphB2 decreased the kinase activity of endogenous Abl. 0.514 SIGNOR-109668 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 19951971 YES lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. 0.748 SIGNOR-249629 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 22153608 YES Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation. gcesareni Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner. 0.45 SIGNOR-195221 FGF12 protein P61328 UNIPROT SCN1A protein P35498 UNIPROT down-regulates activity binding 9606 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.386 SIGNOR-253420 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM7 protein Q9C029 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271216 paclitaxel chemical CHEBI:45863 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 28298489 YES miannu Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. 0.8 SIGNOR-259346 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT down-regulates activity binding 9606 21976273 YES miannu Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS). 0.688 SIGNOR-252420 AKT proteinfamily SIGNOR-PF24 SIGNOR GAB2 protein Q9UQC2 UNIPROT down-regulates phosphorylation Ser159 LLRERKSsAPSHSSQ 9606 11782427 YES lperfetto Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation. 0.2 SIGNOR-113669 CHRM5 protein P08912 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257125 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.764 SIGNOR-260581 CBS protein P35520 UNIPROT L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI up-regulates quantity chemical modification 9606 23981774 YES lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 0.8 SIGNOR-275830 D-106669 chemical CID:16048654 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252649 CREB1 protein P16220 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 YES Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB 0.2 SIGNOR-256105 acetyl-CoA smallmolecule CHEBI:15351 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 15507492 YES Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬¨‚Ćde novo¬¨‚Ćbiosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬¨‚Ć 0.8 SIGNOR-267209 NPC complex SIGNOR-C263 SIGNOR XPOT protein O43592 UNIPROT up-regulates quantity relocalization 9606 9660920 YES miannu Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus. 0.464 SIGNOR-261394 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 12058027 YES gcesareni Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. 0.2 SIGNOR-89419 ERBB2 protein P04626 UNIPROT FASN protein P49327 UNIPROT up-regulates activity phosphorylation 9606 27692180 YES miannu Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression ( xref ; xref ).|Conversely, HER2 directly phosphorylates and activates FASN, while it also promotes FASN gene expression. 0.442 SIGNOR-278399 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg25 ECPTGGGrGRGMRSR 9606 24726729 YES miannu Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding 0.369 SIGNOR-204958 PAK5 protein Q9P286 UNIPROT SYNJ1 protein O43426 UNIPROT up-regulates activity phosphorylation -1 22371566 YES miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 0.2 SIGNOR-263026 GABA-A proteinfamily SIGNOR-PF61 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268599 quetiapine chemical CHEBI:8707 ChEBI HTR2A protein P28223 UNIPROT up-regulates activity chemical activation 10090 BTO:0000331 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258532 LEP protein P41159 UNIPROT LEPR protein P48357 UNIPROT up-regulates binding 9606 9463481 YES gcesareni Both ob-ra and ob-rb bind leptin with the same affinity, whereas only ob-rb can elicit intracellular response 0.813 SIGNOR-55656 SH2B2 protein O14492 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000975 11498022 YES gcesareni Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor. The aps adapter protein couples theinsulinreceptor to the phosphorylation of c-cbl and facilitates ligand-stimulated ubiquitination of theinsulinreceptor. 0.646 SIGNOR-109691 SMAD7 protein O15105 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates binding 9606 11737269 YES lpetrilli Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads. 0.579 SIGNOR-112645 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.397 SIGNOR-275772 F2RL1 protein P55085 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.459 SIGNOR-257359 STAT1 protein P42224 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21433395 NO miannu The signal transducer and activator of transcription (STAT) family of transcription factors transduce signals from a variety of extracellular stimuli, and are important mediators of inflammation, cell survival, differentiation, and proliferation. STATs are activated in response to growth factors, cytokines, and G-CSF binding to cell surface receptor tyrosine kinases. Although structurally similar, the seven STAT family members possess diverse biological roles. For example, STAT1 activation is pro-inflammatory and anti-proliferative, while STAT3 activation is anti-inflammatory and pro-apoptotic. 0.7 SIGNOR-263651 PPARD protein Q03181 UNIPROT TXN protein P10599 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001950 18048767 NO miannu Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. 0.2 SIGNOR-255052 CDK1 protein P06493 UNIPROT KRT18 protein P05783 UNIPROT up-regulates phosphorylation Ser34 RPVSSAAsVYAGAGG 9606 9524113 YES lperfetto We identified k18 ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. K18 ser33 phosphorylation dictates binding to 14_3_3 proteins 0.339 SIGNOR-55994 HTR1D protein P28221 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256721 mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 NO lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. 0.7 SIGNOR-268322 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MYC protein P01106 UNIPROT up-regulates activity phosphorylation -1 32482868 YES inferred from 70% family members lperfetto ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation 0.2 SIGNOR-270030 CD3 complex SIGNOR-C432 SIGNOR ZAP70 protein P43403 UNIPROT up-regulates activity binding 9534 1423621 YES We have recently identified a 70 kd tyrosine phosphoprotein (ZAP-70) that associates with zeta and undergoes tyrosine phosphorylation following TCR stimulation|Moreover, tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP-70 may interact to mediate TCR signal transduction. 0.695 SIGNOR-252304 MECP2 protein P51608 UNIPROT TET1 protein Q8NFU7 UNIPROT up-regulates activity binding 28594324 YES lperfetto MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naı ̈ve but dissociate during conditioning|Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing. 0.428 SIGNOR-277701 sunitinib chemical CHEBI:38940 ChEBI CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition 9606 17367763 YES miannu Sunitinib (SU-11248, Sutent) inhibits at least eight receptor protein-tyrosine kinases including vascular endothelial growth factor receptors 1-3 (VEGFR1-VEGFR3), platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta), stem cell factor receptor (Kit), Flt-3, and colony-stimulating factor-1 receptor (CSF-1R). 0.8 SIGNOR-259319 STK11 protein Q15831 UNIPROT NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Thr211 QKDKFLQtFCGSPLY 9606 14976552 YES llicata A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold. 0.545 SIGNOR-122686 MTHFR protein P42898 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI down-regulates quantity chemical modification 9606 10720211 YES lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. 0.8 SIGNOR-268228 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser393 LTPEKGQsQGLIWDF 9606 BTO:0002181 31843895 YES miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. 0.289 SIGNOR-276764 PKA proteinfamily SIGNOR-PF17 SIGNOR ARHGEF6 protein Q15052 UNIPROT down-regulates activity phosphorylation Ser684 GSSTRKDsIPQVLLP 9606 BTO:0000132 26507661 YES lperfetto Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex. 0.2 SIGNOR-272160 ATF4 protein P18848 UNIPROT FGF21 protein Q9NSA1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22233381 NO miannu These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation. 0.428 SIGNOR-253748 EPHA3 protein P29320 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Tyr535 MDSYSGPyGDMRLET 9606 20570899 YES miannu Src and Etk share some common substrates due to the high degree of homology of their kinase domains, thus we examined whether the increased Etk expression could also contribute to AR Y534 phosphorylation.|This is supported by our observations that the association between Etk and AR is increased after castration and Etk induces tyrosine phosphorylation of AR, leading an increase in AR stability and transcriptional activity under androgen depleted conditions. 0.273 SIGNOR-279370 PRKCA protein P17252 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 YES miannu Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress 0.534 SIGNOR-91826 NEDD4 protein P46934 UNIPROT DCUN1D1 protein Q96GG9 UNIPROT up-regulates quantity monoubiquitination Lys 143 KLKAQIPkMEQELKE 9606 BTO:0000007 21813641 YES miannu Here we revealed a previously unknown mechanism that regulates hDCNL1. In cultured mammalian cells ectopically expressed hDCNL1 was mono-ubiquitinated predominantly at K143, K149, and K171. Using a classical chromatographic purification strategy, we identified Nedd4-1 as an E3 ligase that can catalyze mono-ubiquitination of hDCNL1 in a reconstituted ubiquitination system.Taken together, these results suggest a mono-ubiquitination-mediated mechanism that governs nuclear-cytoplasmic trafficking of hDCNL1, 0.368 SIGNOR-272717 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19860666 YES gcesareni GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin 0.708 SIGNOR-188884 EGR1 protein P18146 UNIPROT PITX1 protein P78337 UNIPROT up-regulates activity binding 10090 19106114 YES miannu GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. 0.514 SIGNOR-254916 RPS6KA5 protein O75582 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser7 sSAEGAAK 12213813 YES lperfetto HMGN1 (formerly known as HMG-14) phosphorylation at Ser6 occurs concomitantly with IE gene expression. | MSK2 seems to be the most important kinase responsible for this modification |Accordingly, it was suggested that HMGN1 phosphorylation reduces binding of the protein to the nucleosomes 0.619 SIGNOR-262988 SNAPIN protein O95295 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 YES lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. 0.722 SIGNOR-265935 UBE3A protein Q05086 UNIPROT TSC2 protein P49815 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18298802 YES miannu  An in vivo ubiquitination assay was done to reveal that E6AP promoted the ubiquitination of TSC2 independent of HPV16 E6. We further found that TSC2 bound E6AP in the presence as well as in the absence of HPV16 E6. The binding regions on E6AP and TSC2 have been identified as amino acid (aa) 260-316, aa 428-500 and aa 1-175, aa 1251-1807, respectively. Taken together, degradation of TSC2 is mediated by E6AP ubiquitin ligase. 0.628 SIGNOR-271396 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI vitamin K smallmolecule CHEBI:28384 ChEBI up-regulates quantity precursor of 9606 31226734 YES lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) 0.8 SIGNOR-265907 TMPRSS2 protein O15393 UNIPROT S protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 32142651 YES miannu Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. The Cellular Serine Protease TMPRSS2 Primes SARS-2- S for Entry, and a Serine Protease Inhibitor Blocks SARS-CoV-2 Infection of Lung Cells 0.2 SIGNOR-260736 FURIN protein P09958 UNIPROT S protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 BTO:0002750 32362314 YES Luana Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. 0.2 SIGNOR-262305 FURIN protein P09958 UNIPROT S protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 BTO:0002750 32362314 YES Luana Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. 0.2 SIGNOR-262303 TMPRSS4 protein Q9NRS4 UNIPROT S protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 32404436 YES Luana TMPRSS2 and TMPRSS4 serine proteases mediate this process by inducing cleavage of the S protein and enhancing membrane fusion. 0.2 SIGNOR-262304 TMPRSS4 protein Q9NRS4 UNIPROT S protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 32404436 YES Luana TMPRSS2 and TMPRSS4 serine proteases mediate this process by inducing cleavage of the S protein and enhancing membrane fusion. 0.2 SIGNOR-262306 CHEK2 protein O96017 UNIPROT VHL protein P40337 UNIPROT up-regulates phosphorylation Ser111 GTGRRIHsYRGHLWL 9606 BTO:0000680 22071692 YES llicata We demonstrated that checkpoint kinase-2 (chk2) binds to the beta-domain of pvhl and phosphorylates ser 111 on dna damage. Notably, this modification enhances pvhl-mediated transactivation of p53 by recruiting p300 and tip60 to the chromatin of p53 target gene 0.455 SIGNOR-177091 ITGB2 protein P05107 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.559 SIGNOR-257711 RECQL4 protein O94761 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 9606 27287744 NO RECQL4 is important for genome stability and DNA damage repair. 0.7 SIGNOR-258951 SNAI1 protein O95863 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 NO miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. 0.757 SIGNOR-255156 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 21454675 YES Receptor-type protein tyrosine phosphatase beta (RPTP-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (HGFR/Met) function.|Expression of RPTP-β in primary human keratinocytes reduces both basal and HGF-induced Met phosphorylation at tyrosine 1356 and inhibits downstream MEK1/2 and Erk activation 0.365 SIGNOR-248440 DYRK1A protein Q13627 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 19383720 YES gcesareni Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch . 0.396 SIGNOR-185494 AAAS protein Q9NRG9 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.541 SIGNOR-262067 DHFR2 protein Q86XF0 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 21876184 YES lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. |We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR. 0.8 SIGNOR-268261 PTGFR protein P43088 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.372 SIGNOR-256810 MACF1 protein Q9UPN3 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization 9606 16815997 NO gcesareni In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes. 0.405 SIGNOR-147448 SLC9A8 protein Q9Y2E8 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265607 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser434 SFEPKIRsPRRFIGS 9823 BTO:0004712 23486913 YES lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway 0.96 SIGNOR-201534 MTOR protein P42345 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.73 SIGNOR-262534 SPAST protein Q9UBP0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9534 BTO:0000298 15716377 NO Gianni Using purified components, we also show that Spastin interacts directly with microtubules and is sufficient for severing. These studies suggest that defects in microtubule severing are a cause of axonal degeneration in human disease. 0.7 SIGNOR-269045 CREB1 protein P16220 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000157 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.296 SIGNOR-253797 UBR1 protein Q8IWV7 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 YES miannu The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells 0.492 SIGNOR-128169 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 YES gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.679 SIGNOR-249407 CDK11A protein Q9UQ88 UNIPROT SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser243 TDSEVDSsCSGQPIH 9606 BTO:0000007 26885618 YES lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| 0.356 SIGNOR-273022 PAK1 protein Q13153 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 12560069 YES miannu Pak1 efficiently phosphorylated GST-FKHR. 0.359 SIGNOR-279242 MAPK1 protein P28482 UNIPROT PBK protein Q96KB5 UNIPROT up-regulates activity phosphorylation 9606 35546143 YES miannuccelli In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2.|TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC. 0.284 SIGNOR-279744 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 YES lperfetto We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. 0.405 SIGNOR-216690 CCKAR protein P32238 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.252 SIGNOR-257035 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR SUDS3 protein Q9H7L9 UNIPROT up-regulates activity phosphorylation Ser228 RTLNKLKsPKRPASP 9606 BTO:0000007 15489224 YES miannu Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repression of transcription. the dimerization of the phosphorylation-deficient mutant of mSds3 (S228A) was not greatly enhanced by p35 when compared with wild type (Fig. 5D). This finding suggests that the phosphorylation of mSds3 by active Cdk5 increases the homodimerization potential of mSds3. 0.282 SIGNOR-262739 EXOSC3 protein Q9NQT5 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.967 SIGNOR-261382 purmorphamine chemical CHEBI:63053 ChEBI SMO protein Q99835 UNIPROT up-regulates chemical activation 9606 17419683 YES gcesareni The activity of smo toward gi was stimulated severalfold with the synthetic agonist purmorphamine and inhibited almost completely by cyclopamine and other antagonists of shh. 0.8 SIGNOR-154282 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Glu) smallmolecule CHEBI:29175 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270379 MID1IP1 protein Q9NPA3 UNIPROT ACACA protein Q13085 UNIPROT up-regulates activity binding 10029 BTO:0000457 20952656 YES miannu Recently, we reported the discovery that MIG12, a 183 amino acid protein, binds to ACC1 and ACC2, which induces polymerization and subsequently increases the enzymatic activity of the protein 0.375 SIGNOR-267111 PRKCA protein P17252 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1360 VLRSPSGsQRPSVSD 9606 15121854 YES lperfetto Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures 0.53 SIGNOR-124494 KIF2C protein Q99661 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272529 ERGIC1 protein Q969X5 UNIPROT ERGIC3 protein Q9Y282 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000599 15308636 YES Giorgia Among novel cycling proteins we have characterized ERGIC-32, a new ERGIC protein that interacts with human Erv46, a protein previously characterized in yeast and functioning in ER to Golgi protein trafficking. ERGIC-32 interacts with human Erv46 (hErv46) as revealed by covalent cross-linking and mistargeting experiments, and silencing of ERGIC-32 by small interfering RNAs increases the turnover of hErv46. We propose that ERGIC-32 functions as a modulator of the hErv41-hErv46 complex by stabilizing hErv46. 0.374 SIGNOR-260637 EIF3L protein Q9Y262 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.924 SIGNOR-266389 NBR1 protein Q14596 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 YES gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. 0.74 SIGNOR-184267 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF4 protein Q9P2E8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271044 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT up-regulates activity transcriptional regulation 10090 PMC3619734 NO areggio Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1induction. 0.2 SIGNOR-254990 CPS1 protein P31327 UNIPROT Pyrimidine biosynthesis phenotype SIGNOR-PH187 SIGNOR up-regulates activity 9606 15096496 NO CPSase catalyzes the rate-limiting step in de novo pyrimidine biosynthesis and, as discussed below, controls the flux through the pathway 0.7 SIGNOR-267195 GSK3B protein P49841 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates activity phosphorylation Ser571 RDTYSDRsGSSSPDS 9606 BTO:0000007 17681942 YES miannu Mutation of Ser-571 demonstrated that Ser-571 was the major site phosphorylated by GSK3 in intact human embryonic kidney 293 cells by GSK3 in vitro. Furthermore, mutation of Ser-575 prevented the phosphorylation of Ser-571, suggesting that phosphorylation of Ser-575 was necessary for priming the GSK3 phosphorylation of Ser-571. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. 0.2 SIGNOR-276070 ERBB2 protein P04626 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity phosphorylation 9606 22964581 YES miannu Importantly, we found that overexpression of HER2 alone is sufficient to induce MED1 phosphorylation at Thr (1032), a key site that is known to be critical for its functions, whereas blockage of HER2 or its downstream MAP kinase diminishes its phosphor ylation levels in these cells. 0.2 SIGNOR-279408 FER protein P16591 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 19339212 YES miannu The Fer mediated phosphorylation of specific tyrosine residues of FAK was abolished by cotransfection of shRNA against Fer (i.e., shFer), but not by control shRNA, indicating that the phosphorylation of Tyr577, 861, or 925 of FAK in suspended cells was indeed caused by Fer. 0.251 SIGNOR-279409 CNR1 protein P21554 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.54 SIGNOR-256724 PRKCZ protein Q05513 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 10022904 YES lperfetto Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation. 0.515 SIGNOR-249016 C4A protein P0C0L4 UNIPROT C3 convertase complex complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 YES complement C4b fragment: PRO_0000005970 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex 0.623 SIGNOR-263400 CAMK2A protein Q9UQM7 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.279 SIGNOR-275786 NUP62 protein P37198 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.702 SIGNOR-262079 Immunoglobulin delta heavy chain protein P0DOX3 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 20176268 YES scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. 0.2 SIGNOR-268199 MAPK1 protein P28482 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000007;BTO:0000150 21502402 YES gcesareni We identified the serine 68 (s68) as a major phosphorylation site of twist1 by mass spectrometry and with specific antibodies. This s68 is phosphorylated by p38, jnk and erk1/2 in vitro, and its phosphorylation levels positively correlate with twist1 protein levels in hek293 and breast cancer cells. 0.304 SIGNOR-173401 PRKCD protein Q05655 UNIPROT GNAZ protein P19086 UNIPROT unknown phosphorylation Ser27 DRHLRSEsQRQRREI 9606 8429024 YES lperfetto Gz alpha variants containing selected substitutions of alanine for serine residues were expressed in human kidney 293 cells, and the ability of each to be phosphorylated in response to phorbol 12-myristate 13-acetate was examined. A focus was placed on Ser25 and Ser27, the 2 serine residues within a sequence of Gz alpha used to obtain a phosphorylation-sensitive antibody. The results demonstrate that Ser27 is the primary site of phosphorylation. Conversion of Ser27 to an alanine resulted in a 65% decrease in incorporation of [32P] phosphate; conversion of Ser25 had no effect. 0.529 SIGNOR-248932 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser21 KEEPKRRsARLSAKP 9606 10739259 YES lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. 0.307 SIGNOR-76282 linifanib chemical CHEBI:91435 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258243 AURKA protein O14965 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 10090 12234980 YES gcesareni In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis. 0.2 SIGNOR-265356 ASXL1 protein Q8IXJ9 UNIPROT RARA protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 NO irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. 0.445 SIGNOR-255933 MST1 protein P26927 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Thr228 PQWNESFtFKLKPSD 9606 BTO:0002181 26414765 YES miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  0.2 SIGNOR-277178 CDK5 protein Q00535 UNIPROT TLN1 protein Q9Y490 UNIPROT up-regulates phosphorylation Ser425 TMLEDSVsPKKSTVL 9606 19363486 YES lperfetto Cdk5 phosphorylated talin head at ser 425, inhibiting its binding to smurf1, thus preventing talin head ubiquitylation and degradation. 0.459 SIGNOR-185210 GRIA2 protein P42262 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264948 PRKN protein O60260 UNIPROT SEPTIN5 protein Q99719 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 14559152 YES miannu SEPT5_v2 is highly homologous to another septin, SEPT5, which was recently identified as a target for parkin-mediated ubiquitination. SEPT5_v2 binds to parkin at the amino terminus and in the ring finger domains.Parkin ubiquitinates SEPT5_v2 in vitro, and both SEPT5_v1 and SEPT5_v2 accumulate in brains of patients with ARJP, suggesting that parkin is essential for the normal metabolism of these proteins. 0.2 SIGNOR-272673 RAP1GDS1 protein P52306 UNIPROT RHOC protein P08134 UNIPROT up-regulates binding 9606 21242305 YES miannu Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc 0.299 SIGNOR-171399 CRYGC protein P07315 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 10521291 NO The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. 0.7 SIGNOR-253624 PRKCA protein P17252 UNIPROT UGT1A3 protein P35503 UNIPROT up-regulates activity phosphorylation Ser43 IDGSHWLsMREVLRE -1 26094731 YES done miannu Curcumin and calphostin C suppressed the activity and phosphorylation of recombinant UGT1A3 expressed in Sf9 cells. These results indicate that UGT1A3 undergoes phosphorylation, which is required for its catalytic activity. Calphostin C is a highly specific protein kinase C (PKC) inhibitor, so three predicted PKC phosphorylation sites in UGT1A3 were examined. In conclusion, phosphorylation plays an important role in UGT1A3 activity, and the serine at site 43 in UGT1A3 is most likely a phosphorylation site. 0.2 SIGNOR-273823 olodaterol chemical CHEBI:82700 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation -1 20371707 YES Luana In vitro, olodaterol showed a potent, nearly full agonistic response at the hbeta(2)-AR (EC(50) = 0.1 nM; intrinsic activity = 88% compared with isoprenaline) and a significant selectivity profile (241- and 2299-fold [corrected] against the hbeta(1)- and hbeta(3)-ARs, respectively).  0.8 SIGNOR-257834 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 9731215 YES inferred from 70% family members lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. 0.2 SIGNOR-270182 MAP4K1 protein Q92918 UNIPROT GRAP2 protein O75791 UNIPROT down-regulates activity phosphorylation 9606 22105350 YES miannu Serine/threonine phosphorylation of the T cell adaptor proteins SLP76 and GADS by HPK1 induces their release from signaling microclusters and subsequent termination of the T cell response. 0.834 SIGNOR-279421 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Thr291 EDEESYDtESEFTEF 9606 BTO:0000782 8622692 YES llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. 0.58 SIGNOR-40514 HIPK3 protein Q9H422 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation 9606 18793336 YES miannu We show that Yak1 directly phosphorylates Hsf1 in vitro, leading to the increase in DNA binding activity of Hsf1. 0.335 SIGNOR-279054 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 12223490 YES gcesareni We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage. 0.528 SIGNOR-92593 AKT2 protein P31751 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation Ser193 GLPERSVsLTGAPES 10116 17177604 YES lperfetto AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP’s ability to promote rapid mRNA decay. 0.343 SIGNOR-151220 BAZ1B protein Q9UIG0 UNIPROT MDC1 protein Q14676 UNIPROT down-regulates 9606 20965415 NO gcesareni H2ax tyr142 is constitutively phosphorylated by the kinase wstf, a member of the baz/wal family of chromatin remodelling enzymes, and blocks mdc1 recruitment 0.363 SIGNOR-168831 MRPS31 protein Q92665 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.709 SIGNOR-261445 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr100 TNTYYLQtFGHNTMD 9606 BTO:0000007 21321328 YES miannu We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. 0.578 SIGNOR-263129 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266477 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.444 SIGNOR-248299 CLIP1 protein P30622 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates binding 17889670 YES lperfetto Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170) 0.7 SIGNOR-264830 PRKCB protein P05771 UNIPROT VTN protein P04004 UNIPROT up-regulates quantity by stabilization phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 YES lperfetto Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin. 0.303 SIGNOR-248963 CIITA protein P33076 UNIPROT HLA-C protein P10321 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002269 11053628 NO miannu Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression. 0.474 SIGNOR-253775 MAPKAPK5 protein Q8IW41 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 32690100 YES miannu Consequently, our study clearly determined that p38 MAP kinase-activated MK5 could trigger the activity of c-Jun through phosphorylation of c-Jun, which then bound to the SNAI1 promoter to promote SNAI1-mediated EMT.It has been reported that altering extracellular responses and intracellular signal transduction, such as enhancing the activity of p38MAPK [48], JNK [49] and eIF4 [39] signaling pathways, leads to carcinogenesis and aggravates metastasis.|Western blot analysis showed that MK5 could promote the phosphorylation of c-Jun S63 site and the expression of SNAI1 (Fig.\u00a05a). 0.384 SIGNOR-279422 PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 21918248 YES gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. 0.8 SIGNOR-176606 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr417 SLPQATVtPPRKEER 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 YES lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex 0.49 SIGNOR-118584 CDK1 protein P06493 UNIPROT USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1616 NSHSPAGsAAISQQD 9606 BTO:0000018 27991932 YES lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. 0.2 SIGNOR-275605 NAA35 protein Q5VZE5 UNIPROT NatC complex SIGNOR-C417 SIGNOR form complex binding 9606 19398576 YES miannu We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation. 0.76 SIGNOR-267234 PXN protein P49023 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR up-regulates activity relocalization 16493410 YES lperfetto Integrin-linked kinase (ILK), and isoforms of particularly interesting Cys-His-rich protein (PINCH) and parvin form the IPP complex (Fig. 2) in the cytoplasm, and this complex is recruited to focal adhesions through interactions with other factors, such as paxillin. 0.58 SIGNOR-265767 FLT3 protein P36888 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 NO FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells 0.252 SIGNOR-261550 MDC1 protein Q14676 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19230643 YES gcesareni Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1. 0.834 SIGNOR-184141 PRKACA protein P17612 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Thr316 GTASSRKtLWNQELY -1 21880142 YES miannu PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. 0.307 SIGNOR-266308 PLK1 protein P53350 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates activity phosphorylation 9606 33288550 YES miannu Phosphorylation of the astrin N-terminal domain by Plk1 contributes to kinetochore\u2013microtubule attachment stability.|Taken together with the localisation data in XREF_FIG B, these data suggest that the presence of the Plk1 phosphorylated astrin N-terminus promotes the accumulation of the astrin complex at attached kinetochores, without which attachments appear more prone to dissociate. 0.394 SIGNOR-279423 SLA protein Q13239 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000661 phosphorylation:Tyr594 TYVDPHTyEDPNQAV 24457997 YES lperfetto These data are consistent with a model where SLAP induces Ephrin-independent EPHA2 degradation. | This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2. 0.415 SIGNOR-262964 GRIPAP1 protein Q4V328 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity binding 9606 BTO:0002181;BTO:0000142 17761173 YES Giorgia To examine whether GRASP‐1 interacts with MEKK1 and JNK1 in neurons, co‐immunoprecipitation experiments were performed with detergent‐solubilized extracts from cultured cortical neurons. Both antiJNK1 and anti‐MEKK1 antibodies immunoprecipitated GRASP‐1 from neuronal lysates. These results suggest that GRASP‐1 interacts with MEKK1 and JNK1 in neurons. 0.312 SIGNOR-260640 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates quantity by destabilization phosphorylation Ser265 PRSSSNAsSVSTRLS 9606 BTO:0001109 28945225 YES miannu Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268.  0.2 SIGNOR-277325 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser83 PKFKVKSsPLIEKLQ -1 15850461 YES miannu CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.286 SIGNOR-263086 CSNK1A1 protein P48729 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.286 SIGNOR-250785 LYN protein P07948 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 21423214 YES gcesareni We previously reported that y88 phosphorylation of p27(kip1) by oncogenic tyrosine kinases impairs p27(kip1)-mediated cdk inhibition, and initiates its ubiquitin-dependent proteasomal degradation. 0.552 SIGNOR-172904 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.288 SIGNOR-276091 IFNG protein P01579 UNIPROT HLA-B protein P01889 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 2507660 NO Regulation miannu HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2 0.331 SIGNOR-251926 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester chemical CHEBI:92418 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258635 SRC protein P12931 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation 9606 26114632 YES miannu In addition, the c-Src inhibitor 4-(4\u2019-phenoxyanilino)-6,7-dimethoxyquinazoline prevented SP-induced activation of HER2.|On the other hand, c-Src directly phosphorylates the cytoplasmic tails of both EGFR and HER2, allowing the binding of scaffold proteins that will further activate signal transduction. 0.614 SIGNOR-279432 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr266 TDSIRDEyAFLQKKY 9606 29022905 YES miannu Interestingly, we found that Drp1 was a substrate of c-Abl kinase and ectopic expression of c-Abl increased Drp1 's mitochondrial localization and GTPase activity.|c-Abl phosphorylates Drp1 at Y266, Y368 and Y449. 0.26 SIGNOR-278462 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 YES lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. 0.2 SIGNOR-251523 CREB1 protein P16220 UNIPROT NR4A3 protein Q92570 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 17668895 NO gcesareni Phosphorylation of creb by msk has been linked to the transcription of nur77, nor1 and c-fos downstream of mapk signalling in various cell types. 0.333 SIGNOR-157154 HDAC1 protein Q13547 UNIPROT CCND1 protein P24385 UNIPROT up-regulates binding 9606 15713663 YES gcesareni Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5. 0.696 SIGNOR-134059 SMARCC2 protein Q8TAQ2 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.843 SIGNOR-270746 PLK2 protein Q9NYY3 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates phosphorylation Ser176 KRKLDHGsEVRSFSL 9606 22399798 YES lperfetto Plk2 regulates centriole duplication through phosphorylation-mediated degradation of fbxw7 (human cdc4).Plk2 phosphorylates fbxw7 on serine 176 0.484 SIGNOR-196448 PLAG1 protein Q6DJT9 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 11888928 NO miannu Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis 0.7 SIGNOR-256658 RUNX1 protein Q01196 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR down-regulates activity binding 9606 22021368 YES apalma We found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-κB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-κB signaling 0.2 SIGNOR-255690 LRIG1 protein Q96JA1 UNIPROT EGFR protein P00533 UNIPROT down-regulates binding 9606 BTO:0001253 15282549 YES gcesareni Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation 0.735 SIGNOR-127304 FBXO21 protein O94952 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 26085330 YES miannu SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO) 0.61 SIGNOR-272430 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TFAP2C protein Q92754 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.374 SIGNOR-269256 CCKBR protein P32239 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.265 SIGNOR-256765 FHIT protein P49789 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 18077326 YES miannu Fhit interacts with _-catenin in vitro and in vivo / the tumor suppressor fhit acts as a repressor of _-catenin transcriptional activity 0.51 SIGNOR-159873 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11847100 YES lperfetto c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. 0.537 SIGNOR-246311 RUSC1 protein Q9BVN2 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates binding 9606 15024033 NO miannu Overexpression studies in PC12 cells indicate that Nesca facilitates neurotrophin-dependent neurite outgrowth at nonsaturating doses of nerve growth factor (NGF). 0.7 SIGNOR-272776 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR -1 19494114 YES Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases|Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2. 0.46 SIGNOR-248707 GSK3B protein P49841 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates activity phosphorylation Ser22 RSRQNPQsPPQDSSV 9606 20520769 YES miannu GSK3beta was found to co-localize with HDAC6 in hippocampal neurons, and inhibition of GSK3beta resulted in decreased binding of antibody to phosphoserine-22, a potential GSK3beta phosphorylation site in HDAC6.|This suggests that GSK3\u03b2 may directly phosphorylate HDAC6 at this site, although further work with purified proteins is needed to determine whether this is the case.|The fact that HDAC6 is the predominant cytoplasmic deacetylase in neurons suggests that GSK3beta dependent phosphorylation may enhance HDAC6 activity, resulting in a decrease in acetylation of tubulin and an inhibition of both mitochondrial motility and the transport of other kinesin-1 dependent cargoes. 0.381 SIGNOR-278941 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9136927 YES lperfetto Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro 0.664 SIGNOR-210079 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 YES gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. 0.2 SIGNOR-164298 DLX5 protein P56178 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity transcriptional regulation 9606 19497851 YES gcesareni Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian cells 0.274 SIGNOR-241914 SMARCD1 protein Q96GM5 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.797 SIGNOR-270707 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 YES gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.2 SIGNOR-163270 NLGN4X protein Q8N0W4 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.769 SIGNOR-264150 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 YES lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity 0.91 SIGNOR-252834 AURKA protein O14965 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation Ser235 DPVTGRQsVVVPYEP 9606 22340593 YES miannu Aurora-A inhibits p73 and p53 transactivation functions through a common molecular mechanism.|We report that Aurora-A phosphorylation of p73 at serine235 abrogates its transactivation function and causes cytoplasmic sequestration in a complex with the chaperon protein mortalin. 0.45 SIGNOR-278263 DNA_damage stimulus SIGNOR-ST1 SIGNOR TP53 protein P04637 UNIPROT up-regulates quantity 9606 19879762 NO lperfetto In the case of DNA-damage, phosphorylation of both p53 and Mdm2 by the checkpoint kinases ATM, ATR, Chk1 and Chk2 contributes to the dissociation of the Mdm2-p53 complex, leading to enhanced cellular p53 levels that primarily accumulate in the nucleus. 0.7 SIGNOR-209690 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 YES miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 0.2 SIGNOR-268218 malonyl-CoA smallmolecule CHEBI:15531 ChEBI hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity precursor of 9606 15507492 YES miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-268090 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR SEC31A protein O94979 UNIPROT up-regulates activity monoubiquitination lys647 9606 BTO:0000567 22358839 YES miannu By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division. 0.377 SIGNOR-272012 CDK5 protein Q00535 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr509 PVFDLTTtPKGGTPA 9606 16611631 YES lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.602 SIGNOR-145967 TLE5 protein Q08117 UNIPROT SIX6 protein O95475 UNIPROT down-regulates activity binding -1 12441302 YES lperfetto Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes 0.2 SIGNOR-234589 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser403 DLAHSSEsQETISSM 9606 16943424 YES lperfetto Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm. 0.734 SIGNOR-149300 MAPKAPK2 protein P49137 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser244 PPLRRSPsRTEKQEE -1 15850461 YES miannu Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.478 SIGNOR-263080 PRKACA protein P17612 UNIPROT PHKA2 protein P46019 UNIPROT down-regulates activity phosphorylation 9606 10487978 YES Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. 0.324 SIGNOR-267410 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Ser451 STSTPAPsRTASFSE 10653665 YES Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3) 0.365 SIGNOR-251218 GRK2 protein P25098 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Ser1104 PRAEAEDsFL 9606 15271984 YES miannu In 293 cells, GRK2 overexpression reduced PDGFRbeta/NHERF association by 60%. 0.2 SIGNOR-278379 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Ser268 LKSVRMLsGSKEKDR 9606 BTO:0000671 10908300 YES gcesareni The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization. 0.2 SIGNOR-79678 ESR1 protein P03372 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 NO miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice 0.2 SIGNOR-253471 PTK2 protein Q05397 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity phosphorylation Tyr486 YPAEDSTyDEYENDL 9606 22952866 YES miannu FAK directly phosphorylates cortactin at Y421 and Y466 and over-expression of cortactin Y421, Y466, and Y482 mutated to phenylalanine (3YF) prevented FAK-enhanced FA turnover and cell motility.|GFP-FAK re-expression in FAK-/- MEFs enhances FA turnover (XREF_FIG) and cortactin knockdown slows FA turnover (XREF_FIG). 0.744 SIGNOR-278285 TSHR protein P16473 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 25878058 YES scontino The primary signal transduction pathway for TSH receptor is activation of adenylate cyclase via a Gαs G protein-coupled receptor. 0.662 SIGNOR-267136 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 10090 17158101 YES gcesareni Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis. 0.804 SIGNOR-236867 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.564 SIGNOR-161561 SRC protein P12931 UNIPROT GRIK2 protein Q13002 UNIPROT up-regulates activity phosphorylation Tyr590 RFSPYEWyNPHPCNP 9606 BTO:0000007 25201974 YES miannu GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. 0.372 SIGNOR-276850 CBLC protein Q9ULV8 UNIPROT LRIG1 protein Q96JA1 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 15282549 YES gcesareni Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation 0.2 SIGNOR-127292 FYN protein P06241 UNIPROT TGFB1I1 protein O43294 UNIPROT up-regulates activity phosphorylation Tyr60 SGDKDHLySTVCKPR 9534 10838081 YES miannu Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5. 0.341 SIGNOR-262875 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 21415216 YES irozzo We also found that phosphorylation of both the mitogen-activated proteinkinase (MAPK) ERK and STAT3 was markedly increased inthe cells expressing either variant of EML4-ALK[.]. Oncogenic EML4-ALK tyrosine kinase activates ERKand STAT3 signaling pathways 0.2 SIGNOR-259174 EEF1A1P5 protein Q5VTE0 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269556 MAPKAPK5 protein Q8IW41 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser215 NSIRHNLsLHSRFMR 9606 21329882 YES miannu Analysis of mutant alleles of FoxO3a showed that MK5 phosphorylated FoxO3a predominantly at S215, but that mutation of four of the identified sites was required to essentially abolish phosphorylation of FoxO3a by MK5 (\u201c4A\u201d) ( Figure\u00a04 C and data not shown).|MK5 phosphorylates and activates the transcription factor FoxO3a and potentially other FoxO factors. 0.473 SIGNOR-279469 CDK1 protein P06493 UNIPROT CSNK2B protein P67870 UNIPROT up-regulates phosphorylation Ser209 QAASNFKsPVKTIR 9606 BTO:0000785 7578274 YES lperfetto In cells, the casein kinase ii beta-subunit is phosphorylated at an autophosphorylation site and at a site (ser-209) that is maximally phosphorylated in mitotic cells. These studies provide strong biochemical evidence that p34cdc2 is the enzyme that phosphorylates ser-209 on the beta-subunit of ckii in mitotic cells. 0.459 SIGNOR-29462 FHIT protein P49789 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates 9606 BTO:0000551 16407838 NO miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis 0.249 SIGNOR-143706 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9534 BTO:0004055 14993270 YES lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. 0.758 SIGNOR-244862 CSNK2A1 protein P68400 UNIPROT MUS81 protein Q96NY9 UNIPROT up-regulates activity phosphorylation Ser87 RLQRHRTsGGDHAPD 9606 BTO:0000007 29850896 YES miannu Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex.  0.2 SIGNOR-273626 PSMD3 protein O43242 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.896 SIGNOR-263353 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser503 NDEITDEsLENFPSS 9606 16874298 YES lperfetto The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo 0.618 SIGNOR-148315 MYOG protein P15173 UNIPROT DES protein P17661 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 25653159 NO lperfetto Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated. 0.254 SIGNOR-241501 CRTC2 protein Q53ET0 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9600 BTO:0000567 26652733 YES inferred from family member Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB 0.279 SIGNOR-270253 zolpidem chemical CHEBI:10125 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). 0.8 SIGNOR-263802 BHLHE41 protein Q9C0J9 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14672706 NO lperfetto We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. 0.532 SIGNOR-253714 JAK1 protein P23458 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Tyr384 KLQDEANyHLYGSRM 9606 36329033 YES miannu In addition , our results suggest JAK1 could be recruited to TNF-RSC to modulate RIPK1 activity .|In this study, we show that non-receptor tyrosine kinases JAK1 and SRC could phosphorylate RIPK1 on tyrosine 384 (Y384) in human RIPK1 (Y383 in mouse RIPK1), and serve as essential regulators of RIPK1 in the TNFR1 signaling pathway. 0.2 SIGNOR-278948 PRKACA protein P17612 UNIPROT AQP5 protein P55064 UNIPROT up-regulates activity phosphorylation Ser156 STDSRRTsPVGSPAL 9606 BTO:0000007 26569106 YES lperfetto AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation. 0.2 SIGNOR-272088 GAS7 protein O60861 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23840221 NO miannu Downregulation of gas7 using short-hairpin rna decreased the expression of runx2, a master regulator of osteogenesis, and its target genes (alkaline phosphatase, type i collagen, osteocalcin, and osteopontin). 0.2 SIGNOR-202242 MEF2D protein Q14814 UNIPROT Myog/SWI/SNF complex complex SIGNOR-C94 SIGNOR form complex binding 9606 BTO:0001103 17194702 YES miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle 0.645 SIGNOR-151679 MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 10090 BTO:0003432 10217414 YES lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor. 0.847 SIGNOR-67143 CDK1 protein P06493 UNIPROT NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser29 WLKDQELsPREPVLP 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275591 JAK2 protein O60674 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity phosphorylation 9606 21907792 YES miannu From these results, it can be concluded that JAK2 negatively regulates ERalpha protein level.We next analyzed by which mechanisms JAK2 could regulate ERalpha protein level.|We investigated whether JAK2 phosphorylates ER\u03b1 resulting in its ubiquitination and proteasomal degradation. 0.435 SIGNOR-278949 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH1 protein P12830 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265841 silodosin chemical CHEBI:135929 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258450 ADRA2A protein P08913 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.502 SIGNOR-257093 Ub:E2 complex SIGNOR-C497 SIGNOR UBE4B protein O95155 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271275 CDK5 protein Q00535 UNIPROT HTT protein P42858 UNIPROT up-regulates phosphorylation Ser1179 LTNPPSLsPIRRKGK 9606 BTO:0000938 17611284 YES lperfetto Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage. 0.447 SIGNOR-156836 S1PR1 protein P21453 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.503 SIGNOR-256856 CALM1 protein P0DP23 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 YES gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.752 SIGNOR-114098 PIK-90 chemical CID:6857685 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252653 FGFR1 protein P11362 UNIPROT SYNCRIP protein O60506 UNIPROT down-regulates phosphorylation Tyr373 RVKKLKDyAFIHFDE 9606 12601080 YES lperfetto Novel in vivo tyrosine phosphorylation sites were found in the fgfr-1, phospholipase cgamma, p90 ribosomal s6 kinase, cortactin, and ns-1-associated protein-1. Syncrip, was very recently found to be phosphorylated in response to insulin treatment of 3t3-l1 adipocytes (32). Phosphorylation of syncrip was accommodated by the insulin receptor tyrosine kinase in vitro but was inhibited upon binding of rna. Tyrosine phosphorylation at tyr-373 in the third rna recognition motif domain of nsap1/syncrip can possibly influence its rna binding properties and thus link fgfr-1 signaling to mrna metabolism. 0.2 SIGNOR-98704 PRKACA protein P17612 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr34 MIRRRRPtPAMLFRL 10604473 YES miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  0.503 SIGNOR-250031 SOHLH1 protein Q5JUK2 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0002181 22328502 YES Luana Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression. 0.347 SIGNOR-266205 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Thr173 FRGDRCKtLLEKPKL 9606 BTO:0000150 21555521 YES gcesareni Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. 0.351 SIGNOR-173663 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 YES Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop. 0.337 SIGNOR-248492 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser212 EENGPPSsPDLDRIA -1 SIGNOR-C3 SIGNOR-C3 18372248 YES lperfetto In this study, we used two-dimensional phosphopeptide mapping in conjunction with mutational analysis to show that in addition to ser-183, mtorc1 also phosphorylates ser-212 and ser-221 in pras40 when assayed in vitro. 0.904 SIGNOR-178124 CHEK1 protein O14757 UNIPROT E2F3 protein O00716 UNIPROT up-regulates phosphorylation Ser124 PALGRGGsGGGGGPP 9606 19917728 YES llicata These results suggest that e2f3a is directly phosphorylated by chk kinases and that the phosphorylation of serine 124 is required for the posttranslational induction of e2f3a protein by chemotherapy. 0.328 SIGNOR-161758 LIMK2 protein P53671 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates activity phosphorylation Ser185 KTKRKQLsSELGDLE 9606 34066036 YES miannu LIMK2 also downregulates NKX3.1 mRNA levels.|While WT-NKX3.1 was efficiently phosphorylated, the S185A mutant showed no phosphorylation ( xref A), confirming that LIMK2 only phosphorylates the S185 site in NKX3.1. 0.2 SIGNOR-278951 SHANK3 protein Q9BYB0 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 NO miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. 0.7 SIGNOR-264607 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0003031 26868148 YES methylated tp53 lperfetto We demonstrate here that SCFFbxo22-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCFFbxo22 ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. |SCFFbxo22 forms a ternary complex with p53 and KDM4A that targets methylated p53 for degradation. 0.388 SIGNOR-273449 PRKDC protein P78527 UNIPROT TOP1 protein P11387 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 GDHLHNDsQIEADFR 9606 BTO:0002201 28415827 YES miannu Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1.  0.449 SIGNOR-277352 AKT proteinfamily SIGNOR-PF24 SIGNOR DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser143 RTPRRSKsDGEAKPE 9606 21151116 YES lperfetto Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1. 0.2 SIGNOR-244232 BRSK1 protein Q8TDC3 UNIPROT CAST protein P20810 UNIPROT up-regulates activity phosphorylation Ser45 KSQSTKLsVVHEKKS 10090 BTO:0000142 27626661 YES miannu Here, we show that an AZ cytomatrix protein CAST and an AZ-associated protein kinase SAD-B coordinately regulate STD by controlling reloading of the AZ with release-ready synaptic vesicles. SAD-B phosphorylates the N-terminal serine (S45) of CAST, and S45 phosphorylation increases with higher firing rate. 0.2 SIGNOR-263051 ULK2 protein Q8IYT8 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser472 THRRMVVsMPNLQDI 9606 25925668 YES lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. 0.2 SIGNOR-264732 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr454 VRGFPTIyFSPANKK -1 8631326 YES miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). 0.2 SIGNOR-262895 NDUFS8 protein O00217 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. 0.853 SIGNOR-262182 Normorphine chemical CHEBI:7633 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258822 MAPK8 protein P45983 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 10090 BTO:0001086 24913968 YES SP600125 prevented phosphorylation of STAT1 at Tyr701 site [..] Western blot analysis confirmed that blocking p-JNK using SP600125 markedly reduced STAT3 localization in the nucleus and STAT1 phosphorylation 0.446 SIGNOR-251101 LIMK2 protein P53671 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity phosphorylation 9606 30716360 YES miannu LIMK2 directly phosphorylated TWIST1, indicating that LIMK2 also regulates TWIST1 post-translationally (XREF_FIG).|LIMK2 positively regulates TWIST1 protein levels. 0.2 SIGNOR-278952 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 YES lperfetto Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1. 0.651 SIGNOR-252892 GNAI2 protein P04899 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR down-regulates 9606 BTO:0001950 20054866 YES Marta Tosoni GNAI2 can significantly inhibit HCC cell migration and invasion 0.7 SIGNOR-278881 LRRK2 protein Q5S007 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity phosphorylation Ser176 KWRMMSLsQSRSSKS 9606 27830463 YES miannu Altogether, our results indicate a scenario that LRRK2 physically interacts with Rip2 and promotes phosphorylation of Rip2.|Taken together, our results show that LRRK2 enhances Rip2 activity by promoting the phosphorylation of Rip2 at Ser176. 0.377 SIGNOR-278953 EP300 protein Q09472 UNIPROT RUNX2/EP300 complex SIGNOR-C211 SIGNOR form complex binding 10116 BTO:0002648 12697832 YES Giulio Giuliani More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex. 0.453 SIGNOR-255418 KDM3A protein Q9Y4C1 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 YES miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  0.2 SIGNOR-276845 CTSS protein P25774 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 YES miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 0.309 SIGNOR-256323 ATM protein Q13315 UNIPROT RNF138 protein Q8WVD3 UNIPROT up-regulates activity phosphorylation Ser124 IIPNFQIsQDSVGNS 9606 27195665 YES miannu We further confirm that RNF138 is phosphorylated by ATM at Ser124. 0.2 SIGNOR-279505 ACSS2 protein Q9NR19 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI down-regulates quantity chemical modification 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271827 ATM protein Q13315 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Thr367 IIYTQDFtVPGQVPE 9606 BTO:0000848 12234250 YES gcesareni We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo. 0.572 SIGNOR-92873 CDK2 protein P24941 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation 9606 23972993 YES miannu Because the APC and Cdh1 E3 ubiquitin ligase activity is inhibited by Cdk2 and cyclin A in the late G1/S phase, these results indicate that an as-yet-unidentified E3 ligase, other than Cdh1 itself, might be responsible for mediating the degradation of Cdh1 during this period.|Taken together, these results indicate that phosphorylation of Cdh1 by the Cdk2 and cyclin A complex not only is responsible for terminating the E3 ligase activity of Cdh1, but may also serve as a degradation signal for Cdh1. 0.43 SIGNOR-279512 AKT3 protein Q9Y243 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.483 SIGNOR-251626 ATG3 protein Q9NT62 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates activity binding -1 16303767 YES lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) 0.872 SIGNOR-141926 CHMP7 protein Q8WUX9 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.617 SIGNOR-265525 PAK1 protein Q13153 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser298 RTPGRPLsSYGMDSR 9606 BTO:0001955 12876277 YES lperfetto We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation. 0.58 SIGNOR-236002 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 12213813 YES lperfetto In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E 0.67 SIGNOR-262991 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270367 MAP3K7 protein O43318 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 30385786 YES miannu TAK1 inhibits YAP activity through beta-TRCP.|Thus, our data indicate that TAK1 directly phosphorylates YAP at multiple sites.|These observations prompted us to test whether TAK1 phosphorylates YAP at S127. 0.339 SIGNOR-278956 CDK2 protein P24941 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser47 DGPGLERsPGEPGGA 9606 27991597 YES miannu Sirt1 is in turn phosphorylated by Cdk2, which may further regulate its activity.|Taken together, these data demonstrate that Cdk2 deletion does not decrease Hif1\u03b1 expression induced by HX, and strongly suggests that the phosphorylation of Sirt1 at Ser47 by Cdk2 requires Sirt1 deacetylase activity. 0.466 SIGNOR-279513 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 9606 SIGNOR-C83 9840932 YES lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk4 0.718 SIGNOR-62365 CAMK2D protein Q13557 UNIPROT CAMK2D protein Q13557 UNIPROT up-regulates phosphorylation 9606 19725819 YES areggio Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels. 0.2 SIGNOR-255954 SHC1 protein P29353 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity 10090 BTO:0000944 17673906 NO lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. 0.627 SIGNOR-242625 TFEB protein P19484 UNIPROT ATP6V0E1 protein O15342 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.31 SIGNOR-276534 PBX2 protein P40425 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.251 SIGNOR-265804 FOXA1 protein P55317 UNIPROT NFIB protein O00712 UNIPROT up-regulates binding 9606 24801505 YES miannu Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex. 0.314 SIGNOR-205027 BIRC5 protein O15392 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 10587640 YES gcesareni Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21. 0.49 SIGNOR-72882 DENND3 protein A2RUS2 UNIPROT RAB12 protein Q6IQ22 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 25925668 YES lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.|active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy. 0.622 SIGNOR-264734 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 17289999 YES gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma 0.824 SIGNOR-152929 MDM2 protein Q00987 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 12821780 YES miannu We could prove that Mdm2 physically associates with IGF-1R and that Mdm2 causes IGF-1R ubiquitination in an in vitro assay. 0.66 SIGNOR-278571 MAPK1 protein P28482 UNIPROT NR2C1 protein P13056 UNIPROT down-regulates activity phosphorylation 9606 19204783 YES miannu We also reported that ERK2-phosphorylated TR2 is recruited to PML nuclear bodies (PML NBs) for its subsequent small ubiquitin-like modification (SUMOylation) and function as a potent transcriptional repressor xref , xref . 0.2 SIGNOR-278957 ARNTL protein O00327 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 16556735 YES miannu We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. 0.595 SIGNOR-268025 JAG2 protein Q9Y219 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 10958687 YES inferred from 70% of family members gcesareni Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2 0.643 SIGNOR-269935 CSNK2A2 protein P19784 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Ser483 KRSRAIHsSDEGEDQ 9606 12769847 YES llicata We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.  0.348 SIGNOR-251048 BRSK1 protein Q8TDC3 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser216 SGLYRSPsMPENLNR 9606 9543386 YES lperfetto Overexpression of hssad1 resulted in an increased phosphorylation of cdc25c on ser-216 in vivo.Phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.484 SIGNOR-56473 CNOT3 protein O75175 UNIPROT CAND2 protein O75155 UNIPROT unknown binding 10090 12207886 YES lperfetto Hnot3l is associated with tip120b / tip120b presumably affects tissue-specific transcriptional regulation via interaction with not3. 0.332 SIGNOR-235593 MTCH2 protein Q9Y6C9 UNIPROT BID protein P55957 UNIPROT up-regulates binding 9606 21295084 YES gcesareni Mtch2/mimp and its role in bid recruitment may synergise with cl-induced mitosome formation to facilitate momp. 0.303 SIGNOR-171773 HAUS7 protein Q99871 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 YES lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) 0.681 SIGNOR-262318 SLC46A1 protein Q96NT5 UNIPROT heme smallmolecule CHEBI:30413 ChEBI up-regulates quantity relocalization 9606 BTO:0000575 32621820 YES lperfetto SLC46A1 contributes to hepatic iron metabolism by importing heme in hepatocytes. 0.8 SIGNOR-268265 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.428 SIGNOR-269248 FYN protein P06241 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Tyr15 EKIGEGTyGTVFKAK 9606 14757045 YES Constitutively active Fyn phosphorylated Tyr15 of Cdk5. Fyn Facilitates Kinase Activity of Cdk5 Via Tyr15 Phosphorylation 0.607 SIGNOR-251156 EPN1 protein Q9Y6I3 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 YES lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth 0.66 SIGNOR-260716 P2RY13 protein Q9BPV8 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256749 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 YES gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. 0.305 SIGNOR-76092 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 YES gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. 0.655 SIGNOR-141428 PAK2 protein Q13177 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser9 NYLRRRLsDSNFMAN 10116 12237306 YES miannu Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues. 0.327 SIGNOR-250236 NLGN3 protein Q9NZ94 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.839 SIGNOR-264142 CTSL protein P07711 UNIPROT S protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 BTO:0000195 32142651 YES miannu SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. 0.2 SIGNOR-260737 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 YES In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. 0.2 SIGNOR-251326 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.2 SIGNOR-275958 UNG protein P13051 UNIPROT 5-fluorouracil chemical CHEBI:46345 ChEBI down-regulates quantity by destabilization chemical modification 9606 27875297 YES lperfetto Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents.  0.8 SIGNOR-264888 MDM2 protein Q00987 UNIPROT POLQ protein O75417 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22056306 YES miannu In addition, we showed that Mdm2 is able to promote the PolH ubiquitination and degradation.|In contrast, ectopically expression of Mdm2 decreases PolH expression, which can be abrogated by the proteasome inhibitor MG132. 0.2 SIGNOR-278827 PRKACA protein P17612 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity phosphorylation 9606 28934360 YES miannu Mutagenesis indicated that PKACalpha phosphorylated wild-type VISA and the VISA mutants VISA (S100A), VISA (T234A) and VISA (S238A) but not VISA (T54A) (XREF_FIG, panel C).|We found that PKACalpha caused degradation of wild-type VISA but not VISA (T54A) or VISA (K7/500R), in which either the PKACs mediated phosphorylation or MARCH5 mediated K48 linked polyubiquitination residues are mutated (XREF_FIG, panel G). 0.283 SIGNOR-279649 dehydroepiandrosterone chemical CHEBI:28689 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9489820 YES systemic lupus erythematosus gcesareni 0.8 SIGNOR-251707 TNF protein P01375 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 NO miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 0.2 SIGNOR-254809 GSK3B protein P49841 UNIPROT PSEN1 protein P49768 UNIPROT down-regulates activity phosphorylation Ser353 SHLGPHRsTPESRAA 9606 BTO:0000007 SIGNOR-C110 17360711 YES gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. 0.587 SIGNOR-153627 EDNRB protein P24530 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.448 SIGNOR-257053 S protein P59594 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16940539 NO miannu Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein. 0.2 SIGNOR-260351 NOD2 protein Q9HC29 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000567 19898471 NO miannu Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. 0.7 SIGNOR-252403 TAB1 protein Q15750 UNIPROT ROR2 protein Q01974 UNIPROT down-regulates phosphorylation 9606 18762249 YES gcesareni Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain 0.278 SIGNOR-180566 PRKCE protein Q02156 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 BTO:0000944 12052829 YES lperfetto Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms. 0.2 SIGNOR-263048 MAPK14 protein Q16539 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 NO Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). 0.2 SIGNOR-251838 MAPK4 protein P31152 UNIPROT DUSP2 protein Q05923 UNIPROT up-regulates activity phosphorylation 9606 28252035 YES miannu However, co-expression of ERK4 significantly increased the half-life of DUSP2 (XREF_FIG).|In support of the latter notion we have shown that wild-type ERK4 can phosphorylate DUSP2 in vitro and future studies will be aimed at identifying the relevant site (s) of modification and determining their influence on DUSP2 stability. 0.354 SIGNOR-278959 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT up-regulates quantity transcriptional regulation 10090 29106906 YES Gianni We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. 0.421 SIGNOR-268870 ERG protein P11308 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19396168 NO miannu ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. 0.2 SIGNOR-253911 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12707358 YES lperfetto These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. 0.377 SIGNOR-217442 BAG1 protein Q99933 UNIPROT HSPA8 protein P11142 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0001538 11676916 YES miannu BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association 0.895 SIGNOR-272589 SLC2A1 protein P11166 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 23506862 YES miannu GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells. 0.8 SIGNOR-267458 RAB6C protein Q9H0N0 UNIPROT VPS13B protein Q7Z7G8 UNIPROT up-regulates activity binding 10116 BTO:0003102 25492866 YES miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. COH1 Interacts with All Three Mammalian RAB6 Homologues 0.2 SIGNOR-266871 MAPK1 protein P28482 UNIPROT YBX1 protein P67809 UNIPROT up-regulates activity phosphorylation 9606 19036157 YES miannu ERK2 may also directly phosphorylate YB-1 and therefore promotes its ability to transactivate target genes. 0.471 SIGNOR-279227 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser103 EGISQESsEEEQ -1 2806554 YES llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. 0.328 SIGNOR-251005 STK17A protein Q9UEE5 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000776 17339337 YES gcesareni Genetic and biochemical studies have shown that ser20 phosphorylation in the transactivation domain of p53 mediates p300-catalyzed dna-dependent p53 acetylation and b-cell tumor suppression. a cell-free ser20 phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser20 kinases. 0.286 SIGNOR-153532 ARID1A protein O14497 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.787 SIGNOR-270729 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1092 TFLPVPEyINQSVPK 9606 BTO:0000567 10653583 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. 0.2 SIGNOR-236479 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 9405416 YES Inactive c-Jun NH2-terminal kinase (JNK). gcesareni C-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk).Phosphorylation By activated jnk protects c-jun from ubiquitination. 0.884 SIGNOR-53791 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser293 SSGYFSSsPTLSSSP 9606 22017875 YES llicata Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome. 0.754 SIGNOR-176849 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Thr326 GCYSVPTtPEDFLSN 26375055 YES lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity 0.258 SIGNOR-276519 SOX9 protein P48436 UNIPROT MITF protein O75030 UNIPROT up-regulates activity binding 10090 20530484 YES miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. 0.384 SIGNOR-255183 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser831 EPVEQDSsQPSLPLV 9606 22621922 YES gcesareni Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm. 0.873 SIGNOR-197615 452342-67-5 chemical CID:10202642 PUBCHEM TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 BTO:0000671 18075500 YES gcesareni Gw788388 is a new tgf-beta type i receptor inhibitor with a much improved pharmacokinetic profile compared with sb431542. 0.8 SIGNOR-159863 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT up-regulates activity phosphorylation Tyr302 GYRDSGYyWEVPPSE 9534 9020159 YES lperfetto A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation 0.487 SIGNOR-236459 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1D protein P25100 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190642 PLCG2 protein P16885 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10116 BTO:0002013 29430764 NO Marta Tosoni PLCγ2 induces apoptosis in rat hepatocytes in vitro. 0.7 SIGNOR-278087 SP1 protein P08047 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15479157 NO miannu we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity. 0.2 SIGNOR-255204 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp638 KLVFFAEdVGSNKGA -1 8943232 YES lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261764 RPS6K proteinfamily SIGNOR-PF26 SIGNOR SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 YES gcesareni The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange. 0.2 SIGNOR-252792 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269375 PTK2B protein Q14289 UNIPROT ID3 protein Q02535 UNIPROT up-regulates quantity phosphorylation 9606 25090023 YES miannu Taken together these findings demonstrated that Pyk2 mediates the expression of ID3 protein.|Together these findings from the combined MS+MS/MS data confirm that Flag tagged ID3 is phosphorylated by active recombinant Pyk2 kinase; and support the phospho-Tyr band that was detected at the corresponding MW ~ 13 kDA for Flag-ID3 by immunoblot. 0.2 SIGNOR-278496 MAPK1 protein P28482 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates phosphorylation Ser74 DKATQTLsPASPSQG 9606 BTO:0000785 22258404 YES llicata Phosphomimetic mutation of this site (s74d) moderately enhanced bmf apoptotic activity in vivo.22 here, we demonstrate a previously unrecognized mode of regulation of bmf. We show that b-raf-mek-erk2 signaling regulates bmf phosphorylation at serine 74 and serine 77. Phosphorylation of serine 77 downregulates the pro-apoptotic activity of bmf. 0.253 SIGNOR-195471 CDK1 protein P06493 UNIPROT STMN1 protein P16949 UNIPROT up-regulates activity phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 8125092 YES lperfetto 0.64 SIGNOR-279802 NR5A1 protein Q13285 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 NO miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.48 SIGNOR-254871 EGFR protein P00533 UNIPROT STAM2 protein O75886 UNIPROT unknown phosphorylation Tyr192 HTETKSLyPSSEIQL -1 11687594 YES llicata Another major tyrosine phosphorylation site of STAM2 was identified as Tyr-192 0.605 SIGNOR-251097 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2A complex SIGNOR-C347 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 YES lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically 0.8 SIGNOR-268277 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser364 LQSPITTsPSC 9606 10617468 YES lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. 0.805 SIGNOR-73625 TFAP2A protein P05549 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19745029 NO miannu Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2. 0.2 SIGNOR-255189 MAPK3 protein P27361 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Ser21 KRTSSPRsPPSSSEI 9606 25728771 YES lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation 0.2 SIGNOR-264773 CSNK2B protein P67870 UNIPROT OCLN protein Q16625 UNIPROT unknown phosphorylation Ser408 DYTTGGEsCDELEED 9606 BTO:0002043 12804768 YES llicata Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin. 0.416 SIGNOR-251079 DAPK1 protein P53355 UNIPROT PIN1 protein Q13526 UNIPROT down-regulates activity phosphorylation Ser71 HSQSRRPsSWRQEKI 9606 21497122 YES miannu DAPK1 inhibits Pin1 nuclear localization and cellular function.|DAPK1 interacts with and phosphorylates Pin1 on Ser71 in vitro and in vivo. 0.369 SIGNOR-278160 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 16440056 NO lperfetto A second cytoplasmic dynein complex, cytoplasmic dynein 2, has a role in intraflagellar transport (IFT), a process required for ciliary/flagellar assembly 0.7 SIGNOR-265022 IKBKE protein Q14164 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation 9606 29425491 YES miannu While IKK\u03b5 phosphorylates and activates PDE3B to induce catecholamine resistance, TBK1 inhibits AMPK activity to reduce catabolism via this pathway. 0.2 SIGNOR-278517 FOXA2 protein Q9Y261 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14739090 NO lperfetto The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma. 0.2 SIGNOR-268987 PRKCB protein P05771 UNIPROT CYTH2 protein Q99418 UNIPROT down-regulates activity phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 BTO:0000567 10531036 YES lperfetto ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'. 0.307 SIGNOR-249024 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation 9606 19047375 YES gcesareni B2 adrenergic receptor stimulation induces the pka dependent phosphorylation of heptp and releases bound p38 mapk 0.362 SIGNOR-182522 ULK1 protein O75385 UNIPROT FUNDC1 protein Q8IVP5 UNIPROT up-regulates activity phosphorylation Ser17 DYESDDDsYEVLDLT 9606 27757847 YES miannu As we have mentioned previously, ULK1 kinase promotes the phosphorylation of FUNDC1 Ser17, enhancing the interaction with LC3B during mitophagy. 0.594 SIGNOR-279001 WNT10B protein O00744 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.609 SIGNOR-131631 PTPN2 protein P17706 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 12612081 NO acerquone We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling. 0.357 SIGNOR-252640 NUMA1 protein Q14980 UNIPROT TUBA1C protein Q9BQE3 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.259 SIGNOR-116677 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 0.2 SIGNOR-22577 RNF216 protein Q9NWF9 UNIPROT TIRAP protein P58753 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16968706 YES miannu Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins. 0.387 SIGNOR-271607 alanine smallmolecule CHEBI:16449 ChEBI Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates quantity precursor of 9606 32314272 YES miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). 0.8 SIGNOR-270452 VEPH1 protein Q14D04 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 NO In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 0.2 SIGNOR-269858 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 YES lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases 0.34 SIGNOR-101306 Calprotectin complex complex SIGNOR-C293 SIGNOR Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000876 16690079 YES miannu Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner 0.2 SIGNOR-262827 RPS13 protein P62277 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.895 SIGNOR-262439 MDM4 protein O15151 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization binding 9606 10218570 YES miannu MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2. 0.732 SIGNOR-272932 PPM1A protein P35813 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity dephosphorylation Ser536 SGDEDFSsIADMDFS 9606 23812431 YES lperfetto We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-kappaB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1 and chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis.|18 Wild-type, but not phosphatase-dead, PPM1A dephosphorylated the pS536 peptide with equivalent efficacy as the known RelA S536 phosphatase, Wip1 (XREF_FIG, compare lanes 4 and 7).|Taken together, these data suggest that dephosphorylation of S276 by PPM1A may contribute to inhibit RelA transcriptional activity, but the majority of PPM1A activity to inhibit RelA transcription relies on dephos phorylation of S536 of RelA. 0.353 SIGNOR-276964 SMDT1 protein Q9H4I9 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.634 SIGNOR-270866 CHEK1 protein O14757 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT down-regulates activity phosphorylation Ser251 RRLRRSHsGPAGSFN -1 22505024 YES miannu Our results suggest that Chk1 phosphorylates Mig-6 on Ser 251, resulting in the inhibition of Mig-6, and that Chk1 acts as a positive regulator of EGF signalling. This is a novel function of Chk1. 0.327 SIGNOR-276411 TUFM protein P49411 UNIPROT ATG5 protein Q9H1Y0 UNIPROT down-regulates activity binding 9606 33113344 YES miannu PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy. 0.424 SIGNOR-266383 MAOB protein P27338 UNIPROT (R)-adrenaline smallmolecule CHEBI:28918 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 YES Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. 0.8 SIGNOR-269746 AMPA proteinfamily SIGNOR-PF58 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 NO inferred from family member Luana AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by na√Øve ones. 0.7 SIGNOR-267783 CDK1 protein P06493 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity phosphorylation Ser668 DTQSRTAsPNRAGKG 9606 24189531 YES miannu In vitro kinase assays reveal that CDK1 directly phosphorylates HIF-1\u03b1 at a previously unidentified regulatory site, Ser668.|Overexpression of CDK1 and/or cyclin B1 is sufficient to stabilize HIF-1alpha under normoxic conditions, whereas inhibition of CDK1 enhances the proteasomal degradation of HIF-1alpha, reducing its half-life and steady-state levels. 0.274 SIGNOR-279599 CHKA protein P35790 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 20708156 YES miannu The data presented here provides evidence for a molecular mechanism by which CKI-dependent phosphorylation of Mdm2 at multiple sites triggers SCF \u03b2-TRCP -mediated Mdm2 destruction ( xref ). 0.274 SIGNOR-279606 PDGFRB protein P09619 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation 9606 15994317 YES miannu The platelet-derived growth factor receptor-beta phosphorylates and activates G protein-coupled receptor kinase-2.|We conclude that the activated PDGFRbeta itself phosphorylates GRK2 tyrosyl residues and thereby activates GRK2, which then serine phosphorylates and desensitizes the PDGFRbeta. 0.2 SIGNOR-278972 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT up-regulates activity phosphorylation 9606 31938050 YES miannu These novel findings establish a direct connection between the ubiquitination of UCK1 by KLHL2 and phosphorylation of USP28 and UCK1 by ATM, which are involved in mediating drug resistance against 5'-AZA in AML patients. 0.312 SIGNOR-279007 DYRK1A protein Q13627 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 16959772 YES lperfetto In vitro kinase assay of anti-dyrk1a immunocomplexes demonstrated that dyrk1a could phosphorylate alpha-synuclein at ser-87. Furthermore, aggregates formed by phosphorylated alpha-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type alpha-synuclein. These findings suggest alpha-synuclein inclusion formation regulated by dyrk1a, potentially affecting neuronal cell viability. 0.562 SIGNOR-149393 SLBP protein Q14493 UNIPROT H2BW2 protein P0C1H6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265395 ARTN protein Q5T4W7 UNIPROT GFRA3 protein O60609 UNIPROT up-regulates binding 9606 BTO:0000938 9883723 YES gcesareni Here, we report the identification of artemin, a novel member of the gdnf family, and demonstrate that it is the ligand for the former orphan receptor gfralpha3-ret. Artemin can also activate the gfralpha1-ret complex. 0.761 SIGNOR-63009 PRKCA protein P17252 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Ser48 RQGGRTSsQRQRDPE 9606 BTO:0001130 11980664 YES llicata Phosphorylation of wild-type nkx3.1 decreased the apparent binding affinity of the protein for the consensus sequence by 3-fold relative to the nonphosphorylated protein (fig. 3) _ . 0.2 SIGNOR-86723 CDH2 protein P19022 UNIPROT CDON protein Q4KMG0 UNIPROT up-regulates binding 9606 SIGNOR-C21 20160094 YES gcesareni We report here that n-cadherin ligation activates p38alpha/beta in myoblasts in a cdo-, bnip-2-, and jlp-dependent manner 0.647 SIGNOR-163844 ERCC8 protein Q13216 UNIPROT RAD23B protein P54727 UNIPROT up-regulates activity 24086043 NO lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.552 SIGNOR-275693 ATIC protein P31939 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI down-regulates quantity chemical modification 9606 33179964 YES miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. 0.8 SIGNOR-267325 CDK8 protein P49336 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. 0.2 SIGNOR-273175 CAPRIN1 protein Q14444 UNIPROT G3BP1 protein Q13283 UNIPROT up-regulates activity binding 9606 17210633 YES SARA Caprin-1 and G3BP-1 were directly or indirectly associated in a stable complex. The Caprin-1/G3BP-1 complex occurs in cytoplasmic RNA granules 0.589 SIGNOR-260982 EIF2S1 protein P05198 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24714526 NO miannu Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy. 0.2 SIGNOR-251819 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 9606 24252238 YES miannu Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates. 0.473 SIGNOR-255679 TGFB1 protein P01137 UNIPROT SLC20A1 protein Q8WUM9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000249 20930330 NO miannu TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line. 0.2 SIGNOR-252202 LATS2 protein Q9NRM7 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT down-regulates activity phosphorylation Ser159 HGHVRSLsERLLQLS 24225952 YES lperfetto The N-terminal regions of Amot proteins contain a conserved HXRXXS consensus site for LATS1/2-mediated phosphorylation.|Amot family members. Knockdown of LATS1 and LATS2 endogenously reduced the phosphorylation of Amots detected by the phospho-specific antibodies. Mutation of the serine to alanine within this HXRXXS site in Amot and AmotL2 established that this site was essential for Hippo core kinase-mediated phosphorylation. Wild-type and non-phosphorylated Amot (Amot-S175A) were targeted to actin filaments, whereas phospho-mimic Amot (Amot-S175D) failed to be localized with actin. 0.727 SIGNOR-272084 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser643 CFTPKGSsLKIEERA 9606 BTO:0000887;BTO:0001260 8182108 YES gcesareni Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase. 0.357 SIGNOR-36788 FYN protein P06241 UNIPROT MED28 protein Q9H204 UNIPROT up-regulates phosphorylation Tyr64 ASLVSQDyVNGTDQE 9606 BTO:0001271;BTO:0000661 16899217 YES fstefani To unravel the cellular functions of magicin, we used a yeast two-hybrid system and identified fyn tyrosine kinase as a specific binding partner for magicin. Fyn phosphorylates magicin in vitro. 0.446 SIGNOR-148700 JNK proteinfamily SIGNOR-PF15 SIGNOR BAX protein Q07812 UNIPROT up-regulates 9606 15071501 NO inferred from 70% family members gcesareni Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria; these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins. 0.2 SIGNOR-269977 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120188 Caspase 6 complex complex SIGNOR-C228 SIGNOR CASP8 protein Q14790 UNIPROT up-regulates cleavage 9606 11455969 YES gcesareni This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8. 0.735 SIGNOR-256468 ACLY protein P53396 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity by destabilization chemical modification 9606 19286649 YES miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. 0.8 SIGNOR-268082 SAGA complex complex SIGNOR-C465 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269638 ROS stimulus SIGNOR-ST2 SIGNOR MAP3K5 protein Q99683 UNIPROT up-regulates 9606 11266364 NO lperfetto TNF- but not Fas-induced apoptosis requires ROS-dependent activation of ASK1_JNK/p38 pathways. Thus, ASK1 is selectively required for TNF- and oxidative stress-induced sustained activations of JNK/p38 and apoptosis. 0.7 SIGNOR-226609 COX7B protein P24311 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.664 SIGNOR-267745 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 21900390 YES miannu BRAFV600E has been shown to initiate thyroid follicular cell transformation. The BRAFV600E mutation disrupts the hydrophobic interaction, enabling the BRAF kinase to fold into a catalytically active formation, resulting in an almost 500-fold increase in kinase activity. Mutant BRAF can dimerize and activate MEK without Ras activation. 0.789 SIGNOR-251988 MRPS26 protein Q9BYN8 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.705 SIGNOR-261447 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0000552 11013220 YES irozzo TGF-β induces the formation and nuclear translocation of a trimeric Smad complex, which in this case is likely to consist of one monomer each of Smad2, Smad3 and Smad4. Smad2 and Smad4 associate directly with Sp1 and co-activate the transcriptional activity of Sp1. 0.6 SIGNOR-256288 dimethyloxalylglycine chemical CHEBI:102218 ChEBI EGLN3 protein Q9H6Z9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000018 28900510 YES lperfetto We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1. 0.8 SIGNOR-261993 SGK1 protein O00141 UNIPROT KMT2D protein O14686 UNIPROT down-regulates activity phosphorylation Ser1331 RGRARLKsTASSIET 9606 BTO:0002181 30943409 YES miannu  Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity.  0.283 SIGNOR-277447 TWIST1 protein Q15672 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.481 SIGNOR-255526 ZMYND8 protein Q9ULU4 UNIPROT NAV2 protein Q8IVL1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 21620140 YES Luana We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.  0.2 SIGNOR-266209 APC2 protein O95996 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 9601641 YES acerquone Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells. 0.77 SIGNOR-57673 FYN protein P06241 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation 9606 26848862 YES miannu FYN phosphorylates FLT3 on tyrosine residues (A\u2013B) COS1 cells were transfected with plasmids expressing FLT3 wild-type and FYN wild-type or mutants.|It was not completely unexpected that FYN associates wild-type FLT3 in the absence of ligand stimulation in COS-1 cells, as overexpression of wild-type FLT3 results in ligand independent activation of FLT3 (data not shown). 0.293 SIGNOR-279715 glutamic acid smallmolecule CHEBI:18237 ChEBI AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity chemical activation 9606 15919192 YES miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. 0.8 SIGNOR-264696 PYGB protein P11216 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267952 PRKCB protein P05771 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 11700305 YES lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | 0.353 SIGNOR-249122 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268596 ALDH1A1 protein P00352 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI down-regulates quantity chemical modification 9606 21621639 YES lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. 0.8 SIGNOR-265122 SMAD9 protein O15198 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR form complex binding 10116 9371779 YES ggiuliani As shown in Fig. 2, immunoprecipitation of Smad8 with an anti-myc antibody could bring down the Flag-tagged Smad4 only in the presence of CA-ALK-2, indicating that only activation of ALK-2 but not ALK-4 could induce the heteromerization of Smad8 with Smad4. 0.684 SIGNOR-255776 3-methyladenine chemical CHEBI:38635 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205639 Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 10090 9388774 NO gcesareni Myogenic precursor cells withdraw irreversibly from the cell cycle as they differentiate into mature myotubes. Cell cycle exit occurs early during the differentiation program and is required for normal expression of the contractile phenotype. 0.7 SIGNOR-243206 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Thr211 DHPYASLtLPDDAAA 33850055 YES lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o 0.2 SIGNOR-275647 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 YES The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. 0.342 SIGNOR-138916 ATR protein Q13535 UNIPROT BLM protein P54132 UNIPROT up-regulates activity phosphorylation 9606 11916980 YES miannu It is noteworthy that an active BLM seems to be unnecessary to the activation of BRCA1, either after gamma-rays or HU, even though BRCA1 and BLM helicase are activated by ATR in response to stalled replication, and despite the fact that they colocalize after replication arrest.|These results show that BLM phosphorylation by ATR after replication fork arrest is not important for its relocalization. 0.851 SIGNOR-278978 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr118 VGEEEHVySFPNKQK 9606 15688067 YES miannu Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites. 0.914 SIGNOR-28243 HNRNPA2B1 protein P22626 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24792867 NO miannu Hnrnpa2/b1 protein directly interacts with the r1 and r2 regions ofcdk5r13_-utr and displays a negative regulatory activity on its expression 0.2 SIGNOR-205023 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-252975 USF1 protein P22415 UNIPROT FOSL1 protein P15407 UNIPROT down-regulates activity binding 10090 9160889 YES 2 miannu USF specifically interacts with Fra1. USF was repressing this modest Fra1 transactivation 0.466 SIGNOR-240975 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 20444238 YES gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.423 SIGNOR-165212 CSNK1A1 protein P48729 UNIPROT RHOB protein P62745 UNIPROT down-regulates phosphorylation Ser185 ALQKRYGsQNGCINC 9606 BTO:0000567 18590726 YES llicata Mass spectrometry analysis demonstrates that rhob is monophosphorylated by ck1, in its c-terminal end, on serine 185. lastly we show that the inhibition of ck1 activates rhob and promotes rhob dependent actin fiber formation and egf-r level. 0.2 SIGNOR-179255 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2039 GLGQVGIsPLKPGTV 9606 BTO:0000551 24530506 YES miannu In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels.  0.2 SIGNOR-276458 CSNK2B protein P67870 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275760 belinostat chemical CHEBI:61076 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257956 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Thr154 SSKRSPStATLSLPS 9606 BTO:0001061 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276777 MBD1 protein Q9UIS9 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 15657354 NO Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT. 0.251 SIGNOR-254036 RAN protein P62826 UNIPROT XPO1 protein O14980 UNIPROT up-regulates activity binding 31075303 YES Ran ID inferred from sequence: KRHLTGEFEKKYVATLGVEV lperfetto The nuclear export by CRM1 requires an interaction with the small GTPase Ras-related nuclear antigen (Ran), which cycles between GTP- and GDP-bound states. The binding of Ran GTP to CRM1 in the nucleus increases the affinity of CRM1 for cargo proteins 0.928 SIGNOR-275848 MCRS1 protein Q96EZ8 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.523 SIGNOR-270844 SP1 protein P08047 UNIPROT HYAL1 protein Q12794 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004796 18718911 NO miannu in cells which do not express HYAL-1, we found SP1 binding to the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription. 0.2 SIGNOR-253879 MASTL protein Q96GX5 UNIPROT ARPP19 protein P56211 UNIPROT up-regulates activity phosphorylation Ser62 KGQKYFDsGDYNMAK -1 21164014 YES gcesareni We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. 0.729 SIGNOR-243611 clobetasol chemical CHEBI:205919 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation 9606 4594577 YES SimoneGraziosi The clinical evaluation of a new topical corticosteroid, clobetasol propionate. An international controlled trial. 0.8 SIGNOR-269217 GTF2I protein P78347 UNIPROT ARID3A protein Q99856 UNIPROT up-regulates activity binding 9606 BTO:0000776 16738337 YES lperfetto In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels. 0.35 SIGNOR-268533 LRP6 protein O75581 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity 15229249 NO We speculate that DKK1 produced by βAP-treated neurons suppresses the canonical Wnt signaling pathway by interacting with LRP5/6 and therefore facilitates GSK3β activation. 0.793 SIGNOR-255484 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR4 protein Q13639 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257524 RPGRIP1 protein Q96KN7 UNIPROT RPGR protein Q92834 UNIPROT down-regulates activity binding 9606 20631154 YES miannu The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. As RPGRIP1 appears to link RPGR to the cilium, it is possible that RPGR's effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments. 0.715 SIGNOR-253031 DOCK1 protein Q14185 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0001909 25533347 YES miannu We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth. 0.734 SIGNOR-266822 CDK1 protein P06493 UNIPROT LBR protein Q14739 UNIPROT down-regulates phosphorylation Ser71 KGGSTSSsPSRRRGS 9606 14718546 YES lperfetto The binding of the nk fragment to chromatin pretreated with an s-phase extract was suppressed by incubation with an m-phase extract. Enzyme inhibitor experiments revealed that multiple kinases participate in the suppression. One of these kinases was shown to be cdc2 experiments involving a mutant nk fragment showed that the phosphorylation of serine 71 by cdc2 kinase is responsible for the suppression. 0.396 SIGNOR-121335 PFKFB3 protein Q16875 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity chemical modification 9606 9404080 YES A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. 0.8 SIGNOR-267260 SGK1 protein O00141 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation 9606 30382187 YES miannu Notably, A\u03b2-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1\u2013368). 0.252 SIGNOR-279281 PRKCA protein P17252 UNIPROT PITPNC1 protein Q9UKF7 UNIPROT up-regulates activity phosphorylation Ser274 SVRSAPSsAPSTPLS 9534 BTO:0000298 21728994 YES done miannu Only BIM-I caused a reduction in 14-3-3 binding (Figure 3B), suggesting that PKC could be responsible for one or both of the serine phosphorylations, pSer274 and pSer299. 0.32 SIGNOR-273800 WNT5A protein P41221 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 9054360 YES gcesareni These results identify hfz5 as a receptor for wnt-5a. 0.831 SIGNOR-46897 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 YES lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 0.8 SIGNOR-265118 ERG protein P11308 UNIPROT EPB41L4B protein Q9H329 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20860828 NO miannu EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. 0.2 SIGNOR-253919 zotepine chemical CHEBI:32316 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258554 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.282 SIGNOR-275792 PRKACA protein P17612 UNIPROT CDK18 protein Q07002 UNIPROT up-regulates activity phosphorylation Ser14 KNFKRRFsLSVPRTE 28361970 YES lperfetto We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro.  0.225 SIGNOR-264560 PGM2 protein Q96G03 UNIPROT 2-deoxy-D-ribose 5-phosphate smallmolecule CHEBI:16132 ChEBI up-regulates quantity chemical modification 9606 17804405 YES miannu Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. 0.8 SIGNOR-267095 ERG protein P11308 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25277175 NO miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. 0.335 SIGNOR-251556 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr175 HDTSFAKtFVGTPYY 9606 17197699 YES gcesareni Enzymatic activity, induced; 0.2 SIGNOR-151763 PRKCD protein Q05655 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 YES gcesareni Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. 0.343 SIGNOR-115722 PCSK7 protein Q16549 UNIPROT RELA protein Q04206 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 NO lperfetto Treatment with sb203580 significantly reduced this cooperation, consistent with the idea that p38 indirectly stimulates the transactivating activity of p65 through a mechanism involving cbp. 0.2 SIGNOR-235734 CSNK2A1 protein P68400 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Ser87 GDDEDACsDTEATEA -1 8288648 YES llicata Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action. 0.307 SIGNOR-250929 PIK-90 chemical CID:6857685 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206223 GNAQ protein P50148 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity binding 10090 BTO:0000944 12024019 YES Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. 0.42 SIGNOR-256520 IKBKB protein O14920 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 9606 30478303 YES miannu Here , we show that IKKbeta modulates the activity of p53 in response to glutamine depletion to promote cancer cell adaptation .|Taken together, these results indicate that IKK\u03b2 phosphorylates p53 on Ser392 as an early response to glutamine deprivation and possibly later facilitates its phosphorylation at Ser15 and transcriptional activity. 0.521 SIGNOR-278516 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR LARP7 protein Q4G0J3 UNIPROT down-regulates quantity by destabilization ubiquitination 32726637 YES lperfetto Here, we demonstrate that upon genotoxic stress, BRCA1 together with BARD1 catalyzes the K48 polyubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degrades it through the 26S ubiquitin-proteasome pathway. 0.2 SIGNOR-275581 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TCF3 protein P15923 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 BTO:0000944 14592976 YES inferred from 70% family members lperfetto Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG) 0.2 SIGNOR-270139 AP3M1 protein Q9Y2T2 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 YES lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) 0.872 SIGNOR-260682 STAT5A protein P42229 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 25506346 YES lperfetto The GM-CSF receptor forms a dodecamer structure and recruits JAK2, leading to the activation of STAT5, extracellular signal-regulated kinase (ERK), V-Akt murine thymoma viral oncogene homolog 1 (AKT), and the nuclear translocation of NF-kappaB and IRF5 0.287 SIGNOR-249508 PTK6 protein Q13882 UNIPROT CBL protein P22681 UNIPROT down-regulates activity phosphorylation 9606 23352614 YES miannu Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl. 0.487 SIGNOR-279348 CRKL protein P46109 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 9606 BTO:0005029 28723560 YES irozzo Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation.In conclusion, our study identified CRKL as an important regulator of PI3K activity in PTEN-deficient tumor cells through its association with p110β/p85. 0.472 SIGNOR-255821 PRKAA1 protein Q13131 UNIPROT GAPDH protein P04406 UNIPROT up-regulates activity phosphorylation Ser122 GAKRVIIsAPSADAP 10090 26626483 YES Luana  Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated.  0.293 SIGNOR-259857 POFUT1 protein Q9H488 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 12909620 YES Fucosylation gcesareni Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling. 0.744 SIGNOR-104627 PKA proteinfamily SIGNOR-PF17 SIGNOR PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Ser189 GGGERFDsLTDLVEH 9606 BTO:0002181 25802336 YES miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  0.2 SIGNOR-276894 ERO1A protein Q96HE7 UNIPROT ERP44 protein Q9BS26 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 11847130 YES Simone Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits. 0.2 SIGNOR-261049 MRPL58 protein Q14197 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.2 SIGNOR-262344 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr13 AVLADVSyLMAMEKS 9606 BTO:0000007 16725308 YES miannu Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.  0.2 SIGNOR-266307 metyrapone chemical CHEBI:44241 ChEBI CYP11B1 protein P15538 UNIPROT down-regulates activity chemical inhibition -1 21129965 YES Luana In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades. 0.8 SIGNOR-257884 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.632 SIGNOR-249464 PYCARD protein Q9ULZ3 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.651 SIGNOR-256405 GLUL protein P15104 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI down-regulates quantity chemical modification 9606 30158707 YES miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. 0.8 SIGNOR-267825 DUSP7 protein Q16829 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation 10029 BTO:0000246 12907755 YES Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR 0.314 SIGNOR-248726 OPHN1 protein O60890 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 BTO:0000938 12932438 NO miannu These results based on the immunodetection of the endogenous protein clearly show that OPHN1 colocalizes with F-actin in both neuronal and glial cells and suggest that OPHN-1 interacts with actin. 0.7 SIGNOR-268400 USP9X protein Q93008 UNIPROT UBA52 protein P62987 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.61 SIGNOR-270825 AMPK complex SIGNOR-C15 SIGNOR ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 17097062 YES lperfetto Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp. 0.2 SIGNOR-216519 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR up-regulates relocalization 9606 25627476 YES lperfetto One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP.  0.2 SIGNOR-267006 RARA protein P10276 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 10607566 NO gcesareni We shown that retinoic acid (ra) decreases the activity of the beta-catenin-lef/tcf signaling pathway 0.376 SIGNOR-73274 RHCE protein P18577 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.322 SIGNOR-266022 Ub:E2 complex SIGNOR-C497 SIGNOR PLAGL1 protein Q9UM63 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270997 S protein P59594 UNIPROT CXCL8 protein P10145 UNIPROT up-regulates quantity 9606 BTO:0000801 17412287 NO lperfetto The ability of S-protein to induce TNF-a 0.2 SIGNOR-260279 POLR2K protein P53803 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.827 SIGNOR-266168 FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14592841 NO Thus, induction of C/EBPα and PU.1 expression is inhibited in 32D cells due to the expression of FLT3/ITD 0.631 SIGNOR-261529 PRKCB protein P05771 UNIPROT MSX2 protein P35548 UNIPROT up-regulates quantity phosphorylation Thr141 CTLRKHKtNRKPRTP 9606 22633971 YES miannu PKCbeta increased the level of overexpressed Msx2, but PKC alpha, delta and zeta did not have any significant effects.|Thr135 and Thr141 in Msx2 can be phosphorylated by PKC\u03b2, and Thr135 is important for regulating the protein stability of Msx2 by PKCs. 0.322 SIGNOR-278983 PRKG2 protein Q13237 UNIPROT SOX9 protein P48436 UNIPROT down-regulates activity phosphorylation 9606 19543319 YES miannu Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines|Prkg2 transfected glioma cell lines express a functional cGKII that can phosphorylate VASP and Sox9. 0.502 SIGNOR-278985 PTK2 protein Q05397 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation 9606 25472995 YES miannu Inhibition of FAK by its small molecule inhibitor attenuated IL-33-induced tyrosine 216 phosphorylation of GSK3beta in a both time- and dose dependent manner (XREF_FIG).|The current study indicates that FAK activated GSK3beta modulates ST2L internalization and signaling. 0.365 SIGNOR-278986 MYO5A protein Q9Y4I1 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 21077886 NO miannu Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis 0.7 SIGNOR-269279 PRKCA protein P17252 UNIPROT ACO1 protein P21399 UNIPROT down-regulates phosphorylation Ser711 REFNSYGsRRGNDAV 9606 BTO:0000671 15636585 YES gcesareni Irp1 ser-711 is a phosphorylation site, critical for regulation of rna-binding and aconitase activities. 0.2 SIGNOR-133188 RAB7A protein P51149 UNIPROT ALS2 protein Q96Q42 UNIPROT down-regulates activity binding 9606 BTO:0000567 30485418 YES miannu The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis 0.305 SIGNOR-277778 Av/b5 integrin complex SIGNOR-C178 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.648 SIGNOR-257723 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity phosphorylation Thr251 TRPQEQStGDTMGRD -1 21775627 YES lperfetto Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition 0.65 SIGNOR-265010 LTF protein P02788 UNIPROT ITLN1 protein Q8WWA0 UNIPROT up-regulates activity binding 9606 23921499 YES Intelectin 1 (IntL) is known as a lectin expressed in intestinal epithelia and also as a receptor for an iron-binding protein, lactoferrin (LF).  0.363 SIGNOR-272500 CHUK protein O15111 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT up-regulates activity phosphorylation Ser593 NYKELKRsLENPAER 10090 BTO:0002572 21765415 YES The effect has been demonstrated using Q86VP1-2 lperfetto Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, But not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1). 0.383 SIGNOR-175058 CSNK2A2 protein P19784 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser717 LKEAEEEsSEDD 9606 11500362 YES llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  0.37 SIGNOR-250989 STAT1 protein P42224 UNIPROT IL12B protein P29460 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 19029990 NO lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. 0.466 SIGNOR-249500 SGK1 protein O00141 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation Thr23 EMRERLGtGGFGNVC 9606 19088076 YES miannu SGK1 directly phosphorylates IKKalpha at Thr 23 and indirectly activates IKKalpha at Ser 180.|SGK1 directly phosphorylates IKKalpha at Thr-23 and indirectly activates IKKalpha at Ser-180. 0.26 SIGNOR-278987 SGK1 protein O00141 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates quantity phosphorylation Ser104 LTFDSSFsPNTGKKN 9606 30929899 YES miannu As hypothesized based upon our observation that activated SGK-1 reduces VDAC-1 protein levels, sgk-1 overexpression normalizes the shortened lifespan of vdac-1 transgenics .|Taken together, these data indicate that Ser104 phosphorylation of VDAC1 by SGK1 increases its ubiquitination and subsequent cellular clearance. 0.2 SIGNOR-278988 SRC protein P12931 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation 9606 24196445 YES miannu Using mass spectrometry we identified 9 Src-mediated Tyr-phosphorylation sites within HIPK2, 5 of them positioned in the kinase domain.|We demonstrate that ectopic expression of Src increases the half-life of HIPK2 by interfering with Siah-1-mediated HIPK2 degradation. 0.308 SIGNOR-278989 TNC protein P24821 UNIPROT Av/b1 integrin complex SIGNOR-C175 SIGNOR up-regulates activity binding 9606 BTO:0001521 38058842 YES miannu TNC is shown to bind to integrin receptors expressed in adjacent PAAD cells, thereby inducing EMT. In addition, TNC expression in CAFs had significant positive correlations with ITGαV, ITGβ1, or ITGβ3 expression in cancer cells, which supports our speculations that the TNC-integrin signaling axis promotes the EMT pathway in cancer cells. 0.429 SIGNOR-277735 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 9606 15276472 YES gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-252308 TIM22 complex complex SIGNOR-C424 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 32901109 NO lperfetto The TIM22 complex is responsible for the translocation and insertion of hydrophobic membrane proteins, including mitochondrial carrier proteins and translocase subunits (Tim17, Tim22 and Tim23) 0.7 SIGNOR-267710 BMP7 protein P18075 UNIPROT ACVR2A protein P27037 UNIPROT up-regulates binding 9606 9748228 YES fspada We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes 0.764 SIGNOR-60237 NOTCH proteinfamily SIGNOR-PF30 SIGNOR JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20953350 NO gcesareni Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip. 0.2 SIGNOR-254348 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 11160424 YES gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. 0.8 SIGNOR-104939 NFE2L2 protein Q16236 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493435 YES miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 0.45 SIGNOR-254652 GSK3B protein P49841 UNIPROT USF2 protein Q15853 UNIPROT up-regulates activity phosphorylation Ser155 NPFSNGGsPAAEAVS 9606 25238393 YES miannu Although no study has yet correlated the activity of GSK3beta with the activity of USF2 in a certain tumor setting, the findings of the present study would favor the tumor promoting aspects of GSK3beta and USF2 since GSK3beta activated USF2 enhanced cell migration which may be important in terms of tumor cell metastasis.|First, it was found that GSK3beta phosphorylates USF2 at S155 and T230. 0.284 SIGNOR-278157 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 21798082 YES lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation. 0.8 SIGNOR-236349 AIM2 inflammasome complex SIGNOR-C222 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.2 SIGNOR-256382 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates quantity phosphorylation Thr493 YTEVKTVtVKISQKN 9606 28193222 YES miannu AURKA phosphorylates ALDH1A1 at T267, T442, and T493.|Our data revealed that AURKA increases ALDH1A1 levels by inhibiting its ubiquitylation; thus, we examined whether 3A-ALDH1A1 was impervious to AURKA mediated protein stability. 0.372 SIGNOR-278165 GHITM protein Q9H3K2 UNIPROT CYCS protein P99999 UNIPROT down-regulates quantity relocalization 9606 BTO:0000567 18417609 YES Giulio MICS1 was clearly coprecipitated with cytochrome c-3FLAG and the amount was DSP concentration-dependent (Figure 6A). Together with the finding that overexpression of exogenous MICS1 delayed the apoptotic release of cytochrome c in normal-serum level medium (Figure 4A), these results suggest that MICS1 helps to retain cytochrome c in the inner membrane, apart from the morphological changes. 0.255 SIGNOR-260294 GNA12 protein Q03113 UNIPROT AKAP13 protein Q12802 UNIPROT up-regulates activity binding 9606 BTO:0000007 11546812 YES Marta Tosoni These data suggest that G12 is an upstream activator of AKAP-Lbc in the Rho signaling pathway. 0.523 SIGNOR-278882 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser122 PKPPPAAsPGVRAGH -1 29945972 YES miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. 0.2 SIGNOR-277878 GSK3B protein P49841 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation Ser163 PDKQFLIsPPASPPV 10090 BTO:0000165 12063245 YES lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 0.485 SIGNOR-249359 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates activity phosphorylation Thr312 QATQPLAtPVVSVTT 9606 9858528 YES lperfetto We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a 0.66 SIGNOR-62780 NDUFB9 protein Q9Y6M9 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 0.811 SIGNOR-262172 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr243 LDDSTGGtPLTPAAR 9606 BTO:0000007 16682949 YES done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 0.543 SIGNOR-274084 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser221 DLDRIAAsMRALVLR -1 SIGNOR-C3 SIGNOR-C3 18372248 YES lperfetto We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1. 0.904 SIGNOR-178128 PRKCQ protein Q04759 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates activity phosphorylation Thr217 LEPEALHtPTLMTTP 9606 27816489 YES Manara PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors. 0.2 SIGNOR-260878 STK25 protein O00506 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation 9606 30948712 YES miannu Collectively, our data demonstrate that loss of STK25 promotes YAP/TAZ activation.|Lastly, we assessed if STK25 is able to promote YAP phosphorylation in the absence of LATS-HM phosphorylation, based on our in vitro kinase assay results. 0.265 SIGNOR-278993 PTEN protein P60484 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr179 FQNRRYKtKRKQLSS 9606 31213464 YES lperfetto Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression.|PTEN was also able to dephosphorylate NKX3.1 at threonine 179, a target of protein kinase C, but not threonine residues 89 and 93, targeted by casein kinase 2 . 0.442 SIGNOR-277026 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 YES miannu Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. 0.2 SIGNOR-260095 CDK1 protein P06493 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Thr34 FLEGCACtPERMAEA 9606 11861764 YES gcesareni Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo 0.685 SIGNOR-115129 INS protein P01308 UNIPROT TRIP10 protein Q15642 UNIPROT up-regulates 9606 12242347 NO gcesareni The specific interaction of active tc10 with cip4 2 suggested thatinsulinmight induce a change in the subcellular localization of cip4 2 0.266 SIGNOR-93062 ZFYVE26 protein Q68DK2 UNIPROT TTC19 protein Q6DKK2 UNIPROT up-regulates activity binding 9606 BTO:0000567 20208530 YES miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. FYVE-CENT binds directly to TTC19 and KIF13A. 0.462 SIGNOR-265542 EP300 protein Q09472 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20660310 NO amattioni Switch to beta-catenin/p300-mediated gene expression is an essential first step in initiating normal cellular differentiation 0.7 SIGNOR-229780 GPR37 protein O15354 UNIPROT ER stress stimulus SIGNOR-ST9 SIGNOR up-regulates 9606 12666095 NO lperfetto Parkin-associated endothelin receptor-like receptor (Pael-R). Overexpression of this protein causes it to become ubiquinated, insoluble, and unfolded, leading to endoplasmic reticulum stress and cell death. Furthermore, an insoluble form of Pael-R has been demonstrated to accumulate in the brains of patients with Parkin mutations, suggesting a possible toxic mechanism. 0.7 SIGNOR-249701 CIITA protein P33076 UNIPROT HLA-DOA protein P06340 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11823510 NO Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. 0.336 SIGNOR-254005 GSK3B protein P49841 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by destabilization phosphorylation Ser98 RPPSPSAsPASEKSM 9606 BTO:0000498 31289136 YES miannu GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. 0.2 SIGNOR-277465 asparagine smallmolecule CHEBI:22653 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270460 PRDM1 protein O75626 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12626569 YES miannu The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b 0.436 SIGNOR-99119 RNF111 protein Q6ZNA4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates binding 9606 14657019 YES gcesareni Arkadia physically interacts with inhibitory smad, smad7, and induces its poly-ubiquitination and degradation. 0.735 SIGNOR-119663 MTOR protein P42345 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT down-regulates activity phosphorylation Ser759 SSSQRAAsLDSVATS 25998128 YES lperfetto AMOTL2 is phosphorylated at serine 760 by mTORC2. Mutation of AMOTL2 mimicking constitutive Ser(760) phosphorylation blocks its ability to bind and repress YAP leading to increased relative expression of known YAP gene targets. 0.2 SIGNOR-272086 RNF183 protein Q96D59 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29507230 YES miannu As an E3 ligase, RNF183 ubiquitinates Bcl-xL, causing its degradation and subsequent apoptosis. 0.385 SIGNOR-278595 SRC protein P12931 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr218 GDGSDHPyYNSIPSK -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.575 SIGNOR-273919 MAP2K1 protein Q02750 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 23360980 YES miannu In addition, though MEK-1 was able to induce C-Raf phosphorylation at the S338 site, which was shown to play a role in C-Raf activation by certain growth factors [ xref ], MEK-1 was able to bind and activate the S338/339A C-Raf mutant, suggesting that the MEK-1-induced C-Raf activation does not require phosphorylation at these sites ( xref , lanes 4, 5, left panel and lanes 6\u20139, right panel).|MEK-1-induced C-Raf activation is Ras independent. 0.748 SIGNOR-279627 MAP3K1 protein Q13233 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity phosphorylation 9606 27806347 YES miannu As a result, MEKK1 suppresses the Notch1 intracellular domain protein stability and transcriptional activity.|We confirmed that MEKK1 binds to Notch1 intracellular domain and phosphorylates the Notch1 intracellular domain Threonine 2512 residue. 0.367 SIGNOR-279628 CDH10 protein Q9Y6N8 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.585 SIGNOR-265850 CDKN2A protein Q8N726 UNIPROT NPM1 protein P06748 UNIPROT down-regulates quantity by destabilization binding 9606 14636574 YES gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division 0.553 SIGNOR-245077 F2 protein P00734 UNIPROT Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR form complex binding 9606 BTO:0000131 29880919 YES lperfetto Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). 0.905 SIGNOR-263550 ZFPM1 protein Q8IX07 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates activity 10090 BTO:0000725 22068055 NO We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment. 0.7 SIGNOR-259963 PPP2CA protein P67775 UNIPROT RBL2 protein Q08999 UNIPROT up-regulates dephosphorylation 9606 15467457 YES miannu Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation. 0.58 SIGNOR-129752 MYF5 protein P13349 UNIPROT mir-206 mirna URS0000389B41_9606 RNAcentral up-regulates quantity transcriptional regulation 10090 16731620 YES Moreover, both loci encoding miR-1, miR-1-1, and miR-1-2, and two of the three encoding miR-133, miR-133a-1 and miR-133a-2, are strongly induced during myogenesis.[…]By using CHIP analysis, we demonstrate that the myogenic factors Myogenin and MyoD bind to regions upstream of these microRNAs and, therefore, are likely to regulate their expression. 0.4 SIGNOR-255917 PRKCD protein Q05655 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser932 DDTPEKDsFRARSTS 9606 BTO:0002181 30684133 YES miannu In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC. 0.2 SIGNOR-277426 ADK protein P55263 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 33961946 YES miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 0.8 SIGNOR-267840 STK26 protein Q9P289 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Thr83 KTANVPQtVPMRLRK 9606 32271880 YES miannu Further, and consistent with our aforementioned finding that MST4 inactivates YAP in response to serum starvation, this stress condition enhanced the YAP\u2013MST4 interaction ( xref ).|Here, we revealed that the MST4 kinase-mediated Thr83 phosphorylation of YAP represents such an additional mechanism of YAP inactivation. 0.2 SIGNOR-278994 mTORC1 complex SIGNOR-C3 SIGNOR TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 22343943 YES Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity. 0.363 SIGNOR-255309 phenformin chemical CHEBI:8064 ChEBI KCNJ11 protein Q14654 UNIPROT down-regulates activity chemical inhibition 9606 20188727 YES lperfetto Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). 0.8 SIGNOR-262031 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR LCN2 protein P80188 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15536164 NO miannu Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. 0.35 SIGNOR-254796 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBG1 protein P23258 UNIPROT down-regulates activity chemical inhibition 9606 15579115 YES miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 0.8 SIGNOR-259259 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Thr375 AQNEATStPHRIRRK 9606 11931757 YES lperfetto Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. 0.636 SIGNOR-116329 CDK1 protein P06493 UNIPROT HMGA2 protein P52926 UNIPROT down-regulates phosphorylation Ser59 PKGSKNKsPSKAAQK 9606 10636877 YES lperfetto Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone. 0.375 SIGNOR-74098 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1230 RHSLAARyYNWVSFP 9606 BTO:0000394 12881528 YES lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. 0.2 SIGNOR-104072 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257450 PRKACA protein P17612 UNIPROT MIP protein P30301 UNIPROT down-regulates activity phosphorylation Ser229 LLFPRLKsISERLSV -1 2176601 YES miannu Phosphorylation at one of these sites (serine 243) could be increased by A kinase in vitro. phosphorylation of MIP reconstituted into single bilayers increased the voltage dependence and long-term closures of the channels observed. 0.312 SIGNOR-250018 TGFB1 protein P01137 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7592908 NO gcesareni The steadystate level of p15ink4b mrna was induced 30-fold upon tgf-beta treatment, implicating p15ink4b as a primary effector of the tgf-beta-mediated cell cycle arrest 0.282 SIGNOR-29582 clozapine chemical CHEBI:3766 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258681 FRAT1 protein Q92837 UNIPROT GSK3B protein P49841 UNIPROT up-regulates binding 9606 SIGNOR-C110 9635432 YES gcesareni The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway 0.775 SIGNOR-58219 SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR FN1 protein P02751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452;BTO:0002625 22223884 NO alessandro Taken together, our results indicate that Snail1, p65NF-κB and PARP1 interact to activate the expression of fibronectin and other ECM genes involved in cell movement. This mechanism is functional not only in epithelial cells undergoing EMT but also in fibroblasts. 0.411 SIGNOR-254529 PITRM1 protein Q5JRX3 UNIPROT APP protein P05067 UNIPROT down-regulates activity cleavage 9606 BTO:0000142 16849325 YES Giorgia In the present study we have identified and characterized the human PreP homologue, hPreP, in brain mitochondria, and we show its capacity to degrade the amyloid beta-protein (Abeta). PreP belongs to the pitrilysin oligopeptidase family M16C containing an inverted zinc-binding motif. We show that hPreP is localized to the mitochondrial matrix. In situ immuno-inactivation studies in human brain mitochondria using anti-hPreP antibodies showed complete inhibition of proteolytic activity against Abeta. 0.374 SIGNOR-260661 CASP3 protein P42574 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization cleavage Asp1155 ETPDDLLdDGEIKED 9606 12149654 YES miannu We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable. 0.474 SIGNOR-256326 ERAP2 protein Q6P179 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 15908954 YES The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases | We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2. 0.8 SIGNOR-272495 EIF2S2 protein P20042 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 YES lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. 0.956 SIGNOR-269115 FBXW7 protein Q969H0 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 11585921 YES gcesareni We show here that the f-box/wd40 repeat protein sel-10 negatively regulates notch receptor activity by targeting the intracellular domain of notch receptors for ubiquitin-mediated protein degradation. in conclusion, hsel-10 physically associates with mouse notch4(int-3) through the wd40 domain, whereas the f-box domain is not required for this interaction. 0.5 SIGNOR-110955 TPR protein P12270 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates binding 9606 BTO:0000567 18981471 YES miannu Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20). 0.487 SIGNOR-181918 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates activity phosphorylation Ser382 LKRASFAkSVIGTPE 9606 12374799 YES Manara Activation of WNKs requires autophosphorylation of at least one serine residue, serine 382 in WNK1, within the WNK activation loop. 0.2 SIGNOR-260826 TTBK2 protein Q6IQ55 UNIPROT MPHOSPH9 protein Q99550 UNIPROT down-regulates quantity phosphorylation 9606 30375385 YES miannu Additionally, in vivo ubiquitin assays showed that expression of either the kinase-dead TTBK2 or the MPP9-S629 and S636-2A mutant significantly decreased the ubiquitination level of MPP9.|Also, the S629A mutant almost abolished the phosphorylation of MPP9 by TTBK2 in the kinase assay in vitro, suggesting that S629 is the main site for MPP9 phosphorylation by TTBK2. 0.2 SIGNOR-278998 SUPT7L protein O94864 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.667 SIGNOR-269585 AKT1 protein P31749 UNIPROT GATA2 protein P23769 UNIPROT down-regulates phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 YES PI-3K/Akt-dependent manner. fspada We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity 0.525 SIGNOR-135614 DOCK7 protein Q96N67 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0000132 29187380 YES lperfetto As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover. 0.544 SIGNOR-261887 BUB1B protein O60566 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 20888775 NO gcesareni The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac) 0.7 SIGNOR-168195 TWIST2 protein Q8WVJ9 UNIPROT MYB protein P10242 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255495 CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 19436055 YES miannu As a consequence of Jak2 activation and tyrosine phosphorylation of the cytoplasmic tail of Œ≤c, Src homology 2 and phosphotyrosine binding domain proteins are recruited to the active receptor and initiate the major tyrosine phosphorylation-dependent signaling pathways, including the Jak/signal transducer and activator of transcription, Ras/mitogen-activated protein kinase, and phosphatidylinositol 3 (PI-3) kinase pathways 0.468 SIGNOR-255585 2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol chemical CHEBI:93773 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 12970777 YES gcesareni The raf inhibitor l-779,450. This raf inhibitor was less effective on b-raf- or mek1-responsive cells, demonstrating the specificity of this drug. 0.8 SIGNOR-100358 GSK3B protein P49841 UNIPROT PSEN1 protein P49768 UNIPROT down-regulates activity phosphorylation Ser357 PHRSTPEsRAAVQEL 9606 BTO:0000007 SIGNOR-C110 17360711 YES gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. 0.587 SIGNOR-153631 ABL1 protein P00519 UNIPROT SPTLC1 protein O15269 UNIPROT down-regulates phosphorylation Tyr164 KTEEAIIySYGFATI 9606 23629659 YES llicata We demonstrated that the er-resident human protein serine palmitoyltransferase long chain-1 (sptlc1), which is the first enzyme of sphingolipid biosynthesis, is phosphorylated at tyr(164) by the tyrosine kinase abl. this occurred through the specific abl-mediated phosphorylation of sptlc1 on tyr164, leading to the attenuation of its activity. 0.2 SIGNOR-202003 FYN protein P06241 UNIPROT CNN3 protein Q15417 UNIPROT down-regulates activity phosphorylation Tyr261 SQKGMSVyGLGRQVY 9534 BTO:0000298 15206927 YES We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin 0.333 SIGNOR-251159 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 NO areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX)8, are markedly induced in almost all types of atrophy. 0.7 SIGNOR-254994 PRKACA protein P17612 UNIPROT CHCHD3 protein Q9NX63 UNIPROT unknown phosphorylation Thr11 TTSTRRVtFEADENE -1 17242405 YES miannu Identification of ChChd3 as a novel substrate of the cAMP-dependent protein kinase (PKA) using an analog-sensitive catalytic subunit. we used the recombinant GST-ChChd3 for an in vitro kinase assays to determine whether in vitro phosphorylation by PKA was direct. Fig. 6 demonstrates that PKA directly phosphorylates recombinant Chchd3 with a stoichiometry of 0.3 mol of phosphate incorporated per mol of ChChd3. Although three potential PKA phosphorylation sites exist in ChChd3, Thr10 represents the most likely site to be phosphorylated. 0.2 SIGNOR-263116 TTK protein P33981 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity phosphorylation -1 18541701 YES miannu Furthermore, although catalytically inactive Mps1 can restore kinetochore localization of Mad1, only the active kinase restores Mad2 localization.|Indeed, Mps1 can phosphorylate Mad1 in vitro. 0.819 SIGNOR-279000 SOSTDC1 protein Q6X4U4 UNIPROT WNT5B protein Q9H1J7 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.277 SIGNOR-242727 PPM1A protein P35813 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity dephosphorylation Ser172 EDDEQFVsLYGTEEY 9606 27419230 YES lperfetto Furthermore, PPM1A, but not PPM1B, serves as an efficient phosphatase to dephosphorylate Ser 172 residue of both TBK1 and IKKepsilon kinases, which is critical for their kinase activities.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon. 0.41 SIGNOR-276966 XPO1 protein O14980 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity relocalization 9606 17891139 YES miannu We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus. 0.55 SIGNOR-260067 ATM protein Q13315 UNIPROT RBBP8 protein Q99708 UNIPROT down-regulates phosphorylation Ser745 SCLADSFsQAADEEE 9606 BTO:0000150 10910365 YES llicata Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45 0.828 SIGNOR-79876 CDK1 protein P06493 UNIPROT CLASP2 protein O75122 UNIPROT up-regulates activity phosphorylation Ser1234 QGYDNSEsSVRKACV 9606 23045552 YES miannu Overall, these results support the idea that phosphorylation of CLASP2 on S1234 by Cdk1, but not phosphorylation of the CLASP2 C terminal by Plk1, is required to maintain mitotic spindle bipolarity.|We propose that Cdk1 and Plk1 mediate a CLASP2 phospho-switch that is necessary to stabilize KT-MT attachments in human cells. 0.567 SIGNOR-278233 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258090 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1303753 YES gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. 0.577 SIGNOR-16239 KDM5C protein P41229 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 31691806 NO miannu The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. 0.329 SIGNOR-264313 (S)-(-)-sulpiride chemical CHEBI:64119 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258734 TFEB protein P19484 UNIPROT DRAM1 protein Q8N682 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) 0.277 SIGNOR-276788 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser468 DLTIDSSsDEEEEEP 9606 19217413 YES llicata Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process. 0.332 SIGNOR-184047 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr209 LCEISRGtHNFSEEL 9606 BTO:0000007 14625308 YES lperfetto Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signalingthis identifies irak-1 as a novel type of adapter protein, which employs its own kinase activity to introduce negative charges adjacent to the protein interaction domain, which anchors irak-1 at the active receptor complex. Thus, irak-1 regulates its own availability as an adapter molecule by sequential autophosphorylation 0.2 SIGNOR-119212 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9534 BTO:0004055 14993270 YES lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. 0.754 SIGNOR-244916 LHX3 protein Q9UBR4 UNIPROT CGA protein P01215 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 10931853 YES scontino Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim binds to CBP in TRH-dependent manner on this site and that these proteins synergistically activate the human α-GSU promoter during TRH stimulation. 0.388 SIGNOR-267207 SRC protein P12931 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity phosphorylation Tyr284 EELAMDVyDEVDRRE 9534 BTO:0000298 24699139 YES miannu Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin. 0.543 SIGNOR-276627 TOP2A protein P11388 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 15942022 NO lperfetto Down-regulation of DNA topoisomerase IIalpha leads to prolonged cell cycle transit in G2 and early M phases and increased survival to microtubule-interacting agents 0.7 SIGNOR-242537 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR ALDH3A1 protein P30838 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001078 26124079 YES miannu We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members. 0.265 SIGNOR-272817 CSNK2A1 protein P68400 UNIPROT C1R protein P00736 UNIPROT down-regulates activity phosphorylation Ser206 TEASGYIsSLEYPRS -1 8635594 YES llicata We provide evidence that this kinase phosphorylates Clr at the level of Ser189. | Accessibility of Ser189 was low in intact C1r, due in part to the presence of one of the oligosaccharides borne by the alpha region, further reduced in the presence of calcium, and abolished when C1r was incorporated into the C1s-C1r-C1r-C1s tetramer or the C1 complex. 0.307 SIGNOR-250833 Wnt proteinfamily SIGNOR-PF40 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 YES Gianni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.2 SIGNOR-131577 GLIS1 protein Q8NBF1 UNIPROT WNT5A protein P41221 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32047936 YES miannu GLIS1, a novel hypoxia-inducible transcription factor, promotes breast cancer cell motility via activation of WNT5A 0.248 SIGNOR-269040 NLGN3 protein Q9NZ94 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 YES brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. 0.754 SIGNOR-264189 EBV gH:gL:gp42 complex SIGNOR-C403 SIGNOR HLA-DRB1 protein P01911 UNIPROT up-regulates activity binding 9606 BTO:0000776 8764069 YES scontino In EBV, the gH and gL proteins form a stable complex with a third glycoprotein, termed gp42, the product of the BZLF2 open reading frame, that appears to play a role in the infection of specific cells by EBV. The extracellular domain of BZLF2 binds specifically to a b-chain allele of the major histocompatibility complex (MHC) class II HLA-DR locus 0.2 SIGNOR-266629 doramapimod chemical CHEBI:40953 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258208 SRC protein P12931 UNIPROT TLR4 protein O00206 UNIPROT up-regulates activity phosphorylation 9606 21712022 YES miannu Src dependent phosphorylation of TLR4 is significantly increased in Cftr-KO cholangiocytes.|TLR4 can be activated through the phosphorylation of its TIR domains by Src, a non receptor tyrosine kinase 28. 0.589 SIGNOR-279658 PRKACA protein P17612 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates activity phosphorylation Ser4520 GGHGSRHsLASTDEK 10029 11158305 YES miannu LRP phosphorylation is mediated by PKA at residue serine 76 of its cytoplasmic tail and that this phosphorylation contributes to receptor-mediated endocytosis. 0.325 SIGNOR-250000 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr444 TKSSKSStPVPSKQS 9606 16247472 YES lperfetto Here we show that two mitotic kinases, cdk1 and polo-like kinase 1 (plk1), phosphorylate ect2 in vitro.Moreover, ect2 t412a, but not phosphomimic t412d, displayed a diminished accumulation of gtp-bound rhoa compared with wt ect2, suggesting that phosphorylation of thr-412 is critical for the catalytic activity of ect2. 0.578 SIGNOR-141175 17beta-estradiol 3-sulfate(1-) smallmolecule CHEBI:136582 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of -1 7779757 YES Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. 0.8 SIGNOR-269748 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 9606 SIGNOR-C3 18722121 YES llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity 0.547 SIGNOR-180466 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser366 GCSSQSIsPMRSISE -1 28130417 YES lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. 0.264 SIGNOR-264872 MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 10480932 YES Luana P38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. 0.744 SIGNOR-260720 LCK protein P06239 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 YES We show that during TCR signaling, the tyrosines Y239, Y240 and Y317 of Shc are the primary sites of tyrosine phosphorylation. CD4/Lck-dependent tyrosine phosphorylation on Shc was markedly diminished when Y317 was mutated, suggesting a preference of Lck for the Y317 site. tyrosine phosphorylation of Shc may play a key role in T lymphocyte proliferation via interaction of phosphorylated Shc with downstream molecules involved in activation of Ras and Myc proteins 0.743 SIGNOR-251388 FUS protein P35637 UNIPROT SMN1 protein Q16637 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 23022481 YES lperfetto Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells 0.37 SIGNOR-262107 PRKG1 protein Q13976 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 9606 BTO:0000887;BTO:0001260 15051728 YES lperfetto Pkgi also directly phosphorylates fhod1, and studies with wild-type and mutant fhod1-derived peptides identify ser-1131 in the fhod1 c terminus as the unique pkgi phosphorylation site in fhod1. phosphorylation of three conserved residues within the dad domain activates fhod1 while binding to rac regulates fhod1 subcellular localization 0.355 SIGNOR-123646 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr284 LPQNDDHyVMQEHRK -1 16472662 YES Purified ACK1 undergoes autophosphorylation at Tyr284, and autophosphorylation increases kinase activity 0.2 SIGNOR-251184 SRPK2 protein P78362 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation 9606 33602301 YES miannu In contrast, SRPK1 or SRPK2 overexpression upregulated the phosphorylation and nucleus accumulation of SRSF1.|Therefore, SRPK1 and SRPK2 may directly phosphorylate SRSF1 and promote it nucleus translocation, subsequently modulate MKNK2 alternative splicing. 0.617 SIGNOR-279660 FAM20C protein Q8IXL6 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates activity phosphorylation Ser47 ELVLALRsEEDGLAE 9606 31553664 YES miannu Herein, we report that Fam20C and Fam20A significantly eliminate the Furin-cleavage of PCSK9 (XREF_FIG, lanes 5, 6), thereby enhancing the pPCSK9 activity|Herein, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668 and 688. 0.535 SIGNOR-278935 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 YES lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. 0.269 SIGNOR-198130 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY 12893243 YES lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time. 0.314 SIGNOR-249224 ADARB1 protein P78563 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 BTO:0000661 19605474 YES miannu Both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation. 0.461 SIGNOR-266359 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258916 Ile(5)-angiotensin II smallmolecule CHEBI:2719 ChEBI AGTR1 protein P30556 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257459 ATM protein Q13315 UNIPROT MPG protein P29372 UNIPROT up-regulates activity phosphorylation Ser172 YFCMNISsQGDGACV 9606 25100205 YES miannu ATM phosphorylates MPG at serine 172 (XREF_FIG).|In summary, our results show that ATM and MPG are directly associated in vitro and in vivo, phosphorylation of MPG at serine 172 is dependent on ATM and that of loss of phospho ATM reduces MPG glycosylase activity. 0.265 SIGNOR-279004 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 11163210 YES lperfetto Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. 0.709 SIGNOR-104999 STK3 protein Q13188 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser438 EKNYQLKsRQILGMR 9606 21076410 YES lperfetto Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins 0.244 SIGNOR-169539 APC-c complex SIGNOR-C150 SIGNOR TK1 protein P04183 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 14701726 YES miannu We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. 0.248 SIGNOR-272946 GPHN protein Q9NQX3 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity by stabilization binding 10116 BTO:0000938 21994384 YES miannu we demonstrate that GABA(A)Rs and gephyrin are intimately associated at inhibitory synapses in cultured rat neurons. Our results suggest that the direct binding of gephyrin to residues 360-375 of the α1 subunit and its modulation are likely to be important determinants for the stabilization of GABA(A)Rs at synaptic sites, thereby modulating the strength of synaptic inhibition. 0.2 SIGNOR-264964 PRKCA protein P17252 UNIPROT PLCB1 protein Q9NQ66 UNIPROT unknown phosphorylation Ser887 HSQPAPGsVKAPAKT 10090 BTO:0005065 11278470 YES lperfetto . Two-dimensional phosphopeptide mapping and site-directed mutagenesis demonstrated that PKC promoted phosphorylation of PLC beta1 at serine 887 in the nucleus of IGF-I-treated cells. Overexpression of either a PLC beta1 mutant in which the PKC phosphorylation site Ser(887) was replaced by alanine, or a dominant-negative PKC alpha, resulted in a sustained activation of nuclear PLC following IGF-I stimulation. 0.713 SIGNOR-249081 BTRC protein Q9Y297 UNIPROT CDC25A protein P30304 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 15340381 YES gcesareni Scfb-trcp has recently been shown to degrade phosphorylated cdc25a in the s and g2 phases. 0.494 SIGNOR-128436 TFE3 protein P19532 UNIPROT CD63 protein P08962 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.2 SIGNOR-276812 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269368 CDK1 protein P06493 UNIPROT NUSAP1 protein Q9BXS6 UNIPROT down-regulates phosphorylation Thr300 HKRSLTKtPARKSAH 9606 22101338 YES llicata We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo. 0.431 SIGNOR-177545 PKN1 protein Q16512 UNIPROT MEFV protein O15553 UNIPROT down-regulates activity phosphorylation Ser242 SGKMRPRsLEVTIST 10090 BTO:0004732 27270401 YES no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 0.384 SIGNOR-275461 EGFR protein P00533 UNIPROT SCAMP1 protein O15126 UNIPROT up-regulates activity phosphorylation Tyr37 VPPGLDEyNPFSDSR -1 9658162 YES miannu In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation 0.336 SIGNOR-262857 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 YES Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts 0.827 SIGNOR-122075 ATM protein Q13315 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity phosphorylation Ser547 MDFSALLsQISS 9606 24957606 YES miannu Interestingly, another group has identified that in the VP-16 induced NF-\u03baB activation, ATM binds to RelA directly and phosphorylates RelA on Ser 547, a post-translational modification that represses a subset of NF-\u03baB-dependent genes ( xref ).|Our findings that ablation of ATM reduces RelA serine 276 phosphorylation, suggests a mechanism for how ROS mediates RelA serine 276 phosphorylation in the TNF pathway (Figure -D). 0.503 SIGNOR-279006 MAPK13 protein O15264 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 YES lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. 0.2 SIGNOR-114075 PNPLA6 protein Q8IY17 UNIPROT 2-(((R)-2,3-Dihydroxypropyl)phosphoryloxy)-N,N,N-trimethylethanaminium smallmolecule CID:439285 PUBCHEM up-regulates quantity chemical modification 9606 25033069 YES PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus 0.8 SIGNOR-253611 OPHN1 protein O60890 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000938 12932438 YES miannu OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro 0.635 SIGNOR-268397 DVL2 protein O14641 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates activity binding 10029 BTO:0000457 23132247 YES gcesareni Mechanistically, Dishevelled binds and directly inhibits CSL transcription factors downstream of Notch receptors, reducing their activity. Furthermore, our data suggest that this crosstalk mechanism is conserved between vertebrate and invertebrate homologues. Thus, we identify a dual function for Dishevelled as an inhibitor of Notch signalling and an activator of the Wnt pathway that sharpens the distinction between opposing Wnt and Notch responses, allowing for robust cell-fate decisions. 0.269 SIGNOR-243999 CCR4-NOT complex complex SIGNOR-C439 SIGNOR PUM2 protein Q8TB72 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 YES lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins 0.367 SIGNOR-268347 COL1A1 protein P02452 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.567 SIGNOR-253247 MAPK8 protein P45983 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates phosphorylation Ser95 TSSSSATsPASASFK 9606 17023523 YES llicata We also identified the exact phosphorylation site of jnk to be serine 95 at the n terminus of tr3, around which a classical jnk phosphorylation motif exists. Furthermore, we demonstrated that tr3 phosphorylation by jnk coincided with its ubiquitination and degradation, resulting in the loss of its mitogenic activity. 0.501 SIGNOR-149998 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 YES gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.697 SIGNOR-163266 CHUK protein O15111 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 15808510 YES miannu These results demonstrated an estrogen-mediated increase in the phosphorylation of ER\u03b1 at serine residue 118 by IKK\u03b1 ( Figure 5 H, bottom).|Wt IKKalpha, but not the IKKalpha kinase mutant, increased both estrogen dependent and -independent ERalpha activation. 0.471 SIGNOR-279696 MRPL14 protein Q6P1L8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.654 SIGNOR-262379 PRKAA2 protein P54646 UNIPROT ACACA protein Q13085 UNIPROT down-regulates phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 12015362 YES gcesareni Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed. 0.696 SIGNOR-87583 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270431 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser93 RVPKDRPsLTVTPKR 9606 BTO:0000567 21658950 YES miannu Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis 0.2 SIGNOR-262657 STK4 protein Q13043 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 YES lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 0.343 SIGNOR-181060 NKX2-5 protein P52952 UNIPROT TBX5 protein Q99593 UNIPROT up-regulates quantity by expression transcriptional regulation 15095414 NO Mutation at the potential TBE-B and -C sites, and at the GC box and NKX2.5 sites significantly decreased luciferase activity, suggesting that the GC box and the potential TBE-B, -C, and NKX2.5 sites are functionally important for the activation of the promoter function. 0.771 SIGNOR-253650 CSNK1E protein P49674 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation 9606 18991847 YES miannu CKIepsilon phosphorylates and activates DARPP-32, a key molecule in various complex signaling pathways, including dopamine and glutamine signaling, which have both been demonstrated to be main pathways in substance dependence. 0.322 SIGNOR-279701 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 11323411 YES These results suggest that Tyr(P)-627 and Tyr(P)-659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) that binds and activates SHP2.|Thus, physical association of activated SHP2 with Gab1 is necessary and sufficient to mediate the ERK mitogen-activated protein kinase activation. Phosphopeptides derived from Gab1 were dephosphorylated by active SHP2 in vitro. 0.952 SIGNOR-248674 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity relocalization 9606 21791611 YES lperfetto One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2 0.882 SIGNOR-175269 SARM1 protein Q6SZW1 UNIPROT TICAM1 protein Q8IUC6 UNIPROT down-regulates binding 10090 17667936 YES gcesareni SARM utilizes its TIR domain to negatively regulate TRIF 0.53 SIGNOR-252068 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F8 protein P00451 UNIPROT down-regulates activity cleavage Arg391 SPSFIQIrSVAKKHP -1 10350471 YES lperfetto N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin. 0.455 SIGNOR-263642 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 9445476 YES gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.608 SIGNOR-55371 regorafenib chemical CHEBI:68647 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition 9606 26254357 YES miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF 0.8 SIGNOR-259179 ING1 protein Q9UK53 UNIPROT CASP3 protein P42574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 15662138 NO miannu Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. 0.258 SIGNOR-254489 MRPL11 protein Q9Y3B7 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.76 SIGNOR-262382 LNX1 protein Q8TBB1 UNIPROT BCR protein P11274 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22889411 YES miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. 0.267 SIGNOR-272903 SKP1 protein P63208 UNIPROT Skp1-Pam E3 complex SIGNOR-C537 SIGNOR form complex binding 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.417 SIGNOR-272185 DDB1 protein Q16531 UNIPROT RAD23A protein P54725 UNIPROT up-regulates 24086044 NO lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). 0.601 SIGNOR-275687 EGFR protein P00533 UNIPROT GLUD1 protein P00367 UNIPROT up-regulates activity phosphorylation Tyr135 SWEVIEGyRAQHSQH 9606 36516759 YES miannu EGFR phosphorylates GDH1 at Y135 and contributes to GDH1 activation.|Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135 and, together with RSK2, enhances the cAMP response element-binding protein (CREB) activity via CaMKIV signaling, thereby promoting metastasis. 0.2 SIGNOR-279706 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr468 DSGISTDySSGDSQG 12441334 YES JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 0.811 SIGNOR-251352 PLK1 protein P53350 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates activity phosphorylation Ser312 ASLKRSPsASSLSSM -1 24451569 YES lperfetto Plk1 phosphorylates CLIP-170 and regulates its binding to microtubules for chromosome alignment|Here, we show that phosphorylation at Ser312 in the third serine-rich region of CLIP-170 is increased during mitosis. Polo-like kinase 1 (Plk1) is responsible for this phosphorylation during the mitotic phase of dividing cells. In vitro analysis using a purified CLIP-170 N-terminal fragment showed that phosphorylation by Plk1 diminishes CLIP-170 binding to the MT ends 0.702 SIGNOR-264575 JAK2 protein O60674 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates phosphorylation Tyr693 TERGDKGyVPSVFIP 9606 BTO:0000782 16324152 YES gcesareni Janus family tyrosine kinases jak2 and tyk2, which in turn phosphorylate stat4 on tyrosine 693. The p38 mitogen-activated protein kinase (mapk) signaling pathway is also activated in response to il-12, followed by phosphorylation of stat4 on serine 721, which is required for stat4 full transcriptional activity 0.675 SIGNOR-142736 PRKAR2B protein P31323 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.881 SIGNOR-258754 CEBPB protein P17676 UNIPROT SLC5A8 protein Q8N695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20082847 YES Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription. 0.2 SIGNOR-254054 GABRB1 protein P18505 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.62 SIGNOR-263754 GPR183 protein P32249 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.417 SIGNOR-256715 2-oxoglutaric acid smallmolecule CHEBI:30915 ChEBI OXGR1 protein Q96P68 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257555 GRK2 protein P25098 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity phosphorylation Ser18 LKKLSEDsLTKQPEE 9606 23904266 YES miannu Taken together, these studies support a role for GRK2 phosphorylation of Mst2 residues Ser-18 and Ser-316 in EGF-promoted centrosome separation.|Thus GRK2 appears to mediate EGF promoted cleavage and activation of Mst2. 0.2 SIGNOR-278207 reserpine chemical CHEBI:28487 ChEBI SLC18A2 protein Q05940 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000318 8643547 YES miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. 0.8 SIGNOR-258490 DYRK3 protein O43781 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates phosphorylation 9606 23415227 YES lperfetto When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40 0.288 SIGNOR-217571 ARF6 protein P62330 UNIPROT Macropinosomes recycle phenotype SIGNOR-PH230 SIGNOR up-regulates 9606 39000072 YES miannu ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane  0.7 SIGNOR-277785 MTA3 protein Q9BTC8 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.784 SIGNOR-263852 SMO protein Q99835 UNIPROT OPALIN protein Q96PE5 UNIPROT up-regulates quantity transcriptional regulation 10090 35082605 NO Non-canonical pathway (Gli1-indipendent): SMO/AMPK SimoneGraziosi We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. 0.2 SIGNOR-269225 RAC1 protein P63000 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003009; BTO:0000018 22549160 NO irozzo The small GTPase Rac1 regulates many cellular processes, including cytoskeletal reorganization, cell migration, proliferation, and survival. We found that silencing of Rac1 expression decreases NSCLC migration and proliferation [.] 0.7 SIGNOR-259088 ZBED1 protein O96006 UNIPROT RPS6 protein P62753 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 17220279 YES Luana HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid. 0.2 SIGNOR-266082 ADORA1 protein P30542 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.336 SIGNOR-257092 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 23450633 NO gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. 0.7 SIGNOR-192783 FGFR4 protein P22455 UNIPROT STK4 protein Q13043 UNIPROT down-regulates activity phosphorylation 9606 30903103 YES miannu FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2 dependent apoptosis.|We provide evidence suggesting that by Y433-MST1 phosphorylation , FGFR4 inhibits MST1 / 2 activation . 0.2 SIGNOR-279714 SCF-betaTRCP complex SIGNOR-C5 SIGNOR FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys356 AILEAPEkQRTLNEI 9606 BTO:0002181 27432879 YES miannu The ubiquitination site of Foxp3 is Lys356 0.259 SIGNOR-277246 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 BTO:0000567 16899510 YES gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. 0.962 SIGNOR-148713 FGF13 protein Q92913 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.269 SIGNOR-253427 SIN3B protein O75182 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity binding 9606 BTO:0001109 26181367 YES miannu The present study shows that under bleomycin-induced stress, expression of Sin3B gets up-regulated and it gets recruited by p53 at its target promoters. Knockdown of Sin3B leads to impaired negative regulation of p53 target genes and thus exemplifies Sin3B as a critical player in down-regulation of p53 subset target genes. 0.497 SIGNOR-266776 RAB3GAP1 protein Q15042 UNIPROT RAB3A protein P20336 UNIPROT down-regulates activity gtpase-activating protein 10116 BTO:0000142 11809763 YES miannu Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). 0.44 SIGNOR-265580 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr304 PNEPVSDyINANIIM 9534 BTO:0004055 8995399 YES lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 0.793 SIGNOR-236266 HSP90AA1 protein P07900 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 18591668 YES lpetrilli The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs. 0.385 SIGNOR-179271 NFIX protein Q14938 UNIPROT SLIT1 protein O75093 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268906 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline chemical CHEBI:91387 ChEBI ACVR1 protein Q04771 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193639 CTSB protein P07858 UNIPROT S protein P0DTC2 UNIPROT up-regulates activity cleavage 9606 BTO:0000195 32142651 YES miannu SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. 0.2 SIGNOR-260738 ILK protein Q13418 UNIPROT PPP1R14C protein Q8TAE6 UNIPROT up-regulates activity phosphorylation Thr73 RHQQGKVtVKYDRKE 9606 12804574 YES lperfetto Pka predominantly phosphorylated a site distinct from the inhibitory t73 in kepi. Integrin-linked kinase phosphorylated KEPI (T73) and this dramatically increased inhibition of PP1c 0.545 SIGNOR-101835 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 9315650 YES llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. 0.436 SIGNOR-269325 MRGPRX2 protein Q96LB1 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257434 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr76 LRASRLGtTRTPSSY 9606 BTO:0000971 10574968 YES lperfetto We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin 0.317 SIGNOR-249031 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TNF protein P01375 UNIPROT down-regulates quantity BTO:0000801 22933625 NO apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype 0.7 SIGNOR-255446 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 10581258 YES gcesareni In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.461 SIGNOR-72687 SB 203580 chemical CHEBI:90705 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 BTO:0000222 15208625 YES fstefani Pharmacological blockade of p38?/? Kinases by sb203580 inhibits the myogenic program3_5 by repressing the transcription of early (myogenin;myog) and late (muscle-creatine kinase;ckm) muscle genes in myoblasts induced to differentiate 0.8 SIGNOR-126052 CDC25C protein P30307 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity dephosphorylation 9606 25949173 YES miannu Cdc25C is an activator of Cdc2 kinase and dephosphorylates and activates the CyclinB-Cdc2 complex shortly before the entry into the mitosis. 0.831 SIGNOR-277099 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 YES gcesareni Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin 0.481 SIGNOR-182844 regorafenib chemical CHEBI:68647 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 26254357 YES miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF 0.8 SIGNOR-259181 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser70 LTKSERYsSSGSPAN 9606 BTO:0000093 35513296 YES miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings 0.342 SIGNOR-277908 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. 0.427 SIGNOR-81149 PHF21A protein Q96BD5 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 YES miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells 0.741 SIGNOR-264502 FGA protein P02671 UNIPROT ITGAX protein P20702 UNIPROT up-regulates binding 9606 7679388 YES gcesareni To map the binding sites for four distinct ligands for mac-l: ic3b, fibrinogen, icam-1. __the i domain on the ot chain of mac-1 is an important recognition site for all four ligands. 0.385 SIGNOR-31320 ME2 protein P23368 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 YES miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle 0.8 SIGNOR-267054 NEK1 protein Q96PY6 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates phosphorylation Ser193 DGTEFGGsIYQKVNK 9606 20230784 YES lperfetto Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux. 0.424 SIGNOR-164222 CDK1 protein P06493 UNIPROT NUMA1 protein Q14980 UNIPROT down-regulates phosphorylation Thr2055 MAFSILNtPKKLGNS 9606 23921553 YES llicata Cdk1-mediated phosphorylation at t2055 negatively regulates numa cortical localization and that this phosphorylation is counteracted by ppp2ca phosphatase activity. 0.585 SIGNOR-194825 estrone smallmolecule CHEBI:17263 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258583 CDK14 protein O94921 UNIPROT TAGLN2 protein P37802 UNIPROT down-regulates activity phosphorylation Ser163 KENPRNFsDNQLQEG 21577206 YES lperfetto This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity. 0.315 SIGNOR-265105 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.312 SIGNOR-262979 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 BTO:0000093 12777400 YES lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases 0.404 SIGNOR-101302 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.668 SIGNOR-16466 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates activity binding 9606 BTO:0000567 15573378 YES ggiuliani The Runx2 WT and deletion constructs (1 √¢‚Ǩ‚Äú495, 1√¢‚Ǩ‚Äú464, and 1√¢‚Ǩ‚Äú432) all physically interact with the BMP2 responsive Smad 1 0.593 SIGNOR-255834 JMJD1C protein Q15652 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 BTO:0000007 32034158 YES miannu We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state. 0.2 SIGNOR-265331 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK3 protein Q00526 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189987 CDK1 protein P06493 UNIPROT TAZ protein Q16635 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 26183396 YES miannu Our studies suggest that phosphorylation and degradation of TAZ by Cdk1 may play important roles in apoptosis induced by antitubulin drugs. 0.266 SIGNOR-278240 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide chemical CHEBI:49868 ChEBI PLK1 protein P53350 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258078 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser41 EAAGPAPsPMRAANR 9606 BTO:0000567 15525512 YES llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  0.992 SIGNOR-250606 MAPK8IP3 protein Q9UPT6 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10523642 YES gcesareni Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct. 0.541 SIGNOR-71471 FHIT protein P49789 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 BTO:0000551 16407838 NO miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis 0.373 SIGNOR-252625 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr81 APAPAAPtPAAPAPA 9606 12531896 YES gcesareni Wr1065 activates the jnk (c-jun n-terminal kinase), decreases complex formation between p53 and inactive jnk, and phosphorylates p53 at thr-81, a known site of phosphorylation by jnk. 0.796 SIGNOR-97405 PIK3CG protein P48736 UNIPROT SET protein Q01105 UNIPROT up-regulates activity phosphorylation 9606 21419339 YES miannu We show that PI3Kgamma phosphorylates I2PP2A on serine 9 and 93 residues resulting in enhanced interaction of I2PP2A with PP2A. 0.337 SIGNOR-278320 SIRT5 protein Q9NXA8 UNIPROT CPS1 protein P31327 UNIPROT up-regulates activity post translational modification 9606 BTO:0000567 24703693 YES deglutarylation lperfetto Glutarylation suppresses CPS1 activity, which is targeted by SIRT5 for removal|SIRT5 can catalyze the enzymatic removal of lysine glutarylation 0.508 SIGNOR-267643 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-166355 TACR3 protein P29371 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256794 AR protein P10275 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression binding 9606 9162033 YES lperfetto Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity 0.545 SIGNOR-48513 PRLHR protein P49683 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.278 SIGNOR-256837 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21798082 YES gcesareni Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). 0.762 SIGNOR-175291 Gbeta proteinfamily SIGNOR-PF4 SIGNOR AMPH protein P49418 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 15262992 YES inferred from 70% family members lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. 0.2 SIGNOR-270102 TP53 protein P04637 UNIPROT CCNG1 protein P51959 UNIPROT up-regulates quantity by expression transcriptional regulation 7957050 YES lperfetto Using a DNA binding assay, a specific p53 binding site was identified upstream from the cyclin G gene, which functioned as a p53-dependent cis-acting element in a transient transfection assay. 0.79 SIGNOR-268960 GRK5 protein P34947 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates quantity phosphorylation Ser339 GKRGGHSsVSTESES 9606 24632620 YES miannuccelli Conversely, GRK5 knock-down in cells with low WIP1 expression inhibited CXCR4 phosphorylation, increased cell membrane expression of CXCR4, and promoted medulloblastoma growth.|Transfection of GRK5 into D556-WIP1 cells increased Ser339 phosphorylation of CXCR4 and reduced proliferation. 0.458 SIGNOR-279740 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 21078818 YES gcesareni Phosphorylated lrp5/6 leads to inhibition of the so-called beta-catenin destruction complex (which includes axin, gsk3, dvl, ck1, and the tumor suppressor adenomatous polyposis coli), resulting in the stabilization and translocation of beta-catenin in the nucleus, where it activates target genes through binding to tcf/lef transcription factors. 0.917 SIGNOR-169632 EP300 protein Q09472 UNIPROT MN1 protein Q10571 UNIPROT up-regulates binding 9606 12569362 YES miannu Our results indicate that mn1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate rar/rxr-mediated transcription through interaction with p160 and p300. 0.343 SIGNOR-97899 MTHFD2L protein Q9H903 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity chemical modification 10116 21163947 YES lperfetto Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH(2)-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified.  0.8 SIGNOR-268252 LRP5 protein O75197 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity relocalization 10090 11336703 YES amattioni Axin is a protein that interacts with the intracellular domain of LRP-5. LRP-5 active form bind Axin and induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin. 0.83 SIGNOR-236997 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser801 VPLLREAsARDRQSA 9606 BTO:0000007 11884385 YES lperfetto Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP. 0.2 SIGNOR-249142 GSK3B protein P49841 UNIPROT SIK1 protein P57059 UNIPROT up-regulates activity phosphorylation 9606 18348280 YES miannuccelli Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates Ser/Thr residues located at the fourth position ahead of the pre-phosphorylated Ser/Thr residues, and inhibitors of GSK-3beta reduce the phosphorylation at Thr182. The results of an in vitro reconstitution assay also indicate that GSK-3beta could be the SIK1 kinase. However, overexpression and knockdown of GSK-3beta in LKB1-defective HeLa cells suggests that GSK-3beta alone may not be able to phosphorylate or activate SIK1, indicating that LKB1 may play a crucial role by phosphorylating SIK1 at Thr182, possibly as an initiator of the autophosphorylation cascade, and GSK-3beta may phosphorylate SIK1 at Thr182 by recognizing the priming-autophosphorylation at Ser186 in cultured cells. 0.2 SIGNOR-279742 ALDH9A1 protein P49189 UNIPROT NADH(2-) smallmolecule CHEBI:57945 ChEBI up-regulates quantity chemical modification 9606 11802770 YES miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 0.8 SIGNOR-269695 ITCH protein Q96J02 UNIPROT SPART protein Q8N0X7 UNIPROT up-regulates activity binding 9606 BTO:0000567 20719964 YES Sara SPG20 Protein Spartin Is Recruited to Midbodies by ESCRT-III Protein Ist1 and Participates in Cytokinesis. Spartin colocalizes with Ist1 at the midbody, and depletion of Ist1 in cells significantly decreases the number of cells where spartin is present at midbodies. 0.2 SIGNOR-261308 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 BTO:0003892 11731619 YES PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site 0.378 SIGNOR-248658 FRZB protein Q92765 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 YES gcesareni We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos, 0.485 SIGNOR-51798 TP53 protein P04637 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7958853 NO gcesareni The p53 tumor suppressor protein trans-activates mdm2 itself, which is therefore considered a component of a p53 negative feedback loop. 0.968 SIGNOR-34962 FFAR1 protein O14842 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256799 calcium(2+) smallmolecule CHEBI:29108 ChEBI SYT1 protein P21579 UNIPROT up-regulates activity chemical activation 9606 16679567 YES miannu Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion 0.8 SIGNOR-263976 ULK1 protein O75385 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR form complex binding 9606 23863160 YES lperfetto In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. 0.915 SIGNOR-209890 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI DIO proteinfamily SIGNOR-PF83 SIGNOR up-regulates quantity by expression 9606 29892818 NO inferred from family member scontino Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity. 0.8 SIGNOR-270243 PLK1 protein P53350 UNIPROT RANBP1 protein P43487 UNIPROT up-regulates activity phosphorylation 9606 21813642 YES miannuccelli Here, we demonstrated in vitro and in vivo phosphorylation of RanBP1 by Plk1 as well as the importance of phosphorylation of RanBP1 in the interaction between Plk1 and Ran during early mitosis. 0.359 SIGNOR-279751 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu63 VQGNLEReCMEEKCS 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263689 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0002572 10026169 YES lperfetto Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. 0.708 SIGNOR-236512 PRKCE protein Q02156 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates activity phosphorylation Thr200 LPMWSNQtWNNSTWS 9606 23708658 YES miannu Taken together, our results demonstrate that PKC\u03b5-mediated phosphorylation at T200 and T280 enhances Nanog protein stability in head and neck squamous cell carcinoma.|These observations confirm that PKCepsilon modulates Nanog transcriptional activity and demonstrate that Nanog is phosphorylated by PKCepsilon at T200 and T280 in vivo. 0.33 SIGNOR-278203 STK10 protein O94804 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation Tyr565 MRQGRDKyKTLRQIR 9606 28430576 YES miannu Ezrin activation by LOK phosphorylation involves a PIP 2 -dependent wedge mechanism.|The specificity of kinases depends on local peptide consensus sequences, which in the case of ezrin phosphorylation by LOK involves the hydrophobic residue Y565 positioned -2 residues from T567. 0.473 SIGNOR-278204 2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)-1-oxopropyl]amino]-1-oxoethyl]amino]-1-oxoethyl]amino]-1-oxo-3-phenylpropyl]amino]-4-methylpentanoic acid chemical CHEBI:91634 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258806 CCP110 protein O43303 UNIPROT CETN3 protein O15182 UNIPROT up-regulates activity binding 9606 16760425 YES miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. 0.419 SIGNOR-265968 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-267530 CDK5 protein Q00535 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates quantity phosphorylation Ser1116 YRRRPPRsPDHKRYF 9606 24607229 YES miannu Cdk5 phosphorylates NR2B at Ser1116 and controls surface level expression.|Reduction in Cdk5 activity, as well as disruption of Cdk5-NR2B interactions consistently increased NR2B surface levels and facilitated NMDA mediated synaptic function. 0.444 SIGNOR-278265 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 NO irozzo To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity. 0.661 SIGNOR-256291 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. 0.382 SIGNOR-216801 p38 proteinfamily SIGNOR-PF16 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 17254968 YES inferred from 70% family members gcesareni We show that prak activates p53 by direct phosphorylation. 0.2 SIGNOR-270126 SL0101 chemical CID:10459196 PUBCHEM RPS6KA3 protein P51812 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207075 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser210 MSSTARRsRAASSQR 9606 22724069 YES lperfetto Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation 0.47 SIGNOR-197967 AKT1 protein P31749 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 YES gcesareni The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1. 0.431 SIGNOR-124365 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000007 17035229 YES SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.514 SIGNOR-248795 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation 9606 12792650 YES inferred from 70% family members lperfetto Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk 0.2 SIGNOR-270184 ATF6 protein P18850 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 YES miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network 0.656 SIGNOR-260184 VRK1 protein Q99986 UNIPROT COIL protein P38432 UNIPROT up-regulates quantity by stabilization phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 26068304 YES miannuccelli The active murine VRK1, but not its kinase-dead mutant (K179E), also phosphorylates coilin in Ser184 ( xref ). 0.361 SIGNOR-279772 AKT1 protein P31749 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Ser601 INFRRFTsASDVWMF 9606 31138602 YES miannuccelli In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis . 0.431 SIGNOR-279775 AKT1 protein P31749 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Ser695 EERMRMEsRRQATVS 9606 31138602 YES miannuccelli In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis . 0.431 SIGNOR-279776 Elongator complex complex SIGNOR-C466 SIGNOR TUBA3C protein P0DPH7 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 YES miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. α-Tubulin Acetylation Promotes Radial Migration and Branching of Cortical Projection Neurons 0.252 SIGNOR-269716 POU2F1 protein P14859 UNIPROT IL4 protein P05112 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 11781715 NO Here we show that NFAT proteins are unable to bind to a combined octamer/NFAT site unless the octamer proteins are competed away 0.2 SIGNOR-254505 NR3C1 protein P04150 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 YES Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB 0.2 SIGNOR-256104 PPP1CA protein P62136 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 BTO:0001271 21750978 YES miannu Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway 0.279 SIGNOR-174859 ATP6V1E2 protein Q96A05 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.745 SIGNOR-277748 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 9502314 NO lperfetto Inclusion body formation and other aggregates formed during protein folding have been assumed to arise from hydrophobic aggregation of the unfolded or denatured states 0.7 SIGNOR-262268 SOX2 protein P48431 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 NO flangone Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes. 0.7 SIGNOR-242064 NAE complex SIGNOR-C131 SIGNOR CUL1 protein Q13616 UNIPROT up-regulates activity neddylation 9606 25504797 YES lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. 0.745 SIGNOR-243151 paracetamol chemical CHEBI:46195 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000876 17884974 YES Luana Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man 0.8 SIGNOR-257757 CTF1 protein Q16619 UNIPROT TH protein P07101 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12859689 NO miannu CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. 0.2 SIGNOR-252219 sulpiride chemical CHEBI:32168 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition -1 7576010 YES miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I). 0.8 SIGNOR-258431 GRIK1 protein P39086 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264342 SETD1B protein Q9UPS6 UNIPROT MLL/SET subcomplex complex SIGNOR-C87 SIGNOR form complex binding 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.897 SIGNOR-268796 IL4R protein P24394 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 BTO:0000776 7538655 NO gcesareni The overlapping and distinct protein tyrosine phosphorylation and activation of the same jak1 kinase in t lymphocytes strongly suggests that il-4 and il-9 share the common signal transduction pathways. 0.675 SIGNOR-28399 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251589 PRKCI protein P41743 UNIPROT VIM protein P08670 UNIPROT up-regulates activity phosphorylation Ser34 SRSYVTTsTRTYSLG 9606 BTO:0001033 33525953 YES miannu Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells. 0.2 SIGNOR-277623 SMARCA4 protein P51532 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates binding 9606 10078207 YES miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. 0.95 SIGNOR-65441 PHKA1 protein P46020 UNIPROT PHKG1 protein Q16816 UNIPROT down-regulates activity binding 9606 10487978 YES Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. 0.69 SIGNOR-267405 PCDHA11 protein Q9Y5I1 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265670 CXCL12 protein P48061 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0000093 15882617 NO lperfetto Stromal fibroblast-derived SDF-1 enhances tumor growth both by stimulating angiogenesis through recruiting circulating EPCs into the tumor mass (endocrine effect) and by direct paracrine stimulation of tumor cells through CXCR4 expressed on carcinoma cells 0.7 SIGNOR-252267 ISL1 protein P61371 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR form complex binding 9606 9452425 YES miannu Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas. 0.34 SIGNOR-220131 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263785 AminoAcids stimulus SIGNOR-ST5 SIGNOR LAMTOR complex SIGNOR-C26 SIGNOR up-regulates 9606 BTO:0000007 SIGNOR-C3 20381137 NO lperfetto The trimeric Ragulator complex, which comprises the p18, p14, and MP1 proteins, anchors the Rag GTPases to the lysosome, and, like the Rags, is necessary for mTORC1 activation by amino acids 0.7 SIGNOR-228152 leucine smallmolecule CHEBI:25017 ChEBI SESN2 protein P58004 UNIPROT down-regulates activity chemical inhibition 9606 26449471 YES We find that leucine, but not arginine, disrupts the Sestrin2- GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20micromolar, which is the leucine concentration that half-maximally activates mTORC1 0.8 SIGNOR-254897 MIB1 protein Q86YT6 UNIPROT KIAA0586 protein Q9BVV6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27146717 YES miannu Conversely, expression of active, but not inactive, Mib1 likewise drastically reduced the levels of centriolar Talpid3 (XREF_FIG).|Mib1 promotes the poly-ubiquitylation of Talpid3, Cep131, and PCM1. 0.2 SIGNOR-278829 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR JUN protein P05412 UNIPROT down-regulates activity sumoylation Lys226 HPRLQALkEEPQTVP 9606 BTO:0000567 SIGNOR-C154 16055711 YES lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 0.254 SIGNOR-263006 P2RY13 protein Q9BPV8 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257027 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL20 protein P78556 UNIPROT up-regulates quantity by expression transcriptional regulation 22319003 YES lperfetto Combined stimulation with IL-6, sIL-6R, and IL-17 increased the recruitment of phosphorylated NF-B to the CCL20 promoter, increased binding of coactivators such as p300 and CBP, and enhanced H3 and H4 histone acetylation, consistent with a transcriptionally active gene. 0.302 SIGNOR-271680 SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 9566874 YES lperfetto Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein.We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis. 0.788 SIGNOR-235445 nintedanib chemical CHEBI:85164 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190299 CSNK2A1 protein P68400 UNIPROT YWHAQ protein P27348 UNIPROT down-regulates activity phosphorylation Ser232 LTLWTSDsAGEECDA 9606 25862939 YES lperfetto The neuroprotective effect of 14-3-3theta against rotenone toxicity is dependent on the inhibition of the pro-apoptotic factor Bax|Phosphorylation at S232 induced by rotenone is reduced by casein kinase inhibitors, and is not dependent on alphasyn.| The S232D mutant partially reduced the ability of 14-3-3theta to inhibit Bax activation in response to rotenone. Based on these findings, we propose that phosphorylation of 14-3-3s at serine 232 contributes to the neurodegenerative process in PD. 0.348 SIGNOR-264405 MAP2K6 protein P52564 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation Thr183 RQADSEMtGYVVTRW 9606 19230643 YES gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases 0.658 SIGNOR-184134 ZFHX3 protein Q15911 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11314020 NO miannu We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1. 0.416 SIGNOR-254436 PCDH9 protein Q9HC56 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-269035 LAMTOR1 protein Q6IAA8 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 YES lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant 0.926 SIGNOR-164769 ropinirole chemical CHEBI:8888 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 9057850 YES miannu Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively) 0.8 SIGNOR-258601 IKBKB protein O14920 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates activity phosphorylation Ser123 RERQRTQsLNEAFAA 9606 23375009 YES miannu Hence, our current study supports the pivotal role of beta-TRCP in IKKbeta mediated Twist degradation.|More importantly, IKKbeta dependent phosphorylation of Twist at T125 and S127 governs its nuclear localization. 0.332 SIGNOR-278405 ANGPTL1 protein O95841 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 10051567 YES gcesareni Ang3 and ang4 are agonists of tie2, but mouse ang3 has strong activity only on endothelial cells of its own species. 0.507 SIGNOR-65110 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser772 LVTPRKKsKSKLEEK -1 14657015 YES lperfetto Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin. 0.2 SIGNOR-271842 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.929 SIGNOR-253680 CD40 protein P25942 UNIPROT BIK protein Q13323 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 12324477 NO gcesareni Bik expression was weakly but significantly down-regulated by cd27 but up-regulated by cd40. 0.2 SIGNOR-93390 CCNT1 protein O60563 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15546612 NO gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. 0.2 SIGNOR-130634 TRAF2 protein Q12933 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys158 ALIHRDLkPPNLLLV 9606 BTO:0000007 20038579 YES lperfetto Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. 0.596 SIGNOR-162638 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 9606 BTO:0000848 21087211 YES gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3) 0.2 SIGNOR-252778 SNX6 protein Q9UNH7 UNIPROT IGF2R protein P11717 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 YES miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. 0.364 SIGNOR-269443 panobinostat chemical CHEBI:85990 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257755 CDC26 protein Q8NHZ8 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.851 SIGNOR-252011 MDM2 protein Q00987 UNIPROT KAT2B protein Q92831 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 14769800 YES miannu Consistently, overexpression of MDM2 in p53 null cells caused the reduction of the protein level of PCAF, but not the mRNA level.|MDM2 ubiquitinated PCAF in vitro and in cells. 0.62 SIGNOR-278825 TFAP2B protein Q92481 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization binding 9606 21556774 YES miannu These data suggest that AP-2Œ≤ enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2Œ≤ interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2Œ≤ up-regulates the transcription of the CRYAB gene through stabilizing p53. 0.336 SIGNOR-255422 RIN1 protein Q13671 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 11784866 YES gcesareni We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1. 0.597 SIGNOR-113970 anastrozole chemical CHEBI:2704 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189614 PTPN1 protein P18031 UNIPROT STAM2 protein O75886 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr291 KSEPEPVyIDEDKMD 9606 20504764 YES Together, the results presented here demonstrate that PTP1B can influence RTK signaling in a previously unrecognized manner. We show that PTP1B directly targets STAM2, part of the ESCRT-0 endosomal sorting complex, and we provide the first evidence that tyrosine phosphorylation affects STAM localization and function. This regulatory mechanism could impact signaling downstream of numerous cell surface receptors that are ubiquitinated and recognized by this conserved sorting machinery. 0.473 SIGNOR-248406 PPP2CA protein P67775 UNIPROT CARD11 protein Q9BXL7 UNIPROT down-regulates activity dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 YES NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. 0.31 SIGNOR-248650 TUBA3E protein Q6PEY2 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 NO miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. 0.7 SIGNOR-269726 STAT5A protein P42229 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12468433 YES We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling 0.666 SIGNOR-261547 DOK1 protein Q99704 UNIPROT ITGB8 protein P26012 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.2 SIGNOR-257698 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser39 TTSTRTYsLGSALRP 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248885 NR2E3 protein Q9Y5X4 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates binding 9606 15190009 YES gcesareni All four proteins, nr2e3, nr1d1, nrl and crx, could be co-immunoprecipitated from the bovine retinal nuclear extract, suggesting their existence in a multi-protein transcriptional regulatory complex in vivo. 0.4 SIGNOR-125661 PTPRJ protein Q12913 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12771128 YES inferred from 70% of family members gcesareni A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. 0.46 SIGNOR-269919 MAPK8 protein P45983 UNIPROT SARM1 protein Q6SZW1 UNIPROT down-regulates activity phosphorylation Ser548 AAREMLHsPLPCTGG 30333228 YES lperfetto C-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration|Here, we report that NAD+ cleavage activity of SARM1 is regulated by its own phosphorylation at serine 548. The phosphorylation of SARM1 was mediated by c-jun N-terminal kinase (JNK) under oxidative stress conditions, resulting in inhibition of mitochondrial respiration concomitant with enhanced activity of NAD+ cleavage. Nonphosphorylatable mutation of Ser-548 or treatment with a JNK inhibitor decreased SARM1 activity. 0.424 SIGNOR-275554 SEH1L protein Q96EE3 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.625 SIGNOR-262092 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 19282669 YES lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.593 SIGNOR-184577 FAM13B protein Q9NYF5 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.433 SIGNOR-260503 HOXB13 protein Q92826 UNIPROT TCF4 protein P15884 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 15928669 NO miannu In prostate cancers, HOXB13 negatively regulates beta-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth.  0.2 SIGNOR-254476 RPS6KA1 protein Q15418 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.53 SIGNOR-262999 WWTR1 protein Q9GZV5 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 22153608 YES Activation of Wnt signaling induces the hyperphosphorylation of Dishevelled (DVL), and this, via a poorly understood mechanism, ultimately leads to a rise in beta-Catenin levels and to the activation of beta-Catenin target genes. gcesareni Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation. 0.358 SIGNOR-195212 CAMKK1 protein Q8N5S9 UNIPROT CAMK1D protein Q8IU85 UNIPROT up-regulates activity phosphorylation Thr180 GKGDVMStACGTPGY BTO:0000567 12935886 YES llicata CaM-KIdelta exhibits Ca(2+)/CaM-dependent activity that is enhanced (approximately 30-fold) in vitro by phosphorylation of its Thr180 by CaM-K kinase (CaM-KK)alpha, consistent with detection of CaM-KIdelta-activating activity in HeLa cells. | This sustained activation of CaM-KIdelta was completely abolished by Thr180Ala mutation and inhibited by CaM-KK inhibitor, STO-609, indicating a functional CaM-KK/CaM-KIdelta cascade in HeLa cells. 0.417 SIGNOR-250715 CYSLTR2 protein Q9NS75 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.515 SIGNOR-257024 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 NO miannu Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton 0.7 SIGNOR-266596 APC-c complex SIGNOR-C150 SIGNOR ANLN protein Q9NQW6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16040610 YES miannu  Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin. 0.263 SIGNOR-272655 UBXN1 protein Q04323 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 15362974 NO miannu Our working hypothesis is that SAKS1 acts as scaffolding protein to enhance the unfolding and proteolytic destruction of a subset of proteins. PNGase removes high-mannose-containing oligosaccharides from MGPs [30], and our results suggest this may be facilitated by the formation of a complex between PNGase, VCP, SAKS1 and ubiquitinated MGPs, as illustrated schematically in Figure 7(B). PNGase has been reported to bind to the S4 component of the proteasome [30], so that the deglycosylation of MGPs by PNGase, followed by VCP-catalysed unfolding, may facilitate their destruction by the proteasome. 0.7 SIGNOR-261059 BRIP1 protein Q9BX63 UNIPROT BLM protein P54132 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 21240188 YES irozzo In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. 0.655 SIGNOR-259186 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI PTGER2 protein P43116 UNIPROT up-regulates chemical activation 9606 15299086 YES gcesareni Pge2 acts via four ep receptors termed ep1 to ep4. 0.8 SIGNOR-127735 bexarotene chemical CHEBI:50859 ChEBI RXRA protein P19793 UNIPROT up-regulates activity chemical activation 9606 BTO:0002058 17483357 YES miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. 0.8 SIGNOR-259230 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Arg) smallmolecule CHEBI:29171 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269481 AURKA protein O14965 UNIPROT CEP192 protein Q8TEP8 UNIPROT up-regulates activity phosphorylation 9606 25042804 YES lperfetto Thus, following their sequential activation in Cep192 complexes, both AurA and Plx1 phosphorylate Cep192.|We found that Cep192 1\u20131000 -wt promoted AurA and Plx1 activation and itself underwent phosphorylation irrespective of whether it was bound to the endogenous or recombinant Plx1 (i.e. whether Plx1 was docked onto T46 or not) (lanes 6 and 8). 0.795 SIGNOR-279797 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.344 SIGNOR-134617 PSMB6 protein P28072 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.853 SIGNOR-263361 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity deacetylation 9606 16613856 YES lperfetto HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation 0.525 SIGNOR-227547 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 YES Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism 0.732 SIGNOR-252055 GAB2 protein Q9UQC2 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 YES milica The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival 0.465 SIGNOR-204966 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IL17A protein Q16552 UNIPROT up-regulates quantity 9606 BTO:0002417 32454942 NO miannu interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology 0.7 SIGNOR-263819 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 9187659 YES gcesareni We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence. 0.857 SIGNOR-49126 pazopanib hydrochloride chemical CHEBI:71217 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 17620431 YES miannu The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. 0.8 SIGNOR-259167 PELI3 protein Q8N2H9 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity ubiquitination 9606 25526310 YES miannu Finally, we used coexpression studies to directly demonstrate that Pellino3 inhibits the ability of wild-type TRAF6 to stabilize HIF-1alpha but not the stabilizing effects of the K124A TRAF6 mutant that is resistant to ubiquitination.|In the present study, Pellino3 ubiquitinates TRAF6 with lysine 63-linked polyubiquitin chains to block the interaction of TRAF6 with HIF-1\u03b1. 0.629 SIGNOR-278707 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 22722787 YES XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. gcesareni Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4). 0.8 SIGNOR-197959 Melanotan II chemical CID:92432 PUBCHEM MC3R protein P41968 UNIPROT up-regulates activity binding BTO:0000614 17702843 YES lperfetto Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases. 0.8 SIGNOR-253065 AURKA protein O14965 UNIPROT VHL protein P40337 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 28114281 YES lperfetto Conversely, AURKA can phosphorylate VHL at serine 72, a priming phosphorylation for GSK3beta, which regulates VHL 's role in microtubule stability. 0.407 SIGNOR-279800 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1009 LDTSSVLyTAVQPNE -1 7545675 YES Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides 0.69 SIGNOR-248416 DOK4 protein Q8TEW6 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 YES gcesareni Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells. 0.46 SIGNOR-100996 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 YES lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 0.61 SIGNOR-249199 LPCAT2 protein Q7L5N7 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI up-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272764 EIF4A3 protein P38919 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 YES miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. 0.948 SIGNOR-265240 IL1A protein P01583 UNIPROT MC1R protein Q01726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 9767234 NO miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. 0.2 SIGNOR-252387 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA6 protein Q9Y5G7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265694 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MCM10 protein Q7L590 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 22570418 YES miannu By screening the known DDB1 interacting proteins, we discovered that VprBP is the substrate recognition subunit that targets Mcm10 for degradation. Hence, these results establish that Cul4-DDB1-VprBP ubiquitin ligase mediates the stress-induced proteolysis of replication factor, Mcm10. 0.384 SIGNOR-272045 MRAP2 protein Q96G30 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. 0.492 SIGNOR-252365 SYK protein P43405 UNIPROT CGAS protein Q8N884 UNIPROT up-regulates activity phosphorylation Tyr214 GLLNTGSyYEHVKIS 10090 BTO:0003292 36252040 YES miannu Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation. 0.2 SIGNOR-277844 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 9130707 YES gcesareni We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase. 0.525 SIGNOR-47634 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Tyr405 STSSSIIySSQEDVK 9606 21081495 YES lperfetto Mdm2 has three known c-abl phosphorylation sites (tyr276, tyr394, and tyr405)these data show that c-abl is important for reducing mdm2 and mdmx protein levels after genotoxic stress and suggest another cellular mechanism for the stabilization and activation of p53. 0.715 SIGNOR-169703 PRKCA protein P17252 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser686 WTETKKQsFKQTGEF -1 1377674 YES lperfetto Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC. 0.399 SIGNOR-248849 POU4F1 protein Q01851 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity binding 9606 9448000 YES 2 miannu The POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect. 0.551 SIGNOR-241275 RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates activity binding 10090 BTO:0000944 19171758 YES miannu In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells. 0.739 SIGNOR-265554 BLVRA protein P53004 UNIPROT biliverdin(2-) smallmolecule CHEBI:57991 ChEBI up-regulates quantity chemical modification 9606 BTO:0000759 7929092 YES lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 0.8 SIGNOR-275521 GNAS protein P63092 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9606 8245028 YES MIANNU The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits. 0.324 SIGNOR-265066 26S Proteasome complex SIGNOR-C307 SIGNOR Ubiquitinated-Viral_Protein complex SIGNOR-C427 SIGNOR down-regulates quantity cleavage 9606 15571818 YES scontino The proteasome system is the central proteolytic system of the eukaryotic cell [1] and plays an important role in the generation of MHC-class I peptides. The enzyme complex responsible for the selectivity of intracellular protein degradation is the 26S proteasome that degrades poly-ubiquitinated substrates. 0.2 SIGNOR-267769 RPS6KA3 protein P51812 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates quantity phosphorylation Ser789 DTRSSTCsSGEDSVF 9606 BTO:0001938 24141780 YES miannu  Both in vitro and in vivo experiments confirmed the interaction and we show that phosphorylated RSK2 binds to and phosphorylates serine 789 in the C-terminal tail of FGFR1.prevention of FGFR1 phosphorylation by inhibition of RSK2 activity or mutation of serine 789 to alanine reduced FGFR1 endocytosis and ubiquitination explaining mechanistically the prolonged signaling activity. 0.357 SIGNOR-276599 NFE2L2 protein Q16236 UNIPROT GSTA1 protein P08263 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22459801 NO miannu Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed. 0.342 SIGNOR-254644 SEMA3A protein Q14563 UNIPROT PLXNA1 protein Q9UIW2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 YES miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  0.769 SIGNOR-261813 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 YES gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk 0.636 SIGNOR-64172 estramustine chemical CHEBI:4868 ChEBI MAP1A protein P78559 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001332 1647395 YES miannu Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion. 0.8 SIGNOR-259297 ARNTL protein O00327 UNIPROT CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.933 SIGNOR-253627 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser89 KQKQPSFsAKKMTEK 9606 BTO:0000567 24781523 YES miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase 0.295 SIGNOR-276380 IKBKB protein O14920 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 24290981 YES miannu Taken together, these results indicate that IKK\u03b2-dependent phosphorylation of RAPGEF2 is required for RAPGEF2 degradation induced by HGF and mediated by \u03b2TrCP. 0.2 SIGNOR-279805 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser20 PLSQETFsDLWKLLP 9606 20562916 YES miannu We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37. 0.367 SIGNOR-166258 IKBKE protein Q14164 UNIPROT IRF1 protein P10914 UNIPROT down-regulates activity phosphorylation Ser221 VSPMPSTsEATTDED 9606 BTO:0000007 24396068 YES miannu We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.  0.35 SIGNOR-276479 ARNT protein P27540 UNIPROT TH protein P07101 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003945 17457889 NO lperfetto Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter. 0.2 SIGNOR-253701 UBE2E3 protein Q969T4 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization sumoylation Lys21 EGPRDGLkKERLLDD 9606 BTO:0000007;BTO:0000567 10582246 YES lperfetto In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to IkappaBalpha primarily on K21, which is also utilized for ubiquitin modification. Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation.  0.347 SIGNOR-270545 ATM protein Q13315 UNIPROT LARP7 protein Q4G0J3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr440 ANREECRtQEKVNAT 32726637 YES lperfetto Altogether, the results suggest that ATM-mediated T440 phosphorylation enhances LARP7-BARD1 interaction and facilitates BRCA1/BARD1-mediated LARP7 ubiquitination and degradation. 0.2 SIGNOR-275580 ATM protein Q13315 UNIPROT WRN protein Q14191 UNIPROT unknown phosphorylation Ser1292 MTIGMHLsQAVKAGC -1 10608806 YES llicata We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself. 0.826 SIGNOR-250578 RTKs proteinfamily SIGNOR-PF38 SIGNOR ITGB4 protein P16144 UNIPROT up-regulates activity phosphorylation 9606 30889378 YES miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. 0.2 SIGNOR-259031 POU5F1 protein Q01860 UNIPROT DLX5 protein P56178 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.31 SIGNOR-254935 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1623 SPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248780 EGLN3 protein Q9H6Z9 UNIPROT BCL2L11 protein O43521-1 UNIPROT up-regulates quantity by stabilization hydroxylation Pro67 PQGPLAPpASPGPFA 9606 31375625 YES lperfetto EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues 0.254 SIGNOR-262003 PTPN1 protein P18031 UNIPROT PTK6 protein Q13882 UNIPROT down-regulates activity dephosphorylation Tyr342 RLIKEDVyLSHDHNI 9606 29142193 YES miannu Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342. 0.573 SIGNOR-277082 CSNK2A2 protein P19784 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 YES llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  0.307 SIGNOR-251037 P2RY11 protein Q96G91 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257173 NFE2L2 protein Q16236 UNIPROT PXDN protein Q92626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567; BTO:0000007 29953917 YES miannu PXDN expression in response to H2O2 and the Nrf2-specific inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN), was determined by western blotting and immunofluorescence microscopy, in HeLa and HEK293 cells.We found that Nrf2 binds to and increases luciferase reporter gene expression from the PXDN promoter via a putative Nrf2-binding site. In summary, we show that PXDN is a novel target of the redox sensitive transcription factor Nrf2. 0.2 SIGNOR-265248 albuterol sulfate chemical CHEBI:2550 ChEBI ADRB2 protein P07550 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206682 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 SIGNOR-C15 21892142 YES gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) 0.342 SIGNOR-176483 ATXN2L protein Q8WWM7 UNIPROT MPL protein P40238 UNIPROT down-regulates binding 9606 11784712 YES miannu A2d binds to cytokine receptors mpl and epo-r. A2d is associated with these unoccupied receptorsin vivo,and stimulation with tpo or epo causes the rapid dissociation of a2d from the activated receptor. 0.354 SIGNOR-113891 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates binding 9606 21902831 YES lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.265 SIGNOR-216966 INSR protein P06213 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Tyr27 GFDLDLTyIYPNIIA -1 23995781 YES miannu Our results show that the kinase region of IRβ subunit physically binds to PTEN and phosphorylates on Y27 and Y174. In the current study, we discovered that IR also downregulates PTEN through tyrosine phosphorylation and suggest that Y27 and 174 are the two key tyrosines. 0.443 SIGNOR-276470 VKORC1 protein Q9BQB6 UNIPROT vitamin K epoxide smallmolecule CHEBI:28371 ChEBI down-regulates quantity chemical modification 9606 31226734 YES lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form 0.8 SIGNOR-265900 NUP58 protein Q9BVL2 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR form complex binding 10116 BTO:0000154 2050741 YES Simone Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. 0.2 SIGNOR-261260 DHFR protein P00374 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 21876184 YES lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. 0.8 SIGNOR-268258 PDPK1 protein O15530 UNIPROT TSSK3 protein Q96PN8 UNIPROT up-regulates activity phosphorylation Thr168 SHRELSQtFCGSTAY -1 16336268 YES Manara We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation. 0.261 SIGNOR-260786 STAG2 protein Q8N3U4 UNIPROT RAD21 protein O60216 UNIPROT up-regulates quantity by stabilization binding 9606 28430577 YES miannu Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin 0.965 SIGNOR-261511 sapitinib chemical CHEBI:132986 ChEBI SHC3 protein Q92529 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 20145185 YES gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. 0.8 SIGNOR-163733 JQ1 chemical CHEBI:137113 ChEBI BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition -1 20871596 YES lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. 0.8 SIGNOR-261987 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser525 TSMKPRSsRGSIFTF -1 12242273 YES miannu These results demonstrate that the effect of PKA stimulation to increase cardiac INa requires at least 2 processes: phosphorylation of consensus sites in the I-II interdomain linker, and one or more additional molecular events mediated by the kinase, that could include phosphorylation of other substrates/proteins. 0.2 SIGNOR-275991 MLNR protein O43193 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257016 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Ala92 PAFISEDaSGYLTSS -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.42 SIGNOR-263576 PRKCA protein P17252 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 11781100 YES lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. 0.324 SIGNOR-249138 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4517 LYMGGHGsRHSLAST 9606 15272003 YES lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. 0.2 SIGNOR-126958 GATA2 protein P23769 UNIPROT TRH protein P20396 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000318 33201916 YES scontino The rat prepro-TRH gene is activated by GATA2. 0.263 SIGNOR-267259 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr826 SRKVGPGyLGSGGSR 9534 BTO:0004055 8621380 YES lperfetto Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map  0.2 SIGNOR-248942 COL1A1 protein P02452 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 YES lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  0.424 SIGNOR-272342 SMARCA4 protein P51532 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.758 SIGNOR-270726 RNF7 protein Q9UBF6 UNIPROT Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR form complex binding 10090 BTO:0000165 19300455 YES miannu Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation.  Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb. 0.931 SIGNOR-271799 EXOC7 protein Q9UPT5 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.941 SIGNOR-270790 Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR Microtubule-based_movement phenotype SIGNOR-PH170 SIGNOR up-regulates 16440056 NO lperfetto Dyneins are large multi-subunit protein complexes that undertake a wide range of roles within the cell. They are adenosine triphosphate (ATP)–driven, microtubule minus-end-directed molecular motors that can be divided, based on function, into two classes: axonemal and cytoplasmic dyneins 0.7 SIGNOR-265020 KAT6A protein Q92794 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 SIGNOR-C54 11965546 YES miannu Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation. 0.308 SIGNOR-117332 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr332 VNIMRTYtYEKLLWT 9606 BTO:0000938 24117889 YES lperfetto Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552. 0.289 SIGNOR-202829 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu637 QKLVFFAeDVGSNKG -1 8943232 YES lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261768 RNF7 protein Q9UBF6 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity ubiquitination 9606 23136067 YES miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 0.2 SIGNOR-271451 MAPK1 protein P28482 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 YES gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. 0.301 SIGNOR-169001 CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser273 PGQGGSTsAFEQLQR 9534 11733001 YES miannu P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed. 0.493 SIGNOR-273183 CDKN2C protein P42773 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 YES miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. 0.879 SIGNOR-44601 arecoline chemical CHEBI:2814 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258640 DNMT1 protein P26358 UNIPROT MBD2 protein Q9UBB5 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 15618232 NO lperfetto We then examined the levels of DNMT1 and methylated DNA-binding protein 2 (MBD2) expressions in these cells to determine whether this reduction in uPA expression is associated with changes in the DNA methylation machinery. Our results showed that ectopic expression of RAS induced DNMT1 expression and activity and inhibited MBD2 expression. 0.704 SIGNOR-254128 bexarotene chemical CHEBI:50859 ChEBI RXRG protein P48443 UNIPROT up-regulates activity chemical activation 9606 BTO:0002058 17483357 YES miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. 0.8 SIGNOR-259232 UBE4B protein O95155 UNIPROT FEZ1 protein Q99689 UNIPROT up-regulates activity polyubiquitination 10116 BTO:0001009 15466860 YES K27 miannu  E4B mediated the polyubiquitylation of FEZ1 but did not affect its intracellular stability, suggesting that such modification of FEZ1 is not a signal for its proteolysis. Polyubiquitylation of FEZ1 by E4B required Lys(27) of ubiquitin. Expression of a dominant-negative mutant of E4B in rat pheochromocytoma PC12 cells resulted in inhibition of neurite extension induced either by nerve growth factor or by coexpression of FEZ1 and constitutively active PKCzeta. These findings indicate that E4B serves as a ubiquitin ligase for FEZ1 and thereby regulates its function but not its degradation. The polyubiquitin chain attached by E4B to FEZ1 might therefore facilitate the interaction of FEZ1 with an unidentified target that functions in neuritogenesis. 0.392 SIGNOR-271510 CSNK1E protein P49674 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 YES lperfetto Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846 0.26 SIGNOR-274047 AMBRA1 protein Q9C0C7 UNIPROT HUWE1 protein Q7Z6Z7 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 phosphorylation:Ser1043 CRPEALNsGVEYYWD 30217973 YES lperfetto AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome 0.2 SIGNOR-272962 MAPK3 protein P27361 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 YES llicata We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro. 0.27 SIGNOR-203290 RPS6K proteinfamily SIGNOR-PF26 SIGNOR YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 YES lperfetto We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue. 0.2 SIGNOR-252804 WAS protein P42768 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 YES lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. 0.81 SIGNOR-261001 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 YES lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. 0.729 SIGNOR-248925 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr749 FGLSKKIySGDYYRQ 9606 8702477 YES gcesareni By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain. 0.2 SIGNOR-42914 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 17977820 YES lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I 0.93 SIGNOR-209784 PRKACA protein P17612 UNIPROT CACNA1H protein O95180 UNIPROT down-regulates activity phosphorylation Ser1107 LPDSRRGsSSSGDPP 9606 19131331 YES miannu Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity. 0.2 SIGNOR-263110 ATF2 protein P15336 UNIPROT IL6 protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 NO JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes 0.298 SIGNOR-254512 KLHL9 protein Q9P2J3 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000527 25303533 YES miannu KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ. 0.2 SIGNOR-272458 FCRL3 protein Q96P31 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity binding -1 12051764 YES miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. 0.391 SIGNOR-274013 ADCY10 protein Q96PN6 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-265008 ATR protein Q13535 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11865061 YES gcesareni Nhibition of atr kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation. 0.741 SIGNOR-115134 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 YES lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. 0.914 SIGNOR-235983 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.604 SIGNOR-263438 LNX2 protein Q8N448 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 26451611 YES miannu Polyubiquitination of Human Numb by LNX2. The Zn-RING-Zn domain of LNX2 is a dimer and assumes a rigid elongated structure that undergoes autoubiquitination and undergoes N-terminal polyubiquitination. LNX2 can bind numb and induce its ubiquitination and subsequent proteasomal degradation 0.606 SIGNOR-272423 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr112 EGMQIPStQFDAAHP 9606 12432063 YES llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin 0.6 SIGNOR-251067 BMP2 protein P12643 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 22298955 NO gcesareni FGF-2 null mice have impaired nuclear accumulation of Runx2 and hindered BMP-2 induced bone formation and ALP activity 0.436 SIGNOR-114589 CACNA1D protein Q01668 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 NO miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). 0.7 SIGNOR-264331 NFIX protein Q14938 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268887 ZBTB43 protein O43298 UNIPROT BDP1 protein A6H8Y1 UNIPROT unknown binding 9606 16542149 YES miannu The zinc finger protein ZNF297B interacts with BDP1, a subunit of TFIIIB. Due to the essential role of BDP1 in Pol III transcription, we propose that ZNF297B may also regulate these transcriptional pathways. 0.454 SIGNOR-225852 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu60 LERECMEeTCSYEEA -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263669 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257924 GNAI3 protein P08754 UNIPROT ADCY5 protein O95622 UNIPROT down-regulates activity binding 7108 BTO:0001240 8119955 YES Marta Tosoni Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3 0.518 SIGNOR-278076 palbociclib chemical CHEBI:85993 ChEBI CCND1 protein P24385 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189693 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA12 protein O60330 UNIPROT up-regulates activity binding 9606 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265676 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Thr507 KFRTKSRtWAGEKSK 9606 20068082 YES gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); 0.856 SIGNOR-163154 SPX protein Q9BT56 UNIPROT GALR2 protein O43603 UNIPROT up-regulates activity binding 9606 BTO:0000007 24517231 YES lperfetto Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III. 0.339 SIGNOR-268574 AURKB protein Q96GD4 UNIPROT CDCA2 protein Q69YH5 UNIPROT down-regulates activity phosphorylation Ser977 EPGKRRKsFCISTLA 9606 BTO:0000567 32938714 YES done miannu This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin. 0.447 SIGNOR-274004 SATB1 protein Q01826 UNIPROT IGFBP2 protein P18065 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 17343824 NO miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 0.2 SIGNOR-255129 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9823 BTO:0004007 10523831 YES lperfetto Phosphorylation of the adapter protein shc by growth factor receptors provides association sites for grb2-sos, thereby activating the ras/map kinase pathway. 0.965 SIGNOR-235615 LCK protein P06239 UNIPROT ITK protein Q08881 UNIPROT up-regulates phosphorylation Tyr512 RFVLDDQyTSSTGTK -1 9312162 YES Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. The major site of Lck phosphorylation on Itk was mapped to the conserved tyrosine (Tyr511) in the activation loop of the Itk kinase domain. 0.553 SIGNOR-251380 BRAP protein Q7Z569 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23105109 YES miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. 0.66 SIGNOR-272028 VCP protein P55072 UNIPROT RQC complex complex SIGNOR-C559 SIGNOR form complex binding 28528489 YES lperfetto The ribosome-bound quality control (RQC) complex is a multi-protein complex conserved throughout eukaryotes and composed of the E3 ubiquitin ligase Ltn1/Listerin, the ATPase Cdc48/p97 with its co-factors Ufd1/UFD1L and Npl4/NPLOC4, as well as the factors Rqc1/TCF25 and Rqc2/NEMF (Fig. 1). 0.585 SIGNOR-277695 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258630 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 7535770 YES gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. 0.333 SIGNOR-28063 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates quantity by destabilization phosphorylation Ser110 GEDSLEQsPLLEDKY 10090 BTO:0000944 25733682 YES miannu  MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding.  0.265 SIGNOR-276888 BMP1 protein P13497 UNIPROT COL7A1 protein Q02388 UNIPROT up-regulates quantity cleavage Ala2821 RPLPSYAaDTAGSQL 9606 BTO:0000667 11986329 YES miannu  We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA/DTAG within the NC-2 domain. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen. 0.603 SIGNOR-256338 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser607 NLIDLAGsERCSTAH 9606 BTO:0000565 28630147 YES miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 0.371 SIGNOR-266417 PPP2CA protein P67775 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 15510216 YES Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro. 0.333 SIGNOR-248644 NEK6 protein Q9HC98 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 20595392 YES done miannu Our data also show that NEK6 interacts with STAT3, an oncogenic transcription factor, and phosphorylates STAT3 on Ser(727), which is important for transcriptional activation. These results demonstrate that NEK6 interacts with and phosphorylates STAT3, an event that could play an important role in oncogenesis. For the maximal activation of STAT3 signaling, phosphorylation of both Tyr705 and Ser727 is required. Phosphorylation of Tyr705 induces dimerization, nuclear translocation, and DNA binding of the STAT3 protein, whereas phosphorylation of Ser727 is important for transcriptional activation. 0.332 SIGNOR-273901 buprenorphine chemical CHEBI:3216 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258769 USP13 protein Q92995 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 SIGNOR-C242 21962518 YES Giulio Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E) 0.529 SIGNOR-260295 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252329 ITGA2B protein P08514 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.948 SIGNOR-253197 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.706 SIGNOR-131838 BST1 protein Q10588 UNIPROT NAD(+) smallmolecule CHEBI:15846 ChEBI down-regulates quantity chemical modification 9606 18626062 YES miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. 0.8 SIGNOR-264250 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates phosphorylation Ser321 LNSEDDVsDEEGQEL 9606 11278496 YES llicata Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity. 0.677 SIGNOR-105745 MRGPRX2 protein Q96LB1 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257172 clemastine chemical CHEBI:3738 ChEBI P2RX7 protein Q99572 UNIPROT up-regulates activity chemical activation 9606 21262970 YES Luana Clemastine potentiates the human P2X7 receptor by sensitizing it to lower ATP concentrations. 0.8 SIGNOR-257893 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189969 CDR2 protein Q01850 UNIPROT MYC protein P01106 UNIPROT up-regulates activity binding 20383333 YES lperfetto Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. 0.499 SIGNOR-252000 SLIT2 protein O94813 UNIPROT ROBO4 protein Q8WZ75 UNIPROT up-regulates binding 9606 BTO:0000938 12941633 YES gcesareni We show that robo4 binds slit and inhibits cellular migration in a heterologous expression system, analogous to the role of known robo receptors in the nervous system. 0.636 SIGNOR-86380 SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 NO miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.7 SIGNOR-269828 CDX2 protein Q99626 UNIPROT UGT1A10 protein Q9HAW8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 YES Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. 0.257 SIGNOR-253968 VHL protein P40337 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity binding 9606 BTO:0000567 17936701 YES We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. 0.394 SIGNOR-266899 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.2 SIGNOR-250557 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 YES We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction 0.644 SIGNOR-259921 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.759 SIGNOR-219324 S protein P59594 UNIPROT HSP90B1 protein P14625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16940539 NO miannu Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein. 0.2 SIGNOR-260352 sabcomeline chemical CHEBI:134846 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10116 9399977 YES miannu SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes 0.8 SIGNOR-258675 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR PSEN1 protein P49768 UNIPROT down-regulates activity phosphorylation Ser353 SHLGPHRsTPESRAA 9606 BTO:0000007 17360711 YES gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. 0.395 SIGNOR-228018 MAPK1 protein P28482 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 9606 16314496 YES fstefani We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription. 0.354 SIGNOR-142458 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.271 SIGNOR-265777 ponatinib chemical CHEBI:78543 ChEBI FGFR4 protein P22455 UNIPROT down-regulates activity chemical inhibition 9606 23468082 YES miannu Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. 0.8 SIGNOR-259280 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Ser882 DGSKTSSsDTLSEEK 9606 BTO:0000567 31167143 YES miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  0.2 SIGNOR-276730 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.6 SIGNOR-34669 VIM protein P08670 UNIPROT LARP6 protein Q9BRS8 UNIPROT up-regulates activity binding 9606 21746880 YES miannu Interaction of LARP6 with vimentin.Here, we report that vimentin filaments associate with collagen mRNAs in a 5'SL- and LARP6-dependent manner and stabilize collagen mRNAs. LARP6 interacts with vimentin filaments through its La domain and colocalizes with the filaments in vivo. 0.271 SIGNOR-277624 CDKN2C protein P42773 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 8891723 YES miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. 0.871 SIGNOR-44598 PAFAH1B2 protein P68402 UNIPROT APP protein P05067 UNIPROT up-regulates 9606 23238734 NO miannu We provide evidence that the loss of pafah1b2 potently reduces a_ by promoting the degradation of its immediate precursor, the _ctf. 0.2 SIGNOR-200188 SKIL protein P12757 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 SIGNOR-C85 12419246 YES gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7 0.483 SIGNOR-195636 NOTCH1 protein P46531 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19165418 NO lperfetto Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1. 0.771 SIGNOR-183507 CDH19 protein Q9H159 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.315 SIGNOR-265858 SUN5 protein Q8TC36 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.323 SIGNOR-263289 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH13 protein P55290 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265831 TRIM58 protein Q8NG06 UNIPROT DYNC1I2 protein Q13409 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 25241935 YES miannu Trim58 ubiquitinates dynein and promotes its proteasomal degradation. Trim58 binds DIC directly, polyubiquitinates it in vitro, and induces proteasomal degradation of the dynein holocomplex in vivo. 0.298 SIGNOR-272841 EPAS1 protein Q99814 UNIPROT CACNA1A protein O00555 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15833863 NO miannu A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Ten genes were preferentially activated by HIF-2alpha, including two (CACNA1A and PTPRZ1) implicated in neurologic diseases. 0.2 SIGNOR-264332 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr642 TRQPVELtPTDKLFI 9606 17115692 YES lperfetto The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif 0.2 SIGNOR-150865 TMEM258 protein P61165 UNIPROT OST-A complex complex SIGNOR-C535 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.479 SIGNOR-272060 4-[2-(2-chloro-4-fluoroanilino)-5-methyl-4-pyrimidinyl]-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-1H-pyrrole-2-carboxamide chemical CHEBI:95049 ChEBI MAPK1 protein P28482 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001271 31482470 YES miannu In the present study, we have shown that ERK2 inhibitor VX-11e demonstrates a potent synergy with voreloxin in leukemia cell lines and that this effect is associated with the inhibition of proliferation, cell cycle arrest and induction of apoptosis. 0.8 SIGNOR-262244 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation 9606 14988395 YES inferred from 70% family members lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. 0.2 SIGNOR-270012 AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 NO miannu Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2. 0.7 SIGNOR-251550 PIK3R3 protein Q92569 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0000007 32606738 YES miannu N this study, we aimed to explore the interaction of p55PIK with p53 and the role of p55PIK in regulating p53-dependent apoptosis in cancer cells. We found that p55PIK directly binds to the DBD domain of p53 via N24 domain. Moreover, the upregulation of p55PIK expression increases transcriptional levels of p53-dependent apoptosis-related genes including GADD45α, S100A9, MDM2 and AIP1. Furthermore, synthetic N24 translocated to nucleus can significantly inhibit cancer cell growth. 0.296 SIGNOR-261492 HSP90AB1 protein P08238 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 27353360 YES miannu Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. 0.2 SIGNOR-261418 CREB1 protein P16220 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 34751390 YES scontino CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription. 0.267 SIGNOR-267137 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 14645234 YES gcesareni Pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. Furthermore, phosphorylation of either serine 16 or 63 is sufficient to inhibit op18/stathmin in vitro. 0.375 SIGNOR-119483 IDH3B protein O43837 UNIPROT IDH complex SIGNOR-C396 SIGNOR form complex binding 9606 28139779 YES miannu Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 0.698 SIGNOR-266249 buprenorphine chemical CHEBI:3216 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258940 RRAGA protein Q7L523 UNIPROT RAGAC complex SIGNOR-C113 SIGNOR form complex binding 9606 20381137 YES gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant 0.781 SIGNOR-228164 SIRT2 protein Q8IXJ6 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14522900 NO miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. 0.309 SIGNOR-254481 MFGE8 protein Q08431 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 9606 21901532 NO miannu In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production 0.276 SIGNOR-260654 RXRA protein P19793 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 10976919 YES gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr). 0.662 SIGNOR-81446 JAK2 protein O60674 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr248 EESEDPDyYQYNIQA 10090 BTO:0000944 11313464 YES lperfetto Jak2 activates tfii-i and regulates its interaction with extracellular signal-regulated kinase the interaction between tfii-i and erk, which is essential for its activity, can be regulated by jak2 through phosphorylation of tfii-i at tyrosine 248 0.328 SIGNOR-235313 AKT proteinfamily SIGNOR-PF24 SIGNOR ARHGAP22 protein Q7Z5H3 UNIPROT up-regulates activity phosphorylation Ser16 ARRARSKsLVMGEQS 9606 BTO:0000007 21969604 YES miannu Akt phosphorylates RhoGAP22 at the 14-3-3 binding site and is required for insulin-stimulated 14-3-3 binding. we have demonstrated that Akt is the kinase responsible for phosphorylation of Ser16 in order to mediate 14-3-3 binding to RhoGAP22. 0.2 SIGNOR-262613 MAPK9 protein P45984 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 YES gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.663 SIGNOR-134576 ITGB1 protein P05556 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.915 SIGNOR-253178 MAPK3 protein P27361 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser62 SYTPTPRsPRFIGRR 9606 7901013 YES gcesareni In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11 0.482 SIGNOR-34678 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10116 15735685 YES The rat tyrosine phosphatase eta increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue 0.635 SIGNOR-248705 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Thr501 QMDSGYNtQNCGSNI 9606 18378770 YES gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). 0.787 SIGNOR-178154 nifedipine chemical CHEBI:7565 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9606 9770465 YES miannu In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR. 0.8 SIGNOR-259066 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM2 protein P0DP24 UNIPROT up-regulates chemical activation 10090 10448861 YES miannu Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. 0.8 SIGNOR-266318 PPP1CA protein P62136 UNIPROT CCND3 protein P30281 UNIPROT up-regulates dephosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 YES lperfetto These results support the hypothesis that pp1 constitutively keeps cyclin d3 in a stable, dephosphorylated state 0.246 SIGNOR-142884 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr248 EESEDPDyYQYNIQA 9534 BTO:0004055 11373296 YES lperfetto These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation. 0.517 SIGNOR-108338 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 BTO:0000567 BTO:0000887;BTO:0001103 8454633 YES gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. 0.378 SIGNOR-39159 LMNA protein P02545 UNIPROT SUN2 protein Q9UH99 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 16380439 YES Sara In the case of Sun2, there is some evidence that A-type lamins might contribute to Sun2 localization in the INM. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation. 0.623 SIGNOR-261310 AMFR protein Q9UKV5 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 23427266 YES miannu Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2. 0.31 SIGNOR-272886 DYRK2 protein Q92630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates quantity by destabilization phosphorylation Ser527 QDIDSRLsPGGSLAD 9606 BTO:0000007 26407194 YES miannu  We further found that DYRK2 phosphorylated Ser527 of TBK1, which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade TBK1.  0.413 SIGNOR-276939 MAPK14 protein Q16539 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser116 VTPHSPSsPVGSVLL 9606 BTO:0000007 16713578 YES miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles 0.317 SIGNOR-262949 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser178 LFTQRQNsAPARMLS 9606 14559997 YES Phosphorylation is the signal for ubiquitination gcesareni The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro. 0.842 SIGNOR-118759 YAP1 protein P46937 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.27 SIGNOR-276564 STAT6 protein P42226 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 BTO:0000801 10982806 YES lperfetto STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site 0.417 SIGNOR-249553 AMG 900 chemical CID:24856041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189492 ATIC protein P31939 UNIPROT 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI up-regulates quantity chemical modification 9606 33179964 YES miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. 0.8 SIGNOR-267327 PRKACA protein P17612 UNIPROT RAP1A protein P62834 UNIPROT down-regulates activity phosphorylation Ser180 KKKPKKKsCLLL 9534 9867809 YES miannu Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells. 0.52 SIGNOR-250042 LRP5 protein O75197 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23209147 YES Gianni The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization. 0.687 SIGNOR-262525 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; 0.2 SIGNOR-106510 FAM83E protein Q2M2I3 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273767 NCOR2 protein Q9Y618 UNIPROT AR protein P10275 UNIPROT down-regulates acetylation 9606 BTO:0000150;BTO:0001130 12771131 YES gcesareni In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases. 0.563 SIGNOR-101286 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK8 protein P45983 UNIPROT down-regulates chemical inhibition 9606 11717429 YES gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). 0.8 SIGNOR-111983 GSPT1 protein P15170 UNIPROT Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR form complex binding 9606 29735640 YES miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. 0.973 SIGNOR-270814 MSH6 protein P52701 UNIPROT BLM protein P54132 UNIPROT up-regulates binding 9606 SIGNOR-C60 15064730 YES miannu We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro 0.601 SIGNOR-123705 RAD23B protein P54727 UNIPROT RPA4 protein Q13156 UNIPROT up-regulates activity binding 24086043 YES lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.26 SIGNOR-275701 IKK-complex complex SIGNOR-C14 SIGNOR MTURN protein Q8N3F0 UNIPROT down-regulates activity phosphorylation Ser58 GDNFHVWsESEDCLP 10090 BTO:0002572 28704656 YES miannu Here we report that viral infection induced upregulation of INKIT, an inhibitor for NF-κB and IRF3 that restricted innate antiviral responses by blocking phosphorylation of p65 and IRF3. Viral infection induced IKK-mediated phosphorylation of INKIT at Ser58, resulting in its dissociation from the IKKs. INKIT is associated with IKKα/β and TBK1/IKKɛ and inhibits the recruitment and phosphorylation of p65 and IRF3, respectively. IKKα and TBK1 phosphorylate INKIT at Ser58, which results in disassociation of INKIT from IKKα or TBK1 and thereby allows for the subsequent recruitment and phosphorylation of p65 and IRF3 0.2 SIGNOR-273641 IFNG protein P01579 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001760 11009425 NO gcesareni In contrast, in differentiated myotubes, tnf plus interferon-gamma (ifn-gamma) signaling was required for nf-kappab-dependent down-regulation of myod and dysfunction of skeletal myofibers. 0.29 SIGNOR-82467 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT up-regulates activity phosphorylation Ser404 RSRGRASsHSSQTQG -1 7925482 YES lperfetto Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence. 0.362 SIGNOR-248904 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr219 DGSDHPYyNSIPSKM -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.617 SIGNOR-273912 TNKS2 protein Q9H2K2 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 19759537 YES lperfetto Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin. 0.704 SIGNOR-263378 VAC14 protein Q08AM6 UNIPROT FIG4 protein Q92562 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 20630877 YES miannu Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction. 0.921 SIGNOR-253534 HRH2 protein P25021 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.374 SIGNOR-256920 TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10346818 YES amattioni Oligomerization of the traf2 effector domain results in specific binding to mekk1, a protein kinase capable of jnk, p38, and ikk activation 0.717 SIGNOR-67552 CASP7 protein P55210 UNIPROT PARP1 protein P09874 UNIPROT down-regulates cleavage 9606 11058599 YES amattioni Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis. 0.718 SIGNOR-83703 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.444 SIGNOR-248296 TGFB1 protein P01137 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates activity binding 9606 16885528 YES lperfetto The active form of TGF-beta is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge. 0.2 SIGNOR-148605 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2251 ASPLASSerPVRKNL -1 26051540 YES irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. 0.472 SIGNOR-259119 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Ser18 ANRTPPKsPGDPSKD -1 17693641 YES miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. 0.403 SIGNOR-262932 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR ALDH3B1 protein P43353 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001078 26124079 YES miannu We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members. 0.2 SIGNOR-272819 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Ser974 EESLAEMsIMTTELQ 9606 18055457 YES lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta 0.272 SIGNOR-159574 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 YES llicata Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291. 0.2 SIGNOR-176871 CDK2 protein P24941 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity phosphorylation Ser151 DVSPYSLsPVSNKSQ BTO:0000007 12560341 YES llicata  A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.  0.744 SIGNOR-250732 SH3RF1 protein Q7Z6J0 UNIPROT HGS protein O14964 UNIPROT down-regulates quantity ubiquitination 9606 16084064 YES miannu Importantly, ubiquitination of Hrs mediated by POSH caused the reduction of Hrs level via the ubiquitin-proteasome pathway. 0.246 SIGNOR-278575 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA -1 11313365 YES miannu ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner. 0.778 SIGNOR-252596 RAD9A protein Q99638 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 YES gcesareni The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner 0.825 SIGNOR-179382 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 9030586 YES lperfetto Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively. 0.323 SIGNOR-248960 PGM1 protein P36871 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-267929 PDK1 protein Q15118 UNIPROT PKN2 protein Q16513 UNIPROT up-regulates activity phosphorylation Thr816 GYGDRTStFCGTPEF 9606 BTO:0000007 10753910 YES miannu PDK1 phosphorylates the PRKs at their conserved activation loop threonines (Thr-774 and Thr-816 for PRK1 and PRK2, respectively) both in vitro and in vivo. 0.339 SIGNOR-250265 PTPN11 protein Q06124 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates dephosphorylation Tyr1023 DLVDAEEyLVPQQGF -1 32024694 YES lperfetto ...which in turn suggests the importance SHP2 dephosphorylation of pTyr992 in EGFR and pTyr1023 in HER2 to mediate signaling.|More specifically, we show that acidic residues N-terminal to the substrate pTyr in EGFR and HER2 mediate specific binding by the SHP2 active site, leading to blockade of RasGAP binding and optimal signaling by the two receptors. 0.838 SIGNOR-262957 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI up-regulates quantity precursor of 9606 31586547 YES miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). 0.8 SIGNOR-267056 SUN1 protein O94901 UNIPROT TERB1 protein Q8NA31 UNIPROT up-regulates activity binding 9606 BTO:0000007 SIGNOR-C303 SIGNOR-C305 33015044 YES lperfetto In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex. 0.2 SIGNOR-263299 vitamin K smallmolecule CHEBI:28384 ChEBI Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity precursor of 9606 31226734 YES lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) 0.8 SIGNOR-265915 FOXP3 protein Q9BZS1 UNIPROT CCL5 protein P13501 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 38339310 YES miannu Given its role as a potent chemoattractant for T cells, CCL5 can be utilized to attract Tregs to malignant epithelial cells. Wang et al. demonstrated that Forkheadbox protein 3 (FOXP3), a key transcription factor for Tregs, was highly ex- pressed in pancreatic cancer cell lines, which, in turn, upregulated CCL5 expression 0.435 SIGNOR-277727 ABL1 protein P00519 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 BTO:0000007;BTO:0000567 17254966 YES gcesareni A conserved tyrosine residue (Y88) in the Cdk-binding domain of p27 can be phosphorylated by the Src-family kinase Lyn and the oncogene product BCR-ABL 0.594 SIGNOR-245293 P2RY1 protein P47900 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257442 CAMK2G protein Q13555 UNIPROT CHAT protein P28329 UNIPROT up-regulates activity phosphorylation Thr574 VDNIRSAtPEALAFV BTO:0000932 12486117 YES llicata Using mass spectrometry, we identified threonine 456 as a new phosphorylation site in choline acetyltransferase from A beta-(1-42)-treated cells and in purified recombinant ChAT phosphorylated in vitro by calcium/calmodulin-dependent protein kinase II (CaM kinase II). | This phosphorylation combination was observed in choline acetyltransferase from A beta-(1-42)-treated cells. Treatment of cells with A beta-(1-42) resulted in two phases of activation of choline acetyltransferase, the first within 30 min and associated with phosphorylation by protein kinase C and the second by 10 h and associated with phosphorylation by both CaM kinase II and protein kinase C. 0.307 SIGNOR-250693 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser317 TPQGSRTsPGAPPPA -1 15133517 YES miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. 0.2 SIGNOR-263060 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120084 RUNX2 protein Q13950 UNIPROT VEGFC protein P49767 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 NO miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. 0.2 SIGNOR-255081 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser251 GKLGGQDsFESIESY 9606 BTO:0000782 12475968 YES lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition 0.31 SIGNOR-96330 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser174 DKENGSVsSSETPPP 9606 11861906 YES llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. 0.395 SIGNOR-250861 RPS6KB1 protein P23443 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 YES gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. 0.612 SIGNOR-150144 ULK1 protein O75385 UNIPROT YAP1 protein P46937 UNIPROT up-regulates quantity by stabilization phosphorylation Ser227 VQQNMMNsASGPLPD 9606 BTO:0003491 34345207 YES miannu Mechanistically, hypoxia stimulates ULK1 to translocate into nucleus, where it interacts with and phosphorylates yes-associated protein (YAP) at Ser227, resulting in YAP stabilization through blockade of ubiquitin-proteasome system (UPS), which in turn facilitates PKM2 transcription, glycolysis, cell proliferation in vitro as well as PDAC growth in mice. 0.2 SIGNOR-277570 IGF1R protein P08069 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000951 17200203 NO Indirect:regulation of expression miannu Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts 0.294 SIGNOR-251863 CDC20 protein Q12834 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 11285280 YES miannu These results suggested that cyclin A is a target of the Cdc20-associated APC/C in human cells. 0.968 SIGNOR-272578 MYO10 protein Q9HD67 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 27580874 NO miannu Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments. 0.7 SIGNOR-268283 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr526 LRADENYyKAQTHGK 9606 BTO:0000776 9820500 YES lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 0.2 SIGNOR-246621 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-119233 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9823 BTO:0001840 SIGNOR-C3 23486913 YES lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation 0.926 SIGNOR-219266 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr280 HRFHPEPyGLEDDQR -1 11382764 YES lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 0.922 SIGNOR-246492 GUCY1B2 protein O75343 UNIPROT GUCY1A3-B2 complex SIGNOR-C139 SIGNOR form complex binding 9606 10977868 YES gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity 0.2 SIGNOR-244119 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252342 RANBP2 protein P49792 UNIPROT BICD2 protein Q8TD16 UNIPROT up-regulates quantity relocalization 9606 BTO:0000567 20386726 YES irozzo We show that the dynein/dynactin adaptor BICD2 is specifically recruited to the NPC in G2phase through a direct interaction with the NPC componentRanBP2. 0.506 SIGNOR-259122 FKBP15 protein Q5T1M5 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000007 19121306 YES Giulio However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. 0.2 SIGNOR-260595 KAT2A protein Q92830 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269608 STAT5A protein P42229 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR form complex binding 9606 8878484 YES fspada We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter. 0.531 SIGNOR-44379 PSTPIP1 protein O43586 UNIPROT DNM2 protein P50570 UNIPROT down-regulates binding 9606 18480402 YES miannu We show that pstpip1 associates with the regulator of endocytosis, dynamin 2, and pstpip1 expression impairs transferrin uptake and endocytosis 0.375 SIGNOR-178628 ASNS protein P08243 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-267534 KCNMA1 protein Q12791 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31152168 YES miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. 0.8 SIGNOR-269198 MRPS18B protein Q9Y676 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.768 SIGNOR-261452 CD3 complex SIGNOR-C432 SIGNOR NCK1 protein P16333 UNIPROT up-regulates activity relocalization 9606 12110186 YES We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck. 0.338 SIGNOR-259935 GLI3 protein P10071 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17419683 NO gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. 0.586 SIGNOR-154234 N protein P59595 UNIPROT ATF2 protein P15336 UNIPROT up-regulates quantity by expression transcriptional regulation -1 14623261 YES Luana The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well 0.2 SIGNOR-260727 TGFBR1 protein P36897 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 26194464 NO MARCO ROSINA TbRI phosphorylates not only the C-termini of R-Smads but also activates various protein kinases including mitogen-activated protein kinases (MAPKs): extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK (p38), which then phosphorylate the variable linker regions of R-Smad 0.313 SIGNOR-255033 CAK complex complex SIGNOR-C456 SIGNOR CDK12 protein Q9NYV4 UNIPROT up-regulates activity phosphorylation Thr893 SEESRPYtNKVITLW 24662513 YES lperfetto Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b). 0.537 SIGNOR-275510 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Leu) smallmolecule CHEBI:29169 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270411 PRKCQ protein Q04759 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT up-regulates phosphorylation Ser960 KKRVRRSsFLNAKKL 9606 BTO:0000782 18796635 YES lperfetto After t-cell activation, the direct phosphorylation of rapgef2 at ser960 by pkc- theta regulates rap1 activation as well as lfa-1 adhesiveness to icam-1. Pkc- theta and its effector rapgef2 are critical factors in tcr signaling to rap1 0.2 SIGNOR-181186 MAPK1 protein P28482 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Ser21 KRTSSPRsPPSSSEI 9606 25728771 YES lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation 0.2 SIGNOR-264775 FGF2 protein P09038 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8142649 NO Regulation miannu Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. 0.2 SIGNOR-251796 EGFR protein P00533 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity phosphorylation Tyr393 ASFNTDPyVREFGIM 9606 25137592 YES miannu Furthermore, AGO2 function is directly modulated by EGFR signaling in ERalpha negative breast cancer under states of hypoxic stress.|Here, EGFR can directly bind and phosphorylate residue Y393 of AGO2[ xref ]. 0.535 SIGNOR-278931 IL18 protein Q14116 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 NO miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement. 0.465 SIGNOR-260858 FGFR2 protein P21802 UNIPROT GRB2 protein P62993 UNIPROT up-regulates phosphorylation 9606 22726438 YES gcesareni Inhibition of basal fgf receptor signaling by dimeric grb2. 0.772 SIGNOR-197980 CDKN1A protein P38936 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity 9606 10439039 NO gcesareni P21 may inhibit cell cycle progression by preventing the phosphorylation of prb. 0.714 SIGNOR-69925 LAT protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 23150273 YES Phosphorylated tyrosines 171, 191, and 226 [in LAT] bind to the SH2 domains of the Grb2 family of adaptor proteins and must be present for optimal signalling 0.804 SIGNOR-251520 MMP21 protein Q8N119 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272366 MARCHF8 protein Q5T0T0 UNIPROT TNFRSF10A protein O00220 UNIPROT down-regulates quantity ubiquitination 9606 23300075 YES miannu The collective data indicate that endogenous MARCH-8 ubiquitinates TRAIL-R1 to attenuate its cell surface expression. 0.2 SIGNOR-278570 CTNNB1 protein P35222 UNIPROT TRRAP protein Q9Y4A5 UNIPROT up-regulates binding 9606 16510874 YES gcesareni The beta-cat c-terminal activation domain associates with trrap/tip60 and mixed-lineage-leukemia (mll1/mll2) set1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. 0.579 SIGNOR-144966 IRX2 protein Q9BZI1 UNIPROT CXCL10 protein P02778 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003885 26560478 NO Luana Our results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression.  0.2 SIGNOR-266042 doxorubicin chemical CHEBI:28748 ChEBI ABCC1 protein P33527 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002206 9647783 YES Simone Vumbaca Unconjugated Dox and Dau failed to inhibit the transport of LTC4, whereas 30 microM GS-Dox or GS-Dau conjugates completely inhibited the transport. 0.8 SIGNOR-261085 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates binding 9606 12782713 YES miannu Mif binds to the extracellular domain of cd74, and cd74 is required for mif-induced activation of the extracellular signal-regulated kinase-1/2 map kinase cascade, cell proliferation, and pge2 production. 0.734 SIGNOR-101526 FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 YES lperfetto We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 0.762 SIGNOR-249638 GSK3B protein P49841 UNIPROT TOP2A protein P11388 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1361 SPPKTKTsPKLSNKE 9606 BTO:0003492 21254166 YES miannu  This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361. 0.349 SIGNOR-276301 IRF4 protein Q15306 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 NO lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. 0.7 SIGNOR-249561 VARS1 protein P26640 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates quantity chemical modification 9606 30755602 YES miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 0.8 SIGNOR-270530 SIRT7 protein Q9NRC8 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity deacetylation Lys3016 VLMRLQEkLKGVEEG 30944854 YES lperfetto Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016 0.36 SIGNOR-275890 AKT3 protein Q9Y243 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 YES gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity. 0.289 SIGNOR-78693 PPARGC1A protein Q9UBK2 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001103 17609368 NO gcesareni Pgc-1alpha protein is required for ampk action on glut4 gene expression and mitochondrial function. 0.625 SIGNOR-156769 KAT2A protein Q92830 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269603 CSNK2A1 protein P68400 UNIPROT PTPRCAP protein Q14761 UNIPROT up-regulates quantity by stabilization phosphorylation Ser153 RAEEARDsDTEGDLV -1 30482149 YES miannu We demonstrated for the first time that LPAP is a substrate for protein kinase CK2 that phosphorylates it at Ser153, presumably ensuring LPAP resistance to degradation. 0.2 SIGNOR-273629 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 7736585 YES gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, 0.964 SIGNOR-32295 KIF13A protein Q9H1H9 UNIPROT TTC19 protein Q6DKK2 UNIPROT up-regulates activity binding 9606 20208530 YES miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. 0.433 SIGNOR-265540 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 BTO:0000007 BTO:0000671 18270262 YES gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1). 0.447 SIGNOR-160842 C5AR2 protein Q9P296 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 NO lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. 0.7 SIGNOR-263459 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser230 PKYSRQFsLEHVHGS 9606 35080342 YES miannu AKT1 and AKT2 phosphorylate HSF1 at S326 but only AKT1 activates HSF1.|Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. 0.405 SIGNOR-278373 teniposide chemical CHEBI:75988 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 1329225 YES miannu Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme. 0.8 SIGNOR-259330 RBBP7 protein Q16576 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.838 SIGNOR-263848 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr792 PRNSAELtVIKVSSQ 9606 17376779 YES gcesareni Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1 0.84 SIGNOR-153867 RPL41 protein P62945 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.2 SIGNOR-262458 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser5 sPPLRDVD 9606 BTO:0000222 14749395 YES lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. 0.319 SIGNOR-216924 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1004 SEHDSDEsSDDDSDS 9606 BTO:0000661 10066810 YES llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  0.435 SIGNOR-251029 CSNK2A2 protein P19784 UNIPROT CAV1 protein Q03135 UNIPROT unknown phosphorylation Ser88 FDGIWKAsFTTFTVT -1 8058322 YES llicata Here, we have identified this serine kinase activity as a casein kinase II-like enzyme, since the phosphorylation of caveolin-rich membrane domains is stimulated and inhibited by known effectors of casein kinase II (poly-L-lysine, endogenous polyamines, and a casein kinase II inhibitor peptide), but is unaffected by modulators of other known kinases. In support of these observations, caveolin contains a consensus sequence for casein kinase II phosphorylation in its cytoplasmic N-terminal domain (Ser-88) 0.356 SIGNOR-250981 CAMK4 protein Q16566 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 7925472 YES gcesareni Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr. 0.488 SIGNOR-34743 GPER1 protein Q99527 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 11897506 YES gcesareni Gpcr-mediated transactivation of egfrs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the egf-like effects of estrogen 0.39 SIGNOR-115988 TNKS protein O95271 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 19759537 YES lperfetto Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin. 0.772 SIGNOR-263381 silodosin chemical CHEBI:135929 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258451 HMBOX1 protein Q6NT76 UNIPROT IFNG protein P01579 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002030 21839858 YES Luana Additionally, by luciferase reporter assay, HMBOX1 displayed suppressive effect on the transcription activity of IFN-γ promoter.  0.2 SIGNOR-261625 NDN protein Q99608 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000671 24349431 YES lperfetto Deletion mapping demonstrated that the C-terminus of cystin and both termini of necdin are required for their mutual interaction. Speculating that these two proteins may function to regulate gene expression, we developed a luciferase reporter assay and observed that necdin strongly activated the Myc P1 promoter, and cystin did so more modestly. 0.265 SIGNOR-253381 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser2612 MFVETQAsQGTLQTR 9606 BTO:0000773 12186630 YES lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. 0.2 SIGNOR-249155 ATR protein Q13535 UNIPROT USP20 protein Q9Y2K6 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 BTO:0000007 25355518 YES miannu USP20 phosphorylation by ATR is important for its stabilization and checkpoint activation 0.306 SIGNOR-272822 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017876 YES llicata Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation. 0.659 SIGNOR-176862 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CD4 protein P01730 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 11893391 YES miannu Degradation of the HIV receptor CD4 by the proteasome, mediated by the HIV-1 protein Vpu, is crucial for the release of fully infectious virions. To promote CD4 degradation Vpu has to be phosphorylated on a motif DSGXXS, which is conserved in several signalling proteins known to be degraded by the proteasome upon phosphorylation. Such phosphorylation is required for the interaction of Vpu with the ubiquitin ligase SCF-beta-TrCP that triggers CD4 degradation by the proteasome. 0.252 SIGNOR-272615 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.632 SIGNOR-249463 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1074 QRGSSGHtPPPSGPP 26190112 YES Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. 0.297 SIGNOR-253543 TRAF6 protein Q9Y4K3 UNIPROT LAT protein O43561 UNIPROT up-regulates activity ubiquitination 9606 23514740 YES miannu Interestingly, this study has demonstrated that the membrane-proximal region of linker for activation of T cells preceding tyrosine-132 mediates its association with TRAF6, which promotes the ubiquitination of linker for activation of T cells and, in turn, the phosphorylation of tyrosine residues on linker for activation of T cells.|Moreover, LAT was ubiquitinated at Lysine 88 by TRAF6 via K63 linked chain. 0.345 SIGNOR-278675 EIF2B4 protein Q9UI10 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.753 SIGNOR-269132 AP-3 complex complex SIGNOR-C247 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 22203680 NO lperfetto Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes 0.7 SIGNOR-265941 OGDC complex SIGNOR-C397 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity chemical modification 9606 15953811 YES miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. 0.8 SIGNOR-266258 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr236 FYDETYDyGGFTMMF 9606 12052863 YES lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). 0.603 SIGNOR-88911 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 11901158 YES lperfetto Thus, activation of chk2 in irradiated cells may occur through oligomerization of chk2 via binding of the thr-68-phosphorylated region of one chk2 to the fha domain of another. Oligomerization of chk2 may therefore increase the efficiency of trans-autophosphorylation resulting in the release of active chk2 monomers that proceed to enforce checkpoint control in irradiated cells. 0.2 SIGNOR-116135 HSPA1A protein P0DMV8 UNIPROT ACOT4 protein Q8N9L9 UNIPROT down-regulates quantity by destabilization binding 33148467 YES lperfetto HSPA1A binds unphosphorylated ACOT4 and promotes its degradation 0.2 SIGNOR-271819 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI up-regulates quantity precursor of 9606 11802770 YES miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. 0.8 SIGNOR-269690 8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid chemical CID:92577 PUBCHEM PTPN6 protein P29350 UNIPROT down-regulates activity chemical inhibition -1 19233143 YES lperfetto In this study, we screened protein tyrosine phosphatases (PTPs) by in vitro phosphatase assays to identify PTPs that are inhibited by 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), a potent inhibitor of SHP-1 and SHP-2 PTPs. 0.8 SIGNOR-261978 AHSA1 protein O95433 UNIPROT GCH1 protein P30793 UNIPROT up-regulates activity binding 9606 BTO:0001519 16696853 YES miannu The interaction of GCH1 with Aha1 may recruit GCH1 into the eNOS/Hsp90 complex so as to support local changes in nitric oxide production by endothelial cells. 0.297 SIGNOR-252213 COL4A1 protein P02462 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 YES Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) 0.7 SIGNOR-254665 AMPK complex SIGNOR-C15 SIGNOR RAC1 protein P63000 UNIPROT up-regulates activity 9606 BTO:0000584 29572236 NO miannu The discovery that AMPK activation is a general requirement for macropinosome formation in cancer cells dramatically extends our understanding of the regulation of this process. By increasing RAC1-GTP levels, AMPK activation stimulates macropinosome formation (Fig. 2I–K; Supplementary Fig. S5).  0.263 SIGNOR-277766 PKC proteinfamily SIGNOR-PF53 SIGNOR PPP1R14B protein Q96C90 UNIPROT up-regulates activity phosphorylation Thr57 VRRQGKVtVKYDRKE 10606530 YES lperfetto Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold. 0.2 SIGNOR-265740 RET protein P07949 UNIPROT DOK4 protein Q8TEW6 UNIPROT up-regulates binding 9606 BTO:0000938 11470823 YES gcesareni We identified two new family members, dok-4 and dok-5, that can directly associate with y1062 of c-ret dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase 0.574 SIGNOR-109513 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser160 SSTFDALsPSPAIPS 9606 23166821 YES llicata We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5 0.2 SIGNOR-199781 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr271 CQLGQRIyQYIQSRF 9606 10910078 YES lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site 0.2 SIGNOR-79806 USP8 protein P40818 UNIPROT MET protein P08581 UNIPROT down-regulates quantity destabilization 9606 BTO:0000567 16520378 YES Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation. 0.454 SIGNOR-266903 KIT protein P10721 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation 9606 15315962 YES miannu The activated KIT in turn induces phosphorylation and activation of Cbl proteins. 0.617 SIGNOR-279199 BFAR protein Q9NZS9 UNIPROT TMBIM6 protein P55061 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21068390 YES miannu BAR overexpression promotes BI-1 ubiquitination and proteasomal degradation.We show here that bifunctional apoptosis regulator (BAR) functions as an ER-associated RING-type E3 ligase, interacts with BI-1, and promotes proteasomal degradation of BI-1.  0.392 SIGNOR-272778 pictrelisib chemical CHEBI:65326 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 BTO:0000149 21876152 YES gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed 0.8 SIGNOR-176295 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 10521487 YES gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. 0.2 SIGNOR-71419 GPR17 protein Q13304 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.385 SIGNOR-256835 APC protein P25054 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity binding 9606 22083140 YES amattioni Apc binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. APC cooperates with Axin to promote the phosphorylation of _-catenin by GSK3 [which requires priming phosphorylation by casein kinase 1, _-isoform (CK1_)]. 0.921 SIGNOR-177230 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150 17693255 YES gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. 0.641 SIGNOR-157296 calcium(2+) smallmolecule CHEBI:29108 ChEBI SLC25A12 protein O75746 UNIPROT up-regulates activity chemical activation 9606 12084073 YES miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 0.8 SIGNOR-265152 PRKCA protein P17252 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 YES lperfetto Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E . 0.383 SIGNOR-248945 FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000848 9006895 YES gcesareni Sek-1 binds directly and specifically to the actin-binding protein abp-280. As a consequence, active sek-1 is capable of phosphorylating and activating in vitro added bacterial recombinant sapk. 0.522 SIGNOR-45887 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP2K4 protein P45985 UNIPROT down-regulates phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0000007 11707464 YES lperfetto Akt phosphorylated sek1 on serine 78. 0.2 SIGNOR-244285 CUL3 protein Q13618 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19782033 YES miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. 0.397 SIGNOR-264238 ARNT protein P27540 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 16115918 NO miannu Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1. 0.4 SIGNOR-253740 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser721 TPRLRSVsSYGNIRA 9606 SIGNOR-C3 18722121 YES llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity 0.2 SIGNOR-252774 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1071 SFLQRYSsDPTGALT 9606 BTO:0000007 10347170 YES llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  0.371 SIGNOR-250621 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1654 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248771 JNK proteinfamily SIGNOR-PF15 SIGNOR ATN1 protein P54259 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000142 12812981 YES inferred from 70% family members lperfetto Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment, 0.2 SIGNOR-269978 Hypoxia stimulus SIGNOR-ST25 SIGNOR EGLN3 protein Q9H6Z9 UNIPROT down-regulates 9606 24990963 NO lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization 0.7 SIGNOR-262002 TFEB protein P19484 UNIPROT CTSA protein P10619 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants 0.298 SIGNOR-276549 ETS1 protein P14921 UNIPROT ATP2A3 protein Q93084 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000255 12119294 YES Luana Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold. 0.326 SIGNOR-261601 FZR1 protein Q9UM11 UNIPROT DNM1L protein O00429 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000567 21325626 YES Barakat Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1 catalyzed by the APC/Ccdh1 (anaphase-promoting complex/cyclosome and its coactivator (Cdh1) E3 ubiquiting ligase complex 0.35 SIGNOR-274127 PJA2 protein O43164 UNIPROT PRKAR1A protein P10644 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 YES miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits 0.38 SIGNOR-271855 GSK3B protein P49841 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates activity phosphorylation 9606 18675800 YES miannu In T-cells, calcineurin de-phosphorylates NFATc1, leading to its nuclear import, while glycogen synthase kinase 3 beta (GSK3beta) phosphorylates NFATc1 and promotes its nuclear export.|We conclude that GSK3beta negatively regulates NFATc1 in vSMCs, and GSK3beta must be inactivated to allow NFAT activation during wound repair.Male Sprague-Dawley rats were obtained from Charles River (Montreal, PQ, Canada). 0.586 SIGNOR-279185 P2RY10 protein O00398 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257121 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.569 SIGNOR-257717 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu63 LERECVEeTCSYEEA -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263680 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258288 CREB5 protein Q02930 UNIPROT DGKG protein P49619 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002810 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253803 DHRS9 protein Q9BPW9 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI down-regulates quantity chemical modification 9606 21621639 YES lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10 0.8 SIGNOR-265116 AP2B1 protein P63010 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR form complex binding 31671891 YES lperfetto The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit 0.861 SIGNOR-260422 PELI3 protein Q8N2H9 UNIPROT ELK1 protein P19419 UNIPROT up-regulates 9606 12874243 NO gcesareni Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab. 0.2 SIGNOR-103986 pazopanib chemical CHEBI:71219 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 YES Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. 0.8 SIGNOR-257736 EPHB1 protein P54762 UNIPROT CASKIN1 protein Q8WXD9 UNIPROT up-regulates activity phosphorylation Tyr336 TGNDRVGyFPSSLGE 9534 23181695 YES miannu EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation. 0.284 SIGNOR-262861 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD -1 8576253 YES giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). 0.722 SIGNOR-255961 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 26687681 YES miannu Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1 0.2 SIGNOR-272417 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser407 SNGVESKsLTPALCR 9606 16216881 YES lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. 0.2 SIGNOR-141006 WNT4 protein P56705 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.647 SIGNOR-131835 IL11 protein P20809 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9143707 YES gcesareni Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-4 0.714 SIGNOR-48033 ATG7 protein O95352 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates binding 9606 22170151 YES gcesareni These results indicated that the fap motif of atg7 is indispensable for formation of the atg3-lc3 e2-substrate intermediate through the interaction of atg7 with atg3. 0.873 SIGNOR-195239 ULK1 protein O75385 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates quantity by destabilization phosphorylation Ser403 ESLSQMLsMGFSDEG 9606 25040165 YES miannu ULK1 phosphorylates p62 at the Ser403 site. 0.568 SIGNOR-278349 LPAR1 protein Q92633 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257200 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser50 SPTFRSDsPVPTAPT 9606 BTO:0000007 33217317 YES miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.272 SIGNOR-265945 DAMPS stimulus SIGNOR-ST18 SIGNOR NAIP protein Q13075 UNIPROT up-regulates activity 16037825 NO lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-256420 GATA3 protein P23771 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 15632071 NO fspada Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity 0.348 SIGNOR-132955 PIM proteinfamily SIGNOR-PF34 SIGNOR MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002552 19749799 YES lperfetto Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation 0.2 SIGNOR-259410 ATR protein Q13535 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity phosphorylation Ser140 GKKATQAsQEY 9606 27442013 YES miannu ATR and ATM also phosphorylate histone H2AX at Ser 139 (gammaH2AX) in response to DNA double-strand breaks (DSBs), which spreads along the DNA up to 200-400 kb and helps in the recruitment of proteins involved in DNA damage repair and checkpoint activation . 0.2 SIGNOR-279356 ECM stimulus SIGNOR-ST20 SIGNOR Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259036 AMPK complex SIGNOR-C15 SIGNOR SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation Ser563 LAFIRSPsTDNVVNV 9606 BTO:0000195 38047302 YES miannu AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) phosphorylated NHE3 at S555. S555 is the primary site of phosphorylation by protein kinase A (PKA), but AMPK phosphorylated S555 independently of PKA. We conclude that AMPK activation inhibits NHE3 activity and NHE3 inhibition is associated with phosphorylation of NHE3 at S555 and S563. 0.2 SIGNOR-277848 AP-1 complex complex SIGNOR-C248 SIGNOR SORT1 protein Q99523 UNIPROT up-regulates quantity binding 9606 BTO:0000007 31767632 YES miannu The short intracellular domain of sortilin binds several cytoplasmic adaptor proteins (e.g., the AP-1 complex and GGA1 to -3), most of which target two well-defined motifs: a C-terminal acidic cluster dileucine motif and a YXXΦ motif in the proximal third of the domain. Both motifs contribute to endocytosis as well as Golgi-endosome trafficking of sortilin. 0.459 SIGNOR-273720 HRH2 protein P25021 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257250 ATM protein Q13315 UNIPROT PPP2R5C protein Q13362-1 UNIPROT up-regulates activity phosphorylation Ser520 CRADELAsQDGR 9606 BTO:0001938 21460856 YES miannu In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth. 0.379 SIGNOR-276318 PLK1 protein P53350 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity phosphorylation Thr91 GPLELDLtGDLESFK 9606 BTO:0000567 38355643 YES miannu PLK1 phosphorylates RhoGDI1 at Thr7/91 residue in vitro and in vivo. Collectively, we demonstrate that the phosphorylation of RhoGDI1 by PLK1 promotes cancer cell migration and invasion through RhoA activation. 0.2 SIGNOR-277882 Laminin-10 complex SIGNOR-C182 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.566 SIGNOR-253222 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Thr718 KEDLPVItIDPASPQ 9606 11604491 YES llicata Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728. 0.57 SIGNOR-111051 CERK protein Q8TCT0 UNIPROT ceramide 1-phosphate(2-) smallmolecule CHEBI:84404 ChEBI up-regulates quantity chemical modification 9606 34202192 YES miannu Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). 0.8 SIGNOR-268499 MEIS1 protein O00470 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0001271 19109563 NO irozzo To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells. 0.7 SIGNOR-256648 AX/b2 integrin complex SIGNOR-C171 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.451 SIGNOR-257714 FCRL3 protein Q96P31 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding -1 12051764 YES miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. 0.365 SIGNOR-274012 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr217 MAEEKKAyKKAKERE 9606 19059208 YES miannu We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. 0.2 SIGNOR-262853 N protein P59595 UNIPROT CREB1 protein P16220 UNIPROT up-regulates quantity by expression transcriptional regulation -1 14623261 YES Luana The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well 0.2 SIGNOR-260729 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 YES miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. 0.528 SIGNOR-256180 8-OH-DPAT chemical CHEBI:73364 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258847 PI4KA protein P42356 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI down-regulates quantity chemical modification 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269095 TFIID complex SIGNOR-C343 SIGNOR TFIIA complex SIGNOR-C395 SIGNOR up-regulates activity relocalization 9606 8990153 YES lperfetto PIC assembly begins with TFIID recognizing the TATA element, followed by coordinated accretion of TFIIB, the nonphosphorylated form of pol II (pol IIA) plus TFIIF, TFIIE, and TFIIH. 0.616 SIGNOR-269307 HOXA9 protein P31269 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 NO miannu HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. 0.288 SIGNOR-254213 ITPRIPL1 protein Q6GPH6 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates binding 9606 BTO:0000938 21368195 YES Induces Ca2+ release that increases the binding affinity of Shh for Boc. gcesareni Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores. 0.2 SIGNOR-172497 sertindole chemical CHEBI:9122 ChEBI HTR1F protein P30939 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258544 KDM3B protein Q7LBC6 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 YES miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. 0.2 SIGNOR-266635 SMN1 protein Q16637 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 YES lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. 0.737 SIGNOR-253115 CSNK2A1 protein P68400 UNIPROT EXOSC9 protein Q06265 UNIPROT up-regulates phosphorylation Ser394 APIILSDsEEEEMII 9606 19217413 YES lperfetto Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay 0.2 SIGNOR-184035 PPP2R1A protein P30153 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates binding 9606 16039140 YES miannu Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme 0.891 SIGNOR-138886 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 YES lperfetto These results indicate that cyclin d2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by thr280 phosphorylation by gsk3beta or p38 0.2 SIGNOR-154672 ARHGAP20 protein Q9P2F6 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.434 SIGNOR-260473 rivaroxaban chemical CHEBI:68579 ChEBI F10 protein P00742 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206550 AURKA protein O14965 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation 9606 27003257 YES lperfetto However, this study identified that CFL-1 also acts as a direct substrate of Aur-A, which phosphorylates CFL-1 at multiple sites, including S3, S8, and T25, resulting in its inactivation.|In early cell mitotic phases, LIMK1 and Aur-A phosphorylate and inactivate CFL-1, while at the later stages, SSH-1 inactivates LIMK1 and dephosphorylates and activates CFL-1 [33] . 0.316 SIGNOR-279798 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity phosphorylation Thr345 KFAQTVMtSRIVGTT 9606 BTO:0000876 24567333 YES lperfetto We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity 0.2 SIGNOR-204661 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 BTO:0000150 16504004 YES gcesareni Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover. 0.783 SIGNOR-144818 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 NO irozzo These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. 0.342 SIGNOR-256126 PEA15 protein Q15121 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates 9606 11702783 NO gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. 0.867 SIGNOR-111499 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22198637 YES lperfetto Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 0.524 SIGNOR-253712 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 YES Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. 0.358 SIGNOR-248643 SMARCE1 protein Q969G3 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.838 SIGNOR-270691 BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18997794 YES lperfetto Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3. 0.872 SIGNOR-182128 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 YES lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. 0.2 SIGNOR-244296 EPHB1 protein P54762 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 29079839 YES miannu By integrating mouse in vivo and in vitro models with human iPSC derived astrocytes, we provide direct evidence that EphB1 can induce early astrocytic STAT3 activation via ephrin-B1 signalling.|We confirmed that EphB1 activates astrocytes by inducing ephrin-B1 dependent STAT3 phosphorylation. 0.353 SIGNOR-279709 LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 BTO:0000782;BTO:0001271 8992971 YES lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor 0.754 SIGNOR-45524 ERLIN1 protein O75477 UNIPROT Erlin complex SIGNOR-C532 SIGNOR form complex binding 10119 BTO:0003293 19240031 YES miannu Here we report that the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex that binds to IP(3)R tetramers immediately after their activation and is required for their processing. The complex is ring-shaped (diameter approximately 250A(),) and RNA interference-mediated depletion of SPFH1 and SPFH2 blocks IP(3)R polyubiquitination and degradation. 0.65 SIGNOR-275392 CDK2 protein P24941 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL -1 9199329 YES lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. 0.291 SIGNOR-249427 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation 9606 19620713 YES lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.731 SIGNOR-255263 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation Lys594 KEVEDIEkYLEDQVN 9606 BTO:0000007 21726808 YES lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 0.544 SIGNOR-267604 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1401 LQGEEIKsQNSQEST 9606 12086603 YES lperfetto These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint 0.788 SIGNOR-90109 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.384 SIGNOR-129276 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr811 ADDSSSStSSDSLGG -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.32 SIGNOR-251075 GABRA4 protein P48169 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.615 SIGNOR-263759 MAPK11 protein Q15759 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates activity phosphorylation Thr180 RQADEEMtGYVATRW -1 26976637 YES miannu P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261 0.2 SIGNOR-277216 ceritinib chemical CHEBI:78432 ChEBI ALK protein Q9UM73 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 24670165 YES miannu Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. 0.8 SIGNOR-259263 PAK1 protein Q13153 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 18775988 YES gcesareni P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339. 0.601 SIGNOR-180812 lapatinib chemical CHEBI:49603 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 YES Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. 0.8 SIGNOR-257898 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 YES gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt. 0.2 SIGNOR-244184 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI AXL protein P30530 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258109 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO inferred from family member miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.2 SIGNOR-270249 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr57 RAGETRFtDTRKDEQ 9606 8386634 YES gcesareni The eef-2 kinase could phosphorylate a synthetic peptide based on residues 49-60 of eef-2 (ragetrftdtrk), albeit only at a very low rate, and with a very high km, compared to eef-2 itself. 0.787 SIGNOR-38552 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 YES miannu GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments. 0.283 SIGNOR-249711 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC18 protein Q5QNW6 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271987 LOX protein P28300 UNIPROT EFEMP2 protein O95967 UNIPROT up-regulates activity binding 9606 19570982 YES miannu Fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking. 0.562 SIGNOR-252135 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg737 LAAALGIrSFRNSSL -1 10026263 YES lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 0.499 SIGNOR-263646 DLL1 protein O00548 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 23111325 YES gcesareni In this study, we demonstrate that dll1 can activate notch signaling mostly through notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human mm cells. 0.635 SIGNOR-199320 BCL2 protein P10415 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 14585074 NO amattioni Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi 0.491 SIGNOR-88885 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.543 SIGNOR-270888 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248522 S protein P59594 UNIPROT ATF6 protein P18850 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 31226023 NO miannu Activation of the ATF6 pathway by HCoV infection is less studied, and most studies have relied on indirect methods, such as luciferase reporter, due to the lack of a specific antibody. No ATF6 cleavage was detected in cells infected with SARS-CoV, and overexpression of SARSCoV S protein failed to activate ATF6 luciferase reporter. 0.2 SIGNOR-260349 CAMK2A protein Q9UQM7 UNIPROT DLGAP1 protein O14490 UNIPROT down-regulates quantity by destabilization phosphorylation Ser356 KAMGDEDsGDSDTSP -1 23143515 YES miannu  CaMKIIα activated by the NMDA receptor phosphorylates GKAP Ser54 to induce polyubiquitination of GKAP.  0.398 SIGNOR-276429 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 11724780 YES gcesareni Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk 0.45 SIGNOR-112289 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser166 EPRSRHLsVSSQNPG 9606 12761204 YES lperfetto Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1 0.2 SIGNOR-101211 MAPK14 protein Q16539 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Thr692 QAAYYGQtPGPGGPQ 10090 BTO:0000165 16364914 YES lperfetto KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery 0.57 SIGNOR-235856 EXOC7 protein Q9UPT5 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.914 SIGNOR-270782 VRK1 protein Q99986 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 YES miannu The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells./ Vrk1 knockdown resulted in the defective formation of 53bp1 foci in response to ir both in number and size 0.4 SIGNOR-197625 AMPK complex SIGNOR-C15 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser94 RLRKLPDsFFKPPEP 9606 BTO:0002181 25751140 YES miannu Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction. 0.3 SIGNOR-277638 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR SEC31A protein O94979 UNIPROT up-regulates activity monoubiquitination lys1217 9606 BTO:0000567 22358839 YES miannu By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division. 0.377 SIGNOR-272013 ERBB4 protein Q15303 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16829981 YES gcesareni Like erbb1, erbb4 recruits grb2, shc and stat5. 0.496 SIGNOR-147850 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity deacetylation 10090 24003218 YES lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 0.911 SIGNOR-217972 PTHLH protein P12272 UNIPROT PTH1R protein Q03431 UNIPROT up-regulates activity binding -1 8683730 YES lperfetto Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production. 0.76 SIGNOR-270549 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) 0.8 SIGNOR-257878 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 12686604 YES lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. 0.439 SIGNOR-100169 GSK3B protein P49841 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 16107342 YES lperfetto Gsk3beta Phosphorylates pten at thr-366 in intact cells phosphorylation of pten at thr-366 reduces the activity of pten in cells 0.424 SIGNOR-236641 MAPK1 protein P28482 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 19282669 YES gcesareni Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. 0.717 SIGNOR-161515 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT up-regulates activity phosphorylation Thr148 KETQPPEtVQNWIEL -1 BTO:0000567 24485452 YES In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents 0.318 SIGNOR-253558 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys74 DTGRILSkLHTVQPK -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 0.464 SIGNOR-272742 E2F1 protein Q01094 UNIPROT CTNND2 protein Q9UQB3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001033 21106062 NO miannu Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression. 0.2 SIGNOR-251876 N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. 0.8 SIGNOR-268103 CAD protein P27708 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267421 PINK1 protein Q9BXM7 UNIPROT ZNF746 protein Q6NUN9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser613 APPDPFKsPASKGPL 9606 BTO:0000793 28122242 YES miannu PINK1 is required for Parkin ubiquitination and degradation of PARIS. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. 0.37 SIGNOR-273725 GPR132 protein Q9UNW8 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257074 TNF protein P01375 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 24507514 NO miannu TNF-a is the most comprehensively studied cytokine in both EAE and MS. Most TNF-a overexpressing transgenic animals showed spontaneous pathology, characterized by progressive demyelination and macrophage infiltration 0.7 SIGNOR-263834 CAMK4 protein Q16566 UNIPROT HNRNPL protein P14866 UNIPROT up-regulates phosphorylation Ser544 GKSERSSsGLLEWES 9606 22570490 YES lperfetto Here we show that the regulation of the stress axis-regulated exon of the slo1 potassium channel transcripts by membrane depolarization requires a highly conserved camkiv target serine (ser-513) of the heterogeneous ribonucleoprotein l. Ser-513 phosphorylation within the rna recognition motif 4 enhanced heterogeneous ribonucleoprotein l interaction with the camkiv-responsive rna element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the u2 auxiliary factor u2af65. 0.379 SIGNOR-197367 FYN protein P06241 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates phosphorylation Tyr353 NAQEKMVySLVSVPE 9606 14761954 YES lperfetto We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm). 0.488 SIGNOR-121795 ATF4 protein P18848 UNIPROT TARS2 protein Q9BW92 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269428 FBXW2 protein Q9UKT8 UNIPROT MSX2 protein P35548 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 31548378 YES miannu  Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase.  Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation. 0.2 SIGNOR-272259 SMO protein Q99835 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity 10090 BTO:0000011 16399502 NO fferrentino In mammalian models [...] Hh signaling also inhibits mammalian adipogenesis. Hh signals elicit this function early in adipogenesis, upstream of PPARγ, potentially diverting preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis and toward osteogenesis. Hh may elicit these effects by inducing the expression of antiadipogenic transcription factors such as Gata2. 0.2 SIGNOR-251656 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT down-regulates activity phosphorylation Tyr258 KKSISLMyGGSKRKS 9534 BTO:0001538 24284075 YES miannu Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity 0.2 SIGNOR-263141 GRK6 protein P43250 UNIPROT GRK6 protein P43250 UNIPROT unknown phosphorylation Ser484 VLDIEQFsTVKGVEL 9534 BTO:0000298 10334944 YES GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established. 0.2 SIGNOR-251211 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264285 NRCAM protein Q92823 UNIPROT ANK1 protein P16157 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 YES miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. 0.543 SIGNOR-266721 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser47 LGSALRPsTSRSLYA -1 2500966 YES miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. 0.309 SIGNOR-250070 PTEN protein P60484 UNIPROT STAT5A protein P42229 UNIPROT down-regulates dephosphorylation 9606 20596030 YES miannu The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. 0.44 SIGNOR-166481 MAPK6 protein Q16659 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000551 22505454 YES gcesareni Here, we report that erk3 interacted with and phosphorylated steroid receptor coactivator 3 (src-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (s857) 0.48 SIGNOR-196957 PDPK2P protein Q6A1A2 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 10191262 YES gcesareni Our results are consistent with a model in which activation of sgk by igf-1 or hydrogen peroxide is initiated by a ptdins(3,4, 5)p3-dependent activation of pdk2, which phosphorylates ser422. 0.2 SIGNOR-66234 PIAS4 protein Q8N2W9 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 11248056 YES gcesareni First, piasy interacts with stat1 both in vitro and in vivo. The in vivo piasy__stat1 interaction is dependent on cytokine stimulation. Second, piasy can inhibit stat1-mediated gene activation without blocking the dna binding activity of stat1. 0.56 SIGNOR-105723 TAX1BP1 protein Q86VP1 UNIPROT TNFAIP3 protein P21580 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0001271 10435631 YES lperfetto Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb. 0.682 SIGNOR-69921 CCND3 protein P30281 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000165 21898542 NO gcesareni Our findings suggest that cyclin D3 primes myoblasts for differentiation by enhancing muscle specific gene expression and cell cycle exit 0.7 SIGNOR-241960 ROCK1 protein Q13464 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 19279717 NO areggio To date it is not clear whether any genes are transcribed downstream of these two GTPases for non-canonical signaling. The prevailing dogma remains that their primary roles are indeed solely for cytoskeletal modulation 0.7 SIGNOR-258975 PRKCD protein Q05655 UNIPROT KCNJ1 protein P48048 UNIPROT up-regulates activity 9606 8621594 YES lperfetto To determine whether this channel is a substrate for PKA, ROMK tagged with the hemagglutinin epitope was transiently transfected into HEK293 cells. In vitro labeling of immunoprecipitated proteins from transfected cells showed that ROMK could be phosphorylated by PKA. | Taken together, these results provide strong evidence that direct phosphorylation of the channel polypeptide by PKA is involved in channel regulation and PKA-dependent phosphorylation is essential for ROMK channel activity. 0.307 SIGNOR-248943 CREB1 protein P16220 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 NO gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 0.25 SIGNOR-142103 STAT6 protein P42226 UNIPROT CHI3L1 protein P36222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 NO lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. 0.281 SIGNOR-249537 GTF2F2 protein P13984 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR form complex binding -1 18218714 YES lperfetto Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system. 0.962 SIGNOR-266195 ESR1 protein P03372 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18588516 NO miannu The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor). 0.421 SIGNOR-254230 SALL4 protein Q9UJQ4 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 23954296 NO miannu Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1. 0.253 SIGNOR-255123 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 25287865 YES miannu YAP and TAZ were repeatedly isolated as binding proteins for Smads, key transducer of the TGF- and BMP signaling pathways (2, 207, 208). Cytoplasmic YAP/TAZ participate in Smad2/3 cytoplasmic retention, even overruling the ef- fects of high levels of TGF- ligands 0.2 SIGNOR-277662 E2F1 protein Q01094 UNIPROT RASGRP1 protein O95267 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18396012 NO miannu We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation. 0.2 SIGNOR-253850 PTGS2 protein P35354 UNIPROT prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI up-regulates quantity chemical modification 9606 16540375 YES Arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES) 0.8 SIGNOR-255684 furtrethonium chemical CHEBI:134764 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258644 EGFR protein P00533 UNIPROT ASAP3 protein Q8TDY4 UNIPROT up-regulates activity phosphorylation Tyr34 FAAKMPRyRGAALAR 9606 BTO:0000599 23776207 YES lperfetto How ACAP4 regulates membrane dynamics and curvature in response to EGF stimulation is unknown. Here, we show that phosphorylation of the N-terminal region of ACAP4, named the Bin, Amphiphysin, and RSV161/167 (BAR) domain, at Tyr34 is necessary for EGF-elicited membrane remodeling. |EGF stimulation of cells causes phosphorylation of ACAP4 at Tyr34, which subsequently promotes ACAP4 homodimer curvature. 0.2 SIGNOR-272234 BCL6 protein P41182 UNIPROT CD80 protein P33681 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000776 12860928 NO Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. 0.408 SIGNOR-253931 SKI protein P12755 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates binding 9606 12419246 YES gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad6 0.697 SIGNOR-95468 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity precursor of 9606 23000145 YES scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). 0.8 SIGNOR-268451 aclidinium chemical CHEBI:65346 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000131 19653626 YES Luana This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. 0.8 SIGNOR-258049 CDKL1 protein Q00532 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity phosphorylation 9606 28352193 YES miannu We also proved that as a downstream molecule of the P15 pathway, Rb is inhibited after CDKL1 knockdown. Rb is a well-known tumor suppressor in cell cycle regulation.28 Phosphorylation of Rb negatively regulates the cell cycle through E2F repression.29–31 However, Rb contains 13 conserved sites that are phosphorylated by the CDK–P15 complex in cycling cells and phosphorylation will cause site-specific and diverse conformational changes in the complex.32,33 Further studies need to be conducted to decipher the phosphorylated site of Rb related to CDKL1 knockdown. 0.2 SIGNOR-273863 TRIM27 protein P14373 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 12807881 NO miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. 0.2 SIGNOR-102028 CDK2 protein P24941 UNIPROT NFYA protein P23511 UNIPROT up-regulates activity phosphorylation Ser326 FSPKEKDsPHMQDPN 12857729 YES llicata Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa) 0.44 SIGNOR-250743 PRKD1 protein Q15139 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser154 STLYRTQsSSNLAEL 9606 BTO:0000738 23129748 YES miannu  PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration.  0.2 SIGNOR-276426 NOS3 protein P29474 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity chemical modification 9606 24379783 YES lperfetto Nitric oxide (NO) is a major mediator of endothelial function and is synthesized in endothelial cells by endothelial nitric oxide synthase (eNOS). 0.8 SIGNOR-251629 SYN1 protein P17600 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 YES miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. The interaction between synapsin I and Rab3A was confirmed by photoaffinity labeling experiments on purified synaptic vesicles and by the formation of a chemically cross-linked complex between synapsin I and Rab3A in intact nerve terminals. The data indicate that synapsin I is a novel Rab3 interactor on synaptic vesicles and suggest that the synapsin-Rab3 interaction may participate in the regulation of synaptic vesicle trafficking within the nerve terminals. 0.614 SIGNOR-269181 PTK2B protein Q14289 UNIPROT ASAP1 protein Q9ULH1 UNIPROT down-regulates activity phosphorylation Tyr323 QLQGNKEyGSEKKGY 9606 BTO:0000007 12771146 YES miannu The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells.Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation. 0.458 SIGNOR-263186 BAD protein Q92934 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 NO irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. 0.7 SIGNOR-256259 ATR protein Q13535 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 YES lperfetto Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potentialit is, therefore, likely that atm and atr regulate creb phosphorylation collectively in response to stress stimuli. 0.348 SIGNOR-124060 COA3 protein Q9Y2R0 UNIPROT MITRAC complex complex SIGNOR-C538 SIGNOR form complex binding 9606 BTO:0000007 23260140 YES By analyzing MITRAC12 interaction partners, we show that recently identified assembly factors, such as c12orf62, CMC1, and the novel assembly factor MITRAC15, are constituents of MITRAC complexes 0.41 SIGNOR-272484 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.741 SIGNOR-178371 NCOA3 protein Q9Y6Q9 UNIPROT ATF4 protein P18848 UNIPROT up-regulates activity binding 9606 BTO:0000578 31066068 YES miannu Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. 0.2 SIGNOR-275452 CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14592841 YES Activation of C/EBPα induces PU.1 expression, cell cycle arrest, and differentiation in 32D cells expressing FLT3/ITD 0.529 SIGNOR-261531 AKT proteinfamily SIGNOR-PF24 SIGNOR NIBAN1 protein Q9BZQ8 UNIPROT unknown phosphorylation Ser602 ASPARRAsAILPGVL 9606 22510990 YES llicata We demonstrate here that ultraviolet irradiation induces phosphorylation of niban at s602 by akt, which increases the association of niban with nucleophosmin and disassociation of nucleophosmin from the mdm2 complex. 0.2 SIGNOR-197053 Dynorphin B chemical CHEBI:80347 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258796 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 YES amattioni Crk can interact directly with tyrosine kinase receptors (for example pdgfr?) And can transmit signals downstream 0.646 SIGNOR-185664 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 YES lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  0.357 SIGNOR-249073 lisuride chemical CHEBI:51164 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9205951 YES miannu The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. 0.8 SIGNOR-258615 GRB10 protein Q13322 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10090 BTO:0001516 23246379 YES Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation 0.403 SIGNOR-255945 GPR132 protein Q9UNW8 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.42 SIGNOR-257341 P2RY2 protein P41231 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257145 STK38L protein Q9Y2H1 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity phosphorylation Ser495 GVLARKMsLGGGRPY 10090 35670107 YES STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination 0.2 SIGNOR-270348 CSNK1D protein P48730 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation 9606 15747065 YES gcesareni Cki_/_ binds and phosphorylates lef-1, and this phosphorylation disrupts lef-1_-catenin interaction 0.25 SIGNOR-134494 Gbeta proteinfamily SIGNOR-PF4 SIGNOR THRB protein P10828 UNIPROT down-regulates activity phosphorylation 9606 12809513 YES inferred from 70% family members llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. 0.2 SIGNOR-270016 olanzapine chemical CHEBI:7735 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 BTO:0000529 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258510 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19346248 YES lperfetto The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo. 0.989 SIGNOR-184959 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser656 RAEFLNKsVQKSSGV 9606 BTO:0000887;BTO:0001260 8182108 YES gcesareni Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase. 0.357 SIGNOR-36792 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser341 KALASIYsPDHSSNN 9606 19801649 YES llicata Mlk2 inhibits e47 transactivation activity on the trkb promote 0.2 SIGNOR-161523 PRKACA protein P17612 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN -1 11510412 YES miannu Direct phosphorylation of B-Raf by PKA exerts a negative effect on its kinase activity, essentially via phosphorylation of Ser429 0.634 SIGNOR-250339 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT down-regulates transcriptional regulation 9606 19254573 NO fspada Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation 0.326 SIGNOR-210037 FGFR4 protein P22455 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276182 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10029 BTO:0000246 15364919 YES lperfetto Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). 0.645 SIGNOR-249267 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu69 CSYEEAReVFEDSDK -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263672 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation 9606 11343802 YES gcesareni Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation 0.415 SIGNOR-107692 EPHA4 protein P54764 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates activity phosphorylation Tyr596 LNQGVRTyVDPFTYE -1 8622893 YES Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry. 0.2 SIGNOR-251118 ID2 protein Q02363 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.569 SIGNOR-241146 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR2 protein Q92731 UNIPROT up-regulates chemical activation 9606 BTO:0000150 17478088 YES gcesareni Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters. 0.8 SIGNOR-154663 CDK5 protein Q00535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation Ser785 LRGGSDDsSKDPIDV -1 21922195 YES miannu These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage. 0.258 SIGNOR-276358 EPX protein P11678 UNIPROT RNASE2 protein P10153 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 YES miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. 0.476 SIGNOR-261704 MIB1 protein Q86YT6 UNIPROT JAG1 protein P78504 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000938 12530964 YES lperfetto Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum. 0.692 SIGNOR-97388 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM42 protein Q8IWZ5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270978 SYNE3 protein Q6ZMZ3 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.533 SIGNOR-263284 PTP4A3 protein O75365 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 29266303 YES lperfetto As expected, PRL3 clearly reduced PTEN phosphorylation at the tyrosine residue and PTEN protein in PRL3 overexpressing LO2 and HepG2 cell lines, with no significant changes in PRL3 (C104S) mutant cells.|PRL3 down-regulates PTEN expression, a negative regulator of the Akt pathway.11 Phosphorylation of PTEN at Tyr336 is required for maintenance of PTEN protein stability and prevention of PTEN degradation.17 We therefore speculated that PRL3 might dephosphorylate PTEN at tyrosine sites and consequently reduce the PTEN protein level. 0.296 SIGNOR-277010 SAE1 protein Q9UBE0 UNIPROT SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR form complex binding -1 15660128 YES lperfetto E1 enzymes facilitate conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins. Structures of human heterodimeric Sae1/Sae2-Mg.ATP and Sae1/Sae2-SUMO-1-Mg.ATP complexes were determined at 2.2 and 2.75 A resolution, respectively. 0.824 SIGNOR-263003 MYOG protein P15173 UNIPROT mir-133a1 mirna URS00005EB596_9606 RNAcentral up-regulates quantity 9606 18568019 YES miannu In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation. 0.4 SIGNOR-256309 ZNF804A protein Q7Z570 UNIPROT INHBE protein P58166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 YES miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 0.2 SIGNOR-269462 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates activity sumoylation Lys160 EAHQWFLkHEARPLA 9534 BTO:0000298 9756909 YES lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. 0.779 SIGNOR-270540 PRKCG protein P05129 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276019 ULK3 protein Q6PHR2 UNIPROT CHMP4C protein Q96CF2 UNIPROT down-regulates activity phosphorylation 9606 26011858 YES miannuccelli CHMP4C was phosphorylated by recombinant ULK3 in these experiments, whereas CHMP4A and CHMP4B were not (Figure 7\u2014figure supplement 1A). 0.286 SIGNOR-279771 ARMC10 protein Q8N2F6 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity binding 9606 BTO:0000971;BTO:0005814 17904127 YES miannu Co-immunoprecipitation and GST pull-down assays have demonstrated that SVH-B directly interacts with p53. In both BEL-7404 cells and p53-null Saos-2 cells transfected with a temperature-sensitive mutant of p53, V143A, ectopically expressed SVH-B suppresses the transcriptional activity of p53, and suppression of SVH by RNA interference increases the transcriptional activity of p53. Our results suggested the function of SVH-B in accelerating growth and inhibition of apoptosis is related to its inhibitory binding to p53. 0.2 SIGNOR-266414 TEF protein Q10587 UNIPROT NPPB protein P16860 UNIPROT unknown transcriptional regulation 15837525 NO In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription. 0.2 SIGNOR-253652 SRC protein P12931 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates activity phosphorylation Tyr4507 TNFTNPVyATLYMGG 9606 BTO:0000007 12789267 YES lperfetto We recently observed that the ldl receptor-related protein 1 (lrp-1) is tyrosine phosphorylated in v-src-transformed cells.Of the four tyrosine residues present in the cytoplasmic domain of lrp-1, only tyr 63 is phosphorylated by v-src in vivo or in vitro. Using fibroblasts deficient in src, yes and fyn, we were able to show that there are multiple kinases present in the cell that can phosphorylate lrp-1. Tyrosine-phosphorylated lrp-1 associates with shc, a ptb and sh2 domain containing signaling protein that is involved in the activation of ras 0.394 SIGNOR-101535 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KAT5 protein Q92993 UNIPROT up-regulates activity phosphorylation Ser86 TKNGLPGsRPGSPER 9606 BTO:0000567 12468530 YES llicata Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex. 0.419 SIGNOR-250641 Calcineurin complex SIGNOR-C155 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 15829723 NO apalma Calcineurin can activate the transcription factors myocyte enhancer factor-2 and MyoD, which leads to the subsequent induction of myogenin and muscle differentiation (22). In addition, inhibition of calcineurin prevents the initiation of early stages of muscle differentiation 0.265 SIGNOR-255103 YAP1 protein P46937 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 21808241 YES The WW domain of YAP binds to PPXY-containing p73 family members. gcesareni Yap also interacts with p73, a p53 family pro-apoptotic transcription factor, to induce expression of genes such as bax, puma and pml. 0.715 SIGNOR-175934 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 10217147 YES Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. 0.2 SIGNOR-251478 NFATC2 protein Q13469 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001260 17079331 YES lperfetto The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. 0.4 SIGNOR-251731 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity chemical modification 9606 10490932 YES Regulation miannu Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme 0.8 SIGNOR-251911 CHUK protein O15111 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation 9606 16612387 YES gcesareni Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production. 0.688 SIGNOR-146116 PKC proteinfamily SIGNOR-PF53 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser189 DEEFREPsTGKTCLP -1 19661060 YES miannu Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.2 SIGNOR-276230 TRIM33 protein Q9UPN9 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 16751102 YES gcesareni The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. In human hematopoietic stem/progenitor cells, where tgfbeta inhibits proliferation and stimulates erythroid differentiation, tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses. 0.584 SIGNOR-146986 SIAH1 protein Q8IUQ4 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20940030 YES gcesareni The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation 0.26 SIGNOR-254330 p38 proteinfamily SIGNOR-PF16 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules 0.2 SIGNOR-171062 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT up-regulates quantity transcriptional regulation 10090 29106906 YES Gianni We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. 0.421 SIGNOR-268869 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC4 protein P62807 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271986 RAI1 protein Q7Z5J4 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22578325 NO miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 0.309 SIGNOR-266840 AMPK complex SIGNOR-C15 SIGNOR MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 9606 BTO:0001938 26816379 YES gcesareni A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. 0.2 SIGNOR-245948 PP1 proteinfamily SIGNOR-PF54 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases 0.2 SIGNOR-269901 MAPK8 protein P45983 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 BTO:0000007;BTO:0000567 10551811 YES lperfetto The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. 0.557 SIGNOR-236384 DLL3 protein Q9NYJ7 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. 0.489 SIGNOR-254316 bisphenol A chemical CHEBI:33216 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9751507 YES miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings. 0.8 SIGNOR-268738 PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16239230 YES gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. 0.516 SIGNOR-243538 CSNK2A2 protein P19784 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates activity phosphorylation Thr23 ALGPFPDtQDDFLKW 10090 BTO:0004475 9722526 YES 2 miannu Regulation of erythroid Krppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. the transactivation capability of EKLF is augmented by co-transfection of CKIIalpha. in vitro assays demonstrate that CKIIalpha interacts with EKLF, and that the EKLF interaction domain is phosphorylated by CKII only at Thr-41 0.343 SIGNOR-241365 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9575217 YES lperfetto Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein 0.866 SIGNOR-249507 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 20562916 YES miannu We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37. 0.367 SIGNOR-166262 TGFB2 protein P61812 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 22326956 YES miannu Tgf-? Signaling mediates a wide range of biological activities in development and disease. Tgf-? Ligands signal through heterodimeric type i and type ii receptors (tgf-? Receptor type i [t?RI, also known as alk5 and tgfbr1] and t?RII) that are members of the serine/threonine kinase family. 0.744 SIGNOR-196025 HERC4 protein Q5GLZ8 UNIPROT SMO protein Q99835 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 30925584 YES miannu Our data showed that Herc4 mediated Smo degradation by proteasome and lysosome, but mainly by proteasome.|Using the cell based ubiquitination assay, we found that both Myc-SmoK13R and Myc-SmoK49R exhibited reduced ubiquitination compared with Myc-Smo by Herc4, but Myc-SmoK49R resulted in a more dramatic reduction in Smo ubiquitination (XREF_FIG), suggesting that Smo is ubiquitinated by Herc4 at multiple Lys residues. 0.2 SIGNOR-278521 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.564 SIGNOR-89201 MYOD1 protein P15172 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR form complex binding 9606 16847330 YES 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. 0.702 SIGNOR-241100 MECP2 protein P51608 UNIPROT DLX5 protein P56178 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19195802 NO Expression of DLX5 is controlled by MECP2, and defect in MECP2 induced an over-expression of DLX5 in lymphocytes as well as in the brain 0.378 SIGNOR-254034 RPS6K proteinfamily SIGNOR-PF26 SIGNOR EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 YES gcesareni S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function. 0.2 SIGNOR-252783 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1387 GRCPSDPyKHSLPSQ -1 10195142 YES lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. 0.733 SIGNOR-247159 NEDD4 protein P46934 UNIPROT GUCD1 protein Q96NT3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24743017 YES miannu The E3 ligase NEDD4 regulates GUCD1 degradation. many polyubiquitinylated species of GUCD1 appeared as high molecular weight forms, suggesting that GUCD1 is degraded by the proteasome, after polyubiquitin chain formation, in the presence of NEDD4-1. 0.42 SIGNOR-272846 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252330 ADSL protein P30566 UNIPROT fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity chemical modification 9606 22812634 YES miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case 0.8 SIGNOR-266606 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 YES gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have 0.789 SIGNOR-169660 NDN protein Q99608 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization binding 9606 24911587 YES lperfetto Necdin bound to PIAS1 central domains that are highly conserved among PIAS family proteins and suppressed PIAS1-dependent sumoylation of the substrates STAT1 and PML (promyelocytic leukemia protein). Remarkably, necdin promoted degradation of PIAS1 via the ubiquitin-proteasome pathway. In transfected HEK293A cells, amino- and carboxyl-terminally truncated mutants of PIAS1 bound to necdin but failed to undergo necdin-dependent ubiquitination. 0.298 SIGNOR-253387 PRKCB protein P05771 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 8288587 YES gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619. 0.443 SIGNOR-37478 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 19737929 YES lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity 0.762 SIGNOR-216837 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser214 AVDQGNEsIVAKTTV 9606 19468302 YES llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. 0.639 SIGNOR-185754 dexchlorpheniramine chemical CHEBI:4464 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 YES miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. 0.8 SIGNOR-258873 AKT proteinfamily SIGNOR-PF24 SIGNOR STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 YES gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. 0.2 SIGNOR-201121 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 14593115 YES gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. 0.652 SIGNOR-118936 EGR1 protein P18146 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000574 7565762 NO miannu TPA induced EGR1 binding to the -69/+20 promoter sequences over a time course which correlated with increased MDR1 promoter activity and increased steady-state MDR1 RNA levels. These data suggest a role for EGR1 in modulating MDR1 promoter activity in hematopoietic cells. 0.366 SIGNOR-253871 GOT1 protein P17174 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-267506 SEMA3C protein Q99985 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 YES gcesareni Our experiments establish that small peptides containing the consensus decd sequence of sperm fertilinbeta bind specifically to an alpha6beta1 integrin receptor on the egg membrane. We conclude that fertilinbeta binds directly to the alpha6beta1 integrin on the egg surface and this partnership mediates sperm-egg fusion. 0.586 SIGNOR-147564 SYNE1 protein Q8NF91 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.563 SIGNOR-263287 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 TRSVSSSsYRRMFGG -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248877 L-tryptophan smallmolecule CHEBI:16828 ChEBI 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity precursor of 9606 31024440 YES brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. 0.8 SIGNOR-264184 PPP2R1A protein P30153 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates binding 9606 16039140 YES miannu Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme 0.959 SIGNOR-138883 CyclinY/CDK16 complex SIGNOR-C540 SIGNOR CDK16 protein Q00536 UNIPROT up-regulates activity phosphorylation Ser336 PPDILLGsTDYSTQI SIGNOR-C540 32723157 YES lperfetto Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16. 0.67 SIGNOR-273006 TBP protein P20226 UNIPROT LIN28B protein Q6ZN17 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 23494474 NO miannu We conclude that the oncoprotein HBXIP as a co-activator of TF II D transactivates Lin28B promoter via directly binding to TBP to upregulate the expression of Lin28B in promotion of proliferation of breast cancer cells, in which Lin28B maintains the high level of HBXIP through suppressing miR-520b in a feedback manner. 0.249 SIGNOR-255252 GIT1 protein Q9Y2X7 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 14523024 YES gcesareni Git1 interaction with plcgamma is required for plcgamma activation based on inhibition of tyrosine phosphorylation 0.556 SIGNOR-118454 hsa-miR-200a-5p mirna URS000023B77E_9606 RNAcentral GNA13 protein Q14344 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001061 23329838 YES Parnian Taken together these data indicate that GNA13 is an important target of miR-182 and -200a, which bind to the 3 -UTR of GNA13 and down-regulate its protein expression in PC3 cells. 0.4 SIGNOR-278022 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT up-regulates activity phosphorylation Ser548 KSSLEAAsFWGE -1 21880710 YES miannu Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. 0.429 SIGNOR-262939 CLTB protein P09497 UNIPROT AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.769 SIGNOR-260671 YBX1 protein P67809 UNIPROT TYMS protein P04818 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001023 17072343 NO miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 0.247 SIGNOR-255613 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 28646232 YES inferred from 70% family members Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3Œ≤ at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3Œ≤ activity and restores protein synthesis in Tsc2 ‚àí/‚àí MEFs to normal levels 0.2 SIGNOR-270068 EXOC8 protein Q8IYI6 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.914 SIGNOR-270783 D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR CHEK2 protein O96017 UNIPROT up-regulates activity 9606 BTO:0000567 23438602 NO lperfetto Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation. 0.475 SIGNOR-263262 SRC protein P12931 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates activity phosphorylation Tyr491 CAAWHGYySVAKALC 9606 BTO:0002181 17803936 YES miannu  Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.  0.273 SIGNOR-276073 NMDA receptor_2B complex SIGNOR-C348 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor 0.807 SIGNOR-264223 PPP2CA protein P67775 UNIPROT RAF1 protein P04049 UNIPROT up-regulates dephosphorylation 9606 BTO:0000671 16239230 YES miannu Both pp2a holoenzymes were found to associate with raf1 and catalyze dephosphorylation of inhibitory phospho-ser-259. Together these findings indicate that pp2a abalphac and abdeltac holoenzymes function as positive regulators of raf1-mek1/2-erk1/2 signaling by targeting raf1. 0.591 SIGNOR-141170 hsa-miR-202-5p mirna URS00003D8730_9606 RNAcentral LRP6 protein O75581 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 24704686 YES Parnian Taken together, our results suggested that LRP6 mRNA is a direct target of miR-202 in HCC cells. 0.4 SIGNOR-278841 TFEB protein P19484 UNIPROT MOGAT2 protein Q3SYC2 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 NO lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 0.2 SIGNOR-276799 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 YES gcesareni The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions. 0.674 SIGNOR-44361 serotonin smallmolecule CHEBI:28790 ChEBI HTR6 protein P50406 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264295 AIP protein O00170 UNIPROT GREB1 protein Q4ZG55 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 21984905 NO miannu We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. 0.2 SIGNOR-253735 NFE2L2 protein Q16236 UNIPROT PGD protein P52209 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 NO miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 0.281 SIGNOR-267355 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.497 SIGNOR-248801 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258218 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates phosphorylation Ser1112 LLEDGSEsPAKRICP 9606 12006580 YES gcesareni When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity 0.849 SIGNOR-87492 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257929 BLLF1 protein P03200 UNIPROT CR2 protein P20023 UNIPROT up-regulates activity binding 9606 BTO:0000776 18786993 YES scontino The binding of the Epstein-Barr virus glycoprotein gp350 by complement receptor type 2 (CR2) is critical for viral attachment to B lymphocytes. 0.2 SIGNOR-266624 CALM2 protein P0DP24 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 YES miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.583 SIGNOR-266327 CD19 protein P15391 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10090 10201980 YES lperfetto Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. 0.584 SIGNOR-249608 DOK4 protein Q8TEW6 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 YES gcesareni Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells. 0.42 SIGNOR-101002 PRKCE protein Q02156 UNIPROT MIIP protein Q5JXC2 UNIPROT up-regulates activity phosphorylation Ser303 YHIHRRKsFDASDTL 9606 BTO:0001109 29038521 YES done miannu Here, we show that EGF stimulation induces PKCε-dependent phosphorylation of migration and invasion inhibitory protein (MIIP) at Ser303; this phosphorylation promotes the interaction between MIIP and RelA in the nucleus, by which MIIP prevents histone deacetylase 6 (HDAC6)-mediated RelA deacetylation, and thus enhances transcriptional activity of RelA and facilitates tumor metastasis.  0.2 SIGNOR-273828 GOLGA7 protein Q7Z5G4 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 YES miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. 0.397 SIGNOR-261354 PIN1 protein Q13526 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity isomerization 9606 BTO:0000599 23720771 YES lperfetto In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events 0.2 SIGNOR-265757 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21620960 YES gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. 0.762 SIGNOR-252515 PRKCE protein Q02156 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 1374067 YES lperfetto In conclusion, we have shown that the PKCe catalytic fragment physically associates with and phosphorylates CK8/18 HT29 cells. The nature of this association and its physiological significance remain to be determined. 0.329 SIGNOR-248847 CEP290 protein O15078 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity binding 9606 18694559 YES miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CEP290 recruits Rab8a to centrosomes. Depletion of CEP290 results in a significant decrease of Rab8a at the centrosome and at the cilium, raising the possibility that CEP290 first recruits Rab8a through direct protein-protein interactions to the centrosome in cycling cells and later promotes ciliogenesis by allowing the entry of Rab8a into the cilium 0.741 SIGNOR-252146 PRKAA2 protein P54646 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 SIGNOR-C15 17082196 YES lperfetto Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology. 0.2 SIGNOR-150462 LYN protein P07948 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 17146444 YES miannu An in vitro phosphorylation assay showed that Lyn directly phosphorylates STAT3. 0.658 SIGNOR-279062 XL-647 chemical CID:10458325 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 22722787 YES gcesareni Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4). 0.8 SIGNOR-197962 LYN protein P07948 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates activity phosphorylation Tyr120 PPTYNADyGYKSWEA -1 24970799 YES miannu We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity. FYN and LYN kinases phosphorylate COX2 on two distinct residues in vitro. 0.386 SIGNOR-276643 MAPK14 protein Q16539 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 NO Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). 0.2 SIGNOR-251837 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 YES lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex 0.49 SIGNOR-118580 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763;BTO:0000149 10197981 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.2 SIGNOR-244719 FBXO2 protein Q9UK22 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 23604317 YES miannu  FBXL2 interacts with the pool of p85β that is free of p110 PI(3)K catalytic subunits and targets this pool for ubiquitylation and subsequent proteasomal degradation.This result suggests that FBXL2 localization to cell membranes facilitates substrate binding, which in turn stimulates CUL1 neddylation and activation of ubiquitin ligase activity. 0.69 SIGNOR-271937 GOT2 protein P00505 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 31422819 YES miannu This is a pyridoxal 5√ɬ¢√¢‚Äö¬¨√Ǭ≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √É≈Ω√Ǭ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-268057 MAPK14 protein Q16539 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 YES lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif ((68)nqsllspl) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase.The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. 0.591 SIGNOR-114079 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Ser27 SFGFTRTsARRRLAD -1 21880142 YES miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. 0.307 SIGNOR-266311 CRTC3 protein Q6UUV7 UNIPROT BCL3 protein P20749 UNIPROT up-regulates binding 9606 BTO:0001271;BTO:0000776;BTO:0000786 17644518 YES miannu The ankyrin repeat domain of bcl3 interacted with torc3 / we determined that bcl3 inhibited transcription from the htlv-1 ltr in a manner dependent on torc3 0.361 SIGNOR-156950 CASP8 protein Q14790 UNIPROT BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 YES amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity 0.879 SIGNOR-59655 FGF2 protein P09038 UNIPROT ANKH protein Q9HCJ1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004473 19049325 NO miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. 0.2 SIGNOR-252193 ATF2 protein P15336 UNIPROT FGF21 protein Q9NSA1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 25055037 NO miannu The increased production of reactive oxygen species, subsequent induction of p38 MAPK (mitogen-activated protein kinase) and activation of an ATF2 (activating transcription factor 2)-binding site at the proximal promoter region of the FGF21 gene was found to be a major mechanism linking mitochondrial dysfunction with enhanced FGF21 gene transcription in myogenic cells. 0.346 SIGNOR-253743 ADSS1 protein Q8N142 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-267346 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1070 DSFLQRYsSDPTGAL 9606 BTO:0000007 10347170 YES llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  0.371 SIGNOR-250620 TRIM32 protein Q13049 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19269368 YES miannu TRIM32 ubiquitinates and degrades the transcription factor c-Myc but also binds Argonaute-1 and thereby increases the activity of specific microRNAs. 0.456 SIGNOR-278676 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser727 PMGSFEPsPYPTTSS 9606 BTO:0000567 34198826 YES miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. 0.25 SIGNOR-276659 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 10090 BTO:0001516 14981546 YES These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. 0.431 SIGNOR-261522 PRKCG protein P05129 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 YES lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. 0.399 SIGNOR-249085 PTPRA protein P18433 UNIPROT FYN protein P06241 UNIPROT up-regulates dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 17507376 YES gcesareni Ptpalpha is a more widely expressed transmembrane ptp that has been shown to regulate the src family kinases, src and fyn, and is also present in t cells. 0.657 SIGNOR-154796 hsa-miR-148a-3p mirna URS00003BBF48_9606 RNAcentral CDH1 protein P12830 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 BTO:0002745 33026174 NO Parnian MiR-148a-3p overexpression increased the expression of E-cadherin, accompanying decreased N-cadherin and vimentin expression. 0.4 SIGNOR-278852 PKC proteinfamily SIGNOR-PF53 SIGNOR GAD2 protein Q05329 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000142 15147202 YES miannu Here, we report the effect of phosphorylation on the two well-defined GAD isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 and GAD67. GAD65 was activated by phosphorylation, while GAD67 was inhibited by phosphorylation.We further demonstrate that protein kinase A (PKA) and protein kinase C isoform epsilon are the protein kinases responsible for phosphorylation and regulation of GAD67 and GAD65, respectively. 0.2 SIGNOR-276010 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser285 NHTLAPAsPAPARPR 9606 BTO:0000142 15262992 YES lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd 0.396 SIGNOR-126851 PRKAA1 protein Q13131 UNIPROT TBC1D1 protein Q86TI0 UNIPROT down-regulates phosphorylation Ser237 RPMRKSFsQPGLRSL 9606 BTO:0001760 SIGNOR-C15 17995453 YES gcesareni In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar 0.424 SIGNOR-159048 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser236 AKRRRLSsLRASTSK -1 1985906 YES miannu The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide. 0.31 SIGNOR-250232 DPP3 protein Q9NY33 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT down-regulates quantity by destabilization cleavage -1 34770898 YES miannu Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. The binding of Ang II to hDPP III may lead to changes in the shape and size of subsite S1, an important catalytic site, so as to promote the decomposition of the substrate. 0.2 SIGNOR-268463 FLT3 protein P36888 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates activity relocalization 10090 14982881 NO We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. 0.257 SIGNOR-261538 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 FSGIESSsPEVKGYW 9606 BTO:0000664 17475908 YES miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 0.319 SIGNOR-262912 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 10802669 YES gcesareni We show that atm physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (s343a) does not completely complement radiosensitivity in nbs cells. 0.855 SIGNOR-77149 CDC14A protein Q9UNH5 UNIPROT KMT5A protein Q9NQR1 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 YES The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis. 0.2 SIGNOR-248835 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 10090 BTO:0002882 16122376 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work 0.2 SIGNOR-236527 ERBB2 protein P04626 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 12049736 YES lperfetto Phosphorylation on tyrosine-15 of p34(cdc2) by erbb2 inhibits p34(cdc2) activation and is involved in resistance to taxol-induced apoptosis 0.274 SIGNOR-88671 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser68 GGGAGPVsPQHHELT 9606 22878263 YES llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. 0.411 SIGNOR-198729 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser383 ELPRRVNsASSSNPP 9606 15341740 YES llicata Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites. 0.765 SIGNOR-128495 FZD3 protein Q9NPG1 UNIPROT GNGT1 protein P63211 UNIPROT up-regulates binding 9606 17251915 YES gcesareni In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat. 0.396 SIGNOR-152606 SMARCD3 protein Q6STE5 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.749 SIGNOR-270732 RPS6KA1 protein Q15418 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 YES lperfetto Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK. 0.288 SIGNOR-209871 CyclinC/CDK19 complex SIGNOR-C544 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.39 SIGNOR-273162 NAB2 protein Q15742 UNIPROT EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000414 20506119 NO miannu Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. 0.594 SIGNOR-253886 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269378 CDK5 protein Q00535 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Ser522 PAPSAKSsPSKHQPP 9606 BTO:0000938 18003833 YES lperfetto These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness. 0.621 SIGNOR-159314 TRAF6 protein Q9Y4K3 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity ubiquitination 9606 21980489 YES miannu TTRAP is ubiquitylated by TRAF6 and promotes TRAF6 dependent ubiquitylation of TAK1.|In addition, we noted that the presence of TRAF6 strengthened the interaction between TTRAP and the TGF-\u03b2 receptor complex (see also later). 0.378 SIGNOR-278717 MAPK15 protein Q8TD08 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 12169099 YES gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation. 0.428 SIGNOR-91371 DPY30 protein Q9C005 UNIPROT MLL/SET subcomplex complex SIGNOR-C87 SIGNOR form complex binding 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.889 SIGNOR-204747 NF1 protein P21359 UNIPROT ADCY4 protein Q8NFM4 UNIPROT up-regulates 9606 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.287 SIGNOR-204091 SGK1 protein O00141 UNIPROT APBB1 protein O00213 UNIPROT down-regulates activity phosphorylation Ser610 ECRVRFLsFLAVGRD 9606 26188042 YES miannu In the present study, we demonstrated that phosphorylation of FE65 Ser 610 by SGK1 attenuates the interaction between FE65 and APP (XREF_FIG).|In this regard, we demonstrated that phosphorylation of FE65 Ser 610 by SGK1 abolishes the effect of FE65 on APP processing and the amount of secreted Abeta is comparable to APP + Mock control (XREF_FIG). 0.345 SIGNOR-278220 SF3B1 protein O75533 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000664;BTO:0000565 25428262 NO irozzo Taken together, these data show that SF3B1 knockdown results in inhibition of cell growth, induction of cell cycle arrest and impairment of erythroid differentiation in myeloid cell lines.[…]SF3B1 knockdown compared with the scramble control, suggesting that normal SF3B1 function is required for erythroid differentiation. 0.7 SIGNOR-256004 WWTR1 protein Q9GZV5 UNIPROT PAX8 protein Q06710 UNIPROT up-regulates binding 9606 BTO:0000763 19010321 YES miannu Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation. 0.303 SIGNOR-182253 PGM2 protein Q96G03 UNIPROT 2-deoxy-alpha-D-ribose 1-phosphate smallmolecule CHEBI:11563 ChEBI down-regulates quantity chemical modification 9606 17804405 YES miannu Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. 0.8 SIGNOR-267094 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 YES lperfetto Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation 0.308 SIGNOR-181655 AURKA protein O14965 UNIPROT STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation 9606 33037191 YES miannu Inhibition of AURKA activity activates stathmin function via reduced phosphorylation and facilitates microtubule destabilization in RB1 -/- cells, heavily impacting the bipolar spindle formation and inducing mitotic cell death selectively in RB1 -/- cells.|Two serine phosphorylation sites, Ser16 and Ser63, in stathmin contain a consensus sequence for AURKA phosphorylation and the mutations in these two serine sites abolished stathmin phosphorylation by AURKA, suggesting that stathmin is a substrate of AURKA for phosphorylation xref , xref . 0.388 SIGNOR-278913 LYN protein P07948 UNIPROT FCGR2B protein P31994 UNIPROT up-regulates activity phosphorylation Tyr292 GAENTITySLLMHPD -1 8756631 YES lperfetto Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn 0.43 SIGNOR-249380 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT up-regulates activity chemical activation 9606 31226734 YES lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form 0.8 SIGNOR-265914 trichostatin A chemical CHEBI:46024 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258016 PBRM1 protein Q86U86 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.779 SIGNOR-270596 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1137 RSRGNRKsLRRTLKS 9606 18239683 YES lperfetto Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres. 0.309 SIGNOR-160548 NUMB protein P49757 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates binding 9606 20940030 YES gcesareni Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53 0.445 SIGNOR-168454 MRPL35 protein Q9NZE8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.644 SIGNOR-262362 AKT1 protein P31749 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by stabilization phosphorylation Thr118 RPRRKTKtLMKKDKY 9606 25042802 YES miannu In contrast, phosphorylation of Sox2 by AKT1 at T118 blocks K119me by Set7 and stabilizes Sox2. 0.533 SIGNOR-279003 NPM1 protein P06748 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30205049 YES miannu In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. 0.352 SIGNOR-260138 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser54 QPLPPRPsPAALPGG 9606 27308327 YES miannu HIPK2 phosphorylates WIP1 at Ser54 and Ser85, and phosphorylated WIP1 is subject to proteasomal degradation so that WIP1 is maintained at low levels. 0.42 SIGNOR-278229 EIF2AK2 protein P19525 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 10348343 YES gcesareni The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. 0.57 SIGNOR-68033 MLLT11 protein Q13015 UNIPROT TCF7 protein P36402 UNIPROT up-regulates activity binding -1 26079538 YES irozzo Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. Super-shift and electrophoretic mobility shift assay (EMSA) further confirmed that AF1q directly interacted with TCF7 and enhanced the binding affinity of the complex 0.464 SIGNOR-259108 FIG4 protein Q92562 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT up-regulates activity 9606 23165282 NO miannu PI(3,5)P2 begins to be synthesized on endosomal membranes and is additionally required for the activation of lysosomal TRPML1/MCOLN1 channels. Thus, a deficiency of FIG4/PI(3,5)P2 would impair TRPML1/MCOLN1 channel function, leading to the accumulation of calcium in the lysosomes. 0.355 SIGNOR-253536 Ub:E2 complex SIGNOR-C497 SIGNOR RNF133 protein Q8WVZ7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271205 PSEN1 protein P49768 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 9606 SIGNOR-C98 10593990 YES Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. gcesareni Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. 0.796 SIGNOR-254308 PTEN protein P60484 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity dephosphorylation Ser307 TRRSRTEsITATSPA 10090 25645159 YES miannu In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser 307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN dependent manner.|In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon Hepatitis C virus infection occurred in a PTEN-dependent manner. 0.577 SIGNOR-277078 SMAD6 protein O43541 UNIPROT HOXC8 protein P31273 UNIPROT up-regulates activity binding 9606 10722652 YES gcesareni Smad6 interacts with hox transcription factors as part of the negative feedback circuit in the bmp signaling pathway 0.53 SIGNOR-75823 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation 9606 16331690 YES The effect has been demonstrated using Q13507-3 llicata The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263. 0.408 SIGNOR-142964 LTN1 protein O94822 UNIPROT RPS6KA1 protein Q15418 UNIPROT down-regulates activity ubiquitination 9606 29540532 YES miannu Ltn1 ubiquitylation of RSK1, RSK2, and TWY3 could either result in degradation or impart a regulatory function on target proteins distinct from degradation. 0.2 SIGNOR-278757 CHL1 protein O00533 UNIPROT ANK2 protein Q01484 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 YES miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. 0.409 SIGNOR-266722 PHLPP2 protein Q6ZVD8 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 BTO:0001544 19261608 YES The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. 0.603 SIGNOR-248729 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation 10029 BTO:0000246 12907755 YES Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR 0.315 SIGNOR-248505 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates quantity by destabilization phosphorylation Ser621 ALIPGNLsKEEEELS 9606 BTO:0000567 25504441 YES miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. 0.811 SIGNOR-276862 DYRK1A protein Q13627 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation Ser408 GPLPRAPsISTVEPK 9606 28735864 YES miannu Here, we have used an in vitro kinase assay and phospho-peptide mass spectrometry analysis to identify site(s) of direct phosphorylation of GLI1 by DYRK1A and have determined that DYRK1A phosphorylates GLI1 at Ser408 within its nuclear localization sequence.|The kinase DYRK1A (dual-specificity tyrosine phosphorylation regulated kinase 1a) has been shown to activate GLI1 via a phosphorylation event, leading to the translocation of GLI1 from the cytoplasm to the nucleus . 0.514 SIGNOR-278930 EGFR protein P00533 UNIPROT TLR3 protein O15455 UNIPROT up-regulates activity phosphorylation Tyr858 FLEEIPDyKLNHALC 9606 25022196 YES miannu Although both the ErbB1 and the ErbB2 isoforms of EGFR can bind to activated TLR3, functionally, only ErbB1 can trigger TLR3 signaling.|There is a high degree of specificity of the targets of the two PTKs, EGFR and Src 0.427 SIGNOR-278932 LPAR3 protein Q9UBY5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 11093753 YES gcesareni Lpa3 can couple to gi/o 0.456 SIGNOR-84562 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22863277 YES miannu Lats1/2 inhibit yap by direct phosphorylation at s127, which results in yap binding to 14-3-3 and cytoplasmic sequestration 0.82 SIGNOR-198514 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YBX1 protein P67809 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16797541 YES miannu Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1 0.323 SIGNOR-271606 PDX1 protein P52945 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000627 8866550 NO inferred from family member miannu The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. 0.604 SIGNOR-267798 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser151 VNFGRSRsAQEPARK 9606 24309468 YES lperfetto Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1. 0.461 SIGNOR-203460 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269344 CDH11 protein P55287 UNIPROT CTNNA1 protein P35221 UNIPROT unknown binding 9606 BTO:0000150 10029089 YES miannu Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin 0.487 SIGNOR-64859 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 15774499 YES gcesareni The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. 0.385 SIGNOR-134654 DMXL2 protein Q8TDJ6 UNIPROT RAB3GAP1 protein Q15042 UNIPROT up-regulates quantity binding 10116 BTO:0000142 11809763 YES miannu We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles. 0.541 SIGNOR-265582 FYN protein P06241 UNIPROT JUP protein P14923 UNIPROT up-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 14517306 YES Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 and that it phosphorylated Tyr133 with a much lower activity 0.56 SIGNOR-251176 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr255 EEEGAPDyENLQELN 9606 11368773 YES lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. 0.769 SIGNOR-247034 ATM protein Q13315 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 YES llicata Atm and dna?PK Phosphorylate rpa32 thr21in vitro and in vivo 0.809 SIGNOR-121865 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser493 CPPECPEsLHDLMCQ 9606 33388549 YES miannu P -Ser9 GSK-3\u03b2 phosphorylates Ser43, Ser51, and Ser493 residues of src, regulating src activity. 0.383 SIGNOR-278444 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 31422819 YES miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-267513 CTNNB1 protein P35222 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510874 NO gcesareni Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro.Chromatin Immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. 0.745 SIGNOR-19153 DUSP1 protein P28562 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity dephosphorylation Ser118 AELVRTDsPNFLCSV 9606 27031422 YES miannu In a separate study, MKP-1 was shown to induce osteogenesis by dephosphorylating Ser125 on Runx2 isoform type II (37).|MKP-1 increases RUNX2 activity and downregulates MAPK, cyclin D1 in differentiated osteoblasts inducing growth arrest and mineralization. 0.354 SIGNOR-277143 Ub:E2 complex SIGNOR-C497 SIGNOR NEURL1 protein O76050 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271043 CDK8 protein P49336 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates phosphorylation 9606 15546612 YES gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. 0.551 SIGNOR-254312 UHRF2 protein Q96PU4 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 21952639 YES miannu We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1. 0.332 SIGNOR-271886 sabcomeline chemical CHEBI:134846 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10116 9399977 YES miannu SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes 0.8 SIGNOR-258678 KMT2D protein O14686 UNIPROT MLL2 complex complex SIGNOR-C88 SIGNOR form complex binding 9606 24680668 YES miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. 0.2 SIGNOR-204816 PD173955 chemical CHEBI:49791 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258263 ITCH protein Q96J02 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates ubiquitination 9606 15350225 YES gcesareni Itch promotes ubiquitination of smad2 and augments smad2 phosphorylation that requires an intact ligase activity of itch. Moreover, itch facilitates complex formation between tgf-beta receptor and smad2 and enhances tgf-beta-induced transcription. 0.454 SIGNOR-128647 PRKCG protein P05129 UNIPROT EIF4E protein P06730 UNIPROT unknown phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 YES lperfetto Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins. 0.307 SIGNOR-248947 Telatinib chemical CID:9808844 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207230 MAPK3 protein P27361 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 16778989 YES gcesareni Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells. 0.421 SIGNOR-147174 ZNF503 protein Q96F45 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25538248 NO Monia We asked whether higher pFAK staining in cells expressing Zpo2 correlates with reduced E-cadherin levels. Immunostaining for E-cadherin in the EpH4.9 and PyMT stable cell lines indicated a decrease in overall E-cadherin staining in Zpo2-overexpressing cells compared with the control (Fig. 6C). Similarly, Western blot analysis indicated a reduction in E-cadherin expression in Zpo2-expressing cells compared with the control (Fig. 6D). 0.2 SIGNOR-261190 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273089 MAP1LC3C protein Q9BXW4 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 NO lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation 0.7 SIGNOR-219399 EGFR protein P00533 UNIPROT HGS protein O14964 UNIPROT up-regulates phosphorylation Tyr329 IDPELARyLNRNYWE 9606 12953068 YES lperfetto We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation 0.636 SIGNOR-86689 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 YES llicata We show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro. 0.58 SIGNOR-121873 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.822 SIGNOR-178420 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 YES Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. 0.755 SIGNOR-255840 carfilzomib chemical CHEBI:65347 ChEBI PSMB5 protein P28074 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000873 19348473 YES Luana Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes. 0.8 SIGNOR-257818 LTB4R2 protein Q9NPC1 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256817 CACNA1H protein O95180 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 BTO:0000142 30736831 YES miannu Certain types of sensory neurons express Cav3.2 calcium channels [12, 13] These channels belong to the family of low-voltage gated T-type calcium channels 0.8 SIGNOR-269278 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser8 MWNSGFEsYGSSSYG 9606 20016603 YES gcesareni Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation 0.2 SIGNOR-162164 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 20940307 YES gcesareni Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis 0.336 SIGNOR-168469 GLUD2 protein P49448 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9913 11254391 YES miannu Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. 0.8 SIGNOR-268558 APBA1 protein Q02410 UNIPROT CASK-Mint1-Veli complex complex SIGNOR-C561 SIGNOR form complex binding 9606 BTO:0000938 16842202 YES miannu The CASK-Mint1-Veli complex acts as an adaptor protein complex interacting with beta-neurexin, the current model proposes that the CASK- Mint1-Veli complex functions as a nucleation site for the assembly of proteins involved in synaptic junctions and synaptic vesicle exocytosis (Fig. 3a). 0.784 SIGNOR-278898 BCAR1 protein P56945 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 18321991 YES gcesareni In this study, we show that, after tyrosine phosphorylation of p130cas mediated by integrin signaling, the phosphorylated p130cas is able to interact with phosphorylated smad3 and in turn prevent transcriptional activation by smad3 0.277 SIGNOR-161265 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 BTO:0000944 12052829 YES lperfetto Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms. 0.402 SIGNOR-263047 CBY1 protein Q9Y3M2 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 12712206 YES gcesareni Here we report a conserved nuclear protein, named chibby, which was identified in a screen for proteins that directly interact with the c-terminal region of beta-catenin. In mammalian cultured cells we demonstrate that chibby inhibits beta-catenin-mediated transcriptional activation by competing with lef-1 to bind to beta-catenin. 0.692 SIGNOR-100835 PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity 9606 21798082 YES lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). 0.8 SIGNOR-252722 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser262 GHGLRRSsKFCLKEH -1 1848190 YES lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. 0.352 SIGNOR-248855 INSIG2 protein Q9Y5U4 UNIPROT SCAP protein Q12770 UNIPROT down-regulates activity binding 10029 BTO:0000246 12242332 YES insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. 0.716 SIGNOR-256209 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CTTN protein Q14247 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 20444238 YES inferred from 70% family members gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.2 SIGNOR-270164 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser37 KHSSYPDsEGAPDSL 9606 10618498 YES lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability 0.43 SIGNOR-73891 acyl-CoA smallmolecule CHEBI:17984 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of -1 18772128 YES miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. 0.8 SIGNOR-268106 UFD1 protein Q92890 UNIPROT CD4 protein P01730 UNIPROT down-regulates quantity by destabilization binding 9606 20442859 YES miannu These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. 0.2 SIGNOR-252421 TBK1 protein Q9UHD2 UNIPROT TNIP1 protein Q15025 UNIPROT down-regulates quantity by destabilization phosphorylation Ser122 KPPSSGTsSEFEVVT 36574265 YES lperfetto TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1 0.375 SIGNOR-275733 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.762 SIGNOR-252486 PPP1CB protein P62140 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 YES Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1. 0.2 SIGNOR-248571 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser345 PLVSDEKsSELIITD -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276198 DIO1 protein P49895 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity chemical modification 9606 1400883 YES scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. 0.8 SIGNOR-266944 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR2A protein P13861 UNIPROT down-regulates activity chemical inhibition 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.8 SIGNOR-258761 MIB2 protein Q96AX9 UNIPROT JAG2 protein Q9Y219 UNIPROT up-regulates ubiquitination 9606 15920166 YES gcesareni Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2. 0.809 SIGNOR-137922 DNM2 protein P50570 UNIPROT VAV1 protein P15498 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000584 23537630 YES Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability. 0.488 SIGNOR-259080 PRDM1 protein O75626 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 NO SimoneGraziosi SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. 0.7 SIGNOR-269263 ADCY2 protein Q08462 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-265004 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr577 YMEDSTYyKASKGKL -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.244 SIGNOR-254718 Fatty acid stimulus SIGNOR-ST19 SIGNOR PPARG protein P37231 UNIPROT up-regulates 9606 29369787 YES miannu Omega 3 fatty acids and fibrates are considered as natural and pharmacological ligands of PPARα, respectively, that reduce inflammation and arteriosclerosis in cardiovascular system 0.7 SIGNOR-256189 PEX14 protein O75381 UNIPROT PEX7 protein O00628 UNIPROT up-regulates activity binding -1 15798189 YES miannu The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7. 0.89 SIGNOR-253028 TP53BP1 protein Q12888 UNIPROT RIF1 protein Q5UIP0 UNIPROT up-regulates activity binding 10090 23333305 YES miannu RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination. 0.685 SIGNOR-259058 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 14711813 YES llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. taken together, the results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity. 0.2 SIGNOR-121165 SLBP protein Q14493 UNIPROT H2AC6 protein Q93077 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265400 AURKB protein Q96GD4 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-98293 TICAM2 protein Q86XR7 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 9606 BTO:0000801 14519765 YES lperfetto Tram binds trif directly and recruits it to tlr4 0.585 SIGNOR-118367 NFE2 protein Q16621 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 NO Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. 0.499 SIGNOR-251842 PTPRG protein P23470 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity 9606 25624455 NO miannu PTPRG activation inhibits chemoattractant induced LFA-1 affinity triggering and mediated adhesion in human primary monocytes.we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation. 0.261 SIGNOR-254735 CDK5 protein Q00535 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Ser131 HTDSRKDsPPAGSPA 9606 BTO:0000142 17327227 YES llicata Phosphorylation by cdk5 decreased the auto-ubiquitylation of parkin both in vitro and in vivo. 0.2 SIGNOR-153445 BHLHE40 protein O14503 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 14672706 NO lperfetto Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression 0.473 SIGNOR-253717 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr203 SSLATPPtLSSTVLI 9606 BTO:0001938 12815053 YES lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. 0.54 SIGNOR-249220 TLR8 protein Q9NR97 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity 9606 BTO:0004721;BTO:0002900 15661881 NO miannu TLR8 functions in monocytes and myeloid DC and is involved in the production of proinflammatory cytokines such as TNF-α. 0.448 SIGNOR-259249 PRKACA protein P17612 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Thr73 YGGEKFAtLAELVQY 9606 BTO:0002181 25802336 YES miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  0.45 SIGNOR-276891 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser101 GSHRDQGsSALSGVG 9606 BTO:0001271 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway 0.2 SIGNOR-174840 SSTR1 protein P30872 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256958 SNAI1 protein O95863 UNIPROT HPGD protein P15428 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19010907 NO miannu We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. 0.291 SIGNOR-254237 NRTN protein Q99748 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 YES gcesareni A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling 0.737 SIGNOR-49119 CDK13 protein Q14004 UNIPROT EIF4EBP1 protein Q13541 UNIPROT up-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0001109 36882522 YES lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. 0.2 SIGNOR-273113 RELA protein Q04206 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR form complex binding 9606 9450761 YES gcesareni Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna 0.713 SIGNOR-55381 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by stabilization phosphorylation Ser352 TRPTALTsPELSSWS 9606 BTO:0001109 28945223 YES miannu In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.  0.2 SIGNOR-276743 LRFN3 protein Q9BTN0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 NO miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. 0.7 SIGNOR-264101 FES protein P07332 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15003822 YES miannu Fes also induced Tyr 705 phosphorylation and DNA binding activity of STAT3, in agreement with the idea that Fes can regulate transcriptional activation through Fes dependent phosphorylation of transcription factors.On the basis of these findings, we propose that Fes activation of critical transcriptional regulators such as PU.1 is part of the mechanism by which this kinase induces macrophage differentiation of myeloid progenitors.|We conclude that Fes may regulate granulocytic differentiation at least in part through activation of C/EBP-alpha and STAT3.In 32D cells, Fes activated STAT3 and C/EBP-alpha, two important regulators of granulocytic differentiation [14,15]. 0.402 SIGNOR-278937 PTPN6 protein P29350 UNIPROT SYK protein P43405 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 10458769 YES miannu We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene. 0.736 SIGNOR-70234 ARID1B protein Q8NFD5 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES lperfetto We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.784 SIGNOR-241713 CASP3 protein P42574 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 YES amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process 0.775 SIGNOR-116178 CDC20 protein Q12834 UNIPROT FBXO31 protein Q5XUX0 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 YES miannu Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT. 0.396 SIGNOR-277378 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity relocalization 9606 20515759 YES lperfetto Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor. 0.86 SIGNOR-59145 RAD18 protein Q9NS91 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity ubiquitination Lys1268 DGTEVERkVTEETEE 9606 19228710 YES miannu RAD18 associates with 53BP1 and is recruited to DSB sites in a 53BP1 dependent manner specifically during G1-phase, RAD18 monoubiquitinates KBD domain of 53BP1 at lysine 1268 in vitro.|These results suggest that RAD18 directed modification at Lysine 1268 of 53BP1 promotes the retention of 53BP1 at DSBs. 0.612 SIGNOR-278593 PPM1E protein Q8WY54 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 11864573 YES The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. 0.303 SIGNOR-248761 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK11 protein Q15759 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni 0.8 SIGNOR-189675 SMURF1 protein Q9HCE7 UNIPROT TRIB2 protein Q92519 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 24089522 YES miannu  In this study, we found that TRIB2 was up-regulated and exhibited high stability in liver cancer cells compared with other cells. We performed a structure-function analysis of TRIB2 and identified a domain (amino acids 1-5) at the N terminus that interacted with the E3 ubiquitin ligase Smurf1 and was critical for protein stability. Deletion of this domain extended TRIB2 half-life time accompanied with a more significant malignant property compared with wild type TRIB2. 0.411 SIGNOR-275432 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser293 GSTKRRKsMSGASPK 9606 12676583 YES Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. 0.842 SIGNOR-99733 N-(2-(4-(7-Methoxy-1-naphthalenyl)-1-piperazinyl)ethyl)-2-thiophenecarboxamide chemical CID:131907 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258866 FOXO1 protein Q12778 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17873901 NO gcesareni Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity 0.303 SIGNOR-157794 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 19282669 YES lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.593 SIGNOR-184569 BRD2 protein P25440 UNIPROT ZMYND8 protein Q9ULU4 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 29018219 YES lperfetto ZMYND8 and BRD2 therefore work together to protect H4Ac domains from HDAC activity.|Further, when BRD2 was depleted, ZMYND8 accumulation was lost (Fig. 2e), indicating that either BRD2, or the underlying H4Ac, is required for ZMYND8 loading. 0.287 SIGNOR-262036 PTPRK protein Q15262 UNIPROT EGFR protein P00533 UNIPROT unknown dephosphorylation Tyr1092 TFLPVPEyINQSVPK 10029 BTO:0000246 16263724 YES RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro. 0.616 SIGNOR-248722 GDF5 protein P43026 UNIPROT Cartilage_development phenotype SIGNOR-PH75 SIGNOR up-regulates 9606 21976273 NO miannu Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. 0.7 SIGNOR-252418 EEF1A2 protein Q05639 UNIPROT Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269527 GSK3B protein P49841 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by stabilization phosphorylation Ser160 KRPATDDsSTQNKRA 9606 21439087 YES miannu GSK-3\u03b2 phosphorylates p27 Kip1 at S160 and S161, resulting in increased p27 Kip1 stability [ xref ]. 0.389 SIGNOR-278938 GSK3B protein P49841 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by stabilization phosphorylation Ser161 RPATDDSsTQNKRAN 9606 21439087 YES miannu GSK-3\u03b2 phosphorylates p27 Kip1 at S160 and S161, resulting in increased p27 Kip1 stability [ xref ]. 0.389 SIGNOR-278939 MID1 protein O15344 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0004725 11685209 YES miannu MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation 0.454 SIGNOR-271467 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 YES miannu AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively.  0.254 SIGNOR-277894 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation 9606 21902831 YES lperfetto As a permissive environment is created at these loci, p38 further stimulates gene expression through the phosphorylation of additional myogenic transcription factors, including mef2c and e47. 0.695 SIGNOR-176551 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 YES flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. 0.36 SIGNOR-75938 ACAN protein P16112 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 10922468 YES lperfetto Degradation of aggrecan, the major proteoglycan of the cartilage ECM responsible for the load-bearing and elastic properties of this tissue, is one of the earliest detectable events in arthritic cartilage degeneration. MMPs have been implicated in proteolysis and the subsequent loss of aggrecan from cartilage during arthritis 0.7 SIGNOR-266982 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser482 SSMQPDNsSDSDYDL 9606 9834084 YES lperfetto In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461) 0.343 SIGNOR-62303 PRKCA protein P17252 UNIPROT DNM1 protein Q05193 UNIPROT unknown phosphorylation Ser795 VPPARPGsRGPAPGP -1 10766777 YES lperfetto Phosphorylation of dynamin I on Ser-795 by protein kinase C blocks its association with phospholipids. 0.334 SIGNOR-249039 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by stabilization deacetylation Lys594 KEVEDIEkYLEDQVN 9606 BTO:0000007 21726808 YES lperfetto Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 0.426 SIGNOR-267602 ARHGAP23 protein Q9P227 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.428 SIGNOR-260480 EGFR protein P00533 UNIPROT LYN protein P07948 UNIPROT up-regulates activity phosphorylation Tyr32 RNTERTIyVRDPTSN 9606 23764002 YES miannu EGFR phosphorylates p56 Lyn at Y32.|In the presence of EGFR, p56 Lyn -mediated MCM7 phosphorylation was significantly augmented, suggesting that EGFR signaling potentiates p56 Lyn kinase activity for MCM7 phosphorylation. 0.585 SIGNOR-279369 ASTN2 protein O75129 UNIPROT ASTN1 protein O14525 UNIPROT down-regulates quantity binding 9606 BTO:0000007 20573900 YES miannu Biochemical and flow cytometry experiments show that ASTN2 forms a complex with ASTN1 and regulates surface expression of ASTN1. Coexpression with ASTN2 reduces the cell surface localization of ASTN1. 0.2 SIGNOR-269813 PRKCA protein P17252 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates phosphorylation Ser132 GGDAPSPsKRPWARQ 9606 18710826 YES tpavlidou Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity. 0.363 SIGNOR-180199 RELA protein Q04206 UNIPROT B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 NO miannu The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m. 0.262 SIGNOR-254657 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CAD protein P27708 UNIPROT up-regulates phosphorylation 9606 15890648 YES inferred from 70% family members lperfetto Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol 0.2 SIGNOR-269998 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TCF3 protein P15923 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 BTO:0000944 14592976 YES inferred from 70% family members lperfetto Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG) 0.2 SIGNOR-270009 SRC protein P12931 UNIPROT RRAS protein P10301 UNIPROT down-regulates activity phosphorylation Tyr66 DPTIEDSyTKICSVD 9606 BTO:0000007 11682467 YES lperfetto The small gtpase, r-ras, affects cell adhesion by maintaining integrin activity. Activated src oncogene phosphorylates r-ras and suppresses integrin activity. the src phosphorylation site in r-ras was tyrosine 66 0.579 SIGNOR-111189 IL6 protein P05231 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 NO lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS 0.7 SIGNOR-260256 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser249 LSPIDMEsQERIKAE 9606 1846781 YES lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. 0.331 SIGNOR-21780 LYN protein P07948 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation 9606 30104977 YES miannu Lyn phosphorylates and activates Syk and LAT. 0.609 SIGNOR-279415 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates activity binding 9606 BTO:0000222 16982699 YES lperfetto More importantly, the consequences of phosphorylation of either Thr145 or Ser146 are distinct. When p21 is phosphorylated on Thr145, it localizes to the nucleus and results in the disruption of the association between proliferating cell nuclear antigen and p21. Furthermore, phosphorylation of Thr145 promotes stabilization of p21 0.2 SIGNOR-244187 EVL protein Q9UI08 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 NO miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. 0.7 SIGNOR-268391 PRKCZ protein Q05513 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 15381704 YES The effect has been demonstrated using P28329-3 gcesareni Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity. 0.289 SIGNOR-129340 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 YES lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.469 SIGNOR-169534 GSTA1 protein P08263 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000018 29928434 NO irozzo Accordingly, downregulation of GSTA1 suppressed tumor growth. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line. 0.7 SIGNOR-256296 RPS6KA1 protein Q15418 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 YES lperfetto In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway 0.316 SIGNOR-178586 AKT proteinfamily SIGNOR-PF24 SIGNOR BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 9606 BTO:0001033 22505453 YES lperfetto The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate 0.2 SIGNOR-249581 ADNP protein Q9H2P0 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR form complex binding 10090 BTO:0002896 29795351 YES miannu Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. we have discovered ChAHP, a gene-regulatory complex that consists of the chromatin remodeller CHD4, the DNA-binding factor ADNP, and the heterochromatin proteins HP1β and HP1γ. By locally restricting access to DNA, ChAHP prevents endodermal gene transcription in mouse ES cells and during neuroectodermal differentiation. 0.296 SIGNOR-266751 HIC1 protein Q14526 UNIPROT EFNA1 protein P20827 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20154726 NO miannu we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers. 0.36 SIGNOR-254240 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-119366 SIAH1 protein Q8IUQ4 UNIPROT JADE1 protein Q6IE81 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23001567 YES miannu Siah-1 decreases Jade-1 abundance and enhances Jade-1 ubiquitination 0.292 SIGNOR-272915 CLOCK protein O15516 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.944 SIGNOR-253631 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12151396 YES gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. 0.341 SIGNOR-91067 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates activity 9606 23685857 NO Tumor necrosis factor α (TNF-α, also known as cachectin) is a strong pro-inflammatory cytokine which plays an important role in the immune system during inflammation, cell proliferation, differentiation and apoptosis 0.7 SIGNOR-258988 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.755 SIGNOR-273924 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. 0.64 SIGNOR-164412 NRP1 protein O14786 UNIPROT PHACTR1 protein Q9C0D0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21939755 NO miannu Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect. 0.2 SIGNOR-260061 EDA protein Q92838 UNIPROT EDAR protein Q9UNE0 UNIPROT up-regulates binding 9606 18304980 YES gcesareni Ultimately, in mammals, eda-a1 and eda-a2 trimers each bind a different receptor, edar and xedar, respectively, through their trimerized tnf domain. 0.75 SIGNOR-161109 CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.405 SIGNOR-261749 CDK2 protein P24941 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 12435275 YES gcesareni Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase. 0.296 SIGNOR-95578 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19114991 YES lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity 0.757 SIGNOR-182822 PRKG1 protein Q13976 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates activity phosphorylation Ser1105 LDRKRHNsISEAKMR 10116 BTO:0004576 11278298 YES lperfetto PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG. 0.538 SIGNOR-249077 PIM1 protein P11309 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates quantity by stabilization phosphorylation Thr455 LAMSPLPtAETPKPL 9606 BTO:0002181 34211090 YES miannu PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. 0.2 SIGNOR-277311 COX5B protein P10606 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 BTO:0000165 18701479 NO lperfetto Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS. 0.7 SIGNOR-253104 CDK2 protein P24941 UNIPROT COIL protein P38432 UNIPROT up-regulates phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 SIGNOR-C16 11102515 YES lperfetto In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1_248) was observed 0.382 SIGNOR-84949 HIPK2 protein Q9H2X6 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 21715331 YES lperfetto Homeodomain-interacting protein kinase-2 stabilizes p27(kip1) by its phosphorylation at serine 10 and contributes to cell motility 0.254 SIGNOR-174617 ELK1 protein P19419 UNIPROT PRKCA protein P17252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16297876 NO irozzo We demonstrated that both Elk-1 and MZF-1 were highly expressed in human poor differentiated HCC cells and involved in the up-regulation of PKCa, which was essential for cell migration and invasion. Over-expression assay confirmed that the PKCa expression may be modulated by these two factors at the transcriptional level. 0.44 SIGNOR-256282 gemcitabine chemical CHEBI:175901 ChEBI RRM1 protein P23921 UNIPROT down-regulates activity chemical inhibition -1 2233693 YES miannu Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase. 0.8 SIGNOR-258386 AURKB protein Q96GD4 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity phosphorylation Ser404 KYGEGNWsKILLHYK -1 29040668 YES miannu Our data indicate that AURKB can phosphorylate the integral telomere DNA-binding Shelterin protein TERF1 at S404 (within the DNA-binding domain) in vitro . 0.366 SIGNOR-279440 GH1 protein P01241 UNIPROT GHR protein P10912 UNIPROT up-regulates activity binding 9606 7862673 YES miannu Although growth hormone (GH) receptors (GHRs) in many species bind human (h) GH as well as their own GH, the hGHR only binds primate GH. 0.859 SIGNOR-255451 CHUK protein O15111 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Ser201 KPPDEGPsEYQTIPL -1 31950832 YES lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. 0.325 SIGNOR-275507 TGFA protein P01135 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252281 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr839 DTQGRNStPLHLAAG 9606 BTO:0000567 21818122 YES miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  0.428 SIGNOR-276245 PFDN5 protein Q99471 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 YES miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) 0.965 SIGNOR-270934 CASP3 protein P42574 UNIPROT GSN protein P06396 UNIPROT down-regulates activity cleavage Asp403 WRDPDQTdGLGLSYL 9606 9671712 YES miannu We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death. 0.638 SIGNOR-256357 MAPK1 protein P28482 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr245 GFGTSPLtPSARISA -1 12556484 YES done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites 0.287 SIGNOR-274075 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258460 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2274 KNREGLNyMVLATEC 9606 11266449 YES gcesareni Phosphorylated ros strongly and directly associates with shp-1.Overexpression Of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation 0.368 SIGNOR-105919 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 9606 BTO:0000801 10973958 NO lperfetto NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters. 0.331 SIGNOR-249554 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 9606 16293724 YES lperfetto We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. 0.541 SIGNOR-227952 INTS13 protein Q9NVM9 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.2 SIGNOR-261469 BAG6 protein P46379 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation 9606 BTO:0000007 21726808 YES lperfetto These results indicate that BAT3 and P300 can both exist in the PEPCK1 protein complex, suggesting the possibility that BAT3 could be an enhancer of PEPCK1 acetylation. | indicating a synergistic effect of BAT3 and P300 to promote PEPCK1 acetylation. 0.34 SIGNOR-267598 bisphenol A chemical CHEBI:33216 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 31995776 YES miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 0.8 SIGNOR-268732 PDE6G protein P18545 UNIPROT PDE6A protein P16499 UNIPROT down-regulates activity binding 9606 20940301 YES Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B 0.866 SIGNOR-260010 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr280 VEFMCKVySDPQPHI 9606 12601080 YES lperfetto Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways. 0.2 SIGNOR-98626 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by stabilization phosphorylation Thr305 IDYGKVAtQCTCRKD 9606 BTO:0001109 28945223 YES miannu In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.  0.2 SIGNOR-276741 hsa-miR-29c-5p mirna URS0000497496_9606 RNAcentral PTP4A1 protein Q93096 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000675 25193986 YES Parnian These data provide evidence that PTP4A1 and GNA13 are direct targets of miR-29c, and that their expression is negatively regulated by miR-29c in CRC cells. | miR-29c directly targets PTP4A1 and GNA13 3'-UTR. 0.4 SIGNOR-278025 Riluzole chemical CHEBI:8863 ChEBI KCNN2 protein Q9H2S1 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 YES Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  0.8 SIGNOR-258020 IGF1R protein P08069 UNIPROT PIK3C2A protein O00443 UNIPROT up-regulates phosphorylation 9606 7692086 YES gcesareni Analysis of the ability of the full-length igfr and its mutant receptors described above to associate with phosphatidylinositol 3 kinase indicated that the association required ptk activity and tyrosine [?] Phosphorylation of the receptors and correlated well with their transforming activities 0.275 SIGNOR-32076 ETV3 protein P41162 UNIPROT DDX20 protein Q9UHI6 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22028472 YES miannu ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation. 0.738 SIGNOR-262779 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 1396585 YES llicata These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021. 0.2 SIGNOR-18579 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR CDT1 protein Q9H211 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 14578910 YES miannu We show that radiation-mediated CDT1 proteolysis is independent of ATM and CHK2 and can occur in G1-phase cells. Loss of the COP9-signalosome (CSN) or CUL4-ROC1 complexes completely suppresses CDT1 proteolysis. CDT1 is specifically polyubiquitinated by CUL4 complexes and the interaction between CDT1 and CUL4 is regulated in part by gamma-irradiation. Our study reveals an evolutionarily conserved and uncharacterized G1 checkpoint that induces CDT1 proteolysis by the CUL4-ROC1 ubiquitin E3 ligase and CSN complexes in response to DNA damage. 0.517 SIGNOR-272810 FOXO3 protein O43524 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 YES miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. 0.248 SIGNOR-260089 INSR protein P06213 UNIPROT CALM2 protein P0DP24 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 YES miannu The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. 0.352 SIGNOR-266320 STAP1 protein Q9ULZ2 UNIPROT KIT protein P10721 UNIPROT up-regulates activity binding 9606 BTO:0000007 10679268 YES miannu STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells. 0.506 SIGNOR-261822 MRPS23 protein Q9Y3D9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.686 SIGNOR-261435 CTNNA1 protein P35221 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23431053 YES milica The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. 0.353 SIGNOR-201173 RNF8 protein O76064 UNIPROT RAD18 protein Q9NS91 UNIPROT up-regulates binding 9606 19396164 YES gcesareni Rnf8 depletion also significantly reduced the accumulation of rad18 to chromatin fraction after ir 0.415 SIGNOR-185593 GSK3B protein P49841 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity phosphorylation 9606 17786208 YES miannu Collectively, these data demonstrate that the kinase activity of GSK-3beta suppresses the Runx2 transcriptional activity.|In vitro kinase assay confirmed that the Runx2 phosphorylation by GSK-3\u03b2 was reduced by the S369-S373-S377 mutation ( xref ). 0.302 SIGNOR-279051 CDR2 protein Q01850 UNIPROT AURKA protein O14965 UNIPROT up-regulates quantity by expression transcriptional regulation 20383333 NO lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology 0.2 SIGNOR-252023 CDK1 protein P06493 UNIPROT MORC2 protein Q9Y6X9 UNIPROT down-regulates quantity by destabilization phosphorylation Thr717 PSPKVIKtPVVKKTE 9606 BTO:0000567 36967563 YES miannu Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation. 0.2 SIGNOR-277837 PCGF2 protein P35227 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 YES miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b 0.777 SIGNOR-266813 SP1 protein P08047 UNIPROT TNC protein P24821 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452 15001984 YES Luana Sp1 and Ets1 are potent transactivators of the TN-C promoter. 0.2 SIGNOR-261600 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 YES gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. 0.636 SIGNOR-181327 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr576 NSCRSSTtTCPEQDF 9606 BTO:0000007 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249300 Laminin-1 complex SIGNOR-C183 SIGNOR A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9361014 YES lperfetto Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI. 0.545 SIGNOR-253255 asparagine smallmolecule CHEBI:22653 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270468 MDM2 protein Q00987 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity binding 9606 17700533 YES miannu Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. 0.837 SIGNOR-255470 CSNK2A1 protein P68400 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates phosphorylation Ser1364 DDLNNYDsDDQEKQS 9606 20664522 YES lperfetto Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis 0.293 SIGNOR-167168 NFIA protein Q12857 UNIPROT GAS6 protein Q14393 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268876 TWIST1 protein Q15672 UNIPROT MYB protein P10242 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.246 SIGNOR-255529 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2G2 protein P60604 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.721 SIGNOR-271310 Diprenorphine chemical CHEBI:4650 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.8 SIGNOR-258662 AKT proteinfamily SIGNOR-PF24 SIGNOR ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 YES llicata Akt phosphorylates s554 in acap1 0.2 SIGNOR-141343 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 YES Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. 0.91 SIGNOR-252838 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.8 SIGNOR-270440 SREBF2 protein Q12772 UNIPROT HMGCR protein P04035 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000759 31848472 YES miannu The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription 0.493 SIGNOR-265161 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser434 PPPSDAGsPFQSSPL 9606 BTO:0000007 19126544 YES lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. 0.486 SIGNOR-235797 MAPK3 protein P27361 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation Ser167 FLISPPAsPPVGWKQ 10090 BTO:0000165 12063245 YES lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 0.381 SIGNOR-249478 AHR protein P35869 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR form complex binding -1 9020169 YES 2 miannu SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix·PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. SIM1 inhibits binding of the AHR·ARNT dimer to the xenobiotic response element in vitro Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR·ARNT dimer. 0.754 SIGNOR-240817 POMC protein P01189 UNIPROT MC3R protein P41968 UNIPROT up-regulates activity binding BTO:0000614 17702843 YES lperfetto Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases. 0.758 SIGNOR-253073 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation 6239 SIGNOR-C15 17900900 YES lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. 0.517 SIGNOR-252983 FASN protein P49327 UNIPROT hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity chemical modification 9606 12689621 YES An organizational model for animal FAS was proposed in which the two subunits depicted in domains I, II, and III were arranged in an antiparallel fashion, thereby generating two sites for palmitate synthesis. Initiation of the series of condensation reactions leading to the production of palmitic acid requires the translocation of one acetyl and seven malonyl moieties, from CoA thioester to the phosphopantetheine thiol of the ACP domain. 0.8 SIGNOR-267373 FBXW11 protein Q9UKB1 UNIPROT BTRC protein Q9Y297 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002419 31406304 YES miannu Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1.  0.59 SIGNOR-277476 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser129 PYPSPVLsEEEDLPL 9606 10618498 YES lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability 0.43 SIGNOR-73879 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr443 REHPYGRy 9606 BTO:0000567 16179349 YES lperfetto We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. 0.747 SIGNOR-249292 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR -1 12432067 YES miannu Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146 0.307 SIGNOR-250074 ECM stimulus SIGNOR-ST20 SIGNOR AX/b2 integrin complex SIGNOR-C171 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259053 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates 10090 BTO:0002314 22045613 NO gcesareni Notch signaling is active in quiescent SCs. SC-specific deletion of recombining binding protein-J (RBP-J), a nuclear factor required for Notch signaling, resulted in the depletion of the SC pool and muscles that lacked any ability to regenerate in response to injury. 0.7 SIGNOR-244004 IL15RA protein Q13261 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 30029643 YES Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 0.5 SIGNOR-256226 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT up-regulates activity phosphorylation Tyr199 RKGQRDLySGLNQRR 9534 11855827 YES Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways. 0.691 SIGNOR-251369 lenalidomide chemical CHEBI:63791 ChEBI IKZF3 protein Q9UKT9 UNIPROT down-regulates quantity by destabilization chemical inhibition 9606 24328678 YES gcesareni Members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3 respectively), are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment. 0.8 SIGNOR-236925 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 10581258 YES lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.772 SIGNOR-72703 CDK14 protein O94921 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1490 AILNPPPsPATERSH 9606 20059949 YES gcesareni Low-density lipoprotein receptor related proteins 5 and 6 (lrp5/6) are transmembrane receptors that initiate wnt/beta-catenin signaling. Phosphorylation of pppsp motifs in the lrp6 cytoplasmic domain is crucial for signal transduction. Using a kinome-wide rnai screen, we show that pppsp phosphorylation requires the drosophila cyclin-dependent kinase (cdk) l63. L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6. 0.333 SIGNOR-162924 GRIP1 protein Q9Y3R0 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 YES gcesareni The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis. 0.401 SIGNOR-83883 ABL1 protein P00519 UNIPROT GMNN protein O75496 UNIPROT up-regulates activity phosphorylation Tyr150 EVAEHVQyMAELIER 9606 24789045 YES miannu Taken together, suggests that c-Abl binds and phosphorylates geminin on Y150 in G2/M/early G1 phases. 0.355 SIGNOR-278505 GATA1 protein P15976 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004475 19825991 NO miannu Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. 0.403 SIGNOR-254189 SNTB1 protein Q13884 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding BTO:0001103 29681515 YES apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated 0.503 SIGNOR-255979 DTX1 protein Q86Y01 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16554461 NO gcesareni Notch1-induced erbb2 expression in cerebellar astroglia occurs via dtx1 0.2 SIGNOR-145319 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser181 RAKGPSEsSKERNTP -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.321 SIGNOR-273966 VAV2 protein P52735 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10618391 YES tpavlidou Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo. 0.593 SIGNOR-73874 (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity precursor of 9606 32439610 YES lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 0.8 SIGNOR-268225 USP5 protein P45974 UNIPROT UBC protein P0CG48 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.846 SIGNOR-270822 HAUS3 protein Q68CZ6 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 YES lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) 0.675 SIGNOR-262322 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 10482988 YES miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. 0.445 SIGNOR-251146 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 YES inferred from 70% family members gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity. 0.2 SIGNOR-270204 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Thr309 SDGATMKtFCGTPEY 9606 15743829 YES lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation. 0.731 SIGNOR-134485 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr210 LSASTVLtAQESFSG -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276219 MAPK14 protein Q16539 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser347 FTGLKCPsLAGKPKV 9606 BTO:0000130 14970175 YES amattioni P38-mapk can directly phosphorylate and inhibit the activities of caspase-8 0.551 SIGNOR-122103 GXYLT1 protein Q4G148 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22117070 YES gcesareni We have previously identified two human genes, gxylt1 and gxylt2, encoding glucoside xylosyltransferases responsible for the transfer of xylose to o-linked glucose. The identity of the enzyme further elongating the glycan to generate the final trisaccharide xylose-xylose-glucose, however, remained unknown. Here, we describe that the human gene c3orf21 encodes a udp-xylose:alfa-xyloside alfa1,3-xylosyltransferase, acting on xylose-alfa1,3-glucosebeta1-containing acceptor structures. We have, therefore, renamed it xxylt1 (xyloside xylosyltransferase 1). Xxylt1 cannot act on a synthetic acceptor containing an alfa-linked xylose alone, but requires the presence of the underlying glucose. Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. The enzyme was shown to be a typical type ii membrane-bound glycosyltransferase localized in the endoplasmic reticulum. 0.337 SIGNOR-177694 CTNNB1 protein P35222 UNIPROT KLF4 protein O43474 UNIPROT up-regulates activity binding 10090 24482235 YES flangone The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes. 0.685 SIGNOR-242100 SCNN1G protein P51170 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 26772908 YES miannu The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. 0.8 SIGNOR-269277 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 YES gcesareni Rsk1/2 phosphorylates the transcription factor c-fos on s362 and increases its activity. 0.392 SIGNOR-37216 MARCHF5 protein Q9NX47 UNIPROT FIS1 protein Q9Y3D6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 16874301 YES Barakat MITOL associates with and ubiquitinates mitochondrial fission protein hFis1. (A) Ubiquitination of hFis1 by MITOL. Thus, MITOL may control the protein expression level of hFis1 through the ubiquitin‚Äìproteasome pathway. 0.2 SIGNOR-274141 OXTR protein P30559 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256936 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser44 ESEESQDsSDSIGSS 9606 20730097 YES lperfetto These data suggested that atf1 is always hyperphosphorylated on the ck sites in vivo. Also, the antibody reactivity suggested that in addition to ser-36 and ser-41, ser-38 and ser-44 were phosphorylated in vivo. To accommodate these findings, we propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. 0.297 SIGNOR-167556 cytidine smallmolecule CHEBI:17562 ChEBI cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity precursor of 11306702 YES lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 0.8 SIGNOR-275857 4-[4-(2-fluorophenyl)phenyl]-N-(4-hydroxyphenyl)butanamide chemical CHEBI:92949 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 15362850 YES gcesareni In steady-state kinetics experiments, cmpd1 was observed to prevent the p38alpha-dependent phosphorylation (k(i)(app) = 330 nm) of the splice variant of mitogen-activated protein kinase-activated protein kinase 2 (mk2a) that contains a docking domain for p38alpha and p38beta 0.8 SIGNOR-128864 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu61 EFVQGNLeRECMEEK 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263688 USP7 protein Q93009 UNIPROT MDM4 protein O15151 UNIPROT up-regulates deubiquitination 9606 16082221 YES gcesareni Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins. 0.756 SIGNOR-139453 PHLPP2 protein Q6ZVD8 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 18162466 YES These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms, 0.329 SIGNOR-248727 G6PC3 protein Q9BUM1 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266570 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser369 AKKAKADsPVNGLPK 9534 BTO:0000298 14623875 YES llicata DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase. 0.573 SIGNOR-251089 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 23070005 YES miannu For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling. 0.925 SIGNOR-199091 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide chemical CHEBI:49868 ChEBI PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190281 MAPK1 protein P28482 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser21 LEAGDLEsPLSEEFL 9606 BTO:0000599 10187842 YES lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. 0.576 SIGNOR-249434 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.41 SIGNOR-249678 SPRY2 protein O43597 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates 9606 12414790 NO gcesareni Therefore, we conclude that an increase in soluble ptp1b activity contributes to the anti-migratory, but not anti-mitogenic, actions of hspry2. 0.449 SIGNOR-95313 PRKCE protein Q02156 UNIPROT ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr202 KLGPALAtGNVVVMK -1 28056995 YES lperfetto Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. 0.281 SIGNOR-271865 BBS5 protein Q8N3I7 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 YES lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 0.88 SIGNOR-262559 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser487 AQLAGSDsDLDSDDE 9606 23263282 YES lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) 0.2 SIGNOR-200202 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser196 EKSPSVCsPLNMTSS 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.35 SIGNOR-276102 PINK1 protein Q9BXM7 UNIPROT TUFM protein P49411 UNIPROT down-regulates activity phosphorylation Ser219 ETPVIVGsALCALEG 9606 BTO:0000567 33113344 YES miannu PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy. 0.2 SIGNOR-266382 PPP1CB protein P62140 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 YES Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. 0.286 SIGNOR-248572 MAP3K8 protein P41279 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 BTO:0000567 12207013 YES miannu Xplkk1 phosphorylates and activates mammalian plk / xplkk1 phosphorylates thr-210 0.2 SIGNOR-92274 NMBR protein P28336 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257315 regorafenib chemical CHEBI:68647 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259209 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176833 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.765 SIGNOR-252742 GAD2 protein Q05329 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 32041144 YES miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. 0.8 SIGNOR-267554 BECN1 protein Q14457 UNIPROT USP10 protein Q14694 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0003704 21962518 YES lperfetto Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities. 0.507 SIGNOR-260298 POU5F1 protein Q01860 UNIPROT SOX2/POU5F1 complex SIGNOR-C73 SIGNOR form complex binding 9606 7590241 YES miannu Sox2 can form a ternary complex with either the ubiquitous oct-1 or the embryonic-specific oct-3 protein on fgf-4 enhancer dna sequences. However, only the sox2/oct-3 complex is able to promote transcriptional activation. 0.839 SIGNOR-29509 TRAF6 protein Q9Y4K3 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates polyubiquitination 9606 20047764 YES miannu Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1 0.83 SIGNOR-271428 TNIK protein Q9UKE5 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates phosphorylation Ser177 QALKDARsPSPAHIV 9606 BTO:0000586 20530691 YES llicata Here, we report that tnik is an activating kinase for tcf4 and essential for colorectal cancer growth. Tnik, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of tcf4. 0.554 SIGNOR-165946 SCN5A protein Q14524 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 NO miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. 0.7 SIGNOR-253447 BUB1 protein O43683 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity relocalization 11402067 YES lperfetto Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity 0.83 SIGNOR-252016 Galanin smallmolecule CHEBI:80161 ChEBI GALR1 protein P47211 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257494 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr647 RDVHNLDyYKKTTNG 9606 BTO:0000007 11294897 YES lperfetto Ligand stimulation leads to autophosphorylation of fgfr3 the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3. 0.2 SIGNOR-106730 Ub:E2 complex SIGNOR-C497 SIGNOR PDZRN3 protein Q9UPQ7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271069 USF1 protein P22415 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28624438 YES miannu The promoter region of ADAM10 contains several transcription factor binding sites that can stimulate its transcription. These include binding sites for transcription factors SP1 and USF, and the spliced form of the X-box binding protein (XBP)-1 as well as a retinoic acid-responsive element 0.27 SIGNOR-259837 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Ala36 PESKATNaTLDPRSF -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus 0.431 SIGNOR-263565 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation Thr155 SHAVHPLtPLITYSD 9606 12556497 YES gcesareni Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. 0.759 SIGNOR-97812 MMP23B protein O75900 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272367 ERCC3 protein P19447 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 YES lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.889 SIGNOR-269313 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates phosphorylation Tyr531 HEEDADSyENMDNPD 9606 10933394 YES llicata Experiments with purified proteins demonstrated that cd19-y513 was lyn's initial phosphorylation and binding site. This led to processive phosphorylation of cd19-y482, which recruited a second lyn molecule, allowing for transphosphorylation and amplification of lyn activation. 0.772 SIGNOR-80294 H4C1 protein P62805 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 YES miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. 0.2 SIGNOR-263712 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser394 EDAVHEDsGDEDGED 9606 BTO:0000567 12082111 YES llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. 0.39 SIGNOR-251001 E2F1 protein Q01094 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.496 SIGNOR-253855 PRKCA protein P17252 UNIPROT GJB1 protein P08034 UNIPROT up-regulates activity phosphorylation Ser229 QRRSNPPsRKGSGFG -1 8390988 YES lperfetto Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b). 0.362 SIGNOR-248919 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 BTO:0000801;BTO:0000876 17658244 YES gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. 0.2 SIGNOR-157093 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus 0.811 SIGNOR-235385 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 12110590 YES inferred from 70% family members gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. 0.2 SIGNOR-270073 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Thr269 GGKRSRLtPVSPESS 9606 BTO:0000551 20974803 YES lperfetto Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. 0.349 SIGNOR-216936 WNT4 protein P56705 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.648 SIGNOR-131832 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2516 FLTPSPEsPDQWSSS -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.551 SIGNOR-273177 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Ala86 PLQKQLPaFISEDAS -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.431 SIGNOR-263566 TBCA protein O75347 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 28158450 YES miannu These intermediates interact with a series of five tubulin-specific chaperones (termed TBCA-E); these function together as a nanomachine that assembles the α/β tubulin heterodimer 0.2 SIGNOR-261169 GRK3 protein P35626 UNIPROT TBXA2R protein P21731-2 UNIPROT down-regulates activity phosphorylation Ser239 AQQRPRDsEVEMMAQ 9606 16956790 YES done miannu  These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization. 0.2 SIGNOR-274090 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr102 RAAMFPEtLDEGMQI -1 12432063 YES miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  0.555 SIGNOR-275996 MAPK14 protein Q16539 UNIPROT MAPKAPK3 protein Q16644 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 11157753 YES lperfetto These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38. 0.713 SIGNOR-235451 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. 0.91 SIGNOR-252831 PRKCE protein Q02156 UNIPROT NLRP5 protein P59047 UNIPROT up-regulates activity phosphorylation Ser331 MQRKKESsVTEFISR 9606 BTO:0000007 19542546 YES miannu MATER protein as substrate of PKCepsilon in human cumulus cells. we performed coimmunoprecipitation experiments using HEK293T cells expressing human MATER; a similar approach was then followed in human cumulus/follicular cells. In MATER(+)HEK293T cells, we observed that this protein acts as a phosphorylation substrate of PKCepsilon. Since PKCepsilon is known to collaborate with antiapoptotic signalling pathways, this suggests a novel mechanism for the function of MATER in follicular maturation. 0.2 SIGNOR-263175 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser249 AVIPINGsPRTPRRG 9606 15809340 YES gcesareni Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively. 0.929 SIGNOR-135181 DLG5 protein Q8TDM6 UNIPROT Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.31 SIGNOR-270901 HOXB6 protein P17509 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15269212 YES Luana HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion. 0.2 SIGNOR-261638 CKMT2 protein P17540 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265789 FGFR1 protein P11362 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT up-regulates activity phosphorylation Tyr107 KGEELPTyEEAKAHS 9606 BTO:0000007 21937427 YES lperfetto These data support an idea that Amotl2 Tyr-103 can be phosphorylated by FGF receptor tyrosine kinase activity. We then determined whether Amotl2 Tyr-103 is required for its interaction with c-Src. |Amotl2 promotes MAPK/ERK activation via c-Src, which is dependent on phosphorylation of tyrosine residue at position 103 but independent of the C-terminal PDZ-binding domain. 0.2 SIGNOR-271869 Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT Alamandine chemical CID:44192273 PUBCHEM up-regulates activity catalytic activity -1 24389733 YES Luana Newly discovered peptide, alamandine, have been identified. Alamandine is generated by catalysis of Ang A via ACE2 or directly from Ang-(1–7). 0.8 SIGNOR-262307 CUDC-101 chemical CID:24756910 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262256 MVD protein P53602 UNIPROT KRAS protein P01116 UNIPROT up-regulates quantity by stabilization 9534 12646231 NO miannu An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B) 0.2 SIGNOR-265887 AGTR1 protein P30556 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.497 SIGNOR-257223 TFE3 protein P19532 UNIPROT PIP4P1 protein Q86T03 UNIPROT up-regulates quantity by expression transcriptional regulation 29146937 NO lperfetto TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes 0.2 SIGNOR-276806 FAM83H protein Q6ZRV2 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.388 SIGNOR-273747 SMAD5 protein Q99717 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR form complex binding 9606 BTO:0000165;BTO:0002974; BTO:0002809 9442019 YES ggiuliani These data suggest that activation of Smad5 and subsequent Smad5-DPC4 complex formation are key steps in the BMP signaling pathway, which mediates BMP-2-induced osteoblastic differentiation of the C2C12 mesenchymal cells. 0.674 SIGNOR-255775 FFAR1 protein O14842 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257338 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NOS2 protein P35228 UNIPROT up-regulates transcriptional regulation BTO:0001103 20219869 NO Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. 0.453 SIGNOR-256250 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCGR1A protein P12314 UNIPROT up-regulates activity 9606 BTO:0000801 18064051 NO lperfetto Immune complexes bind to activating Fc receptors (FcR) and inhibitory FcRs that are expressed by innate immune effector cells such as basophils, mast cells, neutrophils, monocytes and macrophages, in which they trigger the indicated effector responses. 0.7 SIGNOR-249521 ANXA1 protein P04083 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 27426034 NO miannu Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups 0.377 SIGNOR-261940 IGF1 protein P05019 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 BTO:0000150;BTO:0000680 16039586 YES lperfetto Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. This pathway is a general signal, as it was also observed in cell lines in which erk-primed inactivation of gsk-3beta was regulated by igf-1, tgf-beta, and receptor tyrosine kinase her2 0.336 SIGNOR-227948 STUB1 protein Q9UNE7 UNIPROT FMR1 protein Q06787 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25268320 YES miannu The results showed that FMR1 was ubiquitinated by CHIP WT or CHIP K30A. Also, ubiquitinated FMR1 accumulated in the presence of MG132, indicating that CHIP ubiquitinates FMR1 for proteasomal degradation ( Fig. 3 B). 0.388 SIGNOR-278599 SP3 protein Q02447 UNIPROT SLC9A3 protein P48764 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 16464174 NO Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity 0.2 SIGNOR-254271 FYN protein P06241 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 16938345 YES gcesareni Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk. 0.748 SIGNOR-148931 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr751 SKDESVDyVPMLDMK -1 7545675 YES Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides 0.749 SIGNOR-248668 PPARGC1A protein Q9UBK2 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001103 17609368 NO lperfetto Furthermore, ampk directly phosphorylates pgc-1?, And this phosphorylation mediates an increase in pgc-1? Protein action on the pgc-1? Promoter. 0.2 SIGNOR-156783 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 YES The activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. 0.2 SIGNOR-252926 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr511 SKLQNLSyTEILKIR 9606 15952790 YES llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. 0.605 SIGNOR-138154 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2S protein Q16763 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.644 SIGNOR-271343 PRKCD protein Q05655 UNIPROT VRK1 protein Q99986 UNIPROT down-regulates activity phosphorylation Thr355 GLKAKTItKKRKKEI 9606 21346188 YES miannu PKC\u03b4 phosphorylates VRK1 on Ser-355 in vitro.|PKCdelta negatively regulates VRK1 kinase activity in vitro. 0.285 SIGNOR-278219 HOXA7 protein P31268 UNIPROT IVL protein P07476 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 11435435 NO miannu Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. 0.2 SIGNOR-254473 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 YES lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. 0.744 SIGNOR-236116 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 YES miannu JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein. 0.339 SIGNOR-250081 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation 9606 17396146 YES gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. 0.418 SIGNOR-154178 AKT proteinfamily SIGNOR-PF24 SIGNOR CDCA7 protein Q9BWT1 UNIPROT down-regulates phosphorylation Thr163 SRRPRRRtFPGVASR 9606 23166294 YES llicata The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus. 0.2 SIGNOR-199776 PRKD1 protein Q15139 UNIPROT DLC1 protein Q96QB1 UNIPROT down-regulates phosphorylation Ser1244 NTLKRENsSPRVMQR 9606 21087603 YES gcesareni The tumor suppressor protein dlc1 is regulated by pkd-mediated gap domain phosphorylation.Our results thus show that pkd-mediated phosphorylation of dlc1 on serine 807 negatively regulates dlc1 cellular function. 0.372 SIGNOR-169994 KU-55933 chemical CID:5278396 PUBCHEM ATM protein Q13315 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 28341201 YES miannu KU-55933 blocked phosphorylation of ATM in H2O2 and Dox models of cell damage. the neuroprotective efficacy of KU-55933, a potent inhibitor of ATM, against cell damage evoked by oxidative stress (hydrogen peroxide, H2O2) has been studied in human neuroblastoma SH-SY5Y cells and compared with the efficacy of this agent in models of doxorubicin (Dox)- and staurosporine (St)-evoked cell death. 0.8 SIGNOR-262536 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser110 SFSEQTRsLDGRLQV 9606 SIGNOR-C8 11027280 YES gcesareni Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgf-beta-dependent smad2-smad3 interactions. 0.548 SIGNOR-82966 CLU protein P10909 UNIPROT LRP2 protein P98164 UNIPROT up-regulates quantity binding 10090 32332780 YES miannu Our results demonstrate that circulating ApoJ is retained in muscle via LRP2 and that LRP2 signaling could play a role in the maintenance of ApoJ homeostasis in circulation, at least in part. 0.561 SIGNOR-265256 ARHGAP12 protein Q8IWW6 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.544 SIGNOR-260469 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Thr507 FGESRAStFCGTPDY 10090 BTO:0000944 11959144 YES PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex 0.3 SIGNOR-248594 PRKCD protein Q05655 UNIPROT PPP1R14B protein Q96C90 UNIPROT up-regulates activity phosphorylation Thr57 VRRQGKVtVKYDRKE 10606530 YES lperfetto Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold. 0.2 SIGNOR-265739 ETS1 protein P14921 UNIPROT CD8A protein P01732 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8413295 NO miannu Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity. 0.256 SIGNOR-254078 MAPK9 protein P45984 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates quantity by stabilization phosphorylation Ser115 SQFSDCSsAKARGDL 9606 BTO:0002932 34048060 YES miannu Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. 0.2 SIGNOR-277563 BLOC1S6 protein Q9UL45 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 BTO:0002946 22203680 YES lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. 0.734 SIGNOR-265931 AP1 complex SIGNOR-C154 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 31340499 NO Luana AP-1 Transcription Factors as Regulators of Immune Responses in Cancer 0.7 SIGNOR-260766 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR SMURF1 protein Q9HCE7-2 UNIPROT down-regulates quantity by destabilization polyubiquitination LYS355 YERDLVQkLKVLRHE 9606 BTO:0000007 21572392 YES miannu Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation.  FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells. 0.502 SIGNOR-271911 USP13 protein Q92995 UNIPROT UBL4A protein P11441 UNIPROT up-regulates activity deubiquitination Lys48 QRLLFKGkALADGKR 9606 BTO:0000007 24424410 YES miannu USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding. 0.611 SIGNOR-272857 MECP2 protein P51608 UNIPROT DLL1 protein O00548 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25420914 YES Luana As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1  0.2 SIGNOR-264674 AMPK complex SIGNOR-C15 SIGNOR MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 9606 BTO:0001938 26816379 YES gcesareni A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. 0.2 SIGNOR-249655 SOD3 protein P08294 UNIPROT dioxygen smallmolecule CHEBI:15379 ChEBI up-regulates quantity chemical modification 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272272 CDK11A protein Q9UQ88 UNIPROT SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser238 SEESWTDsEVDSSCS 9606 BTO:0000007 26885618 YES lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| 0.356 SIGNOR-273020 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273045 OXGR1 protein Q96P68 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256770 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser27 ADREAASsPAGEPLR 9606 20027304 YES This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. 0.602 SIGNOR-162314 PHF1 protein O43189 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 YES miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. 0.285 SIGNOR-260071 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT up-regulates activity phosphorylation Tyr426 LLRASGIyYVPKGKA -1 20417104 YES miannu Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C). 0.285 SIGNOR-262606 ADAM17 protein P78536 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity cleavage 9606 BTO:0000782 9034190 YES lperfetto We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified. 0.703 SIGNOR-46754 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates activity phosphorylation Tyr51 ASPHCPVyVPDPTST 9606 BTO:0000007 10934191 YES Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. autophosphorylation of Tyr-29 contributes significantly to the activation of Hck. 0.2 SIGNOR-251265 HMGA2 protein P52926 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 25300915 NO miannu This study unraveled a novel function ofhmga2in induction of apoptosis in human primary cell lines 0.7 SIGNOR-205465 TLE2 protein Q04725 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates binding 9606 19460168 YES gcesareni Mapping studies reveal that groucho/tle binds two regions in lef-1. 0.637 SIGNOR-185736 ITGB1BP1 protein O14713 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257647 APOH protein P02749 UNIPROT cardiolipin smallmolecule CHEBI:28494 ChEBI down-regulates quantity by destabilization binding 9606 9596664 YES lperfetto The most relevant physiological role of beta2GPI is supposed to be the regulation of the function of anionic phospholipids like cardiolipin (CL). |Anticardiolipin antibodies or lupus anticoagulants are strongly associated with thrombosis. In these autoimmune diseases with anti-phospholipid antibody syndrome, beta2GPI is a cofactor in the recognition of the phospholipid antigen, CL, by anti-CL antibodies. 0.8 SIGNOR-266998 LEPR protein P48357 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 BTO:0000007 11018044 YES miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. 0.758 SIGNOR-263495 LPAR4 protein Q99677 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257258 APC-c complex SIGNOR-C150 SIGNOR REV1 protein Q9UBZ9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23287467 YES miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. 0.337 SIGNOR-272895 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 9606 17360704 YES gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. 0.59 SIGNOR-153618 XIAP protein P98170 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination -1 15749826 YES lperfetto Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis. 0.914 SIGNOR-134504 IRF2 protein P14316 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity by expression transcriptional regulation 11464288 YES lperfetto In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays. 0.524 SIGNOR-271681 HSD17B2 protein P37059 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification -1 8099587 YES Luana 17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone.  0.8 SIGNOR-269762 RB1 protein P06400 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 21902831 YES gcesareni Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation. 0.395 SIGNOR-176563 PINK1 protein Q9BXM7 UNIPROT LETM1 protein O95202 UNIPROT up-regulates activity phosphorylation Thr192 ILNGHSLtRRERRQF -1 29123128 YES lperfetto Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro.|Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria. 0.358 SIGNOR-262540 ECM stimulus SIGNOR-ST20 SIGNOR A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259043 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16885213 YES gcesareni In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation 0.467 SIGNOR-148478 MAPK14 protein Q16539 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15824134 NO Andrea Inhibition of p38 / MAPKs (a) promotes exit from the cell cycle, (b) prevents differentiation, and (c) insulates the cell from most external stimuli allowing the satellite cell to maintain a quiescent state. Activation of satellite cells and p38 / MAPKs occurs concomitantly, providing further support that these MAPKs function as a molecular switch for satellite cell activation 0.7 SIGNOR-255745 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr52 DSSKPAVyNYPEGAA 9606 BTO:0000150 20101225 YES gcesareni Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes. 0.447 SIGNOR-163566 Ast-487 chemical CID:11409972 PUBCHEM KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259694 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 YES lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. 0.2 SIGNOR-26590 AKT proteinfamily SIGNOR-PF24 SIGNOR ARFIP2 protein P53365 UNIPROT unknown phosphorylation Ser260 GTRGRLEsAQATFQA 9606 BTO:0000938 15809304 YES llicata Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells. 0.2 SIGNOR-135105 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr252 PINGSPRtPRRGQNR 9606 1756735 YES lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. 0.687 SIGNOR-21560 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR INCA1 protein Q0VD86 UNIPROT unknown phosphorylation Ser191 GRAQLLWsPWSPLDQ -1 15159402 YES miannu  GST-INCA1 was phosphorylated in vitro by cyclin A2-CDK2 but not by CDK2 or either cyclin alone.  Mutation of Ser23, Thr167, and Ser176 strongly reduced in vitro phosphorylation of INCA1.Cyclin A1 and Cyclin A2 in Complex with CDK2 Phosphorylated INCA1 in Vitro Predominantly at Ser176 0.329 SIGNOR-273592 H3C1 protein P68431 UNIPROT Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR up-regulates activity 9606 22266761 NO Gianni Widely described to be associated with active chromatin, H3K36 methylation has also been implicated in transcriptional repression, alternative splicing, dosage compensation, DNA replication and repair 0.7 SIGNOR-269072 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 YES lperfetto Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation 0.404 SIGNOR-181663 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269386 ADP chemical CHEBI:16761 ChEBI PRPS1 protein P60891 UNIPROT down-regulates activity chemical inhibition 29074724 YES lperfetto PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP 0.8 SIGNOR-265736 RPS6KB1 protein P23443 UNIPROT LTC4S protein Q16873 UNIPROT down-regulates activity phosphorylation Ser36 ARRAFRVsPPLTTGP -1 27365393 YES miannu Here, we identified Ser(36) as the major p70S6k phosphorylation site, along with a low frequency site at Thr(40), using an in vitro phosphorylation assay combined with mass spectrometry. Cellular LTC4S activity is suppressed by PKC-mediated phosphorylation, and recently a downstream p70S6k was shown to play an important role in this process. 0.2 SIGNOR-277256 MOV10 protein Q9HCE1 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 BTO:0000007 27016603 YES miannu MOV10 enhances IRF3 activation and IRF3-mediated gene induction. This indicated that MOV10-mediated antiviral activity is most likely mediated through IKKε and not through TBK1. Involvement of IKKε was further established by examining the physical interaction of MOV10 and IKKε. 0.2 SIGNOR-261138 TUBA3C protein P0DPH7 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 NO miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. 0.7 SIGNOR-269724 PRKAA1 protein Q13131 UNIPROT GFPT1 protein Q06210 UNIPROT down-regulates phosphorylation Ser242 SKFTRWGsQGERGKD 9606 19170765 YES lperfetto Amp-activated protein kinase phosphorylates glutamine : fructose-6-phosphate amidotransferase 1 at ser243 to modulate its enzymatic activityhe 2-dg induced phosphorylation of gfat1 . The assay of the gfat enzymatic activity in the cell lysates indicated that the 2-dg-treatment inhibited the enzymatic activity 0.2 SIGNOR-183528 DDAH2 protein O95865 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity 33850055 NO lperfetto Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of dynamin-related protein 1 (Drp1) 0.8 SIGNOR-275649 LYN protein P07948 UNIPROT MCM7 protein P33993 UNIPROT up-regulates activity phosphorylation Tyr600 WASKDATyTSARTLL 9606 23764002 YES miannu Lyn phosphorylates MCM7 at Y600.|These evidences suggest that Lyn mediated Y600 phosphorylation may regulate MCM7 function in DNA replication licensing. 0.454 SIGNOR-278407 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.272 SIGNOR-275787 GATAD2A protein Q86YP4 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. 0.832 SIGNOR-263858 PPP2CA protein P67775 UNIPROT FCAR protein P24071 UNIPROT up-regulates activity dephosphorylation Ser284 LTFARTPsVCK -1 30766540 YES lperfetto Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail 0.323 SIGNOR-264858 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000007;BTO:0000567 SIGNOR-C14 SIGNOR-C13 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. 0.847 SIGNOR-129931 PGAM1 protein P18669 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity chemical modification 9606 24786789 YES miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. 0.8 SIGNOR-266514 PYGB protein P11216 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 YES miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267396 trichostatin A chemical CHEBI:46024 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258017 BBOX1 protein O75936 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 11802770 YES miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. 0.8 SIGNOR-269700 CDH1 protein P12830 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 18662541 YES lperfetto In early mitosis, APC/C is activated through binding to Cdc20, and in late M, Cdc20 is replaced by Cdh1, the second activator of APC/C. 0.388 SIGNOR-274058 DUSP2 protein Q05923 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates activity dephosphorylation 9606 28252035 YES miannu DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5. 0.376 SIGNOR-277069 TBX22 protein Q9Y458 UNIPROT DLX5 protein P56178 UNIPROT down-regulates quantity by repression transcriptional regulation 9031 BTO:0005956 20033915 YES miannu the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22. 0.308 SIGNOR-265566 MAPK3 protein P27361 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 YES llicata Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4. 0.419 SIGNOR-101664 PTCHD1 protein Q96NR3 UNIPROT DLG4 protein P78352 UNIPROT up-regulates quantity binding 10090 BTO:0000142 29118110 YES miannu Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus 0.2 SIGNOR-266652 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 11157752 YES lperfetto Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. 0.708 SIGNOR-235947 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 11279118 YES lperfetto Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells 0.669 SIGNOR-106462 MYO7A protein Q13402 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 YES lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. 0.611 SIGNOR-262577 ARRB1 protein P49407 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity relocalization 21296876 YES lperfetto Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs) 0.402 SIGNOR-275505 FBXO31 protein Q5XUX0 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0002181 29343641 YES miannu FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. 0.606 SIGNOR-277382 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 21993628 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-176754 AKT1 protein P31749 UNIPROT TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 YES gcesareni Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. 0.731 SIGNOR-67313 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation 10090 20921139 YES lperfetto When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation. 0.667 SIGNOR-219388 AMPK complex SIGNOR-C15 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 20647423 YES lperfetto Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions. 0.2 SIGNOR-216471 PTPN11 protein Q06124 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 12270932 YES SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity. 0.742 SIGNOR-248672 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser285 VDAQGTLsKIFKLGG -1 2413024 YES lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 0.49 SIGNOR-248874 Gbeta proteinfamily SIGNOR-PF4 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18519666 YES inferred from 70% family members lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ 0.2 SIGNOR-270095 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr244 AETHSSStPVQHPIK 9606 BTO:0000567 30021153 YES lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. 0.2 SIGNOR-265032 PAPOLB protein Q9NRJ5 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 19224921 NO lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. 0.7 SIGNOR-268326 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 21205641 YES lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.49 SIGNOR-216461 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 YES lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . 0.373 SIGNOR-217367 POLR2A protein P24928 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.863 SIGNOR-266160 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1035 IETDKEYyTVKDDRD 10090 11909529 YES The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP 0.766 SIGNOR-248396 U2 snRNP complex complex SIGNOR-C479 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 NO lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.7 SIGNOR-270676 GABBR2 protein O75899 UNIPROT GABA-B receptor complex SIGNOR-C336 SIGNOR form complex binding 9606 BTO:0000007 9872316 YES brain lperfetto Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2. 0.692 SIGNOR-263743 verteporfin chemical CHEBI:32293 ChEBI SFN protein P31947 UNIPROT up-regulates quantity chemical activation 9606 BTO:0005079 27073720 YES Verteporfin increases the level of 14-3-3σ, which promotes the translocation of YAP from nucleus to cytoplasm. 0.8 SIGNOR-278129 FBXO45 protein P0C2W1 UNIPROT PAWR protein Q96IZ0 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 24992930 YES miannu Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis.Fbxo45 forms an atypical ubiquitin ligase complex that contains Skp1 and the Ring-finger protein PAM (protein-associated with myc) also known as MYCBP2 (myc-binding protein 2). 0.381 SIGNOR-272223 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Thr256 SQMKSMStFIEEAYK 9606 BTO:0000567 25670858 YES lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 0.587 SIGNOR-265229 minoxidil chemical CHEBI:6942 ChEBI PLOD1 protein Q02809 UNIPROT down-regulates quantity by repression chemical inhibition 10090 BTO:0000763 30481795 YES Monia treatment with minoxidil repressed the expression of the PLOD1, PLOD2, and PLOD3 genes and their encoded LH proteins, it exerted the most profound effects on PLOD1/LH1, 0.8 SIGNOR-261071 cyproheptadine chemical CHEBI:4046 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 YES miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. 0.8 SIGNOR-258869 dopamine smallmolecule CHEBI:18243 ChEBI DRD5 protein P21918 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257481 PPP2CA protein P67775 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Ser12 KSKPKDAsQRRRSLE 9606 BTO:0001938 18069897 YES gcesareni We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC 0.43 SIGNOR-247970 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000142 20308788 YES The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. 0.2 SIGNOR-164667 CXCR4 protein P61073 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0000007 33073183 YES Marta Tosoni Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner 0.477 SIGNOR-278104 CIITA protein P33076 UNIPROT HLA-DRA protein P01903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002417 10886240 NO These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. 0.616 SIGNOR-254008 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 8940173 YES lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor 0.581 SIGNOR-45130 MIPOL1 protein Q8TD10 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 31609475 NO miannu In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9 0.2 SIGNOR-261135 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248690 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr590 PALLEHRtGRYAPTI 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.332 SIGNOR-262921 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser364 LQSPITTsPSC 9606 10617468 YES lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. 0.786 SIGNOR-73633 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity 9606 BTO:0001103 15829723 YES apalma GSK-3beta activity can be inhibited by Akt phosphorylation (12), which may provide a mechanism for Akt to promote muscle growth through inhibition of the negative regulator GSK-3beta. 0.792 SIGNOR-255109 SLC36A1 protein Q7Z2H8 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity relocalization 9606 12748860 YES lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. 0.8 SIGNOR-264737 DAPK1 protein P53355 UNIPROT RPL5 protein P46777 UNIPROT unknown phosphorylation 9606 18283219 YES lperfetto Here we adapted this strategy to successfully screen for dapk substrates. We report the identification of two substrates, ribosomal protein l5 and mcm3. 0.2 SIGNOR-160954 ETFBKMT protein Q8IXQ9 UNIPROT ETFB protein P38117 UNIPROT down-regulates activity methylation Lys200 ATLPNIMkAKKKKIE -1 25416781 YES miannu Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases. 0.2 SIGNOR-269450 vorinostat chemical CHEBI:45716 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257919 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR DYSF protein O75923 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.343 SIGNOR-136497 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT up-regulates activity phosphorylation Thr125 MIPQKNQtASGDSLD 9606 BTO:0001938 22535524 YES lperfetto We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors. 0.659 SIGNOR-252049 AURKA protein O14965 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser83 ALREIRYsLLPFANE 9606 15147269 YES lperfetto On the basis of these observations, we conclude that s83 of lats2 is a phosphorylation target of aurora-a and this phosphorylation plays a role of the centrosomal localization of lats2. 0.381 SIGNOR-124830 CCNT1 protein O60563 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR form complex binding -1 34955012 YES lperfetto Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb).  0.964 SIGNOR-267739 C5 protein P01031 UNIPROT C5AR2 protein Q9P296 UNIPROT up-regulates binding 9606 cleavage:Arg751;Arg677 HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE 11773063 YES complement C5a (anaphylatoxin) fragment: PRO_0000005988 gcesareni Here we report that the orphan receptor c5l2/gpr77, which shares 35% amino acid identity with cd88, binds c5a with high affinity. 0.661 SIGNOR-113558 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Ser336 PGPQPPKsPGPHSEE 9606 BTO:0000567 12734188 YES lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. 0.362 SIGNOR-101051 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1784 TPTSPNYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248826 H3C1 protein P68431 UNIPROT Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR form complex binding -1 24311584 YES miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. 0.2 SIGNOR-263717 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr203 HQHYYYDtHTNTYYL 9606 12145304 YES gcesareni The secretory na-k-cl cotransporter nkcc1 is activated by secretagogues through a phosphorylation-dependent mechanism. three phosphoacceptor sites were identified in the n-terminal domain of the protein (at thr184, thr189, and thr202) none of these residues occurs in the context of strong consensus sites for known ser/thr kinases. 0.525 SIGNOR-90927 PI3K complex SIGNOR-C156 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 NO lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.7 SIGNOR-252706 SCF(TBL1) complex SIGNOR-C533 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys666 LFRMSEDkPQDYKKR 9606 BTO:0000007 20181957 YES miannu Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC).  0.728 SIGNOR-271946 PRKCG protein P05129 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates phosphorylation Ser415 QRKITRPsQRPKTPP 9606 17911614 YES gcesareni Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover. 0.2 SIGNOR-158133 ANGPT1 protein Q15389 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 9204896 YES gcesareni Angiopoietin-1 (ang1) is an angiogenic factor that signals through the endothelial cell-specific tie2 receptor tyrosine kinase. 0.795 SIGNOR-49355 KIF13A protein Q9H1H9 UNIPROT ZFYVE26 protein Q68DK2 UNIPROT up-regulates activity binding 9606 BTO:0000567 20208530 YES miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. 0.416 SIGNOR-265539 TBL1X protein O60907 UNIPROT SCF(TBL1) complex SIGNOR-C533 SIGNOR form complex binding 9606 BTO:0000007 20181957 YES miannu Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC).  0.456 SIGNOR-271948 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT down-regulates activity phosphorylation Ser426 CSLLLDSsLSSNWDD -1 12738781 YES miannu Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site. 0.72 SIGNOR-263096 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR ARF6 protein P62330 UNIPROT down-regulates quantity by destabilization 9534 BTO:0000298 18094045 YES miannu Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A). 0.2 SIGNOR-271766 LYN protein P07948 UNIPROT BTK protein Q06187 UNIPROT up-regulates phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 BTO:0000776 8630736 YES lperfetto Phosphorylation at y551 requires lyn kinase activity, indicating that y551 is a transphosphorylation site \ this transphosphorylation at y551 is followed by phosphorylation at a second site, which is dependent on btk catalytic activity. 0.544 SIGNOR-41607 ARSA protein P15289 UNIPROT HBB protein P68871 UNIPROT up-regulates activity acetylation 9606 237937 YES Regulation miannu ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction. 0.2 SIGNOR-251772 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 BTO:0000007 17761173 YES lperfetto We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3 0.728 SIGNOR-260615 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 15870273 YES Simone Vumbaca We suggest that the interaction between MyoD and Pbx is necessary to initially target MyoD to the myogenin promoter 0.459 SIGNOR-255639 CEP192 protein Q8TEP8 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 9606 26012549 YES miannu These findings demonstrated that Cep192 mediates the AurA-Plk1 interaction and that the formation of the Cep192-AurA-Plk1 complex could be important for activating AurA and Plk1. 0.795 SIGNOR-266406 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1092 TFLPVPEyINQSVPK 10090 BTO:0002882 16122376 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work 0.2 SIGNOR-236523 STK11 protein Q15831 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates activity phosphorylation Thr183 SDGEFLRtSCGSPNY -1 14976552 YES lperfetto We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP_activated protein kinase (AMPK). 0.598 SIGNOR-122721 UBE3A protein Q05086 UNIPROT PSMC2 protein P35998 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28559284 YES lperfetto Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits. 0.386 SIGNOR-265132 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Thr446 LKNDGKRtRSKGTLR 4932 11337501 YES Trans-autophosphorylation of Thr-446 and Thr-451 by the two kinase moieties in a PKR dimer. autophosphorylation in the activation loop would promote proper alignment of key catalytic residues, or the correct orientation of the two lobes of the PKR kinase domain, required for substrate binding or phosphoryl transfer 0.2 SIGNOR-251110 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.547 SIGNOR-204724 PRKD3 protein O94806 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates activity phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 YES lperfetto Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase 0.286 SIGNOR-275938 NUAK2 protein Q9H093 UNIPROT LATS1 protein O95835 UNIPROT down-regulates phosphorylation Ser464 NIPVRSNsFNNPLGN 9606 19927127 YES gcesareni Phosphorylation at ser-464 by nuak1 and nuak2 leads to decreased protein level and is required to regulate cellular senescence and cellular ploidy 0.307 SIGNOR-161796 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA7 protein Q9Y5G6 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265709 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 16613856 YES lperfetto HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation 0.459 SIGNOR-227550 PPM1D protein O15297 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity dephosphorylation 9606 23907458 YES lperfetto 34 In this study, a novel function of Wip1 was identified, that is, its ability to dephosphorylate directly and thus inactivate apoptotic BAX protein in response to gamma irradiation.|To ascertain whether Wip1 dephosphorylates BAX, recombinant Wip1 was incubated with previously reported BAX-derived phosphopeptides containing Ser87, Ser163, Thr167, and Ser184 in an in vitro phosphatase assay. xref , xref Peptides containing phospho-Thr180 from p38 MAPK and phospho-Thr31 from UNG2 were used as a positive and negative control, respectively.  xref  As shown in xref , purified Wip1 did not dephosphorylate the four BAX-derived phosphopeptides. 0.2 SIGNOR-276993 Dihydromorphine chemical CHEBI:4575 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258786 MEST protein Q5EB52 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates transcriptional regulation 9606 24827625 NO areggio Our data demonstrate that Mest alleviated CCl4-induced collagen deposition in liver tissue and improved the condition of the liver in rats. Mest also significantly reduced the expression and distribution of β-catenin, α-SMA and Smad3 both in vivo and in vitro, in addition to the viability of HSCs in vitro. 0.251 SIGNOR-258982 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser794 QHLRLSTsSGRLLYA 9606 12624099 YES gcesareni These results suggest that highly expressed sik2 in insulin-stimulated adipocytes phosphorylates ser794_ of irs-1 and, as a result, might modulate the efficiency ofinsulinsignal transduction 0.568 SIGNOR-99055 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser641 KVTSKCGsLGNIHHK 9606 BTO:0000590 7706316 YES lperfetto Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. 0.43 SIGNOR-249342 FOXO3 protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0004245 10783894 YES gcesareni AFX transcriptionally activates p27kip1, resulting in increased protein levels. 0.746 SIGNOR-238610 AKT3 protein Q9Y243 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. 0.286 SIGNOR-186780 PRKACA protein P17612 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Ser11 TGSTPCSsMSNHTKE -1 22142472 YES miannu GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress. 0.295 SIGNOR-276390 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser29 FLGLHIAsPPNFRLT 9534 BTO:0000298 12756254 YES miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. 0.879 SIGNOR-250125 GPER1 protein Q99527 UNIPROT GNG2 protein P59768 UNIPROT up-regulates activity binding 10696571 YES GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNG2 stands for the subunit γ, which dissociates from the receptor after the binding of GTP on α-subunit. 0.383 SIGNOR-251104 CBX1 protein P83916 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-264491 TAF13 protein Q15543 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.873 SIGNOR-263923 SAV1 protein Q9H4B6 UNIPROT STK4 protein Q13043 UNIPROT up-regulates quantity by stabilization binding 9606 16930133 YES Hippo pathway Gianni Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. 0.886 SIGNOR-261958 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE 9606 20940307 YES gcesareni Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis 0.336 SIGNOR-168473 GPR119 protein Q8TDV5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257366 A6/b1 integrin complex SIGNOR-C164 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.388 SIGNOR-253278 USF2 protein Q15853 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 9731700 NO miannu Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription. 0.41 SIGNOR-255594 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser385 PRRVNSAsSSNPPAE 9606 15341740 YES llicata Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites. 0.765 SIGNOR-128499 SERPINE1 protein P05121 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 29474926 NO miannu Plasminogen activator inhibitor-1 (PAI-1) formed in the injured alveolar epithelium also contributes to pulmonary fibrosis in a manner that involves vitronectin binding. 0.7 SIGNOR-260588 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000575 16469705 YES gcesareni This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, 0.654 SIGNOR-245310 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates 9606 22683405 NO inferred from 70% of family members milica In response to growth inhibitory signal (e.g. cell¬ñcell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127. 0.7 SIGNOR-269943 SLBP protein Q14493 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265420 STIP1 protein P31948 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 YES miannu Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle4. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine. 0.854 SIGNOR-261412 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 YES lperfetto We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. 0.2 SIGNOR-244349 BICDL1 protein Q6ZP65 UNIPROT KIF1C protein O43896 UNIPROT up-regulates activity binding -1 20360680 YES miannu BICDR-1 interacts with the dynein/dynactin motor complex. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. These results show that BICDR-1 regulates recruitment and/or activity of the anterograde kinesin motor Kif1C on Rab6 secretory carriers. 0.2 SIGNOR-266876 STAT5A protein P42229 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates transcriptional regulation 9606 12540601 NO fspada We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner. 0.7 SIGNOR-210146 MRAP2 protein Q96G30 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. 0.503 SIGNOR-252369 PPM1A protein P35813 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16931515 YES lpetrilli In this study, we have found that ppm1a, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates smad1 both in vitro and in vivo. considering the highly conserved nature of the sxs motif in all r-smads, we reasoned that ppm1a might also recognize the sxs motif in the bmp-activated smad1. 0.537 SIGNOR-149077 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7222 FRSRGRRsKPSSRAA 9606 BTO:0004905 21295697 YES lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. 0.436 SIGNOR-264426 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT down-regulates phosphorylation Tyr981 LPLDKDYyVVREPGQ 9606 9391116 YES gcesareni We found that jak3 is autophosphorylated on multiple sites including y980 and y981. Compared with the activity of wild-type (wt) jak3, mutant y980f demonstrated markedly decreased kinase activity, and optimal phosphorylation of jak3 on other sites was dependent on y980 phosphorylation. The mutant y980f also exhibited reduced phosphorylation of its substrates, gammac and stat5a. In contrast, mutant y981f had greatly increased kinase activity, whereas the double mutant, yy980/981ff, had intermediate activity. 0.2 SIGNOR-53594 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser733 TVREQDQsFTALDWS 9606 18957422 YES lperfetto Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma 0.343 SIGNOR-181798 FYN protein P06241 UNIPROT CD300LB protein A8K4G0 UNIPROT up-regulates activity phosphorylation Tyr188 EPGEQPIyMNFSEPL 9534 16920917 YES lperfetto As CD300b phosphorylation was occurring only in the presence of both c-Fyn and DAP-12, we addressed whether tyrosine phosphorylation was required for association of CD300b and DAP-12. For this purpose, we generated a set of HA-tagged CD300b mutants affecting the transmembrane lysine (K158L), the cytoplasmic tyrosine (Y188F) or both residues.|As expected, the CD300b double mutant could neither recruit DAP-12 nor become phosphorylated in the presence of c-Fyn kinase (Fig. 5⇑C). Association between CD300b and DAP-12 was maintained in absence of the c-Fyn kinase, indicating that phosphorylation of the adaptor was not essential for the formation of the complex (data not shown) 0.308 SIGNOR-264771 trichostatin A chemical CHEBI:46024 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257935 NFIL3 protein Q16649 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 10090 BTO:0003104 10082541 NO lperfetto NFIL3 inhibits apoptosis without affecting Bcl-xL expression. 0.7 SIGNOR-256653 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 YES llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  0.365 SIGNOR-250799 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. 0.2 SIGNOR-255852 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275755 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys377 HLHTDILkRGSEMDN 31476572 YES lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. 0.2 SIGNOR-275678 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser1798 GQRKRLIsSVEDFTE 9606 BTO:0000007 15342917 YES lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 0.2 SIGNOR-252801 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser43 FGYQRRAsDDGKLTD 10090 BTO:0000944 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.631 SIGNOR-249439 SREBF1 protein P36956 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12923220 YES lperfetto IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells|evidence that IDH1 may regulate lipogenesis in hepatic cells 0.282 SIGNOR-253132 VEGFC protein P49767 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252277 RNF11 protein Q9Y3C5 UNIPROT STAMBP protein O95630 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 14755250 YES miannu RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome. 0.532 SIGNOR-272953 AKAP11 protein Q9UKA4 UNIPROT IQGAP2 protein Q13576 UNIPROT up-regulates activity binding 9606 21776420 YES miannu We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP. 0.437 SIGNOR-273740 TADA1 protein Q96BN2 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.708 SIGNOR-269583 Cyclopamine chemical CHEBI:4021 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9534 BTO:0000298 12414725 YES gcesareni The steroidal alkaloid cyclopamine has both teratogenic and antitumor activities arising from its ability to specifically block cellular responses to vertebrate Hedgehog signaling. We show here, using photoaffinity and fluorescent derivatives, that this inhibitory effect is mediated by direct binding of cyclopamine to the heptahelical bundle of Smoothened (Smo) 0.8 SIGNOR-95270 CDK5 protein Q00535 UNIPROT KALRN protein O60229 UNIPROT up-regulates activity phosphorylation 9606 18628310 YES miannu We then demonstrated that Cdk5 phosphorylates Kalirin 7 on Thr 1590 , increasing its GEF activity slightly and changing its solubility properties. 0.4 SIGNOR-279603 EPM2A protein O95278 UNIPROT GSK3B protein P49841 UNIPROT unknown dephosphorylation Ser9 SGRPRTTsFAESCKP 10090 16959610 YES Epm2a-encoded laforin is a phosphatase for GSK-3beta and an important repressor in the Wnt signaling pathway| only GSK-3β phosphorylation on Ser9 was affected by overexpression of laforin|Although GSK-3β is inactivated by phosphorylation at the Ser9 position, it is unclear if the inactivated enzyme can be reactivated by dephosphorylation. 0.463 SIGNOR-248345 RAP1GDS1 protein P52306 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 21242305 YES miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob 0.483 SIGNOR-171418 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.564 SIGNOR-257403 SMAD3 protein P84022 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16766264 NO irozzo This protection is conferred by Smad3’s ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter. 0.2 SIGNOR-256294 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ -1 15946941 YES miannu  We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. 0.2 SIGNOR-276034 HTR7 protein P34969 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.281 SIGNOR-257168 E2F1 protein Q01094 UNIPROT RASGEF1B protein Q0VAM2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18396012 NO miannu We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation. 0.2 SIGNOR-253851 PDE1A protein P54750 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 YES PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values 0.8 SIGNOR-253398 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 YES gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity 0.526 SIGNOR-123243 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19185596 NO miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection. 0.646 SIGNOR-260974 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr310 VPPLPKVtPTKELQQ 9606 BTO:0000142 15262992 YES lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd 0.396 SIGNOR-126855 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation Ser166 TYSDEHFsPGSHPSH 9606 12556497 YES gcesareni Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. 0.759 SIGNOR-97808 PLAGL1 protein Q9UM63 UNIPROT ABCC6 protein O95255 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000599 18850323 NO miannu We identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins. Both these factors are shown to bind to the same single consensus-binding element in the ABCC6 proximal promoter in cell lines of hepatic and renal origin by reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. PLAG-mediated ABCC6 transactivation may play an important role in determining the level of tissue-specific expression of this gene. The described mechanism can also find potential application in therapeutic interventions in forms of PXE related to impaired ABCC6 expression. 0.369 SIGNOR-254926 DYRK1B protein Q9Y463 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by destabilization phosphorylation Ser185 KTKRKQLsSELGDLE 9606 25777618 YES miannu In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover. 0.333 SIGNOR-279610 BTRC protein Q9Y297 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 9606 11359933 YES gcesareni An e3 ubiquitin ligase complex roc1-scffbw1a consisting of roc1, skp1, cullin1, and fbw1a (also termed trcp1) induces ubiquitination of smad3. 0.39 SIGNOR-108237 EIF2AK2 protein P19525 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 25360179 YES miannu Silencing PKR gene expression in HepG2 cells with siRNA reduced STAT3 phosphorylation at Tyr705 and Ser727 (XREF_FIG).|The results also revealed that PKR activates STAT3, a transcription factor associated with primary liver tumors, which is suggested to promote tumor cell proliferation. 0.611 SIGNOR-279612 Survival Factors stimulus SIGNOR-ST8 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity 19282669 NO lperfetto Activation of receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) by growth factors or mitogens leads to the recruitment of an adaptor protein Grb2 (growth factor receptor bound protein) and the guanine nucleotide exchange factor (SOS). The SOS activates Ras to recruit and activate Raf at the plasma membrane by phosphorylation at multiple sites. MEK1/2 is which then phosphorylated at two serine residues that subsequently phosphorylates ERK1/2 on both threonine and tyrosine. Activated ERK1/2 phosphorylates RSK and both RSK and ERK translocate to the nucleus where they activates multiple transcription factors ultimately resulting in effector protein synthesis and causing changes in cell proliferation and survival. ERK phosphorylation of MEK and possibly Raf can inactivate the pathway at those steps creating a negative feedback loop. 0.7 SIGNOR-250559 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB6 protein Q9Y5F9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265706 FOXO proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 NO lperfetto Sirt1 inhibited foxo3's ability to induce cell death. 0.7 SIGNOR-252939 GSK3B protein P49841 UNIPROT HNRNPD protein Q14103 UNIPROT down-regulates activity phosphorylation Ser83 DEGHSNSsPRHSEAA 9606 BTO:0001271 11903055 YES lperfetto In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation. 0.347 SIGNOR-102582 ZDHHC9 protein Q9Y397 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 YES miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. 0.405 SIGNOR-261355 GMNN protein O75496 UNIPROT CDT1 protein Q9H211 UNIPROT down-regulates activity binding 9606 BTO:0002181 11125146 YES Here we show that geminin interacts tightly with Cdt1, a recently identified replication initiation factor necessary for MCM loading. 0.972 SIGNOR-261680 RELA protein Q04206 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 27337441 YES lperfetto Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation 0.691 SIGNOR-251737 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser793 PRPSPLPsPQPAPRR 9606 20005250 YES miannu Further, investigation revealed that MLK3 was phosphorylated at two residues Ser789 and Ser793 by GSK3\u03b2 ( xref ).|When, these two sites on MLK3 were mutated to non-phosphorable Ala, the activation of MLK3 by GSK3\u03b2 was blocked, and neuronal cell death upon NGF withdrawal also prevented ( xref ). 0.336 SIGNOR-279615 HOXC13 protein P31276 UNIPROT LAMB2 protein P55268 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000298 10835276 YES Luana The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells. 0.2 SIGNOR-261644 CSNK1D protein P48730 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 YES lperfetto Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846 0.27 SIGNOR-274046 MAGT1 protein Q9H0U3 UNIPROT OST-B complex complex SIGNOR-C536 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.699 SIGNOR-272071 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser342 LAHDRAPsRKDSLES 9606 23337587 YES gcesareni Interestingly, sufu stability is regulated via dual phosphorylation at ser342/ser346 by pka and gsk3, and blocking sufu phosphorylation either by mutating ser346 to ala or by treating cultured cells with pka inhibitors attenuates sufu ciliary accumulation, whereas phospho-mimetic forms of sufu exhibits increased ciliary localization 0.466 SIGNOR-200492 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 SVKSPVSsPNNVTLR 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.287 SIGNOR-276104 EFNA3 protein P52797 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 YES gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells. 0.803 SIGNOR-52312 CDH2 protein P19022 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.818 SIGNOR-265864 OXGR1 protein Q96P68 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257042 PKA proteinfamily SIGNOR-PF17 SIGNOR HSPB8 protein Q9UJY1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser57 DWALPRLsSAWPGTL -1 18298377 YES miannu Human small heat shock protein with molecular mass 22 kD (HSP22, HspB8) contains two Ser residues (Ser24 and Ser57) in consensus sequence RXS and is effectively phosphorylated by cAMP-dependent protein kinase in vitro. Mutation S24D did not affect, whereas mutations S57D or S24,57D prevented phosphorylation of HSP22 by cAMP-dependent protein kinase thus indicating that Ser57 is the primary site of phosphorylation. Phosphorylation (or mutation) of Ser57 (or Ser24 and Ser57) resulted in changes of the local environment of tryptophan residues and increased HSP22 susceptibility to chymotrypsinolysis.  0.2 SIGNOR-276151 BID protein P55957 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000093 22464442 YES lperfetto Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer. 0.858 SIGNOR-209675 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity dephosphorylation Tyr315 MPMDTSVyESPYSDP -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.261 SIGNOR-254733 EFNA5 protein P52803 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.945 SIGNOR-52473 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI RAB21 protein Q9UL25 UNIPROT down-regulates activity binding 9606 19693279 YES miannu It was demonstrated that wild-type Rab21 was transiently associated with macropinosomes. Rab21 was recruited to the macropinosomes after a decrease in PI(4,5)P(2) and PI(3,4,5)P(3) levels. Although Rab21 was largely colocalized with Rab5, the recruitment of Rab21 to the macropinosomes lagged a minute behind that of Rab5, and preceded that of Rab7. 0.8 SIGNOR-277781 MAPK9 protein P45984 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 YES JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8 gcesareni Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-189 0.2 SIGNOR-124027 TFE3 protein P19532 UNIPROT ATG9B protein Q674R7 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells 0.2 SIGNOR-276808 GPR35 protein Q9HC97 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257204 PTGER2 protein P43116 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 BTO:0000586 17251915 NO gcesareni Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa). 0.295 SIGNOR-152805 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT down-regulates phosphorylation Ser46 PAAAPASsSDPAAAA 9606 12446680 YES lperfetto The interaction between cdk11p46 and eif3 p47 occurs in vitro and in vivo. In addition, cdk11 protein kinase isolated from cells undergoing apoptosis can phosphorylate eif3 p47in vitro, and serine phosphorylation of eif3 p47 occurs in cells during apoptosis.Purified recombinant cdk11p46 inhibited translation of a reporter gene in vitro in a dose-dependent manner.These data suggest that the function of the caspase-processed cdk11p110 isoform may be to inhibit translation during apoptosis. However, whether or not this inhibition of protein translation occurs in an eif3 p47-dependent or -independent manner remains to be clarified. 0.516 SIGNOR-95762 AMPK complex SIGNOR-C15 SIGNOR TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 14651849 YES lperfetto Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity. 0.433 SIGNOR-216441 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr59 GETRFTDtRKDEQER 9606 phosphorylation:Thr59 GETRFTDtRKDEQER 8386634 YES gcesareni Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2 0.405 SIGNOR-38566 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 YES lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. 0.35 SIGNOR-249162 LPCAT4 protein Q643R3 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI down-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272773 ketoconazole chemical CHEBI:47519 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258060 propionyl-CoA(4-) smallmolecule CHEBI:57392 ChEBI (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI up-regulates quantity precursor of 9606 15890657 YES miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. 0.8 SIGNOR-267185 POU5F1 protein Q01860 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.839 SIGNOR-254942 CDC42 protein P60953 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity binding 9606 BTO:0000567 9418861 YES lperfetto Myotonic dystrophy kinase-related Cdc42-binding kinase acts as a Cdc42 effector in promoting cytoskeletal reorganization|MRCK alpha and Cdc42V12 colocalize, particularly at the cell periphery in transfected HeLa cells. Microinjection of plasmid encoding MRCK alpha resulted in actin and myosin reorganization. 0.792 SIGNOR-262593 CHEK1 protein O14757 UNIPROT DIAPH1 protein O60610 UNIPROT down-regulates activity phosphorylation 9606 28697335 YES miannu Chk1 Phosphorylates Drf1 for beta-Trcp-Dependent Degradation.|From this we conclude that Chk1 inhibits Drf1, but not the other three limiting factors at the MBT. 0.2 SIGNOR-279026 HOXA9 protein P31269 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25252870 NO miannu Hoxa9bound directly to the putative promoter and a dnase-hypersensitive region in the first intron of the igf1 gene. Transcription rates of the igf1 gene paralleledhoxa9activity 0.2 SIGNOR-205308 APOBEC3B protein Q9UH17 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 NO lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). 0.7 SIGNOR-261331 BPLF1 protein P03186 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity deubiquitination 9606 24586164 YES scontino In the current study, we have found that BPLF1 interferes with innate immune activation by targeting multiple intermediates along the TLR signal transduction pathway, including TRAF6, NEMO, and IκBα. BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes. 0.2 SIGNOR-266744 NRXN1 protein Q9ULB1 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 YES miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites. 0.824 SIGNOR-265452 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys122 SPVEDNEkDLVKLAK -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). 0.404 SIGNOR-272739 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC15 protein Q99877 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271993 MARCHF9 protein Q86YJ5 UNIPROT PTPRA protein P18433 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271540 PTPN11 protein Q06124 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity dephosphorylation Ser727 TDNLLPMsPEEFDEV 9606 BTO:0000007 12270932 YES SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity. 0.742 SIGNOR-248673 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC 9606 27784766 YES Luana These data indicate a novel regulatory role of PKC to inhibit AMPKα1 in human cells. As PKC activation is associated with insulin resistance and obesity, PKC may underlie the reduced Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487. | AMPK activity reported in response to overnutrition in insulin-resistant metabolic and vascular tissues. 0.422 SIGNOR-259865 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.491 SIGNOR-275777 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9335504 YES llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. 0.642 SIGNOR-52666 ATM protein Q13315 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 YES lperfetto Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro. 0.809 SIGNOR-121861 SMAD6 protein O43541 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity binding 10116 11737269 YES lperfetto Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads. 0.569 SIGNOR-235571 ponatinib chemical CHEBI:78543 ChEBI LYN protein P07948 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000830 23539538 YES miannu Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells 0.8 SIGNOR-259273 UBN2 protein Q6ZU65 UNIPROT HIRA complex 2 complex SIGNOR-C462 SIGNOR form complex binding 9606 30285846 YES miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. 0.374 SIGNOR-269436 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Thr896 KNSECDPtPSHRGQL 9606 BTO:0000567 31167143 YES miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  0.2 SIGNOR-276733 GAS2 protein O43903 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 24706950 NO miannu Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs.  0.7 SIGNOR-273701 ATF4 protein P18848 UNIPROT CARS2 protein Q9HA77 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.257 SIGNOR-269417 AMP smallmolecule CHEBI:456215 ChEBI PRPS1 protein P60891 UNIPROT down-regulates activity chemical inhibition 29074724 YES lperfetto PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP 0.8 SIGNOR-265737 CDC25C protein P30307 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity dephosphorylation 9606 32518522 YES miannu At the interval CDC25C inhibits ASK1, dephosphorylating pThr838 in its activation loop.|CDC25C dephosphorylates ASK1 to inhibit its activity during the interphase. 0.288 SIGNOR-277100 MRGPRX1 protein Q96LB2 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256929 belinostat chemical CHEBI:61076 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257748 KIF1C protein O43896 UNIPROT RAB6A protein P20340 UNIPROT up-regulates quantity relocalization -1 20360680 YES miannu Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. 0.409 SIGNOR-266877 IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 YES lperfetto Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway 0.541 SIGNOR-209769 Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR ATP smallmolecule CHEBI:15422 ChEBI down-regulates quantity chemical modification 9606 11376933 YES miannu To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis. 0.8 SIGNOR-267843 CSNK1E protein P49674 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 YES gcesareni However, ck1epsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the beta-catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated ck1epsilon as a candidate s45-kinase in several assays, both in vitro and in vivo. 0.656 SIGNOR-87448 hsa-miR-146a mirna URS00005E1F00_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001949 20023696 YES Expression of CXCR4 was downregulated in clinical samples of KS and this was accompanied by increased expression of miR-146a. Our results demonstrate that K13-induced NF-κB activity suppresses CXCR4 via upregulation of miR-146a. Downregulation of CXCR4 expression by K13 may contribute to KS development by promoting the premature release of KSHV-infected endothelial progenitors into the circulation. 0.4 SIGNOR-277938 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 21902831 YES lperfetto Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis. 0.319 SIGNOR-216860 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 21084559 YES gcesareni Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. 0.554 SIGNOR-169841 MRPS24 protein Q96EL2 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.661 SIGNOR-261436 HTR3A protein P46098 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 NO miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  0.7 SIGNOR-264316 BRAF protein P15056 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates quantity by destabilization phosphorylation Thr88 ETSKYYVtIIDAPGH -1 22378069 YES miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  0.262 SIGNOR-276405 SRC protein P12931 UNIPROT YAP1 protein P46937-3 UNIPROT up-regulates activity phosphorylation Tyr357 SGLSMSSySVPRTPD 10090 27013234 YES done miannu We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation. 0.63 SIGNOR-274025 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5A protein P29375 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273467 dexmedetomidine chemical CHEBI:4466 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258906 MARCHF1 protein Q8TCQ1 UNIPROT CD86 protein P42081 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21849678 YES miannu Among nine family members examined, forced expression of MARCH1, -2, and -8 induced a significant reduction of surface CD86 in several cell lines.|CD86 is ubiquitinated by MARCH1. 0.2 SIGNOR-278628 EGFR protein P00533 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Tyr21 IENEEQEyVQTVKSS 9606 24103589 YES lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf 0.509 SIGNOR-202776 IDH complex SIGNOR-C396 SIGNOR 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 28139779 YES miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 0.8 SIGNOR-266252 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SP3 protein Q02447 UNIPROT up-regulates phosphorylation 9606 17685427 YES inferred from 70% family members gcesareni Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. 0.2 SIGNOR-270053 LPAR5 protein Q9H1C0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.348 SIGNOR-257284 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1710 HVTSKCGsLKNIRHR -1 8631898 YES miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 0.419 SIGNOR-250165 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 16403219 YES miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. 0.392 SIGNOR-250395 FOXP2 protein O15409 UNIPROT RELN protein P78509 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25232744 YES miannu By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets. 0.365 SIGNOR-266833 PER2 protein O15055 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 NO miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. 0.2 SIGNOR-254153 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259794 SRC protein P12931 UNIPROT TRPC6 protein Q9Y210 UNIPROT up-regulates activity phosphorylation Tyr31 RRNESQDyLLMDSEL 9606 21471003 YES miannu TRPC6 Y31 and Y284 are phosphorylated by Src family kinase in isolated glomeruli. 0.436 SIGNOR-279659 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Arg534 KSRSLDRrGIQRAAD -1 7989361 YES lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. 0.6 SIGNOR-263629 NCOA1 protein Q15788 UNIPROT APOC3 protein P02656 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.2 SIGNOR-255065 AKT proteinfamily SIGNOR-PF24 SIGNOR BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Thr509 LKRKRRPtSGLHPED 9606 BTO:0000150 17428466 YES lperfetto Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation 0.2 SIGNOR-244168 PIPP smallmolecule CID:24755493 PUBCHEM LRP6 protein O75581 UNIPROT up-regulates 9606 18772438 NO gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490 0.8 SIGNOR-180797 AGTR1 protein P30556 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 32201502 NO MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. 0.7 SIGNOR-260234 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 21880741 YES gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. 0.628 SIGNOR-176373 CDH15 protein P55291 UNIPROT CDON protein Q4KMG0 UNIPROT up-regulates activity binding 9606 12634428 YES lperfetto Cdo binds promyogenic cadherins form complexes with n- and m-cadherin. 0.498 SIGNOR-99250 MRGPRX1 protein Q96LB2 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.343 SIGNOR-257384 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser362 TLKNKTEsSLLAKLE -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.2 SIGNOR-276201 acyl-CoA smallmolecule CHEBI:17984 ChEBI 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 ChEBI up-regulates quantity precursor of -1 18772128 YES miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. 0.8 SIGNOR-267243 RHEB protein Q15382 UNIPROT FKBP8 protein Q14318 UNIPROT down-regulates activity gtpase-activating protein 9606 19222999 YES lperfetto Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1. 0.536 SIGNOR-233568 ACTR5 protein Q9H9F9 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.703 SIGNOR-270850 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT down-regulates activity phosphorylation Ser713 KKKFRTPsFLKKSKK -1 8810272 YES miannu Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin. 0.283 SIGNOR-250332 Gbeta proteinfamily SIGNOR-PF4 SIGNOR IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation -1 15133517 YES inferred from 70% family members miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291‚Äì356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. 0.2 SIGNOR-270097 PLAG1 protein Q6DJT9 UNIPROT ABCC6 protein O95255 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000599 18850323 NO miannu We identified ABCC6 as a target gene for transcriptional induction by PLAG1 and PLAGL1, transcription factors from the PLAG family of cell cycle progression-related DNA-binding proteins. Both these factors are shown to bind to the same single consensus-binding element in the ABCC6 proximal promoter in cell lines of hepatic and renal origin by reporter gene assay, electrophoretic mobility shift assay and chromatin immunoprecipitation. PLAG-mediated ABCC6 transactivation may play an important role in determining the level of tissue-specific expression of this gene. The described mechanism can also find potential application in therapeutic interventions in forms of PXE related to impaired ABCC6 expression. 0.38 SIGNOR-254925 NEDD4 protein P46934 UNIPROT SNCA protein P37840 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21953697 YES miannu Here we show that the ubiquitin ligase Nedd4, which functions in the endosomal-lysosomal pathway, robustly ubiquitinates alpha-synuclein, unlike ligases previously implicated in its degradation. 0.372 SIGNOR-278611 UBE2J1 protein Q9Y385 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys244 KIAYLGGkGPFSYNL 9606 BTO:0001379 29892818 YES scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. 0.379 SIGNOR-267482 SMARCC1 protein Q92922 UNIPROT SMARCE1 protein Q969G3 UNIPROT up-regulates quantity by stabilization 9606 20829358 NO miannu We show that the mechanism of baf155-mediated stabilization of baf57 involves blocking its ubiquitination by preventing interaction with trip12, an e3 ubiquitin ligase. 0.898 SIGNOR-167869 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser92 AAQMEVAsFLLSKEN 9606 BTO:0000567 15525512 YES llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  0.992 SIGNOR-250608 PRKCD protein Q05655 UNIPROT SDC4 protein P31431 UNIPROT up-regulates activity phosphorylation Ser179 MKKKDEGsYDLGKKP 10116 11916978 YES lperfetto The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant. 0.527 SIGNOR-116265 MAP4K4 protein O95819 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates binding 9606 10807933 YES gcesareni The existence of an at least trimolecular complex consisting of nik, tak1, and ikk2, although the precise sequence of activation as well as the possible location of the kinases within the signalosome remains to be elucidated. 0.581 SIGNOR-77404 CDK1 protein P06493 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 YES gcesareni Here, we demonstrate that sirt2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1. Overexpression of sirt2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation. 0.412 SIGNOR-154681 MKX protein Q8IYA7 UNIPROT SCX protein Q7RTU7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001592 33115953 YES miannu MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). 0.416 SIGNOR-267213 UBE3A protein Q05086 UNIPROT SCRIB protein Q14160 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 11027293 YES miannu Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase 0.551 SIGNOR-272573 ANGPT1 protein Q15389 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 NO lperfetto Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. 0.257 SIGNOR-241554 BANP protein Q8N9N5 UNIPROT KHDRBS1 protein Q07666 UNIPROT down-regulates activity binding 9606 BTO:0000567 26080397 YES miannu SMAR1 Interacts with Sam68 in a Signal-Dependent Manner. HDAC6 in complex with SMAR1 deacetylates Sam68. Here, we document that SMAR1, in cooperation with histone deacetylase 6 (HDAC6), interacts with Sam68 and maintains it in a deacetylated state, concomitantly inhibiting the inclusion of CD44 alternate exons. 0.309 SIGNOR-266201 PSMD14 protein O00487 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.899 SIGNOR-263346 PTPN11 protein Q06124 UNIPROT CTNNA1 protein P35221 UNIPROT down-regulates dephosphorylation Tyr148 LADMADVyKLLVQLK 9606 16767162 YES gcesareni Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals. 0.433 SIGNOR-147075 CREBBP protein Q92793 UNIPROT LHX3 protein Q9UBR4 UNIPROT up-regulates activity binding 9606 10931853 YES scontino Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim and CBP Act Synergistically in TRH Stimulation of the Human α-GSU Promoter. 0.2 SIGNOR-267206 EVX1 protein P49640 UNIPROT GSC protein P56915 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 22178155 NO miannu We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin. 0.253 SIGNOR-254139 SIRT7 protein Q9NRC8 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity deacetylation Lys38 K-->P 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275885 Normorphine chemical CHEBI:7633 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258824 UQCRC2 protein P22695 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.901 SIGNOR-262191 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser916 TGEAPTLsPPRDARP 9606 BTO:0000567 31981797 YES miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. 0.434 SIGNOR-276832 MAPK8IP2 protein Q13387 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 10490659 YES These data demonstrated that JIP2 increases JNK activation by the MLK signaling pathway gcesareni These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins. 0.57 SIGNOR-70866 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT up-regulates activity phosphorylation Tyr210 SMAIHEVyQELIQDV -1 12923183 YES In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck 0.501 SIGNOR-251372 PRKG1 protein Q13976 UNIPROT TRPC7 protein Q9HCX4 UNIPROT up-regulates activity phosphorylation Thr15 KNMQRRHtTLREKGR 9534 BTO:0000298 21402151 YES miannu In vitro and in vivo kinase assays have revealed that cGK-Iα phosphorylates mouse TRPC7 but not mouse TRPC3. Site-directed mutagenesis analysis revealed that TRPC7 was phosphorylated by cGK-Iα at threonine 15. Phosphorylation of TRPC7 significantly suppressed carbachol-induced calcium influx and CREB phosphorylation. These data indicate that cGK-Iα interacts with and phosphorylates TRPC7, contributing to the quick and accurate regulation of calcium influx and CREB phosphorylation. 0.2 SIGNOR-263184 mTORC1 complex SIGNOR-C3 SIGNOR ULK1 protein O75385 UNIPROT down-regulates phosphorylation 9606 19690328 YES lperfetto The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated. 0.634 SIGNOR-217133 OXGR1 protein Q96P68 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257417 YAP1 protein P46937 UNIPROT FBXO32 protein Q969P5 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 NO gcesareni The downregulation of fbox32 expression by high yap activity in activated satellite cells may contribute to sustaining high levels of myod in activated satellite cells. 0.2 SIGNOR-199069 phentolamine chemical CHEBI:8081 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258445 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258456 CTSS protein P25774 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 31810556 YES scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. 0.8 SIGNOR-267868 olanzapine chemical CHEBI:7735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). 0.8 SIGNOR-258834 PREX2 protein Q70Z35 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity binding 9606 BTO:0000007 24367090 YES irozzo Here, we report that P-REX2 interacts with PTEN via two interfaces. In summary, P-REX2 docks to the PDZ-BD of PTEN through its C-terminal domain, reads the phosphorylation state of the PTEN tail via the DH domain, and inhibits PTEN activity by unleashing the PH domain 0.619 SIGNOR-259189 RUNX2 protein Q13950 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 NO miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. 0.446 SIGNOR-255084 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr588 QLKPLKTyVDPHTYE 9606 18387945 YES lperfetto The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells. 0.2 SIGNOR-178169 Immunoglobulin lambda-1 light chain protein P0DOX8 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 20176268 YES scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. 0.2 SIGNOR-268198 IRAK1 protein P51617 UNIPROT GLIPR2 protein Q9H4G4 UNIPROT up-regulates activity phosphorylation Ser58 ILKHSPEsSRGQCGE 9606 BTO:0001370 25544559 YES miannu We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion. 0.325 SIGNOR-262887 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 23729744 YES apalma Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster), which in turn facilitates a further crucial signaling cleavage within the Notch transmembrane domain by a γ-secretase complex that contains Presenilin (S3 cleavage) 0.677 SIGNOR-255372 ITGB4 protein P16144 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9428518 YES gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. 0.423 SIGNOR-252697 tetra-mu3-sulfido-tetrairon chemical CHEBI:49883 ChEBI Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. 0.8 SIGNOR-267733 SMARCB1 protein Q12824 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.854 SIGNOR-270710 CSNK2A2 protein P19784 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 24962073 YES lperfetto CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1 0.2 SIGNOR-267667 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR NABP2 protein Q9BQ15 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000018 25249620 YES miannu Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation. 0.293 SIGNOR-271656 EP300 protein Q09472 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates binding 9606 24058639 YES miannu P300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380 0.291 SIGNOR-202682 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules 0.762 SIGNOR-171022 OSBP2 protein Q969R2 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity relocalization 30925160 YES lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. 0.8 SIGNOR-264879 INCENP protein Q9NQS7 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates binding 9606 12925766 YES gcesareni Using recombinant proteins, we found that aurora b kinase activity was stimulated by incenp and that the c-terminal region of incenp was sufficient for activation. 0.974 SIGNOR-86218 TPO protein P07202 UNIPROT L-alanine zwitterion smallmolecule CHEBI:57972 ChEBI up-regulates quantity chemical modification 9606 28153798 YES scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. 0.8 SIGNOR-267041 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT up-regulates activity phosphorylation Thr417 WGIKCRLtLQKPSCL 9606 20663873 YES miannu We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. 0.341 SIGNOR-259817 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 YES gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.468 SIGNOR-169678 SETD1A protein O15047 UNIPROT Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR form complex binding 9606 BTO:0000567 12670868 YES miannu Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles. 0.899 SIGNOR-264478 RPS6KA1 protein Q15418 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 YES lperfetto These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf 0.333 SIGNOR-137482 HDAC3 protein O15379 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 23213415 YES gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes. 0.495 SIGNOR-199961 MARCHF5 protein Q9NX47 UNIPROT DNM1L protein O00429 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16874301 YES miannu We found that MITOL associated with and ubiquitinated mitochondrial fission protein hFis1 and Drp1.Pulse–chase experiment also indicated that MITOL overexpression promoted Drp1 turnover. 0.2 SIGNOR-271894 SRC protein P12931 UNIPROT ITGAL protein P20701 UNIPROT down-regulates activity phosphorylation 9606 25624455 YES miannu PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role. 0.42 SIGNOR-254741 WNK3 protein Q9BYP7 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates activity phosphorylation Ser382 KRASFAKsVIGTPEF 9606 22032326 YES Manara We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro. 0.282 SIGNOR-260789 AKT1 protein P31749 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser346 LLCLRRSsLKAYGNG 9606 11809767 YES lperfetto Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation. 0.355 SIGNOR-252470 LRRK2 protein Q5S007 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23754980 YES gcesareni Subsequent assays confirmed a direct interaction between the lrrk2 roccor domain and all three human dvl proteins, these data are consistent with a role for lrrk2 in the activation of canonical wnt signaling bringing dvl proteins to cellular membranes. 0.48 SIGNOR-202187 CALM3 protein P0DP25 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 9822657 YES miannu The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk. 0.589 SIGNOR-266345 CAMK2B protein Q13554 UNIPROT RETREG1 protein Q9H6L5 UNIPROT up-regulates activity phosphorylation Ser151 AQLWRSLsESWEVIN -1 31930741 YES miannu Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy.  0.2 SIGNOR-273554 PRKD1 protein Q15139 UNIPROT CDH1 protein P12830 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 15695390 YES gcesareni Our study has identified e-cadherin as a novel substrate of pkd1, and phosphorylation of e-cadherin by pkd1 is associated with increased cellular aggregation and decreased cellular motility in prostate cancer. 0.452 SIGNOR-133856 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190203 P2RY13 protein Q9BPV8 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257231 Ub:E2 complex SIGNOR-C497 SIGNOR RING E3 ligase proteinfamily SIGNOR-PF106 SIGNOR up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270944 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 YES gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.706 SIGNOR-249409 TSHZ3 protein Q63HK5 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 19343227 YES miannu We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex.Endogenous HDAC1 was co-immunoprecipitated with FE65 when both FE65 and Teashirt3 were co-transfected (lane 4), but not when Teashirt3 or FE65 was omitted (lane 5 and 6), confirming that the association of HDAC1 with FE65 is dependent on, and mediated, by Teashirt3. 0.2 SIGNOR-264814 DDX3X protein O00571 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 33627125 YES miannu DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2 0.354 SIGNOR-269202 MAPK3 protein P27361 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates phosphorylation Thr292 YTAMDVAtGQEVAIK 9606 14993270 YES gcesareni Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation. 0.338 SIGNOR-123074 2-(6-Bromo-1,3-benzodioxol-5-yl)-N-(4-cyanophenyl)-1-[(1S)-1-cyclohexylethyl]benzimidazole-5-carboxamide chemical CID:126961335 PUBCHEM F2RL1 protein P55085 UNIPROT down-regulates activity chemical inhibition -1 28445455 YES Simone Vumbaca The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. 0.8 SIGNOR-261119 ULBP2 protein Q9BZM5 UNIPROT KLRK1 protein P26718 UNIPROT up-regulates binding 9606 BTO:0000782 10894171 YES gcesareni Here we describe a family of gpi-anchored cell surface proteins that function as ligands for the mouse activating nkg2d receptor. These molecules are encoded by the retinoic acid early inducible (rae-1) and h60 minor histocompatibility antigen genes on mouse chromosome 10 and show weak homology with mhc class i. 0.587 SIGNOR-79233 ABL1 protein P00519 UNIPROT BTK protein Q06187 UNIPROT unknown phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 BTO:0000567 12445832 YES gcesareni In this report we describe for the first time that c-Abl and Btk physically interact and that c-Abl can phosphorylate tyrosine 223 in the SH3 domain of Btk 0.336 SIGNOR-245278 superoxide smallmolecule CHEBI:18421 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 NO lperfetto The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. 0.7 SIGNOR-272277 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1A protein P50416 UNIPROT down-regulates activity binding 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267114 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser191 SRHAIMRsPQMVSAI 9606 18423204 YES amattioni Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt. 0.67 SIGNOR-178258 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 17151142 YES miannu TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling 0.925 SIGNOR-253591 AKT proteinfamily SIGNOR-PF24 SIGNOR RNF11 protein Q9Y3C5 UNIPROT down-regulates quantity phosphorylation Thr135 DWLMRSFtCPSCMEP 9606 BTO:0003474 16123141 YES gcesareni Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity 0.2 SIGNOR-248085 EXOC1 protein Q9NV70 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.865 SIGNOR-270776 PRKCZ protein Q05513 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser311 RTYETFKsIMKKSPF 9606 SIGNOR-C13 17183360 YES gcesareni Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) 0.554 SIGNOR-151432 PIM1 protein P11309 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 YES fspada Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42). 0.388 SIGNOR-179308 ABCC9 protein O60706 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 YES lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. 0.632 SIGNOR-262057 haloperidol chemical CHEBI:5613 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258520 ARHGAP20 protein Q9P2F6 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.708 SIGNOR-260472 APC protein P25054 UNIPROT SCF(TBL1) complex SIGNOR-C533 SIGNOR form complex binding 9606 BTO:0000007 20181957 YES miannu Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC).  0.492 SIGNOR-271949 SRC protein P12931 UNIPROT TERT protein O14746 UNIPROT down-regulates phosphorylation Tyr707 QDPPPELyFVKVDVT 9606 12808100 YES lperfetto Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via src kinase family-dependent phosphorylation of tyrosine 707 0.419 SIGNOR-102097 SRC protein P12931 UNIPROT HLA-A protein P04439 UNIPROT unknown phosphorylation Tyr344 SDRKGGSyTQAASSD 9606 6304688 YES lperfetto Hla-a2 and hla-b7 antigens are phosphorylated in vitro by rous sarcoma virus kinase (pp60v-src) at a tyrosine residue encoded in a highly conserved exon of the intracellular domain. 0.361 SIGNOR-25566 MAPK14 protein Q16539 UNIPROT ZNHIT1 protein O43257 UNIPROT up-regulates phosphorylation 9606 20473270 YES gcesareni We show that the srcap subunit named znhit1 or p18(hamlet), which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. Furthermore, p18hamlet was phosphorylated during myoblast differentiation in a p38 mapk-dependent manner (dal testo pmc) 0.315 SIGNOR-165571 AURKA protein O14965 UNIPROT TIFA protein Q96CG3 UNIPROT up-regulates activity phosphorylation Thr9 TSFEDADtEETVTCL 9606 BTO:0001545 28069801 YES miannu Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML.  0.2 SIGNOR-273551 CAMK2G protein Q13555 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1071 SFLQRYSsDPTGALT 9606 BTO:0000017 1309762 YES llicata The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity.  0.363 SIGNOR-250695 KDM5B protein Q9UGL1 UNIPROT PAX9 protein P55771 UNIPROT up-regulates activity binding 9606 BTO:0000007 12657635 YES miannu Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression 0.484 SIGNOR-223875 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 NO The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines 0.7 SIGNOR-253588 BRD4 protein O60885 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR up-regulates activity binding 9606 16109377 YES miannu Binding of Brd4 to Core P-TEFb Is Essential for Transcription. 0.601 SIGNOR-266411 EIF2B4 protein Q9UI10 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.869 SIGNOR-269127 MEAF6 protein Q9HAF1 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.746 SIGNOR-269301 NMDA proteinfamily SIGNOR-PF56 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). In contrast, group I mGluRs increase the intracellular Ca2+ concentration via a classical Gq-mediated mechanism that triggers release from intracellular stores through IP3 receptors 0.8 SIGNOR-264931 RPS5 protein P46782 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.889 SIGNOR-262419 RIMS1 protein Q86UR5 UNIPROT RAB3C protein Q96E17 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 YES miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle 0.416 SIGNOR-264382 SRC protein P12931 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 YES lperfetto Further, we identified an interaction between fak's second pro-rich motif and endophilin a2's sh3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow src phosphorylation of endophilin a2 at tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. Together, these results suggest a regulatory mechanism of cell invasion whereby fak promotes cell-surface presentation of mt1-mmp by inhibiting endophilin a2-dependent endocytosis. 0.637 SIGNOR-139150 MMP15 protein P51511 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272383 NTRK1 protein P04629 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 10708759 YES esanto Autophosphorylated trka binds directly to plc?, Abl, and shc. 0.534 SIGNOR-75402 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 15896703 YES gcesareni We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism. 0.2 SIGNOR-137241 MIB2 protein Q96AX9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity by destabilization ubiquitination Lys377 NEPSLQSkLQDEANY 9606 29642005 YES miannu These data suggest that after binding, MIB2 inhibits RIPK1 through a mechanism that is dependent on the E3 ligase activity of MIB2.|Whereas MIB2 readily ubiquitylated wild-type RIPK1, mutating K377 to R significantly reduced MIB2 mediated ubiquitylation of RIPK1 (XREF_SUPPLEMENTARY A). 0.295 SIGNOR-278633 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1120 QPLNPAPsRDPHYQD 9606 BTO:0000007 10347170 YES llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  0.371 SIGNOR-250623 BMP7 protein P18075 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 18719589 NO induction of mitochondrial biogenesis fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways 0.312 SIGNOR-180308 POU5F1 protein Q01860 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 NO flangone Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency.  0.7 SIGNOR-242067 MAP4K1 protein Q92918 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 8824585 NO gcesareni These results demonstrated that the observed jnk1 activation was from hpk1 and not from other hpkl-associated kinases or from cross-reactive kinases precipitated by anti-hpk1 antibody. 0.319 SIGNOR-43999 NFKB1 protein P19838 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 NO gcesareni Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2 0.629 SIGNOR-59951 GSK3B protein P49841 UNIPROT MYCN protein P04198 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 20530674 YES miannu Because GSK3\u03b2 phosphorylates Nmyc at T58, we assessed GSK3\u03b2 activation in Dex-treated MB cells. 0.33 SIGNOR-279722 CDC42 protein P60953 UNIPROT USP6 protein P35125 UNIPROT up-regulates relocalization 9606 12612085 YES miannu In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin. 0.36 SIGNOR-98935 PML protein P29590 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15093545 NO gcesareni The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor 0.7 SIGNOR-124320 SKP2 protein Q13309 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates binding 9606 BTO:0000007 28948618 YES miannu Skp2 induces ubiquitin-dependent degradation of Cygb. To this end, we performed an in vivo ubiquitination assay in HEK293T cells by transfecting relevant plasmids as indicated. The V5-Skp2DN was generated by deleting the N-terminal residues from 1 to 153 containing the F-box domain, which is involved in recruiting Skp2 to the SCF complex. 0.92 SIGNOR-272793 NMB protein P08949 UNIPROT NMBR protein P28336 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 YES gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. 0.766 SIGNOR-107022 methoxamine chemical CHEBI:6839 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258447 RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10882139 YES lperfetto The nuclear receptor ppargamma/rxralpha heterodimer regulates glucose and lipid homeostasis 0.668 SIGNOR-78907 NAT8L protein Q8N9F0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity chemical modification 9606 19524112 YES miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. 0.8 SIGNOR-267523 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser428 EPAPVLSsPPPADVS 9606 SIGNOR-C17 15037602 YES lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain. 0.493 SIGNOR-123516 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268593 F8 protein P00451 UNIPROT Factor VIIIa-IXa complex SIGNOR-C320 SIGNOR form complex binding 10090 BTO:0000131 25769543 YES lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. 0.765 SIGNOR-263553 TOP2B protein Q02880 UNIPROT RELN protein P78509 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 NO lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development 0.2 SIGNOR-242207 CDK1 protein P06493 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Thr135 TVQQHPStPKRHTVL 9606 BTO:0000007 21209322 YES lperfetto High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. we performed in vitro kinase assays using the tonebp/orebp peptide containing t135 as substrate (figure 3b, right panel) and various recombinant kinases. The peptide is strongly phosphorylated by cdk5, less by cdk1. 0.2 SIGNOR-170882 HDAC1 protein Q13547 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.823 SIGNOR-263839 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 10415025 YES fstefani Lc-ptp dephosphorylated erk2 in vitro. the complex formation of lc-ptp with erk is the essential mechanism for the suppression. Taken collectively, these results indicate that lc-ptp suppresses mitogen-activated protein kinase directly in vivo. 0.812 SIGNOR-69448 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 20083114 YES lperfetto A recent study revealed that ampk can inhibit mtorc1 independently of tsc2 by phosphorylating raptor at ser863. 0.467 SIGNOR-216422 SPOP protein O43791 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20463034 YES Gianni RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins 0.709 SIGNOR-268860 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Thr229 HFFKNIVtPRTPPPS 9606 BTO:0000661 12760422 YES lperfetto Thr94 in bovine myelin basic protein is a second phosphorylation site for 42-kDa mitogen-activated protein kinase (ERK2). 0.554 SIGNOR-249419 SMAD1 protein Q15797 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 16621789 YES gcesareni These results identify a potential mechanism whereby bmp-2 antagonizes wnt signaling in osteoblast progenitors by promoting an interaction between smad1 and dvl-1 that restricts beta-catenin activation. 0.347 SIGNOR-146131 MAPKAPK3 protein Q16644 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser179 RRFRRSQsDCGELGD -1 15850461 YES miannu Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.482 SIGNOR-263081 TARS1 protein P26639 UNIPROT threonine smallmolecule CHEBI:26986 ChEBI down-regulates quantity chemical modification 9606 25824639 YES miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 0.8 SIGNOR-270502 NFATC1 protein O95644 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates transcriptional regulation 9606 BTO:0001103 14729474 NO apalma To summarize, these two studies have generated important insights into the control of skeletal muscle hypertrophy by the calcineurin/NFATc1 signaling pathway 0.7 SIGNOR-256215 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0002572 12782654 YES lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. 0.96 SIGNOR-101336 EPHA2 protein P29317 UNIPROT CLDN4 protein O14493 UNIPROT down-regulates activity phosphorylation Tyr208 RSAAASNyV 9534 16236711 YES miannu EphA2 associates with claudin-4 via their extracellular domains. This association, in turn, leads to phosphorylation of the cytoplasmic carboxyl terminus of claudin-4 at Tyr-208. The tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability. These results indicate that EphA2 moderates the function of tight junctions via phosphorylation of claudin-4. 0.478 SIGNOR-262859 LCK protein P06239 UNIPROT CD5 protein P06127 UNIPROT up-regulates activity phosphorylation Tyr453 ASHVDNEySQPPRNS 9606 BTO:0000782 11298344 YES lperfetto Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck 0.542 SIGNOR-106799 TYK2 protein P29597 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 YES miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). 0.729 SIGNOR-260148 SGK1 protein O00141 UNIPROT GLI1 protein P08151 UNIPROT down-regulates binding 9606 25790864 YES gcesareni SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family 0.2 SIGNOR-251672 GRB2 protein P62993 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates binding 9606 12766170 YES Grb2-associated binding (Gab) scaffolding/adapter proteins are a family of three members including mammalian Gab1, Gab2, and Gab3 that are highly conserved. lperfetto The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2 0.872 SIGNOR-235917 N-(6-Chloro-7-methoxy-9H-pyrido[3,4-b]indol-8-yl)-2-methylnicotinamide chemical CID:9929127 PUBCHEM IKBKB protein O14920 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258249 PIK3CB protein P42338 UNIPROT PIK3CB protein P42338 UNIPROT down-regulates activity phosphorylation Ser1070 TVRKDYRs -1 12502714 YES lperfetto Autophosphorylation sites of both pi3k isoforms were mapped to c-terminal serine residues of the catalytic p110 subunit (i.e. serine 1070 of p110 beta and serine 1101 of p110 gamma). autophosphorylation of p110 beta On serine 1070 results in down-regulation of the lipid kinase activity of pi3k beta 0.2 SIGNOR-96776 PHF6 protein Q8IWS0 UNIPROT UBTF protein P17480 UNIPROT down-regulates binding 9606 BTO:0001271 23229552 YES miannu We demonstrate that phf6 is a nucleolus, ribosomal rna promoter-associated protein. Phf6 directly interacts with upstream binding factor (ubf) through its phd1 domain and suppresses ribosomal rna (rrna) transcription by affecting the protein level of ubf 0.28 SIGNOR-200133 SRMS protein Q9H3Y6 UNIPROT MAP2K4 protein P45985 UNIPROT down-regulates activity phosphorylation Tyr307 LATGRFPyPKWNSVF 9606 BTO:0002181 37020040 YES miannu SRMS directly phosphorylates MKK4 and inhibits MKK4-JNK-c-Jun activation upon platinum treatment. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation. 0.2 SIGNOR-277902 MAPK3 protein P27361 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 YES miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. 0.276 SIGNOR-277855 MAPK1 protein P28482 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 BTO:0000007 20110267 YES llicata These results demonstrated a critical role of noxa1 phosphorylation on ser-282 and ser-172 in preventing nox1 hyperactivation through the decrease of noxa1 interaction to nox1 and rac1. 0.326 SIGNOR-163659 CDK1 protein P06493 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 15070733 YES gcesareni We have found also that the major M-phase kinases polo-like kinase 1 (Plk1) and Cdc2 are responsible for the phosphorylation of S53 and S123, respectively, and that in each case phosphorylation generates an unconventional phospho-degron (signal for degradation) that can be recognized by beta-TrCP 0.858 SIGNOR-123824 PRKN protein O60260 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 11590439 YES miannu Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. 0.2 SIGNOR-278550 ROCK1 protein Q13464 UNIPROT RDX protein P35241 UNIPROT unknown phosphorylation Thr573 RQIRQGNtKQRIDEF -1 9456324 YES lperfetto  A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad. 0.679 SIGNOR-248995 TLR4 protein O00206 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001545 28137827 NO miannu S100A9 induces differentiation of acute myeloid leukemia cells through TLR4. 0.7 SIGNOR-261923 TACR3 protein P29371 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.434 SIGNOR-257333 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity phosphorylation Ser250 PTRPQEQsTGDTMGR -1 21775627 YES lperfetto Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition 0.65 SIGNOR-265009 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT down-regulates activity phosphorylation Thr727 QKLRESEtSVTTAQA 9606 BTO:0000007 25755282 YES miannu Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.  0.294 SIGNOR-273578 CCNA2 protein P20248 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR form complex binding 9606 19056339 YES lperfetto We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2. 0.977 SIGNOR-182566 MAPK3 protein P27361 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 8626435 YES esanto Upon activation, several serine residues on the cytosolic oxidase subunit p47phox become phosphorylated. Mitogen-activated protein kinase phophorylated only the peptide containing ser345/348. 0.421 SIGNOR-40821 LRAT protein O95237 UNIPROT all-trans-retinyl ester smallmolecule CHEBI:63410 ChEBI up-regulates quantity chemical modification 10090 18093970 YES lperfetto We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis 0.8 SIGNOR-265111 PAK6 protein Q9NQU5 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Thr158 HLVSRPStSSRRRAI 9606 BTO:0000007 23132866 YES miannu We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation. 0.2 SIGNOR-276428 YY1 protein P25490 UNIPROT ATP2C1 protein P98194 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15955096 NO miannu when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. 0.2 SIGNOR-255193 BDKRB2 protein P30411 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.425 SIGNOR-257281 PPP1CA protein P62136 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates activity dephosphorylation Ser89 AQHVRSHsSPASLQL 9606 21189257 YES miannu PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. 0.541 SIGNOR-277116 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates activity phosphorylation Ser260 SEGGADDsAEEGDLL 9606 15687492 YES gcesareni In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C. 0.355 SIGNOR-133532 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 YES lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. 0.2 SIGNOR-252768 LRP6 protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization relocalization 9606 BTO:0000007 18632848 YES lperfetto The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism. 0.732 SIGNOR-227939 GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 20510530 YES fferrentino GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis 0.369 SIGNOR-132949 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120068 PRKCE protein Q02156 UNIPROT ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr429 MQILKFKtIEEVVGR -1 28056995 YES lperfetto Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. 0.281 SIGNOR-271866 MAPK3 protein P27361 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Thr614 AFRLEPLtPRGVLTV 9606 BTO:0000150 17311928 YES llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 0.52 SIGNOR-153391 MDM2 protein Q00987 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression 9606 18292944 NO amattioni Overexpression of hdm2 resulted in a decrease in the level of p21waf1 0.644 SIGNOR-160977 PRKDC protein P78527 UNIPROT ESR1 protein P03372 UNIPROT up-regulates quantity by stabilization phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 20219974 YES miannu DNA-PK phosphorylates ERalpha at Ser-118.|Phosphorylation resulted in stabilization of ERalpha protein as inhibition of DNA-PK resulted in its proteasomal degradation. 0.386 SIGNOR-279561 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity precursor of -1 10922363 YES Luana Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently. 0.8 SIGNOR-269767 Temsirolimus chemical CHEBI:79699 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 21081844 YES gcesareni Temsirolimus, an inhibitor of mammalian target of rapamycin (mtor) complex 1, is approved for the treatment of metastatic renal cell carcinoma (rcc). 0.8 SIGNOR-169712 naltrexone chemical CHEBI:7465 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258946 IMPDH2 protein P12268 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30518405 NO miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. 0.2 SIGNOR-260960 MAPK1 protein P28482 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 9528799 YES gcesareni Our results provide strong evidence that dsrna binding is required for dimerization of full-length pkr molecules in vivo, leading to autophosphorylation in the activation loop and stimulation of the eif2alpha kinase function of pkr. 0.2 SIGNOR-56337 BCOR protein Q6W2J9 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 YES miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. 0.548 SIGNOR-255276 PRKCA protein P17252 UNIPROT GRIN1 protein Q05586 UNIPROT up-regulates activity phosphorylation Ser896 SSFKRRRsSKDTSTG 10116 BTO:0000938 15936117 YES miannu Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890. 0.418 SIGNOR-263177 AKT proteinfamily SIGNOR-PF24 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 YES lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis 0.784 SIGNOR-251526 NEK6 protein Q9HC98 UNIPROT FOXJ2 protein Q9P0K8 UNIPROT up-regulates activity phosphorylation Ser254 NFQDLSWsFRNLYKS 9606 27899381 YES miannu Additionally, we found that NEK6 phosphorylated FOXJ2 at Thr23 and Ser254 ( xref , lanes 3 and 5), and NCOA5 at Ser21 and Ser151 ( xref , lanes 3 and 4). 0.2 SIGNOR-278965 ERP44 protein Q9BS26 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity binding 9606 BTO:0000567 15652484 YES Simone In this study, we found that ERp44, an ER lumenal protein of the thioredoxin family, directly interacts with the third lumenal loop of IP(3)R type 1 (IP(3)R1) and that the interaction is dependent on pH, Ca(2+) concentration, and redox state. In this study we demonstrated that ERp44 directly interacts with the L3V domain of IP3R1, thereby inhibiting its channel activity. 0.581 SIGNOR-261046 ROCK1 protein Q13464 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation 9606 26241960 YES miannuccelli Additional phosphorylation of PDK1 by ROCK-I improves the stability of the ROCK-I and PDK1 complex. 0.299 SIGNOR-279758 FN1 protein P02751 UNIPROT FN1/SDC4 complex SIGNOR-C210 SIGNOR form complex binding 23290138 YES apalma We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells 0.71 SIGNOR-255285 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258131 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI down-regulates quantity chemical modification 9606 33179964 YES miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). 0.8 SIGNOR-267317 MAPK1 protein P28482 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 9155017 YES gcesareni We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity toward a substrate, eukaryotic initiation factor-4e (eif-4e). 0.593 SIGNOR-48298 NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.2 SIGNOR-256381 Ub:E2 complex SIGNOR-C497 SIGNOR CHFR protein Q96EP1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271061 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser717 LKEAEEEsSEDD 9606 BTO:0000007 11500362 YES llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  0.386 SIGNOR-250859 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT up-regulates activity phosphorylation Ser642 DSFGSLPsPKELSSF 9606 BTO:0002181 25452387 YES miannu The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.  0.2 SIGNOR-276444 CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI PGS1 protein Q32NB8 UNIPROT up-regulates activity chemical activation 9606 29034233 YES lperfetto After activation of PA by the CDP-DAG synthase TAMM41 (Kutik et al., 2008), the phosphatidylglycerol phosphate synthase (PGS1) catalyzes the committed step by converting CDP-DAG to phosphatidylglycerol phosphate (PGP) 0.8 SIGNOR-267024 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258915 CAMK2A protein Q9UQM7 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 15363394 NO miannu In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively. 0.7 SIGNOR-268385 PYGL protein P06737 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267949 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys17 GLGKGGAkRHRKVLR 9606 16227571 YES miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 0.2 SIGNOR-263944 PAX6 protein P26367 UNIPROT PAX6 protein P26367 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001874 17251190 NO Regulation miannu Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling. TGFβ receptor activation represses Pax6 promoter activity by releasing Pax6 from autoregulating its own promoter. 0.2 SIGNOR-251873 ribavirin chemical CHEBI:63580 ChEBI IMPDH2 protein P12268 UNIPROT down-regulates activity chemical inhibition 9606 22555152 YES Federica Ribavirin, a well-known IMPDH inhibitor, was included as a reference drug. As expected, this compound markedly inhibited IMPDH activity in a dose-dependent manner in bothtumour cell lines 0.8 SIGNOR-261079 MYCL protein P12524 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0000724 7882978 NO irozzo These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation. 0.7 SIGNOR-259202 ULK2 protein Q8IYT8 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates phosphorylation 9606 21460634 YES lperfetto We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I 0.302 SIGNOR-217487 SLC11A1 protein P49279 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 11909746 NO Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS) 0.7 SIGNOR-254037 SEC61G protein P60059 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 YES lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER 0.893 SIGNOR-265278 KIF4A protein O95239 UNIPROT PRC1 protein O43663 UNIPROT up-regulates activity binding 9606 15297875 YES miannu These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins 0.569 SIGNOR-265988 HUWE1 protein Q7Z6Z7 UNIPROT ATOH1 protein Q92858 UNIPROT down-regulates quantity ubiquitination 9606 32336296 YES miannu Huwe1 ubiquitinates and degrades Atoh1, and robustly affects development of GNPs that express this transcription factor [ xref ].|This provides further evidence that phosphorylation of Atoh1 affects Huwe1-mediated degradation, and demonstrates that Huwe1 inhibits Atoh1 to affect cellular differentiation in multiple cell types. 0.305 SIGNOR-278693 BRAF protein P15056 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity relocalization 9606 19861538 NO miannu The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression. 0.251 SIGNOR-251987 MAPK1 protein P28482 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates phosphorylation Ser50 GTLFQDPsFPAIPSA 9606 14993287 YES lperfetto Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo. 0.627 SIGNOR-123079 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273107 TFIIH complex SIGNOR-C457 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser403 PEEFISLsPPHEALD 9606 10428966 YES lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase.  here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. 0.319 SIGNOR-269353 PTPN4 protein P29074 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 31025789 YES miannu In terms of molecular mechanisms, we revealed that PTPN4 dephosphorylates pSTAT3 at the Tyr705 residue with a direct interaction, which might provide novel targets for the therapy of CRC.|Loss of PTPN4 Activates STAT3 to Promote the Tumor Growth in Rectal Cancer. 0.255 SIGNOR-277057 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr620 SKSVLPRtPESWRLT 9606 22094256 YES lperfetto We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627) 0.623 SIGNOR-177259 RASGEF1A protein Q8N9B8 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.434 SIGNOR-183823 CSNK1A1 protein P48729 UNIPROT ATM protein Q13315 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1270 SHFDEVKsIANQIQE 9606 BTO:0002181 37075701 YES miannu Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. 0.2 SIGNOR-277918 FBXW8 protein Q8N3Y1 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001109 phosphorylation:Thr286 EEVDLACtPTDVRDV 17205132 YES miannu We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8. 0.511 SIGNOR-271624 NFIX protein Q14938 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268907 MAPK11 protein Q15759 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 20820849 YES gcesareni Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis. 0.353 SIGNOR-167848 CTBP1 protein Q13363 UNIPROT VDR protein P11473 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 18485278 NO miannu We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. 0.352 SIGNOR-255178 FLI1 protein Q01543 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001549 12359731 NO miannu Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter. 0.2 SIGNOR-254157 MAPK8 protein P45983 UNIPROT CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser101 ASESSLSsESSESSD 9606 BTO:0000567 21807946 YES miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). 0.284 SIGNOR-276352 hsa-miR-200b-5p mirna URS000012A1DD_9606 RNAcentral VEGFA protein P15692 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005168 25301739 YES Parnian Taken together, data indicate miR-200b directly repressing VEGF-A protein expression via binding to 3′UTR of human VEGF-A gene. 0.4 SIGNOR-278864 CCL5 protein P13501 UNIPROT hsa-miR-200b-5p mirna URS000012A1DD_9606 RNAcentral down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005168 25301739 NO Parnian CCL5 enhances VEGF-dependent angiogenesis in human chondrosarcoma cells by down-regulating miR-200b through PI3K/Akt signaling pathway. 0.4 SIGNOR-278865 creatine smallmolecule CHEBI:16919 ChEBI CKM protein P06732 UNIPROT up-regulates activity chemical activation 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265784 MRPS22 protein P82650 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.734 SIGNOR-261434 FAM83D protein Q9H4H8 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273757 WNT7A protein O00755 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.647 SIGNOR-131903 HDAC1 protein Q13547 UNIPROT DNMT1 protein P26358 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23242655 NO Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells. 0.786 SIGNOR-254028 FBXO31 protein Q5XUX0 UNIPROT Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR up-regulates activity binding 9606 BTO:0002181 29343641 YES miannu FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. 0.519 SIGNOR-277381 CNBP protein P62633 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 23774591 YES Luana These data verified that the binding of CNBP with c-myc promoter G-quadruplex can indeed down-regulate its associated gene expression for a certain period of time. This result with human CNBP is somehow consistent with previous reports that c-myc G-quadruplex serves as a silencer of c-myc transcription [7] and CNBP promotes the formation of c-myc G-quadruplex. 0.303 SIGNOR-261571 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 19584320 YES lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.49 SIGNOR-216499 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH7 protein Q9ULB5 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265847 FRAT1 protein Q92837 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity binding 10481074 YES lperfetto In contrast to the GS‐1 peptide, glycogen synthase and the eIF2B peptide, the GSK3‐catalysed phosphorylation of Tau was completely inhibited by FRATtide|This prevents GSK3 from phosphorylating and inhibiting glycogen synthase [2, 3] and protein synthesis initiation factor eIF2B 0.289 SIGNOR-262835 GSK690693 chemical CHEBI:90677 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252462 EEF1A2 protein Q05639 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269523 BTG2 protein P78543 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 NO miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 0.369 SIGNOR-254649 BLK protein P51451 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr288 YETADGGyMTLNPRA -1 8756631 YES lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. 0.437 SIGNOR-249311 PPP2R5D protein Q14738 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR form complex binding 9606 23454242 YES gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. 0.857 SIGNOR-243439 RPL5 protein P46777 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 25301064 YES miannu We report that rpl5 and rpl11 can also enhance the transcriptional activity of a p53 homolog tap73 0.341 SIGNOR-205517 RORA protein P35398 UNIPROT PCP4 protein P48539 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 YES miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 0.2 SIGNOR-266848 RPL23A protein P62750 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.859 SIGNOR-262476 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2G2 protein P60604 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.668 SIGNOR-271344 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation -1 9155018 YES These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways 0.671 SIGNOR-253011 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.2 SIGNOR-159369 UDP-D-glucose smallmolecule CHEBI:18066 ChEBI P2RY14 protein Q15391 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257562 TLR4 protein O00206 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9606 28137827 YES miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. 0.416 SIGNOR-261928 RNF8 protein O76064 UNIPROT BCL10 protein O95999 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 24732096 YES miannu Phosphorylated and ubiquitinated BCL10 is stabilized on the damage sites through binding to and presenting UBC13 to RNF168.|We thus concluded that BCL10 is ubiquitinated mainly with K63-linked ubiquitination by RNF8. 0.329 SIGNOR-278778 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257519 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ -1 15946941 YES done miannu PKA Phosphorylates GRK1 on Ser21. Phosphorylation by PKA inhibits GRK1 activity. 0.2 SIGNOR-274079 SRC protein P12931 UNIPROT CTNND2 protein Q9UQB3 UNIPROT up-regulates activity phosphorylation Tyr1157 SRKDYETyQPFQNST 9606 24412473 YES miannu Furthermore, according to our data from immunoprecipitation to py20 antibody, c-Src can phosphorylate delta-catenin on Y1073, Y1176, Y1179 and Y1112, with the predominant sites being Y1073, Y1112 and Y1176.|Interestingly, we found that c-Src can increase the stability of delta-catenin in MEF cells. 0.329 SIGNOR-278327 SB 415286 chemical CHEBI:91107 ChEBI GSK3A protein P49840 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206751 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser85 GSEGDSEsGEEEELG -1 2046671 YES llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Mutation of serine 85 alone had a smaller but significant effect on phosphorylation that may be due to alteration in the protein kinase recognition site. 0.551 SIGNOR-250957 RNF7 protein Q9UBF6 UNIPROT JUN protein P05412 UNIPROT down-regulates activity ubiquitination 9606 23136067 YES miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 0.325 SIGNOR-271452 hsa-let-7a-5p mirna URS0000416056_9606 RNAcentral CCR7 protein P32248 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000815 22251626 YES Let-7a was found to target CCR7 3’UTR directly, thereby downregulating breast cancer cell migration and invasion. 0.4 SIGNOR-277926 FYN protein P06241 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 YES miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. 0.2 SIGNOR-276396 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273054 CX3CL1 protein P78423 UNIPROT CX3CR1 protein P49238 UNIPROT up-regulates binding 9606 11432858 YES gcesareni Fractalkine/cx3cl1 is a membrane-tethered chemokine that functions as a chemoattractant and adhesion protein by interacting with the receptor cx3cr1. 0.784 SIGNOR-109135 SIRT1 protein Q96EB6 UNIPROT COL10A1 protein Q03692 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21337390 NO miannu The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5. 0.2 SIGNOR-255141 F2RL1 protein P55085 UNIPROT RAB3A protein P20336 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254836 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser358 MHPYQGRsGCSSQSI -1 28130417 YES lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. 0.264 SIGNOR-264871 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 NO gcesareni Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression. 0.2 SIGNOR-254344 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 YES lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) 0.957 SIGNOR-209705 POMT complex SIGNOR-C372 SIGNOR DAG1 protein Q14118 UNIPROT up-regulates activity glycosylation 9606 BTO:0000007 14699049 YES miannu we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O-mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O-mannosylation is complex. Further, protein O-mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain. 0.722 SIGNOR-265430 LCK protein P06239 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr354 SSNQELIyEGRRLVL 9606 BTO:0002181 28618271 YES miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  0.2 SIGNOR-276724 ADORA2B protein P29275 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.514 SIGNOR-256767 AKT1 protein P31749 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 YES flangone Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. 0.457 SIGNOR-252545 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR WNK1 protein Q9H4A3 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 23387299 YES miannu CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms. 0.321 SIGNOR-272100 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 14722106 YES gcesareni Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes 0.825 SIGNOR-84038 PKA proteinfamily SIGNOR-PF17 SIGNOR ATG16L1 protein Q676U5-1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser269 RAATKRLsQPAGGLL -1 31580256 YES miannu PKA phosphorylates ATG16L1α at Ser268 and ATG16L1β at Ser269, driving phosphorylation-dependent degradation of ATG16L1 protein.  0.2 SIGNOR-277488 adenosine smallmolecule CHEBI:16335 ChEBI ADORA3 protein P0DMS8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257449 WNK1 protein Q9H4A3 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates phosphorylation Thr1048 YQEKVHMtWTKDKYM 9606 BTO:0000938 BTO:0000142 19665974 YES gcesareni We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases. 0.454 SIGNOR-187560 MAP3K13 protein O43283 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 11726277 YES gcesareni Lzk directly phosphorylated and activated mkk7. 0.583 SIGNOR-112349 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT up-regulates phosphorylation 9606 18042454 YES miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. 0.2 SIGNOR-159473 bisphenol A chemical CHEBI:33216 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9751507 YES miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings.  0.8 SIGNOR-268739 F2RL1 protein P55085 UNIPROT TNFRSF12A protein Q9NP84 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254837 hsa-miR-103a-3p mirna URS0000476BE1_9606 RNAcentral GPRC5A protein Q8NFJ5 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002137 24984703 YES Parnian MiR-103a-3p down-regulates GPRC5A protein by binding to the 5′ UTR of GPRC5A’s mRNA 0.4 SIGNOR-278004 COL1A1 protein P02452 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates binding 9606 9659900 YES gcesareni We report that the collagens serve as ligands for the previously orphan family of discoidin domain-containing receptor-like tyrosine kinases. 0.336 SIGNOR-58779 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 17197020 YES gcesareni We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of ca2+ influx through trpv6 ca2+ channels in hek293 cells. Co-transfection with src led to tyrosine phosphorylation of trpv6 which could be dephosphorylated by ptp1b. y161/162 are essential for tyrosine phosphorylation-dependent modulation of trpv6-mediated ca2+ entry. 0.63 SIGNOR-151711 DUSP6 protein Q16828 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 YES gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). 0.854 SIGNOR-103149 MYC protein P01106 UNIPROT UBTF protein P17480 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000539 15282543 YES lperfetto MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter. 0.357 SIGNOR-269644 SNARE_complex complex SIGNOR-C346 SIGNOR Exocytosis phenotype SIGNOR-PH157 SIGNOR up-regulates 9606 BTO:0000938 30267828 NO miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. 0.7 SIGNOR-263969 PAK1 protein Q13153 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation Ser67 RQLRKVRsVELDQLP 9606 BTO:0000007 12228228 YES lperfetto We found that pak1 phosphorylated mekk1 on serine 67 of its amino-terminal regulatory domain. mekk1 activity was increased modestly following pak phosphorylation. 0.537 SIGNOR-236006 CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 BTO:0000093 11154267 YES lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity 0.891 SIGNOR-245462 AKT1 protein P31749 UNIPROT ZRANB1 protein Q9UGI0 UNIPROT up-regulates activity phosphorylation Thr117 QRRTRSPtESPQSSG 9606 BTO:0000007 29748601 YES miannu Our findings also identify an essential role for activation of Trabid by AKT-mediated phosphorylation at Ser78/Thr117 in negatively regulating Twist1 signaling, which further provides insights into the mechanisms by which Trabid regulates Twist1 ubiquitination. 0.2 SIGNOR-273484 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT3 protein Q9Y243 UNIPROT down-regulates activity chemical inhibition 25309440 YES lperfetto Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway. 0.8 SIGNOR-262012 ABL2 protein P42684 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 YES lperfetto Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised 0.606 SIGNOR-146589 BRAF protein P15056 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates quantity phosphorylation Thr219 AEHQYFMtEYVATRW 9606 29483645 YES miannu Our data indicate that oncogenic BRAF increases ERK5 protein level, phosphorylation at several residues and kinase activity.|Overexpression of oncogenic BRAF induced ERK5 phosphorylation at Thr218 and Tyr220, although to a lower level than that induced by MEK5DD. 0.292 SIGNOR-278352 YY1 protein P25490 UNIPROT SURF1 protein Q15526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10858544 NO miannu We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response. 0.31 SIGNOR-254614 TGFBR2 protein P37173 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0001660 9435577 YES lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. 0.411 SIGNOR-252732 RAB6A protein P20340 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 20360680 NO miannu We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles. 0.7 SIGNOR-266880 IKBKB protein O14920 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 24290981 YES miannuccelli Taken together, these results indicate that IKK\u03b2-dependent phosphorylation of RAPGEF2 is required for RAPGEF2 degradation induced by HGF and mediated by \u03b2TrCP. 0.2 SIGNOR-279807 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 YES The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation. 0.2 SIGNOR-249575 gemcitabine chemical CHEBI:175901 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003207 25562513 YES miannu 2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000. The specific TS inhibitor Raltitrexed (RTX) was included as a positive control. Using the in situ TS activity assay measuring the intracellular conversion of [5-(3)H]-2'-deoxyuridine or [5-(3)H]-2'-deoxycytidine to dTMP and tritiated water, it was observed that dFdC and dFdU inhibited TS. 0.8 SIGNOR-259350 PPP1CA protein P62136 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates activity dephosphorylation Ser311 PYHSREQsTDSGLGL 9606 21189257 YES miannu PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. 0.541 SIGNOR-277115 SKP2 protein Q13309 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0003725 11439327 YES miannu We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line. 0.592 SIGNOR-272575 PRPS2 protein P11908 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI down-regulates quantity chemical modification 9606 16939420 YES miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. 0.8 SIGNOR-267081 FRK protein P42685 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr444 QQNRFPDyLEAIPGT 9606 BTO:0002035 35723276 YES miannu Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.  0.275 SIGNOR-275457 MAPK14 protein Q16539 UNIPROT USP21 protein Q9UK80 UNIPROT up-regulates activity phosphorylation Ser538 VYNDSRVsPVSENQV 9606 BTO:0000567 28254948 YES done miannu In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING. HSV-1 infection recruited USP21 to STING at late stage by p38-mediated phosphorylation of USP21 at Ser538. I 0.253 SIGNOR-273670 IRX1 protein P78414 UNIPROT SPON1 protein Q9HCB6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. 0.2 SIGNOR-261669 PRKCD protein Q05655 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation Thr790 TRNDVAPtLMSVPRY 10029 27203386 YES Manara Phosphorylation of E-cadherin at threonine 790 by protein kinase Cδ reduces β-catenin binding and suppresses the function of E-cadherin. 0.2 SIGNOR-260893 Ub:E2 complex SIGNOR-C497 SIGNOR RCHY1 protein Q96PM5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271021 MDM2 protein Q00987 UNIPROT RUNX3 protein Q13761 UNIPROT down-regulates quantity by destabilization ubiquitination Lys94 KTLPVAFkVVALGDV 9606 19808967 YES miannu RUNX3 protein is ubiquitinated by MDM2 at Lys-94 and Lys-148.|RUNX3 protein is ubiquitinated by MDM2 at Lys 94 and Lys 148.|MDM2 suppresses the transcriptional activity of RUNX3. 0.578 SIGNOR-278557 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MAP3K8 protein P41279 UNIPROT down-regulates binding 9606 22435554 YES lperfetto Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek 0.554 SIGNOR-216289 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 21902831 YES gcesareni Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5. 0.58 SIGNOR-176560 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000527 21419810 YES lperfetto In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer 0.32 SIGNOR-172886 AKT1 protein P31749 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates activity phosphorylation 9534 BTO:0004055 10930578 YES Federica Further, we have demonstrated an in vivo association of IMPDH and PKB/Akt by co‐immunoprecipitation from COS cells expressing a constitutively active form of PKB/Akt. Finally, we were able to show that this constitutively active PKB/Akt could phosphorylate IMPDH in vitro. Thus, the interplay between PKB/Akt and IMPDH reported here could suggest that PKB/Akt activation leads to IMPDH type II activation which in turn prepares the cell for entry into S phase. 0.387 SIGNOR-261262 TOPBP1 protein Q92547 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates binding 9606 20068082 YES gcesareni Topbp1 directly activates atr/atrip and promotes atr-mediated chk1 phosphorylation. 0.795 SIGNOR-163214 dopamine smallmolecule CHEBI:18243 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257479 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18936167 YES These results therefore suggest that the autoactivation residues Y1054 and Y1059 are targeted by DEP-1 and that this results in the inhibition of kinase activity and the consequent general dephosphorylation of VEGFR2. 0.698 SIGNOR-248710 GNRHR protein P30968 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.443 SIGNOR-256792 JAK1 protein P23458 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity phosphorylation Tyr446 AAVAFQGyLRQTRCA 10433356 YES Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). 0.809 SIGNOR-251338 SNAI2 protein O43623 UNIPROT CXCL12 protein P48061 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 22074556 NO miannu We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. 0.408 SIGNOR-255169 WT1 protein P19544 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 NO irozzo Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation. 0.7 SIGNOR-255705 FANCM protein Q8IYD8 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates relocalization 9606 20372056 YES gcesareni The enzymatic activity of fan cm is then required to remodel and stabilize the fork to allow topbp1 access to activate atr , in a 9-1-1-independent manner. 0.419 SIGNOR-164765 DAPK1 protein P53355 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL 9606 20141836 YES miannu DAPK1 Activation Enhances the NR1 and NR2B Channel Conductance.|Thus, an activated DAPK1 enhances NR1 and NR2B receptor channel conductance by phosphorylating NR2B subunit at Ser 1303. 0.497 SIGNOR-278397 AKT1 protein P31749 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000944 12150915 YES lperfetto We have shown thataktregulates the tsc1-tsc2 complex by directly phosphorylating tsc2. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1akt has been shown to directly phosphorylate two sites on tsc2 (s939 and t1462 on the full-length human protein), which are conserved and phosphorylated in drosophila tsc2, and is likely to phosphorylate two or three additional sites (s981 and s1130/s1132). 0.784 SIGNOR-235628 TARS1 protein P26639 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 25824639 YES miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 0.8 SIGNOR-270504 RASGRF2 protein O14827 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.552 SIGNOR-260573 ADRB2 protein P07550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.336 SIGNOR-257081 MKRN3 protein Q13064 UNIPROT PABPC1 protein P11940 UNIPROT down-regulates activity ubiquitination 9606 33744966 YES miannu MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA|Altogether, it is thus clear that the ubiquitination of PABPC1 or PABPC4 by MKRN3 negatively regulates the formation of translation initiation complex (TIC), attenuates their binding to poly (A)-tail contained mRNAs, and leads to the shortened poly (A) tail-length of GNRH1 mRNA. 0.2 SIGNOR-278764 B3GNT3 protein Q9Y2A9 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates activity glycosylation Asn192 KREEKLFNVTSTLRI 9606 BTO:0002548 29438695 YES Barakat These results further suggested that B3GNT3 mediates PD-L1 and PD-1 interaction through N-linked glycosylation instead of O-linked glycosylation 0.2 SIGNOR-275389 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPK14 protein Q16539 UNIPROT down-regulates 9606 BTO:0000801 11842088 NO lperfetto In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. 0.2 SIGNOR-244665 NUTF2 protein P61970 UNIPROT NUP62 protein P37198 UNIPROT up-regulates activity binding 9606 BTO:0000567 7744965 YES Simone Our data suggest that NTF2 interacts directly with NPC protein 1362 and exerts its effect at a relatively late step in the nuclear protein import pathway. We obtained a cDNA encoding NTF2 and showed that the recombinant protein restores transport activity to p62-pretreated cytosol. 0.844 SIGNOR-261255 HSD3B2 protein P26439 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 2243100 YES lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. 0.8 SIGNOR-268634 HLX protein Q14774 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20008130 NO Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. 0.2 SIGNOR-261624 PRKCQ protein Q04759 UNIPROT WIPF1 protein O43516 UNIPROT up-regulates activity phosphorylation Ser488 RNESRSGsNRRERGA -1 12504004 YES lperfetto TCR engagement also causes PKCtheta-dependent phosphorylation of WIP, causing the disengagement of WASP from the WIP-WASP complex, thereby releasing it from WIP inhibition. These results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation. | These results suggest that phosphorylation at S488 disrupts WIP binding to WASP. 0.324 SIGNOR-249181 MAPK3 protein P27361 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 YES llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro 0.328 SIGNOR-173413 NRF1 protein Q16656 UNIPROT RETREG3 protein Q86VR2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23939472 NO miannu We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. 0.2 SIGNOR-261367 AKT2 protein P31751 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity 9606 BTO:0000150 12697749 NO lperfetto Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1 0.426 SIGNOR-100591 TFEB protein P19484 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Notably, TFEB regulates genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (for example, Cd36 and Fabps), and the β-oxidation of FFA in mitochondria (for example, Cpt1, Crat, Acadl, Acads and Hdad) and in peroxisomes (Cyp4a genes). 0.283 SIGNOR-276707 IL6 protein P05231 UNIPROT GCH1 protein P30793 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12859689 NO miannu CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. 0.265 SIGNOR-252220 WIPF1 protein O43516 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR up-regulates 9606 19121306 NO lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. 0.2 SIGNOR-260611 NFATC3 protein Q12968 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21871017 YES miannu NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration 0.279 SIGNOR-264028 NR3C1 protein P04150 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8639160 YES gcesareni We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins 0.599 SIGNOR-251680 RTN4 protein Q9NQC3 UNIPROT LINGO1 protein Q96FE5 UNIPROT up-regulates binding 9606 BTO:0000938 15694321 YES flangone Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1, 0.665 SIGNOR-133752 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr86 YTLSRAQtVVVEYTH -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.767 SIGNOR-276135 NOD1 protein Q9Y239 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates activity binding 9606 BTO:0000567 19898471 YES miannu By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease. 0.68 SIGNOR-252406 PAX3 protein P23760 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 YES FGFR4 is a transcriptional target of PAX3 and the PAX3-FOXO1 fusion protein found in ARMS. 0.365 SIGNOR-251572 DNAJB12 protein Q9NXW2 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates activity binding 9606 BTO:0000007 21148293 YES miannu JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex 0.51 SIGNOR-271491 SNRPG protein P62308 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.797 SIGNOR-270632 PBK protein Q96KB5 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 17631144 YES miannu Phosphorylation of ELK1 or ERK2 increased dramatically compared with controls and suggested that TOPK or ERK2 could enhance ERK2 or TOPK kinase activity by respective and mutual phosphorylation of each other.|The results indicated that active TOPK could strongly phosphorylate ERK2 and very weakly phosphorylate ERK1. 0.284 SIGNOR-278417 YES1 protein P07947 UNIPROT CDK4 protein P11802 UNIPROT down-regulates phosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 18479465 YES lperfetto We purified tyrosine 17 kinases from hela cells and found that the src family non-receptor tyrosine kinase c-yes contributes a large fraction of the tyrosine 17 kinase activity in hela lysatesthis site is equivalent to tyrosine 15 of cyclin dependent kinase 1, which undergoes inhibitory phosphorylation by wee1 and myt1 0.254 SIGNOR-178624 APOBEC3F protein Q8IUX4 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 NO lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). 0.7 SIGNOR-261327 HDAC3 protein O15379 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR up-regulates binding 9606 23213415 YES lperfetto Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes. 0.456 SIGNOR-217358 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity cleavage 9606 BTO:0000567 10882063 YES gcesareni ... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases. 0.739 SIGNOR-254334 RBM10 protein P98175 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0001938 30403180 NO irozzo Osteosarcoma is the most common malignant bone tumor with high incidence in adolescence and poor prognosis. RBM10, a member of RBPs, was reported to be a tumor suppressor in many kinds of cancers. The results showed that U2OS cell growth was significantly inhibited when RBM10 is overexpressed as compared with negative control cells. 0.7 SIGNOR-259149 ARPC5 protein O15511 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 YES The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc 0.96 SIGNOR-251518 POU5F1 protein Q01860 UNIPROT ID2 protein Q02363 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.288 SIGNOR-254937 PLK1 protein P53350 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates quantity by destabilization phosphorylation Ser305 IYQLMDHsNMDCFIC phosphorylation:Ser387 YLEMDLSsPQTRYIP 24484936 YES lperfetto By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non-phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis. 0.371 SIGNOR-272989 NMDA receptor_2D complex SIGNOR-C350 SIGNOR CAMK2A protein Q9UQM7 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD 0.583 SIGNOR-264217 CDK1 protein P06493 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Thr609 SAAQLAStPFHKLPV 9606 16760428 YES gcesareni The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609 0.86 SIGNOR-147065 ICAM1 protein P05362 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 23994464 NO apalma Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. After finding the place for transmigration, neutrophils migrate to the interstitium through transcellular or paracellular routes and begin chemotaxing towards the site of infection/inflammation within the perivascular and interstitial space. 0.7 SIGNOR-255042 RIMS3 protein Q9UJD0 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity binding 9606 BTO:0005822 28642685 YES miannu Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells. 0.2 SIGNOR-264357 FOXO proteinfamily SIGNOR-PF27 SIGNOR IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 YES miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. 0.2 SIGNOR-260088 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 23663276 YES milica Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects. 0.675 SIGNOR-202036 P2RY2 protein P41231 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.406 SIGNOR-257031 CDK5 protein Q00535 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Ser732 SSEGFYPsPQHMVQT 9606 BTO:0000938 12941275 YES gcesareni Here, we show that fak phosphorylation by cdk5 at s732 is important for microtubule organization, nuclear movement, and neuronal migration. In cultured neurons, s732-phosphorylated fak is enriched along a centrosome-associated microtubule fork that abuts the nucleus. Overexpression of the nonphosphorylatable mutant fak s732a results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo. 0.305 SIGNOR-86223 HNuRF complex SIGNOR-C448 SIGNOR EN2 protein P19622 UNIPROT up-regulates quantity by expression 9606 14609955 NO miannu Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. ) ChIP assays localize hNURF specifically to engrailed-1 (en-1) and engrailed-2 (en-2) promoters. 0.304 SIGNOR-268840 GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263811 AMPK complex SIGNOR-C15 SIGNOR ACSS2 protein Q9NR19 UNIPROT up-regulates activity phosphorylation Ser659 PGLPKTRsGKIMRRV 28820290 YES lperfetto This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin α5 for binding. In the nucleus, ACSS2 forms a complex with TFEB (transcription factor EB) and utilizes the acetate generated from histone deacetylation to locally produce acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes. 0.272 SIGNOR-271823 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1100 QGCRRRHsSETFSST 9606 17360977 YES lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 0.2 SIGNOR-235675 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr66 LHQEDNDyINASLIK -1 11506178 YES Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. 0.2 SIGNOR-248423 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.289 SIGNOR-249004 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Lys32 RARRPESkATNATLD -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus 0.624 SIGNOR-263573 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000590 20679343 YES lperfetto Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3? 0.738 SIGNOR-167286 MIS12 protein Q9H081 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR form complex binding -1 27881301 YES lperfetto Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits 0.863 SIGNOR-265190 MAPK7 protein Q13164 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation 9606 BTO:0001271 20832753 YES gcesareni We found that bmk1 interacted with promyelocytic leukemia protein (pml), and inhibited its tumor-suppressor function through phosphorylation. 0.475 SIGNOR-167947 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 11447297 YES lperfetto Xiap promotes the degradation of active-form caspase-3, but not procaspase-3, in living cells. Both the association of XIAP with caspase-3 and the RING finger domain of XIAP were essential for ubiquitination. XIAP promotes the degradation of caspase-3, which enhances its anti-apoptotic effect. 0.939 SIGNOR-109243 RPS6KA1 protein Q15418 UNIPROT NR4A3 protein Q92570 UNIPROT unknown phosphorylation Ser376 GRRGRLPsKPKSPLQ 9606 BTO:0000007 16223362 YES lperfetto We have established that two related proteins, Nurr1 and Nor1, are also phosphorylated on the equivalent site by RSK in cells in response to mitogenic stimulation. | Similar to Nur77, when FLAG€“Nor1 was expressed in HEK-293 cells, its phosphorylation on Ser377 was stimulated by both PMA and EGF 0.315 SIGNOR-249297 Diprenorphine chemical CHEBI:4650 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258790 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser295 LQASVPGsVPGVLGP 9606 16027724 YES llicata Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. 0.476 SIGNOR-250730 SMAD4 protein Q13485 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity 9606 BTO:0000599 10890911 NO lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity 0.685 SIGNOR-229311 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity 9606 BTO:0000007 14976264 NO lperfetto Sirt1 inhibited foxo3's ability to induce cell death. 0.911 SIGNOR-252995 GTF2F1 protein P35269 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR form complex binding -1 18218714 YES lperfetto Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system. 0.962 SIGNOR-266194 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0004479 20570526 YES Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], 0.8 SIGNOR-257848 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity phosphorylation Ser400 EDQPRCQsLDSALLE 9606 BTO:0000007 12138205 YES Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator. 0.557 SIGNOR-252571 HCK protein P08631 UNIPROT CBL protein P22681 UNIPROT unknown phosphorylation 10090 10092522 YES Hck is one member of the Src-family PTKs that is able to phosphorylate Cbl. Upon enzymatic activation of Hck either by pharmacological agents or genetic mutation, Cbl becomes tyrosine phosphorylated. 0.667 SIGNOR-251262 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr417 KENSPCVtPVSTATH 9606 BTO:0001938 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104699 EPHB1 protein P54762 UNIPROT CASKIN1 protein Q8WXD9 UNIPROT up-regulates activity phosphorylation Tyr296 TKDYCNNyDLTSLNV 9534 BTO:0000298 23181695 YES miannu EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation. 0.284 SIGNOR-262860 FABP7 protein O15540 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264461 SYK protein P43405 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation 9606 BTO:0003079 27181361 YES Gianni PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation. 0.422 SIGNOR-269084 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser409 VFPPSITsRGDFLRH 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.742 SIGNOR-262721 PHLPP2 protein Q6ZVD8 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 YES gcesareni Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt. 0.772 SIGNOR-252602 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY2 protein P41231 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257563 ABL2 protein P42684 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Tyr79 GAPAPGVyPGPPSGP 9606 20150913 YES llicata The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3. 0.2 SIGNOR-163747 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.564 SIGNOR-89209 CDKN2A protein P42771 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR down-regulates binding 9606 8891723 YES luana The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. 0.809 SIGNOR-259810 PRKACA protein P17612 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.286 SIGNOR-262751 MAGEL2 protein Q9UJ55 UNIPROT TRIM27 protein P14373 UNIPROT up-regulates activity binding 9606 23452853 YES miannu MAGE proteins are a family of proteins that contain a conserved domain known as the MAGE homology domain. Recently, we showed that MAGE proteins function biochemically to bind to and enhance the activity of E3 RING ubiquitin ligases. The E3 RING ubiquitin ligase TRIM27 was identified as a major binding partner of MAGE-L2. 0.521 SIGNOR-253513 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Thr2638 VAGQIRAtQQQHDFT 9606 BTO:0000773 12186630 YES lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. 0.2 SIGNOR-249159 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Pro54 NPNDKYEpFWEDEEK -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.42 SIGNOR-263578 MYOD1 protein P15172 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001103 16275751 NO andrea cerquone perpetuini Together, these results support the notion that Myf5 functions toward myoblast proliferation, whereas MyoD prepares myoblasts for efficient differentiation. 0.7 SIGNOR-255417 SRC protein P12931 UNIPROT RASA1 protein P20936 UNIPROT down-regulates phosphorylation 9606 11389730 YES lperfetto The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity 0.614 SIGNOR-86008 DACH2 protein Q96NX9 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 17075071 YES Luana We confirmed Dach2 is a Mgn transcriptional repressor that mediates HDAC-dependent regulation by (i) overexpressing Dach2 in myotubes harboring the 133-bp Mgn promoter and (ii) rescuing TSA-mediated Mgn repression by Dach2 knockdown. 0.367 SIGNOR-261579 PKA proteinfamily SIGNOR-PF17 SIGNOR SYN3 protein O14994 UNIPROT down-regulates activity phosphorylation 9606 10571231 YES miannu Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation 0.2 SIGNOR-264110 ULK2 protein Q8IYT8 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser490 ELAPRNSsLRLTDTA 9606 25925668 YES lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. 0.2 SIGNOR-264733 SGCB protein Q16585 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.502 SIGNOR-255986 ANG protein P03950 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252280 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination Lys773 RRNPAGTkWMEHVKL 9606 BTO:0000938 17283082 YES lperfetto Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage. 0.67 SIGNOR-145116 CD19 protein P15391 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10090 25673924 YES lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. 0.584 SIGNOR-242900 BIRC3 protein Q13489 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates ubiquitination 9606 20682767 YES gcesareni Ciap1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate nik for degradation. 0.649 SIGNOR-167298 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys365 SLASQATkDGKKDKK -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 0.464 SIGNOR-272745 ZMIZ1 protein Q9ULJ6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 10090 BTO:0001825 26522984 YES miannu The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions 0.452 SIGNOR-263936 PRKDC protein P78527 UNIPROT PRKAG1 protein P54619 UNIPROT up-regulates activity phosphorylation Thr284 LKCYLHEtLETIINR -1 31983282 YES miannu PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity.  0.2 SIGNOR-277504 SIRT7 protein Q9NRC8 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 YES lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 0.2 SIGNOR-275872 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK 9606 BTO:0000661 10037717 YES lperfetto We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. 0.2 SIGNOR-247053 BAIAP2 protein Q9UQB8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 BTO:0001909 19171758 NO miannu Ectopic expression of IRSp53 in mouse neuroblastoma N1E115 cells induces neurite outgrowth . Kank inhibits IRSp53-mediated neurite outgrowth in N1E115 cells 0.7 SIGNOR-265555 ERG protein P11308 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002398 22140532 YES miannu ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability. 0.2 SIGNOR-259408 LSM-20934 chemical CHEBI:109533 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258726 ABL1 protein P00519 UNIPROT RAPGEF1 protein Q13905 UNIPROT unknown phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 20581864 YES llicata Activation of endogenous c-abl by oxidative stress was associated with phosphorylation of cellular c3g on y504. Inhibition of c3g expression and function using rnai or dominant-negative approaches inhibited c-abl-mediated cell death. 0.537 SIGNOR-166422 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser77 GEKGRALsTRCQPLE -1 2584239 YES lperfetto We have now determined that PKC phosphorylated serine 43 (and/or serine 45), serine 78, and threonine 144 in the free Tn-I subunit 0.344 SIGNOR-248890 ITGB3 protein P05106 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.948 SIGNOR-253198 A1/b1 integrin complex SIGNOR-C159 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.578 SIGNOR-257701 CDK1 protein P06493 UNIPROT NTHL1 protein P78549 UNIPROT up-regulates activity phosphorylation 9606 27203178 YES miannu The main cell cycle kinase Cdk1 directly phosphorylates and activates the trehalase Nth1 to trigger the flux of storage carbohydrates into central carbon metabolism. 0.33 SIGNOR-278916 GATA2 protein P23769 UNIPROT ETV2 protein O00321 UNIPROT up-regulates activity binding 10090 24583263 YES irozzo Transcriptional assays with the Spi1 promoter-reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2.The protein-protein interaction between Etv2 and Gata2 is mediated by the Ets and Gata domains. Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation. 0.43 SIGNOR-256008 SLBP protein Q14493 UNIPROT H2AC1 protein Q96QV6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265401 WDR45B protein Q5MNZ6 UNIPROT TSC complex SIGNOR-C101 SIGNOR up-regulates quantity binding 9606 BTO:0001938 28561066 YES miannu WIPI3 associates with the TSC complex and FIP200. The specific interaction between WIPI3 and the TSC complex was demonstrated by immunopurification of both endogenous TSC1 and TSC2 with GFP-WIPI3 (Fig. 5a). These data suggest that WIPI3 functions in association with the TSC complex to regulate mTOR activity in the lysosomal compartment. 0.2 SIGNOR-268479 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 15611135 YES gcesareni We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. 0.261 SIGNOR-132555 SPOP protein O43791 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity binding 9606 BTO:0000007 15897469 YES miannu Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30). 0.4 SIGNOR-272658 PRKAA2 protein P54646 UNIPROT CDC27 protein P30260 UNIPROT unknown phosphorylation Ser379 NALPRRSsRLFTSDS 9606 SIGNOR-C15 22137581 YES lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379, respectively) resulted in an almost complete loss of ampk phosphorylation in these proteins 0.262 SIGNOR-195106 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267417 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL -1 14709557 YES miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase 0.491 SIGNOR-250402 PRKCE protein Q02156 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 YES inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.396 SIGNOR-270280 CSNK1E protein P49674 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates phosphorylation 9606 15375164 YES gcesareni We also show that ror2 is phosphorylated by ckiepsilon on serine/threonine residues. 0.268 SIGNOR-129117 GATA6 protein Q92908 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression 9606 BTO:0000195 24317510 NO lperfetto Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. 0.367 SIGNOR-253152 RNF4 protein P78317 UNIPROT SUMO2 protein P61956 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 18408734 YES miannu Here we demonstrate that the RING-domain-containing ubiquitin E3 ligase, RNF4 (also known as SNURF), targets poly-SUMO-modified proteins for degradation mediated by ubiquitin. RNF4 depletion or proteasome inhibition led to accumulation of mixed, polyubiquitinated, poly-SUMO chains. PML protein accumulated in RNF4-depleted cells and was ubiquitinated by RNF4 in a SUMO-dependent fashion in vitro.RNF4 preferentially binds to and ubiquitinates SUMO-2 polymers over SUMO-2 monomers in vitro 0.834 SIGNOR-272640 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser662 GLGRSITsPTTLYDR 9606 BTO:0001938 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104683 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT down-regulates phosphorylation Tyr969 PLLQPNNyQFC 9606 BTO:0001271 15297464 YES lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) following ligand binding, the csf-1r is rapidly internalized and degraded. This process begins with multiubiquitination of the csf-1r mediated by c-cbl (20), an e3-type ubiquitin ligase 0.2 SIGNOR-127626 CHEK1 protein O14757 UNIPROT TICRR protein Q7Z2Z1 UNIPROT down-regulates activity phosphorylation 9606 25557548 YES miannu In principle, phosphorylation of Treslin by Chk1 may alter its conformation or directly affect its interactions with other proteins to preclude helicase activation.|The fact that the TRCT domain blocks the binding of Chk1 to Treslin suggests that Chk1 suppresses the initiating function of Treslin. 0.432 SIGNOR-278924 NMBR protein P28336 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.278 SIGNOR-256918 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000567 11672426 NO lperfetto Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MAPK) or p38 MAPK activities in a time-dependent manner. 0.372 SIGNOR-226637 C5AR1 protein P21730 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity by expression 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.8 SIGNOR-263469 WNT10B protein O00744 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.584 SIGNOR-131628 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM61 protein Q5EBN2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271163 UBE2I protein P63279 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation Lys113 KNELKHVkYCQYAFD 9606 12621041 YES gcesareni The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses 0.625 SIGNOR-98993 Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 20498094 NO miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 0.7 SIGNOR-263728 SGK1 protein O00141 UNIPROT SLC1A3 protein P43003 UNIPROT up-regulates activity phosphorylation Thr482 LDRLRTTtNVLGDSL -1 12911626 YES miannu Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1. 0.416 SIGNOR-263075 CDKN1A protein P38936 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates binding 9606 19158493 YES gcesareni P21-mediated degradation of cyclin b1 in response to dna damage is necessary for the maintenance of g2 cell cycle arrest. 0.829 SIGNOR-183498 ARPC2 protein O15144 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 YES The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc 0.96 SIGNOR-251514 Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 20479780 NO lperfetto The genetic causes of PD seem to participate in con­ verging pathways to pathogenesis, but it is unclear whether all or only some of these pathways need to be activated for lewy body deposition and neuronal death to occur. 0.7 SIGNOR-249703 pyruvate smallmolecule CHEBI:15361 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates activity 9606 18613815 NO Pyruvate carboxylase (PC) is a biotin-containing enzyme that catalyses the HCO3−- and MgATP-dependent carboxylation of pyruvate to form oxaloacetate. This is a very important anaplerotic reaction, replenishing oxaloacetate withdrawn from the Krebs cycle for various pivotal biochemical pathways. 0.7 SIGNOR-267384 SYVN1 protein Q86TM6 UNIPROT HERPUD1 protein Q15011 UNIPROT up-regulates activity binding 9606 BTO:0000007 28827405 YES miannu FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp 0.575 SIGNOR-261349 PP1 proteinfamily SIGNOR-PF54 SIGNOR PYGL protein P06737 UNIPROT down-regulates activity dephosphorylation Ser15 QEKRRQIsIRGIVGV 9606 22225877 YES GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation 0.2 SIGNOR-267403 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 BTO:0000150;BTO:0000938 15695813 YES gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. 0.258 SIGNOR-133861 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JUN protein P05412 UNIPROT down-regulates activity binding 9606 BTO:0004136 12393465 YES RUNX1-RUNX1T1 fusion protein (AML-ETO) apalma Here we show that AML1-ETO blocks the transcriptional activity of PU.1 by displacing its coactivator c-Jun. 0.2 SIGNOR-255670 gemcitabine chemical CHEBI:175901 ChEBI RRM2 protein P31350 UNIPROT down-regulates activity chemical inhibition -1 2233693 YES miannu Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase. 0.8 SIGNOR-258387 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 8940173 YES miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.2 SIGNOR-246244 NPFFR1 protein Q9GZQ6 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256987 MBTD1 protein Q05BQ5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.407 SIGNOR-269303 SEPTIN2 protein Q15019 UNIPROT SEPT6/SEPT2 complex SIGNOR-C71 SIGNOR form complex binding 9606 16914550 YES miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. 0.2 SIGNOR-148889 ACSS2 protein Q9NR19 UNIPROT GBA protein P04062 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants 0.2 SIGNOR-276552 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Thr262 IVHQRVHtGEKPYKC 9606 BTO:0002552 31399647 YES miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. 0.2 SIGNOR-276753 CSNK2A1 protein P68400 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates quantity by stabilization phosphorylation Ser385 AGNRTANsEDSDEQD -1 17911614 YES miannu Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far. 0.2 SIGNOR-276077 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr119 AGTAGALtPQHVRAH 9606 BTO:0001938 21364637 YES miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells 0.2 SIGNOR-277641 NANOG protein Q9H9S0 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 NO flangone Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency.  0.7 SIGNOR-242073 MAPK3 protein P27361 UNIPROT EPAS1 protein Q99814 UNIPROT up-regulates quantity by stabilization phosphorylation Ser484 SSCSTPNsPEDYYTS 9606 BTO:0006155 35191554 YES miannu The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells. 0.26 SIGNOR-277584 LPAR6 protein P43657 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.42 SIGNOR-257212 MBTPS2 protein O43462 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity cleavage 10029 BTO:0000246 10419520 YES In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted 0.65 SIGNOR-267499 NARS2 protein Q96I59 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270466 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20712774 NO Regulation miannu BCL11A maintains silencing of gamma-globin expression in adult erythroid cells and functions as a direct transcriptional regulator of the fetal to adult hemoglobin switch in humans. we found that BCL11A plays a central role in the evolutionarily divergent globin gene switches of mammals. As a factor critical for gamma-globin gene silencing, BCL11A should be considered as a therapeutic target to increase HbF in a directed manner in beta-thalassemia patients. 0.446 SIGNOR-251775 CHRM5 protein P08912 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257009 RNF168 protein Q8IYW5 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates quantity ubiquitination 9606 30953555 YES miannu E3 ligase RNF168-mediated 53BP1 ubiquitination through activated the mechanistic target of rapamycin (mTOR)-ribosomal S6 kinase (S6K) signaling and increased 53BP1 protein stability in response to IR|We further found that overexpression of RNF168 enhanced 53BP1 ubiquitination inhibited by G0S2 overexpression in U87 and LN229 cells in response to IR (Fig. xref f). 0.821 SIGNOR-278777 NAN 190 chemical CHEBI:64131 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258855 A4/b1 integrin complex SIGNOR-C162 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.636 SIGNOR-257704 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR AURKB protein Q96GD4 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000567 17543862 YES miannu Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis. 0.436 SIGNOR-271661 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 15381704 YES The effect has been demonstrated using P28329-3 gcesareni Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity. 0.286 SIGNOR-129288 CSNK1E protein P49674 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates activity phosphorylation Ser311 EINFENMsNDDAVRV -1 24993822 YES miannu Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3. 0.668 SIGNOR-276647 NFIB protein O00712 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.246 SIGNOR-268900 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates binding 9606 10490659 YES JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660) gcesareni These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins. 0.769 SIGNOR-70854 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser645 RPASVPPsPSLSRHS 11427888 YES Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. 0.685 SIGNOR-251238 KAT2A protein Q92830 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269604 HOXD12 protein P35452 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 YES 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. 0.423 SIGNOR-241232 OSBPL3 protein Q9H4L5 UNIPROT RRAS protein P10301 UNIPROT down-regulates activity binding 9606 BTO:0000007 18270267 YES miannu We show that ORP3 interacts with R-Ras, a small GTPase regulating cell adhesion, spreading and migration. Gene silencing of ORP3 in HEK293 cells results in altered organization of the actin cytoskeleton, impaired cell-cell adhesion, enhanced cell spreading and an increase of beta1 integrin activity--effects similar to those of constitutively active R-Ras(38V). 0.405 SIGNOR-277221 DLGAP1 protein O14490 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.856 SIGNOR-264586 CASP3 protein P42574 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 NO amattioni Caspase-3 is responsible for apoptosis execution 0.7 SIGNOR-89244 LNX1 protein Q8TBB1 UNIPROT SUFU protein Q9UMX1 UNIPROT down-regulates quantity ubiquitination Lys470 SWPEKKLkVSILPDV 9606 33608498 YES miannu Indeed, they target different lysine residues in the SuFu protein, as LNX1 ubiquitinates SuFu at K59 and K470, and SCF Fbxl17 acts at K257, while Itch ubiquitinates at K321 and K457.|XREF_FIG, ectopic LNX1 expression reduced SuFu protein levels in HEK-293T cells, while shRNA mediated knockdown of LNX1 increased these levels. 0.2 SIGNOR-278626 SF3b complex SIGNOR-C442 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 32140746 NO lperfetto The SF3b complex is an intrinsic component of the functional U2 small nuclear ribonucleoprotein (snRNP). As U2 snRNP enters nuclear pre-mRNA splicing, SF3b plays key roles in recognizing the branch point sequence (BPS) and facilitating spliceosome assembly and activation. 0.7 SIGNOR-268414 HTR2B protein P41595 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.277 SIGNOR-256743 miR-29b mirna URS0000150A7D_9606 RNAcentral DNMT3B protein Q9UBC3 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 26344767 NO Luana We also found that miR-199a expression and blockade (see below for details) potentiated and attenuated, respectively, the phosphorylation levels in neurons of S6 ribosomal protein, which signify the activation of mTOR signaling, indicating that miR-199a positively regulates mTOR signaling activity 0.4 SIGNOR-264544 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB3 protein Q9Y5G1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265707 PTPRM protein P28827 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates quantity dephosphorylation 9606 21998202 YES miannu Specifically, RPTP\u03bc dephosphorylated p120 catenin, subsequently leading to a lower level of cytoplasmic protein compared with that observed with the vector control and RPTP\u03bc-CS. 0.54 SIGNOR-277042 CRH protein P06850 UNIPROT KRT1 protein P04264 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15787816 NO Regulation of expression miannu CRH also increased AP-1 binding activity, cell granularity, cytokeratin 1 and involucrin expression, and inhibited cytokeratin 14 expression. 0.2 SIGNOR-251882 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser358 WPLSRTRsEPLPPSA -1 15738054 YES lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. 0.479 SIGNOR-249274 RPS6KA1 protein Q15418 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 YES gcesareni We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling. 0.53 SIGNOR-37154 NR0B2 protein Q15466 UNIPROT NR1I3 protein Q14994 UNIPROT down-regulates binding 9606 15000748 YES gcesareni The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition. 0.509 SIGNOR-123154 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 11544529 YES gcesareni Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. 0.634 SIGNOR-252063 PRKAA2 protein P54646 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000007 11069105 YES miannu AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells.  activation of PFK-2 was due to the phosphorylation of Ser466 0.442 SIGNOR-250323 LRRK2 protein Q5S007 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr825 LKISDFGtSKRLAGI 9606 BTO:0000007 28888991 YES miannu LRRK2 phosphorylated ASK1 at Thr832 that is adjacent to Thr845, which serves as an autophosphorylation site.  0.325 SIGNOR-277251 TEC protein P42680 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 12573241 YES lperfetto Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the SH3 domain via a transphosphorylation mechanism, which for Bruton's tyrosine kinase (Btk) affects tyrosine 223.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role 0.494 SIGNOR-246652 LARS1 protein Q9P2J5 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.2 SIGNOR-270355 AKT1 protein P31749 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser246 LSRERVFsEDRARFY -1 16549426 YES miannu Autophosphorylation of Akt on Thr-72 and Ser-246 appeared to require prior phosphorylation of Akt on Thr-308 and Ser-473. Compared with wild-type Akt, Akt/T72A/S246A mutant exhibited markedly reduced basal Akt kinase activity and response to cellular stimulation by insulin-like growth factor-1, and also conferred less cellular resistance to doxorubicin-induced apoptosis. 0.2 SIGNOR-276055 SIAH1 protein Q8IUQ4 UNIPROT YBX1 protein P67809 UNIPROT down-regulates quantity by destabilization ubiquitination Lys304 PQDGKETkAADPPAE 9606 35273154 YES miannu Here, we identified that SIAH1 which was downregulated in chemoresistant EOC samples and cell lines functioned as novel E3 ligases to trigger degradation of YBX-1 at cytoplasm by RING finger domain.|SIAH1 ubiquitinated YBX-1 at its K304 through the RING domain. 0.244 SIGNOR-278780 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2A protein Q9BTU6 UNIPROT down-regulates activity chemical inhibition -1 21704602 YES Luana Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity 0.8 SIGNOR-258317 MARK3 protein P27448 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9534 9543386 YES miannu C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function. 0.486 SIGNOR-250176 carfilzomib chemical CHEBI:65347 ChEBI PSMB10 protein P40306 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 YES miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. 0.8 SIGNOR-259308 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY -1 8413257 YES lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. 0.789 SIGNOR-39054 PRKCA protein P17252 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 15730925 NO irozzo PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC. 0.7 SIGNOR-256266 CDC25A protein P30304 UNIPROT CDK4 protein P11802 UNIPROT up-regulates activity dephosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 BTO:0000007 23429262 YES lperfetto Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs. 0.704 SIGNOR-267568 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.392 SIGNOR-263000 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser204 SGAEGDVsSEREP -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.285 SIGNOR-273976 Ub:E2 complex SIGNOR-C497 SIGNOR IRF2BP2 protein Q7Z5L9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271128 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2116 VGRGLQLtPGIGGMQ 9606 18794356 YES miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. 0.375 SIGNOR-181018 ATM protein Q13315 UNIPROT KHDC3L protein Q587J8 UNIPROT up-regulates activity phosphorylation Thr145 IEVREAGtQRSVEVR 9606 BTO:0001086 31609975 YES miannu Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions.  0.2 SIGNOR-273505 Ub:E2 complex SIGNOR-C497 SIGNOR PCGF5 protein Q86SE9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271184 SPATA13 protein Q96N96 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.717 SIGNOR-260576 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 YES lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. 0.79 SIGNOR-75633 EPAS1 protein Q99814 UNIPROT KDM2B protein Q8NHM5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271582 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIF22 protein Q14807 UNIPROT up-regulates phosphorylation Thr463 QGAPLLStPKRERMV 9606 12727876 YES lperfetto Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes 0.367 SIGNOR-216793 RAC1 protein P63000 UNIPROT Phagocyte NADPH oxidase complex complex SIGNOR-C557 SIGNOR form complex binding 9606 37263099 YES miannu NADPH oxidase is composed of essential protein components in its active state: membranous subunits, including p22-phox and gp91-phox, and cytoplasmic subunits, including p47-phox, p67-phox, p40-phox, and RAC2 (in neutrophils), among which NCF4 encodes the cytoplasmic subunit p40-phox 0.606 SIGNOR-277631 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser352 AATNRPNsIDPALRR 9606 BTO:0000150 16551632 YES llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I 0.509 SIGNOR-252491 DUSP6 protein Q16828 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates dephosphorylation 9606 22521266 YES gcesareni Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase). 0.428 SIGNOR-197194 NFE2L2 protein Q16236 UNIPROT TALDO1 protein P37837 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 NO miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 0.367 SIGNOR-267357 CDK2 protein P24941 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity phosphorylation 9606 12202491 YES lperfetto Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity 0.378 SIGNOR-264650 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKACB protein P22694 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258211 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193546 CDK1 protein P06493 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation 9606 BTO:0003918 19917720 YES lperfetto Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis. 0.346 SIGNOR-267987 Survival Factors stimulus SIGNOR-ST8 SIGNOR BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 9346240 NO lperfetto Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death MachineryAkt phosphorylates BAD in vitro and in vivo, and blocks the BAD-induced death of primary neurons in a site-specific manner. 0.7 SIGNOR-209693 PRKACA protein P17612 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT up-regulates activity phosphorylation Thr17 MRNRRNDtLDSTRTL 9606 BTO:0000007 20110357 YES done miannu Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity. 0.2 SIGNOR-273791 DAPK1 protein P53355 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates phosphorylation Thr119 LSRRLKVtGDLFDIM 9606 BTO:0000007 19180116 YES gcesareni The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy. 0.726 SIGNOR-183548 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 10090 BTO:0000165 20016939 YES gcesareni Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4. 0.647 SIGNOR-236855 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser58 ESETNQNsSSDSEAE -1 11711551 YES llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 0.379 SIGNOR-251044 MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17502367 YES gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). 0.619 SIGNOR-154783 S1PR3 protein Q99500 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256933 DLL1 protein O00548 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11006133 YES gcesareni These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors. 0.63 SIGNOR-82398 CHEK1 protein O14757 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 18243098 YES gcesareni We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c. 0.2 SIGNOR-265326 HCRTR1 protein O43613 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.464 SIGNOR-257220 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser130 GPKVNRPsLLEIHEQ 9606 BTO:0000007 21321328 YES miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). 0.578 SIGNOR-276305 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT up-regulates activity phosphorylation Ser500 RLHLPRAsAVALEVQ -1 11171059 YES miannu EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499 0.306 SIGNOR-250444 motesanib chemical CHEBI:51098 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258251 CDK5 protein Q00535 UNIPROT KIF13B protein Q9NQT8 UNIPROT down-regulates activity phosphorylation Thr506 SEGQVMLtPQKNTRT 10029 BTO:0000246 27512725 YES miannu Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B-TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor-cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor-cargo interaction and the cell-permeable TAT-T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport. 0.365 SIGNOR-262737 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9136927 YES fspada Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro 0.731 SIGNOR-210084 BRCA1 protein P38398 UNIPROT SAFB protein Q15424 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 21950761 YES miannu These results suggest that the BRCA1 and BARD1 heterodimer ubiquitinates SAFB and increases SAFB protein levels. 0.2 SIGNOR-278624 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser263 NVGSPLSsPLSSMKS 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.287 SIGNOR-276105 CAMK2G protein Q13555 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR 9677319 YES llicata Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. By deletion and point mutation analysis we show that phosphorylation by CaMKII and PKA occurs on a single serine residue at position 273 0.337 SIGNOR-250703 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. 0.8 SIGNOR-268093 NOX1 protein Q9Y5S8 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.8 SIGNOR-264721 Ub:E2 complex SIGNOR-C497 SIGNOR MKRN2 protein Q9H000 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271220 IL4R protein P24394 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 YES milica Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2. 0.565 SIGNOR-100768 CBX1 protein P83916 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity binding 9606 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-265323 PTPRB protein P23467 UNIPROT CDH5 protein P33151 UNIPROT up-regulates activity dephosphorylation 9606 19015309 YES miannu Because we had shown previously that VE-PTP supports VE-cadherin function when exogenously expressed in transfected cells, we expected it to be expressed at endothelial cell contacts.|Indeed, tyrosine phosphorylation of VE-cadherin is reduced by VE-PTP in COS-7 and CHO cells. 0.582 SIGNOR-277131 PTPRO protein Q16827 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Ser727 NTIDLPMsPRTLDSL 9606 24708807 YES miannu In addition, this group found that PTPRO dephosphorylated STAT3 at Y705 and S727 then attenuated STAT3 signalling. 0.376 SIGNOR-277061 FAM20C protein Q8IXL6 UNIPROT P4HB protein P07237 UNIPROT up-regulates activity phosphorylation Ser357 KIKPHLMsQELPEDW 32149426 YES lperfetto The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. 0.385 SIGNOR-275574 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636-4 UNIPROT down-regulates activity phosphorylation Ser352 PRHLSNVsSTGSIDM -1 21204788 YES miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.255 SIGNOR-273929 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser446 SGIKSHNsALYSQVQ 9606 15574499 YES amattioni Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility. 0.253 SIGNOR-131455 SMURF2 protein Q9HAU4 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11163210 YES miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  0.594 SIGNOR-272939 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 15735019 YES miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates 0.648 SIGNOR-150484 Dacinostat chemical CID:6445533 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 15171259 YES lperfetto We have developed a cinnamic hydroxamic class of histone deacetylase inhibitors of which a prototype was designated as NVP-LAQ824. NVP-LAQ824, inhibits histone deacetylase enzymatic activities in vitro and transcriptionally activated the p21 promoter in reporter gene assays. 0.8 SIGNOR-262032 GAD1 protein Q99259 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 32041144 YES miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. 0.8 SIGNOR-267551 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR TP53 protein P04637 UNIPROT up-regulates quantity by expression 9606 15044535 NO gcesareni These results indicate that nf-kb actions occur upstream of p53 to regulate both p53 levels and activity. 0.486 SIGNOR-123602 SIRT1 protein Q96EB6 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 14976264 NO lperfetto Sirt1 inhibited foxo3's ability to induce cell death. 0.7 SIGNOR-217884 STIL protein Q15468 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates binding 9606 BTO:0001271 16024801 YES miannu Cell cycle-dependent phosphorylation of sil is required for its interaction with pin1, a regulator of mitosis. Point mutation of the seven (s/t)p sites between amino acids 567 and 760 reduces mitotic phosphorylation of sil, pin1 binding, and spindle checkpoint duration. 0.362 SIGNOR-138677 RPA3 protein P35244 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 NO lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.7 SIGNOR-275707 SYCE1 protein Q8N0S2 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 YES miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. 0.667 SIGNOR-264201 HOXB13 protein Q92826 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 15604291 NO miannu These results suggest that HOXB13 functions as an AR repressor to modulate the complex AR signaling and subsequent growth regulation of prostate cancer cells. 0.494 SIGNOR-254475 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates activity phosphorylation Ser661 QNEFAGFsYTNPEFV 9606 17115692 YES lperfetto The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif 0.2 SIGNOR-150861 CASP6 protein P55212 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates cleavage 9606 11455969 YES gcesareni This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8. 0.735 SIGNOR-109411 TWIST1 protein Q15672 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20646316 NO miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. 0.326 SIGNOR-255522 fexofenadine chemical CHEBI:5050 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257785 TYMS protein P04818 UNIPROT Purine biosynthesis phenotype SIGNOR-PH186 SIGNOR up-regulates 9606 21876188 YES lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. 0.7 SIGNOR-253139 LAMTOR3 protein Q9UHA4 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 YES lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant 0.932 SIGNOR-164775 FBXO7 protein Q9Y3I1 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR up-regulates activity binding 9606 BTO:0000007 15145941 YES miannu We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP).Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner. 0.61 SIGNOR-271507 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser361 TLRDVVPsPDTQEKG 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.287 SIGNOR-276109 DISP1 protein Q96F81 UNIPROT SHH protein Q15465 UNIPROT up-regulates activity binding 9606 BTO:0000007 22902404 YES lperfetto We show that the vertebrate homologue, dispatched-a (dispa) interacts with human sonic hedgehog (hshh) via its cholesterol anchor, and that this interaction is necessary for hshh secretion. binding to dispa is necessary but not sufficient for hshh secretion 0.728 SIGNOR-191888 ERCC5 protein P28715 UNIPROT ERCC2 protein P18074 UNIPROT up-regulates quantity by stabilization binding 9606 20840796 YES Regulation of binding The NER protein XPG was also found to associate with the TFIIH complex by interacting directly with XPD stabilizing the interaction between TFIIH and the CAK-XPD complex 0.947 SIGNOR-251974 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRA protein P01903 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.414 SIGNOR-253998 PRKCA protein P17252 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.392 SIGNOR-275953 PRKCD protein Q05655 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 1677563 YES lperfetto Of four other protein kinases tested only protein kinase C (PKC) phosphorylated P(45-56), with complete dependence on phosphatidylserine. Only the residue corresponding to serine-51 in eIF-2 alpha was phosphorylated by HCR, dsI or PKC. 0.311 SIGNOR-248853 DUOX1 protein Q9NRD9 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.8 SIGNOR-264726 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 12163482 YES inferred from 70% family members lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein 0.2 SIGNOR-270099 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR ATP2A1 protein O14983 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.311 SIGNOR-136300 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity precursor of 9606 BTO:0000050 2139411 YES lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. 0.8 SIGNOR-268639 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser68 LRDAIRQsNQILRER 9606 SIGNOR-C14 17977820 YES lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I 0.93 SIGNOR-209788 L3MBTL2 protein Q969R5 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates activity binding 9606 31225475 YES miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. 0.2 SIGNOR-266786 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 20444238 YES gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. 0.706 SIGNOR-165220 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR hsa-mir-223 mirna URS000037EC34_9606 RNAcentral down-regulates quantity by repression transcriptional regulation 10090 25477897 YES miannu The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC 0.4 SIGNOR-255797 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT down-regulates activity phosphorylation Ser311 DALDLEEsSSSDHAE 10029 BTO:0000246 7876239 YES The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization. 0.2 SIGNOR-251440 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258279 ERBB4 protein Q15303 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16829981 YES gcesareni Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength. 0.829 SIGNOR-147847 perfluorooctanoic acid chemical CHEBI:35549 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268768 NFIB protein O00712 UNIPROT NEUROD4 protein Q9HD90 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268898 CDK1 protein P06493 UNIPROT EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2039 GLGQVGIsPLKPGTV 9606 BTO:0000551 24530506 YES miannu In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels.  0.404 SIGNOR-276456 SUPT6H protein Q7KZ85 UNIPROT Iws1:Spt6:CTD complex complex SIGNOR-C548 SIGNOR form complex binding 9606 19141475 YES miannu We showed recently that Spt6, a transcription elongation factor and histone H3 chaperone, binds to the Ser2P CTD and recruits Iws1 and the REF1/Aly mRNA export adaptor to facilitate mRNA export.In vitro, recombinant Spt6 binds selectively to a stretch of uninterrupted consensus repeats located in the N-terminal half of the CTD and recruits Iws1. Thus Iws1 connects two distinct CTD-binding proteins, Spt6 and HYPB/Setd2, in a megacomplex that affects mRNA export as well as the histone modification state of active genes. 0.712 SIGNOR-273498 GNB5 protein O14775 UNIPROT ADCY5 protein O95622 UNIPROT down-regulates activity binding 9606 BTO:0004032 21303898 YES miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC 0.454 SIGNOR-264998 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr323 GCHLLVAtPGRLVDM 9606 SIGNOR-C17 16280325 YES lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. 0.297 SIGNOR-141569 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser851 SLSSLNSsESDKDQD 10090 BTO:0000944 10671552 YES llicata Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | Under these conditions, phosphorylation of the E-cadherin double mutant S853A/S855A was reduced by 25% as compared with wt E-cadherin. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion. 0.402 SIGNOR-250840 Corticotropin protein P01189-PRO_0000024969 UNIPROT CYP11A1 protein P05108 UNIPROT up-regulates quantity 9606 24631756 NO lperfetto CTH signaling promotes the single steroidogenic rate limiting step, which is the conversion of cholesterol to pregnenolone by Cholesterol Side-Chain Cleavage Enzyme (P450scc), encoded in the CYP11A1 gene. This is conferred by a direct stimulating effect of ACTH on the promoter of CYP11A1 (Chung et al., 1997, Liu and Simpson, 1997, Hu et al., 2001). Further, it stimulates conversion of pregnenolone to 17-hydroxypregnenolone by upregulating the expression of 3β hydroxysteroid dehydrogenase enzyme (3β-HSD) 0.2 SIGNOR-268719 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2A protein P29274 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257447 SPRY4 protein Q9C004 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002058 20501643 NO miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 0.267 SIGNOR-253040 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation 10090 11730323 YES Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs 0.2 SIGNOR-258991 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation Tyr589 SHDSEENyVPMNPNL 9606 10068651 YES lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. 0.952 SIGNOR-236258 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ -1 8999860 YES miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules 0.314 SIGNOR-250284 TFAP2B protein Q92481 UNIPROT ADIPOQ protein Q15848 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19325541 NO miannu A transcription factor, TFAP2B, has been shown to participate in the regulation of adipocyte metabolism, by facilitating glucose uptake and lipid accumulation, while simultaneously reducing insulin sensitivity, and recently a direct function for TFAP2B as an inhibitor of adiponectin expression was observed. 0.365 SIGNOR-255421 LRIG1 protein Q96JA1 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates 9606 23723069 NO miannu Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation. 0.403 SIGNOR-202143 PCDHA1 protein Q9Y5I3 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265663 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Thr357 FELRKTQtSMSLGTT -1 24012422 YES gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays 0.753 SIGNOR-266438 DEF6 protein Q9H4E7 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity binding 9606 BTO:0000782 26483383 YES lperfetto Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion. 0.257 SIGNOR-253365 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR ENO3 protein P13929 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.266 SIGNOR-136550 ACSS3 protein Q9H6R3 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI down-regulates quantity chemical modification 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271833 TRAF6 protein Q9Y4K3 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by stabilization ubiquitination Lys32 SGPAGREkTLRQAGA 9606 BTO:0002181 31281496 YES miannu We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. 0.285 SIGNOR-277464 RNGTT protein O60942 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity chemical modification 9606 9512541 YES lperfetto The human mRNA 5'-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNAcappingenzyme1), HCE1A and HCE1B , were isolated from a HeLa cDNA library. The HCE1 cDNA has the longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3'-half of the HCE1 ORF was missing in HCE1A and HCE1B , and, additionally, HCE1B has an early translation termi 0.8 SIGNOR-268357 MAPK1 protein P28482 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 YES miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.274 SIGNOR-265948 Phenelzine chemical CHEBI:8060 ChEBI MAOB protein P27338 UNIPROT down-regulates activity chemical inhibition -1 18426226 YES Luana Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine. 0.8 SIGNOR-257778 CAMK2G protein Q13555 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 11114197 YES gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation. 0.427 SIGNOR-85098 CLN8 protein Q9UBY8 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 BTO:0000007 30453012 YES miannu CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8. 0.2 SIGNOR-265583 PRKD3 protein O94806 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 18692497 YES lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. 0.265 SIGNOR-275926 TRAF6 protein Q9Y4K3 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 30806153 YES miannu TRAF6 catalyzes K63-linked polyubiquitination of LC3B and promotes the formation of the LC3B-ATG7 and LC3B-CTNNB1 complexes. 0.295 SIGNOR-277439 CDK7 protein P50613 UNIPROT CDK4 protein P11802 UNIPROT up-regulates phosphorylation Thr172 YSYQMALtPVVVTLW 9606 8139570 YES lperfetto Phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (cak). therefore, formation of the cyclin d-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for cak activity, serum stimulation is required to promote assembly of the complexes in mammalian cells. 0.586 SIGNOR-36549 MAPK1 protein P28482 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 YES lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity 0.757 SIGNOR-203473 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 20562916 YES Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis 0.367 SIGNOR-248766 SHANK3 protein Q9BYB0 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates quantity binding 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264604 DTL protein Q9NZJ0 UNIPROT TDG protein Q13569 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 24962565 YES miannu TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner 0.359 SIGNOR-272847 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr242 FFQQQMIyDSPPSRA 10090 10978177 YES HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin 0.501 SIGNOR-251310 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr198 PGLRRRQt 9606 12042314 YES miannu Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation. 0.85 SIGNOR-88294 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity binding 9534 BTO:0004055 1310899 YES lperfetto A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2. 0.853 SIGNOR-236080 ESR1 protein P03372 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150;BTO:0000093;BTO:0000567 16144913 YES lperfetto Our data show for the first time that eralpha binds to ppar response element and represses its transactivation 0.281 SIGNOR-140233 RNF144B protein Q7Z419 UNIPROT NPM1 protein P06748 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000772 20864535 YES miannu NPMc degradation was mediated by the ubiquitin-proteasome pathway involving the IBR-type RING-finger E3 ubiquitin ligase IBRDC2, and genetic correction of FA-A or FA-C lymphoblasts prevented NPMc ubiquitination. As shown in Fig. 4C, knockdown of IBRDC2, an IBR-type RING-finger E3 ubiquitin ligase (21), significantly reduced NPMc ubiquitination and restored NPMc stability in FA-A cells 0.2 SIGNOR-271490 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs 0.91 SIGNOR-252833 ABCA1 protein O95477 UNIPROT MEGF10 protein Q96KG7 UNIPROT up-regulates activity binding 9606 BTO:0000567 17205124 YES miannu ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level. 0.332 SIGNOR-265164 PPARGC1A protein Q9UBK2 UNIPROT MSTN protein O14793 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 23217713 YES miannu PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy 0.362 SIGNOR-256151 MAP4K4 protein O95819 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Thr738 EEEPRGGtVSPPPGT 9606 BTO:0000007 34511598 YES miannu The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling. 0.304 SIGNOR-277571 NFKB2 protein Q00653 UNIPROT RELB protein Q01201 UNIPROT up-regulates activity binding 9606 19098713 YES lperfetto The map3k14-activated chuk/ikka homodimer phosphorylates nfkb2/p100 associated with relb, inducing its proteolytic processing to nfkb2/p52 and the formation of nf-kappa-b relb-p52 complexes. The nf-kappa-b heterodimeric relb-p52 complex is a transcriptional activator. 0.761 SIGNOR-182835 IFNL1 protein Q8IU54 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 12469119 YES gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. 0.613 SIGNOR-96177 TRIM59 protein Q8IWR1 UNIPROT ECSIT protein Q9BQ95 UNIPROT down-regulates activity binding 9606 BTO:0000567; BTO:0002181 22588174 YES Giorgia In this study, we showed that one of the TRIM family ubiquitin ligases, TRIM59, interacts with ECSIT as an adaptor protein required for the TLR-mediated transduction pathway. The B-box and RING domains of TRIM59 are important for interaction with ECSIT.|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation.|Luciferase reporter assays using reporter plasmids including NF-kappaB responsive element, interferon beta (IFN-beta) promoter and interferon-sensitive response element (ISRE) showed that overexpression of TRIM59 repressed their transcriptional activities, whereas knockdown of TRIM59 enhanced their transcriptional activities. 0.519 SIGNOR-260369 NFIB protein O00712 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24553933 NO miannu Nfibbinds to the ezh2 promoter and overexpression ofnfibrepresses ezh2 transcription. 0.375 SIGNOR-204643 PRKN protein O60260 UNIPROT RHOT2 protein Q8IXI1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22078885 YES miannu PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner.  0.2 SIGNOR-272726 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18997792 YES gcesareni A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution. 0.892 SIGNOR-182124 NCF1 protein P14598 UNIPROT NOX3 protein Q9HBY0 UNIPROT up-regulates activity binding 9606 12672956 YES miannu Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase. 0.624 SIGNOR-276624 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFV3 protein P56181 UNIPROT up-regulates activity phosphorylation Ser105 QPSSGREsPRH 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275601 LRFN5 protein Q96NI6 UNIPROT PTPRS protein Q13332 UNIPROT up-regulates activity binding 9606 27225731 YES miannu SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). 0.369 SIGNOR-264088 STUB1 protein Q9UNE7 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24613385 YES miannu These results suggest that Smad3 could be easily ubiquitinated and degraded by CHIP when Hsp90 activity was inhibited.To demonstrate the role of Hsp70 and Hsp90 on the regulation of Smad3 by CHIP, we over-expressed Hsp70 and Hsp90 in mammalian cells. 0.568 SIGNOR-278785 SIRT3 protein Q9NTG7 UNIPROT IDH2 protein P48735 UNIPROT up-regulates deacetylation Lys413 VESGAMTkDLAGCIH 9606 22416140 YES miannu Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity. 0.656 SIGNOR-196617 pemetrexed chemical CHEBI:63616 ChEBI TYMS protein P04818 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205933 CAMK2G protein Q13555 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV BTO:0000944 11972023 YES llicata For maximal gene activation, S727 in the transcription activation domain of Stat1 also is inducibly phosphorylated by IFN-gamma. We previously purified a group of nuclear proteins that interact specifically with the Stat1 transcription activation domain. In this report, we identified one of them as the multifunctional Ca(2+)/calmodulin-dependent kinase (CaMK) II. We demonstrate that IFN-gamma mobilizes a Ca(2+) flux in cells and activates CaMKII. CaMKII can interact directly with Stat1 and phosphorylate Stat1 on S727 in vitro. Inhibition of Ca(2+) flux or CaMKII results in a lack of S727 phosphorylation and Stat1-dependent gene activation, suggesting in vivo phosphorylation of Stat1 S727 by CaMKII.  0.506 SIGNOR-250706 FOXO1 protein Q12778 UNIPROT TCF4 protein P15884 UNIPROT down-regulates activity binding 9606 BTO:0000797 18250171 YES Gianni Here we show that the beta-catenin binding to FOXO serves a dual effect. beta-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with beta-catenin, thereby inhibiting TCF transcriptional activity. 0.268 SIGNOR-262529 PFK proteinfamily SIGNOR-PF79 SIGNOR beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266474 CEBPB protein P17676 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 NO fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. 0.702 SIGNOR-210004 17beta-estradiol smallmolecule CHEBI:16469 ChEBI MAPK3 protein P27361 UNIPROT up-regulates 9606 BTO:0000150 11043579 NO gcesareni Estrogen rapidly activates the mitogen-activated protein kinases, erk-1 and erk-2, via an as yet unknown mechanism. 0.8 SIGNOR-83280 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 YES lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. 0.716 SIGNOR-118023 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Thr305 TDAATMKtFCGTPEY 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.737 SIGNOR-248651 SREBF2 protein Q12772 UNIPROT ABCG5 protein Q9H222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21123766 NO miannu these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α. 0.422 SIGNOR-254455 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH3 protein P22223 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265843 PRKACA protein P17612 UNIPROT USP20 protein Q9Y2K6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser333 RMKDRKFsWGQQRTN 9534 BTO:0000298 25666616 YES done miannu Upon β2AR activation, a specific isoform of the second messenger cAMP-dependent protein kinase A (PKAα) rapidly phosphorylates USP20 on serine 333 located in its unique insertion domain. This phosphorylation of USP20 correlates with a characteristic SDS-PAGE mobility shift of the protein, blocks its deubiquitinase activity, promotes its dissociation from the activated β2AR complex, and facilitates trafficking of the ubiquitinated β2AR to autophagosomes, which fuse with lysosomes to form autolysosomes where receptors are degraded. 0.312 SIGNOR-273795 SMARCD2 protein Q92925 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.762 SIGNOR-269821 SREBF2 protein Q12772 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17921436 YES miannu Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9. 0.466 SIGNOR-255223 MAPK1 protein P28482 UNIPROT RSPH3 protein Q86UC2 UNIPROT up-regulates activity phosphorylation Thr286 AFLDRPPtPLFIPAK 9606 19684019 YES miannu ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D). 0.2 SIGNOR-262838 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr395 AKHHQDAyIRIVLEN 9606 15952790 YES llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. 0.605 SIGNOR-138150 TRIM27 protein P14373 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 BTO:0000671 12807881 NO inferred from 70% of family members miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. 0.271 SIGNOR-269915 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269376 Sin3B_complex complex SIGNOR-C409 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity binding 9606 BTO:0000007 21041486 YES inferred from 70% of family members miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.2 SIGNOR-269844 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 YES Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. 0.636 SIGNOR-248411 GHR protein P10912 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005787 BTO:0001103 23612709 YES miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 0.2 SIGNOR-255452 PRKCB protein P05771 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 YES lperfetto A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis. 0.2 SIGNOR-249237 ADRA1A protein P35348 UNIPROT GNA11 protein P29992 UNIPROT up-regulates activity binding 9534 BTO:0000298 1334487 YES In this report, we demonstrate that in transfected cos-7 cells Gal4 and Ga16, like Gaq and Ga11, can activate PIPLC j3l and that all three al-ARs, alA, alB and alC, can activate endogenous PI-PLC by coupling to Gaq or Ga11. 0.571 SIGNOR-278121 PTPN2 protein P17706 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity dephosphorylation 9606 21984578 NO miannu Moreover, it indicates that PTPN2 modulates the apoptotic activity of Bim via regulation of the protein kinase JNK1.|PTPN2 inhibition increased Bim phosphorylation at residue 65 in untreated INS-1E cells, and this effect was prolonged until 4 h of treatment with IFNalpha or 8 h after treatment with IFNgamma (XREF_FIG). 0.268 SIGNOR-277055 NUMB protein P49757 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates binding 9606 20818436 YES gcesareni Numb activates the catalytic activity of itch, releasing it from an inhibitory intramolecular interaction between its homologous to e6-ap c-terminus and ww domains. 0.614 SIGNOR-167844 PRKCE protein Q02156 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates activity phosphorylation Thr280 GLNVIQQtTRYFSTP 9606 23708658 YES miannu PKCepsilon phosphorylates Nanog at T200 and T280 to enhance Nanog stability, homodimerization and Bmi1 promoter occupancy.|Taken together, our results demonstrate that PKC\u03b5-mediated phosphorylation at T200 and T280 enhances Nanog protein stability in head and neck squamous cell carcinoma. 0.33 SIGNOR-278202 calcium(2+) smallmolecule CHEBI:29108 ChEBI S100A9 protein P06702 UNIPROT up-regulates activity chemical activation 9606 BTO:0001044 16690079 YES miannu S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization. 0.8 SIGNOR-261934 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR EIF3F protein O00303 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000165 18354498 YES miannu Mediation of eIF3-f polyubiquitination by the SCFMAFbx. The association of MAFbx with the essential Skp1, Roc 1 and Cul1 proteins, specific components of an E3 ubiquitin–protein ligase (SCFMAFbx), was previously described. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome. 0.35 SIGNOR-271767 ITGB7 protein P26010 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.565 SIGNOR-257726 ATM protein Q13315 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser1037 IGNSNHGsQSPRNVE 29939287 YES phosphorylation site remapping based on Fig 1 lperfetto To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. 0.2 SIGNOR-273433 ASH1L protein Q9NR48 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 35210569 YES Gianni Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis. 0.2 SIGNOR-269058 ATM protein Q13315 UNIPROT UCHL3 protein P15374 UNIPROT up-regulates activity phosphorylation 9606 27941124 YES lperfetto Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. 0.331 SIGNOR-279794 Elongator complex complex SIGNOR-C466 SIGNOR RAB3IL1 protein Q8TBN0 UNIPROT up-regulates activity binding -1 15780940 YES miannu Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. Our results raise the possibility that regulation of polarized exocytosis is an evolutionarily conserved function of the entire Elongator complex and that FD results from a dysregulation of neuronal exocytosis. We show that elp1Δ suppression of sec2ts is not a result of reduced transcriptional elongation and that Elp1p physically associates with Sec2p. The Sec2p interaction domain of Elp1p is necessary for both Elp1p function and for the polarized localization of Sec2p. Mutations in human Elp1p (IKAP) are a known cause of familial dysautonomia (FD). 0.274 SIGNOR-269714 MAML2 protein Q8IZL2 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12370315 NO gcesareni We recently cloned a mammalian homologue of the mastermind gene of drosophila melanogaster, maml1 (mastermind-like-1 molecule) and determined that it functions as a transcriptional coactivator for notch receptors. 0.839 SIGNOR-94065 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRA protein P10827 UNIPROT up-regulates activity chemical activation 10116 BTO:0000759 2158622 YES miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 0.8 SIGNOR-258385 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser28 SRMNGLPsPTHSAHC -1 14741103 YES llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. These were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35 (Figure 3D). However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. | Therefore, S28 residue may be a substrate in vitro, but our best efforts failed to detect phosphorylation of S28 in vivo. 0.405 SIGNOR-250654 MEF2D protein Q14814 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.327 SIGNOR-238712 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser243 TDSEVDSsCSGQPIH 9606 BTO:0000007 26885618 YES lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| 0.356 SIGNOR-273128 PDGFA protein P04085 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763 11803579 YES gcesareni Platelet-derived growth factors (pdgf) constitute a family of four gene products (pdgf-a-d) acting by means of two receptor tyrosine kinases, pdgfr alpha and beta. Three of the ligands (pdgf-a, -b, and -c) bind to pdgfr alpha with high affinity. 0.773 SIGNOR-114268 GFPT1 protein Q06210 UNIPROT Hexosamine_biosynthesis phenotype SIGNOR-PH194 SIGNOR up-regulates 9606 21310273 NO miannu GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. 0.7 SIGNOR-267819 EEF1A1P5 protein Q5VTE0 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269555 ACAT1 protein P24752 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates activity acetylation 34289383 YES lperfetto We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) 0.2 SIGNOR-267634 HMOX2 protein P30519 UNIPROT heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity chemical modification 9606 10490932 YES Regulation miannu Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme 0.8 SIGNOR-251912 AKT1 protein P31749 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 YES gcesareni Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta 0.667 SIGNOR-187006 JUND protein P17535 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 13679379 YES Luana Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.  0.816 SIGNOR-261603 GSK3A protein P49840 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser279 CGIQDTNsKKQSDTH 9606 BTO:0002181 33879767 YES miannu We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. 0.2 SIGNOR-277552 HCRTR1 protein O43613 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.448 SIGNOR-257354 PRKACA protein P17612 UNIPROT SEC14L2 protein O76054 UNIPROT up-regulates activity phosphorylation Ser289 VQISRGSsHQVEYEI -1 15680919 YES miannu These results suggest that phosphorylation of SPF by PKA is a dynamic process and that, in the absence of PKA activity, SPF is rapidly inactivated.Thus, phosphorylation of SPF at Ser-289 appears necessary for maximal stimulation of squalene monooxygenase activity in vitro and absolutely required for the stimulation of cholesterol synthesis in cell culture. 0.2 SIGNOR-276027 CDK20 protein Q8IZL9 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 14597612 YES gcesareni P42 is essential for the phosphorylation of thr-160 and activation of cdk2. 0.388 SIGNOR-118986 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation 9606 14967450 YES gcesareni Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1. 0.85 SIGNOR-121944 PPARG protein P37231 UNIPROT ACADM protein P11310 UNIPROT down-regulates activity binding 9606 BTO:0001370 28974683 YES Federica This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation 0.346 SIGNOR-261264 RAPGEF3 protein O95398 UNIPROT RAP1B protein P61224 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 YES miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. 0.717 SIGNOR-263957 TRAF6 protein Q9Y4K3 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates activity ubiquitination 9606 29202128 YES miannu We have shown that TRAF6 E3 ligase promotes IRF7 K63-linked ubiquitination that is required for EBV LMP1 activation of IRF7 [ xref ]; however, A20, a member with both E3 ligase and deubiquitinase activities in the OTU family, inhibits LMP1-stimulated IRF7 activity by acting as a deubiquitinase [ xref ]. 0.731 SIGNOR-278788 TRIM21 protein P19474 UNIPROT DDX41 protein Q9UJV9 UNIPROT down-regulates quantity ubiquitination 9606 23222971 YES miannu Furthermore, overexpression of TRIM21 in mDCs led to lower expression of DDX41 in these mDCs and up to 70% less IFN-beta production by mDCs in response to intracellular DNA (XREF_FIG).|Here we report that the E3 ligase TRIM21 negatively regulated the type I interferon response in myeloid dendritic cells (mDCs) and monocytes that had been induced by cytosolic double stranded DNA (dsDNA), mainly by promoting the ubiquitination and degradation of DDX41. 0.637 SIGNOR-278790 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser205 LATPPTLsSTVLIVR 9606 BTO:0001938 12815053 YES lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. 0.54 SIGNOR-249218 IMPDH2 protein P12268 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 19480389 YES miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). 0.8 SIGNOR-267334 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192774 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT up-regulates activity phosphorylation Ser328 GQAGSTIsNSHAQPF 10116 BTO:0000067 12270943 YES lperfetto We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation). 0.6 SIGNOR-249330 RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 12887920 YES amattioni Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex 0.909 SIGNOR-104255 EGR1 protein P18146 UNIPROT SF1 protein Q15637 UNIPROT up-regulates activity binding 10090 19106114 YES miannu GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. 0.295 SIGNOR-254914 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT down-regulates activity phosphorylation Ser495 STSTESSsQDVESTF 31938050 YES lperfetto Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization. 0.312 SIGNOR-275854 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr225 LGETKQEtLTNISAV 9606 15611134 YES gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. 0.2 SIGNOR-132463 CNR2 protein P34972 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.451 SIGNOR-256843 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser585 WRGMLKTSKAEELLA 9606 BTO:0000007 17301055 YES Barakat Drp1 was specifically phosphorylated at Ser-585 by Cdk1/cyclin B, which stimulated the mitochondrial fission in mitosis. From these results, we concluded that mitochondrial morphology is regulated by Drp1-dependent mitochondrial fission in mitotic cells 0.371 SIGNOR-274131 PCK2 protein Q16822 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 24632615 YES miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. 0.8 SIGNOR-266557 PXDN protein Q92626 UNIPROT COL4A4 protein P53420 UNIPROT up-regulates quantity by stabilization catalytic activity 9606 BTO:0000567 29305973 YES miannu Peroxidasin (PXDN), an ECM protein with peroxidase activity, is integral to basement membrane consolidation through catalysis of sulfilimine bonds in collagen IV. PXDN has been shown to form dityrosine crosslinks and also catalyses sulfilimine bonds, in the presence of hypohalous acids, to connect collagen IV protomers, which are an integral component of the basement membrane 0.256 SIGNOR-265250 PMS2 protein P54278 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 9500552 NO Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer 0.7 SIGNOR-257596 PTPRF protein P10586 UNIPROT LCK protein P06239 UNIPROT up-regulates dephosphorylation 9606 12496362 YES flangone We confirmed that lar dephosphorylated the phosphorylated tyrosine residues of lck..Activation Of lck and fyn involves tyrosine dephosphorylation of the cooh-terminal regulatory domain of kinases, followed by autophosphorylation of the kinase domain. 0.364 SIGNOR-96771 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser644 NLMFRKFsLERPFRP -1 24548923 YES miannu Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro.  0.523 SIGNOR-276255 CTNNB1 protein P35222 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 22298955 NO gcesareni In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs. 0.442 SIGNOR-195570 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT down-regulates activity phosphorylation Thr107 PKKERRRtESINSAF 10116 BTO:0001556 14636580 YES miannu In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function. 0.296 SIGNOR-249991 A2/b1 integrin complex SIGNOR-C160 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269009 SUFU protein Q9UMX1 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates relocalization 9606 BTO:0001130 16316410 YES gcesareni Negative regulation of gli1 and gli2 activator function by suppressor of fused through multiple mechanisms.Together, these observations reveal that su(fu) regulates the activity of gli1 and gli2 through distinct cytoplasmic and nuclear mechanisms. 0.266 SIGNOR-142608 SPAG4 protein Q9NPE6 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.357 SIGNOR-263285 NRXN2 protein P58401 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 22626542 YES miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 0.262 SIGNOR-265461 STK3 protein Q13188 UNIPROT RCC1 protein P18754 UNIPROT up-regulates phosphorylation Ser2 sPKRIAKR 9606 BTO:0000007 19559616 YES miannu MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets. 0.2 SIGNOR-263146 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Thr23 ESPPVSDtPDEGDEP 9606 BTO:0001271 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway 0.2 SIGNOR-174856 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258176 STK26 protein Q9P289 UNIPROT ASAP3 protein Q8TDY4 UNIPROT up-regulates activity phosphorylation Thr545 HRFARRCtPEPQRLW 9606 BTO:0000007 28808054 YES lperfetto Here we show that MST4 phosphorylates ACAP4, an ARF6 GTPase-activating protein, at Thr545|Significantly, phosphorylation of Thr545 enables ACAP4 to interact with ezrin. Given the location of Thr545 between the GTPase-activating protein domain and the first ankyrin repeat, we reason that MST4 phosphorylation elicits a conformational change that enables ezrin-ACAP4 interaction. 0.2 SIGNOR-272238 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity sumoylation Lys606 EELLAEEKSKPIPIM 9606 BTO:0000007 19638400 YES Barakat Through detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. 0.535 SIGNOR-274129 USP36 protein Q9P275 UNIPROT DHX33 protein Q9H6R0 UNIPROT up-regulates quantity by stabilization deubiquitination 10090 29273634 YES lperfetto Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice. 0.509 SIGNOR-272289 KIF18A protein Q8NI77 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272526 seliciclib chemical CHEBI:45307 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206571 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr1161 FFNPVCAtPNSKILK -1 29771379 YES miannu Kif4A T1161 was phosphorylated by Cdk1/Cyclin B1 in vitro. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization. 0.452 SIGNOR-265995 BMI1 protein P35226 UNIPROT BMI1 protein P35226 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 23239878 YES gcesareni Here, we report that BMI1 autoactivates its own promoter via an E-box present in its promoter. 0.2 SIGNOR-245344 HTR7 protein P34969 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257323 MAP3K4 protein Q9Y6R4 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates activity phosphorylation Thr1494 KLKNNAQtMPGEVNS 9606 17242196 YES lperfetto Gadd45 binding also induced mtk1 dimerization via a dimerization domain containing a coiled-coil motif, which is essential for the trans autophosphorylation of mtk1 at thr-1493 in the kinase activation loop. 0.2 SIGNOR-152408 MAPK14 protein Q16539 UNIPROT MAPT protein P10636 UNIPROT up-regulates phosphorylation 9606 20626350 YES lperfetto A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins. 0.316 SIGNOR-166611 SP7 protein Q8TDD2 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004058; BTO:0000165 11792318 NO Giulio Giuliani To test whether Osx could activate typical osteoblast genes, we transfected an Osx expressing vector into both C2C12 and C3H10T1/2 cells. Our results showed that Osx produced an induction of osteocalcin RNA in both cell types. 0.491 SIGNOR-255409 verteporfin chemical CHEBI:32293 ChEBI Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0005079 27073720 NO Prolonged incubation with Verteporfin induced cell death with the vacuolization in cells 0.7 SIGNOR-278128 ICOSLG protein O75144 UNIPROT ICOS protein Q9Y6W8 UNIPROT up-regulates activity binding 9606 27559335 YES ICOSL expression is largely restricted to professional antigen-presenting cells (APCs), including B cells [in which ICOSL is regulated by BAFFR and non-canonical NFκB signaling (20)], macrophages, and dendritic cells (DCs) (12, 17, 21, 22), but is also expressed by certain endothelial cells (23) and lung epithelium 0.2 SIGNOR-272497 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257932 P-TEFb complex SIGNOR-C238 SIGNOR MLLT1 protein Q03111 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000007 17135274 YES miannu Phosphorylation of Af9 and Enl by P-TEFb promotes their proteolysis 0.718 SIGNOR-266799 GADL1 protein Q6ZQY3 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 22718265 YES miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. 0.8 SIGNOR-267545 CDK5 protein Q00535 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Thr354 HLGPHRStPESRAAV 9606 12056836 YES lperfetto Cyclin-dependent kinase-5/p35 phosphorylates presenilin 1 to regulate carboxy-terminal fragment stabilityhere we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates ps1 on threonine(354) within c-ps1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize c-ps1. 0.511 SIGNOR-89145 CREBBP protein Q92793 UNIPROT DDX21 protein Q9NR30 UNIPROT down-regulates activity acetylation Lys600 HFKQSAEkLIEEKGA 28790157 YES lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. 0.245 SIGNOR-275906 WARS1 protein P23381 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI down-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 0.8 SIGNOR-270510 IL18 protein Q14116 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 10653850 NO miannu IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement. 0.7 SIGNOR-260965 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 YES miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. 0.8 SIGNOR-262253 MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000527 16740698 YES miannu Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor 0.747 SIGNOR-146915 PLK1 protein P53350 UNIPROT RAN protein P62826 UNIPROT up-regulates phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 16930555 YES lperfetto Plk1 is capable of phosphorylating co-immunoprecipitated ran in vitro on serine-135 and ran is phosphorylated in vivo at the same site during mitosis when plk1 is normally activated. Deregulation of ran phosphorylation disrupts normal spindle structure and segregation of chromosomes. 0.264 SIGNOR-149073 OXTR protein P30559 UNIPROT DRD2 protein P14416 UNIPROT up-regulates activity binding 10116 27425032 YES miannu Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. 0.374 SIGNOR-270333 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR PTPN1 protein P18031 UNIPROT up-regulates activity binding 16115959 YES lperfetto N this study, we demonstrate an essential role for protein-tyrosine phosphatase (PTP)-1B in this process. In resting platelets, c-Src forms a complex with alphaIIbbeta3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain c-Src autoinhibition. Fibrinogen binding to alphaIIbbeta3 triggers PTP-1B recruitment to the alphaIIbbeta3-c-Src-Csk complex in a manner that is dependent on c-Src and specific tyrosine (tyrosine 152 and 153) and proline (proline 309 and 310) residues in PTP-1B. Studies of PTP-1B-deficient mouse platelets indicate that PTP-1B is required for fibrinogen-dependent Csk dissociation from alphaIIbbeta3, dephosphorylation of c-Src tyrosine 529, and c-Src activation. 0.48 SIGNOR-261800 FBXW7 protein Q969H0 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28036276 YES lperfetto Mechanistically, we further show that FBW7, an E3 ligase complex component that is frequently downregulated in TNBC, negatively regulates EglN2 protein stability. 0.349 SIGNOR-261997 captopril chemical CHEBI:3380 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 9187274 YES miannu We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range. 0.8 SIGNOR-258612 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273092 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT unknown phosphorylation Tyr706 RDVYSTDyYRVGGHT 10090 BTO:0000944 10533983 YES miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. 0.2 SIGNOR-250206 PRKACA protein P17612 UNIPROT PIN1 protein Q13526 UNIPROT down-regulates activity phosphorylation Ser16 PGWEKRMsRSSGRVY 9606 11723108 YES llicata Pka and pkc readily phosphorylated pin1 and its ww domain in summary, we have demonstrated that phosphorylation of the pin1 ww domain on ser16 regulates its ability to function as a pser/thr-binding module. |To examine the importance of Ser16 of Pin1, it was mutated to Glu to mimic pSer, and the mutant Pin1S16E failed to bind mitotic phosphoproteins 0.2 SIGNOR-112164 MYCT1 protein Q8N699 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity 9606 30283340 NO miannu Herein, we observed that overexpression of MYCT1 induced apoptosis in HL-60 and KG-1a cells, and upregulated Bax, downregulated Bcl-2, and enhanced cleavage of caspase-3 and -9. Similar proapoptotic role of MYCT1 was also found in the AML cell xenografts. These results suggest that MYCT1 affects AML cell apoptosis by modulating the endogenous apoptotic pathways. 0.2 SIGNOR-261942 lidocaine chemical CHEBI:6456 ChEBI SCN2A protein Q99250 UNIPROT down-regulates activity chemical inhibition 10116 1658608 YES miannu This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. 0.8 SIGNOR-258354 C1RL protein Q9NZP8 UNIPROT HP protein P00738 UNIPROT up-regulates activity cleavage Arg161 NPANPVQrILGGHLD 9534 BTO:0001538 15385675 YES miannu We demonstrate that coexpression of the proform of Hp (proHp) and C1r-LP in COS-1 cells effected cleavage of proHp in the endoplasmic reticulum. This cleavage depended on proteolytic activity of C1r-LP because mutation of the putative active-site Ser residue abolished the reaction. Furthermore, incubation of affinity-purified C1r-LP and proHp led to the cleavage of the latter protein. ProHp appeared to be cleaved at the expected site because substitution of Gly for Arg-161 blocked the reaction. 0.375 SIGNOR-256358 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 YES Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. 0.64 SIGNOR-248832 diphenhydramine chemical CHEBI:4636 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257787 SMO protein Q99835 UNIPROT GNB2 protein P62879 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.2 SIGNOR-199177 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 YES lperfetto TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. 0.965 SIGNOR-236366 ATP5PF protein P18859 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261398 KIF21B protein O75037 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 NO In this study, we showed that KIF21B is a highly processive MT plus-end directed motor, which can potently induce pausing of MT plus ends. This activity depends on several regions of this large motor protein. 0.7 SIGNOR-272515 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (FKHR), is phosphorylated at three amino acid residues (Thr-24, Ser-256 and Ser-319) by protein kinase b (PKB)alpha. FKHR (forkhead in rhabdomyosarcoma), AFX (all1 fused gene from chromosome x) and FKHRL1 (FKHR-like 1) are phosphorylated directly by PKB in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus. 0.87 SIGNOR-105459 Ub:E2 complex SIGNOR-C497 SIGNOR RNF182 protein Q8N6D2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271072 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258846 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser100 ESEDSQEsVDSVTDS 9606 9931297 YES lperfetto Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement. 0.312 SIGNOR-64258 PRL protein P01236 UNIPROT PRLR protein P16471 UNIPROT up-regulates binding 9606 10585417 YES gcesareni Prolactin-dependent signaling occurs as the result of ligand-induced dimerization of the prolactin receptor (prlr). 0.924 SIGNOR-72810 CDC16 protein Q13042 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.921 SIGNOR-252006 aldosterone smallmolecule CHEBI:27584 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258712 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates quantity by stabilization phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 BTO:0000567 19789335 YES lperfetto we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1. 0.841 SIGNOR-109684 EP300 protein Q09472 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11796223 YES lperfetto Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription. 0.741 SIGNOR-232159 NFIA protein Q12857 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268875 NRXN2 protein P58401 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626545 YES miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites 0.828 SIGNOR-265455 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 YES gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. 0.91 SIGNOR-252824 KAT2B protein Q92831 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269624 NFX1 protein Q12986 UNIPROT TERT protein O14746 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17267499 YES miannu NFX1-123 positively regulated hTERT expression, as its knockdown decreased hTERT mRNA levels and telomerase activity and its overexpression increased telomerase activity. NFX1-123 was found to interact with cytoplasmic poly(A) binding proteins (PABPCs), and together they synergistically augmented expression from the hTERT promoter when activated by HPV16 E6. 0.519 SIGNOR-261050 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF11 protein A6NNE9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271244 AURKB protein Q96GD4 UNIPROT KIF20A protein O95235 UNIPROT down-regulates activity phosphorylation Ser878 RILRSRRsPLLKSGP 9606 BTO:0000567 27939310 YES miannu We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878. 0.78 SIGNOR-262659 MAPK14 protein Q16539 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO gcesareni (tak1) and tak1 binding protein 1 (tab1) play a pivotal role as upstream sig-nal transducers by activating the mkk3-p38 mapk signaling cascade that leads to the induction of type i collagen expression by tgf-beta1. 0.273 SIGNOR-192796 URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 YES miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  0.576 SIGNOR-270924 PRKAA1 protein Q13131 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser385 RRRKKRTsIETNIRV 9606 1684878 YES lperfetto Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites. 0.2 SIGNOR-20971 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258923 EDNRB protein P24530 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.267 SIGNOR-256924 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 YES gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2). 0.761 SIGNOR-59639 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 19318349 YES gcesareni PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells. 0.652 SIGNOR-248079 DAB2IP protein Q5VWQ8 UNIPROT PROX1 protein Q92786 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27476001 NO miannu DAB2IP regulates EMT and metastasis of prostate cancer through targeting PROX1 transcription and destabilizing HIF1α protein. In this study, based on different PCa cell lines and knockout mice, we showed that PROX1 could be suppressed by DAB2IP, a novel member of the Ras GTPase-activating protein family and a critical player in control of epithelial-mesenchymal transition (EMT) and PCa metastasis. 0.2 SIGNOR-254764 NEK7 protein Q8TDX7 UNIPROT EML4 protein Q9HC35 UNIPROT up-regulates activity phosphorylation Ser146 PQIRASPsPQPSSQP -1 31409757 YES done miannu The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression. 0.274 SIGNOR-273884 NAA10 protein P41227 UNIPROT NatA complex SIGNOR-C415 SIGNOR form complex binding 9606 BTO:0000007 15496142 YES miannu Protein acetyltransferases and deacetylases have been implicated in oncogenesis, apoptosis and cell cycle regulation. Most of the protein acetyltransferases described acetylate epsilon-amino groups of lysine residues within proteins. We now describe the human homologue of Nat1p, NATH (NAT human), as the partner of the hARD1 (human ARD1) protein. Included in the characterization of the NATH and hARD1 proteins is the following: (i) endogenous NATH and hARD1 proteins are expressed in human epithelial, glioma and promyelocytic cell lines; (ii) NATH and hARD1 form a stable complex, as investigated by reciprocal immunoprecipitations followed by MS analysis; (iii) NATH-hARD1 complex expresses N-terminal acetylation activity; (iv) NATH and hARD1 interact with ribosomal subunits, indicating a co-translational acetyltransferase function 0.951 SIGNOR-267224 TRIM41 protein Q8WV44 UNIPROT CGAS protein Q8N884 UNIPROT up-regulates activity ubiquitination 9606 29760876 YES miannu Our finding that RINCK positively regulates cGAS activation by mediating the monoubiquitination of cGAS uncovers the function of RINCK in cGAS mediated innate immunity.|Together, these data suggest that RINCK mediates cGAS monoubiquitination. 0.2 SIGNOR-278794 GNAI1 protein P63096 UNIPROT ADCY5 protein O95622 UNIPROT down-regulates activity binding 7108 BTO:0001240 8119955 YES Marta Tosoni Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3 0.606 SIGNOR-278074 WWP1 protein Q9H0M0 UNIPROT NDFIP1 protein Q9BT67 UNIPROT down-regulates quantity ubiquitination 9606 35264565 YES miannu Accordingly, the ubiquitination assays were performed and the results revealed that knockdown of WWP1 reduced the ubiquitination of NDFIP1 in HuCCT1 and vice versa in HCCC-9810 and RBE (Fig. 7E).|In addition, we found that WWP1 could reduce the protein level of NDFIP1 via ubiquitination. 0.381 SIGNOR-278796 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates activity binding 9606 22312431 YES miannu Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING 0.2 SIGNOR-260247 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 18570871 YES gcesareni In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function. 0.738 SIGNOR-179084 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser371 AHSSHLKsKKGQSTS 9606 9315650 YES llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. 0.459 SIGNOR-51280 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 YES lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities 0.2 SIGNOR-137635 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 14563837 YES gcesareni Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc 0.719 SIGNOR-118844 STK38 protein Q15208 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser76 SNLQRMGsSESTDSG 9606 25936524 YES miannu Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation. 0.248 SIGNOR-279488 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Sec) smallmolecule CHEBI:29264 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269495 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 22898666 YES gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. 0.681 SIGNOR-191851 BMS 794833 chemical CID:44155856 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190419 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser641 KVTSKCGsLGNIHHK 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process 0.43 SIGNOR-171054 clozapine chemical CHEBI:3766 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 BTO:0001311 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258519 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT3 protein Q9NTG7 UNIPROT up-regulates activity phosphorylation Ser159 SGIPDFRsPGSGLYS 9606 BTO:0001109 26141949 YES miannu  Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3.  0.291 SIGNOR-276921 BRCA2 protein P51587 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 YES miannu Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates 0.551 SIGNOR-204538 CSNK2B protein P67870 UNIPROT HOXB6 protein P17509 UNIPROT unknown phosphorylation Ser214 LLSASQLsAEEEEEK -1 10327653 YES llicata Using two-dimensional tryptic phosphopeptide mapping and purified protein kinases, we demonstrate that Hoxb-6 is phosphorylated in vitro by casein kinase II and cAMP-dependent protein kinase. The casein kinase II phosphorylation site was mapped to serine-214.  0.307 SIGNOR-251071 SIAH2 protein O43255 UNIPROT AKAP1 protein Q92667 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18323779 YES miannu Seven In-Absentia Homolog 2 (Siah2), an E3-ubiquitin ligase whose expression is induced in hypoxic conditions, formed a complex and degraded AKAP121. 0.508 SIGNOR-272641 IL10RB protein Q08334 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 YES milica Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor ? Chain) and tyk2 (associated with the il-10 receptor ? Chain) and induces the activation of stat1, stat3, and, in some cells, stat5. 0.647 SIGNOR-68013 RAD51 protein Q06609 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27660832 NO lperfetto Rad51 is a key component of homologous recombination (HR) to repair DNA double-strand breaks and it forms Rad51 recombinase filaments of broken single-stranded DNA to promote HR. In addition to its role in DNA repair and cell cycle progression, Rad51 contributes to the reprogramming process during the generation of induced pluripotent stem cells 0.7 SIGNOR-251508 CDK5 protein Q00535 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 16611631 YES lperfetto In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3. 0.621 SIGNOR-145912 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 16611631 YES lperfetto In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3. 0.469 SIGNOR-145995 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HECTD3 protein Q5T447 UNIPROT up-regulates activity phosphorylation Thr157 ARLVPIDtPNHLQRQ 9606 BTO:0004461 28716524 YES miannu HECTD3 binds and ubiquitinates caspase-9.Phosphorylation of HECTD3 by ERK is required for the association of HECTD3 and caspase-9. HECTD3 suppressing caspase-9 activation is dependent on T157 phosphorylation by ERK. 0.2 SIGNOR-272330 AKT1 protein P31749 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 YES gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. 0.435 SIGNOR-252505 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 YES lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). 0.914 SIGNOR-236756 DUX4 protein Q9UBX2 UNIPROT PITX1 protein P78337 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17984056 YES Luana DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1 0.307 SIGNOR-261590 hydromorphone chemical CHEBI:5790 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258038 NFYB protein P25208 UNIPROT SOX18 protein P35713 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 18496767 NO miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells 0.2 SIGNOR-254819 MC5R protein P33032 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257271 MAPK1 protein P28482 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser770 MMRSKETsSPGTDDV 9606 17209041 YES miannu We have demonstrated that the map kinases extracellular signal-regulated kinases 1 and 2 (erk1/2) are implicated in growth factor activation of nhe1. / our results suggest that amino acids ser770 and ser771 mediate erk-dependent activation of the na+/h+ exchanger in vivo. 0.668 SIGNOR-151925 CDK1 protein P06493 UNIPROT CDC14A protein Q9UNH5 UNIPROT up-regulates activity phosphorylation Ser549 SNGGNLNsPPGPHSA 9606 30089874 YES miannu We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages. 0.541 SIGNOR-278264 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5B protein Q9UGL1 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273476 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 17190791 YES gcesareni We finally establish that full-length wnk1, wnk2 and wnk3, but not wnk4, are capable of directly phosphorylating ser382 of wnk1 in vitro. This supports the notion that t-loop phosphorylation of wnk isoforms is controlled by trans-autophosphorylation. 0.2 SIGNOR-151675 MEF2C protein Q06413 UNIPROT JUN protein P05412 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9069290 NO gcesareni One consequence of mef2c activation is increased c-jun gene transcription. Our results show that p38 may influence host defence and inflammation by maintaining the balance of c-jun protein consumed during infection 0.618 SIGNOR-47139 CDKN2A protein P42771 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000176 7972006 NO Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation. 0.7 SIGNOR-259406 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser164 TSTPGRRsCFGFEGL -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.628 SIGNOR-276113 UFL1 protein O94874 UNIPROT H4C1 protein P62805 UNIPROT up-regulates activity ubiquitination Lys32 DNIQGITkPAIRRLA 9606 BTO:0000007;BTO:0001938 30886146 YES lperfetto Here we report that UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. 0.2 SIGNOR-265072 BIRC5 protein O15392 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates binding 9606 17546047 YES gcesareni Mitochondrial survivin associated with smac/diablo, delaying its release. 0.571 SIGNOR-155361 RPL13 protein P26373 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.794 SIGNOR-262486 leucine smallmolecule CHEBI:25017 ChEBI Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270418 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270376 PPP2CA protein P67775 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT down-regulates dephosphorylation Thr588 PEHQLLKtPSSSSLS 9606 18201571 YES gcesareni We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners. 0.304 SIGNOR-160402 S protein P59594 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates activity transcriptional regulation 9606 17267381 YES Luana Spike protein of SARS‐CoV activated COX‐2 expression in a protein concentration‐dependent manner 0.2 SIGNOR-262315 TANC2 protein Q9HCD6 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10116 21068316 YES miannu In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses. 0.7 SIGNOR-266897 N protein P59595 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates activity transcriptional regulation 9606 BTO:0002181 16546436 YES Luana SARS-CoV N protein activates COX-2 promoter and induces COX-2 protein expression 0.2 SIGNOR-262314 SCRIB protein Q14160 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 19458197 NO miannu Our data supports a model by which scribble functions downstream of beta-catenin to cluster synaptic vesicles at developing synapses. 0.7 SIGNOR-265827 STAT6 protein P42226 UNIPROT SLC26A4 protein O43511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24429829 NO miannu We then examined the ability of STAT6 to bind each of the N4 GAS motifs in vivo with a site-specific ChIP assay, the results of which showed that STAT6 interacted with only the N4 GAS motif that was functionally implicated in increasing the activity of the pendrin promoter following IL-4 treatment. 0.2 SIGNOR-255250 AMFR protein Q9UKV5 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 23427266 YES miannu Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2. 0.3 SIGNOR-272887 S100A9 protein P06702 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR down-regulates 10090 18809714 NO miannu We report here that up-regulation of S100A9 in myeloid precursors in cancer inhibits DC and macrophage differentiation and induces accumulation of MDSCs. This may represent a universal molecular mechanism of tumor-induced abnormalities in myeloid cells in cancer, directly linking inflammation and immune suppression. 0.7 SIGNOR-261933 MDM2 protein Q00987 UNIPROT OVOL2 protein Q9BRP0 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 35896951 YES miannu In breast cancer cells, MDM2 overexpression or p53 KD reduced OVOL2 protein expression, and the proteasome inhibitor MG132 blocked the MDM2 overexpression\u2010 or p53 KD\u2010mediated reduction in OVOL2 expression (Figure\u00a06B,C).|The E3 ubiquitin ligase MDM2 ubiquitinates and degrades the OVOL2 protein. 0.2 SIGNOR-278826 AARS1 protein P49588 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 32314272 YES miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). 0.8 SIGNOR-270449 TBK1 protein Q9UHD2 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates activity phosphorylation Ser13 LNSQKQLsACEDGED 9606 32757223 YES miannu Taken together, our data suggest that TBK1 expression promotes the general cellular clearance mechanism of soluble HTT and prevents its accumulation and aggregation by enhancing autophagy.|This confirmed that TBK1 phosphorylated endogenous HTT at S13 (Fig XREF_FIG G and H). 0.2 SIGNOR-278384 TNIK protein Q9UKE5 UNIPROT NF2 protein P35240 UNIPROT up-regulates activity phosphorylation Thr576 GGSSKHNtIKKLTLQ 9606 33495197 YES miannu Consistently with TNIK modulating Merlin, we also observed reduced YAP levels following TNIK knockdown in LK2 and NCI-H520 cells (Supplementary Fig. S7B).|Using in vitro kinase assays followed by phosphopeptide mapping, and mass spectrometry analysis on Merlin isolated from cells co-expressing TNIK and Merlin, we determined that TNIK could phosphorylate Merlin at S13, T272, S315, and T576 (Fig. 4B, Supplementary Fig. S4D, and Supplementary Table S3). 0.2 SIGNOR-278385 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.491 SIGNOR-275778 GALR2 protein O43603 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.311 SIGNOR-257136 GRK5 protein P34947 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 2787365 YES gcesareni we found that g protein-coupled receptor kinases 5 and 6 (grk5/6), traditionally known to phosphorylate and desensitize 7tm g protein-coupled receptors, directly phosphorylate the pppsp motifs on single transmembrane lrp6 and regulate wnt/lrp6 signaling 0.546 SIGNOR-23330 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 9606 15379552 YES lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) 0.2 SIGNOR-129200 MYCT1 protein Q8N699 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30283340 NO miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 0.2 SIGNOR-261734 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT down-regulates quantity by destabilization cleavage Tyr27 LSSTCVAyVATRDNC -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain 0.2 SIGNOR-263616 CREB1 protein P16220 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001861 19757157 NO lperfetto Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level. 0.2 SIGNOR-254091 AP1 complex SIGNOR-C154 SIGNOR GLIS1 protein Q8NBF1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 24383088 YES miannu Co-transfection experiments revealed that HIF-2α had greater potency on the GLIS1 promoter activation than HIF-1α. Subsequent studies using wild-type and mutant HIF-2α demonstrated that DNA binding activity was not necessary but TADs were critical for GLIS1 induction. Finally, co-transfection experiments indicated that HIF-2α cooperated with AP-1 family members in upregulating GLIS1 transcription. These results suggest that the hypoxic signaling pathway may play a pivotal role in regulating the reprogramming factor GLIS1, via non-canonical mechanisms involving partner transcription factor rather than by direct HIF transactivation. 0.2 SIGNOR-269041 MSX2 protein P35548 UNIPROT SPEN protein Q96T58 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000661 19835636 YES gcesareni Furthermore, in addition to msx2, both tlx1 and nkx2-5 proteins interacted with notch-pathway repressors, spen/mint/sharp and tle1/grg1, representing a potential mechanism for (de)regulation. 0.482 SIGNOR-188572 methiothepin chemical CHEBI:64203 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258687 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 NO apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. 0.579 SIGNOR-255356 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser641 GKVYGKTsHLRAHLR 9606 16943418 YES gcesareni The hdac inhibitor tsa-induced cell-specific phosphatase release from the promoter, which serves as an 'on' mechanism for sp1 phosphorylation by phosphatidylinositol 3-kinase/protein kinase czeta (pi3k/pkczeta) at ser641, leading to p107 repressor derecruitment and lhr transcriptional activation. 0.485 SIGNOR-149287 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR phenylalanine smallmolecule CHEBI:28044 ChEBI down-regulates quantity chemical modification 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.8 SIGNOR-270439 TLK1 protein Q9UKI8 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Ser354 VSLKPLHsVNNPILR 9606 BTO:0000007 35064619 YES miannu We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. 0.2 SIGNOR-276746 F2RL3 protein Q96RI0 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257370 Ub:E2 complex SIGNOR-C497 SIGNOR RNF114 protein Q9Y508 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271076 Caspase 3 complex complex SIGNOR-C221 SIGNOR PSIP1 protein O75475 UNIPROT down-regulates cleavage 9606 BTO:0001130 18708362 YES miannu Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75 0.349 SIGNOR-256469 NODAL protein Q96S42 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0004094 15531507 NO Regulation miannu Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. 0.7 SIGNOR-251934 MEF2C protein Q06413 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 YES miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter 0.492 SIGNOR-265816 FAM20C protein Q8IXL6 UNIPROT HRC protein P23327 UNIPROT up-regulates activity phosphorylation Ser96 EKEDEDVsKEYGHLL 10116 BTO:0001879 28784772 YES miannu Here, we demonstrate that family with sequence similarity 20C (Fam20C), a recently characterized protein kinase in the secretory pathway, phosphorylates HRC on Ser96. HRC Ser96 phosphorylation was confirmed in cells and human hearts.The pSer96-HRC binds tighter to triadin than S96A-HRC, which cannot be phosphorylated. Conversely, S96A-HRC or unphosphorylated Ser96-HRC binds tighter to SERCA2a. This suggests that Ser96-HRC phosphorylation (P) regulates HRC’s interactions with the major SR Ca-cycling proteins. 0.402 SIGNOR-273639 CPT1A protein P50416 UNIPROT O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267129 MDFI protein Q99750 UNIPROT MYOG protein P15173 UNIPROT down-regulates activity binding 10090 BTO:0000944 8797820 YES 2 miannu We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals. 0.375 SIGNOR-240493 IL10 protein P22301 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 NO miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. 0.27 SIGNOR-253499 F12 protein P00748 UNIPROT F11 protein P03951 UNIPROT up-regulates activity cleavage 9606 BTO:0000131 8427954 YES lperfetto Activation of factor XI in plasma is dependent on factor XII | Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. 0.493 SIGNOR-263519 ANAPC2 protein Q9UJX6 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 19805045 YES gcesareni We now report that the anaphase-promoting complex (apc/c) recognizes a d-box motif of dvl and ubiquitylates dvl on a highly conserved lysine residue.We now report that expression of the apc/c subunit anapc2 activates the apc/c-dependent degradation of dvl by disrupting canonical wnt signaling. 0.239 SIGNOR-188393 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser389 LKEAEEEsSGGEEED 9606 BTO:0001938 11861906 YES llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. 0.38 SIGNOR-251069 MICU1 protein Q9BPX6 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.69 SIGNOR-270859 CREB1 protein P16220 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9606 26652733 YES inferred from family member miannu Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB 0.2 SIGNOR-267786 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr594 TYVDPHTyEDPNQAV -1 21538645 YES gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates 0.659 SIGNOR-246039 NFYA protein P23511 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 NO miannu Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response. 0.2 SIGNOR-254815 CDK2 protein P24941 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Ser76 VQDTSGTsPVHDAAR 9606 22558186 YES lperfetto Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation. 0.526 SIGNOR-197270 BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7791754 YES fspada Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. 0.799 SIGNOR-33425 FZD2 protein Q14332 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 25902418 YES areggio Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. 0.687 SIGNOR-258968 CARS1 protein P49589 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates quantity chemical modification 9606 11347887 YES miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. 0.8 SIGNOR-270474 ZDHHC2 protein Q9UIJ5 UNIPROT AKAP5 protein P24588 UNIPROT up-regulates activity palmitoylation Cys129 KSRLKIPcIKFPRGP 10116 25589740 YES Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms 0.331 SIGNOR-261289 17beta-estradiol smallmolecule CHEBI:16469 ChEBI 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI up-regulates quantity precursor of 9606 BTO:0000093 8790407 YES Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. 0.8 SIGNOR-269753 GNG3 protein P63215 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.383 SIGNOR-145125 CASP3 protein P42574 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity cleavage -1 10579725 YES lperfetto P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro 0.641 SIGNOR-72677 PRKCD protein Q05655 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Thr909 PKSYLPQtVRQGGYM -1 12361954 YES lperfetto Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling. 0.334 SIGNOR-249177 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 YES lperfetto Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells 0.2 SIGNOR-264658 SRC protein P12931 UNIPROT WBP2 protein Q969T9 UNIPROT up-regulates activity phosphorylation Tyr192 MMDGAMGyVQPPPPP 9606 BTO:0000093 21642474 YES miannu Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα. 0.297 SIGNOR-273567 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser77 PGPFATRsPLFIFMR 12818176 YES miannu JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. 0.636 SIGNOR-250135 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr659 VADERVDyVVVDQQK 10090 BTO:0000944 10978177 YES HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin 0.501 SIGNOR-251317 CDK1 protein P06493 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Ser1252 QPTLPSSsPVPIPVS 9606 BTO:0000567 37584777 YES phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. 0.2 SIGNOR-272968 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 19934023 YES gcesareni We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657. 0.309 SIGNOR-161824 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT down-regulates activity phosphorylation Ser486 SSWGRTYsFTSAMSR 10090 SIGNOR-C469 21148297 YES miannu RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase. kt2 directly phosphorylated all three sites on RGC2 (Figure 5A). 0.452 SIGNOR-269797 RPS6K proteinfamily SIGNOR-PF26 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15342917 YES lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 0.461 SIGNOR-252796 P2RY14 protein Q15391 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.248 SIGNOR-257002 AMP smallmolecule CHEBI:456215 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity precursor of -1 31461341 YES Luana Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine. 0.8 SIGNOR-269741 CCNE1 protein P24864 UNIPROT CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR form complex binding 37104883 YES lperfetto Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. 0.744 SIGNOR-273186 CDK4 protein P11802 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates 9606 21902831 YES gcesareni Not much is known about how this occurs, but inhibition of mef2c by cdk4 prevents the association of mef2 with its transcriptional coactivator, glucocorticoid receptor-interacting protein 1 (grip1). 0.283 SIGNOR-176521 PTPN13 protein Q12923 UNIPROT PDCD10 protein Q9BUL8 UNIPROT down-regulates activity dephosphorylation 9606 17657516 YES In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling. 0.568 SIGNOR-248714 MAPK3 protein P27361 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Thr82 HSMSVPTtPTLGFST 9606 17604322 YES lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 0.521 SIGNOR-262959 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Thr204 NEAAARFtLGSPLTS 9606 9630228 YES lperfetto Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4. 0.589 SIGNOR-109768 LRIG1 protein Q96JA1 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates ubiquitination 9606 16123311 YES gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. 0.403 SIGNOR-139948 ARX protein Q96QS3 UNIPROT EBF3 protein Q9H4W6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19627984 NO Regulation of expression miannu Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissues partially rescues tangential cell movement. 0.304 SIGNOR-251971 BAP1 protein Q92560 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 26470845 YES lperfetto Since we found that ASXL1 and BAP1 both are enriched at the INK4B locus, our results suggest that activation of the INK4B locus requires ASXL1/BAP1-mediated deubiquitinylation of H2AK119ub1. 0.2 SIGNOR-241656 BRCA1-B complex complex SIGNOR-C298 SIGNOR ATR protein Q13535 UNIPROT up-regulates activity binding 9606 BTO:0001938 16530042 YES lperfetto These results establish that TopBP1 can activate both Xenopus and human ATR. Furthermore, these experiments provide conclusive evidence that the kinase activity that is induced by TopBP1 is intrinsic to the ATR protein itself and is not due to a kinase that associates with ATR. 0.653 SIGNOR-263231 AKT1 protein P31749 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Thr1462 GLRPRGYtISDSAPS 10090 BTO:0000944 12150915 YES lperfetto We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. 0.816 SIGNOR-235515 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser316 VEEEPLNsEDDVSDE -1 11278496 YES llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. 0.38 SIGNOR-250876 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12471034 YES Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. 0.965 SIGNOR-96253 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 10669763 YES gcesareni Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association. 0.559 SIGNOR-74935 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr861 PIGNQHIyQPVGKPD -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.244 SIGNOR-254720 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273052 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MED1 protein Q15648 UNIPROT up-regulates phosphorylation 9606 12356758 YES inferred from 70% family members lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase 0.2 SIGNOR-270106 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr409 TDGLGLSyLSSHIAN -1 10210201 YES llicata Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624. 0.572 SIGNOR-250780 ATM protein Q13315 UNIPROT FANCA protein O15360 UNIPROT up-regulates phosphorylation Ser1449 AAPDADLsQEPHLF 9606 19109555 YES lperfetto The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site 0.407 SIGNOR-182949 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 NO miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. Runx1 is also upregulated in the NUP98‐HOXA9 transcriptosome and is a critical regulator of hematopoietic development and a frequent target for chromosomal translocation in leukemia 0.2 SIGNOR-261499 AKT1 protein P31749 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 YES lperfetto These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf 0.347 SIGNOR-252478 CDK2 protein P24941 UNIPROT ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 SIGNOR-C16 9029153 YES lperfetto Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_ 0.435 SIGNOR-46397 CDK1 protein P06493 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates phosphorylation Thr292 ETPPRPRtPGRPLSS 9606 8114697 YES gcesareni P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well 0.494 SIGNOR-36116 HIPK2 protein Q9H2X6 UNIPROT PAX6 protein P26367 UNIPROT up-regulates activity phosphorylation Thr304 QPIPQPTtPVSSFTS 9606 BTO:0001938 16407227 YES HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. 0.464 SIGNOR-251270 MAPK7 protein Q13164 UNIPROT PML protein P29590 UNIPROT down-regulates activity phosphorylation Thr409 ASPEAAStPRDPIDV 9606 23730625 YES miannu Big MAP kinase 1 (BMK1) also phosphorylates PML at two sites : S403 and T409.|Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation. 0.475 SIGNOR-279074 MAPK7 protein Q13164 UNIPROT PML protein P29590 UNIPROT down-regulates activity phosphorylation Ser403 AAVSKKAsPEAASTP 9606 23730625 YES miannu Big MAP kinase 1 (BMK1) also phosphorylates PML at two sites : S403 and T409.|Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation. 0.475 SIGNOR-279075 RAC1 protein P63000 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 18423204 YES gcesareni We show that rac1 activates jnk2 that in turn phosphorylates beta-catenin on critical residues and controls its nuclear translocation. 0.522 SIGNOR-178265 valine smallmolecule CHEBI:27266 ChEBI Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates quantity precursor of 9606 30755602 YES miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 0.8 SIGNOR-270532 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.407 SIGNOR-275773 TCF3 protein P15923 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 NO miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. 0.426 SIGNOR-197523 CYBA protein P13498 UNIPROT Phagocyte NADPH oxidase complex complex SIGNOR-C557 SIGNOR form complex binding 9606 37263099 YES miannu NADPH oxidase is composed of essential protein components in its active state: membranous subunits, including p22-phox and gp91-phox, and cytoplasmic subunits, including p47-phox, p67-phox, p40-phox, and RAC2 (in neutrophils), among which NCF4 encodes the cytoplasmic subunit p40-phox 0.748 SIGNOR-277634 ARIH1 protein Q9Y4X5 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 33879767 YES miannu E3 ubiquitin ligase ARIH1 directly ubiquitinates PD-L1 and targets it for proteasomal degradation, following EGFR inhibition. 0.2 SIGNOR-278582 DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 19365405 YES gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. 0.822 SIGNOR-185268 ANXA1 protein P04083 UNIPROT FPR2 protein P25090 UNIPROT up-regulates activity binding 9606 BTO:0000007 15187149 YES We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2. 0.642 SIGNOR-259437 EDNRA protein P25101 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257165 RPL10 protein P27635 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.781 SIGNOR-262501 AMPK complex SIGNOR-C15 SIGNOR CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser158 REGTRVQsVEQIREV 9606 23291169 YES lperfetto We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1 0.2 SIGNOR-216604 quetiapine chemical CHEBI:8707 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258531 Ub:E2 complex SIGNOR-C497 SIGNOR ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271012 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr112 EGMQIPStQFDAAHP 9606 BTO:0001130 19141652 YES lperfetto This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity. 0.388 SIGNOR-183384 formestane chemical CHEBI:75172 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates activity chemical inhibition -1 7083195 YES miannu Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes. 0.8 SIGNOR-258407 GATA3 protein P23771 UNIPROT T-lymphocyte_diff phenotype SIGNOR-PH112 SIGNOR up-regulates activity 10090 22267605 NO Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs 0.7 SIGNOR-259953 P2RY10 protein O00398 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256869 PPM1D protein O15297 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 15870257 YES gcesareni Ppm1d dephosphorylates chk1 phospho-ser 345 0.473 SIGNOR-135972 FOXE1 protein O00358 UNIPROT TPO protein P07202 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 27347897 YES scontino TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8 0.382 SIGNOR-267279 MTOR protein P42345 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation 9606 26522726 YES miannu Thus our results indicate that the interaction between ER\u03b1 and raptor is necessary to recruit raptor to the nucleus, where mTOR phosphorylates and activates ER\u03b1. 0.499 SIGNOR-278295 PRKDC protein P78527 UNIPROT MITF protein O75030 UNIPROT up-regulates activity phosphorylation Ser431 S-->C 9606 BTO:0000848 38316520 YES miannu These results suggest that DNA-PK can target MITF-S325 for phosphorylation. In melanocytes and melanoma cells, MITF is rapidly phosphorylated by DNA-PK and interacts with NBS1–RAD50 but not MRE11, destabilizing the MRN complex. 0.2 SIGNOR-277899 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 9606 17900900 YES lperfetto We have recently found that AMPK phosphorylates human FOXO3 in mammalian cells at novel regulatory sites that are distinct from the AKT sites 0.41 SIGNOR-216481 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264923 CUL1 protein Q13616 UNIPROT SCF-FBW2 complex SIGNOR-C525 SIGNOR form complex binding 9606 BTO:0000007 15640526 YES miannu FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system 0.835 SIGNOR-271527 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser672 TLYDRYSsPPASTTR 9606 BTO:0001938 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus) 0.679 SIGNOR-104715 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRC1 protein O43663 UNIPROT unknown phosphorylation Thr481 RRGLAPNtPGKARKL 9885575 YES llicata We have shown that PRC1 is a good in vitro substrate for several CDKs, and that it is also phosphorylated in a cell cycle–dependent manner in vivo at Thr-481 (major mitosis. and Thr-470 (minor site), which are the in vitro phosphorylation sites. 0.346 SIGNOR-250746 SAR1A protein Q9NR31 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR up-regulates quantity binding 30605680 YES lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 0.716 SIGNOR-265304 sorafenib tosylate chemical CHEBI:50928 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 0.8 SIGNOR-259227 GSK3B protein P49841 UNIPROT FOXM1 protein Q08050 UNIPROT down-regulates quantity by destabilization phosphorylation Ser474 S-->A 9606 BTO:0002181 26912724 YES miannu GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7. 0.356 SIGNOR-277208 STAT1 protein P42224 UNIPROT KRT17 protein Q04695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21796151 NO miannu IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. 0.2 SIGNOR-255233 MAPK3 protein P27361 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 YES gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3 0.375 SIGNOR-169879 PAK5 protein Q9P286 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9534 BTO:0000298 12897128 YES miannu P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112 0.2 SIGNOR-250247 48S_initiation_complex complex SIGNOR-C454 SIGNOR MRNA_scanning phenotype SIGNOR-PH208 SIGNOR up-regulates 9606 29401259 NO lperfetto The 48S complex scans mRNA from 5′ to 3′ until it identifies an AUG start codon in an appropriate sequence context (Kozak consensus) 0.7 SIGNOR-269168 AURKB protein Q96GD4 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser180 KKGGGKKsGKKSYLS 9606 23226345 YES lperfetto Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1 0.368 SIGNOR-200075 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249323 SKP1 protein P63208 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR form complex binding 9606 15340381 YES gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. 0.941 SIGNOR-243554 ATXN7 protein O15265 UNIPROT CRX protein O43186 UNIPROT down-regulates activity binding 10090 11580893 YES miannu We found that ataxin-7 and CRX colocalize and coimmunoprecipitate. We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation. 0.608 SIGNOR-223226 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268597 NUMA1 protein Q14980 UNIPROT TUBA3E protein Q6PEY2 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.248 SIGNOR-116738 LARP7 protein Q4G0J3 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR down-regulates activity binding 9606 BTO:0000567 30824372 YES Monia To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system. 0.587 SIGNOR-261184 MAL protein P21145 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 15337780 NO SimoneGraziosi Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes 0.7 SIGNOR-269228 BAG1 protein Q99933 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates activity binding -1 27474739 YES lperfetto Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70. 0.895 SIGNOR-254115 NR4A3 protein Q92570 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30455429 YES miannu Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. 0.2 SIGNOR-259397 LUBAC complex SIGNOR-C527 SIGNOR TRAF1 protein Q13077 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0002748 25996949 YES miannu LUBAC attaches M1-pUb chains to LMP1/TRAF1 complexes, which recruits the IKK complex.we found that LMP1 TES1 domain signaling induced an association between TRAF1 and the linear ubiquitin chain assembly complex (LUBAC), and stimulated linear (M1)-linked polyubiquitin chain attachment to TRAF1 complexes. 0.358 SIGNOR-272435 SIRT5 protein Q9NXA8 UNIPROT SHMT2 protein P34897 UNIPROT down-regulates activity post translational modification Lys280 IVTTTTHkTLRGARS 34929314 YES desuccinylation lperfetto Mitochondrial serine hydroxymethyl transferase (SHMT2) is a rate-limiting enzyme that catalyzes the catabolism of serine and drives the proliferation of osteosarcoma cells and colon cancer cells. SIRT5 directly mediates the desuccinylation of Lysine 280 on SHMT2. Therefore, SIRT5 is a candidate target to inhibit serine catabolism 0.235 SIGNOR-267644 ACTB protein P60709 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.507 SIGNOR-270619 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000007 25081058 YES lperfetto PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. 0.67 SIGNOR-262595 RPS27L protein Q71UM5 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.795 SIGNOR-262445 GLUD1 protein P00367 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9913 11254391 YES Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. 0.8 SIGNOR-266917 LHX4 protein Q969G2 UNIPROT POU1F1 protein P28069 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15998782 NO miannu We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression. 0.514 SIGNOR-254558 AKT proteinfamily SIGNOR-PF24 SIGNOR EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15531580 YES lperfetto Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression 0.2 SIGNOR-244263 AKT2 protein P31751 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 YES lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activitywe have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. 0.569 SIGNOR-152958 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 YES Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization. 0.289 SIGNOR-251193 SH3BP4 protein Q9P0V3 UNIPROT TFRC protein P02786 UNIPROT down-regulates binding 9606 16325581 YES miannu Here, we report that ttp (sh3bp4), a sh3-containing protein, specifically regulates the internalization of the transferrin receptor (tfr). / overexpression of ttp specifically inhibits tfr internalization 0.354 SIGNOR-142840 PAN2 protein Q504Q3 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates activity deubiquitination 9606 BTO:0000007 33097710 YES miannu Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52.  0.2 SIGNOR-273509 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 YES gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.708 SIGNOR-183652 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu46 TRANSFLeEMKKGHL -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263664 TWIST1 protein Q15672 UNIPROT ILK protein Q13418 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.282 SIGNOR-255528 TLN1 protein Q9Y490 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.65 SIGNOR-257610 CFI complex complex SIGNOR-C388 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity cleavage 9606 8626397 YES lperfetto Purification and characterization of human cleavage factor Im involved in the 3' end processing of messenger RNA precursors|Gel retardation experiments confirmed the results obtained by UV cross-linking. In addition, we could show that CF Im stabilizes the binding of the cleavage and polyadenylation specificity factor (CPSF) to pre-mRNA and that CPSF and CF Im together form a slower migrating complex with pre-mRNA than the single protein factors. 0.8 SIGNOR-266125 pentazocine chemical CHEBI:7982 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.8 SIGNOR-258659 PRKDC protein P78527 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 9363941 YES gcesareni We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage. 0.792 SIGNOR-53030 Ruboxistaurin chemical CID:153999 PUBCHEM PRKACB protein P22694 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258275 PI3K complex SIGNOR-C156 SIGNOR Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 23994464 NO apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release 0.7 SIGNOR-255012 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.272 SIGNOR-276093 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2484 LVSFHDDsDEDLLHI 9606 8318012 YES lperfetto The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157. 0.473 SIGNOR-37835 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 SIGNOR-C17 19709076 YES lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. 0.389 SIGNOR-187766 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.2 SIGNOR-183616 ACLY protein P53396 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 19286649 YES miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. 0.8 SIGNOR-267102 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR EDC3 protein Q96F86 UNIPROT down-regulates activity binding 10029 BTO:0000246 20051463 YES miannu 14-3-3 binding to EDC3 resulted in a significant decrease in the binding of several key mRNA regulatory factors such as PABP and Y-box-binding protein 1 to EDC3. 0.2 SIGNOR-262630 PRKCA protein P17252 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 7523419 YES lperfetto Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site. 0.307 SIGNOR-248894 Aflibercept chemical SID:134445687 PUBCHEM VEGFB protein P49765 UNIPROT down-regulates activity chemical inhibition 9606 22813448 YES miannu Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor. 0.8 SIGNOR-259387 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 11333986 YES lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.2 SIGNOR-107412 CID 132010322 chemical CID:132010322 PUBCHEM BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition 9606 31969702 YES Luana ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 0.8 SIGNOR-261103 RNF216 protein Q9NWF9 UNIPROT TICAM1 protein Q8IUC6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16968706 YES miannu Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins. 0.355 SIGNOR-271609 PCCB protein P05166 UNIPROT PCC complex SIGNOR-C414 SIGNOR form complex binding 9606 15890657 YES miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. 0.891 SIGNOR-267183 KLF3 protein P57682 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18391014 NO fspada We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice. 0.3 SIGNOR-161370 CDC73 protein Q6P1J9 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 YES miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  0.933 SIGNOR-269836 5-aza-2'-deoxycytidine chemical CHEBI:50131 ChEBI DNMT1 protein P26358 UNIPROT down-regulates activity chemical inhibition 9606 14585280 YES miannu Both Azacitidine and Decitabine may also exert antitumor activity through induction of DNA hypomethylation, by forming a covalent complex with the major DNA methyltransferase (now termed DNMT1).Azacitidine and Decitabine effectively deplete the cell of functional DNA methylating activity, which results in profound hypomethylation after several rounds of DNA replication (Fig. 2). DNMT1 is considered a bona fide anticancer target at different levels 0.8 SIGNOR-259294 FBXO33 protein Q7Z6M2 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR up-regulates activity binding 9606 BTO:0000007 16797541 YES miannu Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1 0.463 SIGNOR-271605 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176809 LGALS3 protein P17931 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 BTO:0000584 32745890 YES miannu Oncogenic RAS requires a protein scaffold to induce downstream signaling and macropinocytosis, three separate studies have identified upstream and downstream regulators that help drive this process in cancer cells. Anchorage-independent growth of cancer cells is supported by avb3 integrins which can be clustered by the extracellular lectin, galectin-3 to drive mutant RAS-mediated macropinocytosis for nutrient supplementation and growth of anchorage-independent cells. Secreted galectin-3 was found to bind to the N-glycans on surface avb3 integrins, clustering the integrins on the surface of the nonadherent cells for the recruit- ment of mutant KRAS as a signaling platform for inducing macropinocytosis 0.276 SIGNOR-277741 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 YES The effect has been demonstrated using Q01196-8 lperfetto We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.2 SIGNOR-244703 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr696 ARQSRRStQGVTLTD 9606 12030846 YES lperfetto Mypt1 was phosphorylated by ilk and phosphorylation sites in the n- and c-terminal fragments of mypt1 were detected. From sequence analyses, three sites were identified: a primary site at thr(709), and two other sites at thr(695) and thr(495) 0.583 SIGNOR-87924 DYRK1A protein Q13627 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates activity phosphorylation Ser251 NKVIPAKsPPPPTHS -1 34109727 YES miannu Here, we uncovered that dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a kinase critical in Down's syndrome pathogenesis, directly bound to and phosphorylated MEF2D at Ser251 in vitro. Phosphorylation of MEF2D by DYRK1A significantly increased MEF2D protein level but attenuated its transcriptional activity, which resulted in decreased transcriptions of MEF2D target genes. 0.411 SIGNOR-277565 PRKCD protein Q05655 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates activity phosphorylation Ser82 RALSRQLsSGVSEIR 9606 22974980 YES miannu Radioactive kinase assays confirmed that PKC\u03b4 phosphorylated Hsp27 at Ser78 and Ser82 ( Fig. 3 B). 0.515 SIGNOR-278425 NOTCH1 protein P46531 UNIPROT ADAM19 protein Q9H013 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0001454 10933396 NO gcesareni Deltex, meltrin beta, ifi-202, and ifi-204 were also upregulated by notchic in the 2b4.11 t cell hybridoma, whereas ifi-d3 was expressed constitutively at relatively high levels and slightly upregulated by notchic, and pre-talfa was not expressed. Deltex, meltrin beta, pre-talfa, ifi-202, and ifi-204 were upregulated by notchic expression in the akr1 dp thymoma cell line, whereas ifi-d3 was not expressed 0.311 SIGNOR-80330 GSK3A protein P49840 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by destabilization phosphorylation Ser37 REPSTPPsPISSSSS 9606 BTO:0000182 27273097 YES lperfetto Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin 0.265 SIGNOR-253156 HDAC8 protein Q9BY41 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity deacetylation 10090 BTO:0002882 26387755 YES HDAC8 mediates CM-induced deacetylation of p53.Collectively, these results indicate that although binding to p53 and HDAC8 occurs through distinct regions of the CM protein, simultaneous interaction with HDAC8 and p53 is required for aberrant deacetylation and inactivation of p53. 0.457 SIGNOR-255738 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity phosphorylation Tyr290 PDEPIAFyAMGRGSP 9606 BTO:0000782 18541536 YES miannu Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition. 0.579 SIGNOR-262889 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 17015476 YES Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. 0.495 SIGNOR-248615 KLF1 protein Q13351 UNIPROT KLF8 protein O95600 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 18687676 YES Luana Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.  0.25 SIGNOR-266050 SUN1 protein O94901 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates activity binding 9606 BTO:0000567 SIGNOR-C303 28831067 YES lperfetto SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1. 0.354 SIGNOR-263296 CRLS1 protein Q9UJA2 UNIPROT cardiolipin smallmolecule CHEBI:28494 ChEBI up-regulates chemical modification 10090 16678169 YES lperfetto The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase. 0.8 SIGNOR-267028 venlafaxine chemical CHEBI:9943 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 20378347 YES Luana The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD). 0.8 SIGNOR-257836 MEF2C protein Q06413 UNIPROT CTNNA3 protein Q9UI47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 YES miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter 0.241 SIGNOR-265491 HES1 protein Q14469 UNIPROT DTX1 protein Q86Y01 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000970 20208568 NO gcesareni The notch target gene hes1 causes transcriptional inhibition of deltex1 by directly binding to the promoter of deltex1. 0.312 SIGNOR-164071 RPS6KA3 protein P51812 UNIPROT FOXN2 protein P32314 UNIPROT down-regulates quantity by destabilization phosphorylation Ser369 LGDSGYAsQPCAKIS 9606 BTO:0002552 29396548 YES done miannu Importantly, we identified RSK2 kinase as the upstream kinase for the FOXN2 phosphodegron. The Ser365 and Ser369 sites in a conserved DSGYAS motif are responsible for the ubiquitination of FOXN2 by β-Trcp.  0.2 SIGNOR-273841 diisononyl phthalate chemical CHEBI:35459 ChEBI OXER1 protein Q8TDS5 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). 0.8 SIGNOR-268773 (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin chemical CHEBI:272 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258784 UBE2L3 protein P68036 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity ubiquitination -1 19240029 YES miannu Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1). 0.2 SIGNOR-272734 UBE3A protein Q05086 UNIPROT UBE3A protein Q05086 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001968 10864652 YES miannu We show here that HPV16 E6 promotes the ubiquitination and degradation of E6AP itself.  0.2 SIGNOR-271398 MT-ATP8 protein P03928 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261406 CAMK2A protein Q9UQM7 UNIPROT CACNA1S protein Q13698 UNIPROT up-regulates activity phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 YES miannu To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. 0.448 SIGNOR-263113 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1679 NVKSKIGsTDNIKYQ 9606 BTO:0000567 11029056 YES miannu CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA 0.359 SIGNOR-250001 Olopatadine chemical CHEBI:7769 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257782 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr496 HIIENPQyFSDACVH 9606 9099755 YES gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 0.2 SIGNOR-47167 JAK3 protein P52333 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Tyr30 SHWQQQSyLDSGIHS 9606 28821617 YES miannu Jak3 phosphorylates Tyr 30, Tyr 64, and Tyr 86 of beta-catenin in intestinal epithelial cells. 0.444 SIGNOR-278178 JAK3 protein P52333 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Tyr64 VDTSQVLyEWEQGFS 9606 28821617 YES miannu Jak3 phosphorylates Tyr 30, Tyr 64, and Tyr 86 of beta-catenin in intestinal epithelial cells. 0.444 SIGNOR-278179 GLI2 protein P10070 UNIPROT GLI1/GLI2 complex SIGNOR-C450 SIGNOR form complex binding 9606 BTO:0000304 32766732 YES GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. 0.456 SIGNOR-269210 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 YES lperfetto Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity 0.2 SIGNOR-244525 DPF2 protein Q92785 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates activity binding 9606 BTO:0000007 20460684 YES miannu Our current findings indicate that REQ is a novel adaptor protein that links the Brm-type SWI/SNF complex and RelB/p52 and operates at the most downstream stages of the noncanonical NF-κB pathway. 0.609 SIGNOR-261963 PRKCD protein Q05655 UNIPROT TAGLN protein Q01995 UNIPROT down-regulates activity phosphorylation Ser181 VIGLQMGsNRGASQA -1 11053353 YES lperfetto Of the three consensus protein kinase C or casein kinase II phosphorylation sites in SM22, only Ser-181 was readily phosphorylated by protein kinase C in vitro, and such phosphorylation greatly decreased actin binding. 0.327 SIGNOR-249061 USP10 protein Q14694 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 SIGNOR-C242 21962518 YES lperfetto Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E) 0.507 SIGNOR-260299 MAPKAPK2 protein P49137 UNIPROT CEP131 protein Q9UPN4 UNIPROT down-regulates quantity phosphorylation Ser78 NNLRRSNsTTQVSQP 9606 26616734 YES miannu MK2 directly phosphorylates two residues on CEP131, S47 and S78, to create dual binding sites for 14-3-3 proteins.|We identify CEP131 as a major Centriolar satellites-associated substrate of p38-dependent, MK2-mediated phosphorylation on two defined residues and show that these modifications promote binding to 14-3-3 proteins, in turn leading to cytoplasmic sequestration of CEP131 and associated Centriolar satellites factors. 0.291 SIGNOR-278182 RICTOR protein Q6R327 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.833 SIGNOR-205624 TBK1 protein Q9UHD2 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser293 VELFGPIsLEQVRFP 9606 22412986 YES lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated 0.542 SIGNOR-196532 GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 YES Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells 0.2 SIGNOR-254300 PCDHA7 protein Q9UN72 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265667 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile chemical CHEBI:77397 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 18487050 YES Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  0.8 SIGNOR-257794 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates activity phosphorylation Ser959 DHSVRINsVGSTASS 9823 BTO:0004007 7539802 YES lperfetto We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling. 0.53 SIGNOR-248900 CDK2 protein P24941 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 SIGNOR-C83 24173284 YES lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A 0.871 SIGNOR-119379 S1PR5 protein Q9H228 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-256819 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120240 TFAP4 protein Q01664 UNIPROT SALL2 protein Q9Y467 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452 21228219 NO miannu The transcription factor AP4 increases along with SALL2 in quiescent cells and positively regulates SALL2 expression. 0.2 SIGNOR-255426 CABIN1 protein Q9Y6J0 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates 9606 17172641 NO gcesareni Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity. 0.796 SIGNOR-151208 S protein P59594 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16940539 NO miannu Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein. 0.2 SIGNOR-260353 SKP2 protein Q13309 UNIPROT CYGB protein Q8WWM9 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 28948618 YES miannu Skp2 induces ubiquitin-dependent degradation of Cygb. To this end, we performed an in vivo ubiquitination assay in HEK293T cells by transfecting relevant plasmids as indicated. The V5-Skp2DN was generated by deleting the N-terminal residues from 1 to 153 containing the F-box domain, which is involved in recruiting Skp2 to the SCF complex. 0.2 SIGNOR-272792 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM43B protein A6NCK2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271266 Cap-binding complex complex SIGNOR-C440 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates relocalization 9606 32873578 YES lperfetto The largely nuclear cap-binding complex (CBC) binds to the 5′ caps of RNA polymerase II (RNAPII)-synthesized transcripts and serves as a dynamic interaction platform for a myriad of RNA processing factors that regulate gene expression. 0.8 SIGNOR-268360 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates 9606 BTO:0002181 11238441 NO fspada Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m). 0.358 SIGNOR-105500 MAPK6 protein Q16659 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 20734105 YES miannu ERK3, ERK4 and p38 MAPK can all phosphorylate MK5 at Thr 182 , , , - ], but it is not known whether these enzymes also can phosphorylate Ser 115 and whether this modification contributes to ERK3-, ERK4-, or p38 MAPK -regulated subcellular localization of MK5. 0.689 SIGNOR-279073 mTORC1 complex SIGNOR-C3 SIGNOR NRBF2 protein Q96F24 UNIPROT up-regulates activity phosphorylation Ser113 AEDAEGQsPLSQKYS 9606 28059666 YES miannu Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. 0.2 SIGNOR-265876 FANCL protein Q9NW38 UNIPROT UBE2T protein Q9NPD8 UNIPROT down-regulates quantity ubiquitination 9606 16916645 YES miannu Monoubiquitination of UBE2T was enhanced by FANCL introduction, suggesting that FANCL feeds back to UBE2T and can downregulate its activity.Although the FA pathway has been extensively studied, the E2 enzyme cooperating with the FA core complex for monoubiquitination of FANCD2 has not been discovered.|This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T. 0.901 SIGNOR-278809 HUWE1 protein Q7Z6Z7 UNIPROT PPARA protein Q07869 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29331071 YES miannu Furthermore, the E3 ubiquitin ligase HUWE1 was identified to mediate PPARalpha polyubiquitination.|This notion is also supported by our finding that Huwe1 knockdown up-regulated the expression of PPARalpha target genes at the cellular level. 0.2 SIGNOR-278814 HSPA5 protein P11021 UNIPROT Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 28286085 NO lperfetto The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen.|When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. 0.7 SIGNOR-265283 MECP2 protein P51608 UNIPROT CRH protein P06850 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000142 17108082 YES Luana Collectively, these results point to a specific association between WT MeCP2 and the methylated promoter region of Crh in vivo. In contrast, the MeCP2308 protein was not detected at the Crh promoter. | Thus, the results of seqChIP indicate that MeCP2 preferentially associates with a transcriptionally inactive, dimethyl-histone H3 Lys-9-rich form of the Crh promoter in mice. 0.467 SIGNOR-264548 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT up-regulates activity phosphorylation Tyr779 ADCLDGLyALMSRCW -1 9178760 YES llicata Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins 0.2 SIGNOR-250591 NPAS2 protein Q99743 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR form complex binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. 0.538 SIGNOR-267966 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity phosphorylation Ser61 LGALEQGsPPDISPY 10090 BTO:0000783;BTO:0002284 16407209 YES Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity. 0.2 SIGNOR-255543 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser344 QAVALPRsEEPASCN 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 17213202 YES lperfetto The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo. 0.385 SIGNOR-235652 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR KHSRP protein Q92945 UNIPROT down-regulates binding 9606 17177604 YES gcesareni Akt phosphorylates ksrp at a unique serine residue, creating a functional binding site for the molecular chaperone 14-3-3. As a consequence, akt activation impairs ksrp ability to interact with the exoribonucleolytic complex exosome and, in turn, to promote rapid mrna decay. 0.2 SIGNOR-151212 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr809 LIVEYAKyGSLRGFL 9606 14711813 YES llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation. 0.2 SIGNOR-121157 MECP2 protein P51608 UNIPROT RBFOX1 protein Q9NWB1 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000614 18511691 YES Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. 0.28 SIGNOR-264681 SYNJ1 protein O43426 UNIPROT MYO1E protein Q12965 UNIPROT up-regulates activity binding 10116 BTO:0000142 17257598 YES miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. 0.427 SIGNOR-265423 HTR1D protein P28221 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256864 FAM83F protein Q8NEG4 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273759 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester chemical CHEBI:92418 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258636 ERN1 protein O75460 UNIPROT XBP1 protein P17861 UNIPROT up-regulates activity phosphorylation 9606 36001995 YES miannu IRE1\u03b1 phosphorylates and activates the XBP1 transcription factor XBP1 via its kinase activity. 0.646 SIGNOR-279712 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates activity phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 YES miannu We show that TRPC5 channels may become directly phosphorylated by PKA at serine residues 794 and 796, and that this phosphorylation abolishes the receptor-operated nonselective cation current mediated by TRPC5 channels in HEK-293 cells. 0.2 SIGNOR-276339 ZFPM1 protein Q8IX07 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0000725 22068055 NO We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment. 0.7 SIGNOR-259964 ADRA1B protein P35368 UNIPROT GNA11 protein P29992 UNIPROT up-regulates activity binding 9534 BTO:0000298 1334487 YES In this report, we demonstrate that in transfected cos-7 cells Gal4 and Ga16, like Gaq and Ga11, can activate PIPLC j3l and that all three al-ARs, alA, alB and alC, can activate endogenous PI-PLC by coupling to Gaq or Ga11. 0.66 SIGNOR-278122 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 30616754 YES lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle 0.8 SIGNOR-267589 Ionizing radiation stimulus SIGNOR-ST16 SIGNOR CCDC6-RET fusion protein SIGNOR-FP9 SIGNOR up-regulates 9606 23128507 NO miannu In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents 0.7 SIGNOR-251999 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser161 SSLPVPNsAYGGPDF 9606 BTO:0000150 25726523 YES lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 0.2 SIGNOR-275655 DLG4 protein P78352 UNIPROT NOS1 protein P29475 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu Neuronal NOS, a Ca2+-activated form of NOS, can bind to PSD-95 through a class III PDZ domain interaction in which its own amino-terminal PDZ domain binds to a PDZ domain of PSD-95. PSD-95 may concentrate nNOS near the NMDA receptor at postsynaptic sites in these neurons. 0.735 SIGNOR-264227 TRIM47 protein Q96LD4 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000575 29291351 YES gianni CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity 0.2 SIGNOR-266443 MAP3K1 protein Q13233 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 12049732 YES miannu ERK1/2 MAP kinases are important regulators in cellular signaling, whose activity is normally reversibly regulated by threonine-tyrosine phosphorylation. In contrast, we have found that stress-induced ERK1/2 activity is downregulated by ubiquitin/proteasome-mediated degradation of ERK1/2. The PHD domain of MEKK1, a RING finger-like structure, exhibited E3 ubiquitin ligase activity toward ERK2 in vitro and in vivo. Therefore, MEKK1 functions not only as an upstream activator of the ERK and JNK through its kinase domain, but also as an E3 ligase through its PHD domain, providing a negative regulatory mechanism for decreasing ERK1/2 activity. 0.512 SIGNOR-272609 TP53 protein P04637 UNIPROT G6PD protein P11413 UNIPROT down-regulates activity binding 9606 BTO:0001938;BTO:0001109 21336310 YES miannu The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. 0.582 SIGNOR-267468 PCSK7 protein Q16549 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates phosphorylation 9606 11259586 YES gcesareni This together with the rapid kinetics of pp1-pp2a activation following p38 activation suggests that pp1 and/or pp2a complexes are direct targets for p38-mediated phosphorylation 0.2 SIGNOR-105783 BTK protein Q06187 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr224 DSNSKKIyGSQPNFN 9606 12573241 YES lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180 0.335 SIGNOR-98032 Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR down-regulates activity binding 9606 28368393 YES miannu The essential ATP-binding cassette protein ABCE1 splits 80S ribosomes into 60S and 40S subunits after canonical termination or quality-control-based mRNA surveillance processes. Compared to the pre-splitting state, we observe repositioning of ABCE1's iron-sulfur cluster domain, which rotates 150° into a binding pocket on the 40S subunit. This repositioning explains a newly observed anti-association activity of ABCE1. Notably, the movement implies a collision with A-site factors, thus explaining the splitting mechanism. 0.2 SIGNOR-270817 histamine smallmolecule CHEBI:18295 ChEBI HRH4 protein Q9H3N8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257515 TOR1A protein O14656 UNIPROT SNAPIN protein O95295 UNIPROT up-regulates activity binding 9606 BTO:0000793 18167355 YES Monia In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA. 0.424 SIGNOR-261170 RBP1 protein P09455 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI up-regulates quantity relocalization 31963453 YES lperfetto Once in the cytosol, retinol molecules are sequestered by membrane systems and bind to Cellular retinol-binding protein 1 (CRBP1), which plays a role in vitamin A cytoplasmic trafficking 0.8 SIGNOR-265108 NDRG1 protein Q92597 UNIPROT RAB4A protein P20338 UNIPROT up-regulates binding 9606 BTO:0000150;BTO:0001130 17786215 YES miannu In this report evidence is provided that ndrg1 is a rab4a effector protein that localizes to perinuclear recycling/sorting vesicles in the trans golgi network by binding to phophatidylinositol 4-phosphate and is involved in recycling of e-cadherin. This is the first demonstration providing evidence that ndrg1 is a rab4a effector recruiting to recycling/sorting endosomes. 0.322 SIGNOR-157697 RASGEF1B protein Q0VAM2 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.377 SIGNOR-183832 PRKAB1 protein Q9Y478 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 SIGNOR-C15 11729179 YES gcesareni Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. 0.2 SIGNOR-112367 PRKCD protein Q05655 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.348 SIGNOR-249280 STK4 protein Q13043 UNIPROT STK38 protein Q15208 UNIPROT up-regulates activity phosphorylation Thr444 DWVFINYtYKRFEGL 9606 19062280 YES miannu Although MST1, MST2, and MST3 potently activated NDR1 in vitro, MST4 had only a minor effect.|Indeed, NDR1 phosphorylated at Thr444 by MST1 displayed greatly (7-fold) enhanced protein kinase activity. 0.332 SIGNOR-279641 PRKCA protein P17252 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276024 Halcinonide chemical CHEBI:31663 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 YES gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. 0.8 SIGNOR-248265 RFX1 protein P22670 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9583676 YES gcesareni We show that rfxi and c-abl are in direct interaction, in vitro and in cell extracts, through the rfxi proline rich (pxxp) motif and the c-abl sh3 domain. Remarkably, this interaction significantly potentiates c-abl but not v-abl auto-kinase activity 0.2 SIGNOR-57516 MAPK14 protein Q16539 UNIPROT ZNHIT1 protein O43257 UNIPROT up-regulates phosphorylation Thr103 AEGPNYLtACAGPPS 9606 17380123 YES llicata Our results indicate that p38 mapk plays an important role in the regulation of p18hamlet half?life. In particular, p38 mapk activation is required for the accumulation of p18hamlet induced by dna damage?inducing Agents such as uv. We also showed that several sites that are phosphorylated by p38? In vitro are also important for p18hamlet protein stability in cells. the high conservation of thr103 as a phosphorylation site in p18hamlet proteins from different species (figure 1a), together with the in vitro phosphorylation experiments, suggested that this residue could be an important target for p38 mapk 0.315 SIGNOR-153899 GUCY1A1 protein Q02108 UNIPROT GUCY1A3-B2 complex SIGNOR-C139 SIGNOR form complex binding 9606 10977868 YES gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity 0.2 SIGNOR-244116 GPR84 protein Q9NQS5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.285 SIGNOR-256704 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT up-regulates activity phosphorylation Ser518 SPEKEAKsPVKEEAK 10116 BTO:0000938 9592082 YES lperfetto The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. 0.368 SIGNOR-249423 MAFA protein Q8NHW3 UNIPROT GLP1R protein P43220 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 NO miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. 0.334 SIGNOR-254563 CNOT10 protein Q9H9A5 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.745 SIGNOR-268305 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser291 PVSSLQAsVPGSVPG 9606 16027724 YES llicata Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. 0.476 SIGNOR-250729 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT up-regulates quantity by stabilization phosphorylation Ser757 EGMELNSsITSQDVL 9606 BTO:0000007 15987997 YES miannu Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life. 0.75 SIGNOR-262651 PLAG1 protein Q6DJT9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11888928 NO miannu Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis 0.7 SIGNOR-115772 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 10090 BTO:0002572 16341017 YES gcesareni Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin. 0.732 SIGNOR-228014 IFNLR1 protein Q8IU57 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 YES gcesareni Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain. 0.779 SIGNOR-124480 F2RL1 protein P55085 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254838 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 16046550 YES The effect has been demonstrated using Q01196-8 miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 0.2 SIGNOR-138973 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM34 protein Q9BYJ4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270966 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr500 TSLGSQSyEDMRGIL 10090 BTO:0000776 10933394 YES lperfetto Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni 0.772 SIGNOR-249376 CCR3 protein P51677 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000399 10706854 YES Activation of ERK2 and p38 by eotaxin is mediated through CCR3. 0.296 SIGNOR-256093 CDK5 protein Q00535 UNIPROT ADD1 protein P35611 UNIPROT up-regulates activity phosphorylation Thr724 KKKKKFRtPSFLKKS 9606 BTO:0000815 31548578 YES miannu We found that Cdk5 directly phosphorylated the actin-binding protein adducin-1 (ADD1) at T724 in vitro and in intact cells. 0.255 SIGNOR-277487 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 NO gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast 0.489 SIGNOR-107175 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. 0.669 SIGNOR-251320 estriol smallmolecule CHEBI:27974 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258586 SKP2 protein Q13309 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27858941 YES miannu DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1 0.267 SIGNOR-254775 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 11955436 YES lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). 0.894 SIGNOR-227901 TARBP2 protein Q15633 UNIPROT DICER1 protein Q9UPY3 UNIPROT up-regulates binding 9606 16142218 YES miannu Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si? Or mi?RISCs In mammalian cells, but it may also facilitate the cleavage of pre?miRNAs By dicer. 0.94 SIGNOR-140226 NLGN1 protein Q8N2Q7 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.839 SIGNOR-264144 KCNJ8 protein Q15842 UNIPROT NLRP3 protein Q96P20 UNIPROT down-regulates activity binding 9606 31387986 YES lperfetto We further show that Kir6.1 physically associates with NLRP3 and thus inhibits the interactions between the NLRP3 inflammasome subunits. Our results reveal a previously unrecognized function of Kir6.1 as a negative regulator of the NLRP3 inflammasome 0.2 SIGNOR-262034 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid chemical CHEBI:76223 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 22091869 YES Luana  Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2.  0.8 SIGNOR-258323 URI1 protein O94763 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 YES miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR94 0.55 SIGNOR-270917 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT up-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.366 SIGNOR-254705 TRIM26 protein Q12899 UNIPROT NEIL1 protein Q96FI4 UNIPROT down-regulates quantity ubiquitination 9606 27924031 YES miannu Mule and TRIM26 ubiquitylate NEIL1 in vitro within C-terminal lysine residues.|Similar to these previous results, we again demonstrate that a knockdown of Mule or TRIM26 causes an elevation in the protein stability of NEIL1 in comparison to non-targeting siRNA, unirradiated control (Figure and ; compare lanes 1 and 2). 0.247 SIGNOR-278647 SOX6 protein P35712 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 NO Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. 0.301 SIGNOR-251810 CDK1 protein P06493 UNIPROT ABI1 protein Q8IZP0 UNIPROT down-regulates activity phosphorylation Ser216 VPNDYMTsPARLGSQ 9606 BTO:0000567 21900237 YES lperfetto We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly 0.419 SIGNOR-264421 NHLRC1 protein Q6VVB1 UNIPROT DVL2 protein O14641 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22223637 YES miannu We have also found that malin enhances K48- and K63-linked ubiquitination of dishevelled2 that could lead to its degradation through both proteasome and autophagy. Altogether, our results indicate that malin regulates Wnt signaling pathway through the degradation of dishevelled2 and suggest possible deregulation of Wnt signaling in Lafora disease. 0.462 SIGNOR-272005 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL 9606 24101154 YES miannu Specifically, we found that YAP is phosphorylated in vitro and in vivo by the cell cycle kinase CDK1 at T119, S289, and S367 during G2/M phase of the cell cycle. 0.425 SIGNOR-279363 entacapone chemical CHEBI:4798 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition -1 7703232 YES miannu Human soluble (S) and membrane-bound (MB) catechol O-methyltransferase (COMT, EC 2.1.1.6) enzymes have been expressed at sufficiently high levels in Escherichia coli and in baculovirus-infected insect cells to allow kinetic characterization of the enzyme forms. The use of tight-binding inhibitors such as entacapone enabled the estimation of actual enzyme concentrations and, thereby, comparison of velocity parameters, substrate selectivity, and regioselectivity of the methylation of both enzyme forms. 0.8 SIGNOR-258476 MAPK3 protein P27361 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation Ser197 SATDSDGsPLSNSQP 9606 15632084 YES amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 0.854 SIGNOR-132979 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser502 FSTDNSGsQPKQKSD 9606 22123827 YES lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. 0.655 SIGNOR-177805 AP1M1 protein Q9BXS5 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 YES lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) 0.892 SIGNOR-260686 KDM2B protein Q8NHM5 UNIPROT UHRF1 protein Q96T88 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 NO miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. 0.283 SIGNOR-252245 ABL1 protein P00519 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 22590567 YES inferred from 70% of family members llicata We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death. 0.343 SIGNOR-269946 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120244 MYO3A protein Q8NEV4 UNIPROT MYO3A protein Q8NEV4 UNIPROT down-regulates activity phosphorylation Thr908 INLAKGDtGEATRHA 9534 24214986 YES Manara We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work 0.2 SIGNOR-260923 CD47 protein Q08722 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.367 SIGNOR-266016 EGFR protein P00533 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 22693070 YES lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation 0.737 SIGNOR-235689 INPPL1 protein O15357 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 BTO:0000776 10942391 NO lperfetto Taken together, the data presented here demonstrate that ship inhibits akt primarily through regulation of akt membrane localization. 0.649 SIGNOR-244406 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR POLM protein Q9NP87 UNIPROT down-regulates activity phosphorylation Ser12 RRRARVGsPSGDAAS -1 23933132 YES miannu  In vitro kinase assays showed that the S phase-associated Cdk2/cyclin A complex was able to phosphorylate Polμ. We identified Ser12, Thr21 (located in the BRCT domain) and Ser372 (located in loop1) as the target residues. Mutation of these residues to alanine indicated that Ser372 is the main phosphorylation site.Our evidences suggest that Polμ could be regulated in vivo by phosphorylation of the BRCT domain (Ser12/Thr21) and of Ser372, affecting the function of loop1. 0.27 SIGNOR-273597 PPP2CA protein P67775 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates dephosphorylation 9606 BTO:0000848 11591705 YES lperfetto Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela. 0.451 SIGNOR-217421 NPM1 protein P06748 UNIPROT CENPA protein P49450 UNIPROT up-regulates activity binding 9606 BTO:0000567 19410544 YES miannu Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1. 0.565 SIGNOR-263708 FGF14 protein Q92915 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.375 SIGNOR-253429 NUAK1 protein O60285 UNIPROT CASP6 protein P55212 UNIPROT down-regulates activity phosphorylation Ser257 TLVNRKVsQRRVDFC -1 15273717 YES miannu ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system. 0.484 SIGNOR-250209 ATP6AP2 protein O75787 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.511 SIGNOR-277751 CREBBP protein Q92793 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR form complex binding 9606 11559745 YES lperfetto P300/cbp proteins: hats for transcriptional bridges and scaffolds 0.544 SIGNOR-110559 PPARD protein Q03181 UNIPROT CAT protein P04040 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18048767 NO miannu Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. 0.256 SIGNOR-255051 RAD51B protein O15315 UNIPROT RAD51B/RAD51C complex SIGNOR-C65 SIGNOR form complex binding 9606 11751636 YES miannu We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities. 0.659 SIGNOR-111383 ERG protein P11308 UNIPROT WNT1 protein P04628 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001321 23913826 YES Luana Interestingly, our data showed that ERG drastically induced Wnt ligand gene expression. 0.2 SIGNOR-261597 DLGAP1 protein O14490 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 YES miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. 0.932 SIGNOR-264209 PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 15175348 YES lperfetto The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. 0.272 SIGNOR-244938 TP53 protein P04637 UNIPROT TIGAR protein Q9NQ88 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 27803158 YES miannu TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR is the only known phosphatase glycolytic modulator regulated by TP53. The current study delineates the role of TIGAR in OXPHOS and glycolytic metabolic reprogramming in breast cancer. 0.2 SIGNOR-267365 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates activity phosphorylation Ser90 GLFNELAsPFENEFK 9606 BTO:0000599 10085140 YES miannu P38 directly phosphorylates ATF-2 at Thr-69, Thr-71, and Ser-90, resulting in stimulation of its trans-activating capacity. 0.793 SIGNOR-250090 RIMBP2 protein O15034 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.532 SIGNOR-264366 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 YES gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase 0.27 SIGNOR-76076 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269338 FOXJ1 protein Q92949 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.2 SIGNOR-266939 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT down-regulates activity phosphorylation Ser928 SRLATNTsAPDLKNV -1 8631898 YES miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 0.438 SIGNOR-250170 ARID2 protein Q68CP9 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.781 SIGNOR-270597 HTR1B protein P28222 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.465 SIGNOR-256720 RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 23151663 YES gcesareni Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization. 0.809 SIGNOR-199542 NR3C1 protein P04150 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9606 26652733 YES inferred from family member Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB 0.2 SIGNOR-267792 PRKAA1 protein Q13131 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 YES miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex 0.2 SIGNOR-276837 DNAJC3 protein Q13217 UNIPROT EIF2AK4 protein Q9P2K8 UNIPROT down-regulates activity binding 9606 BTO:0000567 25329545 YES gcesareni € we show that p58IPK is a general inhibitor of the eIF2 kinases in that it also interacts with GCN2 0.572 SIGNOR-246204 5-{3-[4-(2,3-Dichlorophenyl)piperidin-1-yl]propoxy}-1,3-benzothiazole chemical CID:56599142 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002181 22025698 YES Luana Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands.  0.8 SIGNOR-258322 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Thr272 LNYWKLEtPAQFRQR 24870244 YES lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) 0.41 SIGNOR-275497 PLK1 protein P53350 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation 21640712 YES lperfetto These data indicated that PLK1 phosphorylates CDC25B and that pre-phosphorylation of CDC25B by CDK1/CyclinB enhances its substrate properties for PLK1 in vitro 0.662 SIGNOR-267560 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 12551925 YES gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. 0.557 SIGNOR-97648 IRAK3 protein Q9Y616 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT down-regulates binding 9606 25290089 YES flangone Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation 0.713 SIGNOR-205434 TLR4 protein O00206 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 9606 28137827 YES miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. 0.428 SIGNOR-261930 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser801 VPLLREAsARDRQSA 9534 14523239 YES lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 0.2 SIGNOR-249232 IL18 protein Q14116 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 NO miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement. 0.465 SIGNOR-260860 HSPA1A protein P0DMV8 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 27353360 YES These data suggest that inhibition of Hsp70 does not lead to an increase in misfolded FLCN but instead to its degradation. 0.2 SIGNOR-256506 PTPRR protein Q15256 UNIPROT PXN protein P49023 UNIPROT down-regulates activity dephosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 20133777 YES Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth, 0.2 SIGNOR-248720 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Thr7 tSAARRSY -1 12686604 YES lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. 0.312 SIGNOR-100192 POT1 protein Q9NUX5 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 17237768 YES miannu We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme. 0.673 SIGNOR-152327 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.75 SIGNOR-249639 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-138483 SP1 protein P08047 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 15708372 YES We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA. 0.2 SIGNOR-253664 ARHGEF25 protein Q86VW2 UNIPROT RHOA protein P61586 UNIPROT up-regulates guanine nucleotide exchange factor 10090 BTO:0000165;BTO:0000222 16314529 YES gcesareni Exogenous expression of geft promotes myogenesis ofc2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process. 0.835 SIGNOR-236885 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM2A protein Q9Y2K7 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273478 PTPN11 protein Q06124 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9615 BTO:0000837 16611743 YES lperfetto In addition, SHP-2 dephosphorylates tyrosine-phosphorylated Stat1/3/5A (Ohtani et al., 2000; Wu et al., 2002; Chen et al., 2003), and downregulates Stat3-mediated biological actions (Ohtani et al., 2000).|Inhibition of collagen-induced Stat3 tyrosine-705 (Stat3-p-Tyr) 0.769 SIGNOR-272404 BHLHE40 protein O14503 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 14672706 NO lperfetto We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. 0.2 SIGNOR-253715 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR -1 9199504 YES miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. 0.524 SIGNOR-250084 MEIS2 protein O14770 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21746878 YES miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. 0.2 SIGNOR-267242 SATB2 protein Q9UPW6 UNIPROT UPF3B protein Q9BZI7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23925499 NO miannu chromatin immunoprecipitation demonstrates that SATB2 binds to the UPF3B promoter, and a luciferase reporter assay confirmed that SATB2 expression significantly activates gene transcription using the UPF3B promoter. 0.334 SIGNOR-255137 NPNT protein Q6UXI9 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 0.7 SIGNOR-255458 MAPK1 protein P28482 UNIPROT NR4A1 protein P22736 UNIPROT up-regulates activity phosphorylation Thr143 CSAPSPStPSFQPPQ 10116 BTO:0001009 11883936 YES lperfetto NGFI-B is an inducible orphan nuclear receptor that initiates apoptosis. Growth factors such as EGF activate the MAP kinase ERK, whose activity may determine if a cell survives or undergoes apoptosis. EGF stimulation of cells leads to phosphorylation of threonine in NGFI-B. Thr-142 of NGFI-B is comprised in a consensus MAP kinase site and was identified as a preferred substrate for ERK2 (but not ERK1) in vitro. 0.668 SIGNOR-249430 ibuprofen chemical CHEBI:5855 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 9057869 YES miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 0.8 SIGNOR-258605 CBL protein P22681 UNIPROT PIK3R2 protein O00459 UNIPROT down-regulates ubiquitination 9606 11526404 YES lperfetto Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner. 0.605 SIGNOR-110063 IGF1 protein P05019 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 NO lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. 0.2 SIGNOR-235828 FLT3 protein P36888 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 BTO:0001516 23246379 NO miannu Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. 0.556 SIGNOR-260083 IGF1R protein P08069 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 10090 BTO:0000165 11715022 NO lperfetto we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy. 0.389 SIGNOR-244403 VDR protein P11473 UNIPROT CYP24A1 protein Q07973 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000067 9687155 NO miannu Repression of basal transcription of a 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) responsive 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter construct as observed in kidney cells in the absence of ligand and this repression was dependent on a functional vitamin D response element (VDRE). Basal repression was also seen with a construct where a consensus DR-3-type VDRE was fused to the thymidine kinase promoter. Expression of a dominant negative vitamin D receptor (VDR) isoform that strongly bound to the VDRE motif in the CYP24 promoter ablated basal repression. 0.566 SIGNOR-255599 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0004419 12840032 YES lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).Mapk activity is tightly regulated by phosphorylation and dephosphorylation. The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase 0.62 SIGNOR-103159 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 YES Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. 0.318 SIGNOR-248499 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12226093 YES The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. 0.762 SIGNOR-92607 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser21 KEEPKRRsARLSAKP 9606 BTO:0000567 11438671 YES lperfetto We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets. 0.365 SIGNOR-249100 GNRHR protein P30968 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.274 SIGNOR-256935 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 9687510 YES gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. 0.616 SIGNOR-59435 SOCS1 protein O15524 UNIPROT JAK3 protein P52333 UNIPROT down-regulates activity binding 9606 21508344 YES lperfetto SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR). 0.708 SIGNOR-238642 PRKCD protein Q05655 UNIPROT IL6ST protein P40189 UNIPROT up-regulates phosphorylation Thr890 GQVERFEtVGMEAAT 9606 12361954 YES fspada This interaction, which does not seem to involve a classical phosphotyrosine sh2-mediated binding, however, significantly enhances the interaction of stat3 and the il-6 receptor subunit glycoprotein (gp) 130, which is the initial step for stat3 activation by il-6. Expression of a dominant negative pkcdelta or depletion of the endogenous pkcdelta by phorbol 12-myristate 3-acetate treatment abrogates the association of stat3 with gp130. At the same time, pkcdelta is recruited to gp130 via association with stat3, which may facilitate its phosphorylation on the gp130 receptor. Finally, we identified thr-890, a putative pkc phosphorylation site on gp130, to be critical for the effect of pkcdelta. Our data indicate that pkcdelta plays important regulatory roles in il-6 signaling. 0.334 SIGNOR-94012 FUBP1 protein Q96AE4 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19637194 NO irozzo In our analysis of FBP1 shRNA-transduced Hep3B cells, we found that p21 mRNA levels increase following FBP1 knockdown, suggesting that FBP1 functions as a repressor of p21. Our results identify the tumor suppressor p21 as the second direct FBP1 target gene in addition to the proto-oncogene c-myc. 0.2 SIGNOR-259125 ANAPC4 protein Q9UJX5 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.903 SIGNOR-252004 PLK1 protein P53350 UNIPROT NPM1 protein P06748 UNIPROT up-regulates phosphorylation Ser4 sMDMDMSP 9606 BTO:0000567 15190079 YES gcesareni Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis. 0.425 SIGNOR-125666 KLHL2 protein O95198 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23838290 YES miannu We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body. 0.52 SIGNOR-272118 LYN protein P07948 UNIPROT CD79A protein P11912 UNIPROT up-regulates activity phosphorylation Tyr188 EYEDENLyEGLNLDD -1 9531288 YES Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b. phosphorylation of Y182 alone can lead to further kinase activation and/or effector focusing necessary for phosphorylation of certain downstream targets, such as p62, p110, and Shc, but not others, such as Vav. 0.738 SIGNOR-251397 USP22 protein Q9UPT9 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 26049753 YES USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. 0.535 SIGNOR-261561 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser234 YRLTRFLsRVIKCDP -1 8058338 YES miannu PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234. 0.334 SIGNOR-250346 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXRB protein P28702 UNIPROT up-regulates activity chemical activation 9606 18321241 YES miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). 0.8 SIGNOR-259238 CHEK2 protein O96017 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity phosphorylation Ser612 MYLSPVRsPKKKGST 9606 BTO:0000093 17380128 YES lperfetto Phosphorylation of prb at ser612 by chk1/2 leads to a complex between prb and e2f-1 after dna damageprb inhibits cell cycle progression through interactions with the e2f family of transcription factors. Here, we report that dna damage induced not only the dephosphorylation of prb at cdk phosphorylation sites and the binding of prb to e2f-1, but also the phosphorylation of prb at ser612. Phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1 0.423 SIGNOR-153908 AVPR1B protein P47901 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.439 SIGNOR-256791 RXR proteinfamily SIGNOR-PF44 SIGNOR RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates activity binding 9606 1310351 YES miannu Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins. 0.725 SIGNOR-256199 DSCAML1 protein Q8TD84 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 YES miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. 0.2 SIGNOR-264278 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 YES lperfetto A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus 0.811 SIGNOR-235380 PPM1D protein O15297 UNIPROT GPI protein P06744 UNIPROT down-regulates activity dephosphorylation 9606 28185954 YES miannu The WIP1 mediated inhibition of NLK activity markedly decreased the phosphorylation of lymphoid enhancer binding factor 1 (LEF1), enhancing its interaction with beta-catenin.|Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development. 0.24 SIGNOR-277155 PTPRB protein P23467 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates dephosphorylation 9606 12840032 YES gcesareni When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well 0.433 SIGNOR-103165 CSNK2A1 protein P68400 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 YES llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  0.345 SIGNOR-250953 MAPK3 protein P27361 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser432 NQNVLLMsPPASDSG 9606 14988395 YES lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. 0.392 SIGNOR-123049 TAX1BP1 protein Q86VP1 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity binding 21885437 YES lperfetto ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. 0.467 SIGNOR-275737 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 YES lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities 0.2 SIGNOR-137639 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser673 RVQSKIGsLDNITHV 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process 0.43 SIGNOR-171058 NALCN protein Q8IZF0 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 32698188 YES miannu Persistently depolarizing sodium (Na+) leak currents enhance electrical excitability. The ion channel responsible for the major background Na+ conductance in neurons is the Na+ leak channel, non-selective (NALCN) 0.8 SIGNOR-265181 Laminin-1 complex SIGNOR-C183 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 9606 BTO:0000414 24184828 YES miannu Integrin α6β4 is a laminin receptor that is mainly expressed in the basal layer of epithelial tissues. The β4-integrin is unique because of its long cytoplasmic tail, which interacts with the intermediate filament network rather than actin. This interaction contributes to the ability of α6β4 to maintain the integrity of tissues normally exposed to shear stress. α6β4 integrin assembles its own signalling platform. 0.524 SIGNOR-258998 SRC protein P12931 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation Tyr130 VLDVLKFyDSNTVKQ 9606 12215529 YES llicata Pak2 became tyrosine phosphorylated in its n-terminal regulatory domain, where y130 was identified as the major phosphoacceptor site. Tyrosine phosphorylation-mediated superactivation of pak2 could be induced by overexpression of different src kinases or by inhibiting cellular tyrosine phosphatases with pervanadate and could be blocked by the src kinase inhibitor pp1 or by mutating the y130 residue. 0.561 SIGNOR-92460 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1223 SSSTRRSsEDLSAYA 9606 BTO:0000975 17360977 YES lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 0.2 SIGNOR-236603 wortmannin chemical CHEBI:52289 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0001271 7503989 YES gcesareni Wortmannin inhibited the activity of partially purified pi3-kinase from calf thymus, as well as the pi3-kinase activity in anti-pi3-kinase p85 immunoprecipitates from rbl-2h3 cells, at a concentration as low as 1.0 nm and with ic50 values of 3.0 nm. 0.8 SIGNOR-252663 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 14699166 YES llicata Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells. 0.528 SIGNOR-120488 WNT9A protein O14904 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 YES gcesareni we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase 0.4 SIGNOR-195975 EGFR protein P00533 UNIPROT SPRED1 protein Q7Z699 UNIPROT down-regulates activity phosphorylation Ser105 KFGLTFQsPADARAF 9606 BTO:0000007 32697994 YES miannu We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions. 0.272 SIGNOR-273638 ANKRD28 protein O15084 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding -1 17023142 YES lperfetto Phosphatase Interactor Targeting K protein (PITK) was previously identified as a novel PP1 targeting subunit implicated in modulating the phosphorylation of the transcriptional regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K) 0.444 SIGNOR-264794 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 12172553 YES gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. 0.728 SIGNOR-91392 ADAM9 protein Q13443 UNIPROT FGFR2 protein P21802 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000007 22632802 YES Giulio Truncated FGFR2 was observed in cells transfected with wild-type ADAM9, but not in those with inactive mutant ADAM9 (Figure 5E). In line with this, cells transfected with wild-type ADAM9 showed reduced pErK1/2 in response to FGF2 as compared to controls or cells expressing mutant ADAM9.|Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, hence protecting FGFR2 from ADAM9-mediated ectodomain shedding on the cell surface. 0.257 SIGNOR-260300 CSNK2A2 protein P19784 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1067 GDVEGSQsQDEGEGS 9606 18442975 YES gcesareni Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm. 0.2 SIGNOR-178487 PRLHR protein P49683 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.275 SIGNOR-257089 Hypoxia stimulus SIGNOR-ST25 SIGNOR hsa-miR-150-3p mirna URS00005EAAAD_9606 RNAcentral down-regulates quantity by repression 9606 BTO:0002745 26622579 NO The results show that miR-150, which normally suppresses CXCR4 expression, is downregulated by hypoxia in pancreatic cancer tissues and cells, leading to increased CXCR4 expression and promoting cancer cell migration and invasion. 0.4 SIGNOR-277941 TAOK2 protein Q9UL54 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10660600 YES gcesareni Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway. 0.2 SIGNOR-74867 FLT3 protein P36888 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12468433 NO We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling 0.429 SIGNOR-261545 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr191 QKQEKPRtPMPSSVE 9606 BTO:0000007 16682949 YES done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 0.543 SIGNOR-274087 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN3 protein Q9UGI6 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 18955585 YES Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  0.8 SIGNOR-258024 CARM1 protein Q86X55 UNIPROT PAX7 protein P23759 UNIPROT up-regulates methylation 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 YES miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.421 SIGNOR-198617 GPC4 protein O75487 UNIPROT WNT5A protein P41221 UNIPROT up-regulates binding 9606 22302992 YES gcesareni Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways 0.373 SIGNOR-195752 phenytoin chemical CHEBI:8107 ChEBI SCN2A protein Q99250 UNIPROT down-regulates activity chemical inhibition 10116 1658608 YES miannu This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. 0.8 SIGNOR-258352 MAPK14 protein Q16539 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 16932740 YES In this case, the phosphorylation of EGFR by p38 or a downstream kinase like MAPKAP-2, triggers receptor internalization. gcesareni In conclusion, the use of pharmacological agents suggests that p38 mapk is the enzyme involved in egfr phosphorylation, as well as internalization, following exposure of cells to various stress-inducing conditions. 0.509 SIGNOR-149089 BCORL1 protein Q5H9F3 UNIPROT CTBP1 protein Q13363 UNIPROT up-regulates activity binding 9606 BTO:0002181 17379597 YES irozzo BCoR-L1 also interacts with the CtBP corepressor through a CtBP-interacting motif in its amino terminus. Furthermore, BCoR-L1 is located on the E-cadherin promoter, a known CtBP-regulated promoter, and represses the E-cadherin promoter activity in a reporter assay. 0.437 SIGNOR-259193 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation Thr255 ITTPELTtPCGSAEY 9606 9155017 YES gcesareni Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38. 0.671 SIGNOR-48346 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT down-regulates phosphorylation Thr3950 GHAFGSAtQFLPVPE 9606 17189255 YES gcesareni Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. 0.2 SIGNOR-151453 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser683 QAQDRKLsTKEALDE 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.2 SIGNOR-272510 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR EIF3F protein O00303 UNIPROT up-regulates activity phosphorylation Ser46 PAAAPASsSDPAAAA 19245811 YES lperfetto EIF3f is phosphorylated by CDK11p46 at Ser46 during apoptosis.|Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis.  0.516 SIGNOR-273134 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser469 DGEFSDDsGADQEKD 9606 BTO:0000007 11500362 YES llicata The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo. 0.324 SIGNOR-250788 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120056 ABL1 protein P00519 UNIPROT UBE3A protein Q05086 UNIPROT down-regulates activity phosphorylation Tyr659 GDSHPVLyQSLKDLL 9606 23581475 YES Manara Our results suggest that c-Abl protects p53 from HPV-E6-E6AP complex-mediated degradation by phosphorylating E6AP and impairing its E3 ligase activity 0.273 SIGNOR-260930 SNAP91 protein O60641 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 YES miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. 0.629 SIGNOR-264112 EEF1A1 protein P68104 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269504 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 BTO:0000567 10653583 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. 0.2 SIGNOR-236467 GNA13 protein Q14344 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 9606 BTO:0004605 37392861 NO Marta Tosoni Our results demonstrate that GNA13 expression is negatively correlated with GBM and can suppress tumor metastasis by inhibiting the ERKs signaling pathway and upregulating FOXO3 expression. 0.2 SIGNOR-278050 ALK protein Q9UM73 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Tyr293 RRPGEKTyTQRCRLF 9606 BTO:0000785 17537995 YES lperfetto Furthermore, psf was shown to be a direct substrate of purified alk kinase domain in vitro, and psf tyr293 was identified as the site of phosphorylation. Psf phosphorylation also increased its binding to rna and decreased the psf-mediated suppression of gage6 expression. 0.2 SIGNOR-155298 DNA polymerase epsilon complex SIGNOR-C377 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 10801849 NO lperfetto HeLa pol epsilon was initially purified as a soluble factor that restored repair synthesis to cytosol-depleted, UV-irradiated permeabilized human fibroblasts (11). By reconstituting the nucleotide excision repair (NER) process from purified proteins, Shivji et al. (12) further showed that mammalian pol epsilon was the most efficient enzyme in performing gap-filling DNA synthesis during NER. 0.7 SIGNOR-265722 PAK1 protein Q13153 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser111 KESLRSRsTRMSTVS 9606 23055517 YES lperfetto Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes 0.385 SIGNOR-199080 PLK1 protein P53350 UNIPROT KIF20A protein O95235 UNIPROT up-regulates activity phosphorylation 9606 12939256 YES miannu MKlp2 treated with Plk1 did not form the regular microtubule bundles seen with MKlp2 only; many single microtubules were seen instead, and the bundles that were formed were loose parallel arrays rather than the dense bundles seen with untreated MKlp2.|We propose that phosphorylation of MKlp2 by Plk1 is necessary for the spatial restriction of Plk1 to the central spindle during anaphase and telophase, and the complex of these two proteins is required for cytokinesis. 0.76 SIGNOR-278201 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser360 RKTQTSMsLGTTREK 10090 24012422 YES gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays 0.753 SIGNOR-266428 DZIP3 protein Q86Y13 UNIPROT H2AC4 protein P04908 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271747 PPP2R5B protein Q15173 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 YES gcesareni Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt. 0.66 SIGNOR-144808 ESR1 protein P03372 UNIPROT TGFA protein P01135 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 NO ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression 0.527 SIGNOR-253942 Ub:E2 complex SIGNOR-C497 SIGNOR RNF113B protein Q8IZP6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271193 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT up-regulates activity phosphorylation Tyr133 NFLSEDKyPLIMVPD 9606 18976935 YES lperfetto Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation. 0.501 SIGNOR-253367 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 12747827 YES lperfetto Our data demonstrate that the TOS motif functions as a docking site for the mTOR/raptor complex, which is required for multisite phosphorylation of 4E-BP1, eIF4E release from 4E-BP1, and cell growth. 0.755 SIGNOR-236678 CDK1 protein P06493 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates activity phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 YES miannu Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. Phosphorylation of Ser-277 is also dramatically increased during mitosis, however this is mediated by Cdk1 and not by ERK. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events. 0.714 SIGNOR-262840 RNF7 protein Q9UBF6 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 23136067 NO miannu We examined potential role of SAG in conferring cellular radioresistance, based upon two pieces of evidence. First, SAG is an antioxidant protein that scavenges ROS. R 0.7 SIGNOR-271445 ZBTB16 protein Q05516 UNIPROT ZBTB16/ZBTB32 complex SIGNOR-C80 SIGNOR form complex binding 9606 10572087 YES miannu We show that fazf is a transcriptional repressor and it readily forms heterodimers with plzf. 0.361 SIGNOR-72377 JNK proteinfamily SIGNOR-PF15 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 14699954 YES inferred from 70% family members amattioni The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53 0.2 SIGNOR-269985 phosphatidic acid smallmolecule CHEBI:16337 ChEBI PIP5K1A protein Q99755 UNIPROT up-regulates chemical activation 9606 17245604 YES gcesareni All pip5k isoforms are stimulated by pa. 0.8 SIGNOR-152542 TRIM9 protein Q9C026 UNIPROT TRIM9 protein Q9C026 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000142 20085810 YES miannu Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N 0.2 SIGNOR-271419 PAX7 protein P23759 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates BTO:0001103 15501225 NO svumbaca We found that ectopic expression of Pax-7 prevented myogenic differentiation and the induction of myogenin protein. 0.7 SIGNOR-255367 ULK2 protein Q8IYT8 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19225151 YES gcesareni Ulks directly phosphorylates atg13. 0.749 SIGNOR-184126 GSK3B protein P49841 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates activity phosphorylation Ser363 GRLPNNSsRPSTPTI 9606 27494834 YES miannu GSK3beta phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3beta upregulates Thr367 phosphorylationin vivo. 0.331 SIGNOR-278176 MAP3K11 protein Q16584 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates phosphorylation Ser257 ISGQLVDsIAKTRDA 9606 15328343 YES gcesareni These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo. 0.624 SIGNOR-128420 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates activity phosphorylation Ser794 SGGARAKsKSVSFNL 9606 BTO:0000007 21734191 YES miannu We show that TRPC5 channels may become directly phosphorylated by PKA at serine residues 794 and 796, and that this phosphorylation abolishes the receptor-operated nonselective cation current mediated by TRPC5 channels in HEK-293 cells. 0.2 SIGNOR-276340 EP300 protein Q09472 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 SIGNOR-C6 12419246 YES gcesareni Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads 0.406 SIGNOR-95462 SLBP protein Q14493 UNIPROT H2AC7 protein P20671 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265399 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM72 protein Q6ZMU5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271172 mTORC1 complex SIGNOR-C3 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity 10090 BTO:0002314 25047835 NO Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program. 0.7 SIGNOR-256273 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 6698284 YES miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). 0.8 SIGNOR-267339 GRK6 protein P43250 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1321 LPLPDRHsGHKAENG -1 22509025 YES miannu GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation 0.306 SIGNOR-276412 MAPK14 protein Q16539 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation 10029 BTO:0005787 25815583 YES TTP appears to be a p38α/β MAPK target and pretreating skeletal muscle with a p38α/β MAPK inhibitor reduces TTP phosphorylation. 0.358 SIGNOR-253596 [5-[5-[5-(hydroxymethyl)-2-thiophenyl]-2-furanyl]-2-thiophenyl]methanol chemical CHEBI:94980 ChEBI TP53 protein P04637 UNIPROT up-regulates chemical activation 9606 19223463 YES gcesareni Rita has been proposed to stabilize p53 by inhibiting the p53-hdm2 interaction. 0.8 SIGNOR-184062 PTPN1 protein P18031 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity dephosphorylation Tyr446 GTEPEPVySMEAADY 9534 BTO:0004055 18387954 YES Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr446, |Cortactin exerts its effects on the actin cytoskeleton by interacting directly with the Arp2/3 complex , F-actin |Src phosphorylates murine cortactin predominantly at three key sites in vitro, Tyr421, Tyr466, and Tyr482 (corresponding to Tyr421, Tyr470, and Try486 in human cortactin), resulting in decreased actin cross-linking activity 0.517 SIGNOR-248432 hsa-miR-451a mirna URS00002E857A_9606 RNAcentral CXCL16 protein Q9H2A7 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000971 25391425 YES Parnian Our data reveal a downregulated expression of miR-451 in osteosarcoma tissues, which is inversely associated with CXCL16 levels. These observations demonstrated that miR-451 may play an important role in tumor growth and metastasis in osteosarcoma. 0.4 SIGNOR-278012 NFYA protein P23511 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 12427542 YES miannu Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response. 0.615 SIGNOR-254816 PROX1 protein Q92786 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0001033 27476001 NO miannu Our present study reveals that DAB2IP prevents EMT and metastasis of prostate cancer through targeting PROX1 gene transcription and destabilizing HIF1α protein, which provides a new insight into mechanism that DAB2IP regulates EMT and PCa metastasis. 0.7 SIGNOR-254767 CDK5RAP2 protein Q96SN8 UNIPROT BUB1B protein O60566 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19282672 YES Giulio These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter 0.27 SIGNOR-260312 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates activity phosphorylation Ser632 RPLSRAQsSPASATF 11470791 YES llicata CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus. 0.619 SIGNOR-250712 romidepsin chemical CHEBI:61080 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257993 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 19584320 YES gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.503 SIGNOR-186633 IGF1R protein P08069 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates binding 9606 phosphorylation:Tyr1346 SFDERQPyAHMNGGR 9415396 YES gcesareni Moreover, we found that the insulin-like growth factor-1 receptor (igf-ir) bound to p55pik;the interaction occurred at the receptor tyrosine 1316 and involved both p55pik sh2 domains. 0.806 SIGNOR-52683 IL10 protein P22301 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 NO miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. 0.2 SIGNOR-253504 PRKACG protein P22612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 YES gcesareni Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. 0.2 SIGNOR-112375 TGFBR2 protein P37173 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 19114990 YES lperfetto In immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K 0.411 SIGNOR-252731 TP53 protein P04637 UNIPROT BID protein P55957 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16151013 YES Nuclear p53 lperfetto Bid is a p53 primary-response gene. 0.517 SIGNOR-140248 PRKCZ protein Q05513 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 YES inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.383 SIGNOR-270274 PRKCA protein P17252 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 YES lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. 0.469 SIGNOR-249086 LIMK2 protein P53671 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11171090 YES lperfetto We report here that limk1 and limk2 phosphorylate both cofilin and actin-depolymerizing factor (adf) specifically at ser-3 and exhibit partially distinct substrate specificity when tested using site-directed cofilin mutants as substrates 0.765 SIGNOR-105098 TRAF2 protein Q12933 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 8069916 YES amattioni Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. 0.635 SIGNOR-35881 Ub:E2 complex SIGNOR-C497 SIGNOR ARIH2 protein O95376 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271011 AKT1 protein P31749 UNIPROT HK1 protein P19367 UNIPROT up-regulates binding 9606 16892082 YES gcesareni The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. 0.445 SIGNOR-252495 IRF2BPL protein Q9H1B7 UNIPROT GNRH1 protein P01148 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 17627301 YES miannu EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function. 0.417 SIGNOR-267154 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 16403219 YES lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. 0.372 SIGNOR-249607 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr470 AYATEAVyESAEAPG 9606 12601080 YES lperfetto Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity 0.801 SIGNOR-98716 YARS1 protein P54577 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 16429158 YES miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr 0.8 SIGNOR-270521 CIITA protein P33076 UNIPROT HLA-DRB1 protein P01911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002417 10886240 NO These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. 0.534 SIGNOR-253976 SMAD5 protein Q99717 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0002729 23993924 NO flangone Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes. 0.7 SIGNOR-242059 NRAS protein P01111 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k 0.668 SIGNOR-175225 CEBPD protein P49716 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 NO CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. 0.272 SIGNOR-254060 PLK1 protein P53350 UNIPROT CEP192 protein Q8TEP8 UNIPROT up-regulates activity phosphorylation Thr44 GLPVAVStLARDRSS 9606 BTO:0000007 26012549 YES miannu In the presence of AurA binding, Plk1 preferentially phosphorylates and interacts with the T44 motif of Cep192 through the “self-priming and binding” mechanism 0.607 SIGNOR-266405 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP9 protein P55211 UNIPROT up-regulates activity -1 10988287 NO lperfetto One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway. 0.576 SIGNOR-256479 ERBB2 protein P04626 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21743488 NO gcesareni We demonstrate that her2 overexpression in this cellular model of dcis drives transcriptional upregulation of multiple components of the notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising notch3, its cleaved intracellular domain and the transcriptional regulator hes1. 0.403 SIGNOR-174747 DUSP5 protein Q16690 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 10224087 YES inferred from 70% of family members gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway 0.781 SIGNOR-269932 MYC protein P01106 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity transcriptional regulation 10116 10823814 YES C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. 0.43 SIGNOR-259987 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.276 SIGNOR-253493 CNOT3 protein O75175 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003292 24550297 YES Luana Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis. 0.2 SIGNOR-261572 Ub:E2 complex SIGNOR-C497 SIGNOR TRAIP protein Q9BWF2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270982 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CAPN2 protein P17655 UNIPROT up-regulates phosphorylation 9606 14993287 YES inferred from 70% family members lperfetto Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo. 0.2 SIGNOR-270179 TFEB protein P19484 UNIPROT BLOC1S3 protein Q6QNY0 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). 0.2 SIGNOR-276683 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 EEGFGSSsPVKSPAA 23051732 YES lperfetto Cdk1 phosphorylates Wee1 on Ser-123, which primes additional phosphorylation by other kinases, leading to the formation of phosphodegrons responsible for SCF (Skp1/cullin/F-box) ubiquitin-mediated degradation of Wee1 0.784 SIGNOR-267471 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser248 SVQSDIWsMGLSLVE 9606 8131746 YES gcesareni Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf 0.573 SIGNOR-36457 CDK2 protein P24941 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR form complex binding 9606 19665013 YES lperfetto The eukaryotic cell cycle is controlled by different cyclins and their associated kinases (murray and hunt, 1993). In mammalian cells, levels of cycline and its associated kinase, cdk2, rise in late g1/early s-phase when dna replication is initiated 0.933 SIGNOR-187457 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 YES tpavlidou Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene. 0.2 SIGNOR-259429 GSK3B protein P49841 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Ser6 sTPCSSMS -1 22142472 YES miannu GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress. 0.278 SIGNOR-276392 DAPK3 protein O43293 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation 9606 20130087 YES miannu We conclude from our results Par-4 operates through a "padlock" model in which binding of Par-4 to MYPT1 activates MP by blocking access to the inhibitory phosphorylation sites, and inhibitory phosphorylation of MYPT1 by ZIPK requires "unlocking" of Par-4 by phosphorylation and displacement of Par-4 from the MP complex.|We have also demonstrated that Par-4 is required for agonist induced, ZIPK mediated inhibition of MYPT1 and thus is an important amplifier of inputs to MP. 0.548 SIGNOR-279030 indometacin chemical CHEBI:49662 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000135 15770365 YES Simone Vumbaca Indomethacin, a nonselective cyclooxygenase inhibitor, may prevent AAA formation by inhibiting cyclooxygenase-2 (COX-2) activity. 0.8 SIGNOR-261089 SNRPD2 protein P62316 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.769 SIGNOR-270661 CSKMT protein A8MUP2 UNIPROT CS protein O75390 UNIPROT down-regulates activity methylation Lys395 LLEQGKAkNPWPNVD 34929314 YES lperfetto A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate. 0.2 SIGNOR-267638 HIC1 protein Q14526 UNIPROT VEGFA protein P15692 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 24067369 NO miannu HIC1 suppressing the VEGF and c-Myc promoter activity and the colony formation of MDA-MB 231 cells were STAT3-dependent. 0.2 SIGNOR-254247 PSENEN protein Q9NZ42 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 YES lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) 0.96 SIGNOR-209708 JAG1 protein P78504 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 7227 18660822 YES Binding Ca-dependent lperfetto We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner. 0.641 SIGNOR-219253 staurosporine chemical CHEBI:15738 ChEBI PRKCH protein P24723 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258286 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT up-regulates activity phosphorylation Thr193 EPEDTTStFCGTPEY 10548550 YES miannu SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. 0.595 SIGNOR-250277 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR JUN protein P05412 UNIPROT up-regulates activity 9606 BTO:0000093 8415704 YES PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site 0.2 SIGNOR-259940 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr276 DGIMYYLtPQWDKIL 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.2 SIGNOR-262926 BMP7 protein P18075 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR up-regulates binding 10090 BTO:0000165 11282024 YES lperfetto Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2 0.805 SIGNOR-235364 STUB1 protein Q9UNE7 UNIPROT SMG5 protein Q9UPR3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16809764 YES miannu Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B.  0.399 SIGNOR-272649 CORT protein O00230 UNIPROT GHSR protein Q92847 UNIPROT up-regulates binding 9606 12161511 YES gcesareni In human tissues cst-14 as well as cst-17 but not ss-14 bind the gh secretagogue receptor (ghs-r). 0.472 SIGNOR-91134 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Thr1031 ASSTDHQtPPTSPVQ 9606 24089523 YES lperfetto Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1 0.427 SIGNOR-202702 TFEB protein P19484 UNIPROT PSAP protein P07602 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.308 SIGNOR-276545 TUBGCP6 protein Q96RT7 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 YES lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” 0.785 SIGNOR-262330 carbachol chemical CHEBI:3385 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258621 GPI protein P06744 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P. 0.8 SIGNOR-266461 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser712 EEEESDSsETEKEDD 21296876 YES lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. 0.2 SIGNOR-275500 ASNS protein P08243 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-267535 CSNK2B protein P67870 UNIPROT CD163 protein Q86VB7 UNIPROT up-regulates activity phosphorylation Ser1085 RQRLAVSsRGENLVH -1 11298324 YES llicata Interaction of CD163 with the regulatory subunit of casein kinase II (CKII) and dependence of CD163 signaling on CKII and protein kinase C. | Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines. 0.307 SIGNOR-251056 DLG4 protein P78352 UNIPROT LRFN1 protein Q9P244 UNIPROT up-regulates activity binding 9606 BTO:0000938 21736948 YES miannu SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses. 0.774 SIGNOR-264095 A4/b1 integrin complex SIGNOR-C162 SIGNOR DLL1 protein O00548 UNIPROT up-regulates quantity by expression 10090 25786978 NO lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. 0.267 SIGNOR-253285 AURKB protein Q96GD4 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates phosphorylation Thr232 APSLRRKtMCGTLDY 9606 14722118 YES lperfetto We report here that human aurora-b is phosphorylated at thr-232 through interaction with the inner centromere protein (incenp) in vivo. The phosphorylation of thr-232 occurs by means of an autophosphorylation mechanism, which is indispensable for the aurora-b kinase activity. 0.2 SIGNOR-121340 GPR84 protein Q9NQS5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257099 CDK1 protein P06493 UNIPROT CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser18 RRLLFACsPPPASQP 9606 12411508 YES lperfetto Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover. 0.842 SIGNOR-95260 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 18697834 YES Simone Vumbaca Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells 0.809 SIGNOR-255650 hsa-miR-520a-5p mirna URS0000534239_9606 RNAcentral CXCL8 protein P10145 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000093 21343296 YES Parnian Overall, these data strongly suggest that the IL-8 gene is a direct target of miR-520b and is involved in breast cancer cell migration. | We then confirmed that the 3 UTR of IL-8 is a target of miR-520b 0.4 SIGNOR-278015 hsa-miR-183-5p mirna URS0000528CBC_9606 RNAcentral DKK3 protein Q9UBP4 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001061 23538390 YES Parnian This is the first report to show that the oncogenic miR-183 activates the Wnt/b-catenin pathway by directly inhibiting tumour suppressors Dkk-3 and SMAD4 in PC.| indicating that Dkk-3 and SMAD4 are direct targets of miR-183. 0.4 SIGNOR-278016 hsa-miR-183-5p mirna URS0000528CBC_9606 RNAcentral SMAD4 protein Q13485 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001061 23538390 YES Parnian This is the first report to show that the oncogenic miR-183 activates the Wnt/b-catenin pathway by directly inhibiting tumour suppressors Dkk-3 and SMAD4 in PC.| indicating that Dkk-3 and SMAD4 are direct targets of miR-183. 0.4 SIGNOR-278017 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 NO Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. 0.8 SIGNOR-268017 CAMK2A protein Q9UQM7 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS BTO:0000944 7523419 YES llicata Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site. Expression of K18 ser-52-->ala mutant in mammalian cells showed minimal phosphorylation but no distinguishable difference in filament assembly when compared with wild-type K18. In contrast, the ser-52 mutation played a clear but nonexclusive role in filament reorganization, 0.286 SIGNOR-250633 CSNK2A1 protein P68400 UNIPROT DEK protein P35659 UNIPROT up-regulates phosphorylation Ser32 MPGPREEsEEEEDED 9606 15199154 YES amattioni Dek is phosphorylated by the protein kinase ck2 in vitro and in vivo on ser32 0.35 SIGNOR-125912 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser289 PPQDQESsPIENDSS 9606 7678037 YES llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase erine threonine phosphorylation and may stimulate CKII activity in B cells. 0.307 SIGNOR-250916 CYSLTR2 protein Q9NS75 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256889 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 15723037 YES gcesareni Modulation of human nuclear receptor lrh-1 activity by phospholipids and shpthe human nuclear receptor liver receptor homolog 1 (hlrh-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor shp 0.564 SIGNOR-134202 ATF4 protein P18848 UNIPROT NARS2 protein Q96I59 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269423 ATM protein Q13315 UNIPROT HNF1A protein P20823 UNIPROT up-regulates phosphorylation Ser249 IQRGVSPsQAQGLGS 9606 24821553 YES lperfetto Serine 249 phosphorylation by atm protein kinase regulates hepatocyte nuclear factor-1_ transactivation 0.256 SIGNOR-205087 Ub:E2 complex SIGNOR-C497 SIGNOR WWP2 protein O00308 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271288 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.8 SIGNOR-260669 TESK1 protein Q15569 UNIPROT TESK1 protein Q15569 UNIPROT up-regulates activity phosphorylation Ser220 EPLAVVGsPYWMAPE 9606 BTO:0000567 10207045 YES lperfetto Site-directed mutagenesis analyses revealed that Ser-215 within the activation loop of the kinase domain is the site of serine autophosphorylation of TESK1. Replacement of Ser-215 by alanine almost completely abolished serine autophosphorylation and histone H3 kinase activities. 0.2 SIGNOR-246667 PRKCB protein P05771 UNIPROT CASR protein P41180 UNIPROT down-regulates activity phosphorylation Thr888 FKVAARAtLRRSNVS 9606 BTO:0000007 12356761 YES lperfetto Expression of a mutant CaR in which the major PKC phosphorylation site is altered by substitution of alanine for threonine (T888A) eliminated oscillatory behavior, producing [Ca(2+)](i) responses almost identical to those produced by the wild type CaR exposed to PKC inhibitors. These results support a model in which phosphorylation of the CaR at the inhibitory threonine 888 by PKC provides the negative feedback needed to cause [Ca(2+)](i) oscillations mediated by this receptor. 0.319 SIGNOR-249176 AURKA protein O14965 UNIPROT MAPRE3 protein Q9UPY8 UNIPROT up-regulates phosphorylation Ser176 MQTSGRLsNVAPPCI 9606 19696028 YES llicata Aurora-a and aurora-b phosphorylate eb3 at ser-176 in a spatial and cell cycle-specific manner, respectively during mitosis two kinases, aurora-a and aurora-b, phosphorylate eb3 at ser-176, and the resulting phosphorylation disrupts the eb3-siah-1 complex. Indeed, eb3 is stabilized during mitosis and facilitates cell cycle progression. 0.443 SIGNOR-187657 UBE2D1 protein P51668 UNIPROT TRIM2 protein Q9C040 UNIPROT up-regulates activity binding 9606 BTO:0000567 18687884 YES miannu Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination. Together, our results indicate that TRIM2 is an ubiquitin ligase that binds to and ubiquitinates NF-L and that TRIM2 deficiency leads to neurodegeneration in mice likely by altering NF-L metabolism with consequent NF-L accumulation in axons and impairment of axonal transport. 0.278 SIGNOR-271775 NFAT5 protein O94916 UNIPROT LCN2 protein P80188 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 22266867 YES done miannu  As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009). 0.329 SIGNOR-274114 GNA13 protein Q14344 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity phosphorylation 9606 BTO:0004605 37392861 NO Marta Tosoni Western blots revealed that GNA13 knockdown and overexpression upregulated and inhibited the phosphorylation of ERKs, respectively. Moreover, GNA13 was the upstream of ERKs signaling to regulating ERKs phosphorylation level 0.301 SIGNOR-278049 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189981 CASP6 protein P55212 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 YES lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. 0.372 SIGNOR-261759 quetiapine chemical CHEBI:8707 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258533 MAP3K7 protein O43318 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 16980613 YES lperfetto We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function 0.2 SIGNOR-149579 TGFB1 protein P01137 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11331591 NO gcesareni Tgf-beta inhibited the expression of the cbfa1 and_ osteocalcin_ genes. 0.371 SIGNOR-107248 PD318088 chemical CID:10231331 PUBCHEM MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck lperfetto 0.8 SIGNOR-244927 FZD4 protein Q9ULV1 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 12958364 YES amattioni Endocytosis of frizzled 4 (fz4) in human embryonic kidney 293 cells was dependent on added wnt5a protein and was accomplished by the multifunctional adaptor protein beta-arrestin 2 (betaarr2), which was recruited to fz4 by binding to phosphorylated dvl2. 0.75 SIGNOR-100274 PICALM protein Q13492 UNIPROT CLTCL1 protein P53675 UNIPROT up-regulates binding 9606 BTO:0001271;BTO:0000785 16491119 YES miannu Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro 0.729 SIGNOR-144733 TAOK2 protein Q9UL54 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 23431053 YES inferred from 70% of family members gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. 0.279 SIGNOR-269939 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW -1 17711846 YES done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). 0.41 SIGNOR-274094 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI up-regulates quantity precursor of 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-268069 ARHGEF7 protein Q14155 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates binding 9606 14505571 YES gcesareni Here, we show that activation of cdc42 protects the egf receptor from the negative regulatory activity of the c-cbl ubiquitin ligase. Activated cdc42 binds to p85cool-1 (for cloned-out-of-library)/beta-pix (for pak-interactive exchange factor), a protein that directly associates with c-cbl. This inhibits the binding of cbl by the egf receptor and thus prevents cbl from catalyzing receptor ubiquitination 0.2 SIGNOR-118135 ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser317 ENVKYSSsQPEPRTG 9606 15775976 YES gcesareni Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase. 0.925 SIGNOR-134712 ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 YES miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase 0.781 SIGNOR-256168 DIO2 protein Q92813 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 YES scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. 0.8 SIGNOR-266953 Ionizing radiation stimulus SIGNOR-ST16 SIGNOR TRIM13 protein O60858 UNIPROT up-regulates 9606 BTO:0000007 21333377 NO miannu These data suggest that irradiation causes RFP2 overexpression, which enhances ionizing radiation-induced apoptosis by increasing p53 stability and decreasing AKT kinase activity through MDM2 and AKT degradation. 0.7 SIGNOR-271854 DNA polymerase delta complex SIGNOR-C376 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9534 BTO:0004055 12930972 NO lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). 0.7 SIGNOR-265513 PJA1 protein Q8NG27 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity ubiquitination 9606 32127355 YES miannu In summary, these results indicated that PJA1 promotes the ubiquitination of phosphorylated SMAD3, resulting in reduced activity of a TGF-\u03b2/SMAD3/\u03b22SP-dependent tumor-suppressing pathway in HCC cells ( xref ). 0.392 SIGNOR-278832 ATF6 protein P18850 UNIPROT ATF6 protein P18850 UNIPROT up-regulates activity binding -1 12805554 YES miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins 0.2 SIGNOR-224202 IL1R1 protein P14778 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9625767 YES lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab 0.2 SIGNOR-249515 PLP1 protein P60201 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 26519753 NO SimoneGraziosi Proteolipid protein (PLP) is a major component only in the CNS myelin of terrestrial species and is involved in compaction of the extracellular apposition. 0.7 SIGNOR-269265 RNF6 protein Q9Y252 UNIPROT LIMK1 protein P53667 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16204183 YES miannu Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons.  0.433 SIGNOR-271481 KCNQ4 protein P56696 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 YES miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. 0.8 SIGNOR-265985 HNF4A protein P41235 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 NO inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.257 SIGNOR-270255 MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity 9606 20626350 NO lperfetto On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment. 0.426 SIGNOR-166591 DUSP2 protein Q05923 UNIPROT MAPK4 protein P31152 UNIPROT down-regulates activity dephosphorylation 9606 28252035 YES miannu DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5. 0.354 SIGNOR-277068 PTGS2 protein P35354 UNIPROT prostaglandin E2 smallmolecule CHEBI:15551 ChEBI up-regulates quantity binding 9606 BTO:0000553 33275396 YES Marta Tosoni Prostaglandin E2 (PGE2) is an end-product of the cyclooxygenase (COX)-2 pathway that has been reported to promote cell survival, cell growth, migration, invasion and angiogenesis 0.8 SIGNOR-278094 ETS1 protein P14921 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20392592 NO miannu High ETS1 expression levels in all resistant MCF-7 sublines may lead to the upregulation of the transcription of MDR1 gene. 0.2 SIGNOR-254077 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 YES Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B 0.742 SIGNOR-248437 ARHGEF7 protein Q14155 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 17562871 NO gcesareni We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1. 0.636 SIGNOR-155744 TLN1 protein Q9Y490 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 10090 BTO:0000132 SIGNOR-C167 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.798 SIGNOR-257593 MDM2 protein Q00987 UNIPROT EID1 protein Q9Y6B2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 11073989 YES miannu Degradation of EID-1 occurs via ubiquitin-dependent proteolysis and correlates with MDM2 binding. These results are consistent with a model wherein destruction of EID-1 is linked to its ability to interact with MDM2 via either p300 or pRB. 0.425 SIGNOR-272582 SMOC1 protein Q9H4F8 UNIPROT SPARC protein P09486 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 NO lperfetto The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells 0.4 SIGNOR-260401 PRKCE protein Q02156 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr52 HKHKHEMtLKFGPAR 9606 BTO:0000848;BTO:0001286 22304920 YES lperfetto Pkc_ phosphorylation of atf2 on thr52. Pkc_ promotes oncogenic functions of atf2 in the nucleus while blocking its apoptotic function at mitochondria 0.288 SIGNOR-195761 MAPK9 protein P45984 UNIPROT JUNB protein P17275 UNIPROT down-regulates binding 9606 9405416 YES gcesareni Jnk targets junb ubiquitination 0.673 SIGNOR-53827 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT up-regulates activity binding 9606 BTO:0000007 17925232 YES PTIP promotes assembly of the ALR complex and H3K4 methylation at a PAX2-binding DNA element. Without PTIP, Pax2 binds to this element but does not assemble the ALR complex 0.571 SIGNOR-251711 NFKB1 protein P19838 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity binding 9606 9450761 YES lperfetto Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna 0.713 SIGNOR-55378 IL1RAPL1 protein Q9NZN1 UNIPROT NCS1 protein P62166 UNIPROT up-regulates activity binding 10116 BTO:0001009 12783849 YES miannu IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction. 0.596 SIGNOR-263962 SND1 protein Q7KZF4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 30365124 NO irozzo SND1 upregulation is a common phenomenon in different human malignant tissues. We found that SND1 overexpression significantly promoted cell proliferation and tumor growth in vitro and in vivo. 0.7 SIGNOR-259135 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu57 EVRKGNLeRECVEET -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263677 fulvestrant chemical CHEBI:31638 ChEBI ESR2 protein Q92731 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000150 12113237 YES miannu Fulvestrant (Faslodex, formerly ICI 182,780) is a potent steroidal antiestrogen that mediates its effects by estrogen receptor downregulation. 0.8 SIGNOR-259304 ARHGAP40 protein Q5TG30 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.43 SIGNOR-260496 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser834 GSHTSGQsNGRDHQA 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.328 SIGNOR-276514 ATM protein Q13315 UNIPROT POLL protein Q9UGP5 UNIPROT up-regulates activity phosphorylation Thr204 EASDGEEtQVSAADL 9606 BTO:0000007 28109743 YES done miannu  We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ.  0.354 SIGNOR-273836 MLXIPL protein Q9NP71 UNIPROT ELOVL6 protein Q9H5J4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 27524233 YES Luana In this study, we clearly show that mouse and human Elovl6 are direct targets of ChREBP.  0.398 SIGNOR-267945 SMAD3 protein P84022 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 22740686 NO lperfetto PD-1 also inhibited phosphorylation of the transcription factor Smad3, which increased its activity. These events induced additional inhibitory checkpoints in the cell cycle by increasing the abundance of the G(1) phase inhibitor p15(INK4) and repressing the Cdk-activating phosphatase Cdc25A 0.567 SIGNOR-245445 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQA1 protein P01909 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.285 SIGNOR-253991 FUBP1 protein Q96AE4 UNIPROT BIK protein Q13323 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 NO irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In particular, elevated expression of the Bcl-2 family members Bik and Noxa was detected. 0.2 SIGNOR-259127 UBQLN2 protein Q9UHD9 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 10090 27477512 NO lperfetto UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. 0.7 SIGNOR-262267 LMO3 protein Q8TAP4 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21573214 NO miannu Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter. 0.342 SIGNOR-254826 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 24556163 YES miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 0.8 SIGNOR-262233 PTK2B protein Q14289 UNIPROT ASAP1 protein Q9ULH1 UNIPROT down-regulates activity phosphorylation Tyr767 RDKQRLSyGAFTNQI 9606 BTO:0000007 12771146 YES miannu The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells.Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation. 0.458 SIGNOR-263187 Calcineurin complex SIGNOR-C155 SIGNOR Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 15363394 NO miannu In this study, we have identified CaMKII and CaN-PP1 as the downstream effectors of localized Ca2+ signals in mediating attractive and repulsive turning responses of growth cones, respectively. Local Ca2+ elevation activates CaMKII and CaN-PP1 for attraction and repulsion, respectively. 0.7 SIGNOR-268386 HNF1B protein P35680 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 7549116 NO miannu HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells. 0.317 SIGNOR-254638 triprolidine chemical CHEBI:84116 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 7925364 YES miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. 0.8 SIGNOR-258870 TGFBR2 protein P37173 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates phosphorylation Ser345 RGDGSGFsL 9606 BTO:0000551 23249950 YES lpetrilli Transforming growth factor ? (tgf-?) Has been shown to regulate cell plasticity through the phosphorylation of par6 on a conserved serine residue (s345) by the type ii tgf-? Receptor. 0.465 SIGNOR-200193 FCGR3A protein P08637 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression 9606 BTO:0000801 10728755 NO lperfetto This study suggests a dominant role for FcgammaRIIIA in the induction of both TNFalpha and IL-1alpha production by human macrophages in rheumatoid arthritis following receptor ligation by small immune complexes. The signaling of TNFalpha production may require the ligation of either 3 FcgammaRIIIA receptors or only 2 FcgammaRIIIA receptors, where one interaction must involve binding via an Fc domain. 0.332 SIGNOR-249526 CTCF protein P49711 UNIPROT MGAT5B protein Q3V5L5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 21771782 NO miannu By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression. 0.2 SIGNOR-253826 ritonavir chemical CHEBI:45409 ChEBI CYP2B6 protein P20813 UNIPROT up-regulates activity chemical activation 9606 18285471 YES Luana These results show that ritonavir induces human CYP2B6 activity.  0.8 SIGNOR-257770 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG -1 7493944 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.581 SIGNOR-246264 GOT2 protein P00505 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 31422819 YES miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-267517 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr162 QLAAKLAyLQILSEE -1 16373505 YES Manara PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR. 0.2 SIGNOR-260783 RPE protein Q96AT9 UNIPROT D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity chemical modification 9606 34775382 YES miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. 0.8 SIGNOR-267068 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 9335553 YES gcesareni These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling. 0.705 SIGNOR-52696 MAPK8 protein P45983 UNIPROT ELK3 protein P41970 UNIPROT down-regulates activity phosphorylation 11042694 YES miannu JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export. 0.323 SIGNOR-250139 PSME3 protein P61289 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 35932807 YES lperfetto While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. 0.643 SIGNOR-275869 aripiprazole chemical CHEBI:31236 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002181 22025698 YES Luana Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands.  0.8 SIGNOR-258319 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity dephosphorylation Tyr570 VRREVGDyGQLHETE 9606 30108215 YES miannu Consistently, JAK2/STAT3 signaling was enhanced by overexpression of SHP2   with decreased levels of pJAK2   and increased levels of pJAK2   and pSTAT3  , while it was found suppressed by overexpression of SHP2   (Fig.\u00a06b).|We demonstrate that SHP2 can dephosphorylate JAK2 at Y570 to promote TGF\u03b2-dependent activation of JAK2 and its downstream mediator STAT3 (Supplementary Fig.\u00a04a). 0.793 SIGNOR-277037 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR MCM3 protein P25205 UNIPROT up-regulates quantity by expression transcriptional regulation 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276580 Fanconi anemia core complex complex SIGNOR-C300 SIGNOR FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 18985065 YES lperfetto Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding 0.77 SIGNOR-263265 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248741 CDK1 protein P06493 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 11986303 YES lperfetto Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%. 0.351 SIGNOR-87097 TOLLIP protein Q9H0E2 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates activity binding 9606 BTO:0000007 10854325 YES lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) 0.798 SIGNOR-251980 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9606 BTO:0000567 9687510 YES lperfetto Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3) 0.759 SIGNOR-59363 mTORC1 complex SIGNOR-C3 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR down-regulates activity phosphorylation 9606 23863160 YES lperfetto Several studies published simultaneously illustrated that the equivalent mammalian ULK1Atg13FIP200 complex was also negatively regulated by mTORC1 in an analogous manner [17,18,24]. In mammalian cells, amino acid starvation or rapamycin treatment causes dephosphorylation of both Atg13 and ULK1, indicating that an mTORC1 input regulates the ULK1Atg13FIP200 complex mTORC1 modulates the kinase activity of ULK1 directly, with rapamycin treatment of cells leading to enhanced ULK1 kinase activity, whereas Rheb overexpression causes a decrease in ULK1 kinase activity 0.572 SIGNOR-209904 RAB32 protein Q13637 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR up-regulates activity relocalization 9606 23247405 YES miannu Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. 0.273 SIGNOR-268524 ADA protein P00813 UNIPROT inosine smallmolecule CHEBI:17596 ChEBI up-regulates quantity chemical modification -1 15926889 YES Luana Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates 0.8 SIGNOR-269737 PRKACA protein P17612 UNIPROT TBXA2R protein P21731 UNIPROT unknown phosphorylation Ser331 STRPRSLsLQPQLTQ 9606 12147288 YES llicata Ser-331 was found to be involved in pka-mediated phosphorylation. 0.492 SIGNOR-90976 DYNLL1 protein P63167 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.273 SIGNOR-260501 GTF2H4 protein Q92759 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 YES lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.91 SIGNOR-269315 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 11432829 YES gcesareni This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway. 0.539 SIGNOR-109035 KTN1 protein Q86UP2 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30683916 NO miannu Collectively, our findings revealed a novel mechanism wherein MALAT1 interacts with c-MYC to transactivate KTN1 for enhancing EGFR protein expression, which finally contributes to the development of cSCC. 0.2 SIGNOR-259906 PP121 chemical CHEBI:50915 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206301 CREB1 protein P16220 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15130492 NO lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA 0.251 SIGNOR-251714 PKN1 protein Q16512 UNIPROT MEFV protein O15553 UNIPROT down-regulates activity phosphorylation Ser208 VRLRRNAsSAGRLQG 10090 BTO:0004732 27270401 YES no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 0.384 SIGNOR-275462 P-TEFb complex SIGNOR-C238 SIGNOR AFF2 protein P51816 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000007 17135274 YES miannu P-TEFb phosphorylates Af4 and down-regulates its transactivation activity. P-TEFb also phosphorylates AF4 which down-regulates its transactivation activity, providing a negative feedback mechanism for the control of P-TEFb elongation activity 0.39 SIGNOR-266798 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates activity dephosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000007 17603999 YES Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524. 0.377 SIGNOR-248561 SRC protein P12931 UNIPROT FBXO5 protein Q9UKT4 UNIPROT up-regulates phosphorylation Tyr142 ALETSRLyEDSGYSS 9606 20717963 YES lperfetto We found that emi1 stability was regulated by phosphorylation and mutation of tyrosine 142 reduced the stability. Our data suggested bcr-abl-induced emi1 phosphorylation might be mediated by src kinase. 0.325 SIGNOR-167529 CSNK2A1 protein P68400 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser112 GSDDEEEsEEAKRLR -1 8547318 YES llicata EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent. 0.344 SIGNOR-250855 RAP1GDS1 protein P52306 UNIPROT RAP1A protein P62834 UNIPROT up-regulates binding 9606 21242305 YES miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob 0.42 SIGNOR-171482 PTPN2 protein P17706 UNIPROT STAT5A protein P42229 UNIPROT down-regulates activity dephosphorylation 9606 15780598 YES lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. 0.733 SIGNOR-133547 PRKACA protein P17612 UNIPROT TFAM protein Q00059 UNIPROT up-regulates phosphorylation Ser55 SCPKKPVsSYLRFSK 9606 23201127 YES llicata Here, we demonstrate that tfam is phosphorylated within its hmg box 1 (hmg1) by camp-dependent protein kinase in mitochondria. Hmg1 phosphorylation impairs the ability of tfam to bind dna and to activate transcription. 0.2 SIGNOR-199934 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A2-B3 complex SIGNOR-C138 SIGNOR up-regulates activity chemical activation 9606 15036565 YES gcesareni One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP) 0.8 SIGNOR-243964 TTN protein Q8WZ42 UNIPROT OBSCN protein Q5VST9 UNIPROT up-regulates quantity relocalization 9606 BTO:0003324 19840192 YES miannu Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. 0.581 SIGNOR-266728 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM2 protein P0DP24 UNIPROT up-regulates chemical activation 9606 10884684 YES miannu Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations 0.8 SIGNOR-266317 SETD2 protein Q9BYW2 UNIPROT TUBA1B protein P68363 UNIPROT up-regulates activity methylation Lys40 DGQMPSDkTIGGGDD 9606 BTO:0000007 27518565 YES Gianni The histone methyltransferase SET-domain-containing 2 (SETD2), which is responsible for H3 lysine 36 trimethylation (H3K36me3) of histones, also methylates α-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy 0.244 SIGNOR-269090 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr169 KRSSRANtVTPAVGR 9606 19530738 YES lperfetto First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form. 0.462 SIGNOR-186143 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates activity phosphorylation Ser25 KDEPQRRsARLSAKP 9606 BTO:0000567 11438671 YES lperfetto We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets. 0.29 SIGNOR-249102 EIF3_complex complex SIGNOR-C401 SIGNOR EIF5 protein P55010 UNIPROT up-regulates activity stabilization 9606 17581632 YES lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 0.695 SIGNOR-269153 CDK1 protein P06493 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 18337751 YES gcesareni Phosphorylation at ser359 inhibits eef2k activity even at high calcium concentrations. we demonstrate that cdc2 contributes to controlling eef2 phosphorylation in cells. inactivation of eef2k by cdc2 may serve to keep eef2 active during mitosis 0.368 SIGNOR-177982 N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide chemical CHEBI:94490 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191274 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248520 DLGAP3 protein O95886 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.787 SIGNOR-264593 ITK protein Q08881 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 YES lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling 0.2 SIGNOR-112471 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.716 SIGNOR-263008 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SP3 protein Q02447 UNIPROT up-regulates phosphorylation 9606 17685427 YES inferred from 70% family members gcesareni Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. 0.2 SIGNOR-270165 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF3 protein Q86UD3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271246 CENP-A nucleosome complex SIGNOR-C321 SIGNOR Centromere_assembly phenotype SIGNOR-PH154 SIGNOR up-regulates 9606 BTO:0000567 20566683 NO miannu Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity. 0.7 SIGNOR-263704 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 12754301 YES llicata The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop 0.391 SIGNOR-248449 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 23630338 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. gcesareni C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates. 0.8 SIGNOR-202007 MC4R protein P32245 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257270 p62_complex complex SIGNOR-C259 SIGNOR Nuclear_pore_function phenotype SIGNOR-PH130 SIGNOR up-regulates 10116 2050741 NO miannu Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. 0.7 SIGNOR-261261 CDKN1A protein P38936 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR down-regulates activity binding 10913154 YES lperfetto P21 Inhibits Thr161 Phosphorylation of Cdc2 to Enforce the G2 DNA Damage Checkpoint|The cyclin-dependent kinase inhibitor p21 is required for a sustained G2 arrest after activation of the DNA damage checkpoint. Here we have addressed the mechanism by which p21 can contribute to this arrest in G2. We show that p21 blocks the activating phosphorylation of Cdc2 on Thr161 0.855 SIGNOR-251498 SPAG9 protein O60271 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 YES lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts 0.356 SIGNOR-235545 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser361 TLRDVVPsPDTQEKG 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.35 SIGNOR-276106 CCL5 protein P13501 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 YES RANTES interacts with specific cell surface receptors, which are coupled to pertussis toxin-sensitive guanine nucleotide regulatory proteins (G protein) to activate effectors such as phospholipase C (PLC), ion channels, phospholipase D, and protein kinase C. In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5 0.771 SIGNOR-254367 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 30230471 NO lperfetto In keeping with the overall improvement in insulin sensitivity we found that insulin-induced IR Y1162/Y1163 tyrosine phosphorylation and activation and downstream PI3K/AKT signaling in the liver (as monitored by AKT Ser-473 phosphorylation) were dramatically enhanced by POMC TCPTP deficiency (Figure 4h).|This would suggest that TCPTP deletion, or decreased TCPTP in POMC neurons in response to feeding, represses HGP by enhancing IR signaling and permitting POMC neurons to be activated by insulin. 0.622 SIGNOR-276957 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI GNB3 protein P16520 UNIPROT up-regulates chemical activation 9606 17251915 YES gcesareni Lpa through galfai and gbetagamma subunits also activates phosphatidylinositol 3-kinase (pi3k), which results in the stimulation of the akt survival pathway and increased protein translation by the activation of the mammalian target of rapamycin (mtor) pathway. 0.8 SIGNOR-152759 PPM1A protein P35813 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates activity dephosphorylation Ser358 VPSTSTMsQEPELLI 9606 25815785 YES lperfetto Collectively, our findings suggest that the overexpression of PPM1A antagonizes the STING- and TBK1-induced type I interferon signaling pathway.|First, PPM1A directly dephosphorylated STING, likely via its S358 site (Figs.|Moreover, our study demonstrates that while TBK1 enhances STING aggregation in a kinase activity-dependent manner, PPM1A suppresses STING aggregation by dephosphorylating both STING and TBK1. 0.2 SIGNOR-276958 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 22898603 YES lperfetto In addition, our work further reveals that above a threshold expression level, DEP-1 can also dephosphorylate Src Y418 and attenuate downstream signaling and biologic responses, consistent with the quiescent behavior of confluent endothelial cells that express the highest levels of endogenous DEP-1. 0.635 SIGNOR-276978 CXCL10 protein P02778 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 NO miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. 0.7 SIGNOR-261025 IMP smallmolecule CHEBI:17202 ChEBI GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity precursor of 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-268130 CAMK2A protein Q9UQM7 UNIPROT CACNA1H protein O95180 UNIPROT down-regulates activity phosphorylation Ser2137 RDLRRLYsVDAQGFL 10090 BTO:0003695 38001892 YES miannu  we also discovered that a novel CaMKII-phosphorylated site, S2137, underwent dephosphorylation by calcineurin.  0.273 SIGNOR-277871 ATM protein Q13315 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser114 EETRTPEsQPDTPPG 9606 21824916 YES lperfetto We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro. 0.462 SIGNOR-176008 PTPN1 protein P18031 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 18253097 YES lperfetto The protein tyrosine phosphatase, PTP1B, is known to negatively regulate EGF-induced signaling in several cell types by dephosphorylating the epidermal growth factor receptor (EGFR).|Together, these findings provide evidence that PTP1B plays a role in the negative regulation of EGFR signaling in rat corneal endothelial cells, at least at the level of Tyr992 phosphorylation. 0.759 SIGNOR-276981 TWIST1 protein Q15672 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 NO miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells 0.291 SIGNOR-255516 CAMK1G protein Q96NX5 UNIPROT EIF4G3 protein O43432 UNIPROT up-regulates phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 22514323 YES lperfetto Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii). 0.2 SIGNOR-197149 CDK1 protein P06493 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 SIGNOR-C17 17389604 YES gcesareni Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1 0.253 SIGNOR-154047 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding -1 12620238 YES lperfetto This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral iap repeat (bir3) of xiap at 2.4 a resolution. X-linked inhibitor-of-apoptosis protein (xiap) interacts with caspase-9 and inhibits its activity. 0.922 SIGNOR-98988 HMOX2 protein P30519 UNIPROT HBA1 protein P69905 UNIPROT down-regulates activity 9606 10490932 YES Regulation miannu Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme 0.255 SIGNOR-251814 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation 9606 10212258 YES gcesareni C-abl phosphorylates rad51 in vitro and in vivo. In assays using purified components, phosphorylation of rad51 by c-abl enhances complex formation between rad51 and rad52, which cooperates with rad51 in recombination and repair 0.772 SIGNOR-67069 PIN4 protein Q9Y237 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity isomerization 9606 BTO:0000599 23720771 YES lperfetto In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events 0.2 SIGNOR-265756 oxytocin smallmolecule CHEBI:7872 ChEBI OXTR protein P30559 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257556 GSK3B protein P49841 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21821001 NO miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. 0.338 SIGNOR-261903 EEF1A1P5 protein Q5VTE0 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269557 PPP2CA protein P67775 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 17079228 YES gcesareni Our results demonstrate that pp6 specifically down-regulates tak1 through dephosphorylation of thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via tak1 signaling pathways. 0.329 SIGNOR-150369 ABI1 protein Q8IZP0 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9010225 YES gcesareni Our results are in agreement with previous report showing that abi-1, the putative mouse homologue of e3b1, is a abl binding protein 0.88 SIGNOR-45994 IKBKB protein O14920 UNIPROT RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Ser209 KPLPDHVsIVEPKDE 9606 21399639 YES miannu IKKbeta overexpression activated NF-kappaB measured by luciferase assays , and also induced the nuclear translocation of wild-type, but not S209A, RPS3 (XREF_FIG).|Therefore, RPS3 S209 phosphorylation by IKK\u03b2 is apparently required for RPS3 in directing NF-\u03baB to a specific subset of target genes. 0.333 SIGNOR-278360 PABPC3 protein Q9H361 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 YES lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. 0.8 SIGNOR-268321 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr503 EAHPNDLyVEGLPEN 9534 11373296 YES lperfetto These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation. 0.517 SIGNOR-108346 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRB protein P10828 UNIPROT up-regulates activity binding 9606 BTO:0001073 29407449 YES scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. 0.8 SIGNOR-267254 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr581 SDGHEYIyVDPMQLP 9606 BTO:0000599 9642269 YES miannu We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins. 0.2 SIGNOR-250255 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT up-regulates transcriptional regulation 9606 19254573 NO fspada Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression. 0.392 SIGNOR-209968 SMURF1 protein Q9HCE7 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002181 15817471 YES In the presence of smad6 or smad7 acting as adaptors lperfetto Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes. 0.744 SIGNOR-236096 SENP1 protein Q9P0U3 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates activity desumoylation 9606 BTO:0000007 21791615 YES miannu We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation. 0.469 SIGNOR-262681 ITGB1BP1 protein O14713 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.282 SIGNOR-257653 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 23290138 YES Simone Vumbaca Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions 0.677 SIGNOR-255646 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr300 TPVVSVAtPTLPGQG 9606 9858528 YES The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain 0.695 SIGNOR-62796 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser19 PAPPVRMsSTIFSTG -1 10075701 YES miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites 0.2 SIGNOR-250224 ATP5PO protein P48047 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261403 MYOG protein P15173 UNIPROT PAX7 protein P23759 UNIPROT down-regulates quantity by destabilization 10090 BTO:0004058 17548510 NO Simone Vumbaca Indeed, we observed a reduction in Pax7 protein levels upon ectopic myogenin expression in MM14 myoblasts, even under proliferation conditions 0.49 SIGNOR-255638 HSP90AA1 protein P07900 UNIPROT NOS3 protein P29474 UNIPROT up-regulates binding 9606 9580552 YES miannu The binding of hsp90 to enos enhances the activation of enos. 0.759 SIGNOR-57211 PARP1 protein P09874 UNIPROT CHD2 protein O14647 UNIPROT up-regulates quantity binding 9606 26895424 YES miannu Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage. 0.2 SIGNOR-264526 GALR2 protein O43603 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-256884 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2Q1 protein Q7Z7E8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.458 SIGNOR-271338 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT up-regulates activity phosphorylation Tyr417 LVPKENDyESISDLQ 9534 16920712 YES miannu Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn. 0.725 SIGNOR-262899 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 21084559 YES lperfetto Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. 0.554 SIGNOR-232098 GSK3A protein P49840 UNIPROT GPSM3 protein Q9Y4H4 UNIPROT down-regulates quantity by destabilization phosphorylation Ser35 STTRPWRsAPPSPPP 9606 BTO:0000876 22843681 YES lperfetto Co-immunoprecipitation of endogenous GPSM3 and 14-3-3 proteins from the human monocytic cell line THP-1 suggests basal phosphorylation of GPSM3 at serine 35 as potentially mediated by GSK3alpha. The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins. 0.2 SIGNOR-264863 ZBTB20 protein Q9HC78 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23776228 YES miannu Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses α-fetoprotein gene transcription in liver. 0.44 SIGNOR-266867 TRIM3 protein O75382 UNIPROT GKAP1 protein Q5VSY0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 20352094 YES miannu Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites. 0.248 SIGNOR-271959 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 YES flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. 0.36 SIGNOR-75926 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 8548810 YES amattioni The c-iaps associate with traf1 and traf2 0.892 SIGNOR-39596 Ubiquitinated-Viral_Protein complex SIGNOR-C427 SIGNOR 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 9606 15571818 YES scontino The proteasome system is the central proteolytic system of the eukaryotic cell [1] and plays an important role in the generation of MHC-class I peptides. The enzyme complex responsible for the selectivity of intracellular protein degradation is the 26S proteasome that degrades poly-ubiquitinated substrates. 0.2 SIGNOR-267767 SAGA complex complex SIGNOR-C465 SIGNOR H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269643 ROBO2 protein Q9HCK4 UNIPROT CFL1 protein P23528 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 16226035 YES miannu Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. 0.257 SIGNOR-268378 RPS6 protein P62753 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.888 SIGNOR-262418 JUN protein P05412 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 19299913 NO lperfetto Promoter deletion and reporter analysis revealed that hypoxia transcriptionally activates a GADD153 promoter through the AP-1 element in neonatal cardiomyocytes. Ectopic overexpression of GADD153 resulted in the downregulation of CARP expression. 0.592 SIGNOR-254123 SMARCB1 protein Q12824 UNIPROT SMARCA4 protein P51532 UNIPROT up-regulates activity binding 9606 10078207 YES miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. 0.943 SIGNOR-65438 GNAI1 protein P63096 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates 9606 23994464 NO apalma The G alpha I subunit inhibits adenylyl cyclase activity and therefore reduces cytoplasmic cAMP levels 0.8 SIGNOR-255008 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Thr431 ASTLDEAtPTLTNQS 9606 19393267 YES lperfetto Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1. 0.823 SIGNOR-185584 PRKCE protein Q02156 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 BTO:0000150;BTO:0001130;BTO:0000551 23542175 YES lperfetto We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation 0.2 SIGNOR-201600 MTARC1 protein Q5VT66 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity chemical modification 9606 24500710 YES miannu our results indicate that mARC can generate nitric oxide (NO) from nitrite when forming an electron transfer chain with NADH, cytochrome b5, and NADH-dependent cytochrome b5 reductase. expression of mARC-1 in HEK cells using a lentivirus vector was used to confirm cellular nitrite reduction to NO. 0.8 SIGNOR-261419 CREB5 protein Q02930 UNIPROT MX1 protein P20591 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002807 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253800 FCAR protein P24071 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 BTO:0000130;BTO:0000801;BTO:0000876;BTO:0000399 30766540 NO lperfetto IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages 0.7 SIGNOR-264862 dacomitinib chemical CHEBI:132268 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates chemical inhibition 9606 23405260 YES inferred from 70% of family members gcesareni The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor. 0.8 SIGNOR-269871 GRM5 protein P41594 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. 0.8 SIGNOR-264936 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 17634129 YES lperfetto The activity of Cdc2 is regulated by the phosphatase Cdc25C. Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis.|Cdc2 is activated by Cdc25C that removes phosphate groups from tyrosine 15 and threonine 14 .|Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis. 0.858 SIGNOR-276945 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr313 HGSGWAEtPRTDRGG 9606 12105215 YES lperfetto We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1 0.346 SIGNOR-216717 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation 9606 17900900 YES lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. 0.411 SIGNOR-252889 CSNK1A1L protein Q8N752 UNIPROT GLI3 protein P10071 UNIPROT up-regulates phosphorylation 9606 16481469 YES gcesareni Ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed 0.334 SIGNOR-144554 CSF2RA protein P15509 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 8977526 YES lperfetto JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation. 0.531 SIGNOR-249502 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Arg737 LAAALGIrSFRNSSL -1 10026263 YES lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 0.882 SIGNOR-263632 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr72 SDDFDSDyENPDEHS 9606 BTO:0000776 12456653 YES llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. 0.805 SIGNOR-96044 ESR1 protein P03372 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 NO miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice 0.2 SIGNOR-253469 NUAK1 protein O60285 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 21317932 YES gcesareni Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo. 0.545 SIGNOR-172012 ADRA2C protein P18825 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.479 SIGNOR-256699 BNIP3 protein Q12983 UNIPROT RHEB protein Q15382 UNIPROT down-regulates binding 9606 17928295 YES gcesareni Bnip3, a hypoxia-inducible bcl-2 homology 3 domain-containing protein, directly binds rheb and inhibits the mtor pathway. Bnip3 decreases rheb gtp levels in a manner depending on the binding to rheb. 0.75 SIGNOR-158274 EFNA1 protein P20827 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9576626 YES tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity 0.822 SIGNOR-56907 AURKA protein O14965 UNIPROT AURKA protein O14965 UNIPROT up-regulates phosphorylation Thr288 APSSRRTtLCGTLDY 9606 24867643 YES lperfetto The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability 0.2 SIGNOR-205106 ERBB4 protein Q15303 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 YES gcesareni Like erbb1, erbb4 recruits grb2, shc and stat5. 0.496 SIGNOR-146891 MAP3K14 protein Q99558 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C14 9520446 YES gcesareni Activation of the transcription factor nf-kappab by inflammatory cytokines involves the successive action of nf-kappab-inducing kinase (nik) and two ikappab kinases, ikk-alpha and ikk-beta. Here we show that nik preferentially phosphorylates ikk-alpha over ikk-beta 0.714 SIGNOR-55949 RCAN1 protein P53805 UNIPROT PPP3CA protein Q08209 UNIPROT down-regulates activity binding 9606 12554096 YES MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure 0.634 SIGNOR-252025 SPC25 protein Q9HBM1 UNIPROT RIOK1 protein Q9BRS2 UNIPROT up-regulates activity binding 9606 BTO:0000948 39488790 YES miannu This study demonstrates that SPC25 acts as a molecular scaffold, mediating SPC25/RIOK1/MYH9 complex formation and triggering the RIOK1‐mediated phosphorylation of MYH9 at Ser1943.Taken together, these results suggested that SPC25 increases MYH9 phosphorylation at Ser1943, enhancing the nuclear accumulation of MYH9 and consequently modulating the transcription of CTNNB1. 0.2 SIGNOR-278893 SPC25 protein Q9HBM1 UNIPROT MYH9 protein P35579 UNIPROT up-regulates activity binding 9606 BTO:0000949 39488790 YES miannu This study demonstrates that SPC25 acts as a molecular scaffold, mediating SPC25/RIOK1/MYH9 complex formation and triggering the RIOK1‐mediated phosphorylation of MYH9 at Ser1943.Taken together, these results suggested that SPC25 increases MYH9 phosphorylation at Ser1943, enhancing the nuclear accumulation of MYH9 and consequently modulating the transcription of CTNNB1. 0.2 SIGNOR-278894 hsa-miR-506-5p mirna URS000051D911_9606 RNAcentral SPHK1 protein Q9NYA1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 26549227 YES Parnian We conclude that miR-506 depresses the angiogenesis of liver cancer through targeting 3' UTR of SPHK1 mRNA. 0.4 SIGNOR-278860 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.6 SIGNOR-34661 quinpirole chemical CHEBI:75401 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 YES miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. 0.8 SIGNOR-258441 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Thr338 VPVKSRKtTLEQPPS 9606 BTO:0001061 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276775 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser171 SALNRTSsDSALHTS 9606 BTO:0000567 16306228 YES lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 0.633 SIGNOR-249172 RNF5 protein Q99942 UNIPROT SLC26A4 protein O43511 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22750442 YES miannu E3 ubiquitin ligase Rma1 is involved in Pendrin degradation 0.2 SIGNOR-271497 SEMA7A protein O75326 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 10090 17377534 YES lperfetto Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin. 0.545 SIGNOR-253249 PHF3 protein Q92576 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR down-regulates activity binding 9606 BTO:0000007 34667177 YES miannu PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2 0.341 SIGNOR-266964 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000393 21903638 YES gcesareni It has been shown that wnt5a activates the calcium signaling pathway in the presence of receptor fz2, 3, 4, 6 and receptor fz 5. 0.706 SIGNOR-176579 PTK2B protein Q14289 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 16760434 YES gcesareni Activated rock phosphorylates fak on ser732, which is essential for phosphorylation of tyr407 and for cell migration. We further show that pyk2 is activated by vegf-induced clustering of integrin v 3 and is responsible for the phosphorylation of tyr407. 0.523 SIGNOR-147070 TGFBR1 protein P36897 UNIPROT VPS39 protein Q96JC1 UNIPROT up-regulates activity binding 9534 12941698 YES miannu TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling. 0.2 SIGNOR-261375 AGTR1 protein P30556 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000007 20181817 NO Stimulation of AT1 R Induces Membrane Blebbing. 0.7 SIGNOR-278126 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12429016 YES gcesareni Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge. 0.512 SIGNOR-95524 HARS1 protein P12081 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 10430027 YES miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 0.8 SIGNOR-270488 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 31422819 YES miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-267511 CDON protein Q4KMG0 UNIPROT SPAG9 protein O60271 UNIPROT up-regulates activity binding 9606 BTO:0000222 18678706 YES p38 together with Bnip-2 and CDC42 to activate p38alfa/beta activity lperfetto During myoblast differentiation, the promyogenic cell surface receptor cdo binds to the p38alpha/beta pathway scaffold protein jlp and, via jlp, p38alpha/beta itself. 0.496 SIGNOR-179870 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 15694340 YES gcesareni Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.. Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1 0.819 SIGNOR-133823 PRKAA1 protein Q13131 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates activity phosphorylation Ser257 GLHRAEQsLHDLQER 10090 BTO:0000452 31381180 YES miannu STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE 0.2 SIGNOR-277299 PINK1 protein Q9BXM7 UNIPROT TRAP1 protein Q12931 UNIPROT up-regulates activity phosphorylation 9606 28358377 YES miannu This would mean that PINK1 knockdown should reduce TRAP1 activity, thereby potentiating BAY induced cell death.|PINK1 can phosphorylate TRAP1 to prevent apoptosis induced by oxidative stress. 0.613 SIGNOR-278186 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19763573 NO miannu PSC833, cyclosporine analogue, downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB. 0.262 SIGNOR-254654 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258466 PARP1 protein P09874 UNIPROT SERPINF1 protein P36955 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001949 18312852 NO miannu Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs. 0.2 SIGNOR-254891 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr842 DIMSDSNyVVRGNAR 10090 BTO:0001516 28271164 YES lperfetto Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD|Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. 0.2 SIGNOR-271924 IKBKE protein Q14164 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation Ser471 GTQREGVsSLDSSSL 9606 10893229 YES gcesareni In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3. 0.686 SIGNOR-79139 PDGFRB protein P09619 UNIPROT GRK5 protein P34947 UNIPROT up-regulates activity phosphorylation 9606 19092051 YES miannu Purified GRK5 was tyrosine-phosphorylated by the wild-type PDGFRbeta to a stoichiometry of 0.8 mol phosphate/mol GRK5, an extent approximately 5 times greater than observed with a Y857F PDGFRbeta mutant that fails to phosphorylate exogenous substrates but autophosphorylates and activates Src normally.|We conclude that GRK5 tyrosyl phosphorylation is required for the activation of GRK5 by the PDGFRbeta, but not by the beta(2)-adrenergic receptor, and that by activating GRK5, the PDGFRbeta triggers its own desensitization. 0.2 SIGNOR-279642 PIK3C3 protein Q8NEB9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates relocalization 9606 10698680 YES lperfetto One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1). 0.435 SIGNOR-252632 PABPC1 protein P11940 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR up-regulates activity binding 9606 30209168 YES miannu The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling 0.826 SIGNOR-260943 CREB1 protein P16220 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10540320 NO miannu Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter 0.429 SIGNOR-254522 NEDD4L protein Q96PU5 UNIPROT TTYH3 protein Q9C0H2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18577513 YES miannu Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein.  0.2 SIGNOR-272633 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity relocalization 9606 27871158 YES lperfetto Integrin αIIbβ3 is retained by the actin cytoskeleton in resting platelets but is released to the cell surface during platelet activation.  0.7 SIGNOR-261864 NLGN4Y protein Q8NFZ3 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 YES brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. 0.2 SIGNOR-264190 CSNK2A1 protein P68400 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Ser267 PPTTSSDsEEEQEDE 9606 BTO:0000007 22025562 YES miannu  Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation. 0.504 SIGNOR-276388 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0001538 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.73 SIGNOR-252759 MECP2 protein P51608 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001412 19781662 NO Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. 0.2 SIGNOR-254062 ATP(4-) smallmolecule CHEBI:30616 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 19286649 YES miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. 0.8 SIGNOR-268084 RNF216 protein Q9NWF9 UNIPROT TLR4 protein O00206 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15107846 YES miannu Here we describe how a RING finger protein, Triad3A, acts as an E3 ubiquitin-protein ligase and enhances ubiquitination and proteolytic degradation of some TLRs. Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling.  0.389 SIGNOR-271504 SMO protein Q99835 UNIPROT GNG3 protein P63215 UNIPROT up-regulates binding 9606 16885213 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.2 SIGNOR-148598 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 16977332 YES lperfetto Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP. 0.791 SIGNOR-149574 GSK3B protein P49841 UNIPROT PPIF protein P30405 UNIPROT up-regulates activity phosphorylation Ser191 IESFGSKsGRTSKKI 9606 BTO:0000007 32814770 YES lperfetto Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion|We conclude that CypD phosphorylation at S191 residue leads to its binding to OSCP and thus sensitizes mPTP opening for the subsequent cell death.|Under baseline condition (WT group), the phosphorylation of CypD by a kinase (e.g. GSK3beta) at S191 induces its translocation to the OSCP, to favor mPTP opening and subsequent cell death at reperfusion. 0.378 SIGNOR-264880 PLK1 protein P53350 UNIPROT PRC1 protein O43663 UNIPROT down-regulates activity phosphorylation 9606 22621898 YES miannu Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis.|Plk1, but not Cdk1, phosphorylates PRC1 on Thr-602 to prevent premature midzone assembly in metaphase. 0.722 SIGNOR-279645 PLK1 protein P53350 UNIPROT TEX14 protein Q8IWB6 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 22405274 YES miannu In addition, we demonstrate that phosphorylation of Tex14 by Plk1 during metaphase promotes APC Cdc20 -mediated Tex14 degradation. 0.354 SIGNOR-279646 entacapone chemical CHEBI:4798 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000759 9681662 YES Simone Vumbaca Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P=0.008), respectively, in the liver; consistent results were obtained with the other tissues. 0.8 SIGNOR-261088 PCDH19 protein Q8TAB3 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity by stabilization binding 10116 BTO:0003102 29360992 YES miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  0.2 SIGNOR-267216 GLI3 protein P10071 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 NO gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. 0.586 SIGNOR-188878 IKBKE protein Q14164 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation Ser472 TQREGVSsLDSSSLS 9606 10893229 YES gcesareni In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3. 0.686 SIGNOR-79143 CCNC protein P24863 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15546612 NO gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. 0.2 SIGNOR-130589 Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 23142081 YES miannu  We provide evidence that mTORC2 can stabilize Fbw8, the substrate-targeting subunit of the CUL7 E3 ligase complex that has been shown to mediate degradation of IRS-1 . 0.347 SIGNOR-271941 EBNA1 protein P03211 UNIPROT STAT1 protein P42224 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007;BTO:0006136 17486072 NO scontino EBNA1 enhances the expression and activity of STAT1. EBNA1 also induced STAT1 expression, with associated enhancement of IFNγ-induced activation. The ability of EBNA1 to enhance IFNγ-induced STAT1 signaling was observed at the protein level by enhanced nuclear translocation of STAT1 (Figure 3b) and at the transcriptional level. 0.2 SIGNOR-267614 1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid chemical CHEBI:93185 ChEBI SLC6A1 protein P30531 UNIPROT down-regulates activity chemical inhibition -1 7851497 YES miannu Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. 0.8 SIGNOR-258480 PRKACA protein P17612 UNIPROT CACNA1H protein O95180 UNIPROT down-regulates activity phosphorylation Ser1144 AWSSRRSsWSSLGRA 9606 19131331 YES miannu Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity. 0.2 SIGNOR-263111 INS protein P01308 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity 9606 10358076 NO lperfetto Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect. 0.479 SIGNOR-68155 AKT proteinfamily SIGNOR-PF24 SIGNOR PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation -1 16340011 YES gcesareni It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase. 0.2 SIGNOR-252740 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Thr233 DDEDDSGtEES 9606 11546811 YES lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. 0.395 SIGNOR-110407 NTN1 protein O95631 UNIPROT DSCAM protein O60469 UNIPROT up-regulates activity binding 10090 BTO:0001279 18585357 YES miannu Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1. 0.733 SIGNOR-268376 NR1I3 protein Q14994 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18303024 NO miannu The CYP2B6 enzyme metabolizes commonly used therapeutics and also activates pro-drugs. The CAR directly binds to the distal enhancer element of the CYP2B6 promoter, which is essential in converging to its drug-sensing function onto promoter activity. However, this binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter. 0.471 SIGNOR-253875 TGFb proteinfamily SIGNOR-PF5 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates 9606 SIGNOR-C9 12524424 NO fspada Because tgf-beta inhibits adipogenesis by signaling through smad3, we examined physical and functional interactions of smad3 and smad4 with c/ebpbeta, c/ebpdelta, and ppargamma2. 0.2 SIGNOR-97123 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr978 AEMSIMTtELQSLCS 9606 18055457 YES lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta 0.272 SIGNOR-159586 CAPN1 protein P07384 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Lys32 RARRPESkATNATLD -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus 0.377 SIGNOR-263559 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E2 complex SIGNOR-C497 SIGNOR form complex ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270839 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr1197 LESEEELySSCRQLR 9606 BTO:0000776 11507089 YES lperfetto These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2. 0.777 SIGNOR-109746 AKT2 protein P31751 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 YES lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. 0.302 SIGNOR-217673 LCK protein P06239 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000782 14583609 YES gcesareni Endogenous notch-1 associates with p56(lck) and pi3k. p56(lck) is required for the notch-1-mediated activation of akt/pkb function 0.457 SIGNOR-118902 tRNA(Asp) smallmolecule CHEBI:29186 ChEBI Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270377 SOX4 protein Q06945 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001271 24183681 NO apalma Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors. 0.7 SIGNOR-255676 PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0001271 20596030 NO lperfetto Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. 0.635 SIGNOR-166478 ACOT4 protein Q8N9L9 UNIPROT glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI down-regulates quantity chemical modification 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271818 serotonin smallmolecule CHEBI:28790 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264288 6 protein P59634 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity relocalization 9606 17108024 NO miannu ORF 6 protein inhibits the translocation of STAT1.SARS-CoV ORF 6 protein, but not ORF 3b or N protein, was able to inhibit the translocation of STAT1-GFP to the nucleus. A higher magnification of the image of ORF 6 protein in cells transfected with STAT1-GFP and treated with IFN-β shows that ORF 6 protein does not colocalize with STAT1, indicating that ORF 6 does not directly interact with STAT1 0.2 SIGNOR-260341 MAPK3 protein P27361 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser333 KGLVSPQsPQKSDCQ 9606 BTO:0000782;BTO:0000785 9649500 YES gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. 0.406 SIGNOR-58489 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR RBPMS protein Q93062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 NO miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The gene for the RNA‐binding protein with multiple splicing (RBPMS) was upregulated in NUP98‐HOXA9–transduced cord blood CD34+ cells and also in the transcriptosomes of normal CD34+ and CD133+ cells. 0.2 SIGNOR-261503 MAPK15 protein Q8TD08 UNIPROT MAPK15 protein Q8TD08 UNIPROT up-regulates phosphorylation Thr175 GPEDQAVtEYVATRW 9606 16336213 YES lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation 0.2 SIGNOR-142969 AURKA protein O14965 UNIPROT WDR62 protein O43379 UNIPROT up-regulates activity phosphorylation Ser33 PARRGQSsPPPAPPI -1 25501809 YES lperfetto AURKA activity promotes WDR62 spindle localization|We next purified recombinant full-length WDR62 (GST–WDR62-FL) for in vitro kinase assays with active AURKA and demonstrated that WDR62 was a direct phosphorylation target of AURKA|In addition, our quantitative phosphoproteomic analysis of in-vitro-phosphorylated WDR62 identified S32 and S33 as significantly phosphorylated in the presence of active AURKA|Alanine replacement of the five putative phosphorylation sites (S32/S33/S49/T50/S52-AAAAA) of WDR62 attenuated interphase microtubule association induced by AURKA coexpression 0.352 SIGNOR-271713 RIPK1 protein Q13546 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT up-regulates activity phosphorylation Ser728 PSPARSSsYSEANEP 9606 27858941 YES miannu Upon TNF stimulation, RIP1 phosphorylates DAB2IP on Serine 604, inducing a conformational switch that allows formation of the complex. 0.427 SIGNOR-254763 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT up-regulates activity phosphorylation Thr119 GAARVIGtLLGTVDK 19245811 YES lperfetto Here, we identified a second eIF3f phosphorylation site (Thr119) by CDK11(p46) during apoptosis. We demonstrated that eIF3f is directly phosphorylated by CDK11(p46) in vivo. Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis.  0.516 SIGNOR-273131 MSL3 protein Q8N5Y2 UNIPROT MSL acetyltransferase complex SIGNOR-C344 SIGNOR form complex binding 9606 BTO:0000567 16227571 YES miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 0.822 SIGNOR-263940 Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 NO miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.7 SIGNOR-270882 EIF2B1 protein Q14232 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.693 SIGNOR-269134 PRKCG protein P05129 UNIPROT GRIN1 protein Q05586 UNIPROT up-regulates activity phosphorylation Ser890 ITSTLASsFKRRRSS 10116 BTO:0000938 15936117 YES miannu Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890. 0.352 SIGNOR-263176 Ub:E2 complex SIGNOR-C497 SIGNOR UNK protein Q9C0B0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271219 BDKRB2 protein P30411 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.4 SIGNOR-256838 NOX4 protein Q9NPH5 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.8 SIGNOR-264724 CUDC-101 chemical CID:24756910 PUBCHEM HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262262 FBXO21 protein O94952 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by destabilization binding -1 26299618 YES miannu Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation.Purified in vitro translated FLAG-tagged P-gp along with E2 (UbcH5c), E3 ligase FBXO21, Cul1, Skp1, Roc1 purified from Sf-9 insect cells were incubated in vitro. 0.325 SIGNOR-272422 MAPK14 protein Q16539 UNIPROT NFATC4 protein Q14934 UNIPROT down-regulates activity phosphorylation Ser170 GGAFFSPsPGSSSLS 10029 BTO:0001131 11997522 YES miannu P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity. 0.403 SIGNOR-250108 STING1 protein Q86WV6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 YES miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. 0.2 SIGNOR-260153 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 YES lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. 0.968 SIGNOR-80528 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB8 protein P26012 UNIPROT up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.2 SIGNOR-259012 AKT1 protein P31749 UNIPROT TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 YES gcesareni Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. 0.731 SIGNOR-67317 MAPK1 protein P28482 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Thr753 YACASPKtPIQAGGY 10116 BTO:0001009 16508002 YES lperfetto Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. 0.627 SIGNOR-236388 sumatriptan chemical CHEBI:10650 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 10193663 YES Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  0.8 SIGNOR-258340 CAMK2A protein Q9UQM7 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Ser155 CLEDIHTsRVVAHVL 9606 17568776 YES lperfetto Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53 0.297 SIGNOR-156064 MRPL21 protein Q7Z2W9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.713 SIGNOR-262372 MAPK7 protein Q13164 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser78 ANPSPPPsPSQQINL 9606 11254654 YES lperfetto Bmk1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinasebmk1 activates sgk by phosphorylation at serine 78. 0.389 SIGNOR-105728 RHEB protein Q15382 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates binding 9606 18550814 YES gcesareni Rheb binds and activates pld1 in vitro in a gtp-dependent manner, strongly suggesting that pld1 is a bona fide effector for rheb. 0.538 SIGNOR-178892 SP1 protein P08047 UNIPROT ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 NO We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. 0.2 SIGNOR-255748 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 YES gcesareni Receptor internalization, altered;intracellular localization 0.568 SIGNOR-97554 ATM protein Q13315 UNIPROT ELF4 protein Q99607 UNIPROT down-regulates activity phosphorylation 9606 21616937 YES miannu Elf4 is phosphorylated by Atm after gamma irradiation, leading to its degradation.|Thus, Atm promotes Elf4 protein degradation after gamma irradiation via phosphorylation at these sites. 0.35 SIGNOR-278466 TLE1 protein Q04724 UNIPROT SIX3 protein O95343 UNIPROT up-regulates activity binding -1 12441302 YES lperfetto Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation 0.401 SIGNOR-234595 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258917 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM50 protein Q86XT4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271190 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258820 AKT1 protein P31749 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation Ser674 PGRERGEsPTTPPTP 9606 BTO:0000938 12458207 YES lperfetto Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation. 0.401 SIGNOR-252592 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 10660534 YES lperfetto Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function 0.727 SIGNOR-74848 MAPK7 protein Q13164 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 0.43 SIGNOR-255455 L-ornithine smallmolecule CHEBI:15729 ChEBI M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates activity 25386178 NO apalma In general, M2 type macrophages act as anti-inflammatory cells via diversion of arginine away from NOS or via the synthesis of downstream products derived from the ornithine that is generated via arginase 0.7 SIGNOR-256075 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr332 ILAIHDSyKPEFHSD 10029 BTO:0000246 12907755 YES PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 0.295 SIGNOR-248391 Hexocyclium chemical CHEBI:5707 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258389 MAPK1 protein P28482 UNIPROT TCF3 protein P15923 UNIPROT down-regulates quantity by destabilization phosphorylation Thr355 NFSSSPStPVGSPQG 10090 14592976 YES lperfetto Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG) 0.361 SIGNOR-249451 CSF1 protein P09603 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000876 BTO:0001103 24890514 YES apalma The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34) 0.938 SIGNOR-255568 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-142153 PRKACA protein P17612 UNIPROT GABBR2 protein O75899 UNIPROT down-regulates activity phosphorylation Ser893 EHIQRRLsLQLPILH 9534 BTO:0001538 11976702 YES miannu Here we show that the functional coupling of GABA(B)R1/GABA(B)R2 receptors to inwardly rectifying K(+) channels rapidly desensitizes. This effect is alleviated after direct phosphorylation of a single serine residue (Ser892) in the cytoplasmic tail of GABA(B)R2 by cyclic AMP (cAMP)-dependent protein kinase (PKA). 0.2 SIGNOR-263150 PTPN11 protein Q06124 UNIPROT SLC25A4 protein P12235 UNIPROT down-regulates activity dephosphorylation 9606 29255148 YES miannu Specifically, SHP2-mediated dephosphorylation of ANT1 at Tyr 191 is essential for mitochondrial homeostasis and mitigation of NLRP3 inflammasome activation.|The interaction between SHP2 and ANT1 (Fig.\u00a0 xref ), and the opposite effects of SHP2 and ANT1 shRNAs in the activation of NLRP3 inflammasome (Figs.\u00a0 xref and xref ) raised the possibility that the SHP2 may inhibit ANT1 to suppress NLRP3 inflammasome activation.|To further determine which tyrosine phosphorylation site of ANT1 is dephosphorylated by SHP2, we created the dephosphorylated mutant of ANT1, in which tyrosine was replaced with phenylalanine (Y to F mutation). 0.271 SIGNOR-277124 STK38L protein Q9Y2H1 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Ser282 NRRQLAYsTVGTPDY 9606 BTO:0000007 16314523 YES lperfetto Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity. 0.2 SIGNOR-142518 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates activity chemical inhibition -1 23515850 YES lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro 0.8 SIGNOR-262024 SMURF1 protein Q9HCE7 UNIPROT ODF2 protein Q5BJF6 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272683 ANK2 protein Q01484 UNIPROT CACNA1A protein O00555 UNIPROT up-regulates quantity binding 10090 24394417 YES miannu Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo. 0.263 SIGNOR-266706 CEP135 protein Q66GS9 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates activity binding -1 27477386 YES miannu Here, we analyzed in detail the microtubule-binding activity of human CEP135 (HsCEP135).  Biochemical, cryo-electron, and fluorescence microscopy analyses revealed that in vitro HsCEP135-N interacts with tubulin, protofilaments, and microtubules and induces the formation of microtubule bundles 0.2 SIGNOR-269678 SH3GLB1 protein Q9Y371 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 BTO:0000567 16227588 YES gcesareni Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change. 0.33 SIGNOR-141166 EEF1B2 protein P24534 UNIPROT EEF1B complex complex SIGNOR-C460 SIGNOR form complex binding 9606 23699257 YES lperfetto An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively) 0.829 SIGNOR-269390 AURKB protein Q96GD4 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr799 PPKLRRRtFSLTEVR -1 28992084 YES miannu Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis. 0.518 SIGNOR-265992 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser338 PAPKLVEsPKEGKGS 9534 BTO:0000298 14623875 YES llicata DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase. 0.573 SIGNOR-251088 SPOP protein O43791 UNIPROT INF2 protein Q27J81 UNIPROT down-regulates activity binding 9606 BTO:0000007 28448495 YES miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 0.2 SIGNOR-272798 SMARCB1 protein Q12824 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.898 SIGNOR-132930 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by stabilization phosphorylation 9606 24142698 YES inferred from family member Manara Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. 0.371 SIGNOR-270287 PITX3 protein O75364 UNIPROT MTA1 protein Q13330 UNIPROT up-regulates activity binding 9606 BTO:0000567 SIGNOR-C123 21368136 YES 1 miannu we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. 0.325 SIGNOR-239770 ADSS1 protein Q8N142 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 10496970 NO miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.7 SIGNOR-267835 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR KLC1 protein Q07866 UNIPROT down-regulates phosphorylation 9606 21385839 YES inferred from 70% family members gcesareni Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro. 0.2 SIGNOR-270176 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 9528863 YES gcesareni Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4. 0.746 SIGNOR-56365 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Ser273 RPASVNGsPSATSES 9606 BTO:0000007 16446428 YES gcesareni Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222 0.654 SIGNOR-249580 SHANK3 protein Q9BYB0 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates quantity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264700 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr299 AGLTPPTtPPHKANQ 9606 BTO:0000887 11741533 YES gcesareni Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298 0.584 SIGNOR-112774 TCF3 protein P15923 UNIPROT BBC3 protein Q96PG8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23684607 NO miannu The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins. 0.272 SIGNOR-255386 TARBP2 protein Q15633 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR form complex binding 9606 16142218 YES lperfetto Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer. 0.904 SIGNOR-140229 MTOR protein P42345 UNIPROT ELP1 protein O95163 UNIPROT up-regulates activity phosphorylation Ser1174 SETSSVVsGSEMSGK 29925953 YES lperfetto Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174 0.2 SIGNOR-275541 ITK protein Q08881 UNIPROT HAVCR2 protein Q8TDQ0 UNIPROT up-regulates activity phosphorylation Tyr265 IRSEENIyTIEENVY 9606 BTO:0000007 17069754 YES miannu When we tested the effect of ITK on the Y265 mutant, we found a pronounced reduction of ITK-mediated tyrosine phosphorylation, suggesting that Y265 is specifically phosphorylated by ITK (Fig. 3B). Our results demonstrate that specific phosphorylation of Y265 of Tim-3 occurs in the presence of galectin-9, probably through a receptor-ligand interaction. Phosphorylation of Y265, which is situated in a highly conserved SH2 binding domain, could result in the recruitment of SH2 containing adaptor proteins and trigger downstream signalling events regulating the fate of Tim-3 expressing T-cells. 0.31 SIGNOR-273644 CCND1 protein P24385 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR form complex binding 9606 7736585 YES gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, 0.964 SIGNOR-32298 Osmotic_stress stimulus SIGNOR-ST28 SIGNOR TARDBP protein Q13148 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 NO We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne 0.7 SIGNOR-262818 NUP107 protein P57740 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.823 SIGNOR-262090 RFXANK protein O14593 UNIPROT RFX complex complex SIGNOR-C104 SIGNOR form complex binding -1 10825209 YES miannu RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes 0.812 SIGNOR-221571 PI-103 chemical CHEBI:90524 ChEBI PIK3CA protein P42336 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258266 GNRH1 protein P01148 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19106114 NO miannu GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. 0.442 SIGNOR-254917 MEF2C protein Q06413 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000167 15356291 NO miannu Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential. 0.2 SIGNOR-254583 HNRNPU protein Q00839 UNIPROT GADD45A protein P24522 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 NO lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. 0.337 SIGNOR-262282 POLD1 protein P28340 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR form complex binding -1 12403614 YES lperfetto Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme. 0.925 SIGNOR-265518 alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P. 0.8 SIGNOR-266460 ACP1 protein P24666 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 10090 17353188 YES Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3 0.322 SIGNOR-248458 EP300 protein Q09472 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 SIGNOR-C6 21131905 YES fspada These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. 0.2 SIGNOR-265328 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation Ser334 PTYQRRGsLQLWQFL 9606 12213813 YES lperfetto Pka targets er81 on ser(334) in vivo. Surprisingly, phosphorylation of ser(334) severely reduces the dna-binding ability of er81 but also enhances the transactivation potential of er81. These counteractive effects of pka phosphorylation on er81-dependent transcription may cause the selective up-regulation of promoters with high but not low affinity for er81. 0.293 SIGNOR-92455 PTPN1 protein P18031 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation 9606 15632081 YES gcesareni Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs 0.741 SIGNOR-252639 SOCS3 protein O14543 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity binding 9606 23454976 YES miannu SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition 0.731 SIGNOR-253051 ABL1 protein P00519 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr580 REDSARVyENVGLMQ 9606 18827006 YES miannu Direct phosphorylation of SHP-2 by Abl kinases (Y580) promotes sustained activation of SHP-2 signaling and proliferation, and c-Abl/Abl-Related Gene-dependent activation of tyrosine kinase X further potentiates SHP-2 signaling by phosphorylating SHP-2 on Y63.|Endogenous Abl kinases phosphorylate SHP-2 on Y580 and induce sustained ERK phosphorylation in response to PDGF. 0.374 SIGNOR-278217 VRK1 protein Q99986 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity phosphorylation Ser140 GKKATQAsQEY 9606 25923214 YES miannu In response to DNA damage induced by ionizing radiation, histone H2AX is phosphorylated in Ser139 by VRK1. 0.2 SIGNOR-278370 LNX2 protein Q8N448 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 32714586 YES miannu Notably LNX2 knockdown caused an increase in NUMB levels and decreased levels of the NOTCH2 intracellular domain , as well as decreased expression of the NOTCH target gene Hes1 .|They also showed for the first time that LNX2 could indeed ubiquitinate NUMB, something that had previously only been shown for LNX1. 0.606 SIGNOR-278818 EGFR protein P00533 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity phosphorylation Tyr153 GEEGQSIyKLTDFGA 9606 27287717 YES miannu EGFR phosphorylates IKBKE at tyrosine-153 and -179 residues.|To understand the mechanism by which IKBKE is activated by mutant EGFR, we first investigated if activating mutation of EGFR is able to form a complex with IKBKE. 0.258 SIGNOR-278223 ERBB2 protein P04626 UNIPROT BBC3 protein Q96PG8 UNIPROT down-regulates activity phosphorylation 9606 24236056 YES miannu These results show for the first time that PUMA can be phosphorylated at tyrosine residues directly by HER2.|Together, our results demonstrate, for the first time, that PUMA can be tyrosine phosphorylated and that HER2-mediated phosphorylation destabilizes PUMA protein. 0.281 SIGNOR-278224 furtrethonium chemical CHEBI:134764 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258645 FFAR2 protein O15552 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257342 CUL7 protein Q14999 UNIPROT Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR form complex binding 9606 BTO:0001109 phosphorylation:Thr286 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1  0.727 SIGNOR-271625 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.464 SIGNOR-257303 KAT2B protein Q92831 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269620 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000176 14967450 YES inferred from 70% family members lperfetto Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.2 SIGNOR-270103 IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation 0.706 SIGNOR-249506 TLR2 protein O60603 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates activity binding 10090 22664090 YES scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.429 SIGNOR-266747 LMTK2 protein Q8IWU2 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 24727471 YES miannu The present study discovered that in human airway epithelial cells CFTR endocytosis is regulated by the LMTK2-mediated phosphorylation of CFTR-Ser737 that decreases the cell surface density of CFTR Cl\u2212 channels and inhibits CFTR-mediated Cl\u2212 secretion.|Together, the above results demonstrate that the LMTK2 phosphorylation of CFTR-Ser737 facilitates CFTR endocytosis and reduces the plasma membrane abundance of CFTR in human airway epithelial cells. 0.401 SIGNOR-278227 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr676 FGMSRDIySTDYYRV 9606 9099755 YES gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 0.2 SIGNOR-47171 EIF3I protein Q13347 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 9774674 YES gcesareni Another receptor-associated protein is trip-1, which interacts with and is phosphorylated by tbrii and contains five wd-40 repeats. The association of wd-40 repeat proteins may then allow them to play a role in signaling by the serine/threonine kinase receptors. 0.325 SIGNOR-60700 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 YES esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. 0.448 SIGNOR-89225 DGC complex SIGNOR-C217 SIGNOR GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265438 PNMT protein P11086 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI down-regulates quantity chemical modification 9606 7961964 YES brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). 0.8 SIGNOR-264008 SIK2 protein Q9H0K1 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates 10090 24841198 NO lperfetto Moreover, SIK2 was shown to down-regulate the carbohydrate-responsive element-binding protein (ChREBP)-mediated lipogenesis in hepatocytes through the inhibitory phosphorylation of p300/Ser89 and to prevent steatosis in mice 0.323 SIGNOR-265746 sapitinib chemical CHEBI:132986 ChEBI ERBB3 protein P21860 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190155 FAM3C protein Q92520 UNIPROT LIFR protein P42702 UNIPROT up-regulates activity binding 9606 BTO:0000584 35680099 YES miannu Interleukin-like EMT inducer (ILEI) a cytokine from the FAM3 family, also functions as a ligand for LIFR-gp130 heterodimer and mediates intracellular signal through STAT activation. 0.2 SIGNOR-277986 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 BTO:0000680;BTO:0001573;BTO:0001286 SIGNOR-C17 14551205 YES lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex 0.49 SIGNOR-118576 CLASP1 protein Q7Z460 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity binding 9606 BTO:0000567 15631994 YES lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 0.724 SIGNOR-265091 Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 16440056 NO lperfetto Axonemal dyneins are responsible for the movement of cilia and flagella. 0.7 SIGNOR-265021 FBXO3 protein Q9UK99 UNIPROT SMURF1 protein Q9HCE7 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25721664 YES miannu F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway. 0.392 SIGNOR-272441 ITCH protein Q96J02 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity ubiquitination 10090 16469705 YES gcesareni Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation. 0.613 SIGNOR-245307 CCNY protein Q8ND76 UNIPROT CyclinY/CDK16 complex SIGNOR-C540 SIGNOR form complex binding 30992425 YES lperfetto CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that forms an active complex with cyclin Y (CCNY). 0.67 SIGNOR-273002 IST1 protein P53990 UNIPROT SPAST protein Q9UBP0 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 23897888 YES Gianni Our results suggest that inclusion of IST1 into the ESCRT complex allows recruitment of spastin to promote fission of recycling tubules from the endosome. Thus, we reveal a novel cellular role for MT severing and identify a mechanism by which endosomal recycling can be coordinated with the degradative machinery. 0.52 SIGNOR-269047 IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 YES miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. 0.8 SIGNOR-253135 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates activity phosphorylation Tyr218 PPRDFAAyRS 8992971 YES EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor. 0.689 SIGNOR-251337 INS protein P01308 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000887;BTO:0001103 8250835 NO gcesareni The results suggest that ser-9 phosphorylation underlies the reported gsk3 beta inhibition by insulin and that gsk3 may represent a point of convergence of two major growth-factor-stimulated protein kinase cascades. 0.457 SIGNOR-37220 CYP27B1 protein O15528 UNIPROT calcitriol smallmolecule CHEBI:17823 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671 12050193 YES lperfetto The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. 0.8 SIGNOR-270559 ZBTB46 protein Q86UZ6 UNIPROT Neuroendocrine cell differentiation phenotype SIGNOR-PH232 SIGNOR up-regulates 9606 BTO:0000584 30312731 NO miannu Most tumors progress to castration-resistant prostate cancer (CRPC) and develop the neuroendocrine (NE) phenotype under androgen deprivation therapy (ADT).Herein, we show that an immunocyte expression protein, ZBTB46, induces inflammatory response gene expression and contributes to NE differentiation of prostate cancer cells. ZBTB46 induces NE marker expressions of prostate cancer. 0.7 SIGNOR-277990 prostaglandin G2(1-) smallmolecule CHEBI:82629 ChEBI prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity precursor of -1 7592599 YES Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, 0.8 SIGNOR-269777 CSNK2A1 protein P68400 UNIPROT CERS5 protein Q8N5B7 UNIPROT up-regulates activity phosphorylation Ser354 DDRSDVEsSSEEEDV 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273985 EVI5 protein O60447 UNIPROT PLK1 protein P53350 UNIPROT down-regulates 9606 16439210 NO gcesareni Evi5 antagonizes scf(betatrcp)-dependent emi1 ubiquitination and destruction by binding to a site adjacent to emi1's dsgxxs degron and blocking both degron phosphorylation by polo-like kinases and subsequent betatrcp binding. 0.585 SIGNOR-143683 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 15383283 YES gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. 0.396 SIGNOR-127064 CDC7 protein O00311 UNIPROT PSIP1 protein O75475 UNIPROT up-regulates phosphorylation Ser206 MVKQPCPsESDIITE 9606 BTO:0001271;BTO:0000785 7231784 YES llicata We now report identification of the cdc7-activator of s-phase kinase (ask) heterodimer as a novel interactor of ledgf. the kinase phosphorylated ledgf in vitro, with ser-206 being the major target, and ledgf phosphorylated at this residue could be detected during s phase of the cell cycle. Ledgf potently stimulated the enzymatic activity of cdc7-ask, increasing phosphorylation of mcm2 in vitro by more than 10-fold. 0.334 SIGNOR-25763 PABPC1 protein P11940 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 YES lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. 0.8 SIGNOR-268318 SOS2 protein Q07890 UNIPROT HRAS protein P01112 UNIPROT up-regulates guanine nucleotide exchange factor 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. 0.789 SIGNOR-175262 NFKBIE protein O00221 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates binding 9606 BTO:0001271 SIGNOR-C13 12835716 YES gcesareni Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe 0.54 SIGNOR-102774 PTPN11 protein Q06124 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 YES irozzo Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. 0.659 SIGNOR-255982 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM47 protein Q96LD4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271001 PPP2CB protein P62714 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 15510216 YES Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro. 0.269 SIGNOR-248601 TP53 protein P04637 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 NO miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. 0.441 SIGNOR-255433 DPYSL2 protein Q16555 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 25040932 NO lperfetto In the non-phosphorylated state, CRMP2 binding to tubulin induces the promotion of tubulin polymerisation leading to dendrite outgrowth while 0.7 SIGNOR-264842 INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 9606 2550426 YES lperfetto Our previous studies indicated that amino acid residues 240-250 in the cysteine-rich region of the human insulin receptor alpha-subunit constitute a site in which insulin binds. 0.934 SIGNOR-23001 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Thr326 GCYSVPTtPEDFLSN 26375055 YES lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity 0.262 SIGNOR-276523 SETD5 protein Q9C0A6 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity methylation Lys37 APATGGVkKPHRYRP -1 31515109 YES miannu SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. 0.2 SIGNOR-264620 DLX5 protein P56178 UNIPROT MSX2 protein P35548 UNIPROT down-regulates activity binding 10090 BTO:0000947 9111364 YES 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. 0.57 SIGNOR-240925 SNUPN protein O95149 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR up-regulates quantity relocalization 9606 BTO:0000567 9670026 YES miannu Here, we describe the isolation and cDNA cloning of a 45 kDa protein, termed snurportin1, which interacts specifically with m3G-cap but not m7G-cap structures. Snurportin1 enhances the m3G-capdependent nuclear import of U snRNPs in both Xenopus laevis oocytes and digitonin-permeabilized HeLa cells, demonstrating that it functions as an snRNP-specific nuclear import receptor. 0.479 SIGNOR-272080 POLD2 protein P49005 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR form complex binding -1 12403614 YES lperfetto Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme. 0.923 SIGNOR-265516 MAP3K7 protein O43318 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 10090 17299140 YES lperfetto Taken together, our data indicate that TAK1 and TAB1 play a pivotal role as upstream signal transducers activating the MKK3-p38 MAPK signaling cascade that leads to the induction of type I collagen expression by TGF-beta(1). In addition, our findings also suggest that TAK1 has a novel function in regulation of the steady-state protein levels of MKK3 and p38 MAPK. 0.503 SIGNOR-42402 Caspase 3 complex complex SIGNOR-C221 SIGNOR PTCH1 protein Q13635 UNIPROT down-regulates cleavage Asp1405 CPGYPETdHGLFEDP 9606 23074268 YES gcesareni Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain. 0.321 SIGNOR-256437 BIRC3 protein Q13489 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys145 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. 0.356 SIGNOR-272709 LMNA protein P02545 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000944 16415042 NO Cleaved by CASP6 amattioni Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy.|We conclude that A-type lamins act as inhibitors of adipocyte differentiation, possibly by affecting PPARgamma2 and insulin signaling. 0.7 SIGNOR-45455 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 YES gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.423 SIGNOR-165208 TFEB protein P19484 UNIPROT GOLPH3L protein Q9H4A5 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 NO lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) 0.2 SIGNOR-276793 AVP protein P01185 UNIPROT AVPR2 protein P30518 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000671;BTO:0001260 1560825 YES gcesareni We report here the cloning of a complementary dna encoding the hepatic v1a arginine vasopressin receptor. The liver cdna encodes a protein with seven putative transmembrane domains, which binds arginine vasopressin. 0.737 SIGNOR-20185 mifepristone chemical CHEBI:50692 ChEBI LIFR protein P42702 UNIPROT down-regulates activity chemical modification 9606 BTO:0000584 36359879 YES miannu In conclusion, we identified a LIF/LIFR pathway that promotes/maintains oncogenicity in PDAC cell lines. Using docking and pharmacological experiments, we have shown that mifepristone, a clinically approved anti-steroidal agent, functions as a LIFR antagonist, directly binding the LIFR complex and preventing its activation in PDAC cell lines. Present results support the repositioning of mifepristone in the treatment of LIFR expressing PDAC. 0.8 SIGNOR-278032 PRKCZ protein Q05513 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.292 SIGNOR-249251 APC-c complex SIGNOR-C150 SIGNOR CDC6 protein Q99741 UNIPROT up-regulates activity binding 9606 BTO:0000567 10995389 YES miannu Furthermore, APC, in association with CDH1, ubiquitinates CDC6 in vitro, and both APC and CDH1 are required and limiting for CDC6 proteolysis in vivo. 0.503 SIGNOR-271386 NUP37 protein Q8NFH4 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.687 SIGNOR-262085 PHKA2 protein P46019 UNIPROT PHKG1 protein Q16816 UNIPROT down-regulates activity binding 9606 10487978 YES Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. 0.696 SIGNOR-267404 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.708 SIGNOR-252876 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 11581251 YES inferred from 70% family members lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. 0.2 SIGNOR-270207 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7824938 YES gcesareni Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain. 0.779 SIGNOR-33914 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257906 CSNK2A1 protein P68400 UNIPROT NASP protein P49321 UNIPROT down-regulates activity phosphorylation Ser497 TEEMPNDsVLENKSL 9606 29733298 YES miannu Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways.  0.2 SIGNOR-273627 WWTR1 protein Q9GZV5 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22470139 NO miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. 0.2 SIGNOR-255606 UNC80 protein Q8N2C7 UNIPROT UNC79 protein Q9P2D8 UNIPROT up-regulates activity binding 9606 BTO:0000142 22196327 YES miannu The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80. 0.803 SIGNOR-265183 KMT2A protein Q03164 UNIPROT MLL1 complex complex SIGNOR-C89 SIGNOR form complex binding 9606 24680668 YES miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. 0.2 SIGNOR-204813 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 20086174 YES llicata We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. 0.357 SIGNOR-163533 SRC protein P12931 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates activity phosphorylation Tyr490 HCAAWHGyYSVAKAL 9606 BTO:0002181 17803936 YES miannu  Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.  0.273 SIGNOR-276074 dabrafenib chemical CHEBI:75045 ChEBI SIK1 protein P57059 UNIPROT down-regulates activity chemical inhibition -1 24720932 YES miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations 0.8 SIGNOR-259219 CDK6 protein Q00534 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 11986303 YES lperfetto Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown). 0.2 SIGNOR-87113 PTPRA protein P18433 UNIPROT VPS33B protein Q9H267 UNIPROT down-regulates activity dephosphorylation 9606 18474358 YES lperfetto Here, we report that VPS33B, a host protein involved in vesicle trafficking, is dephosphorylated by PtpA leading to a block of phagosome maturation by M. tuberculosis.|These data suggest that M. tuberculosis PtpA inhibits phagosome maturation.To assess the role of VPS33B in phagosome maturation, we attenuated the expression of endogenous VPS33B expression in THP-1 cells using a siRNA based approach. 0.2 SIGNOR-277015 CD79B protein P40259 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0000776 12324477 NO gcesareni Bcr ligation resulted in p53 activation including its phosphorylation at ser15 0.308 SIGNOR-93526 creatine smallmolecule CHEBI:16919 ChEBI CKB protein P12277 UNIPROT up-regulates activity chemical activation 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265809 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 YES lperfetto The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. 0.965 SIGNOR-235881 MAPK8IP2 protein Q13387 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 10490659 YES These data demonstrated that JIP2 increases JNK activation by the MLK signaling pathway gcesareni These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins. 0.637 SIGNOR-70860 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr90 AIKIIDKtQLNPTSL 9606 15319445 YES gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. 0.2 SIGNOR-259431 RACGAP1 protein Q9H0H5 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.585 SIGNOR-260512 SGK2 protein Q9HBY8 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000007 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.522 SIGNOR-252991 HIF1A protein Q16665 UNIPROT KDM7A protein Q6ZMT4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271572 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation Ser52 MILLSELsRRRIRSI 9606 25660019 YES Manara We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK). 0.765 SIGNOR-260874 RHOBTB3 protein O94955 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 24145166 YES miannu Here we show that RhoBTB3, a Golgi-associated, Rho-related ATPase, regulates the S/G2 transition of the cell cycle by targeting cyclin E for ubiquitylation. Depletion of RhoBTB3 arrested cells in S phase, triggered Golgi fragmentation, and elevated cyclin E levels. On the Golgi, RhoBTB3 bound cyclin E as part of a Cullin3 (CUL3)-dependent RING-E3 ubiquitin ligase complex comprised of RhoBTB3, CUL3, and RBX1. 0.382 SIGNOR-272132 CCL20 protein P78556 UNIPROT CCR6 protein P51684 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0002042 11035086 YES miannu Liver and activation-regulated chemokine (LARC), also designated macrophage inflammatory protein-3alpha (MIP-3alpha), Exodus, or CCL20, is a C-C chemokine that attracts immature dendritic cells and memory T lymphocytes, both expressing CCR6. LARC/MIP-3α is exerting its activity through binding to CCR6 (11, 12, 18, 19, 20), which is not shared by any other known chemokine. CCR6 is found to be expressed on immature dendritic cells and memory T lymphocytes as well as on B lymphocytes, in various lymphoid organs, and in pancreas 0.2 SIGNOR-278040 LTC4S protein Q16873 UNIPROT leukotriene A4(1-) smallmolecule CHEBI:57463 ChEBI down-regulates quantity chemical modification 9606 27365393 YES miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). 0.8 SIGNOR-277258 AR protein P10275 UNIPROT NAT1 protein P18440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17210686 NO lperfetto Induction of human arylamine N-acetyltransferase type I by androgens in human prostate cancer cells|We show that NAT1 activity is induced by R1881 in androgen receptor (AR)-positive prostate lines 22Rv1 and LNCaP 0.2 SIGNOR-253684 NPFFR1 protein Q9GZQ6 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257103 TIMP1 protein P01033 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity binding 9606 BTO:0003494 36935521 YES Tissue inhibitor of metalloproteinase (TIMP-1) is an inhibitor of MMP-9 that binds to MMP-9 precursors and to the active form. 0.806 SIGNOR-278116 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr228 HEGAVTHtFCGTIEY -1 11733037 YES miannu In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity. 0.834 SIGNOR-250294 MYO10 protein Q9HD67 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 27580874 NO miannu Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments. 0.7 SIGNOR-268284 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.352 SIGNOR-259016 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 NO lperfetto We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 0.687 SIGNOR-235361 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 9267021 YES Cytochrome C released from mitochondria lperfetto Once released from mitochondria, cytochrome c binds to Apaf-1, which may trigger the activation of caspase-3 in the presence of dATP. 0.791 SIGNOR-50585 FOS protein P01100 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 YES miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.346 SIGNOR-254879 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 19920149 YES gcesareni Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7 0.593 SIGNOR-161766 CDK1 protein P06493 UNIPROT NSFL1C protein Q9UNZ2 UNIPROT down-regulates activity phosphorylation Ser140 AVERVTKsPGETSKP 9606 12810701 YES lperfetto Now, we have found that p47, which mainly localizes to the nucleus during interphase, is phosphorylated on serine-140 by cdc2 at mitosis. The phosphorylated p47 does not bind to golgi membranes. 0.326 SIGNOR-102350 FAS protein P25445 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 21959933 YES lperfetto Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd. 0.91 SIGNOR-176651 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 9606 18174237 YES gcesareni Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome. 0.758 SIGNOR-160323 FAM83E protein Q2M2I3 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273758 PCF11 protein O94913 UNIPROT CFII complex complex SIGNOR-C387 SIGNOR form complex binding 9606 BTO:0000567 30139799 YES lperfetto Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. 0.889 SIGNOR-266119 EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 12648462 YES lperfetto The mammalian ligands that bind the egf receptor (egfr [her1, erb-b1]) include egf, transforming growth factor- (tgf), heparin-binding egf-like growth factor (hb-egf), amphiregulin (ar), betacellulin (btc), epiregulin (epr), and epigen 0.949 SIGNOR-22716 EIF2B1 protein Q14232 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.767 SIGNOR-269139 NPY protein P01303 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 7592911 YES gcesareni Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid. 0.691 SIGNOR-29633 FGF2 protein P09038 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 11390973 YES lperfetto we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2).These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. 0.897 SIGNOR-86121 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 YES lperfetto Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation 0.775 SIGNOR-252585 NAMPT protein P43490 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates 19299583 NO lperfetto Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression. 0.611 SIGNOR-253721 LYN protein P07948 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates activity phosphorylation Tyr378 EPEPENDyEDVEEMD 9606 9104825 YES Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252 0.713 SIGNOR-251400 YEATS4 protein O95619 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.768 SIGNOR-269302 Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001109 phosphorylation:Thr286 EEVDLACtPTDVRDV 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1. We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8. 0.46 SIGNOR-271633 SERPING1 protein P05155 UNIPROT F12 protein P00748 UNIPROT down-regulates activity binding 9606 BTO:0000131 26707513 YES lperfetto C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). 0.643 SIGNOR-263517 CSNK2A1 protein P68400 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates activity phosphorylation Ser291 DVHMVSDsDGDDFED 9534 12832043 YES llicata We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites.|Therefore we assume that CK2‐mediated FAF1 phosphorylation influences the nuclear localization of FAF1 | it implies that the major function of FAF1 might not be in the cytoplasm as an interacting partner of Fas. 0.327 SIGNOR-250864 HTR3C protein Q8WXA8 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 NO miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  0.7 SIGNOR-264320 EIF3E protein P60228 UNIPROT MAD2L1 protein Q13257 UNIPROT down-regulates quantity translation regulation 9606 BTO:0000815; BTO:0001938 20453879 NO irozzo Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. 0.263 SIGNOR-259157 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257909 UBE2L3 protein P68036 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity ubiquitination -1 19240029 YES miannu Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1). 0.545 SIGNOR-272735 SF3B5 protein Q9BWJ5 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 YES lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). 0.932 SIGNOR-268407 NDUFV3 protein P56181 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.783 SIGNOR-262185 AIMP1 protein Q12904 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.918 SIGNOR-270359 PTCH1 protein Q13635 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates binding 9606 11331587 YES Type I noncanonical;P-cyclina B (CCNB). gcesareni In addition, we demonstrate that endogenous ptc1 and endogenous cyclin B1 interact in vivo. The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. Thus, we propose that ptc1 participates in a G2/M checkpoint by regulating the localization of MPF. 0.683 SIGNOR-199147 GLI1 protein P08151 UNIPROT GLI1 protein P08151 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 NO lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. 0.2 SIGNOR-209617 alvimopan chemical CHEBI:135686 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition -1 18313920 YES Luana A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors. 0.8 SIGNOR-257773 PKG proteinfamily SIGNOR-PF77 SIGNOR 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. 0.8 SIGNOR-266504 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR SKP2 protein Q13309 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 11032804 YES miannu These results suggest that degradation of Skp2 in G(0)/G(1) is mediated, at least in part, by an autocatalytic mechanism involving a Skp2-bound Cul1-based core ubiquitin ligase and imply a role for this mechanism in the suppression of SCF(Skp2) ubiquitin protein ligase function during the G(0)/G(1) phases of the cell cycle. 0.92 SIGNOR-272574 26S Proteasome complex SIGNOR-C307 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates quantity destabilization 10090 BTO:0003569 9233789 YES Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. 0.415 SIGNOR-270340 MED28 protein Q9H204 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.838 SIGNOR-266674 SMO protein Q99835 UNIPROT GNAT2 protein P19087 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.262 SIGNOR-199171 thiocyanate smallmolecule CHEBI:18022 ChEBI Cell_killing phenotype SIGNOR-PH149 SIGNOR up-regulates 9606 BTO:0000133 9922160 NO lperfetto Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids.| Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity. 0.7 SIGNOR-270592 HTR7 protein P34969 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.32 SIGNOR-257381 ORF6 protein Q19QW5 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity 9534 17596301 NO lperfetto Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. 0.2 SIGNOR-260271 PRKACA protein P17612 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation Ser785 LRGGSDDsSKDPIDV 9606 BTO:0001412 25069723 YES miannu  In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain).  0.2 SIGNOR-276653 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.601 SIGNOR-249398 ENSA protein O43768 UNIPROT PPP2R2D protein Q66LE6 UNIPROT down-regulates activity binding -1 phosphorylation:Ser67 KGQKYFDsGDYNMAK 21164014 YES gcesareni We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. 0.768 SIGNOR-243735 RNA_splicing phenotype SIGNOR-PH201 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates 9606 32140746 NO lperfetto The splicing of introns from nuclear precursors of message RNA (pre-mRNA) is executed by the spliceosome, a ribonucleoprotein (RNP) apparatus that first surfaced in the literature in 1985  0.7 SIGNOR-268402 DNMT3B protein Q9UBC3 UNIPROT DNMT1/DNMT3B complex SIGNOR-C43 SIGNOR form complex binding 9606 12145218 YES miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation 0.789 SIGNOR-90845 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1714 SPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248786 PTGS1 protein P23219 UNIPROT prostaglandin G2(1-) smallmolecule CHEBI:82629 ChEBI up-regulates quantity chemical modification -1 7592599 YES Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, 0.8 SIGNOR-269771 HDAC1 protein Q13547 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16431920 NO fspada These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome 0.436 SIGNOR-143955 MAPK1 protein P28482 UNIPROT DAZAP1 protein Q96EP5 UNIPROT down-regulates activity phosphorylation Thr269 FTSYIVStPPGGFPP 9606 BTO:0000007 16848763 YES miannu Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ 0.2 SIGNOR-262970 ESR2 protein Q92731 UNIPROT CRH protein P06850 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000614 8408641 YES lperfetto Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. 0.386 SIGNOR-268722 linifanib chemical CHEBI:91435 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258242 AKT proteinfamily SIGNOR-PF24 SIGNOR HK1 protein P19367 UNIPROT up-regulates binding 9606 16892082 YES gcesareni The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. 0.2 SIGNOR-148675 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI AHR protein P35869 UNIPROT up-regulates activity chemical activation -1 31995776 YES miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs. 0.8 SIGNOR-268736 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser516 PQVLAQPsTSRKRPR 9606 BTO:0002201 12855706 YES lperfetto Chk2 is also autophosphorylated following dna damage. It is proposed that autophosphorylation of chk2 may contribute to chk2 activation. To fully understand the regulation of chk2, we mapped an in vitro chk2 autophosphorylation site at c-terminal serine 516 site (ser-516). Ser-516 of chk2 is phosphorylated following radiation in vivo, and this phosphorylation depends on the kinase activity of chk2. 0.2 SIGNOR-103544 ACO2 protein Q99798 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI down-regulates quantity chemical modification 9606 24068518 YES miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. 0.8 SIGNOR-266244 cholesterol smallmolecule CHEBI:16113 ChEBI RAC1 protein P63000 UNIPROT up-regulates quantity relocalization 9606 BTO:0000584 31827278 YES miannu Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. In line with these observations, immunohistochemical staining of V-ATPase in human pancreatic ductal adenocarcinoma (PDAC) specimens revealed prominent staining at the cell periphery in neoplastic lesions, in con- trast to the predominantly cytoplasmic staining observed in adjacent normal tissues (Fig. 2e). Thus, mutant RAS-dependent plasma mem- brane V-ATPase displayed preferential accumulation in membrane ruffles, consistent with patterns observed in invasive breast, melanoma and pancreatic cancer cells 0.8 SIGNOR-277761 D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI D-erythrose 4-phosphate(2-) smallmolecule CHEBI:16897 ChEBI up-regulates quantity precursor of 9606 19401148 YES miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 0.8 SIGNOR-268132 TGFB1 protein P01137 UNIPROT DNAH10 protein Q8IVF4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 31836722 NO miannu The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation. 0.2 SIGNOR-265552 BAK1 protein Q16611 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates 9606 21210296 NO gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. 0.296 SIGNOR-170966 GHSR protein Q92847 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.473 SIGNOR-257380 PBK protein Q96KB5 UNIPROT TP53RK protein Q96S44 UNIPROT up-regulates activity phosphorylation Ser250 RLRGRKRsMVG 9606 28412249 YES miannu In this study, we provide evidence showing that TOPK promotes metastasis of colorectal carcinoma, which is mediated through its phosphorylation of PRPK at Ser250.|Therefore, we conclude that TOPK directly promotes metastasis of colorectal cancer by modulating PRPK. 0.418 SIGNOR-278236 NEK2 protein P51955 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates phosphorylation 9606 10880350 YES lperfetto Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2 0.49 SIGNOR-264655 MBOAT7 protein Q96N66 UNIPROT acyl-CoA smallmolecule CHEBI:17984 ChEBI down-regulates quantity chemical modification -1 18772128 YES miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. 0.8 SIGNOR-267244 STAT4 protein Q14765 UNIPROT PRF1 protein P14222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000914 12372421 NO miannu IL-12-induced expression of the perforin gene in NK cells is directly regulated by STAT4, which binds, most likely as a homo-tetramer, to the tandem STAT-binding sequences in the perforin gene promoter. 0.402 SIGNOR-255245 GSK3B protein P49841 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates activity phosphorylation Ser303 RVKEEPPsPPQSPRV -1 8940068 YES Ser-303 is phosphorylated by glycogen synthase kinase 3 (GSK3) through a mechanism dependent on primary phosphorylation of Ser-307 by MAPK. Secondary phosphorylation of Ser-303 by GSK3 may thus repress the activity of HSF-1, and its requirement for priming by MAPK phosphorylation of Ser-307 provides a potential link between the MAPK cascade and HSF-1. 0.556 SIGNOR-251216 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17126298 YES gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. 0.333 SIGNOR-150879 CAMK2A protein Q9UQM7 UNIPROT CLCN3 protein P51790 UNIPROT up-regulates activity phosphorylation Ser109 ERHRRINsKKKESAW 14754994 YES lperfetto Identification of an N-terminal amino acid of the CLC-3 chloride channel critical in phosphorylation-dependent activation of a CaMKII-activated chloride current|The N-terminus of CLC-3, which contains a CaMKII consensus sequence, was phosphorylated by CaMKII in vitro, and mutation of the serine at position 109 (S109A) abolished the CaMKII-dependent Cl(-) conductance, indicating that this residue is important in the gating of CLC-3 at the plasma membrane. 0.337 SIGNOR-275863 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257910 3b protein P59633 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity 9606 21561061 NO Luana An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP 0.2 SIGNOR-260761 lenalidomide chemical CHEBI:63791 ChEBI CSNK1A1 protein P48729 UNIPROT down-regulates quantity by destabilization 9606 BTO:0000670 26131937 NO gcesareni We demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1a) by the E3 ubiquitin ligase CUL4€“RBX1€“DDB1€“CRBN (known as CRL4CRBN) 0.8 SIGNOR-236895 CDK1 protein P06493 UNIPROT EP300 protein Q09472 UNIPROT down-regulates quantity phosphorylation Ser2039 GLGQVGIsPLKPGTV 9606 24530506 YES miannu Loss of CDK1 decreased p300 phosphorylation, but increased the p300 level.|Our results showed that phosphorylation of p300 by CDK1 at Ser1038 and Ser2039 repressed the proliferation and metastasis activity of lung cancer cells in vitro. 0.404 SIGNOR-278238 Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B protein P01584 UNIPROT up-regulates activity cleavage Asp116 DNEAYVHdAPVRSLN -1 1919001 YES lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  0.802 SIGNOR-256376 KMT2E protein Q8IZD2 UNIPROT NCR2 protein O95944 UNIPROT up-regulates activity binding 9606 BTO:0000737 23958951 YES miannu We identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. 0.506 SIGNOR-260045 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser642 PRLGSTFsLDTSMSM 9606 BTO:0000782 11024037 YES lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  0.322 SIGNOR-249057 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 YES gcesareni Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase. 0.678 SIGNOR-33137 PIK3CA protein P42336 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000586 16293724 NO gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. 0.669 SIGNOR-141814 TWIST2 protein Q8WVJ9 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 NO miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells 0.2 SIGNOR-255514 MMUT protein P22033 UNIPROT (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI down-regulates quantity chemical modification 9606 1978672 YES miannu Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). 0.8 SIGNOR-269108 MAPK9 protein P45984 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 YES gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.663 SIGNOR-134572 GSK3B protein P49841 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Thr73 MKIDEPStPYHSMMG 9913 BTO:0000142 11320080 YES Protein phosphatase 1 (PP1) is complexed with inhibitor 2 (I-2) in the cytosol. In rabbit muscle extract PP1.I-2 is activated upon preincubation with ATP/Mg. This activation is caused by phosphorylation of I-2 on Thr(72) by glycogen synthase kinase 3 (GSK3). 0.413 SIGNOR-251257 IL10 protein P22301 UNIPROT SCN4A protein P35499 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 NO miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. 0.2 SIGNOR-253500 ZNF521 protein Q96K83 UNIPROT EBF1 protein Q9UH73 UNIPROT down-regulates binding 9606 BTO:0000776 14630787 YES miannu Ehzf inhibits the transcriptional activity of early b-cell factor (ebf), a transcription factor essential for specification of the b-cell lineage /ability to interact with the neural and hematopoietic transcription factor olf1/ebf1 and inhibit its binding to dna 0.501 SIGNOR-119300 JNK proteinfamily SIGNOR-PF15 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 YES lperfetto Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities. 0.2 SIGNOR-105762 ANK3 protein Q12955 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates quantity relocalization 10090 BTO:0001103 19109891 YES miannu We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4. 0.259 SIGNOR-266714 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 20219869 NO areggio Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. This outcome may be functionally important because ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation. 0.7 SIGNOR-255120 PMAIP1 protein Q13794 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity phosphorylation 9606 9988720 YES Ga16 is phosphorylated in vivo by PMA and by TRH receptor stimulation 0.2 SIGNOR-278131 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Thr430 PPLPPRAtPSRPGEA 9606 11110801 YES llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). 0.442 SIGNOR-85000 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 21059642 YES The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.614 SIGNOR-169330 DGC complex SIGNOR-C217 SIGNOR NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 YES miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. 0.301 SIGNOR-265450 RNF5 protein Q99942 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys461 GPEENEYkSEGTFGI 9606 BTO:0000007 20483786 YES miannu In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase.  0.457 SIGNOR-271489 PRKAA2 protein P54646 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 SIGNOR-C14 21673972 YES lperfetto These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes 0.257 SIGNOR-174405 MAPK1 protein P28482 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Thr82 HSMSVPTtPTLGFST 9606 17604322 YES lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 0.533 SIGNOR-262958 hexestrol chemical CHEBI:31669 ChEBI AKR1C2 protein P52895 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193300 TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 10688666 YES lperfetto Tnf receptor (tnfr) associated factor 2 (traf2), an adapter protein that couples tnfrs to the sapks and p38s, can activate ask1 in vivo and can interact in vivo with the amino- and carboxyl-terminal noncatalytic domains of the ask1 polypeptide 0.736 SIGNOR-75334 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258569 CDK1 protein P06493 UNIPROT EP300 protein Q09472 UNIPROT down-regulates quantity phosphorylation Ser1038 STSATQSsPAPGQSK 9606 24530506 YES miannu Loss of CDK1 decreased p300 phosphorylation, but increased the p300 level.|Our results showed that phosphorylation of p300 by CDK1 at Ser1038 and Ser2039 repressed the proliferation and metastasis activity of lung cancer cells in vitro. 0.404 SIGNOR-278239 PLCD4 protein Q9BRC7 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 8395015 YES gcesareni Hydrolysis of phosphatidylinositol 4,5-bisphosphate (pip2) by phosphatidylinositol-specific phospholipase c (pi-plc) generates two second messengers, inositol 1,4,5-trisphosphate and 1,2-diacylglycerol. 0.8 SIGNOR-39041 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser356 VDGSGDTsSNEEIGS -1 12107178 YES llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. 0.425 SIGNOR-250870 PAK5 protein Q9P286 UNIPROT PACSIN1 protein Q9BY11 UNIPROT up-regulates activity phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 YES miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 0.2 SIGNOR-263025 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr458 CKTPSSNtLDDYMSC -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276222 NEK9 protein Q8TD19 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 14660563 YES lperfetto A previous study (19) using the peptide substrate demonstrated that nek9 was able to phosphorylate in vitro the thr210 residue within the activation loop, thus indicating the potential ability of nek9 to autophosphorylate.Nek9 forms a stable, approximately 600-kda complex with fact in the interphase nuclei. Its active form is characterized by phosphorylation-dependent electrophoretic mobility shift and phosphorylation at a conserved residue within the activation loop (thr(210)) 0.2 SIGNOR-119897 paliperidone chemical CHEBI:82978 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258561 SGK1 protein O00141 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation 9606 11410590 YES miannu Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf.|We observed that SGK inhibits B-Raf activity. 0.344 SIGNOR-279110 MAPK6 protein Q16659 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity phosphorylation Ser60 EMERALNsYFEPPVE 9606 26701725 YES miannu ERK3 phosphorylates TDP2 and promotes its phosphodiesterase activity, thereby upregualting TDP2-mediated DNA damage response and desensitizing lung cancer cells to Top2 inhibitor-induced growth inhibition.|In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2 's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors induced DNA damage and growth inhibition. 0.377 SIGNOR-278245 SLC38A2 protein Q96QD8 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity relocalization 9606 26724577 YES Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. 0.8 SIGNOR-266913 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 YES llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. 0.313 SIGNOR-250947 frovatriptan chemical CHEBI:134991 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation -1 9986723 YES miannu As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold). 0.8 SIGNOR-259075 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 3352609 YES lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex 0.89 SIGNOR-24543 PRKAA2 protein P54646 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 SIGNOR-C15 21945940 YES lperfetto Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion. 0.2 SIGNOR-176642 RPL26L1 protein Q9UNX3 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.768 SIGNOR-262496 PPP3CA protein Q08209 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 YES When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. 0.277 SIGNOR-248676 TAL1 protein P17542 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates activity 10090 BTO:0004911 29713515 NO The truncated form TAL1-s is required for erythroid progenitors differentiation, while the full-length protein TAL1-l is required for megakaryocytic differentiation of progenitor cells. 0.7 SIGNOR-259969 SPI1 protein P17947 UNIPROT Lymphopoiesis phenotype SIGNOR-PH111 SIGNOR up-regulates activity 10090 BTO:0000725 8079170 NO Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor. 0.7 SIGNOR-259956 EPHB1 protein P54762 UNIPROT NRCAM protein Q92823 UNIPROT up-regulates activity phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 YES miannu EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase. 0.412 SIGNOR-262862 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. 0.764 SIGNOR-252868 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 8548810 YES lperfetto The c-iaps associate with traf1 and traf3 0.872 SIGNOR-39527 CDK1 protein P06493 UNIPROT MORC2 protein Q9Y6X9 UNIPROT down-regulates quantity by destabilization phosphorylation Thr733 PIKLSPAtPSRKRSV 9606 BTO:0000567 36967563 YES miannu Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation. 0.2 SIGNOR-277838 SMURF1 protein Q9HCE7 UNIPROT ASCC2 protein Q9H1I8 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272692 PIM1 protein P11309 UNIPROT NDRG1 protein Q92597 UNIPROT down-regulates activity phosphorylation Ser330 LMRSRTAsGSSVTSL 9606 33398037 YES miannu Collectively, we find that PIM1 expression leads to increased levels of NDRG1 pS330, and PIM1 dependent NDRG1 phosphorylation decreases NDRG1 protein stability.|NDRG1 is phosphorylated by PIM1 at serine 330 (pS330), and the level of NDRG1 pS330 is associated higher grade prostate tumors. 0.2 SIGNOR-279308 Tandospirone citrate chemical CHEBI:32182 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258861 MAPK3 protein P27361 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 YES gcesareni Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated sheddingwe show that extracellular signal-regulated kinase (erk) acts as an intermediate in protein kinase c-regulated trka cleavage. We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735. In addition, we show that erk and tace associate. This association is favored by erk activation and by the presence of threonine 735. In contrast to the erk route, the p38 mapk was able to stimulate trka cleavage in cells devoid of tace activity, indicating that other proteases are also involved in trka shedding. 0.362 SIGNOR-89625 hsa-miR-518a-5p mirna URS0000068BEA_9606 RNAcentral CCR6 protein P51684 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000182 24559209 YES MiR-518a-5p functionally interacts with the 3′UTR of CCR6 and down-regulates CCR6 expression in CRC cell lines. 0.4 SIGNOR-277925 NONO protein Q15233 UNIPROT NONO/SFPQ complex SIGNOR-C62 SIGNOR form complex binding 9606 BTO:0000017 9756848 YES miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i 0.711 SIGNOR-60475 HNF1A protein P20823 UNIPROT SLC22A9 protein Q8IVM8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20829431 YES lperfetto Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1 in HepG2 cells. 0.2 SIGNOR-268982 trimipramine chemical CHEBI:9738 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 9537821 YES miannu At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter. 0.8 SIGNOR-258740 LSM4 protein Q9Y4Z0 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.796 SIGNOR-270650 hsa-mir-494-3p mirna URS0000535FDD_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000815 25955111 YES MiR-494 suppresses the progression of breast cancer through the Wnt/β-catenin signaling pathway, which is mediated by CXCR4. 0.4 SIGNOR-277943 RDH5 protein Q92781 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 YES lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 0.8 SIGNOR-265114 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ -1 15946941 YES miannu  We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. 0.2 SIGNOR-276035 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser63 AAEERRKsHEAEVLK 9606 8125092 YES gcesareni Phosphorylation of either serine 16 or 63 is sufficient to inhibit stathmin in vitro. Phosphorylation at ser-63 reduces tubulin binding 10-fold and suppresses the mt polymerization inhibition activity. 0.31 SIGNOR-36374 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser618 APTPPKRsSSFREMD 9606 18161990 YES lperfetto The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl. 0.415 SIGNOR-160215 DEAF1 protein O75398 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14507979 NO lperfetto Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. 0.437 SIGNOR-254124 EEF1A2 protein Q05639 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269535 B4GALT1 protein P15291 UNIPROT lactose smallmolecule CHEBI:17716 ChEBI up-regulates quantity chemical modification 9606 16157350 YES miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 0.8 SIGNOR-268469 6-propyl-2-thiouracil smallmolecule CHEBI:8502 ChEBI DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001379 27347897 YES inferred from family member scontino The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU). 0.8 SIGNOR-270240 BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 8358790 YES lperfetto Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered. 0.635 SIGNOR-249612 denileukin diftitox smallmolecule SID:125240988 PUBCHEM IL2RA protein P01589 UNIPROT up-regulates activity chemical activation 9606 15757436 YES miannu Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells.  0.8 SIGNOR-259392 ZW10 protein O43264 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 20462495 YES lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. 0.837 SIGNOR-265012 TNC protein P24821 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 BTO:0000007 7559467 YES lperfetto The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin. 0.437 SIGNOR-253306 SMAD6 protein O43541 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 SIGNOR-C85 12857866 YES gcesareni Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4 0.578 SIGNOR-103621 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 9606 14579029 YES gcesareni Map kinases and mtor mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632 0.705 SIGNOR-118873 TNFSF11 protein O14788 UNIPROT TNFRSF11B protein O00300 UNIPROT up-regulates binding 9606 11733492 YES gcesareni Receptor activator of nf-kappa b ligand (rankl, also known as odf and opgl), a member of the tumor necrosis factor (tnf) family, triggers osteoclastogenesis by forming a complex with its receptor, rank. 0.942 SIGNOR-112539 NCL protein P19338 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 16508016 YES Regulation miannu Nucleolin binds human β-globin mRNA. A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo 0.2 SIGNOR-251844 UBA3 protein Q8TBC4 UNIPROT NAE complex SIGNOR-C131 SIGNOR form complex binding 9606 25504797 YES lperfetto the NEDD8 E1-activating enzyme (NAE) is a heterodimer of APPBP1 and UBA3 corresponding to the N-terminal and C-terminal of the single polypeptide of the ubiquitin E1 respectively 0.966 SIGNOR-242904 PRKCD protein Q05655 UNIPROT BEST1 protein O76090 UNIPROT down-regulates activity phosphorylation Ser358 SAQFRRAsFMGSTFN 9606 19635817 YES Manara We have identified a PKC phosphorylation site (S358) located in the C terminal region of hBest1 critical for channel rundown. Phosphorylation of this site by PKC activators and PP2A inhibitors reduces channel rundown. 0.2 SIGNOR-260880 SERPINC1 protein P01008 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 YES gcesareni In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp. 0.2 SIGNOR-41232 MNAT1 protein P51948 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 YES Manara Human Estrogen Receptor α Is Phosphorylated at Serine 118 In Vivo by Cdk7 0.398 SIGNOR-260837 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Ser77 YEPEGSAsPTPPYLK -1 17318175 YES lperfetto Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling. 0.784 SIGNOR-249191 phentolamine chemical CHEBI:8081 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258446 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MFN1 protein Q8IWA4 UNIPROT up-regulates activity phosphorylation Thr562 LPRSLASTPTAPTTP 10090 BTO:0002572 25801171 YES Barakat Finally, in Mfn1 -/- cells re-expressing the MFN1 T562A mutant, phosphorylation was undetectable even in the presence of EGF. Taken together, these data indicate that ERK phosphorylates MFN1 at T562. 0.2 SIGNOR-274134 mifepristone chemical CHEBI:50692 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0000318 9727070 YES miannu As shown in Fig. 4 A, hPXR was activated by the synthetic steroids dexamethasone, dexamethasone-t-butylacetate, PCN, RU486, spironolactone, and cyproterone-acetate. Dexamethasone-t-butylacetate and RU486 were the most efficacious activators of hPXR among the synthetic steroids tested. 0.8 SIGNOR-258829 NR3C1 protein P04150 UNIPROT HNF4A protein P41235 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17978169 YES gcesareni Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4alpha to the HNF4-RE and that an interaction of GR and HNF4alpha occurred at this site. 0.37 SIGNOR-251684 CSNK2A1 protein P68400 UNIPROT WAS protein P42768 UNIPROT up-regulates phosphorylation Ser483 KRSRAIHsSDEGEDQ 9606 12769847 YES gcesareni Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule. 0.354 SIGNOR-101264 EIF3_complex complex SIGNOR-C401 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.714 SIGNOR-269162 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.32 SIGNOR-161577 YY1 protein P25490 UNIPROT GDAP1 protein Q8TB36 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19720140 NO miannu Overexpression of YY1 activated the GDAP1 promoter in a reporter gene system as well as increased the level of endogenous mRNA. 0.2 SIGNOR-255618 MAPK3 protein P27361 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 YES gcesareni Wstf, a specific component of two chromatin remodeling complexes (swi/snf-type winac and iswi-type wich), was phosphorylated by the stimulation of mapk cascades in vitro and in vivo. Ser-158 residue in the wac (wstf/acf1/cbpq46) domain, located close to the n terminus of wstf, was identified as a major phosphorylation target 0.2 SIGNOR-188164 Exon junction complex complex SIGNOR-C369 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11532962 NO lperfetto The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay 0.7 SIGNOR-268313 ALPL protein P05186 UNIPROT Bone_mineralization phenotype SIGNOR-PH69 SIGNOR up-regulates 9606 19049325 NO miannu PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate. 0.7 SIGNOR-252196 PRKDC protein P78527 UNIPROT XRCC4 protein Q13426 UNIPROT up-regulates activity phosphorylation Ser327 SLETLRNsSPEDLFD 9606 BTO:0002137 26774286 YES miannu In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.  0.907 SIGNOR-277198 HDAC1 protein Q13547 UNIPROT EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21983014 NO In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression. 0.572 SIGNOR-254257 VRK2 protein Q86Y07 UNIPROT DTNBP1 protein Q96EV8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser297 ELRAKPPsSSSTCTD -1 30062698 YES miannu  We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting.  0.2 SIGNOR-277403 F7 protein P08709 UNIPROT Factor FVIIa:TF complex SIGNOR-C319 SIGNOR form complex binding 9606 BTO:0000131 32665005 YES lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. 0.933 SIGNOR-263555 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258457 VPS41 protein P49754 UNIPROT HOPS tethering complex complex SIGNOR-C549 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.916 SIGNOR-273689 MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 YES lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 0.929 SIGNOR-134185 FBXO44 protein Q9H4M3 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding -1 23086937 YES miannu The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. 0.695 SIGNOR-272038 CSNK1A1 protein P48729 UNIPROT ZRANB1 protein Q9UGI0 UNIPROT up-regulates activity phosphorylation Thr35 RAQRPSGtIITEDPF 9606 BTO:0000007 30686098 YES miannu Interestingly, ZRANB1 is phosphorylated at Thr35, and Ser209 residues by CSNK1A1, and this phosphorylation activates its deubiquitinating activity. 0.2 SIGNOR-273620 CALM1 protein P0DP23 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 11807557 YES miannu Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. 0.452 SIGNOR-253410 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPSTGGV 9606 18508628 YES Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription. gcesareni In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes. 0.2 SIGNOR-178708 monoisononyl phthalate chemical CHEBI:132593 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268781 NSD3 protein Q9BZ95 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0002181 28205554 YES irozzo Indeed, dose-dependent TR-FRET and affinity pull-down assay confirmed the interaction of NSD3-s with MYC. Supporting functional significance of the interaction, co-expression of NSD3-s, but not the MYC-binding defective fragment of NSD3-s (1–347), stabilized MYC protein and increased MYC transcriptional activity as revealed by a MYC-driven reporter assay. 0.2 SIGNOR-259199 GNAQ protein P50148 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 9235901 YES gcesareni Galfaq/11 subunits also activate p21ras 0.64 SIGNOR-50104 solifenacin chemical CHEBI:135530 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition -1 21524581 YES Luana The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference 0.8 SIGNOR-258313 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser20 HVAGGPPsPEVGSPL 9606 11110801 YES llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). 0.442 SIGNOR-84980 MAPK12 protein P53778 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 YES gcesareni Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target 0.541 SIGNOR-65589 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 YES lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 0.493 SIGNOR-176891 YES1 protein P07947 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 23245941 YES miannu In contrast, YES1-mediated phosphorylation of YAP1 activates YAP1 in embryonic stem cell self-renewal ( ), and ABL-mediated phosphorylation of YAP1 in response to DNA damage results in transcription of pro-apoptotic genes ( ).|These observations confirm that YES1 phosphorylates YAP1 at tyrosine 357. 0.72 SIGNOR-278248 MARK4 protein Q96L34 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser420 KHPTPGSsDPLIQPS -1 21204788 YES miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.42 SIGNOR-273936 PRKACA protein P17612 UNIPROT PSEN1 protein P49768 UNIPROT unknown phosphorylation Ser310 PEAQRRVsKNSKYNA -1 14576165 YES miannu PKA-mediated phosphorylation of PS1 is completely inhibited by mutation of Ser310.phosphorylation of Ser310 does not inhibit the caspase-mediated cleavage of PS1, and the biological function of this phosphorylation event remains to be determined in further experiments. 0.49 SIGNOR-250036 PRKCD protein Q05655 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 YES gcesareni Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. 0.259 SIGNOR-97287 USP8 protein P40818 UNIPROT STAM protein Q92783 UNIPROT up-regulates quantity binding 9606 BTO:0000567 16520378 YES Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells. 0.536 SIGNOR-266904 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Thr213 SASFPHTtPSMCLNP 10090 BTO:0000667 17475908 YES miannu All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells. 0.2 SIGNOR-262671 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 23429703 YES lperfetto Mtorc1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein s6 kinase 1 (s6k1), which directly phosphorylates s1859 on cad, the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mtorc1 thus stimulates the production of new nucleotides to accommodate an increase in rna and dna synthesis. 0.372 SIGNOR-201117 SCF-betaTRCP complex SIGNOR-C5 SIGNOR MTSS1 protein O43312 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 24318128 YES miannu Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.  0.319 SIGNOR-276610 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol chemical CHEBI:75722 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258150 AT9283 chemical CID:11696609 PUBCHEM ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190008 DYRK1A protein Q13627 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity phosphorylation Ser10 NVRVSNGsPSLERMD 9606 24806449 YES miannu DYRK1A phosphorylates p27 Kip1 at Ser10 in primary neurons and in vivo.|Thus, our results identify DYRK1A as the predominant kinase that phosphorylates and stabilizes p27Kip1 during neuronal differentiation. 0.332 SIGNOR-278250 HOXA10 protein P31260 UNIPROT IGFBP1 protein P08833 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003697 17350963 NO miannu The functional role of HOXA10 in IGFBP1 expression was further explored using human endometrial stromal cells (HSC). Overexpression of HOXA10 in HSC resulted in a decrease of IGFBP1 mRNA, whereas silencing HOXA10 caused an increase of IGFBP1 mRNA, even in the presence of H + dbcAMP. These data demonstrate that HOXA10 negatively influences IGFBP1 expression in decidualizing cells. 0.409 SIGNOR-254467 CELF6 protein Q96J87 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0001109 31534127 YES miannu CELF6 binds to the 3'UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest. 0.2 SIGNOR-269044 MTOR protein P42345 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 SIGNOR-C3 18570873 YES llicata Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation 0.849 SIGNOR-179113 HTRA2 protein O43464 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates binding 9606 15328349 YES gcesareni Htra2 promotes cell death by binding and degrading the anti-apoptotic protein pea15 0.486 SIGNOR-126966 PDGFRB protein P09619 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr28 SLNQSSGyRYGTDPT -1 9425276 YES miannu PDGF-induced phosphorylation of Tyr28 in the N-terminus of Fyn affects Fyn activation. We show here that Fyn, a member of the Src family, is phosphorylated on Tyr28 in the unique N-terminal part of the molecule after interaction with the intracellular domain of the PDGF beta-receptor. Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. 0.579 SIGNOR-250253 SMAD4 protein Q13485 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. 0.674 SIGNOR-255267 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRC1 protein O43663 UNIPROT unknown phosphorylation Thr470 LYGSAPRtPSKRRGL 9885575 YES llicata We have shown that PRC1 is a good in vitro substrate for several CDKs, and that it is also phosphorylated in a cell cycle–dependent manner in vivo at Thr-481 (major mitosis. and Thr-470 (minor site), which are the in vitro phosphorylation sites. 0.346 SIGNOR-250745 ILK protein Q13418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 27683053 YES miannu ILK can also directly phosphorylates GSK-3\u03b2 at Ser 9, inactivate it, and lead to activation of some transcription factors [ ].|ILK knockdown activates GSK-3beta. 0.689 SIGNOR-278252 CTNNA2 protein P26232 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23431053 YES In keratinocytes, YAP strongly interacts with a-catenin, and this interaction is mediated by 14-3-3. gcesareni The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. 0.33 SIGNOR-201245 POLR2D protein O15514 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.836 SIGNOR-266164 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Leu664 ATVIVITlVMLKKKQ -1 8943232 YES lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261784 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 18636076 YES gcesareni Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian target of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin. 0.8 SIGNOR-179483 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 20626350 YES lperfetto Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2. 0.69 SIGNOR-166619 YY1 protein P25490 UNIPROT POSTN protein Q15063 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21839814 NO miannu In this study we demonstrate that the ability of the human POSTN promoter to drive transcription mostly depends on the activity of YingYang-1 (YY1) zinc finger transcription factor. YY1, whose regulatory role in biology includes, besides transcriptional control, also chromatin remodeling, DNA damage repair and tumorigenesis, acts as a strong negative modulator of the POSTN expression. 0.2 SIGNOR-255621 WASHC5 protein Q12768 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 YES lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. 0.2 SIGNOR-261019 HPS1 protein Q92902 UNIPROT BLOC-3 complex SIGNOR-C253 SIGNOR form complex binding 9606 20048159 YES lperfetto Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer. 0.752 SIGNOR-260691 STAT3 protein P40763 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 19049975 YES miannu We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter. 0.636 SIGNOR-263497 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.407 SIGNOR-275775 SOSTDC1 protein Q6X4U4 UNIPROT WNT7B protein P56706 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.291 SIGNOR-242733 MAPKAPK2 protein P49137 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser377 PPLLRPLsENSGDEN -1 12171600 YES miannu Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity. 0.352 SIGNOR-249710 LCK protein P06239 UNIPROT CHN2 protein P52757 UNIPROT down-regulates activity phosphorylation Tyr153 KMTTNPIyEHIGYAT 9606 BTO:0000661 19201754 YES miannu We now demonstrate Lck-dependent phosphorylation of beta2-chimaerin in response to TCR triggering. We identify Tyr-153 as the Lck-dependent phosphorylation residue and show that its phosphorylation negatively regulates membrane stabilization of beta2-chimaerin, decreasing its GAP activity to Rac.  0.2 SIGNOR-276240 PAC-1 chemical CID:6851947 PUBCHEM CASP3 protein P42574 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-198535 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT up-regulates activity phosphorylation Ser859 RRENSSDsPKELKRR 9606 BTO:0002181 25452387 YES miannu The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.  0.2 SIGNOR-276445 MAT2B protein Q9NZL9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 23325603 NO miannu MAT2B and GIT1 regulate cell growth and increase ERK activity.GIT1 and MAT2B (V1 and V2) require one another to regulate growth and activate ERK 0.7 SIGNOR-261246 CHD8 protein Q9HCK8 UNIPROT CCNE2 protein O96020 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19255092 YES miannu In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes. 0.418 SIGNOR-268804 Nalmefene chemical CHEBI:7457 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258812 SMARCA2 protein P51531 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.636 SIGNOR-269779 E2F1 protein Q01094 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18840615 NO miannu we show that E2F1 represses GRP78/BIP at the transcriptional level, and this requires its DNA binding domain. 0.2 SIGNOR-253845 OXTR protein P30559 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.448 SIGNOR-257065 EGFR protein P00533 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 14967450 YES lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation. 0.879 SIGNOR-121965 AKT1 protein P31749 UNIPROT TTC3 protein P53804 UNIPROT up-regulates phosphorylation Ser378 AYTPRSLsAPIFTTS 9606 20059950 YES llicata Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context 0.396 SIGNOR-252508 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192904 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser36 AEKQARGsTTLQESR 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.2 SIGNOR-275765 MT-ND2 protein P03891 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 0.781 SIGNOR-262144 MAPK3 protein P27361 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser225 ARLGSQHsPGRTASL 9606 21419341 YES gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. 0.452 SIGNOR-172881 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr244 RRLCDLYyINSPELE 9606 22195962 YES llicata Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1 0.347 SIGNOR-193454 PTPN1 protein P18031 UNIPROT KRT8 protein P05787 UNIPROT down-regulates activity dephosphorylation Tyr267 IAEVKAQyEDIANRS 9606 BTO:0000182 24003221 YES lperfetto Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine. 0.2 SIGNOR-265495 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 YES gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function 0.742 SIGNOR-126732 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 YES gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function 0.742 SIGNOR-126736 MYCBP2 protein O75592 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 YES miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 0.2 SIGNOR-267149 leukotriene D4(1-) smallmolecule CHEBI:63166 ChEBI CYSLTR1 protein Q9Y271 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257475 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser233 VSSQHRYsTPHAFTF 9606 12551925 YES gcesareni For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1. 0.557 SIGNOR-37466 VPS39 protein Q96JC1 UNIPROT HOPS tethering complex complex SIGNOR-C549 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.883 SIGNOR-273690 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation Thr200 EHQVLMKtVCGTPGY 9606 15769749 YES gcesareni Phosphorylation of ca(2+)/cam-bound camkiv on its activation loop threonine (residue thr(200) in human camkiv) by ca(2+)/calmodulin-dependent kinase kinase leads to increased camkiv kinase activity. 0.619 SIGNOR-134649 CCNC protein P24863 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 15546612 YES Leads to a following ubiquitination and degradation gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. 0.478 SIGNOR-130592 ITCH protein Q96J02 UNIPROT NFE2 protein Q16621 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 18718448 YES lperfetto Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination| Interestingly, Itch suppressed the transactivation activity of p45/NF-E2 by adding a Lys63-linked polyubiquitin chain. Confocal microscopy revealed that ubiquitinated p45/NF-E2 became localized in the cytoplasm when Itch was over-expressed. Thus, Itch-mediated ubiquitination of p45/NF-E2 does not target the protein for proteasomal degradation, but instead retains p45/NF-E2 in the cytoplasm, where it cannot function as a transactivator. 0.413 SIGNOR-275553 ZMYND11 protein Q15326 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity binding 24675531 YES miannu We found that full-length BS69 specifically interacted with H3K36me3 in native nucleosome co-immunoprecipitation (co-IP) experiments. We propose that BS69 specifically associates with H3K36me3-enriched chromatin through the PWWP domain, which facilitates the recruitment of MYND-bound transcription and chromatin remodeling factors including EZH2, HDAC1, Brg1 and E2F6 to target gene loci, thereby repressing target gene transcription. 0.2 SIGNOR-265353 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR RAPSN protein Q13702 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 19158078 YES miannu We found that rapsyn was polyubiquitinated by KLHL8-containing E3 ligase, but not by KEAP1-containing E3 ligase, clearly indicating that rapsyn is a direct substrate of KLHL8-containing E3 ligase in mammals. We next examined the effect of KLHL-8 depletion on the ubiquitination of rapsyn by performing RNAi experiments in mammalian cells. We found that knockdown of KLHL8 in 3T3 cells reduced the level of rapsyn ubiquitination (Fig. 5C), again indicating that the maintenance mechanism for rapsyn stability is conserved in mammals.The in vitro ubiquitination of mammalian rapsyn by CUL3-containing E3 ligase and the effect of KLHL8 knockdown on the ubiquitination of rapsyn. 0.262 SIGNOR-271782 ATAT1 protein Q5SQI0 UNIPROT TUBA1B protein P68363 UNIPROT up-regulates quantity by stabilization acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 YES lperfetto Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules 0.252 SIGNOR-272245 MAPK14 protein Q16539 UNIPROT MAPK10 protein P53779 UNIPROT down-regulates 9606 20626350 NO gcesareni Jnk and p38 mapk activation have antagonistic effects in many cases. Froma a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab1 0.425 SIGNOR-166608 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK4 protein Q16099 UNIPROT up-regulates activity chemical activation 9606 27586965 YES miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors 0.8 SIGNOR-264473 ACD protein Q96AP0 UNIPROT RPA3 protein P35244 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 YES lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA 0.2 SIGNOR-263329 GNRHR protein P30968 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.473 SIGNOR-257265 CDK5 protein Q00535 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser68 PSDLSPEsPMLSSPP -1 22577147 YES lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta 0.323 SIGNOR-264893 IFNAR1 protein P17181 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation 9606 21631354 YES miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity 0.326 SIGNOR-260435 pictrelisib chemical CHEBI:65326 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0000149 21876152 YES gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed 0.8 SIGNOR-252664 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21892142 YES gcesareni Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk 0.45 SIGNOR-176494 ITGB1BP1 protein O14713 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.314 SIGNOR-257649 CTTNBP2NL protein Q9P2B4 UNIPROT STRN4 protein Q9NRL3 UNIPROT up-regulates activity binding 9606 BTO:0000938 23015759 YES miannu Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A. 0.667 SIGNOR-261701 FYN protein P06241 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.574 SIGNOR-249339 CSNK2A1 protein P68400 UNIPROT CDK1 protein P06493 UNIPROT up-regulates phosphorylation Ser39 MKKIRLEsEEEGVPS 9606 15788687 YES lperfetto Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment. 0.355 SIGNOR-134846 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2C protein O00762 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.726 SIGNOR-271322 AP-2 complex complex SIGNOR-C245 SIGNOR EPS15 protein P42566 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 YES Giorgia Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs 0.667 SIGNOR-260394 CEBPB protein P17676 UNIPROT S100A9 protein P06702 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001370 9706399 YES Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells. 0.2 SIGNOR-254044 KRT1 protein P04264 UNIPROT APC protein P25054 UNIPROT up-regulates activity phosphorylation 9606 18359618 YES Regulation of catabolism miannu Phosphorylation of this central repeat region of APC significantly enhances its affinity for β-catenin. When the repeats are phosphorylated by the cooperative action of CK1 and GSK3β, the binding interaction is significantly altered and enhanced. 0.2 SIGNOR-251879 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 YES lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 0.745 SIGNOR-161706 NMDA receptor_2C complex SIGNOR-C349 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 YES miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  0.8 SIGNOR-264220 UQCRQ protein O14949 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.927 SIGNOR-262197 TGFBR2 protein P37173 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates activity binding 9606 9865696 YES lperfetto Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex 0.568 SIGNOR-245093 CSNK1A1 protein P48729 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Ser39 EMTASSSsDYGQTSK -1 26344095 YES miannu Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites. 0.2 SIGNOR-276935 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Ser242 IPNGFGTsPLTPSAR 10090 BTO:0000142 12796778 YES llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. 0.771 SIGNOR-250677 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr303 GGQYGEVyVGVWKKY -1 34144039 YES miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. 0.303 SIGNOR-277303 AKT2 protein P31751 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 BTO:0000150 12244303 YES gcesareni Akt-induced t157 phosphorylation causes retention of p27(kip1) in the cytoplasm, precluding p27(kip1)-induced g1 arrest.[__]Thus, cytoplasmic relocalization of p27(kip1), secondary to akt-mediated phosphorylation, is a novel mechanism whereby the growth inhibitory properties of p27(kip1) are functionally inactivated and the proliferation of breast cancer cells is sustained. 0.529 SIGNOR-93122 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 BTO:0000527 11514572 YES gcesareni Tc45 dephosphorylated delta egfr in u87mg glioblastoma cells and inhibited mitogen-activated protein kinase erk2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping tc45-d182a mutant, which is capable of forming stable complexes with tc45 substrates, suppressed the activation of erk2 but not phosphatidylinositol 3-kinase. The activation results in reduced egfr phosphorylation after egf stimulation. Introduction of the alpha(1) cytoplasmic domain peptide into cells induces phosphatase activation and inhibits egf-induced cell proliferation and anchorage-independent growth of malignant cells. 0.634 SIGNOR-109804 EXT1 protein Q16394 UNIPROT WNT8B protein Q93098 UNIPROT up-regulates activity 9606 24860992 NO miannu Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern. 0.2 SIGNOR-264020 MRGPRX2 protein Q96LB1 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256787 ASXL1 protein Q8IXJ9 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity binding 9606 21047783 YES miannu Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ.  0.2 SIGNOR-260064 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Thr507 FGESRAStFCGTPDY 9606 11959144 YES PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex 0.378 SIGNOR-248637 CHEK1 protein O14757 UNIPROT PABIR1 protein Q96E09 UNIPROT down-regulates activity phosphorylation Ser37 GGLRRSNsAPLIHGL 9606 BTO:0000018 33108758 YES miannu Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. 0.2 SIGNOR-266380 MRPL19 protein P49406 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.72 SIGNOR-262375 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258272 NR2F2 protein P24468 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 9826778 YES gcesareni The orphan nuclear receptor, coup-tf ii, inactivates myogenesis by post-transcriptional regulation of myod function: coup-tf ii directly interacts with p300 and myod. 0.383 SIGNOR-62248 PTEN protein P60484 UNIPROT PINK1 protein Q9BXM7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 NO miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 0.47 SIGNOR-260056 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI CAPZA1 protein P52907 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 12788695 YES lperfetto We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations. 0.8 SIGNOR-261843 PPP2CB protein P62714 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 17245430 YES A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis 0.435 SIGNOR-248583 MAPK14 protein Q16539 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates activity phosphorylation 9606 21902831 YES lperfetto Through phosphorylation of mef2d, p38 recruits an ash2l-containing complex to myogenic loci during differentiation, which results in the marking of these genes for expression. 0.611 SIGNOR-176554 FKBP5 protein Q13451 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 25790864 YES gcesareni When not associated with glucocorticoids, glucocorticoid receptors are predominantly found in the cytoplasm as part of a multimeric molecular chaperone complex that includes several heat shock proteins (HSPs), such as HSP70 and HSP90, the HSP90_binding protein p23 (also known as PTGES3) and proteins that help to bind HSP90 such as FK506_binding protein 5 (FKBP5). 0.744 SIGNOR-251666 A2M protein P01023 UNIPROT MMP2 protein P08253 UNIPROT down-regulates activity binding -1 9344465 YES lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.635 SIGNOR-261803 BRCA2 protein P51587 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 YES lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer 0.754 SIGNOR-263207 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM52 protein Q96A61 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270956 PTPRF protein P10586 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 10320483 YES lperfetto LAR specifically dephosphorylates and destabilizes p130Cas and may play a role in regulating cell adhesion-mediated cell survival.|Transmembrane tyrosine phosphatase LAR induces apoptosis by dephosphorylating and destabilizing p130Cas. 0.339 SIGNOR-276998 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR5 protein Q9H1C0 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257532 ID3 protein Q02535 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.483 SIGNOR-241158 PRKCE protein Q02156 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation 9606 21660969 YES miannu However, PKCepsilon and Akt can also phosphorylate GSK3beta directly. 0.268 SIGNOR-279101 RNASEK protein Q6P5S7 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.23 SIGNOR-277753 ATF6B protein Q99941 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 14973138 YES Luana  Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β.  0.448 SIGNOR-261566 FGR protein P09769 UNIPROT SDHA protein P31040 UNIPROT unknown phosphorylation Tyr604 YKVRIDEyDYSKPIQ -1 17997986 YES miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. 0.2 SIGNOR-262873 POLR3D protein P05423 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.877 SIGNOR-266130 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 9724739 YES amattioni Activated jnk phosphorylates p53 0.796 SIGNOR-59812 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 10748061 YES Luana RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription. 0.417 SIGNOR-259852 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP -1 9199504 YES miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. 0.524 SIGNOR-250086 PRKCQ protein Q04759 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.291 SIGNOR-249283 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. 0.756 SIGNOR-195621 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 8157000 YES Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. gcesareni To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1. 0.732 SIGNOR-36553 AKT2 protein P31751 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 YES lperfetto We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity 0.327 SIGNOR-148987 GSK3B protein P49841 UNIPROT OGT protein O15294 UNIPROT up-regulates activity phosphorylation Ser4 sVGNVADS 10090 BTO:0000142 23395175 YES miannu We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation. 0.516 SIGNOR-276481 FLI1 protein Q01543 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates activity 10090 BTO:0000725 23320737 NO The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice 0.7 SIGNOR-259972 SDHB protein P21912 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. 0.966 SIGNOR-266272 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120184 SYP protein P08247 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 17331077 YES miannu Synaptophysin I interacts with VAMP2 and controls its subcellular distribution. On the SV membrane, VAMP2 is engaged in a complex with synaptophysin I, which is mutually exclusive with the formation of fusogenic SNARE complexes. This model implicates synaptophysin I in escorting VAMP2 to the sites where exocytosis must take place exclusively after the arrival of the appropriate stimulus. We show that, at early stages along the secretory pathway, synaptophysin I directs sorting of VAMP2 to vesicles exhibiting limited availability for constitutive exocytosis. 0.601 SIGNOR-264102 BCR protein P11274 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 19023129 YES miannu Overexpression of Bcr WT inhibited PPARgamma transcriptional activity (XREF_FIG).|Point-mutation and in vitro kinase analysis showed that PPAR\u03b3 was phosphorylated by Bcr at serine 82. 0.2 SIGNOR-279441 CSNK1A1 protein P48729 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Thr1493 NPPPSPAtERSHYTM 9606 16341017 YES lperfetto We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6) 0.551 SIGNOR-143034 SREBF1 protein P36956 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17921436 YES miannu Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9. 0.428 SIGNOR-255222 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr740 TGESDGGyMDMSKDE -1 7545675 YES Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides 0.749 SIGNOR-248667 COL3A1 protein P02461 UNIPROT ADGRG1 protein Q9Y653 UNIPROT up-regulates activity binding 22238662 YES Using the N-terminal fragment of GPR56 (GPR56(N)) as a probe, we have recently demonstrated that collagen III is the ligand of GPR56 in the developing brain. In this report, we discover a new functional domain in GPR56(N), the ligand binding domain. 0.2 SIGNOR-253979 SYVN1 protein Q86TM6 UNIPROT CPT2 protein P23786 UNIPROT down-regulates quantity ubiquitination 9606 33207079 YES miannu Taken together, these data suggest that HRD1 selectively and specifically downregulates intracellular CPT2 levels.|These results demonstrate that HRD1 ubiquitinates CPT2, which is processed through Lys-48-linked ubiquitin chains. 0.2 SIGNOR-278723 CTNND1 protein O60716 UNIPROT CDH3 protein P22223 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0003564 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.751 SIGNOR-252124 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR LIN28A protein Q9H9Z2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.714 SIGNOR-269238 GSK3B protein P49841 UNIPROT FRAT1 protein Q92837 UNIPROT down-regulates activity phosphorylation Ser188 RLQQRRGsQPETRTG 9606 BTO:0002181 16982607 YES miannu Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells.  Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription. 0.775 SIGNOR-276057 TACR3 protein P29371 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.283 SIGNOR-257438 EZH2 protein Q15910 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 23239736 YES miannu This study demonstrates that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a Polycomb repressor to a transcriptional coactivator of AR (and potentially other factors). 0.541 SIGNOR-251542 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI HTR1A protein P08908 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190687 STK4 protein Q13043 UNIPROT AR protein P10275 UNIPROT down-regulates 21512132 NO lperfetto Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter. 0.2 SIGNOR-151712 TMOD1 protein P28289 UNIPROT TPM3 protein P06753 UNIPROT down-regulates activity binding 9606 8002995 YES irozzo Tropomodulin is a 40.6-kDa protein that binds to one end of the rod-like tropomyosin and inhibits its cooperativity and binding to actin. [.] we demonstrate that it is the N-terminus of tropomyosin that interacts with tropomodulin. Among several tropomyosin isoforms tested, hTM5 encoded by the human gamma-tropomyosin gene has the highest affinity toward human erythrocyte tropomodulin. 0.73 SIGNOR-259111 COLGALT2 protein Q8IYK4 UNIPROT COL3A1 protein P02461 UNIPROT up-regulates activity glycosylation -1 19075007 YES Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. 0.402 SIGNOR-261158 calcitriol smallmolecule CHEBI:17823 ChEBI calcitetrol smallmolecule CHEBI:47799 ChEBI up-regulates quantity precursor of 30080183 YES lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). 0.8 SIGNOR-270570 DOK1 protein Q99704 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257672 CKM complex complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.383 SIGNOR-273158 ZBTB14 protein O43829 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 10080939 NO miannu ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter 0.316 SIGNOR-220537 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269367 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120016 CAST protein P20810 UNIPROT CAPN3 protein P20807 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 YES lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain 0.57 SIGNOR-251603 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr509 PVFDLTTtPKGGTPA 10116 16611631 YES lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.473 SIGNOR-146011 mTORC2 complex SIGNOR-C2 SIGNOR SLC7A11 protein Q9UPY5 UNIPROT down-regulates activity phosphorylation Ser26 NVNGRLPsLGNKEPP 9606 BTO:0002036 28648777 YES miannu MTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity.  0.275 SIGNOR-273682 PRKCA protein P17252 UNIPROT GRM1 protein Q13255 UNIPROT down-regulates activity phosphorylation Thr695 GSKKKICtRKPRFMS 9606 10823959 YES lperfetto Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s). 0.386 SIGNOR-249043 MYO10 protein Q9HD67 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity relocalization 10090 BTO:0000938 17237772 YES miannu Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin. 0.686 SIGNOR-268282 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser230 PEGATPTsPVGHFAK 9606 BTO:0000848 BTO:0001253 20959475 YES lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). 0.713 SIGNOR-252953 ASB9 protein Q96DX5 UNIPROT CKB protein P12277 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17148442 YES miannu We demonstrate that creatine kinase B (CKB) interacts with Asb-9 in a specific, SOCS box-independent manner. This interaction increases the polyubiquitylation of CKB and decreases total CKB levels within the cell. The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme. 0.684 SIGNOR-271623 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT down-regulates activity phosphorylation Ser67 DERVKEPsQDTVATE 31938050 YES lperfetto Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization. 0.312 SIGNOR-275852 PRKCD protein Q05655 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates phosphorylation Thr312 TNGEFKMtDPDEVAR 9606 21321929 YES lperfetto We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter. 0.347 SIGNOR-172113 PRKACA protein P17612 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN 10116 BTO:0001009 11510412 YES The in vitro phosphorylation of a site unique to B-Raf (Ser429) has been proposed to be responsible for the negative regulation of the isoenzyme by Akt. Using phosphopetide mapping and site-directed mutagenesis we showed that Ser429 is phosphorylated upon cAMP elevation in PC12 cells and proposed that PKA is a major kinase phosphorylating the B-Raf-specific site in vivo 0.634 SIGNOR-259922 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser291 EKDASKKsDSNPLTE 9534 23519612 YES miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 0.318 SIGNOR-262710 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257552 PAFAH1B1 protein P43034 UNIPROT Cerebral_cortex_development phenotype SIGNOR-PH66 SIGNOR up-regulates 9606 23973156 NO miannu LIS1, the first gene to be identified as involved in a neuronal migration disease, is a dosage-sensitive gene whose proper levels are required for multiple aspects of cortical development. Deletions in LIS1 result in a severe brain malformation, known as lissencephaly, whereas duplications delay brain development. LIS1 affects the proliferation of progenitors, spindle orientation and interkinetic nuclear movement in the ventricular zone, as well as nucleokinesis and migration of neurons. 0.7 SIGNOR-252165 GSK3A protein P49840 UNIPROT MAF protein O75444 UNIPROT down-regulates phosphorylation 9606 18042454 YES miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. 0.2 SIGNOR-159361 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity chemical activation 9606 18249092 YES gcesareni Furthermore, overall PKB activity, primarily consisting of cytosolic enzyme, was dependent upon levels of PI(3,4)P2, while only membrane-associated PKB activity was dependent upon PI(3,4,5)P3 levels. We conclude that PI(3,4,5)P3 and PI(3,4)P2 have distinct roles in determining PKB phosphorylation and activity. Thus, when investigating PI3K-PKB pathways, the importance of both lipids must be considered 0.8 SIGNOR-252432 Doxorubicin hydrochloride chemical CHEBI:31522 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 1963303 YES miannu DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. 0.8 SIGNOR-259324 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity dephosphorylation Ser386 HQLFRGFsFVAITSD 10090 15206906 YES RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity 0.361 SIGNOR-248322 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser37 EDLTDELsLNKISAD -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276206 CDC42BPA protein Q5VT25 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 YES lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. 0.517 SIGNOR-188785 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 NO �The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation. 0.7 SIGNOR-254977 serotonin smallmolecule CHEBI:28790 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 31024440 YES brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). 0.8 SIGNOR-264187 SFXN1 protein Q9H9B4 UNIPROT L-serine chemical CHEBI:17115 ChEBI up-regulates quantity relocalization 9606 30442778 YES lperfetto SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. 0.8 SIGNOR-268245 motesanib chemical CHEBI:51098 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194569 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates relocalization 9606 18596912 YES fspada The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform 0.458 SIGNOR-179400 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258233 PJA2 protein O43164 UNIPROT MFHAS1 protein Q9Y4C4 UNIPROT up-regulates activity ubiquitination 9606 28471450 YES miannu These results suggest that the ubiquitylation of MFHAS1 by praja2 has a vital role in M1 macrophage polarization and promotes the transformation of M2 macrophages to M1 macrophages through both the JNK and p38 pathways. 0.404 SIGNOR-278559 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation Lys70 EGILRRLkKYDNCWL 9606 BTO:0000007 21726808 YES lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 0.544 SIGNOR-267597 PLK1 protein P53350 UNIPROT NUP35 protein Q8NFH5 UNIPROT down-regulates activity phosphorylation 9606 29065306 YES miannu Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association. 0.415 SIGNOR-279252 ILK protein Q13418 UNIPROT PARVB protein Q9HBI1 UNIPROT up-regulates activity phosphorylation 9606 15159419 YES miannu These results indicate that affixin directly associates with \u03b1-actinin only when its CH2 domain is phosphorylated by ILK.|This may indicate that phosphorylation of the CH2 domain by ILK induces a conformational change of the CH2 domain of affixin, which enables affixin to interact with alpha-actinin to evoke the subsequent maturation of the FA complex. 0.965 SIGNOR-278259 PLCB2 protein Q00722 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate(6-) smallmolecule CHEBI:203600 ChEBI up-regulates quantity chemical modification 9606 23994464 YES apalma The first phase of this signal is likely mediated by phospholipase C≈í‚⧠(PLC≈í‚â§) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores 0.8 SIGNOR-255017 FASTKD5 protein Q7L8L6 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 NO miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. 0.7 SIGNOR-261226 XAF1 protein Q6GPH4 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates binding 9606 17613533 YES gcesareni Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3 0.391 SIGNOR-155288 FBXO9 protein Q9UK97 UNIPROT TTI1 protein O43156 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23263282 YES miannu Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins. 0.468 SIGNOR-271997 PIH1D1 protein Q9NWS0 UNIPROT R2TP core co-chaperone complex SIGNOR-C515 SIGNOR form complex binding 9606 29662061 YES miannu  Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90.  0.843 SIGNOR-270926 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation -1 9793625 YES Mometasone furoate (MF, CAS 83919-23-7, Sch 32088), budesonide (BUD, CAS 51372-29-3), fluticasone propionate (FP, CAS 80474-14-2), and triamcinolone acetonide (TA, CAS-76-25-5) are corticosteroids. All of the test compounds had a higher affinity for the recombinant glucocorticoid receptor than the reference glucocorticoid receptor ligand, dexamethasone (DEX, CAS 50-02-2). All compounds showed greater potency than dexamethasone in stimulating transcription of a synthetic target gene regulated by a glucocorticoid response element. 0.8 SIGNOR-253053 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 10090 BTO:0000944 12169099 YES lperfetto c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells 0.501 SIGNOR-235522 IL13RA1 protein P78552 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 YES milica IL-4R, ?c, and IL-13R1 All contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectivelyil-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells. 0.565 SIGNOR-100756 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 YES gcesareni This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses. 0.244 SIGNOR-191670 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.423 SIGNOR-248293 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 22926518 YES miannu The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors. 0.643 SIGNOR-256181 IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15864272 YES gcesareni The only type ii ifn, ifn-g, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2 0.702 SIGNOR-135952 FCGR2B protein P31994 UNIPROT TLR4 protein O00206 UNIPROT down-regulates activity 9606 24445665 NO lperfetto Triggering of FcgammaRIIB also subverted the normal activation of DCs by the TLR4 agonist lipopolysaccharide. In addition, triggering of FcgammaRIIB by immune complexes might affect the differentiation of moDCs. When moDCs develop from monocytes invitro in the presence of immune complexes, their differentiation is hampered and they no longer produce IL-12 in response to TLR4 agonists. 0.382 SIGNOR-249525 MAP3K7 protein O43318 UNIPROT PTPN3 protein P26045 UNIPROT unknown phosphorylation Ser359 PAMRRSLsVEHLETK 9606 9341175 YES gcesareni Mutation of ser359 and ser853 to alanine significantly reduced the association between 14-3-3beta and ptph1. Furthermore, association of ptph1 and 14-3-3beta was detected in several cell lines and was regulated in response to extracellular signals 0.264 SIGNOR-52781 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 NO lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. 0.7 SIGNOR-216322 EREG protein O14944 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 22891299 YES gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 0.59 SIGNOR-191785 FSTL1 protein Q12841 UNIPROT DIP2A protein Q14689 UNIPROT up-regulates activity binding 9606 BTO:0005562 20054002 YES miannu We identified DIP2A as a novel FSTL1-binding partner from the membrane fraction of endothelial cells. Co-immunoprecipitation assays revealed a direct physical interaction between FSTL1 and DIP2A. The work in the current study identifies DIP2A as a novel receptor for FSTL1 that mediates Akt activation and cell survival and function in cardiovascular cells in vitro. 0.481 SIGNOR-266603 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH23 protein Q9H251 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265839 HNRNPU protein Q00839 UNIPROT ZFY protein P08048 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 NO lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. 0.2 SIGNOR-262287 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Ser58 SRGGARAsPATQPPP 9606 12478298 YES lperfetto In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites 0.665 SIGNOR-96410 SLC24A2 protein Q9UI40 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264399 GRK5 protein P34947 UNIPROT NTSR1 protein P30989 UNIPROT up-regulates activity phosphorylation 9606 26120872 YES miannu Here we report the unique phosphorylation\nof NTSR1 by GRK2 and GRK5, which belong to the GRK2 and GRK4 subfamilies,\nrespectively. 0.592 SIGNOR-278234 ENMD-2076 chemical CID:16041424 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191466 STK4 protein Q13043 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Thr18 PAPNFKAtAVMPDGQ -1 23386615 YES miannu Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183. 0.2 SIGNOR-276486 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser503 NDEITDEsLENFPSS 9606 16874298 YES lperfetto Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin 0.698 SIGNOR-148327 FBXL7 protein Q9UJT9 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 10090 BTO:0002268 25778398 YES miannu Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation. 0.628 SIGNOR-272437 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 YES gcesareni Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells. 0.398 SIGNOR-179404 POMC protein P01189 UNIPROT MC5R protein P33032 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.765 SIGNOR-268715 DAPK3 protein O43293 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000776 17339337 YES gcesareni A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53. 0.407 SIGNOR-153495 SP1 protein P08047 UNIPROT SLC19A1 protein P41440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 15652157 NO Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation. 0.2 SIGNOR-254064 TGFB1 protein P01137 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8142649 NO Regulation miannu Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. 0.2 SIGNOR-251798 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 9047237 YES lperfetto Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient. 0.804 SIGNOR-46855 RUNX3 protein Q13761 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255087 ABRAXAS1 protein Q6UWZ7 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 YES lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  0.2 SIGNOR-263214 PTPN9 protein P43378 UNIPROT NSF protein P46459 UNIPROT down-regulates dephosphorylation Tyr83 QEIEVSLyTFDKAKQ 9606 15322554 YES gcesareni Our results suggest that the molecular mechanism by which ptp-meg2 promotes secretory vesicle fusion involves the local release of nsf from a tyrosine-phosphorylated, inactive state. 0.413 SIGNOR-128348 HTR1B protein P28222 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-256863 PRKCA protein P17252 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates activity phosphorylation Ser879 LIDRNQKsDKKPDRE 9606 22798526 YES miannu PKC\u03b1 phosphorylation of p120 at S879 is a critical phospho-switch mediating disassociation of p120 from VE-cadherin that results in AJ disassembly.|We surmised that PKCalpha may function to disrupt AJs by signaling dissociation of p120 from VE-cadherin. 0.252 SIGNOR-278261 MALT1 protein Q9UDY8 UNIPROT CBM complex SIGNOR-C555 SIGNOR form complex binding 9606 15122200 YES miannu CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways. 0.811 SIGNOR-276295 MC5R protein P33032 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.458 SIGNOR-256798 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 4188963 YES dermatitis gcesareni 0.8 SIGNOR-251705 APP protein P05067 UNIPROT Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR up-regulates 9606 11578751 NO lperfetto Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. The senile plaques are generated by a deposition in the human brain of fibrils of the β-amyloid peptide (Aβ), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). Tau protein is the major component of paired helical filaments (PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs). 0.7 SIGNOR-251638 DIABLO protein Q9NR28 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 10929711 YES gcesareni Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release. 0.571 SIGNOR-80212 CTH protein P32929 UNIPROT L-selenocysteine zwitterion smallmolecule CHEBI:57843 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275821 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 14701738 YES miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. 0.332 SIGNOR-261726 ULK1 protein O75385 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates activity phosphorylation Ser366 QEPELLIsGMEKPLP 9606 24119841 YES miannu Collectively, our data indicates that cGAS is essential for the activation of AMPK and ULK1 suppression of STING (XREF_FIG) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity (XREF_FIG).|Collectively, our data indicates that cGAS is essential for the activation of AMPK/ULK1 suppression of STING ( xref ) and that cGAMPs are responsible for triggering the dephosphorylation of AMPK T172 and activation of ULK1 which phosphorylates STING on S366 to impede its activity ( xref ). 0.2 SIGNOR-279316 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser401 VPSDNIDsQGRNCST -1 8662852 YES we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 0.693 SIGNOR-251196 miR-29b mirna URS0000150A7D_9606 RNAcentral SP1 protein P08047 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 21730352 NO miannu We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation. 0.4 SIGNOR-256244 PRKACA protein P17612 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity phosphorylation Ser863 TSTLPRNsGAGASSG 9606 8663994 YES miannu Phosphorylation of Ser-845 on GluR1 by PKA potentiates its response to glutamate. 0.493 SIGNOR-249987 TLN1 protein Q9Y490 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.603 SIGNOR-257619 BMP2 protein P12643 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 12589053 NO fspada Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma. 0.392 SIGNOR-98369 PIP3 smallmolecule CHEBI:16618 ChEBI WDR45 protein Q9Y484 UNIPROT up-regulates activity chemical activation 9606 BTO:0001938 28561066 YES miannu All WIPI members fold into seven-bladed β-propeller proteins that bind PtdIns3P and co-localize at nascent autophagosomes. 0.8 SIGNOR-268475 LPCAT4 protein Q643R3 UNIPROT 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI down-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272772 PAK4 protein O96013 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by stabilization phosphorylation Ser254 SKTFSRMsLLHKHEE -1 29849120 YES miannu PAK4 bound and directly phosphorylated Slug at two previously unknown sites, S158 and S254, which resulted in its stabilization.  0.2 SIGNOR-277394 KDM5B protein Q9UGL1 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264303 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity phosphorylation Thr602 TAIISIPtPPVTTPE 10116 BTO:0000601 11080179 YES miannu We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP. 0.367 SIGNOR-262935 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.454 SIGNOR-257400 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.474 SIGNOR-256728 AURKA protein O14965 UNIPROT SPIN1 protein Q9Y657 UNIPROT up-regulates activity phosphorylation Ser124 RVATSRIsDAHLADT 9606 BTO:0000567 22258766 YES miannu The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function. 0.243 SIGNOR-273550 2,5-dimethylcelecoxib chemical CHEBI:232608 ChEBI PTGES protein O14684 UNIPROT down-regulates activity post transcriptional regulation 9606 BTO:0000567 21983014 YES Marta Tosoni Dimethylcelecoxib, a non-COX-2 inhibiting derivative of celecoxib, inhibits PGE2 synthesis by transcriptional inhibition of mPGES-1. 0.8 SIGNOR-278100 SCF(TBL1) complex SIGNOR-C533 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys671 EDKPQDYkKRLSVEL 9606 BTO:0000007 20181957 YES miannu Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC).  0.728 SIGNOR-271947 SIRT1 protein Q96EB6 UNIPROT HYOU1 protein Q9Y4L1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 22564731 NO miannu Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress. 0.374 SIGNOR-255143 MAPK1 protein P28482 UNIPROT PPP1R9B protein Q96SB3 UNIPROT unknown phosphorylation Ser15 GPGGPLRsASPHRSA 9606 15728359 YES lperfetto We have identified three sites phosphorylated by ERK2 (Ser-15 and Ser-205) and cyclin-dependent PK 5 (Cdk5) (Ser-17), within the actin-binding domain of spinophilin. 0.464 SIGNOR-249435 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 22640926 NO fspada We conclude that DLK1(PREF1) is well expressed in human ASC and acts as a negative regulator of adipogenesis. 0.7 SIGNOR-197634 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates activity dephosphorylation Ser667 SSLIRKRsTRRSVRG 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.2 SIGNOR-272506 glycogen smallmolecule CHEBI:28087 ChEBI PYGB protein P11216 UNIPROT up-regulates activity chemical activation 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed […] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267951 SLA2 protein Q9H6Q3 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity binding 10090 BTO:0000740 27458164 YES miannu We screened a panel of SH2 domain-containing proteins and identified SLAP2 as a potent interacting partner of FLT3. We demonstrated that interaction occurs when FLT3 is activated, and also, an intact SH2 domain of SLAP2 is required for binding. Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5. 0.248 SIGNOR-256155 SMURF1 protein Q9HCE7 UNIPROT ILRUN protein Q9H6K1 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272697 PRKCG protein P05129 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 BTO:0000887 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.2 SIGNOR-134636 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr315 MPMDTSVyESPYSDP 9606 BTO:0000661 11828374 YES lperfetto We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. 0.2 SIGNOR-247048 MAPK1 protein P28482 UNIPROT MYB protein P10242 UNIPROT unknown phosphorylation Ser532 KIKQEVEsPTDKSGN -1 8960373 YES lperfetto Functional analysis of phosphorylation at serine 532 of human c-Myb by MAP kinase| Expression of a constitutively active form of Ras together with c-Myb in transient transfection experiments had no effect on the transcriptional activity of c-Myb, while expression of a polypeptide containing the c-Myb C-terminal domain stimulated c-Myb activity. This effect is reduced upon MAPK-dependent phosphorylation of serine 532. 0.479 SIGNOR-249420 TIMELESS protein Q9UNS1 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity binding 9534 23418588 YES miannu We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization. 0.795 SIGNOR-268054 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT up-regulates activity phosphorylation Ser44 GLKFMQAsEDLLKEH 9606 BTO:0000093 8245015 YES miannu An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells. 0.2 SIGNOR-250303 PTGS2 protein P35354 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000007 32995789 NO miannu Given our finding that COX-2 signaling does not regulate viral entry or replication, the role of COX-2 induction upon SARS-CoV-2 infection remains an area for future investigation. Rather than directly affecting viral entry or replication, COX-2 induction may regulate the severe lung inflammation and injury seen in COVID-19 patients (35, 36), though it is unclear whether COX-2 would be beneficial, neutral, or detrimental to disease. COX-2 could enhance lung injury in COVID-19, as PGE2 has been reported to induce IL-1β and exacerbate lung injury in bone marrow transplant mice 0.7 SIGNOR-262509 Ub:E2 complex SIGNOR-C497 SIGNOR CUL9 protein Q8IWT3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271114 FFAR1 protein O14842 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.571 SIGNOR-257272 CHEK1 protein O14757 UNIPROT CDC25C protein P30307 UNIPROT down-regulates quantity by destabilization phosphorylation Ser216 SGLYRSPsMPENLNR 9606 20068082 YES gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). 0.85 SIGNOR-163158 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248754 SPAG9 protein O60271 UNIPROT CDON/SPAG9 complex SIGNOR-C21 SIGNOR form complex binding 9606 BTO:0000222 17074887 YES gcesareni In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway. 0.496 SIGNOR-149178 HRH1 protein P35367 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257163 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000938 8387505 YES inferred from 70% family members lperfetto The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases 0.2 SIGNOR-270002 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18570872 YES amattioni In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein. 0.746 SIGNOR-179104 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10090 12808134 YES lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). 0.748 SIGNOR-134477 PRKCA protein P17252 UNIPROT FERMT3 protein Q86UX7 UNIPROT up-regulates activity phosphorylation Ser484 LSLQRTGsGGPGNHP 9606 BTO:0000565 25609252 YES miannu  PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38).  0.2 SIGNOR-266415 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 YES PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. 0.404 SIGNOR-248343 SOCS5 protein O75159 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR up-regulates activity binding 9606 BTO:0000007 15590694 YES miannu SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation. 0.498 SIGNOR-271522 AKT1 protein P31749 UNIPROT PIK3R6 protein Q5UE93 UNIPROT up-regulates activity phosphorylation Thr607 SHRPREVtVSLRATG 25753393 YES lperfetto P84 forms a negative regulatory complex with p110gamma to control PI3Kgamma signalling during cell migration|However, phosphorylation at this site was confirmed using an in vitro kinase assay in which Akt kinase was shown to readily phosphorylate Thr607 using a p84 peptide (Figure 1e), where Thr607 in conjunction with surrounding residues forms an Akt kinase consensus sequence|In contrast, although p84-T607A exhibited basal p110γ dimerisation, this interaction could not be further induced with stimulation 0.448 SIGNOR-275722 SPAG9 protein O60271 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates binding 9606 BTO:0000222 17074887 YES p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors. gcesareni Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants. 0.444 SIGNOR-150147 PRKAR2B protein P31323 UNIPROT PRKAR2B protein P31323 UNIPROT up-regulates activity phosphorylation Ser114 NRFTRRAsVCAEAYN 10090 15822905 YES miannu Ser114 (the autophosphorylation site) of human RII beta. Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A RII beta regulatory subunit to lose its ability to revert transformed fibroblasts. 0.2 SIGNOR-250076 ANKRD11 protein Q6UB99 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0000093 18840648 YES miannu Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53. 0.308 SIGNOR-266734 SWI/SNF complex complex SIGNOR-C92 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18332116 NO irozzo HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a 0.289 SIGNOR-256300 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARA protein P10276 UNIPROT up-regulates activity chemical activation 9606 17132853 YES miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 0.8 SIGNOR-256194 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser29 IEDSQPEsQVLEDDS 9606 12697768 YES llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 0.873 SIGNOR-100645 GSK3B protein P49841 UNIPROT JUNB protein P17275 UNIPROT down-regulates quantity by destabilization phosphorylation Thr255 EARSRDAtPPVSPIN 9606 BTO:0000567 22710716 YES miannu  Thus, JunB phosphorylation at S251 and T255 by GSK3β is primed by phosphorylation at S259 by a yet to-be-identified kinase.Phosphorylation at S251, T255 and S259 is required for JunB degradation. 0.2 SIGNOR-276417 NDUFB10 protein O96000 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 0.823 SIGNOR-262163 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 YES gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf 0.272 SIGNOR-78689 YES1 protein P07947 UNIPROT WBP2 protein Q969T9 UNIPROT up-regulates activity phosphorylation Tyr192 MMDGAMGyVQPPPPP 9606 BTO:0000093 21642474 YES miannu Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα. 0.305 SIGNOR-273581 TEAD1 protein P28347 UNIPROT BMP4 protein P12644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23673366 NO gcesareni Taz induces bmp4 transcription through the tead family of transcription factors, which mediate bmp4 promoter activation through binding to tead response element 1 (tre1). 0.258 SIGNOR-202049 DLD protein P09622 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 YES lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. 0.646 SIGNOR-268243 GTF3A protein Q92664 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR up-regulates activity relocalization 9606 8907699 YES lperfetto One of the major functions of TFIIIA is to program the 5S RNA gene for transcription by binding directly to the ICR, which subsequently directs an ordered assembly of general factors to form a functional transcription complex. 0.532 SIGNOR-269309 DOK1 protein Q99704 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257678 VAV1 protein P15498 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.749 SIGNOR-260580 CD70 protein P32970 UNIPROT CD27 protein P26842 UNIPROT up-regulates binding 9606 BTO:0000776 12324477 YES gcesareni The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. 0.771 SIGNOR-93435 TARS1 protein P26639 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 25824639 YES miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 0.8 SIGNOR-270503 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser206 SSSTYPHsPTSSDPG 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.499 SIGNOR-248302 IL20 protein Q9NYY1 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 11163236 YES gcesareni An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis. 0.769 SIGNOR-151874 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Ser855 PKPKQFSsFEKRAKI 9606 21068236 YES lperfetto Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) in the resting state of the cell and dephosphorylated when cells are infected by rna virus. Mutation at aa position 770 or 854 to 855 of rig-i renders it constitutively active 0.2 SIGNOR-169404 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser255 SSQMKSMsTFIEEAY 9606 BTO:0000567 25670858 YES lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 0.587 SIGNOR-265226 MAPK1 protein P28482 UNIPROT MYO9B protein Q13459 UNIPROT unknown phosphorylation Thr1346 RATGAALtPTEERRT 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.303 SIGNOR-262777 LPAR3 protein Q9UBY5 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22863277 YES gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. 0.399 SIGNOR-198547 FLT3 protein P36888 UNIPROT FZD4 protein Q9ULV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002882 15650056 NO AML-typical Flt3 mutations induce the expression of Frizzled-4 on the mRNA and protein level, mimicking the effects of IL-3. 0.2 SIGNOR-261533 DOK1 protein Q99704 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257677 HECTD4 protein Q9Y4D8 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 YES miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 0.2 SIGNOR-267148 SMARCA4 protein P51532 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 19571879 YES miannu Tert activates wnt reporter plasmids in a brg1-dependent manner. 0.775 SIGNOR-186607 diarsenic trioxide chemical CHEBI:30621 ChEBI PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR down-regulates quantity by destabilization chemical inhibition 9606 24344243 YES ATO was shown to degrade PML-RARa via its PML moiety further reinforcing the idea that APL is addicted to the PML-RARa oncoprotein 0.8 SIGNOR-259924 DLG4 protein P78352 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 9278515 YES brain lperfetto The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses. 0.81 SIGNOR-264194 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.439 SIGNOR-235715 TNKS1BP1 protein Q9C0C2 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.64 SIGNOR-268304 C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR C3 protein P01024 UNIPROT up-regulates activity cleavage Arg748 ASHLGLArSNLDEDI 9606 BTO:0000089 26489954 YES lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). 0.906 SIGNOR-263478 SIRT1 protein Q96EB6 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21633182 YES miannu Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms. 0.694 SIGNOR-268032 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 YES gcesareni Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. 0.699 SIGNOR-252588 CDK5 protein Q00535 UNIPROT PHACTR3 protein Q96KR7 UNIPROT down-regulates quantity phosphorylation Ser318 QGRESKGsPKKRLDV 10116 BTO:0000938 21487013 YES miannu We show that scapinin is phosphorylated at a highly conserved site in the central region of the protein (Ser-277) by Cdk5 in vitro. Expression of a scapinin phospho-mimetic mutant (S277D) restored normal axon elongation without affecting actin binding. Instead, phosphorylated scapinin was sequestered in the cytoplasm of neurons and away from the axon.  0.2 SIGNOR-273607 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Thr404 SSMSTEQtLASDTDS 9606 11062067 YES lperfetto The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro. 0.221 SIGNOR-83715 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 YES lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity 0.2 SIGNOR-252765 NUDT3 protein O95989 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.2 SIGNOR-81759 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr216 VLNSHDLyQKVAQEI 9606 15952790 YES llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. 0.605 SIGNOR-138146 SP1 protein P08047 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12801909 NO miannu It was suggested that mutual interaction of XRE2 and XRE3 is important for transcriptional regulation, and that the Sp1 binding to the Sp1-like motif (-824) enhances both the constitutive and inducible transcriptional activities of the human CYP1B1 gene. 0.267 SIGNOR-255196 ADX-47273 chemical CID:11383075 PUBCHEM MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates chemical activation 9606 Other YES Selleck|inferred from family member gcesareni 0.8 SIGNOR-270276 GNAI1 protein P63096 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR down-regulates 9606 BTO:0003191 23691483 YES Marta Tosoni GNAI1 can signifi cantly inhibit the migration and metastasis of HCC cells. 0.7 SIGNOR-278878 DLL3 protein Q9NYJ7 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. 0.2 SIGNOR-209747 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser386 DDKITQAsQSQESED 9606 BTO:0000007 19816404 YES lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination 0.755 SIGNOR-188408 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 SIGNOR-C17 10864927 YES gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.858 SIGNOR-78432 isoprenaline chemical CHEBI:64317 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8982677 YES miannu K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists. 0.8 SIGNOR-258576 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Pyl) smallmolecule CHEBI:15185 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269494 Av/b1 integrin complex SIGNOR-C175 SIGNOR UTF1 protein Q5T230 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.261 SIGNOR-253275 TGFB1 protein P01137 UNIPROT CCNA2 protein P20248 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 7592630 NO gcesareni Expression of one of these components, cyclin a, is inhibited by tgf-beta treatment. We have identified a 760-base pair fragment of the human cyclin a gene promoter that is sufficient to confer tgf-beta responsiveness. 0.285 SIGNOR-29516 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 11368773 YES lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. 0.769 SIGNOR-247030 WNT3A protein P56704 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 19175684 NO gcesareni Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs. 0.34 SIGNOR-183538 ABL1 protein P00519 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Tyr99 SVPTHSPyAQPSSTF 9606 10391251 YES gcesareni C-abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-abl stimulates p73-mediated transactivation and apoptosis. 0.753 SIGNOR-68931 CDK2 protein P24941 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates activity phosphorylation Thr611 ETLPISStPSKSVLP BTO:0001938 15024056 YES llicata We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins. 0.749 SIGNOR-250731 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 BTO:0000007 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.301 SIGNOR-262981 HES1 protein Q14469 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 BTO:0000887 10066785 NO lperfetto Notch signaling up-regulated hes1 mrna expression within 1 h and subsequently reduced expression of myod mrna. 0.295 SIGNOR-235596 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser186 PVLRQSIsFSGLPSG -1 14688255 YES miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. 0.698 SIGNOR-250152 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser122 DQHLMKCsPAQLLCS 9606 10864927 YES lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.844 SIGNOR-216741 ATG7 protein O95352 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT up-regulates activity binding 10090 22170151 YES lperfetto Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe 0.789 SIGNOR-191540 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.2 SIGNOR-141416 SETD2 protein Q9BYW2 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18158893 NO gcesareni In response to hypoxia, foxo3a transcript levels accumulate in an hif1-dependent way, resulting in enhanced foxo3a activity. 0.2 SIGNOR-160201 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F8 protein P00451 UNIPROT down-regulates activity cleavage Arg759 KNNAIEPrSFSQNSR -1 10350471 YES lperfetto N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin. 0.455 SIGNOR-263644 KAT5 protein Q92993 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.782 SIGNOR-269297 Ast-487 chemical CID:11409972 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258173 PRKAA1 protein Q13131 UNIPROT SCD protein O00767 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21478464 NO miannu Tr4 transactivation is inhibited via phosphorylation by metformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression. 0.275 SIGNOR-173161 SGK2 protein Q9HBY8 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.522 SIGNOR-252990 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser161 QKATPGSsRKTCRYI 9606 BTO:0000567 15525512 YES llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  0.992 SIGNOR-250605 GNA12 protein Q03113 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 23450633 YES gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. 0.557 SIGNOR-192108 TERF2IP protein Q9NYB0 UNIPROT Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 BTO:0000567 15383534 YES lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. 0.833 SIGNOR-263319 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 BTO:0000671 15694384 YES llicata Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925. 0.2 SIGNOR-133841 PPP3CB protein P16298 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 11062529 YES gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.723 SIGNOR-84047 GAN protein Q9H2C0 UNIPROT ATG16L1 protein Q676U5 UNIPROT down-regulates quantity ubiquitination 9534 BTO:0000298 30770803 YES miannu Here we identify Gigaxonin24, an E3 ligase mutated in a fatal neurodegenerative disease called giant axonal neuropathy (GAN)25, as the first regulator of ATG16L1. Gigaxonin poly-ubiquitinates and controls the degradation of ATG16L1, and is essential to activate autophagy. 0.2 SIGNOR-268948 MAPK3 protein P27361 UNIPROT IL16 protein Q14005 UNIPROT up-regulates phosphorylation Ser845 SIRQRISsFETFGSS 9606 14768064 YES lperfetto The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response. 0.266 SIGNOR-121856 UNC5C protein O95185 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 YES miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. 0.668 SIGNOR-268165 KISS1R protein Q969F8 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256893 DNAJC19 protein Q96DA6 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.678 SIGNOR-267694 ARAP2 protein Q8WZ64 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.493 SIGNOR-260455 CDON protein Q4KMG0 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity binding 9606 BTO:0000222 19470755 YES lperfetto Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity 0.517 SIGNOR-185762 LRP1B protein Q9NZR2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002940 27626682 NO irozzo Conversely, in Calu-1 cells, which express higher endogenous levels of the receptor, siRNA-mediated LRP1B knockdown significantly enhanced cellular proliferation. Taken together, these findings demonstrate that, consistent with the postulated tumor suppressor function, overexpression of full-length Lrp1b leads to impaired cellular proliferation, while LRP1B knockdown has the opposite effect. 0.7 SIGNOR-259089 TIAM2 protein Q8IVF5 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.588 SIGNOR-260578 TFE3 protein P19532 UNIPROT HEXA protein P06865 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.2 SIGNOR-276824 TSC2 protein P49815 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates activity binding 9606 BTO:0000142;BTO:0000671 10807585 YES lperfetto Furthermore, tsc2 is directly phosphorylated by akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1. 0.934 SIGNOR-77400 FRAT2 protein O75474 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity binding -1 11738041 YES gcesareni The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation. 0.694 SIGNOR-244030 FYN protein P06241 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Tyr487 DNSSDSDyDLHGAQR -1 11298344 YES Tyrosine-mutated CD5 molecules have been used to show that residues Y429 and Y463 are targeted in vivo by protein tyrosine kinases following cell stimulation with anti-CD3 mAb or pervanadate. This is in agreement with data from direct in vitro kinase assays using purified recombinant Lck and Fyn protein tyrosine kinases. 0.492 SIGNOR-251152 tazarotene chemical CHEBI:32184 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9534 19058965 YES Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  0.8 SIGNOR-258029 RALGAPA1 protein Q6GYQ0 UNIPROT RalGAP1 complex SIGNOR-C468 SIGNOR form complex binding 10090 BTO:0000011 21148297 YES miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. 0.413 SIGNOR-269791 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT down-regulates phosphorylation Ser162 LRRYTTFsKRKTGIM 10090 16537394 YES lperfetto Mimicking phosphorylation of serine-162, a target of protein kinase c-alpha, with an aspartic acid substitution (srf-s162d) completely inhibited srf-dna binding and blocked alpha-actin gene transcription pkc? Highly phosphorylated serine-162. 0.246 SIGNOR-234461 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys206 DLINLAKkRTNIIPV 30540930 YES lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) 0.271 SIGNOR-275893 PAPOLA protein P51003 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 19224921 NO lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. 0.7 SIGNOR-268325 ATF2 protein P15336 UNIPROT YTHDC2 protein Q9H6S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001911 24269672 YES lperfetto Collectively, these data show that YTHDC2 plays an important role in tumor cells growth and activation/recruitment of c-Jun and ATF-2 to the YTHDC2 promoter is necessary for the transcription of YTHDC2, and that HDAC activity is required for the efficient expression of YTHDC2 in both of hepatocyte and HCC cells. 0.275 SIGNOR-269001 LRFN5 protein Q96NI6 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 21736948 NO miannu The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons. 0.7 SIGNOR-264093 PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC -1 22306293 YES PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor 0.443 SIGNOR-267716 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 YES gcesareni Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. 0.474 SIGNOR-166506 SENP3 protein Q9H4L4 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 YES miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. 0.804 SIGNOR-265468 VHL protein P40337 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR down-regulates ubiquitination 9606 10944113 YES miannu Here we show that the product of the von hippel-lindau (vhl) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of hif-1 alpha under normoxic conditions via interaction with the core of the oxygen-dependent degradation domain of hif-1 alpha. 0.678 SIGNOR-80969 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr246 LCFSPNRyWLCAATG 9606 12400005 YES gcesareni We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246 0.2 SIGNOR-94800 SMAD3 protein P84022 UNIPROT NKX2-1 protein P43699 UNIPROT down-regulates activity binding 9606 BTO:0004299 18003659 YES miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function. 0.291 SIGNOR-254169 Brivanib alaninate chemical CID:11154925 PUBCHEM FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190717 BTK protein Q06187 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation 9606 29290977 YES miannu Phosphorylation of MDM2 by BTK suppresses its ubiquitination activity. 0.278 SIGNOR-278330 SYVN1 protein Q86TM6 UNIPROT GPR37 protein O15354 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15572843 YES miannu HRD1 ubiquitinated and degraded Pael-R through its ubiqutin ligase activity. 0.401 SIGNOR-278672 Food intake phenotype SIGNOR-PH152 SIGNOR folic acid smallmolecule CHEBI:27470 ChEBI up-regulates 9606 19706381 NO lperfetto The U.S. Reference Daily Intake (Daily Value) for FA is 0.4 mg for adults to aid in the prevention of birth defects and anemia, or double this amount for pregnant or lactating women. 0.7 SIGNOR-268262 GALR2 protein O43603 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257356 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 YES lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. 0.81 SIGNOR-116274 ZAP70 protein P43403 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates phosphorylation Tyr138 SPTLVIAyLMMRQKM 9606 12447358 YES gcesareni We report here that vhr, a vaccinia virus vh1-related dual-specific protein phosphatase that inactivates the mitogen-activated kinases erk2 and jnk, is phosphorylated at y138 by zap-70. Tyr138 phosphorylation was required for vhr to inhibit the erk2-elk-1 pathway 0.532 SIGNOR-95877 MAPK10 protein P53779 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates phosphorylation Ser73 EAPRTLAsPKKKDLS 9606 11718727 YES gcesareni We demonstrate that purified scg10 can be phosphorylated by two subclasses of mitogen-activated protein (map) kinases, c-jun n-terminal/stress-activated protein kinase (jnk/sapk) and p38 map kinase;jnk3/sapkbeta phosphorylation occurs at ser-62 and ser-73, residues that result in reduced microtubule-destabilizing activity for scg10. 0.445 SIGNOR-112114 PRKG2 protein Q13237 UNIPROT LASP1 protein Q14847 UNIPROT unknown phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 YES lperfetto Recombinant human LASP was phosphorylated by cGMP- and cAMP-dependent protein kinase (cAK) in vitro. Cotransfection of PtK-2 cells with LASP and cGK confirmed phosphorylation of LASP in vivo. Studies with human LASP mutants identified serine 146 as a specific phosphorylation site for cGK and cAK in vivo. LASP is an actin-binding protein, and the phospho-LASP-mimicking mutant S146D showed reduced binding affinity for F-actin in cosedimentation experiments. 0.342 SIGNOR-249197 TACR1 protein P25103 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.497 SIGNOR-257374 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.2 SIGNOR-252945 PRKCG protein P05129 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 11325528 YES lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. 0.283 SIGNOR-249091 DAB2IP protein Q5VWQ8 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 9606 BTO:0002195 27858941 YES miannu In vascular smooth muscle cells (VSMCs) treated with IFN-γ, DAB2IP directly binds to JAK2 and inhibits its kinase activity, limiting JAK-dependent STAT1/3 and PI3K–AKT phosphorylation and activation 0.349 SIGNOR-254760 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr89 VSPLLLTtTNSSEGL 9606 11152499 YES tpavlidou Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites. 0.2 SIGNOR-85785 MYF5 protein P13349 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity BTO:0001103 17495111 NO Simone Vumbaca In summary, the absence of Myf5 clearly reduced the initial expansion of satellite cell-derived transient amplifying cells and resulted in a shift of the ratio of satellite cell subpopulations but did not affect the specification and generation of specific subpopulations of satellite cell-derived cells such as reserve cells, amplifying cells, and differentiating mature myogenic cells. 0.7 SIGNOR-255643 TSC22D3 protein Q99576 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 12671681 NO In this study, we showed that GILZ, which is transcriptionally induced by GCs, inhibits the transcription of the PPAR-γ2 gene and blocks adipocyte differentiation 0.268 SIGNOR-253296 ELF1 protein P32519 UNIPROT CD68 protein P34810 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 12676954 NO Band shift experiments show that PU.1 associates with the -89 site whereas, Elf-1 preferentially binds the -106 Ets binding site and enhances CD68 activity in vitro. 0.2 SIGNOR-254282 PRKDC protein P78527 UNIPROT TDP1 protein Q9NUW8 UNIPROT up-regulates phosphorylation Ser81 PKRQKSGsQEDLGWC 9606 19851285 YES lperfetto Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk) 0.535 SIGNOR-188776 ZAP70 protein P43403 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1203 IFPARDTyHPMSEYP 9606 BTO:0000661 14766232 YES lperfetto Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin. 0.449 SIGNOR-247039 LGALS3 protein P17931 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000664 21821001 NO miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. 0.278 SIGNOR-261906 PPP2CA protein P67775 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates dephosphorylation Thr255 ITTPELTtPCGSAEY 9606 20927323 YES gcesareni Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e. 0.513 SIGNOR-168314 PGAM1 protein P18669 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI down-regulates quantity chemical modification 9606 24786789 YES miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. 0.8 SIGNOR-266511 SOCS5 protein O75159 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity binding 9606 BTO:0000007 15590694 YES miannu SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation. 0.448 SIGNOR-271516 SMAD5 protein Q99717 UNIPROT GADD45G protein O95257 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.2 SIGNOR-268942 AKT3 protein Q9Y243 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 YES gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity. 0.289 SIGNOR-78697 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser537 DNSMSVPsPTSATKT 10090 BTO:0000964 34048556 YES lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. 0.2 SIGNOR-268341 selumetinib chemical CHEBI:90227 ChEBI ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001950 25487801 YES Luana Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections.  0.8 SIGNOR-262313 NDUFB4 protein O95168 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 0.798 SIGNOR-262167 PAK1 protein Q13153 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 10559936 YES lperfetto Activation of lim-kinase by pak1 couplesp21-activated kinase (pak1) phosphorylates lim-kinase at threonine residue 508 within lim-kinase's activation loop 0.613 SIGNOR-72142 COLGALT2 protein Q8IYK4 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates activity glycosylation -1 19075007 YES Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. 0.398 SIGNOR-261157 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 18971378 YES gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) 0.341 SIGNOR-181811 IFNA1 protein P01562 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 YES gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.614 SIGNOR-104641 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 22298955 YES gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation. 0.525 SIGNOR-195603 H4C1 protein P62805 UNIPROT BRD2 protein P25440 UNIPROT up-regulates activity relocalization 9606 acetylation:Lys21 GGAKRHRkVLRDNIQ 12776177 YES lperfetto Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals. 0.2 SIGNOR-262062 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 YES gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.793 SIGNOR-163250 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258082 HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14614508 NO Overexpression of HES-1 fully repressed PPAR-g even in the presence of the ACREB inhibitor, showing that HES-1 acts downstream of CREB 0.248 SIGNOR-254743 FFAR4 protein Q5NUL3 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257158 RPS6KB1 protein P23443 UNIPROT URI1 protein O94763 UNIPROT down-regulates activity phosphorylation Ser372 AKRKRKNsTGSGHSA 9606 BTO:0000567 17936702 YES miannu Here we report that the prefoldin chaperone URI represents a mitochondrial substrate of S6K1. In growth factor-deprived or rapamycin-treated cells, URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria, thereby inhibiting the activity of the bound enzyme. Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371. 0.344 SIGNOR-262943 RPS6KA1 protein Q15418 UNIPROT MAGI1 protein Q96QZ7 UNIPROT up-regulates activity phosphorylation Ser741 QPLERKDsQNSSQHS 9606 BTO:0001949 30944250 YES done miannu  We report herein that p90RSK associates with MAGI1 in ECs and executes 2 independently regulated PTMs of MAGI1: S741 phosphorylation and K931 deSUMOylation. MAGI1-S741 phosphorylation is vital for Rap1 activation. 0.286 SIGNOR-273837 MAPK3 protein P27361 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 YES lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling 0.32 SIGNOR-200884 Ub:E2 complex SIGNOR-C497 SIGNOR RNF123 protein Q5XPI4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271168 RPS6KA1 protein Q15418 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 YES llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. 0.335 SIGNOR-203298 Laminin-5 complex SIGNOR-C184 SIGNOR A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 2032285 YES lperfetto Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes. 0.544 SIGNOR-253252 ITGB1 protein P05556 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.809 SIGNOR-253176 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9020188 YES lperfetto The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g they become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. 0.789 SIGNOR-236239 PTPRH protein Q9HD43 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation 10029 BTO:0000246 12907755 YES Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR 0.295 SIGNOR-248802 GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. 0.448 SIGNOR-252682 MAVS protein Q7Z434 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity binding 9606 24622840 YES miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. 0.2 SIGNOR-260152 PTPN12 protein Q05209 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation Tyr1196 GAVENPEyLTPQGGA 9606 29330094 YES miannu In MDA-MB-231 cells, a human triple negative breast cancer cell line, phosphorylation of PTPN12 on Ser 19 was increased in response to cyclin dependent kinase 2 (CDK2), and this impaired PTPN12 's ability to dephosphorylate HER2 on Y1196.|PTPN12 negatively regulates Her2, by dephosphorylation on Tyr 1196 on Her2. 0.618 SIGNOR-277038 PRKACA protein P17612 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser499 PFGSRRSsAIGIENI -1 1406653 YES miannu We have localized two of the sites of phosphorylation in vitro by cAMP-dependent kinase to serine residues 490 and 499. raplGAP undergoes phosphorylation at specific sites in vivo, the effects of phosphorylation on raplGAP have remained elusive. 0.31 SIGNOR-250044 AKT1 protein P31749 UNIPROT XIAP protein P98170 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 BTO:0001023 14645242 YES lperfetto Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. 0.619 SIGNOR-119488 CENPE protein Q02224 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 20383333 NO lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology 0.7 SIGNOR-252013 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 30060484 NO miannu The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization.  0.7 SIGNOR-249519 BAZ1B protein Q9UIG0 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Tyr143 ATQASQEy 9606 19092802 YES gcesareni We show that wstf phosphorylates tyr 142 of h2a.x, and that wstf activity has an important role in regulating several events that are critical for the dna damage response 0.2 SIGNOR-182831 RACK1 protein P63244 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 24726876 YES miannu RACK1 Mediates the Formation of the IRF3-RACK1-PP2A Complex and Promotes the Dephosphorylation of IRF3.Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. 0.2 SIGNOR-260945 RFX3 protein P48380 UNIPROT FOXJ1 protein Q92949 UNIPROT up-regulates activity binding 9606 BTO:0000939 23822649 YES miannu RFX3 acts as a transcriptional co-activator to FOXJ1 that enhances the expression of cilia-associated genes. FOXJ1 is an important regulator of cilia gene expression during ciliated cell differentiation, with RFX3 as a transcriptional co-activator to FOXJ1, helping to induce the expression of cilia genes in the process of ciliated cell differentiation of basal/progenitor cells. 0.549 SIGNOR-266929 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267879 PPP4C protein P60510 UNIPROT ACACA protein Q13085 UNIPROT up-regulates activity dephosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 BTO:0000599 25050742 YES PP4 was also found to directly interact with pACC1‑Ser79 in human HepG2 cells. In conclusion, the present study showed that PP4 may be a novel regulator in hepatic lipogenesis through dephosphorylating ACC1 on serine 79, suggesting that PP4 may be a promising therapeutic target in lipid metabolism disorders. 0.242 SIGNOR-267724 romidepsin chemical CHEBI:61080 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257989 PFKFB3 protein Q16875 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification -1 9404080 YES A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. 0.8 SIGNOR-267271 MYO1E protein Q12965 UNIPROT Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 10116 BTO:0000142 17257598 NO miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. 0.7 SIGNOR-265425 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates activity phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 YES lperfetto Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase 0.479 SIGNOR-275936 GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263777 PRKCB protein P05771 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.259 SIGNOR-275442 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Ser330 GGLCDLSsRY 9606 12639913 YES gcesareni Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor. 0.2 SIGNOR-249673 ketotifen chemical CHEBI:92511 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257789 E2F1 protein Q01094 UNIPROT CDC25A protein P30304 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 11154267 NO lperfetto Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen 0.553 SIGNOR-245468 PTK6 protein Q13882 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10980601 YES gcesareni The phosphorylation of and association with bks by brk was also dependent on the sh2-like domain present within bks.bks is a substrate for the kinase activity of brk and has the characteristics of an adaptor protein. 0.723 SIGNOR-81489 GSK3B protein P49841 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates activity phosphorylation Ser575 SDRSGSSsPDSEITE 9606 BTO:0000007 17681942 YES miannu We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. 0.2 SIGNOR-276069 SMAD6 protein O43541 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 12857866 YES lperfetto Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4 0.575 SIGNOR-217706 FH protein P07954 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI up-regulates quantity chemical modification 9606 30761759 YES miannu Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. 0.8 SIGNOR-266280 TLN1 protein Q9Y490 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.613 SIGNOR-257609 FHIT protein P49789 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 BTO:0000551 16407838 NO miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis 0.373 SIGNOR-143700 hsa-miR-374b-5p mirna URS000033F45D_9606 RNAcentral AKT1 protein P31749 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003582 26100275 YES Parnian These data suggest that miR-374b may negatively regulate the expression of Wnt16 and AKT1 by directly targeting the 3'-UTR of their mRNA. 0.4 SIGNOR-278856 JAK2 protein O60674 UNIPROT KDM3A protein Q9Y4C1 UNIPROT up-regulates activity phosphorylation Tyr1101 PDLGPKMyNAYGLIT 9606 BTO:0000567 30377265 YES miannu KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2 phosphorylates KDM3A at tyrosine 1101 residue. 0.2 SIGNOR-277884 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000552 20663147 YES gcesareni DeltaNp63alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation 0.843 SIGNOR-167156 PTPN6 protein P29350 UNIPROT STAT6 protein P42226 UNIPROT down-regulates 9606 BTO:0000801 9852037 NO gcesareni Expression of an shp-1 transgene in nih 3t3 cells markedly reduces both il-4-dependent stat6 activation and stat6-mediated transcription of il-4-responsive genes 0.619 SIGNOR-62578 VRK2 protein Q86Y07 UNIPROT TRiC complex SIGNOR-C539 SIGNOR down-regulates quantity by destabilization binding 9606 BTO:0000007 24298020 YES miannu Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme.The results suggest that VRK2 enables the COP1 complex to efficiently attach ubiquitin on the CCT4 by providing a close interaction between CCT4 and the COP1 complex. 0.301 SIGNOR-272875 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 YES lperfetto We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2. 0.791 SIGNOR-235671 TNF protein P01375 UNIPROT SCN11A protein Q9UI33 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.2 SIGNOR-253483 GDF5 protein P43026 UNIPROT ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004291 16716349 NO Regulation miannu GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription. 0.281 SIGNOR-251871 ATP6AP1 protein Q15904 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization 9606 28296633 NO miannu Depletion or inhibition of the V-ATPase stabilises HIF1α in aerobic conditions. 0.2 SIGNOR-261347 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203512 MTHFD2 protein P13995 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity chemical modification 9606 16100107 YES lperfetto Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase|One of the enzymes in this pathway, the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC),5 catalyzes the interconversion of 5,10-methylenetetrahydrofolate (methylene-THF) and 10-formyltetrahydrofolate (formyl-THF) in mammalian mitochondria. 0.8 SIGNOR-268255 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000551 19683496 YES gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. 0.497 SIGNOR-187595 PRKACA protein P17612 UNIPROT ARHGAP17 protein Q68EM7 UNIPROT down-regulates activity phosphorylation Ser702 LSAPRRYsSSLSPIQ 9606 BTO:0000132 26507661 YES lperfetto Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex. 0.2 SIGNOR-272155 ARHGEF10 protein O15013 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.44 SIGNOR-260536 PBK protein Q96KB5 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 16982762 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Pbk/topk could phosphorylate histone h3 at ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone h3 modification. 0.2 SIGNOR-149716 TP53 protein P04637 UNIPROT SLC2A1 protein P11166 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 YES miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. 0.595 SIGNOR-267464 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 11781339 NO gcesareni In these collagen gel cultures, p38 activation was induced more potently by fgf-2 treatment compared with that in proliferating cultures 0.391 SIGNOR-113649 TFEB protein P19484 UNIPROT SACM1L protein Q9NTJ5 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 NO lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 0.2 SIGNOR-276801 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation 0.312 SIGNOR-129312 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5099 DVEFDIKsPKFKAEA 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.256 SIGNOR-262763 PRKCA protein P17252 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser498 RPLSRTQsSPLPQSP 10116 BTO:0002320 15367659 YES lperfetto We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E 0.2 SIGNOR-249269 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 NO gcesareni Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck) 0.349 SIGNOR-142204 WWP1 protein Q9H0M0 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT up-regulates activity ubiquitination Lys347 EKAGRIEkLESEIQR 9606 BTO:0000007 34404733 YES lperfetto AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation|Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408. 0.29 SIGNOR-271873 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 APPSPAWsEPEPEAG 10090 37029927 YES miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. 0.2 SIGNOR-277809 FGF14 protein Q92915 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 BTO:0001103 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.26 SIGNOR-253433 RPS9 protein P46781 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.88 SIGNOR-262415 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0000007 16476742 YES lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin 0.477 SIGNOR-144482 CD3 complex SIGNOR-C432 SIGNOR TCR complex SIGNOR-C153 SIGNOR form complex binding 9606 12507424 YES miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3Œ≥Œµ, CD3Œ¥Œµ, and Œ∂Œ∂ signaling modules.the TCRŒ±-CD3Œ¥Œµ and TCRŒ≤-CD3Œ≥Œµ interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled Œ±Œ≤ TCR-CD3 complexes containing the Œ∂-chain strictly required both CD3Œ≥ and Œ¥ 0.2 SIGNOR-269472 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr439 RLMTGDTyTAHAGAK -1 15735735 YES miannu The results show that Arg is stabilized in response to 0.1 mM H2O2 by autophosphorylation of Y-261, consistent with involvement of the Arg kinase function in regulating Arg levels. The results further demonstrate that c-Abl-mediated phosphorylation of Arg on Y-261 similarly confers Arg stabilization.. These findings indicate that abrogation of the Arg kinase function by the Y261F mutation is dependent on phosphorylation of the Y-439 site.). Our results thus indicate that phosphorylation of Arg on Y-261 plays a dual role in retaining the Arg kinase function and preventing Arg degradation by blocking ubiquitination (Figure 6). 0.2 SIGNOR-276032 CREB1 protein P16220 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16205321 NO gcesareni The results showed that the nuclear pkcalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-creb content, dna-binding activity of creb, and bcl-xl expression. 0.36 SIGNOR-140911 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 12954613 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. gcesareni C1a domain is critical for the dag-induced activation of pkcalfa.Furthermore, calcium and diacylglycerol activate protein kinase c, resulting in the phosphorylation of a large variety of substrates. 0.8 SIGNOR-100254 MYH9 protein P35579 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004953 32685004 YES miannu Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo. 0.274 SIGNOR-269284 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 9606 11741541 YES lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna 0.578 SIGNOR-112813 OTULIN protein Q96BN8 UNIPROT UBC protein P0CG48 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.717 SIGNOR-270820 PRKACA protein P17612 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation Ser235 TTQLRLLsEDTDSQR 9606 BTO:0000007 33110360 YES miannu We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence. 0.2 SIGNOR-277538 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-119225 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT up-regulates activity phosphorylation Ser478 APDILAKsPQSTRAV 9606 BTO:0000599 21189263 YES lperfetto ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking. 0.296 SIGNOR-272296 POU5F1 protein Q01860 UNIPROT PAX6 protein P26367 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.455 SIGNOR-253163 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 11062067 YES phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif gcesareni Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. 0.636 SIGNOR-83744 CDK1 protein P06493 UNIPROT PDCD1 protein Q15116 UNIPROT down-regulates quantity by destabilization phosphorylation Ser261 PSGMGTSsPARRGSA 9606 BTO:0000007 36104103 YES miannu We demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7. 0.2 SIGNOR-277605 IFNB1 protein P01574 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000711 17564708 NO miannu we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ. 0.356 SIGNOR-255438 PRKACA protein P17612 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Ser188 ARRGKKKsGCLVL 10090 12654918 YES miannu PKA phosphorylates RhoA on Ser188. the addition of a negative charge to Ser188 is sufficient to diminish both RhoA activation and activity within the context of a cell. 0.517 SIGNOR-250047 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 YES lperfetto Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. 0.387 SIGNOR-263604 INPP5D protein Q92835 UNIPROT phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI up-regulates quantity chemical modification 9606 23650141 YES gcesareni PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain-containing inositol 5-phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5-position 0.8 SIGNOR-252427 CTDSPL protein O15194 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity dephosphorylation Ser811 IYISPLKsPYKISEG 9606 15051889 YES ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms. 0.298 SIGNOR-248305 NTF4 protein P34130 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates binding 9606 7679912 YES gcesareni Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb. 0.94 SIGNOR-31644 GTF2F1 protein P35269 UNIPROT GTF2F1 protein P35269 UNIPROT down-regulates phosphorylation Thr389 RGNSRPGtPSAEGGS 9606 10428810 YES gcesareni We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process. 0.2 SIGNOR-69771 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 12657630 YES IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376|Thus far, we have no compelling evidence that inducible phosphorylation of these IKKgamma domains is important for their assigned functions. 0.962 SIGNOR-251287 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser179 KTRAKGPsESSKERN -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.321 SIGNOR-273968 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.432 SIGNOR-273147 ITCH protein Q96J02 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys371 PTSMVLTkVSASTVP 9606 BTO:0002181 19881509 YES Giorgia These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation 0.645 SIGNOR-260362 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr178 LKICDFGtACDIQTH -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. 0.2 SIGNOR-227536 HMGB2 protein P26583 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 NO miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 0.2 SIGNOR-254429 GABARAP protein O95166 UNIPROT TBC1D25 protein Q3MII6 UNIPROT up-regulates binding 9606 21383079 YES gcesareni In this study, we report evidence demonstrating that oatl1, a putative rab guanosine triphosphatase-activating protein (gap), is a novel binding partner of atg8 homologues in mammalian cells. Oatl1 is recruited to isolation membranes and autophagosomes through direct interaction with atg8 homologues and is involved in the fusion between autophagosomes and lysosomes through its gap activity. 0.603 SIGNOR-172536 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser175 GPLITPGsGSIYSSP 9606 BTO:0000567 35469017 YES miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. 0.2 SIGNOR-276716 EIF4E protein P06730 UNIPROT MTFP1 protein Q9UDX5 UNIPROT up-regulates activity translation regulation 10090 BTO:0002572 28918902 YES Barakat In this study, we demonstrate that mTORC1 stimulates mitochondrial fission via 4E-BP-mediated translational regulation of the mitochondrial fission factor MTFP1. Suppression of mTORC1 activity by pharmacological or genetic means causes mitochondrial hyperfusion, branching, and circularization. This is a consequence of downregulation of MTFP1 levels via the mTORC1/4E-BP pathway, thereby eliciting changes in phosphorylation and localization of the mitochondrial fission factor DRP1 0.2 SIGNOR-275429 AE/b7 integrin complex SIGNOR-C186 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.48 SIGNOR-257727 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity phosphorylation Ser262 MGRDPGVsFKAVGLQ -1 21775627 YES lperfetto Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition 0.65 SIGNOR-265011 IHH protein Q14623 UNIPROT PTCH2 protein Q9Y6C5 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 YES lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. 0.791 SIGNOR-61314 COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 9606 26497135 YES miannu The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin–proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. The evolutionary conserved ubiquitin proteasome pathway (UPP) mediates degradation of intracellular proteins in all eukaryotes. This essential process requires three protein complexes: E3 ubiquitin ligases as e.g., cullin-RING ligases (CRLs), CSN and the 26S proteasome. 0.323 SIGNOR-270795 RNF168 protein Q8IYW5 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 31225475 NO miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. 0.7 SIGNOR-266789 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates chemical inhibition 9606 18922779 YES inferred from 70% of family members gcesareni Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell. 0.8 SIGNOR-269884 VPS18 protein Q9P253 UNIPROT HOPS tethering complex complex SIGNOR-C549 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.909 SIGNOR-273688 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr489 DGPYSNPyENSLIPA 12441334 YES JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 0.811 SIGNOR-251354 TYK2 protein P29597 UNIPROT KLF10 protein Q13118 UNIPROT down-regulates activity phosphorylation 9606 21471442 YES miannu These data strongly supported that Tyk2 phosphorylates TIEG1.|Tyrosine kinase Tyk2-mediated phosphorylation of TIEG1 at Tyr179 promoted noncanonical K-27-linked polyubiquitination, which inhibited TIEG1 nuclear translocation. 0.439 SIGNOR-279575 RHOBTB3 protein O94955 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 24145166 YES miannu Here we show that RhoBTB3, a Golgi-associated, Rho-related ATPase, regulates the S/G2 transition of the cell cycle by targeting cyclin E for ubiquitylation. Depletion of RhoBTB3 arrested cells in S phase, triggered Golgi fragmentation, and elevated cyclin E levels. On the Golgi, RhoBTB3 bound cyclin E as part of a Cullin3 (CUL3)-dependent RING-E3 ubiquitin ligase complex comprised of RhoBTB3, CUL3, and RBX1. 0.407 SIGNOR-272131 ATIC protein P31939 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 33179964 YES miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. 0.8 SIGNOR-267326 WNK1 protein Q9H4A3 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates phosphorylation Thr991 SAYTYERtLMMEQRS 9606 BTO:0000938 BTO:0000142 19665974 YES gcesareni We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases. 0.454 SIGNOR-187564 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2W protein Q96B02 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.522 SIGNOR-271374 SDC4 protein P31431 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Like other wnt co receptors, syndecan 4 directly interacts with dvl during pcp. 0.257 SIGNOR-199635 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Ser225 TRRVKTQsESGDVSR -1 27292631 YES miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. 0.304 SIGNOR-274060 COP1 protein Q8NHY2 UNIPROT MTA1 protein Q13330 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 19805145 YES miannu Here we report that MTA1 is an ubiquitinated protein and targeted by the RING-finger E3 ubiquitin-protein ligase constitutive photomorphogenesis protein 1 (COP1) for degradation via the ubiquitin-proteasome pathway. 0.2 SIGNOR-271891 L-tryptophan smallmolecule CHEBI:16828 ChEBI 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity precursor of 9606 31024440 YES brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. 0.8 SIGNOR-264185 PTPRG protein P23470 UNIPROT DOK2 protein O60496 UNIPROT up-regulates activity dephosphorylation Tyr139 CMEENELySSAVTVG -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254698 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT up-regulates activity phosphorylation Ser342 RHEAKQRsVQRWREA -1 21423175 YES miannu In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h). 0.2 SIGNOR-276316 LEF1 protein Q9UJU2 UNIPROT PITX2 protein Q99697 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 19850024 NO gcesareni These results suggest that wnt/lef1 signaling regulates epaxial myogenesis via pitx2 but that this link is uncoupled in other regions of the body, emphasizing the unique molecular networks that control the development of various muscles in vertebrates. The pitx2 promoter contains tcf/lef binding sites and expression can be induced by licl, which activates the canonical wnt signaling pathway 0.718 SIGNOR-188730 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.631 SIGNOR-249440 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000671 9335553 YES lperfetto These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling. 0.766 SIGNOR-52700 SACM1L protein Q9NTJ5 UNIPROT phosphatidylinositol 4-phosphate smallmolecule CHEBI:37530 ChEBI down-regulates quantity chemical modification 9534 22253445 YES lperfetto To investigate whether kinase activity could account for the different effects of the PI kinases on SARS-CoV S-mediated entry and to test whether PI4P lipids directly regulate viral entry independent of PI4KB, VeroE6 cells were transiently transfected with the SAC1 gene, a PI phosphatase that specifically converts PI4P lipids back to PI (27).|These results indicate that PI4P is indispensable for SARS-CoV S-mediated entry and suggest that PI4KB mediates SARS-CoV S entry by regulating the level of cellular PI4P. 0.8 SIGNOR-260733 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 YES lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. 0.794 SIGNOR-109547 TNF protein P01375 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18647246 NO miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. 0.353 SIGNOR-252409 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser348 PSLQSSLsNPNLQAS 9606 BTO:0000567 16306228 YES lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 0.633 SIGNOR-249170 MYC protein P01106 UNIPROT CLK3 protein P49761 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002932 32453420 YES done miannu C-Myc enhances transcriptional activation of CLK3 promoter in CCA cells.  0.2 SIGNOR-274123 PTPN1 protein P18031 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates dephosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 8940099 YES gcesareni Ptp1b is able to dephosphorylate phosphorylated-tyr-42 on ikappabalpha 0.354 SIGNOR-45004 MTMR3 protein Q13615 UNIPROT 1-phosphatidyl-1D-myo-inositol 3-phosphate(3-) smallmolecule CHEBI:58088 ChEBI down-regulates quantity chemical modification 9606 18429927 YES miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 0.8 SIGNOR-269810 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR lysine smallmolecule CHEBI:25094 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270405 MECP2 protein P51608 UNIPROT PRPF3 protein O43395 UNIPROT up-regulates activity binding 10090 BTO:0000142 21070191 YES lperfetto MeCP2 interacts directly with Prpf3 and Sdccag1|Notably, Mecp2308/Y mice, which produce a truncated form of MeCP2 and reproduce many of the classical features of RTT [43], have been shown to have multiple genes that are abnormally spliced in the brain [23]. This suggests the C-terminal portion of MeCP2, which we have identified as the putative Sdccag1 interaction domain, plays a critical role in regulating alternative splicing. 0.267 SIGNOR-277691 S1PR2 protein O95136 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257007 CTNNA3 protein Q9UI47 UNIPROT JUP protein P14923 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 YES miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 0.485 SIGNOR-265494 carfilzomib chemical CHEBI:65347 ChEBI PSMB9 protein P28065 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 YES miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. 0.8 SIGNOR-259311 PRKACA protein P17612 UNIPROT CBX3 protein Q13185 UNIPROT up-regulates phosphorylation Ser93 KDGTKRKsLSDSESD 9606 16531993 YES gcesareni We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation. 0.2 SIGNOR-145109 SLC2A3 protein P11169 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 23506862 YES miannu The SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose 0.8 SIGNOR-267459 FLT1 protein P17948 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr320 RKDTKEIyTHFTCAT -1 33139573 YES miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. 0.257 SIGNOR-277231 MDM2 protein Q00987 UNIPROT ASF1A protein Q9Y294 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26336826 YES miannu We found that MDM2 overexpression also decreased the ASF1A half-life time, indicating an accelerated ASF1A degradation.|We next examined whether the presence of RAD6 is essential for MDM2-induced ASF1A ubiquitination. 0.267 SIGNOR-278822 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Thr219 AEHQYFMtEYVATRW 9606 BTO:0000567 20667468 YES miannu ERK5 is a member of the mitogen-activated protein kinase (MAPK) family that, after stimulation, is activated selectively by dual phosphorylation in the TEY motif by MAPK kinase 5 (MEK5). ERK5 is activated selectively by dual phosphorylation on Thr218 and Tyr220 in the TEY motif by its only upstream kinase, MEK5, a member of the MEK 0.702 SIGNOR-259824 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr716 RPPSAELySNALPVG 9606 18567737 YES gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. 0.69 SIGNOR-179072 DRD1 protein P21728 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.282 SIGNOR-257181 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 YES lperfetto The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk). 0.799 SIGNOR-187775 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT down-regulates phosphorylation Ser1406 GAGGRRLsSFVTKGY 9606 17206380 YES gcesareni Protein kinase a phosphorylation at thr456 of the multifunctional protein cad antagonizes activation by the map kinase cascade. 0.307 SIGNOR-151816 cabozantinib chemical CHEBI:72317 ChEBI AXL protein P30530 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000184 26536165 YES miannu Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. 0.8 SIGNOR-262241 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR FBXO28 protein Q9NVF7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31678254 YES miannu Here we report that FBXO28, a poorly characterized F-box protein, is a novel substrate of SCF E3 ligase. Pharmaceutical or genetic inhibition of neddylation pathway that is required for the activation of SCF stabilizes FBXO28 and prolongs its half-life. Meanwhile, FBXO28 is subjected to ubiquitination and cullin1-based SCF complex promotes FBXO28 degradation. CUL1, but not other cullin family members, promotes FBXO28 degradation 0.41 SIGNOR-272217 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser511 RREERSLsAPGNLLT 9606 22778263 YES lperfetto Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity 0.2 SIGNOR-198154 PCSK7 protein Q16549 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation 9606 BTO:0000222 BTO:0000887 16364914 YES gcesareni Ksrp phosphorylated by p38 displays compromised binding to are-containing transcripts and fails to promote their rapid decay,although it retains the ability to interact with the mrna degradation machinery. 0.2 SIGNOR-143167 PI4K2B protein Q8TCG2 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269102 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 8500166 NO This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates. 0.7 SIGNOR-254980 YAP1 protein P46937 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 NO gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. 0.7 SIGNOR-199214 FRS2 protein Q8WU20 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates phosphorylation 9606 9632781 YES gcesareni In addition to the direct interactions with grb2, tyrosine-phosphorylated frs2 forms a complex with the sh2 domain-containing protein tyrosine phosphatase shp2. This interaction results in tyrosine phosphorylation of shp2 and complex formation between shp2 and grb2. the catalytic activity of shp2 is essential for a sustained map kinase response and for potentiation of fgf-induced neurite outgrowth in pc12 cells 0.78 SIGNOR-58196 FBXO45 protein P0C2W1 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.258 SIGNOR-272182 PLD2 protein O14939 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 18423386 NO mrosina Altogether, these data suggest that PLD acting upstream of the MAP kinases ERK1/2 may play a key role in the regulation of IL-2 production by stimulated Jurkat cells. 0.585 SIGNOR-254983 HDAC1 protein Q13547 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity deacetylation -1 11486036 YES miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. 0.797 SIGNOR-268835 STK11 protein Q15831 UNIPROT BRSK1 protein Q8TDC3 UNIPROT up-regulates phosphorylation Thr189 VGDSLLEtSCGSPHY 9606 14976552 YES lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold 0.484 SIGNOR-122413 RIPK1 protein Q13546 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 20404851 YES lperfetto Collectively, TRIF forms a multiprotein signaling complex along with TRAF6, TRADD, Pellino-1 and RIP1 for the activation of TAK1, which in turn activates the NF-_B and MAPK pathways. 0.659 SIGNOR-216325 PAMPs stimulus SIGNOR-ST11 SIGNOR AIM2 inflammasome complex SIGNOR-C222 SIGNOR up-regulates activity 16037825 NO miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-263126 ATM protein Q13315 UNIPROT XPA protein P23025 UNIPROT unknown phosphorylation Ser196 RSLEVWGsQEALEEA -1 16540648 YES llicata Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown). 0.611 SIGNOR-250580 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.394 SIGNOR-89284 ABCG1 protein P45844 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 16054053 NO miannu ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. cholesterol efflux to HDL specifically requires ABCG1, whereas efflux to apoA1 requires ABCA1. These studies identify Abcg1 as a key gene involved in both cholesterol efflux to HDL and in tissue lipid homeostasis. 0.7 SIGNOR-252111 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000142 20654717 NO gcesareni This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1. 0.749 SIGNOR-167073 EDNRA protein P25101 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.273 SIGNOR-257253 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB3 protein P05106 UNIPROT up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.2 SIGNOR-259002 EPM2A protein O95278 UNIPROT NHLRC1 protein Q6VVB1 UNIPROT up-regulates activity binding 10116 BTO:0003234 18029386 YES miannu Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro. 0.786 SIGNOR-271729 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 NO irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. 0.603 SIGNOR-256286 INSR protein P06213 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates activity phosphorylation Tyr362 DPKEDPIyDEPEGLA 10029 BTO:0000246 11551902 YES Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway. 0.561 SIGNOR-251307 AKT1 protein P31749 UNIPROT ZYX protein Q15942 UNIPROT down-regulates phosphorylation Ser142 PQPREKVsSIDLEID 9606 17572661 YES llicata Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation 0.416 SIGNOR-156122 NOG protein Q13253 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR down-regulates binding 9606 22298955 YES Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmpby blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors 0.598 SIGNOR-217529 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000567 11689443 YES lperfetto Pp5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ask1 and thereby inactivated ask1 activity in vitro and in vivo. 0.596 SIGNOR-111301 6 protein P0DTC6 UNIPROT KPNA2 protein P52292 UNIPROT down-regulates activity binding 9606 32979938 YES miannu The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F). 0.2 SIGNOR-262513 ORF6 protein Q19QW5 UNIPROT KPNA2 protein P52292 UNIPROT down-regulates activity relocalization 9534 17596301 YES lperfetto Taken together, these data support a direct interaction between KPNA2 and ORF6 in the context of virus infection.|SARS-CoV, but not SARSdeltaORF6, retains KPNA2 at the ER/Golgi membrane. 0.2 SIGNOR-260272 P2RY11 protein Q96G91 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257261 CAMK2G protein Q13555 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Ser862 IRNKARLsITGSVGE 10366608 YES llicata We found that GluR4 is phosphorylated on serine 842 within the C-terminal domain in vitro and in vivo. Serine 842 is phosphorylated by PKA, PKC, and CaMKII in vitro and is phosphorylated in transfected cells by PKA. 0.527 SIGNOR-250699 DNA_damage stimulus SIGNOR-ST1 SIGNOR RAD23B protein P54727 UNIPROT up-regulates 24086043 NO lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). 0.7 SIGNOR-275688 DYRK1B protein Q9Y463 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates activity phosphorylation Ser153 SMTDFYHsKRRLIFS 10090 15851482 YES lperfetto Mirk exerts its anti-apoptotic effects during muscle differentiation at least in part through effects on the cell cycle inhibitor and pro-survival molecule p21cip1. Overexpression and rna interference experiments demonstrated that mirk phosphorylates p21 within its nuclear localization domain at ser-153 causing a portion of the typically nuclear p21 to localize in the cytoplasm.Translocation to the cytoplasm enables p21 to block apoptosis through inhibitory interaction with pro-apoptotic molecules. 0.258 SIGNOR-235635 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.593 SIGNOR-268704 PKN1 protein Q16512 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 BTO:0000150 12560069 YES lperfetto Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1. 0.2 SIGNOR-97882 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 16407239 YES lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . 0.373 SIGNOR-217430 EEF1A1P5 protein Q5VTE0 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269543 ADCY9 protein O60503 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-265005 ATM protein Q13315 UNIPROT RNF40 protein O75150 UNIPROT up-regulates activity phosphorylation Ser114 ALLRCHEsQGELSSA 9606 BTO:0000007 21362549 YES miannu ATM-Mediated Phosphorylation of RNF20 and RNF40 in Response to DNA Damage and Its Requirement for Damage-Induced H2B Monoubiquitylation  0.444 SIGNOR-276315 TGFBR1 protein P36897 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates activity phosphorylation 9606 29376829 YES miannu This directly demonstrates that TGFBR1 can activate ACVR1 in vivo.|We show that in response to TGF-\u03b2, TGFBRI phosphorylates and activates ACVR1, which phosphorylates SMAD1/5. 0.364 SIGNOR-279490 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 12223490 YES gcesareni We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage. 0.527 SIGNOR-92597 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 9606 19365405 YES gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. 0.583 SIGNOR-185274 TGFB1 protein P01137 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8182090 NO gcesareni Tgf-beta stimulates transcription of the human alpha 2(i) collagen gene (col1a2) promoter by increasing the affinity of an sp1-containing protein complex for its cognate dna-binding site 0.395 SIGNOR-36783 QRICH1 protein Q2TAL8 UNIPROT YARS1 protein P54577 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269412 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22578813 YES miannu We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination. 0.27 SIGNOR-272051 TRIM59 protein Q8IWR1 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity 9606 BTO:0000567; BTO:0002181 22588174 NO Giorgia TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal 0.261 SIGNOR-260373 HRH2 protein P25021 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257424 PYGM protein P11217 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 YES miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267390 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr384 ACQVYFTyDPYSEED -1 10214954 YES Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. 0.643 SIGNOR-251376 ING1 protein Q9UK53 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates activity binding 9606 14522900 YES miannu We found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382). 0.452 SIGNOR-254486 MRPL3 protein P09001 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.712 SIGNOR-262366 SRP72 protein O76094 UNIPROT SRP68 protein Q9UHB9 UNIPROT up-regulates activity binding -1 30649417 YES miannu Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction. 0.99 SIGNOR-261164 FOXO4 protein P98177 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.374 SIGNOR-236554 S100A9 protein P06702 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004730 18809714 NO miannu We report here that up-regulation of S100A9 in myeloid precursors in cancer inhibits DC and macrophage differentiation and induces accumulation of MDSCs. This may represent a universal molecular mechanism of tumor-induced abnormalities in myeloid cells in cancer, directly linking inflammation and immune suppression. 0.7 SIGNOR-261932 AKT1 protein P31749 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Thr700 MESRRQAtVSWDSGG -1 23264741 YES miannu  Here we show that soluble growth factors enhance integrin signaling through Akt phosphorylation of FAK at Ser695 and Thr700.  0.431 SIGNOR-276436 MDM2 protein Q00987 UNIPROT IER3 protein P46695 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26973248 YES miannu FHL2 stimulates MDM2 mediated ubiquitination of IER3 by forming a ternary complex.|Scaffold protein FHL2 facilitates MDM2 mediated degradation of IER3 to regulate proliferation of cervical cancer cells. 0.35 SIGNOR-278824 PINK1 protein Q9BXM7 UNIPROT ZNF746 protein Q6NUN9 UNIPROT up-regulates activity phosphorylation Ser613 APPDPFKsPASKGPL 9606 32169097 YES miannu PINK1 directly phosphorylates PARIS at S322 and S613, priming it for ubiquitination by Parkin, which interacts with the C-terminus zinc finger of PARIS and tags it for destruction [ xref \u2013 xref , xref ].|Thus, by tagging PARIS for destruction, PINK1/Parkin drive the generation of new mitochondria by increasing PGC-1\u03b1 levels (Fig. 1d). 0.37 SIGNOR-278267 HDAC8 protein Q9BY41 UNIPROT SMG5 protein Q9UPR3 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 16809764 YES miannu Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation.  0.641 SIGNOR-272650 RAPGEF5 protein Q92565 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 21791615 YES miannu We found here that cAMP-dependent activation of Epac1 and Rap1 but not PKA is able to activate CaMKI to mediate Ser47 (S47) phosphorylation in GCM1. Epac1 and Epac2 proteins were identified as cAMP-binding proteins with guanine nucleotide exchange factor (GEF) activities for the small GTPases, Rap1 and Rap2 0.647 SIGNOR-262682 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264926 NR3C1 protein P04150 UNIPROT PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 YES miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription 0.268 SIGNOR-268050 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.552 SIGNOR-89154 CSNK2A1 protein P68400 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 12588975 YES gcesareni Phosphorylation at s112 directly affects binding of 4e-bp1 to eif4e without influencing phosphorylation of other sites. 0.341 SIGNOR-98280 EP300 protein Q09472 UNIPROT PLAG1 protein Q6DJT9 UNIPROT up-regulates acetylation 9606 16207715 YES miannu Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7. 0.309 SIGNOR-140915 SPI1 protein P17947 UNIPROT OSCAR protein Q8IYS5 UNIPROT up-regulates quantity by expression transcriptional regulation 16046394 NO lperfetto NFATc1 expression results in the activation of the OSCAR promoter, which was found to be further enhanced by co-expression of PU.1 and microphthalmia-associated transcription factor (MITF). 0.317 SIGNOR-271689 STK4 protein Q13043 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 YES gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. 0.594 SIGNOR-178186 HRAS protein P01112 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9727023 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization. 0.821 SIGNOR-59816 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL -1 8576253 YES giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). 0.722 SIGNOR-255962 PTPN1 protein P18031 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity dephosphorylation Tyr421 RLPSSPVyEDAASFK 9606 27824079 YES lperfetto We conclude that Mena INV promotes invadopodium maturation by inhibiting normal dephosphorylation of cortactin at tyrosine 421 by the phosphatase PTP1B. 0.517 SIGNOR-277027 ATXN7L3 protein Q14CW9 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.769 SIGNOR-269579 ITGB1BP1 protein O14713 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257642 PRKCD protein Q05655 UNIPROT TACSTD2 protein P09758 UNIPROT down-regulates activity phosphorylation Ser322 GELRKEPsL 9606 BTO:0001109 31177095 YES done miannu  Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation. 0.2 SIGNOR-273820 WDFY3 protein Q8IZQ1 UNIPROT ATG5 protein Q9H1Y0 UNIPROT up-regulates quantity binding 9606 BTO:0000452 20417604 YES miannu Alfy is recruited to intracellular inclusions and scaffolds a complex between p62(SQSTM1)-positive proteins and the autophagic effectors Atg5, Atg12, Atg16L and LC3. Alfy directly interacts with Atg5 and can be found in a complex with Atg5, Atg12 and Atg16L 0.599 SIGNOR-266791 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr1253 EGSFESRyQQPFEDF -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.68 SIGNOR-249360 BRAF protein P15056 UNIPROT NIBAN2 protein Q96TA1 UNIPROT down-regulates activity phosphorylation 9606 33684228 YES miannu Overall, this indicates that BRAF-dependent phosphorylation of FAM129B controls its cellular localization and thus its ability to bind to KEAP1 to block NRF2 degradation. 0.2 SIGNOR-279595 NBEAL2 protein Q6ZNJ1 UNIPROT SELP protein P16109 UNIPROT up-regulates 9606 BTO:0000132 28082341 NO lperfetto Recent in vitro megakaryopoiesis studies using HSCs from GPS patients with NBEAL2 mutations showed normal MK differentiation with defective proplatelet formation and reduced α-granule proteins such as von Willebrand factor (VWF), thrombospondin and P-selectin. 0.297 SIGNOR-261885 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr265 RVIGRGSyAKVLLVR 9606 11713277 YES llicata Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. 0.532 SIGNOR-111920 H4C1 protein P62805 UNIPROT BRDT protein Q58F21 UNIPROT up-regulates activity relocalization 9606 acetylation:Lys6;Lys9 kGGKGLGK;SGRGKGGkGLGKGGA 27991587 YES lperfetto BRDT interacts with acetylated nucleosomes via its BD1 domain. Binding may be initiated through non-specific interactions with DNA, which allow BRDT to localize to chromatin. Specificity is generated through recognition of tandem acetylated lysine residues (K5ac/K8ac) on the histone H4 tail, 0.2 SIGNOR-262066 CREB1 protein P16220 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16149046 NO miannu Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2. 0.2 SIGNOR-252227 ATM protein Q13315 UNIPROT NABP2 protein Q9BQ15 UNIPROT up-regulates activity phosphorylation Thr117 EPNPEYStQQAPNKA 10090 BTO:0002245 18449195 YES miannu Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1. 0.502 SIGNOR-262639 ELK1 protein P19419 UNIPROT PRKCA protein P17252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26010542 YES irozzo The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity. 0.44 SIGNOR-256336 PRKAA1 protein Q13131 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 21892142 NO inferred from family member gcesareni Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation 0.2 SIGNOR-270257 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr845 TASDGKLyVSSESRF 9606 16912036 YES Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 0.2 SIGNOR-260815 PINK1 protein Q9BXM7 UNIPROT ZNF746 protein Q6NUN9 UNIPROT up-regulates activity phosphorylation Ser322 QATRFFPsPAQEGAW 9606 32169097 YES miannu PINK1 directly phosphorylates PARIS at S322 and S613, priming it for ubiquitination by Parkin, which interacts with the C-terminus zinc finger of PARIS and tags it for destruction [ xref \u2013 xref , xref ].|Thus, by tagging PARIS for destruction, PINK1/Parkin drive the generation of new mitochondria by increasing PGC-1\u03b1 levels (Fig. 1d). 0.37 SIGNOR-278268 MYO9B protein Q13459 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.774 SIGNOR-260509 CDK1 protein P06493 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates activity phosphorylation Thr346 LEEGVHLtPFRQKVS 9606 24055156 YES lperfetto The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl. 0.2 SIGNOR-265263 MAP3K3 protein Q99759 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000298 9162092 YES lperfetto These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3. 0.557 SIGNOR-48625 DRD2 protein P14416 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.392 SIGNOR-257096 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 19723038 YES gcesareni The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1 0.719 SIGNOR-187779 KAT5 protein Q92993 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity acetylation Lys3016 VLMRLQEkLKGVEEG 30944854 YES lperfetto Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016 0.8 SIGNOR-275891 HMGCS2 protein P54868 UNIPROT (3S)-3-hydroxy-3-methylglutaryl-CoA(5-) smallmolecule CHEBI:43074 ChEBI up-regulates quantity chemical modification 29597274 YES lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis 0.8 SIGNOR-267660 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus. 0.2 SIGNOR-252346 MAPK1 protein P28482 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser454 PSPAPGGs -1 28689659 YES miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  0.475 SIGNOR-277361 HDAC3 protein O15379 UNIPROT FASN protein P49327 UNIPROT up-regulates quantity by stabilization deacetylation 9606 BTO:0000007 27758890 YES Overexpression of HA-HDAC3 decreased the acetylation level of endogenous FASN by 35% in HEK293T cells, while the expression of a catalytic inactive mutant HDAC3Y298H (38) failed to reduce FASN acetylation (Fig. 4C). Conversely, HDAC3 knockdown increased the acetylation level of endogenous FASN by >1.5-fold in HEK293T cells 0.2 SIGNOR-267367 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates activity dephosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000007 17603999 YES Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524. 0.377 SIGNOR-248562 ITGB1BP1 protein O14713 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.287 SIGNOR-257666 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 YES gcesareni The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions. 0.674 SIGNOR-44862 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 YES lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. 0.711 SIGNOR-227914 NR2F1 protein P10589 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 YES lperfetto Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site 0.548 SIGNOR-79440 MAP3K5 protein Q99683 UNIPROT MAP3K6 protein O95382 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 17210579 YES Manara C-terminal region of ASK1 binds to ASK2 and inhibits the degradation of ASK2 0.55 SIGNOR-260831 N protein P59595 UNIPROT FOSB protein P53539 UNIPROT up-regulates quantity by expression transcriptional regulation -1 14623261 YES Luana The transcription factors c-Fos, FosB, CREB-1, and ATF2 were all activated by the addition of SARS-CoV N protein to the sample well 0.2 SIGNOR-260728 CTNND1 protein O60716 UNIPROT CDH5 protein P33151 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0003564 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.775 SIGNOR-252126 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR BMP7 protein P18075 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.313 SIGNOR-269260 EPAS1 protein Q99814 UNIPROT AP1 complex SIGNOR-C154 SIGNOR down-regulates activity binding 9606 BTO:0000093 24383088 YES miannu Co-transfection experiments revealed that HIF-2α had greater potency on the GLIS1 promoter activation than HIF-1α. Subsequent studies using wild-type and mutant HIF-2α demonstrated that DNA binding activity was not necessary but TADs were critical for GLIS1 induction. Finally, co-transfection experiments indicated that HIF-2α cooperated with AP-1 family members in upregulating GLIS1 transcription. These results suggest that the hypoxic signaling pathway may play a pivotal role in regulating the reprogramming factor GLIS1, via non-canonical mechanisms involving partner transcription factor rather than by direct HIF transactivation. 0.345 SIGNOR-269042 HIF-1 complex complex SIGNOR-C418 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity transcriptional regulation 9606 BTO:0000889 17785433 YES Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration 0.355 SIGNOR-267494 STUB1 protein Q9UNE7 UNIPROT ATXN3 protein P54252 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21625540 YES miannu Although our data show that CHIP may associate with Atx3 to ubiquitinate Atx3 in vitro, we still wonder whether CHIP is directly involved in the degradation of Atx3.|As a result, silencing of CHIP significantly increases the amount of Atx3 (XREF_FIG), suggesting that CHIP may down-regulate the Atx3 level. 0.511 SIGNOR-278667 atropine chemical CHEBI:16684 ChEBI CHRM5 protein P08912 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258393 FGF5 protein P12034 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8386828 YES gcesareni Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2 0.702 SIGNOR-38995 glycogen smallmolecule CHEBI:28087 ChEBI α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity precursor of 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267397 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM BTK protein Q06187 UNIPROT down-regulates activity chemical inhibition -1 24556163 YES miannu BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLCγ2 (Tyr759) with an EC50 of 318 nM. 0.8 SIGNOR-262238 CHUK protein O15111 UNIPROT MTURN protein Q8N3F0 UNIPROT down-regulates activity phosphorylation Ser58 GDNFHVWsESEDCLP -1 28704656 YES miannu  INKIT interacted with IKKα/β and TBK1/IKKɛ, impairing the recruitment and phosphorylation of p65 and IRF3. Viral infection induced IKK-mediated phosphorylation of INKIT at Ser58, resulting in its dissociation from the IKKs. Our findings thus uncover INKIT as a regulator of innate antiviral responses. 0.2 SIGNOR-273612 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation 9606 BTO:0001950 21561061 YES Luana 3b Augments c-Fos Levels by Activating the ERK Pathway. | Higher c-Fos levels were observed in 3b-expressing cells than in GFP-expressing control cells 0.2 SIGNOR-260762 AKT2 protein P31751 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 YES lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 0.622 SIGNOR-245420 PRKCA protein P17252 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation 9606 26206583 YES miannu PKCalpha directly promoted the basal phosphorylation of endogenous myocardin at serine and threonine residues. 0.2 SIGNOR-279099 S1PR2 protein O95136 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257123 HIF1A protein Q16665 UNIPROT STC2 protein O76061 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18394600 YES Giorgia With the ChIP assay, we demonstrated the direct binding of HIF-1alpha to STC2 promoter. These findings support the notion that HIF-1 is a potent stimulator of STC2 expression. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression. 0.298 SIGNOR-260389 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys215 TSTHLLLkEDEGVDD 31476572 YES lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. 0.2 SIGNOR-275677 FBXL12 protein Q9NXK8 UNIPROT ALDH3A2 protein P51648 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001078 26124079 YES miannu We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members. 0.321 SIGNOR-272814 Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates binding 9606 24302288 YES lperfetto Spectrin is a member of the F-actin-crosslinking protein superfamily. 0.7 SIGNOR-266031 LEPR protein P48357 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates activity 9606 BTO:0003336 25343030 NO miannu Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake. 0.407 SIGNOR-263510 ponatinib chemical CHEBI:78543 ChEBI RIPK1 protein Q13546 UNIPROT down-regulates activity chemical inhibition 9606 25801024 YES Federica Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3 0.8 SIGNOR-261082 FBXO7 protein Q9Y3I1 UNIPROT DLGAP5 protein Q15398 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 15145941 YES miannu We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP).Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner. 0.451 SIGNOR-271506 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser463 SPHNPISsVS 10090 9748228 YES gcesareni Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif, and also regulated Smad5 and Smad8 phosphorylation. 0.702 SIGNOR-247674 TIM23 complex complex SIGNOR-C423 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 32074073 NO lperfetto Mitochondrial precursor proteins with amino-terminal presequences are imported via the presequence pathway, utilizing the TIM23 complex for inner membrane translocation. Initially, the precursors pass the outer membrane through the TOM complex and are handed over to the TIM23 complex where they are sorted into the inner membrane or translocated into the matrix. 0.7 SIGNOR-267709 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Phe117 MEILRGDfSSANNRD -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain 0.2 SIGNOR-263621 IL2RG protein P31785 UNIPROT JAK3 protein P52333 UNIPROT up-regulates binding 9606 BTO:0000776 18445337 YES milica Jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation. 0.745 SIGNOR-178491 MYOD1 protein P15172 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop-helix (bHLH) motif that mediates dimerization and dna binding. [...] myogenic bHLH proteins form heterodimers with ubiquitous bHLH proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. 0.7 SIGNOR-37458 STAG3 protein Q9UJ98 UNIPROT RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR form complex binding 10090 BTO:0000534 21242291 YES miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. 0.804 SIGNOR-264536 CDK1 protein P06493 UNIPROT FMNL2 protein Q96PY5 UNIPROT up-regulates activity phosphorylation Ser1016 MEQQDPKsPSHKSKR 9606 BTO:0000567 29930204 YES miannu In this study we have identified the formin FMNL2 as a novel substrate for CDK1 that plays a role in maintaining adhesion complexes and facilitates cell cycle–dependent changes in adhesion complexes. Knockdown of FMNL2 or expression of a nonphosphorylatable S1016A mutant resulted in the loss of adhesion complexes and stress fibers within the cell body, with peripheral structures being maintained.  0.2 SIGNOR-273555 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Thr1238 ASWDQPGtPGREPTQ 9606 BTO:0000567 37584777 YES phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. 0.257 SIGNOR-272967 NFATC1 protein O95644 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 YES miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. 0.251 SIGNOR-264022 DHX9 protein Q08211 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity binding 9606 BTO:0000007 30137501 YES miannu A DNA-sensing-independent Role of a Nuclear RNA Helicase, DHX9, in Stimulation of NF-κB-mediated Innate Immunity Against DNA Virus Infection. Taken together, our results show a critical role of nuclear DHX9 (as a transcription coactivator) in the stimulation of NF-κB-mediated innate immunity against DNA virus infection, independently of DHX9's DNA-sensing function. DHX9 interacts with NF-κB p65 and RNAPII in the nucleus during DNA virus infection 0.463 SIGNOR-260947 PPM1D protein O15297 UNIPROT MDM4 protein O15151 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser403 DLAHSSEsQETISSM 33309518 YES lperfetto PPM1D also inhibits p53 activity by dephosphorylating Ser395 and stabilizing MDM2 and by dephosphorylating Ser403 on MDMX 0.431 SIGNOR-275491 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser21 TPPSTALsPGKMSEA 9606 21059642 YES The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.58 SIGNOR-273031 ESR1 protein P03372 UNIPROT AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 18247370 YES miannu The primary conclusion of the results reported here is that ERα and c‐jun, c‐fos and ATF‐2, but not Fra‐2 AP‐1 factors interact “in vivo” with specific estrogen‐responsive regulatory sequences and AP‐1 cis‐elements within the F promoter of the human ERα gene in osteoblast‐like SaOS‐2 cells. 0.72 SIGNOR-263656 PFKM protein P08237 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266471 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr392 QDNDQPDyDSVASDE 9606 16317044 YES fspada Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest. 0.344 SIGNOR-142715 VIP protein P01282 UNIPROT VIPR1 protein P32241 UNIPROT up-regulates binding 9606 11897681 YES gcesareni Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip). 0.863 SIGNOR-116122 F2R protein P25116 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.399 SIGNOR-256875 PDPK1 protein O15530 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr410 GPGDTTStFCGTPNY 9606 11141077 YES gcesareni Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylationcytoskeletal reorganization;tnni1(induces);desmin(induces);tpm1(induces);myo1c(induces);tnnt1(induces); 0.576 SIGNOR-85501 BCAS2 protein O75934 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR form complex binding 9606 BTO:0000567 20176811 YES miannu In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27. 0.897 SIGNOR-271973 ATM protein Q13315 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT up-regulates quantity by stabilization phosphorylation Ser677 RVGKQLAsQKILQLL 9606 BTO:0002181 34188037 YES miannu  Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.  0.27 SIGNOR-277307 IKBKB protein O14920 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22056382 NO Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation 0.2 SIGNOR-253585 MAPK1 protein P28482 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser789 QSVDKVTsPTKV 9606 BTO:0001260 10514499 YES lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. 0.538 SIGNOR-71037 UDP(3-) smallmolecule CHEBI:58223 ChEBI P2RY6 protein Q15077 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257565 PLAUR protein Q03405 UNIPROT KRT1 protein P04264 UNIPROT up-regulates activity binding 9606 14691569 YES Regulation of binding miannu Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored. 0.288 SIGNOR-251880 Ub:E2 complex SIGNOR-C497 SIGNOR RNF130 protein Q86XS8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271031 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM32 protein Q13049 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271035 POLR3A protein O14802 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.868 SIGNOR-266133 RPS6KA1 protein Q15418 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Thr355 NKRRRSVtPPEEQQE 9606 23708659 YES lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. 0.253 SIGNOR-202125 FGG protein P02679 UNIPROT VTN protein P04004 UNIPROT down-regulates activity binding 9606 2243140 YES Regulation miannu Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a). 0.423 SIGNOR-251969 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 YES lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 0.493 SIGNOR-176883 ATF1 protein P18846 UNIPROT FTH1 protein P02794 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17565989 NO miannu Here we found that ATF1 (activating transcription factor 1) is a transcriptional repressor of the ferritin H ARE. 0.2 SIGNOR-253741 PMP22 protein Q01453 UNIPROT MPZ protein P25189 UNIPROT up-regulates activity binding 9606 10212299 YES miannu Our data provide the first direct evidence for the formation of P0–PMP22 complexes at the plasma membrane. These protein interactions probably participate in holding adjacent Schwann cell membranes together and in stabilizing myelin compaction. 0.575 SIGNOR-251898 KLF14 protein Q8TD94 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 24759103 YES Luana KLF14 Is a Transcriptional Activator of SK1 Gene Expression in Endothelial Cells 0.2 SIGNOR-266047 CACNA1D protein Q01668 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 28642685 YES miannu Rab interacting molecules (RIMs) are multi-domain proteins that positively regulate the number of Ca2+ channels at the presynaptic active zone (AZ). Several molecular mechanisms have been demonstrated for RIM-binding to components of the presynaptic Ca2+ channel complex, the key signaling element at the AZ. Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α–subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs).  0.8 SIGNOR-264359 PTAFR protein P25105 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256789 MYCT1 protein Q8N699 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000670;BTO:0000738 30283340 NO miannu Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo 0.7 SIGNOR-261729 GRK3 protein P35626 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Thr182 VKALDFRtPRNAKII 8355 BTO:0000512 11060299 YES gcesareni These results demonstrate that the T180A mutation probably blocks GRK3- and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors 0.2 SIGNOR-247915 F2RL1 protein P55085 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.405 SIGNOR-257300 KAT2A protein Q92830 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269607 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI up-regulates quantity chemical modification 9606 33179964 YES miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). 0.8 SIGNOR-267318 LTA protein P01374 UNIPROT LTBR protein P36941 UNIPROT up-regulates binding 9606 7995952 YES gcesareni These experiments point toward the lt-alpha 1/beta 2 complex as the predominant membrane form of lt on the lymphocyte surface, and this complex is the primary ligand for the lt-beta receptor. 0.845 SIGNOR-35708 Oxotremorine chemical CHEBI:7851 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258650 CTSS protein P25774 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 31810556 YES scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. 0.8 SIGNOR-267867 Ub:E2 complex SIGNOR-C497 SIGNOR BRCA1 protein P38398 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271105 MN1 protein Q10571 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding -1 12569362 YES irozzo Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300. 0.343 SIGNOR-256020 HDAC2 protein Q92769 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 NO miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. 0.382 SIGNOR-254154 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA11 protein Q9Y5H2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265712 MAPK8 protein P45983 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr57 NFDFVTEtPLEGDFA -1 12058028 YES miannu P38Œ± and JNK1 Phosphorylate p21 in Vitro at Thr57 and Ser130. These data suggest that phosphorylation at Thr57 is necessary for stabilization of p21. 0.671 SIGNOR-250118 SMURF2 protein Q9HAU4 UNIPROT SMAD2/SMURF2 complex SIGNOR-C11 SIGNOR form complex binding 9606 11389444 YES gcesareni We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases. 0.778 SIGNOR-108496 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 BTO:0000017 28192398 YES miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  0.65 SIGNOR-277342 DZIP3 protein Q86Y13 UNIPROT H2AC6 protein Q93077 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271759 TRIM71 protein Q2Q1W2 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity ubiquitination 9606 28430184 YES miannu LIN41 promotes ubiquitination of p53 in response to RA.|Loss of LIN41 elevates p53 steady-state levels and reduces p53 ubiquitination. 0.272 SIGNOR-278679 CDKN1A protein P38936 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 24470334 NO The cell cycle regulator p21 is induced early in myoblast differentiation and functions to block cell cycle progression 0.7 SIGNOR-251564 CRTC2 protein Q53ET0 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9606 26652733 YES inferred from family member miannu Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB 0.279 SIGNOR-267788 DGC complex SIGNOR-C217 SIGNOR GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265432 KDR protein P35968 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity relocalization 9825 BTO:0004007 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 9405464 YES VEGF pathway Gianni In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function. 0.685 SIGNOR-261948 NPFFR1 protein Q9GZQ6 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256708 HLA-DRA protein P01903 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000776 21178476 NO scontino Fusion with a B cell requires a ternary complex of gHgLgp42. Fusion is triggered by an interaction between gp42 and HLA class II. 0.7 SIGNOR-266630 FEZF2 protein Q8TBJ5 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by repression transcriptional regulation 23677067 NO lperfetto FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma. 0.2 SIGNOR-268974 vemurafenib chemical CHEBI:63637 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition 9606 23094782 YES miannu Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents; ipilimumab, a humanized, IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and vemurafenib , a BRAF (v-raf murine sarcoma viral oncogene homolog B1) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene. 0.8 SIGNOR-259281 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 8940173 YES miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.2 SIGNOR-246260 PPP6C protein O00743 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 17079228 YES Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway|From proteomic analysis of TAK1-binding proteins, we identified protein phosphatase 6 (PP6), a type-2A phosphatase, and demonstrated that PP6 associated with and inactivated TAK1 by dephosphorylation of Thr-187. 0.372 SIGNOR-248292 HECW2 protein Q9P2P5 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 BTO:0000093 27119228 YES miannu NEDL2 acts as a scaffold protein to promote GDNF-stimulated Akt activation. biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. NEDL2 binds p85, p110 and Akt with different domains 0.2 SIGNOR-269458 FBXO6 protein Q9NRD1 UNIPROT ERO1A protein Q96HE7 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 27855403 YES miannu Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex 0.2 SIGNOR-272326 Ub:E2 complex SIGNOR-C497 SIGNOR RNF14 protein Q9UBS8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271233 LRFN4 protein Q6PJG9 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 21736948 YES miannu SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. One possibility is that SALM3, which is capable of inducing presynaptic differentiation in contacting axons [19], recruits PSD-95 or SAP102 to the sites of early synaptic adhesion. 0.68 SIGNOR-264096 6 protein P59634 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity binding 9606 32353860 YES miannu Orf6 of SARS-CoV antagonizes host interferon signaling by perturbing nuclear transport, and the NUP98-RAE1 interaction with Orf6 may perform the same function for SARS-CoV-2. 0.2 SIGNOR-260976 P2RY13 protein Q9BPV8 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257143 UBR5 protein O95071 UNIPROT TOPBP1 protein Q92547 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 11714696 YES miannu Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks. 0.462 SIGNOR-272667 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2409 LHGDDQDsEDEVLTI 9606 8318012 YES lperfetto The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157. 0.473 SIGNOR-37831 MAP3K7 protein O43318 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 YES lperfetto In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease 0.252 SIGNOR-260266 SRC protein P12931 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr66 DTAGQEDyDRLRPLS 9606 BTO:0000567 23027962 YES lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity 0.667 SIGNOR-271701 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates activity phosphorylation Ser348 PGPQSPGsPLEEERQ -1 24632950 YES miannu Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation.PKCδ phosphorylates p47phox for K-Ras-induced ROS generation. PKCδ binds to the SH3-N domain and phosphorylates Ser348 and Ser379 residues in p47phox for K-RasV12-induced ROS generation and consequent malignant transformation. 0.448 SIGNOR-276623 IL10 protein P22301 UNIPROT SCN1A protein P35498 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 NO miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. 0.2 SIGNOR-253497 ULK1 protein O75385 UNIPROT ATG14 protein Q6ZNE5 UNIPROT up-regulates activity phosphorylation Ser29 LARDLVDsVDDAEGL 9606 27938392 YES miannu ULK1 phosphorylates ATG14 at serine 29. 0.65 SIGNOR-278433 luminespib chemical CHEBI:83656 ChEBI HSP90AB1 protein P08238 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190041 LHFPL5 protein Q8TAF8 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR up-regulates activity binding 10090 BTO:0000630 23217710 YES lperfetto Here we show that TMHS is an auxiliary subunit of the hair cells mechanotransduction channel.|TMHS belongs to the tetraspan family. It binds to PCDH15, controls the assembly of the hair cells mechanotransduction machinery, regulates the properties of their mechanotransduction channels, and is required for adaptation. 0.415 SIGNOR-262574 GSK3A protein P49840 UNIPROT MITF protein O75030 UNIPROT up-regulates phosphorylation Ser405 QARAHGLsLIPSTGL 9606 10587587 YES The effect has been demonstrated using O75030-9 gcesareni Glycogen synthase kinase 3 (gsk3) was found to phosphorylate ser298 in vitro, thereby enhancing the binding of mitf to the tyrosinase promoter 0.294 SIGNOR-72878 TRPV4 protein Q9HBA0 UNIPROT UCP1 protein P25874 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000443 23021218 NO lperfetto TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. 0.287 SIGNOR-253096 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258203 dexamethasone chemical CHEBI:41879 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-106472 CD79A protein P11912 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 32323266 YES scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. 0.656 SIGNOR-268196 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.703 SIGNOR-156860 LAT protein O43561 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 YES lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. 0.412 SIGNOR-246065 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 YES gcesareni In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed in vertebrates, pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation 0.467 SIGNOR-154273 RELA protein Q04206 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 17350185 YES Luana The IL-6 promoter was stimulated by NF-kB RelA protein.  0.691 SIGNOR-266088 MTA1 protein Q13330 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000812 18719363 NO miannu MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. 0.457 SIGNOR-254597 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763;BTO:0000149 10197981 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-66771 CHUK protein O15111 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser181 DQGSLCTsFVGTLQY -1 10022904 YES llicata Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays. 0.669 SIGNOR-250772 SHPK protein Q9UHJ6 UNIPROT sedoheptulose smallmolecule CHEBI:16802 ChEBI down-regulates quantity chemical modification 9606 22682222 YES miannu The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose 0.8 SIGNOR-267083 ATP6V0A2 protein Q9Y487 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.757 SIGNOR-277754 HUWE1 protein Q7Z6Z7 UNIPROT ZBTB17 protein Q13105 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26212014 YES miannu Previously, we reported that K48 linked polyubiquitination of Miz1 by Mule triggers its proteasomal degradation, thereby relieving Miz1 suppression on TNF induced JNK activation and apoptosis. 0.328 SIGNOR-278697 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser280 VDGTGDTsSEEDEDE -1 11278496 YES llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. 0.375 SIGNOR-250995 HIF-1 complex complex SIGNOR-C418 SIGNOR LDHB protein P07195 UNIPROT up-regulates quantity transcriptional regulation 9606 7673128 YES lperfetto Deletional and mutational analysis of the function of mouse LDH-reporter fusion gene constructs in transient transfection assays defined three domains, between -41 and -84 base pairs upstream of the transcription initiation site, which were crucial for oxygen-regulated expression. The most important of these, although not capable of driving hypoxic induction in isolation, had the consensus of a hypoxia-inducible factor 1 (HIF-1) site, and cross-competed for the binding of HIF-1 with functionally active Epo and phosphoglycerate kinase-1 sequences 0.353 SIGNOR-267653 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRP1 protein Q9C000 UNIPROT up-regulates activity 16037825 NO lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-256425 MAPK8IP3 protein Q9UPT6 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 15767678 YES inferred from 70% of family members gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. 0.746 SIGNOR-269886 LAMTOR complex SIGNOR-C26 SIGNOR RAGAC complex SIGNOR-C113 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 YES lperfetto We identify the trimeric Ragulator protein complex as a new component of the mTORC1 pathway that interacts with the Rag GTPases, is essential for localizing them and mTORC1 to the lysosomal surface, and is necessary for the activation of the mTORC1 pathway by amino acids. 0.879 SIGNOR-228155 CAMK1 protein Q14012 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity phosphorylation Thr103 AALLKNNtALQSVSL 9606 28652571 YES miannu In this study, we found that CaMKI phosphorylated GEF-H1 at Thr103, which is located close to the C1 domain. 0.389 SIGNOR-279359 CHCHD1 protein Q96BP2 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.681 SIGNOR-261460 ANKRD6 protein Q9Y2G4 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 20006983 YES gcesareni Our data thus demonstrate that diversin and dishevelled function together in a mutually dependent fashion in zebrafish gastrulation and organ formation 0.474 SIGNOR-162142 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.257 SIGNOR-159450 NFIA protein Q12857 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.284 SIGNOR-268890 PRKCA protein P17252 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Ser1074 GNQRNRCsTFRVKRN -1 36040231 YES miannu PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. 0.2 SIGNOR-276867 SRP54 protein P61011 UNIPROT SRSF2 protein Q01130 UNIPROT up-regulates activity binding -1 8816452 YES Monia We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65). 0.341 SIGNOR-261160 propranolol chemical CHEBI:8499 ChEBI ADRB2 protein P07550 UNIPROT down-regulates activity chemical inhibition 10030 10079020 YES Luana Similarly, the binding affinities of ICI 118–551, CGP 20712A, propranolol, bupranolol and CGP 12177 for human β1-, β2- and β3-adrenoceptors correlate with their affinities at human β1- (P=0.04), β2- (P=0.01) 0.8 SIGNOR-258334 PITX2 protein Q99697 UNIPROT GNRH1 protein P01148 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004467 19106114 NO miannu Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter. 0.261 SIGNOR-254922 PIK3R4 protein Q99570 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 YES lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.919 SIGNOR-260317 CAMK1 protein Q14012 UNIPROT NOS1 protein P29475 UNIPROT down-regulates activity phosphorylation Ser852 SYKVRFNsVSSYSDS -1 10400690 YES llicata It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation. 0.332 SIGNOR-250614 NEK6 protein Q9HC98 UNIPROT KIF20A protein O95235 UNIPROT down-regulates activity phosphorylation Ser244 LSTSLKRsVYIESRI 9606 BTO:0000567 28630147 YES done miannu We show that Nek9, Nek6, and the kinesin Mklp2 form a signaling module, which is required for Mklp2 to localize to the central spindle in anaphase. Nek6 also phosphorylates Mklp2 at Ser244, inhibiting its bundling activity until anaphase onset. 0.347 SIGNOR-273891 POU5F1 protein Q01860 UNIPROT TBX18 protein O95935 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.323 SIGNOR-254945 TNF protein P01375 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.2 SIGNOR-253486 nitric oxide smallmolecule CHEBI:16480 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 NO lperfetto The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. 0.7 SIGNOR-272279 MITF protein O75030 UNIPROT ACP5 protein P13686 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0003292 11481336 NO miannu The combination of MITF and PU.1 synergistically activated the TRAP promoter in transient assays. 0.346 SIGNOR-254584 EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR up-regulates activity binding 9606 20025795 YES miannu The work cycle during which a new amino acid is added to the growing polypeptide chain, referred to as elongation cycle, is a repetitive multistep process encompassing aminoacyl-tRNA (aa-tRNA) selection, peptide bond formation, and mRNA–tRNA translocation (Fig. 1). In the initial binding state, referred to as A/T state, this aa-tRNA is in a ternary complex with the GTPase EF-Tu (eEF1A in eukaryotes) and GTP. When a Watson–Crick codon–anticodon match is recognized by the ribosome, a signal is transmitted to EF-Tu that triggers GTP hydrolysis and thereby causes the dissociation of EF-Tu from the ribosome. The subsequent accommodation of the 3′ acceptor arm of the tRNA in the PTC of the large subunit leads to a rapid peptide bond transfer 0.2 SIGNOR-270810 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr690 PLNSDVQyTEVQVSS 9606 BTO:0000007 12972546 YES miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. 0.276 SIGNOR-262867 PPP1CA protein P62136 UNIPROT CAD protein P27708 UNIPROT down-regulates activity dephosphorylation Ser1406 CSGAGGRrLSSFVTK -1 4092695 YES lperfetto Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2| Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: Ile-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys | Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1- and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2. 0.332 SIGNOR-263741 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 21454698 YES gcesareni Strikingly, when fak and ret kinases were co-incubated in the presence of atp, a marked increased in fak tyr-576/577 and tyr-925 phosphorylation was observed together with a shift in mobility of fak, indicating conversion to an activated state 0.638 SIGNOR-173021 JUN protein P05412 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 NO miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.259 SIGNOR-254875 CEBPD protein P49716 UNIPROT CCL20 protein P78556 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 NO CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. 0.251 SIGNOR-254056 PDX1 protein P52945 UNIPROT NKX6-1 protein P78426 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11309388 YES In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. 0.501 SIGNOR-255542 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 BTO:0000007 7758105 YES lperfetto We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed. 0.805 SIGNOR-32739 PSMC4 protein P43686 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.878 SIGNOR-263371 RFC3 protein P40938 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 YES lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 0.831 SIGNOR-265507 D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity precursor of 9606 11724794 YES miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion 0.8 SIGNOR-266493 FZD7 protein O75084 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 22944199 YES gcesareni Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism. 0.2 SIGNOR-198831 PRKAA2 protein P54646 UNIPROT TFAP2A protein P05549 UNIPROT up-regulates activity phosphorylation Ser219 CSVPGRLsLLSSTSK 9606 22561688 YES miannu Inhibition of AMPKalpha2 with either siRNA or compound C significantly suppressed the AngII- or nicotine enhanced AP-2alpha activity and the binding of AP-2alpha to DNA.|We report that nicotine, a major component of cigarette smoke, activates AMPK in VSMCs and that AMPKalpha2 phosphorylates AP-2alpha at serine 219 resulting in aberrant expression of MMP2 and consequent AAA formation. 0.307 SIGNOR-279648 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT down-regulates activity phosphorylation Ser312 ALDLEESsSSDHAER 10029 BTO:0000246 7876239 YES The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization. 0.2 SIGNOR-251441 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Ser518 KGGTPAGsARGSPTR 10116 16611631 YES lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.473 SIGNOR-146003 PPP1CA protein P62136 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 YES fstefani P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases 0.445 SIGNOR-103155 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 protein Q9Y261 UNIPROT down-regulates activity phosphorylation Thr156 KTYRRSYtHAKPPYS 9606 14500912 YES Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. 0.2 SIGNOR-254974 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 11875057 YES gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. 0.843 SIGNOR-115340 Ub:E2 complex SIGNOR-C497 SIGNOR ZNRF3 protein Q9ULT6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271122 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 26194464 YES MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). 0.846 SIGNOR-255031 IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 23332762 YES lperfetto Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. 0.263 SIGNOR-216399 SLC24A5 protein Q71RS6 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264403 GFPT1 protein Q06210 UNIPROT 2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-) smallmolecule CHEBI:58725 ChEBI up-regulates quantity chemical modification 9606 21310273 YES miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans 0.8 SIGNOR-267817 ECM stimulus SIGNOR-ST20 SIGNOR Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259038 MRPL28 protein Q13084 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.699 SIGNOR-262367 M protein P59596 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity 9606 25271362 NO Luana Taken together, our results demonstrated that expression of M-protein causes activation of both caspases 8 and 9 via the PKB/Akt signalling cascades.  0.2 SIGNOR-260202 3a protein P59632 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity 9606 18632968 NO Luana Thus, caspase-9 activation and cytochrome c release in cells expressing the 3a protein indicated that this viral protein also activates the intrinsic pathway of apoptosis. 0.2 SIGNOR-260213 PRDM1 protein O75626 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 NO miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. 0.436 SIGNOR-253828 RBBP8 protein Q99708 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR up-regulates activity relocalization 24832651 YES lperfetto DNA damage activates ATM and CHK2 kinases, which mediate phosphorylation of CtIP and BRCA1. Phosphorylated CtIP associates with BRCA1 and with the MRN complex leading to the recruitment of the BRCC complex at the site of DNA damage where HR is initiated. 0.607 SIGNOR-263202 NAT10 protein Q9H0A0 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization acetylation Lys120 FLHSGTAkSVTCTYS 9606 BTO:0002552 26882543 YES miannu NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.  0.337 SIGNOR-272406 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser528 KPRSSRGsIFTFRRR 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.2 SIGNOR-275764 NFIA protein Q12857 UNIPROT ETV5 protein P41161 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268874 CTDSPL2 protein Q05D32 UNIPROT PDIK1L protein Q8N165 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser216 SVNKCFLsTACGTDF 9606 BTO:0002181 35021089 YES miannu  We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D). 0.356 SIGNOR-273774 nitric oxide smallmolecule CHEBI:16480 ChEBI Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 32454942 NO miannu Next to their interaction with adaptive immune cells, activated microglia can secrete cytotoxic cytokines and oxidative products, such as ROS and NO radicals in MS lesions thereby promoting oxidative stress and contributing to myelin destruction 0.7 SIGNOR-263829 SEMA3F protein Q13275 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 16816121 YES esanto In the nervous system, neuropilins mediate axon retraction and guidance by binding class iii semaphorins. We found that sema3f could compete with metabolically labeled vegf-c for the binding to np1-ig and np2-ig fusion proteins. 0.613 SIGNOR-147608 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI PP2B proteinfamily SIGNOR-PF18 SIGNOR down-regulates chemical inhibition 9606 15276472 YES inferred from 70% of family members gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-269893 TWIST1 protein Q15672 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255518 neuropeptide FF receptor agonist smallmolecule CHEBI:141000 ChEBI NPFFR1 protein Q9GZQ6 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257549 MAPK14 protein Q16539 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 20626350 NO lperfetto On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment. 0.635 SIGNOR-244461 ERRFI1 protein Q9UJM3 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity binding -1 18046415 YES The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 0.643 SIGNOR-252076 ACSS2 protein Q9NR19 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity chemical modification 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271826 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 BTO:0000782 15623513 YES lperfetto Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus. 0.479 SIGNOR-132898 Ub:E2 complex SIGNOR-C497 SIGNOR MKRN3 protein Q13064 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271132 NR3C1 protein P04150 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 YES miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription 0.498 SIGNOR-268049 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.432 SIGNOR-273142 AminoAcids stimulus SIGNOR-ST5 SIGNOR RAG2 protein P55895 UNIPROT up-regulates 9606 22790199 NO gcesareni Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated. 0.7 SIGNOR-198192 CPSF complex complex SIGNOR-C53 SIGNOR PAPOLB protein Q9NRJ5 UNIPROT up-regulates activity relocalization 9606 14749727 YES lperfetto Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. 0.55 SIGNOR-268324 PLK1 protein P53350 UNIPROT VIM protein P08670 UNIPROT up-regulates phosphorylation Ser83 GVRLLQDsVDFSLAD 9606 BTO:0000150 18056432 YES gcesareni We observed that plk1 phosphorylates vimentin on ser82, which in turn regulates cell surface levels of 1 integrin. 0.2 SIGNOR-159386 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG protein P37231 UNIPROT up-regulates activity phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 YES gcesareni Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells. 0.2 SIGNOR-232236 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 18567737 YES gcesareni Interestingly, resveratrol increased the activity of protein tyrosine phosphatase ptp1b, which dephosphorylates pdgf-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on pdgfr with concomitant reduction in akt and erk1/2 kinase activity. these results for the first time provide evidence that the stilbene resveratrol targets ptp1b to inhibit pdgfr mitogenic signaling. 0.69 SIGNOR-179068 CDON protein Q4KMG0 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 BTO:0000222 18678706 YES lperfetto During myoblast differentiation, the promyogenic cell surface receptor cdo binds to the p38alpha/beta pathway scaffold protein jlp and, via jlp, p38alpha/beta itself 0.463 SIGNOR-179867 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr1048 GMTCAELyEKLPQGY -1 11513602 YES lperfetto Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km. 0.2 SIGNOR-109786 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser347 TFPAQSLsPEPLPQE 9606 14697653 YES lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.259 SIGNOR-120459 IKBKB protein O14920 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C14 23332762 YES gcesareni Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. 0.263 SIGNOR-192614 CYBB protein P04839 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.8 SIGNOR-264723 LRP1B protein Q9NZR2 UNIPROT DVL2 protein O14641 UNIPROT down-regulates activity binding 9606 28408316 YES irozzo In this study, we have shown that LRP1B inhibited the activity of beta-catenin/TCF signaling possibly by interacting with DVL2. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling. 0.385 SIGNOR-259090 PRKAR1B protein P31321 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.88 SIGNOR-258756 FOXO4 protein P98177 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.339 SIGNOR-236557 FUS protein P35637 UNIPROT ATXN2 protein Q99700 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 NO This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease 0.454 SIGNOR-262809 DRD4 protein P21917 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.46 SIGNOR-256982 SPI1 protein P17947 UNIPROT JUN protein P05412 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17041602 NO miannu Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. 0.556 SIGNOR-256065 MAPK10 protein P53779 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 YES gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress. 0.301 SIGNOR-166690 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM69 protein Q86WT6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271188 FURIN protein P09958 UNIPROT INSR protein P06213 UNIPROT up-regulates activity cleavage 9606 BTO:0000666 25527501 YES Giorgia Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. 0.283 SIGNOR-260365 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 YES The effect has been demonstrated using Q01196-8 lperfetto We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.2 SIGNOR-244715 MED27 protein Q6P2C8 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.807 SIGNOR-266662 MAPK9 protein P45984 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 YES gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.663 SIGNOR-134568 Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR GAS6 protein Q14393 UNIPROT up-regulates 9606 BTO:0000130 35022267 NO miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. 0.7 SIGNOR-277724 CBLB protein Q13191 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24885194 YES miannu The ubiquitin ligase Cbl-b also ubiquitinated and degraded IGF-IR and inhibited the Akt/ERK-miR-200c-ZEB2 axis, leading to the repression of IGF-I-induced EMT. 0.421 SIGNOR-278607 ponatinib chemical CHEBI:78543 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 23430109 YES lperfetto AP24534 also inhibited SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (Table 1 and Table S1) 0.8 SIGNOR-261984 SKA2 protein Q8WVK7 UNIPROT SKA complex complex SIGNOR-C364 SIGNOR form complex binding -1 22483620 YES lperfetto We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. 0.902 SIGNOR-265195 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM56 protein Q9BRZ2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270961 CDCA2 protein Q69YH5 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding 9606 BTO:0000567 32938714 YES done miannu This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin. 0.372 SIGNOR-274003 P2RY13 protein Q9BPV8 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257299 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT down-regulates activity dephosphorylation Tyr805 EDNDDDLyG 9606 BTO:0000007 10364224 YES Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs. 0.479 SIGNOR-248461 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser321 QSLSLASsPKGTIEN 9606 BTO:0002181 34363019 YES miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  0.2 SIGNOR-276735 PCM1 protein Q15154 UNIPROT CETN3 protein O15182 UNIPROT up-regulates relocalization 9606 12403812 YES miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome 0.297 SIGNOR-95016 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.2 SIGNOR-244677 nitric oxide smallmolecule CHEBI:16480 ChEBI NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 BTO:0001103 20219869 YES apalma Similarly, exposure of cells to oxidative stress, in particular, nitric oxide (NO) or peroxynitrite (ONOO), can activate NF-kB and cause its translocation. 0.8 SIGNOR-255350 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2D1 protein P51668 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.722 SIGNOR-271345 KNG1 protein P01042 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 YES lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. 0.45 SIGNOR-261858 Ub:E2 complex SIGNOR-C497 SIGNOR ZBTB12 protein Q9Y330 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271022 NANOGP8 protein Q6NSW7 UNIPROT BMP5 protein P22003 UNIPROT down-regulates quantity by repression transcriptional regulation 10900 BTO:0000667 23839044 NO Luana Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. 0.2 SIGNOR-266089 TBCK protein Q8TEA7 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23977024 NO miannu Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule. 0.7 SIGNOR-266700 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates binding 9606 BTO:0000150 15009097 YES lperfetto Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo. 0.687 SIGNOR-217233 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGC4 protein Q9Y5F7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265715 SOS2 protein Q07890 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. 0.712 SIGNOR-175265 CTDNEP1 protein O95476 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates binding 9606 17141153 YES gcesareni We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors 0.426 SIGNOR-151001 GRIN2C protein Q14957 UNIPROT GRIN1 protein Q05586 UNIPROT up-regulates activity binding 10090 BTO:0004278 19477150 YES miannu Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells. 0.611 SIGNOR-262621 D-glucitol smallmolecule CHEBI:17924 ChEBI TARDBP protein Q13148 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 NO We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne 0.8 SIGNOR-262817 DNA_damage stimulus SIGNOR-ST1 SIGNOR CDKN2A protein Q8N726 UNIPROT up-regulates activity 9606 25101116 NO lperfetto ARF: a versatile DNA damage response ally at the crossroads of development and tumorigenesis. Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones. 0.7 SIGNOR-245493 ABL1 protein P00519 UNIPROT CKMT1A protein P12532 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr153 ASKIRSGyFDERYVL 9606 BTO:0001932 30174304 YES miannu Here, we show that oncogenic HER2 tyrosine kinase signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153) in an ABL-dependent manner in breast cancer cells. Y153 phosphorylation, which is commonly upregulated in HER2+ breast cancers, stabilizes MtCK1 to increase the phosphocreatine energy shuttle and promote proliferation.  0.2 SIGNOR-277406 BRCA1 protein P38398 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR up-regulates activity binding 10426999 YES lperfetto BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50.| These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex. 0.776 SIGNOR-251501 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr570 INGNNYVyIDPTQLP 9606 12824176 YES lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated 0.2 SIGNOR-102637 DYRK1A protein Q13627 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity 0.305 SIGNOR-183680 MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004102 14593184 YES Luana Moreover, increased Bdnf transcription involves dissociation of the MeCP2–histone deacetylase–mSin3A repression complex from its promoter. 0.371 SIGNOR-265071 SIAH2 protein O43255 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 16174773 YES lperfetto Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system 0.619 SIGNOR-140651 SNRPD1 protein P62314 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.742 SIGNOR-270660 PTPRG protein P23470 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr716 RPPSAELySNALPVG -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.338 SIGNOR-254715 XRCC5 protein P13010 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002284 16166097 YES miannu The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome. 0.307 SIGNOR-225537 CDK4 protein P11802 UNIPROT TOB2 protein Q14106 UNIPROT up-regulates activity phosphorylation Ser254 PAPQSQLsPNAKEFV -1 32404348 YES miannu Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. 0.2 SIGNOR-273602 RNF135 protein Q8IUD6 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity ubiquitination Lys907 GVQTLYSkWKDFHFE 9606 BTO:0000007 19017631 YES miannu Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region. 0.763 SIGNOR-265568 GSK3B protein P49841 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser847 SEAASLSsLNSSESD -1 10671552 YES Phosphorylation of the E-cadherin Cytoplasmic Domain by CKII and GSK-3β Increases the Binding to β-catenin. pre-phosphorylation by CKII at Ser-855 and/or Ser-853 of E-cadherin is required before GSK-3β can phosphorylate at Ser-849. 0.559 SIGNOR-251225 PTPRC protein P08575 UNIPROT TYK2 protein P29597 UNIPROT down-regulates activity dephosphorylation Tyr1055 VPEGHEYyRVREDGD 10090 11201744 YES CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 0.407 SIGNOR-248358 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 16679294 YES gcesareni Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action 0.261 SIGNOR-146668 IKBKG protein Q9Y6K9 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 SIGNOR-C14 SIGNOR-C13 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. 0.862 SIGNOR-129947 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser287 ATAGPKAsPTPQKTS 9606 BTO:0000007 14741103 YES llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. 0.405 SIGNOR-250655 BECN1 protein Q14457 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 NO miannu Autophagy initiation signaling requires both the ULK1 kinase and the BECLIN 1–VPS34 core complex to generate autophagosomes, double-membraned vesicles that transfer cellular contents to lysosomes. 0.7 SIGNOR-219545 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257528 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL -1 10734133 YES gcesareni Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant. 0.378 SIGNOR-262291 HMG20B protein Q9P0W2 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 YES miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells 0.773 SIGNOR-264503 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 23486913 YES lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation 0.755 SIGNOR-217110 SYK protein P43405 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 11331248 YES gcesareni Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k. 0.92 SIGNOR-107046 GRK2 protein P25098 UNIPROT TBXA2R protein P21731-2 UNIPROT down-regulates activity phosphorylation Ser239 AQQRPRDsEVEMMAQ 9606 16956790 YES done miannu  These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization. 0.2 SIGNOR-274088 PTPN11 protein Q06124 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates activity dephosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 32140036 YES lperfetto In addition, surface expression of GluN2B was not reduced in mutant mice and it remains to be investigated how the direct dephosphorylation of GluN2B Y1252 by Shp2 reduces GluN2B function.|The increased GluN2B Y1472 phosphorylation was reversed by a Src family kinase inhibitor, suggesting that Shp2 may negatively regulate GluN2B Y1472 phosphorylation through suppressing Src activity . 0.469 SIGNOR-276950 DNA_damage stimulus SIGNOR-ST1 SIGNOR TAOK2 protein Q9UL54 UNIPROT up-regulates 9606 17396146 NO lperfetto These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM. 0.7 SIGNOR-226602 HEY2 protein Q9UBP5 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 16682003 YES The NotchIC-RBP-Jkappa complex activates target genes, such as those encoding the Hrt and Hes families. The interaction did not interfere with the formation or DNA-binding of the NotchIC-RBP-Jkappa complex, indicating direct inhibition by Hrt and Hes as co-repressors. gcesareni Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. 0.767 SIGNOR-146690 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP -1 15241418 YES llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo. 0.742 SIGNOR-250749 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser742 QQIINQIsKLHAIID 9606 18680479 YES gcesareni We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity after expression in bacteria or in cultured human cells. 0.2 SIGNOR-179900 APOBEC3A protein P31941 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 NO lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). 0.7 SIGNOR-261332 FBXL5 protein Q9UKA1 UNIPROT IREB2 protein P48200 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 19762596 YES miannu  We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus.  0.745 SIGNOR-271882 SKI protein P12755 UNIPROT EP300 protein Q09472 UNIPROT down-regulates binding 9606 SIGNOR-C6 10575014 YES gcesareni Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling. 0.2 SIGNOR-72664 ATG2A protein Q2TAZ0 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001938 28561066 NO miannu WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. 0.7 SIGNOR-268485 PASK protein Q96RG2 UNIPROT PASK protein Q96RG2 UNIPROT up-regulates activity phosphorylation Thr1165 LFYTFCGtIEYCAPE -1 11459942 YES lperfetto We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity. 0.2 SIGNOR-109485 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Ser211 TLGSPLTsPGGSPGG 9606 BTO:0001131 9630228 YES lperfetto Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4. 0.589 SIGNOR-109763 NPRL2 protein Q8WTW4 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR form complex binding 9606 23723238 YES miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 0.956 SIGNOR-255281 DYRK2 protein Q92630 UNIPROT KATNA1 protein O75449 UNIPROT down-regulates quantity by destabilization phosphorylation Ser42 QMNKYLYsVKDTYLQ 9606 BTO:0000007 19287380 YES miannu DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d). 0.51 SIGNOR-262848 NRG1 protein Q02297 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 YES gcesareni Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3. 0.791 SIGNOR-26875 HMGB1 protein P09429 UNIPROT HOXD11 protein P31277 UNIPROT up-regulates activity binding -1 8890171 YES 2 miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. 0.293 SIGNOR-240559 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Asp) smallmolecule CHEBI:29186 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270371 NEFL protein P07196 UNIPROT Neurofilament L/H complex SIGNOR-C208 SIGNOR form complex binding 9606 BTO:0000938 19468066 YES miannu Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H 0.437 SIGNOR-255272 DCC protein P43146 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity 9606 12827203 YES miannu DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER. 0.297 SIGNOR-268292 CSNK2A1 protein P68400 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Thr23 TQGDDWDtDPDFVND 9606 10806407 YES llicata The in vivo Ser/Thr phosphorylation of HS1 is enhanced by okadaic acid and reduced by specific inhibitors of casein kinase (CK)2. In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme | It is likely therefore that Thr16 and/or Thr23 account for the phosphate incorporated into HS1 threonyl residue(s) upon incubation with CK2. 0.307 SIGNOR-250886 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191406 PPARG protein P37231 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15356291 NO miannu Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential. 0.386 SIGNOR-254581 EIF2S2 protein P20042 UNIPROT EGLN1 protein Q9GZT9 UNIPROT up-regulates quantity translation regulation 9606 BTO:0000007 29530922 YES miannu DAP5 is involved in PHD2 translation. Distinct responses to DAP5 depletion (under hypoxia) of primary MEFs versus malignant glioma cells suggest that DAP5-mediated control of PHD2 may have special significance in cancer. Neoplastic cells may exploit DAP5 for managing chronic oxygen deprivation, possibly contributing to their adaptation to growth/proliferation under hypoxia. 0.2 SIGNOR-266386 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10801407 YES gcesareni The tumour suppressor protein p53 is stabilised and activated in response to ionising radiation. This is known to depend on the kinase atm;recent results suggest atm acts via the downstream kinase chk2/hcds1, which stabilises p53 at least in part by direct phosphorylation of residue serine 20 0.79 SIGNOR-77144 SP1 protein P08047 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8921911 NO miannu Studies using two mutant versions of this promoter, in which the Sp1 and C/EBP-related factor binding sites were deleted, respectively, revealed that Sp1 and C/EBP-related factors activate the transcription of SOD1 gene. the binding of Sp1 to the proximal upstream region of the Cu/Zn SOD might explain the expression of Cu/Zn SOD in a wide variety of cells. 0.293 SIGNOR-253899 PP1 proteinfamily SIGNOR-PF54 SIGNOR SP3 protein Q02447 UNIPROT down-regulates activity dephosphorylation 9606 12684058 YES lperfetto Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. 0.2 SIGNOR-264652 NCAPG2 protein Q86XI2 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.862 SIGNOR-263911 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 17204478 YES lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). 0.798 SIGNOR-263428 SMCR8 protein Q8TEV9 UNIPROT WIPI2 protein Q9Y4P8 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000007 28169830 YES Global mRNA expression analysis revealed that SMCR8 regulates transcription of several other autophagy genes including WIPI2 0.271 SIGNOR-252028 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser171 HLQTCCGsLAYAAPE 9606 16216881 YES gcesareni We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk. 0.2 SIGNOR-140958 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates phosphorylation Tyr1325 RLLEGNFyGSLFSVP 9606 19834457 YES lperfetto The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation sitewe also show that the tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum. 0.568 SIGNOR-188531 SUPT3H protein O75486 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.765 SIGNOR-269590 CTSL protein P07711 UNIPROT S protein P59594 UNIPROT up-regulates activity cleavage -1 16081529 YES miannu A cell-free membrane-fusion system demonstrates that engagement of receptor followed by proteolysis is required for SARS-CoV membrane fusion and indicates that cathepsin L is sufficient to activate membrane fusion by SARS-CoV S. These results suggest that SARS-CoV infection results from a unique, three-step process: receptor binding and induced conformational changes in S glycoprotein followed by cathepsin L proteolysis within endosomes. The requirement for cathepsin L proteolysis identifies a previously uncharacterized class of inhibitor for SARS-CoV infection. 0.2 SIGNOR-260218 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser214 GGKERPGsKEEVDED -1 21204788 YES done miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.255 SIGNOR-273926 RAB6C protein Q9H0N0 UNIPROT VPS13B protein Q7Z7G8 UNIPROT down-regulates activity binding 9606 BTO:0000007 25492866 YES miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues 0.2 SIGNOR-269204 IMP smallmolecule CHEBI:17202 ChEBI 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity precursor of 9606 19480389 YES miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. Humans and other mammals have two IMPDH genes, encoding hIMPDH1 and hIMPDH2. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). 0.8 SIGNOR-267330 E2F1 protein Q01094 UNIPROT RRM1 protein P23921 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.299 SIGNOR-253852 MBL2 protein P11226 UNIPROT S protein P59594 UNIPROT down-regulates activity binding 9606 BTO:0001370 20573835 YES miannu We have demonstrated that MBL selectively binds to SARS-S pseudotyped virus and can inhibit SARS-CoV infection in susceptible cell lines. Our results identified a single N-linked glycosylation site, N330, on S glycoprotein as the target for the specific interactions between MBL and SARS-CoV and provide evidence that the viral interaction with MBL did not affect its interaction with the ACE2 receptor. Binding to MBL did not affect SARS-S interactions with the ACE2 receptor. Furthermore, MBL-mediated inhibition occurred at a step prior to CTSL-mediated activation of SARS-S fusion. Thus, we suggest that the binding of the MBL may interfere with the induction of conformational changes within the S glycoprotein and thus prevent an early, postreceptor-binding event. 0.2 SIGNOR-260285 IFITMs proteinfamily SIGNOR-PF49 SIGNOR S protein P59594 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0004126 29263263 NO miannu All three IFITMs significantly inhibited the infection by lentiviral particles pseudotyped with IAV hemagglutinin 1 (H1) and neuraminidase 1 (N1) (IAVpp), Spike protein (S) of HCoV-229E (229Epp), HCoV-NL63 (NL63pp), SARS-CoV (SARSpp), and MERS-CoV (MERSpp) in both HEK293 (Fig. 1B) and Huh7.5 (Fig. 1C) cells. 0.2 SIGNOR-260230 UBE2I protein P63279 UNIPROT N protein P59595 UNIPROT up-regulates activity sumoylation Lys62 TALTQHGkEELRFPR 9606 BTO:0000567 17037517 YES lperfetto In this study, we identified Ubc9 as a host protein that interacts specifically with SARS-CoV N protein. This interaction was verified both in vivo and in vitro. Furthermore, we showed that, in addition to phosphorylation, the N protein was modified by covalent attachment of SUMO to its lysine 62 residue. Evidence provided demonstrated that sumoylation may promote homo-oligomerization of the protein. 0.2 SIGNOR-260263 FBXO22 protein Q8NEZ5 UNIPROT KDM4A protein O75164 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000356 21768309 YES lperfetto SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation 0.339 SIGNOR-273442 Gbeta proteinfamily SIGNOR-PF4 SIGNOR APBB1 protein O00213 UNIPROT unknown phosphorylation 9606 14697653 YES inferred from 70% family members lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.2 SIGNOR-270054 SRC protein P12931 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates phosphorylation 9606 24841372 YES inferred from family member lperfetto The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways 0.413 SIGNOR-270248 BNIP1 protein Q12981 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000007 21931693 YES miannu RNF185 functions as a ubiquitin E3 ligase, enabling BNIP1-p62 interaction. BNIP1 is polyubiquitinated by RNF185 and associates with autophagy receptor p62. In addition, we checked the endogenous localization of BNIP1 and p62 in HeLa cells (Fig. 7F). Alexa Fluor 488 conjugated endogenous BNIP1 and TRITIC conjugated endogenous p62 overlapped well in the cytoplasm, further providing the locational evidence for the recruitment of p62 by BNIP1. 0.335 SIGNOR-271932 CLIP2 protein Q9UDT6 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 15631994 NO lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 0.7 SIGNOR-265095 CDC25B protein P30305 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 25384584 YES lperfetto CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G 2 /M transition ( xref ).|CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G2/M transition ( ). 0.828 SIGNOR-276970 trandolapril chemical CHEBI:9649 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition 10116 7527095 YES miannu The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. 0.8 SIGNOR-258427 FLNA protein P21333 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity binding 9606 20156194 YES miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself 0.259 SIGNOR-260628 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 10653583 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. 0.2 SIGNOR-236471 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.421 SIGNOR-134605 TCIRG1 protein Q13488 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.704 SIGNOR-277764 DLL4 protein Q9NR61 UNIPROT NRP1 protein O14786 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18339870 NO gcesareni Dll4 down-regulates vascular endothelial growth factor (vegf)_ receptor_ 2 and nrp1 expression and inhibits vegf function 0.362 SIGNOR-178029 VEGFC protein P49767 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 YES gcesareni The functional importance of the interaction of np2 with the lymphangiogenic growth factors was demonstrated by cointernalization of np2 along with vegfr-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with vegf-c or vegf-d. 0.747 SIGNOR-147611 DAB2IP protein Q5VWQ8 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 BTO:0000007 20080667 YES miannu DAB2IP activates GSK-3β and antagonizes Wnt-mediated EMT. GSK-3β appears to directly associate with DAB2IP. Because DAB2IP is not a phosphatase, the mechanism of GSK-3β activation by DAB2IP is likely mediated by a separate phosphatase associated within this complex. PP2A is critical for DAB2IP-mediated GSK-3β activation and MET responses. 0.312 SIGNOR-254752 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.749 SIGNOR-260577 bortezomib chemical CHEBI:52717 ChEBI PSMB2 protein P49721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 YES miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. 0.8 SIGNOR-259309 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser288 PESEDEEsYDTESEF 9606 BTO:0000782 8622692 YES llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. 0.58 SIGNOR-40506 PTBP2 protein Q9UKA9 UNIPROT SRC protein P12931 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000567 11003644 YES lperfetto Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA. 0.285 SIGNOR-261267 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PPARG protein P37231 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-209998 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Ser29 VSHWQQQsYLDSGIH -1 12432063 YES miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  0.555 SIGNOR-275998 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser738 ARIIGEKsFRRSVVG -1 10867018 YES lperfetto The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot 0.2 SIGNOR-249046 AKT1 protein P31749 UNIPROT FSTL1 protein Q12841 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18718903 NO miannu Akt1 Overexpression in Skeletal Muscle Increases Capillary Vessel Formation and Up-regulates Fstl1 Expression 0.383 SIGNOR-266605 KLC2 protein Q9H0B6 UNIPROT FYCO1 protein Q9BQS8 UNIPROT up-regulates activity binding 9606 BTO:0000567 25855459 YES Giulio Interestingly, bead capture assays indicated that the middle part of FYCO1 (residues 585–1233) interacts directly with the KLC2 light chain of kinesin 1 (Fig. 3a and Extended Data Fig. 7a, b). Residues 735–773 of FYCO1 were found to be necessary for its kinesin-1 binding (Fig. 3c and Extended Data Fig. 7b, c), and FYCO1(Δ735–773)-positive LEs failed to translocate to the cell periphery (Extended Data Fig. 7e). 0.345 SIGNOR-260599 KIF14 protein Q15058 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 32348467 NO miannu  We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex.  0.7 SIGNOR-266421 RBP4 protein P02753 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI up-regulates quantity relocalization 9606 31963453 YES lperfetto In the blood, serum retinol travels in association with Retinol-binding protein 4 (RBP4) 0.8 SIGNOR-265106 AMPK complex SIGNOR-C15 SIGNOR KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser592 KCNVKAKsNVDLRRS 9606 BTO:0000007 30279167 YES miannu Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559.  0.291 SIGNOR-273735 IL17A protein Q16552 UNIPROT KLF3 protein P57682 UNIPROT up-regulates transcriptional regulation 9606 23332504 NO fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic.  0.2 SIGNOR-210114 SMO protein Q99835 UNIPROT GNAT1 protein P11488 UNIPROT up-regulates binding 9606 16885213 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.262 SIGNOR-148496 CAMK2A protein Q9UQM7 UNIPROT PDC protein P20941 UNIPROT unknown phosphorylation Ser54 KEILRQMsSPQSRNG 11331285 YES llicata In this study, we report that Pd was rapidly phosphorylated by Ca(2+)/calmodulin-dependent kinase II, resulting in 100-fold greater inhibition of Gbetagamma binding than cAMP-dependent protein kinase phosphorylation. Furthermore, Pd phosphorylation by Ca(2+)/calmodulin-dependent kinase II at Ser-54 and Ser-73 led to binding of the phosphoserine-binding protein 14-3-3. 0.307 SIGNOR-250636 RAB3A protein P20336 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 31679900 NO miannu Here, we identify the SEC4 ortholog RAB3 and its neuronal effector, RIM1, as essential molecules for neuropeptide and neurotrophin release from dense-core vesicles (DCVs) in mammalian neurons.  0.7 SIGNOR-264375 CCT8 protein P50990 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.769 SIGNOR-272862 TLRs proteinfamily SIGNOR-PF20 SIGNOR TICAM2 protein Q86XR7 UNIPROT up-regulates activity binding 9606 20404851 YES lperfetto These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways 0.2 SIGNOR-216307 E2F4 protein Q16254 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by repression transcriptional regulation 18504435 YES lperfetto This TGF-beta response is triggered through a Smad2/3-dependent hypophosphorylation of Rb and the subsequent association of the Rb/E2F4 repressive complex to CDE/CHR elements in the proximal region of the survivin promoter. 0.334 SIGNOR-271678 TNF protein P01375 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 11287630 NO lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase 0.481 SIGNOR-106593 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation Ser180 DQGSLCTsFVGTLQY 9606 SIGNOR-C14 9520446 YES lperfetto NIK preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. 0.698 SIGNOR-55946 heme smallmolecule CHEBI:30413 ChEBI HBA1 protein P69905 UNIPROT up-regulates activity chemical activation 9606 26557657 YES miannu Heme is a prosthetic group comprising ferrous iron (Fe2+) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins. 0.8 SIGNOR-251909 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Ser577 RKPGLRRsPIKKVRK 9606 9840932 YES lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5 0.715 SIGNOR-217252 MAPK1 protein P28482 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation Ser116 FINSRCTsPGGSYGH -1 35831023 YES miannu We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk. 0.323 SIGNOR-277602 KIF5A protein Q12840 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272523 H1-2 protein P16403 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity binding 9606 BTO:0001938 22249259 YES done miannu Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation.  0.2 SIGNOR-273833 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser185 SAPARMLsSNERDSS 9606 BTO:0002181 34363019 YES miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  0.2 SIGNOR-276739 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates phosphorylation Thr455 MRLGKRRtLFQTKNS 9606 17463002 YES llicata These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity. 0.2 SIGNOR-154621 WNT7B protein P56706 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.646 SIGNOR-131978 CDK6 protein Q00534 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15809340 YES gcesareni Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively. 0.768 SIGNOR-135189 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 0.2 SIGNOR-260128 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RORB protein Q92753 UNIPROT down-regulates activity chemical inhibition 9606 12958591 YES miannu ATRA and related retinoids inhibit ROR beta but not ROR alpha transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR beta target genes. Our results identify ROR beta as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action. 0.8 SIGNOR-266845 CREB3L1 protein Q96BA8 UNIPROT CREB3L1 protein Q96BA8 UNIPROT up-regulates activity binding -1 12805554 YES miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins 0.2 SIGNOR-224205 Tosedostat chemical CID:15547703 PUBCHEM LAP3 protein P28838 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207417 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser149 RRGASDLsSEEGWRL -1 8954982 YES llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. 0.324 SIGNOR-251035 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC2 protein Q13490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9916987 NO gcesareni The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop. 0.534 SIGNOR-64100 Ub:E2 complex SIGNOR-C497 SIGNOR RNF122 protein Q9H9V4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271228 NEUROG3 protein Q9Y4Z2 UNIPROT INSM1 protein Q01101 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000944 17300785 NO miannu The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32. 0.594 SIGNOR-253814 ATM protein Q13315 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity by destabilization phosphorylation Ser729 LFFDYRYsQADALKY -1 24162653 YES miannu Enhancer of zeste homolog 2 (EZH2), a core catalytic component of PRC2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability.  0.459 SIGNOR-276602 SIRT1 protein Q96EB6 UNIPROT FOXL2 protein P58012 UNIPROT down-regulates deacetylation 9606 19010791 YES miannu We find that foxl2 activity is repressed by the sirt1 deacetylase. 0.502 SIGNOR-182306 tamoxifen chemical CHEBI:41774 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition 9606 20512796 YES miannu Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. 0.8 SIGNOR-258587 ALK protein Q9UM73 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 BTO:0000785 12185581 YES gcesareni Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc. 0.456 SIGNOR-91534 NCOR2 protein Q9Y618 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22395773 YES FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. 0.744 SIGNOR-253508 FBP2 protein O00757 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 30616754 YES lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle 0.8 SIGNOR-267613 SOX2 protein P48431 UNIPROT SOX2/POU5F1 complex SIGNOR-C73 SIGNOR form complex binding 9606 7590241 YES miannu Sox2 can form a ternary complex with either the ubiquitous oct-1 or the embryonic-specific oct-3 protein on fgf-4 enhancer dna sequences. However, only the sox2/oct-3 complex is able to promote transcriptional activation. 0.839 SIGNOR-29512 FER protein P16591 UNIPROT JUP protein P14923 UNIPROT down-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 YES The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin) 0.525 SIGNOR-251135 YES1 protein P07947 UNIPROT POU2F2 protein P09086 UNIPROT up-regulates activity phosphorylation 9606 26979622 YES miannu These data suggest that Yes1 is the TKI-sensitive kinase that can directly phosphorylate OCT2. 0.2 SIGNOR-279664 COL12A1 protein Q99715 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known 0.7 SIGNOR-254671 VCB-Cul2 complex SIGNOR-C524 SIGNOR PRKCI protein P41743 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11574546 YES miannu The von Hippel-Lindau tumor-suppressor protein (pVHL) forms a protein complex (VCB-Cul2) with elongin C, elongin B, Cul-2, and Rbx1, which functions as a ubiquitin-protein ligase (E3). The alpha-subunits of the hypoxia-inducible factors have been identified as targets for the VCB-Cul2 ubiquitin ligase. we show that PKClambda can be ubiquitinated in vitro in a cell-free ubiquitination assay using purified recombinant components including VCB-Cul2. Given the known function of aPKC in the regulation of cell polarity and cell growth, PKClambda may be a target of pVHL in its function as a tumor suppressor.Degradation of the Ubiquitin-conjugated Active Form of PKCλ Is Blocked by a Proteasome Inhibitor in Vivo 0.361 SIGNOR-272591 G6PC3 protein Q9BUM1 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266566 PRKN protein O60260 UNIPROT BAX protein Q07812 UNIPROT down-regulates quantity by destabilization ubiquitination Lys128 VLKALCTkVPELIRT 9606 28760928 YES miannu The E3 ligase parkin, which is known to trigger mitochondria specific autophagy, ubiquitylates BAX K128 and targets the pro apoptotic BCL-2 protein for proteasomal degradation. 0.2 SIGNOR-278529 AMPK complex SIGNOR-C15 SIGNOR PAQR3 protein Q6TCH7 UNIPROT up-regulates activity phosphorylation Thr32 PRGIRLYtYEQIPGS 9606 BTO:0000007 26834238 YES miannu Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation.  0.2 SIGNOR-273737 PRKCA protein P17252 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000599 15730925 NO irozzo PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC. 0.7 SIGNOR-256267 CoREST-HDAC complex complex SIGNOR-C105 SIGNOR SCN3A protein Q9NY46 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 16140033 NO lperfetto This suggests that the HDACs in the LSD1 complex are likely to function upstream of CoREST/LSD1, generating a hypoacetylated histone substrate, which can then be better recognized by CoREST/LSD1. Further supporting this model, we found that inhibition of HDAC activity by TSA resulted in derepression of two LSD1 target genes, the human neuronal-specific sodium channel (SCN) genes, SCNA2 and SCNA3 (Figure 1H). 0.249 SIGNOR-268542 TAF9 protein Q16594 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.62 SIGNOR-263920 ARVCF protein O00192 UNIPROT ERBIN protein Q96RT1 UNIPROT up-regulates activity binding 9606 BTO:0000938 11821434 YES miannu We characterized the interactions between the Erbin PDZ domain and both ARVCF and δ-catenin in vitro and in vivo. endogenous δ-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that δ-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex. 0.2 SIGNOR-252119 ceramide smallmolecule CHEBI:17761 ChEBI glycosphingolipid smallmolecule CHEBI:24402 ChEBI up-regulates quantity precursor of 9606 18184806 YES miannu Ceramide is a common precursor for both sphingomyelin and glycosphingolipids, which are ubiquitous components of membranes in mammalian cells and play important roles in cell growth, differentiation, and apoptosis 0.8 SIGNOR-268498 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity. 0.286 SIGNOR-129280 AURKB protein Q96GD4 UNIPROT SSU72 protein Q9NP77 UNIPROT down-regulates activity phosphorylation Ser19 CSSNQNRsMEAHNIL 24149858 YES lperfetto Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. 0.254 SIGNOR-275530 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 YES lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | 0.33 SIGNOR-249124 ELK1 protein P19419 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23426362 NO lperfetto AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions 0.7 SIGNOR-233471 RHO protein P08100 UNIPROT GNAT1 protein P11488 UNIPROT up-regulates activity binding 9606 8673138 YES We report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade. 0.793 SIGNOR-260007 AKT proteinfamily SIGNOR-PF24 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro 0.2 SIGNOR-244275 DBP protein Q10586 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 8617210 NO lperfetto While TEF stimulates transcription from the albumin promoter more potently than DBP, only DBP is capable of activating transcription efficiently from the cholesterol 7 alpha hydroxylase (C7alphaH) promoter. 0.362 SIGNOR-254121 FAM83B protein Q5T0W9 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.344 SIGNOR-273746 PTPN6 protein P29350 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates dephosphorylation Tyr402 CSIESDIyAEIPDET 9606 10521452 YES gcesareni Raftk binds constitutively to the protein tyrosine phosphatase shptp1.SHPTP1 Plays a negative role in pyk2/raftk signaling by dephosphorylating raftk on tyr-402, thereby inhibiting the interaction of the sh2 domain of c-src with raftk 0.359 SIGNOR-71414 JAG1 protein P78504 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10958687 YES Binding Calcium-dependent. gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. 0.638 SIGNOR-81364 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr194 NMMDILTtPSMAKPR 8355 22354989 YES gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop 0.529 SIGNOR-243403 MAP4K3 protein Q8IVH8 UNIPROT TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser3 sRIGLRMQ 9606 29507340 YES miannu However, although our results indicate that MAP4K3 initiates TFEB repression, MAP4K3 also promotes robust mTORC1 activation upon amino acid stimulation - ; hence, MAP4K3 and mTORC1 must ultimately work together to achieve robust suppression of autophagy.|Moreover, MAP4K3 serine 3 phosphorylation of TFEB is required for TFEB interaction with mTORC1-Rag GTPase-Ragulator complex and TFEB cytosolic sequestration. 0.25 SIGNOR-278282 NOTCH1 protein P46531 UNIPROT LFNG protein Q8NES3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15207708 NO gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. 0.756 SIGNOR-236845 PTK2 protein Q05397 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity phosphorylation Tyr470 AYATEAVyESAEAPG 9606 22952866 YES miannu FAK directly phosphorylates cortactin at Y421 and Y466 and over-expression of cortactin Y421, Y466, and Y482 mutated to phenylalanine (3YF) prevented FAK-enhanced FA turnover and cell motility.|GFP-FAK re-expression in FAK-/- MEFs enhances FA turnover (XREF_FIG) and cortactin knockdown slows FA turnover (XREF_FIG). 0.744 SIGNOR-278283 FZD3 protein Q9NPG1 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 17251915 YES gcesareni In the non-canonical wnt signalling pathway, frizzled uses galphaq or galphai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat. 0.383 SIGNOR-152600 A6/b4 integrin complex SIGNOR-C174 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.512 SIGNOR-257721 ponatinib chemical CHEBI:78543 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206277 PTPN1 protein P18031 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF -1 8621392 YES We have shown previously that amino acid residues flanking the phosphotyrosine are important for efficient PTP1 catalysis (Table 1 and Refs. 9, 10, and 17). For example, the kcat/Km value for the undecapeptide, EGFR988-989 (epidermal growth factor autophosphorylation site Tyr992, residues 988-998) (Asp-Ala-Asp-Glu-pTyr-Leu-Ile-Pro-Gln-Gln-Gly) is 3220-fold higher than that of phosphotyrosine (Table 1). We further demonstrated that a minimum of six amino acid residues are required for the most efficient PTP1 binding and catalysis. 0.759 SIGNOR-248407 PRKCD protein Q05655 UNIPROT HNRNPK protein P61978 UNIPROT unknown phosphorylation Ser302 GRGGRGGsRARNLPL 9606 10329716 YES Manara We have shown that PKCδ binds and phosphorylates K protein. These observations broaden the range of K protein interactions. PKCδ targets Ser302, which is located in the middle of what appears to be a highly interactive KI domain 0.345 SIGNOR-260877 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates chemical activation 9606 16794003 YES gcesareni The evidence suggests that s1p acting on s1p receptors coupled to gq 0.8 SIGNOR-147233 NCOA4 protein Q13772 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 10347167 YES miannu We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar. 0.86 SIGNOR-67684 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR5 protein P35346 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257585 denileukin diftitox smallmolecule SID:125240988 PUBCHEM IL2RB protein P14784 UNIPROT up-regulates activity chemical activation 9606 15757436 YES miannu Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells.  0.8 SIGNOR-259393 PTPN7 protein P35236 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation Tyr182 TDDEMTGyVATRWYR 9606 BTO:0000661 10206983 YES In Jurkat cells, LC-PTP suppressed the ERK and p38 mitogen-activated protein kinase cascades 0.59 SIGNOR-248485 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide chemical CHEBI:95082 ChEBI BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition -1 24015967 YES Gianni This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation 0.8 SIGNOR-262204 A6/b1 integrin complex SIGNOR-C164 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.369 SIGNOR-253279 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser527 PHLDGPPsPRSPVIG 9606 BTO:0001271 15093545 YES The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). 0.36 SIGNOR-124252 RHOA protein P61586 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity binding 10090 BTO:0004732 27270401 YES no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 0.852 SIGNOR-275465 AKT3 protein Q9Y243 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 YES gcesareni Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155. 0.54 SIGNOR-81118 UBQLN2 protein Q9UHD9 UNIPROT HNRNPU protein Q00839 UNIPROT up-regulates quantity by stabilization binding 25616961 YES lperfetto Confirmation of binding of recombinant full-length hnRNPA1 and hnRNPU proteins with ubiquilin-2 by GST-pull-down assays|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein 0.334 SIGNOR-262271 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 YES gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.747 SIGNOR-122059 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 11504915 YES lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. 0.2 SIGNOR-244292 RAP1A protein P62834 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 10090 BTO:0003104 12808052 YES lperfetto The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. 0.48 SIGNOR-253362 CDKN2A protein P42771 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 16161044 YES gcesareni The cdk-inhibitor p16 is a tumor suppressor gene that is inactivated in many forms of cancer. In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm. 0.905 SIGNOR-140409 MMP13 protein P45452 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 YES lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. 0.314 SIGNOR-263609 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.822 SIGNOR-178391 RAB32 protein Q13637 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR up-regulates activity relocalization 9606 23247405 YES lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. 0.302 SIGNOR-260695 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser139 DARDLEMsKKVRRSY -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.628 SIGNOR-276114 CHFR protein Q96EP1 UNIPROT HLTF protein Q14527 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 20388495 YES miannu CHFR functions as a ubiquitin ligase for HLTF to regulate its stability and functions. CHFR negatively regulates and ubiquitinates HLTF. Taken together, this is the first report identifying the regulatory mechanism of HLTF by CHFR, suggesting that CHFR-mediated downregulation of HLTF may help protect against cancer. 0.483 SIGNOR-271460 SUCLG1 protein P53597 UNIPROT Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR form complex binding 9606 32627745 YES miannu Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). 0.93 SIGNOR-266263 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248370 NCOA1 protein Q15788 UNIPROT PCK2 protein Q16822 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.281 SIGNOR-255066 STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510571 NO lperfetto Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene. 0.787 SIGNOR-253049 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates activity phosphorylation Ser794 SGGARAKsKSVSFNL 9606 BTO:0000007 21734191 YES done miannu Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A). 0.2 SIGNOR-273790 RORC protein P51449 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24737872 YES miannu As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression. 0.502 SIGNOR-268004 CSNK1D protein P48730 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation Ser480 PVPHSGSsGYGSLGS -1 30425162 YES miannu Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2 0.869 SIGNOR-277420 SPI1 protein P17947 UNIPROT FCER1A protein P12319 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11971001 NO Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells 0.275 SIGNOR-254289 MAP3K3 protein Q99759 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates phosphorylation Ser526 MSGTGMRsVTGTPYW 9606 BTO:0000007 16407301 YES lperfetto Phosphorylation of serine 526 is required for mekk3 activity, and association with 14-3-3 blocks dephosphorylationautophosphorylation of mekk3 at ser526 0.2 SIGNOR-143647 SOCS6 protein O14544 UNIPROT KIT protein P10721 UNIPROT down-regulates ubiquitination 9606 21030588 YES miannu Suppressor of cytokine signaling 6 (socs6) is a member of the socs family of e3 ubiquitin ligases that can interact with c-kit and suppress c-kit-dependent pathways. / we demonstrate that socs6 has ubiquitin ligase activity toward c-kit and regulates c-kit protein turnover in cells 0.677 SIGNOR-169145 MAPK9 protein P45984 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser6 sDPSVEPP 9606 17525747 YES gcesareni Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6. |Role of map kinases in uvb-induced phosphorylation of p53 at serine 20. 0.746 SIGNOR-155209 TYRO3 protein Q06418 UNIPROT CBLB protein Q13191 UNIPROT up-regulates activity phosphorylation Tyr133 KEGKERMyEEQSQDR 9606 31531847 YES miannu TAM receptor Tyro3 phosphorylates tyrosine residues 133 and 363 of Cbl-b. 0.351 SIGNOR-279576 KATNA1 protein O75449 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates 9606 19287380 NO miannu Katanin, one of the best-characterized microtubule (MT) severing proteins, is composed of two subunits: catalytic p60-katanin, and regulatory p80-katanin. p60-katanin triggers MT reorganization by severing them. MT reorganization is essential for both mitotic cells and post-mitotic neurons in numerous vital processes such as intracellular transport, mitosis, cellular differentiation and apoptosis.  0.7 SIGNOR-271794 PIK3CG protein P48736 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 NO lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.7 SIGNOR-242658 PIK-93 chemical CID:6852167 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206241 CIITA protein P33076 UNIPROT HLA-F protein P30511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11137213 NO HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA 0.474 SIGNOR-254018 ASPM protein Q8IZT6 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates quantity by expression transcriptional regulation 16123590 NO Here, we report that downregulation of endogenous ASPM by siRNA decreases protein levels of endogenous BRCA1. ASPM localizes to the centrosome in interphase and to the spindle poles from prophase through telophase. These findings indicate that ASPM may be involved in mitotic spindle function, possibly, through regulation of BRCA1. 0.273 SIGNOR-253936 SIAH2 protein O43255 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 0.433 SIGNOR-272748 PAMPs stimulus SIGNOR-ST11 SIGNOR SLC11A1 protein P49279 UNIPROT up-regulates 9606 BTO:0000801 11909746 NO Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS) 0.7 SIGNOR-254039 PRKG1 protein Q13976 UNIPROT PRKG1 protein Q13976 UNIPROT up-regulates phosphorylation Ser65 TTRAQGIsAEPQTYR 9606 12080049 YES miannu Serines 64 and 79 are homologous residues that are juxtaposed to the autoinhibitory pseudosubstrate site in cgmp-dependent protein kinase type ialpha and type ibeta (pkg-ialpha and pkg-ibeta), respectively. Autophosphorylation of this residue is associated with activation of type i pkgs. 0.2 SIGNOR-89839 GNB/GNG complex SIGNOR-C202 SIGNOR ADCY6 protein O43306 UNIPROT down-regulates activity binding 9534 BTO:0000298 9707174 YES Marta Tosoni These results demonstrate that adenylyl cyclase types V and Vi are inhibited by Gbetagamma dimers. 0.449 SIGNOR-278047 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 YES lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites 0.79 SIGNOR-153475 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii 0.777 SIGNOR-203532 PP1 proteinfamily SIGNOR-PF54 SIGNOR SP1 protein P08047 UNIPROT down-regulates activity dephosphorylation 9606 12684058 YES lperfetto Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. 0.2 SIGNOR-264669 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273091 GUCY1B2 protein O75343 UNIPROT GUCY1A2-B2 complex SIGNOR-C137 SIGNOR form complex binding 9606 10977868 YES gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity 0.2 SIGNOR-243974 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates activity phosphorylation Thr215 ATGSVPStPIAHRGP 9606 BTO:0000007 12556484 YES lperfetto Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did 0.375 SIGNOR-249422 sirolimus chemical CHEBI:9168 ChEBI CD86 protein P42081 UNIPROT down-regulates quantity by repression 9606 18652845 NO miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. 0.8 SIGNOR-255479 UDP-D-galactose smallmolecule CHEBI:18307 ChEBI UDP(3-) smallmolecule CHEBI:58223 ChEBI up-regulates quantity precursor of 9606 16157350 YES miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 0.8 SIGNOR-268473 WNT3A protein P56704 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity 9606 18772438 NO gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. 0.688 SIGNOR-180803 KLHL3 protein Q9UH77 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23453970 YES miannu Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein. 0.586 SIGNOR-272105 PTPRE protein P23469 UNIPROT KCNB1 protein Q14721 UNIPROT down-regulates activity dephosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000007 10921884 YES Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon 0.356 SIGNOR-248450 MCHR2 protein Q969V1 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257180 RNF8 protein O76064 UNIPROT XRN2 protein Q9H0D6 UNIPROT up-regulates activity ubiquitination 9606 37697435 YES miannu Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. 0.2 SIGNOR-277195 VKORC1L1 protein Q8N0U8 UNIPROT vitamin K smallmolecule CHEBI:28384 ChEBI up-regulates quantity chemical modification 9606 31226734 YES lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form 0.8 SIGNOR-265903 PRKCZ protein Q05513 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity. 0.289 SIGNOR-129336 RAD50 protein Q92878 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 21763684 YES gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. 0.813 SIGNOR-175053 AKT1 protein P31749 UNIPROT BTK protein Q06187 UNIPROT down-regulates quantity by destabilization phosphorylation Thr495 EMRHRFQtQQLLEMC 9606 BTO:0003289 23754751 YES miannu The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain.  0.296 SIGNOR-276465 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB2 protein Q9Y5G2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265710 TP53INP1 protein Q96A56 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates binding 9606 22421968 YES gcesareni Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir) 0.297 SIGNOR-196673 ORC2 protein Q13416 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 YES lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA 0.97 SIGNOR-267566 SF3B6 protein Q9Y3B4 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.607 SIGNOR-270675 KLF15 protein Q9UIH9 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates transcriptional regulation 10090 BTO:0002572 20956975 NO lperfetto Our results provide a new mechanism for understanding glucocorticoids-dependent adipogenesis and that GR promotes adipogenesis via KLF15 gene expression as a transcriptional direct target. 0.7 SIGNOR-236230 SIM2 protein Q14190 UNIPROT ARNT protein P27540 UNIPROT up-regulates activity binding -1 9020169 YES 2 miannu We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer. 0.498 SIGNOR-240808 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 BTO:0000562 17075052 YES gcesareni The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment. 0.2 SIGNOR-150355 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257965 wortmannin chemical CHEBI:52289 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 8162590 YES gcesareni The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. 0.8 SIGNOR-252666 LIMK1 protein P53667 UNIPROT CFL2 protein Q9Y281 UNIPROT down-regulates activity phosphorylation Ser3 sGVTVNDE 9606 9655398 YES lperfetto Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3;. Here we show that lim-kinase 1 (limk-1), a serine/threonine kinase containing lim and pdz domains, phosphorylates cofilin at ser 3, both in vitro and in vivo 0.702 SIGNOR-58596 ibuprofen chemical CHEBI:5855 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 9544212 YES miannu The IC50 values for two benchmark compounds were determined for comparison. The marketed NSAID ibuprofen was a modestly selective COX-1 inhibitor, while Searle's SC-5766614 was a highly selective (>100-fold) COX-2 inhibitor, results consistent with literature reports. 0.8 SIGNOR-258883 EIF2B5 protein Q13144 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.817 SIGNOR-269138 L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275815 SLC24A3 protein Q9HC58 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264401 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr172 EDGGDDIyEDIIKVE 9606 12454019 YES miannu To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor. 0.593 SIGNOR-95980 TMPRSS2 protein O15393 UNIPROT S protein P59594 UNIPROT up-regulates activity cleavage 9606 32142651 YES miannu Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. 0.2 SIGNOR-260217 CASP6 protein P55212 UNIPROT N protein P59595 UNIPROT up-regulates activity cleavage Asp403 LPAADMDdFSRQLQN 9534 BTO:0001444 18155731 YES Luana Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403 0.2 SIGNOR-260212 FBXO3 protein Q9UK99 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0004573 18809579 YES miannu O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.  0.405 SIGNOR-271741 MBD3 protein O95983 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.808 SIGNOR-263847 EFNA1 protein P20827 UNIPROT EPHA1 protein P21709 UNIPROT up-regulates binding 9606 9576626 YES tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity 0.83 SIGNOR-56898 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Thr931 VCDSGVEtSFRKLSF 9606 BTO:0000567 SIGNOR-C13 10469655 YES lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). 0.746 SIGNOR-70461 ALK protein Q9UM73 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000785 14968112 YES gcesareni Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1. 0.545 SIGNOR-122082 DLX2 protein Q07687 UNIPROT ARX protein Q96QS3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18923043 NO Regulation miannu Dlx overexpression induces ectopic expression of endogenous Arx and its isolated enhancer, whereas loss of Dlx expression results in reduced Arx expression 0.275 SIGNOR-251972 NFY complex SIGNOR-C1 SIGNOR ZDHHC5 protein Q9C0B5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28775165 YES Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y 0.2 SIGNOR-261151 P2RY4 protein P51582 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257214 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 BTO:0000150 19085255 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase. 0.595 SIGNOR-182808 PRKCD protein Q05655 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation 9606 17183360 YES gcesareni By contrast, after uv stimulation, rela directly induces the expression of pkcdelta, which in turn activates jnk. 0.499 SIGNOR-151428 CNTF protein P26441 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9143707 YES gcesareni Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2. 0.681 SIGNOR-47991 PTK6 protein Q13882 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation Tyr331 LVNIMRTyTYEKLLW 9606 20026641 YES miannu PTK6 directly phosphorylates beta-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64.|The ability of PTK6 to negatively regulate beta-catenin and TCF transcription by modulating levels of TCF4 and TLE and Groucho could contribute to its growth-inhibitory activities in vivo. 0.305 SIGNOR-278287 PRKAR1B protein P31321 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.856 SIGNOR-258753 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser485 QDNGAEDsGDTEDEL 9606 20471329 YES lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair 0.396 SIGNOR-165419 STUB1 protein Q9UNE7 UNIPROT ATCAY protein Q86WG3 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 16275660 YES miannu CHIP e.g. was found to efficiently polyubiquitinate caytaxin in vitro, suggesting that it might influence caytaxin degradation in vivo. 0.378 SIGNOR-272651 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 19910923 YES gcesareni Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway.Wnt5a Internalized fz2 probably with ror1 or ror2 through the clathrin-mediated route, whereas wnt5a competed with wnt3a for binding to fz2 to inhibit the beta-catenin pathway. 0.765 SIGNOR-189120 PTK6 protein Q13882 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr165 PSPATDLyQVPPGPG 9606 22084245 YES lperfetto Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro 0.598 SIGNOR-177238 ASIP protein P42127 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 9606 BTO:0000847 14500544 YES miannu The antagonist agouti signal protein (ASP) interacts with the Mc1r and blocks its stimulation by MSH. 0.738 SIGNOR-252378 ITSN1 protein Q15811 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000567 30540523 YES lperfetto Significantly, here we identify the long isoform of ITSN-1, which has Cdc42 GEF activity| We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A). 0.848 SIGNOR-260612 MARCHF5 protein Q9NX47 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0004055 19741096 YES lperfetto Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation 0.2 SIGNOR-272982 CDC42 protein P60953 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity 9606 18976935 NO lperfetto Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. 0.276 SIGNOR-253370 IMPDH2 protein P12268 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30518405 NO miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. 0.2 SIGNOR-260957 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser444 GKDSATTsTLSKDSL 9606 BTO:0000567 34198826 YES miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. 0.25 SIGNOR-276664 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STAT5A protein P42229 UNIPROT up-regulates phosphorylation 9606 BTO:0000975 10194762 YES inferred from 70% family members gcesareni Serine 780 is the only substrate in full-length stat5a for active erk 0.2 SIGNOR-270136 hsa-miR-148a-5p mirna URS00003E16E5_9606 RNAcentral WNT1 protein P04628 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000815 26707142 YES Parnian We found that miR-148a could inhibit the migration and invasion of breast cancer cells by directly targeting WNT-1 and inhibiting the activation of Wnt/β-catenin pathway. 0.4 SIGNOR-278850 GABRA4 protein P48169 UNIPROT GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.527 SIGNOR-263745 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERN1 protein O75460 UNIPROT up-regulates 9606 31226023 NO miannu Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain 0.7 SIGNOR-260175 TNF protein P01375 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20509143 NO miannu we show that TNFα treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-κB/HIF1α signaling, which is strongly enhanced by p53 inactivation. 0.307 SIGNOR-255152 bivalirudin chemical CHEBI:59173 ChEBI F2 protein P00734 UNIPROT down-regulates activity chemical inhibition -1 1290488 YES miannu These data demonstrate that hirulog-1 is a specific inhibitor of thrombin forms with high fibrinogen-procoagulant activities and that its Arg-3-Pro-4 bond is slowly cleaved by these thrombin forms. 0.8 SIGNOR-258346 CERS2 protein Q96G23 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 YES done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  0.8 SIGNOR-273994 NR3C1 protein P04150 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates activity 10090 11742987 NO gcesareni GR-mediated inhibition of c-Jun N-terminal kinase (JNK) activity 0.637 SIGNOR-251676 HAUS complex complex SIGNOR-C281 SIGNOR NEDD1 protein Q8NHV4 UNIPROT up-regulates activity relocalization 9606 19427217 YES lperfetto Under NuMA and HAUS6 codepletion conditions, NEDD1 levels on spindle microtubules remained low, suggesting that the suppression observed is not caused by more efficient localization of NEDD1 to spindle microtubules (Figure S9D). Taken together, our results suggest that HAUS and NuMA exert opposing activities necessary for robust bipolar spindle formation. 0.544 SIGNOR-262331 TRIM25 protein Q14258 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys10 FAEDKTYkYICRNFS 9606 BTO:0000007 22626058 YES k48 miannu We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling.  0.769 SIGNOR-272042 RABEPK protein Q7Z6M1 UNIPROT IGF2R protein P11717 UNIPROT up-regulates activity relocalization 9230071 YES lperfetto P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking. 0.383 SIGNOR-253090 IL1B protein P01584 UNIPROT ITGA3 protein P26006 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001596 1744142 NO lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. 0.2 SIGNOR-253355 NDC1 protein Q9BTX1 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.528 SIGNOR-262073 PRKCD protein Q05655 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates phosphorylation Thr312 TNGEFKMtDPDEVAR 9606 24058639 YES miannu After tgf-_ stimulation, fli1 phosphorylation by protein kinase c-_ induces disassembly of this transcription repressor complex and the acetylation of fli1 by pcaf, leading to the loss of fli1 dna binding. / phosphorylation of fli1 at threonine 312 decreases its interactions with p300 and hdac1 0.347 SIGNOR-202693 solifenacin chemical CHEBI:135530 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition -1 21524581 YES Luana The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference 0.8 SIGNOR-258311 WNK1 protein Q9H4A3 UNIPROT SYT2 protein Q8N9I0 UNIPROT up-regulates activity phosphorylation Thr199 ETKVHRKtLNPAFNE 9606 BTO:0000007 15350218 YES miannu Endogenous WNK1 and Syt2 coimmunoprecipitate and colocalize on a subset of secretory granules in INS-1 cells. Phosphorylation by WNK1 increases the amount of Ca2+ required for Syt2 binding to phospholipid vesicles; mutation of threonine 202, a WNK1 phosphorylation site, partially prevents this change. These findings suggest that phosphorylation of Syts by WNK1 can regulate Ca2+ sensing and the subsequent Ca2+-dependent interactions mediated by Syt C2 domains. . In contrast, WNK1 phosphorylated Syt2 on T202 and T386 within the C2 domains (Figure 6B). 0.604 SIGNOR-263049 Caspase 1 complex complex SIGNOR-C220 SIGNOR GSDMD protein P57764 UNIPROT up-regulates activity cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 YES lperfetto Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence | 0.643 SIGNOR-256415 ACVR2B protein Q13705 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates activity phosphorylation Thr206 VQRTVARtIVLQEII 9606 8622651 YES miannu Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. 0.69 SIGNOR-235146 HRC protein P23327 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity binding 10116 BTO:0001879 28784772 YES miannu Furthermore, a Ser96Asp HRC variant, which mimics constitutive phosphorylation of Ser96, diminished delayed aftercontractions in HRC null cardiac myocytes. This HRC phosphomimetic variant was also able to rescue the aftercontractions elicited by the Ser96Ala variant, demonstrating that phosphorylation of Ser96 is critical for the cardioprotective function of HRC. Phosphorylation of HRC on Ser96 regulated the interactions of HRC with both triadin and SERCA2a, suggesting a unique mechanism for regulation of SR Ca homeostasis.  0.375 SIGNOR-273662 HTR1A protein P08908 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.301 SIGNOR-257088 ZBED1 protein O96006 UNIPROT RPS10 protein P46783 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 17220279 YES Luana HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid. 0.2 SIGNOR-266083 PPM1G protein O15355 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity dephosphorylation Thr198 PGLRRRQt 9606 27822412 YES miannu By using genomic phosphatase screening, we identified a PPM family phosphatase, PPM1G, which could reduce p27 phosphorylation at T198.|Functionally, ectopic expression of PPM1G enhanced p27 protein stability and delayed cell cycle progression from G1 to S phase. 0.2 SIGNOR-277112 RBBP4 protein Q09028 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.82 SIGNOR-263837 MAPK8 protein P45983 UNIPROT WDR62 protein O43379 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1053 PSSSLPQtPEQEKFL 9606 BTO:0000007 30566428 YES lperfetto WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053 0.557 SIGNOR-271710 PTPN6 protein P29350 UNIPROT SH3BP2 protein P78314 UNIPROT down-regulates dephosphorylation 9606 16649996 YES gcesareni Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling 0.569 SIGNOR-146508 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation 10841026 YES inferred from 70% family members lperfetto More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis. 0.2 SIGNOR-270029 ADK protein P55263 UNIPROT ATP smallmolecule CHEBI:15422 ChEBI down-regulates quantity chemical modification 9606 33961946 YES miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 0.8 SIGNOR-267839 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates relocalization 9606 14718519 YES lpetrilli We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI. 0.697 SIGNOR-120734 PABPC4 protein Q13310 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 YES lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. 0.8 SIGNOR-268319 SRC protein P12931 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT up-regulates phosphorylation Tyr1105 RNEEENIySVPHDST 9606 9819392 YES lperfetto Phosphorylation of y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-src than by the egf receptor and was efficiently catalyzed by c-src in vitro. Mutation of y1105 from tyr to phe resulted in complete loss of p-tyr-dependent complex formation, indicating that p-y1105 was the sole p-tyr residue mediating binding to p120 0.771 SIGNOR-61670 KIF16B protein Q96L93 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272527 EYA1 protein Q99502 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Tyr143 ATQASQEy 9606 20965415 YES gcesareni Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3. 0.2 SIGNOR-168879 PRKD2 protein Q9BZL6 UNIPROT BCL6 protein P41182 UNIPROT down-regulates activity phosphorylation 9606 31980486 YES miannu Prkd2 directly binds to Bcl6 and Prkd2-dependent phosphorylation of Bcl6 is necessary to constrain Bcl6 to the cytoplasm, thereby limiting TFH development. 0.2 SIGNOR-279651 MCM5 protein P33992 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 YES The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. 0.775 SIGNOR-261675 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Ser65 IDLGTTNsCVAVMEG 9606 17573779 YES lperfetto Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin 0.2 SIGNOR-156181 LCK protein P06239 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1229 SSTDRSPyEKVSAGN BTO:0000661 14766232 YES lperfetto The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and beta-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and beta-catenin 0.461 SIGNOR-249358 INPP4B protein O15327 UNIPROT phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI down-regulates quantity chemical modification 9606 21127264 YES gcesareni Collectively this data indicates INPP4B is the only PtdIns(3,4)P2 4-phosphatase expressed in breast cancer cells and suggests a correlation between INPP4B and hormone receptor status in human breast cancer 0.8 SIGNOR-252433 N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide chemical CHEBI:91617 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190323 C5AR2 protein Q9P296 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.7 SIGNOR-263461 MCTS1 protein Q9ULC4 UNIPROT DENR protein O43583 UNIPROT up-regulates activity binding 9606 BTO:0000007 17878526 YES miannu The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon.  0.748 SIGNOR-269674 HDAC9 protein Q9UKV0 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 YES lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner 0.631 SIGNOR-235642 WDR48 protein Q8TAF3 UNIPROT USP1 protein O94782 UNIPROT up-regulates activity binding 9606 BTO:0000567 18082604 YES lperfetto In vitro reconstitution of USP1 deubiquitinating enzyme activity, using either ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) or purified monoubiquitinated FANCD2 protein as substrates, demonstrates that UAF1 functions as an activator of USP1. UAF1 binding increases the catalytic turnover (kcat) but does not increase the affinity of the USP1 enzyme for the substrate (KM). 0.946 SIGNOR-263274 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT up-regulates activity binding 10090 BTO:0000944 1333047 YES We show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues 0.577 SIGNOR-252089 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT down-regulates phosphorylation Ser330 LMRSRTAsGSSVTSL 9606 20416281 YES llicata Ndrg1/cap43 is phosphorylated at serine/threonine sites in its c-terminal domain by serum- and glucocorticoid-regulated kinase 1 (sgk1). we further introduced mutations at the serine and threonine sites at 328 [t328a], 330 [s330a] and 346 [t346a], which are susceptible to phosphorylation by sgk1, and also constructed double mutants [t328a, s330a], [t328a, t346a] and [s330a, t346a]. Expression of all these mutants, with the exception of [s330a, t346a], suppressed the production of cxc chemokine to similar levels as their wild-type counterpart. 0.57 SIGNOR-164898 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0001538 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.73 SIGNOR-252756 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR NF2 protein P35240 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18332868 YES miannu VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation. 0.327 SIGNOR-271674 MASTL protein Q96GX5 UNIPROT ENSA protein O43768 UNIPROT up-regulates activity phosphorylation Ser67 KGQKYFDsGDYNMAK -1 21164014 YES gcesareni We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. 0.731 SIGNOR-243690 AP1S1 protein P61966 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 YES lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) 0.867 SIGNOR-260684 NLGN4X protein Q8N0W4 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.767 SIGNOR-264170 BGJ-398 chemical CHEBI:63451 ChEBI FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190263 FFAR2 protein O15552 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256946 CALM1 protein P0DP23 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 YES gcesareni The calmodulin-binding region is located between amino acids 51 and 96 0.466 SIGNOR-82505 GRM1 protein Q13255 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. 0.8 SIGNOR-264932 SCF-betaTRCP complex SIGNOR-C5 SIGNOR LPCAT1 protein Q8NF37 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys221 RTCLITFkPGAFIPG 10090 BTO:0004299 21068446 YES miannu Here, we show that lipopolysaccharide (LPS) causes LPCAT1 degradation using the Skp1-Cullin-F-box ubiquitin E3 ligase component, β-transducin repeat-containing protein (β-TrCP), that polyubiquitinates LPCAT1, thereby targeting the enzyme for proteasomal degradation.Lys221 Is a Bona Fide Site for LPCAT1 Ubiquitination 0.328 SIGNOR-272759 diisononyl phthalate chemical CHEBI:35459 ChEBI monoisononyl phthalate chemical CHEBI:132593 ChEBI up-regulates quantity precursor of -1 33125036 YES miannu The primary metabolite of DiNP is monoisononyl-phthalate (MiNP) and the secondary metabolites include three oxidative derivatives of DiNP, which have been identified mainly in urine: mono-oxoisononyl phthalate (MOINP or oxo-MiNP), mono-carboxyisooctyl phthalate (MCIOP, MCOP or cx-MiNP), and mono-hydroxyisononyl phthalate (MHINP or OH-MiNP). 0.8 SIGNOR-268771 MNAT1 protein P51948 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 30477538 YES miannu Collectively, these results indicate that MNAT1 increases p53 ubiquitination, thus promoting its proteasomal degradation.|These suggest that MNAT1 decreases p53 expression by the proteasome. 0.352 SIGNOR-278831 PTK2 protein Q05397 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity phosphorylation 9606 22163037 YES miannu Both Src and FAK phosphorylate Rac1 at tyrosine 64.|Our investigations of direct interactions between Rac1, Src, and FAK were motivated by our previous insights into FAK augmentation of Rac1 activation during cell spreading, and the Cerione lab 's work on the interactions between Src and Cdc42 , . 0.572 SIGNOR-279652 F2R protein P25116 UNIPROT KLF6 protein Q99612 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254849 PPP1CB protein P62140 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 YES The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation 0.2 SIGNOR-248574 FBXL2 protein Q9UKC9 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000018 22024926 YES miannu Here, we show that a relatively new E3 ligase component belonging to the SCF (Skip-Cullin1-F-box protein) E3 ligase family, SCF (FBXL2) , impairs cell proliferation by mediating cyclin D3 polyubiquitination and degradation.  0.622 SIGNOR-271889 BCL2L2 protein Q92843 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17452531 YES gcesareni Bcl-w may protect largely via its ability to associate with bax because it could efficiently protect xem from tbid and bid, bad, hrk, and bmf bh3 peptides 0.478 SIGNOR-154518 AP2A2 protein O94973 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR form complex binding 31671891 YES lperfetto The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit 0.857 SIGNOR-260423 PAX7 protein P23759 UNIPROT PAX7/MLL1 complex complex SIGNOR-C90 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 YES miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.2 SIGNOR-198632 ERG protein P11308 UNIPROT TDRD1 protein Q9BXT4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 23555854 NO miannu we report that ERG and TDRD1 are co-expressed in human prostate cancers and we provide a mechanistic explanation for the observed co-expression. We demonstrate that ERG activates TDRD1 transcription by inducing loss of DNA methylation at the TDRD1 promoter-associated CpG island. 0.2 SIGNOR-254068 NFE2L2 protein Q16236 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 26194347 NO irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. 0.7 SIGNOR-256262 MAPK3 protein P27361 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 YES lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 0.521 SIGNOR-88662 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys262 DSDDALLkMTISQQE -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). 0.404 SIGNOR-272740 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CRKL protein P46109 UNIPROT up-regulates phosphorylation Tyr207 IPEPAHAyAQPQTTT 9606 BTO:0001271 9053848 YES lperfetto Tyrosine 207 in crkl is the bcr/abl phosphorylation sitephosphorylation of y207 provides a binding site for the crkl sh2 domain and potentially for other sh2-containing proteins. 0.2 SIGNOR-46893 COL2A1 protein P02458 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates binding 9606 7688313 YES gcesareni Both a2b1- and a1b1- integrins are implicated in chondrocyte adhesion to native collagene i and ii 0.472 SIGNOR-31881 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr19 GAVPSEAtKRDQNLK 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.332 SIGNOR-262919 AKT proteinfamily SIGNOR-PF24 SIGNOR RGCC protein Q9H4X1-2 UNIPROT up-regulates activity phosphorylation Ser45 ERMKRRSsASVSDSS 9606 BTO:0000567 19162005 YES miannu Akt phosphorylated GST-RGC-32 in vitro, and CDC2 was also able to phosphorylate RGC-32.  Akt failed to phosphorylate RGC-32 S45A-S47A mutant. These data indicate that Ser 45 and Ser 47 may be the RGC-32 phosphorylation sites for Akt kinase. 0.2 SIGNOR-262629 TRAF6 protein Q9Y4K3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity ubiquitination Lys134 AEAWSPRkLPSSAST 9606 BTO:0000007 18347055 YES K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B 0.913 SIGNOR-262298 PPP2CA protein P67775 UNIPROT TFCP2 protein Q12800 UNIPROT up-regulates dephosphorylation Ser309 SLGEGNGsPNHQPEP 9606 20682773 YES lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a 0.2 SIGNOR-167389 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM17 protein Q9Y577 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271237 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR miR-495 mirna URS000075C517_9606 RNAcentral down-regulates quantity by repression transcriptional regulation 9606 24332853 NO miannu We have found that PRMT4 is highly expressed in HSPCs, where it functions as an inhibitor of myeloid differentiation (Figure 7G). In these cells, PRMT4 methylates RUNX1 at R223, promoting the assembly of a DPF2-containing transcriptional co-repressive complex, and repressing transcription at the miR-223 locus. 0.4 SIGNOR-261971 KDM5C protein P41229 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-265354 MIB2 protein Q96AX9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity polyubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000815 29642005 YES miannu Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation.  We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. MIB2 Ubiquitylates RIPK1 at Lysines K377 and K634 0.295 SIGNOR-272662 taurine smallmolecule CHEBI:15891 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9009272 YES miannu For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system. 0.8 SIGNOR-258579 RPS6KA1 protein Q15418 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity phosphorylation Thr198 PGLRRRQt 9606 19470470 YES miannu As for other PI3K effectors, RSK1 phosphorylates p27 at T198.|RSK1 overexpression increases p27pT198, p27-cyclin D1-Cdk4 complexes, and p27 stability. 0.394 SIGNOR-279653 VEGFC protein P49767 UNIPROT FLT4 protein P35916 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 YES gcesareni Vegf-c, was isolated as a ligand for the tyrosine kinase vegfr-3 (flt4) 0.935 SIGNOR-55205 HCRTR2 protein O43614 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257350 KRT1 protein P04264 UNIPROT MPO protein P05164 UNIPROT up-regulates quantity binding 9606 17591979 YES Regulation of binding miannu CK1 and CK9 specifically bind MPO. MPO is internalized by endothelial cells through a direct interaction with the endothelial surface protein CK1 0.247 SIGNOR-251886 LCK protein P06239 UNIPROT SH2B3 protein Q9UQQ2 UNIPROT up-regulates phosphorylation Tyr273 LEMPDNLyTFVLKVK 9606 9169414 YES lperfetto In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation. 0.569 SIGNOR-48850 DVL1 protein O14640 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 27571105 YES areggio Although there are other activators of PCP, Wnt5a can activate the PCP pathway by forming a complex with Fzd and Ror2 receptors, activating DVL, which in turn activates Rho-family small GTPases, including RhoA and Rac, and their downstream effectors, Rho-associated protein kinase (ROCK), the actin-binding protein, Filamin A and c-Jun N-terminal protein kinase (JNK) 0.623 SIGNOR-258971 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Thr305 TDAATMKtFCGTPEY 10090 15367694 YES Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes 0.737 SIGNOR-248654 PBX3 protein P40426 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.2 SIGNOR-265805 JAK1 protein P23458 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates activity phosphorylation 9606 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. 0.659 SIGNOR-249491 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 YES lperfetto Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites 0.2 SIGNOR-112354 MCHR1 protein Q99705 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-257147 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 BTO:0001538 10748061 YES miannu That phosphorylation of serines 77 and 79 by cdk7 could be responsible for efficient transcription was further supported by the observation that overexpressed cdk7 significantly enhanced transcription by hRARγ1WT but not by hRARγ1S77A/S79A (Fig. 9 B).  0.417 SIGNOR-277897 ERAP2 protein Q6P179 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 15908954 YES The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases | We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2. 0.8 SIGNOR-272496 MYC protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 20551174 NO lperfetto In tissue culture, ectopic expression of Myc suppresses the cell cycle arrest that occurs in response to several anti-mitogenic signals such as transforming growth factor β (TGFβ), since Myc represses expression of the cyclin-dependent kinase inhibitors (CKIs) p15ink4b, p21cip1, and p57kip2 via interaction with Miz1 0.778 SIGNOR-267574 Enolase proteinfamily SIGNOR-PF74 SIGNOR phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266527 CAPZA1 protein P52907 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 BTO:0000132 27871158 YES lperfetto Finally, the capZ protein recaps the barbed filament ends to complete the assembly and these actin cytoskeletons can be used for cellular contraction, resulting in the final activated platelet shape 0.7 SIGNOR-261855 IRAK2 protein O43187 UNIPROT SRSF1 protein Q07955 UNIPROT down-regulates activity phosphorylation 9606 28990926 YES miannu IRAK2 phosphorylates SRSF1 and thereby reduces SRSF1 binding to the target mRNAs. 0.348 SIGNOR-278406 ZEB2 protein O60315 UNIPROT MEOX2 protein P50222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20516212 YES Luisa ZEB2 represses GAX transcription through multiple up- stream consensus binding sites. 0.318 SIGNOR-268951 RWDD3 protein Q9Y3V2 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates sumoylation 9606 17956732 YES lperfetto Rsume,_a small_rwd-containing protein, enhances sumo conjugation and stabilizes hif-1alpha during hypoxia 0.458 SIGNOR-158590 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity phosphorylation Ser133 SPSPMETsGCAPAEE 9606 BTO:0000567 11242082 YES lperfetto Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation. 0.922 SIGNOR-105715 DOCK4 protein Q8N1I0 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0001976 32009906 YES miannu DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia.  0.585 SIGNOR-266823 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline smallmolecule CHEBI:94276 ChEBI GLI2 protein P10070 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0001130 17494766 YES gcesareni Gant61 was able to efficiently block gli1 as well as gli2-induced transcription 0.8 SIGNOR-154756 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. 0.2 SIGNOR-232153 TFIIA complex SIGNOR-C395 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity relocalization 9606 7724559 YES lperfetto The human general transcription factor TFIIA is one of several factors involved in specific transcription by RNA polymerase II 0.665 SIGNOR-266200 STUB1 protein Q9UNE7 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization destabilization 9606 BTO:0002806 28813410 YES Barakat Deletion of STUB1 resulted in a more profound increase in PD-L1 levels in CMTM6 deficient than in CMTM6 proficient cells, identifying STUB1 as an E3 ligase that causes destabilization of PD-L1 (Fig. 4f,g), either by direct modification of one of the lysines in the PD-L1 cytoplasmic domain or indirectly 0.2 SIGNOR-274979 LYN protein P07948 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0000007 10574931 YES Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity. 0.733 SIGNOR-251409 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 YRPKPSSsPVIFAGG 9606 BTO:0000664 17475908 YES miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 0.319 SIGNOR-262911 SRC protein P12931 UNIPROT GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 YES inferred from family member gcesareni These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit. 0.27 SIGNOR-267796 alvocidib chemical CHEBI:47344 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258171 KDM4C protein Q9H3R0 UNIPROT H2AC4 protein P04908 UNIPROT down-regulates activity demethylation Lys 37 RVHRLLRkGNYSERV 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-263862 BDKRB2 protein P30411 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-256695 CSNK2A1 protein P68400 UNIPROT PTGES3 protein Q15185 UNIPROT up-regulates phosphorylation Ser118 DDSDEDMsNFDRFSE 9606 15040786 YES gcesareni Cpges-activating protein kinase is ck-ii (casein kinase ii). Mutations of either of two predicted ck-ii phosphorylation sites on cpges (ser113 and ser118) abrogated its phosphorylation and activation both in vitro and in vivo. Hypoxia induced the mitogen-activated protein kinase-mediated phosphorylation of a single serine residue, ser(122), in the protein, and site-directed mutagenesis demonstrated that ser(122) phosphorylation was necessary for hypoxic acceleration of tal1 turnover. 0.354 SIGNOR-123598 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1540 KSPEKRSsLPRPSSI -1 8631898 YES miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 0.419 SIGNOR-250163 CDK2 protein P24941 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 YES gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. 0.264 SIGNOR-158612 GMPS protein P49915 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 6698284 YES miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). 0.8 SIGNOR-267340 CAMKK2 protein Q96RR4 UNIPROT CAMK1 protein Q14012 UNIPROT up-regulates activity phosphorylation Thr177 DPGSVLStACGTPGY 7641687 YES llicata Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase. 0.413 SIGNOR-250716 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr382 DHYRYSDtTDSDPEN 9606 22413754 YES miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites 0.2 SIGNOR-248546 ACVR2B protein Q13705 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 10090 21966641 YES areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains 0.775 SIGNOR-254984 CCNB1 protein P14635 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR form complex binding 9606 25603287 YES lperfetto The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase. 1 SIGNOR-205590 tyramine smallmolecule CHEBI:15760 ChEBI dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† 0.8 SIGNOR-264176 PRKN protein O60260 UNIPROT HSD17B10 protein Q99714 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 25591737 YES miannu  This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-β hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate. 0.2 SIGNOR-272823 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT RPS3 protein P23396 UNIPROT down-regulates activity binding -1 33188728 YES miannu Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5. 0.2 SIGNOR-262507 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 16146838 YES lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. 0.41 SIGNOR-249622 NKX2-1 protein P43699 UNIPROT TPO protein P07202 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 27347897 YES scontino TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8. 0.379 SIGNOR-267278 DUSP1 protein P28562 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 10617468 YES inferred from 70% of family members gcesareni The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1. 0.2 SIGNOR-269910 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser323 HCSAEAGsPAMAVLD 9606 16286470 YES lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain 0.805 SIGNOR-141601 S100A8 protein P05109 UNIPROT Calprotectin complex complex SIGNOR-C293 SIGNOR form complex binding 9867828 YES lperfetto Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse. 0.73 SIGNOR-262832 FOXO1 protein Q12778 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 16308421 NO gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. 0.579 SIGNOR-142150 PKD1 protein P98161 UNIPROT JADE1 protein Q6IE81 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23001567 YES miannu Full-length PC1 bound, stabilized and colocalized with Jade-1 and inhibited Jade-1 ubiquitination. Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1. 0.328 SIGNOR-272917 CDK1 protein P06493 UNIPROT CENPA protein P49450 UNIPROT down-regulates quantity by destabilization phosphorylation Ser68 LIRKLPFsRLAREIC 9606 BTO:0000567 34758320 YES miannu Here, we report that the phosphorylation of CENP-A Ser68 primes the ubiquitin-proteasome-mediated proteolysis of CENP-A during mitotic phase in human cultured cells.the mitotic CENP-A degradation specifically depends on Cdk1 activity. 0.679 SIGNOR-277576 SF3a complex SIGNOR-C345 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 8349644 NO miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. 0.7 SIGNOR-263950 SLBP protein Q14493 UNIPROT H3Y1 protein P0DPK2 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265419 HNuRF complex SIGNOR-C448 SIGNOR Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000142 14609955 NO miannu Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. 0.7 SIGNOR-268838 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000801 17337443 YES lperfetto Analyses of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice demonstrate lack of cellular responsiveness to stimulation with IL-1beta or a Toll-like receptor 7 (TLR7) agonist. IRAK-4 kinase deficiency prevents the recruitment of IRAK-1 to the IL-1 receptor complex and its subsequent phosphorylation and degradation. 0.686 SIGNOR-153458 AR protein P10275 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 20069563 YES TH1 also associates with AR at the active androgen-responsive prostate-specific antigen (PSA) promoter in the nucleus of LNCaP cells. Decrease of endogenous AR protein by TH1 interferes with androgen-induced luciferase reporter expression and reduces endogenous PSA expression. 0.821 SIGNOR-253657 ARHGEF17 protein Q96PE2 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.547 SIGNOR-260542 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates activity phosphorylation Ser632 EELSSQMsSFNEAMT 9606 BTO:0000567 25504441 YES miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. 0.811 SIGNOR-276863 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation 9606 12912994 YES gcesareni Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5. 0.762 SIGNOR-104634 RPS6KB1 protein P23443 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation 9606 33353667 YES miannu D1R-PKA appears intact and elevated DARPP-32(pT34) in Rheb(S16H) mice is reduced by S6K1 inhibition (Figure 3).|S6K1 directly phosphorylates DARPP-32. 0.257 SIGNOR-279654 neuropeptide FF receptor agonist smallmolecule CHEBI:141000 ChEBI NPFFR2 protein Q9Y5X5 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257550 KLF4 protein O43474 UNIPROT NPNT protein Q6UXI9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 BTO:0001103 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 0.2 SIGNOR-255457 GRK2 protein P25098 UNIPROT PDCL protein Q13371 UNIPROT down-regulates activity phosphorylation 9606 10884381 YES miannu The phosphorylation of purified phosducin and PhLP by recombinant GRK2 proceeds rapidly and stoichiometrically (0.82 +/- 0.1 and 0.83 +/- 0.09 mol of P (i)/mol of protein, respectively). 0.2 SIGNOR-279178 TFDP1 protein Q14186 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.569 SIGNOR-253857 RAPGEF2 protein Q9Y4G8 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0002181 24290981 YES miannu Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis). 0.789 SIGNOR-276609 CDK1 protein P06493 UNIPROT UBE2I protein P63279 UNIPROT up-regulates activity phosphorylation 9606 22509284 YES miannu Overall, these results suggest that Cdk1 and cyclin B mediates the phosphorylation of Ubc9 at serine 71. 0.513 SIGNOR-278174 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser276 PLPSPTAsPNHTLAP -1 11113134 YES llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  0.355 SIGNOR-250645 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser923 DELRDSDsVCDSGVE 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 YES lperfetto The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. 0.746 SIGNOR-235434 METTL21C protein Q5VZV1 UNIPROT VCP protein P55072 UNIPROT up-regulates activity methylation Lys315 AIAPKREkTHGEVER 10090 BTO:0002319 29719249 YES We reveal that METTL21C trimethylates p97 on the Lys315 residue and found that loss of this modification reduced p97 hexamer formation and ATPase activity in vivo. 0.308 SIGNOR-255918 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 YES llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  0.392 SIGNOR-250790 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser235 SPQDSPPsKASPAQD 9606 21215781 YES lperfetto Cdk5 regulates app (amyloid precursor protein) processing and tau hyperphosphorylationtau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules 0.704 SIGNOR-251587 ruxolitinib phosphate chemical CHEBI:66917 ChEBI JAK1 protein P23458 UNIPROT down-regulates activity chemical inhibition 9606 23061804 YES miannu Ruxolitinib is a selective inhibitor of Janus kinases (JAK) 1 and 2, which are involved in the signalling pathway of various cytokines and growth factors essential to haematopoiesis. 0.8 SIGNOR-259170 CNOT11 protein Q9UKZ1 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.822 SIGNOR-268308 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser780 STRPPTLsPIPHIPR 9606 SIGNOR-C18 23336272 YES gcesareni Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. 0.929 SIGNOR-200483 SMC3 protein Q9UQE7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 YES lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin 0.912 SIGNOR-263312 SMC5/6 complex SIGNOR-C374 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 27427983 NO miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks 0.7 SIGNOR-265488 FYN protein P06241 UNIPROT KIRREL1 protein Q96J84 UNIPROT up-regulates activity phosphorylation Tyr606 KDPTNGYyNVRAHED 9606 BTO:0000007 18258597 YES miannu Here we have characterized Neph1, another SD component, as a novel substrate of SFK. Fyn interacts with and phosphorylates the cytoplasmic domain of Neph1 in vitro and in intact cells. Both tyrosine 637 and 638 of Neph1 are crucial for Neph1-Grb2 binding. 0.2 SIGNOR-262746 NACC1 protein Q96RE7 UNIPROT ZBTB14 protein O43829 UNIPROT up-regulates activity binding -1 19121354 YES miannu NAC1 potentiated ZF5 mediated repression in Gal4-DBD fusion transient assays. GST pulldown assays further confirmed protein–protein interactions between these proteins and NAC1. 0.289 SIGNOR-226443 creatine smallmolecule CHEBI:16919 ChEBI CKMT2 protein P17540 UNIPROT up-regulates activity chemical activation 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265785 PKM protein P14618 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates activity binding 9606 BTO:0000567 21620138 YES PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, 0.389 SIGNOR-267473 NEK2 protein P51955 UNIPROT GAS2L1 protein Q99501 UNIPROT up-regulates activity phosphorylation Ser352 HPRSRRYsGDSDSSA 9606 32289147 YES miannu Nek2A mediates G2/M phosphorylation of GAS2L1. GAS2L1 and its Ser352 phosphorylation are required for proper spindle organization and chromosome segregation.  0.2 SIGNOR-273683 O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI up-regulates quantity precursor of 3702 30034403 YES lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. 0.8 SIGNOR-268564 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 9271428 YES gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. 0.2 SIGNOR-50594 RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR NFAT5 protein O94916 UNIPROT up-regulates activity binding 9606 BTO:0000815 22266867 YES done miannu In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration.  0.353 SIGNOR-274113 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.248 SIGNOR-268602 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr852 NDPTAPPyDSLLVFD 9606 16371504 YES lperfetto Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated. 0.398 SIGNOR-143234 CCKBR protein P32239 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.451 SIGNOR-257363 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR SDE2 protein Q6IQ49 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 27906959 YES miannu Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction. The cleaved SDE2 products need to be degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner, and failure to degrade SDE2 impairs S phase progression and cellular survival. 0.251 SIGNOR-272809 FAM83G protein A6ND36 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.373 SIGNOR-273745 PIGF protein Q07326 UNIPROT PIGO protein Q8TEQ8 UNIPROT down-regulates quantity by destabilization 10029 BTO:0000246 15632136 NO miannu We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O. 0.709 SIGNOR-261360 IQGAP1 protein P46940 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity binding 15695813 YES lperfetto Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.  0.81 SIGNOR-261888 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763 12193595 YES lperfetto Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction. 0.2 SIGNOR-244731 mycophenolic acid chemical CHEBI:168396 ChEBI IMPDH2 protein P12268 UNIPROT down-regulates activity chemical inhibition -1 10677226 YES Federica Mycophenolic acid (MPA) is a species-specific inhibitor of IMPDH; mammalian IMPDHsare very sensitive to MPA 0.8 SIGNOR-261077 PF-3845 chemical CID:25154867 PUBCHEM FAAH protein O00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206049 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser343 TRLEPVYsPPGSPPP 9606 BTO:0000567 10806207 YES llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. 0.603 SIGNOR-77208 RNF126 protein Q9BV68 UNIPROT FXN protein Q16595 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28228265 YES miannu Depletion of RNF126 by specific small interfering RNA delays the degradation of frataxin precursor and increases its stability.|Here we report on the identification of really interesting new gene finger protein 126 (RNF126) as the E3 ligase that ubiquitinates frataxin. 0.385 SIGNOR-278663 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser1217 SHHFRRRsFRGFWLT 9606 19144650 YES llicata We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade 0.2 SIGNOR-183445 GALR1 protein P47211 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.45 SIGNOR-256830 QRICH1 protein Q2TAL8 UNIPROT EARS2 protein Q5JPH6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269402 SIN3A protein Q96ST3 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 16254079 YES Chromatin immunoprecipitation (ChIP) and DNA affinity precipitation analysis demonstrated that Ebp1 and Sin3A associate at the PSA and E2F1 promoters. Functionally, Sin3A enhanced the ability of Ebp1 to repress transcription of androgen receptor (AR) and E2F1 regulated genes. 0.2 SIGNOR-253663 YY2 protein O15391 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 15087442 YES Luana YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter. 0.393 SIGNOR-266212 SYDE2 protein Q5VT97 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.4 SIGNOR-260522 CUDC-907 chemical CID:54575456 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252661 PGLS protein O95336 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI up-regulates quantity chemical modification 9606 31586547 YES miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). 0.8 SIGNOR-267058 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 YES lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. 0.716 SIGNOR-33909 FAM83E protein Q2M2I3 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273763 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser4 sPLSKKRR 9606 BTO:0000150 7673335 YES lperfetto Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1 0.406 SIGNOR-31157 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 11427888 YES Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. 0.685 SIGNOR-251239 RPS6KB2 protein Q9UBS0 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser283 ILSLRSCsLGSLGAL -1 27407113 YES miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  0.334 SIGNOR-274066 HTR3B protein O95264 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 NO miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  0.7 SIGNOR-264317 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270388 Ub:E2 complex SIGNOR-C497 SIGNOR RNF25 protein Q96BH1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271207 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr289 AGPKASPtPQKTSAK 9606 14741103 YES llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. 0.405 SIGNOR-250656 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000007 17035229 YES SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.432 SIGNOR-248793 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 SIGNOR-C14 11460167 YES lperfetto Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta. 0.755 SIGNOR-109494 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000150 18372406 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.67 SIGNOR-178133 AMFR protein Q9UKV5 UNIPROT APOB protein P04114 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 33591966 YES miannu In physiological condition, the unnecessary apoB is usually ubiquitinated by E3 ligase AMFR, and subsequently degraded by ubiquitination proteasomes. 0.291 SIGNOR-278685 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR CDC7 protein O00311 UNIPROT up-regulates activity phosphorylation Thr376 QVAPRAGtPGFRAPE 10846177 YES llicata Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks. 0.584 SIGNOR-250726 CSNK2A1 protein P68400 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.286 SIGNOR-250830 RIMBP3B protein A6NNM3 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.358 SIGNOR-264369 HIRA complex 1 complex SIGNOR-C461 SIGNOR H3-3A protein P84243 UNIPROT up-regulates quantity by stabilization binding 9606 30285846 YES miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. 0.2 SIGNOR-269439 SLC4A1 protein P02730 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.406 SIGNOR-266015 BMP1 protein P13497 UNIPROT COL5A2 protein P05997 UNIPROT up-regulates activity cleavage Glu1253 SEVKMDAeFRHDSGY 9606 BTO:0002974 11741999 YES miannu BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro. BMP-1 efficiently cleaves pro-α2(V) C-propeptides at a single site between residues 1250 (Glu) and 1251 (Asp). 0.606 SIGNOR-256343 IRS4 protein O14654 UNIPROT SSH1 protein Q8WYL5 UNIPROT up-regulates activity binding 9606 BTO:0002181 25100728 YES miannu Insulin Receptor Substrate-4 Binds to Slingshot-1 Phosphatase and Promotes Cofilin Dephosphorylation. In addition, IRS4 co-localized with SSH1 in F-actin-rich membrane protrusions in insulin-stimulated cells, which suggests that the association of IRS4 with SSH1 contributes to localized activation of cofilin in membrane protrusions. 0.311 SIGNOR-277617 ARHGAP26 protein Q9UNA1 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.628 SIGNOR-260481 Wnt proteinfamily SIGNOR-PF40 SIGNOR FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES inferred from 70% family members gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.2 SIGNOR-269960 TWIST1 protein Q15672 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 NO miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells 0.264 SIGNOR-255515 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0000887;BTO:0001260 11983427 YES amattioni The actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759. This phosphorylation leads to markedly diminished actin affinity. 0.476 SIGNOR-86741 PLX-4720 chemical CHEBI:90295 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258267 FOXA1 protein P55317 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24875621 YES miannu FOXA1 directly inhibits AR expression and thus the transcription of its target genes. FOXA1 inhibits AR gene expression in prostate cancer. oss of FOXA1 may lead to androgen-independent AR signaling and thus castration-resistant prostate cancer progression. Indeed, we have recently reported that FOXA1 is downregulated in CRPC 0.765 SIGNOR-251541 MAPT protein P10636 UNIPROT Neurofibrillary tangle formation phenotype SIGNOR-PH58 SIGNOR up-regulates 9606 11578751 NO lperfetto Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly 0.7 SIGNOR-251642 IRF5 protein Q13568 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21240265 NO miannu Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1Œ±), RANTES, CD1A, CD40, CD86 and CCR7 0.453 SIGNOR-254518 ITGAV protein P06756 UNIPROT Av/b1 integrin complex SIGNOR-C175 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.835 SIGNOR-253201 RXRB protein P28702 UNIPROT PPARD protein Q03181 UNIPROT up-regulates binding 9606 11237216 YES gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology 0.554 SIGNOR-105451 ARP2/3 complex SIGNOR-C146 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 BTO:0000132 27871158 YES lperfetto The Arp2/3 complex stimulates the assembly of actin filaments. 0.7 SIGNOR-261838 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257933 PHIP protein Q8WWQ0 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity binding 9534 BTO:0001538 12242307 YES miannu We have recently reported the isolation of a PH domain-interacting protein, PHIP, which selectively binds to the IRS-1 PH domain and is stably associated with IRS-1 in mammalian cells. Here we demonstrate that overexpression of PHIP in fibroblasts enhances insulin-induced transcriptional responses in a mitogen-activated protein kinase-dependent manner. 0.513 SIGNOR-266962 UMPS protein P11172 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 2912371 YES miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). 0.8 SIGNOR-267437 MAPK14 protein Q16539 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates phosphorylation Ser721 PSDLLPMsPSVYAVL 9606 17502367 YES gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). 0.598 SIGNOR-154787 ketanserin chemical CHEBI:6123 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258685 DERA protein Q9Y315 UNIPROT acetaldehyde smallmolecule CHEBI:15343 ChEBI up-regulates quantity chemical modification 9606 25229427 YES miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. 0.8 SIGNOR-267099 PRPF19 protein Q9UMS4 UNIPROT RPA1 protein P27694 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000567 24332808 YES miannu PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment. 0.507 SIGNOR-272076 LYN protein P07948 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 YES miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. 0.2 SIGNOR-276395 PTK6 protein Q13882 UNIPROT DOK1 protein Q99704 UNIPROT down-regulates activity phosphorylation Tyr362 DPKEDPIyDEPEGLA 9606 24523872 YES miannu BRK downregulates Dok1 via proteasomal degradation.|BRK phosphorylates Dok1 at tyrosine 362. 0.493 SIGNOR-278301 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 11955436 YES gcesareni Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). 0.86 SIGNOR-116520 PLN protein P26678 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity binding 10090 12838339 YES Heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor. 0.751 SIGNOR-252031 CLIP1 protein P30622 UNIPROT DCTN1 protein Q14203 UNIPROT up-regulates activity binding 9606 15381688 YES miannu MT-unbound CLIP-170 can adopt a folded conformation through an intramolecular interaction of its terminal domains. Binding to MTs correlates with the unfolding of CLIP-170, which allows the interaction of the COOH-terminal domain with its binding partners, such as dynactin, resulting in their recruitment to the MT tip. The NH2 terminus of p150Glued binds directly to the COOH terminus of CLIP-170 through its second metal-binding motif. 0.782 SIGNOR-252164 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267426 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser130 GPKVNRPsLLEIHEQ 9606 BTO:0000007 21321328 YES miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). 0.503 SIGNOR-276309 tRNA(Gly) smallmolecule CHEBI:29176 ChEBI Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates quantity precursor of 9606 24898252 YES miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 0.8 SIGNOR-270483 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr74 HKPLEGKyEWQEVEK 9606 17254967 YES lperfetto Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27 0.497 SIGNOR-152831 RNF111 protein Q6ZNA4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 YES lperfetto Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. 0.684 SIGNOR-236873 MYC protein P01106 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 12835716 NO gcesareni These results suggest that e2f1 and cyclin a2 may be induced by c-myc to mediate the onset of mammary cancer, whereas overexpression of cyclins d1 and e may occur later to facilitate tumor progression. 0.417 SIGNOR-102728 MCF2L protein O15068 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.618 SIGNOR-260559 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL -1 19661060 YES miannu We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.2 SIGNOR-276232 CREBBP protein Q92793 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity acetylation Lys390 QKTLTPEkGQSQGLI 9606 BTO:0000007 17923090 YES lperfetto STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation. 0.556 SIGNOR-217891 JAK1 protein P23458 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 17259970 YES milica Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity. 0.535 SIGNOR-152914 CDK5 protein Q00535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation Ser782 YSLLRGGsDDSSKDP -1 21922195 YES miannu These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage. 0.258 SIGNOR-276357 CDK12 protein Q9NYV4 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr169 TEAPAVVtEEEDDDE 9606 BTO:0004828 32483448 YES lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway 0.2 SIGNOR-273110 NOXO1 protein Q8NFA2 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 20943948 YES lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation 0.776 SIGNOR-264709 EPAS1 protein Q99814 UNIPROT KDM3A protein Q9Y4C1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.265 SIGNOR-271583 PRKACA protein P17612 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation 10116 BTO:0001593 18981475 YES gcesareni These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit. 0.2 SIGNOR-181979 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Thr187 ESSKERNtPRKEDRS -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.321 SIGNOR-273964 DCC protein P43146 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 9606 15494734 YES miannu Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling. 0.534 SIGNOR-268372 CALM3 protein P0DP25 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 BTO:0001009 14701738 YES miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. 0.2 SIGNOR-266342 KRAS protein P01116 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. 0.738 SIGNOR-252698 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Ser1035 DHQTPPTsPVQGTTP 9606 24089523 YES lperfetto Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1 0.2 SIGNOR-244545 MYC protein P01106 UNIPROT PTBP1 protein P26599 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20010808 YES We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2, 0.439 SIGNOR-268689 DMTF1 protein Q9Y222 UNIPROT MBD1 protein Q9UIS9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 NO Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  0.2 SIGNOR-261586 LEF1 protein Q9UJU2 UNIPROT ALX4 protein Q9H161 UNIPROT up-regulates quantity by expression binding 10090 BTO:0003952 11696550 YES miannu Alx4 Stably Interacts with LEF-1. LEF-1 enhances Alx4 binding to DNA, suggesting that both interaction with LEF-1 and DNA binding are required to mediate its effects on the N-CAM promoter. 0.446 SIGNOR-254547 ENDOG protein Q14249 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 21210296 NO gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. 0.35 SIGNOR-170972 TFIIIB complex SIGNOR-C393 SIGNOR RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity binding 9606 9308965 YES lperfetto Transcription by RNA polymerase III (Pol III) requires multiple general initiation factors that, in isolated form, assemble onto the promoter in an ordered fashion. Here, it is shown that all components required for transcription of the VA1 and tRNA genes, including TFIIIB, TFIIIC, and RNA Pol III, can be coimmunopurified from a HeLa cell line that constantly expresses a FLAG epitope-tagged subunit of human RNA Pol III. 0.658 SIGNOR-266181 DUSP16 protein Q9BY84 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 BTO:0000938 12524447 YES gcesareni Here we report that jip-1 also binds the dual-specificity phosphatases mkp7 and m3/6 via a region independent of its jnk binding domain. when mkp7 is bound to jip-1 it reduces jnk activation leading to reduced phosphorylation of the jnk target c-jun 0.441 SIGNOR-97173 LMP1 protein P03230 UNIPROT UBE2I protein P63279 UNIPROT up-regulates activity binding 9606 BTO:0002181 22951831 YES scontino One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452. 0.2 SIGNOR-266838 KRAS protein P01116 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR up-regulates activity relocalization 9606 BTO:0000584 31827278 YES KRAS G12R miannu V-ATPase is required for macropinocytosis. oncogenic RAS-dependent recruitment of V-ATPase to the plasma membrane constitutes an essential step in induction of macropinocytosis. Here we identify vacuolar ATPase (V-ATPase) as an essential regulator of RAS-induced macropinocytosis. Oncogenic RAS promotes the translocation of V-ATPase from intracellular membranes to the plasma membrane via a pathway that requires the activation of protein kinase A by a bicarbonate- dependent soluble adenylate cyclase. 0.28 SIGNOR-277759 CNOT4 protein O95628 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.777 SIGNOR-268302 ATM protein Q13315 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 18158901 YES gcesareni H2ax interacts with numerous proteins required for dna damage signaling and repair when phosphorylated on ser-140. Phosphorylation of ser-140 (h2ax139ph) in response to ionizing radiation is mediated by both atm and prkdc. Our data showed that h2ax is phosphorylated by uva-activated jnk. 0.2 SIGNOR-160206 GSK3B protein P49841 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 21658600 YES gcesareni We demonstrate that gsk-3 phosphorylates serine 86 of the p53-acetyltransferase tip60. A tip60(s86a) mutant was less active to induce p53 k120 acetylation, histone 4 acetylation, and expression of puma 0.368 SIGNOR-174049 NCKAP1 protein Q9Y2A7 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 YES lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  0.928 SIGNOR-261874 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC4R protein P32245 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.2 SIGNOR-268711 PKA proteinfamily SIGNOR-PF17 SIGNOR CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser39 TPKRRRAsSLSRDAE 27149373 YES lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. 0.2 SIGNOR-275632 NOTCH1 protein P46531 UNIPROT FABP7 protein O15540 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16554461 NO gcesareni Here we demonstrate that neuronal induction of radial glia formation is the result of sequential signaling through notch1 and erbb receptors. First, notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes. 0.546 SIGNOR-145365 SDHA protein P31040 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 30030361 YES lperfetto Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites 0.952 SIGNOR-262188 PTPN6 protein P29350 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates dephosphorylation 9606 12361947 YES gcesareni Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1. 0.2 SIGNOR-94007 NEK6 protein Q9HC98 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity phosphorylation Ser1033 GINTLERsKVEETTE 9606 BTO:0001938 19001501 YES done miannu Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.  0.445 SIGNOR-273886 PTPN5 protein P54829 UNIPROT GRIN2A protein Q12879 UNIPROT down-regulates activity dephosphorylation 9606 27857196 YES miannu STEP inhibition by TC-2153 enhanced Tyr phosphorylation of GluN2A (XREF_FIG, 1 EGTA+TC-2153, n = 5, P < 0.05 compared with 1mM EGTA) without altering phosphorylation of Src (XREF_FIG, 1 EGTA+TC-2153, n = 5, P> 0.05 compared with 1 EGTA).|These findings confirm that not only GluN2B and Fyn but also GluN2A are substrates of STEP. 0.433 SIGNOR-277089 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr360 VSPSPTTyRMFRDKS 9534 8622703 YES Manara These results indicate that tyrosine phosphorylation of Bcr by Bcr-Abl inhibits Bcr‚Äôs serine/threonine kinase activity. 0.2 SIGNOR-262530 TNFRSF17 protein Q02223 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates 9606 10903733 NO miannu Overexpression of bcma activates jnk 0.2 SIGNOR-79507 PRKCA protein P17252 UNIPROT GJB1 protein P08034 UNIPROT up-regulates activity phosphorylation Ser233 NPPSRKGsGFGHRLS 8390988 YES lperfetto Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b). 0.362 SIGNOR-248920 ATM protein Q13315 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates activity phosphorylation Ser100 DEDSGKGsQPPSPPS 9606 23891091 YES miannu ATM-mediated Snail Serine 100 phosphorylation regulates cellular radiosensitivity. 0.483 SIGNOR-279587 POLR3C protein Q9BUI4 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.882 SIGNOR-266131 CSNK1G1 protein Q9HCP0 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Thr1479 SSSSTKGtYFPAILN 9606 16341016 YES gcesareni Ck1gamma is associated with lrp6, which has multiple, modular ck1 phosphorylation sites. Wnt treatment induces the rapid ck1gamma-mediated phosphorylation of these sites within lrp6 0.544 SIGNOR-143029 LRRK2 protein Q5S007 UNIPROT RAB10 protein P61026 UNIPROT down-regulates activity phosphorylation Thr73 AGQERFHtITTSYYR 9606 BTO:0000007 26824392 YES Giulio To investigate whether the phosphorylation of Rab10 by LRRK2 is direct, we performed an in vitro kinase assay using recombinant components. Notably, we found that both wt and LRRK2-G2019S, but neither kinase inactive D1994A mutant nor small molecule-inhibited LRRK2, efficiently phosphorylated Rab10, proving a direct kinase-substrate relationship (Figure 2C). Furthermore, incubation of Rab10 with LRRK2 followed by tryptic digestion and MS analysis unambiguously identified T73 as the major phosphorylation site (Figure 2—figure supplement 1B)|In pathogenic conditions, in which LRRK2 is hyperactive, RabGTPases have strongly diminished affinities for GDIs. 0.331 SIGNOR-261277 KDM4C protein Q9H3R0 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding 9606 BTO:0001033 29207681 YES miannu JMJD2C was found to be co-localized with AR and LSD1 in the epithelium of prostate carcinoma and normal prostate cells. For the detailed mechanism, JMJD2C, AR and LSD1 assembled on the chromatin to remove the methyl groups from mono-, di- and trimethylated H3K9. Importantly, JMJD2C specifically removed the demethylation of the trimethyl H3K9 marks and modulated the transcriptional activity of AR. Moreover, JMJD2C cooperated with LSD1 and activated AR-mediated gene expression via decreasing H3K9me3 at the promoter of AR targeting genes KLK2 and PSA. 0.2 SIGNOR-263880 MAPK8IP1 protein Q9UQF2 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 20508646 YES Interferes with binding to Noth1-ICD. gcesareni Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them. 0.2 SIGNOR-165713 NIN protein Q8N4C6 UNIPROT JAK2 protein O60674 UNIPROT down-regulates binding 9606 25332239 YES miannu We showed that jak2 directly phosphorylates the n-terminus ofnineinwhile the c-terminus ofnineininhibits jak2 kinase activity in vitro. 0.242 SIGNOR-205581 CDC42 protein P60953 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 YES gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. 0.885 SIGNOR-248253 PRKAA1 protein Q13131 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 9606 26816379 YES gcesareni A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. 0.2 SIGNOR-249656 SUFU protein Q9UMX1 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 YES miannu Hsu(fu) associated with itself / homo- or heterodimers of hsu(fu) might function to bring together other effector proteins 0.2 SIGNOR-72311 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser48 VEIIRMAsIYSEEGN 9534 BTO:0000298 11483516 YES llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. 0.291 SIGNOR-250600 NEK2 protein P51955 UNIPROT CCDC102B protein Q68D86 UNIPROT down-regulates activity phosphorylation 30404835 YES lperfetto CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis. 0.2 SIGNOR-275626 N-acetylserotonin smallmolecule CHEBI:17697 ChEBI ASMT protein P46597 UNIPROT up-regulates activity chemical activation -1 22775292 YES miannu Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS. 0.8 SIGNOR-265476 WWP1 protein Q9H0M0 UNIPROT AMOT protein Q4VCS5 UNIPROT up-regulates quantity by stabilization ubiquitination 24101513 YES lperfetto Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130 0.275 SIGNOR-275847 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr128 LGGTETEySLLHMPS -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.356 SIGNOR-273573 SLIT2 protein O94813 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 YES gcesareni Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis. 0.603 SIGNOR-68428 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr198 EDVEDPVyQYIVFEA 10090 BTO:0000938 11279201 YES lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. 0.421 SIGNOR-247076 apomorphine chemical CHEBI:48538 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258375 FLT3 protein P36888 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity 9606 28213513 NO Our finding that RUNX1 protein levels are dependent on FLT3-ITD signaling in AML cells and that, together, they synergize to generate AML. […]Our work demonstrated that Tyr phosphorylation within the ID region of RUNX1 is critical for its oncogenic potential, 0.362 SIGNOR-256307 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC11 protein P06899 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271980 SHANK3 protein Q9BYB0 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264585 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002552 33188728 NO miannu We present here data demonstrating that among all viral proteins, Nsp1 causes the most severe viability reduction in the cells of human lung origin. We found that introduction of Nsp1, but not other viral proteins, induced apoptosis in H1299 cells 0.7 SIGNOR-262506 SPTB proteinfamily SIGNOR-PF73 SIGNOR Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR form complex binding 9606 24302288 YES lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell 0.2 SIGNOR-266027 ABI1 protein Q8IZP0 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 17395426 YES gcesareni Here we uncover a novel interaction between abi-1 and the cbl ubiquitin ligase and show that abi-1 mediates cbl accumulation to the plasma membrane upon stimulation by egf. 0.372 SIGNOR-154162 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Thr1031 ASSTDHQtPPTSPVQ 9606 24089523 YES lperfetto Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1 0.2 SIGNOR-244549 MLKL protein Q8NB16 UNIPROT CNR2 protein P34972 UNIPROT down-regulates quantity by destabilization phosphorylation Ser352 KITPWPDsRDLDLSD 9606 BTO:0000007 10400664; 36448459 YES done miannu Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. 0.2 SIGNOR-274121 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273040 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT up-regulates activity phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0002181 24841198 YES miannu CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15 0.396 SIGNOR-277827 clozapine chemical CHEBI:3766 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 BTO:0000529 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258515 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates dephosphorylation 9606 11711533 YES gcesareni Furthermore, we demonstrate that pstpip serves as a scaffold protein between ptp-pest and wasp and allows ptp-pest to dephosphorylate wasp. This finding suggests a possible mechanism for ptp-pest to directly modulate actin remodeling through the pstpip-wasp interaction. 0.445 SIGNOR-111688 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 YES lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity, 0.742 SIGNOR-217734 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation 9606 16508002 YES inferred from 70% family members gcesareni Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. 0.2 SIGNOR-270043 HDAC2 protein Q92769 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity deacetylation -1 11486036 YES miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. 0.769 SIGNOR-268836 MMP2 protein P08253 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR up-regulates activity cleavage 9211848 YES lperfetto Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling. 0.459 SIGNOR-253239 CHD7 protein Q9P2D1 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR form complex binding 10090 21952300 YES FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43. 0.499 SIGNOR-253526 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr245 GFGTSPLtPSARISA 10090 BTO:0000142 12796778 YES llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. 0.2 SIGNOR-250652 SGK1 protein O00141 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates activity phosphorylation Ser353 S-->K -1 28545025 YES miannu We show that SGK1 phosphorylates MNK1 at a conserved site, which represses its activity.  0.2 SIGNOR-277357 ELOC protein Q15369 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 BTO:0000672 22001063 YES gcesareni Using proteomic techniques, several components of the elongin c complex were identified as candidate notch4(icd) interactors. Elongin c complexes can function as ubiquitin ligases capable of regulating proteasomal degradation of specific protein substrates. Our studies indicate that ectopic elongin c expression stimulates notch4(icd) degradation and inhibits its transcriptional activity in human kidney tubule hk11 cells. 0.2 SIGNOR-176779 methylnaltrexone chemical CHEBI:136007 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258042 JAG1 protein P78504 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10551863 YES Binding Calcium-dependent. gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. 0.638 SIGNOR-72112 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser605 LFVQLLYsPIENIQR 9606 18423204 YES amattioni Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt. 0.67 SIGNOR-178262 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr811 ADDSSSStSSDSLGG -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.34 SIGNOR-250910 TNKS2 protein Q9H2K2 UNIPROT BLZF1 protein Q9H2G9 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 21478859 YES lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.2 SIGNOR-263384 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257973 MMP2 protein P08253 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272387 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr346 GTRSRSHtSEGTRSR 9606 18787837 YES llicata Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1. 0.57 SIGNOR-180821 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 17078951 YES The effect has been demonstrated using P10636-8 lperfetto Here, we found that prephosphorylation by pka promotes gsk-3beta-catalyzed tau phosphorylation at thr181, ser199, ser202, thr205, thr217, thr231, ser396 and ser422 0.738 SIGNOR-150360 CSNK2B protein P67870 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275756 CPSF complex complex SIGNOR-C53 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity relocalization 9606 14749727 YES lperfetto Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. 0.795 SIGNOR-268323 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN 9606 BTO:0000007 10869359 YES Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo 0.459 SIGNOR-251472 AKT1 protein P31749 UNIPROT USP4 protein Q13107 UNIPROT up-regulates quantity by stabilization phosphorylation Ser445 NHRLRNDsVIVDTFH 9606 22706160 YES miannu AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability.  0.466 SIGNOR-273482 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120176 MYD88 protein Q99836 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 28404732 YES miannu In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity 0.921 SIGNOR-260160 GHR protein P10912 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates 9606 23612709 NO miannu Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin. Possible stimuli for NFATc2 activation are PGF2α and GH. 0.2 SIGNOR-255459 CASP6 protein P55212 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 YES lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. 0.372 SIGNOR-261753 BRAP protein Q7Z569 UNIPROT CDC14A protein Q9UNH5 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 19152073 YES k63 miannu Brap2 promotes Lys-63 linked ubiquitination of HsCdc14A. Collectively, these results support the idea that Brap2 facilitates Lys-63 linked ubiquitin modification of HsCdc14A, which may not be targeted for degradation, but mainly for protein–protein interactions or other regulatory functions. 0.338 SIGNOR-271777 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity binding 9606 15688067 YES miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.914 SIGNOR-257732 PROX1 protein Q92786 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates quantity by stabilization 9606 27476001 NO miannu PROX1 is important to maintain HIF1Œ± protein stability by inhibiting the proteasome activity after DAB2IP loss, since our immunoprecipitation data showed that knocking-down PROX1 could enhance the protein‚Äìprotein interaction between HIF1Œ± and ubiquitin in DAB2IP-deficient LAPC-4 and RWPE-1 KD cells. we found that knocking-down PROX1 could decrease HIF1Œ± protein stability, because HIF1Œ± protein degradation was significantly blocked by MG132 treatment in LAPC-4 and RWPE-1 KD cells 0.257 SIGNOR-254766 CDK4 protein P11802 UNIPROT KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Thr272 LNYWKLEtPAQFRQR 24870244 YES lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) 0.361 SIGNOR-275495 B2M protein P61769 UNIPROT Class I MHC complex SIGNOR-C425 SIGNOR form complex binding -1 28367149 YES scontino One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER) 0.2 SIGNOR-267777 ITGAL protein P20701 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 YES apalma This leads to further neutrophil-endothelial cell interactions through the binding of LFA-1 to its endothelial counterreceptor ICAM-1 during the slow rolling phase 0.922 SIGNOR-255040 NCOA1 protein Q15788 UNIPROT OTC protein P00480 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.2 SIGNOR-255062 CTH protein P32929 UNIPROT L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275818 NMUR2 protein Q9GZQ4 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257292 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273061 MAP1LC3C protein Q9BXW4 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates activity binding 10090 BTO:0002572 22170151 YES lperfetto Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe 0.781 SIGNOR-191552 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Ser144 NAGNKRLsTIDESGS 9606 BTO:0000567 14744859 YES llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 0.779 SIGNOR-250586 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 9812896 YES gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity 0.526 SIGNOR-61561 ENPP1 protein P22413 UNIPROT INSR protein P06213 UNIPROT down-regulates activity binding 9606 10615944 YES miannu Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit. 0.389 SIGNOR-252190 CD3G protein P09693 UNIPROT CD3 complex SIGNOR-C432 SIGNOR form complex binding 9606 12507424 YES miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules. 0.648 SIGNOR-255296 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 protein P04637 UNIPROT down-regulates activity binding 10090 BTO:0002882 26387755 YES Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8).Altogether, these results indicate that CM fusion protein binds to p53 and impairs acetylation and activation of p53. 0.2 SIGNOR-255737 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser198 IRTHLSQsPRVPSKC 10090 19560418 YES These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 0.26 SIGNOR-248380 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 15618519 YES gcesareni Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. 0.2 SIGNOR-132672 XRCC4 protein Q13426 UNIPROT Lig4-Xrcc4 complex complex SIGNOR-C354 SIGNOR form complex binding -1 19837014 YES miannu The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. 0.951 SIGNOR-264532 MYLK protein Q15746 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser744 GLKVGVSsRINEWLT 9606 20536391 YES gcesareni Phosphorylation of caldesmon by myosin light chain kinase increases its binding affinity for phosphorylated myosin filaments. 0.639 SIGNOR-166049 gamma-secretase complex SIGNOR-C98 SIGNOR DSCAM protein O60469 UNIPROT down-regulates quantity cleavage 9606 BTO:0000938 30745319 YES miannu γ‐secretase‐mediated intra‐membrane cleavage of DSCAM receptors results in the release of the DSCAM ICD, which is likely proceeded by shedding of the DSCAM ectodomain. Interaction of IPO5 with the NLS of DSCAM then leads to importin‐mediated nuclear import of the DSCAM ICD. In the nucleus, the DSCAM ICD may regulate the transcription of genes involved in neuronal development and function, thereby regulating processes such as neurite outgrowth, branching, and repulsion, as well as synapse formation, axon guidance, and neuronal cell death and survival. 0.2 SIGNOR-264271 CCL2 protein P13500 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32446778 NO Luana In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNŒ±, IFNŒ≥, IL-1Œ≤, IL-6, IL-12, IL-18, IL-33,TNFŒ±, TGFŒ≤) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatory response. 0.7 SIGNOR-261317 GSK3B protein P49841 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates activity phosphorylation Ser551 TEAKNPFsTQDTDLD 9606 23210979 YES miannu Glycogen synthase kinase 3 \u03b2 (GSK3\u03b2) phosphorylates HIF-1\u03b1 at three serine residues (Ser-551, Ser-555, and Ser-589) located within its oxygen-dependent degradation domain (ODDD) [12] (Figure 5). Phosphorylation at these residues by GSK3\u03b2 enhances HIF-1\u03b1 degradation in a pVHL-independent manner, resulting in suppression of the HIF-1 activity [12,13].|Phosphorylation at these residues by GSK3beta enhances HIF-1alpha degradation in a pVHL independent manner, resulting in suppression of the HIF-1 activity , ]. 0.332 SIGNOR-278294 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXRA protein P19793 UNIPROT up-regulates activity chemical activation 9606 18321241 YES miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). 0.8 SIGNOR-259237 ARF6 protein P62330 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 NO lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface 0.7 SIGNOR-272153 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser183 PPTQKPPsPPMSGRG 9606 21419341 YES lperfetto Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex. 0.443 SIGNOR-172869 CSNK1A1 protein P48729 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1244 ASLDAADsGRGSWTS 9606 BTO:0002181 24290981 YES miannu Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. 0.2 SIGNOR-276605 (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity precursor of 9606 1978672 YES miannu Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). 0.8 SIGNOR-269110 ETFA protein P13804 UNIPROT ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 YES miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. 0.946 SIGNOR-269453 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser20 ADDSLSNsEEEPDRQ 9606 21559372 YES llicata Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist. 0.2 SIGNOR-173672 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 22505454 YES gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. 0.363 SIGNOR-196961 MLLT11 protein Q13015 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001939; BTO:0002768; BTO:0000815 26079538 NO irozzo In addition, enhanced AF1q expression promotes breast cancer cell proliferation, migration, mammosphere formation, and chemo-resistance. 0.7 SIGNOR-259107 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity binding 9606 23431053 YES miannu The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. 0.2 SIGNOR-265823 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser161 SSLPVPNsAYGGPDF 9606 25726523 YES miannu These observations suggest that EMT induced by GATA1 is dependent on the phosphorylation of GATA1 by PAK5 at both Ser161 and Ser 187 sites. 0.2 SIGNOR-278296 FASN protein P49327 UNIPROT WNT1 protein P04628 UNIPROT up-regulates activity 9606 18838960 NO lperfetto Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer 0.25 SIGNOR-242881 CDK1 protein P06493 UNIPROT NDUFS2 protein O75306 UNIPROT up-regulates activity phosphorylation Ser364 KVDDAKVsPPKRAEM 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275592 YY1 protein P25490 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates quantity by expression 17158804 YES YY1 REPO domain is necessary and sufficient for PcG transcriptional repression, Polycomb recruitment to DNA, and methylation of histone H3 on lysine 27 0.602 SIGNOR-253595 SRC protein P12931 UNIPROT SRCIN1 protein Q9C0H9 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 8647432 YES miannu Phosphorylation of multiple tyrosine-containing motifs found on Sin correlated with c-Crk and cellular phosphoprotein binding to Sin as well as increased c-Src activity. These data suggest that (1) SH2 and SH3 ligand sites on Sin cooperatively activate the signaling potential of c-Src, (2) Sin acts as both an activator and a substrate for c-Src, and (3) phosphorylated Sin may serve as a signaling effector molecule for Src by binding to multiple cellular proteins. 0.497 SIGNOR-263196 ADRA2B protein P18089 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.311 SIGNOR-256993 TP73 protein O15350 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17700533 NO miannu Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. 0.371 SIGNOR-255468 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser31 LKLGSGPsIKALDGR 9606 BTO:0000567 24781523 YES miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase 0.295 SIGNOR-276379 LEF1 protein Q9UJU2 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 NO gcesareni Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation 0.633 SIGNOR-245351 lurasidone chemical CHEBI:70735 ChEBI HTR7 protein P34969 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 20404009 YES Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. 0.8 SIGNOR-257840 TGFBR1 protein P36897 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0001660 9435577 YES lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. 0.348 SIGNOR-252730 JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12370803 NO irozzo In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells.  0.451 SIGNOR-255811 COL4A2 protein P08572 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 YES lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. 0.488 SIGNOR-272348 CDK1 protein P06493 UNIPROT NDUFV3 protein P56181 UNIPROT up-regulates activity phosphorylation Ser105 QPSSGREsPRH 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275593 ZWILCH protein Q9H900 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 BTO:0000567 20462495 YES lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. 0.749 SIGNOR-265014 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser289 PPQDQESsPIENDSS 9606 BTO:0000776 7678037 YES llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells. 0.307 SIGNOR-251012 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser291 CDVKTDDsVVPCFMK -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276199 SUB1 protein P53999 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR up-regulates activity binding 9606 20080105 YES 1 miannu We have found that PC4 directly interacts with the REST–CoREST complex. we found that there was a substantial reduction of REST–CoREST complex on the SCN2 promoter upon PC4 silencing in 293T cells. 0.32 SIGNOR-239325 PRKN protein O60260 UNIPROT APP protein P05067 UNIPROT down-regulates quantity ubiquitination 9606 32344772 YES miannu Similarly, in transgenic AD mice models, lentiviral parkin expression ubiquitinates Abeta to reduce its intracellular levels while preventing plaque deposition, and this is associated with induction of beclin dependent autophagy .|Thus, parkin reduces Abeta levels by enhancing both UPS- and autophagy dependent clearance of Abeta. 0.2 SIGNOR-278709 CSNK2A1 protein P68400 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser559 PTSRGGAsVEETDQS 9606 BTO:0000150;BTO:0000567 20043841 YES lperfetto Additionally protein kinase ck2 was identified as a kinase that phosphorylated eralpha at s282 and s559 s282 and s559 represent the second and third sites of er_ regulation by ck2. Remarkably, mutation of s282 or s559 to alanine resulted in near opposite functional effects on er_ as compared to mutation of s167 to alanine. Er_ ligand independent transcriptional activity was markedly enhanced upon mutation of s282 and s559 to alanine 0.246 SIGNOR-162657 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC17 protein P23527 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271982 6 protein P59634 UNIPROT RAE1 protein P78406 UNIPROT down-regulates activity binding 9606 32353859 YES miannu Orf6 of SARS-CoV antagonizes host interferon signaling by perturbing nuclear transport, and the NUP98-RAE1 interaction with Orf6 may perform the same function for SARS-CoV-2. 0.2 SIGNOR-260975 LY2603618 chemical CID:11955855 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates activity chemical inhibition 9606 33261142 YES miannu Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. 0.8 SIGNOR-262538 CSNK2A1 protein P68400 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Thr161 LGLPEEEtELDNLTE -1 9407077 YES llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. 0.472 SIGNOR-250931 RUNX2 protein Q13950 UNIPROT SNAI3 protein Q3KNW1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 NO miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. 0.2 SIGNOR-255083 CDC5L protein Q99459 UNIPROT HNRNPM protein P52272 UNIPROT up-regulates activity binding 9606 BTO:0000567 20467437 YES 1 miannu hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay. 0.634 SIGNOR-239410 maraviroc chemical CHEBI:63608 ChEBI CCL4L1 protein Q8NHW4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194009 ACSS2 protein Q9NR19 UNIPROT CTSA protein P10619 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants 0.2 SIGNOR-276550 ARFGEF1 protein Q9Y6D6 UNIPROT ARF3 protein P61204 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000599 14973189 YES lperfetto Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) is an approximately 200-kDa brefeldin A-inhibited guanine nucleotide-exchange protein that preferentially activates ADP-ribosylation factor 1 (ARF1) and ARF3.  0.366 SIGNOR-272148 SEMA3B protein Q13214 UNIPROT NRP2 protein O60462 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 YES miannu Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction. 0.591 SIGNOR-261816 MARCHF9 protein Q86YJ5 UNIPROT PTPRF protein P10586 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271536 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PCYT1A protein P49585 UNIPROT down-regulates phosphorylation 9606 BTO:0000763 15788406 YES inferred from 70% family members gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. 0.2 SIGNOR-270151 PTPRF protein P10586 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 15896785 YES 10226025:Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. acerquone Knock-down of lar by the l3 sirna probe markedly inhibited the insulin-stimulated increase in the phosphorylation of protein kinase b (pkb, also called akt) on serine 473 by >90% 0.342 SIGNOR-137246 PIK3CA protein P42336 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 21779497 NO gcesareni Pi3k can also activate rac, and this activation is involved in cytoskeleton reorganization. 0.569 SIGNOR-175238 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 YES lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. 0.79 SIGNOR-252359 FBXW8 protein Q8N3Y1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0001109 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1. We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8. 0.761 SIGNOR-271632 BCL2 protein P10415 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates 9606 14585074 NO amattioni Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi 0.251 SIGNOR-89189 ATM protein Q13315 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 YES lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively 0.403 SIGNOR-180755 FGF12 protein P61328 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.58 SIGNOR-253416 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser742 GEKSFRRsVVGTPAY -1 10867018 YES lperfetto The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot 0.2 SIGNOR-249047 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273055 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR2 protein Q9GZQ4 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257592 histidine smallmolecule CHEBI:27570 ChEBI His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates quantity precursor of 9606 10430027 YES miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 0.8 SIGNOR-270492 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr161 DDYHNPGyLVVLPDS 9606 11368773 YES lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. 0.769 SIGNOR-247022 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI HNF4A protein P41235 UNIPROT down-regulates quantity by repression 9606 9792724 NO miannu Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment. 0.8 SIGNOR-254445 CSNK2A1 protein P68400 UNIPROT CBX1 protein P83916 UNIPROT down-regulates phosphorylation Thr51 GFSDEDNtWEPEENL 9606 19657222 YES lperfetto Two recent papers suggest that hp1 recruitment to damage sites, rather than its rapid mobilization, is the predominant behaviour exhibited by this protein. Our findings reconcile recent findings in a new model, wherein rapid hp1beta mobilization from dsbs is mediated by its phosphorylation on thr51 by ck2 0.304 SIGNOR-187450 Hemoglobin complex SIGNOR-C209 SIGNOR hb:hp complex SIGNOR-C149 SIGNOR form complex binding 9606 11854029 YES miannu CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis. 0.733 SIGNOR-255284 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr440 GAYREHPyGRY 9606 BTO:0000567 16179349 YES lperfetto We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. |Tyrosine 440 was identified as a principal modulator of Sam68 localization and this site was phosphorylated in response to EGF treatment in human breast tumor cell lines. 0.747 SIGNOR-249294 SCAP protein Q12770 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity relocalization 10029 BTO:0000246 12202038 YES SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function 0.694 SIGNOR-267501 PKA proteinfamily SIGNOR-PF17 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser951 GFHPRRSsQGATQMP 19018281 YES miannu  Our results demonstrate that PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650.  0.2 SIGNOR-276175 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 8845374 YES lperfetto The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site 0.624 SIGNOR-44239 MELK protein Q14680 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser219 HALAEWAsRREAFAQ 9606 BTO:0001938 12400006 YES In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323[Ä] Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase 0.534 SIGNOR-255655 OPRM1 protein P35372 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.511 SIGNOR-256854 iodide smallmolecule CHEBI:16382 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 23349248 YES miannu After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). 0.8 SIGNOR-259913 SGI-1776 chemical CID:24795070 PUBCHEM PIM1 protein P11309 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206859 CDC27 protein P30260 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.892 SIGNOR-252003 TYK2 protein P29597 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates phosphorylation Tyr138 SPTLVIAyLMMRQKM 9606 17785772 YES lperfetto Phosphorylation of vhr at tyr(138) was required for its phosphatase activity toward stat5. In addition, the src homology 2 domain of stat5 was required for the effective dephosphorylation of stat5 by vhr. The tyrosine kinase tyk2, which mediates the phosphorylation of stat5, was also responsible for the phosphorylation of vhr at tyr(138). 0.265 SIGNOR-157655 bremazocine chemical CHEBI:3171 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258777 EED protein O75530 UNIPROT SUZ12/EED complex SIGNOR-C76 SIGNOR form complex binding 9606 16712789 YES miannu Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2. 0.944 SIGNOR-146755 SRC protein P12931 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity phosphorylation Tyr246 PDHKNGHyIIPQMAD 9534 BTO:0000298 24699139 YES miannu Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin. 0.543 SIGNOR-276626 P-TEFb complex SIGNOR-C238 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 20153263 YES miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. 0.787 SIGNOR-239237 TCF3 protein P15923 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23684607 NO miannu The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins. 0.314 SIGNOR-255385 CSNK1D protein P48730 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization phosphorylation Ser31 PGAMLGPsPGPSPGS 9606 BTO:0001225 30177679 YES miannu  We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.  0.2 SIGNOR-277408 CD40 protein P25942 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 9606 18635759 YES lperfetto Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3. 0.918 SIGNOR-250560 D-thyroxine smallmolecule CHEBI:30659 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 9606 BTO:0003736 6777394 YES inferred from 70% of family members miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. 0.8 SIGNOR-269878 cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI calciol smallmolecule CHEBI:28940 ChEBI up-regulates quantity precursor of 9606 BTO:0001253 30080183 YES lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin 0.8 SIGNOR-270561 TAGLN2 protein P37802 UNIPROT ACTB protein P60709 UNIPROT down-regulates activity binding 21577206 YES lperfetto Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation. 0.413 SIGNOR-265104 MPG protein P29372 UNIPROT STK36 protein Q9NRP7 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 25278022 YES miannu  Here, we show that MID1 catalyzes the ubiquitination and proteasomal cleavage of the GLI3 regulator Fu. 0.2 SIGNOR-272466 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) 0.8 SIGNOR-257876 SYK protein P43405 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates activity phosphorylation Tyr138 SPTLVIAyLMMRQKM 9534 BTO:0001538 12447358 YES miannu ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).  0.364 SIGNOR-275999 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275762 CDK5 protein Q00535 UNIPROT NES protein P48681 UNIPROT unknown phosphorylation Thr1299 GETLPDStPLGFYLR 10090 12832492 YES llicata We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts. 0.548 SIGNOR-250669 DUSP4 protein Q13115 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Thr202 HDHTGFLtEYVATRW 10116 7535768 YES Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK 0.708 SIGNOR-248715 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Ser12 YSSSQRVsSYRRTFG -1 12686604 YES lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro. 0.545 SIGNOR-100107 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). 0.91 SIGNOR-252820 MTMR4 protein Q9NYA4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates dephosphorylation 9606 20061380 YES gcesareni Here we demonstrate that myotubularin-related protein 4 (mtmr4), a fyve domain-containing dual-specificity protein phosphatase (dsp), attenuates tgfbeta signaling by reducing the phosphorylation level of r-smads in early endosomes. 0.529 SIGNOR-163031 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 15024053 YES llicata Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta) 0.27 SIGNOR-123449 YBX1 protein P67809 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17072343 NO miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 0.269 SIGNOR-255611 Calcineurin complex SIGNOR-C155 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression 10090 18177723 NO lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy 0.253 SIGNOR-252340 ZDHHC2 protein Q9UIJ5 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity palmitoylation Cys5 cIVTTKKY 9606 23836932 YES Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation. 0.38 SIGNOR-261290 PIAS1 protein O75925 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity sumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 YES gcesareni Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. 0.379 SIGNOR-252737 MAP3K11 protein Q16584 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Thr277 LAREWHKtTQMSAAG 9606 11053428 YES gcesareni These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites. 0.2 SIGNOR-83411 EIF3H protein O15372 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.918 SIGNOR-266393 DLGAP1 protein O14490 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.826 SIGNOR-264587 MARCHF9 protein Q86YJ5 UNIPROT PLXNC1 protein O60486 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271532 CYP27B1 protein O15528 UNIPROT calcidiol smallmolecule CHEBI:17933 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671 12050193 YES lperfetto The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. 0.8 SIGNOR-270560 PINK1 protein Q9BXM7 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser179 RRYVYYYsYLLKNHL 9606 BTO:0000948 37940999 YES miannu PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import.  0.47 SIGNOR-277915 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR1 protein Q9HB89 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257591 PRKCA protein P17252 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 10197446 YES llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. 0.44 SIGNOR-66670 Exosome_Complex complex SIGNOR-C255 SIGNOR XBP1 protein P17861-2 UNIPROT up-regulates quantity relocalization 9606 30319453 YES miannu When the ER stress-induced unfolded protein response (UPR) is activated, the X-box binding protein 1 (XBP1) mRNA is spliced by inositol-requiring enzyme-1α (IRE1α) to produce the spliced form of XBP1 (sXBP1). In the present study, we found that sXBP1 mRNA in the cell may be incorporated into the exosomes and was released extracellularly. Spliced form of XBP1 mRNA was incorporated into the exosomes of HEK293T cells, which overexpress IRE1α. We found that one of the ER stress signal-induced transcripts, sXBP1, was incorporated into the exosomes. Our results suggest that exosomes may play a vital role in the extracellular release of ER stress signals. 0.2 SIGNOR-260946 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.264 SIGNOR-276098 CERF complex SIGNOR-C340 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000227 15640247 NO miannu CERF is an ATP-dependent chromatin remodeler. CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. 0.7 SIGNOR-263892 TRIM21 protein P19474 UNIPROT TRIM5 protein Q9C035 UNIPROT up-regulates quantity monoubiquitination 9606 BTO:0000567 18312418 YES miannu Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B. Thus, the ubiquitination of TRIM5alpha is catalyzed by itself and Ro52. Unexpectedly, although TRIM5alpha is ubiquitinated, our results have revealed that the proteasome inhibitors MG115 and MG132 do not stabilize it in HeLa cells, suggesting that the ubiquitination of TRIM5alpha does not lead to proteasomal degradation. Importantly, TRIM5alpha is clearly conjugated by a single ubiquitin molecule (monoubiquitination). Our monoubiquitin-fusion assay suggests that monoubiquitination is a signal for TRIM5alpha to translocate from cytoplasmic bodies to the cytoplasm. 0.345 SIGNOR-271672 SREBF1 protein P36956 UNIPROT ACLY protein P53396 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11994399 NO Luana SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16:0]). 0.461 SIGNOR-267956 N protein P59595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 18055455 YES miannu In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis. 0.2 SIGNOR-260434 ZNF420 protein Q8TAQ5 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity binding 9606 BTO:0001109 19377469 YES done miannu These results indicate that Apak is a genuine substrate of ATM kinase. Apak phosphorylation on Ser 68 is critical for p53-mediated apoptosis. in response to DNA damage, ATM is rapidly activated by autophosphorylation and mediates p53 activation through disruption of the Apak–p53 complex by phosphorylating Apak on Ser 68. 0.2 SIGNOR-273512 SIRT7 protein Q9NRC8 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity deacetylation Lys37 APATGGVkKPHRYRP 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275876 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 YES gcesareni Analysis of the expression of the fzd receptors during somitogenesis demonstrated that fzd7 is expressed in the hypaxial region of the somite, suggesting an interaction with wnt7a. 0.677 SIGNOR-198919 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation 9606 23616010 YES lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. 0.2 SIGNOR-233520 SMAD7 protein O15105 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR form complex binding 9606 23213415 YES gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes 0.453 SIGNOR-199970 ARID5B protein Q14865 UNIPROT TAL1 protein P17542 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 NO miannu ARID5B positively regulates the expression of TAL1 and its regulatory partners. we also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). 0.265 SIGNOR-256157 UBE2D3 protein P61077 UNIPROT MPG protein P29372 UNIPROT up-regulates activity binding -1 25207814 YES miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E) 0.2 SIGNOR-271928 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT up-regulates phosphorylation Ser1450 LQTSKYFsPPPPARS 9606 BTO:0000938 BTO:0000142 22220831 YES gcesareni Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __ 0.498 SIGNOR-195329 ATP6V1D protein Q9Y5K8 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.8 SIGNOR-277756 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 17350953 YES gcesareni Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian target of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin. 0.8 SIGNOR-153608 GLI2 protein P10070 UNIPROT FOXF1 protein Q12946 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005738 23034409 NO miannu we propose that chromatin looping between SDR and FOXF1 allows GLI2 to increase FOXF1 activity specifically in lung endothelium. 0.394 SIGNOR-254216 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF5 protein Q9NX47 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271247 RPS6KB1 protein P23443 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation Ser84 LTKKRALsISPLSDA 9606 22439934 YES gcesareni In this study, we found that an activated mtor/s6k1 pathway promotes gli1 transcriptional activity and oncogenic function through s6k1-mediated gli1 phosphorylation at ser84, which releases gli1 from its endogenous inhibitor, sufu. 0.524 SIGNOR-196756 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates activity phosphorylation Thr80 MARKMKDtDSEEEIR -1 26675311 YES miannu Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. 0.423 SIGNOR-266356 AKT proteinfamily SIGNOR-PF24 SIGNOR ACOT4 protein Q8N9L9 UNIPROT up-regulates quantity by stabilization phosphorylation Ser392 GGEPRAHsKAQEDAW 9606 BTO:0001861 33148467 YES lperfetto HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. |AKT phosphorylates ACOT4 at S392 and promotes ACOT4 stability 0.2 SIGNOR-271821 regorafenib chemical CHEBI:68647 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259205 GW 791343 HYDROCHLORIDE chemical CID:9848159 PUBCHEM P2RX7 protein Q99572 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193116 hsa-miR-23a-5p mirna URS00005070A9_9606 RNAcentral CXCL8 protein P10145 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005250 26314966 YES Parnian Our previous study has confirmed that IL-8 is the direct target of miR-23a in NPC cells.| our results demonstrated that upregulation of miR-23a increased NPC cell radiosensitivity through targeting IL-8. 0.4 SIGNOR-278013 CASP3 protein P42574 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 NO miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice 0.7 SIGNOR-255336 DDX5 protein P17844 UNIPROT RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103 17011493 YES lperfetto We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod. 0.426 SIGNOR-149964 NEXMIF protein Q5QGS0 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000938 27822498 NO miannu Xpn regulates N-cadherin and β1-integrin expression at the transcriptional level in PC12 cells 0.2 SIGNOR-269661 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR WNK4 protein Q96J92 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23453970 YES miannu Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein. 0.389 SIGNOR-272107 EGFR protein P00533 UNIPROT ABCA1 protein O95477 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2054 GGNKRKLsTAMALIG 9606 BTO:0000567 12196520 YES lperfetto We further provide in vitro evidence that epidermal growth factor receptor (EGFR)-mediated phosphorylation regulated ABCA1 ubiquitination |The EGFR selective inhibitor PD168393 blocked the EGFR-ABCA1 interaction and abolished ABCA1Ser2054 phosphorylation| 0.295 SIGNOR-264419 PTK2 protein Q05397 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 9416004 YES gcesareni Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors. 0.554 SIGNOR-53979 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 YES lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. 0.269 SIGNOR-198122 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser288 QKSGQDVsQAQRQIK 9606 BTO:0000130 17217339 YES lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation. 0.38 SIGNOR-152011 ropinirole chemical CHEBI:8888 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 9057850 YES miannu Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively) 0.8 SIGNOR-258600 MAGED1 protein Q9Y5V3 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 9606 BTO:0001760 20646279 NO gcesareni By comparing in vitro differentiation of myoblasts derived from wild-type or maged1 knockout mice, we observed that maged1 deficiency results in reduced levels of p21cip1/waf1, defective cell cycle exit and impaired myotube maturation. 0.2 SIGNOR-166893 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248756 F2R protein P25116 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.446 SIGNOR-257127 DNA_damage stimulus SIGNOR-ST1 SIGNOR TAOK1 protein Q7L7X3 UNIPROT up-regulates 9606 17396146 NO lperfetto These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM. 0.7 SIGNOR-226599 Skp1-Pam E3 complex SIGNOR-C537 SIGNOR SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.257 SIGNOR-272189 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 22021368 NO apalma Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB. 0.7 SIGNOR-255693 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT down-regulates activity phosphorylation Ser522 PAGSARGsPTRPNPP 10116 BTO:0000938 16611631 YES lperfetto Primary rat cortical neurons were treated with purvalanol, a more potent inhibitor of cdk5 and dyrk2 than roscovitine (25). Phosphorylation was monitored using antibodies that specifically recognize crmp2 when phosphorylated at thr514/thr509, or crmp4 when phosphorylated at thr509. Loss of phosphorylation of ser522 will prevent subsequent phosphorylation of ser518/thr514/thr509 by gsk3. Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.473 SIGNOR-146007 AMPK complex SIGNOR-C15 SIGNOR PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser505 GSVKRVTsGPSLGSL 9606 BTO:0000887;BTO:0001103 20231899 YES lperfetto Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp. 0.242 SIGNOR-216643 AHSA1 protein O95433 UNIPROT HSP90AB1 protein P08238 UNIPROT up-regulates activity binding 9606 16696853 YES miannu The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity 0.663 SIGNOR-252212 Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI vitamin K epoxide smallmolecule CHEBI:28371 ChEBI up-regulates quantity precursor of 9606 31226734 YES lperfetto GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. 0.8 SIGNOR-265909 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity precursor of 9606 9914248 YES miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. 0.8 SIGNOR-267292 ELF3 protein P78545 UNIPROT SPRR2A protein P35326 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 10773884 NO Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter. 0.398 SIGNOR-254292 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu59 RKGNLEReCVEETCS -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263678 MC2R protein Q01718 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity 9606 BTO:0000047 20371771 NO lperfetto Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). 0.8 SIGNOR-268621 GPI protein P06744 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P. 0.8 SIGNOR-266462 EFTUD2 protein Q15029 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.797 SIGNOR-270639 MLL1 complex complex SIGNOR-C89 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.2 SIGNOR-268803 LMAN2 protein Q12907 UNIPROT SERPINA1 protein P01009 UNIPROT up-regulates quantity by stabilization binding 9606 20477988 YES miannu Identification of α1‐antitrypsin as interaction partner of VIP36. The complex formed by VIP36 and alpha1-AT in the Golgi recycled back to the ER. The combined data are most consistent with a function of VIP36 in post-ER quality control of alpha1-AT. We propose that VIP36 acts in post‐ER quality control in the Golgi by binding incompletely folded α1‐AT, which inadvertently escaped ER quality control, and by recycling it back to the ER for an additional round of quality control. 0.432 SIGNOR-261356 SNAI1 protein O95863 UNIPROT PLAU protein P00749 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19055748 NO lperfetto We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. 0.32 SIGNOR-252263 pimozide chemical CHEBI:8212 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258718 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser139 RRGLLYDsDEEDEER 9606 BTO:0000567 16899510 YES gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. 0.962 SIGNOR-148709 APC-c complex SIGNOR-C150 SIGNOR DTYMK protein P23919 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16103219 YES miannu We demonstrate that TMPK is recognized and degraded by APC/C-Cdc20/Cdh1-mediated pathways from mitosis to the early G1 phase, whereas TK1 is targeted for degradation by APC/C-Cdh1 after mitotic exit.  0.287 SIGNOR-272653 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates BTO:0001103 15501225 NO svumbaca Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell. 0.7 SIGNOR-255366 YAP1 protein P46937 UNIPROT TEAD1 protein P28347 UNIPROT up-regulates binding 9606 23431053 YES Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4 gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. 0.905 SIGNOR-201465 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.59 SIGNOR-270895 MIB1 protein Q86YT6 UNIPROT CEP131 protein Q9UPN4 UNIPROT down-regulates ubiquitination 9606 BTO:0001938 24121310 YES miannu  We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation. Whereas these proteins are degraded prior to the ciliation process, MIB1 appears to maintain its targets in a latent state through inhibitory ubiquitylation that is reversed during ciliogenesis and in response to cell stress.The precise mechanism by which MIB1 inhibits primary cilium formation through ubiquitylation of ciliogenesis-promoting target proteins such as AZI1 and PCM1 remains to be determined. 0.43 SIGNOR-272876 MTA1/DJ1 complex complex SIGNOR-C123 SIGNOR TH protein P07101 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000793 21368136 NO 1 miannu we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. 0.454 SIGNOR-239773 RAB5A protein P20339 UNIPROT INPP5B protein P32019 UNIPROT up-regulates activity binding 9606 33722976 YES miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis 0.448 SIGNOR-277770 INPP5B protein P32019 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI down-regulates quantity chemical modification 9606 33722976 YES miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis 0.8 SIGNOR-277772 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.708 SIGNOR-252879 WARS1 protein P23381 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 0.8 SIGNOR-270513 MC4R protein P32245 UNIPROT Food intake phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0000614 33094623 NO miannu Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. Adipose tissue derived hormone leptin induces negative energy balance by stimulating α-MSH and melanocortin-4 receptor (MC4R) (Friedman 1997, Kask et al. 1998). Increased melanocortin signaling in hypotalamus leads not only to decreased food intake but also increases sympathetic nervous system outflow to skeletal muscle, energy expenditure and physical activity 0.7 SIGNOR-263504 aloxistatin chemical CHEBI:101381 ChEBI CTSB protein P07858 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 32142651 YES miannu Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. 0.8 SIGNOR-260281 Caspase 3 complex complex SIGNOR-C221 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity cleavage -1 10579725 YES lperfetto P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro 0.641 SIGNOR-256446 EEF1D protein P29692 UNIPROT EEF1B complex complex SIGNOR-C460 SIGNOR form complex binding 9606 23699257 YES lperfetto An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively) 0.823 SIGNOR-269392 STK24 protein Q9Y6E0 UNIPROT STK24 protein Q9Y6E0 UNIPROT up-regulates phosphorylation Thr190 DTQIKRNtFVGTPFW 9606 BTO:0000671 17046825 YES gcesareni Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (mst3) involves paxillin and protein-tyrosine phosphatase-pest. 0.2 SIGNOR-150131 GRK6 protein P43250 UNIPROT SLC9A3R1 protein O14745 UNIPROT down-regulates activity phosphorylation Ser290 PALVRSAsSDTSEEL 9606 10446210 YES GRK6A phosphorylates NHERF on Ser289, the primary site of constitutive phosphorylation of NHERF in HEK-293 cells. The interaction of NHERF and NHE3 is mediated by the region of NHERF encompassing the second PDZ domain and the tail (25), and it is therefore reasonable that phosphorylation of the serine-rich stretch in the center of this region (including Ser289) might affect the physical interaction of NHERF with NHE3. 0.406 SIGNOR-251214 MAP4 protein P27816 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 10791892 NO miannu We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region. Mutation of Ser787 to Glu strikingly reduced the MAP4's MT-polymerization activity, while Glu-mutation at Ser696 did not. These results suggest that Ser787 could be the critical phosphorylation site causing MTs to be dynamic at mitosis. 0.7 SIGNOR-277460 CRP protein P02741 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity post transcriptional regulation 9606 16917108 NO Regulation miannu CRP significantly decreased IL-10 mRNA stability 0.466 SIGNOR-251825 CDK1 protein P06493 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr245 GFGTSPLtPSARISA -1 12556484 YES done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites 0.659 SIGNOR-274072 MAPK14 protein Q16539 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12181443 NO lperfetto We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek. 0.635 SIGNOR-244465 NOTCH1 protein P46531 UNIPROT PAX7 protein P23759 UNIPROT up-regulates quantity by expression 9606 BTO:0001103;BTO:0002314 22493066 NO lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells 0.391 SIGNOR-219374 ASH2L protein Q9UBL3 UNIPROT GATA3 protein P23771 UNIPROT up-regulates binding 9606 BTO:0000150 25258321 YES miannu We identifiedgata3as the binding protein of ash2l. Ash2l was shown to potentiate the transcriptional activity ofgata3. 0.25 SIGNOR-205312 GATA3 protein P23771 UNIPROT GLS2 protein Q9UI32 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 31577957 YES Luana Thus, GATA3 contributes to the elevated expression of GLS2 in luminal-subtype breast cancers. 0.332 SIGNOR-268034 ESRRA protein P11474 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000154 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.35 SIGNOR-253794 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser196 RKEDRSAsSGAEGDV -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.321 SIGNOR-273962 B4GALT1 protein P15291 UNIPROT D-glucopyranose smallmolecule CHEBI:4167 ChEBI down-regulates quantity chemical modification 9606 16157350 YES miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 0.8 SIGNOR-268468 SMO protein Q99835 UNIPROT MAG protein P20916 UNIPROT up-regulates quantity transcriptional regulation 27639396 NO SimoneGraziosi We found that inactivation of Shh signaling caused a dose-dependent decrease in myelin basic protein (MBP) and myelin associated glycoprotein (MAG) in differentiating OLGs. 0.2 SIGNOR-269227 perifosine chemical CHEBI:67272 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 22090271 YES Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation gcesareni Perifosine is an alkylphospholipid that targets the pleckstrin homology domain of akt and blocks its membrane translocation, hence preventing akt phosphorylation and activation 0.8 SIGNOR-252630 IQSEC2 protein Q5JU85 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 10090 BTO:0000142 18164504 YES miannu Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6. 0.473 SIGNOR-264907 RIN1 protein Q13671 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation 9606 BTO:0000149 15886098 YES CrkL forms a constitutive complex with Abl, thus explaining the strong preference of Bcr-Abl for CrkL. gcesareni Rin1 binds to the abl sh3 and sh2 domains, and these inetractions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl 0.615 SIGNOR-136961 AURKA protein O14965 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser405 FDDTGKSsLGDMFSP 9606 BTO:0001938 31028180 YES lperfetto Microtubule nucleation during central spindle assembly requires NEDD1 phosphorylation on serine 405 by Aurora A| In the absence of Aurora A, the HURP (also known as DLGAP5) and NEDD1 proteins that are involved in nucleation of microtubules fail to concentrate in the midzone. 0.556 SIGNOR-272965 H2AC4 protein P04908 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 YES miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. 0.2 SIGNOR-263874 CYP11B2 protein P19099 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 33117906 YES lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone 0.8 SIGNOR-268681 TPX2 protein Q9ULW0 UNIPROT CLASP1 protein Q7Z460 UNIPROT up-regulates activity binding 9606 BTO:0000567 phosphorylation:Ser121;Ser125 PAQPQRRsLRLSAQK;QRRSLRLsAQKDLEQ 26240182 YES lperfetto Phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells 0.497 SIGNOR-265090 INO80C protein Q6PI98 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.652 SIGNOR-270851 CHRM3 protein P20309 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.577 SIGNOR-257018 SNTB1 protein Q13884 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates binding 10090 BTO:0002314 BTO:0001103 29681515 YES apalma Basal localization of the p38g/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through b1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38g/b1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation 0.369 SIGNOR-255901 MYC protein P01106 UNIPROT ENO1 protein P06733 UNIPROT up-regulates quantity transcriptional regulation 10116 10823814 YES C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. 0.412 SIGNOR-259989 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Thr1077 RGKSQQLtVSAAQKP -1 15358237 YES miannu Certain phosphopeptides were detected only in samples phosphorylated in vitro under conditions that favor CaMKII activity (Mg2+-ATP, Ca2+, calmodulin, and peptide inhibitors of PKA and PKC). In samples phosphorylated in vitro in the presence of Ca2+/calmodulin, we also detected the peptide (R)GKS*QQLT*VSAAQKPR with phosphorylated residues corresponding to S-1058 and T-1062 of synaptic ras GTPase activating protein (SynGAP). 0.43 SIGNOR-262691 AVPR1B protein P47901 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257063 SRC protein P12931 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity phosphorylation Tyr64 DTAGQEEySAMRDQY 9606 34725361 YES miannu Src phosphorylation promotes the intrinsic exchange rate of KRAS Q61H.|Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells. 0.657 SIGNOR-278991 SATB1 protein Q01826 UNIPROT SPARC protein P09486 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 17343824 NO miannu In this study, a SATB1 eukaryotic expression plasmid was transfected into the human erythroleukemia K562 cell line and individual clones that stably over-expressed the SATB1 protein were isolated. Microarray analysis revealed that hundreds of genes were either up- or down-regulated in the SATB1 over-expressing K562 cell lines. One of these was the extra-cellular matrix glycoprotein, SPARC (human secreted protein acidic and rich in cysteine). siRNA knock-down of SATB1 also reduced SPARC expression, which was consistent with elevated SPARC levels in the SATB1 over-expressing cell line. 0.2 SIGNOR-255128 NODAL protein Q96S42 UNIPROT MMP2 protein P08253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20383200 NO Regulation miannu Ectopic expression of Nodal or activation of Nodal signaling by addition of rNodal increased MMP-2 protein level and cell invasion. the expression level of Nodal correlates well with MMP-2 expression and cell invasion. 0.2 SIGNOR-251940 3a protein P59632 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity 9606 18632968 NO Luana Thus, caspase-9 activation and cytochrome c release in cells expressing the 3a protein indicated that this viral protein also activates the intrinsic pathway of apoptosis. 0.2 SIGNOR-260214 HIF1A protein Q16665 UNIPROT TM9SF4 protein Q92544 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001545 25961573 YES miannu Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion. 0.2 SIGNOR-266705 chloramphenicol chemical CHEBI:17698 ChEBI MT-CO1 protein P00395 UNIPROT down-regulates quantity chemical inhibition 9606 BTO:0002552 23148581 YES Monia Chloramphenicol treatment suppressed mitochondria translation of mtDNA-encoded cytochrome c oxidase subunit I (Cox I) in H1299 cell. 0.8 SIGNOR-261068 MAPK1 protein P28482 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity phosphorylation Thr212 VIEPLPVtPTRDVAT 10116 BTO:0001260 15542607 YES lperfetto We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal 0.403 SIGNOR-249432 JAK2 protein O60674 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation 0.706 SIGNOR-249493 PTPRA protein P18433 UNIPROT FYN protein P06241 UNIPROT up-regulates activity dephosphorylation Tyr531 FTATEPQyQPGENL 10090 BTO:0000255 9535845 YES In a coexpression system, PTPalpha effected a dose-dependent tyrosine dephosphorylation and activation of p59(fyn), where maximal dephosphorylation correlated with a 5-fold increase in kinase activity.|the increased p59fyn catalytic activity and SH2 availability for binding are consistent with a PTPα-mediated dephosphorylation of the C-terminal Tyr-531 of p59fyn. 0.657 SIGNOR-248435 PRKCB protein P05771 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates activity phosphorylation Ser415 QRKITRPsQRPKTPP -1 17911614 YES miannu Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. 0.2 SIGNOR-276079 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 22187936 YES gcesareni Rsk1/2 stabilize c-fos and increases its activity. 0.392 SIGNOR-191678 MAML1 protein Q92585 UNIPROT EP300 protein Q09472 UNIPROT up-regulates relocalization 9606 19304754 YES gcesareni We show that maml1 potentiates p300 autoacetylation and p300 transcriptional activation. Maml1 directly enhances p300 hat activity, and this coincides with the translocation of maml1, p300 and acetylated histones to nuclear bodies. 0.65 SIGNOR-184853 KPNA2 protein P52292 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity relocalization 9606 32979938 YES miannu The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F). 0.2 SIGNOR-262514 ROCK1 protein Q13464 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 10652353 YES lperfetto Rho-associated kinase rock activates lim-kinase 1 by phosphorylation at threonine 508 within the activation loop. 0.616 SIGNOR-74569 TGFB1 protein P01137 UNIPROT MYOCD protein Q8IZQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 21673106 NO gcesareni These results indicate that (i) tgf- and klf4 regulate myocd transcription positively and negatively, respectively. When __90% of smad4 was down-regulated myocd mrna induction by tgf- was abolished, suggesting that smad4 plays a critical role in transcriptional activation of the myocd gene 0.268 SIGNOR-174396 clonidine chemical CHEBI:46631 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258903 A6/b1 integrin complex SIGNOR-C164 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.378 SIGNOR-253282 MYC protein P01106 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 YES miannu Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The mRNA levels of IMPDH1 and IMPDH2, the rate-limiting enzyme in purine de novo synthesis, increased with MYC induction both in vitro and in vivo. 0.294 SIGNOR-267377 acadesine chemical CHEBI:28498 ChEBI AMPK complex SIGNOR-C15 SIGNOR up-regulates chemical activation 9606 16879084 YES lperfetto The activation of the ampk pathway by exendin-4 was induced by aicar, which was inhibited by compound c. 0.8 SIGNOR-217478 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120024 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 YES lperfetto We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation. 0.676 SIGNOR-252621 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation 0.2 SIGNOR-252351 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 10488065 YES gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13. 0.474 SIGNOR-70664 SMARCE1 protein Q969G3 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.823 SIGNOR-270602 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BGN protein P21810 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15536164 NO miannu Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. 0.2 SIGNOR-254797 ZMYND8 protein Q9ULU4 UNIPROT MMP1 protein P03956 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 YES lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported 0.2 SIGNOR-262042 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 14699166 YES llicata Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells. 0.528 SIGNOR-120492 CMA1 protein P23946 UNIPROT EDN3 protein P14138 UNIPROT up-regulates activity cleavage Tyr127 TPEQTVPyGLSNYRG 9606 BTO:0000830 9257865 YES miannu Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products. 0.375 SIGNOR-256355 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser831 SAEGSHTsGQSNGRD 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.328 SIGNOR-276513 SRC protein P12931 UNIPROT ENG protein P17813 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr614 TAALWYIySHTRSPS 9606 BTO:0002828 25070888 YES miannu We identified epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as Src-activators that induce endoglin turnover following (612)YIY(614) phosphorylation.  0.385 SIGNOR-276654 TAF1D protein Q9H5J8 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 YES lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. 0.812 SIGNOR-269563 Terfenadine chemical CHEBI:9453 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 19660947 YES Luana  hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7 0.8 SIGNOR-257825 LPAR1 protein Q92633 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.455 SIGNOR-257282 CSNK2A1 protein P68400 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates phosphorylation Ser121 YRIQEQEsSGEEDSD 9606 9405437 YES gcesareni Recombinant inh2 was phosphorylated by kinases in cytosols prepared from g1 and s phase cells. The amount of inh2 kinase attributed to casein kinase 2, based on inhibition by heparin, increased 2.6-fold from g1 to s phase 0.307 SIGNOR-53857 AGPAT5 protein Q9NUQ2 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 21173190 YES lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† 0.8 SIGNOR-267011 GSK3B protein P49841 UNIPROT ARNTL protein O00327 UNIPROT down-regulates phosphorylation Ser17 STISDFMsPGPTDLL 9606 20049328 YES lperfetto Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened. 0.382 SIGNOR-162786 quizartinib chemical CHEBI:90217 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258271 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22703233 YES lperfetto TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. 0.846 SIGNOR-249548 LATS1 protein O95835 UNIPROT VEPH1 protein Q14D04 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 NO In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r8 0.2 SIGNOR-177068 FOXO1 protein Q12778 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 20577053 NO gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. 0.579 SIGNOR-166352 PRKACA protein P17612 UNIPROT ACACA protein Q13085 UNIPROT down-regulates activity phosphorylation Ser1201 IPTLNRMsFSSNLNH -1 2900138 YES TC1 = Ser-2Ser(P)-Met-3Ser(P)-Gly-Leu; TC2 = Arg-Met-1Ser(P)-Phe- Cyclic-AMP-dependent protein kinase phosphorylates sites 1 and 2 exclusively, whereas the AMP-activated protein kinase phosphorylates sites 1 and 3, plus at least one other minor site.[…]The results suggest that phosphorylation of site 3 is primarily responsible for the large decrease in Vmax produced by the AMP-activated protein kinase, while phosphorylation of site 1 may be primarily responsible for the increase in A0.5 for citrate and more modest depression of Vmax produced by cyclic-AMP-dependent protein kinase and ACK2 0.2 SIGNOR-267714 Integrator complex complex SIGNOR-C265 SIGNOR FOSL1 protein P15407 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25675981 NO lperfetto The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes. 0.2 SIGNOR-261477 AKT1 protein P31749 UNIPROT TBC1D4 protein O60343 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 12637568 YES gcesareni Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt 0.763 SIGNOR-252594 TP53 protein P04637 UNIPROT PHB protein P35232 UNIPROT up-regulates activity binding 16918502 YES lperfetto Our previous studies have shown that prohibitin physically interacts with the marked-box domain of E2F family members and represses their transcriptional activity; in contrast, prohibitin could bind to and enhance the transcriptional activity of p53. 0.444 SIGNOR-268978 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 11502070 YES lperfetto Binding of tnf to the extracellular domain of tnfrsf1a leads to homotrimerization. 0.925 SIGNOR-109716 SIN3A protein Q96ST3 UNIPROT TERT protein O14746 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18505829 NO miannu We investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression. 0.306 SIGNOR-226363 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser954 QKSKKKKsAKRKLTP 9606 BTO:0000007 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h). 0.2 SIGNOR-264512 ING1 protein Q9UK53 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 15662138 NO miannu Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. 0.481 SIGNOR-254490 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A13 protein Q9NSD5 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207066 CPSF2 protein Q9P2I0 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 BTO:0000007 19224921 YES lperfetto The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30. 0.897 SIGNOR-268335 SDHC protein Q99643 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. 0.955 SIGNOR-266273 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 17217339 YES lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.These results strongly support the observation that irak-4 is a kinase for p47phox in vivo. We also detected the signature of phosphorylation at ser320 and ser345 0.38 SIGNOR-152019 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 BTO:0000848 15024089 YES gcesareni We show that the n-terminal kinase domain of rsk phosphorylates flna on ser(2152) in response to mitogens 0.2 SIGNOR-252790 MC4R protein P32245 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.52 SIGNOR-268707 PTPN14 protein Q15678 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates activity dephosphorylation 9606 32152405 YES miannu Finally, PTPN14 overexpression in B16F10 cells reduced the ability of CAV1 to induce metastasis in vivo.|Moreover, the CAV1 (Y14F) mutant protein was shown to co-immunoprecipitate with PTPN14 even in the absence of E-cadherin, and overexpression of PTPN14 reduced CAV1 phosphorylation on tyrosine 14, as well as suppressed CAV1 enhanced cell migration, invasion and Rac-1 activation in B16F10, metastatic colon [HT29 (US)] and breast cancer (MDA-MB-231) cell lines. 0.2 SIGNOR-277054 HECTD3 protein Q5T447 UNIPROT TRIOBP protein Q9H2D6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18194665 YES miannu Here, we identify a novel Tara-binding protein HECTD3, a putative member of HECT E3 ubiquitin ligases. HECTD3 directly binds Tara in vitro and forms a complex with Tara in vivo. Overexpression of HECTD3 enhances the ubiquitination of Tara in vivo and promotes the turnover of Tara, whereas depletion of HECTD3 by small interfering RNA decreases Tara degradation. 0.439 SIGNOR-271770 PRKACA protein P17612 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates activity phosphorylation Ser58 VVGARRSsWRVVSSI 9606 16376338 YES llicata Phosphorylation by pka leads to modulation of 14-3-3zeta dimerization and affect its interaction with partner proteins. Substitution of ser58 to ala completely abolished phosphorylation of 14-3-3zeta by pka. 0.565 SIGNOR-143373 etanercept chemical CHEBI:4875 ChEBI TNF protein P01375 UNIPROT down-regulates activity binding 9606 25455504 YES Etanercept is a recombinant human TNF receptor p75Fc fusion protein that binds with high affinity to the soluble and transmembrane forms of TNF, thereby acting as a decoy receptor for TNF and, prevents TNF-mediated inflammatory cellular responses by competitive inhibition 0.8 SIGNOR-272490 PRKCB protein P05771 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.29 SIGNOR-249253 CSNK2A1 protein P68400 UNIPROT ARNT protein P27540 UNIPROT down-regulates phosphorylation Ser77 DKERFARsDDEQSSA 9606 16129408 YES gcesareni Here, we show that arnt and alt arnt proteins are differentially phosphorylated by protein kinase ckii in vitro. Phosphorylation had an inhibitory effect on dna-binding to an e-box probe by alt arnt, but not arnt, homodimers. This inhibitory phosphorylation occurs through ser77. 0.34 SIGNOR-140034 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser423 LNSGDDVsEQDVPDL -1 12107178 YES llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. 0.415 SIGNOR-250994 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser700 FGEKRKNsILNPINS -1 1377674 YES lperfetto Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC. 0.507 SIGNOR-248850 AURKA protein O14965 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12234980 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis. 0.2 SIGNOR-118886 STK4 protein Q13043 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 18394876 YES gcesareni The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1 0.425 SIGNOR-178193 KIF14 protein Q15058 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272524 COL21A1 protein Q96P44 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 YES lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  0.2 SIGNOR-272341 MAP2K1 protein Q02750 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 12792650 YES lperfetto Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2 0.44 SIGNOR-249385 PTEN protein P60484 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 NO miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 0.393 SIGNOR-260054 PZP protein P20742 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity binding -1 9344465 YES lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.35 SIGNOR-261802 PSMC2 protein P35998 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.879 SIGNOR-263374 HP protein P00738 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity binding 9606 9315856 YES Regulation of binding miannu Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers. 0.738 SIGNOR-251816 ASXL2 protein Q76L83 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28516957 NO miannu Interestingly, this identified a number of genes known to promote leukemogenesis (either alone or in the context of AML1-ETO leukemia) as differentially expressed by ASXL2 loss. These include downregulation of TET2 as well as NOTCH2 with ASXL2 loss in human AML1-ETO-expressing cells, downregulation of which have been previously shown to functionally promote myeloid leukemogenesis when altered in expression 0.337 SIGNOR-260074 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RB protein P32927 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005248 8758906 YES irozzo We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine. 0.2 SIGNOR-255814 AURKB protein Q96GD4 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 10464286 YES gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-265321 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser240 SDQQLNQsMDTGSPA 9606 SIGNOR-C8 11027280 YES gcesareni Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgfbeta-dependent smad2-smad3 interactions. 0.548 SIGNOR-82970 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 19029990 NO lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. 0.538 SIGNOR-249498 APEX1 protein P27695 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto An essential role of BER has been documented by inactivating functions of proteins in the common steps of BER. Thus, the major AP-endonuclease in mammalian cells, APE1, is essential for survival, as shown using knockout mice (Friedberg and Meira 2006). APE1 (also called HAP1 and Apex) carries both an AP-endonuclease activity and a redox function required for activation of several transcription factors 0.7 SIGNOR-275721 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity dephosphorylation 9606 15780598 YES lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. 0.733 SIGNOR-133279 Sanglifehrin A chemical CID:5388925 PUBCHEM IMPDH2 protein P12268 UNIPROT down-regulates activity chemical inhibition 9606 28076787 YES Monia We show that the mammalian target of SFA is inosine-50 -monophosphate dehydrogenase 2 (IMPDH2); Biochemical characterization reveals that PPIA-SFA does not inhibit the catalytic activity of IMPDH2 but rather, it modulates cell growth via binding to the cystathionine-b-synthase (CBS) domain. 0.8 SIGNOR-261099 AKT1 protein P31749 UNIPROT BCL3 protein P20749 UNIPROT up-regulates quantity by stabilization phosphorylation Ser41 KRPLRAPsPEPAAPR -1 28689659 YES miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  0.495 SIGNOR-277358 PGK2 protein P07205 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. 0.8 SIGNOR-266506 RAP1A protein P62834 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 BTO:0002181 24290981 YES miannu Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis). 0.691 SIGNOR-276608 HTR2B protein P41595 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.265 SIGNOR-256886 CSNK2A1 protein P68400 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser81 TQDQQSLsDVEGAYS -1 7983041 YES llicata Although human PR contains 11 potential CKII consensus sequences, CKII in vitro phosphorylated purified PR-B only at Ser81 suggesting that this may be an authentic site for CKII in vivo. 0.352 SIGNOR-250926 TG101209 chemical CHEBI:90304 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207263 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT down-regulates activity 9606 BTO:0000801 10973958 NO lperfetto NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters. 0.712 SIGNOR-249557 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258232 RFXAP protein O00287 UNIPROT RFX complex complex SIGNOR-C104 SIGNOR form complex binding -1 10825209 YES miannu RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes 0.815 SIGNOR-221568 Endothelin-1 smallmolecule CHEBI:80240 ChEBI EDNRA protein P25101 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257482 Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates activity binding 9606 32201502 YES MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways 0.2 SIGNOR-260238 CDC25A protein P30304 UNIPROT RAF1 protein P04049 UNIPROT down-regulates dephosphorylation 9606 7744247 YES gcesareni Cdc25a can act on substrates other than cdks, since it dephosphorylates the homeodomain transcription factor cut and interacts with and dephosphorylates the proto-oncogene raf-1, resulting in a significant decrease in raf-1 kinase activity 0.395 SIGNOR-32548 STAT6 protein P42226 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20508200 NO lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. 0.256 SIGNOR-249538 ZNRF3 protein Q9ULT6 UNIPROT FZD8 protein Q9H461 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 YES Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. 0.537 SIGNOR-260111 ILF2 protein Q12905 UNIPROT NF90-NF45 complex SIGNOR-C443 SIGNOR form complex binding -1 18458058 YES miannu Nuclear factor 90 (NF90) and its C-terminally extended isoform, NF110, have been isolated as DNA- and RNA-binding proteins together with the less-studied protein NF45. These complexes have been implicated in gene regulation, but little is known about their cellular roles and whether they are redundant or functionally distinct. We show that heterodimeric core complexes, NF90-NF45 and NF110-NF45, exist within larger complexes that are more labile and contain multiple NF90/110 isoforms and additional proteins. This study identified NF45 as an unstable regulatory subunit of NF90-NF45 complexes and uncovered their critical role in normal cell division. Furthermore, the study revealed that NF90 is functionally distinct from NF110 and is more important for cell growth. 0.577 SIGNOR-268487 DMAP1 protein Q9NPF5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.777 SIGNOR-269298 MDM2 protein Q00987 UNIPROT PBXIP1 protein Q96AQ6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000093 24488098 YES miannu . Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1.  0.29 SIGNOR-272850 PPP2CA protein P67775 UNIPROT PRKCB protein P05771 UNIPROT down-regulates activity dephosphorylation Thr500 WDGVTTKtFCGTPDY 10116 8749392 YES Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. 0.445 SIGNOR-248620 GABRA4 protein P48169 UNIPROT GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.521 SIGNOR-263748 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR MLXIPL protein Q9NP71 UNIPROT down-regulates activity relocalization 10116 26984404 YES AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions 0.2 SIGNOR-255667 ACP1 protein P24666 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 10090 17353188 YES Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3 0.2 SIGNOR-248457 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 SIGNOR-C3 12747827 YES lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. 0.926 SIGNOR-101115 USP4 protein Q13107 UNIPROT BRAP protein Q7Z569 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 23105109 YES miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. 0.268 SIGNOR-272031 MYC protein P01106 UNIPROT HLA-G protein P17693 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 NO miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. 0.26 SIGNOR-254607 KLHL12 protein Q53G59 UNIPROT SEC31A protein O94979 UNIPROT up-regulates activity binding 9606 BTO:0000567 22358839 YES miannu By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division. 0.605 SIGNOR-272010 HIF3A protein Q9Y2N7 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000972 21479871 YES Luana None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2.  0.523 SIGNOR-261615 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser639 PDVPRLGsTFSLDTS 9606 BTO:0000782 11024037 YES lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  0.322 SIGNOR-249056 Ub:E2 complex SIGNOR-C497 SIGNOR RNF170 protein Q96K19 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271214 PPM1K protein Q8N3J5 UNIPROT BCKDHA protein P12694 UNIPROT up-regulates activity dephosphorylation Ser337 TYRIGHHsTSDDSSA 10090 19411760 YES BCKD is inhibited by phosphorylation of its E1alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates 0.783 SIGNOR-248758 PRKACA protein P17612 UNIPROT NF2 protein P35240 UNIPROT up-regulates phosphorylation Ser10 GAIASRMsFSSLKRK 9606 18071304 YES lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, 0.403 SIGNOR-159840 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.2 SIGNOR-183612 KDM5C protein P41229 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30921702 NO miannu KDM5C performs its oncogenic function by suppressing PTEN epigenetically. 0.336 SIGNOR-264312 ASXL3 protein Q9C0F0 UNIPROT THRB protein P10828 UNIPROT down-regulates activity binding 9606 BTO:0000972 25450400 YES miannu We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRα and TRβ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRα target genes through its recruitment to the LXR-response elements. 0.2 SIGNOR-266766 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser128 QHVRAHSsPASLQLG -1 29967145 YES miannu CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro. 0.322 SIGNOR-277649 TESK2 protein Q96S53 UNIPROT DSTN protein P60981 UNIPROT down-regulates activity phosphorylation Ser3 sGVQVADE 9606 BTO:0001363 11418599 YES lperfetto The present study provides evidence that TESK2 can phosphorylate cofilin and ADF specifically at Ser-3. Since actin-depolymerizing and -severing activities of cofilin/ADF are abrogated by phosphorylation at Ser-3, TESK2 seems to play an important role in actin filament dynamics by inhibiting cofilin/ADF activity. 0.423 SIGNOR-246707 SRC protein P12931 UNIPROT SLC11A1 protein P49279 UNIPROT up-regulates activity phosphorylation Tyr15 QRLSGSSyGSISSPT 9606 29723216 YES miannu In this study, we provide evidence that SLC11A1 is phosphorylated by Src family kinases at tyrosine 15 present in a conserved tyrosine-based motif (YGSI) among all species. 0.281 SIGNOR-278500 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191433 taurine smallmolecule CHEBI:15891 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 BTO:0000007 9009272 YES inferred from family member miannu For each mutant GlyR we examined the agonist efficacies of taurine and Œ≤-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where Œ≤-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human Œ±1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and Œ≤-alanine act as full agonists of human Œ±1 GlyRs when expressed in this system. 0.8 SIGNOR-270259 ARIH2 protein O95376 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity ubiquitination 9606 30755589 YES miannu ARIH2 can ubiquitinate NLRP3 via the NACHT domain of NLRP3, and the RING2 domain of ARIH2 is required for NLRP3 ubiquitination 65.|Overexpression of ARIH2 promotes NLRP3 ubiquitination and inhibits NLRP3 inflammasome activation 65. 0.445 SIGNOR-278686 BIRC2 protein Q13490 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity ubiquitination 9606 22345097 YES miannu Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability.|Thus, we conclude that API-1 reduces c-FLIP levels by facilitating its degradation through the ubiquitin and proteasome dependent pathway. 0.662 SIGNOR-278687 CSNK2A1 protein P68400 UNIPROT SLK protein Q9H2G2 UNIPROT down-regulates phosphorylation Ser347 SSDLSIAsSEEDKLS 9606 16837460 YES gcesareni Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity. 0.2 SIGNOR-147879 GRK6 protein P43250 UNIPROT GRK6 protein P43250 UNIPROT unknown phosphorylation Thr485 LDIEQFStVKGVELE 9534 BTO:0000298 10334944 YES GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established. 0.2 SIGNOR-251212 hsa-miR-613 mirna URS000075B7E4_9606 RNAcentral FZD7 protein O75084 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001061 26703210 YES Parnian Overall, these results indicate that miR-613 negatively regulates Fzd7 expression in prostate cancer cells. 0.4 SIGNOR-277957 GRIA1 protein P42261 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 NO miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses 0.7 SIGNOR-264615 CLASP2 protein O75122 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates activity binding 9534 BTO:0004055 19638411 YES lperfetto GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells 0.631 SIGNOR-264829 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity dephosphorylation Tyr397 SVSETDDyAEIIDEE -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.244 SIGNOR-254717 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates activity phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 BTO:0002181 23429703 YES miannu CAD as a direct substrate of S6K1. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. The direct regulation of CAD by S6K1 serves as a mechanism to increase the pool of nucleotides available for the RNA and DNA synthesis that accompanies cell growth. 0.372 SIGNOR-267443 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser34 SRSYVTTsTRTYSLG -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248880 CYP11B1 protein P15538 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 YES lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone 0.8 SIGNOR-268682 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR BACE1 protein P56817 UNIPROT up-regulates activity phosphorylation Thr252 YTGSLWYtPIRREWY 10116 BTO:0001009 26317805 YES miannu First, we show that BACE1 is phosphorylated by the p25/Cdk5 complex at Thr252 and that this phosphorylation increases BACE1 activity.  0.375 SIGNOR-276934 SNTG1 protein Q9NSN8 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.47 SIGNOR-255994 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 17828307 YES gcesareni Fak y397 phosphorylation promotes src sh2 domain binding to fak, presumably leading to conformational src activation with a fak-src complex. 0.2 SIGNOR-157763 SMAD4 protein Q13485 UNIPROT SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. 0.2 SIGNOR-255832 bevacizumab antibody DB00112 DRUGBANK VEGFA protein P15692 UNIPROT down-regulates activity binding 9606 BTO:0001615 15961063 YES miannu Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. 0.4 SIGNOR-259884 MRPL55 protein Q7Z7F7 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.612 SIGNOR-262335 STUB1 protein Q9UNE7 UNIPROT CFTR protein P13569 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11146634 YES miannu Here we show that CHIP functions with Hsc70 to sense the folded state of CFTR and targets aberrant forms for proteasomal degradation by promoting their ubiquitination.  0.471 SIGNOR-272584 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates activity phosphorylation -1 14976552 YES lperfetto We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP_activated protein kinase (AMPK). 0.61 SIGNOR-242602 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 EPLSPVSsLQASVPG 9606 16027724 YES llicata Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. 0.476 SIGNOR-250728 UNG protein P13051 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 27875297 NO lperfetto Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents.  0.7 SIGNOR-264889 MAP4K5 protein Q9Y4K4 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates 9606 9405407 NO gcesareni Here we report the identification of a tnf-responsive serine/threonine protein kinase termed gck related (gckr) that likely signals via mitogen-activated protein kinase (mapk)/extracellular signal-regulated kinase (erk) kinase kinase 1 (mekk1) to activate the sapk pathway. 0.453 SIGNOR-53779 KATP channel complex SIGNOR-C274 SIGNOR potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 28842488 YES lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. 0.8 SIGNOR-262053 PCDHAC2 protein Q9Y5I4 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-269038 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 YES Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2 0.664 SIGNOR-248535 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates phosphorylation Thr320 AISDTTTtFCGTPEY 9606 16790420 YES llicata Full-length sgk3 contains a complete phox homology (px) domain that targets the protein to endosomes. Both a functional px domain and pi3k activation are necessary for phosphorylation of sgk3 at two regulatory sites (thr-320 and ser-486) and subsequent induction of kinase activity. Pdk1 phosphorylates endosome-associated sgk3 at thr-320 0.462 SIGNOR-147213 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser8 MPKRKVSsAEGAAKE 9606 10739259 YES gcesareni Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at ser24 and ser28 in hmg-17, and ser20 and ser24 in hmg-14 a third phosphorylation site in hmg-14 was located at either ser6 or ser7phosphorylation of ser6 and ser7 may compromise the binding of hmgn1 protein to the binding domain of importin proteins, which in turn affects the nuclear transport and sub-cellular localization of hmgn1 protein. Protein kinase ck2 could potentially be an enzyme that regulates this process. 0.2 SIGNOR-76270 ZNF503 protein Q96F45 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 28258171 NO Monia Intriguingly, ZPO2/ZNF503 levels were higher in breast cancer samples with WT GATA3 than in those with mutated GATA3 (Fig. 1B). We found that Zpo2 down-regulated GATA3 levels, whereas shRNA-mediated Zpo2 knockdown enhanced GATA3 expression 0.257 SIGNOR-261189 SLC8B1 protein Q6J4K2 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 23056385 YES lperfetto This study focuses on NCLX, the recently discovered mitochondrial Na(+)/Ca(2+) exchanger that is linked to Ca(2+) signalling in MIN6 and primary β cells. Suppression either of NCLX expression, using a siRNA construct (siNCLX) or of its activity, by a dominant negative construct (dnNCLX), enhanced mitochondrial Ca(2+) influx and blocked efflux induced by glucose or by cell depolarization. 0.8 SIGNOR-275732 SEC23IP protein Q9Y6Y8 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269651 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 YES llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. 0.389 SIGNOR-188123 AKT1 protein P31749 UNIPROT LARP1 protein Q6PKG0 UNIPROT down-regulates activity phosphorylation Ser1056 EGRKRCPsQSSSRPA 9606 BTO:0002181 28650797 YES SARA LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. 0.288 SIGNOR-260992 2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)-1-oxopropyl]amino]-1-oxoethyl]amino]-1-oxoethyl]amino]-1-oxo-3-phenylpropyl]amino]-4-methylpentanoic acid chemical CHEBI:91634 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258805 SRC protein P12931 UNIPROT TRIM25 protein Q14258 UNIPROT up-regulates activity phosphorylation Tyr278 NSKFDTIyQILLKKK 9606 BTO:0002181 30100205 YES miannu Here, we demonstrated that TRIM25 interacted with c-Src and underwent tyrosine phosphorylation by c-Src kinase upon viral infection and the phosphorylation is required for the complete activation of RIG-I signaling. Analysis using a c-Src inhibitor and TRIM25 mutant, in which tyrosine 278 is substituted by phenylalanine (Y278F), suggested that the phosphorylation positively regulates K63-linked polyubiquitination of RIG-I and subsequent antiviral signaling.  0.271 SIGNOR-277405 PTK2 protein Q05397 UNIPROT CTNNB1 protein P35222 UNIPROT unknown phosphorylation Tyr142 AVVNLINyQDDAELA 10090 22264731 YES VEGF pathway Gianni VEGF promotes tension-independent FAK activation, rapid FAK localization to cell-cell junctions, binding of the FAK FERM domain to the vascular endothelial cadherin (VE-cadherin) cytoplasmic tail, and direct FAK phosphorylation of β-catenin at tyrosine-142 (Y142) facilitating VE-cadherin-β-catenin dissociation and EC junctional breakdown. 0.403 SIGNOR-261946 DPP3 protein Q9NY33 UNIPROT KEAP1 protein Q14145 UNIPROT down-regulates quantity by destabilization cleavage 9606 35278345 YES miannu The influence of DPP3 on the Keap1-Nrf2/ARE signal pathway suggest a direct involvement of DPP3 in the oxidative stress response [8,14,31,53,99,100]. It was shown that DPP3 competes with Nrf2 through the ETGE motif to bind to Keap1 and consequently enhances the translocation of Nrf2 to the nucleus, thereby driving the expression of an array of genes encoding antioxidative enzymes [99]. More specifically, binding of DPP3 to Keap1 releases Nrf2, and thus, prevents its degradation through the 26S proteasome 0.6 SIGNOR-268464 CDK2 protein P24941 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser770 LISRPRPsPLRSRID -1 35843311 YES miannu Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases. 0.2 SIGNOR-277604 Ub:E2 complex SIGNOR-C497 SIGNOR AREL1 protein O15033 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271286 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270383 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser31 DLQEVLSsDENGGTY 9606 BTO:0000567 12876286 YES llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites 0.345 SIGNOR-250853 FYN protein P06241 UNIPROT DCC protein P43146 UNIPROT up-regulates activity phosphorylation Tyr1261 PTLESAQyPGILPSP 10090 BTO:0001909 15557120 YES miannu Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo. 0.57 SIGNOR-268175 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 20185585 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-163947 PRKCA protein P17252 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 BTO:0000007 11085981 YES lperfetto In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism. 0.349 SIGNOR-249062 LIMK2 protein P53671 UNIPROT SPOP protein O43791 UNIPROT down-regulates activity phosphorylation Ser59 IKSSTFSsGANDKLK 9606 33311589 YES miannu LIMK2 phosphorylates SPOP at S59, S171 and S226.|Together, these results depict that LIMK2-mediated SPOP degradation is a key mechanism that regulates AR stability. 0.2 SIGNOR-278337 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258633 ROCK1 protein Q13464 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates activity phosphorylation 9606 25723491 YES miannu ROCK1 phosphorylates and activates ZIPK suggesting that at least some of these physiological functions may require both enzymes. 0.306 SIGNOR-279102 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 YES gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.793 SIGNOR-163246 NPTX1 protein Q15818 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 NO lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control 0.2 SIGNOR-260412 NEK9 protein Q8TD19 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity phosphorylation 9606 33500736 YES miannu The phosphorylation of ARHGEF2 by NEK9 is the key step of this process. 0.2 SIGNOR-279638 PDGFRB protein P09619 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr226 KRNKPTVyGVSPNYD 9606 19275932 YES miannu Here, we show that PDGFR-beta-phosphorylation of Abl kinases has functional consequences as PDGFR-beta phosphorylates Abl kinases on Y245 and Y412, sites known to be required for activation of Abl kinases. 0.526 SIGNOR-278319 PLK1 protein P53350 UNIPROT CLASP2 protein O75122 UNIPROT up-regulates activity phosphorylation Ser1234 QGYDNSEsSVRKACV 9606 23045552 YES miannu Cdk1 and Plk1 mediate a CLASP2 phospho-switch that stabilizes kinetochore-microtubule attachments.|Finally, we demonstrate that CLASP2 phosphorylation on S1234 and S1255 by Cdk1 and Plk1, respectively, increases with conditions that allow the establishment and stabilization of KT\u2013MT attachments ( xref ). 0.62 SIGNOR-278321 TACR2 protein P21452 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.431 SIGNOR-257131 STAT5A protein P42229 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 NO miannu The alternative survival and proliferation pathway triggered by higher concentrations of GM-CSF is dependent on the dodecamer assembly and involves the Jak/STAT, Ras/mitogen-activated protein kinase, and PI-3 kinase pathways 0.7 SIGNOR-255578 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 YES lperfetto The SH3 domains of c-Abl and Arg bound directly to catalase at a P293FNP site. c-Abl and Arg phosphorylated catalase at Tyr231 and Tyr386 in vitro and in the response of cells to H2O2 0.404 SIGNOR-101298 PRKDC protein P78527 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser446 STMQVSHsQVQEPGG -1 8407951 YES lperfetto  The carboxyl-terminal transcription activation domain was mapped within a 71-amino acid region that contains both DNA-PK phosphorylation sites. Amino acid substitutions that interfered with phosphorylation by DNA-PK at Ser-435/446 in GAL4-SRF fusion proteins were reduced in transactivation potency. From these data we suggest that DNA-PK phosphorylation may modulate SRF activity in vivo. 0.406 SIGNOR-248922 Caspase 3 complex complex SIGNOR-C221 SIGNOR ROCK1 protein Q13464 UNIPROT up-regulates cleavage 9606 11283607 YES gcesareni Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity. 0.733 SIGNOR-256460 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester chemical CHEBI:92418 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258634 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.423 SIGNOR-248295 TFAP2A protein P05549 UNIPROT SULT1E1 protein P49888 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17187826 NO miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 0.2 SIGNOR-255397 PDGFRB protein P09619 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 BTO:0002057 15489898 YES gcesareni The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. 0.603 SIGNOR-247979 GTF2E2 protein P29084 UNIPROT TFIIE complex SIGNOR-C458 SIGNOR form complex binding 9606 31064989 YES lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. 0.942 SIGNOR-269361 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Ser88 RPSDEDSsSLESAAS -1 12852856 YES lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction 0.699 SIGNOR-103356 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser29 VSHWQQQsYLDSGIH 9606 BTO:0000007 12432063 YES llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin 0.555 SIGNOR-250846 BIRC2 protein Q13490 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity ubiquitination 9606 28542143 YES miannu The ability of cIAP1 to promote wt E2F1 transcriptional activity was retained by all E2F1 mutants, except the K161R/164R mutant for which cIAP1 was completely inactive and the K185R whose basal transactivation activity was weakly enhanced by cIAP1 (XREF_FIG).|Here, we demonstrated that the E3-ubiquitin ligase cellular inhibitor of apoptosis 1 (cIAP1) increases E2F1 K63-poly-ubiquitination on the lysine residue 161/164 cluster, which is associated with the transcriptional factor stability and activity. 0.336 SIGNOR-278688 hsa-miR-199a-5p mirna URS0000554A4F_9606 RNAcentral FZD7 protein O75084 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003227 25313882 YES Parnian These results suggested that miR-199a could significantly suppress the expression of FZD7 through targeting the 3'UTR of its mRNA. 0.4 SIGNOR-277958 GMIP protein Q9P107 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.642 SIGNOR-260505 MAPK1 protein P28482 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser64 QAATGFGsPLQYSAD -1 15133517 YES miannu We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation. 0.2 SIGNOR-263053 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI STING1 protein Q86WV6 UNIPROT up-regulates activity binding 23258413 YES lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. 0.8 SIGNOR-276596 JAK2 protein O60674 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation Tyr1964 HETSEPTyLRFIKSL -1 30944118 YES miannu Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin.  0.419 SIGNOR-277289 CIB2 protein O75838 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity binding 10090 34162842 YES miannu Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to 'nucleotide empty' or inactive GDP-loaded Rheb.  0.263 SIGNOR-269663 Ub:E2 complex SIGNOR-C497 SIGNOR ZNRF4 protein Q8WWF5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271206 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr352 TEVYESPyADPEEIR 9606 9820500 YES lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 0.2 SIGNOR-246613 CIITA protein P33076 UNIPROT HLA-DRB4 protein P13762 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002417 10886240 NO These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. 0.2 SIGNOR-254012 CBL protein P22681 UNIPROT SYK protein P43405 UNIPROT down-regulates quantity ubiquitination 9606 19081591 YES miannu Thus, c-Cbl specifically downregulates Syk levels in the presence of LMP2A.|c-Cbl promoted LMP2A degradation through ubiquitination, specifically degraded the Syk protein tyrosine kinase in the presence of LMP2A, and inhibited LMP2A induction of the EBV lytic cycle 0.815 SIGNOR-278689 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Thr2511 VPEHPFLtPSPESPD -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.243 SIGNOR-273167 LMX1A protein Q8TE12 UNIPROT CUX2 protein O14529 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 30770393 YES miannu Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem 0.285 SIGNOR-263961 MAPKAPK2 protein P49137 UNIPROT LSP1 protein P33241 UNIPROT unknown phosphorylation Ser252 PKLARQAsIELPSMA -1 8995217 YES miannu LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. . Inspection of the human LSP1 protein sequence (22) identifies two serine residues at positions 204 and 252 as potential phosphorylation sites. The results show that LSP1 is a substrate for MAPKAP kinase 2 in vitro and that the phosphorylation site(s) are located in the C-terminal 152 amino acid residues, as predicted from the sequence. 0.637 SIGNOR-250148 MAP2K6 protein P52564 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation 9606 8974401 YES gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) 0.471 SIGNOR-45369 BBC3 protein Q9BXH1 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 1557433 YES gcesareni The first Helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma 0.49 SIGNOR-20064 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1717 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248775 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates activity phosphorylation Tyr481 PSSSIDEyFSEQPLK 9606 7526154 YES lperfetto In this report, we demonstrate that the alpha subunit of the type I IFN receptor (IFN-R) corresponds to the product of a previously cloned receptor subunit cDNA and, further, that the p135tyk2 tyrosine kinase directly binds and tyrosine phosphorylates this receptor subunit.These data support the hypothesis that the Tyk2 protein functions as part of a receptor complex to initiate intracellular signaling in response to type I IFNs 0.91 SIGNOR-246939 PEX2 protein P28328 UNIPROT UBE2D2 protein P62837 UNIPROT up-regulates activity binding -1 19687296 YES miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 0.61 SIGNOR-253025 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD 9606 8702756 YES miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. 0.646 SIGNOR-261719 BTRC protein Q9Y297 UNIPROT PER1 protein O15534 UNIPROT down-regulates ubiquitination 9606 15917223 YES miannu We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1 0.569 SIGNOR-137755 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser527 RFRKRTHsAGTSPTI 10090 BTO:0002572 18498745 YES lperfetto In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8 0.787 SIGNOR-236595 FZD3 protein Q9NPG1 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 17251915 YES gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. 0.383 SIGNOR-152603 idarubicin chemical CHEBI:42068 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 20824055 YES miannu Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells. 0.8 SIGNOR-259328 PHLPP2 protein Q6ZVD8 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 17386267 YES gcesareni Knockdown studies reveal that PHLPP1 specifically modulates the phosphorylation of HDM2 and GSK-3alpha through Akt2, whereas PHLPP2 specifically modulates the phosphorylation of p27 through Akt3 0.682 SIGNOR-237439 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.7 SIGNOR-269173 clofarabine chemical CHEBI:681569 ChEBI PRIM2 protein P49643 UNIPROT down-regulates activity chemical inhibition 9606 1707752 YES miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. 0.8 SIGNOR-258360 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Tyr350 RRSSLKAyGNGYSSN 10029 BTO:0000246 8557631 YES Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. 0.377 SIGNOR-251301 MTOR protein P42345 UNIPROT ULK2 protein Q8IYT8 UNIPROT down-regulates phosphorylation 9606 19211836 YES gcesareni Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2 0.776 SIGNOR-183961 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206127 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 19153083 YES gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation 0.715 SIGNOR-183484 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser80 PPNPEDRsPSPEPIY 9606 23175611 YES The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. 0.407 SIGNOR-199793 hsa-miR-513c-5p mirna URS00002A7CF3_9606 RNAcentral LRP6 protein O75581 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003761 26063413 YES Parnian A luciferase reporter assay demonstrated that the downregulation of LRP6 was mediated by miR‑513c through the LRP6 3'‑UTR. These results demonstrated that LRP6 is a bona fide target of miR‑513c.| LRP6 is a direct target of miRNA‑513c. 0.4 SIGNOR-278838 hsa-miR-610 mirna URS00004DC583_9606 RNAcentral LRP6 protein O75581 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005814 25491321 YES Parnian Results indicate that miR-610 negatively regulated these proteins via directly binding to their 3’UTRs. These data further confirm that miR-610 suppresses HCC cell tumorigenicity by inhibiting the activity of β-catenin via targeting LRP6 and TBL1X. 0.4 SIGNOR-278839 hsa-miR-610 mirna URS00004DC583_9606 RNAcentral TBL1X protein O60907 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005814 25491321 YES Parnian Results indicate that miR-610 negatively regulated these proteins via directly binding to their 3’UTRs. These data further confirm that miR-610 suppresses HCC cell tumorigenicity by inhibiting the activity of β-catenin via targeting LRP6 and TBL1X. 0.4 SIGNOR-278840 PRKAA2 protein P54646 UNIPROT PROX1 protein Q92786 UNIPROT down-regulates quantity by destabilization phosphorylation Ser79 KLLKRANsYEDAMMP 9606 BTO:0002181 36433955 YES miannu Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. 0.2 SIGNOR-277608 Hypoxia stimulus SIGNOR-ST25 SIGNOR hsa-miR-181a-5p mirna URS00003DA300_9606 RNAcentral up-regulates post transcriptional regulation 9606 BTO:0000250 26013170 NO Parnian We have identified miR-181a as a potential oncomiR that is upregulated by hypoxia in chondrosarcoma. 0.4 SIGNOR-278844 HIC1 protein Q14526 UNIPROT ACKR3 protein P25106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23340301 NO miannu we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression. 0.286 SIGNOR-254238 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 11731619 YES gcesareni In intact hc11 cells, ptp-pest was constitutively associated with jak2, and in response to egf treatment there was an increased level of ptp-pest in jak2 complexes. An in vitro phosphatase assay, using prl-activated jak2 as the substrate and lysates from hc11 cells as the source of ptp-pest, revealed that jak2 could serve as a ptp-pest substrate. 0.378 SIGNOR-112383 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser222 EEQDRPRsPTGPSNS 9534 BTO:0001538 23519612 YES miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 0.318 SIGNOR-262707 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 20551172 YES miannu We characterize a new Myc-interacting factor, TRPC4AP (transient receptor potential cation channel, subfamily C, member 4-associated protein)/TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein), which is the receptor for a DDB1 (damage-specific DNA-binding protein 1)-CUL4 (Cullin 4) E3 ligase complex for selective Myc degradation through the proteasome. TRPC4AP/TRUSS binds specifically to the Myc C terminus and promotes its ubiquitination and destruction through the recognition of evolutionarily conserved domains in the Myc N terminus.  0.377 SIGNOR-271965 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1087 HGHVSNAsISLGESV -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262901 Noncanonical PRC1 complex SIGNOR-C151 SIGNOR UHRF1 protein Q96T88 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 NO miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. 0.268 SIGNOR-252250 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 BTO:0000007 8955135 YES Mutagenesis of BCR Tyr-177 to Phe completely abolished FES-induced BCR binding to the GRB2 SH2 domain, identifying Tyr-177 as an additional phosphorylation site for FES. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1. 0.368 SIGNOR-251136 PRKD3 protein O94806 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity phosphorylation Ser155 FPLRKTVsEPNLKLR 18692497 YES Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7 lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. 0.2 SIGNOR-275932 PBX2 protein P40425 UNIPROT EMX2 protein Q04743 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15494461 NO miannu EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation. 0.391 SIGNOR-254466 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Ser143 FHPNVSSsHENLEPE 9606 22609948 YES lperfetto We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle 0.692 SIGNOR-197063 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 YES Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism 0.732 SIGNOR-252056 Complement C1 complex complex SIGNOR-C309 SIGNOR C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.642 SIGNOR-263427 P2RY2 protein P41231 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.383 SIGNOR-256759 ASPA protein P45381 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 17194761 YES miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. 0.8 SIGNOR-267528 hsa-miR-22-5p mirna URS0000142DC3_9606 RNAcentral WNT1 protein P04628 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004953 23851184 YES Parnian MiR-200b and miR-22 directly targeted Wnt-1 gene and synergistically inhibited Wnt signaling pathway. The miR-200b and miR-22 have putative binding sites in the 3' UTRs of Wnt1. 0.4 SIGNOR-278848 hsa-miR-200b-5p mirna URS000012A1DD_9606 RNAcentral WNT1 protein P04628 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004953 23851184 YES Parnian MiR-200b and miR-22 directly targeted Wnt-1 gene and synergistically inhibited Wnt signaling pathway. The miR-200b and miR-22 have putative binding sites in the 3' UTRs of Wnt1. 0.4 SIGNOR-278849 MECOM protein Q03112 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 9665135 YES miannu Evi-1 interacts with smad3, an intracellular mediator of tgf-beta signalling, thereby suppressing the transcriptional activity of smad3. 0.491 SIGNOR-59132 CHUK protein O15111 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates activity phosphorylation 9606 23715268 YES miannu Sam68 is phosphorylated by IKK\u03b1 in the nucleus. 0.2 SIGNOR-278439 PAK2 protein Q13177 UNIPROT MYC protein P01106 UNIPROT down-regulates activity phosphorylation Thr400 T-->E 9606 14749374 YES miannu Here we demonstrate that Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo. 0.648 SIGNOR-278490 JAK3 protein P52333 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity phosphorylation Tyr244 AEELKEKyKELTEQQ 9606 28868240 YES miannu These results demonstrate that phosphorylation of EZH2 by JAK3 on the Y244 increases the interaction with Polymerase II and decreases the association with PRC2 components promoting the expression of non-canonical genes.|To explore the mechanism of JAK3 mediated EZH2 activation, the authors performed co-immunoprecipitation assays, which revealed interaction of EZH2 with JAK3 and polymerase II. 0.428 SIGNOR-278518 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr482 SSQPKVStPVVKQGP 9606 BTO:0000567 30021153 YES lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. 0.2 SIGNOR-265033 PCC complex SIGNOR-C414 SIGNOR (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI up-regulates quantity chemical modification 9606 15890657 YES miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. 0.8 SIGNOR-267186 PYCARD protein Q9ULZ3 UNIPROT BAX protein Q07812 UNIPROT up-regulates relocalization 9606 16964285 YES gcesareni Asc directly induces bax-mediated apoptosis. Asc induces the translocation of bax to the mitochondria, bax-dependent cycs release from the mitochondria and casp9 activation. 0.354 SIGNOR-149522 WNT10A protein Q9GZT5 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.57 SIGNOR-131619 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273065 PP2B proteinfamily SIGNOR-PF18 SIGNOR BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation 9606 BTO:0000007 10195903 YES inferred from 70% family members Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 0.2 SIGNOR-269992 ACTN1 protein P12814 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 17243894 NO miannu On most principal neurons in the mammalian brain (e.g., pyramidal neurons of cortex and hippocampus, Purkinje cells of cerebellum, medium spiny neurons of striatum), the postsynaptic specialization is housed on tiny actin rich protrusions called dendritic spines The size, shape, motility, and stability of dendritic spines depend largely on actin, the primary cytoskeleton within spines. 0.7 SIGNOR-264618 MAPK1 protein P28482 UNIPROT CITED2 protein Q99967 UNIPROT up-regulates activity phosphorylation Ser85 VNGGHPPsALAPAAR 9606 23082118 YES miannu CITED2 coactivation is enhanced by activation of MAPK1 and requires T166.|CITED2 is phosphorylated by MAPK1 at S85, T166 and T175. 0.455 SIGNOR-278409 SGX-523 chemical CHEBI:90624 ChEBI MET protein P08581 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258282 PRKDC protein P78527 UNIPROT FH protein P07954 UNIPROT up-regulates activity phosphorylation Thr236 IKIGRTHtQDAVPLT -1 26237645 YES miannu We show that exposure to ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions.  0.2 SIGNOR-266349 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates chemical activation 10090 10448861 YES miannu Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. 0.8 SIGNOR-266334 PLEKHF2 protein Q9H8W4 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates activity binding -1 22816767 YES Giulio In yeast two-hybrid analysis we identified Phafin2 as a novel interactor of the endosomal-tethering protein EEA1, and Phafin2 colocalized strongly with EEA1 in microdomains of the endosome membrane. Our results suggest that Phafin2 controls receptor trafficking and fluid-phase transport through early endosomes by facilitating endosome fusion in concert with EEA1. 0.248 SIGNOR-261276 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT up-regulates activity 9606 BTO:0000131 29880919 YES lperfetto Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind 0.882 SIGNOR-263530 IKBKE protein Q14164 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 19481526 YES miannu CYLD is phosphorylated by IKK\u03b5 at Ser418.|Together, these observations demonstrate that I\u03baB kinase\u03b5-mediated phosphorylation of CYLD at Ser418 inhibits CYLD deubiquitinase activity. 0.442 SIGNOR-278311 JAK2 protein O60674 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity phosphorylation Tyr333 QRYRLVPyGNHSYLE 9606 34131122 YES miannu Importantly, JAK2 knockdown significantly abolished the increased levels of p-BECN1 (Y333) induced by IL-6 stimulation in both SW48 and LoVo cells (Fig. 3k and Supplementary Fig. 4f).|Taken together, these data indicate that JAK2 specifically phosphorylates BECN1 at Y333. 0.298 SIGNOR-278312 Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.7 SIGNOR-267958 MFNG protein O00587 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 10935626 YES Fucosylation gcesareni Manic fringe elongates the o-linked fucose saccharides on full-length notch1 and notch1 egf repeats 1923. 0.719 SIGNOR-80555 E2F1 protein Q01094 UNIPROT CD2AP protein Q9Y5K6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 22880102 NO lperfetto Transcriptional activation of the human CD2AP promoter by E2F1 0.2 SIGNOR-254129 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Ser121 LMRRSTVsLLDTYQK 23871434 YES Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro 0.249 SIGNOR-275483 EP300 protein Q09472 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 9606 11796223 YES lperfetto Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription. 0.86 SIGNOR-232165 SCF-SKP2 complex SIGNOR-C136 SIGNOR IDH1 protein O75874 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Thr157 GKVEITYtPSDGTQK 34929314 YES lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome 0.2 SIGNOR-267623 LIMK2 protein P53671 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation 9606 32931887 YES miannu LIMK2 inhibits PTEN phosphatase activity in vitro and in cells.|PTEN phosphorylation and downregulation by LIMK2 promotes tumorigenesis and EMT in vivo. 0.274 SIGNOR-278363 CSAD protein Q9Y600 UNIPROT beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity chemical modification 9606 22718265 YES miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. 0.8 SIGNOR-267549 TRIM25 protein Q14258 UNIPROT SFN protein P31947 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 12075357 YES miannu Here we show that Efp is a RING-finger-dependent ubiquitin ligase (E3) that targets proteolysis of 14-3-3 sigma, a negative cell cycle regulator that causes G2 arrest. 0.572 SIGNOR-271548 CSF3 protein P09919 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 YES gcesareni Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta). 0.465 SIGNOR-72511 GRPR protein P30550 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256917 GATA1 protein P15976 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12377757 NO miannu We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment. 0.281 SIGNOR-254081 glutamic acid smallmolecule CHEBI:18237 ChEBI Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270386 TNIK protein Q9UKE5 UNIPROT NF2 protein P35240 UNIPROT up-regulates activity phosphorylation Ser315 MRRRKADsLEVQQMK 9606 33495197 YES miannu Consistently with TNIK modulating Merlin, we also observed reduced YAP levels following TNIK knockdown in LK2 and NCI-H520 cells (Supplementary Fig. S7B).|Using in vitro kinase assays followed by phosphopeptide mapping, and mass spectrometry analysis on Merlin isolated from cells co-expressing TNIK and Merlin, we determined that TNIK could phosphorylate Merlin at S13, T272, S315, and T576 (Fig. 4B, Supplementary Fig. S4D, and Supplementary Table S3). 0.2 SIGNOR-278387 ATM protein Q13315 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Thr91 ESIRREKtQNFLIQK 9606 24732096 YES miannu Upon DNA damage, ATM phosphorylates the residue T91 of BCL10, promoting binding of BCL10 to RNF8 and simultaneously presenting UBC13 to RNF8.|When cells were pre-treated with different PIKK inhibitors, the ATM specific inhibitor KU55933 efficiently reduced etoposide induced focus formation of BCL10, whereas pretreatment of cells with NU6027, an ATR specific inhibitor, or NU7026, a DNA-PKcs-specific inhibitor, did not compromise etoposide induced focus formation of BCL10 (XREF_FIG). 0.469 SIGNOR-278392 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-252808 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys982 ALLADIRkGFQLRKT 9606 BTO:0000007 28448495 YES miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 0.2 SIGNOR-272806 BCL2L1 protein Q07817 UNIPROT APAF1 protein O14727 UNIPROT down-regulates activity binding 9606 9539746 YES lperfetto These experiments demonstrate that bcl-xl associates with caspase-9 and apaf-1, and show that bcl-xl inhibits the maturation of caspase-9 mediated by apaf-1. 0.841 SIGNOR-56399 NEK2 protein P51955 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates phosphorylation Thr318 TPPRGMItKQAKK 9606 10880350 YES gcesareni Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. 0.489 SIGNOR-78603 SMURF1 protein Q9HCE7 UNIPROT TBX6 protein O95947 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 19561075 YES miannu Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. 0.257 SIGNOR-272784 CSNK1A1 protein P48729 UNIPROT YWHAQ protein P27348 UNIPROT down-regulates activity phosphorylation Ser232 LTLWTSDsAGEECDA -1 9360956 YES llicata This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins.  0.515 SIGNOR-250795 MAPK3 protein P27361 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 YES lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. 0.375 SIGNOR-74304 DLG2 protein Q15700 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.5 SIGNOR-270881 HOXA9 protein P31269 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000661 21261500 NO miannu Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC 0.333 SIGNOR-254211 PPP1CB protein P62140 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 14633703 YES Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells 0.387 SIGNOR-248575 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates quantity by destabilization cleavage Asp390 LPQLTLPdSLTSAAS 9606 11815631 YES Giulio Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage 0.396 SIGNOR-260604 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA3 protein Q9Y5H0 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265699 CSF2RA protein P15509 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR form complex binding 9606 9680354 YES apalma The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors. 0.869 SIGNOR-255582 CCR7 protein P32248 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 15054093 YES B-Arrestin-2 is recruited to CCR7 following stimulation with CCL19, but not CCL21. 0.375 SIGNOR-278124 GFs stimulus SIGNOR-ST12 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 23300340 NO lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation 0.7 SIGNOR-245402 CHD2 protein O14647 UNIPROT H3-3A protein P84243 UNIPROT up-regulates quantity relocalization 9606 26895424 YES miannu Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage. 0.2 SIGNOR-264527 PRKDC protein P78527 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity phosphorylation Ser1987 GSQSTTIsSLSEKSK 9606 32832608 YES miannu It has also been reported that DNA-PKcs could inhibit ATM activity by directly phosphorylating ATM at T86 / T373 and T1985 / S1987 / S1988 sites .|It has also been reported that DNA-PKcs could inhibit ATM activity by directly phosphorylating ATM at T86 and T373 and T1985/S1987/S1988 sites. 0.701 SIGNOR-278324 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 YES gcesareni DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. 0.86 SIGNOR-184785 EGLN3 protein Q9H6Z9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates activity hydroxylation 9606 BTO:0000567 21620138 YES Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1Œ± and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. 0.436 SIGNOR-268146 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203572 PAK1 protein Q13153 UNIPROT AJUBA protein Q96IF1 UNIPROT up-regulates activity phosphorylation 9606 22105346 YES miannu The Rac effector PAK1 was also transiently activated upon cell-cell adhesion and directly phosphorylated Ajuba (Thr172). 0.256 SIGNOR-278449 EGR1 protein P18146 UNIPROT PTGES protein O14684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21983014 NO In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression.|EGR1 downregulation seems to be the major effect of DMC leading to transcriptional inhibition of mPGES-1 0.336 SIGNOR-254249 HHEX protein Q03014 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity 10090 BTO:0000089 26728554 NO Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal. 0.7 SIGNOR-256306 FUS protein P35637 UNIPROT DHX9 protein Q08211 UNIPROT down-regulates activity relocalization 9606 BTO:0000793 27460707 YES P35637:p.Pro525Leu (mutation causing interaction) We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons 0.48 SIGNOR-262810 MAPKAPK2 protein P49137 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser90 IPPARMMsTESANSF 9606 25693418 YES miannu Beclin 1 S90 is phosphorylated by MAPKAPK2 (MK2) and MAPKAPK3 (MK3). 0.433 SIGNOR-278342 nalbuphine chemical CHEBI:7454 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.8 SIGNOR-258658 SLBP protein Q14493 UNIPROT H2AB2 protein P0C5Z0 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265407 PRKN protein O60260 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0000007 11590439 YES miannu Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. Co-expression of alpha-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions.  0.2 SIGNOR-272595 IKBKB protein O14920 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Thr205 EGPSEYQtIPLNKIE -1 31950832 YES lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. 0.331 SIGNOR-275519 Non-structural protein 10 protein P0C6X7-PRO_0000037317 UNIPROT MT-ND4L protein P03901 UNIPROT down-regulates activity binding 9606 BTO:0000764 16157265 YES lperfetto This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication. 0.2 SIGNOR-260253 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1256 KGCSNEPyFGSLTAL 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 YES llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate 0.409 SIGNOR-187851 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates activity phosphorylation Tyr206 PGPTRKHyQPYAPPR 8992971 YES EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor. 0.689 SIGNOR-251334 JAK2 protein O60674 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR up-regulates activity phosphorylation 9606 15526160 YES miannu Downstream of JAKs are the signal transducers and activators of transcription (STATs), which are phosphorylated by JAKs. 0.811 SIGNOR-254999 DEPTOR protein Q8TB45 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR down-regulates activity binding 9606 BTO:0000007 19446321 YES DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival 0.724 SIGNOR-251659 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 34674502 YES scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† 0.8 SIGNOR-267044 OPRM1 protein P35372 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.602 SIGNOR-256711 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4A protein O75164 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273465 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 YES lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. 0.2 SIGNOR-244798 IFNA2 protein P01563 UNIPROT HLA-B protein P01889 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 2507660 NO Regulation miannu HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2 0.258 SIGNOR-251925 SMARCA5 protein O60264 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 YES miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 0.501 SIGNOR-268825 XAV939 chemical CHEBI:62878 ChEBI AXIN1 protein O15169 UNIPROT up-regulates 9606 19759537 NO gcesareni Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2 0.8 SIGNOR-188045 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10230394 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.541 SIGNOR-67387 CEBPG protein P53567 UNIPROT SFTPD protein P35247 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11912209 YES Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D. 0.2 SIGNOR-254058 Quadazocine chemical CID:115077 PUBCHEM OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258420 PTPN13 protein Q12923 UNIPROT PDCD10 protein Q9BUL8 UNIPROT down-regulates dephosphorylation 9606 17657516 YES gcesareni We also show that ccm3 directly binds to serine/threonine kinase 25 (stk25, ysk1, sok1) and the phosphatase domain of fas-associated phosphatase-1 (fap-1, ptpn13, ptp-bas, ptp-bl). 0.568 SIGNOR-157076 ZBTB16 protein Q05516 UNIPROT RSAD2 protein Q8WXG1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003846 19523849 YES lperfetto Promoter regions from the PLZF-regulated transcripts Rsad2 and Ifit2 were fused to luciferase and activity was measured after IFN treatment. Overexpression of PLZF in RCC1 or ACHN cells produced a dose-dependent induction of the reporter promoters.  0.2 SIGNOR-261023 Class I MHC:Antigen complex SIGNOR-C426 SIGNOR CD8A protein P01732 UNIPROT up-regulates activity binding 9606 21954283 YES scontino Molecular recognition of pMHCI complexes is mediated primarily by clonally distributed TCRs expressed on the surface of CTLs. The coreceptor CD8 contributes to this antigen-recognition process by binding to a largely invariant region of the MHCI molecule and by promoting intracellular signaling, the effects of which serve to enhance TCR stimuli triggered by cognate ligands. 0.2 SIGNOR-267991 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser285 QRVPSYDsFDSEDYP BTO:0003637 12475968 YES llicata Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1  0.31 SIGNOR-250687 phosphatidylinositol chemical CHEBI:28874 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR form complex binding 9606 25627476 YES lperfetto The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition. 0.8 SIGNOR-267001 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates binding 9606 BTO:0001130 1010227 YES gcesareni Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner. 0.2 SIGNOR-15849 YAP1 protein P46937 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.324 SIGNOR-276563 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT down-regulates activity phosphorylation Ser138 KPRTIYSsYQLAALQ -1 11343707 YES lperfetto Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3. 0.307 SIGNOR-249096 SKIL protein P12757 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 YES lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway 0.841 SIGNOR-253303 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR up-regulates activity binding 9606 19454274 YES The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux 0.8 SIGNOR-267262 HERC2 protein O95714 UNIPROT NEURL4 protein Q96JN8 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22261722 YES miannu Here we used interaction proteomics to identify the E3 ligase HERC2 and the neuralized homologue NEURL4 as novel interaction partners of the centrosomal protein CP110.NEURL4 is a substrate of HERC2, and together these results indicate that the NEURL4-HERC2 complex participates in the ubiquitin-dependent regulation of centrosome architecture. In further support of the possibility that NEURL4 is regulated by proteasomal degradation, we detected robust ubiquitylation of a FLAG-NEURL4 protein in HEK293T cells (Fig. 5B). 0.457 SIGNOR-272910 TSC22D1 protein Q15714 UNIPROT NPPC protein P23582 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 9022669 YES Luana TSC-22 significantly enhanced CNP promoter activity in GH3 cells. 0.257 SIGNOR-266226 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys70 GKAVRGAkGHHHPHP 9606 15831498 YES gcesareni Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300 0.464 SIGNOR-135473 CTNNB1 protein P35222 UNIPROT TCF7 protein P36402 UNIPROT up-regulates binding 9606 BTO:0000782 15735151 YES gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 0.758 SIGNOR-134282 MYC protein P01106 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates 9606 11804592 NO in cancer lperfetto Oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads 0.683 SIGNOR-114281 MCHR1 protein Q99705 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256905 HUWE1 protein Q7Z6Z7 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity ubiquitination 9606 22277673 YES miannu Importantly, addition of WT HUWE1 to a proteolytic reaction mixture enhanced the degradation of MyoD.|Mass-spectrometry analyses show that HUWE1 can ubiquitinate MyoD at its N-terminal residue, though the preferred sites are - at least in a cell free system - the internal lysines of the protein. 0.344 SIGNOR-278694 ketoprofen chemical CHEBI:6128 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001061 18667313 YES Luana Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2.  0.8 SIGNOR-257810 HUWE1 protein Q7Z6Z7 UNIPROT TBP protein P20226 UNIPROT down-regulates quantity ubiquitination 9606 26393420 YES miannu Having established that Huwe1 mediates TBP ubiquitination in vitro, we then asked which E2 conjugating enzymes work best with Huwe1 in this reaction.|Upregulation of Huwe1 expression during myogenesis induces TBP degradation and myotube differentiation. 0.338 SIGNOR-278696 STK4 protein Q13043 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Thr183 GWKPGSDtIKPDVQK -1 23386615 YES miannu Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183. 0.2 SIGNOR-276485 Activated PSC phenotype SIGNOR-PH224 SIGNOR IL11 protein P20809 UNIPROT up-regulates 9606 BTO:0000584 30996350 YES miannu IL6 has been implicated in PDAC, and all its family members, like LIF, bind to receptor complexes containing GP130 to activate similar signal cascades, such as the STAT3 pathway. In our initial screens, IL6 and IL11 were also found to be produced by PSCs 0.7 SIGNOR-278037 TBK1 protein Q9UHD2 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity phosphorylation Ser358 VPSTSTMsQEPELLI 9606 BTO:0000007 18818105 YES miannu MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3. Our results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity. Consistent with its inability to activate IRF-E, the mutation of S358 to alanine impaired the ability of MITA to interact with TBK1 and to enhance the interaction between TBK1 and IRF3 0.2 SIGNOR-263136 MYC protein P01106 UNIPROT ST3GAL4 protein Q11206 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 NO We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 0.2 SIGNOR-253959 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr677 LPITGPEyATPIIMD -1 23770091 YES done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. 0.351 SIGNOR-273943 PPP2CA protein P67775 UNIPROT RELA protein Q04206 UNIPROT down-regulates dephosphorylation 9606 BTO:0000848 SIGNOR-C13 11591705 YES gcesareni Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela. 0.482 SIGNOR-110959 COL4A5 protein P29400 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 YES lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. 0.447 SIGNOR-272349 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser63 NVKVETQsDEENGRA 9606 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo 0.2 SIGNOR-174852 TFEB protein P19484 UNIPROT CTSF protein Q9UBX1 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 NO lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 0.365 SIGNOR-276805 PRKN protein O60260 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates quantity ubiquitination 9606 19663908 YES miannu In order to address the functional role of parkin ubiquitination of PLCgamma1, we investigated PLC activity in human neuroblastoma SH-SY5Y cell lines stably transfected with either WT, or mutant R42P or G328E parkin.|WT parkin expression significantly reduced the levels of PLCgamma1 in human neuroblastoma. 0.2 SIGNOR-278592 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser102 GGFPPLNsVSPSPLM 9606 16076840 YES gcesareni The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex. 0.34 SIGNOR-139312 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1619 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248804 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser750 RRKMKKTsTSTETRS 9606 15568999 YES lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. 0.2 SIGNOR-131399 MDM2 protein Q00987 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates quantity ubiquitination 9606 24777531 YES miannu MDM2 negatively regulates NFATc2 and T cell activation.|The E3 ubiquitin ligase MDM2 is known to induce NFATc2 ubiquitination in a breast cancer cell line 24. 0.306 SIGNOR-278657 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263817 SPRY4 protein Q9C004 UNIPROT TESK1 protein Q15569 UNIPROT down-regulates activity binding 9606 15584898 YES miannu Spry4 negatively regulates the kinase activity of TESK1 by associating with it through the C-terminal cysteine-rich region of Spry4 0.566 SIGNOR-253032 ATG12 protein O94817 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 4932 23321721 NO lperfetto Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation 0.7 SIGNOR-219396 HERC2 protein O95714 UNIPROT USP20 protein Q9Y2K6 UNIPROT down-regulates quantity ubiquitination 9606 25326330 YES miannu HERC2 promotes USP20 degradation.|Under unperturbed condition, HERC2 ubiquitinates USP20 and promotes ubiquitination mediated proteasomal degradation of USP20, regulating the status of K48 linked polyubiquitination of CLASPIN and ensuring appropriate protein levels of CLASPIN during the S-phase. 0.373 SIGNOR-278692 FGF11 protein Q92914 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253446 selumetinib chemical CHEBI:90227 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258280 YWHAE protein P62258 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity binding 9606 BTO:0000938 17202468 YES miannu 14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. 14-3-3ε binds to NUDEL phosphorylated by cyclin-dependent kinase (cdk5) and maintains NUDEL phosphorylation. Deficiency of 14-3-3ε causes mislocalization of the NUDEL/LIS1 complex from axons, suggesting that 14-3-3ε regulates the axonal targeting of the NUDEL/LIS1 complex by sustaining NUDEL phosphorylation 0.666 SIGNOR-252160 TRAF6 protein Q9Y4K3 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates ubiquitination 9606 BTO:0000782 17948050 YES gcesareni Traf6 associates with malt1 in response to t-cell activation and can function as an e3 ligase for malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of malt1. Multiple lysine residues in the c-terminus of malt1 serve as acceptor sites for the assembly of polyubiquitin chains. (articolo-abstract) 0.754 SIGNOR-158554 LCK protein P06239 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT 10880360 YES lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. 0.645 SIGNOR-249373 ATM protein Q13315 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates activity phosphorylation Ser585 GDGNLSPsQPPLKNL 9606 25086746 YES miannu Mechanistically, ATM kinase phosphorylates and stabilizes ZEB1 in response to DNA damage, and ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitinate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation.|Therefore, ATM dependent phosphorylation of ZEB1 at S585 is crucial for IR induced stabilization of ZEB1 but not the interaction between ZEB1 and USP7. 0.475 SIGNOR-278329 AKT proteinfamily SIGNOR-PF24 SIGNOR IRAK1 protein P51617 UNIPROT down-regulates activity phosphorylation Thr100 LRARDIItAWHPPAP 9606 BTO:0000007 11976320 YES gcesareni CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation. 0.2 SIGNOR-248008 PINK1 protein Q9BXM7 UNIPROT ZNF746 protein Q6NUN9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser322 QATRFFPsPAQEGAW 9606 BTO:0000793 28122242 YES miannu PINK1 is required for Parkin ubiquitination and degradation of PARIS. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. 0.37 SIGNOR-273724 PRKACA protein P17612 UNIPROT GJB1 protein P08034 UNIPROT unknown phosphorylation Ser233 NPPSRKGsGFGHRLS -1 8390988 YES miannu connexin- 32 is proteolyzed by pcalpain and mcalpain. phosphorylation of connexin-32 by protein kinase C, but not by protein kinase A, efficiently prevents its proteolysis by both calpain isoforms. major phosphorylation sites: Ser233(for protein kinase A). Phosphorylation of connexin-32 by protein kinase C,but not by protein kinase A, prevents the proteolytic attack of p-calpain and m-calpain. Phosphorylation of connexin-32 by protein kinase A and protein kinase C does not prevent its proteolysis by papain, a-chymotrypsin, proteinase K, and trypsin 0.307 SIGNOR-249715 CASP3 protein P42574 UNIPROT PSIP1 protein O75475 UNIPROT down-regulates cleavage 9606 BTO:0001130 18708362 YES miannu Ledgf/ p75 has a cooh-terminally truncated splice variant, p52 / during apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the nh2-terminal pwwp domain and failed to transactivate the hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of ledgf/p75 0.349 SIGNOR-180144 Ub:E2 complex SIGNOR-C497 SIGNOR PEX2 protein P28328 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271058 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Tyr141 AITSPFKyQSLLTKN 10029 BTO:0000246 8557631 YES Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. 0.377 SIGNOR-251300 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 BTO:0000150;BTO:0000782 SIGNOR-C13 16046471 YES lperfetto Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k). We now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. Ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. 0.885 SIGNOR-138903 MRPS5 protein P82675 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.745 SIGNOR-261441 AXIN2 protein Q9Y2T1 UNIPROT APC protein P25054 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 YES gcesareni It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. 0.839 SIGNOR-79944 MAP3K5 protein Q99683 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity phosphorylation 9606 25249581 YES miannu ASK1 may directly phosphorylate IRE1\u03b1 at sites other than the IRE1\u03b1 autophosphorylation site. 0.618 SIGNOR-279213 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr425 KKCLELFtELAEDKE 9606 24117238 YES lperfetto Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity. 0.258 SIGNOR-202816 PRKACA protein P17612 UNIPROT THOP1 protein P52888 UNIPROT up-regulates activity phosphorylation Ser643 KVGMDYRsCILRPGG -1 10969067 YES miannu PKA phosphorylation is suggested to play a regulatory role in EP24.15 enzyme activity. Mutation analysis of each putative PKA site, in vitro phosphorylation, and phosphopeptide mapping indicated serine 644 as the phosphorylation site. The most dramatic change upon PKA phosphorylation was a substrate-specific, 7-fold increase in both K(m) and k(cat) for GnRH. 0.307 SIGNOR-250060 GSK3B protein P49841 UNIPROT CEBPA protein P49715 UNIPROT up-regulates activity phosphorylation Thr226 HLQPGHPtPPPTPVP 10090 BTO:0000944 10567568 YES Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes. 0.38 SIGNOR-251231 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser330 ASTGKSKsPCQTLGG 9606 23977114 YES lperfetto Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined 0.344 SIGNOR-202536 A2M protein P01023 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity binding -1 9344465 YES lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.491 SIGNOR-261801 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257923 SULT1E1 protein P49888 UNIPROT 17beta-estradiol 3-sulfate(1-) smallmolecule CHEBI:136582 ChEBI up-regulates quantity chemical modification -1 7779757 YES Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. 0.8 SIGNOR-269751 HIPK1 protein Q86Z02 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates activity phosphorylation Ser668 KKICTLPsPPSPLAS 9606 12529400 YES Manara HIPK1 phosphorylates Daxx on Ser 669, and phosphorylation of this site is important in modulating the ability of Daxx to function as a transcriptional repressor. | Therefore, phosphorylation at Ser 669 by HIPK1 diminishes the ability of Daxx to repress transcription. 0.612 SIGNOR-260842 IPO5 protein O00410 UNIPROT DSCAM protein O60469 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 30745319 YES miannu DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs. 0.2 SIGNOR-264273 motesanib chemical CHEBI:51098 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258253 MYC protein P01106 UNIPROT DHODH protein Q02127 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 YES miannu PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria. 0.346 SIGNOR-267382 GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.248 SIGNOR-268606 IL15RA protein Q13261 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates 9606 30029643 NO areggio Since recent study demonstrated desert Hedgehog (DHH) signaling can repressed FAP-derived adipocyte differentiation through Timp3 [30], we tested the mRNA expression of DHH and Timp3 in injured muscle with injection of IL-15. As expected, mRNA levels of DHH and Timp3 were both upregulated (Fig. 2f). 0.2 SIGNOR-256232 MTFP1 protein Q9UDX5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity relocalization 10090 BTO:0002572 28918902 NO Barakat Regardless of the precise mechanism, our data establish MTFP1 as an essential regulator of mitochondrial fission through the modulation of DRP1 phosphorylation and recruitment to the mitochondrion. 0.396 SIGNOR-275449 FBXW7 protein Q969H0 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR form complex binding 9606 15340381 YES gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. 0.905 SIGNOR-243766 CTF1 protein Q16619 UNIPROT GCH1 protein P30793 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12859689 NO miannu CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA. 0.2 SIGNOR-252218 CCKAR protein P32238 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 10088 BTO:0000944 12853286 YES Marta Tosoni Our studies indi-cate that CCK-A receptors inserted into NIH3T3 cellsalso activate RhoA through G12/13 0.25 SIGNOR-278063 GNA13 protein Q14344 UNIPROT ARHGEF28 protein Q8N1W1 UNIPROT up-regulates activity binding 9606 BTO:0000007 25922072 YES Marta Tosoni Taken together, the results suggest that active G13 and Gq form a complex with Rgnef and that G13 and Gq are upstream activators of Rgnef. 0.342 SIGNOR-278064 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation 9606 31226734 YES lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. 0.682 SIGNOR-265920 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 19115199 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-182996 GTF2H2 protein Q13888 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 YES lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.866 SIGNOR-269311 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser420 KHPTPGSsDPLIQPS -1 21204788 YES miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.255 SIGNOR-273931 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258287 MARCHF5 protein Q9NX47 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23253261 YES miannu Mfn1 is ubiquitylated by MARCH5 at G 2 / M phase and degraded in a proteasome dependent manner. 0.2 SIGNOR-278569 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser176 SSPTASGsSVSPGLY 9606 BTO:0000567 35469017 YES miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. 0.2 SIGNOR-276720 ATM protein Q13315 UNIPROT RRM2B protein Q7LG56 UNIPROT up-regulates phosphorylation Ser72 TAEEVDLsKDLPHWN 9606 19015526 YES lperfetto Atm-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53r2 protein against mdm2 to dna damage 0.513 SIGNOR-182423 PLIN3 protein O60664 UNIPROT M6PR protein P20645 UNIPROT up-regulates activity relocalization 9534 BTO:0004055 9590177 YES lperfetto TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi. 0.729 SIGNOR-253093 ZFP91 protein Q96JP5 UNIPROT HNRNPF protein P52597 UNIPROT down-regulates quantity ubiquitination Lys185 HRYIEVFkSSQEEVR 9606 29706618 YES miannu Collectively, our results indicate that ZFP91 polyubiquitinated hnRNP F at Lys 185.|We found that silencing ZFP91 increased hnRNP F protein levels, but not hnRNP F mRNA levels, while ectopically expressing ZFP91 decreased hnRNP F protein levels, but not hnRNP F mRNA levels. 0.2 SIGNOR-278802 PRKCA protein P17252 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates phosphorylation Ser25 KDEPQRRsARLSAKP 9606 10739259 YES lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. 0.29 SIGNOR-76320 TRAF2 protein Q12933 UNIPROT MAP4K2 protein Q12851 UNIPROT up-regulates binding 9606 9712898 YES gcesareni Both full-lenght gck and the gck-ctd can form complexes in vivo with traf2. 0.534 SIGNOR-59685 APEX1 protein P27695 UNIPROT TG protein P01266 UNIPROT up-regulates quantity by expression transcriptional regulation 9813166 YES lperfetto In co-transfection experiments, Ref-1 increases the Pax-8 activating effect on thyroglobulin promoter. 0.2 SIGNOR-271694 Caspase 3 complex complex SIGNOR-C221 SIGNOR Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 25787076 NO miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice. 0.7 SIGNOR-256476 CYCS protein P99999 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR form complex binding -1 10206961 YES lperfetto  APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9.  0.835 SIGNOR-256430 PRKN protein O60260 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization ubiquitination Lys477 LNQEVALkLEPNPES 9606 29180628 YES miannu These results indicate that Parkin inhibits HIF-1alpha transcriptional activity.|Ubiquitination of HIF-1alpha at lysine 477 by Parkin. 0.2 SIGNOR-278542 GNAS protein P63092 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 16293724 YES gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. 0.382 SIGNOR-141789 AKT2 protein P31751 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity phosphorylation Thr151 FCNGRGNtSGSHIVN 9606 BTO:0002181 35675814 YES miannu AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity 0.2 SIGNOR-277595 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 12832467 YES inferred from 70% family members lperfetto Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. 0.2 SIGNOR-270006 KCNJ8 protein Q15842 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 YES lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. 0.651 SIGNOR-262054 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.617 SIGNOR-273911 LRFN5 protein Q96NI6 UNIPROT PTPRF protein P10586 UNIPROT up-regulates activity binding 9606 BTO:0000938 27225731 YES miannu SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). 0.351 SIGNOR-264087 SRC protein P12931 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity phosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 25157176 YES Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis 0.774 SIGNOR-252093 MAPK1 protein P28482 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser62 SYTPTPRsPRFIGRR 9606 7901013 YES The effect has been demonstrated using P07101-2 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylase in vitro at comparable rates to other proteins thought to be physiological substrates of these protein kinases.The effect on activity of phosphorylating both ser31 and ser40 was not additive. The possible roles of mapkap kinase-1, mapkap kinase-2 and map kinase in the regulation of tyrosine hydroxylase in vivo are discussed. 0.442 SIGNOR-34674 NUP62 protein P37198 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates activity binding 9606 BTO:0000567 24107630 YES Simone Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles. 0.2 SIGNOR-261257 PRKCE protein Q02156 UNIPROT KCNK3 protein O14649 UNIPROT down-regulates activity phosphorylation Thr383 TGLHSLStFRGLMKR -1 23229553 YES miannu We have previously shown that carbamylated PAF-induced repolarization abnormalities result from the protein kinase C (PKC) ε-dependent phosphorylation of the two-pore domain potassium channel TASK-1. Further studies identified threonine 383 in the C terminus of human and canine TASK-1 as the phosphorylation site required for PAF-dependent inhibition of the channel. 0.2 SIGNOR-276431 VPS13B protein Q7Z7G8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 NO miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons 0.7 SIGNOR-266872 PRKD3 protein O94806 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 34010649 YES lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-275946 pemetrexed disodium chemical CHEBI:63722 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 YES miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). 0.8 SIGNOR-259290 UBE3C protein Q15386 UNIPROT CAND2 protein O75155 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000165 12692129 YES miannu We show that KIAA10 indeed associates with 26 S proteasomes in mammalian cells but that this interaction is likely to depend on contacts with a subunit(s) besides S2/Rpn1. Most importantly, we provide strong evidence that TIP120B (TBP-interacting protein 120B (22)) is a specific substrate that is targeted for degradation in skeletal muscle through KIAA10-catalyzed polyubiquitination. 0.391 SIGNOR-271454 Integrator complex complex SIGNOR-C265 SIGNOR H4C1 protein P62805 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 25675981 NO lperfetto Integrator-dependent function at promoter proximal sites that is unrelated to NELF-regulated pausing. Given its termination function at both the U2 snRNA and Histone H4 genes, we favor a model in which Integrator also has a termination function at promoter proximal sites. 0.2 SIGNOR-261481 FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 24627466 YES lperfetto Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. FST315-deltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. 0.728 SIGNOR-251717 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 9679146 YES gcesareni Pkc phosphorylation of native and recombinant adducin inhibited actin capping measured using pyrene-actin polymerization and abolished activity of adducin in recruiting spectrin to ends and sides of actin filaments 0.2 SIGNOR-59299 CHEK2 protein O96017 UNIPROT DNA2 protein P51530 UNIPROT up-regulates activity phosphorylation 9606 22682245 YES miannuccelli We later observed that Dna2 phosphorylation by Cds1 is necessary for Dna2 association with chromatin in HU treated cells. 0.526 SIGNOR-279729 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr472 EPIQEANyVPMTPGT 10090 10978177 YES HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin 0.501 SIGNOR-251314 BMPR1A protein P36894 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity 10090 8533096 NO ggiuliani We also examined whether TAK1 was activated by bone morphogenetic protein (BMP). BMP-4 also stimulated TAK1 activity in a time- and dose-dependent manner 0.41 SIGNOR-255815 EGFR protein P00533 UNIPROT GPRC5A protein Q8NFJ5 UNIPROT down-regulates activity phosphorylation Tyr317 EETGDTLyAPYSTHF 9606 25311788 YES miannu EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells. 0.387 SIGNOR-278333 TLN1 protein Q9Y490 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.585 SIGNOR-257617 CTDP1 protein Q9Y5B0 UNIPROT MASTL protein Q96GX5 UNIPROT down-regulates activity dephosphorylation Ser453 NFELVDSsPCKKIIQ 9606 26653855 YES lperfetto Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl. 0.434 SIGNOR-276971 FOXO proteinfamily SIGNOR-PF27 SIGNOR FASLG protein P48023 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10102273 NO gcesareni Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene. 0.2 SIGNOR-252942 PRKCD protein Q05655 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser60 VVGARRSsWRVISSI 9606 16024783 YES gcesareni We provide a mechanism for these observations through the phosphorylation of 14-3-3 by ikk and pkc on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm. 0.494 SIGNOR-138612 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser33 LRRSQRKsGSELPSI -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.71 SIGNOR-276124 SIRT7 protein Q9NRC8 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity deacetylation Lys600 HFKQSAEkLIEEKGA 28790157 YES lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. 0.26 SIGNOR-275905 ANO6 protein Q4KMQ2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 24663380 NO miannu Using a shRNA KD approach, we show that Ano6-KD C2C12 myoblasts exhibit reduced proliferation capacity. Our data demonstrate that Ano6 is required to maintain the proliferative status of myoblasts. 0.7 SIGNOR-261213 tryptophan smallmolecule CHEBI:27897 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264743 MIPOL1 protein Q8TD10 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity 9606 31609475 NO miannu In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9 0.2 SIGNOR-261136 ARHGAP11A protein Q6P4F7 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.547 SIGNOR-260466 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr191 LDGSREyVNVSQE 9606 29915297 YES Isoform O43561-2 Barakat In the presence of the catalytically inactive LckK273R, the phosphorylation of LAT Y132 and Y191 residues by Zap70K362E were considerably increased 0.769 SIGNOR-274562 PAK3 protein O75914 UNIPROT PAK3 protein O75914 UNIPROT up-regulates activity phosphorylation Ser154 VNNQKYMsFTSGDKS -1 11278486 YES miannu Both in vivo and in vitro analyses demonstrate that, although most phosphorylation events in the PAK N-terminal regulatory domain play no direct role in activation, a phosphorylation of alphaPAK serine 144 or betaPAK serine 139, which lie in the kinase inhibitory domain, significantly contribute to activation.  0.2 SIGNOR-250245 SMAD4 protein Q13485 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 0.721 SIGNOR-235178 HTR4 protein Q13639 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257367 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251591 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM25 protein Q14258 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271155 ASB4 protein Q9Y574 UNIPROT ID2 protein Q02363 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001975 24586788 YES miannu Using JAR placental cells, we determined that ASB4 ubiquitinates and represses ID2 expression in a proteasome-dependent fashion.  0.341 SIGNOR-272053 NFATC1 protein O95644 UNIPROT PLAUR protein Q03405 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23015147 YES Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays. 0.2 SIGNOR-253336 bortezomib chemical CHEBI:52717 ChEBI PSMB5 protein P28074 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000567 19428245 YES Luana MG-132, which was one of the first synthetic inhibitors, interacts reversibly with the N-terminal threonine residue of the β5 active site. 0.8 SIGNOR-257820 NCL protein P19338 UNIPROT MYB protein P10242 UNIPROT down-regulates activity binding 9606 BTO:0000007 10660576 YES miannu We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity. 0.402 SIGNOR-221236 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB4 protein Q9UN71 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265679 PTBP2 protein Q9UKA9 UNIPROT KHSRP protein Q92945 UNIPROT up-regulates activity binding 9606 BTO:0000567 11003644 YES lperfetto Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA. 0.464 SIGNOR-261268 Galanin smallmolecule CHEBI:80161 ChEBI GALR3 protein O60755 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257496 PTEN protein P60484 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000356 10400703 YES The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN dephosphorylates phosphatidylinositol 3,4, 5-trisphosphate (PIP3) and focal adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and focal adhesions. We investigated molecular interactions of PTEN and FAK in glioblastoma and breast cancer cells lacking PTEN. The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr397 0.821 SIGNOR-248547 CAMK2G protein Q13555 UNIPROT PLCB3 protein Q01970 UNIPROT unknown phosphorylation Ser537 PSLEPQKsLGDEGLN 11325525 YES llicata CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment 0.378 SIGNOR-250702 JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 24315690 YES miannu In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity 0.817 SIGNOR-253340 FOXO proteinfamily SIGNOR-PF27 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 18423396 NO fspada Akt1/pkbalpha was found to be the major regulator of phosphorylation and nuclear export offoxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. 0.7 SIGNOR-252911 PPP2CA protein P67775 UNIPROT STK4 protein Q13043 UNIPROT down-regulates dephosphorylation Thr183 DTMAKRNtVIGTPFW 9606 23431053 YES gcesareni Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively. 0.368 SIGNOR-201270 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0000680 16039586 YES inferred from 70% family members lperfetto Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. 0.2 SIGNOR-270059 WEE1 protein P30291 UNIPROT PLRG1 protein O43660 UNIPROT down-regulates activity phosphorylation 9606 33450002 YES miannu These results indicate that WEE1 promotes PRL1 phosphorylation.|WEE1 promotes PRL1 degradation . 0.2 SIGNOR-279579 RIMS2 protein Q9UQ26 UNIPROT UNC13B protein O14795 UNIPROT up-regulates activity relocalization 9606 31679900 YES miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle 0.358 SIGNOR-264383 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 YES lperfetto Erk phosphorylates threonine 42 residue of ribosomal protein s3. 0.351 SIGNOR-137175 N protein P59595 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates activity binding 9606 18448518 YES lperfetto The nucleocapsid protein of severe acute respiratory syndrome coronavirus inhibits cell cytokinesis and proliferation by interacting with translation elongation factor 1alpha 0.2 SIGNOR-260260 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 YES The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. 0.2 SIGNOR-270069 MYO5A protein Q9Y4I1 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 21077886 YES miannu Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis 0.41 SIGNOR-269280 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1387 GRCPSDPyKHSLPSQ -1 10195142 YES lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. 0.568 SIGNOR-247171 RIOK3 protein O14730 UNIPROT IFIH1 protein Q9BYX4 UNIPROT down-regulates activity phosphorylation Ser828 GRARADEsTYVLVAH 9606 BTO:0000007 25865883 YES lperfetto RIOK3 mediates phosphorylation of MDA5 Ser-828|RIOK3-mediated phosphorylation of MDA5 interferes with its assembly and attenuates the innate immune response 0.468 SIGNOR-264576 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys206 DLINLAKkRTNIIPV 30540930 YES lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) 0.27 SIGNOR-275897 APC protein P25054 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR form complex binding 9606 9734785 YES lperfetto Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level. 0.851 SIGNOR-227296 TINF2 protein Q9BSI4 UNIPROT Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 BTO:0000567 15383534 YES lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. 0.887 SIGNOR-263320 EGFR protein P00533 UNIPROT GPRC5A protein Q8NFJ5 UNIPROT down-regulates activity phosphorylation Tyr347 AHAWPSPyKDYEVKK 9606 25311788 YES miannu EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells. 0.387 SIGNOR-278335 PHF2 protein O75151 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000007 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. 0.2 SIGNOR-264518 NFKB1 protein P19838 UNIPROT CTCF protein P49711 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21912613 NO miannu In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription. 0.304 SIGNOR-254788 DZIP3 protein Q86Y13 UNIPROT H2AC20 protein Q16777 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHKA 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271754 PKA proteinfamily SIGNOR-PF17 SIGNOR GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1166 SDDFKRDsVSGGGPC 9606 BTO:0000007 24431445 YES miannu Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. 0.2 SIGNOR-276617 Ub:E2 complex SIGNOR-C497 SIGNOR RFWD3 protein Q6PCD5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270991 DDX3X protein O00571 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 33627125 YES miannu DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2 0.354 SIGNOR-269195 TBX2 protein Q13207 UNIPROT MYOG protein P15173 UNIPROT down-regulates activity binding 9606 24470334 YES We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity. 0.249 SIGNOR-251561 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259792 BRCC3 protein P46736 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 YES lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  0.928 SIGNOR-263213 SMG1 protein Q96Q15 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 15175154 YES gcesareni Hsmg-1 is a stress-activated kinase that phosphorylates p53 and hupf1 in vitrothe observation that hsmg-1 exhibits p53 (ser-15) kinase activity in vitro suggested that this pikk might be involved in genotoxic stress-induced p53 phosphorylation and stabilization in intact cells. 0.412 SIGNOR-125135 RUNX2 protein Q13950 UNIPROT ALPL protein P05186 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 NO gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast 0.46 SIGNOR-107123 PAK2 protein Q13177 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation 9606 14673144 YES miannu This is supported by in vitro studies showing that Pak2 phosphorylates and activates Syk. 0.271 SIGNOR-279083 ARHGEF3 protein Q9NR81 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.776 SIGNOR-260530 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Ser27 PFRDSPLsSRLLDDG 9606 22721717 YES lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation 0.341 SIGNOR-197932 SRC protein P12931 UNIPROT NELFCD protein Q8IXH7 UNIPROT down-regulates activity phosphorylation Tyr14 GAIMDEDyYGSAAEW 9534 22238675 YES miannu  Here we show that c-Src interacts with TH1 by GST-pull down assay, coimmunoprecipitation and confocal microscopy assay. The interaction leads to phosphorylation of TH1 at Tyr-6 in vivo and in vitro. Phosphorylation of TH1 decreases its association with A-Raf and PAK1. 0.337 SIGNOR-276402 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 9677429 YES MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. lperfetto The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. 0.2 SIGNOR-244802 CDK1 protein P06493 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates phosphorylation Ser668 IGEETDSsPGRKKFP 9606 19881501 YES gcesareni Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce. 0.345 SIGNOR-189017 IDH2 protein P48735 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI down-regulates quantity 9606 26178471 YES lperfetto Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG) 0.8 SIGNOR-253136 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Val72 GLTEYRLvSINKSSP -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.431 SIGNOR-263567 AKT proteinfamily SIGNOR-PF24 SIGNOR S1PR1 protein P21453 UNIPROT up-regulates activity phosphorylation Thr236 RTRSRRLtFRKNISK 9606 11583630 YES lperfetto Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis 0.2 SIGNOR-110845 EP300 protein Q09472 UNIPROT PLAGL2 protein Q9UPG8 UNIPROT up-regulates acetylation 9606 16207715 YES miannu Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7. 0.2 SIGNOR-140947 LNX1 protein Q8TBB1 UNIPROT ABCA1 protein O95477 UNIPROT down-regulates quantity by destabilization ubiquitination -1 22889411 YES miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. 0.242 SIGNOR-272902 CEBPB protein P17676 UNIPROT GOT1 protein P17174 UNIPROT up-regulates quantity by expression transcriptional regulation 8454627 YES In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells. Deletion studies revealed that regions P2 and P4 are critical for promoter activity. In gel retardation experiments, the P4 region bound different C/EBP-related proteins in different tissues 0.2 SIGNOR-254051 MAPK1 protein P28482 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates phosphorylation Ser77 TQTLSPAsPSQGVML 9606 BTO:0000785 22258404 YES llicata Phosphomimetic mutation of this site (s74d) moderately enhanced bmf apoptotic activity in vivo.22 here, we demonstrate a previously unrecognized mode of regulation of bmf. We show that b-raf-mek-erk2 signaling regulates bmf phosphorylation at serine 74 and serine 77. Phosphorylation of serine 77 downregulates the pro-apoptotic activity of bmf. 0.253 SIGNOR-195475 NOTCH1 protein P46531 UNIPROT IL7R protein P16871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 NO miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. 0.321 SIGNOR-197452 PML protein P29590 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 15356634 YES lperfetto Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. 0.546 SIGNOR-232090 SH3PXD2A protein Q5TCZ1 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 YES lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation 0.409 SIGNOR-264708 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 9606 BTO:0000567 9398320 YES lperfetto Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)]. 0.498 SIGNOR-53739 ANXA3 protein P12429 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 27995049 NO miannu We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. 0.281 SIGNOR-262212 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT up-regulates activity phosphorylation Ser825 GGGQAKTsPKPAVVE 9606 BTO:0000567 25097229 YES miannu Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins. 0.2 SIGNOR-277833 PTK2B protein Q14289 UNIPROT TGFB1I1 protein O43294 UNIPROT up-regulates activity phosphorylation Tyr60 SGDKDHLySTVCKPR 9534 10838081 YES miannu Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5. 0.712 SIGNOR-262876 CDC20 protein Q12834 UNIPROT SP100 protein P23497 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 22086178 YES miannu Cdc20 is a co-activator of the anaphase-promoting complex/cyclosome (APC/C complex), which recruits substrates at particular phases of the cell cycle and mediates their degradation. Overexpression of Cdc20 resulted in decreased levels of both endogenous Sp100 protein and overexpressed Sp100 mRNA in HEK 293 cells. Our results suggested that sp100 is a novel substrate of Cdc20 and it is degraded by the ubiquitination pathway. The intact D-box of Sp100 was necessary for this process. 0.2 SIGNOR-272724 PLK1 protein P53350 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Ser20 FLKDHRIsTFKNWPF 9606 21148584 YES lperfetto Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation|SUR (survivin) 0.582 SIGNOR-170460 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1724 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248776 mTORC1 complex SIGNOR-C3 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 19593385 NO lperfetto Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation. 0.7 SIGNOR-235349 F2RL1 protein P55085 UNIPROT DUSP6 protein Q16828 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254853 LYN protein P07948 UNIPROT NLRP3 protein Q96P20 UNIPROT down-regulates phosphorylation Tyr918 NQNLTHLyLRGNTLG 9606 34699250 YES miannu Lyn phosphorylates NLRP3 at Tyr 918 and controls NLRP3 ubiquitination.|Therefore, our data collectively indicate that Lyn inhibits the NLRP3 inflammasome in vivo. 0.29 SIGNOR-278485 MRGPRX2 protein Q96LB1 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256930 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.334 SIGNOR-269258 CSK protein P41240 UNIPROT FGR protein P09769 UNIPROT down-regulates activity phosphorylation Tyr523 FTSAEPQyQPGDQT -1 7515063 YES llicata CSK catalyzed phosphorylation affects Tyr-511 of c-Fgr, homologous to Tyr-527 of c-Src and it prevents the autophosphorylation normally occurring at c-Fgr Tyr-400, homologous to c-Src Tyr-416. | Once phosphorylated at Tyr-511 and down-regulated by CSK, c-Fgr is no more susceptible to polylysine stimulation. 0.536 SIGNOR-250779 PTPN6 protein P29350 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 YES SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397 0.733 SIGNOR-248471 IL6ST protein P40189 UNIPROT YES1 protein P07947 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000584 31296870 YES miannu Binding of LIF to the LIFR-gp130 receptor complex has been previously shown to activate YES and YAP/TAZ-TEAD -dependent transcription, which is required to maintain self-renewal in embryonic stem cells 0.2 SIGNOR-278033 GDP smallmolecule CHEBI:17552 ChEBI GNAS protein P63092 UNIPROT down-regulates chemical inhibition 9606 17095603 YES gcesareni Galfa subunits cycle between inactive (GDP-bound) and active (GTP-bound) states, and the lifetime of the active state is limited by GTP hydrolysis. 0.8 SIGNOR-253072 PFDN2 protein Q9UHV9 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 YES miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) 0.951 SIGNOR-270931 WNT9B protein O14905 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 YES gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. 0.2 SIGNOR-195978 prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI up-regulates quantity precursor of -1 10922363 YES Luana Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently. 0.8 SIGNOR-269765 CCL2 protein P13500 UNIPROT Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 NO miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. 0.7 SIGNOR-260849 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.322 SIGNOR-129324 PTEN protein P60484 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 BTO:0001332 19903340 NO lperfetto PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression 0.635 SIGNOR-189105 MAPK14 protein Q16539 UNIPROT NFATC4 protein Q14934 UNIPROT down-regulates activity phosphorylation Ser168 QGGGAFFsPSPGSSS 10029 BTO:0001131 11997522 YES miannu P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity. 0.403 SIGNOR-250107 everolimus chemical CHEBI:68478 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 20689758 YES gcesareni M14, m288, and skmel28 (sensitive and resistant) were exposed to rad001, an mtor inhibitor, and to ly294002, a pi3k inhibitor. 0.8 SIGNOR-167402 GATA1 protein P15976 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity binding 9606 17725493 YES miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation. 0.642 SIGNOR-254194 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 12869565 YES gcesareni Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols. 0.537 SIGNOR-103721 MKNK1 protein Q9BUB5 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007 10978317 YES lperfetto The results suggest that MNK1 or a closely related kinase is responsible for in vivo phosphorylation of cPLA2 on Ser-727. 0.576 SIGNOR-226633 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9534 BTO:0004055 11445557 YES lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. 0.676 SIGNOR-246368 ROS stimulus SIGNOR-ST2 SIGNOR Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 9606 32454942 NO miannu Next to their interaction with adaptive immune cells, activated microglia can secrete cytotoxic cytokines and oxidative products, such as ROS and NO radicals in MS lesions thereby promoting oxidative stress and contributing to myelin destruction 0.7 SIGNOR-263828 WDR45 protein Q9Y484 UNIPROT ATG2B protein Q96BY7 UNIPROT up-regulates activity binding 9606 BTO:0001938 28561066 YES miannu WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. 0.649 SIGNOR-268484 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.2 SIGNOR-275952 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr740 TGESDGGyMDMSKDE -1 7545675 YES Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides 0.69 SIGNOR-248413 ARID2 protein Q68CP9 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES lperfetto We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.722 SIGNOR-241756 CREBBP protein Q92793 UNIPROT DDX21 protein Q9NR30 UNIPROT down-regulates activity acetylation Lys137 PKKMKKEkEMNGETR 28790157 YES lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. 0.245 SIGNOR-275904 HDAC2 protein Q92769 UNIPROT MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR form complex binding 9606 BTO:0000567 9620804 YES Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. 0.722 SIGNOR-267736 ZAP70 protein P43403 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates activity phosphorylation Tyr138 SPTLVIAyLMMRQKM 9534 BTO:0001538 12447358 YES miannu ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).  0.532 SIGNOR-276000 RAD50 protein Q92878 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 YES gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. 0.813 SIGNOR-181634 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna 0.428 SIGNOR-171030 WNT11 protein O96014 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 7227 10862746 YES gcesareni Consistent with this, xfz7 biochemically and functionally interacts with xwnt11 0.711 SIGNOR-78406 KLHL42 protein Q9P2K6 UNIPROT PPP2R5E protein Q16537 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys84 MDTLSDLkMKEYKRS 9606 BTO:0000764 32071084 YES miannu PPP2R5ϵ is a KLHL42 substrate and affects TGF-β signaling in SSc. Lys-84 is a candidate ubiquitin acceptor site within PPP2R5ϵ. 0.2 SIGNOR-272205 RAC1 protein P63000 UNIPROT USP6 protein P35125 UNIPROT up-regulates relocalization 9606 12612085 YES miannu In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin. 0.339 SIGNOR-98938 DNA_damage stimulus SIGNOR-ST1 SIGNOR ERCC6 protein Q03468 UNIPROT up-regulates 24086043 NO lperfetto TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. 0.7 SIGNOR-275691 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT down-regulates activity phosphorylation Thr198 DEEEEIAtPPPPPPP 10090 BTO:0000944 14754904 YES miannu Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. A lower level of phosphorylation was observed for the double mutant, suggesting that T332 might also be phosphorylated by cdc2 kinase. 0.265 SIGNOR-262727 ZFP36 protein P26651 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 25815583 YES The TTP binding site in the 3′ UTR of MyoD would permit TTP-mediated mRNA decay 0.292 SIGNOR-253597 TLN1 protein Q9Y490 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.528 SIGNOR-257637 GLI2 protein P10070 UNIPROT IFITM5 protein A6NNB3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23530031 NO miannu Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation. 0.2 SIGNOR-254217 Laminin-8 complex SIGNOR-C181 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.537 SIGNOR-253220 CDK2 protein P24941 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 18617527 YES miannu Interaction between SHP-1 and Cdk2 was confirmed by co-immunoprecipitations whereby co-precipitated Cdk2 phosphorylated SHP-1 protein. 0.287 SIGNOR-279147 MAPK8 protein P45983 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates activity phosphorylation 9606 10075927 YES miannu JNK1 phosphorylates E2F1 in vitro, and co-transfection of JNK1 reduces the DNA binding activity of E2F1 0.277 SIGNOR-279218 CSNK2A1 protein P68400 UNIPROT HOXB7 protein P09629 UNIPROT down-regulates activity phosphorylation Thr204 KTAGPGTtGQDRAEA 10090 BTO:0002882 11290787 YES llicata Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation. 0.345 SIGNOR-250897 Caspase 3 complex complex SIGNOR-C221 SIGNOR DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 10200555 NO amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation 0.7 SIGNOR-256478 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR LAMP2 protein P13473 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 28743755 YES miannu Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment.We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy. 0.258 SIGNOR-272324 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-268116 carbachol chemical CHEBI:3385 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258618 ZNHIT1 protein O43257 UNIPROT H2AZ1 protein P0C0S5 UNIPROT unknown 9606 BTO:0000887 20473270 NO gcesareni The chromatin-remodelling complex snf2-related cbp activator protein (srcap) regulates chromatin structure in yeast by modulating the exchange of histone h2a for the h2a.z variant. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation. 0.2 SIGNOR-165610 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000661 15870263 YES gianni In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits. 0.547 SIGNOR-266436 EEF1A1P5 protein Q5VTE0 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269550 HMOX1 protein P09601 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000356 26722274 NO irozzo Heme oxygenase-1 (HO-1) protects endothelial cells (EC) from undergoing apoptosis. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy. 0.7 SIGNOR-256559 ULK2 protein Q8IYT8 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity phosphorylation Ser74 EATWESVsMMLQLGG 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274043 Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT IFIH1 protein Q9BYX4 UNIPROT down-regulates activity 9606 28158275 NO miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. 0.2 SIGNOR-260245 MDM2 protein Q00987 UNIPROT HEXIM1 protein O94992 UNIPROT up-regulates activity ubiquitination 9606 19617712 YES miannu Here we report that human double minute-2 protein (HDM2), a p53-specific E3 ubiquitin ligase, specifically ubiquitinates HEXIM1 through the lysine residues located within the basic region of HEXIM1.|However, the HDM2-induced HEXIM1 ubiquitination does not lead to proteasome-mediated protein degradation. 0.466 SIGNOR-278701 CEBPB protein P17676 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12493739 NO miannu The C/EBP5 motif, which is located between the TATA-box and the translation start point, is essential for the C/EBP-mediated constitutive and most of the cAMP-stimulated expression as its mutation nearly abolished IL-10 promoter activity. Our results suggest a dominant role of C/EBP transcription factors relative to CREB/ATF in tissue-specific and differentiation-dependent IL-10 transcription 0.356 SIGNOR-254523 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT up-regulates activity phosphorylation Tyr448 GDDSDEDyEKVPLPN 9534 BTO:0004055 12709437 YES lperfetto By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk. 0.553 SIGNOR-246596 TBX5 protein Q99593 UNIPROT MTSS1 protein O43312 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20802524 NO miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. 0.25 SIGNOR-255254 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-201695 Ub:E2 complex SIGNOR-C497 SIGNOR TMEM129 protein A0AVI4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271265 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 21779440 YES gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity 0.679 SIGNOR-89818 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 21415216 YES irozzo We also found that phosphorylation of both the mitogen-activated proteinkinase (MAPK) ERK and STAT3 was markedly increased inthe cells expressing either variant of EML4-ALK[.]. Oncogenic EML4-ALK tyrosine kinase activates ERKand STAT3 signaling pathways 0.2 SIGNOR-259203 RPL22 protein P35268 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.856 SIGNOR-262499 RIPK2 protein O43353 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser435 EMFSGELsWSADSIR 9606 22412986 YES lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay 0.305 SIGNOR-196520 LRRK2 protein Q5S007 UNIPROT SNAPIN protein O95295 UNIPROT down-regulates phosphorylation Thr117 NHSVAKEtARRRAML 9606 BTO:0000938 BTO:0000142 23949442 YES lperfetto Lrrk2 phosphorylates snapin and inhibits interaction of snapin with snap-25. these data suggest that lrrk2 may regulate neurotransmitter release via control of snapin function by inhibitory phosphorylation. hreonine 117 of snapin is one of the sites phosphorylated by lrrk2 0.515 SIGNOR-202436 AGTR1 protein P30556 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.642 SIGNOR-257017 MDM2 protein Q00987 UNIPROT SIRT6 protein Q8N6T7 UNIPROT down-regulates quantity ubiquitination 9606 25074979 YES miannu These results suggest that MDM2 degrades SIRT6 in a proteasome dependent manner.|USP10 has been shown to deubiquitinate and stabilize p53, a well-known substrate of MDM2, suggesting a mechanism whereby SIRT6 is ubiquitinated and destabilized by MDM2, which could be reversed by USP10 mediated deubiquitination. 0.416 SIGNOR-278702 ATF4 protein P18848 UNIPROT AARS2 protein Q5JTZ9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.244 SIGNOR-269415 AKT proteinfamily SIGNOR-PF24 SIGNOR RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Thr70 GRRIRELtAVVQKRF 10116 BTO:0003060 20605787 YES miannu Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage. 0.2 SIGNOR-259816 ELOB protein Q15370 UNIPROT Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR form complex binding 10090 BTO:0000165 19300455 YES miannu Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation.  Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb. 0.2 SIGNOR-271796 IL4R protein P24394 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity 10090 23582327 NO Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes 0.7 SIGNOR-256482 FOXJ1 protein Q92949 UNIPROT CETN2 protein P41208 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.353 SIGNOR-266930 HNF1A protein P20823 UNIPROT UGT1A8 protein Q9HAW9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 YES Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. 0.281 SIGNOR-253972 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257746 RBL2 protein Q08999 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 10090 BTO:0000165 10801445 NO gcesareni Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program. 0.7 SIGNOR-241946 CSNK1E protein P49674 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 12000790 YES gcesareni We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms. 0.746 SIGNOR-87444 AAK1 protein Q2M2I8 UNIPROT AP2M1 protein Q96CW1 UNIPROT up-regulates phosphorylation Thr156 SQITSQVtGQIGWRR 9606 BTO:0000938 11877461 YES lperfetto Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis. 0.79 SIGNOR-115657 NAA20 protein P61599 UNIPROT NatB complex SIGNOR-C416 SIGNOR form complex binding 9606 18570629 YES miannu In the present study we present the components of hNatB (human NatB complex). It consists of the Nat3p homologue hNAT3 (human N-acetyltransferase 3) and the Mdm20p homologue hMDM20 (human mitochondrial distribution and morphology 20). They form a stable complex and in vitro display sequence-specific N(alpha)-acetyltransferase activity on a peptide with the N-terminus Met-Asp-. 0.89 SIGNOR-267230 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.91 SIGNOR-252821 CLK2 protein P49760 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation -1 8617202 YES miannu In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors. 0.298 SIGNOR-273858 SYK protein P43405 UNIPROT LAX1 protein Q8IWV1 UNIPROT up-regulates activity phosphorylation Tyr193 SSEDSHDyVNVPTAE 9606 BTO:0000007 12359715 YES miannu Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85.  0.378 SIGNOR-273532 PRKACA protein P17612 UNIPROT CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser40 PKRRRASsLSRDAER 27149373 YES lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. 0.253 SIGNOR-275629 MAPK10 protein P53779 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 14699954 YES amattioni The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53 0.628 SIGNOR-120552 HOXA13 protein P31271 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16314414 NO miannu We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation. 0.291 SIGNOR-142428 BCL3 protein P20749 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates activity binding 9606 BTO:0004298 21912613 YES miannu In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription. 0.586 SIGNOR-254789 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 SIGNOR-C110 23579495 YES lperfetto Phosphorylation by GSK3 kept Axin activated (open) for _-catenin interaction and poised for engagement of LRP6. 0.92 SIGNOR-201683 ZDHHC2 protein Q9UIJ5 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity palmitoylation Cys3 cLCIVTTK 9606 23836932 YES Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation. 0.38 SIGNOR-262296 EIF1AY protein O14602 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity relocalization 9606 12514125 YES lperfetto Translation initiation factor 1A (eIF1A) is predicted to bind in the decoding site of the 40S ribosome and has been implicated in recruitment of the eIF2-GTP-Met-tRNA i Met ternary complex (TC) and ribosomal scanning.  0.2 SIGNOR-269148 GRP protein P07492 UNIPROT GRPR protein P30550 UNIPROT up-regulates binding 9606 17251915 YES gcesareni Indeed, many potent mitogens such as thrombin, lysophosphatidic acid (lpa), gastrin-releasing peptide (grp), endothelin and prostaglandins stimulate cell proliferation by acting on their cognate gpcrs in various cell types. 0.784 SIGNOR-152676 PTK2B protein Q14289 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity phosphorylation Tyr486 YPAEDSTyDEYENDL 9606 29133485 YES miannu In conclusion, these data suggest that Pyk2 phosphorylates cortactin on tyrosine residues Y421, Y466, and Y482.|To confirm the direct and indirect effects of Pyk2 on cortactin phosphorylation, we used cells overexpressing Arg YFP and treated with Pyk2 siRNA or a nonsilencing siRNA. 0.366 SIGNOR-278345 RFX5 protein P48382 UNIPROT RFX complex complex SIGNOR-C104 SIGNOR form complex binding -1 10825209 YES miannu RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes 0.892 SIGNOR-221565 HES1 protein Q14469 UNIPROT CTNND2 protein Q9UQB3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001033 21106062 NO miannu Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression. 0.346 SIGNOR-251877 SP1 protein P08047 UNIPROT SCNN1A protein P37088 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 12684058 NO Regulation of expression miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. 0.2 SIGNOR-251950 SRC protein P12931 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 11483655 YES lperfetto We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases 0.56 SIGNOR-247180 ERG protein P11308 UNIPROT ENG protein P17813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22235125 NO miannu It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1. 0.2 SIGNOR-253916 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr133 EMPSEEGyQDYEPEA 9606 BTO:0000975;BTO:0000142 11744621 YES llicata Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers. 0.53 SIGNOR-113065 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val48 KVDGTSHvTGKGVTV -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.374 SIGNOR-263598 MUL1 protein Q969V5 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity ubiquitination Lys224 PNIRFLDkLPQQTGD 9606 28763789 YES miannu Identification of MUL1 as an essential activator of dsDNA mediated STING dependent pathway.|We further report that the mitochondrial E3 ubiquitin protein ligase 1 (MUL1, also known as GIDE/MAPL/MULAN/RNF218) ubiquitinates STING on K224 via K63-linked polyubiquitination, which facilitates optimal STING trafficking and the transcription of host defense genes. 0.2 SIGNOR-278634 7a protein P59635 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 17428862 YES Luana In this study, we show that the overexpression of Bcl-XL, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family. 0.2 SIGNOR-261075 E protein P59637 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity 9606 BTO:0000661 16048439 NO Luana SARS-CoV E protein induces apoptosis by ‘sequestering’ Bcl-xL to the membranes of ER and Golgi, where the SARS-CoV E protein is located. As a consequence, the existing balance between pro-survival protein Bcl-xL and pro-apoptotic proteins, including Bax and BH3-domain-only proteins, is tipped by SARS CoV E protein, so that sequestered Bcl-xL could not fulfil its normal function in inhibition of apoptosis. | This result implied that SARS-CoV E protein might induce T-cell apoptosis via a pathway antagonistic to the mitochondrion-dependent mechanism of Bcl-xL. 0.2 SIGNOR-260586 FN1/SDC4 complex SIGNOR-C210 SIGNOR WNT7A protein O00755 UNIPROT up-regulates 23290138 YES apalma We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells 0.312 SIGNOR-255287 PTAFR protein P25105 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257329 USP22 protein Q9UPT9 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.664 SIGNOR-269578 BLOC1S2 protein Q6QNY1 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 YES lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. 0.726 SIGNOR-265937 CDC25A protein P30304 UNIPROT DYRK2 protein Q92630 UNIPROT down-regulates activity dephosphorylation 9606 34363019 YES miannu Finally, DYRK2 is dephosphorylated by CDC25A, suggesting a feedback regulatory loop.|Notably, the co-expression of CDC25A inhibited the DYRK2 pro-apoptotic effect (Fig.\u00a06D), concurring with a possible inhibitory role on DYRK2 activity and further suggesting that the effect of DYRK2 was dependent on CDC25A. 0.2 SIGNOR-277098 PRKCG protein P05129 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser619 SLPKINRsASEPSLH 9606 8288587 YES gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. 0.401 SIGNOR-37545 SGK1 protein O00141 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates activity phosphorylation Ser274 LERERPLsLLQLLGS 8355 BTO:0000887 17382906 YES lperfetto We evaluated the putative role of sgk1 in the modulation of glut4. Coexpression of the kinase along with glut4 in xenopus oocytes stimulated glucose transport. The enhanced glut4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the sgk1 phosphorylation site on glut4 ((s274a)glut4) abrogated the stimulating effect of sgk1. In summary, sgk1 promotes glucose transporter membrane abundance via glut4 phosphorylation at ser274. 0.313 SIGNOR-236653 SNCA protein P37840 UNIPROT CADPS2 protein Q86UW7 UNIPROT down-regulates quantity transcriptional regulation 9606 28647363 NO gianni This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells. 0.275 SIGNOR-268929 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser546 SMSEFLEsEDGEVEQ 25855382 YES lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro 0.362 SIGNOR-275556 CKM complex complex SIGNOR-C406 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates activity phosphorylation Ser375 PVDEDRLsPLVAADS 9606 18794899 YES lperfetto E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. 0.362 SIGNOR-273149 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser441 GHSPLSLsAQSVMEE 9606 BTO:0000938 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.542 SIGNOR-204708 EFNA2 protein O43921 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 10072375 YES tpavlidou Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8) 0.815 SIGNOR-65413 PIAS4 protein Q8N2W9 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 12904571 YES lperfetto Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity. 0.602 SIGNOR-217731 SMAD2 protein Q15796 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 9670020 YES lperfetto Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4 0.2 SIGNOR-232149 CSKMT protein A8MUP2 UNIPROT CS protein O75390 UNIPROT down-regulates activity methylation Lys395 LLEQGKAkNPWPNVD 34929314 YES lperfetto A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate. 0.2 SIGNOR-267637 ADORA2A protein P29274 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.316 SIGNOR-256909 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr651 ALGGKAAyRTSPRLK -1 10210201 YES llicata Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624. 0.572 SIGNOR-250783 CDX2 protein Q99626 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR form complex binding 9606 10506141 YES lperfetto In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300. 0.366 SIGNOR-70954 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L6 protein O14933 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.647 SIGNOR-271319 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser5 sSQKRHWT 9606 10993082 YES gcesareni Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth. 0.646 SIGNOR-82037 KCNS1 protein Q96KK3 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 10029 BTO:0000246 10484328 YES miannu We describe the cloning and characterization of the first human members, hKv9.1 and hKv9.3, of the electrically silent delayed-rectifying-like K+ channel subfamily. 0.8 SIGNOR-269449 HDAC2 protein Q92769 UNIPROT HPGD protein P15428 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19010907 NO miannu We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. 0.2 SIGNOR-254236 DUSP3 protein P51452 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 YES Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2 0.671 SIGNOR-248536 LHX2 protein P50458 UNIPROT MSX1 protein P28360 UNIPROT down-regulates activity binding -1 9697309 YES 2 miannu Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity 0.478 SIGNOR-241327 ADAM12 protein O43184 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 BTO:0000975 12509413 YES gcesareni The adam12 cysteine-rich domain (radam12-cys) supports cell attachment using syndecan-4 as a primary cell surface receptor that subsequently triggers beta(1) integrin-dependent cell spreading, stress fiber assembly, and focal adhesion formation. 0.464 SIGNOR-96931 ESRRA protein P11474 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000159 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.2 SIGNOR-253799 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257988 PPP2R1A protein P30153 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR form complex binding 9606 23454242 YES gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. 0.887 SIGNOR-243445 POU5F1 protein Q01860 UNIPROT RARG protein P13631 UNIPROT up-regulates quantity 27499297 NO SimoneGraziosi OCT4 positively controls the level of RARgamma 0.302 SIGNOR-269222 POLR2E protein P19388 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 YES miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  0.2 SIGNOR-270923 PRKCE protein Q02156 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276020 sorafenib chemical CHEBI:50924 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258284 NEDD4 protein P46934 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity ubiquitination 9606 24340059 YES miannu In line with the previous result (XREF_FIG), overexpression of NEDD4-1 reduced the level of CNrasGEF significantly (XREF_FIG).|NEDD4-1 ubiquitinates CNrasGEF in glioma cells. 0.402 SIGNOR-278705 Caspase 8 complex complex SIGNOR-C231 SIGNOR RIPK1 protein Q13546 UNIPROT down-regulates activity cleavage Asp324 RMQSLQLdCVAVPSS 9606 BTO:0000007;BTO:0000093;BTO:0000567 10521396 YES amattioni These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability. 0.909 SIGNOR-256442 NELFA protein Q9H3P2 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 YES miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 0.886 SIGNOR-271401 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120200 GRK2 protein P25098 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity phosphorylation Ser316 LEEEEENsDEDELDS 9606 23904266 YES miannu Taken together, these studies support a role for GRK2 phosphorylation of Mst2 residues Ser-18 and Ser-316 in EGF-promoted centrosome separation.|Thus GRK2 appears to mediate EGF promoted cleavage and activation of Mst2. 0.2 SIGNOR-278206 KLK2 protein P20151 UNIPROT NCOA4 protein Q13772 UNIPROT up-regulates 9606 BTO:0001130 24122203 NO miannu Klk2may cooperate with the ar coregulator, ara70, to enhance ar transactivation 0.306 SIGNOR-202885 LUBAC complex SIGNOR-C527 SIGNOR DDX58 protein O95786 UNIPROT down-regulates activity binding 9606 BTO:0000007 21292167 YES miannu HOIL-1L/HOIP LUBAC induces TRIM25 ubiquitination and degradation Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner. 0.392 SIGNOR-271860 E2F1 protein Q01094 UNIPROT BBC3 protein Q96PG8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003476 17263886 NO miannu Up-regulation of the PUMA gene and protein by E2F-1 overexpression was detected by real-time PCR and Western blot analysis in the SK-MEL-2 melanoma cell line 0.431 SIGNOR-253843 NEDD4L protein Q96PU5 UNIPROT SLC1A2 protein P43004 UNIPROT down-regulates quantity ubiquitination 9606 28151476 YES miannu Our results confirm that Nedd4-2 knockdown in MPTP treated mice increased GLT-1 expression at the membrane protein level (XREF_FIG; P < 0.01).|These results suggest that Nedd4-2 mediates the ubiquitination of both GLT-1 and GLAST in the midbrain in MPTP treated mice, and Nedd4-2 maybe a potential target in regulating glutamate transporters in PD. 0.305 SIGNOR-278706 CDK2 protein P24941 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 YES gcesareni We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5 0.343 SIGNOR-173681 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT up-regulates activity dephosphorylation Tyr505 FTATEGQyQPQP 9606 11259588 YES Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity 0.796 SIGNOR-248350 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 BTO:0001253 7673243 YES lperfetto We have isolated a cdna encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type ii receptor that binds bmp-4. This receptor (brk-3) is distantly related to other known type ii receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain. 0.851 SIGNOR-217535 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258127 TP53 protein P04637 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11965534 NO acerquone Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53. 0.56 SIGNOR-117328 PIM1 protein P11309 UNIPROT EPAS1 protein Q99814 UNIPROT up-regulates quantity by stabilization phosphorylation Ser435 GKAILPPsQPWATEL 9606 BTO:0002181 34211090 YES miannu PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Moreover, phosphorylation of the analogous site in HIF-2α (S435) stabilizes the protein through the same mechanism, indicating post-translational modification within the oxygen-dependent degradation domain as a mechanism of regulating the HIF-α subunits. 0.2 SIGNOR-277310 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr1223 AEREGPGtPPTTLAR 9606 15125835 YES lperfetto Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis. 0.2 SIGNOR-124646 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Thr393 DFVGHQGtVPSDNID -1 8662852 YES we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 0.693 SIGNOR-251200 PSMB7 protein Q99436 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.862 SIGNOR-263360 NUP62 protein P37198 UNIPROT SASS6 protein Q6UVJ0 UNIPROT up-regulates activity binding 9606 BTO:0000567 24107630 YES Simone Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles. 0.2 SIGNOR-261256 F7 protein P08709 UNIPROT F9 protein P00740 UNIPROT up-regulates activity binding 9606 BTO:0000131 SIGNOR-C319 29880919 YES lperfetto TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively. 0.549 SIGNOR-263544 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15677482 YES gcesareni Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of enac. Sgk1 catalyzed phosphorylation of hnedd4-2 at ser-468 maintaining hnedd4-2 in an inactive phosphorylated state. 0.787 SIGNOR-133438 SMARCA2 protein P51531 UNIPROT CERF complex SIGNOR-C340 SIGNOR form complex binding 9606 BTO:0000227 15640247 YES miannu Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation. 0.386 SIGNOR-263890 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.2 SIGNOR-159381 UHMK1 protein Q8TAS1 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser438 GSHGQTPsPGALPLG 9606 10880969 YES lperfetto We also identified a tryptic peptide of synapsin i phosphorylated by kis 0.373 SIGNOR-78899 RPS6 protein P62753 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates -1 19812304 NO Luana The stimulation of S6K1 activity by mTORC1 leads to increases in mRNA biogenesis, cap-dependent translation and elongation, and the translation of ribosomal proteins through regulation of the activity of many proteins, such as S6K1 aly/REF-like target (SKAR), programmed cell death 4 (PDCD4), eukaryotic elongation factor 2 kinase (eEF2K) and ribosomal protein S6  0.7 SIGNOR-264617 MARK4 protein Q96L34 UNIPROT MAPT protein P10636-4 UNIPROT down-regulates activity phosphorylation Ser353 RHLSNVSsTGSIDMV -1 21204788 YES miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.42 SIGNOR-273934 GRPEL1 protein Q9HAV7 UNIPROT HSPA8 protein P11142 UNIPROT down-regulates activity binding 9606 BTO:0000793 11311562 YES miannu As we had observed earlier,HMGE bound avidly to DnaK (Fig. 5A). In addition, bothMt-Hsp70 and Hsc70 bound to GST-HMGE, but Hsc70 appeared to bind with lower affinity. HMGE inhibitedthe co-chaperone enhancement of Hsc70 ATPase activity byapproximately 50% (Table 1). 0.621 SIGNOR-261241 BLVRB protein P30043 UNIPROT biliverdin(2-) smallmolecule CHEBI:57991 ChEBI up-regulates quantity chemical modification 9606 BTO:0000759 7929092 YES lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 0.8 SIGNOR-275524 AURKB protein Q96GD4 UNIPROT SKA1 protein Q96BD8 UNIPROT up-regulates activity phosphorylation -1 22371557 YES miannu Aurora B directly phosphorylated Ska1 and Ska3 in vitro, and expression of phosphomimetic mutants of Ska1 and Ska3 impaired Ska KT recruitment and formation of stable KT-MT fibers (K-fibers), disrupting mitotic progression. We propose that Aurora B phosphorylation antagonizes the interaction between the Ska complex and the KMN network, thereby controlling Ska recruitment to KTs and stabilization of KT-MT attachments. 0.735 SIGNOR-262662 ADD2 protein P35612 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 YES lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] 0.378 SIGNOR-266039 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267900 GATA2 protein P23769 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates activity 10090 21605981 NO GATA1 and GATA2 are expressed principally in hematopoietic lineages, and have essential roles in the development of multiple hematopoietic cells, including erythrocytes and megakaryocytes. 0.7 SIGNOR-259960 PDGFRB protein P09619 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr320 RKDTKEIyTHFTCAT -1 33139573 YES miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. 0.2 SIGNOR-277234 NLGN2 protein Q8NFZ4 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.824 SIGNOR-264171 ERAP1 protein Q9NZ08 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 31810556 YES scontino While peptides loaded onto MHC class I molecules are 8‚Äì11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1. 0.8 SIGNOR-267771 TBK1 protein Q9UHD2 UNIPROT HTT protein P42858 UNIPROT up-regulates activity phosphorylation Ser13 KLMKAFEsLKSFQQQ 9606 BTO:0000007 32757223 YES Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity. 0.289 SIGNOR-270350 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr722 EEDDEENyENVPRVL -1 12051764 YES miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. 0.2 SIGNOR-274009 hsa-miR-146a mirna URS00005E1F00_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001412 26045293 YES MiR-146a overexpression in U937 cells induces a decrease of CXCR4 protein 0.4 SIGNOR-277939 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 BTO:0000887;BTO:0001103 11500363 YES lperfetto Sapk4/p38delta phosphorylated eef2k at ser359 in vitro, causing its inactivation. 0.577 SIGNOR-109703 TNF protein P01375 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 NO doi: 10.1016/j.cytogfr.2020.05.003 miannu Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α) 0.504 SIGNOR-260856 CHRM1 protein P11229 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.342 SIGNOR-256878 TIMM29 protein Q9BSF4 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 YES lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). 0.2 SIGNOR-267707 AURKA protein O14965 UNIPROT AURKAIP1 protein Q9NWT8 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 MLVPRKMsVSPLESW 9606 BTO:0000567 17957726 YES miannu AIP is phosphorylated on Serine 70 by Aurora‐A but not Aurora‐B and expression of phosphorylation mimic mutant of AIP results in prolonged protein stability compared to unphosphorylatable mutant. Phosphorylation of AIP Prolongs its Protein Stability 0.68 SIGNOR-262648 NR0B2 protein Q15466 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 17909097 NO inferred from family member gcesareni As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells 0.2 SIGNOR-267791 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.243 SIGNOR-273169 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 YES esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. 0.448 SIGNOR-89248 Rix1 complex complex SIGNOR-C373 SIGNOR Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 9606 BTO:0000007 22190736 NO miannu In this study, we show that LAS1L forms a protein complex with PELP1, TEX10, NOL9, SENP3, and WDR18. Our data demonstrate that all the components of the LAS1L complex cosediment with the pre-60S ribosomal particle and are required for proper processing of the 32S rRNA intermediate.These findings demonstrate that the LAS1L complex is critical for ribosome biogenesis and cell proliferation and provide additional evidence that multiple protein complexes have distinct functions in the synthesis of eukaryotic ribosomes. 0.7 SIGNOR-265473 CAMTA1 protein Q9Y6Y1 UNIPROT NPPA protein P01160 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002004 21857646 YES Luana CAMTA1 itself stimulates the expression of the anti-proliferative peptide NPPA. 0.429 SIGNOR-261570 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 YES lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 0.2 SIGNOR-245428 PRKCQ protein Q04759 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.303 SIGNOR-249250 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.2 SIGNOR-275950 TAGAP protein Q8N103 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.4 SIGNOR-260524 CDK3 protein Q00526 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser624 KMFKDKVsPLQNLAS 33082307 YES lperfetto The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. 0.2 SIGNOR-273431 ABL1 protein P00519 UNIPROT YAP1 protein P46937 UNIPROT up-regulates phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 18280240 YES llicata In this study, we show that c-abl directly phosphorylates yap1 at position y357 in response to dna damage. Tyrosine-phosphorylated yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes. 0.718 SIGNOR-160860 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC14 protein Q99879 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271994 SIRT1 protein Q96EB6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates deacetylation 9606 22223095 YES gcesareni The acetylation marks on notch1-icd are removed by the deacetylase sirt1, suggesting that both deacetylation of notch1-icd and of histones inhibit notch signaling. 0.424 SIGNOR-195333 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 YES Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. 0.762 SIGNOR-252568 STK33 protein Q9BYT3 UNIPROT HPD protein P32754 UNIPROT down-regulates quantity by destabilization phosphorylation Thr382 QNLRGNLtNMETNGV 10090 BTO:0003036 31537781 YES lperfetto Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. 0.2 SIGNOR-272958 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.444 SIGNOR-248298 RAPGEF4 protein Q8WZA2 UNIPROT RAP1B protein P61224 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 YES miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. 0.811 SIGNOR-263955 cardiolipin smallmolecule CHEBI:28494 ChEBI Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR form complex binding 9606 25627476 YES lperfetto The lipid composition of the IMM varies from that of the OMM. PC and PE are still the most abundant phospholipids in the IMM, comprising about 75 % of total lipids.|One of the biggest differences between OMM and IMM lipid composition is the greater concentration of CL that is found in the IMM. Here, CL makes up about 15–20 % of the total phospholipid mass 0.8 SIGNOR-267004 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258120 CTTNBP2 protein Q8WZ74 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity binding 10116 BTO:0000938 22262902 YES miannu Fluorescence recovery after photobleaching further suggested that CTTNBP2 modulates the mobility of cortactin in neurons. CTTNBP2 may thus help to immobilize cortactin in dendritic spines and control the density of dendritic spines. 0.511 SIGNOR-269703 POGZ protein Q7Z3K3 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates activity binding 9606 BTO:0000932 20562864 YES miannu POGZ is required for the correct activation and dissociation of Aurora B kinase from chromosome arms during M phase. These results reveal POGZ as an essential protein that links HP1alpha dissociation with Aurora B kinase activation during mitosis. 0.323 SIGNOR-264497 LTBR protein P36941 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 17633025 NO lperfetto The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense. 0.7 SIGNOR-156899 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257451 PDPK1 protein O15530 UNIPROT OXTR protein P30559 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 35104164 YES lperfetto We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1).|In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop. 0.2 SIGNOR-268577 IL1R1 protein P14778 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9625767 YES lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab 0.379 SIGNOR-249513 ERCC6 protein Q03468 UNIPROT APEX1 protein P27695 UNIPROT down-regulates activity binding 9606 17567611 YES Regulation miannu CSB stimulates the AP site incision activity of APE1 on normal (i.e. fully paired) and bubble AP-DNA substrates, with the latter being more pronounced (up to 6-fold). This activation is ATP-independent, and specific for the human CSB and full-length APE1 protein. CSB and APE1 were also found in a common protein complex in human cell extracts, and recombinant CSB, when added back to CSB-deficient whole cell extracts, resulted in increased total AP site incision capacity. 0.418 SIGNOR-251932 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273066 PRKACG protein P22612 UNIPROT PHKA1 protein P46020 UNIPROT down-regulates activity phosphorylation 9606 10487978 YES Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. 0.324 SIGNOR-267415 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 YES lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  0.34 SIGNOR-249071 GNAI1 protein P63096 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity binding 10090 BTO:0000944 11099498 YES These findings indicate that both G alpha(i) and G beta gamma stimulate Rac and Cdc42 pathways with lysophosphatidic acid-induced cell spreading on fibronectin 0.521 SIGNOR-256531 SNRPB protein P14678 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.779 SIGNOR-270628 TAOK1 protein Q7L7X3 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates activity phosphorylation Thr208 TFGNKLDtFCGSPPY -1 18424437 YES miannu MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. 0.415 SIGNOR-276164 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 YES irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. 0.2 SIGNOR-255877 FYN protein P06241 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr294 YETADGGyMTLNPRA -1 8756631 YES miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation 0.2 SIGNOR-262677 PRKN protein O60260 UNIPROT SEPTIN5 protein Q99719 UNIPROT down-regulates quantity ubiquitination 9606 11078524 YES miannu Furthermore, Parkin ubiquitinates and promotes the degradation of CDCrel-1.|Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. 0.2 SIGNOR-278711 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Thr27 KFRFRKEtNNAAIIM -1 9030586 YES lperfetto Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively. 0.323 SIGNOR-248961 MECP2 protein P51608 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 11865062 NO We have established that methyl-CpG binding protein 2 (MeCP2) is involved in methylation-dependent silencing of human MDR1 in cells that lack the known transcriptional repressors MBD2 and MBD3. In the repressed state the MDR1 promoter is methylated and assembled into chromatin enriched with MeCP2 and deacetylated histone. TSA induced significant acetylation of histones H3 and H4 but did not activate transcription. 5aC induced DNA demethylation, leading to the release of MeCP2, promoter acetylation, and partial relief of repression 0.2 SIGNOR-254033 CUL1 protein Q13616 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR form complex binding 9606 BTO:0001109 phosphorylation:Thr286 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1  0.956 SIGNOR-271628 Ub:E2 complex SIGNOR-C497 SIGNOR IRF2BPL protein Q9H1B7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271003 MET protein P08581 UNIPROT RANBP9 protein Q96S59 UNIPROT up-regulates binding 9606 12147692 YES gcesareni Our data suggest that ranbpm, functioning as an adaptor protein for the met tyrosine kinase domain, can augment the hgf-met signaling pathway. 0.556 SIGNOR-91028 PRKCQ protein Q04759 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.2 SIGNOR-251636 FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001103 19319192 YES gcesareni Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy. 0.561 SIGNOR-184861 NatA complex SIGNOR-C415 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 NO miannu About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity. 0.7 SIGNOR-267229 RAC2 protein P15153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 9705280 YES gcesareni This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2. 0.778 SIGNOR-59546 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates activity dephosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 16778204 YES The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels 0.277 SIGNOR-248701 GPR35 protein Q9HC97 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257283 PAF1 protein Q8N7H5 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 YES miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  0.883 SIGNOR-269833 NANOGP8 protein Q6NSW7 UNIPROT KDM3A protein Q9Y4C1 UNIPROT down-regulates quantity by repression transcriptional regulation 10900 BTO:0000667 23918801 NO Luana Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. 0.2 SIGNOR-266092 GNAI2 protein P04899 UNIPROT ADCY5 protein O95622 UNIPROT down-regulates activity binding 7108 BTO:0001240 8119955 YES Marta Tosoni Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3 0.524 SIGNOR-278075 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI up-regulates quantity precursor of 9606 11802770 YES miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 0.8 SIGNOR-269696 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 11258706 YES lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.772 SIGNOR-105737 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 19864431 YES lperfetto Here we focus primarily although not exclusively on raptor Ser(863) phosphorylation. We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser(863) via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. mTORC1 activation by other stimuli (e.g. amino acids, epidermal growth factor/MAPK signaling, and cellular energy) also promote raptor Ser(863) phosphorylation. 0.384 SIGNOR-217559 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 10455013 YES lperfetto Pdk1 is itself phosphorylated in vivo and whether phosphorylation plays a role in regulating its activity/ phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1 0.2 SIGNOR-236789 POU5F1 protein Q01860 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004180 23041284 YES flangone Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription. 0.457 SIGNOR-252635 GEMIN5 protein Q8TEQ6 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 YES lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. 0.747 SIGNOR-253119 EVL protein Q9UI08 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 NO miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. 0.7 SIGNOR-268394 MAPK9 protein P45984 UNIPROT ATN1 protein P54259 UNIPROT down-regulates activity phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 YES lperfetto Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment, 0.2 SIGNOR-102402 EIF2S3 protein P41091 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 YES lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. 0.94 SIGNOR-269116 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT up-regulates activity phosphorylation Tyr364 SCFTNQGyFFFHLPD 9534 8700888 YES In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. 0.63 SIGNOR-251342 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 34010649 YES lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-275942 CDK1 protein P06493 UNIPROT RAB5B protein P61020 UNIPROT unknown phosphorylation Ser123 KELQRQAsPSIVIAL 9606 10403367 YES lperfetto Cdc2 kinase preferentially phosphorylates ser-123 of rab5b. More work will be required to establish how phosphorylation of the three rab5 isoforms influences their function in the endocytic pathway 0.327 SIGNOR-69233 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 10090 BTO:0002295 31063459 NO lperfetto Mitochondrial fission is governed primarily by the cytoplasmic dynamin-related protein 1 (Drp1). Drp1 is a conserved dynamin GTPase superfamily protein that is translocated from its cytoplasmic pool to the outer mitochondrial membrane, where Drp1 then assembles into constrictive ring-like multimeric structures, ultimately driving mitochondrial fragmentation through a GTP-dependent mechanism|We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes 0.7 SIGNOR-262553 AKT1 protein P31749 UNIPROT LONP1 protein P36776 UNIPROT up-regulates activity phosphorylation Ser181 NESDVVEsLDEIYHT 9606 BTO:0001061 31406245 YES lperfetto In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity. 0.253 SIGNOR-265725 HCK protein P08631 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.551 SIGNOR-249364 AKT1 protein P31749 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity phosphorylation Ser71 YDRLRPLsYPQTDVF 9606 BTO:0000848 10617634 YES Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1 0.724 SIGNOR-252576 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 21798082 YES gcesareni Pip3 acts in turn as a docking site for two kinases, phosphoinositidedependent kinase 1 (pdk1) and akt, and the subsequent phosphorylation of akt at serine 308 by pdk1, leading to akt activation. 0.748 SIGNOR-175675 PAK3 protein O75914 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser150 TLRRVRIsADAMMQA 9606 BTO:0000887 15769444 YES lperfetto In vitro addition of pak3 to skinned rat cardiac fibres increased myofilament ca2+ sensitivity with no change in maximal ca2+-activated force [67]. These effects were associated with pak3-induced phosphorylation of myofilament proteins, including ctni which was phosphorylated at a novel site, ser149, located in the region forming a ca2+-sensitive interaction with the n-terminal regulatory domain of tnc. 0.2 SIGNOR-134593 CUL2 protein Q13617 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 YES miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro 0.608 SIGNOR-271440 GPR34 protein Q9UPC5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256831 SYK protein P43405 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Tyr658 SDFEGFSyVNPQFVH 9606 BTO:0000830 12881490 YES lperfetto We present evidence that Tyr-662 and Tyr-658 of PKCbetaI and PKCalpha, respectively, are phosphorylated by Syk in the membrane compartment of FcepsilonRI-stimulated mast cells. These phosphorylations require prior PKC autophosphorylation of the adjacent serine residues (Ser-661 and Ser-657, respectively) and generate a binding site for the SH2 domain of the adaptor protein Grb-2. 0.392 SIGNOR-246581 ASAP2 protein O43150 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity gtpase-activating protein -1 10022920 YES miannu Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. 0.654 SIGNOR-269705 XRCC5 protein P13010 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR form complex binding 9606 BTO:0002419 17308091 YES miannu complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established 0.958 SIGNOR-226019 TRAF3 protein Q13114 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 YES miannu MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1. 0.903 SIGNOR-260156 JAK2 protein O60674 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity phosphorylation Tyr139 ILLTIDRyLAIVHAV 9606 9670957 YES JAK2 phosphorylates CCR2 at the Tyr139 position and promotes JAK2/STAT3 complex association to the receptor.  0.605 SIGNOR-251345 NRXN3 protein Q9Y4C0 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 22626542 YES miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 0.2 SIGNOR-265463 TNF protein P01375 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.258 SIGNOR-253489 ZMYND8 protein Q9ULU4 UNIPROT ADORA1 protein P30542 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 21620140 YES Luana We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.  0.2 SIGNOR-266208 MIB2 protein Q96AX9 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates quantity ubiquitination 9606 20604708 YES miannu Mib2 is localized to the PSD of dendrites in hippocampal neurons and directly ubiquitinates GluN2B in a manner dependent on the non receptor tyrosine kinase Fyn.|These findings suggest that Mib2 mediates proteasome dependent degradation of GluN2B subunits, which may provide a reciprocal mechanism to SCF Fbx2 regulation of GluN2A. 0.367 SIGNOR-278762 RRAGC protein Q9HB90 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates binding 9606 SIGNOR-C3 20006481 YES gcesareni Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor. 0.941 SIGNOR-162054 PAX1 protein P15863 UNIPROT MEOX1 protein P50221 UNIPROT up-regulates activity binding -1 11423130 YES miannu We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family. 0.513 SIGNOR-222193 AP1 complex SIGNOR-C154 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates activity binding 9606 BTO:0000782 15928679 YES Activator protein 1 (AP1) proteins are the main transcriptional partners of NFAT during T-cell activation 0.661 SIGNOR-253004 HMGN1 protein P05114 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR down-regulates -1 12213813 NO lperfetto In vitro, binding of HMGN1 proteins to the nucleosomes reduces chromatin compaction and promotes overall accessibility to the nucleosomes 0.7 SIGNOR-262989 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT down-regulates activity phosphorylation Thr715 PMRFRSAtTSGAPGV 10090 SIGNOR-C469 21148297 YES miannu RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase 0.452 SIGNOR-269799 ALK protein Q9UM73 UNIPROT STAT3 protein P40763 UNIPROT up-regulates binding 9606 BTO:0000785 16084951 YES gcesareni Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1. 0.44 SIGNOR-139460 NOTCH1 protein P46531 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001253 12107827 NO gcesareni Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression. 0.34 SIGNOR-90455 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser633 GISQCGYsSTIVHVP 9534 BTO:0000298 11865049 YES llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  0.74 SIGNOR-250818 AKT1 protein P31749 UNIPROT HMOX1 protein P09601 UNIPROT unknown phosphorylation Ser188 LYRSRMNsLEMTPAV 9606 BTO:0000007 15581622 YES llicata We have identified a putative consensus sequence for phosphorylation by akt/pkb of ho-1 at ser188. although the changes in activity are small, this study provides the first evidence for a role of the survival kinase akt in the regulation of ho-1. 0.56 SIGNOR-252506 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 12773393 YES lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 0.2 SIGNOR-249214 NEU1 protein Q99519 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 9606 19151752 NO Giorgia One of the major molecular changes by NEU1 was decreased sialylation of integrin beta4, assessed by PNA- and MAL-II-lectin blotting of immunoprecipitates with anti-integrin beta4 antibody. The desialylation was accompanied by decreased phosphorylation of the integrin followed by attenuation of focal adhesion kinase and Erk1/2 pathway. 0.249 SIGNOR-260656 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1672 SPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248784 CABIN1 protein Q9Y6J0 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates 9606 17172641 NO gcesareni Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity. 0.68 SIGNOR-151202 MAPK3 protein P27361 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 16554440 YES lperfetto Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002). 0.42 SIGNOR-249468 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 18372406 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.703 SIGNOR-178145 STK24 protein Q9Y6E0 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 9606 BTO:0000007 16314523 YES lperfetto Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity. 0.382 SIGNOR-142467 NFKB1 protein P19838 UNIPROT MAP3K8 protein P41279 UNIPROT down-regulates binding 9606 SIGNOR-C13 22435554 YES gcesareni Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek 0.687 SIGNOR-196747 ATR protein Q13535 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser539 GLITINSsQEHLTVQ 9606 22123827 YES lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. 0.655 SIGNOR-177809 PTPN2 protein P17706 UNIPROT JAK3 protein P52333 UNIPROT down-regulates activity dephosphorylation 9606 15780598 YES lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. 0.696 SIGNOR-133078 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPATGGV 9606 11856369 YES Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription. gcesareni Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation 0.2 SIGNOR-114852 regorafenib chemical CHEBI:68647 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206412 POLE3 protein Q9NRF9 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR form complex binding 9606 BTO:0000567 10801849 YES lperfetto Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon. 0.905 SIGNOR-265522 PRKD1 protein Q15139 UNIPROT ARFIP1 protein P53367 UNIPROT up-regulates phosphorylation Ser132 LELVRKWsLNTYKCT 9606 23695357 YES lperfetto We report that arfaptins contain an amphipathic helix (ah) preceding the bar domain, which is essential for their binding to phosphatidylinositol 4-phosphate (pi(4)p)-containing liposomes and the tgn of mammalian cells. The binding of arfaptin1, but not arfaptin2, to pi(4)p is regulated by protein kinase d (pkd) mediated phosphorylation at ser100 within the ah. We also found that only arfaptin1 is required for the pkd-dependent trafficking of chromogranin a by the regulated secretory pathway. 0.386 SIGNOR-202101 AMPK complex SIGNOR-C15 SIGNOR AMPK complex SIGNOR-C15 SIGNOR unknown phosphorylation 9606 BTO:0000007 11171104 YES lperfetto In contrast, the phosphorylation site mutations, ss24, 25aa and s182a, while having no effects on enzyme activity, are associated with nuclear redistribution of the subunit. 0.803 SIGNOR-216415 CSNK2A1 protein P68400 UNIPROT IP6K2 protein Q9UHH9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser347 RPEVVLDsDAEDLED 9606 BTO:0000007 21262846 YES miannu CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. 0.255 SIGNOR-273624 Ub:E2 complex SIGNOR-C497 SIGNOR RNF212B protein A8MTL3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271257 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser213 SGAPVKPsPQAAAVE 9606 11110801 YES llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). 0.442 SIGNOR-84984 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 YES gcesareni Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. 0.624 SIGNOR-180548 DAB2IP protein Q5VWQ8 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization 9606 27476001 NO miannu DAB2IP destabilizes HIF1Œ± protein to inhibit EMT in PCa cells. DAB2IP may destabilize HIF1Œ± protein in PCa cells via an ubiquitin-proteasome system. 0.2 SIGNOR-254765 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251590 Ub:E2 complex SIGNOR-C497 SIGNOR RNF103 protein O00237 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271093 SIRT5 protein Q9NXA8 UNIPROT SIRT3 protein Q9NTG7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31608237 NO Monia In U2OS cells, SIRT5 silencing resulted in downregulation of SIRT1 and SIRT3 protein levels (Figures 4Ai,ii, compare bars 1 to 5). 0.404 SIGNOR-261209 GSK3A protein P49840 UNIPROT STMN3 protein Q9NZ72 UNIPROT up-regulates activity phosphorylation Ser60 SFEVILKsPSDLSPE -1 22577147 YES lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta 0.252 SIGNOR-264883 3-N-Me-Phe-morphiceptin chemical CID:115335 PUBCHEM OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258417 MKRN1 protein Q9UHC7 UNIPROT RPS10 protein P46783 UNIPROT up-regulates activity ubiquitination Lys107 ETGRPRPkGLEGERP 9606 BTO:0000007 31640799 YES miannu We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1.Our data show that MKRN1 associates with polysomes and ubiquitylates RPS10, indicating a role in translational control. We hypothesize that ribosomes encountering the MKRN1-PABPC1 complex are stalled, possibly via ubiquitylation of RPS10 on K107 and other MKRN1 substrates. 0.2 SIGNOR-272216 OXTR protein P30559 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257332 CDK1 protein P06493 UNIPROT TERT protein O14746 UNIPROT up-regulates activity phosphorylation Thr249 AAPEPERtPVGQGSW 9606 BTO:0000567 32214089 YES miannu Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1.These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomere independent manner. 0.324 SIGNOR-277517 SMAD6 protein O43541 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 20663871 YES lperfetto The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. 0.74 SIGNOR-167160 F2RL1 protein P55085 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257144 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser310 LDVQRVPsFESFEDD 9606 19182667 YES lperfetto Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters 0.2 SIGNOR-183600 MOAP1 protein Q96BY2 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates activity binding 9606 26269600 YES miannu Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax.  0.573 SIGNOR-272914 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 BTO:0000007 28630438 YES miannu NUP98-HOXA9 has an activator-repressor role in transcriptional regulation driven by p300 and HDAC1 interactions. The chromosomal translocation t(7;11)(p15, p15), encoding the fusion protein NUP98-HOXA9 (NHA9), is a rare poor risk cytogenetic event in AML associated with a particularly poor prognosis.In summary, NHA9 deregulates the expression of key leukemic genes, including MEIS1-HOXA9-PBX3 complex, through the enhancer binding and the direct interaction of the fusion protein with HDAC and p300 transcriptional regulators. 0.2 SIGNOR-261497 EGFR protein P00533 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity phosphorylation Tyr153 GEEGQSIyKLTDFGA 9606 27287717 YES miannu EGFRL858R/T790M phosphorylates IKBKE at tyrosine residues. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179.  0.258 SIGNOR-277242 SERPINA5 protein P05154 UNIPROT FN1 protein P02751 UNIPROT down-regulates activity binding 9606 BTO:0000594 24388360 YES miannu SERPINA5 inhibits HCC cell migration by directly interacting with fibronectin. SERPINA5 disrupts the fibronectin–integrin β1 signaling pathway. 0.313 SIGNOR-265881 D-glucopyranose smallmolecule CHEBI:4167 ChEBI UDP(3-) smallmolecule CHEBI:58223 ChEBI up-regulates quantity precursor of 9606 16157350 YES miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 0.8 SIGNOR-268472 SUN1 protein O94901 UNIPROT SPDYA protein Q5MJ70 UNIPROT up-regulates activity binding 9606 BTO:0000007 SIGNOR-C305 33015044 YES lperfetto In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | Taken together, we speculate that speedy A is likely capable of interacting with both telomeres and the LINC complex and thus might function as the missing linkage between telomeres and the LINC complex during prophase I, stabilizing the telomere–NE connection 0.247 SIGNOR-263301 ATF4 protein P18848 UNIPROT EPRS1 protein P07814 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269419 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001412 8394219 NO We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. 0.7 SIGNOR-255722 DDB1 protein Q16531 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR form complex binding 9606 22649780 YES gcesareni The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors 0.919 SIGNOR-234802 FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 SIGNOR-C135 20852628 YES gcesareni We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. 0.762 SIGNOR-243545 CSNK1A1 protein P48729 UNIPROT MDM4 protein O15151 UNIPROT up-regulates phosphorylation Ser289 DDLEDSKsLSDDTDV 9606 23028042 YES lperfetto Previous studies showed that casein kinase 1? (ck1?) Stably associates with mdmx, stimulates mdmx-p53 binding, and cooperates with mdmx to inactivate p53ck1? Binding to the mdmx central domain and phosphorylation of s289 disrupts the intramolecular interaction, allowing the n terminus to bind p53 with increased affinity. After dna damage, the mdmx-ck1? Complex is disrupted by chk2-mediated phosphorylation of mdmx at s367, leading to reduced mdmx-p53 binding. 0.371 SIGNOR-199015 ATG4B protein Q9Y4P1 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates activity cleavage -1 16303767 YES lperfetto In mammals, at least three atg8 homologs, lc3, gabarap, and gate-16, have been identified (fig. 1a), all of which have structural ubiquitin folds (1416). In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly 0.843 SIGNOR-141932 PP1 proteinfamily SIGNOR-PF54 SIGNOR PYGM protein P11217 UNIPROT down-regulates activity dephosphorylation Ser15 QEKRKQIsVRGLAGV 9606 BTO:0002049 22225877 YES GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation 0.2 SIGNOR-267402 cabozantinib chemical CHEBI:72317 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000184 26536165 YES miannu Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. 0.8 SIGNOR-262243 CSNK1D protein P48730 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Ser143 FHPNVSSsHENLEPE 9606 22609948 YES lperfetto Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle 0.533 SIGNOR-197547 PSMD12 protein O00232 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.918 SIGNOR-263352 PTPRK protein Q15262 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 25612622 YES miannu In this study, we investigated whether receptor-type tyrosine protein phosphatase kappa (PTPRK), the only protein tyrosine phosphatase at 6q that contains a STAT3 specifying motif, negatively regulates STAT3 activation in NKTCL.|Phosphatase substrate-trapping mutant assays demonstrated the binding of PTPRK to STAT3, and phosphatase assays showed that PTPRK directly dephosphorylated phospho-STAT3(Tyr705). 0.374 SIGNOR-277060 KAT2A protein Q92830 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269600 KIF11 protein P52732 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272521 MAPK8 protein P45983 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 YES gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. 0.795 SIGNOR-196038 CLASP2 protein O75122 UNIPROT CLIP2 protein Q9UDT6 UNIPROT up-regulates activity binding 9606 BTO:0000567 15631994 YES lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 0.59 SIGNOR-265093 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Thr119 PTCRGALtPSIRNLA 9606 22878263 YES llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. 0.411 SIGNOR-198733 WNT5A protein P41221 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity 9606 21078818 NO lperfetto We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3) 0.423 SIGNOR-227961 TAGAP protein Q8N103 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.446 SIGNOR-260523 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 18394876 YES lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity 0.2 SIGNOR-66032 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 YES flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. 0.622 SIGNOR-75914 CDK2 protein P24941 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser301 IQSNLDFsPVNSASS 9606 21765472 YES lperfetto Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency 0.553 SIGNOR-175083 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248737 PKA proteinfamily SIGNOR-PF17 SIGNOR V-ATPase complex SIGNOR-C560 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 31827278 YES miannu It is worth noting that CA-PKA failed to rescue macropinocytosis in KRAS-knockdown cells, indicating that whereas PKA activation is necessary for mutant KRAS-dependent plasma membrane translocation of V-ATPase and induction of macropinocytosis, it is not sufficient (Extended Data Fig. 6e). 0.296 SIGNOR-277763 CSNK2B protein P67870 UNIPROT RNF7 protein Q9UBF6 UNIPROT up-regulates activity phosphorylation Thr10 DVEDGEEtCALASHS 9606 BTO:0000567 12748192 YES llicata In the present study, we show the evidence that CKBBP1 is phosphorylated on threonine residue at position 10 by CKII in vitro and in vivo. Most importantly, disruption of this phosphorylation in CKBBP1 results in accumulation of IκBα and p27Kip1 in HeLa cells and inhibits cell proliferation that appears to be linked to defects in G1/S transition. 0.33 SIGNOR-251081 ARHGEF19 protein Q8IW93 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.635 SIGNOR-260543 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser46 VKVNGDAsPAAAESG -1 8034575 YES lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites. 0.729 SIGNOR-248908 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser627 KKRVRRPsESDKEDE -1 14657015 YES lperfetto Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin. 0.2 SIGNOR-271841 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763;BTO:0000149 10197981 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.2 SIGNOR-244723 PTPN11 protein Q06124 UNIPROT SYK protein P43405 UNIPROT down-regulates activity dephosphorylation 9606 23182168 YES miannu Another SHP isoform, SHP-2, has been linked to negative regulation of Syk.|Syk and LAT are differentially dephosphorylated by SHP-2 and SHP-1, respectively. 0.544 SIGNOR-277085 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270428 TFE3 protein P19532 UNIPROT GLA protein P06280 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.2 SIGNOR-276823 MAPK8 protein P45983 UNIPROT ATN1 protein P54259 UNIPROT down-regulates activity phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 YES lperfetto Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment, 0.376 SIGNOR-102398 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser464 QAIHQLRsVKMEQRK 9606 16513649 YES llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization 0.2 SIGNOR-145028 LFNG protein Q8NES3 UNIPROT JAG1 protein P78504 UNIPROT down-regulates binding 9606 BTO:0000007 15574878 YES gcesareni Although jagged1-induced signaling was suppressed by lfng and mfng 0.487 SIGNOR-131560 IL1R1 protein P14778 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 BTO:0003432 10217414 YES lperfetto Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. 0.945 SIGNOR-67140 ATM protein Q13315 UNIPROT KAT8 protein Q9H7Z6 UNIPROT up-regulates activity phosphorylation Thr392 LSQMTSItQNDIIST 9606 24953651 YES miannu In this study we present evidence that MOF is phosphorylated at the threonine 392 residue (pT392-MOF) by ATM subsequent to IR induced DNA damage.|Interestingly, ATM dependent-MOF phosphorylation increases MOF retention on DNA post-irradiation in S/G2-phase cells. 0.47 SIGNOR-278350 AURKA protein O14965 UNIPROT RALA protein P11233 UNIPROT up-regulates activity phosphorylation Ser194 NGKKKRKsLAKRIRE 9606 21822277 YES miannu Specifically, the mitotic kinase Aurora A phosphorylates Ser 194 of RALA, relocalizing it to the mitochondria, where it concentrates RALBP1 and DRP1.|These data suggest that Aurora A promotes mitochondrial fission at mitosis through RalA and RalBP1. 0.45 SIGNOR-278351 SOD2 protein P04179 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI down-regulates quantity chemical modification 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272281 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr735 KYLANMNyVHRDLAA 9606 18387945 YES lperfetto The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells. 0.2 SIGNOR-178177 DOT1L protein Q8TEK3 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 NO irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. 0.449 SIGNOR-256141 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 YES llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  0.392 SIGNOR-250791 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267124 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser138 NNLSRSNsDESNFSE 9606 BTO:0000007 16818229 YES miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. 0.772 SIGNOR-276292 SMO protein Q99835 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 9606 18455992 YES gcesareni Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion. 0.424 SIGNOR-178607 2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol chemical CHEBI:93235 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258728 MAPK3 protein P27361 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 10828059 YES The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. 0.252 SIGNOR-77578 EIF1 protein P41567 UNIPROT 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.641 SIGNOR-269161 AKT1 protein P31749 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 YES gcesareni Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. 0.877 SIGNOR-112363 TLE1 protein Q04724 UNIPROT SIX6 protein O95475 UNIPROT up-regulates activity binding -1 12441302 YES lperfetto Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation 0.396 SIGNOR-234592 BTRC protein Q9Y297 UNIPROT WEE1 protein P30291 UNIPROT down-regulates binding 9606 SIGNOR-C5 15340381 YES gcesareni Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1. 0.394 SIGNOR-128439 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.2 SIGNOR-141420 HERC5 protein Q9UII4 UNIPROT NME2 protein P22392 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0000007 18535780 YES miannu HERC5 is required for ubiquitination of Nm23B. In summary, Nm23B ubiquitination is mediated by HERC5. Stable Nm23B protein in presence of HERC5 as well as proteasome-independent ubiquitination suggest that ubiquitination of Nm23B serves a different purpose than marking it for degradation. 0.307 SIGNOR-271778 ABL1 protein P00519 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Tyr28 AVHSLSRiGDELYLE 9606 11971963 YES Manara The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. | c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL |these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress. 0.478 SIGNOR-260843 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 17289999 YES gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members. 0.822 SIGNOR-152992 Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10090 23217710 YES lperfetto Despite this progress, it is not known which genes encode subunits of the mechanotransduction channel of hair cells. Ca2+ enters stereocilia upon mechanical stimulation near the lower tip-link insertion site, indicating that transduction channels are present in proximity to PCDH15 0.8 SIGNOR-262573 SPI1 protein P17947 UNIPROT GATA1 protein P15976 UNIPROT down-regulates activity binding 10090 10364157 YES irozzo We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation. 0.621 SIGNOR-256049 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT up-regulates quantity by stabilization phosphorylation Ser1466 YSRASINsLLSDKRS 10090 29301787 YES lperfetto Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466 0.261 SIGNOR-272270 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 21779497 YES lperfetto Active raf phosphorylates mek. 0.753 SIGNOR-244809 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ECT2 protein Q9H8V3 UNIPROT down-regulates phosphorylation Thr373 VSMLSLNtPNSNRKR 9606 16170345 YES lperfetto We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341 0.488 SIGNOR-216864 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr5 yLDPNLNH 9606 20802513 YES llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. 0.552 SIGNOR-167662 ASIP protein P42127 UNIPROT MC2R protein Q01718 UNIPROT down-regulates activity binding 9606 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.499 SIGNOR-268695 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 23729744 YES apalma The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes 0.95 SIGNOR-255378 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity 0.2 SIGNOR-251359 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176813 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 18039567 YES gcesareni Ly2157299, a new type i receptor tgf-beta kinase antagonist, was 0.8 SIGNOR-159354 Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 NO lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. 0.7 SIGNOR-273454 TRIM25 protein Q14258 UNIPROT KLF5 protein Q13887 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 21542805 YES miannu  The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked.  0.483 SIGNOR-271908 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000567 16120644 YES irozzo Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells. 0.71 SIGNOR-259103 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser196 RKEDRSAsSGAEGDV -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.285 SIGNOR-273971 CSRP3 protein P50461 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 10090 BTO:0004058 9234731 YES 2 miannu we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. 0.468 SIGNOR-241116 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120048 9b protein P59636 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates quantity by destabilization 9606 25135833 NO miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. 0.2 SIGNOR-260242 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14701735 NO irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. 0.2 SIGNOR-255863 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 YES The effect has been demonstrated using P10636-8 gcesareni Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase. 0.738 SIGNOR-60655 venetoclax chemical CHEBI:133021 ChEBI BCL2 protein P10415 UNIPROT down-regulates activity chemical inhibition 9606 23291630 YES miannu Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers. 0.8 SIGNOR-261938 Nalorphine chemical CHEBI:7458 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258815 F10 protein P00742 UNIPROT APOH protein P02749 UNIPROT down-regulates activity cleavage Lys336 HSSLAFWKTDASDVK -1 9596664 YES lperfetto In the previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). |The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI. 0.386 SIGNOR-266997 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Ser328 VLPSISLsPGPQPPK 9606 BTO:0000567 12734188 YES lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. 0.362 SIGNOR-101047 GSK3B protein P49841 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by destabilization phosphorylation Ser37 REPSTPPsPISSSSS 9606 BTO:0000182 27273097 YES miannu We identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin.  0.309 SIGNOR-277241 LPAR5 protein Q9H1C0 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.417 SIGNOR-256861 Ub:E2 complex SIGNOR-C497 SIGNOR OBI1 protein Q5W0B1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271167 etorphine chemical CHEBI:4912 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258802 STUB1 protein Q9UNE7 UNIPROT BACE1 protein P56817 UNIPROT down-regulates quantity ubiquitination 9606 25773675 YES miannu This result establishes that CHIP negatively regulates BACE1 stability.|Thus, both deletion mutants of CHIP could not enhance the ubiquitination of BACE1, suggesting that both domains of CHIP were essential for ubiquitination and degradation of BACE1. 0.379 SIGNOR-278719 GFI1 protein Q99684 UNIPROT SPI1 protein P17947 UNIPROT down-regulates activity binding 10090 BTO:0000725 17197705 YES miannu Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line. 0.595 SIGNOR-256043 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr500 WDGVTTKtFCGTPDY 9606 17115692 YES lperfetto The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif 0.52 SIGNOR-150857 AKT1 protein P31749 UNIPROT DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 21619873 YES gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. 0.264 SIGNOR-252513 TRAF2 protein Q12933 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 18635759 YES gcesareni Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades. 0.717 SIGNOR-179476 miR-155 mirna URS000062749E_9606 RNAcentral JUN protein P05412 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 24708856 YES miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. 0.4 SIGNOR-255761 UBQLN2 protein Q9UHD9 UNIPROT TARDBP protein Q13148 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0003704 23541532 YES lperfetto Here, we describe a high affinity interaction between UBQLN2 and TDP-43 and demonstrate that overexpression of both UBQLN2 and TDP-43 reduces levels of both exogenous and endogenous TDP-43 in human H4 cells.|Consequently, these data suggest that UBQLN2 enhances the clearance of TDP-43 0.584 SIGNOR-262112 CDK1 protein P06493 UNIPROT PSRC1 protein Q6PGN9 UNIPROT down-regulates activity phosphorylation 9606 21473853 YES miannu MT-polymerizing activity was decreased from samples with DDA3 phosphorylated by Cdk1 ( xref , lanes 4 vs 6) and Aurora A ( xref , lanes 14 vs 16).|Taken together, the mitotic Cdk1 and Aurora A kinases inhibit MT polymerization activities and MT bundling activities of DDA3. 0.236 SIGNOR-279601 AMPK complex SIGNOR-C15 SIGNOR GBF1 protein Q92538 UNIPROT down-regulates phosphorylation Thr1337 GKIHRSAtDADVVNS 9606 18063581 YES lperfetto These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration. 0.2 SIGNOR-216588 GABRB2 protein P47870 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.479 SIGNOR-263769 PDP1 protein Q9P0J1 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16510868 YES lpetrilli We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1. 0.243 SIGNOR-144876 KDR protein P35968 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 10090 22264731 YES VEGF pathway Gianni Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation 0.495 SIGNOR-261945 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258592 SMC2 protein O95347 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.926 SIGNOR-263903 PKA proteinfamily SIGNOR-PF17 SIGNOR RAP1A protein P62834 UNIPROT up-regulates activity phosphorylation Ser180 KKKPKKKsCLLL 9606 BTO:0000751 17068197 YES Marta Tosoni Rap1 is phosphorylated and activated by PKA in neutrophils and platelets 0.2 SIGNOR-278057 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 22452896 YES Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. gcesareni Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors. 0.8 SIGNOR-196760 CSNK1D protein P48730 UNIPROT PRH1 protein P02810 UNIPROT up-regulates phosphorylation Ser24 QDLDEDVsQEDVPLV 9606 BTO:0000007 BTO:0000671 10684652 YES lperfetto Ser22 may be phosphorylated by a g-ck that recognizes an atypical substrate sequence or by a novel kinase. While prp1 secreted from salivary glands is fully phosphorylated at ser8 and 22 0.2 SIGNOR-75272 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRB4 protein P13762 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 YES miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. 0.2 SIGNOR-271409 HNF4A protein P41235 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000398 21123766 NO miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. 0.268 SIGNOR-254451 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR KIF23 protein Q02241 UNIPROT up-regulates quantity by expression transcriptional regulation 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276579 NCBP1 protein Q09161 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 26382858 NO lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 0.7 SIGNOR-268361 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR4 protein Q99677 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257531 GIP protein P09681 UNIPROT GIPR protein P48546 UNIPROT up-regulates activity binding 9606 BTO:0000783 35065096 YES miannu GLP-1 and GIP exert their physiological actions via stimulation of the two G protein-coupled receptors (GPCRs): the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR), respectively. 0.876 SIGNOR-278134 ITGB7 protein P26010 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.858 SIGNOR-253294 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.52 SIGNOR-269244 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000304 30519351 YES miannu The results showed that TNC induced the cytoplasmic translocation of pFOXO1 via regulation of AKT activation. As shown in Fig. 3C, stimulation of PANC-1 cells with exogenous TNC markedly increased the phosphorylation of AKT and FOXO1. Our study showed that pFOXO1 translocates from the nucleus to the cell cytoplasm after exogenous TNC treatment, which indicates that its transcriptional activity was inhibited. 0.2 SIGNOR-277740 RHOQ protein P17081 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 12242347 NO gcesareni Tc10 is activated afte rinsulin stimulation, and its activation is required for insulin-stimulated glucose uptake and glut4 translocation 0.467 SIGNOR-93117 EGFR protein P00533 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates activity phosphorylation Tyr233 EAQYQREySEFKRQQ 9606 24034250 YES miannu The mechanism by which EGFR suppresses Beclin 1 function involves EGFR interaction with two domains (BH3 and ECD) of Beclin 1; EGFR mediated multisite tyrosine phosphorylation of Beclin 1 on residues Y229, Y233 and Y352; and EGFR mediated alterations in the Beclin 1 interactome (increased binding to the negative regulators, Bcl-2 and Rubicon, and decreased binding to the VPS34 lipid kinase).|Thus, EGFR signaling suppresses autophagy via its interaction with Beclin 1 during normal mitogenic signaling as well as during aberrant cell proliferation in cancer cells. 0.522 SIGNOR-278357 GSK3B protein P49841 UNIPROT APBB1 protein O00213 UNIPROT up-regulates quantity phosphorylation Thr579 SSSREQWtPSHVSVA 9606 28963516 YES miannu In this regards, GSK3beta may promote amyloidogenic processing of APP by regulating the cellular level of monomeric FE65 for the formation of LRP1, FE65, and APP complex.|In this study, we showed that FE65 is phosphorylated at T579 by GSK3beta. 0.293 SIGNOR-278359 UBE2A protein P49459 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination Lys164 AVVISCAkDGVKFSA 9606 12226657 YES gcesareni Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18. 0.477 SIGNOR-92737 KAT2B protein Q92831 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269626 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263790 belinostat chemical CHEBI:61076 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257954 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 15448698 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-129418 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LIFR protein P42702 UNIPROT down-regulates phosphorylation 9606 7777512 YES inferred from 70% family members gcesareni Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044. 0.2 SIGNOR-270001 cyclosporin A chemical CHEBI:4031 ChEBI TTN protein Q8WZ42 UNIPROT up-regulates 9606 17636278 NO Regulation of transcription Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells. 0.8 SIGNOR-251975 TBK1 protein Q9UHD2 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates activity phosphorylation Ser479 SLDSSSLsLCLSSAN 9606 22787218 YES miannu In most cell types, IRF7 is phosphorylated and activated by IKK\u03b5 and TBK1 after viral infection.|We found that phosphorylation of IRF7 on Ser477 and Ser479 by IKK\u03b5 or TBK1 is inhibited by ORF45. 0.767 SIGNOR-278216 MAPK1 protein P28482 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser291 TYVNNSPsPGFNSSH 9606 19237534 YES lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. 0.335 SIGNOR-184168 biphenyl-4,4'-diol chemical CHEBI:34367 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9751507 YES miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings.  0.8 SIGNOR-268741 PIAS1 protein O75925 UNIPROT PRDM1 protein O75626 UNIPROT up-regulates sumoylation Lys816 PLVPVKVkQETVEPM 9606 22555612 YES miannu Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor. 0.324 SIGNOR-197265 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser780 MARGLNSsMDMARLP -1 14970204 YES miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. We identify four major sites of phosphorylation, serines 1123, 1058, 750/751/756, and 764/765. 0.43 SIGNOR-262690 SYN1 protein P17600 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 NO miannu Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. 0.7 SIGNOR-264105 cabozantinib chemical CHEBI:72317 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000184 26536165 YES miannu Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. 0.8 SIGNOR-262242 hsa-miR-338-3p mirna URS00000254A6_9606 RNAcentral SMO protein Q99835 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004169 29069716 YES Parnian MiR-338-3p suppresses the invasiveness and metastasis of HCC cells by directly targeting the Smoothened (SMO) protein 0.4 SIGNOR-277973 YAP1 protein P46937 UNIPROT TOP2A protein P11388 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276570 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation 10090 11730323 YES Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs 0.752 SIGNOR-258994 NELF complex SIGNOR-C521 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR down-regulates activity binding 9606 18628398 YES miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 0.406 SIGNOR-271403 PRKCA protein P17252 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 16574739 YES flangone We show that pkcalpha is likely to be directly involved in ser24 phosphorylation...These observations are entirely consistent with a recent independent study demonstrating that the IRS1-S24D mutant shows impaired insulin-stimulated IR-IRS-1 interactions, tyrosine phosphorylation of IRS-1, recruitment/activation of PI 3-Kinase, and insulin-stimulated Glut4 translocation 0.386 SIGNOR-145398 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr564 LEEADNQtLDSYRNE -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276214 Caspase 3 complex complex SIGNOR-C221 SIGNOR CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 YES lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation 0.638 SIGNOR-256453 CSNK2A1 protein P68400 UNIPROT CCNF protein P41002 UNIPROT down-regulates activity phosphorylation Ser621 GYEGDQEsEGEKEGD 9606 29021214 YES miannu We determined that casein kinase II (CK2) can phosphorylate Ser621 and thereby regulate the E3 ligase activity of the SCF(cyclin F) complex. 0.249 SIGNOR-266373 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-264178 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr295 AEALNQVtQRASRRS 9606 19366211 YES gcesareni These results implicate pkcdelta-thr(295) autophosphorylation as a lipid-dependent modification that links pkcdelta-thr(505) phosphorylation to src-dependent regulation of pkcdelta catalytic function. 0.2 SIGNOR-185283 5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine chemical CHEBI:91338 ChEBI ALK protein Q9UM73 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207132 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 8816480 YES lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 0.713 SIGNOR-235929 RHOA protein P61586 UNIPROT PFN1 protein P07737 UNIPROT up-regulates activity 9606 BTO:0000815 22820501 YES lperfetto We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells. 0.568 SIGNOR-253109 DTNBP1 protein Q96EV8 UNIPROT WASF2 protein Q9Y6W5 UNIPROT up-regulates activity binding 10116 BTO:0000601 20531346 YES miannu Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. 0.343 SIGNOR-265659 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr453 PEALHYDyIDVEMSA 9534 9655255 YES lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. 0.573 SIGNOR-246355 CDK1 protein P06493 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Thr487 APAEDVDtPPRKKKR 9606 21659531 YES lperfetto Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome 0.576 SIGNOR-174058 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 12167717 NO lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, 0.816 SIGNOR-236353 GDNF protein P39905 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 YES gcesareni A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling 0.799 SIGNOR-49091 DAD1 protein P61803 UNIPROT OST-A complex complex SIGNOR-C535 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.74 SIGNOR-272059 KAT6A protein Q92794 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates binding 9606 SIGNOR-C54 11742995 YES miannu The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription 0.465 SIGNOR-113056 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49B protein A6NDI0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271267 POLG protein P54098 UNIPROT DNA polymerase gamma complex SIGNOR-C378 SIGNOR form complex binding -1 19837034 YES lperfetto Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit. 0.716 SIGNOR-265719 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9136927 YES fspada Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro 0.731 SIGNOR-249649 MYCBP2 protein O75592 UNIPROT TSC2 protein P49815 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 18308511 YES miannu We show that Pam associates with E2 ubiquitin conjugating enzymes, and tuberin can be ubiquitinated by Pam through its RING finger domain. 0.356 SIGNOR-278704 KIF2B protein Q8N4N8 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 22535524 NO lperfetto The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation. 0.7 SIGNOR-252051 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 9832503 YES gcesareni Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover. 0.783 SIGNOR-62265 resiquimod chemical CHEBI:36706 ChEBI TLR7 protein Q9NYK1 UNIPROT up-regulates activity chemical activation 9606 15661881 YES miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. 0.8 SIGNOR-259246 APC2 protein O95996 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization relocalization 9606 BTO:0000038 10980707 YES lperfetto The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation. 0.79 SIGNOR-81545 GABRG2 protein P18507 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.641 SIGNOR-263761 LATS2 protein Q9NRM7 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Thr203 QGHVRTHtGEKPFSC 9606 21952048 YES lperfetto Lats2 kinase potentiates snail1 activity by promoting nuclear retention upon phosphorylation. during tgf_-induced emt lats2 is activated and snail1 phosphorylated at t203. 0.529 SIGNOR-176647 ID2 protein Q02363 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.546 SIGNOR-241143 LATS2 protein Q9NRM7 UNIPROT YWHAG protein P61981 UNIPROT up-regulates phosphorylation Ser59 VVGARRSsWRVISSI 9606 21118956 YES lperfetto Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions, 0.331 SIGNOR-170139 DLL1 protein O00548 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. 0.626 SIGNOR-209732 WNK3 protein Q9BYP7 UNIPROT SLC12A5 protein Q9H2X9 UNIPROT down-regulates activity phosphorylation 21613606 YES lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs 0.46 SIGNOR-264628 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr760 TVTSTDEyLDLSAPF 9606 BTO:0000007 11294897 YES lperfetto Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation. 0.2 SIGNOR-106742 PRPS2 protein P11908 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 BTO:0006038 29074724 NO lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. 0.7 SIGNOR-265734 MAGEA3 protein P43357 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity binding 9606 BTO:0000594 28394358 YES lperfetto In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. 0.436 SIGNOR-267592 PRKCA protein P17252 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Ser21 ADFRLNDsHKHKDKH -1 18408216 YES miannu In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells. 0.2 SIGNOR-276154 CSNK2A1 protein P68400 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr350 PEVKKEEtLLDLDFD 9606 BTO:0000567 16945112 YES lperfetto Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin. 0.2 SIGNOR-149314 RABEPK protein Q7Z6M1 UNIPROT M6PR protein P20645 UNIPROT up-regulates activity relocalization 9230071 YES lperfetto P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking. 0.383 SIGNOR-253091 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 7493944 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.581 SIGNOR-246272 levomethadone chemical CHEBI:136003 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258807 UFD1 protein Q92890 UNIPROT RQC complex complex SIGNOR-C559 SIGNOR form complex binding 28528489 YES lperfetto The ribosome-bound quality control (RQC) complex is a multi-protein complex conserved throughout eukaryotes and composed of the E3 ubiquitin ligase Ltn1/Listerin, the ATPase Cdc48/p97 with its co-factors Ufd1/UFD1L and Npl4/NPLOC4, as well as the factors Rqc1/TCF25 and Rqc2/NEMF (Fig. 1). 0.2 SIGNOR-277696 CCND1 protein P24385 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates binding 9606 15713663 YES gcesareni Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function. 0.412 SIGNOR-134056 CHKA protein P35790 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation 9606 11818547 YES miannu The data suggest that CKI phosphorylates and destabilizes the beta-catenin degradation complex, likely through the dissociation of PP2A, providing a mechanism by which CKI stabilizes beta-catenin and propagates the Wnt signal. 0.286 SIGNOR-279161 SHC1 protein P29353 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates activity 10090 BTO:0000944 17673906 NO inferred from 70% of family members lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. 0.2 SIGNOR-269903 NAA38 protein Q9BRA0 UNIPROT NatC complex SIGNOR-C417 SIGNOR form complex binding 9606 19398576 YES miannu We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation. 0.684 SIGNOR-267235 PRKACA protein P17612 UNIPROT MYOM2 protein P54296 UNIPROT down-regulates phosphorylation Ser76 RVCAKRVsTQEDEEQ 9606 BTO:0000887 9529381 YES llicata This binding is regulated in vitro by phosphorylation of a single serine residue (ser76) in the immediately adjacent amino-terminal domain mp1. M-protein phosphorylation by camp-dependent kinase a inhibits binding to myosin lmm. 0.2 SIGNOR-56395 DDX20 protein Q9UHI6 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates binding 9606 BTO:0000975 16153597 YES miannu Dp103 further increased the cell killing effect induced by foxl2 probably due to the direct association of dp103 with foxl2 protein. 0.445 SIGNOR-140388 PTPN11 protein Q06124 UNIPROT NTRK2 protein Q16620 UNIPROT down-regulates activity dephosphorylation 9606 28947394 YES miannu Conversely, PTPN11 knockdown lead to increased Y 515 phosphorylation of TrkB compared to the scramble control in the neuronal cells.|This study established that TrkB activation as demonstrated by receptor phosphorylation at Tyr 515 in the SH-SY5Y cells is negatively regulated by PTPN11 actions. 0.706 SIGNOR-277123 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA8 protein Q9Y5G5 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265702 BDP1 protein A6H8Y1 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR form complex binding 29378333 YES lperfetto Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1). 0.883 SIGNOR-266189 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249326 CDX2 protein Q99626 UNIPROT INS protein P01308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000120 12783165 NO miannu In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. 0.308 SIGNOR-254906 FZR1 protein Q9UM11 UNIPROT PFKFB3 protein Q16875 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000793 20080744 YES miannu We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. Cdh1 promotes PFKFB3 degradation in the nucleus. 0.262 SIGNOR-271436 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 21205641 YES gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.503 SIGNOR-170859 PSMA6 protein P60900 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.833 SIGNOR-263368 hsa-miR-124-5p mirna URS00003AA409_9606 RNAcentral FZD5 protein Q13467 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0006204 25861751 YES Parnian The current study showed that miR-124 was downregulated in vinblastine- and doxorubicin-resistant renal cancer cells, accompanied by increased levels of FZD5 and P-gp. | Meanwhile, miR-124 targeted FZD5 and abolished its presentation 0.4 SIGNOR-277969 OGT protein O15294 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity glycosylation Ser109 KSHSRQAsTDAGTAG 34155345 YES lperfetto Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation. 0.283 SIGNOR-276942 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr766 ALTSNQEyLDLSMPL 10116 19224897 YES lperfetto This second-stage autophosphorylation occurs on y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of y463 in the juxtamembrane region, y766 in the c-terminal tail, and y585 in the kinase insert region (1). The third-stage autophosphorylation takes place on the second tyrosine in the activation loop (y654), resulting in an additional 10-fold increase in the intrinsic tyrosine kinase activity of fgfr1. 0.2 SIGNOR-236203 CCR3 protein P51677 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 11591790 NO We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation 0.296 SIGNOR-254357 EIF2AK2 protein P19525 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 YES miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. 0.326 SIGNOR-263119 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF10 protein Q8NA82 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271047 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 BTO:0004553 24614225 YES gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. 0.307 SIGNOR-266442 miR-23b mirna URS0000283D0A_9606 RNAcentral GLS protein O94925 UNIPROT down-regulates quantity post transcriptional regulation 10090 21135128 YES MiR-130 reduces adipogenesis by repressing PPARγ biosynthesis and suggest that perturbations in this regulation is linked to human obesity. 0.4 SIGNOR-255930 PRKAA1 protein Q13131 UNIPROT MCU protein Q8NE86 UNIPROT up-regulates activity phosphorylation Ser57 TVHQRIAsWQNLGAV -1 30858581 YES lperfetto Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57 0.2 SIGNOR-275547 PPP1R9B protein Q96SB3 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates quantity binding 9534 BTO:0000298 12531897 YES miannu Spinophilin binding promotes the plasma membrane localization of Tiam1 and enhances the ability of Tiam1 to activate p70 S6 kinase. 0.423 SIGNOR-269175 KDM1A protein O60341 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 YES miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells 0.803 SIGNOR-264501 BMP15 protein O95972 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 BTO:0000975 16446785 YES lperfetto Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle. 0.515 SIGNOR-217538 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity deacetylation 9606 14976264 YES lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress 0.911 SIGNOR-122405 MAML3 protein Q96JK9 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 12370315 YES gcesareni We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors. 0.755 SIGNOR-94097 SMAD5 protein Q99717 UNIPROT SATB2 protein Q9UPW6 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.259 SIGNOR-268939 FBXO2 protein Q9UK22 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 10090 BTO:0000938 20854419 YES miannu SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production. 0.69 SIGNOR-271902 DLGAP1 protein O14490 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264588 PTPN3 protein P26045 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 12907755 YES PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 0.43 SIGNOR-248459 UBA52 protein P62987 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.809 SIGNOR-262459 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000552 14744793 YES gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. 0.652 SIGNOR-248062 FLI1 protein Q01543 UNIPROT MPL protein P40238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002581 15466856 NO miannu Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. 0.246 SIGNOR-254163 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser337 EAPERASsVYTRSTG 9534 BTO:0000298 10085131 YES Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism 0.2 SIGNOR-251464 7alpha,25-dihydroxycholesterol smallmolecule CHEBI:37623 ChEBI GPR183 protein P32249 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257504 PIP5K1C protein O60331 UNIPROT 1-phosphatidyl-1D-myo-inositol 4-phosphate(3-) smallmolecule CHEBI:58178 ChEBI down-regulates activity chemical modification 9606 9367159 YES miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities 0.8 SIGNOR-277284 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 21035469 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.595 SIGNOR-169150 DDIT3 protein P35638 UNIPROT ASNS protein P08243 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 18940792 NO miannu C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. 0.373 SIGNOR-253837 KAT8 protein Q9H7Z6 UNIPROT FASN protein P49327 UNIPROT down-regulates quantity by destabilization acetylation 9606 BTO:0000007 27758890 YES Overexpression of Myc-KAT8 increased the acetylation level of endogenous FASN by 2.2-fold (Fig. 3C). In contrast, knockdown of KAT8 decreased endogenous FASN acetylation by as much as 55% 0.2 SIGNOR-267366 PLK1 protein P53350 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates activity phosphorylation Ser1399 KVNFSDDsDLEDPVS 9606 BTO:0002181 17974570 YES miannu Although mutation of serine 1126 and threonine 1346 to alanine had no effect (lanes 2 and 5), additional mutation of threonine 1363 and serine 1399 rendered separase almost completely resistant to phosphorylation (lane 3). Serine 1399 seems to be the one residue within this large separase fragment that is most efficiently phosphorylated by polo-like kinase, because a corresponding point mutation was sufficient to reduce the labeling by 80% compared with wild type (lane 6). 0.771 SIGNOR-276082 RAC1 protein P63000 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates activity 23290138 NO Simone Vumbaca This result strongly supports the assertion that Wnt7a and FN stimulate PCP signaling to drive the symmetric expansion of satellite stem cells during regenerative myogenesis. 0.7 SIGNOR-255648 NF1 protein P21359 UNIPROT ADCY2 protein Q08462 UNIPROT up-regulates 9606 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.287 SIGNOR-203983 AARS1 protein P49588 UNIPROT tRNA(Ala) smallmolecule CHEBI:29170 ChEBI down-regulates quantity chemical modification 9606 32314272 YES miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). 0.8 SIGNOR-270445 BCS1L protein Q9Y276 UNIPROT LETM1 protein O95202 UNIPROT up-regulates activity binding 9606 BTO:0000567 18628306 YES lperfetto LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels, suggesting that BCS1L stimulates the assembly of the LETM1 complex. 0.465 SIGNOR-262543 CDK1 protein P06493 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Thr19 GSRRGRAtPAQTPRS 9606 BTO:0000567 12714602 YES lperfetto We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex. 0.593 SIGNOR-100877 STUB1 protein Q9UNE7 UNIPROT CIB1 protein Q99828 UNIPROT down-regulates quantity ubiquitination 9606 33082516 YES miannu All those were suggesting that CHIP promotes CIB1 ubiquitination via the Lys 48 residue of ubiquitin.|K10 and K65 were the Lysine (K) residues for CHIP mediated CIB1 degradation. 0.2 SIGNOR-278721 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192859 FLT3 protein P36888 UNIPROT IDH2 protein P48735 UNIPROT down-regulates activity phosphorylation Tyr107 SALATQKySVAVKCA 9606 BTO:0001545 34289383 YES lperfetto FLT3 promotes mIDH2 acetylation through Y107 phosphorylation of mIDH2 that enhances ACAT1 recruitment, 0.421 SIGNOR-267632 PRKCZ protein Q05513 UNIPROT MYH10 protein P35580 UNIPROT down-regulates phosphorylation Ser1937 RGGPISFsSSRSGRR 9606 16611744 YES lperfetto After egf stimulation, apkc_ translocates from the nucleus to the cytoplasm (figure 3) and is therefore able to interact with myosin ii-b. apkc_ phosphorylates nmhc ii-b on ser1937, which is located on the nonhelical tailpiece, leading to filament disassembly at certain sites of the cell 0.27 SIGNOR-146100 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR INCA1 protein Q0VD86 UNIPROT unknown phosphorylation Ser23 CSRVVSRsPPPRLPS -1 15159402 YES miannu  GST-INCA1 was phosphorylated in vitro by cyclin A2-CDK2 but not by CDK2 or either cyclin alone.  Mutation of Ser23, Thr167, and Ser176 strongly reduced in vitro phosphorylation of INCA1.Cyclin A1 and Cyclin A2 in Complex with CDK2 Phosphorylated INCA1 in Vitro Predominantly at Ser176 0.329 SIGNOR-273593 PLK1 protein P53350 UNIPROT CEP85 protein Q6P2H3 UNIPROT up-regulates activity phosphorylation 9606 30611117 YES miannu In summary, our results identify Cep85 as a platform to directly relay the activities of Plk1 and Mst2 to Nek2A activation at centrosomes through phospho-Nek2A-assistant Cep85 phosphorylation by Plk1 at the onset of mitosis.|Plk1 Heavily Phosphorylates the Nek2A-Binding Domain in Cep85 at Centrosomes in Late G2. 0.248 SIGNOR-278367 HOXB2 protein P14652 UNIPROT OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000946 9556594 YES Luana Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively 0.259 SIGNOR-261634 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 YES Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 0.363 SIGNOR-248384 CTH protein P32929 UNIPROT L-selenocystathionine zwitterion smallmolecule CHEBI:62226 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275823 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.759 SIGNOR-219316 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Thr142 DSVTKLLtDVQLMKG 9606 35080342 YES miannu AKT1 and AKT2 phosphorylate HSF1 at S326 but only AKT1 activates HSF1.|Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. 0.405 SIGNOR-278372 ACD protein Q96AP0 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 YES lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA 0.2 SIGNOR-263327 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr205 IMLNSKGyTKSIDIW 9606 BTO:0000007 19494114 YES lperfetto In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo. 0.407 SIGNOR-101276 H4C1 protein P62805 UNIPROT Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR form complex binding -1 24311584 YES miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. 0.2 SIGNOR-263718 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.322 SIGNOR-129320 TARS1 protein P26639 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270799 TSC complex SIGNOR-C101 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 NO lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor 0.62 SIGNOR-251527 PRKCE protein Q02156 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 21251911 YES lperfetto We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation 0.2 SIGNOR-171712 pembrolizumab antibody DB09037 DRUGBANK PDCD1 protein Q15116 UNIPROT down-regulates activity binding 9606 BTO:0000848; BTO:0002058 25685857 YES miannu Preclinical studies described PD-1 blockade resulting in tumor growth suppression and even decreased metastasis. This has led to the development of pembrolizumab (MK-3475), a highly selective, humanized monoclonal IgG4-kappa isotype antibody against PD-1. Early clinical trials have shown high tumor response rates and long duration of effect in previously treated advanced melanoma resulting in accelerated FDA approval for the drug in this situation. Pembrolizumab has also had success in non-small cell lung cancer and is being tested in multiple other tumor types. 0.4 SIGNOR-259899 GATA1 protein P15976 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0004911 12032775 NO The zinc finger transcription factor GATA-1, a central mediator of erythroid gene expression, interacts with multiple proteins including FOG-1, EKLF, SP1, CBP/p300 and PU.1. 0.7 SIGNOR-259962 RalGAP1 complex SIGNOR-C468 SIGNOR RALA protein P11233 UNIPROT down-regulates activity guanine nucleotide exchange factor 10090 BTO:0000011 21148297 YES miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. 0.436 SIGNOR-269795 CDK1 protein P06493 UNIPROT PTTG2 protein Q9NZH5 UNIPROT up-regulates activity phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 BTO:0000567 10656688 YES miannu HPTTG is phosphorylated by Cdc2 at Ser165. we show that hPTTG is phosphorylated during mitosis. The direct phosphorylation of hPTTG by Cdc2 is interesting in itself since the substrates of this master mitotic kinase are supposed to play important roles in the initiation and progression of mitosis. 0.291 SIGNOR-262700 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT up-regulates quantity binding 9606 BTO:0000567 25296192 YES miannu In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. 0.848 SIGNOR-266312 TEX12 protein Q9BXU0 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 YES miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. 0.652 SIGNOR-264203 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-267507 KIRREL3 protein Q8IZU9 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32503885 NO miannu We demonstrate that ectopic Kirrel3 expression in CA1 neurons specifically induces ectopic DG synapse formation, providing direct evidence that Kirrel3 plays an instructive role in synapse development. 0.7 SIGNOR-269077 CDK1 protein P06493 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates phosphorylation Thr286 VEGDAAEtPPRPRTP 9606 8114697 YES gcesareni P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well 0.494 SIGNOR-36112 H2AC11 protein P0C0S8 UNIPROT RNF168 protein Q8IYW5 UNIPROT up-regulates binding 9606 19203578 YES gcesareni Rnf168 is recruited to sites of dna damage by binding to ubiquitylated histone h2a. 0.2 SIGNOR-183890 Avasimibe chemical CID:166558 PUBCHEM SOAT1 protein P35610 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190119 AKT proteinfamily SIGNOR-PF24 SIGNOR EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 18836482 YES gcesareni Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b. 0.2 SIGNOR-181536 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566092 YES lperfetto Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. 0.685 SIGNOR-209590 quetiapine chemical CHEBI:8707 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258534 MAP2K3 protein P46734 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation 9606 11062067 YES fstefani Mkk3, mkk4 and mkk6 all show a strong preference for phosphorylation of the tyrosine residue of the thr-gly-tyr motifs in their known substrates sapk2a/p38, sapk3/p38 gamma and sapk4/p38 delta. we therefore examined the phosphorylation of sapk2a/p38, sapk3/p38? And sapk4/p38? By mkk3, mkk4 and mkk6, which are all known to be capable of activating these enzymes in vitro. 0.648 SIGNOR-83718 FYN protein P06241 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.633 SIGNOR-268210 PIH1D2 protein Q8WWB5 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 YES miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. 0.468 SIGNOR-270937 CLN8 protein Q9UBY8 UNIPROT SET protein Q01105 UNIPROT down-regulates activity binding 9606 BTO:0000007 30453012 YES miannu CLN8 interacts with ceramide binding proteins PP2A and I2PP2A. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3β, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8-deficient cells. The phosphorylation levels of PP2A substrates are decreased in the absence of CLN8. 0.2 SIGNOR-265584 KDM3A protein Q9Y4C1 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 YES miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  0.2 SIGNOR-276846 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser6 sKKRKPKV 9606 BTO:0000801;BTO:0000876 15221008 YES llicata We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling. 0.327 SIGNOR-126572 PPP1CA protein P62136 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 YES gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3) 0.447 SIGNOR-103152 CAMK2D protein Q13557 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates phosphorylation Ser210 YGKTQHSsLDQSSPP 9606 17179159 YES lperfetto These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2 0.358 SIGNOR-151418 CCND1 protein P24385 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates binding 9606 15713663 YES gcesareni Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5. 0.47 SIGNOR-134053 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser486 RPLSRAQsSPAAPAS -1 15738054 YES lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. 0.479 SIGNOR-249276 PPP2CA protein P67775 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 YES Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform 0.445 SIGNOR-248621 STAT3 protein P40763 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25194572 NO miannu Here we show that IL-6-activated Stat3 signaling regulates satellite cell behavior, promoting myogenic lineage progression through myogenic differentiation 1 (Myod1) regulation. IL-6 stimulation promoted an increase in the mRNA levels of both Stat3 and Myod1. Stat3 mediated this effect, as IL-6‚Äìdependent Myod1 upregulation was impaired after infection with the shStat3 lentivirus. 0.521 SIGNOR-255416 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation Ser1452 LPSSSPRsPSGLRPR 9606 BTO:0000007 32294430 YES done miannu We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452.  0.469 SIGNOR-274100 histamine smallmolecule CHEBI:18295 ChEBI HRH3 protein Q9Y5N1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257514 PHKG1 protein Q16816 UNIPROT PYGM protein P11217 UNIPROT up-regulates activity phosphorylation Ser15 QEKRKQIsVRGLAGV 9606 BTO:0002049 22225877 YES It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 0.683 SIGNOR-267398 MTOR protein P42345 UNIPROT EIF4EBP2 protein Q13542 UNIPROT down-regulates phosphorylation 9606 14967450 YES gcesareni Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2). 0.66 SIGNOR-122014 hsa-mir-126-5p mirna URS00001D69F6_9606 RNAcentral SPRED1 protein Q7Z699 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001949 18694565 YES Parnian MiR-126 strongly repressed expression of the Spred-1 3’ UTR luciferase reporter 0.4 SIGNOR-278011 ADK protein P55263 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 33961946 YES miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 0.8 SIGNOR-267841 ITCH protein Q96J02 UNIPROT TNIP2 protein Q8NFZ5 UNIPROT down-regulates ubiquitination 9606 16469705 YES gcesareni Here we show that tnfa-mediated jnk activation accelerates turnover of the NF-kappaBinduced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activationof the e3ubiquitin ligaseitch, which speci?cally Ubiquitinates c-flip and induces its proteasomal degradation. 0.269 SIGNOR-144453 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR MLL/SET subcomplex complex SIGNOR-C87 SIGNOR form complex binding 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.858 SIGNOR-204744 lofexidine chemical CHEBI:51368 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 22341244 YES Luana Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism.  0.8 SIGNOR-258330 MRPS14 protein O60783 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 BTO:0000934 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.73 SIGNOR-261456 MECP2 protein P51608 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000601 25420914 NO Luana Our current study highlights the phosphorylation, but not the overall expression level, of MeCP2 as a significant regulatory mechanism in regulating adult neurogenesis in the hippocampus.  0.7 SIGNOR-264967 PPP3CB protein P16298 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 YES When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. 0.278 SIGNOR-248361 FCN2 protein Q15485 UNIPROT MASP2 protein O00187 UNIPROT up-regulates activity binding 17204478 YES lperfetto In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2) 0.609 SIGNOR-263413 MAPK1 protein P28482 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser432 NQNVLLMsPPASDSG 9606 14988395 YES lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. 0.359 SIGNOR-123041 WT1 protein P19544 UNIPROT NPHS1 protein O60500 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15504938 YES The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner 0.488 SIGNOR-252299 FUS protein P35637 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0000007 33082139 NO P35637:p.Pro525Leu (mutation increasing interaction); P35637:p.Pro521Gly (mutation increasing interaction) When mTORC2 is inhibited, FUS is recruited to polyribosomes to promote translation inhibition and polyribosome stalling. Panel iv, ALS-FUS R521G and P525L mutants that localize more prominently to the cytoplasm also associate more abundantly with polyribosomes to inhibit translation and protein synthesis. 0.7 SIGNOR-262820 LARP7 protein Q4G0J3 UNIPROT HEXIM1 protein O94992 UNIPROT down-regulates activity binding 9606 BTO:0000567 30824372 YES Monia To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system. 0.687 SIGNOR-261183 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2B protein P29275 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257448 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR HDAC5 protein Q9UQL6 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 12058061 YES gcesareni In the cytoplasm, 14-3-3 proteins bind the phosphorylated hdac5 and retain it in the cytosol. 0.2 SIGNOR-89444 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity precursor of 9606 9404080 YES A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. 0.8 SIGNOR-267261 PAM16 protein Q9Y3D7 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.676 SIGNOR-267699 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM68 protein Q6AZZ1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271169 hsa-miR-410-3p mirna URS000047E765_9606 RNAcentral AGTR1 protein P30556 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000304 25646808 YES Parnian These data indicate that miR-410 downregulates AGTR1 expression via direct interaction. 0.4 SIGNOR-277996 BLOC1S4 protein Q9NUP1 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 BTO:0002946 22203680 YES lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. 0.627 SIGNOR-265932 POLR2E protein P19388 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.921 SIGNOR-266147 P2RY1 protein P47900 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257273 NKX3-1 protein Q99801 UNIPROT ACTG2 protein P63267 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19797053 NO miannu These results demonstrate the ability of MYOCD to discriminate among several juxtaposed CArG elements, presumably through its novel partnership with NKX3.1, to optimally transactivate the human ACTG2 promoter. 0.286 SIGNOR-254619 AE/b7 integrin complex SIGNOR-C186 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269030 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 YES lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 0.2 SIGNOR-252799 axitinib chemical CHEBI:66910 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 YES gcesareni The inhibitory effect of four tkis (axitinib, imatinib, masitinib, and vatalanib) for proliferation and phosphorylation of c-kit receptor as well as the expression and function of abcb1 were investigated in three cmct cell lines (hrmc, vimc1, and cmmc1). 0.8 SIGNOR-171866 VRK3 protein Q8IV63 UNIPROT BANF1 protein O75531 UNIPROT down-regulates activity phosphorylation Ser4 sQKHRDFV -1 25899223 YES lperfetto Although VRK3 has been regarded as a genuine pseudokinase from structural and biochemical studies, recent reports suggest that VRK3 acts as an active kinase as well as a signaling scaffold in cells. Here, we demonstrate that VRK3 phosphorylates the nuclear envelope protein barrier-to-autointegration factor (BAF) on Ser4.|Ectopic expression of VRK3 induces the translocation of BAF from the nucleus to the cytoplasm. I 0.492 SIGNOR-264564 RNF168 protein Q8IYW5 UNIPROT BLM protein P54132 UNIPROT up-regulates activity ubiquitination 9606 BTO:0001938 23708797 YES miannu Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of RAP80.  0.262 SIGNOR-272114 ACP1 protein P24666 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 10090 17353188 YES Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3 0.2 SIGNOR-248456 CSNK2A1 protein P68400 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates phosphorylation Ser1479 HVYEKLSsIESDV 9606 BTO:0000938 15537897 YES gcesareni Here we show that casein kinase ii (ck2) phosphorylates the serine residue (ser1480) within the c-terminal pdz ligand (iesdv) of the nr2b subunit of nmdar in vitro and in vivo. Phosphorylation of ser1480 disrupts the interaction of nr2b with the pdz domains of psd-95 and sap102 and decreases surface nr2b expression in neurons. 0.324 SIGNOR-130336 SMAD6 protein O43541 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 9892110 YES lperfetto Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3 0.495 SIGNOR-64071 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 14556242 YES gcesareni Two genes were newly identified to be shh responsive in neuroepithelial cell line mns-70: the metal-binding protein ceruloplasmin (cp) and the serine protease inhibitor inter-alpha-trypsine inhibitor heavy chain h3 (itih3). cp appeared to be regulated by gli-independent pathways. 0.2 SIGNOR-118612 exemestane chemical CHEBI:4953 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191520 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258538 PRKN protein O60260 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28656059 YES miannu Next, we defined whether pJNK is involved in parkin mediated p21 degradation.|Parkin ubiquitinates p21 in vivo and in vitro in an E3 ligase-substrate dependent manner. 0.2 SIGNOR-278640 MAPK3 protein P27361 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation Ser337 QLAKCVSsPHFQVAE 9606 16456541 YES gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. 0.418 SIGNOR-144317 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Thr161 ASRFHNHtTHMSLVG 9606 15342622 YES gcesareni Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation. 0.2 SIGNOR-128577 dactolisib chemical CHEBI:71952 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 YES ATP-competitive inhibitor of PI3K and mTOR gcesareni The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific 0.8 SIGNOR-175715 PRKCA protein P17252 UNIPROT KCNJ4 protein P48050 UNIPROT down-regulates activity phosphorylation Thr53 IFTTCVDtRWRYMLM -1 10206975 YES miannu These results therefore indicate that Kir2.3 is directly modulated by PKC phosphorylation of its channel protein and threonine 53 is the PKC phosphorylation site in Kir2.3. 0.2 SIGNOR-275965 AT9283 chemical CID:11696609 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190011 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT up-regulates quantity by expression transcriptional regulation 14565864 NO lperfetto Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner. 0.246 SIGNOR-268993 RAP1GDS1 protein P52306 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 21242305 YES miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob 0.501 SIGNOR-171421 IKBKE protein Q14164 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation 9606 22384232 YES miannu Indeed, using an in vitro kinase assay, we demonstrated that both JNK and IKKepsilon phosphorylated c-Jun (XREF_FIG and XREF_SUPPLEMENTARY). 0.317 SIGNOR-279621 FGFR1 protein P11362 UNIPROT PDP1 protein Q9P0J1 UNIPROT down-regulates activity phosphorylation Tyr94 SILKANEySFKVPEF 10090 BTO:0000944 24962578 YES miannu Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.  0.293 SIGNOR-276640 S1PR2 protein O95136 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.469 SIGNOR-257349 AURKB protein Q96GD4 UNIPROT H1-4 protein P10412 UNIPROT up-regulates quantity by stabilization phosphorylation Ser27 VKKKARKsAGAAKRK 9606 BTO:0000093 21511733 YES miannu we showed previously that phosphorylation of S27 in human histone H1.4 (H1.4S27-P), prevents binding of heterochromatin protein 1 (HP1) family members (officially known as chromobox protein homologs) to the neighboring dimethylated K26. Here, we present the first functional characterization of H1.4S27-P in vivo and in vitro. We show that H1.4S27 phosphorylation is cell-cycle-regulated and its levels peak on metaphase chromosomes. We identify further Aurora B as the kinase phosphorylating H1.4S27. 0.2 SIGNOR-262658 AKT1 protein P31749 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 BTO:0003473 14766748 YES lperfetto Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members 0.487 SIGNOR-252538 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000671 9228058 YES lperfetto The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl) 0.903 SIGNOR-49688 LEPR protein P48357 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001282 18718905 YES miannu These observations indicate that leptin stimulates tyrosine phosphorylation of STAT3 via LEPRb but independent of JAK2. 0.758 SIGNOR-263492 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Phe64 TVFSVDEfSASVLTG -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.526 SIGNOR-263586 CBX2 protein Q14781 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 YES miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b 0.772 SIGNOR-266808 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1330 QMRHQSEsQGVGLSD 9606 BTO:0000150 10550055 YES lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks 0.819 SIGNOR-72048 RBM10 protein P98175 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30403180 NO irozzo In this study, we report that RBM10 acts as a tumor suppressor in osteosarcoma via the inhibition of cell growth, cell migration and invasion and the induction of cell apoptosis by inhibiting Bcl-2, activating caspase-3, and producing TNF-α. We also found that RBM10 overexpression significantly inhibited the expression of Bcl-2 and induced the expression of caspase-3 0.2 SIGNOR-259151 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.2 SIGNOR-159398 MAPK9 protein P45984 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Thr320 SKYNAEStERESQDT 9606 18667537 YES llicata This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity. 0.376 SIGNOR-179680 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 16046550 YES The effect has been demonstrated using Q01196-8 gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.2 SIGNOR-138928 MAP4K3 protein Q8IVH8 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 9820741 YES gcesareni With regard to at least mekk1, serine/threonine kinases such as nik,glkand hpk1 appear also to be important for regulation 0.451 SIGNOR-61814 SIRT5 protein Q9NXA8 UNIPROT LDHB protein P07195 UNIPROT up-regulates activity deacetylation Lys329 DTLWDIQkDLKDL 9606 BTO:0001615 34929314 YES lperfetto In colorectal cancer, SIRT5 binds to lactate dehydrogenase B (LDHB) to deacetylate it at Lysine 329, thereby increasing its enzymatic activity. 0.2 SIGNOR-267645 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val53 SHVTGKGvTVETVFS -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.395 SIGNOR-263590 RPS6KA1 protein Q15418 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 YES gcesareni The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange. 0.452 SIGNOR-69171 SIM1 protein P81133 UNIPROT ARNT protein P27540 UNIPROT up-regulates activity binding -1 9020169 YES 2 miannu We demonstrate that both SIM1 and SIM2 can heterodimerize via their helix-loop-helix·PAS regions with ARNT, but not with AHR, and that they do not form homodimers. Furthermore, SIM1 may have a dual role, both negatively affecting AHR·ARNT binding to the XRE and also acting in concert with ARNT as a novel DNA-binding heterodimer. 0.532 SIGNOR-240759 PRKCG protein P05129 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 YES lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. 0.569 SIGNOR-249050 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser390 KEAEEESsGGEEEDE 9606 16227438 YES gcesareni We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2. 0.395 SIGNOR-141159 YES1 protein P07947 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates activity phosphorylation Tyr305 PFLNGGPyHSREQST 9606 BTO:0000578 35041461 YES miannu Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). 0.318 SIGNOR-277654 SRC protein P12931 UNIPROT NEDD4 protein P46934-4 UNIPROT up-regulates activity phosphorylation Tyr43 ILGASDPyVRVTLYD 9606 25292214 YES miannu Activation of c-Src by epidermal growth factor (EGF) also promoted tyrosine phosphorylation and enhanced the activity of NEDD4.  0.417 SIGNOR-276859 CADPS2 protein Q86UW7 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 YES miannu CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1 0.357 SIGNOR-264337 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000017;BTO:0000195 10753475 YES Canertinib is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC50 0.8 nM), HER-2 (IC50 19 nM) and ErbB-4 (IC50 7 nM). gcesareni Quinazoline analogues with 7-alkoxyamine solubilizing s were potent irreversible inhibitors of the isolated egfr enzyme, with ic(50[app]) values from 2 to 4 nm, and potently inhibited both egfr and erbb2 autophosphorylation in cells. 0.8 SIGNOR-76554 POLR2L protein P62875 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.837 SIGNOR-266142 ADAM17 protein P78536 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 20626350 NO gcesareni Such phosphorylation is required for tace mediated ectodomain shedding of tgfalfa family ligands, which results in the activation of egfr and cell proliferation. 0.459 SIGNOR-166568 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 19115199 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-183004 CDK4 protein P11802 UNIPROT PAX3 protein P23760 UNIPROT up-regulates activity phosphorylation Ser430 TTVSASCsQRLDHMK 9606 23469153 YES miannu In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro . 0.296 SIGNOR-278512 OPTN protein Q96CV9 UNIPROT BDNF protein P23560 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 NO same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. 0.28 SIGNOR-259878 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT unknown phosphorylation Ser25 SSSEDEDsDHEDKDR 9606 16717095 YES lperfetto Together, these data make a strong case for ck2 phosphorylation events within the serines 18-20 and 25 sites in vivo. hey also show that phosphorylation of ser-25 and ser-296 plays no additional role in g__ expression. 0.385 SIGNOR-146837 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257970 CNOT1 protein A5YKK6 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.894 SIGNOR-268300 USP13 protein Q92995 UNIPROT ATG5 protein Q9H1Y0 UNIPROT up-regulates quantity by stabilization deubiquitination 36528756 YES lperfetto Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. 0.274 SIGNOR-275838 Gbeta proteinfamily SIGNOR-PF4 SIGNOR IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation 9606 12510059 YES inferred from 70% family members gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.2 SIGNOR-269997 TRIM27 protein P14373 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 BTO:0000671 12807881 NO miannu Rfp expression in hek 293 cells activated jnk1 0.257 SIGNOR-102034 MAPK1 protein P28482 UNIPROT TP53BP2 protein Q13625 UNIPROT up-regulates activity phosphorylation Ser827 NSDMPAPsPGLDYEP -1 24312625 YES lperfetto Hence ASPP2 can be phosphorylated at serine 827 by MAPK1 in vitro.|Phosphorylation of ASPP2 by MAPK is required for RAS-induced increased binding to p53 and increased transactivation of pro-apoptotic genes. 0.263 SIGNOR-264414 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 BTO:0000007 11007774 YES gcesareni Incubation of the inactivated c-Src with PTP1B results in a dose-dependent reactivation of c-Src tyrosine kinase activity. Incubation of c-Src with 2 or 10 g of PTP1B results in partial or full restoration of c-Src kinase activity, respectively. The activation is accompanied by dephosphorylation of c-Src, both of Tyr-419 and of Tyr-530 0.78 SIGNOR-245299 P2RY1 protein P47900 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257185 PP2B proteinfamily SIGNOR-PF18 SIGNOR FLNA protein P21333 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 16442073 YES inferred from 70% family members Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation. 0.2 SIGNOR-269986 trichostatin A chemical CHEBI:46024 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257940 MAF1 protein Q9H063 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR down-regulates activity binding 29378333 YES lperfetto The synthesis of transfer RNA (tRNA) is directed by RNA polymerase III (Pol III) specialized in high-level transcription of short DNA templates. Pol III recruitment to tRNA genes is controlled by two general initiation factors, TFIIIB and TFIIIC. |Under stress conditions, tRNA synthesis is negatively regulated by the MAF1 protein, which interacts directly with Pol III. 0.388 SIGNOR-266198 LETM1 protein O95202 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR up-regulates 9606 BTO:0000567 18628306 NO lperfetto LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected. 0.287 SIGNOR-262546 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10116 BTO:0000575 15738637 YES In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. 0.286 SIGNOR-248446 STK38 protein Q15208 UNIPROT RAB11FIP5 protein Q9BXF6 UNIPROT up-regulates activity phosphorylation Ser307 FTHKRTYsDEANQMR 10090 BTO:0000142 22445341 YES miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. 0.2 SIGNOR-263035 STK11 protein Q15831 UNIPROT BRSK2 protein Q8IWQ3 UNIPROT up-regulates phosphorylation Thr174 VGDSLLEtSCGSPHY 9606 14976552 YES lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold 0.501 SIGNOR-122485 Shelterin complex complex SIGNOR-C306 SIGNOR ATM protein Q13315 UNIPROT down-regulates activity binding 18680434 YES lperfetto It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex 0.487 SIGNOR-263322 perfluorononanoic acid chemical CHEBI:38397 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 YES miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. 0.8 SIGNOR-268756 ATP smallmolecule CHEBI:15422 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates chemical inhibition 9606 21399626 YES lperfetto Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive 0.8 SIGNOR-217481 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser161 IADLGLAsFKMWSKL -1 18408713 YES miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) 0.2 SIGNOR-276158 CDK2 protein P24941 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 17361108 YES gcesareni Our results demonstrate that cdk2 is capable of autophosphorylation at thr160. 0.2 SIGNOR-153636 ANAPC13 protein Q9BS18 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.835 SIGNOR-252012 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates transcriptional regulation 9606 23332504 NO fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic.  0.284 SIGNOR-210111 ABL1 protein P00519 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Tyr213 PPTVPNDyMTSPARL 9606 21320496 YES lperfetto Abi-1 is an adaptor protein for abelson kinase (c-abl). Here, we identified a new phosphorylation site (y398) in the sh3 domain of abi1, and disruption of y398, combined with the previously identified phosphorylation site y213, significantly weakens the binding of abi-1 to c-abl. Phosphorylation of abi-1 is dependent on c-abl kinase 0.88 SIGNOR-172017 PRKACA protein P17612 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 BTO:0000011 20638365 NO Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-gamma 0.2 SIGNOR-253019 ETS1 protein P14921 UNIPROT TBX22 protein Q9Y458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 25373698 YES miannu TBX22 is an X-linked gene, which encodes a T-box-containing transcription factor. Loss-of-function mutation in the X-linked TBX22 promoter disrupts an ETS-1 binding site and leads to cleft palate. We first link the transcription factor ETS-1 to TBX22 pathway during embryonic palatogenesis. 0.2 SIGNOR-265565 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.301 SIGNOR-262978 SOD1 protein P00441 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 10090 BTO:0004488 18519638 NO P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) To investigate the role of ASK1 in the motor neurotoxicity by SOD1mut, we examined whether SOD1mut activates ASK1 as assessed by in vitro kinase assay. Expression of SOD1mut, but not SOD1wt, activated endogenous ASK1 (Fig. 4A, top panel). We next examined whether SOD1mut-induced ASK1 activation is mediated by ER stress. 0.367 SIGNOR-262789 WAC protein Q9BTA9 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9606 BTO:0000567 30021153 YES lperfetto Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1.  0.2 SIGNOR-265036 CERS4 protein Q9HA82 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 YES done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  0.8 SIGNOR-273998 SIAH1 protein Q8IUQ4 UNIPROT SCF(TBL1) complex SIGNOR-C533 SIGNOR form complex binding 9606 BTO:0000007 20181957 YES miannu Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC).  0.485 SIGNOR-271952 MAPK3 protein P27361 UNIPROT LIN28A protein Q9H9Z2 UNIPROT down-regulates activity phosphorylation Ser200 EEEEEIHsPTLLPEA 9606 BTO:0000567 28179426 YES miannu Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200.  0.277 SIGNOR-277337 PLK1 protein P53350 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser739 SKILLDIsFPGLDED 9606 19737929 YES lperfetto It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression 0.704 SIGNOR-187892 USP7 protein Q93009 UNIPROT TP53 protein P04637 UNIPROT up-regulates deubiquitination 9606 16082221 YES gcesareni Hausp counteracts the destabilizing effect of mdm2 by direct deubiquitination of p53. 0.74 SIGNOR-139456 CSNK1G1 protein Q9HCP0 UNIPROT LYN protein P07948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser13 SKGKDSLsDDGVDLK 9606 BTO:0000007 33004926 YES miannu Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane. 0.2 SIGNOR-275396 SRSF2 protein Q01130 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27524244 YES miannu Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2. 0.279 SIGNOR-260076 ID1 protein P41134 UNIPROT TCF4 protein P15884 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C129 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.629 SIGNOR-241385 RXRB protein P28702 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11237216 YES gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology 0.563 SIGNOR-105448 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 15381704 YES The effect has been demonstrated using P28329-3 gcesareni Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity. 0.286 SIGNOR-129284 DPF3 protein Q92784 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.745 SIGNOR-270703 SLC9A3 protein P48764 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265593 AXL protein P30530 UNIPROT TNS2 protein Q63HR2 UNIPROT up-regulates quantity phosphorylation Tyr483 GPLDGSPyAQVQRPP 9606 30419905 YES miannu In this study, however, we demonstrate for the first time that Axl directly binds to and phosphorylates TNS2 at Y483.|Overall these results suggest that Axl positively regulates TNS2 expression. 0.2 SIGNOR-278471 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273038 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9534 BTO:0000298 phosphorylation:Tyr177 8402896 YES gcesareni BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation 0.2 SIGNOR-248199 haloperidol chemical CHEBI:5613 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258680 FUS protein P35637 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates activity sumoylation Lys93 VCHFSPLkSDQDYIL 9606 BTO:0000007 19946338 YES gcesareni Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity. 0.337 SIGNOR-236904 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A3-B2 complex SIGNOR-C139 SIGNOR up-regulates activity chemical activation 9606 15036565 YES gcesareni One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP) 0.8 SIGNOR-244113 TTN protein Q8WZ42 UNIPROT TCAP protein O15273 UNIPROT unknown phosphorylation Ser157 GALRRSLsRSMSQEA 10090 9804419 YES lperfetto These data indicate that the activation of titin kinase in differentiating myocytes and the resulting phosphorylation of telethonin are involved in the reorganization of the cytoskeleton during myofibrillogenesis. 0.908 SIGNOR-246925 PRKAA1 protein Q13131 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by stabilization phosphorylation Thr198 PGLRRRQt 10090 30033086 YES Luana P27Kip1-Mediated Cell Survival Is Dependent on AMPK-Specific Thr198 Phosphorylation|AMPK-dependent phosphorylation of p27Kip1 on Thr198 promotes p27Kip1 protein stability, resulting in more autophagy and less apoptosis. 0.267 SIGNOR-259859 CEBPB protein P17676 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003697 18583320 YES Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells. 0.365 SIGNOR-254046 hsa-miR-101-5p mirna URS000017D10B_9606 RNAcentral CXCL12 protein P48061 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000018 26349988 YES Parnian MiR-101 suppressed the transcription activity of the CXCL12 gene by targeting the binding site in the 3'UTR of CXCL12 mRNA independently. | We observed that upon transfection with miR-101, the expression of CXCL12 protein and mRNA were both decreased. Collectively, these findings suggest that miR-101 regulates the expression of CXCL12 post-transcriptionally. 0.4 SIGNOR-278008 HNuRF complex SIGNOR-C448 SIGNOR EN1 protein Q05925 UNIPROT up-regulates quantity by expression 9606 14609955 NO miannu Human NURF (hNURF) is enriched in brain, and we demonstrate that it regulates human Engrailed, a homeodomain protein that regulates neuronal development in the mid-hindbrain. Furthermore, we show that hNURF potentiates neurite outgrowth in cell culture. Taken together, our data suggess a role for an ISWI complex in neuronal growth. ) ChIP assays localize hNURF specifically to engrailed-1 (en-1) and engrailed-2 (en-2) promoters. 0.318 SIGNOR-268839 KPNA6 protein O60684 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 YES gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling. 0.2 SIGNOR-165343 S1PR3 protein Q99500 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 10488065 YES gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13 0.492 SIGNOR-70713 PRKCZ protein Q05513 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Thr376 GSKFFMGtVVKKYEE 9606 BTO:0006398 32559461 YES miannu To further evaluate cPLA2 as a candidate substrate for PKCζ, we developed a custom antibody recognizing the cPLA2 T376 phosphorylation site. Specificity was validated in both serum starved/stimulated samples 0.328 SIGNOR-277518 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr89 QSSNGHItTTPTPTQ 9606 BTO:0000848 21177766 YES lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) 0.268 SIGNOR-170772 192927-92-7 chemical CID:11957576 PUBCHEM HTR1D protein P28221 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193814 SPRY4 protein Q9C004 UNIPROT Cell_invasion phenotype SIGNOR-PH226 SIGNOR down-regulates 9606 BTO:0002283 20501643 NO Re-expression of Spry4 inhibits migration and invasion in NSCLC cells. 0.7 SIGNOR-278112 CBL protein P22681 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20332299 YES lperfetto Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface. 0.886 SIGNOR-65642 oxybutynin chemical CHEBI:7856 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 22243489 YES Luana  Interestingly, unlike the methiodide 5, the tertiary amine 17 and to a lesser extent its (S)-eutomer preferentially block the M3 receptor subtype with respect to the M2, with an M3/M2 selectivity ratio slightly higher than those of oxybutynin and the conventional M3selective antagonist 4-DAMP.  0.8 SIGNOR-258327 MAPK14 protein Q16539 UNIPROT SMARCD3 protein Q6STE5 UNIPROT up-regulates activity phosphorylation 9606 21902831 YES lperfetto P38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci. 0.368 SIGNOR-176557 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser27 DRHLRSEsQRQRREI 9606 BTO:0000671 9166747 YES gcesareni Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling. 0.441 SIGNOR-48681 NUP98 Fusion fusion protein SIGNOR-FP16 SIGNOR CDK6 protein Q00534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32344427 NO miannu NUP98-fusion proteins directly regulate leukemia-associated gene expression programs in AML. CDK6 expression is under direct transcriptional control of NUP98-fusions and NUP98-fusion AML is particularly sensitive to CDK6 inhibition. 0.2 SIGNOR-261505 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 YES gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation 0.642 SIGNOR-252441 PRKD1 protein Q15139 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 20179209 YES lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated 0.307 SIGNOR-163924 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 YES lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.2 SIGNOR-124851 NMDA receptor_2B complex SIGNOR-C348 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264133 EID3 protein Q8N140 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 23720823 NO miannu Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene. 0.7 SIGNOR-266641 NFATC3 protein Q12968 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16219765 NO miannu Overexpression of NFAT3 enhanced both ERalpha and ERbeta transcriptional activities in a ligand-independent manner and up-regulated downstream estrogen-responsive genes including pS2 and cathepsin D. Reduction of endogenous NFAT3 with NFAT3 small interfering RNA or overexpression of NFAT3 deletion mutants that lack the ER-binding sites reduced the NFAT3 coactivation of ERalpha and ERbeta. 0.2 SIGNOR-254640 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates activity phosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000007;BTO:0000356 11751923 YES llicata We have shown that EGF activates STAT5b not only in a HEK293 cell model in which the EGFR is stably overexpressed but also in the MDA-MB468 breast cancer cell line. Furthermore, EGF (but not GH) is able to activate tyrosine phosphorylation of a Tyr-699 mutant of STAT5b. | Fig. 2 A (bottom panels) demonstrates that EGF-induced phosphorylation of tyrosine 699 (the well-described site of STAT5b phosphorylation) is detected only in the EGFR-overexpressing MDA-MB468 cells and not the MCF-7 cells. 0.829 SIGNOR-251098 AHR protein P35869 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 16115918 NO miannu Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1. 0.49 SIGNOR-253733 SRC protein P12931 UNIPROT CASP7 protein P55210 UNIPROT up-regulates activity phosphorylation 9606 24407236 YES miannu Src enhances caspase-7 activity in vitro and in cells.|When all four sites were mutated to phenylalanine, the in vitro kinase assay results showed that phosphorylation of the Mut-caspase-7 protein by Src decreased dramatically compared with Wt-caspase-7, suggesting that these four sites, Tyr58, Tyr151, Tyr229 and Tyr230, are the most important sites of caspase-7 to be phosphorylated by Src (XREF_FIG). 0.395 SIGNOR-278455 SCF-FBW7 complex SIGNOR-C135 SIGNOR GATA2 protein P23769 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 25670854 YES miannu GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1).  0.338 SIGNOR-276885 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257454 Ub:E2 complex SIGNOR-C497 SIGNOR RNF207 protein Q6ZRF8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271066 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr771 ADIESSNyMAPYDNY 10090 BTO:0002572 14966296 YES The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP. 0.563 SIGNOR-248389 SHOC2 protein Q9UQ13 UNIPROT MRAS protein O14807 UNIPROT up-regulates binding 9606 10783161 YES gcesareni Sur-8 interacts with ras and raf and is able to form a ternary complex with the two proteins. Thus, sur-8 may function as a scaffold that enhances ras-map kinase signal transduction by facilitating the interaction between ras and raf. 0.689 SIGNOR-77082 NHLRC1 protein Q6VVB1 UNIPROT PPP1R3C protein Q9UQK1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 19171932 YES miannu We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.  0.74 SIGNOR-276238 GDP smallmolecule CHEBI:17552 ChEBI GNAI1 protein P63096 UNIPROT down-regulates chemical inhibition 9606 12040175 YES gcesareni Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis. 0.8 SIGNOR-88226 TRAF6 protein Q9Y4K3 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates quantity ubiquitination 9606 27990298 YES miannu Consistently, TRAF6 reduced G6pase gene expression or reporter activity induced by wild-type CRTC1 and CRTC2 but not TRAF6-interaction-defective CRTC1 and CRTC2 (XREF_FIG and XREF_SUPPLEMENTARY).|Indeed, TRAF6, the E3 ubiquitin ligase activated by IL-1beta associates with and ubiquitinates CRTC2. 0.307 SIGNOR-278725 SP1 protein P08047 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21854868 NO miannu Doxorubixin-evoked β-TrCP up-regulation promoted Sp1 degradation, which subsequently suppressed ADAM10 expression in MCF-7 and MCF-7/Dox cells. 0.2 SIGNOR-255192 LPAR6 protein P43657 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 15856019 YES gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. 0.409 SIGNOR-135822 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation 9606 28114302 YES miannu A secondary genome-wide screen revealed CSNK1A1 as the kinase that phosphorylates AGO2 on these sites. 0.369 SIGNOR-279699 CLCN3 protein P51790 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 9606 29845874 YES miannu ClC-3 is a strongly outwardly rectifying, electrogenic 2Cl/H exchanger with biophysical properties that closely resemble those of its close homologues ClC-4 and ClC-5 0.8 SIGNOR-265422 PTH1R protein Q03431 UNIPROT SLC34A1 protein Q06495 UNIPROT down-regulates quantity 28363951 NO lperfetto PTH inhibits reabsorption of phosphate from the glomerular filtrate in RPT by decreasing the abundance of sodium-phosphate co-transporters NPT2a and NPT2c on the apical membrane, thus enhancing renal phosphate excretion 0.308 SIGNOR-270556 NCOA1 protein Q15788 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.472 SIGNOR-255063 HIPK2 protein Q9H2X6 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser257 PGVVMASsPALPTQP 9606 20573984 YES lperfetto Ere we found that homeodomain-interacting protein kinase 2 (hipk2), a dna-damage responsive nuclear kinase, is a new creb kinase for phosphorylation at ser-271 but not ser-133, and activates creb transactivation function 0.389 SIGNOR-166338 AKT3 protein Q9Y243 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 YES lperfetto the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate 0.258 SIGNOR-249583 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000142 8668348 YES gcesareni We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. 0.75 SIGNOR-42668 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 16076840 YES gcesareni The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex. 0.34 SIGNOR-139320 GATOR2 complex SIGNOR-C193 SIGNOR GATOR1 complex SIGNOR-C192 SIGNOR down-regulates activity binding 7227 23723238 YES Thus, GATOR2 is an inhibitor of an inhibitor (GATOR1) of the amino acid sensing branch of the TORC1 pathway 0.83 SIGNOR-253564 HNF4A protein P41235 UNIPROT GK protein P32189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription 0.2 SIGNOR-181274 IRF3 protein Q14653 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 NO miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. 0.2 SIGNOR-260330 PPP2CA protein P67775 UNIPROT STK3 protein Q13188 UNIPROT down-regulates dephosphorylation Thr180 DTMAKRNtVIGTPFW 9606 23431053 YES gcesareni Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively. 0.693 SIGNOR-201266 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 YES gcesareni Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression. 0.466 SIGNOR-156891 TPO protein P07202 UNIPROT L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI down-regulates quantity chemical modification 9606 16098474 YES scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 0.8 SIGNOR-266956 RUVBL2 protein Q9Y230 UNIPROT R2TP core co-chaperone complex SIGNOR-C515 SIGNOR form complex binding 9606 29662061 YES miannu  Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90.  0.808 SIGNOR-270929 RNF7 protein Q9UBF6 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity ubiquitination 9606 23136067 YES miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 0.2 SIGNOR-271448 CUL3 protein Q13618 UNIPROT MAP1B protein P46821 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000142 18680552 YES miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. 0.254 SIGNOR-268946 GNAI3 protein P08754 UNIPROT ADCY6 protein O43306 UNIPROT down-regulates activity binding 7108 BTO:0001240 8119955 YES Marta Tosoni Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3 0.509 SIGNOR-278079 HACD proteinfamily SIGNOR-PF86 SIGNOR very long-chain 2,3-trans-enoyl CoA(4-) smallmolecule CHEBI:83728 ChEBI up-regulates quantity chemical modification 9606 18554507 YES miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. 0.8 SIGNOR-267918 terbutaline chemical CHEBI:9449 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) 0.8 SIGNOR-257871 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr326 KMETQSMyVSELKRT 9606 BTO:0002181 37977223 YES miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. 0.566 SIGNOR-277863 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity precursor of 9606 24786789 YES miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. 0.8 SIGNOR-266508 RBM38 protein Q9H0Z9 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 17050675 YES Luana Here, we found that RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript. 0.318 SIGNOR-275391 CUDC-101 chemical CID:24756910 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262259 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT unknown phosphorylation Tyr691 PKGTQADyAEVKFQ 9606 11733002 YES lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691 0.26 SIGNOR-112499 methoxamine chemical CHEBI:6839 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258455 MAPK1 protein P28482 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 YES gcesareni Activated following phosphorylation at thr-182 by p38-alpha/mapk14, p38-beta/mapk11, erk2/mapk1, erk3/mapk6, and erk4/mapk4. 0.481 SIGNOR-58127 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.35 SIGNOR-259006 2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine chemical CHEBI:95074 ChEBI EHMT2 protein Q96KQ7 UNIPROT down-regulates activity chemical inhibition -1 26320100 YES miannu Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression. 0.8 SIGNOR-262240 NEDD4 protein P46934 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity ubiquitination 9606 27917940 YES miannu First, NEDD4 interacts with and ubiquitinates PPARgamma.|NEDD4 increases PPARgamma stability through the inhibition of its proteasomal degradation. 0.386 SIGNOR-278540 GRK5 protein P34947 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates phosphorylation 9606 32326036 YES miannu We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER. 0.26 SIGNOR-278478 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Thr26 PPPQPQHtPSPAAPP 9606 22878263 YES llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. 0.411 SIGNOR-198737 TRIM21 protein P19474 UNIPROT IRF8 protein Q02556 UNIPROT down-regulates quantity ubiquitination 9606 28592884 YES miannu From these results, we concluded that TRIM21 down-regulated IRF8 and enhanced the secretion of IL-12/23p40 in BD monocytes.|IRF8 is ubiquitinated by TRIM21, which promotes secretion of IL-12/23p40 after TLR/IFN-\u03b3 stimulation xref . 0.637 SIGNOR-278791 CEBPA protein P49715 UNIPROT HSD11B1 protein P28845 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19088256 YES lperfetto Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region. 0.274 SIGNOR-268971 NOX4 protein Q9NPH5 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.7 SIGNOR-264717 PAX2 protein Q02962 UNIPROT Urogenital_tract phenotype SIGNOR-PH71 SIGNOR up-regulates activity 10090 8575306 NO Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases. 0.7 SIGNOR-252301 cabazitaxel chemical CHEBI:63584 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 21770474 YES miannu Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization 0.8 SIGNOR-259445 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr7 tQDQPMEE 9606 BTO:0000567 2507541 YES lperfetto Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha. 0.428 SIGNOR-248888 CSNK2A1 protein P68400 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000527 19941816 YES miannu We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641. 0.391 SIGNOR-265822 STAG2 protein Q8N3U4 UNIPROT CD69 protein Q07108 UNIPROT up-regulates 9606 14660624 NO miannu Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner. 0.2 SIGNOR-119985 CSK protein P41240 UNIPROT CSK protein P41240 UNIPROT up-regulates activity phosphorylation Tyr304 DVCEAMEyLEGNNFV -1 9148770 YES llicata Taken together these results indicate that Csk can be phosphorylated in vivo at Tyr-184 by an as yet unknown tyrosine kinase, and that autophosphorylation of Tyr-304 occurs only at abnormally high Csk concentrations in vitro. Furthermore, Tyr-304 is required for the maintenance of the structure of the Csk kinase domain. 0.2 SIGNOR-250778 FOXA2 protein Q9Y261 UNIPROT DLK1 protein P80370 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12865419 YES Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene. 0.332 SIGNOR-254971 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 20974802 NO gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. 0.391 SIGNOR-168992 RPS6KB1 protein P23443 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser283 ILSLRSCsLGSLGAL -1 27407113 YES miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  0.322 SIGNOR-274065 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205743 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 BTO:0004055 8816480 YES lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 0.2 SIGNOR-244588 EIF3G protein O75821 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.937 SIGNOR-266394 AGTR2 protein P50052 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 YES gcesareni These neuropeptide gpcrs are coupled to the activation of phospholipase c, and therefore to calcium ele- vation and protein kinase c (pkc) activation, through g proteins of the alfaq family 0.503 SIGNOR-106995 PRKCA protein P17252 UNIPROT TTN protein Q8WZ42 UNIPROT up-regulates activity phosphorylation 9606 19679839 YES miannu In summary, titin is a PKC substrate with PKCalpha phosphorylating predominately the full-length titin molecule.|Mechanical experiments with skinned LV myocardium revealed that PKCalpha significantly increases titin based passive tension, an effect that is reversed by PP1. 0.271 SIGNOR-278382 GNAI1 protein P63096 UNIPROT Cell_invasion phenotype SIGNOR-PH226 SIGNOR down-regulates 9606 BTO:0003191 23691483 YES Marta Tosoni Taken together, these observations indicate that GNAI1 is a negative regulator of HCC migration and invasion, similar to its family member GNAI2. 0.7 SIGNOR-278879 AKT1 protein P31749 UNIPROT ATG4B protein Q9Y4P1 UNIPROT up-regulates activity phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000586 29165041 YES lperfetto In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity. 0.311 SIGNOR-275834 DFFB protein O76075 UNIPROT DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 BTO:0000661 9422513 NO Cleavage of ICAD/DFF-45 amattioni The specific cleavage of icad/dff-45 by caspase-3 relieves the inhibition and promotes the endonuclease activity of cad, resulting in apoptotic dna fragmentation 0.7 SIGNOR-54358 RAB1A protein P62820 UNIPROT C9orf72 protein Q96LT7 UNIPROT up-regulates activity binding 9606 27334615 YES lperfetto Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology. 0.475 SIGNOR-261282 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000568 16890161 YES gcesareni Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin. 0.789 SIGNOR-148671 PTEN protein P60484 UNIPROT PIK3CB protein P42338 UNIPROT down-regulates activity 9606 18794881 NO lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). 0.682 SIGNOR-236663 MRPL13 protein Q9BYD1 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.751 SIGNOR-262380 RIMBP3C protein A6NJZ7 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.265 SIGNOR-264372 CITED2 protein Q99967 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003859 12960175 NO miannu CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway. 0.369 SIGNOR-253777 BRCA1 protein P38398 UNIPROT BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR form complex binding 25400280 YES lperfetto Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks. 0.795 SIGNOR-263224 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser60 ETNQNSSsDSEAERR -1 11711551 YES llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 0.359 SIGNOR-250964 canertinib chemical CHEBI:61399 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258094 AKT1 protein P31749 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8940145 NO gcesareni The constitutively active akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3t3-l1 adipocytes directed lipid but not glycogen synthesis 0.549 SIGNOR-252579 EIF3F protein O00303 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates deubiquitination Lys1759 CGVLLSRkRRRQHGQ 9606 21124883 YES gcesareni The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor. 0.422 SIGNOR-170158 JUN protein P05412 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000552 12954631 NO miannu these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter. 0.267 SIGNOR-253905 HES1 protein Q14469 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19891787 NO gcesareni We earlier identified e2f-1 as a crucial transcription factor directly inhibited by hes-1. 0.2 SIGNOR-189061 PCSK7 protein Q16549 UNIPROT ATF6 protein P18850 UNIPROT up-regulates phosphorylation 9606 12076252 YES gcesareni We discovered that azc, an agent that causes the formation of abnormal proteins, stimulates the stress-activated kinase p38 mapk, which phosphorylates atf6 0.2 SIGNOR-89813 MAPK7 protein Q13164 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 9384584 YES lperfetto Bmk1 dramatically enhances the transactivation activity of mef2c by phosphorylating a serine residue at amino acid position 387 in this transcription factor. 0.765 SIGNOR-53545 PLEKHG6 protein Q3KR16 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.582 SIGNOR-260567 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000527 21419810 YES lperfetto In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer 0.32 SIGNOR-172894 GOT1 protein P17174 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-267509 CSNK2A1 protein P68400 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity phosphorylation Ser131 DESLANLsEDEYYSE 9606 BTO:0002181 25999347 YES miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. 0.318 SIGNOR-276902 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser352 AATNRPNsIDPALRR 9606 BTO:0000150 16551632 YES llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I 0.2 SIGNOR-145284 WNK4 protein Q96J92 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates activity phosphorylation 9606 22342722 YES miannu In addition, WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1, which in turn phosphorylate and activate NCC [ xref ; xref ].|Later studies also indicate that WNK4 phosphorylates and activates Ste20-type kinases SPAK and OSR1, which in turn phosphorylates and activates NCC ; ]. 0.481 SIGNOR-278389 eletriptan chemical CHEBI:50922 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 10193663 YES Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  0.8 SIGNOR-258339 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 YES Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175 0.667 SIGNOR-248476 FFAR3 protein O14843 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256957 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR SALL4 protein Q9UJQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.743 SIGNOR-269252 POLR2A protein P24928 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR up-regulates activity relocalization -1 20457598 YES lperfetto The pol II CTD specifically mediates recruitment of Integrator to the promoter of snRNA genes to activate transcription and direct 3' end processing of the transcripts. 0.663 SIGNOR-261476 PRKAA1 protein Q13131 UNIPROT CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21331044 YES gcesareni Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target. 0.285 SIGNOR-172136 SIRT1 protein Q96EB6 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 14976264 NO lperfetto Sirt1 inhibited foxo3's ability to induce cell death. 0.7 SIGNOR-256662 ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 11389842 YES Indirect_regulation of phosphorylation miannu Nodal Induces Smad Phosphorylation through ALK4 in a Cripto-Dependent Manner 0.801 SIGNOR-251943 MCU protein Q8NE86 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.689 SIGNOR-270869 GDNF protein P39905 UNIPROT GFRA2 protein O00451 UNIPROT up-regulates binding 9606 9192898 YES gcesareni Gdnf mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (gpi)-linked protein (designated gdnfr-alpha). 0.672 SIGNOR-49184 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation 9606 21419341 YES inferred from 70% family members gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. 0.2 SIGNOR-270048 DVL2 protein O14641 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity binding 9606 17529994 YES amattioni Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex. 0.668 SIGNOR-155221 DOK7 protein Q18PE1 UNIPROT CRK protein P46108 UNIPROT up-regulates activity binding 10090 BTO:0000165 20603078 YES miannu Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7. 0.358 SIGNOR-273847 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Lys1022 GGKSRLKkSQFLIKT -1 7989361 YES lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. 0.6 SIGNOR-263627 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 YES lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. 0.907 SIGNOR-235766 TP53INP1 protein Q96A56 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT up-regulates binding 9606 22421968 YES gcesareni These data indicate that cell death observed after tp53inp1-lc3 interaction depends on both autophagy and caspase activity. We conclude that tp53inp1 could act as a tumor suppressor by inducing cell death by caspase-dependent autophagy. 0.28 SIGNOR-196676 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr26 SQPHGSVtQSQGSSS 9606 BTO:0000007 12024051 YES gcesareni We show here that autophosphorylation of chk2 produced in a cell-free system requires trans phosphorylation by a wortmannin-sensitive kinase, probably atm or atr 0.834 SIGNOR-87850 chlorpromazine chemical CHEBI:3647 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258836 EFR3B protein Q9Y2G0 UNIPROT PI4KA protein P42356 UNIPROT up-regulates quantity binding 9606 BTO:0000007 34504076 YES miannu PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B 0.51 SIGNOR-269093 KDM5B protein Q9UGL1 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 31776402 YES lperfetto Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. 0.308 SIGNOR-273451 HTR1E protein P28566 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.446 SIGNOR-256848 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 10649448 NO gcesareni The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells 0.393 SIGNOR-255753 YWHAQ protein P27348 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 YES miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. 0.299 SIGNOR-252399 CCNE1 protein P24864 UNIPROT CDK2 protein P24941 UNIPROT up-regulates binding 9606 23437375 YES gcesareni Our results suggest that ad-induced cyclin e activates cdk2 that targets the transcriptional repressor prb/cyclin e activates the cdk2 kinase necessary for the actual initiation of dna replication 0.955 SIGNOR-201506 FRS2 protein Q8WU20 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10116 BTO:0002809 9182757 YES fspada In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. 0.801 SIGNOR-236953 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Thr530 YLSELPPtPLHVSED 9606 20027304 YES This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. 0.602 SIGNOR-162322 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1710 HVTSKCGsLKNIRHR 9606 BTO:0000567 11029056 YES miannu CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA 0.359 SIGNOR-250002 CDK3 protein Q00526 UNIPROT CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR form complex binding 37104883 YES lperfetto Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. 0.744 SIGNOR-273185 STAT1 protein P42224 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 16481475 YES gcesareni Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease. 0.519 SIGNOR-144561 PRKCA protein P17252 UNIPROT VTN protein P04004 UNIPROT up-regulates quantity by stabilization phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 YES lperfetto Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin. 0.318 SIGNOR-248962 RAR proteinfamily SIGNOR-PF45 SIGNOR RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 YES inferred from 70% family members gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.2 SIGNOR-269954 SAGA complex complex SIGNOR-C465 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269628 Ub:E2 complex SIGNOR-C497 SIGNOR BFAR protein Q9NZS9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270983 CCL3 protein P10147 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 15075201 YES lperfetto The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. 0.744 SIGNOR-251724 SRC protein P12931 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Tyr1320 NTTAMTIyENLAPVT 9606 BTO:0000007 22898603 YES miannu  We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. 0.635 SIGNOR-276375 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED -1 10195903 YES lperfetto Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.| Bcl-xL did not coimmunoprecipitate with BAD(S75E, S99E) protein (Fig. 2A), regardless of whether it was coexpressed with DCnA/B¬† 0.47 SIGNOR-263739 BRAF protein P15056 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 YES miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  0.326 SIGNOR-276406 CDC20 protein Q12834 UNIPROT MCC complex SIGNOR-C382 SIGNOR form complex binding 9606 BTO:0000567 25092294 YES miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 0.979 SIGNOR-265976 CSNK2A1 protein P68400 UNIPROT MYB protein P10242 UNIPROT down-regulates activity phosphorylation Ser12 PRHSIYSsDEDDEDF -1 7735324 YES llicata For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants.  0.34 SIGNOR-250919 Ub:E2 complex SIGNOR-C497 SIGNOR RNF125 protein Q96EQ8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271212 PRKCE protein Q02156 UNIPROT NREP protein Q16612 UNIPROT down-regulates quantity by destabilization phosphorylation Ser59 LGSSELRsPRISYLH 9606 BTO:0004605 16229809 YES done miannu Site-directed mutagenesis of S59A retarded P311 degradation and induced glioma cell motility. In contrast, S59D mutation resulted in the rapid degradation of P311 and reduced glioma cell migration.Taken together, our results show that the serine phosphorylation of P311 is dependent on the function of both PKCε and PKCz. 0.2 SIGNOR-273830 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 20640476 YES lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 0.502 SIGNOR-209936 WNT5B protein Q9H1J7 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.624 SIGNOR-131888 FANCG protein O15287 UNIPROT SPTAN1 protein Q13813 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000773 19102630 YES lperfetto In FA cells, deficiencies in FA proteins lead to decreased stability of alphaRIISp |These results demonstrate that one of the FA proteins, FANCG, contains a motif that interacts directly with the SH3 domain of alphaIISp. We propose that this binding of FANCG to alphaIISp may be important for the stability of alphaIISp in cells and the role alphaIISp plays in the DNA repair process.| 0.367 SIGNOR-263275 NVP-BEP800 chemical CID:25210273 PUBCHEM HSP90AB1 protein P08238 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194904 TRIM10 protein Q9UDY6 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity ubiquitination 9606 32343488 YES miannu Collectively, these results indicate that TRIM10 may lead to ubiquitination and degradation of PTEN, which could be an underlying reason for AKT signalling inhibition in cardiac hypertrophy processes (Figure\u00a05D).4\n\nDISCUSSION.|In addition, we found that the effect regulated by TRIM10 was mediated by interactions with phosphatase and tensin homolog (PTEN); specifically, TRIM10 promoted PTEN ubiquitination, thus leading to AKT signalling activation.|The results showed that TRIM10 overexpression decreased PTEN expression, and MG132 reversed the reduction in PTEN (Figure\u00a05C). 0.2 SIGNOR-278729 linifanib chemical CHEBI:91435 ChEBI PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193663 MAPK1 protein P28482 UNIPROT SORBS3 protein O60504 UNIPROT unknown phosphorylation 9606 15184391 YES The effect has been demonstrated using O60504-2 llicata Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _. 0.388 SIGNOR-125224 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by stabilization phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 22558186 YES gcesareni Among these effector proteins, chk1 phosphorylates tlk12 and rad51, while brca, pik3, pml and e2f1 are chk2 substrates. 0.487 SIGNOR-197278 SOD1 protein P00441 UNIPROT dioxygen smallmolecule CHEBI:15379 ChEBI up-regulates quantity chemical modification 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272286 PTPRG protein P23470 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.259 SIGNOR-254729 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 9606 10869359 YES lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf 0.2 SIGNOR-244156 HMGB1 protein P09429 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 10090 25014009 YES gcesareni HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs) 0.802 SIGNOR-252059 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser445 LGLRKTGsYGALAEI 9606 20354225 YES gcesareni Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. 0.507 SIGNOR-164747 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 7888666 YES apalma We found that IL-5 induced two GAS-binding proteins in the nuclear extract from eosinophils. One of them was identified as STAT1 (p91). 0.805 SIGNOR-255071 SIRT1 protein Q96EB6 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity deacetylation 10090 BTO:0002572 27776347 YES SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis. 0.506 SIGNOR-256208 CAD protein P27708 UNIPROT Pyrimidine biosynthesis phenotype SIGNOR-PH187 SIGNOR up-regulates activity 9606 15096496 NO The CPSase activity of CAD is the major locus of control of de novo pyrimidine biosynthesis 0.7 SIGNOR-267196 phosphatidic acid smallmolecule CHEBI:16337 ChEBI RAC1 protein P63000 UNIPROT up-regulates chemical activation 9606 18480413 YES gcesareni The c-terminal polybasic motif of rac1 is responsible for direct interaction with pa, 0.8 SIGNOR-178632 GNAS protein P63092 UNIPROT ADCY9 protein O60503 UNIPROT up-regulates activity binding 9606 BTO:0000007 29292367 YES Marta Tosoni Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The enzyme is weakly activated by forskolin, fully activated by the G protein Gαs subunit and is autoinhibited by the AC9 C-terminus. 0.627 SIGNOR-278883 AKT1 protein P31749 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates activity phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 YES gcesareni This study identifies APS as a novel physiological substrate for PKB and the first serine phosphorylation site on APS 0.401 SIGNOR-252557 Ub:E2 complex SIGNOR-C497 SIGNOR RNF11 protein Q9Y3C5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271038 PPARG protein P37231 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12821652 YES miannu Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation. 0.277 SIGNOR-268022 NOTCH1 protein P46531 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 NO lperfetto Other notch target genes identi?ed In the thymoma cell line were dtx1 (gene for deltex1), i?-202, i?-204, i?-D3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a). 0.2 SIGNOR-149777 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 11904305 YES gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. sa-perk1/2 activates the transcription factor, sp1, via ser59 phosphorylation downstream of pkc_, leading to transcription of p21sdi1 and resulting in replicative senescence of hdf cells. 0.652 SIGNOR-116174 CAMK4 protein Q16566 UNIPROT NOVA2 protein Q9UNW9 UNIPROT unknown phosphorylation Ser194 EQVHKAVsAIVQKVQ 9606 BTO:0000007 32492405 YES miannu CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. Conversely, Nova-2 with single or double mutations to alanine (2A and 1A2A) was predominantly nuclear, like the WT (Figures 5H and ​and5I).5I). In contrast, glutamate mutations at site 3 had no effect on Nova-2 localization (Figures 5H and ​and5I)5I) or on Nova-2 binding to RNA (Figure S5E). These results showed that active CaMKIV reduces Nova-2 nuclear localization by phosphorylating sites 1 and 2 (S25, T27). 0.255 SIGNOR-273519 lysophosphatidylserine 14:0(1-) chemical CHEBI:72402 ChEBI GPR34 protein Q9UPC5 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257505 ETS1 protein P14921 UNIPROT ECE1 protein P42892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000396 9595399 NO miannu Endothelial expression of endothelin-converting enzyme-1 beta mRNA is regulated by the transcription factor Ets-1. We conclude that Ets-1 is involved in transcriptional upregulation of ECE-1 beta mRNA in E.A. hy 926 cells induced by phorbol ester. 0.263 SIGNOR-254080 CSF2RA protein P15509 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 7716810 NO gcesareni A major pathway which mediates the effects of gm-csf on macrophages involves activation of the latent transcription factor stat5a via a janus kinase 2 (jak2)-dependent pathway. 0.59 SIGNOR-32220 NFX1 protein Q12986 UNIPROT HLA-DRA protein P01903 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 7964459 YES Luana A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor 0.396 SIGNOR-266224 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 17998206 YES lperfetto The endoplasmic reticulum (er)-resident protein kinase perk attenuates protein synthesis in response to er stress through the phosphorylation of translation initiation factor eif2_ at serine 51 / a modification that blocks initiation 0.765 SIGNOR-159160 RPS10 protein P46783 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.902 SIGNOR-262442 PCBP2 protein Q15366 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity binding 9606 BTO:0002181 19881509 YES Giorgia Only AIP4 associated with PCBP2 and caused MAVS degradation. The interaction between PCBP2 and AIP4 was abrogated when the linker region or WB2 of PCBP2 was deleted, which confirmed our previous data indicating that this region was critical for PCBP2-mediated degradation of MAVS 0.614 SIGNOR-260361 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 BTO:0001271 17318191 YES lperfetto Bcr_abl_mediated phosphorylation of y86 could induce a conformational change of __catenin impairing its binding to axin 0.2 SIGNOR-153435 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser358 MHPYQGRsGCSSQSI -1 28130417 YES lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. 0.324 SIGNOR-264868 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK10 protein P53779 UNIPROT down-regulates chemical inhibition 9606 18922779 YES gcesareni Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell. 0.8 SIGNOR-181644 WDCP protein Q9H6R7 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity binding 9606 BTO:0000007 30297404 YES miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11.  0.2 SIGNOR-273733 L-thyroxine smallmolecule CHEBI:18332 ChEBI Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 24692351 NO scontino Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form. 0.7 SIGNOR-267620 RZZ complex complex SIGNOR-C357 SIGNOR DCTN2 protein Q13561 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 20462495 YES lperfetto ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores 0.425 SIGNOR-265017 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT up-regulates activity 9606 11090075 YES apalma We show that the ectopic expression of PML-RARα is sufficient to elevate levels of cyclin A1 in U937 myeloid leukemia cells and cyclin A1 is negatively regulated by the RARα pathway. 0.2 SIGNOR-256373 Oxytocin protein P01178-PRO_0000020495 UNIPROT OXTR protein P30559 UNIPROT up-regulates activity binding 9606 11274341 YES lperfetto The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation.| The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. 0.2 SIGNOR-268545 Ub:E2 complex SIGNOR-C497 SIGNOR menB protein P23966 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270976 afatinib chemical CHEBI:61390 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 24643470 YES miannu This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. 0.8 SIGNOR-259295 IFNB1 protein P01574 UNIPROT TYK2 protein P29597 UNIPROT up-regulates 9606 10918594 NO gcesareni Early events in type i ifn signaling are tyrosine phosphorylation of the type i ifn receptor subunits (ifnar1 and ifnar2), and the activation of the receptor-associated tyk-2 and jak-1 janus kinases. 0.552 SIGNOR-80103 HARS1 protein P12081 UNIPROT tRNA(His) smallmolecule CHEBI:29178 ChEBI down-regulates quantity chemical modification 9606 10430027 YES miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 0.8 SIGNOR-270485 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 7529876 YES llicata We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex. 0.2 SIGNOR-27875 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRP1 inflammasome complex SIGNOR-C224 SIGNOR up-regulates activity 16037825 NO miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-263125 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser569 SRRRRSSsTAPPTSS 9606 16513649 YES llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization 0.2 SIGNOR-145044 G6PC1 protein P35575 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266568 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr904 SLRLVMEyLPSGCLR 9606 18250158 YES lperfetto Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro 0.2 SIGNOR-160664 MAPK3 protein P27361 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 15060146 YES miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. 0.318 SIGNOR-123656 D-106669 chemical CID:16048654 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191256 cortisone chemical CHEBI:16962 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 14817168 YES allergy gcesareni 0.8 SIGNOR-251691 hexadecanoic acid smallmolecule CHEBI:15756 ChEBI FFAR1 protein O14842 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257488 MAPK8 protein P45983 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 YES JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8. gcesareni Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax 0.372 SIGNOR-124020 Motilin smallmolecule CHEBI:80269 ChEBI MLNR protein O43193 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257542 RAE1 protein P78406 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.582 SIGNOR-262095 FAM20C protein Q8IXL6 UNIPROT ERO1A protein Q96HE7 UNIPROT up-regulates activity phosphorylation Ser145 GAVDESLsEETQKAV 9606 BTO:0000567 29858230 YES miannu We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding. 0.2 SIGNOR-277395 GPR132 protein Q9UNW8 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256945 PRRX1 protein P54821 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000567 9334314 YES miannu The human homeodomain proteinphox1interacts functionally with serum response factor (srf) to impart serum responsive transcriptional activity to srf-binding sites in a hela cell cotransfection assay. 0.443 SIGNOR-52657 sodium(1+) chemical CHEBI:29101 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29863287 NO miannu Axonal excitability is an important determinant for the accuracy, direction, and velocity of neuronal signaling. The mechanisms underlying spike generation in the axonal initial segment and transmitter release from presynaptic terminals have been intensely studied and revealed a role for several specific ionic conductances, including the persistent sodium current (INaP ). 0.7 SIGNOR-265182 HHAT protein Q5VTY9 UNIPROT SHH protein Q15465 UNIPROT up-regulates palmitoylation 9606 15075292 YES gcesareni Our molecular analysis of knockout mice deficient in skn, the murine homolog of the drosophila ski gene, which catalyzes hh palmitoylation, and gene-targeted mice producting a non palmitoylated form of shh indicates that hh palmitoylation is essential for its activity as well as the generation of a protein gradient in the developing embryos 0.682 SIGNOR-124118 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN2 protein Q9H2S1 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 YES Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  0.8 SIGNOR-258027 STUB1 protein Q9UNE7 UNIPROT PLK1 protein P53350 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27390342 YES miannu As indicated in xref , all three Plk1 fragments were ubiquitinated by CHIP, suggesting that CHIP targets multiple sites of Plk1 for ubiquitination.|Mechanistically, CHIP mediated degradation of AR and Plk1 leads to enhanced efficacy of HSP90 inhibitors. 0.252 SIGNOR-278532 TRIM26 protein Q12899 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization ubiquitination Lys87 FRSALNRkEGLRLAE 9606 25763818 YES miannu To investigate whether TRIM26 promotes IRF3 ubiquitination through K70 and K87, IRF3 mutant K70/87A was transfected into HEK293 cells together with Flag-TRIM26.|All together, these data indicated that active IRF3 was ubiquitinated and degraded by TRIM26 in nucleus. 0.671 SIGNOR-278533 ORF4b protein K9N643 UNIPROT IKBKE protein Q14164 UNIPROT down-regulates activity binding 9606 26631542 YES miannu Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm 0.2 SIGNOR-260592 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.491 SIGNOR-275776 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259807 MC5R protein P33032 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257393 MAPK15 protein Q8TD08 UNIPROT MAPK15 protein Q8TD08 UNIPROT up-regulates phosphorylation Tyr177 EDQAVTEyVATRWYR 9606 16336213 YES lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation 0.2 SIGNOR-142973 STK39 protein Q9UEW8 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 14563843 YES gcesareni Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress, 0.362 SIGNOR-118848 HDAC1 protein Q13547 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates deacetylation Lys380 PTESSMYkYPSDISY 9606 24058639 YES miannu Hdac1 interacts with fli1 and mediates its deacetylation / our previous studies have shown that pcaf-dependent acetylation of fli1 at lysine 380 decreases its protein stability / p300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380 0.2 SIGNOR-202689 PPP2CB protein P62714 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 YES In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. 0.322 SIGNOR-248602 CXCL5 protein P42830 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000584 34237033 NO miannu  We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. 0.7 SIGNOR-277733 SRC protein P12931 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Tyr112 NSYVAGQyDDAASYQ -1 33686238 YES miannu Here, we show that tyrosine kinase c-Src interacts with and phosphorylates G6PD at Tyr 112. This phosphorylation enhances catalytic activity of G6PD by dramatically decreasing its Km value and increasing its Kcat value for substrate glucose-6-phosphate. 0.274 SIGNOR-277550 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258647 MEN1 protein O00255 UNIPROT TERT protein O14746 UNIPROT down-regulates 9606 12837246 NO miannu The tumor suppressor menin, is a direct repressor of htert 0.306 SIGNOR-102874 FGF2 protein P09038 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 15780951 YES gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts. 0.82 SIGNOR-134788 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates activity 9606 31108873 NO De novo biosynthesis of both purines and pyrimidines has been observed to be altered in cancer and requires the generation of 5-phosphoribose-1-pyrophosphate (PRPP), the activated form of ribose derived from ribose 5-phosphate, which is produced through the oxidative and nonoxidative arms of the pentose phosphate pathway (PPP) parallel to glycolysis. 0.7 SIGNOR-267387 GSK3B protein P49841 UNIPROT ZC3HAV1 protein Q7Z2W4 UNIPROT up-regulates activity phosphorylation Ser271 ASASAERsCTPSPDQ 9606 22514281 YES miannu GSK3beta sequentially phosphorylated Ser 270, Ser 266, Ser 262, and Ser 257 of rat ZAP.|Inhibition of GSK3\u03b2 by inhibitor SB216763 or down-regulation of GSK3\u03b2 by RNAi reduced the antiviral activity of Zinc-finger antiviral protein. 0.2 SIGNOR-278401 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8422248 YES lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. 0.729 SIGNOR-248928 CASP3 protein P42574 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 YES amattioni Caspase-3 is required for the activation of caspases 6 0.618 SIGNOR-64179 CTDP1 protein Q9Y5B0 UNIPROT MASTL protein Q96GX5 UNIPROT down-regulates activity dephosphorylation Ser90 DALALSKsPFIVHLY 9606 26653855 YES lperfetto Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl. 0.434 SIGNOR-276972 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 15024053 YES llicata Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta) 0.27 SIGNOR-123453 RIMBP3 protein Q9UFD9 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.358 SIGNOR-264365 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr115 QPQPDSVyLVPTPSK 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246381 NLGN1 protein Q8N2Q7 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.828 SIGNOR-264154 POU5F1 protein Q01860 UNIPROT TBXT protein O15178 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.2 SIGNOR-254929 GPC3 protein P51654 UNIPROT DPP4 protein P27487 UNIPROT down-regulates binding 9606 17549790 YES miannu The interaction occurred with both the glycosylated and unglycosylated forms of gpc3 and led to the inhibition of cd26 peptidase activity. 0.352 SIGNOR-155527 CDK2 protein P24941 UNIPROT KLF10 protein Q13118 UNIPROT up-regulates quantity phosphorylation Ser206 NIPCAAVsPNRSKCE 9606 25728284 YES miannu In this study we have shown that CDK2 phosphorylates KLF10 at residue Ser 206 in vivo and in vitro .|In this study, we have shown that KLF10 protein has tightly controlled expression and that the expression level varies in a cell cycle dependent manner whereby CDK2 up-regulates activity the protein level of KLF10 through interference with the protein 's association with SIAH1. 0.329 SIGNOR-278394 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 22137581 YES lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction 0.2 SIGNOR-216608 KHDRBS1 protein Q07666 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity post transcriptional regulation 10090 BTO:0000232 22196734 YES Gianni Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA binding protein SAM68 which associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system. 0.332 SIGNOR-269057 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-70444 TRIM25 protein Q14258 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity ubiquitination 9606 27626314 YES miannu Since K48 chain linking generally targets proteins for proteasomal degradation, these results are consistent with the premise that TRIM25 promotes proteasomal degradation of ERG.|Using several biochemical assays we show that TRIM25 mediates the polyubiquitination of full-length ERG as well as N-terminally truncated ERG.|We demonstrate that TRIM25 polyubiquitinates ERG in vitro and that inactivation of TRIM25 resulted in reduced polyubiquitination and stabilization of ERG. 0.301 SIGNOR-278731 TFEB protein P19484 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 NO lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 0.289 SIGNOR-276802 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. 0.382 SIGNOR-216797 ALPL protein P05186 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity dephosphorylation 9606 24646911 YES miannu TNAP dephosphorylates overphosphorylated tau once it is released upon neuronal death. 0.2 SIGNOR-277097 Neuronal AP-3 complex SIGNOR-C445 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 22203680 NO miannu Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes 0.7 SIGNOR-268522 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 FSGIESSsPEVKGYW 9606 17475908 YES miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 0.323 SIGNOR-262916 XIAP protein P98170 UNIPROT CDC42 protein P60953 UNIPROT down-regulates quantity ubiquitination 9606 28661476 YES miannu As XIAP can directly ubiquitinate Cdc42, we tested if the RING domain of XIAP is required for modulating the protein levels of Cdc42 in vivo .|We then investigated the molecular mechanisms behind XIAP mediated Cdc42 degradation. 0.399 SIGNOR-278799 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates binding 9606 16282323 YES gcesareni Cytokine stimulation promotes bim(el) binding to 14-3-3 proteins. Akt could directly phosphorylate a gst-bim(el) fusion protein and identified the akt phosphorylation site in the bim(el) domain as ser(87). we propose that ser87 of bimel is an important regulatory site that is targeted byakt to attenuate thepro-apoptotic function of bim el, thereby promoting cell survival. 0.2 SIGNOR-141577 ELAVL1 protein Q15717 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 YES miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure 0.2 SIGNOR-266862 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. 0.641 SIGNOR-183688 ITGB1BP1 protein O14713 UNIPROT ITGB5 protein P18084 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.318 SIGNOR-257660 NTS protein P30990 UNIPROT NTSR1 protein P30989 UNIPROT up-regulates binding 9606 BTO:0000975 1331689 YES gcesareni The rat neurotensin receptor cdna sequence was transfected in chinese hamster ovary cells and cellular clones which stably express the corresponding protein were isolated and characterized. The scatchard analysis of the specific binding of [3h]neurotensin indicated a kd value of 0.45 +/- 0.08 nm and a bmax value of 3.27 +/- 0.29 pmol/mg of protein. ...Neurotensin Stimulated the phosphoinositides hydrolysis 0.929 SIGNOR-17369 PRKCD protein Q05655 UNIPROT APC protein P25054 UNIPROT down-regulates activity phosphorylation 9606 23520519 YES miannu APC is Phosphorylated by PKCdelta in Intact RKO Cells. 0.2 SIGNOR-279650 SMC5/6 complex SIGNOR-C374 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 27427983 NO miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks 0.7 SIGNOR-265487 SMARCB1 protein Q12824 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates 9606 12226744 NO miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. 0.247 SIGNOR-92788 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 YES lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  0.8 SIGNOR-260664 BABAM1 protein Q9NWV8 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 YES lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  0.926 SIGNOR-263215 CDK1 protein P06493 UNIPROT UBXN2B protein Q14CS0 UNIPROT down-regulates activity phosphorylation Ser56 PKATVFKsPRTPPQR 23500464 YES lperfetto At mitosis, Cdc2 kinase phosphorylates p47 on Serine-140 and p37 on Serine-56 and Threonine-59, respectively. The phosphorylated p47 and p37 are unable to bind to Golgi membranes, resulting in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively. 0.2 SIGNOR-265040 PKN2 protein Q16513 UNIPROT MEFV protein O15553 UNIPROT down-regulates activity phosphorylation Ser242 SGKMRPRsLEVTIST 10090 BTO:0004732 27270401 YES no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 0.349 SIGNOR-275463 CDK2 protein P24941 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 SIGNOR-C16 20530684 YES gcesareni The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry. 0.754 SIGNOR-165872 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT down-regulates relocalization 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 YES gcesareni Su(fu) is a negative regulator of shh that interacts with all three gli proteins to retain them in the cytosol. 0.888 SIGNOR-72308 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 YES gcesareni Rip1 is known to directly interact with traf2 0.895 SIGNOR-245032 TP53 protein P04637 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14522900 NO miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction 0.437 SIGNOR-254482 SMO protein Q99835 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.383 SIGNOR-199174 DCAF11 protein Q8TEB1 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000007 31409866 YES miannu (WDR23) isoforms differentially ubiquitinate (GEN1). In the presence of the necessary components for a successful ubiquitination reaction (CUL4A-DDB1-WDR23 complex, UBE1, UBE2D1, ubiquitin, and ATP) GEN1 receives the addition of ubiquitin in a time dependent manner. 0.611 SIGNOR-272262 CSNK2A1 protein P68400 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser575 AGESLDQsMEEEEEE 9606 BTO:0000567 12591939 YES llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 0.374 SIGNOR-250844 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 19130553 YES gcesareni Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna 0.234 SIGNOR-183158 Daunorubicin hydrochloride chemical CHEBI:31456 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 1963303 YES miannu DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. 0.8 SIGNOR-259322 FBXO4 protein Q9UKT5 UNIPROT FXR1 protein P51114 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 29142209 YES miannu Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinomaThe Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4.  0.456 SIGNOR-272795 4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid chemical CHEBI:64210 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 YES Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  0.8 SIGNOR-258035 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 20150555 YES lperfetto Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis. 0.415 SIGNOR-216940 CCL25 protein O15444 UNIPROT CCR9 protein P51686 UNIPROT up-regulates binding 9606 11159507 YES gcesareni Ccr9 is a specific receptor for the beta-chemokine teck/ccl25. 0.804 SIGNOR-104902 PRKCA protein P17252 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation Thr638 TRGQPVLtPPDQLVI 9606 15277524 YES lperfetto Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function 0.2 SIGNOR-127257 SMARCC1 protein Q92922 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.83 SIGNOR-270709 LUBAC complex SIGNOR-C527 SIGNOR GLYR1 protein Q49A26 UNIPROT down-regulates quantity by destabilization ubiquitination Lys338 VSDPKAAkDLVLGPS 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 0.2 SIGNOR-272836 tRNA(Ala) smallmolecule CHEBI:29170 ChEBI Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates quantity precursor of 9606 32314272 YES miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). 0.8 SIGNOR-270451 MRAP protein Q8TCY5 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. 0.35 SIGNOR-252364 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. 0.799 SIGNOR-253590 GDC-0879 chemical CHEBI:83405 ChEBI BRAF protein P15056 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192592 MAPK8 protein P45983 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 YES gcesareni Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells. 0.345 SIGNOR-178930 Caspase 3 complex complex SIGNOR-C221 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000142 10200555 NO amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation 0.7 SIGNOR-256477 GABRD protein O14764 UNIPROT GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.4 SIGNOR-263749 BDKRB1 protein P46663 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257149 ZMYND8 protein Q9ULU4 UNIPROT MMP3 protein P08254 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 YES lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported 0.2 SIGNOR-262043 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20651737 YES lperfetto Under resting conditions cellular inhibitor of apoptosis (ciap) proteins target nuclear factor-kb (nf-kb)-inducing kinase (nik) for ubiquitylation and proteasomal degradation. 0.585 SIGNOR-167066 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR PTPRC protein P08575 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 NO miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. 0.2 SIGNOR-255686 ARRB2 protein P32121 UNIPROT ADRB1 protein P08588 UNIPROT down-regulates activity binding -1 2163110 YES The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors 0.47 SIGNOR-256502 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 11691836 YES lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 0.658 SIGNOR-249390 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263789 AKT1 protein P31749 UNIPROT RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Thr70 GRRIRELtAVVQKRF 10116 BTO:0003060 20605787 YES miannu Here, we show that human RPS3 is a physiological target of Akt kinase and a novel mediator of neuronal apoptosis. NGF stimulation resulted in phosphorylation of threonine 70 of RPS3 by Akt, and this phosphorylation was required for Akt binding to RPS3.our experiment demonstrated that Akt up-regulates the endonuclease activity of RPS3 via phosphorylation and led us to believe that Akt phosphorylation of RPS3 after DNA damage is an antiapoptotic signal or a molecular switch that extends the life of a cell after DNA damage. 0.368 SIGNOR-259815 UBE2I protein P63279 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation Lys159 APSSMMVkDEYVHDF 9606 12621041 YES gcesareni The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses 0.625 SIGNOR-98997 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 15469984 YES gcesareni Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering scfbetatrcp-dependent destruction of the apc inhibitor emi1. 0.782 SIGNOR-129813 CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 16103124 YES gcesareni Moreover, app stabilized tip60 through cdk-dependent phosphorylation 0.479 SIGNOR-139649 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9823 BTO:0001840 SIGNOR-C3 23486913 YES lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation 0.926 SIGNOR-219257 SF1 protein Q15637 UNIPROT LHB protein P01229 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004467 19106114 NO miannu The human LHB promoter also contains low and high affinity SF1 binding sites. Mutation of these elements or depletion of endogenous SF1 impaired basal and ligand-induced transcription. 0.2 SIGNOR-254915 Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR CLEC1B protein Q9P126 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 19785988 YES miannu In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex 0.2 SIGNOR-272783 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192777 FGR protein P09769 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Tyr222 MEAPTTAyKKTTPIE -1 10066823 YES We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn. this interaction is weakened by phosphorylation of Tyr-222, through an allosteric mechanism that ultimately causes the detachment of fully phosphorylated HS1 from c-Fgr. 0.438 SIGNOR-251144 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Thr670 IAKPIPQtPESAGNK 9606 21335236 YES gcesareni We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks. 0.398 SIGNOR-172225 SREBF2 protein Q12772 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21123766 YES miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. 0.466 SIGNOR-254459 letrozole chemical CHEBI:6413 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193651 CDK5 protein Q00535 UNIPROT PLD2 protein O14939 UNIPROT up-regulates activity phosphorylation Ser134 ARFAVAYsPARDAGN 9606 18625302 YES miannu In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion.|We determined that Cdk5 phosphorylates PLD2 at Ser 134 of PLD2 and that this phosphorylation was suggested to be important for EGF-dependent insulin secretion. 0.368 SIGNOR-278395 EPHA3 protein P29320 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Tyr153 TDKSAEDyNSSNALN 9606 26944939 YES miannu Etk kinase directly phosphorylates and activates PAK1 in response to estrogen.|We demonstrated that estrogen-activated Etk directly phosphorylated PAK1 on Tyr153. 0.278 SIGNOR-278398 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser269 SEEGQELsDEDDEVY 9606 12167711 YES gcesareni Hypophosphorylation of mdm2 augments p53 stability. 0.346 SIGNOR-91191 RELA protein Q04206 UNIPROT COMT protein P21964 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000100 19291302 NO Regulation of expression miannu TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression. 0.2 SIGNOR-251964 PREX2 protein Q70Z35 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.608 SIGNOR-260571 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser587 YLRPRIPsPIGFTPG 9606 22966201 YES llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. 0.322 SIGNOR-198996 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 18701453 YES lperfetto Gsk3_ phosphorylates eif2b_ at ser-539 (ser-535 in the rat sequence) and inactivates it 0.578 SIGNOR-180022 PTGER3 protein P43115 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.28 SIGNOR-256995 TRIP12 protein Q14669 UNIPROT SOX6 protein P35712 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23663701 YES miannu In this article, we focused on Trip 12, an E3 ubiquitin ligase, which polyubiquitinates Sox6.|Therefore, Sox6 is a specific substrate to Trip12, by which it is polyubiquitinated and degraded. 0.398 SIGNOR-278579 messenger RNA smallmolecule CHEBI:33699 ChEBI 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.8 SIGNOR-269172 PTH protein P01270 UNIPROT PTH2R protein P49190 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671 11861531 YES gcesareni Pth was shown to efficiently activate the human type 2 pth receptor (pth2 receptor) 0.699 SIGNOR-115104 PP1 proteinfamily SIGNOR-PF54 SIGNOR MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 YES lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3) 0.2 SIGNOR-264664 MMP7 protein P09237 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Glu30 GLFDFMLeDEASGIG -1 9148753 YES miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. 0.609 SIGNOR-256351 AKT proteinfamily SIGNOR-PF24 SIGNOR HJURP protein Q8NCD3 UNIPROT up-regulates activity phosphorylation Ser486 GLETRRLsLPSSKAK -1 17256767 YES miannu These data define a new protein complex in mammalian cells where 14‐3‐3 associates with FAKTS through phosphorylated S479. Our research identifies a widely expressed eukaryotic protein FAKTS, as a new Akt/PKB substrate localized in the nucleus. Akt/PKB promotes FAKTS association with 14‐3‐3, placing FAKTS under the control of 14‐3‐3 proteins. FAKTS may play an important role in transmitting Akt/PKB‐mediated signals in the complex network of intracellular signal transduction. 0.2 SIGNOR-262623 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 BTO:0000567 15208625 YES gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. 0.8 SIGNOR-126055 YAP1 protein P46937 UNIPROT KIF23 protein Q02241 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276567 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9741627 YES lperfetto Shc is subsequently phosphorylated at tyrosine 317 and recruits grb2 0.731 SIGNOR-60160 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation 9606 15209375 YES gcesareni One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.52 SIGNOR-126069 MAPK3 protein P27361 UNIPROT STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 9731215 YES lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. 0.576 SIGNOR-249483 PTPN2 protein P17706 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 9606 12612081 NO acerquone We found that insulin-induced ir tyrosine phosphorylation and pkb/akt sig- naling were enhanced in tcptp- cells and suppressed upon tcptp reconstitution, providing persuasive evidence that tcptp can regulate ir activation and signaling. 0.357 SIGNOR-98811 CDKN1B protein P46527 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002392 22343731 NO fcortellessa The results of the MTT assay and growth curves revealed that the cells transfected with pEGFP-p27kip1 had a significant growth inhibition when compared with cells transfected with pEGFP-NC (Fig. 5B and D). These data indicated that overexpression of p27kip1 could arrest cell-cycle progression and decrease proliferation of SGC-7901 cells. 0.7 SIGNOR-261687 F2RL2 protein O00254 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.412 SIGNOR-257360 NANOGP8 protein Q6NSW7 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by repression transcriptional regulation 10900 BTO:0000667 23839044 NO Luana Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. 0.2 SIGNOR-266091 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 16896351 YES lperfetto In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1 0.877 SIGNOR-252014 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates activity binding 9606 12629049 YES Activation of PKC depends on the availability of DAG,a signaling lipid that is tightly and dynamically regulated. 0.8 SIGNOR-251559 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR DPPA4 protein Q7L190 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.474 SIGNOR-269243 2-N,6-N-Bis(2,3-dihydroxy-N-benzoyl)-L-serine amide chemical CHEBI:1219 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 YES miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. 0.8 SIGNOR-258437 GYS2 protein P54840 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI down-regulates quantity chemical modification 9606 26882899 YES miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. 0.8 SIGNOR-267937 GSK3B protein P49841 UNIPROT ZC3HAV1 protein Q7Z2W4 UNIPROT up-regulates activity phosphorylation Ser267 FLASASAsAERSCTP 9606 22514281 YES miannu GSK3beta sequentially phosphorylated Ser 270, Ser 266, Ser 262, and Ser 257 of rat ZAP.|Inhibition of GSK3\u03b2 by inhibitor SB216763 or down-regulation of GSK3\u03b2 by RNAi reduced the antiviral activity of Zinc-finger antiviral protein. 0.2 SIGNOR-278402 SRC protein P12931 UNIPROT VAV3 protein Q9UKW4 UNIPROT up-regulates phosphorylation Tyr173 EDEGGEVyEDLMKAE 9606 BTO:0000785 17998938 YES gcesareni Activation of rac1 and the exchange factor vav3 are involved in npm-alk signaling in anaplastic large cell lymphomas. 0.325 SIGNOR-159240 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Thr150 LVHQRSHtGEKPYLC 9606 BTO:0002552 31399647 YES miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. 0.2 SIGNOR-276754 AMPK complex SIGNOR-C15 SIGNOR GYS2 protein P54840 UNIPROT down-regulates activity phosphorylation Ser8 MLRGRSLsVTSLGGL -1 22233421 YES miannu Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations). 0.41 SIGNOR-263101 AR protein P10275 UNIPROT AKR1C3 protein P42330 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 22971343 NO miannu Both AR antagonism and androgen deprivation can upregulate AKR1C3. 0.449 SIGNOR-253737 silodosin chemical CHEBI:135929 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258449 MIR1-1 mirna URS000075CF56_9606 RNAcentral IGF1 protein P05019 UNIPROT down-regulates quantity post transcriptional regulation 9606 25477897 YES miannu The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT1 0.4 SIGNOR-255793 1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester chemical CHEBI:92418 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258637 GDNF protein P39905 UNIPROT NCAM1 protein P13591 UNIPROT up-regulates activity binding 10116 BTO:0002881 15212950 YES miannu Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable. 0.699 SIGNOR-252189 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val42 GRSLIGKvDGTSHVT -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.395 SIGNOR-263588 EGFR protein P00533 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Tyr154 PPFTARIyAAGFDSS 9606 BTO:0000815 36841821 YES miannu EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase.  EGFR phosphorylated PELI1 leading to its K63-linked auto-ubiquitination. 0.2 SIGNOR-277873 TRIM63 protein Q969Q1 UNIPROT PPP3CA protein Q08209 UNIPROT down-regulates quantity ubiquitination 9606 24526353 YES miannu First, downregulation of MuRF1 significantly attenuates degradation of CnA in cardiomyocytes in vitro, indicating that endogenous MuRF1 negatively regulates the stability of CnA in a cell-autonomous manner.|Furthermore, MuRF1 directly ubiquitinated CnA in vitro.|These results suggest that MuRF1 directly polyubiquitinates CnA. 0.26 SIGNOR-278736 TBK1 protein Q9UHD2 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser2159 RIQSIAPsLQVITSK 9606 32854217 YES miannu They later demonstrated that TANK-binding kinase 1 (TBK1) interacts with and phosphorylates mTOR on Ser 2159, to promote catalytic activity of mTOR [216]. 0.42 SIGNOR-278237 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7330 RASSRRGsDASDFDL 9606 BTO:0004905 21295697 YES lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. 0.436 SIGNOR-264435 hsa-miR-27a-5p mirna URS00001B341F_9606 RNAcentral FZD7 protein O75084 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004050 24018051 YES Parnian Our observations indicate that FZD7 is a target of miR-27a and miR-27a mediates FZD7 expression via posttranslational suppression. 0.4 SIGNOR-277966 MBD2/NuRD complex complex SIGNOR-C337 SIGNOR NOTCH2 protein Q04721 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000578 31659254 YES miannu Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. 0.272 SIGNOR-265560 RNF20 protein Q5VTR2 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates activity ubiquitination 9606 24425205 YES miannu Here, we reveal that RNF20-induced SREBP1c ubiquitination down-regulates hepatic lipogenic activity upon PKA activation.|Overexpression of RNF20 represses SREBP1c activity, leading to a decrease in the expression of lipogenic genes. 0.425 SIGNOR-278643 TTC3 protein P53804 UNIPROT SMURF2 protein Q9HAU4 UNIPROT down-regulates quantity ubiquitination 9606 33718111 YES miannu Tribbles homolog 3 ( TRB3 ) and Tetratricopeptide Repeat Domain 3 ( TTC3 ) directly ubiquitinate Smurf2 , thereby mediating Smurf2 degradation in a proteasome-dependent manner .|Tribbles homolog 3 (TRB3) and Tetratricopeptide Repeat Domain 3 (TTC3) directly ubiquitinate Smurf2, thereby mediating Smurf2 degradation in a proteasome dependent manner. 0.2 SIGNOR-278739 FLT3 protein P36888 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 10090 18192505 NO Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity 0.2 SIGNOR-261536 EGR1 protein P18146 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18303024 NO miannu The CYP2B6 enzyme metabolizes commonly used therapeutics and also activates pro-drugs. The CAR directly binds to the distal enhancer element of the CYP2B6 promoter, which is essential in converging to its drug-sensing function onto promoter activity. However, this binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter. 0.258 SIGNOR-253874 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI NTRK1 protein P04629 UNIPROT down-regulates chemical inhibition 9606 21159646 YES gcesareni In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases. 0.8 SIGNOR-170617 TRIM31 protein Q9BZY9 UNIPROT NLRP3 protein Q96P20 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27929086 YES miannu Taken together, these data indicated that TRIM31 directly induced the K48-linked ubiquitination of NLRP3 through its E3 ligase activity.|Taken together, these results indicated that TRIM31 could promote proteasomal degradation of NLRP3. 0.49 SIGNOR-278603 AEP complex complex SIGNOR-C117 SIGNOR MEIS1 protein O00470 UNIPROT up-regulates quantity by expression 9606 20854876 NO irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. 0.382 SIGNOR-256144 ECM stimulus SIGNOR-ST20 SIGNOR A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259044 KNTC1 protein P50748 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 BTO:0000567 20462495 YES lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. 0.762 SIGNOR-265015 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. 0.64 SIGNOR-254315 BRLF1 protein P03209 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 20381110 YES scontino EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs. 0.2 SIGNOR-266644 RPS6KA5 protein O75582 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12773393 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 0.2 SIGNOR-249213 BGLF4 protein P13288 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity phosphorylation Ser123 DFSQPDTsPDTNGGG 9606 BTO:0002181 19052084 YES scontino BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity. 0.2 SIGNOR-266647 BGLF4 protein P13288 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 BTO:0002181 19052084 YES scontino BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity. 0.2 SIGNOR-266648 BGLF4 protein P13288 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity phosphorylation Thr180 SPSLDNPtPFPNLGP 9606 BTO:0002181 19052084 YES scontino BGLF4 kinase interacts physically with and phosphorylates IRF3, which is the initial activator of transcription in the innate immune response. BGLF4 suppresses IRF3-dependent transcriptional activation. Data here suggest that Ser123, Ser173, and Thr180 contribute additively to the BGLF4-mediated repression of the IRF3 transactivation activity. 0.2 SIGNOR-266649 N protein P59595 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity 9606 17108024 NO miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. 0.2 SIGNOR-260337 3b protein P59633 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity 9606 17108024 NO miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. 0.2 SIGNOR-260338 6 protein P59634 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity 9606 17108024 NO miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein.ORF 3b, ORF 6, and N proteins all effectively inhibit phosphorylation of IRF-3.SARS-CoV ORF 3b, ORF 6, and N proteins all inhibit activation of IRF-3 by phosphorylation and binding of IRF-3 to a promoter with IRF-3 binding sites. 0.2 SIGNOR-260339 A10/b1 integrin complex SIGNOR-C167 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.555 SIGNOR-257709 TNFRSF1A protein P19438 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization 10090 BTO:0002572;BTO:0000801 21232017 NO lperfetto Tnfr1-induced phosforylation and degradarionn of ikb are almost completely abolished in tradd-deficient mefs,these hallmarks of classical nf-kn signaling are only attenuated in tradd-deficient macrophage. 0.556 SIGNOR-235789 SLC12A5 protein Q9H2X9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 21613606 YES lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  0.8 SIGNOR-264637 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Thr250 KEEVVGLtETSSQPK 9606 BTO:0000776 7678037 YES llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells. 0.307 SIGNOR-251013 ABCA1 protein O95477 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 23077142 NO miannu Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL). 0.7 SIGNOR-252109 RPS6KA5 protein O75582 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 27196759 YES miannu Co-transfection of MSK1 increased beta-catenin transcriptional activity in a dose dependent manner (XREF_FIG).|Our in vitro kinase assay showed that MSK1 can directly phosphorylate beta-catenin at Ser 552. 0.2 SIGNOR-278247 8a protein Q7TFA0 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 YES miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. Overexpression of 8b and 8ab resulted in the reduction of poly (I:C)-induced IRF3 dimerization and inhibition of the IFN-β signaling pathway. 0.2 SIGNOR-260239 8b protein Q80H93 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity binding 9606 29294448 YES miannu Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3.We also found that proteins 8b and 8ab could physically interact with IRF3. This counteracting effect was partially mediated by protein 8b/8ab-induced degradation of IRF3 in a ubiquitin-proteasome-dependent manner. Taken together, we propose that SARS-CoV may exploit the unique functions of proteins 8b and 8ab as novel mechanisms to overcome the effect of IFN response during virus infection.. 0.2 SIGNOR-260240 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT up-regulates activity phosphorylation Ser557 LEEFDVFsPKQDLVP 9606 BTO:0002181 25452387 YES miannu The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.  0.2 SIGNOR-276443 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser99 KEEEEGIsQESSEEE -1 2806554 YES llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol. 0.331 SIGNOR-250894 CDK1 protein P06493 UNIPROT PPP6R2 protein O75170 UNIPROT down-regulates activity phosphorylation Ser771 ESGPRCSsPVDTECS -1 29764989 YES done miannu We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit. 0.261 SIGNOR-273587 DPF3 protein Q92784 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.747 SIGNOR-270730 CDK1 protein P06493 UNIPROT NUSAP1 protein Q9BXS6 UNIPROT down-regulates phosphorylation Thr338 GNSAAVItPFKLTTE 9606 22101338 YES llicata We report here that cdk1 phosphorylates nusap at threonine 300 and 338 in early mitosis. Phosphorylation of nusap inhibits its microtubule-binding activity in vitro and in vivo. 0.431 SIGNOR-177549 NQO1 protein P15559 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003934 28599455 NO irozzo The results demonstrated that NQO1 siRNA-mediated knockdown effectively impaired colony formation capacity, induced cell cycle arrest at the G1 phase and suppressed migration of KKU-100 cells. 0.7 SIGNOR-256265 NR0B2 protein Q15466 UNIPROT NR1H3 protein Q13133 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000195 12198243 NO gcesareni Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter. T 0.478 SIGNOR-91996 WNT5A protein P41221 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 YES gcesareni Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis. 0.775 SIGNOR-199647 ANXA3 protein P12429 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000018 27995049 NO miannu We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. 0.277 SIGNOR-262211 PKI-587 chemical CID:44516953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252650 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 BTO:0004980 17242212 YES gcesareni Our data suggest that il-6 impairs the vasodilator effects of insulin that are mediated by the irs-1/pi3-kinase/akt/enos pathway through activation of jnk and erk1/2. 0.679 SIGNOR-152418 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPATGGV 9606 20129940 YES gcesareni Upon activation of the erk and p38 mapk pathways, the msk1/2-mediated nucleosomal response, including h3 phosphorylation at serine 28 or 10, is coupled with the induction of immediate-early (ie) gene transcription. 0.2 SIGNOR-163712 ATM protein Q13315 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates phosphorylation Ser135 EWETPDLsQAEIEQK 9606 19962312 YES llicata We show that, upon dna damage, rassf1a is phosphorylated by atm on ser131 and is involved in the activation of both mst2 and lats1, leading to the stabilization of p73. 0.551 SIGNOR-161934 BRF1 protein Q92994 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR form complex binding 29378333 YES lperfetto Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1). 0.712 SIGNOR-266190 GSK3B protein P49841 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates activity phosphorylation Thr367 NNSSRPStPTINVLE 9606 27494834 YES miannu GSK3\u03b2 phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3\u03b2 upregulates Thr367 phosphorylationin vivo. 0.331 SIGNOR-278175 SMAD1 protein Q15797 UNIPROT SATB2 protein Q9UPW6 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.2 SIGNOR-268934 FGB protein P02675 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 NO lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. 0.7 SIGNOR-253374 DCK protein P27707 UNIPROT 2'-deoxycytosine 5'-monophosphate(2-) smallmolecule CHEBI:57566 ChEBI up-regulates quantity chemical modification 20637175 YES lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis 0.8 SIGNOR-275807 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 YES milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity 0.9 SIGNOR-201310 ABL1 protein P00519 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0001271 23399893 YES gcesareni We show that the grb2-related adapter protein, gads, also associates with bcr-abl, specifically through y177 and demonstrate that bcr-abl-driven lymphoid disease requires gads 0.267 SIGNOR-200871 ARP2/3 complex SIGNOR-C146 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 12479800 NO lperfetto The Arp2/3 complex concentrates at leading edges, where it catalyzes the growth of branched actin networks that are believed to provide the protrusive force for leading edge extension. 0.7 SIGNOR-251511 RPS15 protein P62841 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.904 SIGNOR-262437 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266523 NAA15 protein Q9BXJ9 UNIPROT NatA complex SIGNOR-C415 SIGNOR form complex binding 9606 BTO:0000007 15496142 YES miannu Protein acetyltransferases and deacetylases have been implicated in oncogenesis, apoptosis and cell cycle regulation. Most of the protein acetyltransferases described acetylate epsilon-amino groups of lysine residues within proteins. We now describe the human homologue of Nat1p, NATH (NAT human), as the partner of the hARD1 (human ARD1) protein. Included in the characterization of the NATH and hARD1 proteins is the following: (i) endogenous NATH and hARD1 proteins are expressed in human epithelial, glioma and promyelocytic cell lines; (ii) NATH and hARD1 form a stable complex, as investigated by reciprocal immunoprecipitations followed by MS analysis; (iii) NATH-hARD1 complex expresses N-terminal acetylation activity; (iv) NATH and hARD1 interact with ribosomal subunits, indicating a co-translational acetyltransferase function 0.951 SIGNOR-267225 TRAF6 protein Q9Y4K3 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity ubiquitination 9606 23185365 YES miannu TRAF6 Interacts with STAT3 and Mediates the Ubiquitination of STAT3.|TRAF6 Represses the Transcriptional Activity of STAT3. 0.471 SIGNOR-278618 PDYN protein P01213 UNIPROT OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.666 SIGNOR-258415 CDX2 protein Q99626 UNIPROT CDH17 protein Q12864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972;BTO:0004168 20568120 YES The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC|we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L) 0.406 SIGNOR-253963 AP2M1 protein Q96CW1 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR form complex binding 31671891 YES lperfetto The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit 0.918 SIGNOR-260420 PLK1 protein P53350 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity phosphorylation Thr424 VKTEVEDtLTPPPSD 9606 27579997 YES miannu As illustrated in , the turnover of nuclear SREBP1a was attenuated in the presence of Plk1, confirming that Plk1 stabilizes nuclear SREBP1 by reducing its degradation.|Plk1 phosphorylates T424, S467 and S486 in nuclear SREBP1 during mitosis. 0.442 SIGNOR-279381 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 11259588 YES Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity 0.796 SIGNOR-248351 linagliptin chemical CHEBI:68610 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 18052023 YES Luana Herein, we report the discovery of the novel, potent, and selective DPP-4 inhibitor 1 (BI 1356)9 originating from the class of xanthines (Chart 1) 0.8 SIGNOR-257764 TLK2 protein Q86UE8 UNIPROT ASF1B protein Q9NVP2 UNIPROT unknown phosphorylation Ser198 PGLLPENsMDCI 9606 20016786 YES Manara We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | hASF1b stability does not appear to depend on phosphorylation by TLKs, but recently it has been shown that hASF1b transcription is controlled by the cell-cycle regulated E2F transcription factors 0.699 SIGNOR-260788 SMARCB1 protein Q12824 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.867 SIGNOR-269825 D-glucitol smallmolecule CHEBI:17924 ChEBI FUS protein P35637 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 NO We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne 0.8 SIGNOR-262813 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 YES lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively 0.2 SIGNOR-180775 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM2B protein Q8NHM5 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273472 ATM protein Q13315 UNIPROT UFL1 protein O94874 UNIPROT up-regulates activity phosphorylation Ser462 DDDSDDEsQSSHTGK 9606 BTO:0001938 30886146 YES lperfetto Furthermore, ATM phosphorylates UFL1 at serine 462, enhancing UFL1 E3 ligase activity and promoting ATM activation in a positive feedback loop. 0.2 SIGNOR-265075 OST-B complex complex SIGNOR-C536 SIGNOR Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.7 SIGNOR-272056 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 YES In the present study, we demonstrate that BCR Tyr-246 and at least one of the closely spaced tyrosine residues, Tyr-279, Tyr-283, and Tyr-289 (3Y cluster), are phosphorylated by FES both in vitro and in 32Pi-labeled cells. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1.  0.368 SIGNOR-251137 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser592 KCNVKAKsNVDLRRS 9606 BTO:0000007 30279167 YES miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser560 0.2 SIGNOR-277800 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 18362890 YES inferred from 70% family members gcesareni These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1 0.2 SIGNOR-270220 RPS6KA1 protein Q15418 UNIPROT ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 12213813 YES lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. 0.35 SIGNOR-249163 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A4/b7 integrin complex SIGNOR-C187 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.319 SIGNOR-259011 5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide chemical CHEBI:91333 ChEBI PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192991 NARS2 protein Q96I59 UNIPROT asparagine smallmolecule CHEBI:22653 ChEBI down-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270462 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates activity phosphorylation Thr451 PIPKALGtPVLTPPT 10090 11689711 YES gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. 0.2 SIGNOR-248003 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1654 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248807 tandutinib chemical CHEBI:90237 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258297 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0001103 28163303 NO apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function 0.7 SIGNOR-255112 adenosine smallmolecule CHEBI:16335 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 18957298 YES miannu Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. Given adenosine's important role in modulating synaptic transmission, several mechanisms exist to regulate its extracellular availability. One of these is the intracellular enzyme adenosine kinase (ADK), which phosphorylates adenosine to AMP. 0.8 SIGNOR-265465 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0003316 11777913 YES miannu 4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. 0.434 SIGNOR-250097 CAPN1 protein P07384 UNIPROT GSK3A protein P49840 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 YES lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase 0.2 SIGNOR-251585 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 14701738 YES miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. 0.332 SIGNOR-261716 NEUROG3 protein Q9Y4Z2 UNIPROT ASH1L protein Q9NR48 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19028584 NO miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. 0.2 SIGNOR-254629 GDP smallmolecule CHEBI:17552 ChEBI PRPS1 protein P60891 UNIPROT down-regulates activity chemical inhibition 29074724 YES lperfetto PRPS1 is inhibited by the nucleotide biosynthesis products ADP, AMP, and GDP 0.8 SIGNOR-265738 ENPP1 protein P22413 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 20923972 YES Phosphodiesterases Catalyze Hydrolysis of cAMP-bound to Regulatory Subunit of Protein Kinase A and Mediate Signal Termination 0.8 SIGNOR-253018 Kisspeptin-10 smallmolecule CHEBI:80307 ChEBI KISS1R protein Q969F8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257527 Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 9606 24168260 NO miannu We hypothesized that the ACE2/Ang-(1-7)/Mas axis protects against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway.In summary, our study demonstrate that exogenous Ang-(1-7) and ACE2 overexpression protect against BLM- or AngII-induced pulmonary fibrosis by down-regulating the MAPK/NF-κB pathway. However, constant infusion of Ang-(1-7) paradoxically initiates an inflammatory response in the lungs. The antifibrotic effects of Ang-(1-7) noted here make the heptapeptide a strong candidate for a therapeutic target in humans with pulmonary fibrosis. 0.2 SIGNOR-260447 EPB42 protein P16452 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.396 SIGNOR-266014 UBE3A protein Q05086 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR down-regulates activity ubiquitination 9606 BTO:0000007 28559284 YES Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A 0.308 SIGNOR-270339 MDM2 protein Q00987 UNIPROT ATXN1 protein P54253 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28212558 YES miannu NICD and MDM2 ubiquitinate and degrade ATXN1.|These results suggest that NICD and MDM2 synergistically reduce ATXN1 expression at the posttranscriptional level. 0.334 SIGNOR-278823 CDK1 protein P06493 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 YES lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. 0.2 SIGNOR-264878 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 BTO:0001130 23633519 YES lperfetto Akt is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates pips) with phosphate groups at positions 3,4 and 3,4,5 on the inositol ring. 0.8 SIGNOR-236490 PTPRB protein P23467 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members gcesareni When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well 0.2 SIGNOR-269911 CCN2 protein P29279 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 33358571 NO miannu As a matricellular protein, connective tissue growth factor (CTGF) functions beyond its classical role in extracellular matrix (ECM) remolding. Increasing evidence emphasizes the notion that CTGF is pivotal in cancer initiation and progression. 0.7 SIGNOR-277683 CYP19A1 protein P11511 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI down-regulates quantity chemical modification 9606 BTO:0000975 27702664 YES lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively 0.8 SIGNOR-268672 Isoetharine chemical CHEBI:6005 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 YES miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. 0.8 SIGNOR-258432 ZBTB16 protein Q05516 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0002882 9710637 NO fcortellessa PLZF expression in 32DG/GM cells is associated with growth suppression and G1 arrest. 0.7 SIGNOR-261685 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr398 SQFTKYWtESNGVES 9606 16216881 YES lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. 0.2 SIGNOR-141026 LINC complex complex SIGNOR-C303 SIGNOR NPC complex SIGNOR-C263 SIGNOR up-regulates activity binding 9606 BTO:0000567 28831067 YES lperfetto The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export. 0.2 SIGNOR-263292 MAPK3 protein P27361 UNIPROT SOX9 protein P48436 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20457810 NO fspada Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression. 0.382 SIGNOR-165353 HOXA9 protein P31269 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 NO irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. 0.7 SIGNOR-255864 PURA protein Q00577 UNIPROT MYH6 protein P13533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12933792 NO miannu In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene. 0.2 SIGNOR-253902 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser305 QPGVDSLsPVASLPK 25855382 YES lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant 0.376 SIGNOR-275558 STRN protein O43815 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 YES miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms 0.639 SIGNOR-261698 PRKCD protein Q05655 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr566 FIQRWNFtKTTKAKY 9606 20733000 YES Translocation from Cytoplasm to the Edge of Lamellipodia gcesareni Finally, we show that thr566 of pld2 is directly phosphorylated by pkc and that pld2 mutation in this region prevents pld2 activation, pld2 translocation to the edge of lamellipodia, rac translocation, and cell spreading after integrin activation 0.464 SIGNOR-167577 RARA protein P10276 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 YES inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.536 SIGNOR-270293 ATM protein Q13315 UNIPROT NOP53 protein Q9NZM5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr289 PATEQAAtQESTFQE 9606 BTO:0000007 27829214 YES miannu PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1.  0.2 SIGNOR-273507 AKT1 protein P31749 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 20086174 YES inferred from 70% of family members llicata We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. 0.398 SIGNOR-269945 ATP7A protein Q04656 UNIPROT copper(1+) smallmolecule CHEBI:49552 ChEBI up-regulates quantity relocalization 28389643 YES lperfetto Menkes disease (MD) is caused by mutations in ATP7A, encoding a copper- transporting P-type ATPase which exhibits copper-dependent trafficking. ATP7A is found in the Trans-Golgi Network (TGN) at low copper concentrations, and in the post-Golgi compartments and the plasma membrane at higher concentrations.  0.8 SIGNOR-272298 Blood vessel damage stimulus SIGNOR-ST26 SIGNOR F12 protein P00748 UNIPROT up-regulates NBK482253 NO lperfetto It begins with the activation of Factor XII (a zymogen, inactivated serine protease) which becomes Factor XIIA (activated serine protease) after exposure to endothelial collagen. Endothelial collagen is only exposed when endothelial damage occurs. 0.7 SIGNOR-263514 MYC protein P01106 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 NO miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 0.52 SIGNOR-267363 ARNTL protein O00327 UNIPROT PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.733 SIGNOR-253628 RAB5A protein P20339 UNIPROT RAB7A protein P51149 UNIPROT down-regulates activity binding 9606 BTO:0000567 30485418 YES miannu The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis 0.698 SIGNOR-277780 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000599 10187842 YES inferred from 70% family members lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. 0.2 SIGNOR-270079 RBPJ protein Q06330 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by repression transcriptional regulation 23729744 NO apalma In the absence of NICD, CSL forms complexes with a variety of co-repressors to suppress the transcription of Notch target genes 0.95 SIGNOR-255373 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity binding 9606 21041483 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.2 SIGNOR-266971 MICU1 protein Q9BPX6 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.696 SIGNOR-270867 HIPK2 protein Q9H2X6 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000452 19820693 NO Luana We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner. 0.7 SIGNOR-264551 ATF4 protein P18848 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16205636 NO miannu Suppression of ATF4 expression by small interfering RNA (siRNA) partially inhibited the celecoxib-dependent upregulation of GRP78. 0.665 SIGNOR-253749 PRKAA2 protein P54646 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Thr1116 AALGSTGtVAHLVAS 23871434 YES Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro 0.2 SIGNOR-275487 PREX2 protein Q70Z35 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity catalytic activity 9606 BTO:0000007 25829446 YES irozzo Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity. 0.608 SIGNOR-259191 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC1R protein Q01726 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257536 NEDD4 protein P46934 UNIPROT DCUN1D1 protein Q96GG9 UNIPROT up-regulates quantity monoubiquitination Lys149 PKMEQELkEPGRFKD 9606 BTO:0000007 21813641 YES miannu Here we revealed a previously unknown mechanism that regulates hDCNL1. In cultured mammalian cells ectopically expressed hDCNL1 was mono-ubiquitinated predominantly at K143, K149, and K171. Using a classical chromatographic purification strategy, we identified Nedd4-1 as an E3 ligase that can catalyze mono-ubiquitination of hDCNL1 in a reconstituted ubiquitination system.Taken together, these results suggest a mono-ubiquitination-mediated mechanism that governs nuclear-cytoplasmic trafficking of hDCNL1, 0.368 SIGNOR-272718 GABA-B receptor complex SIGNOR-C336 SIGNOR GNB/GNG complex SIGNOR-C202 SIGNOR up-regulates activity binding 9606 BTO:0000938 20655485 YES miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. 0.41 SIGNOR-265068 NKX2-5 protein P52952 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21261500 NO Taken together, our results indicate that the expression of MEF2C in T-ALL cells is principally deregulated via activating leukemic transcription factors GFI1B or NKX2-5 and by escaping inhibitory developmental STAT5 signaling. 0.739 SIGNOR-253656 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 11864573 YES The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. 0.391 SIGNOR-248531 mTORC2 complex SIGNOR-C2 SIGNOR AMOTL2 protein Q9Y2J4 UNIPROT down-regulates activity phosphorylation Ser759 SSSQRAAsLDSVATS 25998128 YES lperfetto AMOTL2 is phosphorylated at serine 760 by mTORC2. Mutation of AMOTL2 mimicking constitutive Ser(760) phosphorylation blocks its ability to bind and repress YAP leading to increased relative expression of known YAP gene targets. 0.2 SIGNOR-272085 TRIM2 protein Q9C040 UNIPROT NEFL protein P07196 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 18687884 YES miannu Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination. 0.431 SIGNOR-271776 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr424 IREYPPItSDQQRQL 9606 21545357 YES lperfetto Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions. 0.2 SIGNOR-173639 EXOC6 protein Q8TAG9 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.941 SIGNOR-270789 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr142 QEWIPPStPYK 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275595 WNT7A protein O00755 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity 9606 BTO:0001103 21902831 NO gcesareni Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors. 0.2 SIGNOR-176575 ABL1 protein P00519 UNIPROT DDB2 protein Q92466 UNIPROT down-regulates phosphorylation 9606 12107171 YES miannu C-abl might act as a negative regulator of uv-ddb by phosphorylating ddb2 0.459 SIGNOR-90446 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser614 RRPSVASsVSEEYFE -1 24554596 YES lperfetto These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. 0.374 SIGNOR-264766 NLGN4Y protein Q8NFZ3 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.2 SIGNOR-264168 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr653 QDSPDGQyENSEGGW 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246417 RBMX2 protein Q9Y388 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.563 SIGNOR-270674 PRKCH protein P24723 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276015 PTK2 protein Q05397 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity phosphorylation Tyr421 RLPSSPVyEDAASFK 9606 22952866 YES miannu FAK can directly phosphorylate cortactin at Y421 and Y466, and these sites are also phosphorylated by Src and Abl/Arg tyrosine kinases.|GFP-FAK re-expression in FAK-/- MEFs enhances FA turnover (XREF_FIG) and cortactin knockdown slows FA turnover (XREF_FIG). 0.744 SIGNOR-278284 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 NO We observed GR binding on or near Cebpβ, Cebpδ, Klf5, Klf9, Cebpα, and Pparγ gene loci at 4 h but not at 0 h of adipogenesis. Thus, at least one of the mechanisms by which GR promotes adipogenesis in culture is by directly activating the expression of multiple adipogenic TFs. 0.393 SIGNOR-256120 GTF2I protein P78347 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 16611241 NO lperfetto For example, TFII-I binds to the Inr element of the T cell receptor Vbeta gene and activates its transcription in reporter gene assays (Cheriyath et al. 1998). TFII-I also activates transcription of c-fos and Goosecoid through binding to the serum response element and the distal element, respectively (Grueneberg et al. 1997; Ku et al. 2005). 0.321 SIGNOR-268535 LTK protein P29376 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 YES gcesareni Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells. 0.314 SIGNOR-49531 AKT1 protein P31749 UNIPROT FAS protein P25445 UNIPROT down-regulates 9606 15004527 NO gcesareni Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27 0.385 SIGNOR-252473 hsa-miR-148a-3p mirna URS00003BBF48_9606 RNAcentral VIM protein P08670 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002745 33026174 NO Parnian MiR-148a-3p overexpression increased the expression of E-cadherin, accompanying decreased N-cadherin and vimentin expression. 0.4 SIGNOR-278854 MZF1 protein P28698 UNIPROT CCN3 protein P48745 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25899830 NO miannu we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV. 0.2 SIGNOR-226356 NFIA protein Q12857 UNIPROT WNT5A protein P41221 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268877 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 11062529 YES gcesareni Mckinsey et al. report that calcium/calmodulin-dependent kinase (camk), stimulates myogenesis and prevents formation of mef2/hdac complexes by inducing phosphorylation and nuclear export of hdacs 4 and 5. 0.619 SIGNOR-83837 USH1G protein Q495M9 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 YES lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. 0.572 SIGNOR-262578 PAPOLA protein P51003 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 YES lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. 0.8 SIGNOR-268327 USP7 protein Q93009 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity deubiquitination 24317448 YES lperfetto BCR-ABL disrupts PTEN nuclear-cytoplasmic shuttling through phosphorylation-dependent activation of HAUSP|hese data indicate that BCR-ABL phosphorylation of HAUSP modulates HAUSP’s deubiquitinase activity toward PTEN. 0.741 SIGNOR-276533 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser597 VPMNPNLsSEDPNLF 9606 15379552 YES lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) 0.2 SIGNOR-129192 CREB5 protein Q02930 UNIPROT RASGRP3 protein Q8IV61 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002815 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253808 RPS6K proteinfamily SIGNOR-PF26 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 YES lperfetto Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK. 0.2 SIGNOR-252805 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation 9606 26119734 YES miannu As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the spindle assembly checkpoint components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores.|When assayed in vitro, Plk1 readily phosphorylated kinase-dead Mps1, confirming earlier data (Dou et al., 2011). 0.381 SIGNOR-278246 DNMT3A protein Q9Y6K1 UNIPROT DPP6 protein P42658 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000596 23409053 YES lperfetto In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells. 0.2 SIGNOR-268962 PTGS2 protein P35354 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000586 16293724 NO lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. 0.409 SIGNOR-141783 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates activity binding 9606 12244043 YES areggio Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes 0.638 SIGNOR-254986 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 YES milica In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. 0.2 SIGNOR-230713 CDK2 protein P24941 UNIPROT HIRA protein P54198 UNIPROT up-regulates activity phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 BTO:0001938 SIGNOR-C16 11238922 YES lperfetto Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle. 0.326 SIGNOR-105548 mTORC1 complex SIGNOR-C3 SIGNOR APOB protein P04114 UNIPROT down-regulates quantity by repression translation regulation 9606 23721961 NO miannu Activation of mTORC1 also has dual effects on ApoB synthesis: it inhibits ApoB secretion by decreasing ApoB translation, but promotes ApoB secretion by inhibiting sortilin. 0.27 SIGNOR-252117 ABL1 protein P00519 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0002181 12652307 YES miannu C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity. 0.589 SIGNOR-276001 PDZRN3 protein Q9UPQ7 UNIPROT MUSK protein O15146 UNIPROT down-regulates quantity ubiquitination 9534 BTO:0000298 17576800 YES miannu We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Together, these data demonstrate that PDZRN3 is a catalytically active RING-type E3 ubiquitin ligase 0.544 SIGNOR-271664 GSK3B protein P49841 UNIPROT ZC3HAV1 protein Q7Z2W4 UNIPROT up-regulates activity phosphorylation Ser257 RDRFFQGsQEFLASA 9606 22514281 YES miannu GSK3beta sequentially phosphorylated Ser 270, Ser 266, Ser 262, and Ser 257 of rat ZAP.|Inhibition of GSK3\u03b2 by inhibitor SB216763 or down-regulation of GSK3\u03b2 by RNAi reduced the antiviral activity of Zinc-finger antiviral protein. 0.2 SIGNOR-278403 IL19 protein Q9UHD0 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 17208301 YES gcesareni Il-19 signals only through the type i il-20r complex. 0.718 SIGNOR-151820 M protein P59596 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity 9606 25271362 NO Luana Taken together, our results demonstrated that expression of M-protein causes activation of both caspases 8 and 9 via the PKB/Akt signalling cascades.  0.2 SIGNOR-260201 GLI1 protein P08151 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 NO gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin 0.713 SIGNOR-188875 IKBKB protein O14920 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates activity phosphorylation Thr121 NVRERQRtQSLNEAF 9606 23375009 YES miannu Hence, our current study supports the pivotal role of beta-TRCP in IKKbeta mediated Twist degradation.|More importantly, IKK\u03b2-dependent phosphorylation of Twist at T125 and S127 governs its nuclear localization. 0.332 SIGNOR-278404 CTNNBIP1 protein Q9NSA3 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity binding -1 12408824 YES llicata The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. 0.816 SIGNOR-238012 PPP1CB protein P62140 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 YES Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. 0.286 SIGNOR-248573 HSD3B1 protein P14060 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity chemical modification 10116 BTO:0000534;BTO:0000056 1537836 YES lperfetto We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids. 0.8 SIGNOR-268637 NPTX1 protein Q15818 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity relocalization 10090 BTO:0000938 23069675 YES lperfetto Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential 0.2 SIGNOR-261483 Ub:E2 complex SIGNOR-C497 SIGNOR RNF144B protein Q7Z419 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271181 LSM2 protein Q9Y333 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.836 SIGNOR-270648 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser849 NMLNRRDsSASTISS 9606 10693759 YES lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. 0.467 SIGNOR-75343 POMC protein P01189 UNIPROT MC5R protein P33032 UNIPROT up-regulates binding 9606 BTO:0000007 11785979 YES gcesareni The purpose of this study was to identify the peptide that functions as a natural ligand at the mc5r in the skin. alpha-msh, acth1-39, acth1-17, acth1-10, and acth4-10 all increased the production of camp in hek293 cells transfected with the mouse mc5r. alpha-msh and acth1-17 were the most potent in this respect. In addition, all peptides stimulated a rapid and transient increase in [ca(2+)](i). 0.765 SIGNOR-114058 PRKCQ protein Q04759 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000782 26284074 YES Barakat PKC-θ-mediated phosphorylation of serine and tyrosine residues of c-Cbl prevents its inhibitory effect. Phosphorylation of c-Cbl by PKC-θ inhibits the recruitment of Sh2-containing proteins and subsequent association of cbl E3 ubiquitin ligase with its target proteins 0.356 SIGNOR-274144 GDNF protein P39905 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.453 SIGNOR-252184 EIF4E protein P06730 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR form complex binding 9606 11408474 YES miannu Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f. 0.844 SIGNOR-108515 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation 9606 15657420 YES inferred from 70% family members lperfetto The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity. 0.2 SIGNOR-270047 PRKCZ protein Q05513 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates activity phosphorylation Ser472 RPHFPQFsYSASGRE 9534 BTO:0001538 12162751 YES lperfetto Full activation of the PKB enzyme requires phosphorylation of a threonine in the activation 0.545 SIGNOR-249153 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1349 STFIGEHyVHVNATY 9606 BTO:0000007 12475979 YES When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)), 0.607 SIGNOR-248702 DCTPP1 protein Q9H773 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003878 27612427 NO Monia DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically; Moreover, low expression of DCTPP1 led to the increase in intracellular 5-methyl-dCTP, which was strongly associated with the promoter hyper-methylation, leading to the subsequent low-expression of MDR1 and the increased intracellular accumulation of 5-FU in DCTPP1-knockdown BGC-823 cells. These results provide new insights into the roles of DCTPP1 as a chemosensitizer in clinical application. 0.328 SIGNOR-261178 tRNA(Lys) smallmolecule CHEBI:29185 ChEBI Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270409 PP1 proteinfamily SIGNOR-PF54 SIGNOR AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 YES lperfetto Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1. 0.2 SIGNOR-264657 MAPK3 protein P27361 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates activity phosphorylation 9606 12809513 YES inferred from family member llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. 0.443 SIGNOR-270301 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 20186153 YES lperfetto Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival. 0.426 SIGNOR-244436 UNC5B protein Q8IZJ1 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 YES miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. 0.657 SIGNOR-268166 VBP1 protein P61758 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 YES miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) 0.953 SIGNOR-270935 YAP1 protein P46937 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 NO gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. 0.7 SIGNOR-199217 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 SIGNOR-C14 17977820 YES lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. 0.962 SIGNOR-158655 zinc(2+) chemical CHEBI:29105 ChEBI BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 YES lperfetto The BRCA1‚ÄìC complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 0.8 SIGNOR-269478 Tocilizumab antibody DB06273 DRUGBANK IL6R protein P08887 UNIPROT down-regulates activity binding 9606 32446778 YES doi: 10.1016/j.cytogfr.2020.05.003 miannu Tocilizumab is a humanized anti-IL-6 receptor IgG1 monoclonal antibody used for the treatment of rheumatoid arthritis and other chronic inflammatory diseases [14]. By blocking the IL-6-receptor interaction, Tocilizumab inhibits the IL-6-mediated signal transduction. Although clinical data on the use of Tocilizumab in COVID-19 patients derive from small series, some authors recommend its use in critically ill COVID-19 patients with significantly elevated IL-6 levels. 0.4 SIGNOR-260857 TLR4 protein O00206 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates binding 9606 18221795 YES fstefani Mappit analysis of early toll-like receptor signalling events. 0.732 SIGNOR-160424 CCAN complex complex SIGNOR-C365 SIGNOR Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 18007590 NO lperfetto Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis. 0.7 SIGNOR-265214 WNT3A protein P56704 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 21078818 YES gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have 0.698 SIGNOR-169657 G1/S_transition phenotype SIGNOR-PH50 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 21524151 NO lperfetto In addition to the successive phosphorylation of pRb by active Cyclin/Cdk complexes, other factors can also impact upon S-phase entry Subsequently, the initiation of replication requires the formation of a pre-initiation complex (pre-IC) that is initiated by phosphorylation of Mcm2-7 by CyclinE/Cdk2 and DDK (Dbf4- and Drf1-dependent kinase) and recruitment of Cdc45 onto the chromatin (Figure 1). This recruitment is thought to be the critical step for the activation of the Mcm2-7 helicase activity and replication initiation. Finally, unwinding of the chromatin enables DNA-polymerase _ to initiate DNA synthesis and DNA-polymerase _ to continue replication 0.7 SIGNOR-245489 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 NO gcesareni The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types. 0.7 SIGNOR-245043 ROR1 protein Q01973 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation 9606 BTO:0000551 22439932 YES miannu Ror1 binds to and phosphorylates c-src / ror1 kinase-dependent c-src activation 0.319 SIGNOR-196751 ITGAV protein P06756 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.664 SIGNOR-253203 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248517 MT-ND3 protein P03897 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 0.78 SIGNOR-262145 Z-RNA stimulus SIGNOR-ST29 SIGNOR ZBP1 protein Q9H171 UNIPROT up-regulates activity binding 10090 32200799 YES gianni Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. 0.7 SIGNOR-266432 ORF6 protein Q19QW5 UNIPROT KPNB1 protein Q14974 UNIPROT down-regulates activity relocalization 9534 17596301 YES lperfetto ORF6 also retained KPNB1 at the ER/Golgi membrane in complex with KPNA2. Deletion of the N terminus of KPNA2, which binds KPNB1, no longer retained KPNB1 at the ER/Golgi membrane in the presence of ORF6 and did not antagonize STAT1 nuclear import in response to IFN-beta 0.2 SIGNOR-260275 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser293 FNTLAFPsMKRKDVV -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.767 SIGNOR-276137 SYK protein P43405 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates phosphorylation Ser364 GTPRSNHsAQDSAVE 9606 BTO:0001271 23071339 YES miannu Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function. 0.404 SIGNOR-199100 CDH23 protein Q9H251 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 YES lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. 0.614 SIGNOR-262579 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252326 SEPTIN4 protein O43236 UNIPROT XIAP protein P98170 UNIPROT down-regulates quantity binding 9534 BTO:0004055 15029247 YES lperfetto The mitochondrial ARTS protein promotes apoptosis through targeting XIAP.|Binding of ARTS to XIAP is direct, as recombinant ARTS and XIAP proteins can bind to each other in vitro. ARTS binding to XIAP is specific and related to its pro-apoptotic function, as mutant forms of ARTS (or related septins) that fail to bind XIAP failed to induce apoptosis. ARTS leads to decreased XIAP protein levels and caspase activation. Our data suggest that ARTS induces apoptosis by antagonizing IAPs. 0.2 SIGNOR-267671 GSK3B protein P49841 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity phosphorylation Thr1966 TPEKTDMtPSTTSPP 9606 BTO:0000938 32599005 YES lperfetto Glycogen synthase kinase 3β (GSK3beta) phosphorylates the Nav1.2C-terminal tail at T1966, suppressing Na+ currents and channel trafficking to the plasma membrane 0.2 SIGNOR-275748 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 YES flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. 0.36 SIGNOR-75930 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248739 MAPK14 protein Q16539 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates phosphorylation 9606 16138080 YES gcesareni We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes. 0.459 SIGNOR-140085 OTULIN protein Q96BN8 UNIPROT UBB protein P0CG47 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.671 SIGNOR-270819 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 12150915 YES gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. 0.728 SIGNOR-91041 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr368 CGGARICyIFHETFG 9606 BTO:0000793 29022905 YES miannu In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation. 0.26 SIGNOR-277329 midostaurin chemical CHEBI:63452 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 12124173 YES PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors. 0.8 SIGNOR-256308 MARCHF5 protein Q9NX47 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity ubiquitination Lys481 LQHQQFQkELEKIQL 9606 31368599 YES miannu MITOL promotes K63-linked chain ubiquitination of IRE1\u03b1 at lysine 481 (K481), thereby preventing hyper-oligomerization of IRE1\u03b1 and regulated IRE1\u03b1-dependent decay (RIDD). 0.2 SIGNOR-278609 ASXL1 protein Q8IXJ9 UNIPROT RARA protein P10276 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 YES irozzo Therefore, ASXL1, a vertebrate PcG/TrxG protein, may mediate RA-regulated cell growth by modulating RAR activity.Finally, the ASXL1-induced accumulation of acetylated H3 may enhance the RAR-mediated transcriptional activity. In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells. 0.445 SIGNOR-255910 SCN4A protein P35499 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 NO miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. 0.7 SIGNOR-253451 ALPL protein P05186 UNIPROT SPP1 protein P10451 UNIPROT down-regulates activity dephosphorylation 10090 23427088 YES miannu This result suggests that endogenous mouse TNAP dephosphorylates OPN in osteoblasts and that overexpressed human TNAP dephosphorylates OPN, compensating for the lack of endogenous TNAP in [Col1a1-Tnap +/\u2212 ;Alpl \u2212/\u2212 ] cells. 0.442 SIGNOR-277045 PRKCG protein P05129 UNIPROT OCLN protein Q16625 UNIPROT up-regulates activity phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 11502742 YES lperfetto Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. 0.307 SIGNOR-249107 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 YES gcesareni PKA activated Src both in vitro and in vivo by phosphorylating Src on serine 17 within its amino terminus 0.361 SIGNOR-247988 FUS protein P35637 UNIPROT SNRNP70 protein P08621 UNIPROT up-regulates activity binding 9606 26124092 YES FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP 0.467 SIGNOR-262823 PIM1 protein P11309 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002552 19749799 YES lperfetto Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation 0.28 SIGNOR-187905 P2RY12 protein Q9H244 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257107 EIF2AK4 protein Q9P2K8 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation Ser52 MILLSELsRRRIRSI 9606 32513922 YES gcesareni Translation initiation factor 2α [eukaryotic translation initiation factor 2α (eIF2α)] kinase phosphorylates serine51 (Ser51) of eIF2α and downregulates cellular protein synthesis. 0.914 SIGNOR-246157 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Phe) smallmolecule CHEBI:29184 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269492 FN1 protein P02751 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 BTO:0000007 7559467 YES lperfetto The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin. 0.681 SIGNOR-253305 H3C1 protein P68431 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 YES miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.2 SIGNOR-263721 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 24585778 YES miannu Length-dependent activation is modulated by cardiac troponin i bisphosphorylation at ser23 and ser24 but not by thr143 phosphorylation. Thr143 is a known target of protein kinase c (pkc) whose activity is increased in cardiac disease 0.272 SIGNOR-204666 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC5 protein Q9Y5F6 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265683 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273039 RARB protein P10826 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 15650024 YES inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs 0.421 SIGNOR-267807 CTBP1 protein Q13363 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 16287852 YES gcesareni We identify the ctip and ctbp corepressors as novel components of the human rbp-jkappa/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. Functionally, ctip and ctbp augment sharp-mediated repression. 0.266 SIGNOR-141613 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000785 18467333 YES gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. 0.389 SIGNOR-178619 NOTCH1 protein P46531 UNIPROT BCL11B protein Q9C0K0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 NO miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. 0.393 SIGNOR-197449 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 YES amattioni Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation. 0.34 SIGNOR-85179 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr989 VPSSRGDyMTMQMSC 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). 0.868 SIGNOR-157758 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248685 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 BTO:0000567 19836242 YES We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173 0.491 SIGNOR-248699 SSH2 protein Q76I76 UNIPROT CFL1 protein P23528 UNIPROT up-regulates activity dephosphorylation Ser3 sGVAVSDG 9606 14531860 YES Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH). 0.731 SIGNOR-248733 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176793 ITGA1 protein P56199 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.757 SIGNOR-253169 TGFBR2 protein P37173 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates phosphorylation Ser345 RGDGSGFsL 9606 BTO:0004183 15761148 YES lperfetto We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345. 0.465 SIGNOR-227484 CASP3 protein P42574 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 NO amattioni Caspase-3 is responsible for apoptosis execution 0.7 SIGNOR-256638 PDE4DIP protein Q5VU43 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates binding 9606 21569246 YES miannu This study ascribes a novel function to mmgl isoform 4: it meets all criteria for classification as an akap, and we show that is involved in the phosphorylation of cmybpc as well as ctni, hence mmgl is an important regulator of cardiac contractility. 0.311 SIGNOR-173766 GOLGA7 protein Q7Z5G4 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 YES miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. 0.35 SIGNOR-261351 CSNK2A1 protein P68400 UNIPROT PACS1 protein Q6VY07 UNIPROT up-regulates activity phosphorylation Ser278 SPDIDNYsEEEEESF 10090 BTO:0003532 14633983 YES llicata Phosphorylation of Ser278 by CK2 or a Ser278-->Asp mutation increased the interaction between PACS-1 and cargo, whereas a Ser278-->Ala substitution decreased this interaction. Moreover, the Ser278-->Ala mutation yields a dominant-negative PACS-1 molecule that selectively blocks retrieval of PACS-1-regulated cargo molecules to the TGN. 0.546 SIGNOR-250925 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR CABLES1 protein Q8TDN4 UNIPROT down-regulates activity binding -1 25361894 YES miannu Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. 0.2 SIGNOR-276758 PRKAA1 protein Q13131 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 SIGNOR-C15 15866171 YES gcesareni Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest 0.478 SIGNOR-135960 CHFR protein Q96EP1 UNIPROT SMARCB1 protein Q12824 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 YES miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. 0.316 SIGNOR-271458 CDK11A protein Q9UQ88 UNIPROT CDK11B protein P21127 UNIPROT up-regulates phosphorylation Thr726 KHEYFREtPLPIDPS 9606 21078675 YES lperfetto Overall, our data indicated that thr-370 is responsible for the autophosphorylation, dimerization, and kinase activity of cdk11(p58) 0.306 SIGNOR-169628 DISC1 protein Q9NRI5 UNIPROT PAFAH1B1 protein P43034 UNIPROT up-regulates activity binding 9606 BTO:0000938 17202468 YES miannu Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology  0.476 SIGNOR-252163 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 BTO:0000007 11691836 YES lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 0.658 SIGNOR-249391 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAMAC protein Q9BTL3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 YLKRPPEsPPIVEEW 9606 27452456 YES miannu During differentiation, ERK1/2 phosphorylates RAM serine-36, targeting it for ubiquitination and proteasomal degradation, ultimately resulting in changes in gene expression associated with loss of pluripotency. 0.2 SIGNOR-277267 GNA13 protein Q14344 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 23450633 YES gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. 0.572 SIGNOR-192111 PTPN6 protein P29350 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 11021818 YES gcesareni The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase. 0.687 SIGNOR-82764 PRKACA protein P17612 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser279 KVAERRSsPLLRRKD 9606 22865920 YES lperfetto PKA/Cdk5-mediated phosphorylation of HDAC5 at Ser279 within the NLS promotes nuclear localization of HDAC5 and interaction with the nuclear corepressor complex 0.2 SIGNOR-198658 AR protein P10275 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 NO After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. 0.356 SIGNOR-253675 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 10197981 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 0.721 SIGNOR-66738 FOXN4 protein Q96NZ1 UNIPROT PTF1A protein Q7RTS3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001175 17075007 NO Luana  We conclude that Foxn4 functions upstream of Ptf1a to activate its expression, thereby regulating the generation of amacrine and horizontal cells during retinogenesis. 0.461 SIGNOR-261608 DAPT chemical CHEBI:86193 ChEBI APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191292 MAPKAPK2 protein P49137 UNIPROT PDE4A protein P27815 UNIPROT down-regulates activity phosphorylation Ser152 SFLYRSDsDYDMSPK 9606 BTO:0000801 21323643 YES miannu Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP. 0.348 SIGNOR-263078 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser48 KSQRTKQsTVLAPVI 9534 BTO:0001538 23519612 YES miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 0.318 SIGNOR-262711 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 8845374 YES lperfetto Revealed that peptides derived from egfr residues y992, y1086, y1101, and y1148 bound directly to the sh2 domain of c-src (figure 8c). These experiments demonstrate that a specific subset of egfr receptor c-src phosphorylation sites are also ligands for the sh2 domain of c-src.Cellular src functions as a co-transducer of transmembrane signals emanating from a variety of growth factor receptors, including egfr 0.624 SIGNOR-44251 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 YES lperfetto Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase 0.685 SIGNOR-235793 C8G protein P07360 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 YES lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer 0.603 SIGNOR-263446 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser775 EGVKRTLsFSLRSSR 9534 BTO:0000298 14523239 YES lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 0.2 SIGNOR-249231 PPP2CA protein P67775 UNIPROT RB1 protein P06400 UNIPROT up-regulates dephosphorylation 9606 10702384 YES gcesareni This dephosphorylation returns prb to its active, growth suppressive state. 0.504 SIGNOR-75398 SMAD1/4 complex SIGNOR-C85 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates activity binding 9606 15573378 YES ggiuliani The Runx2 WT and deletion constructs (1 –495, 1–464, and 1–432) all physically interact with the BMP2 responsive Smad 1 0.566 SIGNOR-255782 tamoxifen chemical CHEBI:41774 ChEBI ESR2 protein Q92731 UNIPROT down-regulates activity chemical inhibition 9606 20512796 YES miannu Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. 0.8 SIGNOR-258588 CC2D1B protein Q5T0F9 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007;BTO:0000938 19423080 YES nucleus lperfetto Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression|Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK-293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of postsynaptic 5-HT1A receptor-positive cells. 0.335 SIGNOR-268298 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr474 VLLVNRHyAKISDFG 9606 BTO:0000661 9685404 YES lperfetto We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck 0.618 SIGNOR-249375 sunitinib chemical CHEBI:38940 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 BTO:0000776 20185585 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-163944 BRCA1 protein P38398 UNIPROT NSD2 protein O96028 UNIPROT down-regulates quantity by destabilization ubiquitination Lys292 EGEGQFEkLCQESAK 9606 32826945 YES miannu Proteomic data analysis revealed interaction between NSD2 and BRCA1 and further study revealed that BRCA1 ubiquitinates NSD2 at K292 residue.|These results suggested that BRCA1 interacts with and promotes degradation of NSD2 via polyubiquitination . 0.2 SIGNOR-278745 MAGI2 protein Q86UL8 UNIPROT DGC complex SIGNOR-C217 SIGNOR up-regulates activity binding 9606 BTO:0000142 22626542 YES miannu S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 0.256 SIGNOR-265445 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 1377674 YES lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function 0.507 SIGNOR-18249 SARS1 protein P49591 UNIPROT serine smallmolecule CHEBI:17822 ChEBI down-regulates quantity chemical modification 9606 24095058 YES miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis 0.8 SIGNOR-270494 ARHGAP1 protein Q07960 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.864 SIGNOR-260458 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192823 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation 9606 21880741 YES miannu Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. 0.649 SIGNOR-255463 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 YES Translocation from Endosome to Lysosome fspada A specific pkg inhibitor inhibits h1r downregulation in cho cells (37). However, direct activation of pkg in these cells does not cause h1r down-regulation, indicating that more studies are required to clarify the role of pkg in h1r down-regulation. 0.2 SIGNOR-124360 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 BTO:0004136 10208431 YES miannu The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. On physical interaction, AML1/ETO can form a complex with wild-type AML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex 0.2 SIGNOR-260094 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270399 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 12464600 YES gcesareni Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation. 0.2 SIGNOR-96067 PIM proteinfamily SIGNOR-PF34 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser166 SSRRRAIsETEENSD 9606 BTO:0000785 18467333 YES gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. 0.2 SIGNOR-259433 SOD1 protein P00441 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates quantity 9606 BTO:0000312 22051914 NO lperfetto SOD1 inclusions are found in motor neurons of patients with FALS, 0.7 SIGNOR-262279 ING1 protein Q9UK53 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 14522900 NO miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. 0.307 SIGNOR-254483 serine smallmolecule CHEBI:17822 ChEBI Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates quantity precursor of 9606 24095058 YES miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis 0.8 SIGNOR-270500 MYLK protein Q15746 UNIPROT MYL6B protein P14649 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 BTO:0000671 10092231 YES gcesareni Cytoskeletal dynamics are primarily modulated by interactions of actin and myosin ii that are regulated by myosin light chain kinase (mlck)-mediated phosphorylation of the regulatory myosin light chain (mlc). 0.719 SIGNOR-65865 ASXL3 protein Q9C0F0 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates activity binding 9606 BTO:0000972 25450400 YES inferred from family member miannu We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRŒ± and TRŒ≤, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRŒ± and TRŒ≤ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRŒ± target genes through its recruitment to the LXR-response elements. 0.2 SIGNOR-270302 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR1A protein P10644 UNIPROT down-regulates activity chemical inhibition 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.8 SIGNOR-258759 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 YES Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. 0.842 SIGNOR-99721 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 YES The effect has been demonstrated using Q01196-8 lperfetto We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.2 SIGNOR-244707 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2246 SSSVHASerPLASSP -1 26051540 YES irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. 0.472 SIGNOR-259118 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr603 LKTPSAAyLWVGTGA -1 10210201 YES llicata Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624. 0.572 SIGNOR-250782 KCTD17 protein Q8N5Z5 UNIPROT TCHP protein Q9BT92 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0004910 25270598 YES miannu We have identified KCTD17 as a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of KCTD17 specifically arrests ciliogenesis at the initial step of axoneme extension through aberrant trichoplein-Aurora-A activity. Thus, CRL3-KCTD17 targets trichoplein to proteolysis to initiate the axoneme extension during ciliogenesis. 0.337 SIGNOR-272463 mTORC1 complex SIGNOR-C3 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 21659604 YES lperfetto The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase. 0.358 SIGNOR-217063 GYS1 protein P13807 UNIPROT Glycogen_synthesis phenotype SIGNOR-PH39 SIGNOR up-regulates 9534 BTO:0004055 14593110 NO lperfetto Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation. 0.7 SIGNOR-235751 QRICH1 protein Q2TAL8 UNIPROT GARS1 protein P41250 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269405 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267883 RXRA protein P19793 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.725 SIGNOR-16665 AMFR protein Q9UKV5 UNIPROT HMGCR protein P04035 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25003069 YES miannu Gp78 mediates the sterol regulated ubiquitination of HMGCR. 0.493 SIGNOR-278622 DAB2IP protein Q5VWQ8 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity binding 9606 27858941 YES miannu DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene 0.2 SIGNOR-254770 MAP3K14 protein Q99558 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 9020361 NO amattioni Nik stimulates nf-kappab activity 0.352 SIGNOR-46212 PAK4 protein O96013 UNIPROT MZF1 protein P28698 UNIPROT up-regulates activity phosphorylation Ser27 VMVKLEDsEEEGEAA -1 30622337 YES miannu  Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1).  Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1.The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4. 0.2 SIGNOR-277422 LYN protein P07948 UNIPROT PPP1R8 protein Q12972 UNIPROT down-regulates activity phosphorylation Tyr335 NEPKKKKyAKEAWPG -1 11104670 YES Lyn phosphorylates both Tyr-264 and Tyr-335, but that the phosphorylation of Tyr-335 is dependent on the association of NIPP1 with RNA. The inhibitory potency of the C-terminal site of NIPP1 was decreased by phosphorylation of Tyr-335 and by the addition of RNA. 0.313 SIGNOR-251406 A9/b1 integrin complex SIGNOR-C166 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity by expression 9606 24241034 NO lperfetto Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages. 0.305 SIGNOR-253314 PCK1 protein P35558 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 30193097 YES miannu ¬†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).¬† 0.8 SIGNOR-266587 DAGLA protein Q9Y4D2 UNIPROT 2-arachidonoylglycerol smallmolecule CHEBI:52392 ChEBI up-regulates quantity chemical modification 9606 26787883 YES miannu Diacylglycerol lipases (DAGLŒ± and DAGLŒ≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. 0.8 SIGNOR-264264 PRKD2 protein Q9BZL6 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates phosphorylation Ser294 SNLKRTAsNPKVENE 9606 16912074 YES The effect has been demonstrated using Q9UBF8-2 gcesareni Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity. 0.2 SIGNOR-148880 CAMK2A protein Q9UQM7 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 YES gcesareni Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase. 0.2 SIGNOR-58251 BACH1 protein O14867 UNIPROT HMOX1 protein P09601 UNIPROT down-regulates quantity transcriptional regulation 9606 14747657 YES These results indicate that ho-1 regulation involves a competition between the activator Nrf2 and the Bach1 repressor for interactions with the small Maf proteins. 0.361 SIGNOR-259336 PIP5K1C protein O60331 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity chemical modification 9606 9367159 YES miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities 0.8 SIGNOR-277286 STK38 protein Q15208 UNIPROT RBM24 protein Q9BX46 UNIPROT up-regulates activity phosphorylation 9606 28322254 YES miannu Phosphorylation of Rbm24 by Stk38 is crucial for the maintenance of cardiac sarcomeric gene expression in cardiac cells.|These results indicated that Stk38 increases Rbm24 protein stability probably by interfering with the ubiquitin-proteasome protein degradation pathway. 0.355 SIGNOR-278291 EBNA1 protein P03211 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity destabilization 9606 BTO:0000192 17486072 NO scontino The studies described above show that SMAD2 protein levels are reduced by EBNA1 with consequent attenuation of SMAD2 activation in response to TGFβ1. This analysis confirmed the stability of the EBNA1 protein and revealed that the SMAD2 protein is more rapidly degraded in Ad/AH cells expressing EBNA1 as compared to the control cells. 0.2 SIGNOR-267615 PRKCA protein P17252 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation Thr176 ENKNLTGtARYASIN -1 31096047 YES miannu In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity. 0.2 SIGNOR-277450 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG -1 9139719 YES lperfetto In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33. 0.58 SIGNOR-248972 BACH1 protein O14867 UNIPROT MAFK protein O60675 UNIPROT up-regulates activity binding 10090 BTO:0004475 19011633 YES miannu Bach1 forms a heterodimer with the small Maf oncoproteins and binds to the Maf-recognition element (MARE) to inhibit target genes 0.474 SIGNOR-226409 PRKG1 protein Q13976 UNIPROT ITPR1 protein Q14643 UNIPROT unknown phosphorylation Ser1764 RPSGRREsLTSFGNG 10116 BTO:0004578 8132598 YES lperfetto Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic GMP-dependent protein kinase. | The synthetic peptide corresponding to serine 1755 (GRRESLTSFG) was phosphorylated with aKm in the range of 30-40 microM by both kinases. The kinetic analysis revealed that this peptide substrate is the best substrate described for cGMP kinase to date. Vascular smooth muscle cells prelabeled with [32P]orthophosphate and treated with atrial natriuretic peptide or sodium nitroprusside to elevate cGMP also resulted in increased labeling of the IP3 receptor. Phosphorylation of IP3 receptor by cGMP kinase may regulate the function of IP3 receptor in vascular smooth muscle cells and contribute to the effect of cGMP to regulate intracellular calcium levels. 0.461 SIGNOR-248916 INTS9 protein Q9NV88 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.795 SIGNOR-261471 STAT1 protein P42224 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 16481475 YES lperfetto Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease. 0.449 SIGNOR-217418 BAX protein Q07812 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates relocalization 9606 14585074 YES Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi 0.313 SIGNOR-88590 IRF1 protein P10914 UNIPROT IRF8 protein Q02556 UNIPROT up-regulates activity binding 9606 11483597 YES miannu We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. 0.396 SIGNOR-222841 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 YES gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation 0.416 SIGNOR-252443 PRKACA protein P17612 UNIPROT PLN protein P26678 UNIPROT up-regulates activity phosphorylation Ser16 RSAIRRAsTIEMPQQ 10090 10988285 YES miannu Phospholamban (PLB) can be phosphorylated at Ser(16) by cyclic AMP-dependent protein kinase. phosphorylation of Ser(16) is sufficient for mediating the maximal cardiac responses to beta-adrenergic stimulation. 0.49 SIGNOR-250030 NEDD4L protein Q96PU5 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 9606 19917253 YES lperfetto Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation 0.78 SIGNOR-217622 LPAR4 protein Q99677 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257325 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity precursor of 9606 2912371 YES miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). 0.8 SIGNOR-267435 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 YES lperfetto When subjected to phosphorylation by erk, the most efficient decrease in erk phosphorylation was observed with the s353a mutantamong the mechanisms underlying k protein ability to confer increased transcriptional output are interconversion of duplex and single-stranded dna (59) and association with the c/ebp_ (60), each of which could be better affected by the phosphorylated form of the k protein, which may increase affinity to associated proteins or dna. 0.2 SIGNOR-105754 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation Ser863 DPISTDAsRRSSEAS 9606 BTO:0000007 16611981 YES lperfetto The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. 0.561 SIGNOR-249590 CYP11B1 protein P15538 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI down-regulates quantity chemical modification 9606 BTO:0000050 9814482 YES lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. 0.8 SIGNOR-268679 TEAD proteinfamily SIGNOR-PF22 SIGNOR ANKRD1 protein Q15327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 31296870 YES miannu In this model, treatment with LIF, but not IL-6, significantly elevated YAP/TAZ-TEAD transcriptional activity and sequentially increased expression of YAP1-targeted genes, CNTF and ANKRD at mRNA, in human PDAC cells 0.2 SIGNOR-278035 paliperidone chemical CHEBI:82978 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258562 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity 9606 BTO:0000452 BTO:0001279 31623154 NO P00441:p.Gly94Ala (mutation increasing interaction) We demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying SOD1 pathogenic variants. 0.2 SIGNOR-262784 PRKACB protein P22694 UNIPROT PHKA1 protein P46020 UNIPROT down-regulates activity phosphorylation 9606 10487978 YES Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. 0.324 SIGNOR-267413 Laminin-1 complex SIGNOR-C183 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 2351695 YES lperfetto In combination, the anti-alpha 1- and anti-alpha 6-specific antibodies completely inhibited JAR cell attachment to LN and fragment E1. Thus, the alpha 1/beta 1 and alpha 6/beta 1 integrin heterodimers each function as LN receptors and act together to mediate the interactions of human JAR choriocarcinoma cells with LN. 0.554 SIGNOR-253256 TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 18353649 YES lperfetto Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction 0.645 SIGNOR-178053 EIF1B protein O60739 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity 9606 14600024 NO lperfetto Binding of eIF1 to the 40S subunit would block access of the 60S 0.251 SIGNOR-269146 UNC80 protein Q8N2C7 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 9606 BTO:0000007 19535918 YES miannu UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex.  0.351 SIGNOR-265179 PRKCD protein Q05655 UNIPROT LIMK2 protein P53671 UNIPROT down-regulates phosphorylation Ser283 EGTLRRRsLRRSNSI 9606 15923181 YES Translocation from Cytosol to Nucleus flangone Activation of pkc by phorbol ester treatment of endothelial cells stimulated limk2 phosphorylation at ser-283 and inhibited nuclear import of limk2 0.256 SIGNOR-137927 MAPK14 protein Q16539 UNIPROT PAK6 protein Q9NQU5 UNIPROT up-regulates phosphorylation Ser165 MPWPEPQsPRVLPNG 9606 15550393 YES gcesareni The activation of pak6 by both p38 map kinase and mkk6 suggests that pak6 plays a role in the cellular response to stress-related signals. 0.2 SIGNOR-130979 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 BTO:0000150 23336272 YES lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. 0.862 SIGNOR-216992 lidocaine chemical CHEBI:6456 ChEBI SCN5A protein Q14524 UNIPROT down-regulates activity chemical inhibition 8355 BTO:0000964 8786356 YES miannu Surprisingly, hH1-beta 1 Na channels were threefold more sensitive to rested-state block by lidocaine (402 +/- 36 microM, n = 4-22) than were mu 1-beta 1 Na channels (1,168 +/- 34 microM, n = 7-19). 0.8 SIGNOR-258499 ROCK1 protein Q13464 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr853 PREKRRStGVSFWTQ 10090 10601309 YES lperfetto Phosphorylation by Rho-kinase inhibited MP activity and this reflected a decrease in V(max). Activity of MP with different substrates also was inhibited by phosphorylation. Two major sites of phosphorylation on MYPT1 were Thr(695) and Thr(850). 0.774 SIGNOR-249034 SCF-SKP2 complex SIGNOR-C136 SIGNOR CCNE2 protein O96020 UNIPROT down-regulates quantity by destabilization ubiquitination -1 phosphorylation:Ser383;Thr392 FRKGGQLsPVCNGGI;VCNGGIMtPPKSTEK 11533444 YES lperfetto The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro 0.575 SIGNOR-267559 N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide chemical CHEBI:94490 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191280 PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR DCK protein P27707 UNIPROT down-regulates activity dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 YES lperfetto Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation 0.2 SIGNOR-275802 CYP21A2 protein P08686 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 25855791 YES lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively 0.8 SIGNOR-268643 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Ser205 LATPPTLsSTVLIVR 9606 BTO:0001938 12815053 YES lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 0.54 SIGNOR-102490 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273035 F2RL3 protein Q96RI0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 17158345 YES gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13) 0.383 SIGNOR-151162 NUP88 protein Q99567 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.627 SIGNOR-262076 RPS6K proteinfamily SIGNOR-PF26 SIGNOR IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0001103 21798082 YES lperfetto Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization. 0.2 SIGNOR-252787 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 YES lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. 0.669 SIGNOR-249532 Ub:E2 complex SIGNOR-C497 SIGNOR RNF215 protein Q9Y6U7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271238 gamma-secretase complex SIGNOR-C98 SIGNOR DSCAML1 protein Q8TD84 UNIPROT down-regulates quantity cleavage 9606 BTO:0000938 30745319 YES miannu γ‐secretase‐mediated intra‐membrane cleavage of DSCAM receptors results in the release of the DSCAM ICD, which is likely proceeded by shedding of the DSCAM ectodomain. Interaction of IPO5 with the NLS of DSCAM then leads to importin‐mediated nuclear import of the DSCAM ICD. In the nucleus, the DSCAM ICD may regulate the transcription of genes involved in neuronal development and function, thereby regulating processes such as neurite outgrowth, branching, and repulsion, as well as synapse formation, axon guidance, and neuronal cell death and survival. 0.2 SIGNOR-264272 bisphenol F chemical CHEBI:34575 ChEBI AHR protein P35869 UNIPROT up-regulates activity chemical activation -1 31995776 YES miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs. 0.8 SIGNOR-268737 AKT3 protein Q9Y243 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates activity phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 YES miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively 0.2 SIGNOR-276195 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9606 14701738 YES miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. 0.29 SIGNOR-261721 CPT1C protein Q8TCG5 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 ChEBI down-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267122 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 YES lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. 0.2 SIGNOR-176058 CACNA1E protein Q15878 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 NO miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. 0.7 SIGNOR-264327 ADGRG1 protein Q9Y653 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 24949629 YES Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); | We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation. 0.2 SIGNOR-253981 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr383 HYRYSDTtDSDPENE 9606 21779440 YES gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity 0.679 SIGNOR-89830 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887;BTO:0001103 14579029 YES gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.771 SIGNOR-118857 PDK4 protein Q16654 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 BTO:0000887;BTO:0001103 14966024 YES gcesareni Pyruvate dehydrogenase (pdh) activity (pdha) controls the entry of carbohydrate into the tricarboxylic cycle and is regulated by pdh kinase (pdk), which phosphorylates and inactivates the enzyme, and pdh phosphatase, which dephosphorylates the enzyme to the active form 0.546 SIGNOR-121936 P2RY6 protein Q15077 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257343 P-TEFb complex SIGNOR-C238 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation 9606 32048991 YES miannu Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. To perform this task, Pol II needs to be activated by a complex of proteins called P-TEFb; however, P-TEFb is usually found in an inactive form held by another group of proteins. Yet, it is unclear how P-TEFb is released and allowed to activate Pol II. 0.754 SIGNOR-261039 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 12105215 YES lperfetto To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313 0.346 SIGNOR-216666 L-selenocystathionine zwitterion smallmolecule CHEBI:62226 ChEBI L-selenocysteine zwitterion smallmolecule CHEBI:57843 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275817 ATM protein Q13315 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 16497931 YES lperfetto Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export. 0.738 SIGNOR-144813 ADRA1A protein P35348 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.621 SIGNOR-257279 HSD3B1 protein P14060 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 2139411 YES lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. 0.8 SIGNOR-268636 COPS3 protein Q9UNS2 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.917 SIGNOR-270764 PRKACA protein P17612 UNIPROT KCNQ5 protein Q9NR82 UNIPROT up-regulates activity phosphorylation Ser88 GKQGARMsLLGKPLS 9606 BTO:0001660 30061510 YES miannu We conclude that phosphorylation of S53 on the amino terminus of Kv7.5 is essential for PKA-dependent enhancement of channel activity in response to βAR activation in vascular and airway smooth muscle cells. 0.2 SIGNOR-265980 ESR1 protein P03372 UNIPROT TFF1 protein P04155 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 NO ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression 0.753 SIGNOR-253938 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258567 RIPK2 protein O43353 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 10559258 YES miannu RIP2 directly phosphorylates and activates ERK2 in vivo and in vitro. 0.295 SIGNOR-279106 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 YES lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 465 and 467.These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. 0.824 SIGNOR-236107 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 YES llicata Erk phosphorylates threonine 42 residue of ribosomal protein s3. 0.351 SIGNOR-137959 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257913 HUWE1 protein Q7Z6Z7 UNIPROT PTOV1 protein Q86YD1 UNIPROT down-regulates quantity ubiquitination 9606 34654719 YES miannu Our data suggest that HUWE1 can ubiquitinate PTOV1 in vitro and depletion of HUWE1 in cells increases the stability of PTOV1 S36A protein in the nucleus.|Our data suggest that depletion of HUWE1 elevates PTOV1 protein levels, which, in turn, promote the expression of cJun, a pro-growth translational target of PTOV1 (18)\n In our model, we propose that HUWE1 mediates the degradation of PTOV1 in the nucleus. 0.2 SIGNOR-278755 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 YES gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. 0.8 SIGNOR-104921 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT down-regulates activity phosphorylation Thr680 QPLVGIEtLPPDLRD 9606 BTO:0000007 25755282 YES miannu Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.  0.294 SIGNOR-273580 CDK1 protein P06493 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Thr1238 ASWDQPGtPGREPTQ 9606 BTO:0000567 37584777 YES phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. 0.2 SIGNOR-272966 PLK2 protein Q9NYY3 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser589 EQAADEIsFSSNSSF 9606 20531387 YES lperfetto Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. 0.578 SIGNOR-165999 AHCYL2 protein Q96HN2 UNIPROT PAPOLB protein Q9NRJ5 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 YES lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. 0.2 SIGNOR-268332 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI IGF1R protein P08069 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258116 IKBKB protein O14920 UNIPROT ASB8 protein Q9H765 UNIPROT up-regulates activity phosphorylation Ser31 RTIAAIRsFPHDNVE 9606 BTO:0000007 31009856 YES lperfetto We found that ASB8 was phosphorylated at the N-terminal Ser-31 by host IkappaB kinase beta (IKKbeta). In turn, ASB8 facilitated K48-linked ubiquitination and degradation of IKKbeta via the ubiquitin-proteasome pathway, resulting in remarkable inhibition of I-kappa-B-alpha (IkappaBalpha) and of p65 phosphorylation, consequently suppressing NF-kappaB activity. 0.2 SIGNOR-272242 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2279 PVQPNPMsPQQHMLP 9606 17623675 YES lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. 0.2 SIGNOR-244533 GUCY1A3-B2 complex SIGNOR-C139 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 YES gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types 0.8 SIGNOR-244122 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by stabilization deacetylation Lys70 EGILRRLkKYDNCWL 9606 BTO:0000007 21726808 YES lperfetto Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 0.426 SIGNOR-267599 MAPK1 protein P28482 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Ser623 ALDFQPSsPSPHRKP 9606 15356145 YES lperfetto Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623. 0.679 SIGNOR-128727 PAWR protein Q96IZ0 UNIPROT WT1 protein P19544 UNIPROT down-regulates activity binding 9606 BTO:0000007 8943350 YES 2 miannu We identified par-4 (for prostate apoptosis response) as a WT1-interacting protein that itself functions as a transcriptional repressor. Functionally, par-4 inhibited transcription activated by WT1 0.501 SIGNOR-240596 SGK1 protein O00141 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Ser1190 SSRQRRLsKGSFPTS 9606 27517916 YES miannu Constitutively active SGK1 S422D phosphorylates WNK4 at Ser-1169 [ xref ] and Ser-1196 [ xref ], relieving the inhibitory effect of WNK4 on NCC\u2019s activity [ xref , xref ].|SGK1 is thought to modulate NCC activity by inhibiting WNK4 , , ]. 0.416 SIGNOR-278454 SOST protein Q9BQB4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 19874086 NO Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass 0.582 SIGNOR-188964 IGF1R protein P08069 UNIPROT IRS4 protein O14654 UNIPROT up-regulates phosphorylation 9606 9553137 YES gcesareni Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4. 0.656 SIGNOR-56604 ERN1 protein O75460 UNIPROT JUN protein P05412 UNIPROT up-regulates 9606 BTO:0001976 18065414 NO lperfetto The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression 0.384 SIGNOR-253146 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser153 PSSKRSPsTATLSLP 9606 BTO:0001061 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276774 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr556 LNGQPIQyARSTCEA 9606 BTO:0000763 20861316 YES lperfetto Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity 0.3 SIGNOR-167997 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 12817019 YES lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. 0.804 SIGNOR-102507 FADD protein Q13158 UNIPROT CASP10 protein Q92851 UNIPROT up-regulates binding 9606 11717445 YES gcesareni The death-effector domains ofcasp8and -10 bothinteractwith the death-effector domain offadd. Therefore, caspase-10 is recruited into the fas signaling complex and becomes activated like caspase-8 0.793 SIGNOR-112058 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR RAE1 protein P78406 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16036565 NO miannu Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein 0.2 SIGNOR-260869 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. 0.8 SIGNOR-267328 ITCH protein Q96J02 UNIPROT OCLN protein Q16625 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28542131 YES miannu Two mechanisms regarding junction protein turnover were illustrated in this process, that is, the Itch-induced occludin ubiquitination and proteasome degradation, and the caveolae-dependent endocytosis of junction proteins (JAM-A, N-cadherin, and \u03b2 -catenin), both of which led to the instability of junction apparatus between adjacent SCs and a subsequent damaged BTB. 0.349 SIGNOR-278756 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Thr1795 SRSSWRLtSSEMKKS -1 9242537 YES lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity. 0.367 SIGNOR-263634 metaproterenol chemical CHEBI:6792 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) 0.8 SIGNOR-257874 NANOG protein Q9H9S0 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 NO miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 0.44 SIGNOR-254621 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000891 10929712 YES amattioni Diablo may promote apoptosis by binding to iaps and preventing them from inhibiting caspases. 0.791 SIGNOR-80225 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr90 SPLLLTTtNSSEGLS 9606 11152499 YES tpavlidou Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites. 0.2 SIGNOR-85789 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258632 PRPS2 protein P11908 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity chemical modification 9606 16939420 YES miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. 0.8 SIGNOR-267082 NHP2 protein Q9NX24 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 YES lperfetto A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP 0.654 SIGNOR-263330 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Thr382 PRSINTDtLSKETDS 9606 BTO:0000567 19509060 YES lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. 0.617 SIGNOR-272993 PPARD protein Q03181 UNIPROT SLC25A20 protein O43772 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19577614 NO miannu CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting. 0.304 SIGNOR-255048 MARCHF5 protein Q9NX47 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates quantity ubiquitination 9606 32015503 YES miannu MARCH5 promotes ubiquitination of MCL1 and NOXA.|Of note, MARCH5 depletion led to the accumulation of MCL1 and NOXA in asynchronous as well as G2 cells, suggesting that MARCH5 controls NOXA/MCL1 levels throughout the cell cycle. 0.2 SIGNOR-278758 PRKAA1 protein Q13131 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 19491292 NO gcesareni Activation of ampk reduced p21 protein and mrna expression, which was associated with re- duced g1/s cell cycle transition and p21 promoter activity. 0.2 SIGNOR-186061 TBK1 protein Q9UHD2 UNIPROT PRPS1 protein P60891 UNIPROT up-regulates activity phosphorylation Thr228 DMADTCGtICHAADK -1 34343500 YES miannu Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis.  0.2 SIGNOR-277316 MAPK1 protein P28482 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser641 DIKILIAsPSPTHIH 9606 BTO:0000567 18519666 YES lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ 0.585 SIGNOR-178723 TRRAP protein Q9Y4A5 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.738 SIGNOR-269589 estrone smallmolecule CHEBI:17263 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258584 UMPS protein P11172 UNIPROT orotate smallmolecule CHEBI:30839 ChEBI down-regulates quantity chemical modification 9606 2912371 YES miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). 0.8 SIGNOR-267436 PRKACA protein P17612 UNIPROT KCNJ3 protein P48549 UNIPROT unknown phosphorylation Ser385 NSKERHNsVECLDGL 9606 19151997 YES llicata Using this approach, we identified s385 as an in vitro phosphorylation site. Mutation of this residue to alanine resulted in a reduced sensitivity of kir3.1* currents to h89 and forskolin, confirming an in vivo role for this novel site of the kir3.1 channel subunit in its regulation by pka. 0.342 SIGNOR-183475 NFATC2 protein Q13469 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 9606 11796223 YES lperfetto Upon dephosphorylation by calcineurin, nfatc2, also referred to as nfatp/nfat1, translocates to the nucleus where it directly associates with mef2a and -d. Nfatc2 stimulates mef2-dependent transcription by facilitating recruitment of the p300 coactivator to mef2-response elements. 0.408 SIGNOR-117586 MRGPRD protein Q8TDS7 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 10090 BTO:0000801 30918468 NO Luana Our data suggested that both Ang-(1-7) and alamandine, through their respective receptors Mas and MrgD, promote an anti-inflammatory reprogramming of M(LPS+IFN-γ)/M1 macrophages under inflammatory circumstances and potentiate the reprogramming induced by IL-4. 0.7 SIGNOR-262310 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser295 LQASVPGsVPGVLGP -1 16027724 YES GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) 0.381 SIGNOR-251230 SMARCD3 protein Q6STE5 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.756 SIGNOR-269820 LTB4R protein Q15722 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.266 SIGNOR-256970 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR GPSM3 protein Q9Y4H4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000876 phosphorylation:Ser35 STTRPWRsAPPSPPP 22843681 YES lperfetto Mutation of serine 35 completely abrogates the 14-3-3 interaction (e.g. Fig. 2, B–F), suggesting that phosphorylation of serine 35 is obligatory for 14-3-3 binding|The GPSM3/14-3-3 interaction is seen to stabilize GPSM3 from degradation and also support the nuclear exclusion of both proteins. 0.2 SIGNOR-264866 KLF1 protein Q13351 UNIPROT CDKN2C protein P42773 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 17442339 YES Luana Thus, EKLF is a direct regulator of p18INK4c gene expression, and much of EKLF's role in driving erythroid cell differentiation may occur via p18INK4c. 0.266 SIGNOR-266046 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser705 TPSAMKSsPQIPHQT 9606 SIGNOR-C17 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. 0.483 SIGNOR-164495 naloxone chemical CHEBI:7459 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258942 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273082 PAMPs stimulus SIGNOR-ST11 SIGNOR Pr3-ANCA complex SIGNOR-C475 SIGNOR up-regulates quantity 9606 BTO:0000133 15972951 NO lperfetto In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. |using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus. 0.7 SIGNOR-270587 CSNK2A1 protein P68400 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT down-regulates activity phosphorylation Ser393 VCHDSDEsDTAKAVE -1 25066127 YES miannu This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. 0.2 SIGNOR-276649 WWP2 protein O00308 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21532586 YES miannu We have shown that WWP2 interacts with and ubiquitylates PTEN, promoting its degradation. 0.631 SIGNOR-278650 WDR59 protein Q6PJI9 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 YES miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 0.834 SIGNOR-255303 HIF1AN protein Q9NWT6 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates hydroxylation 9606 18299578 YES gcesareni We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation. 0.552 SIGNOR-254324 Avagacestat chemical CID:46883536 PUBCHEM APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190479 ITGB1 protein P05556 UNIPROT Av/b1 integrin complex SIGNOR-C175 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.835 SIGNOR-253202 lenvatinib chemical CHEBI:85994 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191457 EFNB3 protein Q15768 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.821 SIGNOR-52624 Caspase 3 complex complex SIGNOR-C221 SIGNOR GSN protein P06396 UNIPROT down-regulates cleavage 9606 BTO:0000130 9323209 YES amattioni Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation. 0.638 SIGNOR-256461 bevacizumab antibody DB00112 DRUGBANK VEGFD protein O43915 UNIPROT down-regulates activity binding 9606 BTO:0001615 15961063 YES miannu Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. 0.4 SIGNOR-259887 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248744 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 YES gcesareni The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. 0.372 SIGNOR-105770 GSK3A protein P49840 UNIPROT BCL3 protein P20749 UNIPROT down-regulates quantity by destabilization phosphorylation Ser402 LSASPSSsPSQSPPR 9606 BTO:0000007 15469820 YES miannu In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway. 0.393 SIGNOR-276011 PCSK2 protein P16519 UNIPROT IAPP protein P10997 UNIPROT up-regulates activity cleavage Arg33 ESHQVEKrKCNTATC -1 10931181 YES lperfetto The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule 0.466 SIGNOR-261791 PRKN protein O60260 UNIPROT APEX1 protein P27695 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27148961 YES miannu Based on these results, we conclude that Parkin directly ubiquitinates APE1.|These results indicated that degradation of APE1 by Parkin was limited compared to the transiently expressed APE1, suggesting that a large portion of APE1 is not in contact with the Parkin and PINK1 without induction of stresses such as oxidative stress. 0.2 SIGNOR-278531 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 17419683 YES gcesareni In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation 0.467 SIGNOR-154276 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248519 calcium(2+) smallmolecule CHEBI:29108 ChEBI PPP3CA protein Q08209 UNIPROT up-regulates chemical activation 9606 21880741 YES gcesareni Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear. 0.8 SIGNOR-176367 FOXP2 protein O15409 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002881 21832174 YES Gianni FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk. 0.416 SIGNOR-269054 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 YES esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. 0.448 SIGNOR-89241 MRPL45 protein Q9BRJ2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.718 SIGNOR-262351 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr71 TLSEKIVyGHLDDPA -1 17997986 YES miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. 0.2 SIGNOR-262871 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr286 RLEEKVKtLKAQNSE 9606 BTO:0000848 21177766 YES lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) 0.268 SIGNOR-170764 SOSTDC1 protein Q6X4U4 UNIPROT WNT7A protein O00755 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.27 SIGNOR-242710 tRNA(Trp) smallmolecule CHEBI:29181 ChEBI Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates quantity precursor of 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 0.8 SIGNOR-270515 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Thr207 FLTEYVAtRWYRAPE 9606 BTO:0000562 19060905 YES lperfetto Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. 0.2 SIGNOR-244565 hsa-miR-410-5p mirna URS00002233F4_9606 RNAcentral WNT7B protein P56706 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003964 25351956 YES Parnian Downregulated miR329 and miR410 Promote the Proliferation and Invasion of Oral Squamous Cell Carcinoma by Targeting Wnt-7b.| miR329 and miR410 directly target Wnt-7b. 0.4 SIGNOR-278858 7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-2-ol chemical CHEBI:111176 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258724 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr404 HYETDYTtGGESCDE 9606 BTO:0000195 BTO:0000671 21545357 YES lperfetto Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions. 0.2 SIGNOR-173635 ULK1 protein O75385 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser115 ANAILGVsLAVCKAG 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274030 GSK3B protein P49841 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1695 EAEAVLAtPPKQPIV 9606 BTO:0002181 25897075 YES miannu We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability.  0.41 SIGNOR-276898 NEO1 protein Q92859 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 17204444 NO miannu Neogenin, a close relative of the axon guidance receptor Deleted in Colorectal Cancer (DCC), has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) families. While Netrin-1-Neogenin interactions result in a chemoattractive axon guidance response, the interaction between Neogenin and RGMa induces a chemorepulsive response. 0.7 SIGNOR-268395 E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR Ub:E2 complex SIGNOR-C497 SIGNOR form complex ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270842 WASHC3 protein Q9Y3C0 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 YES lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. 0.2 SIGNOR-261017 DLX2 protein Q07687 UNIPROT MSX1 protein P28360 UNIPROT down-regulates activity binding 10090 BTO:0000944 9111364 YES 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. 0.4 SIGNOR-240918 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 10490659 YES JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660). gcesareni These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins. 0.879 SIGNOR-70851 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1377 KPQKSVVsDLEADDV 9606 BTO:0000567 7961967 YES llicata Tryptic phosphopeptide mapping revealed that casein kinase II phosphorylated the C-terminal domain primarily on 2 serine residues in vitro, which were shown to be sites of modification in vivo. Site-directed mutagenesis studies identified these casein kinase II-specific phosphorylation sites as serine 1524 and serine 1376. 0.597 SIGNOR-250965 PRKCB protein P05771 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 YES inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.376 SIGNOR-270277 FBXO33 protein Q7Z6M2 UNIPROT YBX1 protein P67809 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 16797541 YES miannu Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1 0.382 SIGNOR-271604 RUNX1 protein Q01196 UNIPROT ITGA2B protein P08514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17725493 NO miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. 0.492 SIGNOR-254193 Merimepodib chemical CID:153241 PUBCHEM IMPDH2 protein P12268 UNIPROT down-regulates activity chemical inhibition 9606 11288107 YES Federica These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation. 0.8 SIGNOR-261106 RNF34 protein Q969K3 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0005949 36696363 YES miannu Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34.  0.32 SIGNOR-277912 MC5R protein P33032 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257183 CCL21 protein O00585 UNIPROT ACKR4 protein Q9NPB9 UNIPROT up-regulates activity binding 9606 BTO:0001938 23341447 YES Luana  In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines. 0.665 SIGNOR-268417 3a protein P59632 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 9606 BTO:0001950 18632968 NO Luana Severe Acute Respiratory Syndrome Coronavirus 3a Protein Activates the Mitochondrial Death Pathway Through p38 MAP Kinase Activation 0.2 SIGNOR-260444 RANBP17 protein Q9H2T7 UNIPROT TCF3 protein P15923 UNIPROT up-regulates binding 9606 20503194 YES miannu Yeast two-hybrid, mammalian two-hybrid, and co-immunoprecipitation analyses demonstrate specific interaction of e12 with ranbp17, a novel member of the importin-beta superfamily;this interaction maps to the crm1 homology region of ranbp17. Ectopic expression of ranbp17 leads to a approximately 3-fold increase in e2a/myod mediated transactivation of an e-box regulated luciferase reporter gene. 0.2 SIGNOR-165655 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser77 PGPFATRsPLFIFMR 10090 12818176 YES miannu JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. 0.689 SIGNOR-250131 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates quantity precursor of 9606 21173190 YES lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† 0.8 SIGNOR-267010 KATNB1 protein Q9BVA0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates 9606 BTO:0000567 10751153 NO miannu Katanin, a heterodimeric microtubule-severing ATPase, is found localized at mitotic spindle poles. In this paper we demonstrate that human p60 katanin and the C-terminal domain of human p80 katanin both bind microtubules in vitro. Association of these two proteins results in an increased microtubule affinity and increased microtubule-severing activity in vitro. Association of these subunits in transfected HeLa cells increases microtubule disassembly activity and targeting to spindle poles.  0.7 SIGNOR-267181 RBM15 protein Q96T37 UNIPROT SON protein P18583 UNIPROT up-regulates binding 9606 19786495 YES miannu Here we report that the human nxf1-binding protein rbm15 binds specifically to human dbp5 and facilitates its direct contact with mrna in vivo. 0.239 SIGNOR-188264 FBXO11 protein Q86XK2 UNIPROT TP53 protein P04637 UNIPROT down-regulates neddylation Lys320 SSSPQPKkKPLDGEY 9606 17098746 YES miannu Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321 0.67 SIGNOR-150669 PABPC4 protein Q13310 UNIPROT NFX1 protein Q12986 UNIPROT up-regulates activity binding 9606 BTO:0000008 17267499 YES Simone We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123. 0.246 SIGNOR-261051 CYTH2 protein Q99418 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 14565977 NO miannu ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha 0.7 SIGNOR-264909 GPIb-IX-V complex complex SIGNOR-C270 SIGNOR Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 32644488 NO lperfetto Therefore, VWF cannot bind to the GpIb receptors on platelets via the A1 domain to induce platelet aggregation and further hemostasis.  0.7 SIGNOR-261866 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 YES lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. 0.2 SIGNOR-93554 WWTR1 protein Q9GZV5 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 22153608 YES Runx family members play key roles in regulating mesenchymal stem cell differentiation during bone formation, and therefore the regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation. gcesareni Taz binding to the transcription factor runx2 promotes osteoblast lineage specification, whereas taz binding to the transcription factor ppargamma inhibits adipogenesis. 0.507 SIGNOR-195218 crizotinib chemical CHEBI:64310 ChEBI MET protein P08581 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258102 AMPK complex SIGNOR-C15 SIGNOR HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 21892142 YES lperfetto Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). 0.278 SIGNOR-216558 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1090 TNTGFPRyPNDSVYA 9606 14711813 YES llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. 0.2 SIGNOR-121145 SPOP protein O43791 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization binding 9606 24239470 YES miannu Mutations in SPOP represent the most common point mutations in primary prostate cancer,with recurrent mutations in SPOP in 6% to 15% of multiple independent cohorts. Wild-type SPOP will bind and promote the degradation of SRC-3,whereas prostate cancer–derived SPOP mutants lose this ability,leading to increased androgen signaling in certain model systems. 0.48 SIGNOR-251529 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR MOV10 protein Q9HCE1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32496609 NO miannu Mov10 is a processing body (P-body) protein and an interferon-stimulated gene that can affect replication of retroviruses, hepatitis B virus, and hepatitis C virus (HCV). 0.2 SIGNOR-261137 BCL2L2 protein Q92843 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 YES gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax. 0.466 SIGNOR-152989 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr642 CIAGSPLtPRRVTEV 9606 BTO:0001938 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104703 CKM complex complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 15546612 YES gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. 0.383 SIGNOR-273150 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 12361602 YES apalma Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk 0.95 SIGNOR-255379 PRKCB protein P05771 UNIPROT ORAI1 protein Q96D31 UNIPROT down-regulates phosphorylation Ser30 TTSGSRRsRRRSGDG 9606 20534587 YES llicata We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30. 0.2 SIGNOR-166044 KDM6A protein O15550 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 24561908 YES This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. 0.2 SIGNOR-265360 SEC13 protein P55735 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.58 SIGNOR-262091 Ub:E2 complex SIGNOR-C497 SIGNOR RNF152 protein Q8N8N0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271199 AGTR2 protein P50052 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 NO lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 0.7 SIGNOR-252268 MECP2 protein P51608 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000007 24150225 YES Luana MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2 0.27 SIGNOR-264683 TRIM27 protein P14373 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000671 12807881 NO miannu Here we show that ectopic expression of rfp in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria. 0.7 SIGNOR-256667 SRF protein P11831 UNIPROT ACTA2 protein P62736 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 15269336 NO gcesareni The primary goal of the present study was to directly assess the role of the degeneracy of sm ?-Actin cargs in the regulation of smc-selective gene expression in vivo. in addition, our present studies address the possible role of this carg degeneracy, and the smc-selective srf coactivator myocardin, in regulating differential expression of carg-dependent smc genes and growth regulatory genes. 0.424 SIGNOR-126923 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 12763138 YES gcesareni The stat3-mediated transactivation was reduced by blocking the stat3 serine phosphorylation with the mek inhibitor u0126 or by expression of kinase-inactive msk1. 0.386 SIGNOR-101251 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of 9606 BTO:0000093 8790407 YES Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. 0.8 SIGNOR-269755 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser17 ARRSYVSsGEMMVGG -1 7822264 YES llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. 0.428 SIGNOR-250627 KLKB1 protein P03952 UNIPROT MST1 protein P26927 UNIPROT up-regulates activity cleavage Arg483 DQRRSKLrVVGGHPG -1 10068459 YES miannu Proteolytic cleavage of pro-MSP at a single site yields active MSP, a disulfide-linked alphabeta-chain heterodimer. human kallikrein cleaved only at Arg483–Val484, the cleavage site for formation of a- and b-chains. 0.325 SIGNOR-256511 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto Gsk3b phosphorylates tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules 0.738 SIGNOR-171046 SMO protein Q99835 UNIPROT ARRB1 protein P49407 UNIPROT up-regulates binding 9606 15618519 YES The binding occours if Smo is phosphorylated gcesareni Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2 0.634 SIGNOR-132678 PRKD1 protein Q15139 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 19329994 YES lperfetto PKD1 regulates cofilin S3-phosphorylation|Both, oxidative stress as well as RhoA activation enhanced cofilin phosphorylation at S3, implicating an increased inhibition due to PKD1-mediated signalling events 0.334 SIGNOR-275944 PLAUR protein Q03405 UNIPROT ITGB3 protein P05106 UNIPROT up-regulates activity binding 9606 27383564 YES Recent evidence suggests that the activation of b3 integrin in podocytes mediates uPAR-induced cellular events leading to proteinuria 0.469 SIGNOR-253333 SRC protein P12931 UNIPROT MAPRE1 protein Q15691 UNIPROT down-regulates activity phosphorylation Tyr247 QRIVDILyATDEGFV 9606 27698945 YES miannu These data suggest that Src phosphorylates endogenous EB1 at Y247. 0.2 SIGNOR-278215 HSPH1 protein Q92598 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 NO miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. 0.499 SIGNOR-255242 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity chemical modification 9606 16115609 YES The microsomal heme oxygenase system consists of heme oxygenase (HO) and NADPH-cytochrome P450 reductase, and plays a key role in the physiological catabolism of heme which yields biliverdin, carbon monoxide, and iron as the final products. Heme degradation proceeds essentially as a series of autocatalytic oxidation reactions involving heme bound to HO 0.8 SIGNOR-259333 CENPL protein Q8N0S6 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.664 SIGNOR-265199 GLI1 protein P08151 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 NO lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. 0.713 SIGNOR-209620 PPP2CA protein P67775 UNIPROT ELF1 protein P32519 UNIPROT down-regulates activity dephosphorylation Thr231 CPKYIKWtQREKGIF 9606 18714041 YES Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response 0.2 SIGNOR-248634 TSC2 protein P49815 UNIPROT TSC complex SIGNOR-C101 SIGNOR form complex binding 9606 12172553 YES lperfetto TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). 0.934 SIGNOR-217913 MAP4K2 protein Q12851 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 YES done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  0.2 SIGNOR-273900 PPAT protein Q06203 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity chemical modification 9606 9914248 YES miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. 0.8 SIGNOR-267295 SRC protein P12931 UNIPROT DGKA protein P23743 UNIPROT up-regulates phosphorylation Tyr335 ILPPSSIyPSVLASG 9606 17700527 YES llicata Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility. 0.46 SIGNOR-157365 TP63 protein Q9H3D4 UNIPROT PLEC protein Q15149 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 28595999 YES lperfetto Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. 0.2 SIGNOR-263279 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser78 NKDQHSIsYTLSRAQ -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.767 SIGNOR-276133 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr23 SAALDPAyTTLEFEN 9606 22308320 YES lperfetto Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function. 0.365 SIGNOR-195883 PPP2CA protein P67775 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR form complex binding 9606 23454242 YES gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. 0.907 SIGNOR-243433 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.794 SIGNOR-249134 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr139 EKLRVLGyNQNGEWS -1 34144039 YES miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. 0.303 SIGNOR-277302 HSPA5 protein P11021 UNIPROT UPR phenotype SIGNOR-PH131 SIGNOR up-regulates 28286085 NO lperfetto The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen.|When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision. 0.7 SIGNOR-265282 GSK3B protein P49841 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by repression phosphorylation Ser76 SNLQRMGsSESTDSG 9606 BTO:0000567 20348946 YES lperfetto Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a 0.314 SIGNOR-164742 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Ser185 KKREKRRsTSRQFVD 9606 BTO:0000567 14744859 YES llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 0.779 SIGNOR-250587 MYC protein P01106 UNIPROT USP22 protein Q9UPT9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26049753 NO USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. 0.495 SIGNOR-261560 FUS protein P35637 UNIPROT MPHOSPH9 protein Q99550 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 NO This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease 0.2 SIGNOR-262804 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR AMPK complex SIGNOR-C15 SIGNOR down-regulates activity phosphorylation 9606 21460634 YES lperfetto Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit. 0.432 SIGNOR-209916 MAPK3 protein P27361 UNIPROT KARS1 protein Q15046 UNIPROT up-regulates phosphorylation Ser207 PYEITLLsPCLHMLP 9606 19524539 YES gcesareni Lysrs serves as a key signaling molecule in the immune response by regulating gene expression. Lysrs was phosphorylated on serine 207 in a mapk-dependent manner, released from the multisynthetase complex, and translocated into the nucleus. 0.2 SIGNOR-186125 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1B protein Q01064 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. 0.8 SIGNOR-253400 A2/b1 integrin complex SIGNOR-C160 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.602 SIGNOR-257702 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207603 ILK protein Q13418 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser3 sGVAVSDG 9606 18252715 YES gcesareni Actin (de)polymerization is regulated by cofilin, the ser(3) phosphorylation (ps(3)cofilin) of which inhibits its actin-severing activity. To determine how ilk regulates ps(3)cofilin, we examined the effects of ilk on ps(3)cofilin using normal rie1 cells. 0.35 SIGNOR-160756 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10090 BTO:0000944 10698938 YES Protein tyrosine phosphatase alpha (PTPalpha) is believed to dephosphorylate physiologically the Src proto-oncogene at phosphotyrosine (pTyr)527, a critical negative-regulatory residue. It thereby activates Src, and PTPalpha overexpression neoplastically transforms NIH 3T3 cells. 0.742 SIGNOR-248438 vildagliptin chemical CHEBI:135285 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 19149538 YES Luana Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. 0.8 SIGNOR-257812 HSD17B1 protein P14061 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification -1 8994190 YES Luana Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues.  0.8 SIGNOR-269758 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Thr330 TRLSRSRtASLTSAA 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 YES llicata Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344 0.395 SIGNOR-129676 CDK1 protein P06493 UNIPROT USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2604 HLQQGSEsPMMIGEL 9606 BTO:0000018 27991932 YES lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. 0.2 SIGNOR-275603 HARS1 protein P12081 UNIPROT histidine smallmolecule CHEBI:27570 ChEBI down-regulates quantity chemical modification 9606 10430027 YES miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 0.8 SIGNOR-270486 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr7 tPCSSMSN 9606 26057687 YES miannu Our findings illustrate a unique molecular mechanism underlying PLK1 dependent inactivation of NDR1 and define a novel role for PLK1-NDR1 signaling cascade in governing accurate spindle orientation to ensure faithful chromosome segregation in mitosis.|PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1 dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis. 0.316 SIGNOR-278420 SBDS protein Q9Y3A5 UNIPROT EFL1 protein Q7Z2Z2 UNIPROT up-regulates binding 9606 BTO:0001271 21536732 YES miannu Sbds stimulates 60s-dependent gtp hydrolysis by efl1 0.2 SIGNOR-173533 NTHL1 protein P78549 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275717 imatinib methanesulfonate chemical CHEBI:31690 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000740 15206509 YES miannu Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia. 0.8 SIGNOR-259357 GATA2 protein P23769 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12432220 NO irozzo Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression. 0.441 SIGNOR-256056 GGCX protein P38435 UNIPROT F7 protein P08709 UNIPROT up-regulates activity carboxylation 9606 31226734 YES lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. 0.687 SIGNOR-265919 A6/b1 integrin complex SIGNOR-C164 SIGNOR UTF1 protein Q5T230 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.254 SIGNOR-253281 GRK6 protein P43250 UNIPROT LTB4R protein Q15722 UNIPROT down-regulates activity phosphorylation Thr308 VAKLLEGtGSEASST 9534 BTO:0000298 12077128 YES Thr(308) is a major residue involved in GRK6-mediated desensitization of BLT1 signaling. 0.475 SIGNOR-251213 CSNK2A1 protein P68400 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser170 KEGDVDVsDSDDEDD 9606 18559419 YES llicata Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation. 0.206 SIGNOR-178939 HOXC11 protein O43248 UNIPROT HNF1A protein P20823 UNIPROT up-regulates 9606 9582375 NO miannu The observed stimulatory effect of hoxc11 on hnf1_ may be due to a similar stabilizing effect on hnf1_ dna binding and/or an increase in transcriptional activity of hnf1_. 0.307 SIGNOR-57484 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr407 EIKSIDDtSNFDEFP 9606 26057687 YES miannu Our findings illustrate a unique molecular mechanism underlying PLK1 dependent inactivation of NDR1 and define a novel role for PLK1-NDR1 signaling cascade in governing accurate spindle orientation to ensure faithful chromosome segregation in mitosis.|PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1 dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis. 0.316 SIGNOR-278421 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr183 TLLMKKDtLTEEETQ 9606 26057687 YES miannu Our findings illustrate a unique molecular mechanism underlying PLK1 dependent inactivation of NDR1 and define a novel role for PLK1-NDR1 signaling cascade in governing accurate spindle orientation to ensure faithful chromosome segregation in mitosis.|PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1 dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis. 0.316 SIGNOR-278422 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT down-regulates activity phosphorylation 9606 25855382 YES miannu In this study we linked these regulatory events mechanistically, by showing that Plk1 induces proteasomal degradation of SUZ12 and ZNF198 by site specific phosphorylation.|Plk1 phosphorylates SUZ12 and ZNF198 in vitro. 0.362 SIGNOR-278423 GLI2 protein P10070 UNIPROT PPARG protein P37231 UNIPROT down-regulates BTO:0004300 29205155 NO areggio Molecularly, Gli2 is the principle transcription factor in the Gli family to mediate the anti-adipogenic and anti-lipogenic effects of Hh signaling 0.275 SIGNOR-256224 PRKN protein O60260 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates quantity by destabilization ubiquitination Lys13 VKAYLLGkEDAAREI 9606 26746706 YES miannu Once activated, parkin interacts with and subsequently ubiquitinates p62 at the K13 residue, resulting in the degradation of p62 via the proteasomal dependent pathway. 0.2 SIGNOR-278524 UHMK1 protein Q8TAS1 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 19033656 YES gcesareni This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of kis-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation. 0.51 SIGNOR-182489 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.762 SIGNOR-252751 MAPK1 protein P28482 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 YES gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. 0.449 SIGNOR-134837 VAMP2 protein P63027 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 17331077 NO miannu Synaptobrevin 2/VAMP2 (vesicle-associated membrane protein 2), a critical component of the synaptic vesicle-fusion machinery. On the SV membrane, VAMP2 is engaged in a complex with synaptophysin I, which is mutually exclusive with the formation of fusogenic SNARE complexes. 0.7 SIGNOR-264103 PRKCG protein P05129 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.2 SIGNOR-251633 EPC2 protein Q52LR7 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.583 SIGNOR-269306 TWIST1 protein Q15672 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.289 SIGNOR-255511 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258091 Alkannin chemical CHEBI:2578 ChEBI PKM protein P14618 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000093;BTO:0000018 21516121 YES lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. 0.8 SIGNOR-262009 HIF1A protein Q16665 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 16517405 YES miannu Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. 0.47 SIGNOR-267444 SATB1 protein Q01826 UNIPROT MYB protein P10242 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17343824 NO miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 0.2 SIGNOR-255135 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates quantity by stabilization phosphorylation Ser176 TNAENTAsQSPRTRG 9606 BTO:0000567 19789335 YES lperfetto we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1. 0.841 SIGNOR-109680 AATK protein Q6ZMQ8 UNIPROT STK39 protein Q9UEW8 UNIPROT down-regulates 9606 17267545 NO gcesareni Taken together, our data are consistent with aatyk1 indirectly inhibiting the spak/wnk4 activation of the cotransporter by scaffolding an inhibitory phosphatase in proximity to a stimulatory kinase. 0.343 SIGNOR-152921 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 YES Manara Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A 0.842 SIGNOR-260834 AKT1 protein P31749 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21619873 YES gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5 0.423 SIGNOR-252514 NCAPD3 protein P42695 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.886 SIGNOR-263912 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser173 MLETLSQsPPKGVTI 9606 BTO:0000664 17475908 YES miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 0.323 SIGNOR-262914 lapatinib chemical CHEBI:49603 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 YES Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. 0.8 SIGNOR-257901 CSNK2A1 protein P68400 UNIPROT UBE2R2 protein Q712K3 UNIPROT up-regulates activity phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 YES lperfetto Ck2-dependent phosphorylation of the e2 ubiquitin conjugating enzyme ubc3b induces its interaction with beta-trcp and enhances beta-catenin degradation 0.339 SIGNOR-88050 INPP4B protein O15327 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation 9606 24070612 YES miannu Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and PTP activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation.|Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and protein tyrosine phosphatase activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation. 0.374 SIGNOR-277106 NUP210 protein Q8TEM1 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.594 SIGNOR-262072 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207251 PRKD1 protein Q15139 UNIPROT PTRH2 protein Q9Y3E5 UNIPROT up-regulates phosphorylation Ser5 sLVMEYLA 9606 18703509 YES lperfetto Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1 0.3 SIGNOR-180085 HTR2A protein P28223 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-256885 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 16407412 YES inferred from 70% family members gcesareni Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a. 0.2 SIGNOR-270010 dopamine smallmolecule CHEBI:18243 ChEBI DRD4 protein P21917 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257480 BRAF protein P15056 UNIPROT PAX3 protein P23760 UNIPROT up-regulates activity phosphorylation Ser205 APQSDEGsDIDSEPD 9606 27906130 YES miannu BRAF activates PAX3 to control muscle precursor cell migration during forelimb muscle development.|We found that BRAF clearly induced phosphorylation of PAX3 at Ser205 in both cell types (XREF_FIG). 0.308 SIGNOR-278435 ABL1 protein P00519 UNIPROT CRK protein P46108 UNIPROT down-regulates activity phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 21602891 YES lperfetto Abl induces phosphorylation at y251 in vivo, and that the kinetics of phosphorylation at y251 and the negative regulatory y221 site in vitro are similar. 0.76 SIGNOR-173845 CDK1 protein P06493 UNIPROT CREM protein Q03060 UNIPROT down-regulates quantity phosphorylation Ser271 QGVVMAAsPGSLHSP 9606 BTO:0001033 21767532 YES miannu In this report data is presented demonstrating that ICER is phosphorylated by the mitotic kinase cdk1. Phosphorylation of ICER on a discrete residue targeted ICER to be monoubiquitinated. Different from unphosphorylated, phosphorylated and polyubiquitinated ICER, monoubiquitinated ICER was found to be cytosolic. Taken together, these results hinted on a mechanism for the observed abnormal subcellular localization of ICER in human prostate tumors. 0.297 SIGNOR-276346 FYN protein P06241 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 19917775 YES miannu Because Fyn deletion prevented FAK phosphorylation at tyrosine residues 397 and 576 (XREF_FIG), we generated a phosphorylation mimicking mutant of FAK to test whether restoring FAK phosphorylation in the fyn -/- mouse lung could restore lung vascular permeability responses to PAR1 agonist to the level seen in WT mice.|Our findings that interaction of activated FAK with p120-catenins subsequent to Fyn activation of FAK facilitates reannealing of AJ leading to reestablishment of the basal endothelial barrier suggest that the Fyn-FAK pathway plays a critical role in restoring endothelial barrier function. 0.601 SIGNOR-278441 NEK2 protein P51955 UNIPROT MAD2L1 protein Q13257 UNIPROT down-regulates activity phosphorylation 9606 20034488 YES miannu We demonstrated that overexpression of Nek2 can enhance the ability of Mad2 to cause delays in cell division.|We have demonstrated that Nek2 can bind and phosphorylate Mad2 and Cdc20. 0.845 SIGNOR-278446 NEK7 protein Q8TDX7 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity phosphorylation Ser114 AIIHGLSsLTACQLR 9606 28216227 YES miannu Using KR-TRF2 to induce telomeric DNA damage, we found that TRF1 degradation was also exacerbated when ATM was inhibited after damage induction (55.2% of mock treated cells) (XREF_FIG), indicating that the ATM signal pathway is required for Nek7 mediated TRF1 stabilization.|We show that Nek7 phosphorylates TRF1 at Ser114 and in turn maintains stability of the shelterin complex at telomeres. 0.343 SIGNOR-278447 DIO3 protein P55073 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 12746313 YES scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. 0.8 SIGNOR-266942 Immunoglobulin delta heavy chain protein P0DOX3 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 20176268 YES scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. 0.2 SIGNOR-268195 NFATC2 protein Q13469 UNIPROT NF90-NF45 complex SIGNOR-C443 SIGNOR up-regulates activity binding 9606 BTO:0000782 33555115 YES miannu Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2-like sequences in rDNA promoter upon T-cell activation in vitro. NF45/NF90‐mediated rDNA transcription contributes to T‐cell activation by interacting with NFATc2 in the nucleolus 0.251 SIGNOR-268492 CHEK1 protein O14757 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity phosphorylation Ser296 GFSKHIQsNLDFSPV 9606 BTO:0001938 23068608 YES lperfetto TheSer296autophosphorylation ofCHK1is mainly regulated by an intramolecular mechanism in response to DNA damage. 0.2 SIGNOR-217904 DGC complex SIGNOR-C217 SIGNOR GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265433 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT down-regulates phosphorylation Tyr54 HTVEAVAyAPKKELI 9606 9461559 YES llicata Here we demonstrate that c-abl interacts constitutively with rad51. We show that c-abl phosphorylates rad51 on tyr-54 in vitro. The results also show that treatment of cells with ionizing radiation induces c-abl-dependent phosphorylation of rad51. Phosphorylation of rad51 by c-abl inhibits the binding of rad51 to dna and the function of rad51 in atp-dependent dna strand exchange reactions. 0.772 SIGNOR-55482 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192620 SMAD1 protein Q15797 UNIPROT GADD45G protein O95257 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.2 SIGNOR-268937 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 15498859 YES lperfetto Pim-1 is know to be up regulated by signal transducer and activator of transcription 5 (stat5) 0.411 SIGNOR-259436 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 YES llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. 0.307 SIGNOR-250935 ziprasidone chemical CHEBI:10119 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258503 BACE1 protein P56817 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage 28923680 YES Beta-secretase 1 (BACE1) cleaves the type-I transmembrane protein APP to form the N-terminus of Aβ. 0.793 SIGNOR-255480 AKT2 protein P31751 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.502 SIGNOR-251624 HSP90AA1 protein P07900 UNIPROT CBLL1 protein Q75N03 UNIPROT up-regulates quantity binding 9606 BTO:0000007 31952268 YES miannu By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. 0.2 SIGNOR-271474 KARS1 protein Q15046 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.2 SIGNOR-270353 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation Ser141 TVKQKYLsFTPPEKD 9606 BTO:0000007 16204230 YES gcesareni Pak2 is autophosphorylated at eight sites;ser-141 and ser-165 in the regulatory domain and thr-402 in the activation loop are identified as key sites in activation of the protein kinase. 0.2 SIGNOR-140907 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120060 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. 0.87 SIGNOR-236206 CAD protein P27708 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI down-regulates quantity chemical modification 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267419 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys137 KNGETSLkPEDFDFT 31476572 YES lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. 0.2 SIGNOR-275679 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser105 TGAGAAGsPAQQHAH 26375055 YES lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity 0.262 SIGNOR-276524 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 10090 21145499 YES milica Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component. 0.321 SIGNOR-170361 PPM1A protein P35813 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity dephosphorylation Ser127 PQHVRAHsSPASLQL 9606 33630828 YES lperfetto Although the authors show an in vitro kinase assay where PPM1A supposedly dephosphorylates YAP on Ser127, Fig. 4A lacks a positive control to ensure that PPM1A purified from cells is active.|The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration. 0.269 SIGNOR-276984 TOP1 protein P11387 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22904072 YES miannu We examined the mechanism of topoisomerase I (Top1) to understand the role of the unique chromatin structure in Bmal1 gene regulation.  Promoter assays showed that the Top1-binding site is required for transcriptional suppression and that it functions cooperatively with the distal RORE, supporting that Bmal1 transcription is upregulated by Top1 inhibition.  0.342 SIGNOR-277354 MK-2206 chemical CHEBI:67271 ChEBI AKT2 protein P31751 UNIPROT down-regulates chemical inhibition 9606 BTO:0001286 21841310 YES gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. 0.8 SIGNOR-176046 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 YES We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction 0.2 SIGNOR-259919 ATM protein Q13315 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Ser314 SHEDLPAsQERSEVN 9606 22099307 YES lperfetto We also demonstrate that mitotically activated atm phosphorylates bub1, a critical kinetochore protein, on ser314. Atm-mediated bub1 ser314 phosphorylation is required for bub1 activity and is essential for the activation of the spindle checkpoint 0.462 SIGNOR-177276 CDK1 protein P06493 UNIPROT TFCP2L1 protein Q9NZI6 UNIPROT up-regulates activity phosphorylation Thr177 HCISTEFtPRKHGGE 9606 31709755 YES miannu In addition, overexpression of TFCP2L1 and CDK1 in T24 cells increased clonogenic activity in a clonogenic limiting dilution assay (Fig\u00a05H), confirming the importance of CDK1\u2010TFCP2L1 pathways for the stemness features of BC cells.High levels of co\u2010expression of p\u2010TFCP2L1 and CDK1 were associated with distant metastasis in our cohort of BC patients (Table\u00a01).|Tfcp2l1 Thr177 phosphorylation by CDK1 is essential for proliferation and cell cycle progression of ESCs.|Tfcp2l1 is phosphorylated at Thr177 by CDK1. 0.2 SIGNOR-278472 DYRK1A protein Q13627 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Thr530 YLSELPPtPLHVSED 9606 20167603 YES miannu DYRK1A and DYRK3 directly phosphorylate SIRT1 at Thr(522), promoting deacetylation of p53.|DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. 0.541 SIGNOR-278473 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.432 SIGNOR-81161 TRIB2 protein Q92519 UNIPROT PKM protein P14618 UNIPROT up-regulates activity phosphorylation Ser37 MCRLDIDsPPITARN 9606 BTO:0000018 35790734 YES miannu  This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells.  0.2 SIGNOR-275431 ERBB2 protein P04626 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 23027125 YES miannu HER2 stabilizes EGFR and itself by altering autophosphorylation patterns in a manner that overcomes regulatory mechanisms and promotes proliferative and transformation signaling.|While blocking autophosphorylation on the c-Cbl and the Grb2 binding sites, HER2 promotes EGFR phosphorylation on Y1173 and its own phosphorylation on Y1248 and Y1221/1222 ( xref ). 0.613 SIGNOR-278474 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Ser271 ISGRLVDsKAKTRSA 9606 9312068 YES lperfetto Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1 0.723 SIGNOR-51207 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. 0.728 SIGNOR-183636 WNT5A protein P41221 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 16273260 YES gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. 0.833 SIGNOR-253129 CDK2 protein P24941 UNIPROT PTHLH protein P12272 UNIPROT down-regulates phosphorylation Thr121 YKEQPLKtPGKKKKG 9606 10373465 YES llicata Phosphorylation at the cyclin-dependent kinases site (thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization 0.373 SIGNOR-68548 RIMBP2 protein O15034 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.282 SIGNOR-264371 MAPK1 protein P28482 UNIPROT PRDX6 protein P30041 UNIPROT up-regulates phosphorylation Thr177 TAEKRVAtPVDWKDG 9606 BTO:0000763 19140803 YES miannu These results show that the mapks can mediate phosphorylation of prdx6 at thr-177 with a consequent marked increase in its aipla(2) activity. 0.692 SIGNOR-183379 ABT-737 chemical CID:11228183 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271;BTO:0000776;BTO:0000785 17200714 YES gcesareni A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells. 0.8 SIGNOR-151781 quetiapine chemical CHEBI:8707 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258536 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 YES esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. 0.448 SIGNOR-89229 DUSP9 protein Q99956 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 BTO:0000887 11988087 YES This interaction is observed for Mus musculus Pyst3 gene, which encodes for DUSP9 gcesareni These properties define the ability of this enzyme to dephosphorylate and inactivate erk1/2 and p38a, but not jnk (c-jun n-terminal kinase) in vivo. 0.7 SIGNOR-87150 FYN protein P06241 UNIPROT DAB1 protein O75553 UNIPROT down-regulates activity phosphorylation 9606 21534960 YES miannu Tyrosine phosphorylation of Dab1 by Fyn inhibits its interaction with APP, while increasing its interaction with Fyn. 0.613 SIGNOR-278476 FYN protein P06241 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Tyr261 PFEGDNIyKLFENIG 9606 20142099 YES miannu Moreover, Fyn kinase directly phosphorylated LKB1 on tyrosine 261 and 365 residues and mutations of these sites resulted in LKB1 export into the cytoplasm and increased AMPK phosphorylation. 0.327 SIGNOR-278477 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 YES gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. 0.2 SIGNOR-160982 SOX3 protein P41225 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10549281 YES gcesareni Two additional sox proteins, xsox17alfa and xsox3, likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity. 0.495 SIGNOR-72039 PFAS protein O15067 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 33179964 YES miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. 0.8 SIGNOR-267310 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Tyr529 TITKTVEyLHAQGVV 9606 BTO:0000007 18156174 YES llicata Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway. 0.356 SIGNOR-160052 ESR1 protein P03372 UNIPROT PGR protein P06401 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11000528 NO gcesareni We observed the transcriptional inhibition of the progesterone and glucocorticoid receptors when eralpha was cotransfected 0.623 SIGNOR-82161 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCR3 protein P51677 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16604092 NO miannu Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling. 0.258 SIGNOR-254660 FRK protein P42685 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr1552 HDLTETSyLPRQDLE 9606 BTO:0003323 29156836 YES miannu Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. Rak-mediated tyrosine phosphorylation of BRCA1 is essential for its stability and function 0.2 SIGNOR-275454 MALT1 protein Q9UDY8 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates binding 9606 BTO:0000782 17948050 YES gcesareni Tab2/tak1 associate with ubiquitinated malt1 upon t-cell stimulation. 0.605 SIGNOR-158551 GRID2 protein O43424 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264952 TYSND1 protein Q2T9J0 UNIPROT TYSND1 protein Q2T9J0 UNIPROT down-regulates activity cleavage 9606 BTO:0000567 22002062 YES miannu Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer. 0.2 SIGNOR-261053 RNF4 protein P78317 UNIPROT KDM5B protein Q9UGL1 UNIPROT down-regulates quantity by destabilization sumoylation 9606 33859667 YES SaraGualdi Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015). 0.301 SIGNOR-271575 E2F1 protein Q01094 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.699 SIGNOR-253864 XRCC3 protein O43542 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 18212739 YES lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  0.717 SIGNOR-263257 KLF4 protein O43474 UNIPROT THBD protein P07204 UNIPROT up-regulates activity transcriptional regulation 9606 19661484 NO miannu Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. 0.302 SIGNOR-254546 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation Thr526 GEAGGPLtPRRVSSD 9606 7588608 YES lperfetto Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf 0.595 SIGNOR-29505 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BS1 protein P57053 UNIPROT down-regulates activity monoubiquitination Lys35 RKRKRSRkESYSVYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271984 TLR4 protein O00206 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 20596954 NO fstefani Regulation of toll-like receptor signaling in the innate immunity. 0.7 SIGNOR-166485 atomoxetine chemical CHEBI:127342 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition -1 9871604 YES miannu The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. 0.8 SIGNOR-259070 SOAT1 protein P35610 UNIPROT cholesteryl ester smallmolecule CHEBI:17002 ChEBI down-regulates quantity chemical modification 9606 31848472 YES miannu Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters 0.8 SIGNOR-265160 MAK protein P20794 UNIPROT CDH1 protein P12830 UNIPROT down-regulates phosphorylation 9606 21986944 YES miannu Finally, we speculate that there are two mechanisms whereby MAK inactivates CDH1 : the first is kinase dependent inactivation, modeled after CDK, where phosphorylation dissociates CDH1 from APC/C; the second is through physical binding of CDH1 with MAK.|These results suggest a cell cycle-dependent phosphorylation of CDH1 by MAK. 0.283 SIGNOR-278486 MAPK3 protein P27361 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates phosphorylation Ser52 MPHTETVsPLPSSMD 9606 24793005 YES miannu We found that activation of ERK1 signaling inhibited transactivation activity of Nanog.|We showed the direct phosphorylation of Nanog by ERK1 and clearly showed that Ser52 is the major phosphorylation site and Ser65 is weakly phosphorylated by ERK1. 0.492 SIGNOR-278487 MYC protein P01106 UNIPROT GLS protein O94925 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001518 19219026 NO Luana Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.  0.441 SIGNOR-268038 PDPK1 protein O15530 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 15175348 YES lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation 0.272 SIGNOR-244934 GRIP1 protein Q9Y3R0 UNIPROT GRIPAP1 protein Q4V328 UNIPROT up-regulates activity binding 10116 BTO:0000142 10896157 YES Giorgia We have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. GRIP1 has seven PDZ domains, which mediate protein–protein interactions, allowing the recruitment of GRASP-1 to a large signal-transducing complex 0.509 SIGNOR-260638 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT up-regulates activity phosphorylation Ser526 PVKEEAKsPAEAKSP 10116 BTO:0000938 9592082 YES lperfetto The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. 0.368 SIGNOR-249424 TSC22D3 protein Q99576 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity relocalization 9606 BTO:0000738 20018851 YES GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. 0.253 SIGNOR-256148 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates binding 9606 21902831 YES lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.433 SIGNOR-216969 PFKL protein P17858 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266472 TFE3 protein P19532 UNIPROT ATP6V0D1 protein P61421 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.251 SIGNOR-276809 ATM protein Q13315 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation 9606 12607003 YES fstefani We show that, in response to ionizing radiation, mdc1 is hyperphosphorylated in an atm-dependent manner, and rapidly relocalizes to nuclear foci that also contain the mre11 complex, phosphorylated histone h2ax and 53bp1. 0.846 SIGNOR-98798 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 19762596 YES miannu  We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus.  0.956 SIGNOR-271883 PLXNB3 protein Q9ULL4 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity binding 10116 BTO:0000526 20696765 YES miannu Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays. 0.251 SIGNOR-268435 CAMK1 protein Q14012 UNIPROT NUMB protein P49757 UNIPROT down-regulates phosphorylation Ser276 EQLARQGsFRGFPAL 9606 17022975 YES esanto Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2. 0.334 SIGNOR-149993 PRKCA protein P17252 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 25058461 YES miannu As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha. 0.414 SIGNOR-278492 NR5A2 protein O00482 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 NO miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.351 SIGNOR-254870 CDK1 protein P06493 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity phosphorylation Thr926 LDIPTGTtPQRKSYL 9606 19001501 YES done miannu Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.  0.639 SIGNOR-273887 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr180 GSKGQKTtQNRYSFY -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273485 PRKCA protein P17252 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 25058461 YES miannu As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha. 0.414 SIGNOR-278493 SPOP protein O43791 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0005672 29160310 YES Barakat Loss-of-function mutations in SPOP compromise ubiquitination-mediated PD-L1 degradation, leading to increased PD-L1 levels and reduced numbers of tumor-infiltrating lymphocytes (TILs) in mouse tumors and in primary human prostate cancer specimens. 0.326 SIGNOR-274978 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Lys72 SASVLTGkLTTVFLP -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.374 SIGNOR-263594 XCL1 protein P47992 UNIPROT XCR1 protein P46094 UNIPROT up-regulates binding 9606 BTO:0000763 10518929 YES gcesareni Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells. 0.786 SIGNOR-71164 PMCH protein P20382 UNIPROT MCHR1 protein Q99705 UNIPROT up-regulates binding 9606 BTO:0000007 10421367 YES gcesareni Here we show that the 353-amino-acid human orphan g-protein-coupled receptor slc-1 expressed in hek293 cells binds mch with sub-nanomolar affinity, and is stimulated by mch to mobilize intracellular ca2+ and reduce forskolin-elevated cyclic amp levels. 0.712 SIGNOR-69517 mTORC1 complex SIGNOR-C3 SIGNOR SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 18570873 YES lperfetto Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation 0.603 SIGNOR-217078 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Thr8 MSSILPFtPPVVKRL 9606 12193595 YES lperfetto We show that phosphorylation of Smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (ERK1) increases the amount of Smad2 protein and leads to enhanced transcriptional activity.[] A site of ERK-dependent phosphorylation on Smad2 was located to Thr8 0.747 SIGNOR-227514 NCOR2 protein Q9Y618 UNIPROT PGR protein P06401 UNIPROT down-regulates acetylation 9606 BTO:0000150;BTO:0001130 12771131 YES gcesareni In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases. 0.589 SIGNOR-101289 NADPH(4-) smallmolecule CHEBI:57783 ChEBI FASN protein P49327 UNIPROT up-regulates activity binding 9606 34765544 YES miannu We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. 0.8 SIGNOR-267371 MCHR1 protein Q99705 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-257034 TJP2 protein Q9UDY2 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 9606 21808241 YES milica In addition, yap and taz interact with another tight junction protein zo-2, which was reported to increase nuclear localization of yap and tight-junction localization of taz. 0.506 SIGNOR-175931 citrate(3-) smallmolecule CHEBI:16947 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity precursor of 9606 24068518 YES miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. 0.8 SIGNOR-266241 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 16949371 YES Here, we report that deficiency of Wip1 resulted in activation of the ataxia-telangiectasia mutated (ATM) kinase. In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage. Wip1 dephosphorylated ATM Ser1981, a site critical for ATM monomerization and activation 0.488 SIGNOR-248325 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Ser355 SALQGFNsPGMLSLG 9606 BTO:0000567 10849446 YES lperfetto We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. 0.71 SIGNOR-236587 QRICH1 protein Q2TAL8 UNIPROT VARS2 protein Q5ST30 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269409 ATP2B2 protein Q01814 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30535804 YES lperfetto ATP2B2 encodes the PMCA2 Ca(2+) pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca(2+) from the stereocilia to the endolymph. 0.8 SIGNOR-262585 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1715686 YES gcesareni Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta. 0.305 SIGNOR-21299 FGF14 protein Q92915 UNIPROT SCN1A protein P35498 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.361 SIGNOR-253421 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194337 CYSLTR1 protein Q9Y271 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257019 PAK proteinfamily SIGNOR-PF13 SIGNOR VIM protein P08670 UNIPROT down-regulates activity phosphorylation -1 11895474 YES inferred from 70% family members miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.¬† 0.2 SIGNOR-269975 ACHE protein P22303 UNIPROT acetylcholine smallmolecule CHEBI:15355 ChEBI down-regulates quantity chemical modification 15841900 YES Acetylcholinesterase (AChE) is one of the most crucial enzymes for nerve response and function. AChE catalyzes the hydrolysis of acylcholine esters with a relative specificity for acetylcholine.|The intracellular effects of acetylcholine are mediated by the activation of nicotinic and muscarinic acetylcholine receptors (AChRs). AChE terminates transmission of neuronal impulses by rapid hydrolysis of acetylcholine. 0.8 SIGNOR-253983 DLK2 protein Q6UY11 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 21419176 YES gcesareni In this work, we demonstrate, for the first time, that dlk2 interacts with itself, with dlk1, and with the same notch1 receptor region as dlk1 does. We demonstrate also that the interaction of dlk2 with notch1 similarly results in an notch signaling in preadipocytes and mouse embryo fibloblasts. 0.291 SIGNOR-172864 NFIB protein O00712 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268903 CTNNB1 protein P35222 UNIPROT CLDN2 protein P57739 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0003569 14751232 NO lperfetto Furthermore, claudin-2 promoter activity was found to be enhanced by the TCF-4/beta-catenin transcription complex. 0.306 SIGNOR-254114 A6/b1 integrin complex SIGNOR-C164 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.575 SIGNOR-257706 ZNF365 protein Q70YC5 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity binding 9606 23966166 YES We identified ZNF365 as a necessary component of the HR repair pathway. ZNF365 interacts with PARP1 and tethers MRE11 to the nucleolytic resection sites for replication fork recovery 0.2 SIGNOR-272477 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 21454698 YES gcesareni The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation. 0.638 SIGNOR-173017 MEF2D protein Q14814 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 17111365 NO Regulation miannu Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. 0.336 SIGNOR-251957 ABL1 protein P00519 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity phosphorylation Tyr486 YPAEDSTyDEYENDL 9606 20861316 YES miannu Because phosphorylation by c-Abl augments nmMLCK-cortactin interaction to a greater degree than does pp60src phosphorylation, it is likely that phosphorylation sites on nmMLCK unique to c-Abl (i.e., other than Y464 and Y846) are responsible for this enhanced protein-protein interaction.|Moreover, our data indicate that cortactin is itself rapidly phosphorylated on Y486 by c-Abl in EC after S1P (Figure 9). 0.424 SIGNOR-278504 Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT ACE2 protein Q9BYF1 UNIPROT up-regulates activity binding 9606 32201502 YES miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. 0.2 SIGNOR-260226 PRKACA protein P17612 UNIPROT HNRNPD protein Q14103 UNIPROT up-regulates phosphorylation Ser87 SNSSPRHsEAATAQR 9606 11903055 YES gcesareni Protein kinase a enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein d in a hierarchical fashion. 0.349 SIGNOR-116144 POLR2C protein P19387 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.876 SIGNOR-266163 CAMK2B protein Q13554 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000938 20841359 YES gcesareni Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival. 0.291 SIGNOR-167962 PARP1 protein P09874 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates activity relocalization 9606 33859667 YES SaraGualdi The mechanism of KDM5B recruitment is quite specific and requires the presence of nucleosomes containing histone variant MacroH2A1.1 and PARylation by PARP1. 0.354 SIGNOR-271574 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser422 IACDEEFsDSEDEGE 9606 BTO:0000567 12082111 YES llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. 0.619 SIGNOR-250887 HTR6 protein P50406 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257443 MAPKAPK2 protein P49137 UNIPROT KRT20 protein P35900 UNIPROT up-regulates activity phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 YES miannu P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13. 0.2 SIGNOR-263072 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 YES Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. 0.266 SIGNOR-248579 AURKA protein O14965 UNIPROT GMNN protein O75496 UNIPROT up-regulates activity phosphorylation Thr25 NSSVPRRtLKMIQPS 9606 23695679 YES miannu Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis.|Thr25 of geminin is phosphorylated by Aurora-A. 0.511 SIGNOR-278509 GSK3B protein P49841 UNIPROT CTPS1 protein P17812 UNIPROT down-regulates activity phosphorylation Ser574 YSDRSGSsSPDSEIT 9606 BTO:0000007 17681942 YES miannu We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity. 0.2 SIGNOR-276068 SYVN1 protein Q86TM6 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29083378 YES miannu Thus, HRD1 ubiquitinates and degrades denaturated APP as well as unfolded proteins, suggesting that HRD1 affects APP-A\u03b2 dynamics in the brains of AD patients. 0.339 SIGNOR-278616 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1647 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248770 PINK1 protein Q9BXM7 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation 9606 22643835 YES miannu PINK1 also enhances the association between TRAF6 and TAK1, phosphorylates TAK1, and stimulates polyubiquitination of TAK1. 0.33 SIGNOR-279644 IL6ST protein P40189 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 9126968 YES milica Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. 0.346 SIGNOR-250574 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.41 SIGNOR-238813 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 SIGNOR-C15 21205641 YES gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.503 SIGNOR-170863 FUBP1 protein Q96AE4 UNIPROT CDKN2B protein P42772 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 NO irozzo The cell cycle inhibitor p15 was also up-regulated upon FBP1 knockdown. Our analysis of HCC cells after FBP1 knockdown suggests that p15 mRNA levels may also (directly or indirectly) depend on FBP1 activity. 0.257 SIGNOR-259126 CHEK1 protein O14757 UNIPROT E2F8 protein A0AVK6 UNIPROT down-regulates activity phosphorylation 9606 29363506 YES miannu Chk1 inhibits the transcriptional repressor function of E2F7 and E2F8 to promote cell cycle progression and prevent apoptosis.|Here, we demonstrate that Chk1 phosphorylates both E2F7 and E2F8 in response to DNA damage. 0.315 SIGNOR-279693 DLG4 protein P78352 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity relocalization 9606 9278515 YES brain lperfetto The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses. 0.823 SIGNOR-264195 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 9335504 YES llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 0.607 SIGNOR-52691 BTRC protein Q9Y297 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 16611981 YES The interaction between BTRC and Gli2 occur whne Gli2 is phosphorilated. lperfetto The phosphorylated gli2 protein interacts with beta-trcp, and is ubiquitinated and degraded by the proteasome 0.65 SIGNOR-146109 ALYREF protein Q86V81 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 YES miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. 0.887 SIGNOR-268511 CYP11B1 protein P15538 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 9814482 YES lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. 0.8 SIGNOR-268678 Orexin A smallmolecule CHEBI:80319 ChEBI HCRTR1 protein O43613 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257510 EIF2AK2 protein P19525 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates activity phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 32801355 YES miannu This suggests that PKR is critical in the phosphorylation of SPHK1 at Ser225.|We confirmed that phosphorylated PKR activates SPHK1 kinase activity, but it remained necessary to determine whether there has mutual correlation or any reciprocal effect between these two kinases in stressed cells. 0.2 SIGNOR-278514 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT unknown phosphorylation Ser70 EAMNYEGsPIKVTLA 9606 BTO:0001271 19933706 YES gcesareni Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c. 0.562 SIGNOR-161805 CDK14 protein O94921 UNIPROT TAGLN2 protein P37802 UNIPROT down-regulates activity phosphorylation Ser83 PVKKIQAsTMAFKQM 21577206 YES lperfetto This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity. 0.315 SIGNOR-265103 PKA proteinfamily SIGNOR-PF17 SIGNOR DIAPH1 protein O60610 UNIPROT up-regulates quantity by stabilization phosphorylation Thr768 PVLPFGLtPKKLYKP 9606 BTO:0002588 23325789 YES miannu  DIAPH1 is phosphorylated in response to dibutyryl cAMP (Bt2cAMP) at Thr-759 via a pathway that requires extracellular signal-related kinase (ERK).We also show that Bt2cAMP promotes the PKA- and ERK-dependent phosphorylation of DIAPH1 at T759 and that mutation of this site alters the stability of the protein and the rate of cAMP-stimulated mitochondrial movement. 0.2 SIGNOR-276484 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 16151013 YES Cytosolic p53 amattioni P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization. 0.752 SIGNOR-140242 RARG protein P13631 UNIPROT RXRB protein P28702 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. 0.714 SIGNOR-16662 MMP2 protein P08253 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272364 TFEB protein P19484 UNIPROT CYP17A1 protein P05093 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) 0.2 SIGNOR-276786 UBQLN2 protein Q9UHD9 UNIPROT HNRNPA3 protein P51991 UNIPROT up-regulates quantity by stabilization binding 25616961 YES lperfetto We screened a yeast two-hybrid library using the central domain of ubiquilin-2 hoping to identify proteins whose binding is affected by the UBQLN2 mutations.||Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein 0.448 SIGNOR-262272 YWHAE protein P62258 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 YES miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. 0.277 SIGNOR-252398 MECP2 protein P51608 UNIPROT YBX1 protein P67809 UNIPROT up-regulates activity binding 16251272 YES lperfetto In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor. 0.507 SIGNOR-277700 AKT3 protein Q9Y243 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 YES gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. 0.271 SIGNOR-164306 PARP1 protein P09874 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity relocalization 9606 17891139 YES miannu We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus. 0.56 SIGNOR-261321 4-methylumbelliferone chemical CHEBI:17224 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258057 panobinostat chemical CHEBI:85990 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257753 CASP3 protein P42574 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity cleavage 9606 BTO:0000938 15231831 YES lperfetto Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant. 0.534 SIGNOR-126727 SRPK2 protein P78362 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19592491 NO lperfetto Compared with control, srpk2 wild type evidently elevated cyclin d1 transcription, and the catalytic activity was lost in srpk2 kd, suggesting that kinase activity of srpk2 is required for this effect. 0.2 SIGNOR-186763 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser334 PLGDDEAsATVSKTE -1 9099669 YES lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. 0.44 SIGNOR-248966 RPLP2 protein P05387 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.818 SIGNOR-262449 MACROD2 protein A1Z1Q3 UNIPROT 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 ChEBI down-regulates quantity chemical modification 9606 32257385 YES miannu MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins 0.8 SIGNOR-269839 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT down-regulates quantity by destabilization phosphorylation Ser144 DSPALEVsDSESDEA 9606 BTO:0000567 10618498 YES llicata Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo 0.307 SIGNOR-251040 BMS-554417 chemical CID:54754526 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190455 PDCD1 protein Q15116 UNIPROT DNM1L protein O00429 UNIPROT down-regulates activity 9606 BTO:0000782 34535949 NO Barakat Mechanistically, we provided evidence that PD1 signaling downregulates Drp1 activating phosphorylation on Ser616 (and consequently mitochondrial fragmentation) via the inhibition of ERK1/2 and mTOR kinases. 0.2 SIGNOR-275406 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates 9606 10795740 YES We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation 0.895 SIGNOR-256252 Fanconi anemia core complex complex SIGNOR-C300 SIGNOR FANCI protein Q9NVI1 UNIPROT up-regulates activity ubiquitination 18985065 YES lperfetto Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding 0.699 SIGNOR-263267 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 YES gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. 0.384 SIGNOR-158604 Ub:E2 complex SIGNOR-C497 SIGNOR ZNRF2 protein Q8NHG8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270975 CARM1 protein Q86X55 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates activity methylation Arg1064 PGNILGPrVPLTAPN 9606 BTO:0000007;BTO:0000356 24434208 YES CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation. 0.538 SIGNOR-251708 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNA1 protein Q09470 UNIPROT down-regulates quantity phosphorylation Ser446 SDLSRRSsSTMSKSE 9606 BTO:0002178 23774215 YES done miannu Phosphorylation of KCNA1 at Ser446 by PKA is involved on its cytoplasmic retention 0.2 SIGNOR-273777 asparagine smallmolecule CHEBI:22653 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264753 HJURP protein Q8NCD3 UNIPROT CENPA protein P49450 UNIPROT up-regulates activity binding 9606 BTO:0000567 19410544 YES miannu Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURP. Recruitment of new CENP-A into nucleosomes at replicated centromeres is dependent on HJURP. Recognition by HJURP is mediated through the centromere targeting domain (CATD) of CENP-A, a region that we demonstrated previously to induce a unique conformational rigidity to both the subnucleosomal CENP-A heterotetramer and the corresponding assembled nucleosome. We propose HJURP to be a cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly. 0.959 SIGNOR-263707 AKT proteinfamily SIGNOR-PF24 SIGNOR KLHL3 protein Q9UH77 UNIPROT up-regulates activity phosphorylation Ser433 PMNTRRSsVGVGVVE -1 26435498 YES done miannu Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC.  0.2 SIGNOR-273825 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269333 STAT3 protein P40763 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression 9606 BTO:0001103 21408055 NO andrea cerquone perpetuini Additionally, cMyc, a STAT3 downstream gene, was significantly up-regulated in SCs at T24 versus PRE [...]An increase in the number of cMyc+ SCs indicated that human SCs were induced to proliferate under the control of STAT3 signaling. 0.752 SIGNOR-255413 POLR3F protein Q9H1D9 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.885 SIGNOR-266128 RACK1 protein P63244 UNIPROT CLEC1B protein Q9P126 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 19785988 YES miannu In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex 0.2 SIGNOR-272781 PRKCZ protein Q05513 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 BTO:0000938 BTO:0000671 9679146 YES gcesareni These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc. 0.2 SIGNOR-59303 LPAR2 protein Q9HBW0 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.596 SIGNOR-257382 NEDD4L protein Q96PU5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization ubiquitination Lys933 LCLSSTVkQVVRRLN 9606 27932573 YES miannu NEDD4L ubiquitylates ULK1 at lysine 925 and lysine 933.|Next, we found that down-regulation of the ULK1 protein by NEDD4L is blocked by proteasome inhibitors (MG132 and lactacystin), but not by lysosomal inhibitors (leupeptin and Clq; XREF_FIG and S2 C), indicating that NEDD4L triggers ULK1 degradation exclusively through the proteasome pathway. 0.362 SIGNOR-278523 ATP5MC1 protein P05496 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261409 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG -1 11955436 YES β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC) 0.86 SIGNOR-260016 KLHL9 protein Q9P2J3 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000527 25303533 YES miannu KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ. 0.599 SIGNOR-272455 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 YES p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors. gcesareni One way this occurs is via the interaction of JLP with the Cdo cytoplasmic tail. JLP is, in turn, bound to p38α/β. This interaction facilitates p38 activation during differentiation and is important for Cdo's effects in myogenesis. 0.512 SIGNOR-272542 Diisodecyl phthalate chemical CHEBI:34709 ChEBI SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression 10116 16257484 NO miannu DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged. 0.8 SIGNOR-268742 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 YES gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. 0.305 SIGNOR-76088 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 10551811 YES gcesareni The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. 0.359 SIGNOR-72104 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 8754811 NO ggiuliani Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells. 0.393 SIGNOR-255963 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Ser405 EVSRIPAsQTSVPFD 9606 BTO:0000007 10542239 YES llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T 0.2 SIGNOR-250809 TCL1A protein P56279 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES lperfetto Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.825 SIGNOR-244449 SRC protein P12931 UNIPROT CORO7 protein P57737 UNIPROT up-regulates activity phosphorylation Tyr758 GDTRVFLyELLPESP -1 18581049 YES done miannu We establish that Src activity is indispensable for the interaction of Crn7 with Golgi membranes. Crn7 binds Src in vivo and can be phosphorylated by recombinant Src in vitro. We demonstrate that tyrosine-758 is the major Src phosphorylation site.  0.339 SIGNOR-274005 FOXO proteinfamily SIGNOR-PF27 SIGNOR NOTCH3 protein Q9UM47 UNIPROT down-regulates quantity transcriptional regulation 10090 24749067 NO gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. 0.2 SIGNOR-252941 UCK2 protein Q9BZX2 UNIPROT cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity chemical modification 11306702 YES lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 0.8 SIGNOR-275861 TRIM26 protein Q12899 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization ubiquitination Lys70 AYVPGRDkPDLPTWK 9606 25763818 YES miannu To investigate whether TRIM26 promotes IRF3 ubiquitination through K70 and K87, IRF3 mutant K70/87A was transfected into HEK293 cells together with Flag-TRIM26.|All together, these data indicated that active IRF3 was ubiquitinated and degraded by TRIM26 in nucleus. 0.671 SIGNOR-278534 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr826 LPTPTKMtPRSRILV 9606 SIGNOR-C18 9139732 YES miannu We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. 0.929 SIGNOR-47899 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser637 VDLSKVTsKCGSLGN -1 9199504 YES miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. 0.524 SIGNOR-250085 UFD1 protein Q92890 UNIPROT AMFR protein Q9UKV5 UNIPROT up-regulates activity binding 17681147 YES miannu Here we show that Ufd1 directly interacts with gp78 and functions as a cofactor. Ufd1 enhances the E3 activity of gp78, accelerates the ubiquitination and degradation of reductase, and eventually promotes receptor-mediated uptake of low-density lipoprotein. 0.2 SIGNOR-252425 FOXN3 protein O00409 UNIPROT PIM2 protein Q9P1W9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002552 24403608 YES Luana CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis. 0.297 SIGNOR-261607 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser20 PLSQETFsDLWKLLP 9606 20562916 YES Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis 0.367 SIGNOR-248765 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB5 protein Q9Y5G0 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265692 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 8384556 YES gcesareni The nerve growth factor (ngf) receptor/trk associated with and phosphorylated phospholipase c gamma (plc gamma) 0.651 SIGNOR-38538 BTK protein Q06187 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ -1 11413148 YES llicata Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity. 0.468 SIGNOR-250603 GRIA3 protein P42263 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264949 CDK9 protein P50750 UNIPROT MYC protein P01106 UNIPROT down-regulates activity phosphorylation Ser62 S-->E 9606 31311847 YES miannu CDK9 promotes phosphorylation of MYC on Ser 62 . 0.541 SIGNOR-279024 SNAI1 protein O95863 UNIPROT PXDN protein Q92626 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 29305973 YES miannu TGF-β1 induced Snai1 binding to the PXDN promoter (as assessed by chromatin immunoprecipitation-PCR) and significantly repressed luciferase reporter gene expression, as did Snai1 overexpression. 0.2 SIGNOR-265249 ATM protein Q13315 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 22735644 YES lperfetto  Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.  0.585 SIGNOR-267661 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 YES lperfetto We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function. 0.296 SIGNOR-249028 PRKACA protein P17612 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser97 AAEERRKsQEAQVLK 9534 BTO:0000298 9525956 YES miannu Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation 0.31 SIGNOR-250057 L-dopa smallmolecule CHEBI:15765 ChEBI dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal 0.8 SIGNOR-264174 2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide chemical CID:121427831 PUBCHEM BRD2 protein P25440 UNIPROT down-regulates quantity chemical inhibition 9606 29764999 YES Monia DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells 0.8 SIGNOR-261095 FZR1 protein Q9UM11 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 12234927 YES miannu We found that Cdc25 A degradation during mitotic exit and in early G(1) is mediated by the anaphase-promoting complex or cyclosome (APC/C)(Cdh1) ligase, and that a KEN-box motif in the N-terminus of the protein is required for its targeted degradation. 0.465 SIGNOR-271388 FOXO6 protein A8MYZ6 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 YES miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. 0.2 SIGNOR-260103 ACD protein Q96AP0 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 17237768 YES miannu We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme. 0.557 SIGNOR-152321 PCSK5 protein Q92824 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 YES miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. 0.2 SIGNOR-270334 SMO protein Q99835 UNIPROT SUFU protein Q9UMX1 UNIPROT down-regulates activity binding 9606 BTO:0000452 22114142 YES lperfetto In addition to activating g(i), smo signals through its c-terminal tail to inhibit suppressor of fused, resulting in stabilization and activation of the gli family of transcription factors, which execute a transcriptional response to so-called canonical hh signaling. 0.639 SIGNOR-177656 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 YES The effect has been demonstrated using Q01196-8 gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.2 SIGNOR-138940 F2RL1 protein P55085 UNIPROT TSPAN15 protein O95858 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254862 AKT2 protein P31751 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C7 17964260 YES gcesareni Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. 0.327 SIGNOR-158627 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser366 GSYAKLPsPEPSMSP -1 12361598 YES miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) 0.516 SIGNOR-265960 PRKACA protein P17612 UNIPROT PPP2R5D protein Q14738 UNIPROT up-regulates phosphorylation Ser573 KVLLRRKsELPQDVY 9606 17301223 YES gcesareni Protein kinase a activates protein phosphatase 2a by phosphorylation of the b56delta subunit. 0.2 SIGNOR-153218 PB28 dihydrochloride chemical CID:46861545 PUBCHEM TMEM97 protein Q5BJF2 UNIPROT up-regulates activity chemical activation 9606 BTO:0000093 16891467 YES Federica Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer 0.8 SIGNOR-261110 CBL protein P22681 UNIPROT SRC protein P12931 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 12907674 YES miannu Cbl-b also targets active Src for degradation in cells, and Nedd4 similarly reverses Cbl mediated Src degradation.|Cbl-b also targets active Src for degradation in cells, and Nedd4 similarly reverses Cbl-mediated Src degradation 0.737 SIGNOR-278539 CREBBP protein Q92793 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 SIGNOR-C6 11062529 YES gcesareni The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis. 0.689 SIGNOR-83843 PRKCD protein Q05655 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Ser318 GDKILQVsFKTNKSH 9606 20086103 YES lperfetto Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur. 0.636 SIGNOR-163528 ERCC4 protein Q92889 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR form complex binding 9606 16338413 YES miannu Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. 0.953 SIGNOR-142992 PP1 proteinfamily SIGNOR-PF54 SIGNOR CASP2 protein P42575 UNIPROT up-regulates activity dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 YES lperfetto Nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. 0.2 SIGNOR-264661 MAML1 protein Q92585 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000887 17875709 YES gcesareni Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin). 0.276 SIGNOR-157843 DOK7 protein Q18PE1 UNIPROT CRKL protein P46109 UNIPROT up-regulates activity binding 10090 BTO:0000165 20603078 YES miannu Here, we identify two tyrosine residues in Dok-7 that are phosphorylated by Agrin stimulation, and show that two proteins, Crk and Crk-L, are recruited to these phosphorylation sites in Dok-7. 0.344 SIGNOR-273848 HSPA8 protein P11142 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR down-regulates quantity by destabilization binding 24789820 YES lperfetto Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane. 0.543 SIGNOR-260718 propionic acid chemical CHEBI:30768 ChEBI FFAR2 protein O15552 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257489 IL1B protein P01584 UNIPROT CTSK protein P43235 UNIPROT up-regulates quantity by expression transcriptional regulation 11920402 NO lperfetto This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme. 0.333 SIGNOR-253316 FGF4 protein P08620 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 YES gcesareni The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors. 0.757 SIGNOR-42377 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Thr2647 QQHDFTLtQTADGRS 9606 BTO:0000773 12186630 YES lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. 0.2 SIGNOR-249160 IFNAR complex SIGNOR-C243 SIGNOR TYK2 protein P29597 UNIPROT up-regulates activity binding 9606 15120645 YES miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). 0.807 SIGNOR-260146 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr762 SDIQRSLyDRPASYK 9823 9546424 YES miannu Tyr-762 is an autophosphorylation site in the human platelet-derived growth factor (PDGF) alpha-receptor. Crk proteins associate with phosphorylated Tyr-762 in the PDGF a-receptor in vivo 0.2 SIGNOR-249716 PRKD1 protein Q15139 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser356 YALVKAKsVDEIAKI 10029 32570757 YES lperfetto Taken together, these data demonstrate that FAM83G S356 phosphorylation modulates HSP27 phosphorylation and apoptosis regulation and that HSP27 is a counterpart of FAM83G.|an active form of PKD1/PKCm could phosphorylate the FAM83G peptide, including the S356 portion.|We also demonstrated that the phosphorylation of the FAM83G S356 residue was required for the reduction of the live cell number, as the CHO cells were unaffected upon the overexpression of a FAM83G S356A mutant resistant to S356 phosphorylation. 0.2 SIGNOR-264764 SARS1 protein P49591 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates quantity chemical modification 9606 24095058 YES miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis 0.8 SIGNOR-270498 ITGB1BP1 protein O14713 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.349 SIGNOR-257658 UBE2E1 protein P51965 UNIPROT RNF167 protein Q9H6Y7 UNIPROT up-regulates activity binding 9606 BTO:0000007 16314844 YES miannu  Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop. 0.538 SIGNOR-271552 PAK1 protein Q13153 UNIPROT PGM1 protein P36871 UNIPROT up-regulates phosphorylation Thr467 SANDKVYtVEKADNF 9606 BTO:0001271 15378030 YES gcesareni The signaling kinase p21-activated kinase 1 (pak1) binds to, phosphorylates and enhances the enzymatic activity of phosphoglucomutase 1 (pgm), 0.344 SIGNOR-127135 DYRK1A protein Q13627 UNIPROT PLK2 protein Q9NYY3 UNIPROT up-regulates quantity by stabilization phosphorylation Ser358 VPDFHLSsPAKNFFK 9606 BTO:0000007 37387444 YES miannu  In the present study, it was demonstrated that dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) interacts with and phosphorylates PLK2 at Ser358. DYRK1A-mediated phosphorylation of PLK2 increases its protein stability.  0.313 SIGNOR-277805 DNMT3A protein Q9Y6K1 UNIPROT MEIS1 protein O00470 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 28288143 NO miannu Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia. 0.328 SIGNOR-256125 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269382 E2F1 protein Q01094 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR form complex binding 9606 23213415 YES gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes 0.45 SIGNOR-199955 TGFBR1 protein P36897 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates phosphorylation Ser300 EMHHEALsEALPGDN 9606 20832312 YES llicata Phosphorylation of eEF1A1 at Ser300 by T_R-I results in inhibition of mRNA translation 0.343 SIGNOR-167943 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.839 SIGNOR-269253 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 15767683 YES miannu The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. 0.901 SIGNOR-267995 RAI1 protein Q7Z5J4 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000614 22578325 NO miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 0.342 SIGNOR-266842 AURKA protein O14965 UNIPROT LDHB protein P07195 UNIPROT up-regulates activity phosphorylation Ser162 PKHRVIGsGCNLDSA 9606 BTO:0000567 31804482 YES miannu Aurora-A-mediated phosphorylation of LDHB serine 162 significantly increases its activity in reducing pyruvate to lactate, which efficiently promotes NAD+ regeneration, glycolytic flux, lactate production and bio-synthesis with glycolytic intermediates.  0.2 SIGNOR-277493 HERC3 protein Q15034 UNIPROT RELA protein Q04206 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26476452 YES miannu Our data so far suggest that HERC3 reduces NF-kappaB transcriptional activity by binding to the proteasome and delivering RelA for degradation.|We show that HERC3 mediates ubiquitination of RelA on two distinct lysine residues, K195 and K315. 0.326 SIGNOR-278546 IGF1R protein P08069 UNIPROT SIRPA protein P78324 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001260 11779860 NO gcesareni These studies indicate that igf-ir stimulates phosphorylation of shps-1 which is critical for shp-2 recruitment to the plasma membrane and for its recruitment to the igf-ir 0.364 SIGNOR-113640 NFIX protein Q14938 UNIPROT WNT5A protein P41221 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268889 SL-327 chemical CHEBI:92211 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 YES gcesareni Pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity (impey et al., 1999) and neuronal survival (villalba and journot, 1997;meyerfranke et al., 1998;skaper et al., 1998;anderson and tolkovsky, 1999;singer et al., 1999;bi et al., 2000). Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors, (kamakura et al., 1999), suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2. 0.8 SIGNOR-104936 FARSB protein Q9NSD9 UNIPROT Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR form complex binding 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.994 SIGNOR-270435 KDM5C protein P41229 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264306 KAT2B protein Q92831 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269616 NLK protein Q9UBE8 UNIPROT TCF4 protein P15884 UNIPROT down-regulates phosphorylation 9606 2861485 YES gcesareni Whereas lef-1 and tcf-4 phosphorylation by nlk (nemo-like kinase) leads to less lef/tcf/beta-catenin complex binding to dna and to lef-1/tcf-4 degradation 0.2 SIGNOR-24147 MARCHF5 protein Q9NX47 UNIPROT PRKN protein O60260 UNIPROT down-regulates quantity by destabilization ubiquitination Lys220 GAHPTSDkETSVALH 9606 33565245 YES miannu MITOL promotes cell survival by degrading Parkin during mitophagy.|Mechanistically, MITOL mediates ubiquitination of Parkin at lysine 220 residue, which promotes its proteasomal degradation, and thereby fine-tunes mitophagy by controlling the quantity of Parkin. 0.2 SIGNOR-278554 SRC protein P12931 UNIPROT PTTG1IP protein P53801 UNIPROT up-regulates activity phosphorylation Tyr174 LFKEENPyARFENN 9534 BTO:0000298 23678037 YES done miannu Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in PM retention and a markedly reduced ability to bind NIS.  0.2 SIGNOR-273810 PSMA7 protein O14818 UNIPROT XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization binding -1 19941857 YES 1 miannu We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination. 0.317 SIGNOR-239042 RNF168 protein Q8IYW5 UNIPROT H2AX protein P16104 UNIPROT unknown ubiquitination Lys14 TGGKARAkAKSRSSR 9606 22980979 YES lperfetto We find that K63 ubiquitin chains are conjugated to RNF168-dependent H2A/H2AX monoubiquitination at K13-15 and not on K118-119. 0.2 SIGNOR-262063 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 YES lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.725 SIGNOR-120647 FOXO1 protein Q12778 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 NO lperfetto FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. 0.545 SIGNOR-218013 HCK protein P08631 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr394 LNTIGLIyEKISLPK 9606 BTO:0002181 28618271 YES miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  0.2 SIGNOR-276727 FZD9 protein O00144 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0003006 15705594 NO Transfected Wnt-7a and Fzd-9 inhibit proliferation of NSCLC cells. 0.7 SIGNOR-278115 RAB6B protein Q9NRW1 UNIPROT VPS13B protein Q7Z7G8 UNIPROT down-regulates activity binding 9606 BTO:0000007 25492866 YES miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues 0.2 SIGNOR-269205 AURKA protein O14965 UNIPROT FANCA protein O15360 UNIPROT up-regulates activity phosphorylation Ser165 HSMFSRLsFCQELWK 9606 BTO:0002181 27398318 YES miannu E detected interactions between Aurora A kinase and FANCA protein, one of the components of the FA nuclear core complex. These results suggest that S165 phosphorylation by Aurora A kinase is required for proper activation of the FA/BRCA pathway in response to DNA damage. 0.468 SIGNOR-277263 TRIM13 protein O60858 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 30224829 YES miannu These results suggest that Trim13 activity mediates Nur77 ubiquitination, leading to its degradation. 0.2 SIGNOR-278564 TRIM25 protein Q14258 UNIPROT ZC3HAV1 protein Q7Z2W4 UNIPROT up-regulates activity ubiquitination 9606 28060952 YES miannu Our data demonstrates that TRIM25 triggers ubiquitination of ZAP and enhances its antiviral activity through inhibition of viral translation, highlighting the importance of cofactors in the mechanisms of broadly antiviral proteins. 0.399 SIGNOR-278565 RXRB protein P28702 UNIPROT NRIP1 protein P48552 UNIPROT up-regulates binding 9606 12403842 YES gcesareni Receptor interacting protein 140 (rip140) is a coregulator for a large number of transcription factors. Rip140 interacts with retinoic acid receptor (rar) and retinoid x receptor (rxr) with or without ligands 0.602 SIGNOR-95160 JUN protein P05412 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 12553907 NO In contrast, c-Jun is required for the survival of liver tumor cells. Reduced tumor formation strictly correlated with high apoptotic indices in c-Jun-deficient tumors, suggesting that increased apoptosis in c-Jun-deficient liver tumors is the primary cause for impaired tumorigenesis. 0.7 SIGNOR-256560 sildenafil chemical CHEBI:9139 ChEBI PDE5A protein O76074 UNIPROT down-regulates activity chemical inhibition -1 10385692 YES Luana Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. 0.8 SIGNOR-258343 SRC protein P12931 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates activity phosphorylation Tyr597 NTEQRNVyKDYRQLE 9534 BTO:0004055 12011079 YES lperfetto Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. Electron microscopic analyses reveal that tyrosine-phosphorylated dynamin I spontaneously self-assembles into large stacks of rings. Tyrosine 597 was identified as being phosphorylated both in vitro and in cultured cells following epidermal growth factor receptor stimulation. 0.636 SIGNOR-247129 PITX1 protein P78337 UNIPROT POU1F1 protein P28069 UNIPROT up-regulates activity binding -1 8755540 YES miannu A novel OTX-related homeodomain transcription factor has been identified on the basis of its ability to interact with the transactivation domain of the pituitary-specific POU domain protein, Pit-1. P-OTX is able to independently activate and to synergize with Pit-1 on pituitary-specific target gene promoters. 0.471 SIGNOR-219740 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates phosphorylation Tyr500 TSLGSQSyEDMRGIL 9606 10933394 YES llicata Experiments with purified proteins demonstrated that cd19-y513 was lyn's initial phosphorylation and binding site. This led to processive phosphorylation of cd19-y482, which recruited a second lyn molecule, allowing for transphosphorylation and amplification of lyn activation. 0.772 SIGNOR-80290 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr681 QRHKRTHtGEKKFAC 9606 BTO:0000887;BTO:0001260 18258854 YES llicata Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter. 0.485 SIGNOR-160774 SFRP1 protein Q8N474 UNIPROT WNT4 protein P56705 UNIPROT down-regulates binding 9606 BTO:0000671 11287180 YES gcesareni Sfrp-1 binds wnt-4 with considerable avidity and inhibits the dna-binding activity of tcf, an effector of wnt signaling, 0.72 SIGNOR-106556 TRIM65 protein Q6PJ69 UNIPROT NLRP3 protein Q96P20 UNIPROT down-regulates activity ubiquitination 9606 34512673 YES miannu These results suggest that TRIM65 could inhibit the activation of the NLRP3 inflammasome in response to multiple agonists.|Thus, TRIM65 deficiency impairs NLRP3 ubiquitination and enhances NLRP3 inflammasome activation, but has no effects on AIM2 or IPAF inflammasome activation. 0.2 SIGNOR-278566 NEDD4 protein P46934 UNIPROT GRIA1 protein P42261 UNIPROT down-regulates quantity ubiquitination 9606 21148011 YES miannu Finally, we show that ubiquitination of GluA1 by Nedd4-1 becomes more prevalent as neurons mature.|The ability of Nedd4-1 to reduce surface GluA1 levels required its ligase activity, since co-expression of a catalytically-inactive version of Nedd4-1 (Nedd4-1 CS) did not decrease surface GluA1 levels . 0.42 SIGNOR-278572 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser283 NLQMLPEsEDEESYD 9606 BTO:0000782 8622692 YES llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. 0.58 SIGNOR-40502 pemetrexed chemical CHEBI:63616 ChEBI GART protein P22102 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205883 MTHFD1 protein P11586 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity chemical modification -1 18767138 YES lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate 0.8 SIGNOR-268249 LCK protein P06239 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 BTO:0000150;BTO:0000567 9500442 YES gcesareni On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation. 0.383 SIGNOR-55853 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CCND3 protein P30281 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000018 22024926 YES miannu Here, we show that a relatively new E3 ligase component belonging to the SCF (Skip-Cullin1-F-box protein) E3 ligase family, SCF (FBXL2) , impairs cell proliferation by mediating cyclin D3 polyubiquitination and degradation.  0.433 SIGNOR-271888 NDUFS3 protein O75489 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. 0.869 SIGNOR-262177 SLBP protein Q14493 UNIPROT H2AB1 protein P0C5Y9 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265411 PTPN2 protein P17706 UNIPROT WASL protein O00401 UNIPROT down-regulates dephosphorylation Tyr256 RETSKVIyDFIEKTG 9606 16293614 YES gcesareni Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42 0.29 SIGNOR-141652 SRC protein P12931 UNIPROT PBK protein Q96KB5 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr74 NPICNDHyRSVYQKR 9606 BTO:0000038 27016416 YES miannu Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon 0.396 SIGNOR-277218 PRKCB protein P05771 UNIPROT ILF3 protein Q12906 UNIPROT up-regulates activity phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 YES llicata Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our results support a model in which PMA stimulation activates PKCβI to phosphorylate NF90-Ser647, and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA. 0.2 SIGNOR-168173 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol chemical CHEBI:75722 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258149 F2RL1 protein P55085 UNIPROT WWOX protein Q9NZC7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254854 OSM protein P13725 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 YES gcesareni Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2. 0.751 SIGNOR-48114 GNRH1 protein P01148 UNIPROT EGR1 protein P18146 UNIPROT up-regulates activity binding 10090 19106114 YES miannu EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity. 0.442 SIGNOR-254918 RPS6KA5 protein O75582 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007 10978317 YES lperfetto Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases. 0.353 SIGNOR-249051 POU5F1 protein Q01860 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 19968627 NO miannu p21 protein levels were repressed by Oct-4 and were induced by the down-regulation of Oct-4 in ZHBTc4 ES cells. 0.402 SIGNOR-255043 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 YES miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. 0.322 SIGNOR-262866 ADP chemical CHEBI:16761 ChEBI P2RY1 protein P47900 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257557 CSNK2A1 protein P68400 UNIPROT CAV2 protein P51636 UNIPROT up-regulates activity phosphorylation Ser23 DDSYSHHsGLEYADP 9606 BTO:0001130 12743374 YES lperfetto We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae 0.321 SIGNOR-101106 FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.405 SIGNOR-235712 PRKCA protein P17252 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.265 SIGNOR-275441 SRC protein P12931 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates activity phosphorylation 9606 30889378 YES miannu SRC can directly phosphorylate and inhibit LATS 0.383 SIGNOR-259056 KIT protein P10721 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 22806893 YES irozzo SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation. 0.683 SIGNOR-256140 RAB1A protein P62820 UNIPROT USO1 protein O60763 UNIPROT up-regulates activity binding -1 10903204 YES Giulio Here, the tethering factor p115 was shown to be a Rab1 effector that binds directly to activated Rab1. 0.797 SIGNOR-261287 AR protein P10275 UNIPROT ARG2 protein P78540 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20711410 NO The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. 0.262 SIGNOR-253671 AURKA protein O14965 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Ser307 DRSPGAGsLGSPASQ -1 22214762 YES miannu Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology.  0.262 SIGNOR-276399 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:RBR_E3 complex SIGNOR-C520 SIGNOR form complex binding 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 0.2 SIGNOR-271381 FFAR4 protein Q5NUL3 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.25 SIGNOR-256773 PRKCZ protein Q05513 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization phosphorylation Ser249 ARTFSRMsLLHKHQE 9606 BTO:0001939 30804505 YES miannu APKC kinases phosphorylate S249 of SNAI1, which leads to protein degradation. 0.2 SIGNOR-277437 GRIK4 protein Q16099 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 YES lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine 0.8 SIGNOR-268275 RBPJ protein Q06330 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates binding 10090 17158101 YES gcesareni Notch induction of mkp-1 depends on an rbp-j-dependent mechanism. 0.249 SIGNOR-236851 M protein P0DTC5 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity binding 9606 BTO:0000007 33110251 YES miannu Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions. 0.1 SIGNOR-262515 9b protein P59636 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization 9606 25135833 NO miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. 0.2 SIGNOR-260241 TLN1 protein Q9Y490 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.585 SIGNOR-257634 CCP110 protein O43303 UNIPROT CALM2 protein P0DP24 UNIPROT up-regulates activity binding 9606 BTO:0000007 16760425 YES miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. 0.2 SIGNOR-266332 CDK1 protein P06493 UNIPROT KIF22 protein Q14807 UNIPROT up-regulates activity phosphorylation Thr463 QGAPLLStPKRERMV 9606 SIGNOR-C17 12727876 YES lperfetto Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes 0.344 SIGNOR-100964 Noncanonical PRC1 complex SIGNOR-C151 SIGNOR CDK1 protein P06493 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 NO miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. 0.543 SIGNOR-252249 HUWE1 protein Q7Z6Z7 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24472556 YES miannu Collectively, these data indicate that HUWE1 targets BRCA1, but not BARD1, for polyubiquitination and degradation.Because HUWE1 promotes BRCA1 ubiquitination and degradation, we wondered whether it might contribute to the reduced BRCA1 protein levels in sporadic breast cancer. 0.398 SIGNOR-278583 LATS2 protein Q9NRM7 UNIPROT PRPS1 protein P60891 UNIPROT down-regulates quantity by destabilization phosphorylation Ser285 EDKMKHCsKIQVIDI -1 34465890 YES miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. 0.2 SIGNOR-276504 CDK7 protein P50613 UNIPROT RARA protein P10276 UNIPROT up-regulates phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 BTO:0000567 9230306 YES llicata However, only the coexpression of cdk7 stimulated ser-77 phosphorylation in vivo and enhanced transactivation by rar alpha, but not by a s77a rar mutant. 0.545 SIGNOR-49693 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM67 protein Q6ZTA4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271177 KAT2B protein Q92831 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269625 DOK1 protein Q99704 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.335 SIGNOR-257688 FZR1 protein Q9UM11 UNIPROT REV1 protein Q9UBZ9 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23287467 YES miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. 0.241 SIGNOR-272893 sapitinib chemical CHEBI:132986 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates chemical inhibition 9606 BTO:0000551 20145185 YES AZD8931 has a unique pharmacologic profile providing equipotent EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. 0.8 SIGNOR-269874 2-Amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7-(naphthalen-1-YL)-5-oxo-4H-chromene-3-carbonitrile chemical CID:25223366 PUBCHEM SLC1A3 protein P43003 UNIPROT down-regulates activity chemical inhibition 9606 19161278 YES Federica The most potent analogue in the series, 1o, displayed high nanomolar inhibitory activity (IC50) 0.66μM) at EAAT1, with more than 400-foldselectivity compared to EAAT2 and EAAT3. 0.8 SIGNOR-261108 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2B protein P41595 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257522 RPS6KA1 protein Q15418 UNIPROT SENP2 protein Q9HC62 UNIPROT down-regulates activity phosphorylation Thr369 TDDLLELtEDMEKEI 9606 BTO:0001949 25689261 YES done miannu  Here, we determined that d-flow activated the serine/threonine kinase p90RSK, which subsequently phosphorylated threonine 368 (T368) of SENP2. T368 phosphorylation promoted nuclear export of SENP2, leading to downregulation of eNOS expression and upregulation of proinflammatory adhesion molecule expression and apoptosis.  0.2 SIGNOR-273839 AKT3 protein Q9Y243 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 YES gcesareni When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. 0.494 SIGNOR-62257 ARNTL protein O00327 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.747 SIGNOR-253629 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates 9606 22972936 YES milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. 0.598 SIGNOR-192042 RPL7A protein P62424 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.846 SIGNOR-262454 EGR2 protein P11161 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 BTO:0001412 1864967 NO irozzo Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes. 0.7 SIGNOR-256089 FYN protein P06241 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Tyr21 VSSDAEEyQPPIWKS 9606 17560670 YES llicata Ere we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity. 0.2 SIGNOR-155709 hsa-miR-141-5p mirna URS000055E199_9606 RNAcentral CXCL1 protein P09341 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000018 25349304 YES Parnian MiR141 regulated expression of CXCL1 in lung cancer cells, whereas the luciferase test confirmed that CXCL1 is a target of miR141.| hese results of tumor models above demonstrated that miR141 has a potency to inhibit tumor progression through restraining the recruitment of Tregs by inhibiting the production of CXCL1. 0.4 SIGNOR-278007 JAK2 protein O60674 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 4932 9575217 YES gcesareni Our mutational analysis suggests that the Stat5 SH2 domain is essential for the interaction with Jak2 and that the kinase domain of Jak2 is sufficient for Jak2-Stat5 interaction. Therefore, the Jak kinase domain may be all that is needed to cause Stat phosphorylation in situations where receptor docking is dispensable. [...] Most obviously, mutation of Tyr694 (Stat5a) or Tyr699 (Stat5b) to phenylalanine abolishes phosphorylation 0.866 SIGNOR-56827 PRKCA protein P17252 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 YES lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. 0.371 SIGNOR-248976 FN1 protein P02751 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.747 SIGNOR-253250 MDM2 protein Q00987 UNIPROT IRF1 protein P10914 UNIPROT down-regulates quantity ubiquitination 9606 27795392 YES miannu HIV-1 Tat Recruits HDM2 E3 Ligase To Target IRF-1 for Ubiquitination and Proteasomal Degradation.|IRF-1 ubiquitination by HDM2 is specifically increased during HIV-1 infection in the presence of increasing amounts of Tat and is mediated by the formation of a trimeric complex between Tat, IRF-1, and HDM2, as demonstrated by coimmunoprecipitation analysis (XREF_FIG). 0.388 SIGNOR-278590 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 NO Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits 0.608 SIGNOR-254963 IFNGR2 protein P38484 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR form complex binding 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. 0.741 SIGNOR-249486 RNF2 protein Q99496 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates quantity by destabilization ubiquitination Lys45 RWMKWEGkRVELPDS 9606 24980959 YES miannu RNF2 ubiquitinates AMBRA1 at lysine 45.|These data indicate that RNF2 directly accelerates the degradation of AMBRA1. 0.359 SIGNOR-278596 hsa-miR-520a-5p mirna URS0000534239_9606 RNAcentral LAMTOR5 protein O43504 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000093 21343296 YES Parnian These data suggest that miR-520b is able to regulate breast cancer cell migration by directly targeting HBXIP. 0.4 SIGNOR-278014 CSNK2A1 protein P68400 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser529 GLPNGLLsGDEDFSS 9606 10938077 YES gcesareni Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II.|Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential. 0.444 SIGNOR-149635 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM -1 17711846 YES done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). 0.41 SIGNOR-274097 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 YES gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. 0.341 SIGNOR-88748 ARID5B protein Q14865 UNIPROT MYB protein P10242 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 NO miannu We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). 0.2 SIGNOR-256160 KHDRBS1 protein Q07666 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates activity binding 9606 BTO:0000093 12496368 YES miannu These results suggest that Sam68 and CBP interact in vivo in a manner dependent on the FXE/DXXXL motif. Sam68 Represses CBP-dependent Transcriptional Activation 0.38 SIGNOR-266202 PTPRF protein P10586 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 12018405 YES lperfetto Some 10 years ago, Hashimoto et al. (87) had shown that the LAR catalytic domain can dephosphorylate the EGFR receptor in vitro, and more recently, Kulas and colleagues (88) have demonstrated that the antisense mediated suppression of LAR can enhance the growth factor induced activation of EGFR in rat hepatoma cells.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types. 0.337 SIGNOR-277029 CASC3 protein O15234 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 YES miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. 0.924 SIGNOR-265241 TRAF6 protein Q9Y4K3 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 23707529 YES miannu We have also observed that ubiquitination of PS1 by TRAF6 increases the stability of PS1 holoprotein, and TRAF6-deficiency coincides with reduced endogenous PS1 and PS2 levels. 0.558 SIGNOR-278601 sufentanil chemical CHEBI:9316 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10030 21215785 YES Luana Experiments were conducted to obtain K(i)'s for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. The K(i) values obtained ranged from 0.1380 nM (sufentanil) to 12.486 μM (tramadol).  0.8 SIGNOR-257890 (5Z)-5-(quinoxalin-6-ylmethylidene)-1,3-thiazolidine-2,4-dione chemical CHEBI:45302 ChEBI PIK3CG protein P48736 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000099 31195053 YES miannu We identified the protective effect of the PI3Kγ inhibitor AS605240 against stroke-related injury in the mouse model of transient intraluminal middle cerebral artery occlusion (tMCAO). in this study, the effects of AS605240 on astrocytes were studied in cell cultures. 0.8 SIGNOR-262224 ASPA protein P45381 UNIPROT acetic acid smallmolecule CHEBI:15366 ChEBI up-regulates quantity chemical modification 9606 17194761 YES miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. 0.8 SIGNOR-267527 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr112 EGMQIPStQFDAAHP -1 12432063 YES miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  0.47 SIGNOR-275994 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 21349850 YES gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. 0.258 SIGNOR-172235 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.305 SIGNOR-249001 UHRF1 protein Q96T88 UNIPROT LRIF1 protein Q5T3J3 UNIPROT down-regulates activity ubiquitination 9606 26727879 YES miannu In our study, we found the UHRF1 is sufficient to suppress RIF1 accumulation at DSBs in S phase and CtIP functions as a negative regulator of RIF1 only in G2 phase (XREF_FIG; XREF_SUPPLEMENTARY).|UHRF1 ubiquitinates RIF1. 0.2 SIGNOR-278604 FBXW11 protein Q9UKB1 UNIPROT PER1 protein O15534 UNIPROT down-regulates ubiquitination 9606 15917223 YES miannu We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1 0.492 SIGNOR-137758 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. 0.87 SIGNOR-236163 PAX3 protein P23760 UNIPROT PITX2 protein Q99697 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21143873 NO gcesareni Pitx genes, such as pitx2, which is positively regulated by pax3, have been implicated in myogenesis. 0.277 SIGNOR-170343 IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 19029956 YES lperfetto At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family. 0.956 SIGNOR-182484 MAPK1 protein P28482 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 9606 11741541 YES lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna 0.394 SIGNOR-112805 BMP2 protein P12643 UNIPROT OMD protein Q99983 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16970923 NO miannu Bmp-2 up regulates osad 0.311 SIGNOR-149562 CBP/p300 complex SIGNOR-C6 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys28 LATKAARkSAPSTGG 9606 21131905 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. 0.2 SIGNOR-217214 DBP protein Q10586 UNIPROT CYP3A4 protein P08684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 18004209 NO miannu The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock. 0.2 SIGNOR-253835 hsa-miR-582-3p mirna URS00002573C3_9606 RNAcentral AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003009 26468775 YES Parnian MiR-582-3p directly targets multiple negative regulators of the Wnt pathway. | Overall, our results demonstrate that miR-582-3p activates Wnt signalling by targeting AXIN2, DKK3 and SFRP1 enhances stem cell-like traits; and leads to tumour recurrence and poor prognosis in NSCLC patients. 0.4 SIGNOR-278020 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763;BTO:0000149 10197981 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-66767 NR0B2 protein Q15466 UNIPROT AR protein P10275 UNIPROT down-regulates binding 9606 11735420 YES gcesareni We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation 0.416 SIGNOR-112589 ado-trastuzumab emtansine antibody DB05773 DRUGBANK ERBB2 protein P04626 UNIPROT down-regulates activity binding 9606 19010901 YES miannu The anatomy of an antibody–cytotoxic drug conjugate can be divided into three general components: the antibody, the linker, and the cytotoxic drug. The efficacy of any such conjugate is dictated in part by the differential expression of the target antigen in tumor versus normal tissue. HER2 is a clinically validated target for the treatment of breast cancer. Trastuzumab and, more recently, lapatinib are approved for clinical use in women whose breast cancer overexpresses HER2. a trastuzumab conjugate, which simply uses HER2 as an address for the delivery of a potent cytotoxic agent, may offer promise as an effective therapeutic modality. 0.4 SIGNOR-259882 PTPRG protein P23470 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity dephosphorylation Tyr470 AYATEAVyESAEAPG -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254696 FLT1 protein P17948 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 9398617 YES gcesareni We conclude that both flt-1 and kdr have the potential to signal through plc gamma via phosphotyrosine residues located in juxta-membrane and carboxyl tail regions 0.678 SIGNOR-53743 PTPRG protein P23470 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 BTO:0000876 25624455 YES miannu Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG. 0.287 SIGNOR-254690 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RBBP8 protein Q99708 UNIPROT up-regulates activity phosphorylation Ser327 ELPTRVSsPVFGATS 9606 BTO:0000567 15485915 YES lperfetto Ser327 site is a Ser-Pro site, a preferred phosphorylation site by cyclin-dependent kinases|Unlike wild-type CtIP, the S327A mutant did not bind to BRCA1 BRCT domains in vitro (Fig. ​(Fig.1C)1C) and failed to associate with BRCA1 in vivo (Fig. ​(Fig.1D),1D), suggesting that residue Ser327 of CtIP is critical for the CtIP-BRCA1 interaction. 0.564 SIGNOR-263227 RAD18 protein Q9NS91 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity ubiquitination Lys164 AVVISCAkDGVKFSA 9606 20937699 YES miannu Second, these findings suggest the following model (XREF_FIG) : upon replication fork stalling at cisplatin induced DNA lesions, the RAD18 and RAD6 complex ubiquitylates PCNA on Lys164.|The DNA damage-activated E3 ubiquitin ligase RAD18 promotes repair of interstrand DNA cross-links by ubiquitylating PCNA and recruiting FANCL to chromatin. 0.846 SIGNOR-278612 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257999 HOXD12 protein P35452 UNIPROT MAFF protein Q9ULX9 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.381 SIGNOR-221884 CAD protein P27708 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI down-regulates quantity chemical modification 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-268092 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM4 protein Q9C037 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271218 ATM protein Q13315 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by stabilization phosphorylation Ser31 ALRLLDSsQIVIISA 10090 11459832 YES lperfetto Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes. 0.678 SIGNOR-109416 HTR6 protein P50406 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.374 SIGNOR-256944 naproxen chemical CHEBI:7476 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9057869 YES miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 0.8 SIGNOR-258602 morphine chemical CHEBI:17303 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258931 Noncanonical PRC1 complex SIGNOR-C151 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 25533466 NO miannu We show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. 0.7 SIGNOR-252248 SREBF2 protein Q12772 UNIPROT LRP1 protein Q07954 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980003 NO miannu In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression. 0.327 SIGNOR-254461 erlotinib hydrochloride chemical CHEBI:53509 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 17178722 YES JAK2(V617F), a mutant of tyrosine kinase JAK2. Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. gcesareni This study shows that the anti-cancer drug erlotinib (tarceva) is a potent inhibitor of jak2(v617f) activity. 0.8 SIGNOR-151271 3-[(4-Bromophenyl)methyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one chemical CID:10248127 PUBCHEM ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition 9606 17888667 YES Luana AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. 0.8 SIGNOR-257761 RNF144B protein Q7Z419 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001109 12853982 YES miannu P53RFP, a p53-inducible RING-finger protein, regulates the stability of p21WAF1. Here we report the isolation of a novel transcriptional target of p53, designated p53RFP (p53-inducible RING-finger protein), whose product has E3 ubiquitin ligase activity. Its expression was negatively correlated to that of p21(WAF1) protein; p53RFP is likely to play a role in the regulation of this protein, probably through interaction with, and ubiquitination of, p21(WAF1). 0.359 SIGNOR-271478 WNK3 protein Q9BYP7 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates activity phosphorylation 21613606 YES lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs 0.455 SIGNOR-264624 TRAF4 protein Q9BUZ4 UNIPROT SMURF2 protein Q9HAU4 UNIPROT down-regulates quantity by destabilization ubiquitination Lys119 YQRLDLCkLGPNDND 9606 31076633 YES miannu TRAF4 acts as an E3 ubiquitin ligase to ubiquitinate the K119 site of Smurf2 through the K48 ubiquitin chain and degrade Smurf2. 0.361 SIGNOR-278617 ATR protein Q13535 UNIPROT MCC protein P23508 UNIPROT up-regulates activity phosphorylation Ser120 LRSELSQsQHEVNED 9606 BTO:0001109 21779472 YES miannu MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. 0.2 SIGNOR-273515 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 YES Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. 0.64 SIGNOR-248830 8-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:91845 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258693 PES1 protein O00541 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0002882 15169904 NO miannu Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development. 0.7 SIGNOR-260078 PRKD3 protein O94806 UNIPROT PAK4 protein O96013 UNIPROT up-regulates activity phosphorylation Ser474 KEVPRRKsLVGTPYW 23841590 YES lperfetto PAK4 activity is regulated by an autoinhibitory domain that is released upon RhoGTPase binding as well as phosphorylation at Ser474 in the activation loop of the kinase domain. In the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1) 0.252 SIGNOR-275931 TRIM56 protein Q9BRZ2 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity ubiquitination 9606 21074459 YES miannu In contrast, we found that TRIM56 preferentially promoted K63 linked ubiquitination of the same lysine residue of STING that was important for the dimer formation and TBK1 activation.|Specifically, TRIM56 induces STING dimerization during dsDNA triggered signaling to potentiate antiviral responses while RNF5 may induce degradation of mitochondrial STING to suppress RLR induced antiviral responses.The findings that TRIM56 failed to interact with dsDNA and that there was no colocalization between TRIM56 and dsDNA within cells suggest that TRIM56 is unlikely to be a dsDNA sensor, and instead facilitates the STING function by ubiquitination. 0.2 SIGNOR-278621 CASP8 protein Q14790 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 YES lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. 0.369 SIGNOR-261754 DNA_damage stimulus SIGNOR-ST1 SIGNOR Fanconi anemia core complex complex SIGNOR-C300 SIGNOR up-regulates 9606 BTO:0000567 17396147 NO lperfetto The Fanconi anemia (FA) core complex plays a central role in the DNA damage response network involving breast cancer susceptibility gene products, BRCA1 and BRCA2. The complex consists of eight FA proteins, including a ubiquitin ligase (FANCL) and a DNA translocase (FANCM), and is essential for monoubiquitination of FANCD2 in response to DNA damage. 0.7 SIGNOR-263251 ITGB7 protein P26010 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.688 SIGNOR-253292 LNX1 protein Q8TBB1 UNIPROT SUFU protein Q9UMX1 UNIPROT down-regulates quantity ubiquitination Lys59 LQVTAIVkYWLGGPD 9606 33608498 YES miannu Indeed, they target different lysine residues in the SuFu protein, as LNX1 ubiquitinates SuFu at K59 and K470, and SCF Fbxl17 acts at K257, while Itch ubiquitinates at K321 and K457.|XREF_FIG, ectopic LNX1 expression reduced SuFu protein levels in HEK-293T cells, while shRNA mediated knockdown of LNX1 increased these levels. 0.2 SIGNOR-278627 PDPK1 protein O15530 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 15802604 YES gcesareni We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts. 0.571 SIGNOR-134869 PTCRA protein Q6ISU1 UNIPROT LCK protein P06239 UNIPROT up-regulates activity binding 9606 20626350 YES lperfetto However, non-canonical mechanisms of p38alfa activation have been also described. One is apparently specific to antigen receptor stimulated t-lymphocytes. This involves phosphorylation of p38alfa on tyr323 by the tcr-proximal tyrosine kinase zap70 and p56lck. 0.334 SIGNOR-166658 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser266 SLPLTPEsPNDPKGS 9606 BTO:0000887 11741533 YES gcesareni Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298 0.584 SIGNOR-112766 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser329 STISGRLsPIMTEQD 9606 11311120 YES lperfetto The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus 0.507 SIGNOR-252909 PAK3 protein O75914 UNIPROT MYO6 protein Q9UM54 UNIPROT up-regulates activity phosphorylation Thr405 TAGGTKGtVIKVPLK -1 11517222 YES miannu P21-activated kinase 3 phosphorylated myosin VI, and the site was identified as Thr(406). The phosphorylation of myosin VI significantly facilitated the actin-translocating activity of myosin VI.  0.337 SIGNOR-250244 MDM2 protein Q00987 UNIPROT SUV39H1 protein O43463 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23376847 YES miannu A recent report showed that the p53 inducible E3 ligase MDM2 causes SUV39H1 degradation.|Furthermore, it was reported that MDM2 can ubiquitinate and degrade SUV39H1. 0.401 SIGNOR-278631 MIB1 protein Q86YT6 UNIPROT SNRPN protein P63162 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23615451 YES miannu These data indicate that Mib1 reduces SMN protein stability by targeting it for degradation by the proteasome and represents a new modifier of the SMA phenotype.|Through this study, we provide evidence that the E3 ligase Mib1 ubiquitinates and catalyzes SMN protein degradation. 0.2 SIGNOR-278632 ATP6V0E1 protein O15342 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.568 SIGNOR-277747 NEDD4 protein P46934 UNIPROT APOBEC3G protein Q9HC16 UNIPROT up-regulates activity ubiquitination 9606 15581898 YES miannu APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles|This could be explained in at least two ways : first, endogenous Nedd4 is naturally expressed at a level largely sufficient to target APOBEC3G into the VLP or virions. 0.284 SIGNOR-278635 NEDD4 protein P46934 UNIPROT GRIN2D protein O15399 UNIPROT down-regulates activity ubiquitination 9606 23639431 YES miannu Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses.|This suggests that Nedd4 association reduces GluN2D function, mostly likely by promoting GluN2D ubiquitination and internalization. 0.329 SIGNOR-278636 VEGFA protein P15692 UNIPROT FLT1 protein P17948 UNIPROT up-regulates binding 9606 BTO:0004980 14704231 YES gcesareni Vegf exerts its action by binding to vegfr-1 and vegfr-2. 0.843 SIGNOR-121132 CDK1 protein P06493 UNIPROT PPP1R13L protein Q8WUF5 UNIPROT up-regulates activity phosphorylation Ser84 EPFGSRGsPRKAATD 9606 30105797 YES done miannu Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53.  0.506 SIGNOR-273585 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 YES lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity 0.757 SIGNOR-232146 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition 9606 31908417 YES miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. 0.8 SIGNOR-262250 methylnaltrexone chemical CHEBI:136007 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258147 E2F1 protein Q01094 UNIPROT TYMS protein P04818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.527 SIGNOR-253863 FGF9 protein P31371 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 NO FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1. gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts. 0.375 SIGNOR-134794 sirolimus chemical CHEBI:9168 ChEBI LILRB2 protein Q8N423 UNIPROT down-regulates quantity by repression 9606 18652845 NO miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. 0.8 SIGNOR-255477 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 20305697 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-164633 NANOG protein Q9H9S0 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 NO miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 0.349 SIGNOR-254625 Guanabenz chemical CHEBI:5553 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258909 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR 9606 22665060 YES llicata Phosphorylation of lasp-1 by pka at serine 146 induces translocation of the lasp-1/zo-2 complex from the cytoplasm to the nucleus. Interaction occurs within the carboxyterminal proline-rich motif of zo-2 and the sh3 domain in lasp-1. 0.307 SIGNOR-197720 PRKACA protein P17612 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation Ser465 FLQDVSAsTKSLQEL 9606 BTO:0001412 25069723 YES miannu  In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain).  0.2 SIGNOR-276651 BACH1 protein O14867 UNIPROT GAPDH protein P04406 UNIPROT up-regulates quantity transcriptional regulation 9606 31257027 YES BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. 0.2 SIGNOR-259339 E2F5 protein Q15329 UNIPROT CBX5 protein P45973 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 21374739 YES Luana We identified for E2F5 a repressor function for HP1a expression. 0.2 SIGNOR-261591 HEY1 protein Q9Y5J3 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 19917614 NO lperfetto Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis. 0.371 SIGNOR-235822 MLLT11 protein Q13015 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0003295 21715312 NO irozzo Our results indicate that AF1q cooperates with the Notch signaling pathway to foster the emergence of BM prothymocytes and drive subsequent intrathymic specification toward the T-cell lineage. 0.7 SIGNOR-259201 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr276 DGIMYYLtPQWDKIL 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.332 SIGNOR-262920 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD3 protein O94806 UNIPROT up-regulates activity phosphorylation Ser731 ARIIGEKsFRRSVVG 18692497 YES lperfetto The results presented in this study indicate that during mitosis, PKD3 and PKD are phosphorylated at Ser(731) and Ser(744) within their activation loop by a mechanism that requires protein kinase C. Mitosis-associated PKD3 Ser(731) and PKD Ser(744) phosphorylation is related to the catalytic activation of these kinases as evidenced by in vivo phosphorylation of histone deacetylase 5, a substrate of PKD and PKD3. 0.2 SIGNOR-275924 PLCG2 protein P16885 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10116 BTO:0002013 29430764 NO Marta Tosoni PLCγ2 promotes apoptosis while inhibits proliferation in rat hepatocytes through PKCD/JNK MAPK and PKCD/p38 MAPK signalling 0.7 SIGNOR-278088 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 18204439 YES lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. 0.716 SIGNOR-160415 MAPK3 protein P27361 UNIPROT LCK protein P06239 UNIPROT up-regulates activity phosphorylation Ser59 EGSNPPAsPLQDNLV 9606 BTO:0000567 8618896 YES lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. 0.565 SIGNOR-249469 STAT5A protein P42229 UNIPROT CISH protein Q9NSE2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 YES The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD 0.668 SIGNOR-261544 BRCA1 protein P38398 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 16331276 NO miannu We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1. 0.344 SIGNOR-142888 PRKN protein O60260 UNIPROT LTF protein P02788 UNIPROT down-regulates activity ubiquitination Lys649 NGSDCPDkFCLFQSE 9606 32786404 YES miannu We propose that Parkin ubiquitylation of LTF at K649 perturbs LTF\u2019s ability to accumulate intracellular iron levels and that depletion of Parkin, or substitution of K649 on LTF, allows LTF to accumulate intracellular iron levels.|Parkin dependent ubiquitylation of LTF occurred most often on lysines (K) 182 and 649. 0.2 SIGNOR-278641 RNF41 protein Q9H4P4 UNIPROT PRKN protein O60260 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 18541373 YES miannu Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage dependent and proteasome dependent manner.|More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate. 0.2 SIGNOR-278644 D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 19401148 YES miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 0.8 SIGNOR-268134 TALDO1 protein P37837 UNIPROT D-erythrose 4-phosphate(2-) smallmolecule CHEBI:16897 ChEBI up-regulates quantity chemical modification 9606 19401148 YES miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (‚Äúdihydroxyacetone‚Äù) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 0.8 SIGNOR-267092 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser487 AQLAGSDsDLDSDDE 9606 20864032 YES lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) 0.2 SIGNOR-168036 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8422248 YES lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. 0.485 SIGNOR-248930 U50488 chemical CHEBI:73358 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.8 SIGNOR-258666 TLE4 protein Q04727 UNIPROT PAX2/TLE4 complex SIGNOR-C152 SIGNOR form complex binding 9606 16631587 YES miannu Several Pax proteins are able to interact with groucho (TLE) family members. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. 0.456 SIGNOR-256360 STUB1 protein Q9UNE7 UNIPROT INO80 protein Q9ULG1 UNIPROT up-regulates activity ubiquitination 9606 33658435 YES miannu Then, by an in vivo ubiquitination assay under denaturing conditions (hereafter, all in vivo ubiquitination assays were carried out under denaturing conditions), we determined whether CHIP ubiquitinates Ino80.|We also show that CHIP works together with BAP1 to enhance the stabilization of Ino80, leading to its chromatin binding. 0.2 SIGNOR-278646 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser188 RKRHKSDsISLSFDE 9606 BTO:0000671 15169778 YES lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) 0.81 SIGNOR-124953 TCF3 protein P15923 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR form complex binding 10090 BTO:0001103 18094043 YES lperfetto MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells. 0.805 SIGNOR-241551 CRY1 protein Q16526 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. 0.894 SIGNOR-267971 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20308527 YES lperfetto We demonstrate that CHD8 directly associates with AR and that CHD8 and AR simultaneously localize to the TMPRSS2 enhancer after androgen treatment. In the LNCaP cell line, reduction of CHD8 levels by small interfering RNA treatment severely diminishes androgen-dependent activation of the TMPRSS2 gene. We demonstrate that the recruitment of AR to the TMPRSS2 promoter in response to androgen treatment requires CHD8 0.576 SIGNOR-253686 TLX3 protein O43711 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 BTO:0002504 22516263 YES irozzo We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. 0.365 SIGNOR-259098 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT up-regulates binding 9606 24352680 YES fstefani Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain 0.2 SIGNOR-203484 calcium(2+) smallmolecule CHEBI:29108 ChEBI PPP3CA protein Q08209 UNIPROT up-regulates chemical activation 9606 22944199 YES lperfetto Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell). 0.8 SIGNOR-198819 RUSC1 protein Q9BVN2 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000007 19365808 YES miannu NESCA interacts with the IKK complex by the N-terminal region of NEMO. This experiment revealed that the overexpression of NESCA completely abolished the TRAF6-mediated polyubiquitination of NEMO, as it appears by using either anti-HA (Fig. 5A) or anti-NEMO (Fig. 5B) antibodies on immunoprecipitated extracts. 0.308 SIGNOR-272775 CSNK2A1 protein P68400 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Ser59 NKLFQYAsTDMDKVL -1 8663403 YES llicata We show that serine 59 located between the MADS and MEF2 domains of MEF2C is phosphorylated in vivo and can be phosphorylated in vitro by casein kinase-II (CKII). Phosphorylation of this site enhanced the DNA binding and transcriptional activity of MEF2C by increasing its DNA binding activity 5-fold. 0.333 SIGNOR-250914 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR peptide smallmolecule CHEBI:16670 ChEBI up-regulates quantity chemical modification 9606 20025795 YES miannu In the initial binding state, referred to as A/T state, this aa-tRNA is in a ternary complex with the GTPase EF-Tu (eEF1A in eukaryotes) and GTP. When a Watson–Crick codon–anticodon match is recognized by the ribosome, a signal is transmitted to EF-Tu that triggers GTP hydrolysis and thereby causes the dissociation of EF-Tu from the ribosome. The subsequent accommodation of the 3′ acceptor arm of the tRNA in the PTC of the large subunit leads to a rapid peptide bond transfer 0.8 SIGNOR-270811 AXIN2 protein Q9Y2T1 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates activity binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 YES lperfetto It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. 0.74 SIGNOR-228003 LATS1 protein O95835 UNIPROT MTF1 protein Q14872 UNIPROT down-regulates activity phosphorylation Ser152 EGCPRTYsTAGNLRT 35027733 YES lperfetto The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression 0.2 SIGNOR-275473 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr66 DTAGQEDyDRLRPLS 9606 BTO:0000567 23027962 YES lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity 0.2 SIGNOR-271699 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Thr509 LKRKRRPtSGLHPED 9606 BTO:0000150 17428466 YES lperfetto Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation 0.507 SIGNOR-154312 NEK2 protein P51955 UNIPROT NCAPD2 protein Q15021 UNIPROT down-regulates activity phosphorylation 9606 25704143 YES miannu Nek2 phosphorylates C-Nap1, rootletin and beta-catenin to regulate centrosome separation. 0.269 SIGNOR-279234 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser447 YHRSIRHsSIQE 9606 BTO:0000782 20697158 YES miannu Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells. 0.417 SIGNOR-167467 DAB2 protein P98082 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 22491013 YES gcesareni Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin. 0.495 SIGNOR-196925 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser326 SSVDTLLsPTALIDS 9606 35080342 YES miannu AKT1 and AKT2 phosphorylate HSF1 at S326 but only AKT1 activates HSF1.|Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. 0.405 SIGNOR-278374 PIGBOS1 protein A0A0B4J2F0 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 31653868 NO miannu We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels 0.2 SIGNOR-261041 ABL1 protein P00519 UNIPROT STX17 protein P56962 UNIPROT down-regulates activity phosphorylation Tyr157 SQSLTQIyALPEIPQ 9534 BTO:0001538 23006999 YES miannu C-Abl was identified as one of the kinases, which phosphorylates syntaxin 17.Western blot shows phosphorylation of syntaxin 17 on Tyr-156 by overexpression and activation of c-Abl. A phospho-mimicking mutant (Y156E) of syntaxin 17 showed reduced interaction with COPI vesicles. These results suggest that tyrosine phosphorylation of syntaxin 17 is likely to have a role in regulating syntaxin 17 dependent membrane trafficking in the early secretory pathway. 0.2 SIGNOR-273538 MECP2 protein P51608 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000452 19820693 NO Luana We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. | We found increased cell death in each of the tested cell lines not only, as expected, when HIPK2 was overexpressed but also with MeCP2 alone. When both proteins were expressed together, the number of dead cells increased in an additive manner. 0.7 SIGNOR-264550 GGCX protein P38435 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 31539109 NO miannu GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05). 0.2 SIGNOR-261233 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 YES gcesareni The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. 0.595 SIGNOR-111511 CBX3 protein Q13185 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-264494 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0002181 22012064 YES irozzo Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels 0.566 SIGNOR-255707 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000356 29945959 YES lperfetto FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner.  0.266 SIGNOR-273447 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAP3K7 protein O43318 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 22337877 YES lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts 0.2 SIGNOR-235560 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 10037602 YES gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. 0.858 SIGNOR-64972 HTR4 protein Q13639 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257242 AMPK complex SIGNOR-C15 SIGNOR SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 21459323 YES lperfetto Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372 0.317 SIGNOR-216533 GNAI1 protein P63096 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding -1 11007482 YES Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src 0.484 SIGNOR-256526 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Ser281 NRRQLAFsTVGTPDY 9606 BTO:0000007 16314523 YES lperfetto Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity. 0.2 SIGNOR-142514 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity phosphorylation Tyr102 YDLKLQEyQSAIKVE 10090 BTO:0000007;BTO:0000011 25368164 YES We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ. 0.341 SIGNOR-262297 MTCH2 protein Q9Y6C9 UNIPROT BID protein P55957 UNIPROT up-regulates relocalization 9606 20436477 YES In the experiment they use a truncated BID (tBID)-interacting protein. gcesareni Mtch2/mimp (mitochondrial carrier homologue 2/met-induced mitochondrial protein), a novel truncated bid (tbid)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tbid to mitochondria 0.303 SIGNOR-165081 NR2F2 protein P24468 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 YES gcesareni Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site. 0.257 SIGNOR-79443 MAPK8 protein P45983 UNIPROT SYT4 protein Q9H2B2 UNIPROT up-regulates activity phosphorylation Ser135 EGEKESVsPESLKSS 10116 BTO:0001009 18046461 YES done miannu JNK phosphorylates Syt 4 at Ser135 in vitro and in vivo. 0.411 SIGNOR-273673 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2J2 protein Q8N2K1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.601 SIGNOR-271339 NANOG protein Q9H9S0 UNIPROT CGB Family proteinfamily SIGNOR-PF108 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 NO miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 0.2 SIGNOR-254624 PIP3 smallmolecule CHEBI:16618 ChEBI ZFYVE26 protein Q68DK2 UNIPROT up-regulates quantity relocalization 9606 BTO:0000567 20208530 YES miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. 0.8 SIGNOR-265537 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser688 QFHSPVGsPLKSIQA 9606 SIGNOR-C17 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. 0.483 SIGNOR-164491 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser696 EKNYALPsPATTEGG 9606 BTO:0000007 SIGNOR-C3 21071439 YES lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.469 SIGNOR-169526 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser392 FKTEGPDsD 9606 23603988 YES gcesareni We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation 0.535 SIGNOR-201931 ECM stimulus SIGNOR-ST20 SIGNOR A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259048 KISS1R protein Q969F8 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.498 SIGNOR-256750 PRKACB protein P22694 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 31057087 YES miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 0.2 SIGNOR-259403 Caspase 3 complex complex SIGNOR-C221 SIGNOR AKT1 protein P31749 UNIPROT down-regulates activity cleavage -1 10579725 YES lperfetto P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro 0.603 SIGNOR-256447 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT unknown phosphorylation Ser138 KPRTIYSsYQLAALQ 10090 11343707 YES lperfetto Dlx3 is primarily phosphorylated by PKCalpha. By deletion and mutational analysis, we show that the serine residue S138, located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3. | Since DNA binding may reveal only a part of Dlx3 protein function, we cannot rule out the influence of phosphorylation on other biological functions. Thus, the characterization of the full biological function of PKC phosphorylation of Dlx3 protein will require further studies. 0.307 SIGNOR-249095 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 YES milica Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ 0.42 SIGNOR-201165 GSK3A protein P49840 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser509 GVHSPMAsSGNTGNH 9606 BTO:0000093 17574025 YES miannu GSK3 Phosphorylates SRC-3 on S505.In this report, we identified GSK3 as a kinase that phosphorylates SRC-3 on S505 and demonstrated that this phosphorylation modulates SRC-3 transcriptional function and turnover. 0.2 SIGNOR-276067 AMPK complex SIGNOR-C15 SIGNOR CTH protein P32929 UNIPROT up-regulates activity phosphorylation Thr355 AELPAIMtHASVLKN 9606 BTO:0000007 37922764 YES miannu  Here we define an important mechanism of increased persulfide and polysulfide production involving cystathionine gamma lyase (CSE) phosphorylation at serine 346 and threonine 355 in a substrate specific manner, under acute hypoxic conditions. Hypoxic phosphorylation of CSE occurs in an AMP kinase dependent manner increasing enzyme activity involving unique inter- and intramolecular interactions within the tetramer.  0.25 SIGNOR-277793 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9913 11254391 YES miannu Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. 0.8 SIGNOR-266915 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 24449215 NO miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 0.2 SIGNOR-255972 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Ser187 RIMEKADsNKTRIDE 9606 12459461 YES lperfetto This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C 0.353 SIGNOR-249178 IRX1 protein P78414 UNIPROT INHBA protein P08476 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. 0.2 SIGNOR-261666 NEK6 protein Q9HC98 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Ser839 TSRCLIKsPDRLADI -1 21335236 YES done miannu To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization 0.315 SIGNOR-273893 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 21808241 YES The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. 0.816 SIGNOR-175813 EZH2 protein Q15910 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 YES miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. 0.438 SIGNOR-260070 ERG protein P11308 UNIPROT ICAM1 protein P05362 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22235125 NO miannu It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1. 0.2 SIGNOR-253917 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189990 USF1 protein P22415 UNIPROT S100A6 protein P06703 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11118618 NO miannu The results indicate that USF1 binds to an E-box sequence of the calcyclin gene promoter and enhances its transcription activity. 0.2 SIGNOR-255598 CAMK2A protein Q9UQM7 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 YES Translocation from Endosome to Lysosome gcesareni As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2). 0.283 SIGNOR-124344 NLGN4Y protein Q8NFZ3 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.2 SIGNOR-264153 VPS11 protein Q9H270 UNIPROT EZR protein P15311 UNIPROT up-regulates activity binding 9606 BTO:0000567 21148287 YES Sara The interaction between the full-length Vps11 and ezrin was confirmed by immunoprecipitation and GST-pull down. ERM proteins and the HOPS complex are required for the transition from early to late endosomes 0.351 SIGNOR-261311 GSK3B protein P49841 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 28883123 YES miannu Our data suggest that glycogen synthase kinase 3 beta (GSK3beta) phosphorylates IFNGR1 thereby enhancing receptor protein stability by limiting ubiquitin proteasomal degradation. 0.2 SIGNOR-279720 AMPK complex SIGNOR-C15 SIGNOR CTH protein P32929 UNIPROT up-regulates activity phosphorylation Thr355 AELPAIMtHASVLKN 9606 BTO:0000007 37922764 YES miannu  Here we define an important mechanism of increased persulfide and polysulfide production involving cystathionine gamma lyase (CSE) phosphorylation at serine 346 and threonine 355 in a substrate specific manner, under acute hypoxic conditions. Hypoxic phosphorylation of CSE occurs in an AMP kinase dependent manner increasing enzyme activity involving unique inter- and intramolecular interactions within the tetramer.  0.25 SIGNOR-277807 MAP3K8 protein P41279 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 BTO:0000007 15466476 YES lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. 0.434 SIGNOR-129698 PTPN1 protein P18031 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity dephosphorylation 9606 12377785 YES miannu PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.|The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin.|Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function. 0.659 SIGNOR-277121 DNA_damage stimulus SIGNOR-ST1 SIGNOR RAD23A protein P54725 UNIPROT up-regulates 24086043 NO lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). 0.7 SIGNOR-275686 CDK9 protein P50750 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Ser211 VAQTPMPsEYQNMTV 9606 23603988 YES lperfetto We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr. 0.461 SIGNOR-201923 Ub:E2 complex SIGNOR-C497 SIGNOR RNF208 protein Q9H0X6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271013 KAT2B protein Q92831 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates acetylation Lys19 VKRLLGWkKSAGGSG 9606 SIGNOR-C7 17074756 YES gcesareni We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. Smad2 is also acetylated by p/caf. The acetylation of smad2 was significantly higher than that of smad3. Lys(19) in the mh1 domain was identified as the major acetylated residue in both the long and short isoform of smad2.....acetylation of the short isoform of smad2 improves its dna binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity 0.576 SIGNOR-150273 RPS6KA4 protein O75676 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12773393 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 0.2 SIGNOR-249211 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10209155 YES gcesareni Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4. 0.746 SIGNOR-67003 SRC protein P12931 UNIPROT PANX1 protein Q96RD7 UNIPROT up-regulates activity phosphorylation Tyr199 KYPIVEQyLKTKKNS 9606 BTO:0004578 30814251 YES miannu We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198 0.379 SIGNOR-277817 SERPINC1 protein P01008 UNIPROT F2 protein P00734 UNIPROT down-regulates activity cleavage 31030036 YES lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 0.948 SIGNOR-264136 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates activity phosphorylation Thr103 LIDATGDtPGAEDDE 9534 BTO:0000298 12756254 YES miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. 0.879 SIGNOR-250128 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr225 IKGRAQPyDPNFYDE 9606 12052863 YES lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). 0.603 SIGNOR-88899 WHAMM protein Q8TF30 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 YES lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. 0.349 SIGNOR-261004 XRCC3 protein O43542 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity 9606 BTO:0000567 23438602 NO lperfetto Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation. 0.512 SIGNOR-263261 PPP4C protein P60510 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity dephosphorylation Ser137 LELCRRRsLLELHKR 9606 35546066 YES miannu PPP4C dephosphorylated PLK1 at the S137 site, negatively regulating its activity in the DSB response in early embryonic cells. 0.417 SIGNOR-277076 TUBGCP2 protein Q9BSJ2 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 YES lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” 0.805 SIGNOR-262326 MAPK3 protein P27361 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser21 LEAGDLEsPLSEEFL 9606 BTO:0000599 10187842 YES lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. 0.6 SIGNOR-249474 PRKACA protein P17612 UNIPROT TRPC5 protein Q9UL62 UNIPROT down-regulates quantity phosphorylation Ser794 SGGARAKsKSVSFNL 9606 BTO:0000007 21734191 YES miannu Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A). 0.2 SIGNOR-277823 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates quantity phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 YES miannu Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A). 0.2 SIGNOR-277824 ADNP protein Q9H2P0 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 12888219 NO miannu Mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment. 0.7 SIGNOR-266758 CDK1 protein P06493 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser460 STSVLHSsPLNVFMG 21690413 YES lperfetto Mechanistically, we demonstrated that Cdc2-dependent phosphorylation on a γ-tubulin ring complex (γ-TuRC) recruitment protein, Nedd1/GCP-WD, at the previously uncharacterized S460 residue induces the Nedd1-Plk1 interaction 0.583 SIGNOR-272972 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR CEBPD protein P49716 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000527 25303533 YES miannu KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ. 0.2 SIGNOR-272457 MRPS35 protein P82673 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.68 SIGNOR-261442 CSK protein P41240 UNIPROT LCK protein P06239 UNIPROT down-regulates phosphorylation Tyr505 FTATEGQyQPQP 9606 BTO:0000782 1639064 YES gcesareni P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity. 0.537 SIGNOR-20371 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCQ protein Q04759 UNIPROT up-regulates activity binding 9606 14967450 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. 0.8 SIGNOR-242596 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273101 BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 24832651 NO lperfetto The exact function of the BRCC complex in HR is not entirely elucidated, but its E3 ligase activity may promote the mobilization and stabilization of the complex at broken chromatin sites were the complex can stabilize the formation of RAD51 filaments thus facilitating the repair process 0.7 SIGNOR-263204 CTF1 protein Q16619 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9030543 YES gcesareni In the cos-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for ct-1 signaling 0.626 SIGNOR-46509 SEC23B protein Q15437 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.691 SIGNOR-265288 FBXO9 protein Q9UK97 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23263282 YES miannu Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins. 0.442 SIGNOR-271996 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 SIGNOR-C17 10864927 YES gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.858 SIGNOR-78428 PTPRB protein P23467 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity dephosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 YES miannu VE-PTP interacts with eNOS and dephosphorylates Tyr81 0.267 SIGNOR-277521 CSF1R protein P07333 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr228 YPGGSDNyGSLSRVT 9606 21049007 YES miannu In our study, CSF-1R induced the tyrosine phosphorylation of p120 Y904 and Y228 in a SRC-dependent manner ( xref ). 0.27 SIGNOR-278928 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 17035229 YES SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.432 SIGNOR-248791 CSNK2A1 protein P68400 UNIPROT CERS5 protein Q8N5B7 UNIPROT up-regulates activity phosphorylation Ser356 RSDVESSsEEEDVTT 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273986 AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001412 31900833 YES miannu Inactivation of AMPK suppressed the expression of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) in tumor cells. Compound C-induced AMPK suppression causes downregulation TET2 and FOXP3 expression, leading to death of parental and HQ-selected U937 cells. These results confirm the connection of AMPK with the TET2–FOXP3 axis in modulating the survival of AML cells and suggest that suppression of the AMPK–TET2–FOXP3 axis suppresses the progression of AML and HQ-induced malignant transformation of AML cells. 0.2 SIGNOR-260097 POU5F1 protein Q01860 UNIPROT LEFTY1 protein O75610 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.501 SIGNOR-254938 GRM2 protein Q14416 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. 0.8 SIGNOR-264933 DUSP9 protein Q99956 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates binding 9606 21908610 YES inferred from 70% of family members gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. 0.2 SIGNOR-269902 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr1253 EGSFESRyQQPFEDF 9606 BTO:0000142 1689310 YES llicata We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation. 0.84 SIGNOR-20976 PIM3 protein Q86V86 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation -1 31730483 YES miannu In addition to PIM1, also PIM2 and PIM3 were able to phosphorylate WT, but not MM NFATC1 in vitro (Fig. ​(Fig.22c). 0.246 SIGNOR-276773 CARD11 protein Q9BXL7 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates binding 9606 BTO:0000785 20685844 YES gcesareni The carboxy-terminal part of the bcl10 card and a short stretch of 13 amino acids following the card are required for constitutive binding to malt1. 0.804 SIGNOR-167393 AKT1 protein P31749 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.877 SIGNOR-251622 AKT1 protein P31749 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 9415393 NO Translocation from intracellular compartment to cell surface in muscle and adipose tissue gcesareni Akt is not only capable of stimulating the translocation of glut4 to the cell surface. Endogenous akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue 0.549 SIGNOR-252580 CLSPN protein Q9HAW4 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates binding 9606 11090622 YES gcesareni Binding of claspin to xchk1 is highly elevated in the presence of dna templates that trigger a checkpoint arrest of the cell cycle in xenopus egg extracts 0.793 SIGNOR-84474 PRKCA protein P17252 UNIPROT PPP2R5A protein Q15172 UNIPROT down-regulates activity phosphorylation Ser41 RQKRSQGsSQFRSQG -1 24225947 YES miannu  In this study, we identified a novel phosphorylation site at Ser(41) of B56α. This phosphoamino acid residue was efficiently phosphorylated in vitro by PKCα.  0.341 SIGNOR-276603 ILF3 protein Q12906 UNIPROT NF90-NF45 complex SIGNOR-C443 SIGNOR form complex binding -1 18458058 YES miannu Nuclear factor 90 (NF90) and its C-terminally extended isoform, NF110, have been isolated as DNA- and RNA-binding proteins together with the less-studied protein NF45. These complexes have been implicated in gene regulation, but little is known about their cellular roles and whether they are redundant or functionally distinct. We show that heterodimeric core complexes, NF90-NF45 and NF110-NF45, exist within larger complexes that are more labile and contain multiple NF90/110 isoforms and additional proteins. This study identified NF45 as an unstable regulatory subunit of NF90-NF45 complexes and uncovered their critical role in normal cell division. Furthermore, the study revealed that NF90 is functionally distinct from NF110 and is more important for cell growth. 0.577 SIGNOR-268488 IFNG protein P01579 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 10090 23667107 NO Early inhibition of IL-1β expression by IFN-γ is mediated by impaired binding of NF-κB to the IL-1β promoter but is independent of nitric oxide. 0.446 SIGNOR-255937 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates activity phosphorylation Ser787 KAPEKRAsPSKPASA 9606 BTO:0000567 10791892 YES miannu We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region. Mutation of Ser787 to Glu strikingly reduced the MAP4's MT-polymerization activity, while Glu-mutation at Ser696 did not. These results suggest that Ser787 could be the critical phosphorylation site causing MTs to be dynamic at mitosis. 0.498 SIGNOR-277459 NFKB1 protein P19838 UNIPROT THBD protein P07204 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17211835 NO miannu Blocking the transcriptional activation of NF-kappaB prevented the TNFalpha-induced downregulation of TM. 0.2 SIGNOR-254811 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser126 PPGTPLVsQDEKRDA 9606 21824916 YES lperfetto We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro. 0.648 SIGNOR-176020 LRRK2 protein Q5S007 UNIPROT PRDX3 protein P30048 UNIPROT down-regulates activity phosphorylation Thr146 SHLAWINtPRKNGGL 9606 BTO:0000793 21850687 YES miannu Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells. 0.414 SIGNOR-262891 SMURF2 protein Q9HAU4 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.551 SIGNOR-192898 BIRC3 protein Q13489 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys51 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. 0.356 SIGNOR-272707 NEDD1 protein Q8NHV4 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR up-regulates activity binding 9606 19029337 YES miannu It has been reported that NEDD1 directly interacts with and recruits the gamma-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly 0.766 SIGNOR-261422 NFE2L2 protein Q16236 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 26194347 NO irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. 0.7 SIGNOR-256652 ARHGAP22 protein Q7Z5H3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.563 SIGNOR-260476 MKNK2 protein Q9HBH9 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 YES lperfetto Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes. 0.561 SIGNOR-157537 HRH1 protein P35367 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257251 PRKCG protein P05129 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.27 SIGNOR-275445 HIF1A protein Q16665 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 17415528 NO HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate 0.7 SIGNOR-259381 PKC proteinfamily SIGNOR-PF53 SIGNOR SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser113 HVSRQVTsSGVSHGG 9606 BTO:0000567 28831067 YES lperfetto The SUN1-NXF1 association is at least partly regulated by a protein kinase C (PKC) which phosphorylates serine 113 (S113) in the N-terminal domain leading to reduced interaction. 0.2 SIGNOR-263281 AKT1 protein P31749 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 21798082 YES gcesareni Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). 0.647 SIGNOR-175294 MAPK7 protein Q13164 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000007 12637502 YES miannu Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC. 0.539 SIGNOR-250115 NAE complex SIGNOR-C131 SIGNOR CUL3 protein Q13618 UNIPROT up-regulates activity neddylation 9606 25504797 YES lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. 0.589 SIGNOR-243157 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.6 SIGNOR-34653 pipamperone chemical CHEBI:78549 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258574 RPL14 protein P50914 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.873 SIGNOR-262484 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr267 SQYGQEVyDTPPMAV 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246401 GPHN protein Q9NQX3 UNIPROT ARHGEF9 protein O43307 UNIPROT up-regulates activity binding 9606 25882190 YES miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. 0.605 SIGNOR-264973 KMT2D protein O14686 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 16603732 YES miannu A novel estrogen receptor (er)alpha coactivator complex, the mll2 complex, which consists of mll2, ash2, rbq3, and wdr5, was identified / disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity. 0.455 SIGNOR-145865 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser149 SNSLKKSsAELKKIL 9606 BTO:0000671 12628002 YES lperfetto Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149) 0.702 SIGNOR-99139 Ub:E2 complex SIGNOR-C497 SIGNOR MGRN1 protein O60291 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271144 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR PRDM14 protein Q9GZV8 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.628 SIGNOR-269234 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 24168260 NO miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis 0.7 SIGNOR-260445 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr19 LFMDDDSySHHSGLE 9606 12091389 YES lperfetto We show that caveolin-2 undergoes src-induced phosphorylation on tyrosine 19. we conclude that the tyrosine phosphorylation of caveolin-2 (tyr(p)(19)) may function as a signal that is recognized by the cellular machinery to induce the dissociation of caveolin-2 from caveolin-1 oligomers 0.675 SIGNOR-90225 RNF4 protein P78317 UNIPROT SP1 protein P08047 UNIPROT down-regulates quantity ubiquitination 9606 21983342 YES miannu 5, our data also indicate that Sp1 can be ubiquitinated by the ubiquitin E3 ligase RNF4.|These data suggest that RNF4 decreases Sp1 levels by increasing its degradation via a ubiquitin dependent proteasome pathway.We performed an in vitro ubiquitination assay to further characterize RNF4 as a ubiquitin E3 ligase of Sp1. 0.39 SIGNOR-278713 FOXO proteinfamily SIGNOR-PF27 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000007 14976264 NO lperfetto Sirt1 inhibited foxo3's ability to induce cell death. 0.7 SIGNOR-256644 CRP protein P02741 UNIPROT CCL2 protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004910 26961257 NO miannu In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. 0.441 SIGNOR-252144 SMO protein Q99835 UNIPROT GNG3 protein P63215 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.2 SIGNOR-199186 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1063 FGLARDIyKDPDYVR 9606 20431062 YES lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. 0.511 SIGNOR-165035 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Thr145 QKSKKHLtDNEFKDP -1 14523239 YES lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. | Edman sequencing and scintillation counting delineated T144 as the in vitro PKC phosphorylation site 0.2 SIGNOR-249234 MC3R protein P41968 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.546 SIGNOR-268702 EEF1A1 protein P68104 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269516 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14701756 YES miannu CHIP mediates the ubiquitination of Smad1. we demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process.  0.329 SIGNOR-272948 NUP214 protein P35658 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 SIGNOR-C9 12917407 YES gcesareni We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import. 0.549 SIGNOR-117644 NMDA proteinfamily SIGNOR-PF56 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor 0.2 SIGNOR-264704 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 11062529 YES gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.628 SIGNOR-84041 GGCX protein P38435 UNIPROT BGLAP protein P02818 UNIPROT up-regulates activity carboxylation 9606 31226734 YES lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. 0.686 SIGNOR-265922 CDK5 protein Q00535 UNIPROT FOXC2 protein Q99958 UNIPROT up-regulates activity phosphorylation 9606 26327394 YES miannu Cdk5 phosphorylates Foxc2 and activates Foxc2 dependent transcription. 0.35 SIGNOR-279156 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 YES gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf 0.272 SIGNOR-78685 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI MET protein P08581 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258214 MARK4 protein Q96L34 UNIPROT TNK1 protein Q13470 UNIPROT down-regulates activity phosphorylation Ser502 RMKGISRsLESVLSL 9606 BTO:0000018 34504101 YES miannu We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.Phosphorylation of TNK1 at S502 within the proline rich domain is required for TNK1 binding to 14-3-3.MARKs mediate phosphorylation at S502 and 14-3-3 binding to TNK1, which restrains the movement of TNK1 into heavy membrane-associated clusters. 0.2 SIGNOR-273865 prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI prostaglandin G2(1-) smallmolecule CHEBI:82629 ChEBI up-regulates quantity precursor of -1 7592599 YES Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, 0.8 SIGNOR-269769 P2RY6 protein Q15077 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256804 dibutyl phthalate chemical CHEBI:535597 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 10116 33508418 YES miannu Both in vitro and in vivo experiments have proved that DBP is a real activator of PPARα. he current study proves that plasticizer DBP has severe hepatotoxicity and could induce liver dysfunction even at normal doses after prolonged exposure. DBP might accumulate in the liver for a long time to activate PPARα/SREBP-1c/FAS/GPAT/AMPK and result in the accumulation of triglycerides and cholesterol in the liver. 0.8 SIGNOR-268748 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR -1 19494114 YES llicata Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases.|Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2. 0.407 SIGNOR-248708 SRC protein P12931 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr126 AKSVTCTySPALNKM 9606 BTO:0002181 25071020 YES miannu We recently found that ISGylation of the p53 tumor suppressor is an important novel mechanism to control its stability. Here we identified that Isg15-dependent regulation of p53 can be enhanced by different oncogenes. We further show that the Src-mediated phosphorylation of p53 on Tyr126 and Tyr220 has a positive effect on p53 ISGylation by enhancing Herc5 binding. 0.525 SIGNOR-276668 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19864431 YES lperfetto Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855)) 0.989 SIGNOR-188920 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 YES amattioni Bcl9 exert its function by physically linking pygo to beta-catenin. The recruitment of pygo permits beta-catenin to transcriptionally activate wnt target genes. 0.938 SIGNOR-116552 GRB2 protein P62993 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 YES gcesareni The first and second proline-rich motifs containing the grb2 n-sh3-binding consensus sequence (-p-x-x-p-x-r/k-) were implicated in the binding of hpk1 to grb2. 0.454 SIGNOR-63994 DDB1 protein Q16531 UNIPROT EDVP complex SIGNOR-C530 SIGNOR form complex binding 9606 BTO:0000007 19287380 YES miannu We named this E3 ligase complex containing EDD, DDB1 and VPRBP proteins as EDVP complex to distinguish it from the previously identified Cul4-Roc1-DDB1-VPRBP E3 ligase complex.  0.385 SIGNOR-271791 IL2 protein P60568 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 16477002 YES miannu Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c). 0.866 SIGNOR-144543 AVPR2 protein P30518 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.27 SIGNOR-256897 SRC protein P12931 UNIPROT YAP1 protein P46937-3 UNIPROT up-regulates activity phosphorylation Tyr394 QQNRFPDyLEAIPGT 10090 27013234 YES done miannu We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation. 0.63 SIGNOR-274026 MAPK14 protein Q16539 UNIPROT HBP1 protein O60381 UNIPROT up-regulates phosphorylation Ser402 GFSKNCGsPGSSQLS 9606 14612426 YES lperfetto A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression. 0.428 SIGNOR-119138 JAK2 protein O60674 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 10842319 YES Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules. 0.445 SIGNOR-251346 GSK3A protein P49840 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 YES lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. 0.2 SIGNOR-264875 HACD proteinfamily SIGNOR-PF86 SIGNOR very long-chain (R)-3-hydroxyacyl-CoA(4-) smallmolecule CHEBI:85440 ChEBI down-regulates quantity chemical modification 9606 18554507 YES miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. 0.8 SIGNOR-267917 AMPA proteinfamily SIGNOR-PF58 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 15919192 NO miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. 0.7 SIGNOR-264695 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT up-regulates activity phosphorylation Tyr183 HDDEDDSyLEPDSPE 9534 BTO:0004055 12709437 YES lperfetto By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk 0.553 SIGNOR-246592 NR0B2 protein Q15466 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11369442 YES gcesareni Surprisingly, shp potentiated transcription by pparalpha/rxralpha heterodimers from the hd-ppre. This is the first demonstration of positive transcriptional activity attributable to shp. Together, these results suggest that shp can modulate pparalpha/rxralpha-mediated transcription in a response element-specific manner. 0.532 SIGNOR-108252 AKT1 protein P31749 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation -1 16340011 YES gcesareni It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase. 0.293 SIGNOR-252739 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 YES lperfetto We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity. 0.511 SIGNOR-236455 PTPRG protein P23470 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates activity dephosphorylation Tyr84 EHSDSEMyVMPAEEN -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254692 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding -1 10219247 YES gcesareni Nterleukin-4 (il-4) is a principal regulatory cytokine during an immune response and a crucial determinant for allergy and asthma. Il-4 binds with high affinity and specificity to the ectodomain of the il-4 receptor alpha chain (il4-bp). 0.942 SIGNOR-67217 SMAD9 protein O15198 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 20957627 YES gcesareni Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. 0.684 SIGNOR-168740 AVPR1A protein P37288 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.461 SIGNOR-257077 TBK1 protein Q9UHD2 UNIPROT REL protein Q04864 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C68 16888014 YES miannu The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel. 0.578 SIGNOR-148623 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258887 DAAM1 protein Q9Y4D1 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 NO gcesareni In pcp, dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. 0.408 SIGNOR-199381 DYRK3 protein O43781 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation 9606 20167603 YES miannu DYRK1A and DYRK3 directly phosphorylate SIRT1 at Thr (522), promoting deacetylation of p53.|DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. 0.503 SIGNOR-279705 DLGAP2 protein Q9P1A6 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.849 SIGNOR-264590 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004850 23645839 NO miannu AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Here, we show that AE also induces expression of the Cox-2 gene and activates β-catenin in mouse bone marrow cells. 0.2 SIGNOR-255683 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination Lys779 TKWMEHVkLERLKQV 9606 BTO:0000938 17283082 YES lperfetto Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage. 0.67 SIGNOR-249576 PLD1 protein Q13393 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 9873061 YES gcesareni The primary known function of phospholipase d (pld) is to generate phosphatidic acid (pa) via the hydrolysis of phosphatidylcholine. . phospholipase d (pld) hydrolyzes phospholipids to generate phosphatidic acid (pa). 0.8 SIGNOR-62882 SNCA protein P37840 UNIPROT Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR up-regulates 9606 12666095 NO lperfetto A key observation linking alpha-synuclein to PD was the demonstration that it is one of the principal components of Lewy bodies. Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein. 0.7 SIGNOR-249700 PRPF19 protein Q9UMS4 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR form complex binding 9606 BTO:0000567 20176811 YES miannu In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27. 0.793 SIGNOR-271968 CAMK1 protein Q14012 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity phosphorylation Thr198 PGLRRRQt 10090 23707388 YES Monia We also demonstrate that i) CaMKI phosphorylates p27 at Thr157and Thr198 in human cells and at Thr170and Thr197in mouse cells to modulate its subcellular localization;|Collectively, these results suggest that CaMKI is involved in mediating G1 progression by promoting cyclin D1/cdk4 complex formation through site-specific p27 phosphorylation in human lung epithelia. 0.305 SIGNOR-261194 SUCLG1 protein P53597 UNIPROT Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR form complex binding 9606 32627745 YES miannu Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). 0.986 SIGNOR-266261 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203600 TNF protein P01375 UNIPROT TNFRSF21 protein O75509 UNIPROT up-regulates binding 9606 BTO:0000142 9714541 YES gcesareni We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain. 0.337 SIGNOR-59745 KLF13 protein Q9Y2Y9 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 YES miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. 0.433 SIGNOR-222437 PSMA6 protein P60900 UNIPROT XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization binding -1 19941857 YES 1 miannu We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination. 0.304 SIGNOR-239039 PRKACA protein P17612 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates activity phosphorylation Thr2159 NGATEQRtSSKESSP -1 17088250 YES miannu Short C-terminal splice variant of betaII-spectrin (betaIISigma2) is a substrate for phosphorylation. protein kinase A phosphorylates Thr-2159. Mammalian alphaII- and betaII-spectrin subunits form dimers that associate head to head with high affinity to form tetramers In vitro, protein kinase A phosphorylation of an active fragment of betaIISigma2 greatly reduced its interaction with alphaII-spectrin at the tetramerization site. 0.331 SIGNOR-250054 TOMM70 protein O94826 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates activity binding 9534 12526792 YES miannu The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting. 0.2 SIGNOR-261380 SRC protein P12931 UNIPROT AP2B1 protein P63010 UNIPROT down-regulates phosphorylation Tyr737 THRQGHIyMEMNFTN 9606 18938240 YES gcesareni The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin. 0.272 SIGNOR-181743 ATM protein Q13315 UNIPROT BLM protein P54132 UNIPROT up-regulates phosphorylation Thr99 NAPAGQEtQRGGSKS 9606 12034743 YES lperfetto Mitotic phosphorylation of blm was partially dependent on atm, and phosphorylation sites on blm were identified. A phosphospecific antibody against one of these sites (thr-99) revealed radiation-induced phosphorylation, which was defective in ataxia-telangiectasia cells. These data suggest that atm and blm function together in recognizing abnormal dna structures by direct interaction and that these phosphorylation sites in blm are important for radiosensitivity status but not for sce frequency. 0.775 SIGNOR-88010 RDH5 protein Q92781 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI down-regulates quantity chemical modification 9606 21621639 YES lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10 0.8 SIGNOR-265113 TARS1 protein P26639 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates quantity chemical modification 9606 25824639 YES miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 0.8 SIGNOR-270506 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 20185585 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-163941 CEBPD protein P49716 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000792 20385105 NO miannu Expression of CEBPD reduced cisplatin-induced reactive oxygen species (ROS) and apoptosis in NTUB1 cells by inducing the expression of Cu/Zn-superoxide dismutase (SOD1) via direct promoter transactivation. 0.2 SIGNOR-253774 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 7901013 YES The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax 0.267 SIGNOR-34682 calcium(2+) smallmolecule CHEBI:29108 ChEBI GSN protein P06396 UNIPROT up-regulates activity chemical activation 9606 BTO:0000132 27871158 YES lperfetto Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. 0.8 SIGNOR-261844 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr115 LTSQLHItPGTAYQS 9606 10617621 YES lperfetto Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis 0.2 SIGNOR-73638 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000176 14967450 YES lperfetto Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.606 SIGNOR-121997 Ub:E2 complex SIGNOR-C497 SIGNOR NFX1 protein Q12986 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271015 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Ser325 VRRVPGSsGRLHKTE 9606 17190791 YES gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1) 0.485 SIGNOR-151659 TUBE1 protein Q9UJT0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 NO miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation 0.7 SIGNOR-267178 TTL protein Q8NG68 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates tyrosination 9606 22020298 YES miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization 0.2 SIGNOR-266826 DUSP3 protein P51452 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0002552 21262974 YES We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. 0.358 SIGNOR-248532 (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity precursor of 9606 10720211 YES lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. 0.8 SIGNOR-253141 GABRB3 protein P28472 UNIPROT GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR form complex binding 9606 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.475 SIGNOR-263772 ATP6AP1 protein Q15904 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.589 SIGNOR-277752 GPR132 protein Q9UNW8 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256802 NEK8 protein Q86SG6 UNIPROT NEK8 protein Q86SG6 UNIPROT up-regulates activity phosphorylation Thr162 SSKSKAYtVVGTPCY -1 11864968 YES miannu Multimerization and autophosphorylation of Nek8 are important for its activation.Our data suggests that one site for Nek8 autophosphorylation may be Thr-210 within the activation loop. 0.2 SIGNOR-250298 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 BTO:0000848 12793438 YES lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway 0.741 SIGNOR-236155 MAP4K4 protein O95819 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 YES gcesareni Hpk1 binds and phosphorylates mekk1 directly 0.557 SIGNOR-44040 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1644 SPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248781 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 17063185 YES flangone Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively 0.713 SIGNOR-150197 CDK14 protein O94921 UNIPROT CCNY protein Q8ND76 UNIPROT down-regulates quantity by destabilization phosphorylation Ser73 STIFLSKsQTDVREK 9606 BTO:0000599 24794231 YES lperfetto Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation|Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex 0.829 SIGNOR-273007 N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide chemical CHEBI:47322 ChEBI CSNK1E protein P49674 UNIPROT down-regulates chemical inhibition 9606 11524435 YES amattioni Cki-7, an inhibitor of ck1epsilon 0.8 SIGNOR-110053 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 18439900 YES lperfetto The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress. 0.467 SIGNOR-216430 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Thr169 FLPRHRDtGILDSIG -1 2413024 YES miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-165 0.347 SIGNOR-250015 GNAO1 protein P09471 UNIPROT TRIM21 protein P19474 UNIPROT up-regulates activity binding 9606 BTO:0006001 39580518 YES Marta Tosoni These data demonstrate that GNAO1 recruits TRIM21 and mediates CREB ubiquitination and degradation to promote GSC differentiation. 0.2 SIGNOR-278069 ER stress stimulus SIGNOR-ST9 SIGNOR ATF4 protein P18848 UNIPROT up-regulates 9606 23205607 NO lperfetto Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress 0.7 SIGNOR-253728 CASP8AP2 protein Q9UKL3 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates binding 9606 22075988 YES lperfetto In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex. 0.246 SIGNOR-217385 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192617 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 10090 BTO:0002882 16122376 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work 0.2 SIGNOR-235956 IRX1 protein P78414 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.2 SIGNOR-261651 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12603837 YES Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. 0.965 SIGNOR-98724 PKA proteinfamily SIGNOR-PF17 SIGNOR NKD2 protein Q969F2 UNIPROT up-regulates quantity by stabilization phosphorylation Ser223 SAHVRRPsTDPQPCS 9606 BTO:0000007 30941853 YES done miannu VIP and PGE2 rapidly activate protein kinase A (PKA) that then phosphorylates NKD2 at Ser-223, a process that is facilitated by the molecular scaffold A-kinase anchoring protein 12 (AKAP12). This phosphorylation stabilized NKD2, ensuring efficient cell-surface delivery of TGFα and increased EGFR activation. 0.2 SIGNOR-273782 ZNF804A protein Q7Z570 UNIPROT ANKRD1 protein Q15327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 YES miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 0.2 SIGNOR-269461 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 11062067 YES amattioni Jnk full activation requires the phosphorylation of a threonine and a tyrosine residue in a thr-pro-tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (mkk)4 and mkk7. Mkk7 shows a striking preference for the threonine residue (thr-183). 0.698 SIGNOR-83736 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser705 LPEPAKKsEELVAEA 9606 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251283 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT down-regulates activity relocalization 10090 10433919 YES lperfetto Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling 0.888 SIGNOR-129068 IRF5 protein Q13568 UNIPROT IL10 protein P22301 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000801 21240265 NO The role of IRF5 in inhibiting the transcription of the gene encoding IL-10 that we have identified here is important given its well- documented immunosuppressive activity. 0.424 SIGNOR-254514 ATF4 protein P18848 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 26086088 YES miannu Transcription Factor ATF4 Induces NLRP1 Inflammasome Expression During Endoplasmic Reticulum Stress. Here we report that expression of NLRP1, a core inflammasome component, is specifically up-regulated during severe ER stress conditions in human cell lines. Both IRE1α and PERK, but not the ATF6 pathway, modulate NLRP1 gene expression. Furthermore, using mutagenesis, chromatin immunoprecipitation and CRISPR-Cas9-mediated genome editing technology, we demonstrate that ATF4 transcription factor directly binds to NLRP1 promoter during ER stress. 0.282 SIGNOR-260354 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNA13 protein Q14344 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 YES inferred from 70% family members milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. 0.2 SIGNOR-269965 LATS1 protein O95835 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 21808241 YES Together,the YAP/TAZ-TEAD complex promotes proliferative and survival programs. gcesareni Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators. 0.79 SIGNOR-175783 CXCL1 protein P09341 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 YES gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. 0.2 SIGNOR-152591 ACADM protein P11310 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR up-regulates 9606 BTO:0001370 28974683 NO lperfetto This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation 0.7 SIGNOR-261265 Ub:E2 complex SIGNOR-C497 SIGNOR RING1 protein Q06587 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270984 SRR protein Q9GZT4 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 10090 BTO:0000142 12393813 YES lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. 0.8 SIGNOR-268268 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0004573 18809579 YES miannu O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.  0.493 SIGNOR-271746 (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI TET2 protein Q6N021 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001883 29090344 YES miannu Various studies have tried to investigate how the accumulation of R2-HG promotes leukemogenesis in cooperation with other frequently observed mutations in AML. An important role appears to be the ability of R2-HG to competitively inhibit multiple αKG-dependent dioxygenases. While TET2 normally catalyzes the conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), inhibition of TET2 by R2-HG has been found to result in a hypermethylated gene signature in HSPCs, which overlaps with the signatures of both IDH and TET2-mutated leukemic cells. 0.8 SIGNOR-261829 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser497 EFDEDDWsD 9606 19012317 YES gcesareni Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo. 0.2 SIGNOR-182362 AKT1 protein P31749 UNIPROT HTT protein P42858 UNIPROT unknown phosphorylation Ser419 GGRSRSGsIVELIAG 9606 BTO:0000938 12062094 YES llicata We demonstrate that huntingtin is a substrate of akt and that phosphorylation of huntingtin by akt is crucial to mediate the neuroprotective effects of igf-1. 0.553 SIGNOR-252590 SMAD1 protein Q15797 UNIPROT SMAD6 protein O43541 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.578 SIGNOR-268935 PYCARD protein Q9ULZ3 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.822 SIGNOR-256411 PKNOX1 protein P55347 UNIPROT SYP protein P08247 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20864515 NO miannu Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content. 0.2 SIGNOR-254923 BAZ1B protein Q9UIG0 UNIPROT WICH complex SIGNOR-C449 SIGNOR form complex binding 9606 16603771 YES miannu We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling. 0.925 SIGNOR-268828 ID1 protein P41134 UNIPROT TCF12 protein Q99081 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C128 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.584 SIGNOR-241104 PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 29681515 NO apalma Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7, facilitating the recruitment of the ASH2L:MLL1/2:WDR5:RBBP5 histone H3 lysine 4 (H3K4) methyltransferase complex to the proximal promoter of Myf5 resulting in permissive H3K4 tri-methylation (H3K4me3) of the surrounding chromatin 0.492 SIGNOR-255899 FGFR2 protein P21802 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276184 FBXO15 protein Q8NCQ5 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0005816 24703837 YES miannu Fbxo15 Targets CLS1 Protein for Ubiquitination and Degradation to Disrupt Mitochondrial Function. S. aureus infection induces expression of a kinase, PINK1, that phosphorylates an indispensable protein CLS1, which in turn triggers CLS1 ubiquitination and degradation by the F box protein (SCFFbxo15). 0.524 SIGNOR-272171 CD70 protein P32970 UNIPROT CD27 protein P26842 UNIPROT up-regulates binding 9606 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000672 8120384 YES gcesareni The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. 0.771 SIGNOR-36357 HUWE1 protein Q7Z6Z7 UNIPROT POLL protein Q9UGP5 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys27 ASSKVLAkIPRREEG 9606 BTO:0000567 22203964 YES miannu We found that Pol λ can be ubiquitinated by the E3 ligase Mule in vitro and in vivo and that this interaction is functionally connected to the phosphorylation-dependent stabilization of Pol λ by Cdk2/cyclinA.  0.309 SIGNOR-272904 promethazine chemical CHEBI:8461 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257788 HCFC1 protein P51610 UNIPROT ZBTB17 protein Q13105 UNIPROT down-regulates activity binding 9534 BTO:0001538 12244100 YES miannu We show here that HCF-1 directly binds to the Myc-interacting protein Miz-1. HCF-1 Represses Gal4-Miz-1-mediated Transcriptional Activation 0.345 SIGNOR-223590 RAD51C protein O43502 UNIPROT RAD51B/RAD51C complex SIGNOR-C65 SIGNOR form complex binding 9606 11751636 YES miannu We show that two of them, rad51b and rad51c, are associated in a stable complex. Rad51b-rad51c complex has ssdna binding and ssdna-stimulated atpase activities. 0.659 SIGNOR-113388 GNAI1 protein P63096 UNIPROT HCK protein P08631 UNIPROT up-regulates activity binding -1 11007482 YES Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases. 0.346 SIGNOR-256528 Pyridostigmine chemical CHEBI:8665 ChEBI ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition -1 20627738 YES Luana The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors  0.8 SIGNOR-257879 genistein chemical CHEBI:28088 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258599 GAK protein O14976 UNIPROT CLTC protein Q00610 UNIPROT up-regulates activity phosphorylation Thr606 ILGNQMFtHYDRAHI 10090 31272276 YES miannu Clathrin heavy chain (CHC) was phosphorylated at T606 by its association partner cyclin G-associated kinase (GAK). This phosphorylation was required for proper cell proliferation and tumor growth of cells implanted into nude mice.  0.857 SIGNOR-275448 gossypol chemical CHEBI:28584 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 23336025 YES gcesareni Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol. 0.8 SIGNOR-200469 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9753485 YES Crohn's Disease gcesareni 0.8 SIGNOR-251690 RB1CC1 protein Q8TDY2 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR form complex binding 9606 23863160 YES lperfetto In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. 0.916 SIGNOR-209887 PVR protein P15151 UNIPROT CD226 protein Q15762 UNIPROT up-regulates activity binding 9606 BTO:0000914 30591568 YES lperfetto We focused on receptor-ligand interactions between CAFs and NK cell and found that cell-surface poliovirus receptor (PVR/CD155), a ligand of activating NK receptor DNAM-1, was downregulated in the CAFs compared with NEFs. |Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12). 0.82 SIGNOR-261424 FNTA protein P49354 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity 9606 24294527 YES lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. 0.414 SIGNOR-242568 ST6GAL1 protein P15907 UNIPROT CD22 protein P20273 UNIPROT down-regulates activity glycosylation Asn101 FLGDKNKnCTLSIHP -1 8702538 YES lperfetto CD22-ligand interaction is regulated by the activity of a b-galactoside a2,6- sialyltransferase that can inactivate CD22-mediated binding by sialylating the CD22 receptor itself. These observations suggest that N-linked glycosylation sites on the CD22 molecule may play a role in the regulation of CD22-mediated adhesion. 0.472 SIGNOR-261741 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 YES gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.708 SIGNOR-183644 PPARGC1A protein Q9UBK2 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 23277535 NO gcesareni PGC1a is a positive regulator of mitochondrial biogenesis and respiration, adaptive thermogenesis, gluconeogenesis as well as many other metabolic proc 0.7 SIGNOR-228618 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr465 VPVPTNLyGDFFTGD -1 10210201 YES llicata Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624. 0.572 SIGNOR-250784 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257469 CDK1 protein P06493 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 14697231 YES gcesareni Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase. 0.508 SIGNOR-120368 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates phosphorylation Thr531 NTTGSDNtDTEGS 9606 17936701 YES lperfetto Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo 0.346 SIGNOR-158414 HOXA10 protein P31260 UNIPROT PHGDH protein O43175 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19778996 NO miannu PHGDH is expressed in both endometrial epithelial and stromal cells. HOXA10 represses endometrial PHGDH expression. 0.298 SIGNOR-254468 FXN protein Q16595 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 YES lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. 0.769 SIGNOR-262125 Ub:E2 complex SIGNOR-C497 SIGNOR BARD1 protein Q99728 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271102 HAP1 protein P54257 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates activity binding -1 12881483 YES lperfetto We identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2 0.328 SIGNOR-234602 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.2 SIGNOR-258999 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr809 DIMNDSNyIVKGNAR 9606 BTO:0001271 15297464 YES lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. 0.2 SIGNOR-127618 SOHLH1 protein Q5JUK2 UNIPROT LHX8 protein Q68G74 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16690745 YES Luana Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters. 0.486 SIGNOR-266076 PPP1CA protein P62136 UNIPROT NMDA proteinfamily SIGNOR-PF56 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0000142 14751588 YES miannu DARPP-32/PP1 cascade modulates the physiological properties of NMDA and AMPA receptors, and activation of the DARPP-32/PP1 signaling leads to parallel increase in the phosphorylation of NMDA receptor subunits and intracellular Ca2+ levels 0.2 SIGNOR-265061 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules 0.434 SIGNOR-171066 MAX protein P61244 UNIPROT MXD3 protein Q9BW11 UNIPROT up-regulates activity binding 9606 7954804 YES 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. 0.468 SIGNOR-240393 SYVN1 protein Q86TM6 UNIPROT GPR37 protein O15354 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 18241051 YES miannu We demonstrated that endogenous HRD1 interacts with Pael-R, and that HRD1 promotes the degradation of Pael-R and protects cell death caused by the accumulation of Pael-R. 0.401 SIGNOR-272631 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 YES gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. 0.497 SIGNOR-187603 SIRT3 protein Q9NTG7 UNIPROT SOD2 protein P04179 UNIPROT up-regulates activity deacetylation 34929314 YES lperfetto SOD2 is the key substrate of SIRT3 in mitochondria. The combination of SIRT3 and SOD2 leads to the deacetylation and activation of SOD2 0.653 SIGNOR-267646 ZEB1 protein P37275 UNIPROT GRHL2 protein Q6ISB3 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 23814079 NO miannu we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. 0.432 SIGNOR-255623 SRR protein Q9GZT4 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity chemical modification 10090 BTO:0000142 12393813 YES lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. 0.8 SIGNOR-268270 ACTB protein P60709 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.504 SIGNOR-270599 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser279 VLKRPERsQEESPPG 9606 20068082 YES gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); 0.856 SIGNOR-163142 RBBP8 protein Q99708 UNIPROT BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding phosphorylation:Ser327 ELPTRVSsPVFGATS 25400280 YES lperfetto The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2|The interaction between BRCA1 and CtIP within this complex is mediated by CDK‐dependent phosphorylation of CtIP‐S327 0.2 SIGNOR-263220 GRB7 protein Q14451 UNIPROT RND1 protein Q92730 UNIPROT up-regulates binding 9606 BTO:0000150 10664463 YES gcesareni We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo. 0.593 SIGNOR-74914 PPP2CA protein P67775 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 19951945 YES gcesareni Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a. 0.2 SIGNOR-161919 ARHGAP27 protein Q6ZUM4 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.588 SIGNOR-260482 LBX1 protein P52954 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 19651985 YES Luana Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively  0.32 SIGNOR-266053 MFGE8 protein Q08431 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR down-regulates activity 10116 19020771 NO Giorgia In our current study, we have shown that after LPS-stimulation, MFG-E8-mediated apoptotic cell phagocytosis suppresses various ERK1/2, p38, JNK, and NFκB activation, resulting in a lower TNF-α release. We also explored whether MFG-E8 helps to suppress the proinflammatory pathway within RPMs. We hence incubated the macrophages with apoptotic cells and stimulated them with LPS and examined the activation of MAP kinase and NFkB pathways after the exogenous addition of recombinant MFG-E8 (rMFG-E8). While apoptotic cells alone had no effect on these pathways, the addition of rMFG-E8 to apoptotic cells prior to phagocytosis and LPS stimulation had a marked suppressive effect on all of the investigated pathways, particularly on the p38 and NFκB pathways that play a key role in the cytokine response of macrophages 0.246 SIGNOR-260651 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCD protein Q05655 UNIPROT down-regulates chemical inhibition 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-190350 CSNK1D protein P48730 UNIPROT PPP5C protein P53041 UNIPROT up-regulates activity phosphorylation Thr362 LFSEDGVtLDDIRKI 9606 BTO:0000007 29141220 YES miannu  Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90.  0.334 SIGNOR-277373 CALM2 protein P0DP24 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates binding 9606 11796223 YES inferred from 70% of family members miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.588 SIGNOR-269888 JUN protein P05412 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23936544 YES lperfetto MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production 0.541 SIGNOR-251713 nefazodone chemical CHEBI:7494 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition -1 9871604 YES miannu Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency 0.8 SIGNOR-259069 KIF1A protein Q12756 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272522 ATP6V0B protein Q99437 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.702 SIGNOR-277758 Alamandine chemical CID:44192273 PUBCHEM MRGPRD protein Q8TDS7 UNIPROT up-regulates activity binding 10029 BTO:0000246 23446738 YES Luana Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. 0.8 SIGNOR-262308 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr319 TPVVSVTtPSLPPQG 9606 9858528 YES lperfetto We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a 0.66 SIGNOR-62784 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr116 PNLFVALyDFVASGD -1 34144039 YES miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. 0.303 SIGNOR-277304 PAX1 protein P15863 UNIPROT MEOX2 protein P50222 UNIPROT up-regulates activity binding -1 11423130 YES miannu We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family. 0.41 SIGNOR-222232 JAG2 protein Q9Y219 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 9315665 YES gcesareni Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1. 0.624 SIGNOR-236922 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser26 GTASRPSsSRSYVTT -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248882 RPS6KA1 protein Q15418 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 14625384 YES gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-265346 DOT1L protein Q8TEK3 UNIPROT MYCBP2 protein O75592 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 YES miannu Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly. 0.2 SIGNOR-267151 ITGB1BP1 protein O14713 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.314 SIGNOR-257651 PRKCA protein P17252 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 YES lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. 0.522 SIGNOR-249259 PRKCB protein P05771 UNIPROT VIM protein P08670 UNIPROT up-regulates quantity phosphorylation 9606 23974215 YES miannu PKCbeta induces vimentin phosphorylation in MCP-1-activated human monocytes. 0.2 SIGNOR-278984 DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 21034966 NO lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. 0.7 SIGNOR-242612 PCSK2 protein P16519 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 YES miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. 0.2 SIGNOR-270335 DIP2A protein Q14689 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification -1 30672040 YES miannu In this paper, we summarized the conservation of gene sequences and protein domains of DIP2 family members and predicted that they may have a similar functional role in acetyl-coenzyme A (acetyl-CoA) synthesis. We then used the most characterized member, disconnected interacting protein 2 homolog A (DIP2A), for further study. DIP2A is a cytoplasmic protein that is preferentially localized to mitochondria, and its acetyl-CoA synthetase activity has been demonstrated in vitro. Furthermore, the level of acetyl-CoA in HEK293 cells overexpressing DIP2A was increased, which is consistent with its metabolically related function. 0.8 SIGNOR-266590 serotonin smallmolecule CHEBI:28790 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264287 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268655 TET2 protein Q6N021 UNIPROT OGT protein O15294 UNIPROT up-regulates binding 9606 23353889 YES miannu Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation 0.445 SIGNOR-200695 FBXO11 protein Q86XK2 UNIPROT TP53 protein P04637 UNIPROT down-regulates neddylation Lys321 SSPQPKKkPLDGEYF 9606 17098746 YES miannu Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321 0.67 SIGNOR-150673 TWIST2 protein Q8WVJ9 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255506 IL31RA protein Q8NI17 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 18926762 YES gcesareni Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex. 0.381 SIGNOR-161430 PRKAA1 protein Q13131 UNIPROT CCNY protein Q8ND76 UNIPROT up-regulates activity phosphorylation Ser326 SARKRSAsADNLTLP 32723157 YES lperfetto Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16 0.2 SIGNOR-273011 2'-deoxyadenosine smallmolecule CHEBI:17256 ChEBI 2'-deoxyadenosine 5'-monophosphate(2-) smallmolecule CHEBI:58245 ChEBI up-regulates quantity precursor of 20637175 YES lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis 0.8 SIGNOR-275811 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.411 SIGNOR-252881 WNT11 protein O96014 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.571 SIGNOR-131637 ADRB3 protein P13945 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.62 SIGNOR-256753 BCL2 protein P10415 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 NO lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis 0.7 SIGNOR-249611 NRAS protein P01111 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 NO gcesareni Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu) 0.286 SIGNOR-157773 TEAD proteinfamily SIGNOR-PF22 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 26258633 YES miannu YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. 0.353 SIGNOR-277658 PLK1 protein P53350 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity phosphorylation Ser378 AYHEGECsAVFEASG 9606 BTO:0002181 26387737 YES miannu  Parkin Is Phosphorylated by Plk1 at Ser378 and Activated during Mitosis  0.2 SIGNOR-276938 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CEBPA protein P49715 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000011 12270934 NO lperfetto We demonstrate that exposure of post-confluent 3T3-L1 preadipocytes to insulin, isobutylmethylxanthine (MIX), dexamethasone (DEX), and fetal bovine serum induces a rapid but transient activation of MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis. We further show that activation of MEK1 significantly enhances the transactivation of the C/EBPalpha minimal promoter during the early phase of the differentiation process. 0.2 SIGNOR-235322 PRPF19 protein Q9UMS4 UNIPROT PRPF3 protein O43395 UNIPROT up-regulates activity polyubiquitination 9606 20595234 YES k63 miannu Here, we report that the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains. The K63-linked chains increase the affinity of Prp3 for the U5 snRNP component Prp8, thereby allowing for the stabilization of the U4/U6.U5 snRNP.  0.754 SIGNOR-271966 TAF1 protein P21675 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.881 SIGNOR-263932 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 12781173 YES Luana Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine. 0.8 SIGNOR-257896 Naltriben chemical CID:5486827 PUBCHEM OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258426 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.632 SIGNOR-249460 SMARCC1 protein Q92922 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.826 SIGNOR-270617 CDC25A protein P30304 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 BTO:0000093 15672448 YES gcesareni We found that cdc25a physically interacted with and de-phosphorylated phospho-erk both in vitro and in cell culture. 0.396 SIGNOR-133392 SCH 23390 chemical CHEBI:73297 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258732 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 21349850 YES gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. 0.2 SIGNOR-172239 PTPRC protein P08575 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation 9606 11124968 YES lperfetto Taken together, these data indicate that CD45 inhibits PMA dependent PKCdelta activation by impeding PMA dependent PKCdelta tyrosine phosphorylation.|reduction in CD45 expression caused the duration of peak PMA-induced MEK and extracellular signal-regulated kinase (ERK) 1/2 activity to increase from 5 min to 30 min while leading to a 4-fold increase in PMA-dependent PKCdelta activation. 0.297 SIGNOR-277028 SLC24A3 protein Q9HC58 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264391 RYK protein P34925 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 17035295 YES gcesareni Interaction between ryk and fz has been reported, suggesting that the two proteins may form a multi-receptor complex signalling through the canonical pathway 0.71 SIGNOR-150010 ARHGEF15 protein O94989 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.554 SIGNOR-260541 EIF1 protein P41567 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity 9606 14600024 NO lperfetto Binding of eIF1 to the 40S subunit would block access of the 60S 0.26 SIGNOR-269144 MAPK3 protein P27361 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser307 EPPSPPQsPRVEEAS 9606 8940068 YES gcesareni Sequential phosphorylation of hsf1 by mitogen-activated protein kinase and glycogen synthase kinase 3 at ser-303 and ser-307 represses transcriptional activation by heat shock factor-1. 0.63 SIGNOR-44999 MAPK3 protein P27361 UNIPROT MAZ protein P56270 UNIPROT up-regulates phosphorylation Thr72 AAPAPPPtPQAPAAE 9606 11809795 YES lperfetto Together, these results show that activation of saf-1 in response to il-1 and -6 is mediated via map kinase-regulated phosphorylation. 0.3 SIGNOR-114475 GOPC protein Q9HD26 UNIPROT CFTR protein P13569 UNIPROT down-regulates binding 9606 11707463 YES miannu Cal binds to cftr / cal affects insertion of cftr to the plasma membrane as well as its half-life in the plasma membrane. 0.721 SIGNOR-111671 EP300 protein Q09472 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 SIGNOR-C6 11062529 YES gcesareni The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis. 0.741 SIGNOR-83846 PRKACA protein P17612 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr90 NKQDRTLtIVDTGIG 9606 21919888 YES lperfetto Thr90 phosphorylation of hsp90_ by protein kinase a regulates its chaperone machinery 0.48 SIGNOR-176614 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser151 VLPSSKRsPSTATLS 9606 BTO:0001061 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276779 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 YES lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. 0.685 SIGNOR-109617 CSNK2A1 protein P68400 UNIPROT OTUB1 protein Q96FW1 UNIPROT up-regulates activity phosphorylation Ser16 QKQEPLGsDSEGVNC 34785775 YES lperfetto Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. |Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec 0.32 SIGNOR-276527 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11159537 NO miannu STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma. 0.708 SIGNOR-253050 TLN1 protein Q9Y490 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.798 SIGNOR-257607 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 21841788 YES lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. 0.2 SIGNOR-176054 AURKB protein Q96GD4 UNIPROT VIM protein P08670 UNIPROT down-regulates phosphorylation Ser73 SAVRLRSsVPGVRLL 9606 12458200 YES llicata By identifying eight aurora-b phosphorylation sites on vimentin in vitro, we have demonstrated that vimentin-ser-72 is an in vitrophosphorylation site of aurora-b. in vitro analyses revealed that aurora-b phosphorylates vimentin at approximately 2 mol phosphate/mol of substrate for 30 min and that this phosphorylation dramatically inhibits vimentin filament formation. 0.421 SIGNOR-96057 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 YES 14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling. 0.2 SIGNOR-251484 TP53 protein P04637 UNIPROT VCAN protein P13611 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12438652 YES miannu By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53. 0.29 SIGNOR-255441 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269364 KLF6 protein Q99612 UNIPROT DLK1 protein P80370 UNIPROT down-regulates transcriptional regulation 9606 15917248 NO Repression of dlk1 requires hdac3 deacetylase activity fspada We have identified krappel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. 0.282 SIGNOR-210016 CSNK2A1 protein P68400 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Thr145 FYLALPPtVYEAVTK 9606 BTO:0002923 37478541 YES miannu CK2 phosphorylates G6PD T145 under ionizing radiation  0.2 SIGNOR-277890 CAK complex complex SIGNOR-C456 SIGNOR RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser77 SEEMVPSsPSPPPPP 9534 BTO:0000298 10748061 YES miannu Retinoic acid receptor gamma (RARgamma) is phosphorylated in COS-1 cells at two conserved serine residues located in the N-terminal region (serines 77 and 79 in RARgamma1 and serines 66 and 68 in RARgamma2) that contains the activation function AF-1. These serines are phosphorylated in vitro by cdk7, a cyclin-dependent kinase associated to cyclin H and MAT1 in the CAK complex (cdk7.cyclin H. MAT1), that is found either free or as a component of the transcription/DNA repair factor TFIIH.  0.417 SIGNOR-275969 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 25287865 YES miannu YAP and TAZ were repeatedly isolated as binding proteins for Smads, key transducer of the TGF- and BMP signaling pathways (2, 207, 208). Cytoplasmic YAP/TAZ participate in Smad2/3 cytoplasmic retention, even overruling the ef- fects of high levels of TGF- ligands 0.2 SIGNOR-277661 EIF2B4 protein Q9UI10 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.697 SIGNOR-269137 DZIP3 protein Q86Y13 UNIPROT H2AJ protein Q9BTM1 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESQKT 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271763 TP53 protein P04637 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14985507 YES gcesareni Northern blot analysis with a specific probe demonstrates an increase in siah-1b transcription on activation of endogenous and inducible exogenous p53. To explore whether this effect is directly mediated by p53 we analyzed 20 kb of chromosome x dna, containing the siah-1b locus. A p53-binding site was identified in the siah-1b promoter, located at nucleotides -2155/-2103 relative to the translational start site. 0.373 SIGNOR-122986 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9069290 YES The effect has been demonstrated using Q06413-3 lperfetto We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation. 0.695 SIGNOR-47136 belinostat chemical CHEBI:61076 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257955 HTR2C protein P28335 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.297 SIGNOR-257013 PTPRJ protein Q12913 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12771128 YES inferred from 70% of family members gcesareni A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. 0.2 SIGNOR-269897 DDHD2 protein O94830 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269649 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates chemical activation 9606 22944199 YES lperfetto Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell). 0.8 SIGNOR-252320 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 19837374 NO apalma Treatment of monocytes with IL-10 as compared to IL-15 resulted in a two-fold greater level of phagocytosis and binding of latex beads. In summary, IL-10, in comparison to IL-15, induces greater macrophage endocytic function 0.7 SIGNOR-255442 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI CAPZA1 protein P52907 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 12788695 YES lperfetto We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations. 0.8 SIGNOR-261842 erlotinib chemical CHEBI:114785 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258212 VKORC1 protein Q9BQB6 UNIPROT Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity chemical modification 9606 31226734 YES lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) 0.8 SIGNOR-265905 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 12361602 YES apalma Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk 0.95 SIGNOR-255380 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269370 Golimumab (Simponi) antibody DB06674 DRUGBANK TNF protein P01375 UNIPROT down-regulates activity binding 9606 33369527 YES Golimumab is a transgenic anti-TNF monoclonal antibody that acts primarily by targeting and neutralizing TNF, thus preventing inflammation. 0.4 SIGNOR-272491 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR POLR2A protein P24928 UNIPROT down-regulates phosphorylation 9606 14662762 YES inferred from 70% family members lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.2 SIGNOR-270156 BLVRB protein P30043 UNIPROT bilirubin(2-) smallmolecule CHEBI:57977 ChEBI down-regulates quantity chemical modification 9606 BTO:0000759 7929092 YES lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 0.8 SIGNOR-275523 ANXA1 protein P04083 UNIPROT FPR1 protein P21462 UNIPROT up-regulates activity binding 9606 BTO:0000007 15187149 YES We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2. 0.742 SIGNOR-259439 FGF5 protein P12034 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates binding 9606 8386828 YES gcesareni Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2. 0.699 SIGNOR-38704 GSK3B protein P49841 UNIPROT EIF2B2 protein P49770 UNIPROT down-regulates binding 9606 21798082 YES gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). 0.2 SIGNOR-175475 PRKCD protein Q05655 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.567 SIGNOR-251631 STOM protein P27105 UNIPROT SLC2A1 protein P11166 UNIPROT down-regulates activity binding 9606 10562431 YES Giulio Similar to the results obtained in the RBC, Glut1 and stomatin immunoprecipitated with each other in lysates of Clone 9 cells. The above results suggest that stomatin is closely associated with Glut1 in the plasma membrane and that overexpression of stomatin results in a depression in the basal rate of glucose transport. 0.528 SIGNOR-261278 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr183 TLLMKKDtLTEEETQ 9606 BTO:0000567 26057687 YES miannu Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis.  0.316 SIGNOR-276913 FBXO7 protein Q9Y3I1 UNIPROT WDR62 protein O43379 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Thr1053 PSSSLPQtPEQEKFL 30566428 YES lperfetto WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053 0.2 SIGNOR-271711 Ub:E2 complex SIGNOR-C497 SIGNOR HERC3 protein Q15034 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271291 RPA2 protein P15927 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19586055 YES esanto The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. We observe a direct interaction between rpa with both nbs1 and mre11. By utilizing rpa bound to ssdna, we demonstrate that substituting rpa with phosphorylated rpa or a phosphomimetic weakens the interaction with the mrn complex. 0.547 SIGNOR-186651 EEF1A2 protein Q05639 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 NO lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.7 SIGNOR-269394 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 14585074 YES lperfetto Tradd mediates recruitment of the traf2 adaptor protein 0.87 SIGNOR-118770 FBXO11 protein Q86XK2 UNIPROT BCL6 protein P41182 UNIPROT down-regulates binding 9606 BTO:0000785 22113614 YES miannu Fbxo11 targets bcl6 for degradation 0.491 SIGNOR-177652 HIF1A protein Q16665 UNIPROT CCL2 protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001496 17474992 YES lperfetto These findings suggest that both MCP-1 and MCP-5 are HIF-1 target genes and that HIF-1α is involved in transcriptional induction of these two chemokines in astrocytes by hypoxia. 0.403 SIGNOR-251719 Ub:E2 complex SIGNOR-C497 SIGNOR RNF20 protein Q5VTR2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271111 DLL1 protein O00548 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. 0.2 SIGNOR-209741 CDK5 protein Q00535 UNIPROT SYN1 protein P17600 UNIPROT up-regulates phosphorylation Ser551 PAARPPAsPSPQRQA 9606 10880969 YES lperfetto Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin. 0.564 SIGNOR-78883 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR FGFR4 protein P22455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 YES miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. 0.2 SIGNOR-251569 TBX21 protein Q9UL17 UNIPROT IL4 protein P05112 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000782 17541280 NO IL-4 gene transcription is inhibited by T-bet via the suppression of its promoter activity, independently of IFN-gamma. T-bet facilitates Th1 differentiation through not only upregulation of IFN-gamma, but also downregulation of IL-4 gene transcription 0.478 SIGNOR-254496 CDK1 protein P06493 UNIPROT NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser55 NKFLENKsPWRKMVH 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275590 UVB radiation stimulus SIGNOR-ST17 SIGNOR GCH1 protein P30793 UNIPROT up-regulates 9606 9204951 NO miannu UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine. 0.7 SIGNOR-252206 CDK1 protein P06493 UNIPROT SYN3 protein O14994 UNIPROT up-regulates phosphorylation Ser470 PQGQQPLsPQSGSPQ 9606 14732590 YES lperfetto A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. 0.2 SIGNOR-121398 PLK1 protein P53350 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation 23972993 YES For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP 0.297 SIGNOR-274053 TGFB1 protein P01137 UNIPROT PPP2R2A protein P63151 UNIPROT up-regulates activity binding 9606 19114990 YES lperfetto The Balpha subunit interacts directly with activated T_RI. The Balpha interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity 0.383 SIGNOR-217894 isoprenaline chemical CHEBI:64317 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8982677 YES miannu K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists. 0.8 SIGNOR-258578 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 1178183 YES gcesareni Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge. 0.512 SIGNOR-16047 IDH1 protein O75874 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI down-regulates quantity 9606 26178471 YES lperfetto Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG) 0.8 SIGNOR-253137 HTR4 protein Q13639 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257041 MAPK1 protein P28482 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser50 SPTFRSDsPVPTAPT 9606 BTO:0000007 33217317 YES miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.274 SIGNOR-265946 MTHFD1L protein Q6UB35 UNIPROT formate smallmolecule CHEBI:15740 ChEBI up-regulates quantity chemical modification 9606 16171773 YES lperfetto A human mitochondrial isozyme of C1-tetrahydrofolate (THF) synthase was previously identified by its similarity to the human cytoplasmic C1-THF synthase. All C1-THF synthases characterized to date, from yeast to human, are trifunctional, containing the activities of 5,10-methylene-THF dehydrogenase, 5,10-methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase. Here we report on the enzymatic characterization of the recombinant human mitochondrial isozyme. Enzyme assays of purified human mitochondrial C1-THF synthase protein revealed only the presence of 10-formyl-THF synthetase activity. 0.8 SIGNOR-268254 GRM3 protein Q14832 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264353 SRC protein P12931 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Tyr1115 PVWMNYSySSLCLSS 9606 BTO:0002181 25805816 YES miannu Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4.  0.2 SIGNOR-276895 PPM1A protein P35813 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity dephosphorylation -1 10934208 YES miannu Moreover, purified recombinant PP2C alpha and PP2C beta 2 proteins efficiently dephosphorylated monomeric Cdk2/Cdk6 in vitro. 0.292 SIGNOR-277107 YY1 protein P25490 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15899857 NO miannu YY1, a constitutively expressed multifunctional transcription factor, activates the Grp78 promoter only under ER stress conditions. 0.304 SIGNOR-255620 MAPK1 protein P28482 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 YES gcesareni Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability. 0.346 SIGNOR-77651 PRKCZ protein Q05513 UNIPROT ADARB1 protein P78563 UNIPROT up-regulates activity phosphorylation Ser211 GDLSLSAsPVPASLA 9606 BTO:0001615 29694894 YES miannu  Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.  0.2 SIGNOR-277392 Ub:E2 complex SIGNOR-C497 SIGNOR HERC1 protein Q15751 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271306 ELANE protein P08246 UNIPROT SERPIND1 protein P05546 UNIPROT down-regulates activity cleavage Val458 QATTVTTvGFMPLST -1 2318847 YES miannu Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC. 0.451 SIGNOR-256510 AKT proteinfamily SIGNOR-PF24 SIGNOR SH2B2 protein O14492 UNIPROT unknown phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 YES Serine 588 of APS is a newly identified target for protein kinase B in intact cells and in vitro. The precise function of this PKB-mediated phosphorylation event is not entirely clear but may be responsible for regulating cellular localization and will be the subject of future investigation. 0.2 SIGNOR-251487 BZLF1 protein P03206 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity binding 9606 BTO:0002181 20381110 YES scontino We have shown that Epstein-Barr virus (EBV) IE protein Zta (BZLF1) physically interacts with IRF7, inhibiting its ability to activate the IFN-α, IFN-β, and Tap2 promoters 0.2 SIGNOR-266643 BRLF1 protein P03209 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 20381110 YES scontino EBV Rta selectively down-regulates the expression of IRF3 and IRF7, the main regulators of the Type I IFNs. 0.2 SIGNOR-266645 LMP1 protein P03230 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity sumoylation 9606 BTO:0002181 22951831 YES scontino One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. 0.2 SIGNOR-266951 LF2 protein P0C725 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity binding 9606 BTO:0002181 18987133 YES scontino EBV LF2 tegument protein specifically interacts with the central inhibitory association domain of IRF7, and this interaction leads to inhibition of the dimerization of IRF7, which suppresses IFN-alpha production and IFN-mediated immunity. 0.2 SIGNOR-266632 LAMTOR2 protein Q9Y2Q5 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 YES lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant 0.927 SIGNOR-164772 FLI1 protein Q01543 UNIPROT GP9 protein P14770 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002581 15466856 NO miannu Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. 0.248 SIGNOR-254160 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000150 10550055 YES lperfetto Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint. 0.819 SIGNOR-72052 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr771 ADIESSNyMAPYDNY -1 7545675 YES Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides 0.69 SIGNOR-248415 DZIP3 protein Q86Y13 UNIPROT H2AW protein Q7L7L0 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271757 EEF1A1P5 protein Q5VTE0 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269544 GART protein P22102 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 11381136 YES miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. 0.8 SIGNOR-267304 CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 YES lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. 0.638 SIGNOR-133267 CHKA protein P35790 UNIPROT SRC protein P12931 UNIPROT down-regulates activity phosphorylation Tyr530 FTSTEPQyQPGENL 9606 28784162 YES miannuccelli Figure XREF_FIG shows that even though Chk phosphorylated Tyr 527 of Src to a level much lower than that of Csk, it was a much more efficient inhibitor of Src kinase activity.|These results suggest that Chk inhibited Src with a mechanism independent of Tyr-527 phosphorylation. 0.337 SIGNOR-279731 Neuromedin B smallmolecule CHEBI:80139 ChEBI NMBR protein P28336 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257547 PRKCD protein Q05655 UNIPROT ADCY7 protein P51828 UNIPROT up-regulates activity phosphorylation 9606 12454008 YES miannu Immunoprecipitation data indicated that PKCdelta could bind and directly phosphorylate AC7. 0.554 SIGNOR-279258 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser644 NLMFRKFsLERPFRP -1 24548923 YES miannu Akt phosphorylates S637 and S645 in the linker region of Carma1  0.523 SIGNOR-276621 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe709 ENPTYKFfEQMQN -1 8943232 YES lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261777 MPO-ANCA complex SIGNOR-C474 SIGNOR superoxide smallmolecule CHEBI:18421 ChEBI up-regulates 10090 BTO:0000133 15972951 NO lperfetto Anti-MPO IgG (250 μg/ml) induces significant superoxide anion production in TNF-α-primed peritoneal exudate cells from WT C57BL/6 mice (black bars) as compared to normal mouse IgG (250 μg/ml) or buffer alone. 0.8 SIGNOR-270589 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser300 SMSDPGVsYRTREEI -1 11485553 YES lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. 0.794 SIGNOR-109555 TFEB protein P19484 UNIPROT CD36 protein P16671 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) 0.2 SIGNOR-276785 GRB10 protein Q13322 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0001516 23246379 YES Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation 0.334 SIGNOR-255946 SNRPD2 protein P62316 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.838 SIGNOR-270636 PLK1 protein P53350 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Ser1817 GDSIADVsIMYSEEL 9606 BTO:0000567 26192437 YES phosphosite is derived from Fig 2 lperfetto Here we show that LRRK1 is a PLK1 substrate that is phosphorylated on Ser 1790. PLK1 phosphorylation is required for CDK1-mediated activation of LRRK1 at the centrosomes 0.346 SIGNOR-275467 FBP1 protein P09467 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 30616754 YES lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle 0.8 SIGNOR-267611 DLAT protein P10515 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 YES miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. 0.856 SIGNOR-266546 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 YES gcesareni Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical _-catenin pathway 0.7 SIGNOR-198843 ethanol chemical CHEBI:16236 ChEBI SLC44A2 protein Q8IWA5 UNIPROT up-regulates quantity 9606 BTO:0003065 21367571 NO lperfetto Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it 0.8 SIGNOR-260407 TRAF6 protein Q9Y4K3 UNIPROT HK2 protein P52789 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 28980855 YES The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. 0.2 SIGNOR-260003 F2 protein P00734 UNIPROT F7 protein P08709 UNIPROT up-regulates activity 9606 BTO:0000131 29880919 YES lperfetto Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind 0.301 SIGNOR-263529 MAPK1 protein P28482 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 YES lpetrilli Phosphorylation of thr276 is shown to be important for tgf-?-Induced nuclear accumulation and, as a consequence, transcriptional activity of smad4. these results suggest that smad4 can be phosphorylated by erk2 at thr276. 0.511 SIGNOR-101660 MAPK12 protein P53778 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 YES lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 0.2 SIGNOR-264448 MAP2K1 protein Q02750 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 11904294 YES gcesareni We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation. 0.2 SIGNOR-116149 PIP3 smallmolecule CHEBI:16618 ChEBI Macropinosomes formation phenotype SIGNOR-PH227 SIGNOR up-regulates 9606 BTO:0001033 29572236 NO miannu PIP3 produced by type I PI3Ks is required for macropinosome closure; in some cell types, PIP3 is also required for membrane ruffling 0.7 SIGNOR-277769 NDUFA12 protein Q9UI09 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.831 SIGNOR-262152 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr794 LEMLVPStPTSTSGA 9606 15125835 YES lperfetto Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis. 0.2 SIGNOR-124650 ELAVL3 protein Q14576 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 YES miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure 0.2 SIGNOR-266864 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp546 ALQTDIVdLQRSPMG 9606 11741536 YES gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. 0.365 SIGNOR-112796 PRKACA protein P17612 UNIPROT HDAC8 protein Q9BY41 UNIPROT down-regulates phosphorylation Ser39 AKIPKRAsMVHSLIE 9606 14701748 YES lperfetto Negative regulation of histone deacetylase 8 activity by cyclic amp-dependent protein kinase athe pka phosphoacceptor site of hdac8 is ser(39) 0.492 SIGNOR-120643 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates activity phosphorylation Ser39 EPHAKKKsKISASRK -1 11121119 YES lperfetto In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation. 0.344 SIGNOR-249068 CCAR2 protein Q8N163 UNIPROT SIRT1 protein Q96EB6 UNIPROT down-regulates activity binding 9606 22735644 YES lperfetto  Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.  0.744 SIGNOR-267663 PRKCQ protein Q04759 UNIPROT ARHGEF6 protein Q15052 UNIPROT up-regulates activity phosphorylation Ser225 KSSERPLsPKAVKGF 25694429 YES lperfetto Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation.|More specifically, αPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway. 0.2 SIGNOR-272169 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser527 RFRKRTHsAGTSPTI 9606 BTO:0000007 16914728 YES lperfetto Turnover of the active fraction of irs1 involves raptor-mtor- and s6k1-dependent serine phosphorylation in cell culture models of tuberous sclerosiss6k1 phosphorylates irs1 in vitro on multiple residues showing strong preference for rxrxxs/t over s/t,p sites. 0.787 SIGNOR-148903 CDK1 protein P06493 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Ser112 EKENGFSsPPQIKDE -1 18408216 YES miannu In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells. 0.35 SIGNOR-276156 EPHA5 protein P54756 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276183 Erlin complex SIGNOR-C532 SIGNOR RNF170 protein Q96K19 UNIPROT up-regulates activity binding 9606 BTO:0000567 21610068 YES miannu In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound. 0.493 SIGNOR-271917 TDG protein Q13569 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275713 SIRT2 protein Q8IXJ6 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization 9606 23175188 NO miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. 0.466 SIGNOR-255148 HTR2A protein P28223 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.349 SIGNOR-256742 BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20651737 YES lperfetto Engagement of cd40 with its ligand cd40l results in the recruitment of the TRAF3/TRAF2/cIAP Complex to the receptor. At the receptor, traf3 undergoes ciap-dependent k48-linked polyubiquitylation (ub) that targets it for proteasomal degradation. In the absence of traf3, nik protein levels accumulate as it can no longer be recruited to the TRAF2/cIAP Complex. 0.872 SIGNOR-167057 CDK16 protein Q00536 UNIPROT CyclinY/CDK16 complex SIGNOR-C540 SIGNOR form complex binding 30992425 YES lperfetto CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that forms an active complex with cyclin Y (CCNY). 0.67 SIGNOR-273003 Brivanib alaninate chemical CID:11154925 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190729 NSD3 protein Q9BZ95 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity methylation Lys366 RLVMVLysVVPTC 9606 BTO:0002181 29101251 YES irozzo We found that lysine methyltransferase NSD3 interacts with and directly monomethylates IRF3 in the nucleus, leading to the enhanced IRF3 transcriptional activity and antiviral immune responses. 0.2 SIGNOR-259198 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258080 arginine smallmolecule CHEBI:29016 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264756 Ub:E2 complex SIGNOR-C497 SIGNOR FANCL protein Q9NW38 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271099 RAD50 protein Q92878 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 10426999 YES amattioni Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex. 0.788 SIGNOR-69701 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD 9606 8702756 YES miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. 0.646 SIGNOR-261709 PIGBOS1 protein A0A0B4J2F0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0002181 31653868 NO miannu Here, we characterize a microprotein called PIGBOS and reveal a role for a mitochondrial protein in UPR signaling. Together, these results showed that loss of PIGBOS increases cellular sensitivity to ER stress, which in turn increases apoptosis and links PIGBOS levels to the ability of cells to survive stress. 0.7 SIGNOR-261042 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 24929114 YES miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. 0.8 SIGNOR-268142 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN4 protein O15554 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 YES Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  0.8 SIGNOR-258025 CDK9 protein P50750 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15546612 NO gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. 0.2 SIGNOR-130703 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257978 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK8 protein P45983 UNIPROT down-regulates chemical inhibition 9606 18922779 YES BI-78D3 is substrate competitive. gcesareni Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell. 0.8 SIGNOR-181647 CTH protein P32929 UNIPROT L-homocysteine zwitterion smallmolecule CHEBI:58199 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275825 HMOX1 protein P09601 UNIPROT BAD protein Q92934 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26722274 NO irozzo The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells. 0.2 SIGNOR-256304 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser321 SKPSGNDsCELRNLK -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.2 SIGNOR-276213 DMTF1 protein Q9Y222 UNIPROT ECT2 protein Q9H8V3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004532 19816943 NO Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  0.2 SIGNOR-261589 CMC1 protein Q7Z7K0 UNIPROT MITRAC complex complex SIGNOR-C538 SIGNOR form complex binding 9606 BTO:0000007 23260140 YES By analyzing MITRAC12 interaction partners, we show that recently identified assembly factors, such as c12orf62, CMC1, and the novel assembly factor MITRAC15, are constituents of MITRAC complexes 0.35 SIGNOR-272481 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI PPP3CA protein Q08209 UNIPROT down-regulates chemical inhibition 9606 15276472 YES gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-127239 SMURF1 protein Q9HCE7 UNIPROT TOM1L2 protein Q6ZVM7 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.26 SIGNOR-272700 dovitinib; bis(lactic acid) chemical CID:56973714 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191418 TANC1 protein Q9C0D5 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10116 21068316 YES miannu In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses. 0.7 SIGNOR-266896 adenosine smallmolecule CHEBI:16335 ChEBI ADORA1 protein P30542 UNIPROT up-regulates activity binding -1 14662005 YES Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. 0.8 SIGNOR-268419 SHANK1 protein Q9Y566 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.274 SIGNOR-264583 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser439 SIGHSPLsLSAQSVM 9606 BTO:0000938 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.547 SIGNOR-204732 PRKACA protein P17612 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity phosphorylation YES 9606 12536214 YES inferred from family member gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. 0.504 SIGNOR-267784 WNT3 protein P56703 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.648 SIGNOR-131823 coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity precursor of 9606 19286649 YES miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. 0.8 SIGNOR-268083 PRKCE protein Q02156 UNIPROT RAB11A protein P62491 UNIPROT unknown phosphorylation Ser177 TEIYRIVsQKQMSDR -1 22188018 YES miannu This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. 0.27 SIGNOR-263170 AKT1 protein P31749 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates activity phosphorylation Ser21 CWRKRVKsEYMRLRQ 9606 16224021 YES lperfetto Enhancer of zeste homolog 2 (ezh2) is a methyltransferase that plays an important role in many biological processes through its ability to trimethylate lysine 27 in histone h3. Here, we show that akt phosphorylates ezh2 at serine 21 and suppresses its methyltransferase activity by impeding ezh2 binding to histone h3 0.595 SIGNOR-141043 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000150 18372406 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.67 SIGNOR-178137 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Ser93 YPGSYSRsPAGSQQQ 9606 17310276 YES lperfetto Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1 0.341 SIGNOR-153304 PI3K complex SIGNOR-C156 SIGNOR AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000586 16293724 NO gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. 0.643 SIGNOR-252716 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates binding 9606 20006481 YES lperfetto Akt can phosphorylate pras40, a raptor binding protein that also acts as an inhibitor of torc1. Akt-mediated phosphorylation of pras40 again promotes 14-3-3 binding, in this case leading to relief from pras40-mediated inhibition. 0.53 SIGNOR-217565 IKBKE protein Q14164 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19940156 YES lperfetto Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna. 0.341 SIGNOR-161834 BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 YES lperfetto Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2 0.848 SIGNOR-133759 INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 10029 16956584 YES lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. 0.934 SIGNOR-236748 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Thr115 MPDDLLTtLDDTCDL 9606 BTO:0002181 25795775 YES miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA.  0.2 SIGNOR-276447 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263786 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser272 EEPSPLPsPTASPNH 9606 BTO:0000142 15262992 YES lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd 0.396 SIGNOR-126843 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr336 TQTSDTAtNSTLPSA -1 7836371 YES gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. 0.2 SIGNOR-249686 AKT1 protein P31749 UNIPROT RARA protein P10276 UNIPROT down-regulates phosphorylation Ser96 FVCQDKSsGYHYGVS 9606 BTO:0000551 16417524 YES miannu We report that akt, which is constitutively activated in nsclc cells, phosphorylates raralpha and inhibits its transactivation. / mutation of ser96 to alanine abrogated the suppressive effect of akt. 0.6 SIGNOR-252489 SPI1 protein P17947 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10523830 NO irozzo Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression. 0.268 SIGNOR-256054 GTF2B protein Q00403 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR up-regulates activity relocalization 9606 27096372 YES lperfetto Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation. 0.93 SIGNOR-266193 SMAD4 protein Q13485 UNIPROT SMAD4/JUN complex SIGNOR-C10 SIGNOR form complex binding 9606 9312063 YES gcesareni Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter. 0.675 SIGNOR-50589 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr66 CERSGQRtASVLWPW 9534 BTO:0001538 12138165 YES T66E mutations interfered with the ability of IRAK to autophosphorylate. Thr-66 mutations abolished the capacity of IRAK to dimerize. 0.2 SIGNOR-251327 MAPK9 protein P45984 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 YES gcesareni Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation. 0.246 SIGNOR-145301 CSNK2A1 protein P68400 UNIPROT VTN protein P04004 UNIPROT up-regulates activity phosphorylation Thr76 TMPEDEYtVYDDGEE 10090 9733784 YES llicata  Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant 0.328 SIGNOR-250971 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.762 SIGNOR-252748 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 12163482 YES inferred from 70% family members lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein 0.2 SIGNOR-270194 IFNAR1 protein P17181 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR form complex binding 9606 11278538 YES miannu The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. 0.906 SIGNOR-260332 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2D4 protein Q9Y2X8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.695 SIGNOR-271375 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 11483655 YES lperfetto We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases 0.767 SIGNOR-247176 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Thr17 RVSSYRRtFGGAPGF -1 12686604 YES lperfetto The sites phosphorylated by Aurora-B; Thr-7/Ser-13/Ser-38 of GFAP, and Thr-16 of desmin are common with those related to Rho-associated kinase (Rho-kinase), which has been reported to phosphorylate GFAP and desmin at cleavage furrow during cytokinesis. Rho-kinase was found to phosphorylate desmin at Thr-16, Thr-75, and Thr-76 0.317 SIGNOR-100177 SF3B1 protein O75533 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.827 SIGNOR-270653 PPP3R1 protein P63098 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR form complex binding 9606 14623295 YES miannu Calcineurin is a heterodimer consisting of a catalytic subunit with a molecular mass of about 59 kDa (calcienurin A or CNA) and a regulatory subunit with a molecular mass of 19 kDa (calcineurin B or CNB). 0.954 SIGNOR-255289 GCHFR protein P30047 UNIPROT GCH1 protein P30793 UNIPROT down-regulates activity binding 9606 11361142 YES miannu The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine 0.864 SIGNOR-252203 MDM2 protein Q00987 UNIPROT MDM4 protein O15151 UNIPROT down-regulates ubiquitination 9606 16511560 YES lperfetto The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2. 0.732 SIGNOR-144970 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MBP protein P02686 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 16401070 YES inferred from 70% family members lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. 0.2 SIGNOR-270100 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000551 22452896 YES Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases. gcesareni Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors. 0.8 SIGNOR-259440 ALX4 protein Q9H161 UNIPROT NCAM1 protein P13591 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003952 11696550 NO miannu Alx4 Overexpression Represses Endogenous N-CAM Expression 0.2 SIGNOR-254548 AKT1 protein P31749 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates activity phosphorylation Ser234 AQYQREYsEFKRQQL 9606 31852899 YES miannu In addition, pharmacological inhibition of AKT1 enhanced BECN1 stability in both assays, leaving about twice the amount of BECN1 at 90 min compared to control (Fig. 4i\u2013l).|The oncogenic kinase AKT1 phosphorylates BECN1 at positions S234, S295, which leads to sequestration of this peripheral membrane binding protein xref to the cytoskeleton with the result of inhibition of autophagy xref . 0.565 SIGNOR-279666 TFE3 protein P19532 UNIPROT ATP6V0D2 protein Q8N8Y2 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.2 SIGNOR-276810 NHLRC1 protein Q6VVB1 UNIPROT AGL protein P35573 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 17908927 YES miannu The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL. 0.561 SIGNOR-271669 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr12 DLSGRELtIDSIMNK -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276202 SOD1 protein P00441 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 10090 BTO:0004488 29371591 YES P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction) Incubating SOD1G93A or SOD1G85R, another well-established misfolded SOD1 mutant, in the absence of recombinant MIF resulted in an exponential increase in thioflavin T (ThT) fluorescence (which correlates with amyloid aggregate formation) 0.7 SIGNOR-262796 Blood vessel damage stimulus SIGNOR-ST26 SIGNOR F3 protein P13726 UNIPROT up-regulates 9606 BTO:0000131 32665005 NO lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. 0.7 SIGNOR-263541 KIF7 protein Q2M1P5 UNIPROT GLI3 protein P10071 UNIPROT up-regulates quantity by stabilization binding 10090 19592253 YES lperfetto These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh. 0.575 SIGNOR-209614 RET protein P07949 UNIPROT GFRA1 protein P56159 UNIPROT up-regulates binding 9606 10829012 YES gcesareni Gdnfr-alpha-ligand complex, together with the tyrosine kinase receptor (cret) forms a functional receptor that activates downstream signal transduction pathways 0.753 SIGNOR-77587 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10195903 YES Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 0.47 SIGNOR-248695 CLK3 protein P49761 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation -1 8617202 YES miannu In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors. 0.532 SIGNOR-273859 ESR1 protein P03372 UNIPROT ESR2 protein Q92731 UNIPROT up-regulates binding 9606 10022879 YES tpavlidou It was recently shown that er? And er? Could form a heterodimer complex both in vitro and in vivo 0.526 SIGNOR-64427 ITGB8 protein P26012 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.835 SIGNOR-253290 SMAD1/4 complex SIGNOR-C85 SIGNOR BMP4 protein P12644 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 19896409 NO lperfetto BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others. 0.582 SIGNOR-248842 TNKS2 protein Q9H2K2 UNIPROT PSMF1 protein Q92530 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 23622245 YES lperfetto We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31. 0.494 SIGNOR-263386 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser4 sGFESYGS 9606 20016603 YES gcesareni Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation 0.2 SIGNOR-162160 MCHR1 protein Q99705 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.269 SIGNOR-256762 GPR119 protein Q8TDV5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257241 HTR2B protein P41595 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.552 SIGNOR-257138 CAMK2A protein Q9UQM7 UNIPROT DLG1 protein Q12959 UNIPROT down-regulates activity phosphorylation Ser232 ITLERGNsGLGFSIA 9534 BTO:0000298 12933808 YES llicata Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. | We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII. 0.648 SIGNOR-250618 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258196 CCL7 protein P80098 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 14991608 YES For example, 11 chemokines are reported to bind to CC chemokine receptor (CCR) 1, including macrophage inflammatory protein (MIP)‐1α , MIP‐1β, MIP‐1δ, regulated upon activation, normal T cell‐expressed and secreted (RANTES), monocyte chemotactic peptide (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, leukotactin‐1 (Lkn‐1), myeloid progenitor inhibitory factor (MPIF)‐1, and hemofiltrate CC chemokine (HCC)‐1 0.742 SIGNOR-254368 CDK5 protein Q00535 UNIPROT CLOCK protein O15516 UNIPROT up-regulates phosphorylation Thr451 AVSDPSStPTKIPTD 9606 24235147 YES lperfetto Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock. 0.328 SIGNOR-203227 ITGB1BP1 protein O14713 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257640 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser367 DTRSLEIsQSYTTTQ 9606 18265945 YES lperfetto More recently, Shreeram et al.  have also shown that Wip1 dephosphorylates human ATM at Ser367 as well as Ser1981.|Thus, overexpression of Wip1 in an oncogenic context could contribute to tumor promotion by inhibiting both p53 and ATM functions. 0.488 SIGNOR-276955 AKT1 protein P31749 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates activity phosphorylation Ser295 FRLGRLPsVPVEWNE 9606 31852899 YES miannu In addition, pharmacological inhibition of AKT1 enhanced BECN1 stability in both assays, leaving about twice the amount of BECN1 at 90 min compared to control (Fig. 4i\u2013l).|The oncogenic kinase AKT1 phosphorylates BECN1 at positions S234, S295, which leads to sequestration of this peripheral membrane binding protein7 to the cytoskeleton with the result of inhibition of autophagy8. 0.565 SIGNOR-279667 CLTA protein P09496 UNIPROT AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.765 SIGNOR-260678 AKT3 protein Q9Y243 UNIPROT IWS1 protein Q96ST2 UNIPROT up-regulates activity phosphorylation Thr721 QRRRMNStGGQTPRR 9606 BTO:0003536 24462114 YES miannu The data presented in this report confirmed the differential phosphorylation of IWS1 at Ser720/Thr721 by Akt3 and Akt1 and showed that its phosphorylation at this site is required for the recruitment of SetD2 to the Spt6-IWS1-Aly/REF complex. 0.381 SIGNOR-273495 GAB1 protein Q13480 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 11043767 YES lperfetto We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1. 0.511 SIGNOR-252676 SYK protein P43405 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr381 SESSDDDyDDVDIPT 9606 11514608 YES lperfetto BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation. 0.348 SIGNOR-246567 ETS1 protein P14921 UNIPROT ITGA11 protein Q9UKX5 UNIPROT up-regulates quantity by expression 9606 BTO:0001282 16300938 YES lperfetto We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors. 0.281 SIGNOR-253352 MAPK1 protein P28482 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Thr66 EPICSVNtPREVTLH -1 16226275 YES lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| 0.812 SIGNOR-249437 NLGN2 protein Q8NFZ4 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.824 SIGNOR-264146 NFIA protein Q12857 UNIPROT ID3 protein Q02535 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268873 MIR9-1HG protein Q13536 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002874 10995546 YES Luana CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types. 0.2 SIGNOR-261569 RERE protein Q9P2R6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000932 28144959 YES miannu In mammalian cells, RERE co‐immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by over‐expressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes. 0.318 SIGNOR-264486 ASB3 protein Q9Y575 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR up-regulates activity binding 9606 BTO:0000007 15899873 YES miannu While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-alpha by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation 0.287 SIGNOR-271544 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 20729857 NO lperfetto We found Irf4 to be one of the direct targets of Jmjd3-mediated demethylation. Finally, we found that Irf4 is a transcription factor crucial for the induction of M2 macrophage responses. 0.7 SIGNOR-249543 RAP1GDS1 protein P52306 UNIPROT RAP1B protein P61224 UNIPROT up-regulates binding 9606 21242305 YES miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob 0.415 SIGNOR-171552 SIRT1 protein Q96EB6 UNIPROT ADAMTS5 protein Q9UNA0 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21337390 NO miannu The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5. 0.265 SIGNOR-255140 OPTN protein Q96CV9 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 10090 BTO:0005118 22194658 NO same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. 0.7 SIGNOR-259877 XRCC6 protein P12956 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR form complex binding 9606 BTO:0002419 17308091 YES miannu complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established 0.963 SIGNOR-226023 KLHL25 protein Q9H0H3 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 22578813 YES miannu We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination. 0.53 SIGNOR-272050 PRKCA protein P17252 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation Ser181 TGTARYAsINTHLGI -1 31096047 YES miannu In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity. 0.2 SIGNOR-277452 UNII-XH2662798I chemical CID:16156006 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 20068082 YES gcesareni Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation, regulated by wee1- and myt1-mediated phosphorylation and cdc25c-mediated dephosphorylation. Cdc25a may also be involved in cdk1 dephosphorylation in the g2/m-phase checkpoint. 0.8 SIGNOR-163127 EED protein O75530 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 YES lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). 0.903 SIGNOR-241897 PRKDC protein P78527 UNIPROT CASP2 protein P42575 UNIPROT up-regulates phosphorylation Ser139 LSCDYDLsLPFPVCE 9606 19203584 YES lperfetto Here we show that dna damage induced by gamma-radiation triggers the phosphorylation of nuclear caspase-2 at the s122 site within its prodomain, leading to its cleavage and activation. This phosphorylation is carried out by the nuclear serine/threonine protein kinase dna-pkcs 0.297 SIGNOR-183895 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser645 LNEKARLsYSDKNLI 9606 9305920 YES gcesareni Taken together, our results demonstrate that serine 643 of pkc-delta is a major autophosphorylation site, and phosphorylation of this site plays an important role in controlling its enzymatic activity and biological function. The enzymatic activity of pkc-deltas643a mutant as measured by phosphorylating the pkc-delta pseudosubstrate region-derived substrate was also reduced more than 70% in comparison to that of pkc-deltawt. 0.2 SIGNOR-51000 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr7 tPCSSMSN 9606 BTO:0000567 26057687 YES miannu Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis.  0.316 SIGNOR-276914 NUDCD2 protein Q8WVJ2 UNIPROT PAFAH1B1 protein P43034 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 20133715 YES miannu The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability. 0.441 SIGNOR-252167 ELL protein P55199 UNIPROT ELL/ICE2 complex SIGNOR-C49 SIGNOR form complex binding 9606 BTO:0001271 22195968 YES miannu The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes. 0.643 SIGNOR-193461 PTGES2 protein Q9H7Z7 UNIPROT prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity chemical modification -1 10922363 YES Luana Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently. 0.8 SIGNOR-269768 PTPRG protein P23470 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity dephosphorylation Tyr1248 PTAENPEyLGLDVPV -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.29 SIGNOR-254701 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser324 RDLELPLsPSLLGGP 10090 BTO:0000944 7889942 YES lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency. 0.562 SIGNOR-235459 PRKAA2 protein P54646 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 YES miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex 0.2 SIGNOR-276840 TLN1 protein Q9Y490 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.588 SIGNOR-257630 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7566157 YES gcesareni The p21 gene is under the transcriptional control of p53 (ref. 5), suggesting that p21 might promote p53-dependent cell cycle arrest or apoptosis. p21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. p53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting g1/s entry. 0.876 SIGNOR-29248 MRPL4 protein Q9BYD3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.743 SIGNOR-262357 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 23454976 YES miannu SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. The inhibitory protein SOCS3 plays a key part in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus kinases (JAKs) that initiate signaling within the cell. 0.651 SIGNOR-255328 MAPK14 protein Q16539 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Thr118 SGLPRTMtQKDVEDM 9606 19528229 YES lperfetto P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna. 0.524 SIGNOR-186135 LCK protein P06239 UNIPROT LCK protein P06239 UNIPROT up-regulates activity phosphorylation Tyr394 RLIEDNEyTAREGAK 9606 2250907 YES lperfetto They also demonstrate that replacement of the major site of autophosphorylation of p56lck (tyrosine 394) by a phenylalanine residue abolishes the ability to activate p56lck by CD4 cross-linking, implying that this residue is critical for the positive regulation of the Lck tyrosine kinase activity by CD4. 0.2 SIGNOR-81372 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization ubiquitination Lys137 FSGFPFEkGSVQYKK 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). 0.3 SIGNOR-272831 SYN2 protein Q92777 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates activity binding 9606 BTO:0000938 15265865 YES miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 0.7 SIGNOR-269185 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 15618519 YES gcesareni We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins 0.2 SIGNOR-132669 regorafenib chemical CHEBI:68647 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition 9606 26254357 YES miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF 0.8 SIGNOR-259176 cortisol smallmolecule CHEBI:17650 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258708 PSMB1 protein P20618 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.869 SIGNOR-263356 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates activity dephosphorylation Ser661 SSNDSRSsLIRKRST 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.2 SIGNOR-272505 TFIIH complex SIGNOR-C457 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 21157430 YES acerquone Here, we show that the transcription factor tfiih, via its cdk7 kinase, phosphorylates the androgen receptor (ar) at position ar/s515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the mdm2 e3 ligase, the subsequent ubiquitination of ar at the promoter of target genes and its degradation by the proteasome machinery 0.319 SIGNOR-269331 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Thr161 SDEEAEStKEAQNEL -1 12852856 YES lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction 0.699 SIGNOR-103364 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser1219 KNLHSSHsSGLMDKS 9606 BTO:0000565 28630147 YES miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 0.371 SIGNOR-266419 Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 NO miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.7 SIGNOR-270902 SIAH1 protein Q8IUQ4 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 11752454 YES gcesareni We report that siah-1 interacts directly with and promotes the degradation of the cell fate regulator numb. 0.4 SIGNOR-113469 THRA protein P10827 UNIPROT GATA2 protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 YES scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. 0.2 SIGNOR-267257 PPARGC1A protein Q9UBK2 UNIPROT SOD2 protein P04179 UNIPROT up-regulates 10090 18074631 NO lperfetto In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat. 0.373 SIGNOR-253395 TRIM21 protein P19474 UNIPROT GMPS protein P49915 UNIPROT down-regulates ubiquitination 9606 24462112 YES miannu Cytoplasmic sequestration of gmps requires ubiquitylation by trim21, a ubiquitin ligase associated with autoimmune disease. 0.326 SIGNOR-204478 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 SIGNOR-C83 10428798 YES gcesareni Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. 0.478 SIGNOR-69718 SOX4 protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0003104 24970928 YES irozzo The findings in this study raise the possibility that Sox4 may also antagonize Lef1 (Tcf1 is not expressed in pro-B lymphocytes) function by controlling the stability of β-catenin in pro-B lymphocytes. 0.591 SIGNOR-256139 MARK2 protein Q7KZI7 UNIPROT PINK1 protein Q9BXM7 UNIPROT up-regulates activity phosphorylation Thr313 EGLGHGRtLFLVMKN -1 22238344 YES miannu  MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD.  0.367 SIGNOR-276401 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Thr218 TAANSRDtIFQKERF 9606 19366211 YES llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. 0.2 SIGNOR-185303 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8892604 YES lperfetto Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function 0.727 SIGNOR-44669 ITGB1 protein P05556 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.758 SIGNOR-253172 MYC protein P01106 UNIPROT LDHA protein P00338 UNIPROT up-regulates quantity transcriptional regulation 10116 9192621 NO Our studies have linked c-Myc to the induction of LDH-A, whose expression increases lactate production and is necessary for c-Myc-mediated transformation 0.56 SIGNOR-259367 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 0.607 SIGNOR-161593 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR FBXO30 protein Q8TB52 UNIPROT down-regulates 10090 BTO:0000887 24076600 NO BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1) 0.2 SIGNOR-256488 PLEKHG1 protein Q9ULL1 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.324 SIGNOR-260563 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248373 SMURF1 protein Q9HCE7 UNIPROT FKBP3 protein Q00688 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272694 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser99 HFAIAADsEAEQDSW -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.34 SIGNOR-250909 RPL26 protein P61254 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.864 SIGNOR-262497 PRKCA protein P17252 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 YES lperfetto A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis. 0.264 SIGNOR-249236 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 17804415 YES gcesareni Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun. 0.37 SIGNOR-157725 PPARGC1A protein Q9UBK2 UNIPROT COX5B protein P10606 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000443 23021218 NO lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 0.326 SIGNOR-253099 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity deacetylation 10090 BTO:0001103 24003218 YES lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation 0.798 SIGNOR-217963 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser300 KKDQEGDsAAALSLY 9606 20643644 YES Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. 0.2 SIGNOR-260793 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 YES gcesareni ...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. 0.289 SIGNOR-247902 YARS1 protein P54577 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270798 ATR protein Q13535 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by stabilization phosphorylation Ser31 ALRLLDSsQIVIISA 10090 BTO:0001372 11459832 YES lperfetto These results thus suggest that this serine 31 residue is indeed an atm/atr phosphorylation site and in fact is the major site for atm/atr-mediated phosphorylation within e2f1. Thus, it is possible that the atm/atr-mediated phosphorylation inhibits the binding and function of skp2 and thus prevents the normal degradation of e2f1 0.377 SIGNOR-109420 ACTR2 protein P61160 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 YES The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc 0.929 SIGNOR-251512 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser332 STPKSKQsPISTPTS 9606 14741103 YES llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. 0.405 SIGNOR-250667 EEF1G protein P26641 UNIPROT EEF1B complex complex SIGNOR-C460 SIGNOR form complex binding 9606 23699257 YES lperfetto An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively) 0.981 SIGNOR-269391 ACTB protein P60709 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.502 SIGNOR-270698 CENPN protein Q96H22 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.726 SIGNOR-265210 MAPK10 protein P53779 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates phosphorylation Ser62 ELILKPPsPISEAPR 9606 11718727 YES gcesareni We demonstrate that purified scg10 can be phosphorylated by two subclasses of mitogen-activated protein (map) kinases, c-jun n-terminal/stress-activated protein kinase (jnk/sapk) and p38 map kinase;jnk3/sapkbeta phosphorylation occurs at ser-62 and ser-73, residues that result in reduced microtubule-destabilizing activity for scg10. 0.445 SIGNOR-112110 phosphatidic acid smallmolecule CHEBI:16337 ChEBI SOS1 protein Q07889 UNIPROT up-regulates chemical activation 9606 17486115 YES gcesareni Phosphatidic acid interacts with a defined site in the sos ph domain with high affinity and specificity 0.8 SIGNOR-154676 POGZ protein Q7Z3K3 UNIPROT CBX5 protein P45973 UNIPROT down-regulates activity binding 9606 BTO:0000932 20562864 YES miannu POGZ was found to bind to HP1alpha through a zinc-finger-like motif. Binding by POGZ, mediated through its zinc-finger-like motif, competed with PxVxL proteins and destabilized the HP1alpha-chromatin interaction. 0.433 SIGNOR-264487 TFIIH complex SIGNOR-C457 SIGNOR Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 9606 30860024 NO lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair. 0.7 SIGNOR-269322 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 24643073 YES lperfetto At the onset of mitosis, the protein phosphatase Cdc25C activates the Cdc2 and cyclin B1 complex by removing the inhibitory phosphate groups from Thr 14 and Tyr 15 on Cdc2.|Dephosphorylation of Tyr15 of Cdc2 is catalyzed by Cdc25C phosphatases, and this reaction is believed to be the rate limited step for the entrance into mitosis . 0.858 SIGNOR-276944 PCDHA13 protein Q9Y5I0 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265672 H4C1 protein P62805 UNIPROT BRD4 protein O60885 UNIPROT up-regulates activity relocalization 9606 acetylation:Lys21;Lys17 GGAKRHRkVLRDNIQ;GLGKGGAkRHRKVLR 27991587 YES lperfetto BRD4 interacts with acetylated nucleosomes via both its BD1 and BD2 domains. Our results indicate that BRD4-BD1 binds to nucleosomes through the acetylated histone H4 tail and does not additionally interact with DNA. 0.2 SIGNOR-262065 EID2 protein Q8N6I1 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 14612439 YES lperfetto Stable expression of eid-2 in the tgf-beta1-responsive cell line inhibits endogenous smad3-smad4 complex formation and tgf-beta1-induced expression of p21 and p15. These results suggest that eid-2 may function as an endogenous suppressor of tgf-beta signaling. 0.4 SIGNOR-119174 MITF protein O75030 UNIPROT TYR protein P14679 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 10080955 NO miannu Microphthalmia transcription factor MITF, a melanocyte-specific basic helix-loop-helix protein, has been shown to transactivate tyrosinase and TRP-1 genes in vitro by binding to a shared regulatory sequence known as M box. both activation of positive factors such as MITF and inactivation of negative regulatory factors may be required for TRP-1 gene expression during melanocytic differentiation. 0.577 SIGNOR-254593 KCTD10 protein Q9H3F6 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity binding 9606 19782033 YES miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. 0.269 SIGNOR-264237 CAMK4 protein Q16566 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 23103515 YES miannu In summary, we have found that phosphorylation of Notch1-IC by CaMKIV inhibits the proteasomal degradation of Notch1-IC through Fbw7 ( Fig.\u00a07 ). 0.361 SIGNOR-279596 PP121 chemical CHEBI:50915 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206298 CSNK2A2 protein P19784 UNIPROT NOL3 protein O60936 UNIPROT up-regulates activity phosphorylation Thr149 SEAVQSGtPEEPEPE 9606 12191471 YES miannu Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm. 0.2 SIGNOR-262836 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 15952796 YES inferred from 70% family members lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation 0.2 SIGNOR-270077 PRKCA protein P17252 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates phosphorylation Ser591 DKEKSKGsLKRK 9606 15269224 YES llicata Protein kinase calpha therefore critically and negatively regulates shp-1 function, forming part of a mechanism to retain shp-1 in a basal active state through interaction with its sh2 domains, and phosphorylating its c-terminal ser591 upon cellular activation 0.364 SIGNOR-126876 CDX2 protein Q99626 UNIPROT MUC2 protein Q02817 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0004055 12559945 YES COS-7 cells were transiently transfected with a CDX1 or CDX2 expression construct and then used for the luciferase assay, reverse transcription-polymerase chain reaction, and electrophoretic mobility shift assay (EMSA). The CDX2 expression construct activated the MUC2 promoter and increased the endogenous MUC2 mRNA level, while the CDX1 one did not. 0.2 SIGNOR-253966 TRPM7 protein Q96QT4 UNIPROT EEF2K protein O00418 UNIPROT up-regulates activity phosphorylation Ser78 SSGSPANsFHFKEAW 9606 BTO:0000007 21112387 YES miannu TRPM7 interacts with, and phosphorylates mouse eEF2-k at serine site 77 0.314 SIGNOR-277923 PTPN1 protein P18031 UNIPROT MAPK15 protein Q8TD08 UNIPROT down-regulates dephosphorylation Tyr177 EDQAVTEyVATRWYR 9606 16336213 YES lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20% 0.327 SIGNOR-142981 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 YES gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. 0.557 SIGNOR-37470 MAPK7 protein Q13164 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 BTO:0001103 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 0.466 SIGNOR-255454 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBB protein P07437 UNIPROT down-regulates activity chemical inhibition 9606 15579115 YES miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 0.8 SIGNOR-259256 USP10 protein Q14694 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0003704 21962518 YES lperfetto Since USP10 is known as a deubiquitinating protease of p53 (Yuan et al., 2010), inhibition of USP10 by spautin-1 may promote the degradation of p53.  0.661 SIGNOR-260297 JUN protein P05412 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9615 9312063 YES lperfetto Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter. 0.675 SIGNOR-236139 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.358 SIGNOR-269257 SGK3 protein Q96BR1 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.437 SIGNOR-252992 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Tyr204 HTGFLTEyVATRWYR 1712480 YES lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| 0.2 SIGNOR-249472 DRAM2 protein Q6UX65 UNIPROT RAC1 protein P63000 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 NO irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. 0.2 SIGNOR-259141 YWHAQ protein P27348 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 14701738 YES miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase 0.267 SIGNOR-261724 NFIX protein Q14938 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268908 THEM4 protein Q5T1C6 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates binding 9606 11598301 YES lperfetto Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308. 0.698 SIGNOR-244455 CLOCK protein O15516 UNIPROT DPYD protein Q12882 UNIPROT up-regulates quantity by expression transcriptional regulation 17699798 NO Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors| The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. 0.261 SIGNOR-253986 PINK1 protein Q9BXM7 UNIPROT CYCS protein P99999 UNIPROT down-regulates quantity 9606 BTO:0000938 20012177 YES lperfetto There is a strong cyto-protective role of PINK1 in maintaining mitochondrial homeostasis via different mechanisms. Overexpression of wild-type PINK1 in SH-SY5Y neuroblastoma cells stabilizes respiring mitochondrial networks through various mechanisms that include maintaining mitochondrial membrane potential, reducing basal and neurotoxin-induced ROS, suppression of cytochrome c release, reversal of toxin-induced fission, and suppression of autophagy 0.383 SIGNOR-249704 HDAC1 protein Q13547 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity deacetylation 10090 BTO:0000887 24463822 YES Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate that class I HDACs are key regulators of FoxO and the muscle-atrophy program during both nutrient deprivation and skeletal muscle disuse. 0.368 SIGNOR-256485 Ub:E2 complex SIGNOR-C497 SIGNOR RNF168 protein Q8IYW5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271029 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser28 PHGSVTQsQGSSSQS 9606 BTO:0000007 10973490 YES lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to irser28 was also found to be phosphorylated in an atm-dependent manner 0.834 SIGNOR-81395 HNF1A protein P20823 UNIPROT AKR1C4 protein P17516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 2044952 NO 2 miannu Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C. 0.246 SIGNOR-239964 TBK1 protein Q9UHD2 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser536 SGDEDFSsIADMDFS 9606 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. 0.613 SIGNOR-129951 TAF8 protein Q7Z7C8 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.871 SIGNOR-263927 HOXB8 protein P17481 UNIPROT PBX1 protein P40424 UNIPROT up-regulates activity binding 9606 BTO:0001545 11571641 YES miannu the ability of HoxB8 to heterodimerizes with endogenous Pbx proteins on DNA alters gene transcription in a manner that prevents progression through an intrinsic genetic differentiation program. In conjunction with Pbx, HoxB8 could alter transcription of Pbx target genes by direct or indirect mechanisms. 0.5 SIGNOR-223153 MECP2 protein P51608 UNIPROT NEMF protein O60524 UNIPROT up-regulates activity binding 10090 BTO:0000142 21070191 YES lperfetto MeCP2 interacts directly with Prpf3 and Sdccag1|MeCP2’s association with Prpf3, a major component of the spliceosome, supports MeCP2 as having a role in modulating mRNA splicing|Notably, Mecp2308/Y mice, which produce a truncated form of MeCP2 and reproduce many of the classical features of RTT [43], have been shown to have multiple genes that are abnormally spliced in the brain [23]. This suggests the C-terminal portion of MeCP2, which we have identified as the putative Sdccag1 interaction domain, plays a critical role in regulating alternative splicing. 0.2 SIGNOR-277692 UBTF protein P17480 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 7877691 YES lperfetto Rb specifically inhibits the activity of the RNA polymerase I transcription factor UBF (upstream binding factor) in vitro. |These results indicate that there is an additional mechanism by which Rb suppresses cell growth, namely that Rb directly represses transcription of the rRNA genes. 0.7 SIGNOR-262590 EEF1A1 protein P68104 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269518 FUS protein P35637 UNIPROT DUSP22 protein Q9NRW4 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 28515487 NO This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease 0.2 SIGNOR-262803 PPP2CB protein P62714 UNIPROT CARD11 protein Q9BXL7 UNIPROT down-regulates activity dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 YES NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. 0.2 SIGNOR-248607 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.32 SIGNOR-251072 NOTCH proteinfamily SIGNOR-PF30 SIGNOR MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 12386158 YES gcesareni Other than a role in t-cell development, the hox genes may be involved in alternative notchregulated processes in hematopoietic stem cells. Notch signaling is clearly important for self-renewal of hematopoietic progenitors (reviewed by radkte et al. 57). Interestingly, hoxa5, a9 and a10 were found to be part of the stem cell profile' 0.2 SIGNOR-254347 DNA-PK complex SIGNOR-C107 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 10854421 NO miannu The DNA-dependent protein kinase (DNA-PK), consisting of Ku and the DNA-PK catalytic subunit (DNA-PKcs), and the DNA ligase IV-XRCC4 complex function together in the repair of DNA double-strand breaks by non-homologous end joining. 0.7 SIGNOR-264531 EIF2B1 protein Q14232 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.779 SIGNOR-269129 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 14967450 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.595 SIGNOR-121984 NEK2 protein P51955 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization phosphorylation Thr194 EEKLFNVtSTLRINT 10090 BTO:0000584 34315872 YES miannu NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen.  0.2 SIGNOR-277315 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates activity phosphorylation Ser623 KGEKRASsPFRRVRE -1 12167624 YES miannu PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA. 0.307 SIGNOR-250020 MAPK9 protein P45984 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 YES lperfetto However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. 0.489 SIGNOR-247062 DCC protein P43146 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates activity 9606 12827203 YES miannu DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER. 0.2 SIGNOR-268291 FGFR1 protein P11362 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr446 GTEPEPVySMEAADY 9606 12601080 YES lperfetto Cortactin, which is an actin-binding protein that also plays a role in actin cytoskeleton dynamics (45), was phosphorylated on tyr-446 in our assay (by fgfr1).Phosphorylation of these residues attenuates the f-actin cross-linking activity 0.313 SIGNOR-98618 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2D2 protein P62837 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.775 SIGNOR-271357 MAPK11 protein Q15759 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 YES lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 . but the p38_/p38_ mapks were the major kinases phosphorylating ews-fli1. It will be important to investigate how the p38_/p38_-stimulated phosphorylation of ews-fusion proteins affects their ability to transactivate and their oncogenic potential. 0.2 SIGNOR-182774 4-fluoro-N-{2-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]ethyl}benzamide chemical CHEBI:64101 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258858 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 17713585 NO lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB. 0.7 SIGNOR-251503 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR1 protein P21554 UNIPROT up-regulates activity chemical activation 9606 BTO:0000142 29751001 YES miannu Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana. 0.8 SIGNOR-264267 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser181 NPLLRKEsAPPSLRR 9606 18339811 YES Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. 0.318 SIGNOR-248647 romidepsin chemical CHEBI:61080 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257991 DNA_damage stimulus SIGNOR-ST1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates 9606 17891139 NO miannu We identify the major poly(ADP-ribosyl)ated sites of p53 by PARP-1 and find that PARP-1-mediated poly(ADP-ribosyl)ation blocks the interaction between p53 and the nuclear export receptor Crm1, resulting in nuclear accumulation of p53. These findings molecularly link PARP-1 and p53 in the DNA-damage response, providing the mechanism for how p53 accumulates in the nucleus in response to DNA damage.|PARP-1 is super-activated by binding to damaged DNA, and poly(ADP-ribosyl)ates p53. Poly(ADP-ribosyl)ation probably induces a structural change that mask the NES, and thus Crm1 can no longer target p53 to the nuclear export machinery, resulting in accumulation of p53 in the nucleus. 0.7 SIGNOR-260065 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 YES gcesareni The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation. 0.347 SIGNOR-70563 SP1 protein P08047 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10644769 NO miannu these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation. 0.266 SIGNOR-253872 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 9335504 YES llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 0.607 SIGNOR-52678 FBXW7 protein Q969H0 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by destabilization ubiquitination Thr176 HLFGFPPtPPKEVSP 9606 BTO:0000007 25670854 YES irozzo Here, we demonstrate that F-box/WD repeat-containing protein 7 (Fbw7/Fbxw7), a component of Skp1, Cullin 1, F-box-containing complex (SCF)-type E3 ligase, is an E3 ligase for GATA2. GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. 0.389 SIGNOR-256005 JAK3 protein P52333 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 28821617 YES miannu Jak3 phosphorylates Tyr 30, Tyr 64, and Tyr 86 of beta-catenin in intestinal epithelial cells. 0.444 SIGNOR-278180 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 YES irozzo Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. 0.2 SIGNOR-255871 SRC protein P12931 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Tyr1164 KKEIEDLySRLGKQP 9606 BTO:0002181 25805816 YES miannu Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4.  0.2 SIGNOR-276896 MECP2 protein P51608 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 15657354 NO Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT. 0.306 SIGNOR-254035 adenosine smallmolecule CHEBI:16335 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000142 18957298 YES miannu Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. 0.7 SIGNOR-265464 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Trp) smallmolecule CHEBI:29181 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269498 CUL2 protein Q13617 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR form complex binding 9606 11574546 YES miannu The von Hippel-Lindau tumor-suppressor protein (pVHL) forms a protein complex (VCB-Cul2) with elongin C, elongin B, Cul-2, and Rbx1, which functions as a ubiquitin-protein ligase (E3). The alpha-subunits of the hypoxia-inducible factors have been identified as targets for the VCB-Cul2 ubiquitin ligase.  0.894 SIGNOR-271519 NLK protein Q9UBE8 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser128 QHVRAHSsPASLQLG 9606 BTO:0000007 27979971 YES done miannu Here, we report that osmotic stress stimulates transient YAP nuclear localization and increases YAP activity even when YAP Ser127 is phosphorylated. Osmotic stress acts via the NLK kinase to induce YAP Ser128 phosphorylation. Phosphorylation of YAP at Ser128 interferes with its ability to bind to 14-3-3, resulting in YAP nuclear accumulation and induction of downstream target gene expression.  0.2 SIGNOR-273909 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Thr895 KLSFRRRtDKDTEQP 9606 10488078 YES lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) 0.307 SIGNOR-70730 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248510 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT down-regulates activity phosphorylation Ser66 MLTKQNNsFQRSKRR 9534 15228384 YES lperfetto The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain. 0.366 SIGNOR-249265 SREBF1 protein P36956 UNIPROT ACACA protein Q13085 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11994399 NO Luana SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16:0]). 0.456 SIGNOR-267957 CSNK1A1 protein P48729 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser316 FKSIMKKsPFSGPTD -1 26082493 YES miannu These data strongly suggested that CKI phosphorylated Ser-316 of p65. Our data suggested that phosphorylation of p65 on Ser-316 controls the activity and function of NF-κB. Importantly, we found that phosphorylation at the novel Ser-316 site and other two known phosphorylation sites, Ser-529 and Ser-536, either individually or cooperatively, regulated distinct groups of NF-κB-dependent genes, suggesting the unique role of each individual phosphorylation site on NF-κB-dependent gene regulation.  0.2 SIGNOR-276916 SLBP protein Q14493 UNIPROT H2BC18 protein Q5QNW6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265394 AURKA protein O14965 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr799 PPKLRRRtFSLTEVR -1 31881080 YES miannu We show that Aurora A phosphorylates the condensin I-dependent pool of KIF4A and thus actively promotes chromosome congression from the spindle poles to the metaphase plate. In vitro kinase assays showed that recombinant KIF4A can be phosphorylated by Aurora A and that this activity is inhibited by the specific Aurora A inhibitor MLN8537 (Fig. 7 C). 0.42 SIGNOR-265993 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser45 GATTTAPsLSGKGNP -1 17208333 YES llicata We showed that CCND1-CDK6 phosphorylates beta-catenin on serine 45 (S45). This phosphorylation creates a priming site for glycogen synthase kinase 3beta (GSK3beta) and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade. 0.638 SIGNOR-250647 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser608 TAADMYLsPVRSPKK BTO:0001968 10207050 YES llicata In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule. 0.75 SIGNOR-250747 NPR1 protein P16066 UNIPROT ORM2 protein P19652 UNIPROT up-regulates activity phosphorylation 9606 23363605 YES miannuccelli On TORC1 inhibition by rapamycin treatment or nutrient limitation, Npr1 phosphorylates and activates Orm1 and Orm2, which in turn promotes synthesis of complex sphingolipids downstream of SPT.|Thus Npr1 directly phosphorylates Orm1 and Orm2 downstream of TORC1. 0.2 SIGNOR-279747 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269346 CCT6A protein P40227 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.762 SIGNOR-272865 NARS2 protein Q96I59 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270464 GABARAP protein O95166 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates activity binding 9606 BTO:0000938 25882190 YES miannu GABARAP was originally isolated as a binding partner of the GABAA receptor γ2-subunit in a yeast two-hybrid screen, and was suggested to have a role in the targeting and clustering of GABAA receptors. 0.2 SIGNOR-264972 glucose chemical CHEBI:17234 ChEBI Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by stabilization 9606 BTO:0004424 26323688 YES inferred from family member Consistently, treatment of cells with 2-deoxy-d-glucose (2DG), which completely inhibits glucose metabolism, leads to HK2 degradation and cell death in combination with C43 0.8 SIGNOR-270265 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1693 SPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248821 PAR-1 (Protease-Activated Receptor) Selective Activating Peptide smallmolecule CID:71312048 PUBCHEM F2R protein P25116 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257484 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.431 SIGNOR-259000 EIF3E protein P60228 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.942 SIGNOR-266396 BIRC3 protein Q13489 UNIPROT PACS2 protein Q86VP3 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 24633224 YES miannu Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay. 0.286 SIGNOR-272852 miR-155 mirna URS000062749E_9606 RNAcentral JARID2 protein Q92833 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31390932 YES miannu  Mechanically, LINC01133 functioning as a ceRNA targeted miR-4784 to augment AHDC1 expression. Finally, LINCO1133/miR-4784 aggravated the malignant growth and aggressiveness and EMT of cervical cancer in an AHDC1-dependant way. In conclusion, we unveiled that LINC01133 may function as a ceRNA for miR-4784 to advance AHDC1 expression, intensifying CC cell malignant phenotypes and EMT process, which may demonstrate the implied value of LINC01133 as a therapeutic target for CC patients. 0.4 SIGNOR-269188 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 9275162 YES gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.747 SIGNOR-50614 BDKRB1 protein P46663 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.588 SIGNOR-257304 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1893 PANLDSEsEHFFRCC 9606 21149446 YES gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. 0.2 SIGNOR-170465 DOK1 protein Q99704 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257676 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr292 DTLNSDGyTPEPARI 9606 BTO:0000782;BTO:0000776 8756661 YES lperfetto The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492 0.2 SIGNOR-43324 MAPK3 protein P27361 UNIPROT MYL1 protein P05976 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0001130 16854453 YES gcesareni Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein. 0.287 SIGNOR-148002 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Thr119 LLTTLDDtCDLFAPL 9606 BTO:0002181 25795775 YES miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA.  0.2 SIGNOR-276450 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates 9606 31226023 NO miannu PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. 0.7 SIGNOR-260167 CDK2 protein P24941 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser991 PALPPPEsPPKVQPE 9606 20807815 YES llicata We identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we conclude that pelp1 is a novel substrate of interphase cdks and that its phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function. 0.367 SIGNOR-167766 RNF11 protein Q9Y3C5 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9606 BTO:0000007 14755250 YES miannu RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome. 0.541 SIGNOR-272952 diisononyl phthalate chemical CHEBI:35459 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). 0.8 SIGNOR-268775 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5D protein Q9BY66 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273473 CDK1 protein P06493 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates phosphorylation 9606 8114697 YES lperfetto P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well 0.494 SIGNOR-244847 MSTN protein O14793 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates activity binding 10090 11459935 YES gcesareni The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA 0.643 SIGNOR-235153 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser448 HRSIRHSsIQE 9606 BTO:0000782 20697158 YES miannu Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells. 0.417 SIGNOR-167471 TYRO3 protein Q06418 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation 9606 21291561 YES miannu However, the present study in tPA and NMDA treated neurons establishes the link between PS mediated activation of Tyro3 and FKHRL1 phosphorylation which inactivates pro apoptotic FKHRL1 and mediates PS 's beneficial effects.|We also show that inhibition of the extrinsic apoptotic cascade by PS requires Tyro3 mediated phosphorylation of FKHRL1 which in turn inhibits FasL production and FasL dependent caspase-8 activation in the extrinsic pathway. 0.2 SIGNOR-279669 SGK2 protein Q9HBY8 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.52 SIGNOR-249132 ADORA2A protein P29274 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.273 SIGNOR-257038 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.672 SIGNOR-131981 dexamethasone chemical CHEBI:41879 ChEBI SCNN1A protein P37088 UNIPROT up-regulates 9606 BTO:0000018 10722699 NO Regulation of expression miannu Dexamethasone induces α-ENaCmRNA expression in lung epithelial A549 cells 0.8 SIGNOR-251945 SOSTDC1 protein Q6X4U4 UNIPROT WNT4 protein P56705 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.278 SIGNOR-242707 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE8A protein O60658 UNIPROT up-regulates activity phosphorylation Ser359 HKDRRKGsLDVKAVA -1 22673573 YES miannu We show that under elevated cAMP conditions, PKA acts to phosphorylate PDE8A on serine 359 and this action serves to enhance the activity of the enzyme.  0.2 SIGNOR-276416 JNK proteinfamily SIGNOR-PF15 SIGNOR YWHAZ protein P63104 UNIPROT down-regulates phosphorylation 9606 15071501 YES Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190 0.2 SIGNOR-269980 TARDBP protein Q13148 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates quantity 9606 BTO:0000312 22051914 NO lperfetto Pathological protein aggregates, identified as compact or skein-like ubiquitinated inclusions, are a cardinal feature of ALS.4–6 The identification of TDP-43 as the major protein constituent of these inclusions initi- ated a major shift in our understanding of the patho- biology of ALS 0.7 SIGNOR-262278 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser83 PRRSPRIsFFLEKEN -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.71 SIGNOR-276118 AKT proteinfamily SIGNOR-PF24 SIGNOR CELF1 protein Q92879 UNIPROT up-regulates activity phosphorylation Ser28 GQVPRTWsEKDLREL 10090 BTO:0000165 18570922 YES miannu CUG repeat binding protein, CUGBP1, is a key regulator of translation of proteins that are involved in muscle development and differentiation. In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA. 0.2 SIGNOR-262615 PRKCA protein P17252 UNIPROT NRGN protein Q92686 UNIPROT up-regulates activity phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 YES lperfetto Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM. 0.394 SIGNOR-248913 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2T protein Q9NPD8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.461 SIGNOR-271350 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120260 HLA-DRB1 protein P01911 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000776 21178476 NO scontino Fusion with a B cell requires a ternary complex of gHgLgp42. Fusion is triggered by an interaction between gp42 and HLA class II. 0.7 SIGNOR-266631 CENPK protein Q9BS16 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.723 SIGNOR-265212 SLBP protein Q14493 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265374 NMUR2 protein Q9GZQ4 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.463 SIGNOR-257218 GTF2I protein P78347 UNIPROT GSC protein P56915 UNIPROT up-regulates quantity by expression transcriptional regulation 16611241 NO lperfetto For example, TFII-I binds to the Inr element of the T cell receptor Vbeta gene and activates its transcription in reporter gene assays (Cheriyath et al. 1998). TFII-I also activates transcription of c-fos and Goosecoid through binding to the serum response element and the distal element, respectively (Grueneberg et al. 1997; Ku et al. 2005). 0.2 SIGNOR-268536 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu56 KKGHLEReCMEETCS -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263667 PDGFRB protein P09619 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7935391 YES fspada A pathway leading to activation of the gtp-binding protein ras involves the adaptor molecule grb2. Here we show that tyr-716, a novel autophosphorylation site in the pdgf beta-receptor kinase insert, mediates direct binding of grb2 in vitro and in vivo. 0.679 SIGNOR-34765 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1619 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248768 SEMA4D protein Q92854 UNIPROT PLXNB1 protein O43157 UNIPROT up-regulates binding 9606 12198496 YES gcesareni Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors. 0.807 SIGNOR-92201 ROCK1 protein Q13464 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser637 VPVARKLsAREQRDC 10090 31063459 YES lperfetto We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes 0.314 SIGNOR-262549 alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity precursor of 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266577 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr211 EYLDDRNtFRHSVVV 9606 22611192 YES gcesareni We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma). 0.718 SIGNOR-197606 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 9792724 NO miannu AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP. 0.329 SIGNOR-254447 PITX1 protein P78337 UNIPROT GNRH1 protein P01148 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19106114 NO miannu Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter. 0.329 SIGNOR-254921 Ub:E2 complex SIGNOR-C497 SIGNOR HLTF protein Q14527 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271131 IGF1 protein P05019 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 2689937 NO fspada Preadipocytes converted to adipocytes when insulin-like growth factor-1 or insulin was added to a medium depleted of those compounds 0.7 SIGNOR-23166 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. 0.507 SIGNOR-252907 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-252806 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 17178712 YES gcesareni Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna 0.234 SIGNOR-151261 procaterol chemical CHEBI:135209 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257863 PELI3 protein Q8N2H9 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates ubiquitination 9606 17997719 YES gcesareni These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4. 0.728 SIGNOR-159061 AKT proteinfamily SIGNOR-PF24 SIGNOR PIKFYVE protein Q9Y2I7 UNIPROT up-regulates phosphorylation Ser307 PARNRSAsITNLSLD 9606 BTO:0000887 15546921 YES gcesareni Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme. 0.2 SIGNOR-130920 Ub:E2 complex SIGNOR-C497 SIGNOR HECT E3 ligase proteinfamily SIGNOR-PF104 SIGNOR up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270943 MTMR3 protein Q13615 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007 SIGNOR-C3 26787466 YES lperfetto The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity. 0.355 SIGNOR-245105 KAT2B protein Q92831 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR form complex binding 9606 21131905 YES lperfetto Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators. 0.776 SIGNOR-170276 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4F protein A0A1W2PPD8 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273480 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CAPN2 protein P17655 UNIPROT up-regulates phosphorylation 9606 14993287 YES inferred from 70% family members lperfetto Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo. 0.2 SIGNOR-270078 HES5 protein Q5TA89 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 NO lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 0.528 SIGNOR-265147 coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI acyl-CoA(4-) chemical CHEBI:58342 ChEBI up-regulates quantity precursor of 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272769 PRKD1 protein Q15139 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates activity phosphorylation Ser284 ASVRRASsADDIEAM 9606 BTO:0000007 29949809 YES miannu Based on LC-MS results from in vivo and HEK293 cell experiments we chose four KV11.1 mutant candidates for further functional analysis. Ablation of the putative PKD phosphorylation site in the mutant S284A increased the maximal current indicating S284 as a main PKD target in KV11.1. 0.2 SIGNOR-277612 PRKCA protein P17252 UNIPROT APLP2 protein Q06481 UNIPROT unknown phosphorylation Thr723 LRKRQYGtISHGIVE -1 9109675 YES lperfetto We report here that a cytoplasmic domain peptide from APLP1 is phosphorylated in vitro by protein kinase C and that a cytoplasmic domain peptide from APLP2 is phosphorylated in vitro by protein kinase C and cdc2 kinase. 0.341 SIGNOR-248970 IL15RA protein Q13261 UNIPROT IL2RB protein P14784 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 YES milica The il-15 receptor comprises a heterotrimeric complex consisting of the common ?cytokine Receptor (?c), the il-2 ? Receptor subunit (il-2r?), And an il-15-specific ? Receptor (il-15r?) 0.799 SIGNOR-157418 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Thr110 PRSGVRGtPVRQRPD 9606 BTO:0000567 SIGNOR-C83 12714602 YES lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. 0.766 SIGNOR-100889 CDK5 protein Q00535 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 YES lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. 0.2 SIGNOR-197945 CDK5 protein Q00535 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 YES gcesareni Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins 0.371 SIGNOR-175696 CARD10 protein Q9BWT7 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates activity relocalization 9606 31792381 YES TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation 0.433 SIGNOR-272471 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17960585 NO miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. 0.497 SIGNOR-260425 ATM protein Q13315 UNIPROT MRE11 protein P49959 UNIPROT up-regulates phosphorylation Ser264 EQQLFYIsQPGSSVV 9606 10608806 YES lperfetto In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage. 0.2 SIGNOR-73366 retinol smallmolecule CHEBI:50211 ChEBI all-trans-retinyl ester smallmolecule CHEBI:63410 ChEBI up-regulates quantity precursor of 10090 18093970 YES lperfetto We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis 0.8 SIGNOR-265109 AMER1 protein Q5JTC6 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity relocalization 9606 SIGNOR-C110 21304492 YES gcesareni Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6. 0.788 SIGNOR-171886 MAPK1 protein P28482 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 YES lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. 0.622 SIGNOR-249428 CCNC protein P24863 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates phosphorylation 9606 15546612 YES Leads to a following ubiquitination and degradation gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. 0.478 SIGNOR-254309 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000007 19881549 YES lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis 0.703 SIGNOR-236302 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782;BTO:0001271 8125092 YES gcesareni Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase. 0.412 SIGNOR-36362 SPOP protein O43791 UNIPROT TRIM24 protein O15164 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 0.338 SIGNOR-272825 IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 21798082 YES lperfetto Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. 0.956 SIGNOR-175662 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 YES Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs 0.2 SIGNOR-258990 WNT5A protein P41221 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 22773843 YES areggio Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells. 0.783 SIGNOR-258970 GCC2 protein Q8IWJ2 UNIPROT M6PR protein P20645 UNIPROT up-regulates activity relocalization 18195106 YES lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector 0.53 SIGNOR-253086 MIB1 protein Q86YT6 UNIPROT MIB1 protein Q86YT6 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12351649 YES miannu The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system.  0.2 SIGNOR-272603 ADORA2A protein P29274 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.3 SIGNOR-257364 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Ser332 TEDSTQTsDTATNST -1 7836371 YES gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. 0.2 SIGNOR-249680 Guanfacine chemical CHEBI:5558 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258919 ARID1B protein Q8NFD5 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.805 SIGNOR-270702 STAT1 protein P42224 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 19029990 NO lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. 0.7 SIGNOR-249496 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0002058 24643470 YES miannu This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. 0.8 SIGNOR-259443 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14614828 YES gcesareni We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli 0.626 SIGNOR-119179 APC-c complex SIGNOR-C150 SIGNOR PFKFB3 protein Q16875 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000793 20080744 YES miannu We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. 0.2 SIGNOR-271435 POMT1 protein Q9Y6A1 UNIPROT POMT complex SIGNOR-C372 SIGNOR form complex binding 9606 BTO:0000007 16698797 YES miannu  Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex. 0.603 SIGNOR-265428 RIPK1 protein Q13546 UNIPROT MPRIP protein Q6WCQ1 UNIPROT up-regulates activity phosphorylation 9606 24653026 YES miannuccelli Under such conditions, RIP1 phosphorylates and activates RIP3, which in turn phosphorylates its downstream substrate MLKL, leading to plasma membrane rupture and necrosis( xref ). 0.2 SIGNOR-279755 MRGPRX1 protein Q96LB2 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257171 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264929 TWIST2 protein Q8WVJ9 UNIPROT AKR1C2 protein P52895 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255498 MAPK8IP1 protein Q9UQF2 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 20508646 YES Interferes with binding to RBP-J gcesareni Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them. 0.266 SIGNOR-165710 CSNK2A1 protein P68400 UNIPROT ARRB2 protein P32121 UNIPROT unknown phosphorylation Thr382 EFDTNYAtDDDIVFE -1 11877451 YES llicata We found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. | However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex. 0.32 SIGNOR-250829 ETF complex SIGNOR-C463 SIGNOR FAD smallmolecule CHEBI:16238 ChEBI down-regulates quantity chemical modification 9606 33450351 YES miannu ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a). 0.8 SIGNOR-269454 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral EDNRA protein P25101 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004094 26675258 YES Parnian Altogether, these findings demonstrate that miR-30a functionally binds the ETAR 3′UTR, thereby inhibiting ETAR expression and cell proliferation. 0.4 SIGNOR-277997 POLH protein Q9Y253 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 21242293 NO miannu In this study we show that, in human cells, polη becomes phosphorylated by ATR at Ser601 after UV irradiation. Phosphorylation requires physical interaction of polη with Rad18 but is independent of PCNA monoubiquitination. We show that UV-induced phosphorylation of polη is required for normal survival and postreplication repair and is involved in checkpoint control. 0.7 SIGNOR-259061 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000007 18840653 YES We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. 0.565 SIGNOR-248399 KAT2A protein Q92830 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269596 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Thr1141 NRKSLRRtLKSGLGD 9606 18239683 YES lperfetto Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres. 0.309 SIGNOR-160552 RALGAPA2 protein Q2PPJ7 UNIPROT RalGAP2 complex SIGNOR-C469 SIGNOR form complex binding 10090 21148297 YES miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. 0.604 SIGNOR-269793 RIPK1 protein Q13546 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity phosphorylation 9606 26694384 YES miannu In the current scenario, RIPK1 phosphorylates and activates RIPK3, and activated RIPK3 then phosphorylates MLKL. 0.753 SIGNOR-278429 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral CDH1 protein P12830 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 BTO:0003792 26675258 YES Parnian The overexpression of miR-30a restored E-cadherin levels, and inhibited the expression of both vimentin and Snail. 0.4 SIGNOR-277998 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral VIM protein P08670 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003792 26675258 YES Parnian The overexpression of miR-30a restored E-cadherin levels, and inhibited the expression of both vimentin and Snail. 0.4 SIGNOR-277999 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral VEGFA protein P15692 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004094 26675258 YES Parnian Overexpression of miR-30a reverts EMT phenotype and impairs cell invasion and plasticity, and VEGF production 0.4 SIGNOR-278001 hsa-miR-21-5p mirna URS000039ED8D_9606 RNAcentral CCL20 protein P78556 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002210 22001440 YES Parnian MiR-21 may suppress gene expression through miR-21-binding sequences at the 3′-UTR of CCL20 gene . This suggests that miR-21 represses CCL20 expression by targeting the 3′UTR. 0.4 SIGNOR-278006 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.62 SIGNOR-269245 PRMT6 protein Q96LA8 UNIPROT SIRT7 protein Q9NRC8 UNIPROT down-regulates activity methylation Arg388 ILGGWFGrGCTKRTK 30420520 YES lperfetto Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization. 0.26 SIGNOR-275888 EEF1A2 protein Q05639 UNIPROT Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269534 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258472 Verdinexor chemical CID:71492799 PUBCHEM XPO1 protein O14980 UNIPROT down-regulates chemical inhibition 9606 30541831 YES Simone Vumbaca We show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and a reduction inRSV titers. 0.8 SIGNOR-261129 IRF8 protein Q02556 UNIPROT CD68 protein P34810 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000801 12676954 NO However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element. 0.281 SIGNOR-254285 CDK1 protein P06493 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Thr537 LGQNKAHtPFRESKL 9606 20368358 YES llicata We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation. 0.685 SIGNOR-164761 CSNK2A2 protein P19784 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.286 SIGNOR-250978 ROR1 protein Q01973 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates activity phosphorylation 9606 22439932 YES miannu Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation.|ROR1 knockdown decreased phosphorylations of ERBB3, c-Src, and AKT in NKX2-1 + / ROR1 + NCI-H1975, SK-LC-5, and NCI-H358 cells. 0.344 SIGNOR-279279 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr201 DIPEKPKtPQQLWYT 9606 11741541 YES lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna 0.578 SIGNOR-112817 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT up-regulates activity binding 9606 17259966 YES miannu The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells 0.934 SIGNOR-254946 JAK2 protein O60674 UNIPROT ATOH1 protein Q92858 UNIPROT up-regulates quantity phosphorylation Tyr80 CTARAAQyLLHSPEL 9606 BTO:0004328 29168692 YES Gianni We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling. 0.339 SIGNOR-262201 HACE1 protein Q8IYU2 UNIPROT RAC1 protein P63000 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22036506 YES The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation 0.368 SIGNOR-255538 MYD88 protein Q99836 UNIPROT DHX36 protein Q9H2U1 UNIPROT up-regulates activity binding 9606 BTO:0002042 20696886 YES miannu We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing. 0.522 SIGNOR-260956 Ub:E2 complex SIGNOR-C497 SIGNOR RNF181 protein Q9P0P0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271230 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val58 KGVTVETvFSVDEFS -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.395 SIGNOR-263591 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates activity phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 YES done miannu Together, these results suggest that TRPC5 is directly phosphorylated by G(s)/cAMP/PKA at positions S794 and S796. These inhibitory effects were blocked by the protein kinase A (PKA) inhibitors, KT-5720 and H-89, as well as by two point mutations at consensus PKA phosphorylation sites on TRPC5 (S794A and S796A). 0.2 SIGNOR-273789 BCL2L1 protein Q07817 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003328 9393856 NO fcortellessa Bcl-xL Expression Prevents Cytochrome c Redistribution and Subsequent Mitochondrial Depolarization during Apoptosis. Bcl-xL expression prevented both cytochrome c redistribution and mitochondrial membrane depolarization. In contrast, zVAD treatment could not prevent either cytochrome c redistribution or mitochondrial membrane depolarization in control transfectants withdrawn from IL-3. Thus, cytochrome c redistribution from mitochondria is an early apoptotic event that precedes mitochondrial membrane depolarization. Bcl-xL expression functions to inhibit both of these events. In at least some forms of cell death, the ability of Bcl-xL to regulate these mitochondrial events cannot be mimicked by caspase inhibition 0.7 SIGNOR-261683 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser230 PKYSRQFsLEHVHGS -1 35080342 YES miannu Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. 0.405 SIGNOR-277580 NET1 protein Q7Z628 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.831 SIGNOR-260561 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258169 RNF123 protein Q5XPI4 UNIPROT CBX1 protein P83916 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 23077635 YES miannu In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation. 0.2 SIGNOR-272034 TWIST2 protein Q8WVJ9 UNIPROT ILK protein Q13418 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255504 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2D2 protein P62837 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.851 SIGNOR-271323 hsa-miR-582-3p mirna URS00002573C3_9606 RNAcentral DKK3 protein Q9UBP4 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003009 26468775 YES Parnian MiR-582-3p directly targets multiple negative regulators of the Wnt pathway. | Overall, our results demonstrate that miR-582-3p activates Wnt signalling by targeting AXIN2, DKK3 and SFRP1 enhances stem cell-like traits; and leads to tumour recurrence and poor prognosis in NSCLC patients. 0.4 SIGNOR-278018 GTF2H2 protein Q13888 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 YES Manara TFIIH Phosphorylates Human Estrogen Receptor α at Serine 118 | We report here that Cdk7 overexpression stimulates transcription activation by ERα by stimulating phosphorylation of S118 in a ligand-dependent manner. 0.257 SIGNOR-260817 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR MSX2 protein P35548 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31548378 YES miannu  Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase.  Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation. 0.2 SIGNOR-272261 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser326 SSVDTLLsPTALIDS -1 35080342 YES miannu Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. 0.405 SIGNOR-277581 EZH2 protein Q15910 UNIPROT DACT3 protein Q96B18 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 NO miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. 0.251 SIGNOR-254142 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.762 SIGNOR-252752 NMUR1 protein Q9HB89 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256894 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr222 TSHNSLTtPCYTPYY 9606 8846784 YES fstefani Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk. 0.508 SIGNOR-44343 hsa-miR-320c mirna URS0000010D30_9606 RNAcentral GNAI1 protein P63096 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003227 23691483 YES Parnian GNAI1 was a target of miR-320a/c/d in HCC cells.| Western blot assays revealed that miR-320a/c/d dramatically down-regulated the endogenous GNAI1 protein level, which indicates that these miRNAs may directly target GNAI1 in HCC cells.| Taken together, these observations indicate that miR-320a/c/d facilitate the migration and invasion of HCC cells. 0.4 SIGNOR-278027 PAK4 protein O96013 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates quantity by destabilization phosphorylation Thr369 ESSSYGDtLLGLSDS 10090 BTO:0000575 35108418 YES miannu PAK4 directly phosphorylated Nrf2 at T369, and it led to its nuclear export and proteasomal degradation, all of which impaired antioxidant responses in hepatocytes. 0.2 SIGNOR-277583 ATR protein Q13535 UNIPROT FANCA protein O15360 UNIPROT up-regulates phosphorylation Ser1449 AAPDADLsQEPHLF 9606 19109555 YES lperfetto The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site 0.596 SIGNOR-182953 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0000567 10653583 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. 0.2 SIGNOR-236475 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 21295084 YES amattioni Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction. 0.726 SIGNOR-171767 HSP90AA1 protein P07900 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by stabilization binding 9606 23019338 YES miannu Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. 0.348 SIGNOR-252414 SMO protein Q99835 UNIPROT STK36 protein Q9NRP7 UNIPROT up-regulates binding 9606 17089004 YES gcesareni Smo then activates stk36 serine/threonine kinase to stabilize gli family members and to phosphorylate sufu for nuclear accumulation of gli.| sufu binds to the kinesin cos2 to transduce the hh signal downstream of smo 0.481 SIGNOR-150540 MAPK1 protein P28482 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 YES lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. 0.403 SIGNOR-209876 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.675 SIGNOR-263426 ERBB2 protein P04626 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 8816440 YES gcesareni Most breast, skin, lung, ovary, and gastrointestinal tract tumors express erbb-4, and heterodimerization of this receptor with erbb-2, may be involved in some cancer 0.528 SIGNOR-43844 PRKACA protein P17612 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1364 PSGSQRPsVSDDTGC 9606 17615294 YES lperfetto Additionally, we show that s1360 and s1364 of beta4 are the only residues phosphorylated by pkc and pka in cells, respectivelywe have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (s1356, s1360, and s1364), previously implicated in hd regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated 0.2 SIGNOR-156873 hsa-miR-320d mirna URS0000010C72_9606 RNAcentral GNAI1 protein P63096 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003227 23691483 YES Parnian GNAI1 was a target of miR-320a/c/d in HCC cells.| Western blot assays revealed that miR-320a/c/d dramatically down-regulated the endogenous GNAI1 protein level, which indicates that these miRNAs may directly target GNAI1 in HCC cells.| Taken together, these observations indicate that miR-320a/c/d facilitate the migration and invasion of HCC cells. 0.4 SIGNOR-278028 hsa-miR-30d-5p mirna URS000005CF5F_9606 RNAcentral GNAI2 protein P04899 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003227 20054866 YES Parnian MiR-30d Post-transcriptionally Down-regulates GNAI2 Expression by Directly Targeting Its 3' -UTR.| Taken together, these observations suggest that miR-30d is a positive metastatic regulator for HCC. 0.4 SIGNOR-278030 EID1 protein Q9Y6B2 UNIPROT EP300 protein Q09472 UNIPROT down-regulates activity binding 11073989 YES lperfetto Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. 0.422 SIGNOR-253379 ACTL6A protein O96019 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.593 SIGNOR-270847 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 YES Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts 0.827 SIGNOR-175256 CDK1 protein P06493 UNIPROT IREB2 protein P48200 UNIPROT down-regulates phosphorylation Ser157 LQKAGKLsPVKVQPK 9606 SIGNOR-C17 18574241 YES lperfetto Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity 0.353 SIGNOR-179171 NLRC4 inflammasome complex SIGNOR-C223 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 NO miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. 0.7 SIGNOR-263122 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.497 SIGNOR-248310 RYK protein P34925 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 15454084 YES gcesareni Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled. 0.483 SIGNOR-129568 DPH5 protein Q9H2P9 UNIPROT EEF2 protein P13639 UNIPROT down-regulates activity methylation His715 TLHADAIhRGGGQII 9606 23486472 YES Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5. 0.746 SIGNOR-261146 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI ALK protein Q9UM73 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258219 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr230 DSKEIFLtVPVGGGE 9606 19530738 YES lperfetto We found that substitutions at borealin t230, recently identified as an mps1 phosphorylation site, can modulate the dimerization state of borealin. Mutation of this single residue to alanine or valine impairs aurora b activity during mitosis and causes chromosome segregation defects 0.462 SIGNOR-186147 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AX/b2 integrin complex SIGNOR-C171 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.404 SIGNOR-259026 IFNG protein P01579 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 NO miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. 0.7 SIGNOR-261024 AMPK complex SIGNOR-C15 SIGNOR CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser768 LQARRRQsVLNLMTH 9606 19095655 YES Luana AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions 0.417 SIGNOR-72708 NOS1 protein P29475 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity chemical modification 9606 21890489 YES gcesareni Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates 0.8 SIGNOR-243957 PHPT1 protein Q9NRX4 UNIPROT KCNN4 protein O15554 UNIPROT down-regulates activity dephosphorylation His358 FRQVRLKhRKLREQV 9606 18796614 YES miannu We now show that the mammalian protein histidine phosphatase (PHPT-1) directly binds and inhibits KCa3.1 by dephosphorylating histidine 358 on KCa3.1.|Overexpression of wild-type, but not a phosphatase dead, PHPT-1 inhibited KCa3.1 channel activity. 0.55 SIGNOR-277071 RPS6KB1 protein P23443 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 YES gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. 0.247 SIGNOR-49371 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 9445476 YES gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.727 SIGNOR-55306 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation 9606 16456541 YES inferred from 70% family members gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. 0.2 SIGNOR-270101 BCL7A protein Q4VC05 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.502 SIGNOR-270723 EEF1A2 protein Q05639 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269540 SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR DLX5 protein P56178 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 12815054 NO ggiuliani Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining 0.319 SIGNOR-255790 S protein P0DTC2 UNIPROT ACE2 protein Q9BYF1 UNIPROT down-regulates activity binding 9606 32125455 YES miannu SARS-CoV and likely SARS-CoV-2 lead to downregulation of the ACE2 receptor, but not ACE, through binding of the spike protein with ACE2. This leads to viral entry and replication, as well as severe lung injury. 0.2 SIGNOR-260742 S protein P59594 UNIPROT ACE2 protein Q9BYF1 UNIPROT down-regulates activity binding 9534 18554741 YES miannu Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. 0.2 SIGNOR-260283 NMBR protein P28336 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 8026589 YES fspada G-proteins of the q family have been implicated as mediators of bombesin receptors action. This suggests that nmb-r couples to g?q, and that grp-r and nmb-r show distinct g-protein coupling preferences in the xenopus oocyte. 0.47 SIGNOR-35864 S protein P59594 UNIPROT ACE2 protein Q9BYF1 UNIPROT down-regulates activity binding 9606 14670965 YES miannu The coronavirus spike (S) protein mediates infection of receptor-expressing host cells and is a critical target for antiviral neutralizing antibodies. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for the coronavirus (severe acute respiratory syndrome (SARS)-CoV) that causes SARS. Here we demonstrate that a 193-amino acid fragment of the S protein (residues 318-510) bound ACE2 more efficiently than did the full S1 domain (residues 12-672). Smaller S protein fragments, expressing residues 327-510 or 318-490, did not detectably bind ACE2. 0.2 SIGNOR-260216 S protein P59594 UNIPROT ACE2 protein Q9BYF1 UNIPROT down-regulates activity binding 9606 16988814 YES miannu In acute lung injury, such as acid aspiration, pneumonia, or sepsis, the generation of ANG II from ANG I is enhanced by ACE, and ANG II induces acute lung failure through stimulation of the AT1 receptor, while ACE2 and ANG II type 2 receptor negatively regulate this pathway and protect from acute lung failure. On the other hand, SARS-CoV infection is mediated through binding of the SARS-Spike protein to ACE2 or L-SIGN and down-regulates the protective molecule ACE2, and thus leads to severe lung injury and acute lung failure 0.2 SIGNOR-260291 DGC complex SIGNOR-C217 SIGNOR NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 YES miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. 0.281 SIGNOR-265448 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser285 SSASPALsRRGSLGE 10090 17213202 YES lperfetto Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo. 0.385 SIGNOR-234469 PPM1D protein O15297 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 18265945 YES lperfetto Because Chk1 phosphorylates and activates p53, the inhibition of Chk1 by Wip1 also places Wip1 in a negative feedback regulatory loop for p53 .|In vitro phosphatase assays showed that Wip1 dephosphorylated Chk1 at Ser345, but not Ser317. 0.473 SIGNOR-276986 ITCH protein Q96J02 UNIPROT LATS1 protein O95835 UNIPROT down-regulates quantity destabilization 9606 BTO:0002181 31569999 YES Marta Tosoni These findings suggest that Galpha13 induced phosphorilation of LATS1 at S909 recruits ITCH to trigger LATS1 degradation, leading to EMT-related phenotypes 0.517 SIGNOR-278052 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity phosphorylation Thr342 ASEKFAQtVMTSRIV 9606 BTO:0000007 17141195 YES lperfetto The present data indicate that the kinase activity of irak-4 is dependent on the autophosphorylations at t342 0.2 SIGNOR-151006 GSTA1 protein P08263 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000018 29928434 NO irozzo In addition, the downregulation of GSTA1 in A549 cells significantly induced cell apoptosis in vitro. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line. 0.7 SIGNOR-256297 CDK1 protein P06493 UNIPROT CDC16 protein Q13042 UNIPROT up-regulates phosphorylation Ser560 KTLKNIIsPPWDFRE 9606 14657031 YES lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation 0.637 SIGNOR-119762 MDGA2 protein Q7Z553 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 26206665 NO miannu MDGA2 acts as a novel tumour suppressor in gastric cancer through inhibiting cell proliferation, suppressing G1–S cell cycle transition and inducing cell apoptosis. 0.7 SIGNOR-264239 N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI up-regulates quantity precursor of 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-268091 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr341 GQRDSSYyWEIEASE 9606 12551923 YES gcesareni We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain. 0.604 SIGNOR-97639 SRPK1 protein Q96SB4 UNIPROT RBM8A protein Q9Y5S9 UNIPROT down-regulates phosphorylation Ser168 GGRRRSRsPDRRRR 9606 16100109 YES gcesareni We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc. 0.261 SIGNOR-139555 A6/b1 integrin complex SIGNOR-C164 SIGNOR TERT protein O14746 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.307 SIGNOR-253280 ASH2L protein Q9UBL3 UNIPROT TBX1 protein O43435 UNIPROT up-regulates activity binding 9606 20463296 YES Regulation miannu Tbx1 interacts with Ash2l in both yeast and mammalian cells and Ash2l acts as a transcriptional co-activator in luciferase reporter assays. 0.309 SIGNOR-251868 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser62 IDLKRGGsSDDRQIV 9534 BTO:0001538 23519612 YES miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 0.318 SIGNOR-262712 NTSR1 protein P30989 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 10030 BTO:0000457 28341345 YES Marta Tosoni Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways 0.275 SIGNOR-278061 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JUN protein P05412 UNIPROT up-regulates phosphorylation 9606 12169099 YES inferred from 70% family members gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. 0.2 SIGNOR-270033 SRC protein P12931 UNIPROT UGT2B7 protein P16662 UNIPROT up-regulates phosphorylation Tyr438 RVINDPSyKENVMKL 9606 19289110 YES gcesareni Overexpression of regular or active src, but not dominant-negative src, in 2b7-transfected cos-1 cells increased 2b7 activity and phospho-y438-2b7 by 50% 0.344 SIGNOR-184613 EHMT2 protein Q96KQ7 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19822740 NO Regulation of transcription miannu G9a activation of the βmaj globin gene was shown to be independent of G9a MT activity. 0.2 SIGNOR-251788 PRKCD protein Q05655 UNIPROT G6PD protein P11413 UNIPROT up-regulates phosphorylation Ser180 FGRDLQSsDRLSNHI 9606 BTO:0001260 20649491 YES lperfetto A pkc activator, significantly increased g6pd phosphorylation and activity, whereas single (s210a, t266a) and double (s210a/t266a) mutations at sites flanking the g6pd active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity. 0.2 SIGNOR-167049 CPT1C protein Q8TCG5 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267128 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 YES milica The type i il-4 receptors result from association of IL-4R With the common ? Chain (?c), which is also a component of the receptors for il-2, il-7, il-9, and il-15. 0.83 SIGNOR-100765 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 YES Translocation from Endosome to Lysosome fspada The peptide p9-s396a/s398a (both ser396 and ser398 to alanines) was phosphorylated only slightly or not phosphorylated by these kinases. Thus both ser396 and ser398 can be phosphorylated by camk ii and pkc 0.2 SIGNOR-124352 LRRC45 protein Q96CN5 UNIPROT CROCC protein Q5TZA2 UNIPROT up-regulates activity binding 9606 BTO:0000567 24035387 YES miannu Here, we show that LRRC45 is a centrosome linker that localizes at the proximal ends of the centrioles and forms fiber-like structures between them. Depletion of LRRC45 results in centrosome splitting during interphase. LRRC45 interacts with C-Nap1 and rootletin 0.44 SIGNOR-273704 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calprotectin complex complex SIGNOR-C293 SIGNOR up-regulates activity chemical activation 9606 BTO:0001044 16690079 YES miannu S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization. 0.8 SIGNOR-262826 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization ubiquitination Lys84 PFTIAQGkGQKLCEI 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). 0.3 SIGNOR-272829 MMP2 protein P08253 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage His31 LDHDRAIhIQAENGP -1 7694569 YES miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. 0.339 SIGNOR-256327 RALY protein Q9UKM9 UNIPROT PRMT1 protein Q99873 UNIPROT up-regulates quantity post transcriptional regulation 9606 BTO:0000567 30354839 YES lperfetto RALY binds poly-U rich elements within several RNAs and regulates the expression as well as the stability of specific transcripts. Here we show that RALY binds PRMT1 mRNA and regulates its expression.|We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels 0.247 SIGNOR-262273 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser122 DQHLMKCsPAQLLCS 9606 SIGNOR-C17 10864927 YES gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.858 SIGNOR-78416 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 YES miannu Interferons have antiviral, antigrowth and immunomodulatory effects. The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. 0.2 SIGNOR-260331 GHSR protein Q92847 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.283 SIGNOR-256782 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr492 ALGADDSyYTARSAG 9606 8756661 YES lperfetto The data further support a model in which ZAP-70 is first phosphorylated by Lck at Tyr-493 to upregulate the catalytic activity of ZAP-70. This in turn per- mits additional phosphorylation of ZAP-70 mediated, in part, by autophosphorylation at sites including Tyr-292 and -492 0.2 SIGNOR-226624 CFLAR protein O15519 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity binding 9606 14585074 YES amattioni Flip can be incorporated into the disc complex and blocks processing and activation of pro-caspase8 0.77 SIGNOR-96402 NFE2L2 protein Q16236 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493435 YES miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 0.408 SIGNOR-254653 BIRC2 protein Q13490 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys145 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. 0.355 SIGNOR-272708 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266465 calcium(2+) smallmolecule CHEBI:29108 ChEBI FLNA protein P21333 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 27871158 YES lperfetto Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. The actin cross-linking complex, GP1b/IX-filamin, translocates from the plasma membrane to the cytoskeleton during this step. 0.8 SIGNOR-261845 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser124 PALKRSHsDSLDHDI 9606 12676583 YES Manara Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A 0.842 SIGNOR-260835 EXOSC10 protein Q01780 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.945 SIGNOR-261390 ADCY3 protein O60266 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity binding 9606 BTO:0000552 33802009 YES Marta Tosoni Although the generated cAMP is primarily involved in transmitting odor information to the olfactory bulbs in the brain, it has been demonstrated that an increase in cellular cAMP by ADCY3 could stimulate protein kinase A (PKA) signaling, which is well-known to regulate diverse physiological and pathological processes 0.533 SIGNOR-278073 CAMKK2 protein Q96RR4 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 YES gcesareni Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli. 0.603 SIGNOR-176602 MRGPRX2 protein Q96LB1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257059 FKBP1A protein P62942 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 BTO:0005493 8756725 YES lperfetto Blocking fkbp12/type i receptor interaction with fk506 nonfunctional derivatives enhances the ligand activity, indicating that fkbp12 binding is inhibitory to the signaling pathways of the tgf beta family ligands 0.853 SIGNOR-236142 PKA proteinfamily SIGNOR-PF17 SIGNOR HSPB8 protein Q9UJY1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser24 RRDPFRDsPLSSRLL -1 18298377 YES miannu Human small heat shock protein with molecular mass 22 kD (HSP22, HspB8) contains two Ser residues (Ser24 and Ser57) in consensus sequence RXS and is effectively phosphorylated by cAMP-dependent protein kinase in vitro. Mutation S24D did not affect, whereas mutations S57D or S24,57D prevented phosphorylation of HSP22 by cAMP-dependent protein kinase thus indicating that Ser57 is the primary site of phosphorylation. Phosphorylation (or mutation) of Ser57 (or Ser24 and Ser57) resulted in changes of the local environment of tryptophan residues and increased HSP22 susceptibility to chymotrypsinolysis.  0.2 SIGNOR-276152 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 16943424 YES lperfetto Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm. 0.734 SIGNOR-149296 GHRL protein Q9UBU3 UNIPROT GHSR protein Q92847 UNIPROT up-regulates binding 9606 15070777 YES fspada In contrast to wild-type mice, acute treatment of ghsr- mice with ghrelin stimulated neither gh release nor food intake, showing that the ghsr is a biologically relevant ghrelin receptor. 0.722 SIGNOR-123948 fentanyl chemical CHEBI:119915 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258938 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Thr185 EGSRQALtLQDWAAQ -1 18184589 YES Manara Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition. 0.2 SIGNOR-260803 FGF2 protein P09038 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 20974802 NO inferred from 70% of family members gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. 0.612 SIGNOR-269929 GNAQ protein P50148 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity binding 7108 BTO:0001240 9305846 YES Marta Tosoni AlF− 4-activated Gaq-GDP increased Btk activity as expected, whereas AlF− 4 alone had no stimulatory effect (Table 1), so we conclude that Gaq directly stimulates Btk kinase activity 0.351 SIGNOR-278083 tetrafluoroaluminate(1-) chemical CHEBI:30111 ChEBI GNAQ protein P50148 UNIPROT up-regulates activity chemical activation 7108 BTO:0001240 9305846 YES Marta Tosoni Aluminium tetrafluoride (AlF−4) interacts with Gα-bound GDP to mimic GTP and to activate G proteins13. AlF−4-activated Gαq-GDP increased Btk activity as expected 0.8 SIGNOR-278084 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation 9606 BTO:0002181 16293724 YES Marta Tosoni Free Gbg subunits liberated upon Gas activation,directly stimulate the activity of PI3K and Akt, leading to phosphorylation and inactivation of GSK-3b. Ultimately, these processes result in the stabilization and nuclear translocation of b-catenin, thereby stimulating LEF and b-catenin–dependent gene expression and the aberrant growth of colon cancer cells. 0.2 SIGNOR-278095 BMP7 protein P18075 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 10090 BTO:0000165 SIGNOR-C30 11282024 YES gcesareni Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2 0.806 SIGNOR-236913 FANCL protein Q9NW38 UNIPROT FANCI protein Q9NVI1 UNIPROT up-regulates activity ubiquitination SIGNOR-C300 18985065 YES lperfetto Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding 0.842 SIGNOR-263266 SMARCC1 protein Q92922 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.738 SIGNOR-270724 abiraterone chemical CHEBI:68642 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-204810 PI3K complex SIGNOR-C156 SIGNOR BTK protein Q06187 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000899 10201980 YES lperfetto Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation 0.484 SIGNOR-252709 RCHY1 protein Q96PM5 UNIPROT COPE protein O14579 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17721809 YES miannu PIRH2 promotes the ubiquitylation of epsilon-COP in vitro and in vivo and consequently promotes the degradation of epsilon-COP.  0.471 SIGNOR-272630 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 YES milica Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ 0.42 SIGNOR-201154 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 24117889 YES lperfetto Camkii represses transcriptionally active beta-catenin to mediate acute ethanol neurodegeneration and can phosphorylate beta-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human beta-catenin at t332, t472, and s552 0.289 SIGNOR-202825 MAP3K7 protein O43318 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser465 HNPISSVs 9606 19536134 YES miannu This analysis showed that phosphorylation of Smad1 at the C-terminal serines S463 and S465 was increased by co-expression of constitutively active TAK1. 0.374 SIGNOR-279420 APC-c complex SIGNOR-C150 SIGNOR KIF2C protein Q99661 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 25504441 YES miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. 0.278 SIGNOR-276864 RET protein P07949 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates binding 9606 8631863 YES gcesareni Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell 0.542 SIGNOR-41699 GPR50 protein Q13585 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates activity binding 9606 BTO:0000599 32405532 YES Marta Tosoni GPR50 and ADAM17 can directly interact with each other (as both are cell membrane proteins), which was confirmed via coimmunoprecipitation (coIP; Figure 6C), indicating that ligand-independent Notch signaling activation is mediated through the GPR50-ADAM17 interaction 0.2 SIGNOR-278099 WNT1 protein P04628 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 YES gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling. 0.827 SIGNOR-169648 CDK1 protein P06493 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Thr317 RGALVRGtPVRGAIT 9606 9315091 YES lperfetto Phosphorylation of sam68 by purified cdc2. 0.536 SIGNOR-51275 AKT proteinfamily SIGNOR-PF24 SIGNOR MST1R protein Q04912 UNIPROT up-regulates phosphorylation Ser1394 VRRPRPLsEPPRPT 9606 14505491 YES lperfetto Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing 0.2 SIGNOR-118053 DOT1L protein Q8TEK3 UNIPROT H3-3A protein P84243 UNIPROT unknown methylation Lys80 REIAQDFkTDLRFQS 9606 12123582 YES miannu HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase. 0.2 SIGNOR-267143 NOTCH1 protein P46531 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 BTO:0000776 9528794 YES gcesareni We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk. 0.426 SIGNOR-56150 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 YES milica The protease-activated receptors (PAR)2 are a class of G protein-coupled receptors (GPCR) that are activated by the proteolysis of the N-terminal exodomain. Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13). 0.598 SIGNOR-196006 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK9 protein P50750 UNIPROT down-regulates activity chemical inhibition -1 29901072 YES miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. 0.8 SIGNOR-262217 FZD7 protein O75084 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR form complex binding 9606 BTO:0002314 BTO:0001103 23290138 YES apalma We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells. 0.556 SIGNOR-255848 OST-A complex complex SIGNOR-C535 SIGNOR Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.7 SIGNOR-272055 ZNF503 protein Q96F45 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 10090 25538248 NO Monia Zpo2-overexpressing cells demonstrated high levels of pFAK compared with the control (Fig. 6A). Additionally, Western blot analysis indicated that, in response to Zpo2 expression, both EpH4.9 and PyMT cells increase FAK activity, as demonstrated by higher levels of pFAK staining (Fig. 6B). 0.2 SIGNOR-261191 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Ile847 LQPDVTGiRLLSLGA -1 9242537 YES lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex. 0.367 SIGNOR-263637 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 16199882 YES gcesareni Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro. 0.477 SIGNOR-140902 KDM6A protein O15550 UNIPROT HOXA11 protein P31270 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.263 SIGNOR-260021 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF7 protein Q9H992 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270948 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191021 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 YES lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2 0.2 SIGNOR-112483 4-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]aniline chemical CHEBI:92250 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258852 LAMTOR3 protein Q9UHA4 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates binding 9606 15547943 YES lperfetto We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations. 0.615 SIGNOR-244874 VKORC1L1 protein Q8N0U8 UNIPROT vitamin K epoxide smallmolecule CHEBI:28371 ChEBI down-regulates quantity chemical modification 9606 31226734 YES lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form 0.8 SIGNOR-265902 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr509 PVFDLTTtPKGGTPA 9606 16611631 YES lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.364 SIGNOR-145979 HMGA1 protein P17096 UNIPROT SLC2A3 protein P11169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22706202 NO miannu CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. 0.2 SIGNOR-254427 KIF17 protein Q9P2E2 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272530 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Ser54 ELQPMPTsPGVDLQS 9606 BTO:0000567 12714602 YES lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. 0.699 SIGNOR-217348 ADRA2A protein P08913 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.555 SIGNOR-256698 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 YES lperfetto Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2. 0.731 SIGNOR-59631 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.538 SIGNOR-270904 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr417 SLPQATVtPPRKEER 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 YES lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex 0.416 SIGNOR-216953 AURKC protein Q9UQB9 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 12588998 YES gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-265357 HSPA1B protein P0DMV9 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity post transcriptional regulation 9606 19083193 YES miannu We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. 0.2 SIGNOR-252198 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 17110930 YES Barakat Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK 0.593 SIGNOR-274148 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL -1 29967145 YES miannu CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro. 0.322 SIGNOR-277651 BRCA1 protein P38398 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates ubiquitination 9606 16818604 YES gcesareni In conclusion, our data show that ctip is a physiological substrate of the brca1 e3 ligase. Brca1 recruits ctip through its c-terminal brct domains and promotes ctip ubiquitination through its n-terminal ring domain. The ubiquitinated ctip is not targeted for degradation. Instead, ubiquitinated ctip binds to chromatin following dna damage and is likely to be involved in dna damage checkpoint control. 0.841 SIGNOR-147711 creatine smallmolecule CHEBI:16919 ChEBI CKB protein P12277 UNIPROT up-regulates activity chemical activation 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265783 PTPRG protein P23470 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1054 FGLARDIyKDPDYVR -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.253 SIGNOR-254707 CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 YES lperfetto Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome 0.791 SIGNOR-165022 SCN11A protein Q9UI33 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 YES miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. 0.8 SIGNOR-253407 BRCC3 protein P46736 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 YES lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer 0.545 SIGNOR-263205 SRC protein P12931 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 12810717 YES gcesareni Tiam1 cooperated with src to induce activation of rac1 in vivo and the formation of membrane ruffles. 0.656 SIGNOR-102354 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.8 SIGNOR-270437 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 YES The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. 0.816 SIGNOR-175817 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR TRIM71 protein Q2Q1W2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.294 SIGNOR-269239 AMPK complex SIGNOR-C15 SIGNOR CTH protein P32929 UNIPROT up-regulates activity phosphorylation Ser346 ESLGGFEsLAELPAI 9606 BTO:0000007 37922764 YES miannu  Here we define an important mechanism of increased persulfide and polysulfide production involving cystathionine gamma lyase (CSE) phosphorylation at serine 346 and threonine 355 in a substrate specific manner, under acute hypoxic conditions. Hypoxic phosphorylation of CSE occurs in an AMP kinase dependent manner increasing enzyme activity involving unique inter- and intramolecular interactions within the tetramer.  0.25 SIGNOR-277794 lisinopril chemical CHEBI:43755 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 9187274 YES miannu We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range. 0.8 SIGNOR-258611 INPPL1 protein O15357 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates binding 9606 BTO:0000567 15668240 YES gcesareni This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor. 0.2 SIGNOR-133388 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15809340 YES gcesareni Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively. 0.929 SIGNOR-135185 RBPJ protein Q06330 UNIPROT MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 21873209 YES gcesareni When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects 0.87 SIGNOR-176197 Ub:E2 complex SIGNOR-C497 SIGNOR RNF138 protein Q8WVD3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271027 S protein P59594 UNIPROT CLEC4M protein Q9H2X3 UNIPROT up-regulates activity binding 9606 15479853 YES lperfetto Here we show that DC-SIGN and DC-SIGNR enhance infection mediated by the glycoprotein (GP) of Marburg virus (MARV) and the S protein of severe acute respiratory syndrome coronavirus and might promote viral dissemination. 0.2 SIGNOR-260269 MSX1 protein P28360 UNIPROT LHX2 protein P50458 UNIPROT down-regulates activity binding -1 9697309 YES 2 miannu Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity 0.478 SIGNOR-241330 GOLPH3 protein Q9H4A6 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 19553991 NO Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. 0.295 SIGNOR-253555 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr666 GQEVYHAyAEPLPIT -1 23770091 YES done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. 0.351 SIGNOR-273946 azelastine chemical CHEBI:2950 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 21381763 YES Luana Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively.  0.8 SIGNOR-257894 FGF11 protein Q92914 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253442 XIAP protein P98170 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 YES miannu In this study, we report that in addition to RIP1 and RIP2, also RIP3 and RIP4 directly interact with XIAP, cIAP1 and cIAP2. When comparing the ability of these IAPs to directly conjugate RIP1–RIP4 with ubiquitin chains, we found that cIAP1 was the most effective E3 and was capable of ubiquitinating all four RIPs in the presence of the E2 component UbcH5a. On the contrary, XIAP was only capable of inducing weak ubiquitination of RIP4. 0.333 SIGNOR-272716 EGFR protein P00533 UNIPROT EPS15 protein P42566 UNIPROT up-regulates phosphorylation Tyr849 NFANFSAyPSEEDMI 9606 24269888 YES lperfetto Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly; 0.754 SIGNOR-203311 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val76 LTGKLTTvFLPIVYT -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.395 SIGNOR-263592 NCOR2 protein Q9Y618 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 12897056 YES gcesareni The spen protein, sharp (smrt/hdac1-associated repressor protein), was identified as a component of transcriptional repression complexes in both nuclear receptor and notch/rbp-jkappa signaling pathways. 0.2 SIGNOR-104489 FAAP24 protein Q9BTP7 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.2 SIGNOR-263239 BDKRB1 protein P46663 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257036 GAD1 protein Q99259 UNIPROT gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity chemical modification 9606 32041144 YES miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. 0.8 SIGNOR-267552 PYHIN1 protein Q6K0P9 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 18247378 NO miannu We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1. 0.291 SIGNOR-268495 CCP110 protein O43303 UNIPROT CETN1 protein Q12798 UNIPROT up-regulates activity binding 9606 16760425 YES miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. 0.484 SIGNOR-265966 FAM83H protein Q6ZRV2 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.331 SIGNOR-273764 SNAI2 protein O43623 UNIPROT VDR protein P11473 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 18485278 NO miannu We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. 0.375 SIGNOR-255177 SLC9A2 protein Q9UBY0 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265601 AKT proteinfamily SIGNOR-PF24 SIGNOR USP14 protein P54578 UNIPROT up-regulates activity phosphorylation Ser432 THQGRSSsSGHYVSW 9606 BTO:0000007 26523394 YES lperfetto Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt. 0.2 SIGNOR-265055 CDK1 protein P06493 UNIPROT CGAS protein Q8N884 UNIPROT down-regulates activity phosphorylation Ser305 MKRKRGGsPAVTLLI 32351706 YES lperfetto The major mitotic kinase CDK1-cyclin B complex phosphorylates human cGAS at S305 or mouse cGAS at S291, which inhibits its ability to synthesize cGAMP upon mitotic entry. 0.2 SIGNOR-276526 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 YES lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. 0.2 SIGNOR-264443 ZC3HAV1 protein Q7Z2W4 UNIPROT PARN protein O95453 UNIPROT up-regulates activity binding 9606 BTO:0000007 21876179 YES We provide evidence indicating that ZAP selectively recruits cellular poly(A)-specific ribonuclease (PARN) to shorten the poly(A) tail of target viral mRNA and recruits the RNA exosome to degrade the RNA body from the 3′ end. 0.414 SIGNOR-261296 NR1H4 protein Q96RI1 UNIPROT ABCB4 protein P21439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000575 14527955 NO miannu Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor alpha heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (-1970 to -1958). 0.417 SIGNOR-254833 FOXO4 protein P98177 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 YES miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. 0.264 SIGNOR-260102 EEF1A1P5 protein Q5VTE0 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 NO lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.7 SIGNOR-269395 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK13 protein O15264 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni 0.8 SIGNOR-189696 TBK1 protein Q9UHD2 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation 9606 33310066 YES miannuccelli It was found that TBK1 phosphorylates both Cdc20 as well as Cdh1 (Figure 2F). 0.2 SIGNOR-279766 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:RING_E3 complex SIGNOR-C519 SIGNOR form complex binding 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 0.2 SIGNOR-271380 GTF2A2 protein P52657 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR form complex binding 9606 BTO:0000567 7724559 YES lperfetto TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit. 0.94 SIGNOR-266196 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C15 SIGNOR-C3 21460634 YES lperfetto Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2. 0.686 SIGNOR-173035 5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylidene]thiazolidine-2,4-dione chemical CHEBI:94690 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189912 PPARG protein P37231 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19041764 YES miannu  Rosiglitazone treatment induced aortic expression of Bmal1 mRNA, and ChIP and promoter assays revealed that Bmal1 is a direct PPARgamma target gene. These studies have uncovered a role for vascular PPARgamma as a peripheral factor participating in regulation of cardiovascular rhythms. 0.399 SIGNOR-268026 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Macropinosomes formation phenotype SIGNOR-PH227 SIGNOR up-regulates 9606 39000072 NO miannu The signaling for the regulation of macropinocytosis normally starts with the activation of RAS protein by macropinocytic stimulators, which in turn initiate signaling cascades involving RAC1 and phosphatidylinositol kinases and their downstream effectors or product that lead to actin cytoskeleton remodeling for plasma membrane ruffle and macropinocytic cup formation. Macropinosomes are further matured by regulation of the small GTPases RAC1 and CDC42 as well as phosphatidylinositol lipids, and matured macropinosomes undergo recycling or degradation processes. 0.7 SIGNOR-277767 POU3F2 protein P20265 UNIPROT GNRH1 protein P01148 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11875100 NO miannu Functional studies demonstrated that Brn-2 increased promoter activity of the human and mouse GnRH genes. 0.279 SIGNOR-254928 AKT1 protein P31749 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Ser985 THLSRVRsLDLDDWP 9606 BTO:0001130 19176382 YES llicata In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2. 0.498 SIGNOR-183543 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP 9606 8692915 YES Manara The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites. 0.414 SIGNOR-260820 SKP2 protein Q13309 UNIPROT CDT1 protein Q9H211 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10790373 YES miannu  Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3. 0.661 SIGNOR-272565 Core Binding Factor complex complex SIGNOR-C214 SIGNOR SPI1 protein P17947 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0002884 22012064 YES irozzo Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression. 0.547 SIGNOR-255875 COPS7B protein Q9H9Q2 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.896 SIGNOR-270760 ABT-737 chemical CID:11228183 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271;BTO:0000776;BTO:0000785 17200714 YES gcesareni A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells. 0.8 SIGNOR-151784 ENO1 protein P06733 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266524 SSTR2 protein P30874 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.354 SIGNOR-256963 XPOT protein O43592 UNIPROT NPC complex SIGNOR-C263 SIGNOR up-regulates activity binding 9606 BTO:0000007 9660920 YES miannu Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus. 0.464 SIGNOR-261393 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.762 SIGNOR-252484 bosutinib chemical CHEBI:39112 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258088 CSNK2A1 protein P68400 UNIPROT CREB3 protein O43889 UNIPROT down-regulates quantity by destabilization phosphorylation Ser46 LPLSEVPsDWEVDDL -1 31941600 YES miannu Here, we found that human CREB3 is phosphorylated within its transcription activation domain on serine 46 by protein kinase CK2. However, phosphorylation at serine 46 reduced the stability of CREB3. 0.2 SIGNOR-277501 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr347 RKKSWEVyQGVCQKG 9606 16226010 YES lperfetto Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway. 0.262 SIGNOR-141107 aclidinium chemical CHEBI:65346 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000131 19653626 YES Luana This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. 0.8 SIGNOR-258152 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1080 IFYYFSNsPSKRLRE 9606 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104671 HUWE1 protein Q7Z6Z7 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 30217973 YES lperfetto AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome 0.421 SIGNOR-272978 NDUFB1 protein O75438 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 0.776 SIGNOR-262162 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000773 11278964 YES lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. 0.8 SIGNOR-106436 ER stress stimulus SIGNOR-ST9 SIGNOR ERN1 protein O75460 UNIPROT up-regulates 9606 18065414 NO miannu Our findings suggest that MTHFR is up-regulated by ER stress and that this effect is mediated by IRE1 and c-Jun. 0.7 SIGNOR-253145 AMPK complex SIGNOR-C15 SIGNOR SIRT7 protein Q9NRC8 UNIPROT down-regulates quantity by destabilization phosphorylation Thr153 TLTHMSItRLHEQKL 27511885 YES lperfetto Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ. 0.2 SIGNOR-275865 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.759 SIGNOR-219308 TBX5 protein Q99593 UNIPROT SNCG protein O76070 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20802524 NO miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. 0.2 SIGNOR-255255 PRKAB1 protein Q9Y478 UNIPROT PROX1 protein Q92786 UNIPROT down-regulates quantity by destabilization phosphorylation Ser79 KLLKRANsYEDAMMP 9606 BTO:0002181 36433955 YES miannu Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. 0.2 SIGNOR-277609 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269383 RBM10 protein P98175 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001938 30403180 NO irozzo Cell apoptosis is an important event in cancer progression. Overexpression of RBM10 dramatically induced U2OS cell apoptosis compared with negative control cells. 0.7 SIGNOR-259150 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002552 23479728 YES lperfetto Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists| 0.378 SIGNOR-267668 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190404 CPT1A protein P50416 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267132 amitriptyline chemical CHEBI:2666 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258704 CDK4 protein P11802 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser477 ADALKLRsPRGSPDG 9606 BTO:0000150 20807815 YES llicata Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function. 0.352 SIGNOR-167770 CDC34 protein P49427 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR up-regulates activity binding 9606 25425648 YES miannu The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. 0.774 SIGNOR-277331 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 9712898 YES lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. 0.895 SIGNOR-59689 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1114 HGHVSNAsIRVGENV -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262902 PARK7 protein Q99497 UNIPROT MTA1/DJ1 complex complex SIGNOR-C123 SIGNOR form complex binding 9606 BTO:0000567 21368136 YES 1 miannu we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. 0.328 SIGNOR-239448 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation Ser407 STEQTLAsDTDSSLD -1 11062067 YES MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. 0.636 SIGNOR-251416 NCOA2 protein Q15596 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 24239470 YES miannu The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis 0.901 SIGNOR-251530 Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 21812398 NO miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.7 SIGNOR-263723 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 NO These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK. 0.36 SIGNOR-256107 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT up-regulates binding 9606 10734056 YES CCR1 is also activated by MIP-1α, MCP-2, and MCP-3, although maximum responses are only obtained with RANTES and MIP-1α. 0.71 SIGNOR-254366 HLTF protein Q14527 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity ubiquitination 9606 21845734 YES miannu HLTF promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen (PCNA) that is required for maintaining genomic stability. 0.78 SIGNOR-278608 SRC protein P12931 UNIPROT CEACAM1 protein P13688 UNIPROT up-regulates activity phosphorylation Tyr493 NKMNEVTySTLNFEA 9606 BTO:0000007 9867848 YES lperfetto Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515 0.426 SIGNOR-246471 MTF1 protein Q14872 UNIPROT GCLC protein P48506 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15378601 NO miannu MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase. 0.286 SIGNOR-254599 MAPK1 protein P28482 UNIPROT SCNN1B protein P51168 UNIPROT down-regulates quantity by destabilization phosphorylation Thr615 QALPIPGtPPPNYDS -1 11805112 YES lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. 0.29 SIGNOR-249446 ERG protein P11308 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25277175 NO miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. 0.283 SIGNOR-251554 TP53BP1 protein Q12888 UNIPROT H4C1 protein P62805 UNIPROT unknown binding 9606 17190600 YES gcesareni Here we demonstrate that this link occurs through direct binding of 53bp1 and crb2 to histone h4. 0.2 SIGNOR-151654 RPL19 protein P84098 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.885 SIGNOR-262479 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus 0.2 SIGNOR-252349 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 BTO:0000782 SIGNOR-C13 16407239 YES gcesareni Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . 0.358 SIGNOR-143581 DYRK2 protein Q92630 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation Ser16 PSANKPCsKQPPPQP 9606 22878263 YES llicata In the present study, we identify the serine/threonine kinase dyrk2 as siah2 interaction partner that phosphorylates siah2 at five residues (ser16, thr26, ser28, ser68, and thr119). accordingly, phosphorylated siah2 is more active than the wild-type e3 ligase and shows an increased ability to trigger the hif-1?-Mediated transcriptional response and angiogenesis. 0.411 SIGNOR-198721 WT1 protein P19544 UNIPROT SRY protein Q05066 UNIPROT up-regulates binding 9606 12970737 YES miannu Here we report that wt1 binds to and acts synergistically with sry to activate transcription from a promoter containing sry-binding sites 0.2 SIGNOR-100345 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.552 SIGNOR-89178 SH2B1 protein Q9NRF2 UNIPROT SYK protein P43405 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 32323266 YES scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. 0.2 SIGNOR-268445 PRKAA1 protein Q13131 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates phosphorylation Ser351 HVISRDQsTPIIEVE 9606 SIGNOR-C15 21478464 YES gcesareni Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression 0.2 SIGNOR-173118 PDK2 protein Q15119 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 YES gcesareni Kinetic and regulatory properties of recombinant human pdh2 and pdh1 were compared in this study. Site-specific phosphorylation/dephosphorylation of the three phosphorylation sites by four pdh kinases (pdk1-4) and two pdh phosphatases (pdp1-2) were investigated by substituting serines with alanine or glutamate in pdhs. 0.546 SIGNOR-143970 KLHL2 protein O95198 UNIPROT UCK1 protein Q9HA47 UNIPROT down-regulates quantity by destabilization ubiquitination Lys81 EQKAKALkGQYNFDH 31938050 YES lperfetto We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. 0.347 SIGNOR-275962 GIT1 protein Q9Y2X7 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 39000072 YES miannu Activated RAC1 interacts with GIT1, a GAP protein of ARF6, and causes the inactivation of ARF6 [78]. As ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane, the inactivation of ARF6 by RAC1 reduces the recycling of macropinosomes. 0.713 SIGNOR-277784 NME1 protein P15531 UNIPROT KSR1 protein Q8IVT5 UNIPROT unknown phosphorylation Ser406 TRLRRTEsVPSDINN -1 12105213 YES miannu Mutation of Ser392 to alanine consistently reduced Nm23-H1 phosphorylation, confirming it as a site of Nm23-H1 kinase activity The unique phosphorylation pattern of KSR by Nm23-H1 will be the subject of further investigation to determine its effects on KSR protein binding, subcellular localization, response to various signals, etc. 0.544 SIGNOR-250299 CSNK2A1 protein P68400 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates activity phosphorylation Ser289 ITDVHMVsDSDGDDF 9534 12832043 YES llicata We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites.|Therefore we assume that CK2‐mediated FAF1 phosphorylation influences the nuclear localization of FAF1 | it implies that the major function of FAF1 might not be in the cytoplasm as an interacting partner of Fas. 0.327 SIGNOR-250863 AMPK complex SIGNOR-C15 SIGNOR TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 YES We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo 0.2 SIGNOR-256135 PDPK1 protein O15530 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 16207722 YES miannu We found that PDK1 directly phosphorylates IKKbeta at the Ser(181) residue in the activation loop, leading to NF-kappaB nuclear translocation and NF-kappaB-dependent anti-apoptotic gene expression. 0.472 SIGNOR-279088 NODAL protein Q96S42 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates activity binding 9606 19874624 YES Regulation miannu Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors. 0.641 SIGNOR-251939 CD3D protein P04234 UNIPROT CD3 complex SIGNOR-C432 SIGNOR form complex binding 9606 12507424 YES miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules. 0.736 SIGNOR-255295 PDPK1 protein O15530 UNIPROT PGK1 protein P00558 UNIPROT up-regulates activity phosphorylation Thr243 IGGGMAFtFLKVLNN 9606 BTO:0002036 30029001 YES miannu PDPK1 Phosphorylates PGK1 T243. Macrophages increase PGK1 pT243 to reduce the 3-PG affinity of PGK1, which alters the equilibrium of the PGK1-catalyzed reaction toward glycolysis, promoting tumor cell proliferation. 0.2 SIGNOR-277402 CHEK2 protein O96017 UNIPROT PPP2R5C protein Q13362 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 15380617 YES gcesareni Found that chk2 associated with the b' regulatory subunit of protein phosphatase pp2a. In vitro kinase assays showed that b'gamma3 was a potent chk2 substrate. This phosphorylation increased the catalytic phosphatase activity of pp2a. 0.322 SIGNOR-129255 TFEB protein P19484 UNIPROT HEXA protein P06865 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.306 SIGNOR-276541 SMURF1 protein Q9HCE7 UNIPROT TPM4 protein P67936 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272684 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR ERBB4 protein Q15303 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277671 UBE3A protein Q05086 UNIPROT PSMD7 protein P51665 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28559284 YES lperfetto Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits. 0.271 SIGNOR-265134 DACT1 protein Q9NYF0 UNIPROT DVL2 protein O14641 UNIPROT down-regulates binding 9606 16446366 YES gcesareni Dapper 1 antagonizes wnt signaling by promoting dishevelled degradation 0.79 SIGNOR-144053 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000130;BTO:0000801;BTO:0000876 7535770 YES lperfetto Recently, two map kinase kinases (mkk3 and mkk4) that activate p38 map kinase have been identified. the mechanism of p38 activation is mediated by dual phosphorylation on thr-180 and tyr-182. 0.727 SIGNOR-236103 CECR2 protein Q9BXF3 UNIPROT CERF complex SIGNOR-C340 SIGNOR form complex binding 9606 BTO:0000227 15640247 YES miannu Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation. 0.386 SIGNOR-263891 AUTS2 protein Q8WXX7 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 28505103 NO miannu Cytoplasmic AUTS2 regulates actin cytoskeleton to control neuronal migration and neurite extension, while nuclear AUTS2 controls transcription of various genes as a component of the polycomb complex 1 (PRC1). 0.7 SIGNOR-266816 POU5F1 protein Q01860 UNIPROT EOMES protein O95936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.422 SIGNOR-254930 ADORA2B protein P29275 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257307 FZD9 protein O00144 UNIPROT SPRY4 protein Q9C004 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15705594 NO miannu In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity. 0.281 SIGNOR-253035 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT up-regulates activity phosphorylation Ser825 GGGQAKTsPKPAVVE 9606 BTO:0000567 25097229 YES miannu Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins.  0.2 SIGNOR-276670 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNC2 protein P02585 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.342 SIGNOR-136755 Tomivosertib chemical CID:118598754 PUBCHEM MKNK2 protein Q9HBH9 UNIPROT down-regulates activity chemical inhibition 9606 29526098 YES Simone Vumbaca Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. 0.8 SIGNOR-261117 ECM stimulus SIGNOR-ST20 SIGNOR A4/b7 integrin complex SIGNOR-C187 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259041 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr382 DHYRYSDtTDSDPEN 9606 21779440 YES gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity 0.679 SIGNOR-89826 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 16537444 YES gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. 0.636 SIGNOR-145141 GPER1 protein Q99527 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 10696571 YES GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; the activated receptor induces a conformational change in the associated G protein α-subunit leading to release of GDP followed by binding of GTP and α-subunit dissociation from the receptor. 0.375 SIGNOR-251102 CDK5 protein Q00535 UNIPROT BAG3 protein O95817 UNIPROT down-regulates quantity by destabilization phosphorylation Ser291 STPLHSPsPIRVHTV 9606 BTO:0002181 31955914 YES miannu CDK5-mediated phosphorylation on S297 promotes BAG3 degradation. 0.2 SIGNOR-277502 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Ser328 ERALTEDsTQTSDTA -1 7836371 YES gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. 0.2 SIGNOR-247763 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR miR-495 mirna URS000075C517_9606 RNAcentral down-regulates quantity by repression transcriptional regulation 10090 21730352 NO miannu We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation. 0.4 SIGNOR-256242 S protein P59594 UNIPROT CD209 protein Q9NNX6 UNIPROT up-regulates activity binding 9606 15479853 YES lperfetto Here we show that DC-SIGN and DC-SIGNR enhance infection mediated by the glycoprotein (GP) of Marburg virus (MARV) and the S protein of severe acute respiratory syndrome coronavirus and might promote viral dissemination. 0.2 SIGNOR-260270 CHD8 protein Q9HCK8 UNIPROT NEFM protein P07197 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.2 SIGNOR-268917 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates activity binding 9534 10712517 YES lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). 0.624 SIGNOR-219291 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Gln) smallmolecule CHEBI:29168 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269485 CDK3 protein Q00526 UNIPROT LIN9 protein Q5TKA1 UNIPROT up-regulates phosphorylation Thr96 KFTATMStPDKKASQ 9606 BTO:0002181 24475316 YES lperfetto In this report, we demonstrate that cyclin e1/cdk3 phosphorylates lin-9 on thr-96. Mutating thr-96 to alanine inhibits activation of cyclins a2 and b1 promoters, whereas a phosphomimetic asp mutant strongly activates their promoters and triggers accelerated entry into g2/m phase in 293t cells. 0.2 SIGNOR-204529 PRKG1 protein Q13976 UNIPROT EVL protein Q9UI08 UNIPROT down-regulates activity phosphorylation 9606 15066263 YES miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts 0.2 SIGNOR-268290 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 9606 9973379 YES CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.  Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. 0.77 SIGNOR-251160 PRKCA protein P17252 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 YES lperfetto Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka). 0.358 SIGNOR-188581 SETD2 protein Q9BYW2 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity methylation Lys525 QLNMLGEkLLGPNAS 9606 BTO:0000007 28753426 YES Gianni SETD2 enhances antiviral immunity by directly methylating STAT1 on K525. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. 0.266 SIGNOR-269091 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1377674 YES lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function 0.507 SIGNOR-18253 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates chemical activation 9606 10884684 YES miannu Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations 0.8 SIGNOR-266333 PPARGC1A protein Q9UBK2 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17476214 YES miannu Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. 0.517 SIGNOR-268031 CSNK1G3 protein Q9Y6M4 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1479 SSSSTKGtYFPAILN 9606 35487243 YES miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 0.288 SIGNOR-275400 KDR protein P35968 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 11278468 YES Gianni These results demonstrate that activation of VEGFR-2 results in activation of PI3K and that activation of PI3K/S6kinase pathway, but not Ras/MAPK, is responsible for VEGFR-2-mediated cell growth. 0.57 SIGNOR-261916 SH2B1 protein Q9NRF2 UNIPROT CD79B protein P40259 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 SIGNOR-C433; SIGNOR-C434; SIGNOR-C435; SIGNOR-C436 32323266 YES scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. 0.2 SIGNOR-268458 RAB7A protein P51149 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 10116 16040606 YES Sara Rab7-Rac1 interaction may mediate late endosomal transport between microtubules and microfilaments 0.277 SIGNOR-261304 PRKCD protein Q05655 UNIPROT KCNE3 protein Q9Y6H6 UNIPROT up-regulates activity phosphorylation Ser82 LILGYTRsRKVDKRS 21911611 YES lperfetto Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit (mutation of the site for PKCdelta-promoted phosphorylation and modulation of the activity of KCNE3) showed rapid run-down and insensitivity to E2.  0.2 SIGNOR-275964 AMPK complex SIGNOR-C15 SIGNOR TBC1D1 protein Q86TI0 UNIPROT down-regulates phosphorylation Ser237 RPMRKSFsQPGLRSL 9606 17995453 YES lperfetto In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar 0.439 SIGNOR-216631 tRNA(Gln) smallmolecule CHEBI:29168 ChEBI Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270393 NVP-BSK805 dihydrochloride chemical CID:57339395 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194934 cysteine smallmolecule CHEBI:15356 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264759 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. 0.764 SIGNOR-252869 VPS4A protein Q9UN37 UNIPROT CHMP3 protein Q9Y3E7 UNIPROT up-regulates activity cleavage -1 30989108 YES Giorgia Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission. 0.626 SIGNOR-260847 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 9305639 YES lperfetto These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1. 0.656 SIGNOR-50894 SLC5A5 protein Q92911 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates activity chemical activation 9606 14623893 YES miannu Iodide is an essential element in thyroid physiology as a critical component of thyroxine and triiodothyronine molecules and a key regulator of thyroid gland function. The first step in iodide metabolism is represented by thyroid trapping, which is achieved by an active, energy-dependent transport process across the basolateral plasma membrane of the thyrocytes. The protein responsible for this process, the sodium/iodide symporter (NIS),1 is an intrinsic plasma membrane protein that mediates active transport of I- in the thyroid, lactating mammary gland, stomach, and salivary glands 0.8 SIGNOR-251996 TNFRSF17 protein Q02223 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 10903733 NO miannu Overexpression of bcma activates the p38 mapk 0.2 SIGNOR-79501 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT up-regulates activity phosphorylation Tyr171 NNANYTEyVATRWYR -1 16935860 YES miannu Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. 0.2 SIGNOR-245876 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys70 GKAVRGAkGHHHPHP 9606 12408818 YES gcesareni Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300 0.464 SIGNOR-95169 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2J2 protein Q8N2K1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.486 SIGNOR-271373 bethanechol chemical CHEBI:3084 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258623 STAP1 protein Q9ULZ2 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity binding 9606 BTO:0000007 10679268 YES miannu STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells. 0.419 SIGNOR-261821 amitriptyline chemical CHEBI:2666 ChEBI CHRM5 protein P08912 UNIPROT down-regulates activity chemical inhibition 10029 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258701 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258187 NT5E protein P21589 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI down-regulates quantity chemical modification -1 31461341 YES Luana Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine. 0.8 SIGNOR-269743 BBIP1 protein A8MTZ0 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 YES lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 0.665 SIGNOR-262561 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12777400 YES Manara These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386 0.404 SIGNOR-260769 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1200 ASSLHSVsSKSFRDF 9606 BTO:0000776 21482705 YES llicata We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane. 0.329 SIGNOR-173383 AKT proteinfamily SIGNOR-PF24 SIGNOR NR4A1 protein P22736 UNIPROT down-regulates activity phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000782 11274386 YES lperfetto We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350 0.2 SIGNOR-105927 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 16403219 YES miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. 0.372 SIGNOR-250390 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Thr478 CNENFKKtFKRILHI 9606 BTO:0000975 15107581 YES Translocation from Endosome to Lysosome fspada The peptide p10-t478a (thr478 to alanine) was not phosphorylated by pkc, indicating that thr478 can be phosphorylated by pkc. 0.2 SIGNOR-124356 EZH2 protein Q15910 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 YES lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). 0.914 SIGNOR-241894 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10611223 YES lperfetto Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau. 0.336 SIGNOR-73529 SRC protein P12931 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr104 RSPSTGLyDNLEKYH 9606 BTO:0000007 24996174 YES miannu In this study, we investigated the potential regulation of SIRT2 function by c-Src. We found that the protein levels of SIRT2 were decreased by c-Src, and subsequently rescued by the addition of a Src specific inhibitor, SU6656, or by siRNA-mediated knockdown of c-Src. The c-Src interacts with and phosphorylates SIRT2 at Tyr104. 0.292 SIGNOR-263104 nilotinib chemical CHEBI:52172 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258257 SIRT1 protein Q96EB6 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 YES gcesareni We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation. 0.601 SIGNOR-252445 AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR RABGEF1 protein Q9UJ41 UNIPROT up-regulates activity relocalization 10090 27411398 YES lperfetto AP-1/sigma1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation. 0.322 SIGNOR-260706 ALG1 protein Q9BT22 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI up-regulates quantity chemical modification 9606 28575298 YES lperfetto The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. 0.8 SIGNOR-260418 ABL1 protein P00519 UNIPROT CRKL protein P46109 UNIPROT down-regulates 9606 21779437 NO lperfetto Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl 0.714 SIGNOR-175138 ATF4 protein P18848 UNIPROT ASNS protein P08243 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002182 18940792 NO miannu C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. 0.649 SIGNOR-253838 SP1 protein P08047 UNIPROT CHGA protein P10645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12456801 YES Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. 0.2 SIGNOR-254273 COPS3 protein Q9UNS2 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates quantity by stabilization binding 9606 30631038 YES miannu Our observations characterizing the interaction between CSN3 and the Sos1 HD suggest that this domain not only functions regulating Sos-GEF autoinhibition but is also involved in other functional roles, such as the control of Sos protein stability and homeostasis by modulating the degradation and intracellular levels of Sos1. 0.2 SIGNOR-256217 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.893 SIGNOR-248655 F2RL3 protein Q96RI0 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257157 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 SIGNOR-C2 21157483 YES lperfetto Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism 0.929 SIGNOR-170604 MAP3K3 protein Q99759 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 16126726 YES gcesareni Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation 0.449 SIGNOR-138945 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT down-regulates activity phosphorylation Ser378 RICMRNFsRSDHLTT 10090 BTO:0000944 8662759 YES llicata Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10. 0.465 SIGNOR-250856 GRPR protein P30550 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257314 GFs stimulus SIGNOR-ST12 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 23300340 NO lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation 0.7 SIGNOR-245411 MRPS12 protein O15235 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.686 SIGNOR-261457 CSNK2A1 protein P68400 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation -1 8954982 YES llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. 0.326 SIGNOR-250951 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. 0.2 SIGNOR-255854 SMARCB1 protein Q12824 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.857 SIGNOR-270618 TWIST1 protein Q15672 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20646316 NO miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. 0.476 SIGNOR-255524 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 12213813 YES lperfetto In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E 0.67 SIGNOR-262993 GIT1 protein Q9Y2X7 UNIPROT ARHGEF6 protein Q15052 UNIPROT up-regulates activity binding 9606 BTO:0000132 26507661 YES lperfetto Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex. 0.849 SIGNOR-272165 SYK protein P43405 UNIPROT CGAS protein Q8N884 UNIPROT up-regulates activity phosphorylation Tyr215 LLNTGSYyEHVKISA 10090 BTO:0003292 36252040 YES miannu Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation. 0.2 SIGNOR-277845 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Thr141 DLSSRSKtDLDCIFG 9606 20573420 YES lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. 0.362 SIGNOR-166329 glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates activity 10090 BTO:0000222 18477450 NO Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). 0.8 SIGNOR-256137 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR GYS1 protein P13807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.2 SIGNOR-136553 glycine smallmolecule CHEBI:15428 ChEBI GLRA2 protein P23416 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 YES miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 0.8 SIGNOR-264981 BAG3 protein O95817 UNIPROT SIRT5 protein Q9NXA8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30910998 NO Monia Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. we demonstrated that BAG3 overexpression decreased SIRT5 expression in HepG2 cells (Fig. 5d). 0.2 SIGNOR-261205 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0001321 15659650 YES lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 0.779 SIGNOR-217791 HNF1A protein P20823 UNIPROT SLC22A10 protein Q63ZE4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20829431 YES lperfetto Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1 in HepG2 cells. 0.2 SIGNOR-268983 ADCY5 protein O95622 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-264999 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Tyr354 LKAYGNGySSNGNTG 10029 BTO:0000246 8557631 YES Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. 0.377 SIGNOR-251302 2-deoxy-D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:62877 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 25229427 YES miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. 0.8 SIGNOR-267096 CD55 protein P08174 UNIPROT ADGRE5 protein P48960 UNIPROT up-regulates binding 9606 BTO:0000142 12417446 YES gcesareni This interaction may facilitate cell activation and migration through the blood-brain barrier. In addition, cd97-cd55 interactions in the parenchyma of the brain may contribute to the inflammation. 0.2 SIGNOR-95458 BRCA1-C complex complex SIGNOR-C299 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 25400280 NO lperfetto The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 0.7 SIGNOR-263228 CALM2 protein P0DP24 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 YES miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.512 SIGNOR-266322 RAR proteinfamily SIGNOR-PF45 SIGNOR THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 YES inferred from 70% family members gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.2 SIGNOR-269955 SGI-1776 chemical CID:24795070 PUBCHEM PIM2 protein Q9P1W9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206862 FOXP2 protein O15409 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25232744 YES miannu By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets. 0.318 SIGNOR-266834 BGLF5 protein P03217 UNIPROT TLR9 protein Q9NR96 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 21191071 YES scontino The EBV lytic-phase protein BGLF5 reduces TLR9 expression through mRNA degradation. We established that the EBV early protein BGLF5 degrades TLR9 mRNA in vitro, providing a mechanism for its contribution to TLR9 downregulation. 0.2 SIGNOR-266633 LMP1 protein P03230 UNIPROT TLR9 protein Q9NR96 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000726 20980631 NO scontino We determined that the EBV oncoprotein latent membrane protein 1 (LMP1) is a strong inhibitor of TLR9 transcription. These data show that the oncoprotein LMP1 downregulates TLR9 promoter activity in B cells. 0.2 SIGNOR-266804 TLN1 protein Q9Y490 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.69 SIGNOR-257626 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser316 EKKGKDQsGEVLSSV 9615 11742978 YES llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. 0.338 SIGNOR-250976 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation Thr277 GSRTAPYtPNLPHHQ 9606 12801888 YES lperfetto Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4. 0.2 SIGNOR-244739 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 YES gcesareni Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. 0.403 SIGNOR-252971 ABL2 protein P42684 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10090 33622779 NO miannu Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. 0.7 SIGNOR-266594 JAK2 protein O60674 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Tyr718 IPERDSRySQPLHEE 9606 19287004 YES lperfetto Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively. 0.368 SIGNOR-184600 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 12510059 YES gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.771 SIGNOR-96936 HNRNPA3 protein P51991 UNIPROT C9orf72 protein Q96LT7 UNIPROT down-regulates quantity 9606 BTO:0000142 27461252 NO lperfetto Thus, reduced hnRNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci. 0.406 SIGNOR-262117 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 YES miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. 0.392 SIGNOR-276060 CDH7 protein Q9ULB5 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.567 SIGNOR-265869 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 YES Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. 0.2 SIGNOR-251477 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 31995776 YES miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 0.8 SIGNOR-268730 APOE protein P02649 UNIPROT SORL1 protein Q92673 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11557679 YES gcesareni Lr11 binds the apolipoprotein e (apoe)-rich lipoproteins, beta-very low density lipoproteins (vldls), with a high affinity similar to that of other members, such as the ldlr and vldl receptor.Incubation For 48 hours with beta-vldl of lr11-overexpressing cells, but not of control cells, promotes the appearance of numerous intracellular lipid droplets. 0.62 SIGNOR-110555 STK4 protein Q13043 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 YES lperfetto The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells 0.2 SIGNOR-171009 NPFFR2 protein Q9Y5X5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256709 PTPN6 protein P29350 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 9534 8943354 YES Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1 0.728 SIGNOR-248466 CYFIP1 protein Q7L576 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 9606 20332100 YES miannu We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge. 0.2 SIGNOR-253575 TAC1 protein P20366 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity 35045339 NO lperfetto Social touch-like tactile stimulation activates a tachykinin 1-oxytocin pathway to promote social interactions|Functionally, activation of PVH-projecting Tac1+ neurons increases firing of oxytocin neurons, promotes social interactions, and increases preference for the social touch context, whereas reducing activity of Tac1+ neurons abolishes ST-induced oxytocin neuronal firing. 0.59 SIGNOR-268576 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Thr770 DSILRLQtWDEAVFR 9606 21068236 YES lperfetto Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) in the resting state of the cell and dephosphorylated when cells are infected by rna virus. Mutation at aa position 770 or 854 to 855 of rig-i renders it constitutively active 0.2 SIGNOR-169408 olanzapine chemical CHEBI:7735 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258511 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 YES lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. 0.2 SIGNOR-251525 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-238804 SMURF1 protein Q9HCE7 UNIPROT OTUD6B protein Q8N6M0 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272687 CSNK1D protein P48730 UNIPROT UHRF1 protein Q96T88 UNIPROT up-regulates phosphorylation Ser95 SELSDTDsGCCLGQS 9606 23297342 YES llicata We further show that uhrf1 physically interacts with _-trcp1 in a manner dependent on phosphorylation of serine 108 (s108(uhrf1)) within the dsg degron. Furthermore, we demonstrate that s108(uhrf1) phosphorylation is catalyzed by casein kinase 1 delta (ck1_) and is important for the recognition of uhrf1 by scf(_-trcp). 0.245 SIGNOR-200349 TLR9 protein Q9NR96 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates activity binding 10090 22664090 YES scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.402 SIGNOR-266750 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 31422819 YES miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-267516 SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 YES apalma This steady-state rolling is primarily mediated by the interaction of endothelial P-selectins with their neutrophil glycoprotein counterreceptors, primarily PSGL-1. 0.926 SIGNOR-255038 ethanol chemical CHEBI:16236 ChEBI GLRA2 protein P23416 UNIPROT up-regulates activity chemical activation 8355 BTO:0000964 8700149 YES miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. 0.8 SIGNOR-258496 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Ser309 RPNKQEEsESPVERP 9606 22727668 YES llicata We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1 0.2 SIGNOR-197985 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000773 11278964 YES lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. 0.8 SIGNOR-106432 PTGER2 protein P43116 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256899 TBL1XR1 protein Q9BZK7 UNIPROT BCL3 protein P20749 UNIPROT down-regulates ubiquitination 9606 20547759 YES miannu We also defined the e3 ligase tblr1 as a protein involved in bcl-3 degradation 0.402 SIGNOR-166111 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Ser668 DVEFCVMsGTDSQPK 9606 15194694 YES lperfetto Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability. 0.807 SIGNOR-125869 FOXM1 protein Q08050 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0002181 26912724 YES miannu Nuclear FoxM1 then directly interacted with nuclear β‐catenin, which released β‐catenin from ICAT and enhanced recruitment of β‐catenin to the promoter of Wnt target gene, hence increasing the expression of Wnt target gene. 0.519 SIGNOR-277211 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000567 BTO:0000887;BTO:0001103 8454633 YES gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. 0.378 SIGNOR-39151 LPAR1 protein Q92633 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.554 SIGNOR-256696 MTMR3 protein Q13615 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity 9606 BTO:0000007 26787466 YES lperfetto The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity. 0.308 SIGNOR-245108 SNAP23 protein O00161 UNIPROT STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR form complex binding 9606 BTO:0000132 22767500 YES lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  0.732 SIGNOR-261895 GALR3 protein O60755 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257114 ALK protein Q9UM73 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates phosphorylation 9606 BTO:0000785 12185581 YES gcesareni Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc. 0.441 SIGNOR-91537 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Asp62 VETVFSVdEFSASVL -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.374 SIGNOR-263593 MAPK1 protein P28482 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Thr614 AFRLEPLtPRGVLTV 9606 17311928 YES llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 0.45 SIGNOR-153383 ABL1 protein P00519 UNIPROT PAX7 protein P23759 UNIPROT up-regulates activity phosphorylation 9606 33777928 YES miannuccelli Furthermore, we show that c-Abl interacts with and phosphorylates Pax7 protein.|Indeed, reporter gene assays indicate that c-Abl inhibition decreases Pax7 dependent activation of the 6xPRS9-luc reporter. 0.272 SIGNOR-279773 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Thr276 GFRKRWFtMDDRRLM -1 12893243 YES lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time. 0.314 SIGNOR-249226 TAOK1 protein Q7L7X3 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 9786855 YES lperfetto The activation of and binding to MEK3 by TAO1 implicates TAO1 in the regulation of the p38-containing stress-responsive MAP kinase pathway 0.577 SIGNOR-60818 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 19135894 YES gcesareni Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4. 0.647 SIGNOR-183285 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser2996 QECKRNLsDIDQSFN 9606 21149446 YES gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. 0.2 SIGNOR-170473 TWIST2 protein Q8WVJ9 UNIPROT ERBB3 protein P21860 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255501 IL12A protein P29459 UNIPROT IL12B protein P29460 UNIPROT up-regulates binding 9606 7527811 YES fspada However, a proper conformation required for high affinity binding is achieved only when p40 is associated with a p35 subunit or another p40 subunit. When p40 is associated with a p35 subunit, the heterodimer acts as an agonist mediating biologic activity. However, when p40 associates with another p40, the homodimer behaves as an antagonist in vitro 0.848 SIGNOR-27619 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000356 31138683 YES lperfetto SCFFBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis|we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCFFBXO22) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. 0.379 SIGNOR-273441 U2AF1 protein Q01081 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 31144421 NO miannu  Our results further showed that knockdown of U2AF1 significantly Western blot analysis revealed an increase in the protein levels of downstream targets of p53 following U2AF1 knockdown. The data further showed that depletion of U2AF1 altered alternatively spliced apoptosis-associated gene transcripts in CFU-E cells. Our findings elucidate the role of U2AF1 in human erythropoiesis and reveal the underlying mechanisms. 0.2 SIGNOR-261512 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275753 MAOA protein P21397 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI down-regulates quantity chemical modification 9606 31024440 YES brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). 0.8 SIGNOR-264014 MAPK10 protein P53779 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 YES gcesareni Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells. 0.2 SIGNOR-178926 FUS protein P35637 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates quantity 9606 BTO:0000312 22051914 NO lperfetto Similarly, cytoplasmic inclu- sions containing mutant fused in sarcoma (FUS) protein have been observed in some patients with FUS-related FALS. 0.7 SIGNOR-262277 L-thyroxine(1-) chemical CHEBI:60302 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258051 CSNK2A1 protein P68400 UNIPROT IP6K2 protein Q9UHH9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser356 AEDLEDLsEESADES 9606 BTO:0000007 21262846 YES miannu CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. 0.255 SIGNOR-273625 PDRG1 protein Q9NUG6 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 YES miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR92 0.567 SIGNOR-270915 HIPK2 protein Q9H2X6 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser422 AHPPHAPsPGQTVKP 9606 BTO:0002552 15708980 YES lperfetto Homeodomain-interacting protein kinase-2 mediates ctbp phosphorylation and degradation in uv-triggered apoptosishipk2 phosphorylates ctbp at ser-422 0.471 SIGNOR-134040 RAPGEF5 protein Q92565 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.434 SIGNOR-183735 (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester chemical CHEBI:103931 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258465 MGLL protein Q99685 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 26997225 NO irozzo Overexpression of MGLL inhibits proliferation and delays cell cycle progression in QGY-7703 cells. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression [.] 0.7 SIGNOR-259139 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates phosphorylation Tyr970 GEGYKKKyQQVDEEF 9606 BTO:0000150;BTO:0000527 19275932 YES gcesareni These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis. 0.526 SIGNOR-184556 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000586 16293724 NO lperfetto We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt 0.791 SIGNOR-252711 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 YES lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. 0.871 SIGNOR-109613 PPP1CA protein P62136 UNIPROT SP1 protein P08047 UNIPROT down-regulates activity dephosphorylation 9606 12684058 YES miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. 0.266 SIGNOR-251952 TRiC complex SIGNOR-C539 SIGNOR KRAS protein P01116 UNIPROT up-regulates quantity by stabilization binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.266 SIGNOR-272871 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA1 protein P42261 UNIPROT up-regulates activity chemical activation 9606 30825796 YES miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses 0.8 SIGNOR-264616 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MEF2C protein Q06413 UNIPROT down-regulates activity phosphorylation Ser396 NIKSEPVsPPRDRTT BTO:0003166 16478538 YES llicata Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity. | Intriguingly, we show that phosphorylation of S396 in MEF2C, a residue in close proximity to the major sumoylation site (K391) and known to be phosphorylated in vivo, enhances sumoylation of delta- N2-MEF2C in vitro. The S396A mutation reduces sumoylation of MEF2C in vivo and enhances the transcription activity of MEF2C in reporter assays. | CDK1/Cyclin B1 phosphorylated GST-MEF2C-ΔN2-WT to a greater extent than the MEF2C-ΔN2-S396A mutant, suggesting that Cdk1/Cyclin B1 can phosphorylate MEF2C at S396. 0.362 SIGNOR-250719 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CC2D1A protein Q6P1N0 UNIPROT up-regulates activity phosphorylation Ser208 PASTPTYsPAPTQPA 20171170 YES nucleus lperfetto We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation. 0.2 SIGNOR-268296 GRM5 protein P41594 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 YES miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. 0.356 SIGNOR-264078 PRKCA protein P17252 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 16963226 YES gcesareni Pkcalfa, but not pkcbeta, is the predominant cpkc isoenzyme required for cpla2 protein phosphorylation and maximal induction of cpla2 enzymatic activity. 0.563 SIGNOR-149406 SRC protein P12931 UNIPROT NDUFV2 protein P19404 UNIPROT up-regulates activity phosphorylation Tyr193 VQINDNYyEDLTAKD 9606 BTO:0001583 22823520 YES miannu Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants.  0.323 SIGNOR-276419 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser342 LAHDRAPsRKDSLES 9606 21317289 YES gcesareni We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation. 0.466 SIGNOR-171999 HOXB8 protein P17481 UNIPROT TAGLN protein Q01995 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 15886193 YES Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively 0.2 SIGNOR-261642 CDON protein Q4KMG0 UNIPROT BNIP2 protein Q12982 UNIPROT up-regulates activity binding 9606 18678706 YES lperfetto Bnip-2 and jlp are brought together through mutual interaction with cdo. the cdo-bnip-2 interaction stimulates cdc42 activity, which in turn promotes p38alpha/beta activity and cell differentiation. 0.504 SIGNOR-179864 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL6 protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 NO Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2) 0.635 SIGNOR-254511 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser466 VIDLTIDsSSDEEEE 9606 19217413 YES llicata Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process. 0.332 SIGNOR-184039 CP-91149 chemical CID:9843900 PUBCHEM PYGL protein P06737 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191112 CASP3 protein P42574 UNIPROT GAS2 protein O43903 UNIPROT up-regulates cleavage Asp278 MLQISRVdGKTSPIQ 9606 10564664 YES gcesareni We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279. 0.45 SIGNOR-72347 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257977 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser274 TSPSPISsPTFSPIE 9606 23442801 YES lperfetto It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation 0.258 SIGNOR-201515 CDK2 protein P24941 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 SIGNOR-C16 18332217 YES llicata We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2. 0.396 SIGNOR-177972 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 14585074 NO amattioni Activation of the nf-kb pathway regulates a variety of ant-apoptotic factors 0.7 SIGNOR-96834 PKLR protein P30613 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 15996096 YES miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). 0.8 SIGNOR-266537 KDM6A protein O15550 UNIPROT HOXC11 protein O43248 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.303 SIGNOR-260026 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser74 VEIRSRHsSYPAGTE 9606 22096607 YES lperfetto Bad is a pro-apoptotic member of the bcl-2 family of proteins, which can be phosphorylated on numerous sites to modulate binding to bcl-2 and 14-3-3 proteins and inhibit its pro-apoptotic activities. Together, these findings demonstrate that pak1 phosphorylates bad directly at s111, but phosphorylated s112 through raf-1. These two sites of bad serve as redundant regulatory sites for bcl-2 binding 0.336 SIGNOR-177271 NR3C1 protein P04150 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR form complex binding 9606 8878484 YES fspada We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter. 0.531 SIGNOR-44373 FBXL5 protein Q9UKA1 UNIPROT DCTN1 protein Q14203 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 17532294 YES miannu FBXL5 binds to p150(Glued)in vitro and in vivo. FBXL5 and p150(Glued) co-localize primarily in the cytoplasm with peri-nuclear enrichment in HeLa cells. Overexpression of FBXL5 promotes poly-ubiquitination of p150(Glued) and protein turnover of p150(Glued). Our findings provide a potential mechanism by which p150(Glued) protein function is regulated by SCFs. 0.463 SIGNOR-271652 GDNF protein P39905 UNIPROT RET protein P07949 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 YES gcesareni A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling 0.909 SIGNOR-49094 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.394 SIGNOR-89252 PAMPs stimulus SIGNOR-ST11 SIGNOR AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR up-regulates 9606 25720354 NO scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 0.7 SIGNOR-267855 orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI UMP smallmolecule CHEBI:16695 ChEBI up-regulates quantity precursor of 9606 2912371 YES miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). 0.8 SIGNOR-267439 ACLY protein P53396 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 19286649 YES miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. 0.8 SIGNOR-268080 RUNX3 protein Q13761 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.249 SIGNOR-255098 MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 NO The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. 0.7 SIGNOR-255944 CD19 protein P15391 UNIPROT LYN protein P07948 UNIPROT up-regulates activity binding 10090 BTO:0000776 25673924 YES lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. 0.772 SIGNOR-242894 SMARCC1 protein Q92922 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.863 SIGNOR-132933 CDK9 protein P50750 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Thr217 PSEYQNMtVDILCND 9606 23603988 YES lperfetto We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr. 0.461 SIGNOR-201927 sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI D-erythrose 4-phosphate(2-) smallmolecule CHEBI:16897 ChEBI up-regulates quantity precursor of 9606 19401148 YES miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 0.8 SIGNOR-268135 MYLK3 protein Q32MK0 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr80 NEPHESRtNSDIVET 9606 BTO:0000007 21556048 YES lperfetto Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis.|Here, we show that skMLCK directly phosphorylates MEF2C, leading to p300/PCAF recruitment, increased acetylation of skeletal muscle-specific genes, and enhanced skeletal myogenesis 0.27 SIGNOR-264565 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Phe43 ATLDPRSfLLRNPND -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.887 SIGNOR-263570 ATXN1 protein P54253 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21315774 YES Luana Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner  0.343 SIGNOR-261577 MK-2206 chemical CHEBI:67271 ChEBI AKT3 protein Q9Y243 UNIPROT down-regulates chemical inhibition 9606 BTO:0001286 21841310 YES gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. 0.8 SIGNOR-176049 MTHFD1 protein P11586 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity chemical modification -1 18767138 YES lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate 0.8 SIGNOR-268250 ITCH protein Q96J02 UNIPROT H1-2 protein P16403 UNIPROT up-regulates activity polyubiquitination Lys46 PVSELITkAVAASKE 9606 BTO:0000815 30517763 YES miannu ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. The results indicated that ITCH-mediated K46-Ubn is essential for the binding of histone H1.2 to chromatin. 0.2 SIGNOR-272926 SLBP protein Q14493 UNIPROT H2BC15 protein Q99877 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265392 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 YES gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation 0.416 SIGNOR-252440 TOP2B protein Q02880 UNIPROT DAB1 protein O75553 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 NO lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development 0.2 SIGNOR-242210 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. 0.643 SIGNOR-209735 Caspase 3 complex complex SIGNOR-C221 SIGNOR STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp326 NSEEDEMdSGTMVRA 9534 BTO:0004055 11517310 YES lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. 0.616 SIGNOR-256444 VCB-Cul2 complex SIGNOR-C524 SIGNOR USP33 protein Q8TEY7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 12056827 YES miannu VDU1 and VDU2 could be important substrates of pVHL E3 ligase complex. Finally, we demonstrate that VDU2 can also be ubiquitinated and degraded in a pVHL-dependent manner.pVHL mediates the degradation of hVDU2 by proteasome. we have demonstrated that both VDU1 and VDU2 also bind to the β-domain of pVHL and several naturally occurring mutations in the β-domain disrupt the interaction between VDU1/VDU2 and pVHL. If pVHL is mutated either in the α-domain or β-domain, VDU1 and VDU2 would not be ubiquitinated and degraded properly. This could lead to accumulation of these two proteins in the cells. Together, our results suggest that VDU1 and VDU2 might be relevent to pVHL-related tumorigenesis. 0.46 SIGNOR-272607 CHRM1 protein P11229 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.46 SIGNOR-257014 FAM107A protein O95990 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.2 SIGNOR-81800 ACSS3 protein Q9H6R3 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity chemical modification 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271832 CSNK1A1 protein P48729 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser82 GSSESTDsGFCLDSP 9606 20348946 YES lperfetto Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a 0.333 SIGNOR-164738 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Thr160 NKLRRYTtFSKRKTG 10753652 YES llicata Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors. 0.37 SIGNOR-250639 IL20RA protein Q9UHF4 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 YES gcesareni Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain. 0.485 SIGNOR-124486 POU5F1 protein Q01860 UNIPROT TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.687 SIGNOR-254943 PRKCA protein P17252 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 10816576 YES lperfetto Biochemical and morphological analyses indicate that threonine-phosphorylated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surfaceThe inhibitory effects of pkc are mediated by a single threonine residue (threonine 654) of egfr 0.607 SIGNOR-77421 GRIN1 protein Q05586 UNIPROT NMDA receptor_2B complex SIGNOR-C348 SIGNOR form complex binding 9606 BTO:0000938 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits 0.728 SIGNOR-264122 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120020 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Thr309 TMKTFCGtPEYLAPE 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.493 SIGNOR-248612 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 20068082 YES gcesareni Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm). 0.8 SIGNOR-163234 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 12832467 YES lperfetto Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. 0.73 SIGNOR-252760 CDK5 protein Q00535 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown phosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 YES lperfetto In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. 0.372 SIGNOR-249194 ZDHHC9 protein Q9Y397 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 YES miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. 0.436 SIGNOR-261352 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Ser121 YRIQEQEsSGEEDSD -1 8288648 YES llicata Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action. 0.307 SIGNOR-251020 PHC2 protein Q8IXK0 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 YES miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b 0.788 SIGNOR-266810 APLNR protein P35414 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-256960 2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol chemical CHEBI:93235 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258729 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MTHFR protein P42898 UNIPROT down-regulates activity phosphorylation Thr34 KDSSRCStPGLDPER 9606 BTO:0000007;BTO:0000567 24769206 YES miannu We have demonstrated that MTHFR is phosphorylated on T34by CDK1/Cyclin B1 in vivo and this phosphorylation peaks duringmitosis and decreases its enzymatic activity. 0.332 SIGNOR-263888 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr228 YPGGSDNyGSLSRVT -1 11382764 YES lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 0.922 SIGNOR-246484 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Ser577 RKPGLRRsPIKKVRK 9606 SIGNOR-C83 9840932 YES lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5 0.718 SIGNOR-62353 CFD protein P00746 UNIPROT CFB protein P00751 UNIPROT up-regulates activity cleavage Thr25 LLSGGVTtTPWSLAR 9606 BTO:0000089 26489954 YES lperfetto The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb 0.804 SIGNOR-263488 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 YES miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. 0.2 SIGNOR-256187 idelalisib chemical CHEBI:82701 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190813 palbociclib chemical CHEBI:85993 ChEBI CDK6 protein Q00534 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205707 MC4R protein P32245 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.52 SIGNOR-256797 NEDD4L protein Q96PU5 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 YES miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 0.321 SIGNOR-253463 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr247 VKGKSDPyHATSGAL 9606 16916748 YES lperfetto The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites. 0.59 SIGNOR-148913 FGF13 protein Q92913 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253435 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 18794113 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.541 SIGNOR-180906 MAPKAPK2 protein P49137 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 20626350 YES gcesareni Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2 0.519 SIGNOR-166643 GDNF protein P39905 UNIPROT NRN1 protein Q9NPD7 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.26 SIGNOR-252183 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of -1 8994190 YES Luana Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues.  0.8 SIGNOR-269759 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity phosphorylation 6239 10517632 YES gcesareni In addition, CKI bound to and increased the phosphorylation of dishevelled, a known component of the Wnt pathway 0.692 SIGNOR-244097 MYLIP protein Q8WY64 UNIPROT LDLR protein P01130 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 30896554 YES miannu The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells.  0.722 SIGNOR-271485 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser533 ATGTGTFsPGASPGS 9606 BTO:0000567 31981797 YES miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. 0.434 SIGNOR-276834 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 8335191 YES Crohn's Disease gcesareni 0.8 SIGNOR-251701 PRKN protein O60260 UNIPROT SNCA protein P37840 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000938 12666095 YES lperfetto Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R). 0.2 SIGNOR-249705 naltrexone chemical CHEBI:7465 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258767 CHMP3 protein Q9Y3E7 UNIPROT Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates -1 30989108 NO miannu ESCRT-III has been proposed to assemble inside the membrane neck formed at a late stage of a budding vesicle or an enveloped virus. The membrane neck needs to be constricted to proceed to membrane fission, thereby splitting the vesicle or virus from the cellular membrane. CHMP2A and CHMP3 are engaged late in ESCRT-III assembly, recruit VPS4 (31, 42), and block Snf7 (CHMP4) polymerization 0.7 SIGNOR-260845 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser978 SPLKRSHsLAKLGSL 9606 BTO:0000150 19567672 YES llicata Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions 0.479 SIGNOR-186471 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 YES llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR 0.493 SIGNOR-252902 MAD2L1BP protein Q15013 UNIPROT MCC complex SIGNOR-C382 SIGNOR down-regulates quantity by destabilization binding 9606 BTO:0000567 25092294 YES miannu We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). 0.464 SIGNOR-265979 NCOA2 protein Q15596 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11851396 YES gcesareni Here, it is demonstrated that mutation of the h11 phenylalanine residues diminishes the ability of rxr to associate with the p160 coactivators tif2 and p/cip, but has little effect on ligand-dependent interactions of the receptor with the unrelated coactivator tif1. 0.798 SIGNOR-114847 proline smallmolecule CHEBI:26271 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264744 (8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol chemical CHEBI:92234 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258731 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser40 RQPSPSPsPTERAPA 9606 BTO:0001271 15093545 YES llicata We report here that as(2)o(3) treatment induces phosphorylation of the pml protein through a mitogen-activated protein (map) kinase pathway. Increased pml phosphorylation is associated with increased sumoylation of pml and increased pml-mediated apoptosis. 0.36 SIGNOR-124248 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser381 RKFNILTsNQKTLTP 9606 BTO:0002181 31843895 YES miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. 0.289 SIGNOR-276763 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity 9606 BTO:0000801 26260587 YES IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. 0.809 SIGNOR-253589 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr426 NEEWYVSyITRPEAE -1 8702662 YES Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro 0.753 SIGNOR-251382 940929-33-9 chemical CID:49867937 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206724 tibolone chemical CHEBI:32223 ChEBI PGR protein P06401 UNIPROT up-regulates activity chemical activation 9606 19464167 YES Luana In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1). 0.8 SIGNOR-257822 Stress_granules phenotype SIGNOR-PH124 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27920254 NO miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. 0.7 SIGNOR-260867 ABL1 protein P00519 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Tyr15 EKIGEGTyGTVFKAK 9534 BTO:0000298 10896159 YES gcesareni Phosphorylation of Cdk5 by c-Abl occurs on tyrosine 15 (Y15), which is stimulatory for p35/Cdk5 kinase activity. 0.584 SIGNOR-245288 MASTL protein Q96GX5 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Ser875 TAQHLTVsGFSL 8355 phosphorylation:Thr194;Thr207 NMMDILTtPSMAKPR;PRQDYSRtPGQVLSL 22354989 YES gcesareni After this priming step, Gwl can intramolecularly phosphorylate its C-terminal tail at pS883; this site probably plays a role similar to that of the tail/Z motif of other AGC kinases. 0.2 SIGNOR-243409 SRD5A1 protein P18405 UNIPROT 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI up-regulates quantity chemical modification 9606 15861399 YES miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5Œ±-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. 0.8 SIGNOR-251534 PRDM1 protein O75626 UNIPROT CCL2 protein P13500 UNIPROT down-regulates quantity by repression transcriptional regulation 19915049 YES lperfetto Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression. 0.2 SIGNOR-271679 CSF1 protein P09603 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 YES gcesareni Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta). 0.337 SIGNOR-72455 AURKB protein Q96GD4 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 19276349 YES llicata Here, we show that aurora a and b associate with and phosphorylate rassf1a on serine 203 aurora a regulates prometaphase progression by inhibiting the ability of rassf1a to suppress apc-cdc20 activity. 0.439 SIGNOR-184561 CHEK1 protein O14757 UNIPROT TLK2 protein Q86UE8 UNIPROT down-regulates activity phosphorylation Ser750 PHIRKSVsTSSPAGA -1 12955071 YES miannu Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b). 0.269 SIGNOR-262740 PKA proteinfamily SIGNOR-PF17 SIGNOR GATA3 protein P23771 UNIPROT up-regulates activity phosphorylation Ser308 IKPKRRLsAARRAGT 9606 BTO:0000093 16109788 YES miannu  PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469.  0.2 SIGNOR-276042 HBB protein P68871 UNIPROT CYP2E1 protein P05181 UNIPROT up-regulates activity 9606 BTO:0000575 19325051 NO Regulation miannu Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. 0.2 SIGNOR-251764 CDK1 protein P06493 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Ser382 DFIDAFAsPVEAEGT 9606 15125835 YES lperfetto Here we show that, at the onset of mitosis, cdk1 phosphorylates the peripheral golgi protein nir2 at multiple sites;of these, s382 is the most prominent. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis. 0.465 SIGNOR-124638 SLC12A4 protein Q9UP95 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 21613606 YES lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  0.8 SIGNOR-264636 PRKAG2 protein Q9UGJ0 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 YES gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. 0.746 SIGNOR-139176 AKT proteinfamily SIGNOR-PF24 SIGNOR CCDC88A protein Q3V6T2 UNIPROT unknown phosphorylation Ser1417 INRERQKsLTLTPTR 9606 16139227 YES llicata Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells. 0.2 SIGNOR-140216 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16446360 YES gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. 0.962 SIGNOR-143996 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 10090 21145499 YES milica Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component. 0.356 SIGNOR-170364 RPS6KA3 protein P51812 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0001286 17404396 YES gcesareni Our data indicated that phosphorylation of pkr at thr(451) is mediated through erk2 and rsk2, but not through p38 kinase. 0.2 SIGNOR-154183 CD19 protein P15391 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 10090 BTO:0000776 25673924 NO lperfetto CD19 is a crucial regulator of B cell activation. 0.7 SIGNOR-242888 PPM1L protein Q5SGD2 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation -1 12556533 YES miannu Co-immunoprecipitation experiments indicated that PP2Cepsilon associates stably with TAK1 and attenuates the binding of TAK1 to MKK4 or MKK6.|PP2Cepsilon dephosphorylated TAK1 in vitro. 0.586 SIGNOR-277114 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 14560030 YES Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling, 0.869 SIGNOR-248666 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR DCTN1 protein Q14203 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 17532294 YES miannu FBXL5 binds to p150(Glued)in vitro and in vivo. FBXL5 and p150(Glued) co-localize primarily in the cytoplasm with peri-nuclear enrichment in HeLa cells. Overexpression of FBXL5 promotes poly-ubiquitination of p150(Glued) and protein turnover of p150(Glued). Our findings provide a potential mechanism by which p150(Glued) protein function is regulated by SCFs. 0.2 SIGNOR-271653 FAM83G protein A6ND36 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.337 SIGNOR-273753 MEPCE protein Q7L2J0 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR down-regulates activity binding 10090 BTO:0002572 32048991 YES miannu JMJD6 cleaves MePCE. we propose that JMJD6 is the cognate protease of MePCE and cleaves at the R171 site within MePCE. Experiments using purified JMJD6 showed that it could make a cut in an enzyme called MePCE, which belongs to the group of proteins that hold P-TEFb in its inactive form. The levels of activated Pol II were lower in cells without JMJD6 and higher in those without MePCE. Together, the results suggest that JMJD6 cuts MePCE to release P-TEFb, which then activates Pol II. 0.549 SIGNOR-261038 PRKACA protein P17612 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation Ser21 LTEERDGsLNQSSGY 9606 20658524 YES lperfetto The serine 21 (s21) residue of fyn is a protein kinase a (pka) recognition site within an rxxs motif of the amino terminal sh4 domain of fyn. In addition, s21 is critical for fyn kinase-linked cellular signaling. Mutation of s21a blocks pka phosphorylation of fyn and alters its tyrosine kinase activity. 0.457 SIGNOR-167147 GP5 protein P40197 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 BTO:0000132 16293600 YES lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. 0.659 SIGNOR-261849 RLN2 protein P04090 UNIPROT RXFP1 protein Q9HBX9 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 YES gcesareni Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway 0.76 SIGNOR-114549 F2R protein P25116 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.4 SIGNOR-256732 MAPK10 protein P53779 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 YES Translocation from Nucleus to Cytoplasm esanto We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats. 0.443 SIGNOR-74556 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 YES lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively 0.246 SIGNOR-180763 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248367 CASP1 protein P29466 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.797 SIGNOR-256406 selumetinib chemical CHEBI:90227 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190191 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr52 VQKKPTMyPEWKSTF -1 9692543 YES Lyn was found to phosphorylate Lyn-associated and recombinant PKC-delta in vitro and the tyrosine 52 phosphorylated PKC-delta was recruited to associate with the Lyn SH2 domain. 0.556 SIGNOR-251408 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser98 RSSSGYFsFDTDRSP 9606 BTO:0002181 23912711 YES miannu  We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.  0.377 SIGNOR-276246 arginine smallmolecule CHEBI:29016 ChEBI Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270370 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.444 SIGNOR-248297 MAP3K13 protein O43283 UNIPROT TRIM25 protein Q14258 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 CPLAEELsCSICLEP 9606 BTO:0002181 31186535 YES miannu Mechanistically, MAP3K13 phosphorylates the E3 ubiquitin ligase TRIM25 at Ser12 to decrease its polyubiquitination and proteasomal degradation. 0.2 SIGNOR-277456 E4F1 protein Q66K89 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity ubiquitination Lys319 TSSSPQPkKKPLDGE 9606 BTO:0001938 17110336 YES miannu E4F1 Has an Intrinsic Ubiquitin E3 Ligase Activity that Drives K48-type Ubiquitylation of p53. These data demonstrate that E4F1 stimulates the ubiquitylation of p53 on the lysine cluster K319–K321, i.e., at sites distinct from those targeted by Hdm2. p53 forms Ubiquitylated by E4F1 Are Localized on Chromatin. In striking contrast with Ub-p53 forms stimulated by Hdm2, which are mainly cytosoluble and targeted to the proteasome, we found that E4F1-stimulated Ub-p53 forms are tightly associated with chromatin, suggesting that they could be involved in transcription. 0.607 SIGNOR-271394 DUSP14 protein O95147 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity dephosphorylation 9606 24403530 YES miannu DUSP14 directly interacted with TGF-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser (438), leading to TAB1 and TAK1 complex inactivation in T cells. 0.298 SIGNOR-277147 ORF4b protein K9N643 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 26631542 YES miannu Previous studies have shown that MERS-CoV ORF4b antagonizes the early antiviral alpha/beta interferon (IFN-α/β) response, which may significantly contribute to MERS-CoV pathogenesis; however, the underlying mechanism is poorly understood. Here, we found that ORF4b in the cytoplasm could specifically bind to TANK binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε), suppress the molecular interaction between mitochondrial antiviral signaling protein (MAVS) and IKKε, and inhibit IFN regulatory factor 3 (IRF3) phosphorylation and subsequent IFN-β production. these results indicate that MERS-CoV ORF4b inhibits the induction of type I IFN through a direct interaction with IKKε/TBK1 in the cytoplasm 0.2 SIGNOR-260593 CSNK2A1 protein P68400 UNIPROT ACACA protein Q13085 UNIPROT unknown phosphorylation Ser29 GSVSEDNsEDEISNL -1 2900140 YES llicata These results show that casein kinase-2 phosphorylates site 6 exclusively 0.307 SIGNOR-250823 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 21460634 YES lperfetto Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition. 0.49 SIGNOR-216464 FFAR2 protein O15552 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257397 FYN protein P06241 UNIPROT CLIC5 protein Q9NZA1 UNIPROT up-regulates activity phosphorylation Tyr33 EENESPHyDDVHEYL 9606 BTO:0000567 10930415 YES miannu In this paper, we demonstrate that p64 becomes tyrosine phosphorylated when co-expressed with p59(fyn) in HeLa cells. 0.297 SIGNOR-274006 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT down-regulates activity cleavage Ser22 LLSYAVPsCGRSVEG -1 8753751 YES lperfetto Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments. 0.422 SIGNOR-270547 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Thr119 HNLMRRStVSLLDTY 23871434 YES Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro 0.249 SIGNOR-275482 LIMK1 protein P53667 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser3 sGVAVSDG 9606 18079118 YES gcesareni Our results suggest that limk1-mediated cofilin phosphorylation is required for accurate spindle orientation by stabilizing cortical actin networks during mitosis 0.813 SIGNOR-159885 MC1R protein Q01726 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257085 GSK3B protein P49841 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000812 27875297 YES lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation 0.2 SIGNOR-264884 MAPK1 protein P28482 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation Ser130 HLSIGTMsPSLGFPA -1 35831023 YES miannu We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk. 0.323 SIGNOR-277600 DOK1 protein Q99704 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.335 SIGNOR-257686 PKN2 protein Q16513 UNIPROT MEFV protein O15553 UNIPROT down-regulates activity phosphorylation Ser208 VRLRRNAsSAGRLQG 10090 BTO:0004732 27270401 YES no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 0.349 SIGNOR-275464 RPS6KA3 protein P51812 UNIPROT FOXN2 protein P32314 UNIPROT down-regulates quantity by destabilization phosphorylation Ser365 EDDPLGDsGYASQPC 9606 BTO:0002552 29396548 YES done miannu Importantly, we identified RSK2 kinase as the upstream kinase for the FOXN2 phosphodegron. The Ser365 and Ser369 sites in a conserved DSGYAS motif are responsible for the ubiquitination of FOXN2 by β-Trcp.  0.2 SIGNOR-273840 HSP90AB1 protein P08238 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by stabilization binding 9606 23019338 YES miannu Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. 0.322 SIGNOR-252415 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser463 PPISPASsDLSVAGS 9606 BTO:0000007 16141410 YES In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity 0.398 SIGNOR-251246 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR EID1 protein Q9Y6B2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 26085330 YES miannu SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO) 0.257 SIGNOR-272431 GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263781 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus 0.91 SIGNOR-252860 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser14 MGAELPSsPLAIEYV 9606 BTO:0000567 11416124 YES miannu In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro.  0.335 SIGNOR-275976 TLN1 protein Q9Y490 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.646 SIGNOR-257615 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNB/GNG complex SIGNOR-C202 SIGNOR up-regulates activity binding 9606 23994464 YES miannu Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the G gamma/beta subunit. G-protein-coupled receptors in neutrophils primarily signal through the Gβγ heterodimer, activating two parallel pathways through PLCβ2/3 and PI3Kγ. 0.2 SIGNOR-255007 NR4A3 protein Q92570 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000815;BTO:0002552 30455429 NO miannu NR4A3 exhibits p53-independent anti-proliferative functions. Ectopic expression of NR4A3 inhibits the growth of MDA-MB-231 and H1299 cancer cell lines. 0.7 SIGNOR-256201 CDK1 protein P06493 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Thr446 EGKISTItPQIQAFN 9606 14657031 YES lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation 0.703 SIGNOR-119877 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2A protein Q9UQM7 UNIPROT up-regulates activity chemical activation 15621017 YES It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK. 0.8 SIGNOR-255491 PRKCA protein P17252 UNIPROT CYTH2 protein Q99418 UNIPROT down-regulates activity phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 10531036 YES lperfetto ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'. 0.307 SIGNOR-249023 SNW1 protein Q13573 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 YES gcesareni We present evidence that skip interacts with the cbf1 corepressor complex and that skip has a role in orchestrating the conversion of cbf1 from an smrt-hdac-tethered transcriptional repressor to a notchic-tethered activation complex. 0.59 SIGNOR-75785 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT down-regulates activity sumoylation Lys404 VSPTGIkNEKRGTS 9606 16442531 YES We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity. 0.367 SIGNOR-256129 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 17339337 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-153479 MAPK14 protein Q16539 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 19528229 YES gcesareni P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna. 0.524 SIGNOR-186138 MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 YES gcesareni Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. 0.747 SIGNOR-161439 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-166349 CTNNB1 protein P35222 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 10775268 YES gcesareni Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding 0.704 SIGNOR-76987 NPBWR1 protein P48145 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256818 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17442773 NO miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The transcription factor CCAAT enhancer binding protein‐α (C/EBPα), a tumor suppressor gene and a crucial regulator of granulopoiesis through inhibition of c‐JUN, was downmodulated by NUP98‐HOXA9 0.2 SIGNOR-261501 Immune complexes stimulus SIGNOR-ST15 SIGNOR Complement C1q complex SIGNOR-C308 SIGNOR up-regulates activity binding -1 29449492 YES lperfetto We used IgG monoclonal antibodies (mAbs) oligomerized through antigen-binding on liposomes or preformed antibody complexes in solution and applied tomography and single-particle cryo–electron microscopy (cryo-EM) to resolve the mechanisms of C1 binding and activation.|Binding of C1 through its gC1q modules to mediators of inflammation, such as immunoglobulin G (IgG) or IgM antibodies (fig. S1, C and D), on cell surfaces activates the associated proteases and initiates the proteolytic cascade of complement 0.7 SIGNOR-263397 P2RY12 protein Q9H244 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.402 SIGNOR-256855 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT down-regulates activity phosphorylation Ser408 REKSKKYsDVEVPAS -1 8810272 YES miannu Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin. 0.311 SIGNOR-250329 AMBRA1 protein Q9C0C7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 dephosphorylation:Ser52 KRVELPDsPRSTFLL 23524951 YES lperfetto In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. 0.588 SIGNOR-272963 DZIP3 protein Q86Y13 UNIPROT H2AZ2 protein Q71UI9 UNIPROT up-regulates activity monoubiquitination Lys121 IHKSLIGkKGQQKTA 9606 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271756 GNAI1 protein P63096 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates activity binding -1 10224115 YES G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. 0.2 SIGNOR-256538 GNAI1 protein P63096 UNIPROT ADCY6 protein O43306 UNIPROT down-regulates activity binding 7108 BTO:0001240 8119955 YES Marta Tosoni Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3 0.54 SIGNOR-278077 ABL1 protein P00519 UNIPROT ZNF746 protein Q6NUN9 UNIPROT up-regulates activity phosphorylation Tyr137 ETLVSLDyAISKPEV 9606 BTO:0000793 34581802 YES miannu C-Abl-mediated phosphorylation of PARIS at Y137 (within the Krüppel-associated box domain) drives its association with KAP1 and the repression of genes with diverse functions in pathways such as chromatin remodelling and p53-dependent cell death. 0.313 SIGNOR-277626 CSNK2A1 protein P68400 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 YES llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 0.374 SIGNOR-250845 pazopanib hydrochloride chemical CHEBI:71217 ChEBI ITK protein Q08881 UNIPROT down-regulates activity chemical inhibition -1 17620431 YES miannu Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases.  0.8 SIGNOR-259164 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR MYL4 protein P12829 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.3 SIGNOR-136697 TGFB1 protein P01137 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 19114990 YES lperfetto While association of the TGF_RI receptor with p85 requires TGF-_ stimulation. 0.263 SIGNOR-252729 HNF4A protein P41235 UNIPROT ABCG8 protein Q9H221 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000398 21123766 NO miannu these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α. 0.283 SIGNOR-254458 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr700 LSSNPLMtPDILGSS 9606 BTO:0000567 9687510 YES gcesareni Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha 0.614 SIGNOR-59451 Complement C1 complex complex SIGNOR-C309 SIGNOR C2 protein P06681 UNIPROT up-regulates activity cleavage Ser20 LYPGLADsAPSCPQN 31331124 YES lperfetto C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex 0.497 SIGNOR-263421 ATR protein Q13535 UNIPROT RAD17 protein O75943 UNIPROT up-regulates activity phosphorylation Ser646 ETWSLPLsQNSASEL 9606 BTO:0000567 11687627 YES lperfetto Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival. 0.858 SIGNOR-111248 PFAS protein O15067 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity chemical modification 9606 33179964 YES miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. 0.8 SIGNOR-267312 PRKCA protein P17252 UNIPROT CDC42EP4 protein Q9H3Q1 UNIPROT down-regulates activity phosphorylation Ser80 SSKRSLLsRKFRGSK 9606 BTO:0001939 25086031 YES miannu Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes). 0.2 SIGNOR-263161 ESR2 protein Q92731 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 NO miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice 0.2 SIGNOR-253475 CSNK1A1 protein P48729 UNIPROT TIAM1 protein Q13009 UNIPROT down-regulates quantity by destabilization phosphorylation Ser329 DVNAGEGsEFADSGI 9606 BTO:0002181 25124033 YES miannu Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site. 0.309 SIGNOR-276673 alvocidib chemical CHEBI:47344 ChEBI CDK6 protein Q00534 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192385 thalidomide chemical CHEBI:9513 ChEBI CRBN protein Q96SW2 UNIPROT down-regulates activity chemical inhibition 9606 20223979 YES miannu  Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity.  0.8 SIGNOR-272207 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 11931757 YES lperfetto We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. 0.711 SIGNOR-217308 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2NL protein Q5JXB2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271336 CCL2 protein P13500 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 33505964 NO miannu  Exosomes from tumor cells package assorted proteins and chemokines with immunomodulatory capability, including CSF-1, CCL2, and TGF-β, to promote M2-like characterization of TAMs 0.7 SIGNOR-277709 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.398 SIGNOR-251617 CARM1 protein Q86X55 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 24332853 NO miannu PRMT4 blocks myeloid differentiation of human hematopoietic stem/progenitor cells While PRMT4 promotes differentiation in several biological systems including T cell, adipocyte and muscle development, it blocks differentiation in the hematopoietic system, allowing HSPCs to maintain stemness.  0.7 SIGNOR-261968 APOA1 protein P02647 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates quantity by stabilization binding 9606 12869555 YES miannu ApoA-I stabilization of ABCA1 is mediated by reduced PEST sequence phosphorylation, which in turn leads to decreased calpain proteolysis of ABCA1. 0.789 SIGNOR-252101 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269385 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser330 SFRVRASsDGEGTMS -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.32 SIGNOR-251073 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.624 SIGNOR-257056 LRRK2 protein Q5S007 UNIPROT RAB29 protein O14966 UNIPROT up-regulates activity phosphorylation Thr71 IAGQERFtSMTRLYY 9606 29212815 YES miannu In an attempt to mimic phosphorylation of Rab29 by LRRK2, we mutated the phosphorylation sites to Glu and observed that the Rab29[T71E,S72E] mutant failed to activate LRRK2 (Fig\u00a0 xref B).|To test whether phosphorylation of Rab29 at Thr71 and Ser72 by LRRK2 was required for activation of LRRK2, we mutated these sites both to Ala. 0.582 SIGNOR-279475 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49C protein P0CI26 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271268 LTB4R protein Q15722 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256691 SNX6 protein Q9UNH7 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 YES miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. 0.2 SIGNOR-269445 pazopanib hydrochloride chemical CHEBI:71217 ChEBI SH2B3 protein Q9UQQ2 UNIPROT down-regulates activity chemical inhibition -1 17620431 YES miannu Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases.  0.8 SIGNOR-259169 WARS1 protein P23381 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 0.8 SIGNOR-270511 WFS1 protein O76024 UNIPROT ATP1B1 protein P05026 UNIPROT up-regulates quantity binding 9534 BTO:0000298 17947299 YES SARA Sodium-potassium ATPase 1 Subunit Is a Molecular Partner of Wolframin, an Endoplasmic Reticulum Protein Involved in ER Stress|We conclude that the interaction may be important for Na+/K+ ATPase beta1 subunit maturation 0.397 SIGNOR-260999 PKA proteinfamily SIGNOR-PF17 SIGNOR GAD1 protein Q99259 UNIPROT down-regulates activity phosphorylation Thr91 RDARFRRtETDFSNL 9606 BTO:0000142 15147202 YES miannu Here, we report the effect of phosphorylation on the two well-defined GAD isoforms, namely, GAD65 and GAD67, using highly purified preparations of recombinant human brain GAD65 and GAD67. GAD65 was activated by phosphorylation, while GAD67 was inhibited by phosphorylation.We further demonstrate that protein kinase A (PKA) and protein kinase C isoform epsilon are the protein kinases responsible for phosphorylation and regulation of GAD67 and GAD65, respectively. We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. 0.2 SIGNOR-276009 ITGB1BP1 protein O14713 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.349 SIGNOR-257659 CSNK2A2 protein P19784 UNIPROT HSPH1 protein Q92598 UNIPROT down-regulates activity phosphorylation Ser509 PTEENEMsSEADMEC -1 12558502 YES llicata Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro. 0.328 SIGNOR-251008 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.275 SIGNOR-163752 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268588 (S)-(-)-sulpiride chemical CHEBI:64119 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258733 ASPG protein Q86U10 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 24657844 YES miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. 0.8 SIGNOR-267538 SRC protein P12931 UNIPROT DNM2 protein P50570 UNIPROT up-regulates activity phosphorylation Tyr597 NTEQRNVyKDLRQIE 9606 32457704 YES miannu Here, Dyn2 is activated by Src and promotes the induction of endocytosis of the integrins, thus, easing the invasion of the cells.|Src tyrosine kinases are themselves activated by phosphorylation at Y424 residue and phosphorylates its substrate Dyn2 at the residues Y231 and Y597. 0.558 SIGNOR-279486 MECP2 protein P51608 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 15870696 NO miannu Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters 0.272 SIGNOR-254571 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120044 GDF2 protein Q9UK05 UNIPROT ACVRL1 protein P37023 UNIPROT up-regulates binding 9606 17068149 YES gcesareni Finally, we demonstrate that bmp9 and bmp10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of alk1. Taken together, our results suggest that bmp9 and bmp10 are two specific alk1 ligands that may physiologically trigger the effects of alk1 on angiogenesis. 0.907 SIGNOR-150260 FGF11 protein Q92914 UNIPROT SCN1A protein P35498 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.259 SIGNOR-253422 TOMM20 protein Q15388 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 YES lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. 0.703 SIGNOR-267678 PRKACA protein P17612 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 31057087 YES miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 0.2 SIGNOR-259402 (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin chemical CHEBI:272 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258783 SCF-betaTRCP complex SIGNOR-C5 SIGNOR RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 24290981 YES miannu Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. 0.2 SIGNOR-276606 MAPK14 protein Q16539 UNIPROT ELK3 protein P41970 UNIPROT up-regulates phosphorylation Ser357 IHFWSSLsPVAPLSP 9606 9130707 YES gcesareni Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase. 0.379 SIGNOR-47681 PDPK1 protein O15530 UNIPROT PRKCG protein P05129 UNIPROT up-regulates phosphorylation 9606 15209375 YES gcesareni One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.2 SIGNOR-126072 BMP2 protein P12643 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 7791754 YES lperfetto Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. 0.861 SIGNOR-217532 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates activity binding 9606 19880493 YES lperfetto IL-4 and IL-13 have overlapping but distinct effects on MFs, dependent on a common IL-4R, with profound changes in the expression of a range of cellular proteins and functions broadly implicated in the regulation of inflammation and repair. 0.896 SIGNOR-249528 dactolisib chemical CHEBI:71952 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 YES ATP-competitive inhibitor of PI3K and mTOR gcesareni The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific 0.8 SIGNOR-175706 EGF protein P01133 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 YES tpavlidou To better understand the role of the egfr tyrosine kinase, we analyzed signaling by a kinase-inactive egfr (k721m) in erbb-devoid 32d cells. K721m alone exhibited no detectable signaling capacity, whereas coexpression of k721m with erbb2, but not erbb3 or erbb4, resulted in egf-dependent mitogen-activated protein kinase (mapk) activation. The kinase activity, but not tyrosine phosphorylation, of erbb2 was required for egf-induced mapk activation. 0.79 SIGNOR-106497 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.257 SIGNOR-159442 RPS6KA1 protein Q15418 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 YES gcesareni S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function. 0.53 SIGNOR-123993 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.272 SIGNOR-276094 MAPK12 protein P53778 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates quantity phosphorylation Ser467 NSVTPLAsPEPTKKP 9606 32580961 YES miannu KRAS transformation and overexpression of p38gamma increased expression of PFKFB3 and glucose transporter GLUT2 0.2 SIGNOR-279539 RPS6KB1 protein P23443 UNIPROT CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 YES llicata Mass spectrometry and mutagenesis analysis revealed that rsk and s6k1 phosphorylate cct_ ser-260 in vitro and in intact cells 0.2 SIGNOR-184926 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000142 8668348 YES gcesareni We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. 0.75 SIGNOR-42664 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268767 EPHB2 protein P29323 UNIPROT RRAS protein P10301 UNIPROT down-regulates activity phosphorylation Tyr66 DPTIEDSyTKICSVD 9606 10570155 YES Tyrosine 66 of R-Ras is phosphorylated by EphB2|. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. |Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated. 0.611 SIGNOR-251125 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNJ4 protein P48050 UNIPROT up-regulates activity phosphorylation Ser443 NISYRREsAI 9606 BTO:0000007 19635485 YES miannu Kir2.3 can be phosphorylated by PKAin vitro. We further show that the phosphorylation/dephosphorylation of Ser443 within the C-terminal Kir2.3 PDZ-binding motif RRESAI dynamically regulates the Kir2.3/TIP-1 association in heterologous HEK293T cells. These data suggest that TIP-1 may act as an important regulator for the endocytic pathway of Kir2.3. 0.2 SIGNOR-263153 AKT2 protein P31751 UNIPROT XIAP protein P98170 UNIPROT up-regulates phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 14645242 YES llicata Here, we demonstrate that akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. Moreover, autoubiquitination of xiap is also inhibited by akt. 0.421 SIGNOR-119492 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr446 GTEPEPVySMEAADY 9606 12601080 YES lperfetto Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity 0.801 SIGNOR-98712 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 YES gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. 0.59 SIGNOR-153622 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273058 KDM3B protein Q7LBC6 UNIPROT UCP1 protein P25874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005964 19194461 YES miannu We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. 0.2 SIGNOR-266638 IL23A protein Q9NPF7 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 12671732 YES gcesareni Based on these analyses, we propose an integrated model of il-12rbeta1 structure and function. This significantly enhances our molecular understanding of the human il-12 and il-23 systems. 0.644 SIGNOR-99716 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys135 AKRLKKEkVNVDIIN -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 0.464 SIGNOR-272747 CDK1 protein P06493 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr620 RAARFVStPFHEIMS 9606 17785528 YES lperfetto Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions 0.776 SIGNOR-157642 NDUFAB1 protein O14561 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 0.823 SIGNOR-262161 RORA protein P35398 UNIPROT PCP2 protein Q8IVA1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 YES miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 0.2 SIGNOR-266849 TRIM21 protein P19474 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates activity ubiquitination Lys7 kAYLLGKE 9606 26942676 YES miannu TRIM21 directly ubiquitylates p62 at residue K7 to inhibit its oligomerization and sequestration function.|TRIM21 negatively regulates p62 mediated sequestration of Keap1 and antioxidant response. 0.404 SIGNOR-278602 MAPK8IP2 protein Q13387 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10490659 YES gcesareni Both jip1 and jip2 selectively bind the mapkk isoform mkk7. 0.677 SIGNOR-70857 CHMP1A protein Q9HD42 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.639 SIGNOR-265531 ING1 protein Q9UK53 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14522900 NO miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. 0.2 SIGNOR-254480 CAK complex complex SIGNOR-C456 SIGNOR CDK2 protein P24941 UNIPROT up-regulates activity phosphorylation Thr160 GVPVRTYtHEVVTLW -1 10085115 YES llicata Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP. 0.626 SIGNOR-269330 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 6772446 YES Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. 0.685 SIGNOR-253007 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr306 PSNHHAVyDVPPSVS 9606 12601080 YES lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. 0.256 SIGNOR-98496 ALG11 protein Q2TAA5 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI up-regulates quantity chemical modification 9606 28575298 YES lperfetto The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. 0.8 SIGNOR-260417 DHX9 protein Q08211 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 NO miannu These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA. 0.7 SIGNOR-260948 V-ATPase complex SIGNOR-C560 SIGNOR cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity relocalization 9606 BTO:0000584 31827278 YES miannu Accumulation of V-ATPase at the plasma membrane is necessary for the cholesterol-dependent plasma-membrane association of RAC1, a prerequisite for the stimulation of membrane ruffling and macropinocytosis. In line with these observations, immunohistochemical staining of V-ATPase in human pancreatic ductal adenocarcinoma (PDAC) specimens revealed prominent staining at the cell periphery in neoplastic lesions, in con- trast to the predominantly cytoplasmic staining observed in adjacent normal tissues (Fig. 2e). Thus, mutant RAS-dependent plasma mem- brane V-ATPase displayed preferential accumulation in membrane ruffles, consistent with patterns observed in invasive breast, melanoma and pancreatic cancer cells 0.8 SIGNOR-277760 GATA1 protein P15976 UNIPROT RUNX1T1 protein Q06455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002731 20487545 NO Regulation miannu GATA-1 transcription factor binds and transactivates the ETO proximal promoter in an erythroid/megakaryocytic-specific manner. Thus, trans-acting factors that are essential in erythroid/megakaryocytic differentiation govern ETO expression. 0.3 SIGNOR-251929 RB1 protein P06400 UNIPROT ANP32A protein P39687 UNIPROT down-regulates activity binding 9606 phosphorylation:Thr826 LPTPTKMtPRSRILV 15716273 YES We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation. 0.2 SIGNOR-259083 LCK protein P06239 UNIPROT ACP1 protein P24666 UNIPROT up-regulates activity phosphorylation Tyr133 LIIEDPYyGNDSDFE 9534 9038134 YES In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation. 0.355 SIGNOR-251367 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 11062067 YES lperfetto Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). 0.751 SIGNOR-83729 D-ribofuranose smallmolecule CHEBI:47013 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 25749547 YES miannu Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds. 0.8 SIGNOR-267071 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 YES milica Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription. 0.459 SIGNOR-198507 CDH11 protein P55287 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates activity binding 9606 10029089 YES miannu Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin 0.517 SIGNOR-265825 alemtuzumab antibody DB00087 DRUGBANK CD52 protein P31358 UNIPROT down-regulates activity binding 9606 BTO:0000782;BTO:0000776 15757437 YES miannu Alemtuzumab is a humanized monoclonal antibody against CD52, a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes, and on a large proportion of malignant lymphoid cells, but not on hematopoietic progenitor cells. 0.4 SIGNOR-259883 SCF-FBW2 complex SIGNOR-C525 SIGNOR GCM1 protein Q9NP62 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 15640526 YES miannu FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system 0.405 SIGNOR-271528 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Thr402 TEAAQLStKSRAEGR 9606 BTO:0000007;BTO:0000567 12805220 YES lperfetto It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity. 0.2 SIGNOR-101852 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1651 SPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248782 TFE3 protein P19532 UNIPROT WIPI1 protein Q5MNZ9 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells 0.303 SIGNOR-276830 NTNG1 protein Q9Y2I2 UNIPROT LRRC4C protein Q9HCJ2 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 YES miannu The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. 0.771 SIGNOR-264047 GGCX protein P38435 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 31539109 NO miannu GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05). 0.2 SIGNOR-261232 PDGFRB protein P09619 UNIPROT NCK1 protein P16333 UNIPROT up-regulates binding 9606 10026169 YES esanto Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c). 0.637 SIGNOR-64737 ATP1A3 protein P13637 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 22797008 YES miannu The sodium/potassium transporting ATPase subunit alpha-3 (AT1A3; syn.: sodium pump subunit alpha-3; E.C. 3.6.3.9; UniProtKB ID: Q6PIC6) belongs to the cation transport ATPase (P-type) 3.A.3 family catalyzing hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action generates the electrochemical gradient of sodium and potassium ions thus providing energy for active transport of various nutrients. Three sodium/potassium transporting ATPase isoforms are expressed in the brain but AT1A3 is detectable in neurons exclusively. 0.8 SIGNOR-265792 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.2 SIGNOR-252946 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser304 RASRRSDsASSEPVG 9606 19366211 YES llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. 0.2 SIGNOR-185295 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 10102632 YES lperfetto Autophosphorylation of kdr in the kinase domain is required for maximal vegf-stimulated kinase activity and receptor internalizationthe intensity of vegf-induced autophosphorylation is significantly reduced when using receptor mutated at y996, confirming that this is a major site of autophosphorylation. Second, tyrosines 951 and 996 are the only two tyrosines in the receptor's kinase insert domain, and there is strong evidence from studies using the pdgfr and cfms that autophosphorylation of tyrosines in this domain leads to important signaling events. 0.2 SIGNOR-66040 TBX21 protein Q9UL17 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 YES In turn, T-bet is an IFN-gamma activator (Szabo et al., 2000), thus creating an indirect positive feedback. Furthermore, it has been shown that ectopic T-bet is able to induce the transcription of its own gene 0.2 SIGNOR-254294 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191009 DRD5 protein P21918 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.508 SIGNOR-256914 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 YES lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. 0.2 SIGNOR-251524 NUP205 protein Q92621 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.68 SIGNOR-262083 RXRA protein P19793 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 1310351 YES inferred from 70% of family members gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.725 SIGNOR-269850 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 12588871 YES lperfetto Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. hosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). 0.347 SIGNOR-98275 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding -1 10713164 YES llicata SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. 0.6 SIGNOR-237617 IL9 protein P15248 UNIPROT IL9R protein Q01113 UNIPROT up-regulates binding 9606 10642536 YES fspada Interleukin 9 (il-9) exerts its pleiotropic effects through the il-9 receptor (il-9r) complex, which consists of the il-9r alpha-chain, which determines the cytokine specificity, and the il-2 receptor gamma-chain 0.75 SIGNOR-73601 FBN1 protein P35555 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity binding 9606 17242066 YES Regulation of localization miannu We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling. 0.489 SIGNOR-251888 NOTCH3 protein Q9UM47 UNIPROT HEYL protein Q9NQ87 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 11044625 NO gcesareni In the latter, heyl is coexpressed with notch3, so far the only notch pathway gene detected in vascular smooth muscles (fig. 2h,i;joutel et al., 2000). Both genes are also coexpressed during late thymus development and our own promoter studies further suggest a potential regulation of heyl transcription by notch3. 0.607 SIGNOR-83402 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding 9606 25875593 YES irozzo C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site. 0.952 SIGNOR-256368 ZEB1 protein P37275 UNIPROT FBP1 protein P09467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000762 30616754 YES lperfetto Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells|we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells. 0.2 SIGNOR-267596 PTGER2 protein P43116 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.433 SIGNOR-256756 CSF1R protein P07333 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24890514 NO miannu CSF-1R also induces the expression/activation of several other regulators of multipotent progenitor proliferation/differentiation (Fig. 4A). These include [‚Ķ] the adaptor proteins suppressor of cytokine signaling 1 (Socs1) 0.49 SIGNOR-255574 RIF1 protein Q5UIP0 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 15342490 NO miannu This result would suggest that Rif1 acts in an intra-S-phase checkpoint pathway that is separate from the Nbs1 pathway. Although a role for human Rif1 at telomeres is not excluded, our data show that the primary function of Rif1 is in the DNA-damage response. Rif1 localizes to DSBs in an ATM- and 53BP1-dependent manner and functions in the intra-S-phase checkpoint that serves to slow down DNA synthesis when DNA damage has occurred. 0.7 SIGNOR-259060 MACROH2A1 protein O75367 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR down-regulates 16428466 NO miannu These data unambiguously identify mH2A as a strong transcriptional repressor and show that the repressive effect of mH2A is realized on at least two different transcription activation chromatin-dependent pathways: histone acetylation and nucleosome remodeling. 0.7 SIGNOR-272930 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 YES lperfetto We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45) 0.536 SIGNOR-227970 BMI1 protein P35226 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 YES miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b 0.795 SIGNOR-266812 nimodipine chemical CHEBI:7575 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18250364 YES Luana Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression.  0.8 SIGNOR-257765 CAMK4 protein Q16566 UNIPROT NOVA2 protein Q9UNW9 UNIPROT up-regulates quantity phosphorylation Ser25 EVVCTKRsNTGEEGE 9606 BTO:0000007 32492405 YES miannu CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. Conversely, Nova-2 with single or double mutations to alanine (2A and 1A2A) was predominantly nuclear, like the WT (Figures 5H and ​and5I).5I). In contrast, glutamate mutations at site 3 had no effect on Nova-2 localization (Figures 5H and ​and5I)5I) or on Nova-2 binding to RNA (Figure S5E). These results showed that active CaMKIV reduces Nova-2 nuclear localization by phosphorylating sites 1 and 2 (S25, T27). 0.255 SIGNOR-273521 MAD2L1 protein Q13257 UNIPROT MCC complex SIGNOR-C382 SIGNOR form complex binding 9606 BTO:0000567 25092294 YES miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 0.965 SIGNOR-265973 JNK proteinfamily SIGNOR-PF15 SIGNOR IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0004428 12510059 YES lperfetto Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylationOne of the specific Ser phosphorylation sites in IRS-1 that has been proposed to negatively modulate the insulin signal is Ser312 (numbered according to the human sequence). Prior studies have demonstrated that IRS-1 associates with and is phosphorylated by JNK in vitro on Ser312 0.2 SIGNOR-235777 SOSTDC1 protein Q6X4U4 UNIPROT BMP4 protein P12644 UNIPROT down-regulates activity 10090 18032587 NO lperfetto SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7 0.695 SIGNOR-242749 bosutinib chemical CHEBI:39112 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190699 PTK2 protein Q05397 UNIPROT IGF1R protein P08069 UNIPROT up-regulates quantity phosphorylation 9606 19545541 YES miannu Taken together, our data suggest that FAK mediates the phosphorylation of IGF-1R and stabilizes the receptor.In this study we demonstrate that FAK, mainly known for its role in integrin signaling pathways, associates with and phosphorylates IGF-1R independently of IGF-1R 's intrinsic tyrosine kinase activity.|The impact of FAK on the expression levels of IGF-1R could be multilateral 0.534 SIGNOR-279565 ABL1 protein P00519 UNIPROT SNCA protein P37840 UNIPROT up-regulates quantity phosphorylation Tyr39 KTKEGVLyVGSKTKE 9606 29103051 YES miannu C-Abl interacts with alpha-synuclein and phosphorylates alpha-synuclein at Y39 (XREF_FIG) . 0.425 SIGNOR-279582 F10 protein P00742 UNIPROT F2 protein P00734 UNIPROT up-regulates activity cleavage 10090 BTO:0000131 25769543 YES lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. 0.458 SIGNOR-263539 AREL1 protein O15033 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23479728 YES lperfetto Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists 0.406 SIGNOR-267669 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser239 GAKLRKVsKQEEASG 9606 12576312 YES miannu Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro 0.504 SIGNOR-250063 MCHR2 protein Q969V1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257067 PTPN6 protein P29350 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 9733788 YES tpavlidou The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation. 0.416 SIGNOR-59965 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp326 NSEEDEMdSGTMVRA 9534 BTO:0004055 11517310 YES lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. 0.616 SIGNOR-109874 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr296 MGYDDLDyGMMSDYG -1 11382764 YES lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 0.922 SIGNOR-246500 TUBA1B protein P68363 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 NO miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. 0.7 SIGNOR-269727 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 34010649 YES lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-275943 RPA1 protein P27694 UNIPROT BRIP1 protein Q9BX63 UNIPROT up-regulates activity binding 9606 17596542 YES irozzo Our data are consistent with a model in which FANCJ associates with RPA in a DNA damage-inducible manner and through the protein interaction RPA stimulates FANCJ helicase to better unwind duplex DNA substrates. These findings identify RPA as the first regulatory partner of FANCJ. 0.695 SIGNOR-259187 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT up-regulates activity phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000007 12138205 YES Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator. 0.2 SIGNOR-251481 mTORC1 complex SIGNOR-C3 SIGNOR ATP6V1A protein P38606 UNIPROT up-regulates quantity by expression 10090 21804531 NO Giorgia These data suggested that V-ATPase mRNA levels were upregulated by mTORC1 through a transcriptional mechanism. Tfeb is required for mTORC1-induced V-ATPase expression. 0.259 SIGNOR-260636 miR-132 mirna URS00001F4E81_9606 RNAcentral MECP2 protein P51608 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 23132946 NO irozzo In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability. 0.4 SIGNOR-255884 A3/b1 integrin complex SIGNOR-C161 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269010 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.621 SIGNOR-161585 EIF2AK2 protein P19525 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 YES miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. 0.303 SIGNOR-263118 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-119237 RPA1 protein P27694 UNIPROT POLA1 protein P09884 UNIPROT up-regulates activity binding -1 9214288 YES Federica In our studies, we have shown that T antigen, DNA polymerase R, and the activation domain of VP16 all interact with overlapping regions of the 70-kDa subunit of RPA.| In the latter, both the direct protein-protein interaction and ssDNA-binding activities of RPA were needed for RPA to modulate polymerase processivity. We also found that SV40 T antigen inhibited the ability of RPA to increase processivity of DNA polymerase alpha, suggesting that this activity of RPA may be important for elongation but not during the initiation of DNA replication. 0.686 SIGNOR-261272 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263791 CHRM4 protein P08173 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.401 SIGNOR-256829 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190179 F9 protein P00740 UNIPROT Factor VIIIa-IXa complex SIGNOR-C320 SIGNOR form complex binding 10090 BTO:0000131 25769543 YES lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. 0.765 SIGNOR-263552 IL4R protein P24394 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 20824124 YES Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5 0.554 SIGNOR-254298 LRRK2 protein Q5S007 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000007 22012985 NO gcesareni We report that LRRK2 activates a calcium-dependent protein kinase kinase-² (CaMKK-²)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation. 0.7 SIGNOR-237005 RNF168 protein Q8IYW5 UNIPROT H1-2 protein P16403 UNIPROT down-regulates polyubiquitination 9606 BTO:0000815 30517763 YES miannu ITCH biochemically antagonized RNF168 and RNF8 in polyubiquitination of histone H1.2 ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. Both RNF168 and RNF8 elicited higher Ubn levels of K46R-H1.2 compared to WT-H1.2, suggesting that Ubn of H1.2 by both E3 ligases occurs at a site apart from K46. 0.2 SIGNOR-272927 PTPN1 protein P18031 UNIPROT BCR protein P11274 UNIPROT down-regulates dephosphorylation 9606 9566916 YES The effect has been demonstrated using P11274-1 gcesareni These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo. 0.33 SIGNOR-56818 CAMK2G protein Q13555 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.271 SIGNOR-275794 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCGR3A protein P08637 UNIPROT up-regulates activity 9606 BTO:0000801 17558411 NO lperfetto After binding their antibody ligands, FcgRI and FcgRIII deliver activating signals through an association with the FcRg-chain (FcRg), a transmembrane adaptor protein with an immuno-receptor tyrosine-based activation motif in its cytoplasmic domain. 0.7 SIGNOR-249523 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258188 NUAK1 protein O60285 UNIPROT LATS1 protein O95835 UNIPROT down-regulates phosphorylation Ser464 NIPVRSNsFNNPLGN 9606 19927127 YES lperfetto Moreover, we show that nuak1 phosphorylates lats1 at s464 and this has a role in controlling its stabilitycells that constitutively express nuak1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator lats1 0.389 SIGNOR-161792 P2RY1 protein P47900 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.322 SIGNOR-256800 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser215 SGRAREAsGAPTSSK 9606 BTO:0000938 17470458 YES acerquone The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor 0.587 SIGNOR-154631 pictrelisib chemical CHEBI:65326 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 BTO:0000149 21876152 YES gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed 0.8 SIGNOR-176298 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.2 SIGNOR-159390 SIRT1 protein Q96EB6 UNIPROT NHLH2 protein Q02577 UNIPROT up-regulates activity deacetylation Lys49 EEAEGDGkGGSRAAL 10090 BTO:0000142 22169038 YES miannu SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter 0.383 SIGNOR-254830 AKT1 protein P31749 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by stabilization phosphorylation Thr116 KYRPRRKtKTLMKKD 9606 BTO:0002428 30894683 YES miannu Phosphorylation of SOX2 at threonine 116 by AKT inhibits the interaction of UBR5 with SOX2 and thus stabilizes SOX2.  0.533 SIGNOR-277445 IKBKB protein O14920 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 YES gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway 0.691 SIGNOR-124207 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248684 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 YES done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. 0.66 SIGNOR-273952 TNFRSF13C protein Q96RJ3 UNIPROT Lymphoma phenotype SIGNOR-PH14 SIGNOR up-regulates 9606 BTO:0000776 24432023 NO lperfetto Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures. 0.7 SIGNOR-204364 AURKA protein O14965 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 23520446 YES miannu Because AURKA associated with EGFR, we next investigated whether AURKA phosphorylates EGFR at Thr654 and Ser1046.|Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells. 0.394 SIGNOR-279590 CHUK protein O15111 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 SIGNOR-C14 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation 0.896 SIGNOR-52879 GNAI1 protein P63096 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 15922020 YES Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated. 0.55 SIGNOR-256532 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr398 QSHVEDLyVEGLPEG 9534 11373296 YES lperfetto These residues, tyr248, tyr357, and tyr462, were also found to be the major sites for btk-dependent phosphorylation of bap/tfii-i in vivo. Residues tyr357 and tyr462 are contained within the loop regions of adjacent helix-loop-helix-like repeats within bap/tfii-i. Mutation of either tyr248, tyr357, or tyr462 to phenylalanine reduced transcription from a c-fos promoter relative to wild-type bap/tfii-i in transfected cos-7 cells, consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation. 0.517 SIGNOR-108342 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 BTO:0000776 20185585 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-163938 KLF15 protein Q9UIH9 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 NO miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 0.265 SIGNOR-253816 BID protein P55957 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity 9606 9727492 NO Translocation from Mitochondria to Cytosol lperfetto TBID induces first the clustering of mitochondria around the nuclei and release of cytochrome c. 0.589 SIGNOR-59224 CBL protein P22681 UNIPROT SYK protein P43405 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11742985 YES miannu Intact tyrosine kinase-binding and RING finger domains of Cbl were found to be essential for Syk ubiquitylation in 293T cells and for in vitro Syk ubiquitylation. Altogether, our results support an essential role for Cbl ubiquitin ligase activity in the negative regulation of Syk, and establish that ubiquitylation provides a mechanism of Cbl-mediated negative regulation of cytoplasmic targets. 0.815 SIGNOR-272620 ARHGEF15 protein O94989 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.57 SIGNOR-260540 CDK1 protein P06493 UNIPROT CDC5L protein Q99459 UNIPROT up-regulates activity phosphorylation 9606 27210759 YES miannu Cdc5-dependent Net1 phosphorylation and Cdc14 release from the nucleolus require prior Cdc5 activation by Cdk1 and active separase to promote Cdc14 activation.|Cdk1 initially phosphorylates Cdc5, mostly at T242 and T238 (T242 phosphorylation is especially relevant based on our results), and phosphorylation activates its kinase activity, which is essential for anaphase progression. 0.626 SIGNOR-279597 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257458 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 9606 12058027 YES gcesareni Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs. 0.2 SIGNOR-89427 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10710310 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-75637 WAPL protein Q7Z5K2 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR down-regulates activity 9606 BTO:0000567 17113138 YES lperfetto We show that human Wapl interacts with cohesin throughout the cell cycle via cohesin's Scc1 and SA1/SA2 subunits and that Wapl forms a subcomplex with Pds5A|These results indicate that Wapl is required for the release of cohesin from both interphase chromatin and mitotic chromosomes, perhaps by facilitating opening of the cohesin ring or by modulating direct interactions between cohesin and DNA. 0.2 SIGNOR-265265 enalapril chemical CHEBI:4784 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition 10116 7527095 YES miannu The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalaprilat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat. 0.8 SIGNOR-258428 TTC5 protein Q8N0Z6 UNIPROT JMY protein Q8N9B5 UNIPROT up-regulates activity binding 9606 BTO:0001938 15448695 YES miannu DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY 0.529 SIGNOR-262647 CDK3 protein Q00526 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 19118012 YES gcesareni Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation. 0.444 SIGNOR-183013 CDK1 protein P06493 UNIPROT DIAPH1 protein O60610 UNIPROT down-regulates activity phosphorylation 9606 30816115 YES miannu In this study, we found that Cdk1 phosphorylated DIAPH1, which inhibited the interaction between DIAPH1 and profilin1 (PFN1) during metaphase.|Thus, the results suggest that the level of cortical F-actin has to be finely maintained by Cdk1 mediated positive and negative regulation of DIAPH1. 0.2 SIGNOR-279598 IL12A protein P29459 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 NO miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12 0.365 SIGNOR-260859 MITRAC complex complex SIGNOR-C538 SIGNOR COX4I1 protein P13073 UNIPROT up-regulates quantity relocalization 23260140 YES Each association relies on the supply of subunits from either the cytosol or the mitochondrial matrix, suggesting that human TIM21 ushers nuclear-encoded proteins to assembly intermediates. In agreement with this, assembly of the early cytochrome c oxidase subunit COX4-1 requires TIM21, whereas it is dispensable for late-assembling subunits. The finding that TIM21 also interacts with complex I intermediates points to a more general role of TIM21 in respiratory-chain assembly. Furthermore, TIM21 appears to be tightly connected to MITRAC15, which, in contrast to TIM23 and MITRAC12, coimmunoprecipitates with TIM21 under all tested conditions. MITRAC15 associates with MITRAC and is required for complex IV but also complex I assembly. 0.357 SIGNOR-272487 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser342 SKLTHSLsTSDITAI 9606 16943424 YES lperfetto Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm. 0.734 SIGNOR-149292 SMARCD2 protein Q92925 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.783 SIGNOR-270753 ATM protein Q13315 UNIPROT AURKB protein Q96GD4 UNIPROT down-regulates 9606 18250156 NO gcesareni Furthermore, atm-mediated i-2 phosphorylation results in the inhibition of the aurora-b kinase, the down-regulation of histone h3 serine 10 phosphorylation, and the activation of the g2/m checkpoint. 0.431 SIGNOR-160644 MAPK1 protein P28482 UNIPROT LCK protein P06239 UNIPROT up-regulates activity phosphorylation Ser59 EGSNPPAsPLQDNLV 9606 BTO:0000567 8618896 YES lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. 0.582 SIGNOR-249412 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT up-regulates activity phosphorylation 9606 25452387 YES miannu CDK5 kinase phosphorylates DLC1 but not DLC2 or DLC3 protein.|Here, we report that CDK5 coordinately activates multiple DLC1 functions, elucidate the mechanism underlying this activation, and identify a role for DLC1 inactivation in the pro-oncogenic activity CDK5. 0.2 SIGNOR-279602 SNARE_complex complex SIGNOR-C346 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000938 30267828 NO miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. The event directly leading to membrane fusion is theassembly of the C-terminal end of the SNARE-complex,and the linker domains, which couples the releasedenergy directly to the fusion of the membranes 0.7 SIGNOR-263973 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TICRR protein Q7Z2Z1 UNIPROT up-regulates activity phosphorylation Ser1001 DIGVVEEsPEKGDEI -1 21646402 YES miannu  We found that Treslin also associated with TopBP1 in a Cdk-regulated manner in human cells and that Treslin was phosphorylated within a conserved Cdk consensus target sequence (on S976 in X. laevis and S1000 in humans). Recombinant human Cdk2-cyclin E also phosphorylated this residue of Treslin in vitro very effectively. 0.333 SIGNOR-273600 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Thr346 TGENAGQtPMNINPQ 26375055 YES lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity 0.258 SIGNOR-276521 CUL1 protein Q13616 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR form complex binding 9606 15340381 YES gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. 0.927 SIGNOR-243763 DLD protein P09622 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 YES miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. 0.854 SIGNOR-266256 PTEN protein P60484 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 NO miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 0.325 SIGNOR-260053 MAP3K3 protein Q99759 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 BTO:0000298 9162092 YES lperfetto These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3. 0.603 SIGNOR-48628 MAP3K14 protein Q99558 UNIPROT MMP14 protein P50281 UNIPROT up-regulates activity phosphorylation 9606 27270613 YES miannu A post-transcriptional process is indicated because we observed that NIK increases MT1-MMP phosphorylation and activity, but does not affect MT1-MMP mRNA expression (XREF_FIG and XREF_FIG).|NIK increases MT1-MMP pseudopodial localization and enzymatic activity. 0.2 SIGNOR-279631 MAP3K14 protein Q99558 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates activity phosphorylation 9606 11369779 YES miannu The Nck-interacting kinase (NIK) phosphorylates the Na+-H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor.|We now show that NIK binds to and divergently activates the plasma membrane Na(+)-H(+) exchanger NHE1. 0.307 SIGNOR-279632 WNT8B protein Q93098 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.615 SIGNOR-132027 CSNK2A1 protein P68400 UNIPROT MAZ protein P56270 UNIPROT up-regulates phosphorylation Ser460 PTAVGSLsGAEGVPV 9606 BTO:0000567 10448092 YES lperfetto Site-specific mutagenesis of maz revealed that the serine residue at position 480 was the major site of phosphorylation by ckii both in vitro and in vivo. Phosphorylation of maz by ckii at this serine residue was required for maximum binding of maz to the pyrimidine-rich dna of the nuclease-hypersensitive element (nhe) in the 5'-end promoter region of the c-myc gene. Mutation of serine at position 480 to alanine eliminated the dna-binding activity of maz to this element. 0.448 SIGNOR-70082 PPP5C protein P53041 UNIPROT CDC37 protein Q16543 UNIPROT down-regulates activity dephosphorylation Ser13 VWDHIEVsDDEDETH 9606 18922470 YES Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37. 0.67 SIGNOR-248539 HCK protein P08631 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9534 BTO:0000298 12235133 YES done miannu Hck induces tyrosine phosphorylation of WASp. Here we show that the Src family kinase Hck induces phosphorylation of WASp-Tyr(291) independently of Cdc42 and that this causes a shift in the mobility of WASp upon SDS-PAGE. A phospho-mimicking mutant, WASp-Y291E, exhibited an enhanced ability to stimulate actin polymerization in a cell-free system and when microinjected into primary macrophages induced extensive filopodium formation with greater efficiency than wild-type WASp or a Y291F mutant. We propose that phosphorylation of Tyr(291) directly regulates WASp function. 0.556 SIGNOR-273957 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000007 16461343 YES miannu Native ptpn22 dephosphorylated lck and zap70 at their activating tyrosine residues tyr-394 and tyr-493, respectively, but not at the regulatory tyrosines tyr-505 (lck) or tyr-319 (zap70). 0.705 SIGNOR-144345 MAP3K7 protein O43318 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates activity binding 9606 SIGNOR-C14 20038579 YES lperfetto This result suggests that ikkgamma/nemo binds to the polyubiquitinated tak1. 0.815 SIGNOR-162634 FGA protein P02671 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR form complex binding -1 25427968 YES lperfetto Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively). 0.771 SIGNOR-263392 ERG protein P11308 UNIPROT ICAM2 protein P13598 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10574717 NO miannu The Ets family member Erg was found to be constitutively expressed in HUVEC, and TNF-(alpha) down-regulated Erg protein levels. Furthermore, an Erg cDNA transactivated the ICAM-2 promoter when transiently transfected into both HeLa cells and HUVEC. 0.2 SIGNOR-253913 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 NO apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. 0.635 SIGNOR-255357 SRC protein P12931 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation 9606 26598521 YES miannu Src phosphorylates Runx1 on one central and four C-terminal tyrosines.|We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter. 0.41 SIGNOR-279656 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269384 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES miannu Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-255006 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 7578094 YES lperfetto These data are consistent with autophosphorylation on y-419 as predicted. Intermolecular autophosphorylation is consistent with the ability of srctk to dimerize, which is analogous to activation of receptor tyrosine kinases such as the egf receptor kinase in response to growth factors. 0.2 SIGNOR-29369 GPR35 protein Q9HC97 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256717 PAK2 protein Q13177 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation Ser1760 RAIGRLSsMAMISGL -1 10748018 YES miannu PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991. 0.532 SIGNOR-250223 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 YES gcesareni The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1 0.719 SIGNOR-187787 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12565872 YES We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells 0.708 SIGNOR-253583 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 YES lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling 0.26 SIGNOR-112491 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 15611135 YES gcesareni We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. 0.261 SIGNOR-132551 PRKCA protein P17252 UNIPROT RPL10 protein P27635 UNIPROT unknown -1 9016777 YES lperfetto QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun. 0.307 SIGNOR-248957 BACH1 protein O14867 UNIPROT HK2 protein P52789 UNIPROT up-regulates quantity transcriptional regulation 9606 31257027 YES BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. 0.2 SIGNOR-259338 GATA6 protein Q92908 UNIPROT RARB protein P10826 UNIPROT up-regulates quantity by expression 9606 BTO:0000195 24317510 NO lperfetto Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. 0.292 SIGNOR-253154 CD274 protein Q9NZQ7 UNIPROT PDCD1 protein Q15116 UNIPROT up-regulates binding 9606 BTO:0000782 11015443 YES miannu Pd-l1, was found to bind pd-1 specifically. The functional significance of this interaction has been demonstrated in t cell assays, in which engagement of pd-1 by pd-l1 leads to the inhibition of tcr-mediated lymphocyte proliferation and cytokine secretion. 0.936 SIGNOR-82604 CCNK protein O75909 UNIPROT CyclinK/CDK13 complex SIGNOR-C38 SIGNOR form complex binding 9606 22012619 YES miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells 0.917 SIGNOR-176786 KAT2B protein Q92831 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 SIGNOR-C465 34811519 YES lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269610 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 1715686 YES gcesareni Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta. 0.305 SIGNOR-21295 ATR protein Q13535 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 16908529 YES gcesareni Finally, in vitro atr-mediated phosphorylation at the t2609 cluster was further confirmed by western blot analysis using phosphospecific antibodies against t2647 (fig. ?(Fig.7e),7e), suggesting that dna-pkcs could be the direct target of atr kinase. 0.311 SIGNOR-148722 MRPL12 protein P52815 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.656 SIGNOR-262381 RANGAP1 protein P46060 UNIPROT MYCBP2 protein O75592 UNIPROT down-regulates quantity by destabilization relocalization 10090 26304119 YES Monia SUMOylated RanGAP1 Inhibits MYCBP2 Activity and Mediates Its Transport to the Nucleus. Surprisingly, we did not find MYCBP2-dependent ubiquitylation of SUMOylated RanGAP1 but instead a strong inhibition of the ubiquitin ligase activity of MYCBP2 in the presence of SUMOylated RanGAP1, as determined by the presence of ubiquitylated proteins. this effect was specific for SUMOylated RanGAP1, because the unmodified form of RanGAP1 did not affect MYCBP2-dependent protein ubiquitylation. , SUMOylated RanGAP1 inhibited the ubiquitin ligase activity of MYCBP2, and it is tempting to speculate that SUMOylated RanGAP1 inhibits the ubiquitin ligase activity of MYCBP2 to ensure MYCBP2 silencing during its transport to the nucleus 0.315 SIGNOR-261203 SRC protein P12931 UNIPROT TLR3 protein O15455 UNIPROT up-regulates activity phosphorylation Tyr759 EQFEYAAyIIHAYKD 9606 27514533 YES miannu Markedly, Src mediated late TLR3 Pi-Tyr759 leads to the nuclear accumulation of IRF3 and IRF7 and the increase of IFN-beta production.|Src can directly phosphorylate TLR3 Tyr759 in\nvitro and in vivo . 0.527 SIGNOR-279657 MDM2 protein Q00987 UNIPROT APEX1 protein P27695 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21727086 YES miannu Once the reaction proceeds beyond the monoubiquitination stage, MDM2 polyubiquitinates APE1 for degradation. 0.416 SIGNOR-278555 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser438 PGLLRRVsSTWTTTT 9606 19261611 YES llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. 0.2 SIGNOR-184456 STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR up-regulates 9606 BTO:0000782 22767500 NO lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. 0.7 SIGNOR-261902 thioridazine chemical CHEBI:9566 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258839 LPCAT1 protein Q8NF37 UNIPROT 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI down-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272762 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257953 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266475 SLBP protein Q14493 UNIPROT H2AC20 protein Q16777 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265398 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT up-regulates activity binding 9606 BTO:0000776 15644327 YES lperfetto Baff interacts with baff receptor (baffr). 0.784 SIGNOR-133210 ADRA1A protein P35348 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.292 SIGNOR-256812 SHH protein Q15465 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887 17688959 NO gcesareni Most importantly, we report that shh induces mapk/erk and phosphoinositide 3-kinase (pi3k)-dependent akt phosphorylation and that activation of both signaling pathways is essential for shh's signaling in muscle cells. However, the effect of shh on akt phosphorylation is more robust than that on mapk/erk, and data suggest that shh influences these pathways in a manner similar to igf-i. 0.47 SIGNOR-157291 MRPL1 protein Q9BYD6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.67 SIGNOR-262384 LRP2 protein P98164 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity binding 9606 BTO:0000142 26872844 YES miannu LRP2 Promotes SHH Activity in Neurogenic Niches of the Developing and Adult Brain. In the RDVM, LRP2 forms a co-receptor complex with PTCH1 facilitating SHH binding and internalization of SHH/PTCH1 complexes, a prerequisite for pathway activation (Fig. 3B). 0.491 SIGNOR-265257 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1169 VQQDGKDyIPINAIL 9606 9299537 YES lperfetto Tyr-1169 and tyr-1213 on flt-1 were found to be auto-phosphorylated these results strongly suggest that tyr-1169 on flt-1 is a major binding site for plcgamma and important for flt-1 signal transduction within the cell 0.2 SIGNOR-50834 PRKACA protein P17612 UNIPROT MARK2 protein Q7KZI7 UNIPROT down-regulates activity phosphorylation Ser409 NPKQRRFsDQAAGPA 9606 BTO:0000007 25512381 YES miannu Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409.  0.2 SIGNOR-276870 MAPK14 protein Q16539 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser85 HQQPQSSsPVYGSSA 9606 14970194 YES llicata Here, we show that paxillin is phosphorylated by p38mapk in vitro and in nerve growth factor (ngf)-induced pc-12 cells. Ser 85 (ser 83 for endogenous paxillin) is identified as one of major phosphorylation sites by phosphopeptide mapping and mass spectrometry. 0.329 SIGNOR-122108 CDK7 protein P50613 UNIPROT MBD4 protein O95243 UNIPROT down-regulates activity phosphorylation 9606 31466944 YES miannu The mechanistic basis for the phase-separation of MED1 is not well understood, and we hypothesize that this may be due to the phosphorylation of MED1 by CDK7 in response to growth stimuli or nuclear translocation of steroid hormone receptors, such as AR.|Together, we demonstrate that CDK7 inhibition selectively targets MED1 mediated, AR dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC. 0.2 SIGNOR-279686 TRADD protein Q15628 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 10629108 YES amattioni Tradd mediates recruitment of traf1/2 0.693 SIGNOR-73913 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser204 DSRPRSQsSKAAIPP 9534 BTO:0001538 23519612 YES miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 0.318 SIGNOR-262706 ULK1 protein O75385 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity phosphorylation 9606 29671878 YES miannu In the nucleation step of autophagy, The ULK1 complex phosphorylates and activates the Beclin-1-VPS34 complex. 0.712 SIGNOR-279670 PLCG2 protein P16885 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 YES gcesareni Phosphorylation at Ser-146 by PKCδ increases p21 stability 0.2 SIGNOR-262963 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 YES Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 0.363 SIGNOR-248383 EGFR protein P00533 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 BTO:0000150 11483589 YES lperfetto We also show that the activated egf-r phosphorylates the muc1 cytoplasmic tail on tyrosine at a yekv motif that functions as a binding site for the c-src sh2 domain. The results demonstrate that egf-r-mediated phosphorylation of muc1 induces binding of muc1 to c-src in cells 0.578 SIGNOR-109538 testosterone smallmolecule CHEBI:17347 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of 9606 BTO:0000975 27702664 YES lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively 0.8 SIGNOR-268667 F2RL3 protein Q96RI0 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257312 FYN protein P06241 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Ser591 DKEKSKGsLKRK 9606 28811476 YES miannu By contrast, receptor multivalent aggregation induced a Fyn-dependent SHP-1 S591 phosphorylation (Fig.\u00a0 xref ).|Fyn simultaneously activates the PI3K-PKC\u03b1 pathway, leading to SHP-1 phosphorylation on serine 591. 0.55 SIGNOR-279716 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR IDH1 protein O75874 UNIPROT down-regulates quantity by destabilization phosphorylation Thr157 GKVEITYtPSDGTQK 34929314 YES lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome 0.27 SIGNOR-267621 GSK3B protein P49841 UNIPROT JUNB protein P17275 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 25303440 YES miannu GSK-3\u03b2 phosphorylation of JunB is therefore likely to be one of the critical events determining the difference in collagen deposition between normal and SSc fibroblasts.|In contrast, in normal fibroblasts, GSK-3beta is active and targets JunB for proteasomal degradation (XREF_FIG D). 0.2 SIGNOR-279721 ABL1 protein P00519 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation 9606 17615370 YES miannu Abl silencing inhibits CAS mediated process and constriction in resistance arteries.|CAS phosphorylation was catalyzed by Abl in an in vitro study. 0.463 SIGNOR-279671 ABL1 protein P00519 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation 9606 10866655 YES miannu Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage.|The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo. 0.258 SIGNOR-279672 RNF128 protein Q8TEB7 UNIPROT ARHGDIB protein P52566 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000661 17114425 YES miannu We found that RhoGDIα and RhoGDIβ are ubiquitin E3 substrates of GRAIL. GRAIL uses nonlysine 48-ubiquitin linkage in polyubiquitinating RhoGDI. GRAIL was subsequently demonstrated to bind and ubiquitinate RhoGDI, although GRAIL-mediated ubiquitination of RhoGDI did not result in proteosomal degradation. Our data suggest that ubiquitination of RhoGDI by GRAIL does not result in proteolytic degradation. In fact, GRAIL activity appeared to increase RhoGDI stability. 0.2 SIGNOR-271621 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 12747827 YES lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. 0.755 SIGNOR-236698 RAR proteinfamily SIGNOR-PF45 SIGNOR RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity binding 9606 1310351 YES miannu Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins. 0.725 SIGNOR-256198 CSNK2A1 protein P68400 UNIPROT CDC37 protein Q16543 UNIPROT up-regulates activity phosphorylation Ser13 VWDHIEVsDDEDETH -1 12930845 YES llicata Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site. 0.398 SIGNOR-250838 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1B protein Q92523 UNIPROT down-regulates activity binding 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267115 CYCS protein P99999 UNIPROT Oxidative_phosphorylation phenotype SIGNOR-PH78 SIGNOR up-regulates 10090 23021218 NO lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 0.7 SIGNOR-253100 EIF4G1 protein Q04637 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR form complex binding 9606 BTO:0000671 11408474 YES miannu Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f. 0.927 SIGNOR-108518 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1105 CSEVERTyLKTKSSS -1 10195142 YES lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. 0.568 SIGNOR-247163 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 10567572 YES gcesareni G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2.. 0.581 SIGNOR-72125 TUBGCP5 protein Q96RT8 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 YES lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” 0.822 SIGNOR-262329 PRKCA protein P17252 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 YES llicata The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl. 0.554 SIGNOR-17905 PTH1R protein Q03431 UNIPROT SOST protein Q9BQB4 UNIPROT down-regulates quantity 28363951 NO lperfetto Furthermore, PTH acts on osteocytes to suppress the expression of sclerostin, an inhibitor of canonical Wnt signaling (Li, et al. 2005; Semenov, et al. 2005)). PTH action on sclerostin is primarily through cAMP signaling (Keller and Kneissel 2005) and mediated by Myocyte enhancer factor-2 (MEF2) transcriptional regulators (Leupin, et al. 2007). Using the cAMP signaling pathway in osteoblasts, PTH also inhibits the expression of Dickkopf 1 (Dkk1) (Guo et al. 2010a), which is another Wnt pathway inhibitor  0.382 SIGNOR-270552 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser249 AVIPINGsPRTPRRG 9606 1756735 YES lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. 0.687 SIGNOR-21548 TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 17135271 YES These data establish a signaling cascade in which regulated site-specific Lys-63-linked TRAF6 auto-ubiquitination is the critical upstream mediator of IKK. 0.2 SIGNOR-252099 CSNK2A1 protein P68400 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates phosphorylation Ser423 CEEEFSDsEEEGEGG 9606 11602581 YES gcesareni Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1. 0.62 SIGNOR-111015 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser365 RLDRTGSsPTQGIVN 9606 15767678 YES gcesareni Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis. 0.332 SIGNOR-134588 Uridylate-specific endoribonuclease protein P0C6X7-PRO_0000037321 UNIPROT EIF2AK2 protein P19525 UNIPROT down-regulates activity 9606 28158275 NO miannu Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation. 0.2 SIGNOR-260348 MYLIP protein Q8WY64 UNIPROT VLDLR protein P98155 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20427281 YES miannu Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. 0.697 SIGNOR-271487 NEDD4 protein P46934 UNIPROT TUSC2 protein O75896 UNIPROT down-regulates quantity by destabilization ubiquitination Lys71 YEETIVTkNGQKRAK 9606 35167936 YES miannu NEDD4 Degrades TUSC2 to Promote Glioblastoma Progression.|NEDD4 E3 ubiquitin ligase polyubiquitinates TUSC2 at residue K71, and the TUSC2-K71R mutant is resistant to NEDD4-mediated proteasomal degradation. 0.2 SIGNOR-278638 GDNF protein P39905 UNIPROT TUBA1A protein Q71U36 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. 0.2 SIGNOR-252174 SOX6 protein P35712 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003298 26893351 NO We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARŒ≥, C/EBPŒ± and MEST 0.284 SIGNOR-255822 POU5F1 protein Q01860 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.479 SIGNOR-253159 CAMK2A protein Q9UQM7 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL BTO:0003036 8940188 YES llicata By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons. 0.699 SIGNOR-250630 BPLF1 protein P03186 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000007 23365429 YES scontino EBV-encoded BPLF1 interacts with and deubiquitinates TRAF6 to inhibit NF-κB signaling during lytic infection. Once lytic replication is induced, BPLF1 then deubiquitinates and inactivates TRAF6 to further block NF-κB signaling, promoting efficient viral genome replication. 0.2 SIGNOR-266739 9b protein P59636 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization 9606 25135833 NO miannu SARS-coronavirus Open Reading frame-9b Suppresses Innate Immunity by Targeting Mitochondria and the MAVS/TRAF3/TRAF6 Signalosome. Acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. 0.2 SIGNOR-260243 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TRIM71 protein Q2Q1W2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.285 SIGNOR-269247 CTNNBIP1 protein Q9NSA3 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10898789 YES gcesareni We identify a novel beta-catenin-interacting protein, icat, that was found to inhibit the interaction of beta-catenin with tcf-4 and represses beta-catenin-tcf-4-mediated transactivation. 0.816 SIGNOR-79399 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763;BTO:0000149 10197981 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-66775 AMPK complex SIGNOR-C15 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser170 PSALNRTsSDSALHT 9606 21892142 YES lperfetto Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation 0.442 SIGNOR-216541 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 8119945 YES gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. 0.858 SIGNOR-36279 SRC protein P12931 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates phosphorylation Tyr110 RGHAAIDyTQLGLRF 9606 20943948 YES llicata Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation. 0.408 SIGNOR-168545 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser77 PGPFATRsPLFIFMR 10090 12818176 YES miannu Mitochondrially localized JNKs but not their upstream activators MLKs or MKKs phosphorylated BIMEL at Ser65, potentiating its cytotoxicity without altering its subcellular distribution or integration into mitochondrial membranes. JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73 0.758 SIGNOR-250133 ASB8 protein Q9H765 UNIPROT IKBKB protein O14920 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 31009856 YES lperfetto In turn, ASB8 facilitated K48-linked ubiquitination and degradation of IKKbeta via the ubiquitin-proteasome pathway, resulting in remarkable inhibition of I-kappa-B-alpha (IkappaBalpha) and of p65 phosphorylation, consequently suppressing NF-kappaB activity. 0.2 SIGNOR-272253 CSNK1A1 protein P48729 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 YES llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  0.323 SIGNOR-250794 PTPRG protein P23470 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000876 25624455 YES miannu Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG. 0.287 SIGNOR-254689 FOXO6 protein A8MYZ6 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.278 SIGNOR-236560 SRC protein P12931 UNIPROT GAK protein O14976 UNIPROT up-regulates activity phosphorylation Tyr412 KGDLDISyITSRIAV -1 28135906 YES miannu GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149. 0.275 SIGNOR-263197 SPI1 protein P17947 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 20861919 NO irozzo In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation. 0.7 SIGNOR-256085 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr185 KQCEQAVyQTILEED 10090 BTO:0000938 11279201 YES lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. 0.421 SIGNOR-247072 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.275 SIGNOR-163784 PRKAA1 protein Q13131 UNIPROT GBF1 protein Q92538 UNIPROT down-regulates phosphorylation Thr1337 GKIHRSAtDADVVNS 9606 SIGNOR-C15 18063581 YES lperfetto These results indicate that gbf1 is a novel ampk substrate and that the ampk-mediated phosphorylation of gbf1 at thr(1337) has a critical role, presumably by attenuating the function of gbf1, in the disassembly of the golgi apparatus induced under stress conditions that lower the intracellular atp concentration. 0.2 SIGNOR-159639 CDH1 protein P12830 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR up-regulates binding 9606 BTO:0000782 7969453 YES gcesareni Here we show that heterotypic adhesive interactions between epithelial cells and intraepithelial lymphocytes in vitro are mediated by e-cadherin and the alpha e beta 7 integrin. 0.652 SIGNOR-35210 ERCC1 protein P07992 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR form complex binding 9606 16338413 YES miannu Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. 0.953 SIGNOR-142989 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Ile1512 KEFNPLViVGLSKDG -1 9242537 YES lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex. 0.367 SIGNOR-263633 HDAC1 protein Q13547 UNIPROT FSHR protein P23945 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23086931 NO miannu Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. 0.2 SIGNOR-254225 SLBP protein Q14493 UNIPROT H2AC4 protein P04908 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265397 ACLY protein P53396 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity by destabilization chemical modification 9606 19286649 YES miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. 0.8 SIGNOR-268081 EIF2AK3 protein Q9NZJ5 UNIPROT OGT protein O15294 UNIPROT up-regulates activity phosphorylation 9606 33592173 YES miannuccelli Collectively, these results indicate that upon cold and \u03b2-adrenergic stimulation PERK-activated OGT catalyzes the O-GlcNAcylation of CK2\u03b1 and TOM70 which enhances MIC19 import into the mitochondria increasing cristae formation and cell respiration (Figure 7I).|Here, we report that the ER-resident kinase PERK is activated upon cold or \u03b2-adrenergic stimulation and directly phosphorylates OGT. 0.2 SIGNOR-279736 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 BTO:0000801;BTO:0000876 17658244 YES gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. 0.2 SIGNOR-157085 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRB3 protein P79483 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 YES miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. 0.2 SIGNOR-271408 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10656682 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-74823 AKT1 protein P31749 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser371 YARRRRPsQPYMFPR 9606 BTO:0000093 31740618 YES miannu S379 of RARγ is indispensable for the CLDN6-triggered cellular events. The most important finding of the present study is that the CLDN6/SFK/PI3K/AKT signaling controls the RARγ and ERα activities (Fig. 6). 0.466 SIGNOR-277492 IRX1 protein P78414 UNIPROT DKK3 protein Q9UBP4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.262 SIGNOR-261658 PAK6 protein Q9NQU5 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 23132866 YES miannu We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation. 0.2 SIGNOR-276427 RPL12 protein P30050 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.875 SIGNOR-262487 EIF4E2/GIGYF2 complex complex SIGNOR-C257 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0000568 22751931 NO lperfetto A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|m4EHP and/or GIGYF2 proteins repress translation. 0.7 SIGNOR-261013 COMT protein P21964 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-263997 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120100 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR AURKB protein Q96GD4 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000567 17543862 YES miannu Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis. 0.436 SIGNOR-271662 CDK5 protein Q00535 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Ser114 RKLQGRPsPGPPAPE 9606 BTO:0000938 20213743 YES llicata Together, our data suggest that cdk5 can phosphorylate enos at the ser-113 site and down-regulate enos-derived no levels. 0.371 SIGNOR-164080 NOG protein Q13253 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates activity binding 9606 BTO:0001593 BTO:0000140 SIGNOR-C29 22298955 YES Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285) 0.586 SIGNOR-195612 FUS protein P35637 UNIPROT GRIA4 protein P48058 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 NO This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease 0.2 SIGNOR-262806 CSNK1A1 protein P48729 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Ser159 GIPVRCYsAEVVTLW -1 10500146 YES miannu We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2. 0.298 SIGNOR-275966 PICK1 protein Q9NRD5 UNIPROT GRIA2 protein P42262 UNIPROT up-regulates activity binding 9534 BTO:0000298 25784538 YES miannu RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above. 0.807 SIGNOR-264046 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr8 MPPYTVVyFPVRGRC 9606 BTO:0000150 19254954 YES llicata Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly, 0.438 SIGNOR-184387 PPM1B protein O75688 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity dephosphorylation 9606 20538721 YES miannu CDK2 can be dephosphorylated and inactivated by protein phosphatase type 2C beta isoform long (PP2Cbetal), a unique phosphatase that was originally cloned from human liver. 0.362 SIGNOR-277153 A4/b7 integrin complex SIGNOR-C187 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.564 SIGNOR-257728 RIPK4 protein P57078 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity phosphorylation Ser298 DGGIYIGsIMKGGAV 9606 23371553 YES miannuccelli Co-transfection of a RIPK4-GFP fusion increased the percentage of cells containing DVL2 puncta to more than 75% ( and ), suggesting that RIPK4 facilitates DVL2 signalosome formation.|Phosphorylation of DVL2 at Ser 298 and Ser 480 by RIPK4 favored canonical Wnt signaling. 0.441 SIGNOR-279756 TLX1 protein P31314 UNIPROT RB1 protein P06400 UNIPROT down-regulates activity binding 9606 BTO:0000661 15897879 YES 2 miannu ectopic HOX11 expression resulted in hyperphosphorylation of the retinoblastoma protein (Rb), which correlated with inhibition of the major Rb serine/threonine phosphatase PP1. 0.2 SIGNOR-240725 UBE2E2 protein Q96LR5 UNIPROT RNF19B protein Q6ZMZ0 UNIPROT up-regulates activity binding 9606 BTO:0000914 16709802 YES miannu We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and 0.505 SIGNOR-271592 EPAS1 protein Q99814 UNIPROT KDM7A protein Q6ZMT4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271587 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Ser408 RIPASQTsVPFDHLG 9606 BTO:0000007 10542239 YES llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T 0.2 SIGNOR-250810 simvastatin chemical CHEBI:9150 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 1433193 YES miannu Substitution of hydroxy and hydroxyalkyl functionality at C-7 of the hexahydronaphthalene nucleus of simvastatin has provided novel analogs. The synthetic strategy employed epoxidation or Lewis acid-catalyzed aldol reaction of the 8-keto silyl enol ether as a key reactive intermediate. These analogs were evaluated as potential hypocholesterolemic agents via initial determination of their ability to inhibit HMG-CoA reductase in vitro. 0.8 SIGNOR-258348 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR H4C1 protein P62805 UNIPROT up-regulates activity ubiquitination -1 12485996 YES lperfetto Strikingly, as well as H2AX, the nucleosome core histones H2A, H2B, H3 and H4 were all ubiquitylated efficiently by BRCA1/BARD1, while the linker histone H1 was not (Figure 3).| Generally, histone proteins are required for compaction of nuclear DNA into chromatin, and their modification is thought to loosen this compaction. Therefore, one might envisage that ubiquitylation of γH2AX by BRCA1/BARD1 at DNA breaks modulates local chromatin packaging to facilitate the action of DNA repair enzymes. 0.2 SIGNOR-263234 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT down-regulates relocalization 9606 23151663 YES gcesareni This is counteracted by respondin 1, which induces znrf3 internalization 0.802 SIGNOR-199629 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity dephosphorylation Tyr292 DTLNSDGyTPEPARI -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.261 SIGNOR-254732 ODAD4 protein Q96NG3 UNIPROT Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 10090 27486780 NO miannu Our results in mice suggest that TTC25 plays an essential role in the correct function of motile cilia at the ventral node and is therefore important for the development of left-right body asymmetry. 0.7 SIGNOR-265548 ATM protein Q13315 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates phosphorylation Ser387 SDDSRTAsQLDEFQE 9606 16931761 YES lperfetto Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism 0.2 SIGNOR-149082 CHEVI complex complex SIGNOR-C269 SIGNOR Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 27319744 NO lperfetto VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles 0.7 SIGNOR-261833 CSF2RB protein P32927 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR form complex binding 9606 BTO:0000876 BTO:0001103 9680354 YES apalma The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors. 0.869 SIGNOR-255583 FBXW11 protein Q9UKB1 UNIPROT AICDA protein Q9GZX7 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 31092637 YES miannu  Further analysis indicated that CUL7 mediated AID ubiquitination by forming a complex with FBXW11. In a CUL7 fl/fl CD19 cre+ mouse model, we demonstrated that CUL7 knockout significantly enhanced AID protein levels in B cells in the germinal center and increased both the IgG1 and IgA class switching. Collectively, our results reveal a subtle regulation mechanism for tightly controlling AID protein levels. F-box proteins are components of SCF ubiquitin-ligase complexes that contain Skp1, CUL1, or CUL7, and an F-box protein 0.2 SIGNOR-272024 hesperadin chemical CHEBI:70726 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193128 PTGFR protein P43088 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256953 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000562 17075052 YES gcesareni The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment. 0.2 SIGNOR-150347 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192601 HTR2C protein P28335 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.281 SIGNOR-256877 NR0B2 protein Q15466 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 11368516 NO inferred from family member gcesareni Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation. 0.371 SIGNOR-267806 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 22298955 YES gcesareni Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4. 0.647 SIGNOR-195697 Ub:E2 complex SIGNOR-C497 SIGNOR BIRC3 protein Q13489 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271049 CDON protein Q4KMG0 UNIPROT CDON/SPAG9 complex SIGNOR-C21 SIGNOR form complex binding 9606 BTO:0000222 17074887 YES gcesareni In this study, we report that the cdo intracellular region interacts with jlp, a scaffold protein for the p38alpha/beta mapk pathway. 0.496 SIGNOR-150279 HOXB8 protein P17481 UNIPROT MYLK protein Q15746 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 15886193 YES Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively 0.2 SIGNOR-261640 MMP2 protein P08253 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates cleavage 9606 10652271 YES gcesareni We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-beta (tgf-beta), which constitutes a novel mechanism of tgf-beta activation 0.556 SIGNOR-74384 PMP22 protein Q01453 UNIPROT ITGA6 protein P23229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21518455 NO Regulation miannu Peripheral myelin protein-22 (PMP22) modulates alpha 6 integrin expression in the human endometrium. Overexpression of PMP22 was sufficient to increase α6 integrin surface expression with a concominant increase in binding to the extracellular matrix laminin, while a reduction in PMP22 suppressed α6 integrin surface expression. 0.383 SIGNOR-251897 SPI1 protein P17947 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates activity 10090 BTO:0000725 8079170 NO Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor. 0.7 SIGNOR-259954 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser107 NPMRRIHsLPQKLLG 9606 BTO:0002181 34363019 YES miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  0.2 SIGNOR-276738 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 BTO:0000887;BTO:0001103 14579029 YES gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.771 SIGNOR-118861 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.34 SIGNOR-273144 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.257 SIGNOR-159446 RELA protein Q04206 UNIPROT IL1B protein P01584 UNIPROT down-regulates activity transcriptional regulation 10090 BTO:0000801 23667107 YES lperfetto Early Inhibition of IL-1 beta Expression by IFN-gamma Is Mediated by Impaired Binding of NF-kappa B to the IL-1 beta Promoter but Is Independent of Nitric Oxide|We report that IFN-γ suppressed bacterial RNA and LPS induced IL-1β transcription in primary murine macrophages 0.553 SIGNOR-251736 SRC protein P12931 UNIPROT JUP protein P14923 UNIPROT up-regulates activity phosphorylation Tyr644 RNEGTATyAAAVLFR 9606 14517306 YES lperfetto Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcriptionFor instance, Src, which mainly phosphorylates Tyr86 in beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin. 0.668 SIGNOR-247310 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser558 GSSQGRNsPAPAVTA 10090 BTO:0000964 34048556 YES lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. 0.2 SIGNOR-268343 HACE1 protein Q8IYU2 UNIPROT RAC1 protein P63000 UNIPROT down-regulates quantity ubiquitination Lys147 PQGLAMAkEIGAVKY 9606 23864022 YES miannu GTP-bound Rac1 is ubiquitylated by Hace1 at lysine (K)-147 (ref. xref ).|This indicates that Hace1 binds and targets Rac1 once the latter has been recruited to the complex. 0.368 SIGNOR-278810 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr37 LINLGKNyEKAVNAM -1 21840312 YES miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. 0.389 SIGNOR-263041 ETS1 protein P14921 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001861 19757157 YES lperfetto Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level. 0.2 SIGNOR-254098 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser231 KSNIVLLsAEEKKEQ 9606 BTO:0000776 7678037 YES llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells. 0.307 SIGNOR-251011 ULK1 protein O75385 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates phosphorylation 9606 21460634 YES lperfetto Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. 0.49 SIGNOR-217484 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A1 protein P30531 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206960 ATM protein Q13315 UNIPROT BID protein P55957 UNIPROT down-regulates activity phosphorylation 9606 23069655 YES lperfetto Taken together, these results are consistent with the idea that at low levels of DNA damage ATM phosphorylates Bid to keep it away from the mitochondria resulting in low levels of ROS.|Thus, Bid accumulation at the mitochondria, which is negatively regulated by ATM, triggers a metabolic change in mitochondria that includes an increase in ROS and perhaps changes in other metabolites that signal back to the nucleus to regulate gene transcription leading to cell cycle progression (XREF_FIG). 0.461 SIGNOR-279790 BPLF1 protein P03186 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity deubiquitination 9606 24586164 YES scontino In the current study, we have found that BPLF1 interferes with innate immune activation by targeting multiple intermediates along the TLR signal transduction pathway, including TRAF6, NEMO, and IκBα. BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes. 0.2 SIGNOR-266743 MAPK14 protein Q16539 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Ser87 AAAGPALsPVPPVVH 9606 19336399 YES gcesareni The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38mapk 0.334 SIGNOR-184936 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of -1 30553771 YES PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species 0.8 SIGNOR-267274 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269373 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 10482988 YES miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. 0.445 SIGNOR-251147 MAPK8 protein P45983 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 15538382 YES lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. 0.61 SIGNOR-130385 IL12B protein P29460 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 7527811 YES fspada Characterization of the p40 proteins for binding and bioactivity showed that both the p40 monomer and dimer inhibited 125i-labeled il-12 binding to il-12r, but the 80-kda species, having a 50% inhibitory concentration (ic50) of 20 to 70 ng/ml, was at least 20-fold more effective than the monomer. The results suggest that the il-12 p40 subunit contains the essential epitopes for receptor binding. 0.675 SIGNOR-27690 ILK protein Q13418 UNIPROT MYL12B protein O14950 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 11278951 YES lperfetto Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19).Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activa 0.314 SIGNOR-106427 MYC protein P01106 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20010808 YES We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2, 0.457 SIGNOR-268690 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT up-regulates activity phosphorylation Ser45 LGIRSSKsAGALEEG 9606 BTO:0002524 30631047 YES miannu Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Function assay of ARMC10 and ARMC10 phosphorylation at S45. 0.2 SIGNOR-277806 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 23119004 YES lperfetto Binding of igf to igf-ir activates pi3k to generate pip3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including akt and pdk1. 0.8 SIGNOR-252642 MECP2 protein P51608 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0002881 19427855 NO Luana Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2 0.7 SIGNOR-264966 ruxolitinib chemical CHEBI:66919 ChEBI JAK1 protein P23458 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258276 LYN protein P07948 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 BTO:0000801 17890224 YES done miannu We demonstrated that WASP is phosphorylated on tyrosine 291 in macrophages, and the WASP phosphorylation is important for the phagocytic cup formation. In addition, we showed that WASP and WASP-interacting protein (WIP) form a complex at the phagocytic cup and that the WASP.WIP complex plays a critical role in the phagocytic cup formation.  0.378 SIGNOR-273959 SIRT3 protein Q9NTG7 UNIPROT CYP11A1 protein P05108 UNIPROT up-regulates quantity by stabilization deacetylation Lys148 LKKSAAWkKDRVALN 9606 BTO:0002588 22585829 YES lperfetto Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis. 0.2 SIGNOR-268717 SLC36A1 protein Q7Z2H8 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI up-regulates quantity relocalization 9606 12748860 YES lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. 0.8 SIGNOR-264739 MAPK9 protein P45984 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 YES llicata These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells. 0.746 SIGNOR-115835 CAMK2G protein Q13555 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity phosphorylation 12609872 YES inferred from family member llicata Direct phosphorylation of the GluR1 subunit of postsynaptic AMPA receptors by Ca(2+)/calmodulin-dependent protein kinase II (CaM-KII) is believed to be one of the major contributors to the enhanced strength of glutamatergic synapses in CA1 area of hippocampus during long-term potentiation. | Validity of the approach was confirmed by modeling, and silence analysis was applied then to the GluR1 AMPA receptor mutated at S831, the site phosphorylated by CaM-KII during long-term potentiation. Silence analysis indicates that a negative charge at S831 is a critical determinant for the enhanced channel function as a charge carrier. Silence and variance analyses, when applied to the same sets of data, were in agreement on the receptor regulation upon mutations. 0.629 SIGNOR-270234 C1QBP protein Q07021 UNIPROT C1QB protein P02746 UNIPROT down-regulates activity binding SIGNOR-C308 28018340 YES lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. 0.341 SIGNOR-263403 paclitaxel chemical CHEBI:45863 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 28298489 YES miannu Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. 0.8 SIGNOR-259449 POU5F1 protein Q01860 UNIPROT LEFTY2 protein O00292 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.42 SIGNOR-254940 PP1 proteinfamily SIGNOR-PF54 SIGNOR PYG proteinfamily SIGNOR-PF96 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0002049 22225877 YES GP is the first protein whose function was discovered to be regulated by reversible protein phosphorylation, which is controlled by phosphorylase kinase (PhK) and protein phosphatase 1 (PP1). Here we report that lysine acetylation negatively regulates GP activity by both inhibiting enzyme activity directly and promoting dephosphorylation 0.388 SIGNOR-267961 TFAP2A protein P05549 UNIPROT CRABP2 protein P29373 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 NO miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 0.343 SIGNOR-255400 PIN1 protein Q13526 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 BTO:0000150 23716601 YES esanto Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated myc and its coactivators to select promoters during gene activation. 0.572 SIGNOR-202134 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys686 HQGKRNPkSPLACTN 9606 21791603 YES miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). 0.58 SIGNOR-272731 ITCH protein Q96J02 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 10940313 YES gcesareni Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain. 0.643 SIGNOR-80702 BRCA1 protein P38398 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001130 22832221 NO gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. 0.819 SIGNOR-198467 SUZ12 protein Q15022 UNIPROT SUZ12/EED complex SIGNOR-C76 SIGNOR form complex binding 9606 16712789 YES miannu Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2. 0.944 SIGNOR-146761 BLK protein P51451 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.647 SIGNOR-268214 Pituitary adenylate cyclase-activating peptide-27 smallmolecule CHEBI:80303 ChEBI ADCYAP1R1 protein P41586 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257445 HIPK1 protein Q86Z02 UNIPROT PAGE4 protein O60829 UNIPROT up-regulates activity phosphorylation Thr51 PGQEREGtPPIEERK 9606 24559171 YES Manara Here, we have identified homeodomain-interacting protein kinase 1 (HIPK1), also a component of the stress-response pathway, as a kinase that phosphorylates PAGE4 at T51 | We show that phosphorylation of PAGE4 is critical for its transcriptional activity since mutating this T residue abolishes its ability to potentiate c-Jun transactivation. 0.456 SIGNOR-260929 hsa-miR-129-1-3p mirna URS00004CCDA3_9606 RNAcentral BDKRB2 protein P30411 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003878 25008064 YES Parnian Expression of BDKRB2 was negatively related to miR-129-1-3p. Luciferase reporter assay showed that BDKRB2 was the target of the miR-129-1-3p. In summary, miR-129-1-3p inhibits the BGC-823 cell migration by targeting BDKRB2. 0.4 SIGNOR-278003 TLN1 protein Q9Y490 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.468 SIGNOR-257628 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 9606 18769144 YES lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively 0.246 SIGNOR-180759 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2L6 protein O14933 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.635 SIGNOR-271353 ABL1 protein P00519 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 23383209 YES miannu Previously, we showed that c-Abl and Arg promote phosphorylation of the STAT3 transcription factor (Y705) in a variety of cancer cell lines , .|Since c-Abl and Arg activate STAT3, we investigated whether c-Abl and Arg regulate NF-kappaB signaling. 0.446 SIGNOR-279675 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 14976552 YES lperfetto We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli 0.61 SIGNOR-217472 LMTK2 protein Q8IWU2 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12393858 YES gcesareni Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity. 0.571 SIGNOR-94631 HMGA2 protein P52926 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14645522 NO miannu Transcriptional activation of the cyclin a gene by the architectural transcription factor hmga2 0.312 SIGNOR-119496 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257915 Alkannin chemical CHEBI:2578 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000093;BTO:0000018 21516121 YES inferred from family member lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. 0.8 SIGNOR-270284 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207938 SPOP protein O43791 UNIPROT DEK protein P35659 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). 0.439 SIGNOR-272826 Elongator complex complex SIGNOR-C466 SIGNOR TUBA3D protein P0DPH8 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 YES miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. α-Tubulin Acetylation Promotes Radial Migration and Branching of Cortical Projection Neurons 0.252 SIGNOR-269715 SCN8A protein Q9UQD0 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 YES miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. 0.8 SIGNOR-253406 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GRIP1 protein Q9Y3R0 UNIPROT up-regulates activity phosphorylation Ser734 SLKGKPLsEAIHLLQ -1 11301320 YES miannu Here we show that epidermal growth factor regulates the activities of the p160 GRIP1 through the extracellular signal-regulated kinase (ERK) family of mitogen-activated protein kinases. ERKs phosphorylate GRIP1 at a specific site, Ser-736, the integrity of which is required for full growth factor induction of GRIP1 transcriptional activation and coactivator function. 0.2 SIGNOR-263056 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 31422819 YES Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. 0.8 SIGNOR-266922 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763 12193595 YES miannu Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction. 0.721 SIGNOR-91726 MDM2 protein Q00987 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001109 10640274 YES miannu We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. 0.642 SIGNOR-271385 CHIR 99021 chemical CHEBI:91091 ChEBI GSK3A protein P49840 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190997 MAX protein P61244 UNIPROT MNT protein Q99583 UNIPROT up-regulates activity binding 9606 7954804 YES 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. 0.352 SIGNOR-240354 CXCL1 protein P09341 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 38309677 YES miannu CXCL1 produces cellular chemotactic activity by binding to the CXC chemokine receptor 2 (CXCR2). In PC, this chemokine has been associated with a variety of carcinogenic mechanisms, including oncogene-induced senescence (OIS), angiogenesis, cancer metastasis, and immunosuppressive microenvironments  0.776 SIGNOR-277717 ITGA8 protein P53708 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.819 SIGNOR-253181 UCHL5 protein Q9Y5K5 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.614 SIGNOR-270852 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000478 26214522 NO Luana  We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. 0.2 SIGNOR-264552 CASP1 protein P29466 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.761 SIGNOR-256409 UBC protein P0CG48 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding 9606 BTO:0000938 26161729 YES lperfetto Mechanism of phospho-ubiquitin-induced PARKIN activation|PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN|Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. 0.2 SIGNOR-249692 (R)-carnitine smallmolecule CHEBI:16347 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267118 SRC protein P12931 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr47 SGQISNGySAVPSPG 10116 BTO:0000132 21992875 YES miannu We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.  0.259 SIGNOR-276385 F9 protein P00740 UNIPROT F7 protein P08709 UNIPROT up-regulates activity cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 YES lperfetto The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa. 0.549 SIGNOR-263522 MAPK1 protein P28482 UNIPROT IL16 protein Q14005 UNIPROT up-regulates phosphorylation Ser845 SIRQRISsFETFGSS 9606 14768064 YES lperfetto The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response. 0.265 SIGNOR-121852 CDK1 protein P06493 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by destabilization phosphorylation Thr176 HLFGFPPtPPKEVSP 9606 BTO:0000007 25670854 YES miannu GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1).  0.356 SIGNOR-276884 HOXC6 protein P09630 UNIPROT S100B protein P04271 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002253 17488478 YES Luana HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells. 0.2 SIGNOR-261646 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser201 PLQRQPSsPGPTPRN 9606 BTO:0001103 10212242 YES lperfetto Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates. 0.667 SIGNOR-67065 NMBR protein P28336 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257047 FZD2 protein Q14332 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates activity binding 9606 23151663 YES areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  0.639 SIGNOR-258962 ANAPC5 protein Q9UJX4 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.922 SIGNOR-252005 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr3 tSQKHRDF 9606 16495336 YES gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell 0.876 SIGNOR-144791 NR0B2 protein Q15466 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 11368516 NO inferred from family member gcesareni Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation. 0.371 SIGNOR-270298 GABBR1 protein Q9UBS5 UNIPROT GABA-B receptor complex SIGNOR-C336 SIGNOR form complex binding 9606 BTO:0000007 9872316 YES brain lperfetto Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2. 0.692 SIGNOR-263742 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR ACTA1 protein P68133 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.344 SIGNOR-136175 PTPRG protein P23470 UNIPROT SHC1 protein P29353 UNIPROT down-regulates activity dephosphorylation Tyr349 EEPPDHQyYNDFPGK -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254723 UQCRB protein P14927 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.927 SIGNOR-262194 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 NO lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. 0.7 SIGNOR-249559 PYGB protein P11216 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267395 CDK5 protein Q00535 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Ser522 PASSAKTsPAKQQAP 9606 BTO:0000938 25040932 YES lperfetto Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition 0.653 SIGNOR-264838 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 YES gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. 0.577 SIGNOR-76009 GATA1 protein P15976 UNIPROT ITGA2B protein P08514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17725493 NO miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. 0.594 SIGNOR-254192 KMT5C protein Q86Y97 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity methylation Lys21 GGAKRHRkVLRDNIQ -1 24396869 YES miannu SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. 0.2 SIGNOR-266650 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4523 GSRHSLAsTDEKREL 9606 15272003 YES lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. 0.2 SIGNOR-127211 DDR1 protein Q08345 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates activity phosphorylation Tyr513 LLLSNPAyRLLLATY 9606 BTO:0000007;BTO:0000356 9659899 YES llicata The discoidin domain receptor tyrosine kinases are activated by collagen | Here, we present evidence that stimulating DDR1- and DDR2-expressing cells with various types of collagen induces receptor autophosphorylation. 0.2 SIGNOR-251086 CDC7 protein O00311 UNIPROT MCM7 protein P33993 UNIPROT up-regulates phosphorylation 9606 21070963 YES gcesareni We propose that phosphorylation of mcm4/6 s/tp sites, which are already phosphorylated in g1, allows initial mcm2-7 phosphorylation by ddk and initiation from the first origins of replication ( fig. 7ai ). 0.942 SIGNOR-169506 PRKACA protein P17612 UNIPROT CAPN2 protein P17655 UNIPROT down-regulates phosphorylation Thr370 GNWRRGStAGGCRNY 9606 11909964 YES llicata Activation of m-calpain (calpain ii) by epidermal growth factor is limited by protein kinase a phosphorylation of m-calpain.These Data point to a novel mechanism of negative control of calpain activation, direct phosphorylation by pka. 0.262 SIGNOR-116248 SLBP protein Q14493 UNIPROT H2BC1 protein Q96A08 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265393 DLG1 protein Q12959 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity binding 9606 BTO:0000782 17187070 YES Barakat Dlgh1 immunoprecipitates were specifically enriched for activated p38 phosphorylated at Thr180 and Tyr182; phosphorylated p38 was not detected in the unbound fraction from stimulated samples 0.636 SIGNOR-274143 CBS protein P35520 UNIPROT L-homocysteine zwitterion smallmolecule CHEBI:58199 ChEBI down-regulates quantity chemical modification 9606 23981774 YES lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 0.8 SIGNOR-275828 ADSS2 protein P30520 UNIPROT GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity chemical modification 9606 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-267349 ZNF774 protein Q6NX45 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR up-regulates activity binding 9606 BTO:0000578 31659254 YES miannu Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. 0.248 SIGNOR-265558 BTRC protein Q9Y297 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0004055 10514424 YES miannu Interaction with beta-TrCP is also necessary for ubiquitination of IkappaBbeta upon stimulation of cells, and deletion of the F-box in beta-TrCP abolishes its ability to ubiquitinate IkappaBbeta. Therefore, these results indicate that beta-TrCP plays a critical role in the activation of NF-kappaB by assembling the ubiquitin ligase complex for both phosphorylated IkappaBalpha and IkappaBbeta.β-TrCP recognizes IκBα phosphorylated at Ser-32 and Ser-36 through its WD40 domain, whereas the F-box motif recruits additional proteins including Skp1 and Cullin to form the Skp1-cullin-F-box (SCF) ubiquitin ligase complex 0.581 SIGNOR-272554 MAPK3 protein P27361 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser12 ESPLCPLsPLEAGDL 9606 10187842 YES lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. 0.6 SIGNOR-249473 KANSL1 protein Q7Z3B3 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. 0.671 SIGNOR-267164 KIF5B protein P33176 UNIPROT GABBR1 protein Q9UBS5 UNIPROT up-regulates activity relocalization 10090 17532644 YES SARA GABABR1 co-immunoprecipitated with Marlin-1 and kinesin-I, providing evidence for the existence of a complex between these proteins. Kinesin-I modulates GABAB receptor transport. 0.255 SIGNOR-260990 LMP1 protein P03230 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 26428373 NO scontino Soon, it has been recognized that TES1 and 2 coincide with two regions named C-terminal activating regions (CTAR) 1 and 2, respectively, that are responsible for interaction of LMP1 with cellular signaling molecules. Early studies revealed that both CTAR1 and CTAR2 contribute to the activation of NF-κB, Later, it became evident that CTAR1 primarily activates the non-canonical NF-κB pathway, while CTAR2 is responsible for canonical NF-κB activation. 0.2 SIGNOR-267616 HLX protein Q14774 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003980 20008130 YES Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. 0.2 SIGNOR-261619 MAPK3 protein P27361 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Ser284 RRDYDDMsPRRGPPP 9606 16564677 YES gcesareni Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353. 0.345 SIGNOR-145375 MAPK3 protein P27361 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation 9606 9792677 YES lperfetto Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1 0.585 SIGNOR-60998 EFNB2 protein P52799 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 YES gcesareni Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation 0.883 SIGNOR-52583 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 10090 BTO:0002882 16122376 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work 0.2 SIGNOR-236516 JUN protein P05412 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 NO miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 0.2 SIGNOR-254808 RGMA protein Q96B86 UNIPROT NEO1 protein Q92859 UNIPROT down-regulates activity binding 10090 18485097 YES miannu Netrin-1-neogenin interactions mediate chemoattractive axon guidance, while RGMa-neogenin interactions repel axons.  0.786 SIGNOR-268388 ETS1 protein P14921 UNIPROT VWF protein P04275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9444957 NO miannu Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells. 0.294 SIGNOR-253915 N protein P59595 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 9606 17108024 NO miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. IRF-3 activation is inhibited in cells that express ORF 3b, ORF 6, or N protein, and NF-κB is inhibited in cells expressing N protein. 0.2 SIGNOR-260340 TAF3 protein Q5VWG9 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.819 SIGNOR-263930 NFE2 protein Q16621 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 NO Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. 0.512 SIGNOR-251839 SOX17 protein Q9H6I2 UNIPROT SOX17/POU5F1 complex SIGNOR-C451 SIGNOR form complex binding 23474895 YES SimoneGraziosi Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm|We show that Sox17 partners with Oct4 and binds to a unique ‘compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical' binding sites. 0.609 SIGNOR-269220 RIMBP3C protein A6NJZ7 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.265 SIGNOR-264367 MAFA protein Q8NHW3 UNIPROT NKX6-1 protein P78426 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 NO miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. 0.429 SIGNOR-254564 ECM stimulus SIGNOR-ST20 SIGNOR AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259055 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser301 SSSPNNLsPTGWSQP 10090 BTO:0000944 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.631 SIGNOR-249443 CASP6 protein P55212 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.363 SIGNOR-261745 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252319 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2B protein P63146 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.755 SIGNOR-271334 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Ser311 EYTIKSHsSLPPNNS 9606 15611134 YES lperfetto Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311. 0.2 SIGNOR-132455 PTPRG protein P23470 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation Tyr413 TAPESLAyNKFSIKS -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.341 SIGNOR-254691 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser44 ESEESQDsSDSIGSS 9606 20730097 YES lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf4 0.2 SIGNOR-167572 CENPC protein Q03188 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR up-regulates activity binding 9606 BTO:0000567 20566683 YES miannu CENP-C is required for centromere assembly. CENP-C and CENP-N bind to different sites on the same CENP-A nucleosomes. CENP-C, like CENP-N, interacts directly and specifically with CENP-A nucleosomes. 0.731 SIGNOR-263706 PKA proteinfamily SIGNOR-PF17 SIGNOR DNM1L protein O00429 UNIPROT down-regulates activity phosphorylation Ser637 VPVARKLsAREQRDC -1 31063459 YES lperfetto For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission 0.2 SIGNOR-262551 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 10090 15306821 YES lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. 0.787 SIGNOR-127912 CAMK4 protein Q16566 UNIPROT NOS1 protein P29475 UNIPROT down-regulates activity phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 YES llicata It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation. 0.357 SIGNOR-250713 CDK1 protein P06493 UNIPROT UBE2A protein P49459 UNIPROT up-regulates phosphorylation Ser120 LDEPNPNsPANSQAA 9606 11953320 YES llicata Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity. 0.37 SIGNOR-116504 EPAS1 protein Q99814 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271584 MKNK1 protein Q9BUB5 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Ser121 VSSGSRSsTRTSTSS 9606 19864419 YES llicata The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability. 0.529 SIGNOR-188893 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC1 protein Q96A08 UNIPROT down-regulates activity monoubiquitination Lys36 KKRKRTRkESYSIYI 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271992 GABRD protein O14764 UNIPROT GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.405 SIGNOR-263746 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120092 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.305 SIGNOR-249005 ATP6V1C1 protein P21283 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.78 SIGNOR-277743 PRKD1 protein Q15139 UNIPROT KAT7 protein O95251 UNIPROT up-regulates quantity by stabilization phosphorylation Thr331 LRLQGQItEGSNMIK 9606 BTO:0002181 33014433 YES miannu We show that PKD1 directly interacts and phosphorylates KAT7 at Thr97 and Thr331 in vitro and in vivo. PKD1-mediated phosphorylation of KAT7 enhances its expression levels and stability by reducing its ubiquitination-mediated degradation.  0.2 SIGNOR-277828 ULK2 protein Q8IYT8 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser63 HLYGIAGsTNVTGDQ 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274040 EBNA1 protein P03211 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR down-regulates activity 9606 29659505 NO scontino EBNA1 has been reported to block p65 activation by inhibiting IKKα/β through an unknown mechanism, we suggest that, in NPC, NF-κB signaling and EBNA1 may form a regulatory loop which supports EBV latent gene expression, while also limiting NF-κB activity 0.2 SIGNOR-266802 M protein P59596 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR down-regulates activity binding 9534 17705188 YES lperfetto Together, these results indicate that SARS-CoV M suppresses NF-kappaB activity probably through a direct interaction with IKKbeta, resulting in lower Cox-2 expression. 0.2 SIGNOR-260261 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity sumoylation Lys594 GNWRGMLKTSKAEEL 9606 BTO:0000007 19638400 YES Barakat Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. 0.535 SIGNOR-274128 PRKCA protein P17252 UNIPROT F3 protein P13726 UNIPROT up-regulates phosphorylation Ser285 RKAGVGQsWKENSPL 9606 23195225 YES lperfetto We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. The phosphorylation of ser253 is known to be mediated by protein kinase c_ 0.2 SIGNOR-199872 FBXW8 protein Q8N3Y1 UNIPROT Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR up-regulates activity binding 9606 BTO:0001109 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1. We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8. 0.769 SIGNOR-271631 PPARGC1A protein Q9UBK2 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 17476214 YES miannu Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Chromatin immunoprecipitation (ChIP) assays in HepG2 cells indicate that PGC-1α is present near RORE on the proximal Bmal1 promoter.These results indicate that PGC-1α activates Bmal1 transcription by altering the local chromatin environment from a repressive to an active state. 0.521 SIGNOR-268030 MARK2 protein Q7KZI7 UNIPROT KIF13B protein Q9NQT8 UNIPROT down-regulates activity phosphorylation Ser1381 KLSRRSIsSPNVNRL 9534 BTO:0000298 20194617 YES miannu We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410. 0.416 SIGNOR-262955 ADAM17 protein P78536 UNIPROT EREG protein O14944 UNIPROT up-regulates activity cleavage 9606 26284334 YES miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF 0.563 SIGNOR-259843 LMP2 protein P13285 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR down-regulates quantity by destabilization 9606 19718044 NO scontino The EBV-encoded Latent Membrane Proteins, LMP2A and LMP2B, Limit the Actions of Interferon by Targeting Interferon Receptors for Degradation. LMP2A and LMP2B increase the turnover and degradation of IFNAR1 and IFNGR1. LMP2A and LMP2B reduce the half-life of IFNAR1 and IFNGR1. 0.2 SIGNOR-266825 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr100 TNTYYLQtFGHNTMD 9606 BTO:0000007 21321328 YES miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). 0.503 SIGNOR-276311 CDC34 protein P49427 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR up-regulates activity binding 9606 25425648 YES miannu The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. 0.768 SIGNOR-277334 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 12817019 YES lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. 0.804 SIGNOR-102511 ADORA2B protein P29275 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.275 SIGNOR-257414 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna 0.428 SIGNOR-171034 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr120 QFDAAHPtNVQRLAE 9606 BTO:0001130 19141652 YES lperfetto This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity. 0.388 SIGNOR-183388 MRPL27 protein Q9P0M9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.707 SIGNOR-262368 arginine smallmolecule CHEBI:29016 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 NO Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. 0.8 SIGNOR-268013 CCL5 protein P13501 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 9606 BTO:0000584 38339310 YES miannu CCL5, also known RANTES (regulated on activation, normal T cell expressed and secreted), is a potent chemoattractant for a variety of leukocytes, including T cells, mono- cytes, NK cells, and basophils, signaling via the CCR1, CCR3, and CCR5 cell surface receptors [59]. Among these receptors, CCL5 has the highest affinity for CCR5. 0.937 SIGNOR-277726 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.737 SIGNOR-248653 HIC1 protein Q14526 UNIPROT MYC protein P01106 UNIPROT down-regulates activity transcriptional regulation 9606 BTO:0000815 24067369 NO miannu HIC1 suppressing the VEGF and c-Myc promoter activity and the colony formation of MDA-MB 231 cells were STAT3-dependent. 0.324 SIGNOR-254245 COLGALT1 protein Q8NBJ5 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates activity glycosylation -1 19075007 YES Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. 0.427 SIGNOR-261153 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10116 BTO:0000575 15738637 YES In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. 0.286 SIGNOR-248444 SAMM50 protein Q9Y512 UNIPROT SAM complex complex SIGNOR-C422 SIGNOR form complex binding 31387448 YES lperfetto The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. 0.806 SIGNOR-267683 PRKCA protein P17252 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 YES llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. 0.2 SIGNOR-97279 KIT protein P10721 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 17949810 YES miannu These results suggest that active KIT can directly phosphorylate tyrosine residues of beta-catenin. 0.393 SIGNOR-278361 PAK4 protein O96013 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 BTO:0001130 20406887 YES llicata We find that pak4 is localised at focal adhesions, is immunoprecipitated with paxillin and phosphorylates paxillin on serine 272. 0.54 SIGNOR-164889 SRC protein P12931 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr679 DRPKDEVySKYYTPV 9606 12621061 YES llicata Stat5 is activated by a broad spectrum of cytokines, as well as non-receptor tyrosine kinases, such as src. these conformational differences may in part be due to differential effects of prl and src on stat5b tyrosine phosphorylation, since src induced several additional sites of tyrosine phosphorylation of stat5b at residues other than tyr-699, including tyr-724 and tyr-679. 0.579 SIGNOR-99002 MTA1 protein Q13330 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000812 18719363 NO miannu MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. 0.496 SIGNOR-254596 LAMA4 protein Q16363 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR form complex binding 10809728 YES lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 0.523 SIGNOR-253226 SSTR1 protein P30872 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.522 SIGNOR-256679 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Ser281 NRRQLAFsTVGTPDY 9606 12493777 YES lperfetto We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo 0.2 SIGNOR-96679 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.2 SIGNOR-250556 MYO9A protein B2RTY4 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.563 SIGNOR-260508 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 YES lperfetto Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation. 0.412 SIGNOR-247324 LPAR1 protein Q92633 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256975 POLR1G protein O15446 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.2 SIGNOR-266155 CDKN1A protein P38936 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000222 9388774 NO gcesareni The upregulation of the cyclin-dependent kinase inhibitor p21 and the dephosphorylation of retinoblastoma protein (pRb) appear to be critical regulatory events for the establishment ,,, the postmitotic ... states [in myoblasts differentiating into mature myotubes] 0.7 SIGNOR-241956 RXRA protein P19793 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 YES lperfetto We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active. 0.694 SIGNOR-123091 glucocorticoid smallmolecule CHEBI:24261 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity binding 9606 18049904 YES miannu Glucocorticoid action in cells is mediated by a specific receptor protein, the glucocorticoid receptor (GR). GR is a member of a superfamily of ligand-inducible transcription factors that control a variety of physiological functions; such as, metabolism, development, and reproduction. 0.8 SIGNOR-268048 AMER1 protein Q5JTC6 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21304492 YES lperfetto Knockdown of Amer1 reduces Wnt-induced LRP6 phosphorylation, Axin translocation to the plasma membrane and formation of LRP6 signalosomesThe generation of PtdIns(4,5)P2 in regions of receptor activity triggers the recruitment of Amer1 proteins, which in turn promote LRP6 phosphorylation by recruiting Axin/GSK3_ and CK1gamma to LRP6. 0.476 SIGNOR-24265 SEMA3A protein Q14563 UNIPROT PLXNA4 protein Q9HCM2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 YES miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  0.762 SIGNOR-261811 S100A9 protein P06702 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 9606 BTO:0001545 28137827 YES miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33 0.347 SIGNOR-261920 GRIPAP1 protein Q4V328 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity binding 9606 BTO:0002181 17761173 YES Giulio We investigated signal transduction pathways that might lie downstream of GRASP-1 and found that GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1. 0.312 SIGNOR-260607 KAT2B protein Q92831 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 YES gcesareni The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis. 0.572 SIGNOR-84032 GSK3B protein P49841 UNIPROT AURKA protein O14965 UNIPROT down-regulates quantity by destabilization phosphorylation Ser283 GWSVHAPsSRRTTLC 9606 38442201 YES miannu EEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3β, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. 0.558 SIGNOR-277919 PRKCE protein Q02156 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates phosphorylation Ser782 PLEQYSPsYPDTRSS 9606 BTO:0000938 23564461 YES lperfetto Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation 0.2 SIGNOR-201675 LRFN5 protein Q96NI6 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 NO miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. 0.7 SIGNOR-264098 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. 0.382 SIGNOR-216805 MRGPRX1 protein Q96LB2 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257326 Calcineurin complex SIGNOR-C155 SIGNOR BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 YES Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 0.434 SIGNOR-252332 SLITRK5 protein O94991 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 10090 BTO:0001593 34326333 YES miannu SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation. 0.2 SIGNOR-268438 SOX2 protein P48431 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19882665 NO miannu We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression. 0.48 SIGNOR-189036 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR MYH3 protein P11055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.449 SIGNOR-136647 CAMK2B protein Q13554 UNIPROT CAMK2B protein Q13554 UNIPROT up-regulates activity phosphorylation Thr287 SMMHRQEtVECLKKF 2842767 YES llicata Ca2+/calmodulin-dependent protein kinase II: identification of threonine-286 as the autophosphorylation site in the alpha subunit associated with the generation of Ca2+-independent activity. 0.2 SIGNOR-250640 3b protein P59633 UNIPROT AP1 complex SIGNOR-C154 SIGNOR up-regulates activity 9606 21561061 NO Luana SARS-CoV Accessory Protein 3b Induces AP-1 TranscriptionalActivity 0.2 SIGNOR-260757 FBXO25 protein Q8TCJ0 UNIPROT HAX1 protein O00165 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 25419709 YES lperfetto FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. 0.331 SIGNOR-275563 FBXW7 protein Q969H0 UNIPROT PSEN1 protein P49768 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 12354302 YES miannu SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. These observations suggest that SEL-10 mediated ubiquitination of PS1-CTF and PS1-NTF leads to their degradation. 0.494 SIGNOR-272600 MED8 protein Q96G25 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.8 SIGNOR-266659 SIRT7 protein Q9NRC8 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity deacetylation Lys37 APATGGVkKPHRYRP 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275880 SIN3A protein Q96ST3 UNIPROT MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR form complex binding 9606 BTO:0000567 9620804 YES Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. 0.831 SIGNOR-267737 FBXL3 protein Q9UKT7 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 17463251 YES miannu  We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex. This regulation by SCF(Fbxl3) is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. HEK293T cells were transfected with Cry2, Skp1, Cul1, and Roc1 in the absence or presence of either FLAG-tagged Fbxl3 or a FLAG-tagged Fbxl3(ΔF-box) mutant. Fbxl3, but not an inactive Fbxl3(ΔF-box) mutant (4), induced the ubiquitination of Cry2 (Fig. 2D), which supports the notion that the effect of Fbxl3 on Cry2 is direct. 0.676 SIGNOR-271649 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 YES lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  0.342 SIGNOR-249074 KAT2A protein Q92830 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269601 MAPK1 protein P28482 UNIPROT RORA protein P35398 UNIPROT down-regulates phosphorylation Thr183 PGEAEPLtPTYNISA 9606 17512500 YES The effect has been demonstrated using P35398-4 gcesareni We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity 0.26 SIGNOR-154914 PTGER3 protein P43115 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 9606 BTO:0000018 15331179 YES Marta Tosoni These results clearly demonstrate that EP3 contributes to the activation of Src and its related cell growth in A549 cells treated with PGE2. 0.317 SIGNOR-278885 TP53BP2 protein Q13625 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 11839776 YES gcesareni 53bp2 interacts with the tumour suppressor p53 and enhances p53-mediated activation of transcription, possibly by facilitating the dephosphorylation of one or more sites on p53 0.898 SIGNOR-114762 hsa-miR-491-5p mirna URS00001919B0_9606 RNAcentral EGFR protein P00533 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002575 25299770 YES MiR-491-5p induces an important decrease of EGFR protein level in IGROV1-R10 cells and diminishes activation of both AKT and MAPK pathways 0.4 SIGNOR-277949 BIRC3 protein Q13489 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 18997794 YES lperfetto Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3. 0.892 SIGNOR-182131 YWHAH protein Q04917 UNIPROT KCNK18 protein Q7Z418 UNIPROT down-regulates activity binding -1 18397886 YES miannu Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. In the present study, we report that 14-3-3 proteins directly bind to the intracellular loop of TRESK and control the kinetics of the calcium-dependent regulation of the channel. Coexpression of 14-3-3η with TRESK blocked, whereas the coexpression of a dominant negative form of 14-3-3η accelerated the return of the K+ current to the resting state after the activation mediated by calcineurin in Xenopus oocytes. 0.309 SIGNOR-263155 AP1B1 protein Q10567 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 YES lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) 0.821 SIGNOR-260685 ALDH9A1 protein P49189 UNIPROT 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI down-regulates quantity chemical modification 9606 11802770 YES miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 0.8 SIGNOR-269692 NANOG protein Q9H9S0 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 NO miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 0.333 SIGNOR-254622 CSNK2A2 protein P19784 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser13 GFFSSSEsGAPEAAE -1 3128543 YES llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. 0.309 SIGNOR-250984 gemtuzumab ozogamicin antibody DB00056 DRUGBANK CD33 protein P20138 UNIPROT down-regulates activity binding 9606 BTO:0001545 11410481 YES miannu Gemtuzumab ozogamicin (Mylotarg; Wyeth Laboratories, Philadelphia, PA) consists of a semisynthetic derivative of calicheamicin, a cytotoxic antibiotic linked to a recombinant monoclonal antibody directed against the CD33 antigen present on leukemic myeloblasts in most patients with acute myeloid leukemia (AML). 0.4 SIGNOR-259892 RPL4 protein P36578 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.863 SIGNOR-262460 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120208 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser345 RPASVDGsPVSPSTN -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251295 LMP1 protein P03230 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 9606 26428373 NO scontino Activation of the PI3-K/AKT pathway was first linked to LMP1 in the year 2003. Although it is still unclear whether this interaction is direct, expression of LMP1 CTAR1 caused (i) an enrichment of the PI3-K substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3) in the plasma membrane and (ii) the phosphorylation and activation of AKT kinase, also known as protein kinase B, at serine 473. 0.2 SIGNOR-267618 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 12383858 YES gcesareni Here we show that the oncogenic and cell cycle-regulatory protein kinase, polo-like kinase-1 (plk1), phosphorylates mdm2 at one of these residues, ser260, and stimulates mdm2-mediated turnover of p53. These data are consistent with the idea that deregulation of plk1 during tumourigenesis may help suppress p53 function. 0.466 SIGNOR-94272 MAP3K7 protein O43318 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates phosphorylation Ser406 TRLRRTEsVPSDINN 9606 11741534 YES gcesareni C-tak1 constitutively associates with mammalian ksr1 and phosphorylates serine 392 to confer 14-3-3 binding and cytoplasmic sequestration of ksr1 in unstimulated cells. In response to signal activation, the phosphorylation state of s392 is reduced, allowing the ksr1 complex to colocalize with activated ras and raf-1 at the plasma membrane 0.2 SIGNOR-112779 HRH3 protein Q9Y5N1 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.261 SIGNOR-256968 CTSG protein P08311 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 YES miannu Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen. 0.642 SIGNOR-256312 KMT2E protein Q8IZD2 UNIPROT RARA protein P10276 UNIPROT up-regulates activity binding 9606 21205756 YES miannu MLL5 binds to retinoic acid receptor α (RARα) and induces transcriptional activation of RARα target genes by methylation of lysine residues of histone H3. 0.334 SIGNOR-260041 IFNL3 protein Q8IZI9 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 YES gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. 0.849 SIGNOR-96243 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH17 protein Q12864 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265834 JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 YES apalma The GM-CSF receptor does not have intrinsic tyrosine kinase activity, but associates with the tyrosine kinase Jak2 that is required for Œ≤c transphosphorylation and the initiation of signaling and biological activity 0.584 SIGNOR-255584 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001103 20219869 YES apalma Furthermore, NF-kB activation can cause destabilization of MyoD mRNA and degradation of MyoD protein (35, 49), which would further impede muscle differentiation 0.28 SIGNOR-255352 belinostat chemical CHEBI:61076 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257958 Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR BRCA2 protein P51587 UNIPROT up-regulates 18985065 NO lperfetto Once monoubiquitinated, the ID complex becomes associated with chromatin and is redistributed to DNA-damage sites, forming foci that are visible by immunofluorescence and colocalizing with other DNA-repair molecules, notably BRCA1, BRCA2 and γH2AX. 0.79 SIGNOR-263270 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0000938 12040039 YES gcesareni Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun. 0.884 SIGNOR-88208 PTEN protein P60484 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 NO miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 0.2 SIGNOR-260055 ERBB2 protein P04626 UNIPROT BBC3 protein Q9BXH1 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr152 ADDLNAQyERRRQEE 9606 BTO:0000093 24236056 YES miannu HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. 0.281 SIGNOR-276472 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates dephosphorylation Tyr490 HCAAWHGyYSVAKAL 9606 17803936 YES gcesareni Here, we show that the leukocyte common antigen-related (lar) tyrosine phosphatase dephosphorylates dapk at py491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of dapk. 0.2 SIGNOR-157702 2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide chemical CHEBI:91367 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258181 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9576626 YES tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity 0.817 SIGNOR-56904 CDCA8 protein Q53HL2 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 YES miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). 0.856 SIGNOR-275423 MTA1 protein Q13330 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000812 18719363 NO miannu MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. 0.413 SIGNOR-254594 MN1 protein Q10571 UNIPROT MYBBP1A protein Q9BQG0 UNIPROT up-regulates activity binding -1 12569362 YES irozzo Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300. 0.2 SIGNOR-256021 RAB6A protein P20340 UNIPROT VPS13B protein Q7Z7G8 UNIPROT down-regulates activity binding 9606 BTO:0000007 25492866 YES miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues 0.372 SIGNOR-269203 CBX3 protein Q13185 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-264495 TNFRSF11A protein Q9Y6Q6 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 17572386 NO miannu Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation 0.7 SIGNOR-253043 ANKRD11 protein Q6UB99 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 YES miannu Ankrd11 knockdown decreases the levels of bdnf and Trkb mRNAs. Next, we examine whether ANKRD11 accesses the Trkb promoter in cortical neurons. We performed the chromatin immunoprecipitation assay (ChIP) using an ANKRD11 antibody followed by PCR to amplify the Trkb promoter region. We found that ANKRD11 binds to the Trkb promoter (Fig. 6E). As expected, the level of ANKRD11 binding was decreased in the Ankrd11 knockdown condition. 0.2 SIGNOR-266731 RXRB protein P28702 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 YES gcesareni Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site 0.274 SIGNOR-79449 Deltorphin B chemical CHEBI:81498 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258785 CSNK1E protein P49674 UNIPROT APC protein P25054 UNIPROT up-regulates activity phosphorylation Ser1392 SRCTSVSsLDSFESR 9606 BTO:0000038 11487578 YES lperfetto Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin. 0.613 SIGNOR-109664 IKBKE protein Q14164 UNIPROT IRF1 protein P10914 UNIPROT down-regulates activity phosphorylation Ser215 DLYNFQVsPMPSTSE 9606 BTO:0000007 24396068 YES miannu We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.  0.35 SIGNOR-276480 APBA2 protein Q99767 UNIPROT STXBP1 protein P61764 UNIPROT up-regulates activity binding 10116 BTO:0000142 9395480 YES miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. 0.7 SIGNOR-264037 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 YES lperfetto In endothelial cells, tumor necrosis factor alpha (tnf-alpha) induces dephosphorylation and subsequent ubiquitin-dependent degradation of the antiapoptotic protein bcl-2. Here, we investigate the role of different putative phosphorylation sites to facilitate bcl-2 degradation 0.551 SIGNOR-74927 RUNX3 protein Q13761 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255097 MTOR protein P42345 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.9 SIGNOR-205615 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120220 WNT6 protein Q9Y6F9 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.58 SIGNOR-131894 JNJ-28312141 free base chemical CID:11676971 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258228 E2F1 protein Q01094 UNIPROT USP37 protein Q86T82 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21596315 YES lperfetto USP37 was induced by E2F transcription factors in G1|Ectopic E2F1 activated the wild-type promoter, but not the mutant promoter, 3-fold over basal levels in 293T cells (Figure 4F), confirming the functionality of the E2F binding sites in the USP37 promoter. 0.2 SIGNOR-265047 MAPK3 protein P27361 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 8381049 YES gcesareni Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane. 0.657 SIGNOR-38434 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 YES lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. 0.2 SIGNOR-244501 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.2 SIGNOR-251460 CDK2 protein P24941 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser286 TSGGVSEsPSGFSKH 9606 21765472 YES lperfetto Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency 0.553 SIGNOR-175079 CDK1 protein P06493 UNIPROT PRPS1 protein P60891 UNIPROT up-regulates activity phosphorylation Ser103 RQDKKDKsRAPISAK 31253668 YES lperfetto CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103|In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation 0.255 SIGNOR-265728 alanine smallmolecule CHEBI:16449 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264746 ITCH protein Q96J02 UNIPROT JUNB protein P17275 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001045 11828324 YES miannu Itch promotes Ub conjugation to JunB Molecularly, Itch associated with and induced ubiquitination of JunB, a transcription factor that is involved in TH2 differentiation. However, in Itch−/− T cells under the same conditions, degradation of JunB was markedly delayed. 0.409 SIGNOR-272619 RINT1 protein Q6NUQ1 UNIPROT Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR down-regulates 9606 BTO:0004784 16600870 NO lperfetto We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.  0.7 SIGNOR-265031 PCSK5 protein Q92824 UNIPROT OXT protein P01178 UNIPROT down-regulates quantity cleavage 9606 BTO:0001073 11690596 YES miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. 0.248 SIGNOR-270327 Ub:E2 complex SIGNOR-C497 SIGNOR RNF24 protein Q9Y225 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271236 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.305 SIGNOR-249007 INS protein P01308 UNIPROT GATA2 protein P23769 UNIPROT down-regulates 9606 BTO:0000876 15837948 NO fspada We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity 0.315 SIGNOR-135617 MYC protein P01106 UNIPROT PRODH protein O43272 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22615405 NO miannu MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. 0.2 SIGNOR-254608 PRKCD protein Q05655 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser12 KSKPKDAsQRRRSLE 9606 BTO:0001938 18069897 YES gcesareni We conclude that treatment with either UV or PMA induces the phosphorylation of the PKC site Ser12 on c-SRC and that this specific phosphorylation event is significantly diminished in cells overexpressing PR55 0.601 SIGNOR-247974 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr405 VGGSGIGtPPSVLKR BTO:0000007 10593981 YES llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 0.718 SIGNOR-250737 PARP1 protein P09874 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 NO amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process 0.7 SIGNOR-111680 TACR2 protein P21452 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.461 SIGNOR-257015 RARA protein P10276 UNIPROT CCNA1 protein P78396 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002136 11090075 YES miannu RARα is involved in the regulation of cyclin A1. Further studies using ligands selective for various retinoic acid receptors suggested that cyclin A1 expression is negatively regulated by activated RARα. 0.244 SIGNOR-249636 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser396 RPWTRGGsLERSQSR 9534 BTO:0000298 9353340 YES lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  0.391 SIGNOR-248985 DYRK2 protein Q92630 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates activity phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 25603354 YES miannu DYRK2 mediated Snail degradation protects against tumor cell metastasis.|DYRK2 phosphorylation of Snail at Ser104 triggers sequential phosphorylation by GSK3. 0.346 SIGNOR-279328 CDK1 protein P06493 UNIPROT TEX14 protein Q8IWB6 UNIPROT up-regulates activity phosphorylation 9606 22405274 YES miannu Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction.|While, mutation of individual PBDs in Tex14 partially reduces Cdk1 dependent phosphorylation levels and inhibits the ability of Tex14 to interact with Plk1 and to localize to KTs, mutation of all identified PBDs has a much more significant impact on binding. 0.334 SIGNOR-279677 SNAI1 protein O95863 UNIPROT CLDN7 protein O95471 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 19277896 NO lperfetto We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling 0.406 SIGNOR-254104 ITGAV protein P06756 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.869 SIGNOR-253209 olanzapine chemical CHEBI:7735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 BTO:0000601 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258509 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK6 protein Q00534 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192470 APC-c complex SIGNOR-C150 SIGNOR REV1 protein Q9UBZ9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23287467 YES miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. 0.337 SIGNOR-272894 HOXD12 protein P35452 UNIPROT MAF protein O75444 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.368 SIGNOR-221887 PPARGC1A protein Q9UBK2 UNIPROT CYCS protein P99999 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000443 23021218 NO lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 0.381 SIGNOR-253097 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Thr731 FEPSPYPtTSSLEDF 9606 BTO:0000567 34198826 YES miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. 0.25 SIGNOR-276665 GNAQ protein P50148 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates activity binding -1 17606614 YES We show that the C-terminal Rho-specific DH-PH cassette of Trio is similarly activated by Galpha(q) 0.2 SIGNOR-256494 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16287866 YES lperfetto Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. 0.419 SIGNOR-216876 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 YES lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1. 0.936 SIGNOR-105860 NUP153 protein P49790 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.737 SIGNOR-262069 JQ1 chemical CHEBI:137113 ChEBI BRDT protein Q58F21 UNIPROT down-regulates activity chemical inhibition -1 20871596 YES lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. 0.8 SIGNOR-261990 REST protein Q13127 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 17453016 NO NRSF represses neuronal differentiation by binding to conserved NRS elements (NRSEs) in gene promoters in non-neuronal cells, where it associates with one of several large repressor complexes, including the transcriptional co-repressor mSIN3a/b, nuclear receptor co-repressor 1 (N-CoR1), and coREST/histone deacetylase 2 (HDAC2). In this way, NRSF keeps neural-specific genes turned off in non-neuronal cells. 0.7 SIGNOR-268622 KIF20B protein Q96Q89 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272528 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 15209375 YES gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.608 SIGNOR-126076 STT3B protein Q8TCJ2 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization glycosylation 9606 BTO:0001939 29765039 YES Barakat Together, these results support a notion that the two STT3 isoforms regulate EMT-mediated PD-L1 induction through PD-L1 protein N-glycosylation and stabilization. 0.2 SIGNOR-274976 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21193018 YES lperfetto Activated NICD-RBP-Jk complex displaces co-repressors and recruits coactivator (co-A) mediating the transcription of target genes such as Hes-1 (hairy enhancer of split), cyclin D, Hey-1 (hairy/enhancer-of-split related with YRPW motif) and others [1213]. 0.715 SIGNOR-170854 AXIN1 protein O15169 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates binding 9606 SIGNOR-C110 12000790 YES gcesareni Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45). 0.554 SIGNOR-87401 CDK2 protein P24941 UNIPROT LIG3 protein P49916 UNIPROT down-regulates phosphorylation Ser210 TTTGQVTsPVKGASF 9606 17040896 YES llicata Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm. 0.419 SIGNOR-150121 SAG protein P10523 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 25216516 YES miannu Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.  0.413 SIGNOR-272844 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.91 SIGNOR-252849 EEF1A1 protein P68104 UNIPROT Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269507 SNRPA1 protein P09661 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.773 SIGNOR-270655 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 14699954 YES amattioni Neurotrophin binding to p75ntrhas also been shown to induce apoptosis 0.835 SIGNOR-120555 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity phosphorylation Tyr421 RLPSSPVyEDAASFK -1 15169891 YES lperfetto Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP. 0.801 SIGNOR-246513 BCOR protein Q6W2J9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0004850 26847029 NO irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. 0.7 SIGNOR-256011 PRKACA protein P17612 UNIPROT CLDN3 protein O15551 UNIPROT unknown phosphorylation Thr192 PPREKKYtATKVVYS 9606 15905176 YES llicata Our results suggest that claudin-3 phosphorylation by pka, a kinase frequently activated in ovarian cancer, may provide a mechanism for the disruption of tjs in this cancer. 0.307 SIGNOR-137291 metaproterenol chemical CHEBI:6792 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) 0.8 SIGNOR-257875 CIITA protein P33076 UNIPROT HLA-DPB1 protein P04440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 NO Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. 0.508 SIGNOR-254006 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 10747897 YES miannu We demonstrate that anisomycin- and tumor necrosis factor--induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase 0.772 SIGNOR-250114 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser235 SPQDSPPsKASPAQD 9606 21215781 YES lperfetto Cdk5 regulates app (amyloid precursor protein) processing and tau hyperphosphorylationtau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules 0.762 SIGNOR-171018 NRG1 protein Q02297 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 YES gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.903 SIGNOR-122053 KDM5B protein Q9UGL1 UNIPROT FOXG1 protein P55316 UNIPROT up-regulates activity binding 9606 BTO:0000007 12657635 YES miannu Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression 0.403 SIGNOR-223878 MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 8974401 YES lperfetto A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) 0.63 SIGNOR-45373 FANCM protein Q8IYD8 UNIPROT FANCF protein Q9NPI8 UNIPROT up-regulates binding 9606 20064461 YES gcesareni Protein interaction motifs in fancm, designated mm1 and mm2, were identified. Mm1 interacts with the fa core complex by binding to fancf, whereas mm2 interacts with rm1 and topoisomerase iiialpha, components of the bs complex. 0.932 SIGNOR-163101 MAPK3 protein P27361 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 YES gcesareni Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells. 0.481 SIGNOR-188172 3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)-9-phenanthrenyl]-1-propanol chemical CHEBI:94392 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition -1 19222165 YES Luana 4 inhibited cloned hERG potassium ion channel repolarization with an IC50 comparable to other antimalarial agents in this class (Table 6). 0.8 SIGNOR-257816 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 17609368 YES lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. 0.574 SIGNOR-156780 RPEL1 protein Q2QD12 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI down-regulates quantity chemical modification 9606 34775382 YES miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. 0.8 SIGNOR-267066 IL1B protein P01584 UNIPROT GDF5 protein P43026 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003742 19818765 NO Regulation miannu GDF-5 is suppressed by IL-1beta and enhances TGF-beta3-mediated chondrogenic differentiation in human rheumatoid fibroblast-like synoviocytes. 0.264 SIGNOR-251864 AKT1 protein P31749 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by destabilization phosphorylation Thr128 FIGEFAYtYAAMYDK 9606 BTO:0000007 31358653 YES miannu Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.  0.37 SIGNOR-276869 MMP1 protein P03956 UNIPROT COL1A2 protein P08123 UNIPROT down-regulates quantity by destabilization cleavage Gly775 NGPPGPAgSRGDGGP -1 17318226 YES lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  0.401 SIGNOR-272337 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser393 KTCQRKFsRSDHLKT 9606 9366517 YES llicata Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo. 0.341 SIGNOR-53176 BRCA1 protein P38398 UNIPROT CDC25C protein P30307 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23246971 YES miannu BRCA1 mediates cyclin B and Cdc25C ubiquitination.|Thus, BRCA1 dependent proteasomal degradation of cyclin B and Cdc25C precede the subsequent BRCA1 dependent cell cycle arrest. 0.465 SIGNOR-278623 GNB/GNG complex SIGNOR-C202 SIGNOR CACNA1B protein Q00975 UNIPROT down-regulates activity binding 9606 BTO:0000938 20655485 YES miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. 0.413 SIGNOR-265067 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 0.2 SIGNOR-233564 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr101 EGLSMGNyIGLINRI 9606 BTO:0001282 16373505 YES PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation. 0.2 SIGNOR-251112 CASP3 protein P42574 UNIPROT SPTAN1 protein Q13813 UNIPROT down-regulates cleavage 9606 BTO:0000150;BTO:0000567 9624143 YES amattioni Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. 0.674 SIGNOR-57891 MARK2 protein Q7KZI7 UNIPROT RAB11FIP1 protein Q6WKZ4 UNIPROT up-regulates quantity phosphorylation Ser234 QKTPLSQsMSVLPTS -1 28396819 YES done miannu We have now found that MARK2 phosphorylates Rab11-FIP1B/C at serine 234 in a consensus site similar to that previously identified in Rab11-FIP2. 0.341 SIGNOR-273676 MAPK12 protein P53778 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity phosphorylation Ser200 YSGDSDAsSPRSNCS 10090 BTO:0005930 20026657 YES miannu  We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity.  0.444 SIGNOR-276274 NFIL3 protein Q16649 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003104 10082541 NO lperfetto NFIL3 inhibits apoptosis without affecting Bcl-xL expression. 0.7 SIGNOR-256618 IKBKB protein O14920 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates phosphorylation Ser8 MEPAAGSsMEPSADW 9606 20152798 YES lperfetto Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity 0.397 SIGNOR-163801 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.2 SIGNOR-134624 GSK3B protein P49841 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization phosphorylation 7227 11955435 YES lperfetto We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog. 0.535 SIGNOR-219231 LNX1 protein Q8TBB1 UNIPROT CLDN17 protein P56750 UNIPROT down-regulates quantity by destabilization ubiquitination -1 22889411 YES miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. 0.294 SIGNOR-272900 KCNC4 protein Q03721 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 YES miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height 0.8 SIGNOR-265588 CHRNA7 protein P36544 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 27167578 YES Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth. 0.2 SIGNOR-253985 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Arg) smallmolecule CHEBI:29171 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270363 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Ala369 DYAPVIPaNMDKKYR -1 9242537 YES lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity. 0.367 SIGNOR-263635 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr199 AFLASPEyVNLPING 9606 BTO:0000150 19254954 YES llicata Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly, 0.438 SIGNOR-184379 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 YES lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins 0.823 SIGNOR-52863 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT up-regulates activity phosphorylation Tyr498 YAFSSNIyTRGSHLD 9606 BTO:0000007 27738316 YES miannu Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. 0.358 SIGNOR-263189 (S)-duloxetine chemical CHEBI:36795 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition -1 18387300 YES Luana Selective inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake (SNRI) has been shown to be an attractive dual pharmacology approach for the treatment of a number of diseases.1,2 For example, dual 5- HT/NA reuptake inhibitor duloxetine (1) has shown clinical efficacy in the treatment of depression, pain, and urinary incontinence. 0.8 SIGNOR-257775 PPP1CA protein P62136 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity dephosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16888006 YES ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr(125) dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1alpha (PP1alpha) associates with phosphorylated caspase-9. 0.2 SIGNOR-248565 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT down-regulates activity phosphorylation Ser1406 GAGGRRLsSFVTKGY 11986331 YES miannu CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation. 0.307 SIGNOR-250344 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MED1 protein Q15648 UNIPROT up-regulates phosphorylation 9606 12356758 YES inferred from 70% family members lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase 0.2 SIGNOR-270199 CLK4 protein Q9HAZ1 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation -1 8617202 YES miannu In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors. 0.357 SIGNOR-273860 A6/b4 integrin complex SIGNOR-C174 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269023 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser120 GRNIIHGsDSVESAE -1 8810265 YES miannu For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. 0.2 SIGNOR-250300 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270430 CDC25A protein P30304 UNIPROT PKM protein P14618 UNIPROT up-regulates activity dephosphorylation Ser37 MCRLDIDsPPITARN 9606 27485204 YES lperfetto Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.|Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent \u03b2-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop. 0.487 SIGNOR-276967 ATAT1 protein Q5SQI0 UNIPROT TUBA1C protein Q9BQE3 UNIPROT up-regulates quantity by stabilization acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 YES lperfetto Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules 0.246 SIGNOR-272247 E2F1 protein Q01094 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 8649818 NO lperfetto We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB. 0.569 SIGNOR-245471 SMARCC1 protein Q92922 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.831 SIGNOR-270696 PRKCE protein Q02156 UNIPROT SLC4A3 protein P48751 UNIPROT up-regulates activity phosphorylation Ser67 EKPSRSYsERDFEFH 9606 BTO:0000007 11739292 YES lperfetto We conclude that following Ang II stimulation of cells, PKCepsilon phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium. 0.31 SIGNOR-249127 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-70440 Class I MHC:Antigen complex SIGNOR-C426 SIGNOR Cytotoxic_T-lymphocyte_activation phenotype SIGNOR-PH195 SIGNOR up-regulates 9606 31810556 NO scontino High-affinity peptide/MHC class I complexes that successfully pass the aforementioned “quality controls” will be transported through the Golgi apparatus to the cell membrane to elicit antigen-specific CD8+ T cell responses. 0.7 SIGNOR-267875 FYN protein P06241 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.574 SIGNOR-249340 CDKN2AIP protein Q9NXV6 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 16803988 YES miannu In the nucleoplasm, carf interacts with p53 and enhances its function. 0.383 SIGNOR-147360 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR ID2 protein Q02363 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 NO Also comparable with ID1, RARα, RXR, PML, PLZF-RARα, and RARα/RXR did not transactivate the ID2 promoter, whereas PML-RARα did. Together, these data show that like ID1, ID2 may also be transactivated by PML-RARα without direct DNA binding of the fusion protein. 0.2 SIGNOR-255727 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2C protein O00762 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.613 SIGNOR-271356 PRKDC protein P78527 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation 9606 9109492 YES miannu We show that DNA-PK phosphorylates and activates c-Abl in vitro. 0.514 SIGNOR-279268 PYG proteinfamily SIGNOR-PF96 SIGNOR glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267953 NGF protein P01138 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 YES gcesareni Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb. 0.955 SIGNOR-85114 GTF2F2 protein P13984 UNIPROT POLR2E protein P19388 UNIPROT up-regulates activity binding 9534 11278533 YES miannu Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30. 0.921 SIGNOR-261179 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser428 EPAPVLSsPPPADVS 9606 15037602 YES lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain. 0.468 SIGNOR-216781 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001616 16670084 YES gcesareni Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein. 0.489 SIGNOR-245336 POLR1C protein O15160 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.881 SIGNOR-266136 SPI1 protein P17947 UNIPROT ANXA1 protein P04083 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19428102 NO miannu Identification of annexin 1 as a PU.1 target gene in leukemia cells. PU.1 is a master regulator, and critical for the developmen tof a common progenitor for lymphoid-myeloid cell lineages in the hematopoietic system. From microarray analysis, we found that several genes including annexin 1 were markedly induced in K562PU.1KD cells. Annexin 1 is a calcium- and phospholipid-binding protein and increased expression leads to the constitutive activation of extracellular signal-regulated kinase (ERK) 0.2 SIGNOR-261688 SLC9A3R1 protein O14745 UNIPROT ADRB2 protein P07550 UNIPROT up-regulates activity binding -1 9671706 YES lperfetto The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor. 0.597 SIGNOR-262598 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 NO gcesareni GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin 0.575 SIGNOR-188869 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT up-regulates activity phosphorylation Tyr144 MVPDEVEyLLKKVLS 9606 BTO:0000661 18976935 YES lperfetto Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation. 0.501 SIGNOR-253368 DYRK1A protein Q13627 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000938 20696760 YES gcesareni Dyrk1a phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. we found that dyrk1a phosphorylates p53 at ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor h19-7 cells. In addition, dyrk1a-induced p53 phosphorylation at ser-15 led to a robust induction of p53 target genes 0.418 SIGNOR-167407 DRAM2 protein Q6UX65 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 NO irozzo DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. 0.306 SIGNOR-259146 MAPK3 protein P27361 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 BTO:0000007 10574913 YES gcesareni Erk1 phosphorylates grk2 at ser(670). Inhibition of erk activity in hek293 cells potentiates grk2 activity, whereas, conversely, erk activation inhibits grk2 activity. 0.2 SIGNOR-72582 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser251 MIQFAINsTERKRMT 9606 19737929 YES lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1the phosphorylation at ser-251 is critical for the activation of foxm1. 0.762 SIGNOR-216833 (~{s})-(4-Fluoranyl-2-Propyl-Phenyl)-(1~{h}-Imidazol-2-Yl)methanol chemical CID:126961334 PUBCHEM F2RL1 protein P55085 UNIPROT down-regulates activity chemical inhibition -1 28445455 YES Simone Vumbaca The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. 0.8 SIGNOR-261118 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-70432 HIPK2 protein Q9H2X6 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser8 MEPAPARsPRPQQDP 9606 19015637 YES llicata In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death. 0.439 SIGNOR-182432 SNRPE protein P62304 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.728 SIGNOR-270657 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM40 protein Q6P9F5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271170 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271805 Ub:E2 complex SIGNOR-C497 SIGNOR RNF185 protein Q96GF1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271213 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 9677429 YES MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. gcesareni The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. 0.752 SIGNOR-59153 CD300LB protein A8K4G0 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9534 BTO:0004055 20959446 YES lperfetto The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2. 0.463 SIGNOR-264833 PLK1 protein P53350 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity phosphorylation Thr7 tAEQLAQI 9606 BTO:0000567 38355643 YES miannu PLK1 phosphorylates RhoGDI1 at Thr7/91 residue in vitro and in vivo. Collectively, we demonstrate that the phosphorylation of RhoGDI1 by PLK1 promotes cancer cell migration and invasion through RhoA activation. 0.2 SIGNOR-277883 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000165 10066785 YES lperfetto Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis 0.416 SIGNOR-219359 ERCC2 protein P18074 UNIPROT ERCC3 protein P19447 UNIPROT up-regulates binding 9606 10024882 YES miannu Xpd helps xpb in promoter opening and as such participates in the transcription reaction. 0.955 SIGNOR-64672 ZAP70 protein P43403 UNIPROT SH2B3 protein Q9UQQ2 UNIPROT up-regulates phosphorylation Tyr273 LEMPDNLyTFVLKVK 9606 BTO:0000782 9169414 YES lperfetto In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation. 0.364 SIGNOR-48854 PIN1 protein Q13526 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 19151708 YES gcesareni Prolyl-isomerase pin1 interacts with notch1 and affects notch1 activation. Pin1 potentiates notch1 cleavage by gamma-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing notch1. pin1 potentiates notch1 cleavage by gamma-secretase 0.385 SIGNOR-183461 decanoic acid chemical CHEBI:30813 ChEBI GPR84 protein Q9NQS5 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257508 TFPI protein P10646 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 YES gcesareni Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi 0.257 SIGNOR-106353 PLCD4 protein Q9BRC7 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 9125218 YES gcesareni A key pathway is the hydrolysis of PIP2 . This is mediated by PLC, and yields the two second messengers 1,4,5-IP3 and DAG 0.8 SIGNOR-195516 PKD1 protein P98161 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT up-regulates activity binding 9606 BTO:0000007 23001567 YES miannu Full-length PC1 bound, stabilized and colocalized with Jade-1 and inhibited Jade-1 ubiquitination. Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1. 0.333 SIGNOR-272916 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269357 FOXJ1 protein Q92949 UNIPROT DNAI1 protein Q9UI46 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.368 SIGNOR-266932 NR4A1 protein P22736 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 NO gcesareni Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b. 0.324 SIGNOR-132312 COL21A1 protein Q96P44 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 YES lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  0.2 SIGNOR-272343 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 18570871 YES gcesareni Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex. 0.581 SIGNOR-179096 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273105 Cytosolic DNA stimulus SIGNOR-ST30 SIGNOR POLR3A protein O14802 UNIPROT up-regulates 9606 BTO:0000007 19631370 YES miannu These results suggest that RNA Pol-III is a cytosolic DNA sensor involved in innate immune responses. Here we show that the cytosolic poly(dA-dT) DNA is converted into 5′-ppp RNA to induce IFN-β through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5′-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-β induction by transfection of DNA or infection with DNA viruses. 0.7 SIGNOR-265564 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BAD protein Q92934 UNIPROT down-regulates binding 9606 10949026 YES gcesareni 14-3-3 blocks bad activity by promoting ser-155 phosphorylation, which induces the dissociation of bad and bcl-xl. in the presence of survival factor il-3, cells phosphorylated bad on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated bad heterodimerized with bcl-x(l) at membrane sites to promote cell death. 0.2 SIGNOR-81106 SIRT5 protein Q9NXA8 UNIPROT HMGCS2 protein P54868 UNIPROT up-regulates activity post translational modification Lys310 PFCKMVQkSLARLMF 9606 BTO:0000007 24315375 YES desuccinylation lperfetto We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5 0.343 SIGNOR-267642 BAF250b E3 ligase complex SIGNOR-C522 SIGNOR Histone H2B proteinfamily SIGNOR-PF68 SIGNOR down-regulates activity ubiquitination 9606 BTO:0000567 20086098 YES miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro 0.2 SIGNOR-271441 FLT3 protein P36888 UNIPROT IDH1 protein O75874 UNIPROT up-regulates activity phosphorylation Tyr42 VELDLHSyDLGIENR -1 34289383 YES lperfetto Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity 0.424 SIGNOR-267629 GSK3B protein P49841 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates phosphorylation Ser556 AQKSEGKsLPSSPSS 9606 16174773 YES lperfetto Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1 0.487 SIGNOR-140609 BBOX1 protein O75936 UNIPROT carnitine smallmolecule CHEBI:17126 ChEBI up-regulates quantity chemical modification 9606 11802770 YES miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. 0.8 SIGNOR-269699 TNKS protein O95271 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 21478859 YES lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.2 SIGNOR-263383 AKT1 protein P31749 UNIPROT SYTL1 protein Q8IYJ3 UNIPROT down-regulates quantity phosphorylation Ser241 RMLSSSSsVSSLNSS 9606 BTO:0001321 15998322 YES miannu By mutagenesis analysis and subsequent immunoprecipitation (IP), we established that Akt phosphorylates JFC1 at serine 241. Phosphorylation did not alter the ability of JFC1 to bind to Rab27a. Instead, phosphorylation by Akt dramatically decreased when JFC1 was bound to Rab27a. Finally, we show that as a consequence of in vivo phosphorylation, JFC1 dissociates from the membrane, promoting JFC1 redistribution to the cytosol. 0.356 SIGNOR-273540 EIF4B protein P23588 UNIPROT EIF4A1 protein P60842 UNIPROT up-regulates activity binding -1 11418588 YES Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability 0.866 SIGNOR-261293 CDK1 protein P06493 UNIPROT KMT5A protein Q9NQR1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 YES miannu We found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. 0.2 SIGNOR-259832 RPS23 protein P62266 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.897 SIGNOR-262428 MITRAC complex complex SIGNOR-C538 SIGNOR Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR up-regulates quantity relocalization 23260140 YES Each association relies on the supply of subunits from either the cytosol or the mitochondrial matrix, suggesting that human TIM21 ushers nuclear-encoded proteins to assembly intermediates. In agreement with this, assembly of the early cytochrome c oxidase subunit COX4-1 requires TIM21, whereas it is dispensable for late-assembling subunits. The finding that TIM21 also interacts with complex I intermediates points to a more general role of TIM21 in respiratory-chain assembly. Furthermore, TIM21 appears to be tightly connected to MITRAC15, which, in contrast to TIM23 and MITRAC12, coimmunoprecipitates with TIM21 under all tested conditions. MITRAC15 associates with MITRAC and is required for complex IV but also complex I assembly. 0.305 SIGNOR-272485 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation 9606 BTO:0000130 16778989 YES inferred from 70% family members gcesareni Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells. 0.2 SIGNOR-270187 GSK3B protein P49841 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Thr687 PRGMGPGtPAGYGRG 9606 20932480 YES lperfetto We conclude that t687 is the primary site of threonine phosphorylation in psf. Gsk3 directly phosphorylates the splicing regulatory protein psf. In this phosphorylated form, psf is sequestered in a complex with trap150, precluding it from binding the ess1 sequence in cd45 alternatively spliced exons. Upon t?_Cell stimulation, reduced gsk3 activity leads to reduced psf phosphorylation, thereby releasing psf from trap150 and allowing it to participate in activation-induced cd45 exon skipping 0.345 SIGNOR-168389 EIF2B3 protein Q9NR50 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.833 SIGNOR-269126 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257983 MCHR2 protein Q969V1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.586 SIGNOR-257268 SYK protein P43405 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr287 PEETNNDyETADGGY -1 8756631 YES miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation 0.2 SIGNOR-262674 IFNG protein P01579 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 NO lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS 0.7 SIGNOR-260259 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser377 PPFNPNVsGPNDLRH -1 12023960 YES miannu In contrast, we demonstrate for the first time that NEK6 phosphorylates SGK1 efficiently at its hydrophobic motif in vitro and peptide-mapping analysis indicates that this is the major site of phosphorylation (Fig 3). Ser377 is a more minor site of phosphorylation located in the kinase domain of SGK1, which has not been reported to undergo phosphorylation previously. the phosphorylation of the hydrophobic motif of SGK1 in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1 0.339 SIGNOR-262954 WNT9B protein O14905 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.621 SIGNOR-132111 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI DIO2 protein Q92813 UNIPROT up-regulates quantity by expression 9606 29892818 NO scontino Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity. 0.8 SIGNOR-267281 M1_polarization phenotype SIGNOR-PH54 SIGNOR TNF protein P01375 UNIPROT up-regulates 9606 BTO:0000801 32454942 NO miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ 0.7 SIGNOR-263826 PSMB5 protein P28074 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.86 SIGNOR-263357 CDK2 protein P24941 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity phosphorylation Thr8 MSSILPFtPPVVKRL 9606 19201832 YES miannu Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.|Moreover, CDK2 is the predominant cyclin-dependent kinase that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2. 0.488 SIGNOR-279678 PLK1 protein P53350 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Ser14 LEANADTsVEEESFG 9606 26811421 YES miannu Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.|Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase\u2013mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. 0.508 SIGNOR-278187 ZNF774 protein Q6NX45 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR up-regulates activity binding 9606 BTO:0000578 31659254 YES miannu Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. 0.248 SIGNOR-265559 MAOA protein P21397 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-263999 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr31 FLSEETPySYPTGNH 9606 15688067 YES miannu Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites. 0.914 SIGNOR-28247 ARHGEF7 protein Q14155 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 21048939 YES gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Gtpase activity of full-length lrrk2 increases in the presence of recombinant arhgef7. Arhgef7 might act as a guanine nucleotide exchange factor for lrrk2 0.457 SIGNOR-169217 SMURF1 protein Q9HCE7 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 17317136 YES lperfetto Recruitment of WW and HECT domain E3-ubiquitin ligases Smurf1 and 2 to induce type I receptor ubiquitination and subsequent receptor degradation; 0.693 SIGNOR-153414 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MBP protein P02686 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 16401070 YES inferred from 70% family members lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. 0.2 SIGNOR-270195 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser178 TATETQCsVPIQCTD 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.742 SIGNOR-262716 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 14633703 YES lperfetto Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells 0.442 SIGNOR-264659 AURKA protein O14965 UNIPROT FADD protein Q13158 UNIPROT up-regulates phosphorylation Ser203 MSWNSDAsTSEAS 9606 21978935 YES lperfetto Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194 0.343 SIGNOR-176739 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser282 TAPLSPMsPPGYKLV 9606 BTO:0000567 9535909 YES lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. 0.607 SIGNOR-249403 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2029 NAVDDLGkSALHWAA 9606 17636029 YES gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. 0.415 SIGNOR-156911 AKT1 protein P31749 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 NO Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. 0.7 SIGNOR-254372 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CTTN protein Q14247 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 20444238 YES inferred from 70% family members gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.2 SIGNOR-270051 EEF1A2 protein Q05639 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269539 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA4 protein Q9Y5G9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265675 PORCN protein Q9H237 UNIPROT WNT3A protein P56704 UNIPROT up-regulates activity palmitoylation Ser209 KCKCHGLsGSCEVKTC 9606 BTO:0000007 20826466 YES And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane. 0.699 SIGNOR-256598 TGFb proteinfamily SIGNOR-PF5 SIGNOR SNAI1 protein O95863 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 29305973 YES miannu Epithelial-mesenchymal transition (EMT) takes place, namely fibrosis, development and cancer. the process of EMT is integral to a number of physiological and disease states. TGF-β1 is a major effector of this process that activates various key transcription factors such as Snai1. 0.2 SIGNOR-265251 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 YES Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. 0.655 SIGNOR-260112 DNPEP protein Q9ULA0 UNIPROT USP4 protein Q13107 UNIPROT down-regulates quantity by destabilization cleavage 31219614 YES lperfetto A further analysis showed that the hydrolysis pathway contributes to DNPEP-mediated degradation of USP4 (Supporting Information Figs. S3A–S3F). The interaction between USP4 and DNPEP was confirmed by coIP assays 0.2 SIGNOR-275652 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser634 TFLSPQCsPQHSPLG 9606 BTO:0000007 16141410 YES In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity 0.398 SIGNOR-251249 INTS14 protein Q96SY0 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.2 SIGNOR-261474 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 12907755 YES PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 0.5 SIGNOR-248420 MECP2 protein P51608 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25420914 YES Luana As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1  0.29 SIGNOR-264675 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation Thr208 TFGNKLDtFCGSPPY 9606 14976552 YES lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold 0.587 SIGNOR-122628 PTPRG protein P23470 UNIPROT VCL protein P18206 UNIPROT down-regulates activity dephosphorylation Tyr822 KSFLDSGyRILGAVA -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254731 GUCY1A3-B3 complex SIGNOR-C140 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 YES gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types 0.8 SIGNOR-244105 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT up-regulates activity phosphorylation Ser215 KLDTFCGsPPYAAPE 9606 BTO:0000568 12879020 YES lperfetto Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211. 0.315 SIGNOR-104059 5-(1H-indol-3-ylmethyl)-3-methyl-2-sulfanylidene-4-imidazolidinone chemical CHEBI:91658 ChEBI RIPK1 protein Q13546 UNIPROT down-regulates chemical inhibition 9606 19524513 YES gcesareni The interaction between rip1 and rip3 is abolished by the rip1 kinase inhibitor necrostatin-1. 0.8 SIGNOR-186075 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 10469655 YES lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. 0.869 SIGNOR-217400 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 YES lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b 0.815 SIGNOR-217394 SMURF1 protein Q9HCE7 UNIPROT FAF2 protein Q96CS3 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.281 SIGNOR-272698 MFGE8 protein Q08431 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 22114683 NO Giorgia Our study demonstrated the direct anti-inflammatory role of MFG-E8 in terms of attenuating TNF-α production in mouse peritoneal macrophages and RAW264.7 cells treated with LPS 0.311 SIGNOR-260650 AMPK complex SIGNOR-C15 SIGNOR ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr356 GNPFDSKtEQGPQVD 10090 BTO:0000801 30375985 YES lperfetto Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. 0.252 SIGNOR-271862 MMP12 protein P39900 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 YES lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. 0.331 SIGNOR-263611 EGFR protein P00533 UNIPROT PLD2 protein O14939 UNIPROT up-regulates activity phosphorylation Tyr179 RLLTMSFyRNYHAMT 9606 9837959 YES llicata Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold 0.517 SIGNOR-251095 tacrolimus (anhydrous) chemical CHEBI:61049 ChEBI PPP3CB protein P16298 UNIPROT down-regulates chemical inhibition 9606 15276472 YES gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-127242 PRKCI protein P41743 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr359 YLYEKANtPELKKSV 9606 BTO:0000551 21189248 YES gcesareni Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion. 0.475 SIGNOR-170790 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity precursor of 9606 18767138 YES lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate 0.8 SIGNOR-268246 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT down-regulates activity phosphorylation Thr526 TNSFSAStGLSDMTA 10090 BTO:0000944 8662759 YES llicata Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10. 0.465 SIGNOR-250858 Tuberoinfundibular peptide of 39 residues smallmolecule CHEBI:80275 ChEBI PTH2R protein P49190 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257576 HIF1A protein Q16665 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 20682797 NO miannu Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. 0.262 SIGNOR-263738 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 15851026 YES lperfetto Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin. 0.2 SIGNOR-244761 3a protein P59632 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity 9606 BTO:0000567 30761102 NO miannu We found that the ion channel activity of SARS-CoV 3a protein is essential for activation of the NLRP3 inflammasome. In addition, both K+ efflux and mitochondrial ROS production are required for SARS-CoV 3a-mediated IL-1β secretion. In the case of SARS-CoV, the viroporin E forms forms Ca2+-permeable ion channels and activates the NLRP3 inflammasome.the 3a protein of SARS-CoV has the ability to induce the NLRP3 inflammasome activation by multiple mechanisms. 0.2 SIGNOR-260594 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CYGB protein Q8WWM9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 28948618 YES miannu Skp2 induces ubiquitin-dependent degradation of Cygb. To this end, we performed an in vivo ubiquitination assay in HEK293T cells by transfecting relevant plasmids as indicated. The V5-Skp2DN was generated by deleting the N-terminal residues from 1 to 153 containing the F-box domain, which is involved in recruiting Skp2 to the SCF complex. 0.2 SIGNOR-272794 NFIA protein Q12857 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268894 E protein P59637 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity 9606 32133002 NO miannu Viroporins are small, highly hydrophobic proteins derived from viruses, which interact with membranes to modify the host cell's permeability to ions or other small molecules. Several viroporins are observed to localize to the Golgi apparatus and other cytoplasmic structures during viral infection.Examples include 2B proteins from EMCV, poliovirus, enterovirus 71 (EV71), and human rhinoviruses (HRV), the envelope (E) protein of severe acute respiratory syndrome coronavirus (SARS-CoV), as well as influenza virus M2 protein. These viroporins activate the NLRP3 inflammasome by inducing different ionic fluxes.N protein from SARS-CoV, cause the flux of calcium from intracellular storages to the cytosol, which is indispensable for NLRP3 activation 0.2 SIGNOR-261318 8b protein Q80H93 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity binding 9606 31231549 YES miannu We found that ORF8b triggers robust NLRP3 inflammasome activation and IL-1β release. NLRP3 activation was accompanied by direct binding of ORF8b to the LRR domain of NLRP3. 0.2 SIGNOR-260591 testosterone smallmolecule CHEBI:17347 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 15861399 YES miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. 0.8 SIGNOR-251553 MCHR2 protein Q969V1 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256938 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser343 TVSKTETsQVAPA -1 9099669 YES lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. 0.44 SIGNOR-248968 GNGT1 protein P63211 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. 0.407 SIGNOR-199144 MAPK3 protein P27361 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 YES gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. 0.313 SIGNOR-169004 ELF4 protein Q99607 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19380490 NO miannu We found that elf4/mef activates mdm2 expression 0.383 SIGNOR-185490 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 10634209 YES lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors 0.925 SIGNOR-226676 IFNAR complex SIGNOR-C243 SIGNOR CCL7 protein P80098 UNIPROT up-regulates quantity by expression 10090 32283152 NO miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. 0.275 SIGNOR-260852 VX-765 chemical CID:53245642 PUBCHEM CASP1 protein P29466 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207770 INS protein P01308 UNIPROT APOB protein P04114 UNIPROT down-regulates quantity by destabilization 9606 23721961 NO miannu Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. Though insulin does not alter ApoB mRNA levels, it inhibits ApoB translation by promoting the trafficking of ApoB mRNA into P-bodies, aggregates of translationally repressed mRNAs 0.474 SIGNOR-252114 CREBBP protein Q92793 UNIPROT IRF9 protein Q00978 UNIPROT up-regulates activity acetylation Lys81 TGGPAVWkTRLRCAL 9606 BTO:0000007 17923090 YES lperfetto CBP was also the most effective one among the acetyltransferases tested for catalyzing IRF9 acetylation in 293T cells. [²] Figure 5 (F) K81 acetylation is required for IRF9 dimerization between the N-terminal 1-118 and the C-terminal 340-393 regions. In the left panel, Myc-DBD (1- 118) of IRF9 was cotransfected with 118-393, 118-339, or 1-393 (FL) of IRF9 in 293T cells. Anti-IRF9 (C-terminal region) precipitates were analyzed with anti-Myc or anti-IRF9. Anti-IRF9 precipitates, prepared from 293T cells cotransfected with the C-terminal fragment 118-393 of IRF9 and Myctagged DBD of different forms, were analyzed with anti-Myc or anti-IRF9 (right panel). 0.362 SIGNOR-217787 PFKFB4 protein Q16877 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI down-regulates quantity chemical modification -1 30553771 YES PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species 0.8 SIGNOR-267272 FGF2 protein P09038 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 15765505 NO gcesareni Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development. 0.44 SIGNOR-134512 CSNK1D protein P48730 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser247 KTFLSRHsLDMKFSY 9606 20699359 YES lperfetto In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha 0.325 SIGNOR-167476 MYC protein P01106 UNIPROT CDKN2B protein P42772 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001271 12835716 NO gcesareni Miz1 is a zinc finger transcription factor with an n-terminal poz domain. Complexes with myc, bcl-6 or gfi-1 repress expression of genes like cdkn2b (p15(ink4)) or cdkn1a (p21(cip1)). 0.598 SIGNOR-102746 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.2 SIGNOR-250555 S protein P59594 UNIPROT Spike protein-ACE2 complex SIGNOR-C240 SIGNOR form complex binding 9534 BTO:0001444 18554741 YES miannu Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. 0.2 SIGNOR-260287 FBXO45 protein P0C2W1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0001620 19581926 YES miannu The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73.Importantly, SCFFBXO45 ubiquitylates p73 both in vivo and in vitro. Expression of Cul1 dominant negative mutant, but not Cul2, Cul3, Cul4 and Cul5 dominant negative mutants, increased p73 levels (Figure 1c) to an extent similar to that observed in the ts41 cell line at not permissive temperature, suggesting that a Cul1-associated activity is required for p73 protein stability. 0.479 SIGNOR-271878 ACE2 protein Q9BYF1 UNIPROT Spike protein-ACE2 complex SIGNOR-C240 SIGNOR form complex binding 9534 BTO:0001444 18554741 YES miannu Cell entry of severe acute respiratory syndrome coronavirus (SARS-CoV) is mediated by the viral spike (S) protein. Amino acids 319-510 on the S protein have been mapped as the receptor-binding domain (RBD), which mediates binding to the SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) on SARS-CoV susceptible cells. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. 0.2 SIGNOR-260288 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser880 YNVYGIEsVKI 9606 BTO:0000007 10501226 YES lperfetto Here, we show that the C terminus of GluR2 of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor is phosphorylated by protein kinase C and that serine-880 is the major phosphorylation site. This phosphorylation also occurs in human embryonic kidney (HEK) cells by addition of 12-O-tetradecanoylphorbol 13-acetate. 0.708 SIGNOR-249022 IRF2BP2 protein Q7Z5L9 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 BTO:0000567 12799427 YES miannu We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation. 0.633 SIGNOR-224073 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser717 GVARVRKsKGKYAYL -1 8848293 YES lperfetto Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG). 0.708 SIGNOR-248955 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates activity phosphorylation Tyr139 Y-->K -1 18775312 YES miannu In addition, we analyzed Fes SH2-kinase that had been autophosphorylated on the kinase activation segment (Y713) in complex with a substrate peptide. 0.2 SIGNOR-277898 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser279 SSPTAPLsPMSPPGY 9606 BTO:0000567 9535909 YES lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. 0.607 SIGNOR-249402 F2RL1 protein P55085 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254855 PTGES2 protein Q9H7Z7 UNIPROT prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI up-regulates quantity chemical modification -1 10922363 YES Luana Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently. 0.8 SIGNOR-269766 PCM1 protein Q15154 UNIPROT NIN protein Q8N4C6 UNIPROT up-regulates relocalization 9606 12403812 YES miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome 0.406 SIGNOR-95077 MDM2 protein Q00987 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001061 14761977 YES miannu  MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein. 0.644 SIGNOR-272954 PTPRC protein P08575 UNIPROT FYN protein P06241 UNIPROT up-regulates activity dephosphorylation Tyr531 FTATEPQyQPGENL 9606 BTO:0000782 11909961 YES On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction. 0.73 SIGNOR-248352 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR PTGS2 protein P35354 UNIPROT up-regulates quantity by expression 9606 17705188 NO lperfetto Inflammatory stimuli can activate IkappaB kinase (IKK) signalsome and subsequently the nuclear factor kappa B (NF-kappaB), which influences gene expression of cyclooxygenase-2 (Cox-2) along with other transcription factors. 0.365 SIGNOR-260262 PAK1 protein Q13153 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 21822311 YES lperfetto Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin 0.556 SIGNOR-175944 GOLGA3 protein Q08378 UNIPROT GOPC protein Q9HD26 UNIPROT up-regulates activity binding 9606 BTO:0000567 15951434 YES miannu Golgin-160 belongs to the golgin family of Golgi-localized proteins, which have been implicated in Golgi structure and function. PIST (also known as GOPC, CAL, and FIG) has been implicated in the trafficking of a subset of plasma membrane proteins, supporting a role of golgin-160 in vesicular trafficking. binding of golgin-160, TC10, and syntaxin-6 to PIST may coordinate membrane trafficking of some plasma membrane proteins in cell types where these proteins are expressed. 0.481 SIGNOR-261234 3a protein P59632 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR down-regulates quantity 9606 20020050 NO miannu The 3a protein was found to induce serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and to increase IFNAR1 ubiquitination. Confocal microscopic analysis showed increased translocation of IFNAR1 into the lysosomal compartment and flow cytometry showed reduced levels of IFNAR1 in 3a-expressing cells. These results provide further mechanistic details of the pro-apoptotic effects of the SARS-CoV 3a protein, and suggest a potential role for it in attenuating interferon responses and innate immunity. 0.2 SIGNOR-260350 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr771 ADIESSNyMAPYDNY 9606 18567737 YES gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. 0.69 SIGNOR-179080 PELP1 protein Q8IZL8 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 YES miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. 0.801 SIGNOR-265469 NAT10 protein Q9H0A0 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002552 26882543 YES miannu NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.  0.331 SIGNOR-272405 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 12024016 YES gcesareni Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner. 0.819 SIGNOR-87845 calcitriol smallmolecule CHEBI:17823 ChEBI propan-2-ol smallmolecule CHEBI:17824 ChEBI up-regulates quantity precursor of 30080183 YES lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). 0.8 SIGNOR-270573 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT up-regulates phosphorylation Thr182 KSGEPLStWCGSPPY 9606 14976552 YES lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold 0.583 SIGNOR-122784 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 YES gcesareni In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2 0.962 SIGNOR-143984 SP3 protein Q02447 UNIPROT ITGA11 protein Q9UKX5 UNIPROT up-regulates quantity by expression 9606 BTO:0001282 16300938 YES lperfetto We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors. 0.2 SIGNOR-253351 MAPK14 protein Q16539 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity phosphorylation 10029 BTO:0005787 20887952 YES The chromatin redistribution of PRC2 in differentiating SCs is regulated by the p38a kinase, which promotes the formation of a complex containing p38a, EZH2, and YY1, via direct phosphorylation of EZH2. 0.326 SIGNOR-253599 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 10864927 YES lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.844 SIGNOR-216777 GNRHR protein P30968 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257064 SCN1A protein P35498 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 NO miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. 0.7 SIGNOR-253448 RPS6KA5 protein O75582 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 12628924 YES gcesareni Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276. 0.717 SIGNOR-99210 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 9927207 YES llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. 0.591 SIGNOR-64076 SPRY4 protein Q9C004 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR down-regulates 9606 BTO:0002283 20501643 NO These results demonstrate that Spry4 expression reduces cell growth and anchorage-independent growth, two key characteristics of transformed cells. 0.7 SIGNOR-278109 BAX protein Q07812 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 18097445 NO gcesareni This process of mitochondrial outer membrane permeabilization (momp) results in the release of cycs.it is commonly thought that bax and bak form pores in membranes 0.698 SIGNOR-160039 LMP2 protein P13285 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR down-regulates quantity by destabilization 9606 19718044 NO scontino The EBV-encoded Latent Membrane Proteins, LMP2A and LMP2B, Limit the Actions of Interferon by Targeting Interferon Receptors for Degradation.LMP2A and LMP2B increase the turnover and degradation of IFNAR1 and IFNGR1. LMP2A and LMP2B reduce the half-life of IFNAR1 and IFNGR1. 0.2 SIGNOR-266824 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr520 DNTPHTPtPFKNALE 9606 10593981 YES llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 0.718 SIGNOR-250741 GLDC protein P23378 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 YES lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. 0.698 SIGNOR-268240 Spike protein-ACE2 complex SIGNOR-C240 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates 17522231 NO lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins 0.2 SIGNOR-260711 CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates 17522231 NO lperfetto These results suggest that when SARS-CoV binds ACE2 it is internalized and penetrates early endosomes in a clathrin-dependent manner |The clathrin-dependent endocytosis is initiated by the binding of adaptor protein 2 (AP2) complexes to the cytoplasmic tail of the cell-surface receptors, which recruits clathrins 0.2 SIGNOR-260756 CHRM5 protein P08912 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257291 C3 convertase complex complex SIGNOR-C310 SIGNOR C5 convertase complex complex SIGNOR-C312 SIGNOR form complex binding 31331124 YES lperfetto C3b associates with C3 convertase to form C5 convertase and cleaves C5. 0.6 SIGNOR-263447 RIPK1 protein Q13546 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 21133840 YES simone vumbaca RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex 0.552 SIGNOR-256022 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263782 PIGF protein Q07326 UNIPROT PIGG protein Q5H8A4 UNIPROT up-regulates quantity by stabilization binding 10029 BTO:0000246 15632136 YES miannu We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O. 0.644 SIGNOR-261358 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr232 SQKKEGVyDVPKSQP 10090 BTO:0000938 11279201 YES lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. 0.421 SIGNOR-247084 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9927207 YES llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. 0.591 SIGNOR-64190 ETFB protein P38117 UNIPROT ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 YES miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. 0.946 SIGNOR-269452 PRKCB protein P05771 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276022 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273043 CHRM1 protein P11229 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.398 SIGNOR-256735 S protein P0DTC2 UNIPROT CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR form complex binding 9534 BTO:0001444 32155444 YES miannu We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. 0.2 SIGNOR-260739 ACE2 protein Q9BYF1 UNIPROT CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR form complex binding 9534 BTO:0001444 32155444 YES miannu We report here that ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, establishing it as a functional receptor for this newly emerged coronavirus. The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates associated with the 2002–2003 epidemic (i.e., binding with high affinity to hACE2). Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans, as was the case for SARS-CoV. 0.2 SIGNOR-260740 clofarabine chemical CHEBI:681569 ChEBI RRM2 protein P31350 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 1707752 YES miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate 0.8 SIGNOR-258356 AKT1 protein P31749 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates activity phosphorylation Ser971 STRLRQQsSSSKGDS 9606 27858941 YES miannu DAB2IP can be phosphorylated by RIP1 on Ser 604 within the PER domain, and by AKT1 on Ser 847 within the proline-rich domain. Although RIP1-mediated phosphorylation is stimulatory,40 a recent study reported that AKT-mediated phosphorylation inhibits DAB2IP functions 0.498 SIGNOR-254780 CUX1 protein P39880 UNIPROT PIK3IP1 protein Q96FE7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24316979 YES miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. 0.368 SIGNOR-260072 DOK1 protein Q99704 UNIPROT ITGB6 protein P18564 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.2 SIGNOR-257693 DYRK2 protein Q92630 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 19965871 YES lperfetto Phosphorylation of p53 at Ser-46 is indispensable for the commitment to apoptotic cell death. |Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. 0.669 SIGNOR-275578 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5110 KAEAPLPsPKLEGEL 10090 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.256 SIGNOR-262764 PLK1 protein P53350 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 YES lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. 0.351 SIGNOR-189045 Class II MHC:Antigen complex SIGNOR-C429 SIGNOR Helper_T-lymphocyte_activation phenotype SIGNOR-PH196 SIGNOR up-regulates 9606 31810556 NO scontino Once they are formed, peptide/MHC class II molecules complexes are very stable and allow for sustained antigen presentation increasing the chances to encounter the matching CD4+ T lymphocytes. Once CD4+ T cells have become acti- vated, they in turn trigger macrophages to eliminate pathogens that have been previously internalized, and B lymphocytes to produce pathogen- specific antibodies. 0.7 SIGNOR-267874 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 BTO:0000567 9271440 YES gcesareni The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424). 0.385 SIGNOR-50607 LE-TGN SNARE complex SIGNOR-C157 SIGNOR IGF2R protein P11717 UNIPROT up-regulates activity relocalization 9606 18195106 YES lperfetto These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function. 0.485 SIGNOR-253083 PRKACA protein P17612 UNIPROT HTT protein P42858 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2548 TRFGRKLsIIRGIVE -1 35908190 YES miannu Moreover, phosphorylation of C-HEAT Ser2550 by cAMP-dependent protein kinase (PKA), the top hit in kinase activity screens, was found to hasten huntingtin degradation, such that levels of the catalytic subunit (PRKACA) were inversely related to huntingtin levels. 0.2 SIGNOR-277625 GSK3B protein P49841 UNIPROT PGR protein P06401 UNIPROT down-regulates quantity by destabilization phosphorylation Ser554 PDSEASQsPQYSFES 9606 23880761 YES miannu Here, we have found that glycogen synthase kinase (GSK)-3β phosphorylation of progesterone receptor-A (PR-A) facilitates its ubiquitination. GSK-3β-mediated phosphorylation of serine 390 in PR-A regulates its subsequent ubiquitination and protein stability. 0.277 SIGNOR-276498 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 11343802 YES lperfetto Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation 0.611 SIGNOR-107695 PTEN protein P60484 UNIPROT EGR2 protein P11161 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 NO miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 0.306 SIGNOR-260049 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR PI3K complex SIGNOR-C156 SIGNOR down-regulates 26721223 NO Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity. 0.7 SIGNOR-255492 GUCY1B1 protein Q02153 UNIPROT GUCY1A2-B3 complex SIGNOR-C138 SIGNOR form complex binding 9606 10977868 YES gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity 0.2 SIGNOR-243980 HDLBP protein Q00341 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 9925647 NO miannu HBP/vigilin binds HDL and apoA-I on ligand blots; conceivably therefore apoA-I may interact with cytoplasmic vigilin promoting changes in cholesterol flux. 0.7 SIGNOR-266692 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.8 SIGNOR-258763 RREB1 protein Q92766 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 17550981 NO RREB-1 bound to the prostate-specific antigen (PSA) promoter as assessed by chromatin immunoprecipitation. Transient expression of RREB-1 down-regulated AR-mediated promoter activity and suppressed expression of PSA protein. 0.2 SIGNOR-253661 KLF4 protein O43474 UNIPROT PBX1 protein P40424 UNIPROT up-regulates activity binding 9606 BTO:0000093 21746878 YES miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. 0.478 SIGNOR-267237 SSTR4 protein P31391 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-256823 USP1 protein O94782 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000567 SIGNOR-C302 18082604 YES lperfetto The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2|The level of monoubiquitinated FANCD2 protein increases in response to various types of DNA damage in mammalian cells 0.76 SIGNOR-263273 PLK1 protein P53350 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 32704044 YES miannu In conclusion, we provide evidence that PLK1-dependent phosphorylation of FOXO1 induces its nuclear exclusion and negatively regulates FOXO1 transcriptional activity in PCa.|We previously demonstrated that PLK1 inhibits the transcriptional activity of FOXO1 by promoting its nuclear exclusion in U2OS cells . 0.316 SIGNOR-278269 MAPK1 protein P28482 UNIPROT ATP1A1 protein P05023 UNIPROT down-regulates activity phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 YES miannu Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit. 0.518 SIGNOR-262940 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr648 DVHNLDYyKKTTNGR 9606 BTO:0000007 11294897 YES lperfetto Ligand stimulation leads to autophosphorylation of fgfr3the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3. 0.2 SIGNOR-106734 ARID3A protein Q99856 UNIPROT Immunoglobulin delta heavy chain protein P0DOX3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 16738337 YES lperfetto In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure ​3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene. 0.2 SIGNOR-268531 STX1A protein Q16623 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR form complex binding 9606 BTO:0000938 30267828 YES miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. 0.931 SIGNOR-263968 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 BTO:0000801 11842088 NO gcesareni In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. 0.506 SIGNOR-114771 AKT proteinfamily SIGNOR-PF24 SIGNOR ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 YES miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. 0.2 SIGNOR-266357 CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser242 WTDSEVDsSCSGQPI 9606 BTO:0000007 26885618 YES lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| 0.356 SIGNOR-273122 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser118 NQQESSDsGTSVSEN 9606 20708156 YES gcesareni Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase. 0.346 SIGNOR-167497 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249324 FLT3 protein P36888 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 BTO:0001516 23246379 YES These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. 0.364 SIGNOR-255947 terazosin chemical CHEBI:9445 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 9606 9379432 YES miannu Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication 0.8 SIGNOR-258670 HUWE1 protein Q7Z6Z7 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000093 28939105 YES miannu Mule was identified as Mcl-1 ubiquitin ligase E3 to promote Mcl-1 degradation via the proteasomal pathway [46]. We found that knockdown of Mule (Fig. 4C) but not β-TRCP or FBXW7 (data not shown) prevented Mcl-1 downregulation caused by PKCη depletion. 0.503 SIGNOR-261909 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17339337 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-153463 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser40 TQSSGKSsVLESLVG 9606 BTO:0000007 25192600 YES miannu  We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. 0.389 SIGNOR-276849 PPP2CA protein P67775 UNIPROT MAPK15 protein Q8TD08 UNIPROT down-regulates dephosphorylation Thr175 GPEDQAVtEYVATRW 9606 16336213 YES lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20% 0.29 SIGNOR-142977 HECW1 protein Q76N89 UNIPROT DVL1 protein O14640 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0001976 14684739 YES miannu We have also found that NEDL1 targets Dishevelled-1 (Dvl1) for ubiquitination-mediated degradation and that mutant (but not wild-type) SOD1 affects the function of Dvl1.  0.64 SIGNOR-271499 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 NO gcesareni Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck) 0.349 SIGNOR-166358 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ABI1 protein Q8IZP0 UNIPROT down-regulates activity phosphorylation Ser216 VPNDYMTsPARLGSQ 9606 BTO:0000567 21900237 YES lperfetto We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly 0.419 SIGNOR-264452 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 YES lperfetto Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts 0.689 SIGNOR-249144 pimozide chemical CHEBI:8212 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258379 MAP3K10 protein Q02779 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates activity binding -1 12881483 YES lperfetto we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2 0.333 SIGNOR-234599 NRXN1 protein P58400 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626543 YES miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites 0.824 SIGNOR-265453 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191478 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation 9606 SIGNOR-C14 19632174 YES lperfetto Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta. 0.755 SIGNOR-187242 RAD23B protein P54727 UNIPROT ERCC1 protein P07992 UNIPROT up-regulates activity binding 24086043 YES lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.649 SIGNOR-275703 TACR1 protein P25103 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256919 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBD1 protein Q9UJT1 UNIPROT down-regulates activity chemical inhibition 9606 15579115 YES miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 0.8 SIGNOR-259257 NRP1 protein O14786 UNIPROT CoV2 spike protein-NRP1 complex SIGNOR-C267 SIGNOR form complex binding 9606 BTO:0000007 other YES https://doi.org/10.1101/2020.06.07.137802 miannu Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system To determine whether SARS-CoV-2 uses NRP1 for virus entry, we generated replication deficient lentiviruses pseudotyped with SARS-CoV-2 spike protein (S) that drive expression of green fluorescent protein (GFP) upon infection. When expressed alone, ACE2 rendered cells susceptible to infection (Fig. 1a). NRP1 alone allowed lower, yet detectable levels of infection, both in HEK-293T and in Caco2 cells (Fig. 1a,b), while cells transfected with plasmids encoding only TMPRSS2 were not infected (Fig. 1a). The co-expression of TMPRSS2 with either ACE2 or NRP1 potentiated the infection, with ACE2 together with TMPRSS2 being twice as efficient as NRP1 with TMPRSS2 (Fig. 1c) 0.2 SIGNOR-261672 S protein P0DTC2 UNIPROT CoV2 spike protein-NRP1 complex SIGNOR-C267 SIGNOR form complex binding 9606 BTO:0000007 other YES https://doi.org/10.1101/2020.06.07.137802 miannu Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into the central nervous system To determine whether SARS-CoV-2 uses NRP1 for virus entry, we generated replication deficient lentiviruses pseudotyped with SARS-CoV-2 spike protein (S) that drive expression of green fluorescent protein (GFP) upon infection. When expressed alone, ACE2 rendered cells susceptible to infection (Fig. 1a). NRP1 alone allowed lower, yet detectable levels of infection, both in HEK-293T and in Caco2 cells (Fig. 1a,b), while cells transfected with plasmids encoding only TMPRSS2 were not infected (Fig. 1a). The co-expression of TMPRSS2 with either ACE2 or NRP1 potentiated the infection, with ACE2 together with TMPRSS2 being twice as efficient as NRP1 with TMPRSS2 (Fig. 1c) 0.2 SIGNOR-261671 TPO protein P07202 UNIPROT diiodine smallmolecule CHEBI:17606 ChEBI up-regulates quantity chemical modification 9606 28153798 YES scontino TPO is considered the key enzyme in thyroid hormonogenesis. It catalyzes the oxidation of iodide that is necessary for the iodinationof the TG tyrosyl residues (the organification reaction). 0.8 SIGNOR-266959 ID1 protein P41134 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.557 SIGNOR-241128 DYRK1A protein Q13627 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser403 WAKPKPLsPTSYMSP 9606 28235034 YES miannu DYRK1A phosphorylation of NFATc1 and alphaA at S261, S278, S403 and S409 interfered with NFATc1 ubiquitination and ubiquitin-proteasome degradation.|Here, we demonstrated that DYRK1A increased NFATc1 (NFATc1 and alphaA isoform) protein stability, in contrast to the decrease of NFATc2 protein stability by DYRK1A. 0.429 SIGNOR-278277 PRKDC protein P78527 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity by destabilization phosphorylation Thr11 EEQYYAAtQLYKDPC 10090 16166097 YES miannu The interaction of PDX-1 with Ku subunits and its phosphorylation on threonine 11 by the DNA-PK appear to be implicated in its degradation by the proteosome. 0.307 SIGNOR-225542 NEDD4 protein P46934 UNIPROT SAG protein P10523 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25216516 YES miannu Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.  0.374 SIGNOR-272843 UBE2S protein Q16763 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000567 19822757 YES lperfetto Here, we identify the highly conserved Ube2S as a regulator of human and Drosophila APC/C. Ube2S functions as a K11-specific chain elongating E2 of APC/C, which depends on chain initiation by UbcH10. Together, UbcH10 and Ube2S are required for the degradation of all APC/C substrates tested so far, spindle formation, and progression of cells through mitosis. 0.669 SIGNOR-265080 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 22056878 YES Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. gcesareni In estrogen-receptor-negative cellular models showing coamplification of erbb2 and rara, simultaneous targeting of the corresponding gene products with combinations of lapatinib and atra causes synergistic growth inhibition, cyto-differentiation and apoptosis. 0.8 SIGNOR-177081 QRICH1 protein Q2TAL8 UNIPROT IARS1 protein P41252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269406 LPAR3 protein Q9UBY5 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-257406 BCR-Dl complex SIGNOR-C436 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 YES scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). 0.714 SIGNOR-268442 NLRP1 inflammasome complex SIGNOR-C224 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.2 SIGNOR-256380 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 15329413 YES gcesareni Egfr is a tk of the erbb family that is the presumptive target of the tk inhibitor (tki) gefitinib. 0.8 SIGNOR-126976 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A1P5 protein Q5VTE0 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. 0.2 SIGNOR-269389 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273081 CREB5 protein Q02930 UNIPROT CFB protein P00751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002809 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253802 PSMF1 protein Q92530 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR down-regulates activity binding 9606 BTO:0000007 23622245 YES lperfetto We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31. 0.525 SIGNOR-263341 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 BTO:0000093 12777400 YES lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases 0.34 SIGNOR-101310 JAK2 protein O60674 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Tyr641 KNEFISEyCGEIISQ 9606 24469040 YES lperfetto Oncogenic y641 mutations in ezh2 prevent jak2/beta-trcp-mediated degradationbeta-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs beta-trcp-mediated ezh2 degradation. 0.535 SIGNOR-202711 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs 0.2 SIGNOR-252348 CD28 protein P10747 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000782 18006698 YES gcesareni Cd28 can bind directly to pi3k by a well-characterized ymnm binding motif in its cytoplasmic domain. 0.369 SIGNOR-159322 CRHR1 protein P34998 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 23504413 NO lperfetto CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). 0.652 SIGNOR-268612 PIK3CG protein P48736 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates binding 9606 9768361 YES gcesareni Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (pdk-1), which binds with high affinity to the pi 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (ptdins-3,4,5-p), phosphorylates and potently activates two other pi 3-kinase targets, the protein kinases akt/pkb and p70s6k. 0.631 SIGNOR-60567 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser540 HVSEDSSsPERTSPP 9606 19107194 YES lperfetto We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells 0.476 SIGNOR-216841 DLG5 protein Q8TDM6 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.314 SIGNOR-270893 MINK1 protein Q8N4C8 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates binding 9606 9230439 YES miannu Herg, a human homologue of the ether-a-go-go gene of the fruitfly drosophila melanogaster, encodes aproteinthat produces the rapidly activating cardiac delayed rectifier (i[kr]). / our results show that mink physically associates with herg and that the interaction leads to increased ikr current density. 0.285 SIGNOR-49869 PRKCZ protein Q05513 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Thr456 GRLTELRtFNHHHAE 9606 BTO:0000195 18668687 YES The effect has been demonstrated using Q96RI1-2 gcesareni The effect of fic1 on fxr phosphorylation and nuclear localization and its effects on bsep promoter activity could be blocked with protein kinase c zeta (pkc zeta) inhibitors (pseudosubstrate or small interfering rna silencing). Recombinant pkc zeta directly phosphorylated immunoprecipitated fxr. The mutation of threonine 442 of fxr to alanine yielded a dominant negative protein, 0.381 SIGNOR-179771 CIT protein O14578 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD -1 21457715 YES Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. 0.56 SIGNOR-260305 AKT1 protein P31749 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates activity phosphorylation Ser227 QQRRRITsVQPPTGL 9606 BTO:0000567 21620836 YES miannu A reciprocal immunoprecipiation with anti-phospho-Akt substrate antibody followed by immunoblotting with anti-FLAG antibodies confirmed these findings (Fig. 1C). We concluded that Fbw7 is phosphorylated at S227 in vivo. Phosphorylation of Fbw7 is required for its biological activity. 0.41 SIGNOR-276328 PRKCE protein Q02156 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.396 SIGNOR-249281 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM48 protein Q8IWZ4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271192 NIBAN2 protein Q96TA1 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity binding 9606 BTO:0002035 26721396 YES miannu EGFR phosphorylates FAM129B, resulting in binding of phosphorylated FAM129B to H-Ras and reduced the association of p120-RasGAP with H-Ras, thereby enhancing H-Ras activation for ERK1/2-dependent β-catenin transactivation for enhanced Warburg effect, tumor cell proliferation, and brain tumorigenesis. 0.2 SIGNOR-273659 CREB5 protein Q02930 UNIPROT TNFRSF11B protein O00300 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253812 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Ser486 LRTPGRQsPGPGHRS 9606 10581160 YES Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP 0.92 SIGNOR-251221 SAGA complex complex SIGNOR-C465 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269636 PRKCG protein P05129 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 YES gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. 0.701 SIGNOR-97558 STAT3 protein P40763 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 NO miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. 0.317 SIGNOR-255240 COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 9606 26497135 YES miannu The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin–proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. The evolutionary conserved ubiquitin proteasome pathway (UPP) mediates degradation of intracellular proteins in all eukaryotes. This essential process requires three protein complexes: E3 ubiquitin ligases as e.g., cullin-RING ligases (CRLs), CSN and the 26S proteasome. 0.317 SIGNOR-270794 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273062 S1PR2 protein O95136 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000007 10488065 YES gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13. 0.529 SIGNOR-70667 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 YES lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). 0.914 SIGNOR-236741 HBB protein P68871 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000876 11901318 NO Regulation of expression miannu Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes. 0.3 SIGNOR-251752 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1668 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248808 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Tyr394 QSQESEDySQPSTSS 9606 12110584 YES gcesareni C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2. 0.715 SIGNOR-90512 PPM1A protein P35813 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 YES Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2C_ dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity 0.325 SIGNOR-252724 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 9823 BTO:0004712 23486913 YES lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway 0.96 SIGNOR-201538 quetiapine chemical CHEBI:8707 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 YES miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). 0.8 SIGNOR-258842 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser358 ELRKTQTsMSLGTTR 10090 24012422 YES gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays 0.753 SIGNOR-266427 clozapine chemical CHEBI:3766 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). 0.8 SIGNOR-258835 VRK1 protein Q99986 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17938195 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis. 0.2 SIGNOR-158436 MAPK3 protein P27361 UNIPROT SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation Thr622 LGTQVPGtPPPKYNT -1 11805112 YES lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. 0.28 SIGNOR-249449 CHIR-98014 chemical CID:53396311 PUBCHEM GSK3A protein P49840 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190985 P2RY6 protein Q15077 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.399 SIGNOR-257277 APPL1 protein Q9UKG1 UNIPROT STK11 protein Q15831 UNIPROT up-regulates binding 9606 BTO:0000887 19520843 YES milica In this study, we identified lkb1 as a new binding partner of appl1 and showed that the bar domain of appl1 is involved in this interaction.Here we show that in muscle cells adiponectin and metformin induce ampk activation by promoting appl1-dependent lkb1 cytosolic translocation. Appl1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances lkb1 cytosolic localization by anchoring this kinase in the cytosol. 0.317 SIGNOR-186065 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SLC25A27 protein O95847 UNIPROT up-regulates quantity by expression transcriptional regulation 20385226 YES lperfetto We present the first direct evidence that UCP4 is regulated by NF-kappaB, mediated via a functional NF-kappaB site in its promoter region, and that UCP4 has a significant role in NF-kappaB prosurvival signaling, mediating its protection against MPP(+) toxicity.|NF-kappaB inhibition significantly suppressed the MPP(+)-induced increase in UCP4 expression. 0.2 SIGNOR-268984 hsa-miR-150-5p mirna URS000016FD1A_9606 RNAcentral CCR6 protein P51684 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001825 24385540 YES We show here that miR-150 expression is significantly diminished in all examined T-cell lymphoma subtypes tested, and that it has the potential to inhibit tumor invasion and metastasis by targeting the CCR6 chemokine receptor 0.4 SIGNOR-277924 CSNK2A1 protein P68400 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser576 VSDKGSDsEEEETNR 9606 BTO:0000599 23287549 YES lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. 0.291 SIGNOR-265267 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 BTO:0000887;BTO:0001103 19620279 YES miannu We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA. 0.651 SIGNOR-202045 resveratrol chemical CHEBI:27881 ChEBI AHR protein P35869 UNIPROT down-regulates activity chemical inhibition -1 9865727 YES Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. 0.8 SIGNOR-253640 WWTR1 protein Q9GZV5 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 NO gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. 0.7 SIGNOR-199208 MAP3K11 protein Q16584 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001538 9003778 YES lperfetto Immunoprecipitated mlk-3 catalyzed the phosphorylation of sek1 in vitro, and co-transfected mlk-3 induced phosphorylation of sek1 and mkk3 at sites required for activation, suggesting direct regulation of these protein kinases. 0.49 SIGNOR-45788 CBFB protein Q13951 UNIPROT Core Binding Factor complex complex SIGNOR-C214 SIGNOR form complex binding 9606 12495904 YES irozzo The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis 0.847 SIGNOR-255711 BMPR1B protein O00238 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates phosphorylation 9606 19620713 YES gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.707 SIGNOR-187196 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 11965546 YES lperfetto Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation. 0.355 SIGNOR-217204 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2C protein Q06413 UNIPROT down-regulates binding 9606 21902831 YES lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.288 SIGNOR-216963 LYN protein P07948 UNIPROT DOK3 protein Q7L591 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. 0.41 SIGNOR-268447 DLK1 protein P80370 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 10090 BTO:0002572 21419176 YES gcesareni Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts. 0.516 SIGNOR-172830 ID1 protein P41134 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.635 SIGNOR-241107 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition 9606 20570526 YES Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], 0.8 SIGNOR-257850 PRKACA protein P17612 UNIPROT ARFGEF1 protein Q9Y6D6 UNIPROT up-regulates activity phosphorylation Ser883 EIAGKKIsMKETKEL 9606 BTO:0000599 16467138 YES lperfetto Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. |Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site 0.2 SIGNOR-272146 TBX5 protein Q99593 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20802524 NO miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. 0.267 SIGNOR-255253 CSNK1A1 protein P48729 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 YES llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  0.323 SIGNOR-250793 CH5132799 chemical CID:49784945 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190952 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 YES lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. 0.2 SIGNOR-244754 ITCH protein Q96J02 UNIPROT TRPC4 protein Q9UBN4 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 17110928 YES miannu Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. 0.351 SIGNOR-272624 PDHA1 protein P08559 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 YES miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. 0.809 SIGNOR-266544 TAF7 protein Q15545 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.9 SIGNOR-263928 EGR1 protein P18146 UNIPROT CHGA protein P10645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007 12456801 YES Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. 0.2 SIGNOR-254265 FOXL2 protein P58012 UNIPROT CCND2 protein P30279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 NO miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. 0.392 SIGNOR-254178 FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 NO lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. 0.631 SIGNOR-249635 ACO1 protein P21399 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity chemical modification 9606 24068518 YES miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. 0.8 SIGNOR-266245 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 17615152 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. 0.67 SIGNOR-156856 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr806 TPHYGSQtPLHDGSR 9606 16427012 YES lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif 0.776 SIGNOR-143939 GNAQ protein P50148 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 YES gcesareni Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate manymolecules, including phospholipases, ion channels and lipid kinases. 0.283 SIGNOR-152609 arachidonic acid smallmolecule CHEBI:15843 ChEBI PTGS2 protein P35354 UNIPROT up-regulates 9606 15878913 NO miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. 0.8 SIGNOR-255394 RNF34 protein Q969K3 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization ubiquitination 26971449 YES lperfetto We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system. 0.32 SIGNOR-253393 KCNQ2 protein O43526 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 YES miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. 0.8 SIGNOR-265982 ERBB4 protein Q15303 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.559 SIGNOR-252674 SMO protein Q99835 UNIPROT KIF7 protein Q2M1P5 UNIPROT up-regulates activity relocalization 10090 19666503 YES lperfetto Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins. 0.631 SIGNOR-209605 PINK1 protein Q9BXM7 UNIPROT HIF3A protein Q9Y2N7 UNIPROT down-regulates activity phosphorylation Thr12 LQRARSTtELRKEKS 9606 BTO:0000793 27551449 YES Parkinson miannu Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. 0.347 SIGNOR-263090 ZNF318 protein Q5VUA4 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 16469430 YES Monia Using different promoters and cells, we confirmed that AR-mediated transactivation was repressed by TZF in a dose-dependent manner (Fig. 1A and B). Endogenous ARmediated transactivation was also inhibited by expression of TZF; These results indicate that amino acid residues 512–663 are essential for the repressive effect of TZF on AR-mediated transactivation. 0.372 SIGNOR-261187 PRKACA protein P17612 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD -1 9016641 YES miannu PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1. 0.451 SIGNOR-250336 RXRB protein P28702 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.721 SIGNOR-16674 Ub:E2 complex SIGNOR-C497 SIGNOR HECTD2 protein Q5U5R9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271283 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Thr72 PLLPPSAtGPDATVG 9606 12478298 YES lperfetto In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites 0.665 SIGNOR-96414 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120192 NAMPT protein P43490 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI up-regulates quantity chemical modification 9606 12555668 YES gcesareni Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesi 0.8 SIGNOR-238602 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.541 SIGNOR-81137 FBXO31 protein Q5XUX0 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 YES miannu FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. 0.413 SIGNOR-277379 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser410 RKDSLDDsGSCLSGS 9534 BTO:0000298 9353340 YES lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  0.391 SIGNOR-248988 SYK protein P43405 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr955 ADAEEAMyQNVDGRV 9606 24525236 YES miannu Only two mutants, FLT3-KD (V5) Y768A and Y955A, were resistant to SYK mediated FLT3 phosphorylation, suggesting that SYK directly phosphorylates FLT3 at sites Y768 and Y955 (XREF_FIG).|SYK Enhances FLT3 WT and Mutant Activation by Phosphorylation of Residues Y768 and Y955. 0.408 SIGNOR-278430 LPAR6 protein P43657 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256725 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0002524 32989218 YES miannu The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. 0.2 SIGNOR-277815 1038915-60-4 chemical CID:24958200 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194399 GSK3B protein P49841 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 YES lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. 0.2 SIGNOR-264874 Ub:E2 complex SIGNOR-C497 SIGNOR RFPL4A protein A6NLU0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271140 ITGB1BP1 protein O14713 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257648 PRKCA protein P17252 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation Ser53 HPQLHIEsKIYKMMQ -1 31096047 YES miannu In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity. 0.2 SIGNOR-277451 ACVR1 protein Q04771 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR up-regulates phosphorylation 9606 9748228 YES fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 0.2 SIGNOR-210093 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 7822264 YES llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. 0.428 SIGNOR-250626 motesanib chemical CHEBI:51098 ChEBI RET protein P07949 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194572 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 21079800 YES gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.423 SIGNOR-169682 SMURF1 protein Q9HCE7 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR down-regulates ubiquitination 9606 22298955 YES Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps 0.769 SIGNOR-269847 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR RAD51 protein Q06609 UNIPROT up-regulates activity ubiquitination Lys64 KKELINIkGISEAKA -1 25585578 YES miannu The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64. 0.271 SIGNOR-272454 SERPINA1 protein P01009 UNIPROT F12 protein P00748 UNIPROT down-regulates activity binding 9606 BTO:0000131 26707513 YES lperfetto C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). 0.331 SIGNOR-263515 PTK2 protein Q05397 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates activity phosphorylation Tyr35 ICGPEENyPSLQMSS 9606 BTO:0000007 22493428 YES miannu  In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK. 0.274 SIGNOR-276409 ITGB1 protein P05556 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.781 SIGNOR-253184 ixazomib chemical CHEBI:90942 ChEBI PSMB5 protein P28074 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194509 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206139 CUL3 protein Q13618 UNIPROT TNFAIP1 protein Q13829 UNIPROT up-regulates activity binding 9606 19782033 YES miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. 0.461 SIGNOR-264232 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates 9606 23075495 NO inferred from 70% of family members gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. 0.8 SIGNOR-269867 SLBP protein Q14493 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265373 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser838 LVFDYEGsGSEAASL 10090 BTO:0000944 10671552 YES llicata Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | All mutants showed a clear reduction in phosphorylation. Phosphorylation was completely abolished in the single mutant S855A and the double mutant S853/855A, and phosphorylation in S840A and S853A mutants was reduced to 43 and 28% that of wt GST-ECT. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion. 0.402 SIGNOR-250839 EIF3F protein O00303 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates deubiquitination 9606 21124883 YES gcesareni The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor. 0.422 SIGNOR-254327 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR -1 15486195 YES miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. 0.689 SIGNOR-250080 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS1 protein O95835 UNIPROT down-regulates 10090 22863277 NO milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. 0.8 SIGNOR-198517 KAT5 protein Q92993 UNIPROT CHKA protein P35790 UNIPROT up-regulates activity acetylation Lys247 MPFNKEPkWLFGTME 9606 34929314 YES lperfetto Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation. 0.2 SIGNOR-267648 MED12 protein Q93074 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 YES miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. 0.922 SIGNOR-266683 cyclosporin A chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 10116 BTO:0001103 15829723 YES apalma On one hand, inhibition of calcineurin with cyclosporin A (CsA) significantly reduced the growth of both the slow/type I soleus muscle and fast/type II plantaris muscle in normal, ambulatory rats 0.8 SIGNOR-255102 FBXO22 protein Q8NEZ5 UNIPROT KLF4 protein O43474 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000594 26087183 YES lperfetto F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression 0.365 SIGNOR-273444 TFEB protein P19484 UNIPROT CALCOCO1 protein Q9P1Z2 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) 0.2 SIGNOR-276784 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 18377662 YES Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175 0.667 SIGNOR-248475 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-269969 AKT proteinfamily SIGNOR-PF24 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates binding 9606 15048128 YES gcesareni Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis. 0.2 SIGNOR-252345 GRPR protein P30550 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257046 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 11431483 YES miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 0.8 SIGNOR-269686 UTS2R protein Q9UKP6 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.265 SIGNOR-257164 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-B receptor complex SIGNOR-C336 SIGNOR up-regulates activity chemical activation 9606 9872316 YES brain lperfetto GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. 0.8 SIGNOR-263795 p38 proteinfamily SIGNOR-PF16 SIGNOR KRT8 protein P05787 UNIPROT up-regulates phosphorylation 9606 11788583 YES inferred from 70% family members lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. 0.2 SIGNOR-270125 HSPA1A protein P0DMV8 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by stabilization binding 9606 24790089 YES miannu The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease. 0.256 SIGNOR-252416 TNFSF12 protein O43508 UNIPROT MYH3 protein P11055 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000165 17314137 YES miannu TWEAK induces ubiquitination of MyHCf and expression of atrogin-1 and MuRF1 in myotubes. our data show that TWEAK rapidly increases the conjugation of ubiquitin to MyHCf (Fig. 3A) and ubiquitination preceded the degradation of MyHCf (Fig. 2C and Fig. 3A). 0.2 SIGNOR-272628 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 10737616 YES lperfetto Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease. 0.564 SIGNOR-249418 CSNK2A1 protein P68400 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr387 LPWDLWTtSTDLVQP 9606 BTO:0000567 16945112 YES lperfetto Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin. 0.2 SIGNOR-149318 Fluocinonide chemical CHEBI:5109 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 YES gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. 0.8 SIGNOR-248218 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 YES gcesareni We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. 0.519 SIGNOR-120330 CSNK2A1 protein P68400 UNIPROT MME protein P08473 UNIPROT down-regulates phosphorylation Ser6 sQMDITDI 9606 20957047 YES lperfetto The cytoplasmic n-terminal domain of nep interacts with the phosphatase and tensin homologue deleted on chromosome 10 (pten) thereby regulating intracellular signaling via akt. Ser 6 is efficiently phosphorylated by protein kinase ck2. The phosphorylation of the cytoplasmic domain of nep inhibits its interaction with pten. 0.323 SIGNOR-168673 PRKCA protein P17252 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276025 SARS1 protein P49591 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 24095058 YES miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis 0.8 SIGNOR-270495 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates activity chemical inhibition 9606 7566123 YES Monia Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin. 0.8 SIGNOR-261074 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Tyr223 TSFMMTPyVVTRYYR 9606 15911620 YES lperfetto Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19). 0.743 SIGNOR-137605 MAPK1 protein P28482 UNIPROT RBFOX2 protein O43251 UNIPROT unknown phosphorylation Thr7 tPGYHGFP 10090 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262761 Calcineurin complex SIGNOR-C155 SIGNOR PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 YES In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. 0.408 SIGNOR-252334 SSTR3 protein P32745 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.579 SIGNOR-256677 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii 0.777 SIGNOR-203580 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 YES lperfetto Stat1 was phosphorylated at tyr 701 in jak immune complex kinase reaction. The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. 0.789 SIGNOR-30905 PAMPs stimulus SIGNOR-ST11 SIGNOR NAIP protein Q13075 UNIPROT up-regulates activity 16037825 NO lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-256424 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys365 SLASQATkDGKKDKK -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). 0.404 SIGNOR-272741 PHLPP2 protein Q6ZVD8 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates activity dephosphorylation Thr390 DSKFTRQtPVDSPDD 9606 BTO:0000182 21986499 YES gcesareni We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro 0.491 SIGNOR-248247 Gbeta proteinfamily SIGNOR-PF4 SIGNOR DUSP1 protein P28562 UNIPROT down-regulates phosphorylation 9606 16286470 YES inferred from 70% family members lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain 0.2 SIGNOR-270093 CYP11B2 protein P19099 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 YES lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone 0.8 SIGNOR-268680 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 YES Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. 0.2 SIGNOR-248599 RIPK3 protein Q9Y572 UNIPROT PDH complex SIGNOR-C402 SIGNOR up-regulates activity phosphorylation -1 29358703 YES miannu Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. 0.2 SIGNOR-268065 GARS1 protein P41250 UNIPROT tRNA(Gly) smallmolecule CHEBI:29176 ChEBI down-regulates quantity chemical modification 9606 24898252 YES miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 0.8 SIGNOR-270477 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT up-regulates activity phosphorylation Thr182 KSGEPLStWCGSPPY 9606 18946175 YES miannu Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182. 0.583 SIGNOR-262844 GSK3B protein P49841 UNIPROT ZNF281 protein Q9Y2X9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser638 PRVDLHTsGEHSELV 9606 BTO:0001615 29179460 YES lperfetto GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression| 0.2 SIGNOR-264890 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR GSK3B protein P49841 UNIPROT up-regulates activity dephosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 20080667 YES miannu DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation. 0.434 SIGNOR-254754 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr331 LTEDSTQtSDTATNS -1 7836371 YES gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. 0.2 SIGNOR-249676 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 20110348 YES gcesareni Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. 0.403 SIGNOR-163680 L-serine chemical CHEBI:17115 ChEBI glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity precursor of 9606 32439610 YES lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 0.8 SIGNOR-268222 CSNK2A1 protein P68400 UNIPROT PIN4 protein Q9Y237 UNIPROT down-regulates activity phosphorylation Ser19 AGKGGAAsGSDSADK 9606 BTO:0000567 12860119 YES lperfetto As proved by MALDI-TOF mass spectrometry and MS/MS fragmentation, hPar14 is phosphorylated at Ser19 in vitro and in vivo. In human HeLa cells the protein is most likely modified by casein kinase 2 (CK2). |In contrast to wild-type hPar14, the in vitro DNA-binding affinity of the Glu19 mutant is strongly reduced, suggesting that only the dephosphorylated protein is the active DNA-binding form of hPar14 in the nucleus. 0.326 SIGNOR-265753 TP63 protein Q9H3D4 UNIPROT SUN1 protein O94901 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005098 28595999 YES lperfetto Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. 0.2 SIGNOR-263278 GOT1 protein P17174 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-268063 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-74831 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 12058066 YES lperfetto Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. 0.405 SIGNOR-216662 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser821 YLRQFSGsLKPEDAE 9534 BTO:0000298 14523239 YES lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 0.2 SIGNOR-249233 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL11 protein P51671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16604092 NO miannu Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling. 0.262 SIGNOR-254661 MAP1LC3B protein Q9GZQ8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 YES gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. 0.837 SIGNOR-184255 DEPTOR protein Q8TB45 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity binding 9606 BTO:0000007 19446321 YES DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival 0.754 SIGNOR-251657 PRKCA protein P17252 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates activity phosphorylation Ser39 VAYGVREsVFTVEGG 9606 28555617 YES miannu PKC\u03b1 phosphorylates PHB2-S39. 0.2 SIGNOR-279256 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR DCK protein P27707 UNIPROT down-regulates activity dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 YES lperfetto Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation 0.2 SIGNOR-275804 SMARCB1 protein Q12824 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.836 SIGNOR-270747 SH3PXD2B protein A1X283 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 YES lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation 0.347 SIGNOR-264707 AKT proteinfamily SIGNOR-PF24 SIGNOR HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. 0.2 SIGNOR-186772 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRA protein P01903 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys244 FIIKGLRkSNAAERR 9606 19117940 YES miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. 0.2 SIGNOR-271412 MAPK14 protein Q16539 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 YES gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity 0.416 SIGNOR-48349 GNG2 protein P59768 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000938 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. 0.476 SIGNOR-145122 MCU_MICU2_variant complex SIGNOR-C502 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.8 SIGNOR-270878 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser529 KGAKVFGsLERGLDK 9606 16216881 YES lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. 0.2 SIGNOR-141018 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 8754811 NO fspada The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively 0.8 SIGNOR-210068 sorafenib chemical CHEBI:50924 ChEBI BRAF protein P15056 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21654832 YES gcesareni Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression. 0.8 SIGNOR-174036 QRICH1 protein Q2TAL8 UNIPROT WARS1 protein P23381 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269410 UBL4A protein P11441 UNIPROT SGTA protein O43765 UNIPROT up-regulates activity binding 9606 BTO:0000007 24424410 YES miannu USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding. 0.578 SIGNOR-272858 amitriptyline chemical CHEBI:2666 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258702 NAE complex SIGNOR-C131 SIGNOR ANAPC2 protein Q9UJX6 UNIPROT up-regulates activity neddylation 9606 25504797 YES lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. 0.403 SIGNOR-243175 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr826 LPTPTKMtPRSRILV 9606 9139732 YES lperfetto We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. 0.862 SIGNOR-216957 MDM2 protein Q00987 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates ubiquitination 9606 23252402 YES gcesareni Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1. 0.477 SIGNOR-200197 CITED2 protein Q99967 UNIPROT MMP1 protein P03956 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003859 12960175 NO miannu CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway. 0.357 SIGNOR-253778 canertinib chemical CHEBI:61399 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258200 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 7901013 YES The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax 0.267 SIGNOR-34686 PGAM5 protein Q96HS1 UNIPROT ME1 protein P48163 UNIPROT up-regulates activity dephosphorylation Ser336 KKIWLVDsKGLIVKG 31735643 YES lperfetto PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. 0.2 SIGNOR-275569 LYN protein P07948 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr904 EEEGRDEyDEVAMPV -1 10942405 YES Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport. 0.338 SIGNOR-251414 SLC24A4 protein Q8NFF2 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264392 LEF1 protein Q9UJU2 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19620402 NO miannu We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPalpha. 0.349 SIGNOR-254551 HTR1B protein P28222 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257207 tyrosine smallmolecule CHEBI:18186 ChEBI Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates quantity precursor of 9606 16429158 YES miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr 0.8 SIGNOR-270524 STUB1 protein Q9UNE7 UNIPROT S100P protein P25815 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 23344957 YES miannu S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway. 0.293 SIGNOR-272919 STAT3 protein P40763 UNIPROT SALL4 protein Q9UJQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 19151334 NO miannu We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4 expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4. 0.581 SIGNOR-255244 DUSP26 protein Q9BV47 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates activity dephosphorylation 9606 28701747 YES miannu NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells 0.2 SIGNOR-277104 THBS1 protein P07996 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 NO lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 0.7 SIGNOR-252271 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates activity phosphorylation Ser622 KKGEKRAsSPFRRVR -1 12167624 YES miannu PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA. 0.307 SIGNOR-250019 TEAD4 protein Q15561 UNIPROT CCN2 protein P29279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33358571 YES miannu The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter 0.2 SIGNOR-277686 ELMO2 protein Q96JJ3 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0001909 25533347 YES miannu We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth. 0.582 SIGNOR-266821 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser146 RPSQRHGsKYLATAS -1 2413024 YES miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 0.347 SIGNOR-250011 PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 BTO:0000007 22724072 YES PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 0.2 SIGNOR-270345 NCOA1 protein Q15788 UNIPROT RARA protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 NO irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. 0.709 SIGNOR-255932 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19114991 YES lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity 0.742 SIGNOR-182967 dimethyloxalylglycine chemical CHEBI:102218 ChEBI EGLN1 protein Q9GZT9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000018 28900510 YES lperfetto We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1. 0.8 SIGNOR-261991 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.264 SIGNOR-276100 PRKCB protein P05771 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity phosphorylation Ser582 LWHFRYEsLKHPKAY 9606 BTO:0000007 23824069 YES miannu  Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex.As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ. 0.502 SIGNOR-276496 EEF1A1 protein P68104 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.298 SIGNOR-205606 ARHGEF4 protein Q9NR80 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.666 SIGNOR-260531 NUMA1 protein Q14980 UNIPROT TUBB3 protein Q13509 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.2 SIGNOR-116979 ZEB2 protein O60315 UNIPROT CTBP1 protein Q13363 UNIPROT up-regulates activity binding 9606 BTO:0000007 12743039 YES Luisa The two members of the ZEB family of zinc finger factors (ZEB-1/deltaEF1 and ZEB-2/SIP1) regulate TGFbeta/BMP signaling in opposite ways: ZEB-1/deltaEF1 synergizes with Smad-mediated transcriptional activation, while ZEB-2/SIP1 represses it. Here we report that these antagonistic effects by the ZEB proteins arise from the differential recruitment of transcriptional coactivators (p300 and P/CAF) and corepressors (CtBP) to the Smads. Thus, while ZEB-1/deltaEF1 binds to p300 and promotes the formation of a p300-Smad transcriptional complex, ZEB-2/SIP1 acts as a repressor by recruiting CtBP. 0.475 SIGNOR-268953 SLC24A5 protein Q71RS6 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264398 PRKAA1 protein Q13131 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 17900900 YES gcesareni The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation 0.369 SIGNOR-157947 ROBO3 protein Q96MS0 UNIPROT CFL1 protein P23528 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 16226035 YES miannu Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. 0.2 SIGNOR-268379 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Ser32 RSEDARSsPSQRRRG 9606 BTO:0000567 12714602 YES lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. 0.699 SIGNOR-217344 AGT protein P01019 UNIPROT TRPC6 protein Q9Y210 UNIPROT up-regulates activity 9606 24850910 NO We demonstrated that Ang II evokes concentration-dependent activation of podocyte TRPC6 channels 0.305 SIGNOR-253331 IL2 protein P60568 UNIPROT IL2RB protein P14784 UNIPROT up-regulates binding 9606 16477002 YES miannu Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c). 0.869 SIGNOR-144540 PHF20 protein Q9BVI0 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. 0.682 SIGNOR-267159 UBE2I protein P63279 UNIPROT ETV5 protein P41161 UNIPROT down-regulates sumoylation 9606 15857832 YES miannu Here we show that erm interacts with the sumo-conjugating enzyme ubc9 and is modified by sumo. We further show that sumo modification of this ets transcription factor affects its ability to activate transcription. 0.266 SIGNOR-135850 SPAST protein Q9UBP0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates cleavage -1 15716377 NO Gianni Using real-time imaging, we show that Spastin severs microtubules when added to permeabilized, cytosol-depleted cells stably expressing GFP-tubulin. 0.7 SIGNOR-269046 PLK1 protein P53350 UNIPROT CEP68 protein Q76N32 UNIPROT down-regulates quantity by destabilization phosphorylation Ser332 ADPVLQDsGVDLDSF 25503564 YES lperfetto We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCF(βTrCP) (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser 332, allowing recognition by βTrCP. 0.441 SIGNOR-275621 EZR protein P15311 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 BTO:0000132 35267019 NO miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway. 0.7 SIGNOR-268432 E4F1 protein Q66K89 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity ubiquitination Lys321 SSPQPKKkPLDGEYF 9606 BTO:0001938 17110336 YES miannu E4F1 Has an Intrinsic Ubiquitin E3 Ligase Activity that Drives K48-type Ubiquitylation of p53. These data demonstrate that E4F1 stimulates the ubiquitylation of p53 on the lysine cluster K319–K321, i.e., at sites distinct from those targeted by Hdm2. p53 forms Ubiquitylated by E4F1 Are Localized on Chromatin. In striking contrast with Ub-p53 forms stimulated by Hdm2, which are mainly cytosoluble and targeted to the proteasome, we found that E4F1-stimulated Ub-p53 forms are tightly associated with chromatin, suggesting that they could be involved in transcription. 0.607 SIGNOR-271395 CBL protein P22681 UNIPROT JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization ubiquitination Lys970 GMEYLGTkRYIHRDL 9606 28676638 YES miannu K63 linked poly-ubiquitination on K970 of JAK2 kinase domain is promoted by Cbl. 0.586 SIGNOR-278538 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.91 SIGNOR-252830 CASP7 protein P55210 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 YES lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. 0.343 SIGNOR-261757 ECM stimulus SIGNOR-ST20 SIGNOR A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259035 TRAF3 protein Q13114 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization binding 10090 15084608 YES lperfetto Traf3 is physically associated with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome. 0.667 SIGNOR-124236 MRE11 protein P49959 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 YES gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. 0.2 SIGNOR-181628 BCL6 protein P41182 UNIPROT FCER2 protein P06734 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000776 11342629 NO In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability 0.287 SIGNOR-253928 BIRC2 protein Q13490 UNIPROT ENDOG protein Q14249 UNIPROT up-regulates activity ubiquitination 9606 25139236 YES miannu Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death. 0.469 SIGNOR-278605 PRKACA protein P17612 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser50 KQINKRAsGQAFELI 9534 BTO:0000298 9525956 YES miannu Using in vitro phosphorylated recombinant protein, four phosphorylation sites were identified in the SCG10 sequence. Ser-50 and Ser-97 were the target sites for protein kinase A. phosphorylation negatively regulates the microtubule-depolymerizing activity of SCG10 and that all four sites participate in this regulation 0.31 SIGNOR-250056 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 YES miannu  Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities. 0.608 SIGNOR-250272 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser196 EKSPSVCsPLNMTSS 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.287 SIGNOR-276107 RNF7 protein Q9UBF6 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates activity ubiquitination 9606 23136067 YES miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 0.2 SIGNOR-271450 DICER1 protein Q9UPY3 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR form complex binding 9606 23661684 YES miannu 0.896 SIGNOR-143105 RBBP4 protein Q09028 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 YES miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. 0.686 SIGNOR-268816 ARIH1 protein Q9Y4X5 UNIPROT EIF4E2 protein O60573 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 14623119 YES miannu Human homologue of Drosophila ariadne (HHARI) is a RING-IBR-RING domain protein identified through its ability to bind the human ubiquitin-conjugating enzyme, UbcH7. Thus, by promoting the ubiquitin-mediated degradation of 4EHP, HHARI may have a role in both protein degradation and protein translation. 0.678 SIGNOR-268848 CYSLTR1 protein Q9Y271 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256883 ZC3H11A protein O75152 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR up-regulates activity binding 9606 BTO:0000567 22928037 YES miannu PDIP3 and ZC11A Function in mRNA Export. PDIP3 and ZC11A associate with UAP56 and the TREX complex in an ATP-dependent manner. 0.483 SIGNOR-268516 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.2 SIGNOR-183608 ATAT1 protein Q5SQI0 UNIPROT TUBA1A protein Q71U36 UNIPROT up-regulates quantity by stabilization acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 YES lperfetto Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules 0.268 SIGNOR-272251 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser713 KKKFRTPsFLKKSKK -1 8810272 YES lperfetto Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC. 0.285 SIGNOR-248952 FBXL5 protein Q9UKA1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000018 25249620 YES miannu Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation. 0.657 SIGNOR-271654 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2G1 protein P62253 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.713 SIGNOR-271349 SLC12A1 protein Q13621 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 YES lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  0.8 SIGNOR-264635 ATOH1 protein Q92858 UNIPROT HES6 protein Q96HZ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17826772 NO miannu Electrophoretic mobility shift assays and luciferase assays show that ATOH1 activates HES6 transcription through binding to three clustered E boxes of its promoter. 0.44 SIGNOR-253754 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0002181 11726515 YES irozzo However, direct binding of Grb2 to Bcr/Abl also facilitates its tyrosine phosphorylation, which we propose reflects activation of a physiological negative regulatory mechanism by this oncogenic tyrosine kinase.Direct binding of Grb2 to Bcr/Abl facilitates Grb2 phosphorylation. 0.2 SIGNOR-255820 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264920 AKT1 protein P31749 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 10559253 YES esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. 0.56 SIGNOR-252586 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Thr151 RSYSRLEtLGSASTS -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.628 SIGNOR-276117 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation -1 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258442 AKT2 protein P31751 UNIPROT BCL3 protein P20749 UNIPROT up-regulates quantity by stabilization phosphorylation Ser41 KRPLRAPsPEPAAPR -1 28689659 YES miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  0.27 SIGNOR-277359 BCL7C protein Q8WUZ0 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.504 SIGNOR-270715 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269352 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258714 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Thr145 AGNKRLStIDESGSI 9606 BTO:0000567 14744859 YES llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 0.779 SIGNOR-250589 CSNK2A1 protein P68400 UNIPROT STX1A protein Q16623 UNIPROT up-regulates phosphorylation Ser14 ELRTAKDsDDDDDVA 9606 11846792 YES lperfetto In this report, we show that syntaxin-1a is phosphorylated in vitro by cki on thr21. Casein kinase ii (ckii) has been shown previously to phosphorylate syntaxin-1a in vitro and we have identified ser14 as the ckii phosphorylation site. the phosphorylation of syntaxin-1a by ckii enhances its capacity to associate with synaptotagmin [21]. Therefore, phosphorylation of ser14 by ckii suggests an important role for this residue in regulating the interaction between syntaxin-1a and synaptotagmin 0.367 SIGNOR-114840 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR E2F5 protein Q15329 UNIPROT up-regulates activity phosphorylation Thr261 SQSLTPVtPQKSSMA 9606 10783242 YES miannu Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. 0.64 SIGNOR-262732 GSK3A protein P49840 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser280 FHCCQCTsVETVTEL 10116 BTO:0003324 30745182 YES miannu Fatty acids (FAs) upregulate GSK-3α, which phosphorylates PPARα at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPARα targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation.  0.2 SIGNOR-277431 EIF2B5 protein Q13144 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.877 SIGNOR-269128 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser667 SSLIRKRsTRRSVRG 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.2 SIGNOR-272508 cis-(z)-Flupenthixol chemical CHEBI:10454 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258715 CPT1C protein Q8TCG5 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267134 TGFBR1 protein P36897 UNIPROT SPTBN1 protein Q01082 UNIPROT up-regulates phosphorylation 9606 12543979 YES gcesareni This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead. 0.521 SIGNOR-97626 CDK5 protein Q00535 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates phosphorylation Thr159 DGSEPTKtPGRTSST 9606 BTO:0000938 20513426 YES llicata Thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy cdk5/p25, a neuronal cdk shown to play a role in alzheimer's disease, can also phosphorylate thr159 of vps34. 0.357 SIGNOR-165772 SRC protein P12931 UNIPROT HCN2 protein Q9UL51 UNIPROT up-regulates activity phosphorylation Tyr476 LDSSRRQyQEKYKQV 9606 BTO:0000007 26280531 YES miannu We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity. 0.268 SIGNOR-263199 BCL2L11 protein O43521 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000972 17960585 NO miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. 0.7 SIGNOR-260426 PTPRJ protein Q12913 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity dephosphorylation 9606 25386896 YES lperfetto Our data demonstrate that CD148 promotes E-cadherin cell adhesion by regulating Rac1 activity, concomitant with modulation of p120, \u03b2-catenin, and Src tyrosine phosphorylation, and that this effect requires E-cadherin and p120 association.|Taken together, it is likely that CD148 dephosphorylation of \u03b2-catenin enhances the cadherin cell adhesion independent of Rho family GTPases. 0.517 SIGNOR-276992 MFGE8 protein Q08431 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 10116 31958465 YES miannu Milk fat globule-EGF factor 8 (MFGE8), a protein known as lactadherin in humans, contains C domains interacting with extracellular matrices and epidermal growth factor–like domains with an RGD motif binding to integrins αvβ3 and αvβ5. 0.524 SIGNOR-260644 TRAF6 protein Q9Y4K3 UNIPROT ULK1 protein O75385 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0000007 23524951 YES lperfetto AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. 0.547 SIGNOR-273000 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000150 18492217 YES gcesareni Numb can actually interact in vivo with endogenous mdm2 and p53, resulting in a trimeric complex between the three proteins [10]. This interaction appears to regulate the stability of p53, as reduction of numb levels by rna interference (rnai) causes a decrease in the half-life of p53 and consequently a reduction in steady-state levels of the protein. Consistent with this observation, overexpression of numb increases the level of p53 in both unstressed and stressed cells. 0.516 SIGNOR-178668 NFAT5 protein O94916 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 22266867 YES done miannu  As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009). 0.478 SIGNOR-274115 KAT5 protein Q92993 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys21 GGAKRHRkVLRDNIQ 9606 12776177 YES lperfetto Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals. 0.2 SIGNOR-262061 N-hydroxy-2-[4-[[(1-methyl-3-indolyl)methylamino]methyl]-1-piperidinyl]-5-pyrimidinecarboxamide chemical CHEBI:94771 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193513 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser66 GVYATRSsAVRLRSS -1 2500966 YES miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. 0.309 SIGNOR-250068 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser698 PEWPRRAsCTSSTSG -1 2117608 YES llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. 0.33 SIGNOR-250883 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 YES apalma IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt. 0.868 SIGNOR-255104 PRKACA protein P17612 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation Ser119 YGPPSRRsENRVVVS 9606 22393468 YES llicata Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo 0.2 SIGNOR-196397 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates activity phosphorylation Ser99 KNKGKGFsVVADTPE -1 12432067 YES miannu Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146 0.307 SIGNOR-250075 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 YES Two of these, S909 and T1079, were required for Lats1 activation. milica Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1. 0.619 SIGNOR-133544 MYCBP2 protein O75592 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity ubiquitination 9606 31676756 YES miannu Cell-based results demonstrate that the human PHR protein PAM restricts ULK1 protein levels (Fig.\u00a05h, i), and is sufficient to ubiquitinate ULK1 in a proteasome-dependent manner (Fig.\u00a05j).|Human PAM ubiquitinates ULK1 and regulates ULK1 levels. 0.285 SIGNOR-278765 FPR1 protein P21462 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256961 Ub:E2 complex SIGNOR-C497 SIGNOR RNF121 protein Q9H920 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271226 FANCE protein Q9HB96 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.841 SIGNOR-263247 ITGA3 protein P26006 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.803 SIGNOR-253173 SGK3 protein Q96BR1 UNIPROT FLII protein Q13045 UNIPROT up-regulates phosphorylation Ser436 RLRRRKDsAQDDQAK 9606 19293151 YES lperfetto Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator. 0.356 SIGNOR-184688 MRPS28 protein Q9Y2Q9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.638 SIGNOR-267732 IFNG protein P01579 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 20525234 NO miannu Pro-inflammatory cytokines like interferon-γ (IFN-γ) induce expression of GTP-cyclohydrolase I in various brain cells. 0.252 SIGNOR-252223 phosphatidylcholine chemical CHEBI:64482 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR form complex binding 9606 25627476 YES lperfetto The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition. 0.8 SIGNOR-267000 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF3 protein Q13114 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271071 GCC2 protein Q8IWJ2 UNIPROT IGF2R protein P11717 UNIPROT up-regulates activity relocalization 18195106 YES lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector 0.527 SIGNOR-253085 KDM6A protein O15550 UNIPROT HOXC8 protein P31273 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.307 SIGNOR-260029 STK3 protein Q13188 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Ser226 LNPQWNEsFTFKLKP 9606 BTO:0002181 26414765 YES miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  0.2 SIGNOR-277177 PRKAA2 protein P54646 UNIPROT PAK2 protein Q13177 UNIPROT unknown phosphorylation Ser20 APPVRMSsTIFSTGG 9606 SIGNOR-C15 22137581 YES llicata Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells. 0.242 SIGNOR-195110 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 YES lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.518 SIGNOR-188916 STUB1 protein Q9UNE7 UNIPROT CBX4 protein O00257 UNIPROT down-regulates quantity by destabilization ubiquitination Lys280 GMQAVKIkSGEVAEG 9606 BTO:0002181 32111827 YES miannu The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.  0.2 SIGNOR-277514 GPR183 protein P32249 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.26 SIGNOR-257202 CBX5 protein P45973 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-264490 lenalidomide chemical CHEBI:63791 ChEBI CRBN protein Q96SW2 UNIPROT up-regulates activity chemical activation 9606 26131937 YES gcesareni Lenalidomide, like thalidomide and pomalidomide, binds CRBN and induces degradation of specific substrates 0.8 SIGNOR-236891 ADSL protein P30566 UNIPROT N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI down-regulates quantity chemical modification 9606 22812634 YES miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case 0.8 SIGNOR-266612 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2E3 protein Q969T4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.609 SIGNOR-271364 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270412 SB 505124 chemical CHEBI:100922 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 14978253 YES gcesareni Sb-505124 is a selective inhibitor of transforming growth factor-beta type i receptors alk4, alk5, and alk7. 0.8 SIGNOR-122910 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu433 REYHTEKlVTSKGDK -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain 0.2 SIGNOR-263624 AKT1 protein P31749 UNIPROT CCDC88A protein Q3V6T2 UNIPROT unknown phosphorylation Ser1417 INRERQKsLTLTPTR 9606 16139227 YES llicata Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells. 0.597 SIGNOR-252482 EGFR protein P00533 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity phosphorylation Tyr179 SVYGTEEyLHPDMYE 9606 27287717 YES miannu EGFRL858R/T790M phosphorylates IKBKE at tyrosine residues. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179.  0.258 SIGNOR-277243 FUS protein P35637 UNIPROT GEMIN6 protein Q8WXD5 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 23022481 YES lperfetto Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells 0.2 SIGNOR-262106 CDK2 protein P24941 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization Ser123 EEGFGSSsPVKSPAA 9606 BTO:0000567 16085715 YES miannu PS123 primes CK2 to phosphorylate S121, resulting in creation of a β-TrCP phosphodegron (EEGFGpS121) that is responsible for the instability of Wee1A during interphase.  0.665 SIGNOR-276039 CDK2 protein P24941 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser44 LENDFFNsPPRKTVR 9606 SIGNOR-C16 15004009 YES miannu Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia 0.506 SIGNOR-123231 AMPK complex SIGNOR-C15 SIGNOR CSNK1E protein P49674 UNIPROT up-regulates activity phosphorylation Ser389 RGAPANVsSSDLTGR -1 17525164 YES miannu AMPK enhances mPer2 degradation and CKIɛ activity by phosphorylating Ser-389 of CKIɛ. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2.  0.263 SIGNOR-276064 DLL3 protein Q9NYJ7 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. 0.489 SIGNOR-209738 CRYAB protein P02511 UNIPROT CRYGS protein P22914 UNIPROT up-regulates activity binding -1 20621668 YES miannu Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age. 0.539 SIGNOR-253623 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT up-regulates activity phosphorylation Tyr395 CLPGTVEyQVPTSLR 10090 20603078 YES miannu Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. 0.723 SIGNOR-273845 U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 NO lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.7 SIGNOR-270651 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 YES apalma After binding of Wnt to the receptor complex, the signal is transduced to cytoplasmic phosphoprotein Dishevelled (Dsh/Dvl), and studies have uncovered that Dsh can directly interact with Fz 0.2 SIGNOR-255892 PTPRO protein Q16827 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 25301722 YES lperfetto SRC activation triggered by loss of PTPRO leads to c-CBL degradation.|These data corroborate that PTPRO directly dephosphorylates SRC at Y416. 0.423 SIGNOR-277004 CSNK2A1 protein P68400 UNIPROT CACNA1S protein Q13698 UNIPROT up-regulates activity phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 YES miannu To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. 0.2 SIGNOR-263114 3-phenanthryl hydrogen sulfate chemical CHEBI:37459 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition -1 7576010 YES miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. 0.8 SIGNOR-258439 AKT proteinfamily SIGNOR-PF24 SIGNOR TTC3 protein P53804 UNIPROT up-regulates phosphorylation Ser378 AYTPRSLsAPIFTTS 9606 20059950 YES llicata Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context 0.2 SIGNOR-162984 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser25 KRRSARLsAKPPAKV 9606 11438671 YES lperfetto We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets. 0.365 SIGNOR-249101 Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR Cell_shape phenotype SIGNOR-PH182 SIGNOR up-regulates 9606 24302288 NO lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell 0.7 SIGNOR-266033 Ankyrin complex complex SIGNOR-C383 SIGNOR SPTB protein P11277 UNIPROT up-regulates activity binding 9606 BTO:0000424 22465511 YES lperfetto The junctional complex is focused around a hub or ‘junction’ arising from lateral connections between protein 4.1, actin and beta spectrin (the first of which stabilises the actin spectrin association via direct binding to both proteins [8]). 0.43 SIGNOR-266023 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser890 RQRKRKLsFRRRTDK 9606 10488078 YES lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) 0.307 SIGNOR-70726 PDCD1 protein Q15116 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 BTO:0000782 22740686 NO Barakat MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2 0.265 SIGNOR-275410 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates transcriptional regulation 9606 25211658 YES P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells 0.401 SIGNOR-251574 RAF1 protein P04049 UNIPROT STK4 protein Q13043 UNIPROT down-regulates binding 9606 22898666 YES gcesareni Raf1 binding to mst2 sarah domain interdicts mst2 homodimerization and autoactivation, and recruits protein phosphates 2a thereby promoting mst2 inactivation. 0.272 SIGNOR-191843 NR3C1 protein P04150 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7569975 NO andrea cerquone perpetuini Here it is shown that the synthetic glucocorticoid dexamethasone induces the transcription of the IKBc gene, which results in an increased rate of IKBa protein synthesis 0.327 SIGNOR-255688 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 20670887 YES lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribosomal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2)phosphorylation of the 4E-BPs leads to their inhibition and release from eIF4E at the 5_ cap of mRNAs 0.755 SIGNOR-235745 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys122 SPVEDNEkDLVKLAK -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 0.464 SIGNOR-272743 MAPK14 protein Q16539 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 YES gcesareni Moreover, this region (wac domain) was also phosphorylated by recombinant proteins of p38_? And jnk2_? But not by akt1 0.2 SIGNOR-188160 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAMAC protein Q9BTL3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 YLKRPPEsPPIVEEW 9606 BTO:0001581 27452456 YES miannu ERK1/2 phosphorylates RAM serine-36, targeting it for ubiquitination and proteasomal degradation, ultimately resulting in changes in gene expression associated with loss of pluripotency. 0.2 SIGNOR-277819 PKN1 protein Q16512 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser637 VDLSKVTsKCGSLGN 9606 BTO:0000938 BTO:0000975 11104762 YES The effect has been demonstrated using P10636-8 lperfetto Phosphorylation of tau is regulated by pknthere is a pkn-specific phosphorylation site, ser-320, in mbdsthus pkn serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly. 0.329 SIGNOR-84958 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser82 HSISYTLsRAQTVVV 9606 BTO:0000007 12496252 YES lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation 0.767 SIGNOR-96747 FIG4 protein Q92562 UNIPROT 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-) smallmolecule CHEBI:85342 ChEBI down-regulates quantity chemical modification -1 23165282 YES miannu Fig4/Sac3 can decrease PI(3,5)P2 levels via its phosphatase function and also promote PI3,5P2 synthesis by acting as a secondary scaffold for the Fab1/Vac14 interaction. However, the later function appears dominant. 0.8 SIGNOR-253535 PK proteinfamily SIGNOR-PF80 SIGNOR phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 YES miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). 0.8 SIGNOR-266539 PRKACA protein P17612 UNIPROT KCNJ2 protein P63252 UNIPROT down-regulates activity phosphorylation Ser425 PRPLRREsEI -1 19843922 YES miannu PKA consensus site S425 required for PKA-mediated effects on Kir2.1 channels. PKA activation reduced outward IK1 for heteromeric Kir2.1 WT+V227F channels after 2 hours of PKA activation. 0.2 SIGNOR-276267 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation 9606 19188143 YES lperfetto Phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression 0.693 SIGNOR-183695 MMP1 protein P03956 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0005387 19584257 NO lperfetto However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype 0.7 SIGNOR-252265 ATF6 protein P18850 UNIPROT Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 31226023 NO miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network 0.7 SIGNOR-260182 PRC1 protein O43663 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity binding 9606 16431929 YES miannu KIF14 interacts with PRC1 and citron kinase. We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. I 0.633 SIGNOR-266423 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr219 DGSDHPYyNSIPSKM -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.777 SIGNOR-273915 MTOR protein P42345 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates activity phosphorylation Ser571 KGEDLVGsLNGGHAN 9606 BTO:0001938 26139536 YES miannu MTOR phosphorylates UVRAG at serine 550 and serine 571 0.408 SIGNOR-276919 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1105 CSEVERTyLKTKSSS -1 10195142 YES lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. 0.733 SIGNOR-247151 PRKCE protein Q02156 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001253 16418226 YES gcesareni Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation. 0.399 SIGNOR-143832 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207672 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser762 AKFQSERsRARYEMA 9606 20507994 YES llicata Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration. 0.452 SIGNOR-165706 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Thr14 PAKAANRtPPKSPGD -1 17693641 YES miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. 0.403 SIGNOR-262933 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 YES gcesareni Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. 0.81 SIGNOR-124949 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176841 MAPK3 protein P27361 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 YES lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. 0.39 SIGNOR-209880 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 8052307 YES gcesareni In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k 0.924 SIGNOR-35878 PTPRK protein Q15262 UNIPROT PROM1 protein O43490 UNIPROT down-regulates activity dephosphorylation -1 30947381 YES miannu PTPRK dephosphorylates CD133, which is a stem cell marker; phosphorylated CD133 accelerates xenograft tumor growth of colon cancer cells through the activation of AKT, but the functional significance of this has remained elusive.|Together, these observations suggest that PTPRK suppresses CD133\u2010mediated colon cancer growth both in\u00a0vitro and in\u00a0vivo. 0.2 SIGNOR-277133 TFEB protein P19484 UNIPROT LAMP1 protein P11279 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.441 SIGNOR-276542 ACE2 protein Q9BYF1 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT up-regulates activity cleavage His42 RVYIHPFhLVIHNES -1 11815627 YES miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. 0.2 SIGNOR-260221 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.32 SIGNOR-161565 ASF1A protein Q9Y294 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates activity binding 9606 BTO:0002181 33503415 YES miannu Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. 0.311 SIGNOR-277621 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 22343533 YES gcesareni Ror1 and ror2 bind wnt5a. 0.746 SIGNOR-196133 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser105 TGAGAAGsPAQQHAH 26375055 YES lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity 0.258 SIGNOR-276520 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273048 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 30616754 YES lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle 0.8 SIGNOR-267588 CHD8 protein Q9HCK8 UNIPROT SOX11 protein P35716 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.2 SIGNOR-268923 monobenzyl phthalate chemical CHEBI:132612 ChEBI SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression 10116 16257484 NO miannu DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged. 0.8 SIGNOR-268743 UBR5 protein O95071 UNIPROT RNF168 protein Q8IYW5 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0001938 22884692 YES miannu Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. 0.443 SIGNOR-266782 DZIP3 protein Q86Y13 UNIPROT H2AZ1 protein P0C0S5 UNIPROT up-regulates activity monoubiquitination Lys121 IHKSLIGkKGQQKTV 9606 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271748 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. 0.767 SIGNOR-272710 5-(2-propoxyphenyl)-2,3-dihydrotriazolo[4,5-d]pyrimidin-7-one chemical CHEBI:92215 ChEBI GPR35 protein Q9HC97 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257506 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT up-regulates activity phosphorylation Ser274 KKINPENsKLSDLDS 9606 BTO:0000567 12852857 YES lperfetto Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites. 0.729 SIGNOR-103403 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 YES lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. 0.449 SIGNOR-227521 DRAM2 protein Q6UX65 UNIPROT RHOC protein P08134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 NO irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. 0.2 SIGNOR-259143 TLN1 protein Q9Y490 UNIPROT ITGB3 protein P05106 UNIPROT up-regulates activity binding 10090 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.792 SIGNOR-257625 pizotifen chemical CHEBI:50212 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9205951 YES miannu The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. 0.8 SIGNOR-258617 PAX6 protein P26367 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR form complex binding 9606 10506141 YES lperfetto In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300. 0.48 SIGNOR-70963 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr566 SLNQEDIyITTESLT 10029 12907755 YES PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 0.5 SIGNOR-248421 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 BTO:0000671 9335553 NO gcesareni These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling. 0.645 SIGNOR-52707 RUNX3 protein Q13761 UNIPROT CAPN10 protein Q9HC96 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255091 INO80E protein Q8NBZ0 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.65 SIGNOR-270845 STUB1 protein Q9UNE7 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity ubiquitination 9606 23322406 YES miannu Subsequently, the ubiquitination of CARMA1 catalyzed by STUB1 was identified as Lys 27 linked, which is important for CARMA1 mediated NF-kappaB activation. 0.328 SIGNOR-278720 EPHA4 protein P54764 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates activity phosphorylation Tyr602 TYVDPFTyEDPNQAV -1 8622893 YES Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry. Complimentary approaches of in vitro binding assays and BIAcore analysis revealed a high affinity association between the Y602 Sek autophosphorylation site and the cytoplasmic tyrosine kinase p59fyn, an interaction mediated through the SH2 domain of this intracellular signalling molecule. 0.2 SIGNOR-251119 sorafenib tosylate chemical CHEBI:50928 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition -1 16757355 YES miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 0.8 SIGNOR-259454 pirenzepine chemical CHEBI:8247 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258394 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 10693759 YES gcesareni In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation 0.467 SIGNOR-75362 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT down-regulates activity phosphorylation Ser215 SGRAREAsGAPTSSK 9534 BTO:0001538 11404460 YES lperfetto Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790 0.587 SIGNOR-108504 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 20864032 YES lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) 0.2 SIGNOR-168040 RAB3C protein Q96E17 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 31679900 NO miannu Here, we identify the SEC4 ortholog RAB3 and its neuronal effector, RIM1, as essential molecules for neuropeptide and neurotrophin release from dense-core vesicles (DCVs) in mammalian neurons.  0.7 SIGNOR-264376 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275751 TFEB protein P19484 UNIPROT HPS4 protein Q9NQG7 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 NO lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) 0.292 SIGNOR-276795 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser316 VEEEPLNsEDDVSDE 9606 11278496 YES lperfetto Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity. 0.677 SIGNOR-105688 BTAF1 protein O14981 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding 9986 15509807 YES miannu We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP. 0.709 SIGNOR-263919 PRKACA protein P17612 UNIPROT HMGCR protein P04035 UNIPROT down-regulates activity phosphorylation Ser872 SHMIHNRsKINLQDL 10116 2369897 YES miannu The intact, 100 kd microsomal enzyme and the 53 kd catalytic fragment of rat HMG-CoA reductase are both phosphorylated and inactivated by the AMP-activated protein kinase. this site is highly phosphorylated in intact liver under these conditions (Ser872 in the human enzyme). 0.333 SIGNOR-249992 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser266 QGLSTALsVEKTSKR 9534 BTO:0001538 23519612 YES miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 0.318 SIGNOR-262708 APOA1 protein P02647 UNIPROT APOE protein P02649 UNIPROT up-regulates activity relocalization 9606 20642861 YES miannu ApoA-I stimulates apoE secretion in mature human adipocytes. The regulation of apoE secretion by apoA-I, is neither dependent upon an increase in gene transcription, nor upon increased release from the Golgi. It may therefore be assumed that, in macrophage models, apoE is stored mainly in the cytoplasm and/or on the cell surface, with apoA-I enabling secretion of this cytoplasmic pool 0.737 SIGNOR-252105 ABT-737 chemical CID:11228183 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189159 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 14711813 YES lperfetto Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesret short and middle isoforms contain 16 tyrosine residues in their intracellular domains, and ret long isoforms have two additional tyrosines in the c-terminal tail. Among these tyrosines, tyr905, tyr1015, tyr1062, and tyr1096 are thought to be phosphorylated to become binding sites for grb7/grb10, phospholipase c_, shc/snt(frs2)/enigma, and grb2, respectively. 0.2 SIGNOR-121141 PRKDC protein P78527 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser43 PAMLHLPsEQGAPET -1 31932854 YES miannu Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR). 0.297 SIGNOR-277508 SP1 protein P08047 UNIPROT MAOB protein P27338 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11259630 NO miannu Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. 0.274 SIGNOR-253868 B4GALT1 protein P15291 UNIPROT UDP-D-galactose smallmolecule CHEBI:18307 ChEBI down-regulates quantity chemical modification 9606 16157350 YES miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 0.8 SIGNOR-268467 Naloxone benzoylhydrazone chemical CID:9601084 PUBCHEM OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258423 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser835 ELKATLPsPDKLPGF 9606 BTO:0000567 7724583 YES lperfetto Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Thus, the serine at position 835 is a phosphorylation site. Taking these findings into consideration, we consider that cyclin b might be one of the substrates targeted by the specific ubiquitin conjugation pathway activated by the phosphorylation of e1 with cdc2 kinase. 0.406 SIGNOR-32225 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser262 DSEDYSLsEEGQELS 9606 20708156 YES gcesareni Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination 0.346 SIGNOR-167517 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser366 GCSSQSIsPMRSISE -1 28130417 YES lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. 0.324 SIGNOR-264869 MAPK11 protein Q15759 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 YES gcesareni Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target 0.756 SIGNOR-65586 PDGFRA protein P16234 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 BTO:0000567 20802513 YES miannu Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met. 0.427 SIGNOR-259400 clonidine chemical CHEBI:46631 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258905 MTNR1A protein P48039 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.496 SIGNOR-256849 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 YES milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation 0.635 SIGNOR-201298 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr162 SFDAILYyYQSGGRI 9606 BTO:0000938 BTO:0000671 19166614 YES gcesareni Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein. 0.378 SIGNOR-183519 HUWE1 protein Q7Z6Z7 UNIPROT MYCN protein P04198 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 33628735 YES miannu HUWE1 ubiquitinates and directs MYCN degradation to the proteasome. 0.424 SIGNOR-278750 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. 0.91 SIGNOR-252851 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser77 PTAGALYsGSEGDSE -1 2046671 YES llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated. 0.551 SIGNOR-250955 TNKS protein O95271 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19759537 YES lperfetto Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. 0.773 SIGNOR-187972 F2R protein P25116 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.302 SIGNOR-254850 VRK3 protein Q8IV63 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates activity binding 27346674 YES lperfetto Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding 0.703 SIGNOR-275546 ATG4B protein Q9Y4P1 UNIPROT GABARAP protein O95166 UNIPROT up-regulates activity cleavage -1 16303767 YES lperfetto In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly 0.86 SIGNOR-141929 SREBF1 protein P36956 UNIPROT FASN protein P49327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20373869 YES lperfetto Ultimately, both the AKT and MAPK transduction pathways regulate FASN expression through the modulation of expression of sterol regulatory element-binding protein (SREBP)-1c, which binds to regulatory elements in the FASN promoter. Proto-oncogene FBI-1 (Pokemon), a transcription factor of the bric--brac tramtrack broad complex/pox viruses and zinc fingers (BTB/POZ) domain family, interacts directly with SREBP-1c through its DNA-binding domain to synergistically activate the transcription of FASN 0.495 SIGNOR-242884 TMC2 protein Q8TDI7 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 YES lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). 0.394 SIGNOR-262570 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Ser399 GLLTPPQsGKKQSSG 9606 14536078 YES amattioni Phosphorylation-triggered ubiquitination has been proposed to be the major pathway regulating cyclin e protein abundance. Cdk2 activity is required for cyclin e turnover in vivo because it phosphorylates s384. Mutation of ser384 to alanine also rendered cyclin e resistant to degradation 0.955 SIGNOR-118555 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 15735019 YES miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates 0.648 SIGNOR-150480 STYK1 protein Q6J9G0 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser90 IPPARMMsTESANSF 9606 BTO:0000007 31696776 YES lperfetto We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. |The results indicated that the level of BECN1 S90 phosphorylation significantly increased after STYK1 overexpression, but not STYK1K147R mutant.|STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I 0.2 SIGNOR-264568 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser370 PLGPLAGsPVIAAAN 9606 7592773 YES lperfetto Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition 0.355 SIGNOR-29521 IKBKE protein Q14164 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity phosphorylation Thr501 ELRSRLRtLAEVLSR 9606 BTO:0000018 24882218 YES miannu As previously reported, IKKε underwent rapid activation by auto-phosphorylation on T501 upon IFNβ treatment of control A549 cells, which was impaired by TRIM6si (Figure 4D) 0.2 SIGNOR-276637 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser194 TPRKEDRsASSGAEG -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.321 SIGNOR-273961 TNC protein P24821 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 9606 BTO:0000801;BTO:0001336 24241034 YES lperfetto Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C. 0.438 SIGNOR-253312 TSC1 protein Q92574 UNIPROT RHEB protein Q15382 UNIPROT down-regulates activity binding 9606 20006481 YES lperfetto Tsc1 and tsc2 proteins, which together inhibit rheb through the gap activity of tsc2. 0.911 SIGNOR-162096 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258776 DRD3 protein P35462 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.464 SIGNOR-256981 PRKCD protein Q05655 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity phosphorylation Ser405 KTQTPPVsPAPQPTE 10029 26490115 YES Manara Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosphorylation is dependent on PLCβ3-mediated PKCδ activation 0.246 SIGNOR-260889 PTPN9 protein P43378 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22394684 YES lperfetto Results are presented as mean \u00b1 SD from three independent experiments. (B) PTPMeg2 inhibits STAT3-mediated transcriptional activity in a dose dependent manner.|These results indicate that PTPMeg2 inhibits STAT3 activation with certain specificity.|In this study, we demonstrated that PTPMeg2 dephosphorylates STAT3 at the Tyr705 residue by a direct interaction. 0.433 SIGNOR-276976 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB2 protein Q9Y5G2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265688 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ERF protein P50548 UNIPROT down-regulates phosphorylation 9606 7588608 YES lperfetto Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf 0.367 SIGNOR-216852 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser19 KLQYYYSsSEDEDSD 9606 16717095 YES lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. 0.385 SIGNOR-146829 MAPK3 protein P27361 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 YES gcesareni Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. 0.2 SIGNOR-188151 EZH2 protein Q15910 UNIPROT SSTR1 protein P30872 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 NO miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. 0.2 SIGNOR-254143 MYD88 protein Q99836 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity binding 9606 12297423 YES Signaling between MyD88 and TRAF6 is mediated by members of the IL-1R-associated kinase (IRAK) family; however, the exact function of each IRAK protein remains controversial. IRAK-1 is required for the optimal transduction of IL-1R- and TLR-mediated signals, but IRAK-1 can be replaced by other IRAKs. Surprisingly, gene targeting studies show that the newest IRAK protein, IRAK-4, has an essential role in mediating signals initiated by IL-1R and TLR engagement. 0.946 SIGNOR-252097 CSNK2A1 protein P68400 UNIPROT EEF1D protein P29692 UNIPROT unknown phosphorylation Ser162 DDIDLFGsDNEEEDK 9606 BTO:0000567 21936567 YES lperfetto Direct phosphorylation of eef1d by ck2 was shown by performing ck2 assays with eef1d -flag from hela cells. Dramatic increases in eef1d phosphorylation following _-phosphatase treatment and phospho- eef1d antibody recognizing eef1d ps162 indicated phosphorylation at the ck2 site in cells. 0.328 SIGNOR-176632 Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity binding 9606 30205058 YES miannu The exocyst is a multisubunit protein complex that was first identified and characterized in budding yeast. This complex mediates the tethering of secretory vesicles to the plasma membrane prior to fusion mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Sec3 interacts with PI(4,5)P2 (red dots) in the plasma membrane. Its interaction with the t-SNARE protein Sso promotes the assembly of the Sso–Sec9 binary t-SNARE complex. 0.426 SIGNOR-270792 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268652 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT unknown phosphorylation Tyr715 LVMLGASyWYRARLH 9606 11741929 YES llicata Hck, and to a lesser extent lck, phosphorylated the adam15 cytoplasmic domain in vitro in immune complex kinase assays. 0.355 SIGNOR-112927 magnesium(2+) chemical CHEBI:18420 ChEBI Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.8 SIGNOR-267755 ITGAM protein P11215 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 12393465 NO apalma CD11b, another marker for differentiation, was also less expressed in patients with t(8;21) in comparison to patients without t(8;21) 0.7 SIGNOR-255662 NDUFB11 protein Q9NX14 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 0.75 SIGNOR-262164 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 YES milica We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity. 0.622 SIGNOR-133551 GUCY1A2 protein P33402 UNIPROT GUCY1A2-B2 complex SIGNOR-C137 SIGNOR form complex binding 9606 10977868 YES gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity 0.2 SIGNOR-243971 CHEK1 protein O14757 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr182 SHFVRVStAQKSKKG 9606 BTO:0002181 26028025 YES miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. 0.78 SIGNOR-276909 G6PD protein P11413 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 24769394 YES miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress 0.8 SIGNOR-267050 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Tyr336 AKGNLQEyLTRHVIS -1 9169454 YES lperfetto Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor. 0.2 SIGNOR-48863 WNT7A protein O00755 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.589 SIGNOR-131900 NFATC2 protein Q13469 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 YES miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. 0.355 SIGNOR-264021 RASGEF1C protein Q8N431 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.2 SIGNOR-161505 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.75 SIGNOR-249641 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser2 sSKRAKAK 9606 22136066 YES lperfetto Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity. 0.278 SIGNOR-177940 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 19108785 YES irozzo Nilotinib is an oral second-generation bcr-abl TKI indicated for the treatment of imatinib resistant or -intolerant Ph+ CML-CP and -AP in adults. Nilotinib binds to inactive configuration of the abl kinase, thus preventing the tyrosine phosphorylation of proteins involved in bcr-abl signal transduction. Nilotinib binds to the inactive (unphosphorylated) configuration of the abl TK, with the P-Ioop folding over, disrupting the ATP binding site and catalytic activity of the enzyme. 0.8 SIGNOR-255818 ITCH protein Q96J02 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29685903 YES miannu Mechanistically, Itch ubiquitinates Foxo1 for proteasomal degradation. 0.258 SIGNOR-278698 ibuprofen chemical CHEBI:5855 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9057869 YES miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 0.8 SIGNOR-258604 PKI-587 chemical CID:44516953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205992 SEC13 protein P55735 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 YES miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 0.862 SIGNOR-255305 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT unknown phosphorylation Ser552 GTSSFKEsALRKQSL -1 26134678 YES lperfetto In humans, Aurora-A phosphorylates TACC3 on three residues (S34, S552 and S558); these sites are conserved in Maskin and the S558 equivalent site is also present in D-TACC [26,27,30]. In mammalian cells, phosphorylation of S558 promotes accumulation of TACC3 on spindle MTs 0.936 SIGNOR-263698 PCSK7 protein Q16549 UNIPROT ELK4 protein P28324 UNIPROT up-regulates phosphorylation 9606 9130707 YES gcesareni In contrast, the tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387 0.2 SIGNOR-47771 FAM83H protein Q6ZRV2 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.326 SIGNOR-273768 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 17311928 YES inferred from 70% family members llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 0.2 SIGNOR-270154 CDR2 protein Q01850 UNIPROT NUF2 protein Q9BZD4 UNIPROT up-regulates quantity by expression transcriptional regulation 20383333 NO lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology 0.2 SIGNOR-252022 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 10090 BTO:0002572 10988287 YES amattioni The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis. 0.726 SIGNOR-81808 CUDC-101 chemical CID:24756910 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262264 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Thr64 ENLRRATtDLGRSLG -1 10467162 YES lperfetto Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect. 0.2 SIGNOR-249019 EEF1A2 protein Q05639 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269537 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Ser240 RRVSGNNsPSLSNGG 9606 BTO:0000007 16446428 YES gcesareni Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222 0.654 SIGNOR-245323 ARNTL protein O00327 UNIPROT PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.572 SIGNOR-253630 leuprolide chemical CHEBI:6427 ChEBI GNRHR protein P30968 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257499 drospirenone chemical CHEBI:50838 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000671 1493716 YES miannu Dihydrospirorenone is a potent aldosterone antagonist 8 times as potent as spironolactone and antiandrogenic (0.3 times cyproterone acetate). The high binding affinity of dihydrospirorenone to the binding sites of the mineralocorticoid receptor of rat kidney with an RBA value of 230% compared to aldosterone is remarkable. This reflects the strong antimineralocorticoid activity of this compound which was evaluated in adrenalectomized rats. 0.8 SIGNOR-258349 MAPK11 protein Q15759 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 YES lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. 0.426 SIGNOR-114063 MAPK14 protein Q16539 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 10806218 YES gcesareni More importantly, incubation of active erk2 or p38 kinase with h3 protein resulted in phosphorylation of h3 at serine 10 in vitro. These results suggest that erk and p38 kinase are at least two important mediators of phosphorylation of h3 at serine 10. 0.2 SIGNOR-265338 JMY protein Q8N9B5 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 YES lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. 0.309 SIGNOR-261005 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 YES milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) 0.42 SIGNOR-230738 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 10373569 YES gcesareni Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator. 0.401 SIGNOR-238529 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.278 SIGNOR-276087 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-75013 PRKCB protein P05771 UNIPROT OCLN protein Q16625 UNIPROT up-regulates activity phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 BTO:0000837 11502742 YES lperfetto Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. 0.455 SIGNOR-249106 HOXD1 protein Q9GZZ0 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001949 21501586 YES Luana Consistently, ITGB1 promoter activity was decreased by HOXD1 knockdown in ECs. Furthermore, we identified the putative HOXD1-binding sites in the promoter region of ITGB1. Together, these findings suggest that HOXD1 plays a significant role in EC functions by regulating the expression of ITGB1. 0.2 SIGNOR-261648 SYK protein P43405 UNIPROT IL15RA protein Q13261 UNIPROT up-regulates activity phosphorylation Tyr227 AVSLLACyLKSRQTP 9606 BTO:0001154 11714793 YES lperfetto Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells 0.33 SIGNOR-246556 TRIM21 protein P19474 UNIPROT FASN protein P49327 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 27758890 YES FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. 0.2 SIGNOR-267368 ADRA2A protein P08913 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.467 SIGNOR-256841 JAK2 protein O60674 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates activity phosphorylation 9606 25624455 YES miannu PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role. 0.265 SIGNOR-254738 SMAD1 protein Q15797 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR form complex binding 9606 8893010 YES ggiuliani Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta. 0.67 SIGNOR-255774 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Ser252 MEGYRAPsRQDVYGP -1 12885254 YES GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro 0.388 SIGNOR-251234 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk. 0.309 SIGNOR-186955 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM55 protein Q9BYV6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270968 CENPM protein Q9NSP4 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.701 SIGNOR-265211 TFAP2C protein Q92754 UNIPROT SULT1E1 protein P49888 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 NO miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 0.2 SIGNOR-255399 DSCAM protein O60469 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 10116 BTO:0000938 18585357 NO miannu DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. 0.7 SIGNOR-268401 PRKAA1 protein Q13131 UNIPROT USP10 protein Q14694 UNIPROT up-regulates activity phosphorylation Ser76 DTLPRTPsYSISSTL 9606 BTO:0001109 26876938 YES miannu Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10.  0.31 SIGNOR-277207 RPS6KA5 protein O75582 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000567 9687510 YES lperfetto Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. 0.73 SIGNOR-59458 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 BTO:0001253 9811851 YES gcesareni Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. 0.2 SIGNOR-61549 thapsigargin chemical CHEBI:9516 ChEBI ATP2A2 protein P16615 UNIPROT down-regulates activity chemical inhibition 9534 30814986 YES lperfetto Treatment of Vero cells with SERCA-specific inhibitor (Thapsigargin) at a concentration that is nontoxic to the cells significantly reduced Peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV) replication. |Thapsigargin inhibits NDV-induced SERCA2 expression in Vero cells 0.8 SIGNOR-262021 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176829 Silmitasertib chemical CID:24748573 PUBCHEM CSNK2A2 protein P19784 UNIPROT down-regulates activity chemical inhibition 9606 21159648 YES Federica In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2. 0.8 SIGNOR-261130 GNAT1 protein P11488 UNIPROT PDE6G protein P18545 UNIPROT down-regulates activity binding 10090 30962282 YES In the dark, PDE6 activity is suppressed by its inhibitory γ-subunit (Pγ). Rhodopsin-catalyzed activation of the G protein, transducin, relieves this inhibition and enhances PDE6 catalysis. 0.764 SIGNOR-260008 RRAGD protein Q9NQL2 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates binding 9606 20006481 YES lperfetto Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor 0.649 SIGNOR-217550 PRKACA protein P17612 UNIPROT RGS13 protein O14921 UNIPROT up-regulates quantity by stabilization phosphorylation Thr41 SFENLMAtKYGPVVY 20974683 YES miannu Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry. 0.335 SIGNOR-259835 RPS6KA4 protein O75676 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 17183360 YES gcesareni Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) msk 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf-kb isoform p65 and stat 1 and 3. 0.272 SIGNOR-151436 DIP2A protein Q14689 UNIPROT SOD2 protein P04179 UNIPROT up-regulates activity binding 10090 BTO:0000142 33781892 YES miannu DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain. 0.2 SIGNOR-266592 1-phosphatidyl-1D-myo-inositol 4-phosphate(3-) smallmolecule CHEBI:58178 ChEBI 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity precursor of 9606 9367159 YES miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities 0.8 SIGNOR-277288 FASTKD5 protein Q7L8L6 UNIPROT COX4I1 protein P13073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25683715 NO miannu FASTKD5 is required for maturing precursor mRNAs that are not flanked by tRNAs and that therefore cannot be processed by the canonical mRNA maturation pathway. Silencing FASTKD5 rendered mature COX I mRNA almost undetectable, which severely reduced the synthesis of COX I, resulting in a complex IV assembly defect. 0.2 SIGNOR-261223 MPG protein P29372 UNIPROT IGBP1 protein P78318 UNIPROT down-regulates quantity by destabilization monoubiquitination 9606 BTO:0000007 22613722 YES miannu  We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. MID1 serves as the E3 ligase for α4 (2B), leading to a conformational change in α4 whereby the UIM of α4 binds in cis to the covalently attached ubiquitin (Ub; 3). This structural rearrangement then leads to calpain-mediated cleavage of the C terminus of α4 (4), allowing for polyubiquitination of PP2Ac by a currently unknown E3 ligase (5) and subsequent degradation by the proteasome. 0.2 SIGNOR-272040 ATF4 protein P18848 UNIPROT LARS2 protein Q15031 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.252 SIGNOR-269421 PRKACA protein P17612 UNIPROT NOS1 protein P29475 UNIPROT unknown phosphorylation -1 1375933 YES miannu NOS is stoichiometrically phosphorylated by PKA, PKC, and CaMK, with each enzyme predominantly phosphorylating a distinct serine. CPT-CAMP has no effect on NOS activity 0.322 SIGNOR-250021 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 YES gcesareni Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival. 0.426 SIGNOR-163961 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT up-regulates activity deacetylation Lys215 QENREKMkQKKFDKK 9606 30327428 YES miannu SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR 0.512 SIGNOR-258986 CDCA7L protein Q96GN5 UNIPROT MAOB protein P27338 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980443 NO miannu we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), that down-regulate MAO B via MAO B core promoter, which contains Sp1 sites. 0.288 SIGNOR-253768 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity phosphorylation Ser139 RRGLLYDsDEEDEER 9606 16899510 YES Luana Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2. 0.299 SIGNOR-259850 UBE3A protein Q05086 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 9497376 YES miannu E6AP and E6 together provide the E3-ubiquitin protein ligase activity in the transfer of ubiquitin to p53. In vitro studies have shown that E6AP can form a high energy thiolester bond with ubiquitin and, in the presence of E6, transfer ubiquitin to p53. In this study we have addressed the role of E6AP in vivo in the degradation of p53.  0.681 SIGNOR-272552 WNT3A protein P56704 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000222 10601008 YES gcesareni Here we focus on the role of Wnts, their putative receptors Frizzled and the soluble antagonist Frzb1 in regulating mammalian myogenesis. Although it is becoming evident that the signaling downstream of Frizzled receptors is much more complex than anticipated, it is conceivable that it may lead to transcriptional activation of Myf5 and MyoD and to initiation of myogenesis. 0.639 SIGNOR-73039 TGFB1 protein P01137 UNIPROT SFTPB protein P07988 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004299 18003659 NO miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. 0.281 SIGNOR-254170 MAPK3 protein P27361 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 18694962 YES Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. 0.2 SIGNOR-179963 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252335 SOX9 protein P48436 UNIPROT PRAME protein P78395 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000849 19273910 NO miannu Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. 0.317 SIGNOR-255191 SYCP2 protein Q9BX26 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 YES miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. 0.657 SIGNOR-264199 tRNA(Glu) smallmolecule CHEBI:29175 ChEBI Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270385 AKAP8L protein Q9ULX6 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 NO miannu These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA. 0.7 SIGNOR-260949 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 15821101 YES gcesareni Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2 0.796 SIGNOR-134955 BZLF2 protein P03205 UNIPROT EBV gH:gL:gp42 complex SIGNOR-C403 SIGNOR form complex binding 9606 BTO:0000776 9151859 YES scontino Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR. 0.2 SIGNOR-266625 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 17289999 YES lperfetto Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak 0.832 SIGNOR-152986 CDK3 protein Q00526 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates activity phosphorylation Ser259 APGPTPAsPRPASPC 9606 27893713 YES miannu CDK3 enhances the transactivation and transcription activity of NFAT3.|NFAT3 can be phosphorylated by CDK3 at Ser259, which is critical for its transactivation activity and cell transformation. 0.37 SIGNOR-278511 gL protein P03212 UNIPROT EBV gH:gL:gp42 complex SIGNOR-C403 SIGNOR form complex binding 9606 BTO:0000776 9151859 YES scontino Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR. 0.2 SIGNOR-266627 gH protein P03231 UNIPROT EBV gH:gL:gp42 complex SIGNOR-C403 SIGNOR form complex binding 9606 BTO:0000776 9151859 YES scontino Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR. 0.2 SIGNOR-266626 KIF3B protein O15066 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272537 POLR2H protein P52434 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.868 SIGNOR-266140 PHF2 protein O75151 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. 0.2 SIGNOR-264517 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 15210796 YES gcesareni Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. 0.432 SIGNOR-126254 EEF1A1P5 protein Q5VTE0 UNIPROT Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269542 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 17299140 YES lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. 0.929 SIGNOR-153031 3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide chemical CHEBI:92070 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258856 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 19282669 YES lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.593 SIGNOR-184573 CDK5 protein Q00535 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation 9606 22836916 YES miannu Using both the Cdk inhibitor roscovitine and an RNA interference strategy, it was also demonstrated that Cdh1 was phosphorylated by Cdk5, an enzyme that can be persistently activated when bound to p25 [ xref ], the proteolytic product of p35 that has previously been shown to accumulate in the neurons of patients with Alzheimer\u2019s disease [ xref ]. 0.298 SIGNOR-279679 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 9606 BTO:0000007 11544529 YES gcesareni Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. 0.779 SIGNOR-252064 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr149 SVTAPSPyAQPSSTF 9606 19783996 YES Manara In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. 0.541 SIGNOR-260934 anthraflavic acid chemical CHEBI:34250 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258156 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 YES lperfetto Many cellular receptors signal via tyrosine phosphorylation. The tyrosine kinases required for this activity are often recruited upon ligand bindingAlternatively, receptors themselves have kinase activity, like insulin receptors. In either case, the receptors are returned to their original state through the activity of protein-tyrosine phosphatases (PTPs)The major candidate PTPs previously implicated in IRK dephosphorylation are PTP-1b and LAR. 0.577 SIGNOR-76017 SIAH1 protein Q8IUQ4 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 16174773 YES lperfetto Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system 0.675 SIGNOR-140612 PPP1R3C protein Q9UQK1 UNIPROT GYS1 protein P13807 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 YES miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) 0.85 SIGNOR-271733 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 YES miannu In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity. 0.834 SIGNOR-250295 TNKS protein O95271 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0000142 32409565 YES lperfetto Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. 0.2 SIGNOR-262115 P2RX7 protein Q99572 UNIPROT PLD2 protein O14939 UNIPROT up-regulates 9606 8573088 NO mrosina This study shows that extracellular ATP, acting through the P2Z purinoceptor, stimulated PLD activity in human lymphocytes. 0.2 SIGNOR-254966 TFE3 protein P19532 UNIPROT CTSF protein Q9UBX1 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.2 SIGNOR-276817 Ub:E2 complex SIGNOR-C497 SIGNOR RNF44 protein Q7L0R7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271180 CASP6 protein P55212 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Asp616 EISEVKMdAEFRHDS -1 10438520 YES lperfetto Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Ab. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Ab-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons 0.724 SIGNOR-261762 GRIA4 protein P48058 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 NO miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses 0.7 SIGNOR-264614 PRKCA protein P17252 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates phosphorylation Ser1105 LDRKRHNsISEAKMR 9606 9660757 YES gcesareni These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity. 0.479 SIGNOR-58859 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation 9606 23616010 YES lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. 0.2 SIGNOR-233526 LTB4R protein Q15722 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256834 D-thyroxine smallmolecule CHEBI:30659 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 9606 BTO:0003736 6777394 YES inferred from family member miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. 0.8 SIGNOR-267802 CAD protein P27708 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity chemical modification 9606 24332717 YES In animals, the first three reactions of the pathway are catalyzed by CAD, an 240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities 0.8 SIGNOR-267194 PRKACA protein P17612 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser236 IDKNRRKsCQACRLR 9606 9891036 YES lperfetto Phosphorylation of human estrogen receptor alpha by protein kinase a regulates dimerizationeralpha is phosphorylated by protein kinase a (pka) on serine-236 within the dna binding domain. Mutation of serine-236 to glutamic acid prevents dna binding by inhibiting dimerization by eralpha 0.485 SIGNOR-63984 GEMIN2 protein O14893 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 YES lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. 0.871 SIGNOR-253116 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser138 SLQLGAVsPGTLTPT 26933062 YES lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. 0.425 SIGNOR-276589 Laminin-10 complex SIGNOR-C182 SIGNOR Laminin-10 complex SIGNOR-C182 SIGNOR up-regulates activity binding 10090 BTO:0001086 18757303 YES lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.726 SIGNOR-253277 ITGAE protein P38570 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.688 SIGNOR-253291 Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 25195934 NO miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.7 SIGNOR-270741 GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24583263 NO irozzo We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression. 0.578 SIGNOR-256007 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT up-regulates activity phosphorylation Tyr317 EEEISAMySSVNKPG 9534 16920712 YES miannu Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn. 0.725 SIGNOR-262898 PIN1 protein Q13526 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 16699525 YES lperfetto To investigate the temporal regulation of IRF3-dependent transcription by Pin1, we used a rapid-response luciferase reporter gene. Real-time reporter gene assays showed that suppression of endogenous Pin1 expression substantially prolonged both IRF3-dependent transcription and IFN-beta promoter activation after poly(I)dotpoly(C) stimulation (Fig. 4c,d). Consistent with the inhibitory effects of Pin1 on the IFN-beta promoter 0.2 SIGNOR-252289 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity phosphorylation Tyr153 LAYILSMePCGHCLI 9606 15657060 YES Manara We show that ABL1 phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents. ! Moreover, inhibition of ABL1 with STI571 blocked DNA damage-induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3. 0.514 SIGNOR-260792 JAK3 protein P52333 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Tyr371 ADFAPEDySSFQHIR 9606 BTO:0001372 23263556 YES miannu  Here we found that IL-7-Jak3 signals activated the transcription factor NFATc1 in DN thymocytes by phosphorylating Tyr371 in the regulatory region of NFATc1.  0.383 SIGNOR-276435 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 21798082 YES gcesareni Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. 0.868 SIGNOR-175665 MFGE8 protein Q08431 UNIPROT GRK2 protein P25098 UNIPROT up-regulates quantity by expression 10090 BTO:0000763 22634615 NO Giorgia Our findings showed MFG-E8–mediated upregulation of GRK2, which can be correlated with reduction of surface CXCR2. The MFG-E8 effect is mediated by αvβ3 integrin to upregulate GRK2 expression and results in downregulation of surface CXCR2 levels in neutrophils, leading to decrease of neutrophil migration 0.2 SIGNOR-260648 EDNRA protein P25101 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.541 SIGNOR-257378 AKT1 protein P31749 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 YES gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction. 0.84 SIGNOR-149698 RERE protein Q9P2R6 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity relocalization 9606 BTO:0000932 11331249 YES miannu We detected RERE protein mainly in the nucleus, where it colocalizes with the promyelocytic leukemia protein in promyelocytic leukemia oncogenic domains (PODs). Overexpression of RERE recruits a fraction of the proapoptotic protein BAX to PODS: This observation correlates with RERE-induced apoptosis, which occurs in a caspase-dependent manner. 0.2 SIGNOR-264485 RNF146 protein Q9NTX7 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21478859 YES lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.262 SIGNOR-263339 SP3 protein Q02447 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 11867623 YES Luana Sp1 and Sp3 Activate Transcription Driven by the AS Promoter 0.2 SIGNOR-268020 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 18071316 YES llicata This skp2-dependent destruction of rassf1a requires phosphorylation of the latter on serine-203 by cyclin d-cyclin-dependent kinase 4. 0.49 SIGNOR-216976 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser227 FGSFPVHsPITQGTP 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.35 SIGNOR-276111 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1A protein P50416 UNIPROT down-regulates binding 9606 17452323 YES Carnitine palmitoyltransferase 1 (CPT1) catalyzes the conversion of palmitoyl-CoA to palmitoylcarnitine in the presence of l-carnitine, thus facilitating the entry of fatty acids to mitochondria, in a process that is physiologically inhibited by malonyl-CoA 0.8 SIGNOR-267758 CDC42 protein P60953 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates activity binding 9606 BTO:0000452 11696321 YES miannu We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia. 0.863 SIGNOR-268424 4-[4-(6-methoxy-2-naphthalenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine chemical CHEBI:91442 ChEBI TEK protein Q02763 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207287 PHA-680632 chemical CID:11249084 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206100 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser91 ALDCSQVsPPRPATS 9606 BTO:0000567 12851383 YES lperfetto We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner. 0.457 SIGNOR-103254 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr12 DLSGRELtIDSIMNK -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.2 SIGNOR-276203 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EPCAM protein P16422 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11505407 NO miannu The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects. 0.283 SIGNOR-254790 glycine smallmolecule CHEBI:15428 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity precursor of 9606 34283828 YES miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 0.8 SIGNOR-267297 ANK2 protein Q01484 UNIPROT CACNA1B protein Q00975 UNIPROT up-regulates quantity binding 10090 BTO:0000142 24394417 YES miannu Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo. 0.263 SIGNOR-266707 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 NO Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA) 0.574 SIGNOR-254364 SNAP29 protein O95721 UNIPROT STX17-VAMP8 SNARE complex complex SIGNOR-C551 SIGNOR form complex binding 9606 BTO:0000007 23217709 YES miannu Here, we identify syntaxin 17 (Stx17) as the autophagosomal SNARE required for fusion with the endosome/lysosome. Stx17 localizes to the outer membrane of completed autophagosomes but not to the isolation membrane (unclosed intermediate structures); for this reason, the lysosome does not fuse with the isolation membrane. Stx17 interacts with SNAP-29 and the endosomal/lysosomal SNARE VAMP8. 0.943 SIGNOR-273710 DCAF1 protein Q9Y4B6 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000567 22570418 YES miannu By screening the known DDB1 interacting proteins, we discovered that VprBP is the substrate recognition subunit that targets Mcm10 for degradation. Hence, these results establish that Cul4-DDB1-VprBP ubiquitin ligase mediates the stress-induced proteolysis of replication factor, Mcm10. 0.2 SIGNOR-272047 EIF3C protein Q99613 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.933 SIGNOR-266398 UBE2D1 protein P51668 UNIPROT ZSWIM2 protein Q8NEG5 UNIPROT up-regulates activity binding 9606 BTO:0000007 16522193 YES miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  0.32 SIGNOR-271554 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM33 protein Q9UPN9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271077 UBE2D3 protein P61077 UNIPROT UBR5 protein O95071 UNIPROT up-regulates activity ubiquitination -1 11714696 YES miannu Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks. 0.463 SIGNOR-272669 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser139 DARDLEMsKKVRRSY -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.71 SIGNOR-276125 SMARCA2 protein P51531 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.827 SIGNOR-270688 APC-c complex SIGNOR-C150 SIGNOR KIF18A protein Q8NI77 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24510915 YES miannu Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). 0.296 SIGNOR-266110 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser222 LPEILGDsQHADVGK 9606 12086603 YES lperfetto Atm phosphorylates fancd2 on serine 222 in vitro. This site is also phosphorylated in vivo in an atm-dependent manner following ir. Phosphorylation of fancd2 is required for activation of an s phase checkpoint. The atm-dependent phosphorylation of fancd2 on s222 and the fa pathway-dependent monoubiquitination of fancd2 on k561 are independent posttranslational modifications regulating discrete cellular signaling pathways. 0.788 SIGNOR-90121 PRKAA1 protein Q13131 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser92 VAELTSLsDEDSGKG 9606 19923321 YES lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. 0.2 SIGNOR-161783 POLR1D protein P0DPB5 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.895 SIGNOR-266158 MYOD1 protein P15172 UNIPROT ITGA7 protein Q13683 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8798472 YES lperfetto Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development. 0.287 SIGNOR-241518 CTLA4 protein P16410 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000782 16227604 NO Barakat Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation. 0.603 SIGNOR-275409 MAP2K1 protein Q02750 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0001253 15020233 YES lperfetto In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta. 0.344 SIGNOR-236622 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates activity binding 10116 BTO:0004578 17346243 YES AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells) 0.852 SIGNOR-252293 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser772 LFKKIFPsLELNITD 9606 BTO:0004553 24614225 YES gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. 0.307 SIGNOR-266433 HACD proteinfamily SIGNOR-PF86 SIGNOR FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 YES Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, 0.2 SIGNOR-267764 LCK protein P06239 UNIPROT PRDX2 protein P32119 UNIPROT down-regulates activity phosphorylation Tyr193 NVDDSKEyFSKHN -1 20178744 YES miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. 0.2 SIGNOR-276279 RNF125 protein Q96EQ8 UNIPROT IFIH1 protein Q9BYX4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0005029 17460044 YES miannu Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production. 0.656 SIGNOR-271646 SSH1 protein Q8WYL5 UNIPROT CFL1 protein P23528 UNIPROT up-regulates activity dephosphorylation Ser3 sGVAVSDG 9606 14531860 YES Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH). 0.785 SIGNOR-248762 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 BTO:0000975 11145955 YES tpavlidou Subsequent studies with dominant negative elk-1, wild type, and variant gal4-elk-1 fusion proteins confirmed that phosphorylation of elk-1 at serines 383 and 389 in the c-terminal region of elk-1 is an important downstream target associated with activation of an sre by e2. Both e2 (er?-Dependent) and growth factors (er?-Independent) activated the sre in breast cancer cells via the ras/mapk pathway 0.525 SIGNOR-85510 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser33 LRRSQRKsGSELPSI -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.628 SIGNOR-276116 Mequitazine chemical CHEBI:31821 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257780 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192467 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1735 SPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248824 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr126 RDAMVRDyVRQTWKL 9606 BTO:0000661 7961936 YES lperfetto We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. By comparative two-dimensional phosphopeptide mapping, we show that ZAP-70 isolated from Jurkat T cells also autophosphorylates at Tyr-292 and Tyr-126 0.2 SIGNOR-247044 ABL1 protein P00519 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Tyr194 DVQKSKEyFSKQK -1 20178744 YES miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. 0.387 SIGNOR-276278 NANOG protein Q9H9S0 UNIPROT CGA protein P01215 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 NO miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 0.2 SIGNOR-254623 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI DIO proteinfamily SIGNOR-PF83 SIGNOR up-regulates activity chemical activation 9606 BTO:0004055 12746313 YES inferred from family member scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. 0.8 SIGNOR-270246 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 17419683 YES gcesareni Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. 0.2 SIGNOR-154285 SRC protein P12931 UNIPROT PROM1 protein O43490 UNIPROT unknown phosphorylation Tyr828 RMDSEDVyDDVETIP 9606 19296573 YES llicata Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src 0.501 SIGNOR-184772 PRKAA1 protein Q13131 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity phosphorylation Ser374 GDTLLGLsDSEVEEL -1 31805502 YES miannu MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected. 0.2 SIGNOR-277494 PRKN protein O60260 UNIPROT RHOT1 protein Q8IXI2 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24647965 YES miannu We observe that Parkin efficiently ubiquitylates Miro1 at highly conserved lysine residues, 153, 230, 235, 330 and 572, upon phosphorylation by PINK1. 0.2 SIGNOR-278561 AKT proteinfamily SIGNOR-PF24 SIGNOR NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Ser600 PARQRIRsCVSAENF 9606 12409306 YES esanto Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity. 0.2 SIGNOR-95247 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.712 SIGNOR-252818 UBE2D1 protein P51668 UNIPROT MPG protein P29372 UNIPROT up-regulates activity binding -1 25207814 YES miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E) 0.2 SIGNOR-271927 DOK1 protein Q99704 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.297 SIGNOR-257683 ADORA2A protein P29274 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.263 SIGNOR-257151 CHEK2 protein O96017 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser988 PPLFPIKsFVKTKCK 9606 BTO:0000150 14701743 YES gcesareni In this study, we tested the hypothesis that the brca1-mediated regulation of recombination requires the chk2- and atm-dependent phosphorylation sites. 0.787 SIGNOR-120575 RAP1GAP protein P47736 UNIPROT GNAZ protein P19086 UNIPROT down-regulates activity binding 9606 BTO:0000007 10593970 YES Marta Tosoni Biochemical analysis using purified recombinant proteins revealed that the physical interaction between Gaz and Rap1GAP blocks the ability of RGSs (regulators of G protein signaling) to stimulate GTP hydrolysis of the a subunit, and also attenuates the ability of activated Gaz to inhibit adenylyl cyclase. 0.351 SIGNOR-278053 MAPK3 protein P27361 UNIPROT ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation Ser685 PMFSAPSsPMPTSST -1 9525907 YES miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. 0.2 SIGNOR-262945 ATM protein Q13315 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates phosphorylation Ser564 LEEESPVsQLFELEI 9606 23405218 YES gcesareni The main phosphorylation site of daxx is identified to be ser564, which is a direct target of atm. Phosphorylation of endogenous daxx at ser564 occurs rapidly during the dna damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of daxx from mdm2, stabilizes mdm2, and inhibits dna damage-induced p53 activation. 0.5 SIGNOR-200889 PPP1CA protein P62136 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity dephosphorylation Ser824 LPGAGLSsQELSGGP 9606 20424263 YES miannu PP1\u03b1 dephosphorylates KAP1 at Ser 824 . 0.322 SIGNOR-277075 magnesium(2+) chemical CHEBI:18420 ChEBI CIB2 protein O75838 UNIPROT up-regulates activity chemical activation 9606 35408910 YES miannu Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions. 0.8 SIGNOR-269666 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser257 DSFESIEsYDSCDRL 9606 BTO:0000782 12475968 YES lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition 0.31 SIGNOR-96334 FLT3 protein P36888 UNIPROT FZD4 protein Q9ULV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15650056 NO Microarray analyses revealed higher mRNA expression of Frizzled-4, a receptor for Wnt ligands in 32D/Flt3-ITD cells. Findings were verified by quantitative realtime reverse transcription–polymerase chain reaction (RT-PCR) and on the protein level. 0.2 SIGNOR-260121 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 20727996 YES gcesareni Elk-1 is a member of the e-twenty-six (ets) domain superfamily of transcription factors and has been traditionally associated with mitogen-induced immediate early gene transcription upon phosphorylation by mitogen activated protein kinases (erk/mapk). 0.525 SIGNOR-167539 FASN protein P49327 UNIPROT Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 9356448 NO miannu Our model of the native fatty acid synthase (FAS) depicts it as a dimer of two identical multifunctional proteins (Mr approximately 272,000) arranged in an antiparallel configuration so that the active Cys-SH of the beta-ketoacyl synthase of one subunit (where the acyl group is attached) is juxtaposed within 2 A of the pantetheinyl-SH of the second subunit (where the malonyl group is bound). This arrangement generates two active centers for fatty acid synthesis and predicts that if we have two appropriate halves of the monomer, we should be able to reconstitute an active fatty acid-synthesizing site 0.7 SIGNOR-270536 PRKCD protein Q05655 UNIPROT FBXO25 protein Q8TCJ0 UNIPROT up-regulates activity phosphorylation Ser178 DLLQDLSsTLCILIR 10090 BTO:0002572 25419709 YES lperfetto FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells, 0.271 SIGNOR-275561 MYC protein P01106 UNIPROT MYCT1 protein Q8N699 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11909865 YES miannu MT-MC1 is a widely expressed nuclear protein whose overexpression, unlike that of c-Myc targets reported previously, recapitulates multiple c-Myc phenotypes. These include promotion of apoptosis, alteration of morphology, enhancement of anchorage-independent growth, tumorigenic conversion, promotion of genomic instability, and inhibition of hematopoietic differentiation. The MT-MC1 promoter is a direct c-Myc target; it contains two consensus E-box elements, both of which bind c-Myc. 0.298 SIGNOR-261736 PCSK7 protein Q16549 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation 9606 BTO:0000130 19544470 YES gcesareni Addition of active p38a induced phosphorylation of wild-type c/ebp_? (c/ebp_?WT) on serine 21 0.2 SIGNOR-186202 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 22337877 YES lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts 0.356 SIGNOR-235557 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 YES gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.738 SIGNOR-163254 TP53 protein P04637 UNIPROT NLRC4 protein Q9NPP4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15580302 NO miannu Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53. Overexpression of p53 by transfection in U2OS and A549 cells increased Ipaf mRNA levels. 0.448 SIGNOR-255439 CAMK2D protein Q13557 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates 9606 19725819 NO areggio In response toincreases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin 0.452 SIGNOR-255956 POLE2 protein P56282 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR form complex binding 9606 BTO:0000567 10801849 YES lperfetto Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon. 0.921 SIGNOR-265519 RPS6KA5 protein O75582 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 YES The effect has been demonstrated using P07101-3 gcesareni Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax. studies on th from several species suggest that ser40 is the main site involved in direct activation of th 0.338 SIGNOR-95491 STAT5A protein P42229 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21261500 NO miannu STAT5 binds directly to the promoter region and potently mediates repression of MEF2C, probably via HDAC recruitment. 0.278 SIGNOR-254207 mTORC1 complex SIGNOR-C3 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 NO miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity 0.342 SIGNOR-256172 FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 21525013 YES lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 0.79 SIGNOR-173429 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr157 VLCVLATtDRRRRDL 9606 BTO:0000671 17522053 YES llicata Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc). 0.2 SIGNOR-155102 ZMIZ1 protein Q9ULJ6 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 26522984 YES miannu The N-terminal domain (NTD) of Zmiz1 is important for driving Myc transcription and proliferation […] Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites. 0.362 SIGNOR-263939 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120212 GSK3B protein P49841 UNIPROT APC protein P25054 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 SIGNOR-C110 10698523 YES lperfetto Gsk-3beta-dependent phosphorylation of apc. 0.758 SIGNOR-75366 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 15546612 YES gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. 0.551 SIGNOR-130640 CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000975 27702664 YES lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively 0.8 SIGNOR-268669 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 SIGNOR-C17 10864927 YES gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.858 SIGNOR-78420 DNAH17 protein Q9UFH2 UNIPROT Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 9606 BTO:0001277 31178125 NO miannu Our study provides a comprehensive analysis of ODA heavy chain distribution in human spermatozoa and demonstrates the importance of DNAH17 (β-HC) in sperm flagellum structure and motility. We demonstrate that DNAH17 (β-HC) mutations are associated with a loss of ODAs and male infertility but not with PCD. 0.7 SIGNOR-265549 MAPK8 protein P45983 UNIPROT PKMYT1 protein Q99640 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 19204086 YES The results showed that residues 140 to 205 of JNK1 have the ability to interact with Myt1. gcesareni A kinase assay using gst-myt1 revealed that active jnk1 or jnk3, but not jnk2, phosphorylated myt1 in vitro. 0.337 SIGNOR-183899 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15001544 YES lperfetto Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation. 0.706 SIGNOR-123177 TFE3 protein P19532 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells 0.264 SIGNOR-276829 ATRX protein P46100 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 7227 BTO:0001138 22021382 NO 1 miannu XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression. 0.405 SIGNOR-239733 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 27383048 YES miannu Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. 0.87 SIGNOR-42980 EIF2AK2 protein P19525 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 YES miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. 0.309 SIGNOR-263121 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.716 SIGNOR-263012 DAMPS stimulus SIGNOR-ST18 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR up-regulates 9606 25720354 NO scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 0.7 SIGNOR-267858 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR USP37 protein Q86T82 UNIPROT up-regulates activity phosphorylation Ser628 MVNSCITsPSTPSKK 9606 BTO:0000007;BTO:0000567 21596315 YES lperfetto There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity 0.447 SIGNOR-265053 KLHL15 protein Q96M94 UNIPROT PPP2R5B protein Q15173 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23135275 YES miannu Here, we report that KLHL15-Cul3 specifically targets B'β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B'β. 0.2 SIGNOR-272017 LEF1 protein Q9UJU2 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 17081971 NO amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. 0.7 SIGNOR-229767 CSNK2A1 protein P68400 UNIPROT CAPZA1 protein P52907 UNIPROT up-regulates phosphorylation Ser9 ADFDDRVsDEEKVRI 9606 15831458 YES lperfetto We demonstrate that ser9 of cpalpha is phosphorylated by protein kinase ck2 in vitro, that cpalpha is phosphorylated in vivo. Finally, we demonstrate that ckip-1 and ck2 inhibit the activity of actin capping protein at the barbed ends of actin filaments. 0.2 SIGNOR-135422 CDK5 protein Q00535 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT up-regulates activity phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 35443760 YES miannu Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson's disease.|Moreover, the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of SIRT2 at the Ser331 and Ser335 sites appears to be necessary for such nuclear translocation. 0.398 SIGNOR-279684 CSNK2B protein P67870 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Ser215 IKEEDTPsDNDSGIC 9606 BTO:0000567 23123191 YES miannu By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.  0.2 SIGNOR-276424 SMARCA2 protein P51531 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.83 SIGNOR-270701 ROS stimulus SIGNOR-ST2 SIGNOR PAX2 protein Q02962 UNIPROT up-regulates quantity by expression 10090 16985513 NO High glucose-induced Pax-2 gene expression is mediated, at least in part, via ROS generation and activation of the nuclear factor kappa B signaling pathway, but not via protein kinase C, p38 mitogen-activated protein kinase (MAPK), and p44/42 MAPK signaling. 0.7 SIGNOR-252295 CAMK4 protein Q16566 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates activity phosphorylation Ser302 PQLASKQsMVNSLPT BTO:0000938 11970865 YES llicata Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301. 0.634 SIGNOR-250710 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates 25901680 NO lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.7 SIGNOR-262601 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr326 EVLEDNDyGRAVDWW 9534 BTO:0004055 11445557 YES lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. 0.676 SIGNOR-246377 CCL21 protein O00585 UNIPROT CCR7 protein P32248 UNIPROT up-regulates binding 9606 BTO:0000671 11970971 YES gcesareni The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7. 0.785 SIGNOR-117566 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 29901072 YES miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. 0.8 SIGNOR-262219 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Ser277 SHSQDLGsPERHQPV 9606 BTO:0000567 12734188 YES lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. 0.362 SIGNOR-101043 SRPK2 protein P78362 UNIPROT ACIN1 protein Q9UKV3 UNIPROT up-regulates phosphorylation Ser1180 GPRSRSRsRDRRRKE 9606 BTO:0001271 18559500 YES lperfetto Here, we show that srpk2 binds and phosphorylates acinus, an sr protein essential for rna splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin a1 but not a2 up-regulation. Acinus s422d, an srpk2 phosphorylation mimetic, enhances cyclin a1 transcription, whereas acinus s422a, an unphosphorylatable mutant, blocks the stimulatory effect of srpk2 0.477 SIGNOR-179006 CCR6 protein P51684 UNIPROT MMP9 protein P14780 UNIPROT up-regulates activity 9606 BTO:0000584 15652956 YES miannu We hypothesized that MIP-3alpha promotes pancreatic cancer invasion through the up-regulation of MMP-9, a Type 4 collagenase. 0.2 SIGNOR-278042 SMC4 protein Q9NTJ3 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.938 SIGNOR-263904 JAK1 protein P23458 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity phosphorylation Tyr585 NDIKNSGyISRYLTD 10090 BTO:0000099 25113558 YES miannu JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3. 0.2 SIGNOR-276676 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 YES Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. 0.569 SIGNOR-248336 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS 9606 10931940 YES lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform. 0.545 SIGNOR-261773 RPS6KA1 protein Q15418 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 9606 BTO:0000848 21087211 YES gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3) 0.2 SIGNOR-169883 MYCT1 protein Q8N699 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity 9606 30283340 NO miannu Herein, we observed that overexpression of MYCT1 induced apoptosis in HL-60 and KG-1a cells, and upregulated Bax, downregulated Bcl-2, and enhanced cleavage of caspase-3 and -9. Similar proapoptotic role of MYCT1 was also found in the AML cell xenografts. These results suggest that MYCT1 affects AML cell apoptosis by modulating the endogenous apoptotic pathways. 0.2 SIGNOR-261943 TLK1 protein Q9UKI8 UNIPROT NEK1 protein Q96PY6 UNIPROT up-regulates activity phosphorylation Thr141 IFLTKDGtVQLGDFG 28426283 YES lperfetto TLK1 phosphorylated NEK1 at T141, which lies in the kinase domain, and caused an increase in its activity.  0.291 SIGNOR-275840 GRIK4 protein Q16099 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264345 TNF protein P01375 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 11287630 NO lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase 0.318 SIGNOR-106596 SETDB2 protein Q96T68 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity methylation Lys 10 RTKQTARkSTGGKAP 9606 BTO:0000007 20404330 YES miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. 0.2 SIGNOR-263896 CDK5 protein Q00535 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity phosphorylation 9606 12202491 YES lperfetto Pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. Increasing doses of cdk2 resulted in increased phosphorylation of the thr-320 site. Phosphorylation of this site in pp1 corresponded to decreased pp1 activity. 0.472 SIGNOR-264649 AMH protein P03971 UNIPROT AMHR2 protein Q16671 UNIPROT up-regulates binding 9606 8119126 YES acerquone The results point to anti-m?llerian Hormone (amh) being the most likely candidate ligand for c14. 0.805 SIGNOR-36215 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-268077 PAX3 protein P23760 UNIPROT MEOX2 protein P50222 UNIPROT up-regulates activity binding -1 11423130 YES miannu We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family. 0.405 SIGNOR-222238 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser243 DKRKDPSsVDIKKVL -1 10480872 YES llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. 0.347 SIGNOR-250774 UNII-XH2662798I chemical CID:16156006 PUBCHEM Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates 9606 20068082 NO gcesareni Pf-00477736 also significantly enhances docetaxel efficacy in vitro and in vivo, in association with decreased cdc25c cytoplasmic phosphorylation (ser216) and histone h3 phosphorylation (ser10)(42). 0.8 SIGNOR-265352 ELF3 protein P78545 UNIPROT SPRR1B protein P22528 UNIPROT up-regulates quantity by expression transcriptional regulation 12682075 NO Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3 0.2 SIGNOR-254281 ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 15775976 YES gcesareni Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase. 0.925 SIGNOR-134716 CUL3 protein Q13618 UNIPROT MAP1S protein Q66K74 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000142 18680552 YES miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. 0.242 SIGNOR-268947 Ub:E2 complex SIGNOR-C497 SIGNOR ZFPL1 protein O95159 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271151 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 APPSPAWsEPEPEAG 10090 37029927 YES miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. 0.2 SIGNOR-277795 F2RL1 protein P55085 UNIPROT SDC4 protein P31431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254844 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT up-regulates quantity phosphorylation Ser185 KELRELLsISSESLQ 9606 BTO:0000007 23649622 YES done miannu TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.TBK1-SIKE interactions were modulated by SIKE phosphorylation, clustered in the C-terminal portion of SIKE (Ser-133, -185, -187, -188, -190, and -198). Here, we describe the mechanism by which suppressor of IKKε (SIKE) inhibits TBK1-mediated phosphorylation of interferon regulatory factor 3 (IRF3), which is essential to type I interferon production. Kinetic analyses showed that SIKE not only inhibits IRF3 phosphorylation but is also a high affinity TBK1 substrate. 0.717 SIGNOR-273813 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 YES gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk 0.352 SIGNOR-88736 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 BTO:0000142 1411546 YES gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product 0.742 SIGNOR-19240 HTR4 protein Q13639 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257416 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser29 WLKDQELsPREPVLP 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.249 SIGNOR-275599 JAK3 protein P52333 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 18250158 YES gcesareni For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated. 0.854 SIGNOR-160672 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.91 SIGNOR-249626 HSD3B1 protein P14060 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 2139411 YES lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. 0.8 SIGNOR-268638 PRKCB protein P05771 UNIPROT TP73 protein O15350 UNIPROT up-regulates activity phosphorylation Ser388 VPQPLVDsYRQQQQL 9606 19158275 YES miannu Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.  0.2 SIGNOR-276234 DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT up-regulates activity 9606 19151762 NO lperfetto Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68 0.7 SIGNOR-242605 GATA1 protein P15976 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 NO Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. 0.376 SIGNOR-251806 NEK7 protein Q8TDX7 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity phosphorylation Ser1033 GINTLERsKVEETTE 10090 BTO:0000938 29899413 YES done miannu NEK7 regulates these processes in part through phosphorylation of the kinesin Eg5/KIF11, promoting its accumulation on microtubules in distal dendrites.  0.407 SIGNOR-273890 TACR2 protein P21452 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256879 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763 12193595 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-91734 CBLB protein Q13191 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000782 11087752 YES miannu Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.Here it is shown that Cbl-b interacts with and induces ubiquitin conjugation to the p85 regulatory subunit of phosphatidylinositol 3-kinase, an upstream regulator of Vav. 0.516 SIGNOR-272583 PKNOX1 protein P55347 UNIPROT PBX1 protein P40424 UNIPROT up-regulates activity binding -1 9482740 YES 2 miannu we show that Pbx proteins exist as stable heterodimers with a novel homeodomain protein, Prep1. Here we show that Prep1-Pbx interaction presents novel structural features: it is independent of DNA binding and of the integrity of their respective homeodomains, and requires sequences in the N-terminal portions of both proteins. The Prep1-Pbx protein-protein interaction is essential for DNA-binding activity. 0.745 SIGNOR-241212 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 YES miannu In vitro kinase assay revealed that PDHA could be readily phosphorylated by active AMPK complex in a dose-dependent manner (Figure 6C).  0.254 SIGNOR-276835 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 YES lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. 0.2 SIGNOR-131391 CTDSPL2 protein Q05D32 UNIPROT PDIK1L protein Q8N165 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser194 KVADFGLsKVCSASG 9606 BTO:0002181 35021089 YES miannu  We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D). 0.356 SIGNOR-273773 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273069 ASIP protein P42127 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.5 SIGNOR-268713 Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 NO miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.7 SIGNOR-270890 STAT3 protein P40763 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR form complex binding 9606 19723038 YES miannu Sp1 and stat3 seem to synergistically augment renalase transcription. 0.456 SIGNOR-187793 USP37 protein Q86T82 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 21596315 YES lperfetto USP37 Binds, Deubiquitinates, and Stabilizes Cyclin A 0.579 SIGNOR-265052 CDKAL1 protein Q5VV42 UNIPROT tRNA(Lys) smallmolecule CHEBI:29185 ChEBI up-regulates quantity chemical modification 9606 21841312 YES We show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in tRNA(Lys)(UUU) and that it is required for the accurate translation of AAA and AAG codons 0.8 SIGNOR-272474 DCAF7 protein P61962 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181; BTO:0003484 16887337 NO Giorgia HAN11 and mDia1 repressed DYRK1A-dependent GLI1 transcriptional activity. The studies of SZ95 cells suggest that HAN11 reduces GLI1-dependent transcription by decreasing the nuclear pool of GLI1. 0.261 SIGNOR-260634 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI up-regulates quantity precursor of 9606 25406093 YES lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. 0.8 SIGNOR-268565 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 15996096 YES miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). 0.8 SIGNOR-266533 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser645 NLSTNADsQSSSDFE 9606 16600297 YES lperfetto Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin 0.698 SIGNOR-145841 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267903 RFWD3 protein Q6PCD5 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity binding 9606 BTO:0002552 20173098 YES miannu RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage.  0.365 SIGNOR-271945 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 NO lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. 0.7 SIGNOR-216319 IKBKB protein O14920 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates phosphorylation 9606 9346241 YES gcesareni We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation 0.764 SIGNOR-52932 MTMR3 protein Q13615 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity chemical modification 9606 18429927 YES miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 0.8 SIGNOR-269811 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 24710148 YES milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). 0.759 SIGNOR-204847 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268582 IL6ST protein P40189 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 16306329 NO mrosina Upon formation of the IL-6/IL-6Ralpha/gp130 hexameric signaling complex, two distinct signaling pathways are activated: 1) Janus kinase (JAK)/signal transducers and activator of transcription (STAT) and 2) the Src homology 2-containing tyrosine phosphatase (SHP-2)/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathways 0.277 SIGNOR-255022 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser721 TPRLRSVsSYGNIRA 9606 SIGNOR-C3 18722121 YES llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity 0.547 SIGNOR-180462 GNAL protein P38405 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates activity binding 9606 BTO:0004032 21303898 YES miannu D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum. 0.641 SIGNOR-267852 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 YES llicata Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta 0.2 SIGNOR-263043 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser362 QGRSGCSsQSISPMR -1 28130417 YES lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. 0.324 SIGNOR-264867 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0001412 18025157 YES We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. 0.2 SIGNOR-255749 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser293 GSTKRRKsMSGASPK 9606 12676583 YES Manara Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A 0.842 SIGNOR-260836 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 15276472 YES gcesareni Once activated, calcineurin directly dephosphorylates members of the nuclear factor of activated t-cells (nfat) transcription factor family in the cytoplasm, promoting their translocation into the nucleus. 0.825 SIGNOR-127248 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 21159646 YES gcesareni In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases. 0.8 SIGNOR-170611 SRC protein P12931 UNIPROT PLSCR1 protein O15162 UNIPROT up-regulates activity phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 12871937 YES lperfetto Plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77.|The EGF-mediated Interaction between PLSCR1 and Shc Requires Phosphorylation of Tyr69 and Tyr74 in PLSCR1 0.476 SIGNOR-103773 YAP1 protein P46937 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 23431053 YES YAP can specifically recognize the phosphorylated SMAD linker sequence containing the PY motif, and its presence is required for efficient transcription of BMP target genes. gcesareni Yap binds to the phosphorylated smad1 to activate gene transcription. 0.574 SIGNOR-201462 MRPL40 protein Q9NQ50 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.726 SIGNOR-262356 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser222 TSPARLGsQHSPGRT 9606 21419341 YES lperfetto Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex. 0.443 SIGNOR-172873 DVL3 protein Q92997 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 12533515 YES gcesareni Wnt/fz activation of rac and rho is inhibited by rac-n17 and rho-n19, respectively (figs. _(figs.1d,1d, _d,5c,d;5c,d;habas et al. 2001), and requires different dvl domains wnt signaling induces complex formation between dvl and rac. 0.466 SIGNOR-97409 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT up-regulates activity phosphorylation Tyr95 DRRFRGRyRSPYSGP 9606 BTO:0000007 27018250 YES miannu In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner. 0.322 SIGNOR-262609 KIF1C protein O43896 UNIPROT RAB6B protein Q9NRW1 UNIPROT up-regulates quantity relocalization -1 20360680 YES miannu Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. 0.2 SIGNOR-266878 MAP3K8 protein P41279 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 15466476 YES lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. 0.573 SIGNOR-244904 amitriptyline chemical CHEBI:2666 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258700 RPL36AL protein Q969Q0 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.79 SIGNOR-262493 ITK protein Q08881 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 YES lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated 0.405 SIGNOR-98090 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation 9606 20708156 YES gcesareni Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase. 0.346 SIGNOR-167520 GNB1 protein P62873 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.529 SIGNOR-252679 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity phosphorylation Ser1700 VNSDRRDsLQQTNTT -1 19074150 YES miannu We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry. 0.395 SIGNOR-263108 IL7 protein P13232 UNIPROT IL7R protein P16871 UNIPROT up-regulates binding 9606 BTO:0000782 8204885 YES fspada Antibody r34.34 was further found to be directed against an epitope interfering with binding of interleukin-7 (il-7) to pre-alp cells. Expression cloning from a pre-alp cdna library showed that r34.34 antigen is cdw127, the 75- to 80-kd il-7 receptor. Proliferation of the b-lineage all cell lines reh and mieliki was inhibited by il-7, and this effect was specifically reverted by moab r34.34. In addition, antibody r34.34 specifically inhibited il-7-dependent proliferation of normal bcp, pre-alp cells, and peripheral t cells. These results imply that both inhibitory and proliferative effects of il-7 can be mediated through the same receptor on various lineages. 0.914 SIGNOR-37012 TSSK4 protein Q6SA08 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 15964553 YES gcesareni Tssk5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates creb at ser-133, and stimulates the cre/creb responsive pathway. 0.578 SIGNOR-138289 DVL3 protein Q92997 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity 9606 19279717 YES areggio Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin 0.347 SIGNOR-258980 RASSF1 protein Q9NS23 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002552 12024041 NO Luana RASSF1A expression dramatically inhibits native cyclin D1 accumulation | Regulation of cyclin D1 accumulation by RASSF1A is independent of the cyclin D1 promoter and likely occurs through inhibition of mRNA translation. 0.571 SIGNOR-259455 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21041712 YES gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. 0.8 SIGNOR-169203 Ub:E2 complex SIGNOR-C497 SIGNOR RFFL protein Q8WZ73 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270955 FHL2 protein Q14192 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001129 10654935 YES gcesareni Fhl2 contains a strong, autonomous transactivation function and binds specifically to the ar in vitro and in vivo. 0.523 SIGNOR-74703 OTUB1 protein Q96FW1 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization deubiquitination 34785775 YES lperfetto Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec 0.564 SIGNOR-276528 U69593 chemical CHEBI:73357 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258827 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation Tyr1034 AIETDKEyYTVKDDR -1 12559972 YES Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD) 0.535 SIGNOR-251363 KAT2A protein Q92830 UNIPROT H3Y1 protein P0DPK2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269597 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI SPOP protein O43791 UNIPROT up-regulates activity binding 9606 BTO:0000007 18218622 YES Gianni Taken together, these data define a novel mechanism whereby the phosphoinositide PI5P leads to stimulation of Cul3-SPOP ubiquitin ligase activity and also implicate PIPKIIbeta as a key regulator of this signaling pathway through its association with the Cul3-SPOP complex. 0.8 SIGNOR-268863 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity methylation 9606 24987060 YES miannu The presence of trimethylation of H3K27 (H3K27me3) at promoter regions is associated with gene repression. This modification is generated by the Polycomb repressive complex 2 (PRC2), composed of the SET domain-containing histone methyltransferase (HMT) EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1, and core accessory proteins (EED, SUZ12, and RbAp48) (Fig. 1A). 0.2 SIGNOR-265367 SRC protein P12931 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity phosphorylation Tyr1510 LVKLQQTyAALNSKA 9606 BTO:0000815 33087447 YES miannu IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. 0.694 SIGNOR-277533 MZF1 protein P28698 UNIPROT PRKCA protein P17252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26010542 YES irozzo The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity. 0.384 SIGNOR-256337 PRKACA protein P17612 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT up-regulates activity phosphorylation Ser682 EIEKLGRsIVSSPQG -1 29230552 YES miannu PKD2L1 channel activation by PKA phosphorylation. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of β2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation. 0.2 SIGNOR-273563 GATOR1 complex SIGNOR-C192 SIGNOR RRAGB protein Q5VZM2 UNIPROT down-regulates activity gtpase-activating protein -1 23723238 YES GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. 0.737 SIGNOR-253563 CDK2 protein P24941 UNIPROT CROCC protein Q5TZA2 UNIPROT down-regulates phosphorylation Ser1460 APRPVPGsPARDAPA 9606 22610972 YES llicata Finally, phosphorylation of tax1bp2 at serine-763 by cyclin-dependent kinase (cdk)2 abolished the tax1bp2-mediated p38 activation and tumor-suppressive activity, indicating that tax1bp2 can adapt cdk2 signaling to the p38/p53/p21 pathway. 0.2 SIGNOR-197593 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 9305639 YES lperfetto These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1. 0.639 SIGNOR-50891 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR CSNK1A1 protein P48729 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000670 26131937 YES gcesareni We demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1a) by the E3 ubiquitin ligase CUL4€“RBX1€“DDB1€“CRBN (known as CRL4CRBN) 0.386 SIGNOR-236907 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 YES milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. 0.454 SIGNOR-236985 CDK7 protein P50613 UNIPROT XRN2 protein Q9H0D6 UNIPROT up-regulates activity phosphorylation Thr439 FTPSGILtPHALGSR 9606 26728557 YES Luana CDKs and Xrn2 phosphorylation promote transcription termination. | Cdk7 phosphorylated Xrn2-Thr439 but was less efficient than Cdk9. | 0.247 SIGNOR-259851 TUBGCP4 protein Q9UGJ1 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 YES lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” 0.821 SIGNOR-262328 IFNAR complex SIGNOR-C243 SIGNOR Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 NO miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. 0.7 SIGNOR-260848 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 YES gcesareni Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. 0.63 SIGNOR-180545 TNKS protein O95271 UNIPROT TERF1 protein P54274 UNIPROT down-regulates activity ADP-ribosylation -1 11739745 YES lperfetto Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA. 0.802 SIGNOR-263377 LATS2 protein Q9NRM7 UNIPROT MTF1 protein Q14872 UNIPROT down-regulates activity phosphorylation Ser152 EGCPRTYsTAGNLRT 35027733 YES lperfetto The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression 0.2 SIGNOR-275475 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000007 14761950 YES lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. 0.374 SIGNOR-121709 FRK protein P42685 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr391 PFLNSGTyHSRDEST 9606 BTO:0002035 35723276 YES miannu Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.  0.275 SIGNOR-275455 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 20385093 YES gcesareni A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution. 0.892 SIGNOR-164785 CSNK2A1 protein P68400 UNIPROT SERINC3 protein Q13530 UNIPROT up-regulates activity phosphorylation Ser380 ILGDTTTsGASDEED -1 30135209 YES miannu The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro. 0.2 SIGNOR-273631 FLT3 protein P36888 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by repression transcriptional regulation 16146838 NO lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. 0.621 SIGNOR-249634 DNA_damage stimulus SIGNOR-ST1 SIGNOR ERCC8 protein Q13216 UNIPROT up-regulates 24086043 NO lperfetto TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. 0.7 SIGNOR-275690 SCN10A protein Q9Y5Y9 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 NO miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. 0.7 SIGNOR-253454 Caspase 3 complex complex SIGNOR-C221 SIGNOR GAS2 protein O43903 UNIPROT up-regulates cleavage Asp278 MLQISRVdGKTSPIQ 9606 10564664 YES gcesareni We now demonstrate that gas2 is a substrate of caspase-3 but not of caspase-6. Proteolytic processing both in vitro and in vivo is dependent on aspartic residue 279. 0.45 SIGNOR-256439 DHFR protein P00374 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI down-regulates quantity chemical modification 9606 21876184 YES lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. 0.8 SIGNOR-268257 CD79B protein P40259 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 32323266 YES scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. 0.656 SIGNOR-268201 buspirone chemical CHEBI:3223 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258885 PHF7 protein Q9BWX1 UNIPROT SMARCD3 protein Q6STE5 UNIPROT form complex binding 9606 33941892 YES miannu Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, it increases chromatin accessibility and transcription factor binding at these sites. Furthermore, PHF7 recruits cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. PHF7 interacts with SMARCD3 to promote reprogramming. 0.2 SIGNOR-269816 USP1 protein O94782 UNIPROT FANCI protein Q9NVI1 UNIPROT down-regulates activity deubiquitination SIGNOR-C302 18985065 YES lperfetto Phosphorylation of FANCI may also turn the ubiquitinated ID complex into a poor substrate for deubiquitination by the USP1–UAF1 complex, resulting in increased levels of monoubiquitinated FANCD2. 0.664 SIGNOR-263272 RCOR1 protein Q9UKL0 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding -1 16140033 YES miannu CoREST protects LSD1 from proteasomal degradation and also plays an indispensable role in LSD1-mediated demethylation of nucleosomal substrates in vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity. 0.955 SIGNOR-264506 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser192 PRPDHTKsIYTRSVI -1 10075701 YES miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites 0.2 SIGNOR-250225 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR Platelet_Adhesion phenotype SIGNOR-PH137 SIGNOR up-regulates 9606 BTO:0000132 25297919 NO lperfetto VWF binding to GPIb-IX-V induces platelet activation, converting the major integrin αIIbβ3 from a low affinity to a high affinity receptor capable of engaging the C4 domain of VWF. This last step is essential for stable adhesion 0.7 SIGNOR-261867 LYN protein P07948 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.707 SIGNOR-268209 MAPK1 protein P28482 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 YES gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. 0.53 SIGNOR-196030 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser94 QISTIAEsEDSQESV 9606 9931297 YES lperfetto Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement. 0.312 SIGNOR-64250 TOMM5 protein Q8N4H5 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 YES lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. 0.634 SIGNOR-267675 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 YES lperfetto The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions 0.789 SIGNOR-236373 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 22865920 YES lperfetto When phosphorylated by camk/pkd, class iia hdacs bind 14-3-3 chaperone proteins, which facilitates their nuclear export, thereby relieving hdac-mediated transcriptional repression. 0.517 SIGNOR-198662 oligopeptide smallmolecule CHEBI:25676 ChEBI peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity precursor of 9606 31810556 YES scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. 0.8 SIGNOR-267866 LPAR2 protein Q9HBW0 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.387 SIGNOR-256784 OXTR protein P30559 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.551 SIGNOR-257266 betrixaban chemical CHEBI:140421 ChEBI F10 protein P00742 UNIPROT down-regulates activity chemical inhibition -1 19297154 YES Luana Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. 0.8 SIGNOR-257817 MAPK6 protein Q16659 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity phosphorylation Ser60 EMERALNsYFEPPVE -1 26701725 YES miannu In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition.  0.377 SIGNOR-277188 DYRK2 protein Q92630 UNIPROT PSMC4 protein P43686 UNIPROT down-regulates quantity by destabilization phosphorylation Thr25 LSVSRPQtGLSFLGP 26655835 YES lperfetto Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation. 0.284 SIGNOR-275845 CHEK2 protein O96017 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process 0.2 SIGNOR-171026 AKT1 protein P31749 UNIPROT DLC1 protein Q96QB1 UNIPROT unknown phosphorylation Ser766 VTRTRSLsACNKRVG 10116 16338927 YES gcesareni We have demonstrated that Ser-322 is phosphorylated upon insulin stimulation of intact cells and that this site is directly phosphorylated in vitro by PKB and ribosomal S6 kinase, members of the AGC (protein kinases A, G, and C) family of insulin-stimulated protein kinases 0.496 SIGNOR-252550 DLGAP5 protein Q15398 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 YES miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. 0.393 SIGNOR-264213 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12645577 YES lperfetto These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. 0.377 SIGNOR-217439 ITGA9 protein Q13797 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.781 SIGNOR-253183 alpha-D-ribose 1-phosphate(2-) smallmolecule CHEBI:57720 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 17804405 YES miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. 0.8 SIGNOR-267074 PHF12 protein Q96QT6 UNIPROT TLE2 protein Q04725 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 YES miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. 0.2 SIGNOR-266992 USF2 protein Q15853 UNIPROT B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 NO miannu Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation. 0.2 SIGNOR-254656 HARS1 protein P12081 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 10430027 YES miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 0.8 SIGNOR-270487 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Ser287 RQRKGTLsVNFVDLY -1 27292631 YES miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. 0.304 SIGNOR-274062 HERPUD1 protein Q15011 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by stabilization relocalization 9606 29295953 YES miannu A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation.  0.412 SIGNOR-261346 CD2AP protein Q9Y5K6 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 BTO:0000007;BTO:0001938 29175910 YES lperfetto One such regulator is the adaptor protein CD2AP, which delivers capping proteins to the barbed ends of polymerizing F-actin. Capping growing filaments can promote the formation of actin branches by increasing the G-actin pool available to form branches 0.7 SIGNOR-264769 CSNK2A1 protein P68400 UNIPROT PHF8 protein Q9UPP1 UNIPROT up-regulates activity phosphorylation Ser854 DAEYIYPsLESDDDD 9606 BTO:0000567 33010150 YES miannu  The CK2 kinase is responsible for PHF8 phosphorylation at Ser854. PHF8 is phosphorylated by CK2, which regulates binding of PHF8 to TopBP1. The Ser854 residue of PHF8 is required for its interaction with TopBP1. 0.2 SIGNOR-273628 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser101 LESFKKQsFVLKEGV 9606 15225553 YES lperfetto Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174. 0.609 SIGNOR-126650 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser653 PSLSRHSsPHQSEDE -1 2117608 YES llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. 0.33 SIGNOR-250881 GSK3B protein P49841 UNIPROT CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 YES lperfetto Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells 0.453 SIGNOR-154668 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20817722 YES miannu In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. 0.669 SIGNOR-267983 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation 9606 29920310 YES lperfetto It has been reported that the protein tyrosine phosphatase PTP1B could inactivate MET by direct dephosphorylation of Tyr 1234 and 1235 in its activation loop, and that this dephosphorylation takes place in peri-nuclear region of the cell [ xref ]. 0.636 SIGNOR-277001 GALR3 protein O60755 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-256862 WDR83 protein Q9BRX9 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates binding 9606 15118098 YES gcesareni Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. 0.507 SIGNOR-124473 TUBA4A protein P68366 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 NO miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. 0.7 SIGNOR-269730 SOSTDC1 protein Q6X4U4 UNIPROT WNT2B protein Q93097 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.29 SIGNOR-242701 GRM7 protein Q14831 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264350 PROX1 protein Q92786 UNIPROT IFNG protein P01579 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20064070 NO Human PROX1 is involved in biologic functions closely tied to HIV infection, most notably as a negative regulator of interferon (IFN) gamma expression in T cells 0.259 SIGNOR-254506 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation 9606 10770941 YES lperfetto Ca(2+)/calmodulin-dependent protein kinase kinase (CaM-KK) is a novel member of the CaM kinase family, which specifically phosphorylates and activates CaM kinase I and IV 0.619 SIGNOR-232181 KDM5A protein P29375 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization transcriptional regulation 9606 31374292 YES miannu The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL. 0.289 SIGNOR-260079 LPAR4 protein Q99677 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257170 HMGA2 protein P52926 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0001003 11390395 NO Regulation of expression miannu Expression of endogenous alpha-ENaC gene in salivary Pa-4 cells is suppressed by an ectopic HMGI-C overexpression. 0.2 SIGNOR-251946 ASB2 protein Q96Q27 UNIPROT Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR up-regulates activity binding 10090 BTO:0000165 19300455 YES miannu Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation.  Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb. 0.643 SIGNOR-271800 PFKFB4 protein Q16877 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 15170386 YES miannu Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure‚Äì function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2 0.8 SIGNOR-268117 ROCK2 protein O75116 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr853 PREKRRStGVSFWTQ -1 12220642 YES lperfetto Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited. 0.784 SIGNOR-249164 ATF6 protein P18850 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 YES miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network 0.656 SIGNOR-260180 MAPK1 protein P28482 UNIPROT LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser604 FQSTSVKsPKTVSPP 9606 23188829 YES miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. 0.2 SIGNOR-263055 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257972 SNAI1 protein O95863 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity transcriptional regulation 9606 19055748 NO lperfetto Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status. 0.757 SIGNOR-252260 HSD17B11 protein Q8NBQ5 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 YES lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. 0.8 SIGNOR-268664 CXCL8 protein P10145 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 NO lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS 0.7 SIGNOR-260257 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser30 EDLQEVLsSDENGGT 9606 BTO:0000567 12876286 YES llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites 0.345 SIGNOR-250852 FZR1 protein Q9UM11 UNIPROT AURKA protein O14965 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0004055 12023018 YES miannu We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity. 0.559 SIGNOR-272610 STAT6 protein P42226 UNIPROT MRC1 protein P22897 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20508200 NO lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. 0.396 SIGNOR-249535 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr310 VPPLPKVtPTKELQQ 9606 BTO:0000142 16733250 YES lperfetto Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins. 0.396 SIGNOR-146910 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser183 CPHHERCsDSDGLAP 9606 22611192 YES gcesareni We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma). 0.718 SIGNOR-197598 CSNK2A1 protein P68400 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Ser102 NLNENQAsEEEDELG -1 2557337 YES llicata Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase 0.341 SIGNOR-250927 HRH3 protein Q9Y5N1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-256689 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr209 TRKHYQPyAPPRDFA 9606 BTO:0000782;BTO:0001271 8992971 YES lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals 0.689 SIGNOR-45516 LSM-1231 chemical CHEBI:91471 ChEBI NTRK2 protein Q16620 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258239 STUB1 protein Q9UNE7 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 19940151 YES miannu the ubiquitin ligase activity of CHIP regulates HIF-1α degradation. 0.376 SIGNOR-271426 CWC15 protein Q9P013 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR form complex binding 9606 BTO:0000567 20176811 YES miannu In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27. 0.861 SIGNOR-271970 MAPK1 protein P28482 UNIPROT PDE4C protein Q08493 UNIPROT down-regulates phosphorylation Ser641 YQSKIPRsPSDLTNP 9606 11030732 YES The effect has been demonstrated using Q08493-2 gcesareni The short-form pde4b2 isoenzyme was activated by erk2 phosphorylation. sub-family selective actions in the ability of erk2 map kinase to phosphorylate and regulate the activity of pde4 cyclic amp-specific phosphodiesterases 0.256 SIGNOR-83187 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268763 ATR protein Q13535 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates phosphorylation Ser601 EMDLAHNsQSMHASS 9606 21242293 YES lperfetto Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair 0.415 SIGNOR-171290 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TSPYL2 protein Q9H2G4 UNIPROT up-regulates activity phosphorylation Thr340 GRLVSHStPIRWHRG 9606 BTO:0000567 11395479 YES llicata We observed that a CDA1 mutant with the two consensus CDK phosphorylation sites abolished (S20A and T340A) disabled its capacity to inhibit cell growth, indicating that these sites are important for the function of this protein. Furthermore, we showed that these sites are phosphorylated by cyclin/CDKs in vitro, suggesting that these kinases may regulate CDA1 function in vivo.  0.339 SIGNOR-250753 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.2 SIGNOR-251462 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser102 EEGISQEsSEEEQ -1 2806554 YES llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. 0.331 SIGNOR-250892 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21133840 YES miannu RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex 0.729 SIGNOR-256024 VPS18 protein Q9P253 UNIPROT CORVET tethering complex complex SIGNOR-C550 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.863 SIGNOR-273698 RNF41 protein Q9H4P4 UNIPROT ERBB3 protein P21860 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 12411582 YES miannu Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3 0.69 SIGNOR-272599 PAK1 protein Q13153 UNIPROT SYN1 protein P17600 UNIPROT up-regulates activity phosphorylation Ser605 AGPTRQAsQAGPVPR 10116 BTO:0001009 12237306 YES miannu Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release 0.35 SIGNOR-250235 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser1007 TGIMQLKsEIKQVEF -1 10487978 YES miannu Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation) 0.2 SIGNOR-250280 RPL38 protein P63173 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.868 SIGNOR-262461 Gbeta proteinfamily SIGNOR-PF4 SIGNOR KLC1 protein Q07866 UNIPROT down-regulates phosphorylation 9606 21385839 YES inferred from 70% family members gcesareni Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro. 0.2 SIGNOR-270072 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 BTO:0000782 15623513 YES lperfetto Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus. 0.479 SIGNOR-132902 MAP3K6 protein O95382 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 YES Manara These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase 0.2 SIGNOR-260915 ASB11 protein Q8WXH4 UNIPROT RPN1 protein P04843 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 24337577 YES miannu We also demonstrated that ASB11 is a novel endoplasmic reticulum-associated ubiquitin ligase with the ability to interact and promote the ubiquitination of Ribophorin 1, an integral protein of the oligosaccharyltransferase (OST) glycosylation complex. Moreover, expression of ASB11 can increase Ribophorin 1 protein turnover in vivo.  0.357 SIGNOR-272057 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2E1 protein P51965 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.72 SIGNOR-271325 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 9606 BTO:0000150 BTO:0001129 20606012 YES gcesareni Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. 0.474 SIGNOR-252622 Ibutamoren chemical CID:178024 PUBCHEM GHSR protein Q92847 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257497 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RAD52 protein P43351 UNIPROT up-regulates activity phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 23836560 YES Manara Have found that BCR-ABL1 interacts with the C-terminal portion of RAD52, resulting in tyrosine phosphorylation of Y104 located in RAD52 DNA II and enhanced nuclear foci formation 0.2 SIGNOR-262531 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 20887952 NO These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs 0.372 SIGNOR-253602 NatB complex SIGNOR-C416 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 NO miannu About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity. 0.7 SIGNOR-267232 TFAP2A protein P05549 UNIPROT ADM protein P35318 UNIPROT up-regulates quantity by expression transcriptional regulation 9480831 YES These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells. 0.267 SIGNOR-254048 PPP1CC protein P36873 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 YES Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells 0.383 SIGNOR-252605 ETS1 protein P14921 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12377757 NO miannu We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment. 0.2 SIGNOR-254082 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr480 TKEDGHRtSTSAVPN 9606 BTO:0000671 10209029 YES lperfetto Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480 0.377 SIGNOR-66996 WNT8B protein Q93098 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.623 SIGNOR-132024 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity 9606 BTO:0000093 8415704 NO miannu PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site 0.2 SIGNOR-261507 SSH3 protein Q8TE77 UNIPROT CFL1 protein P23528 UNIPROT up-regulates activity dephosphorylation Ser3 sGVAVSDG 9606 14531860 YES Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH). 0.716 SIGNOR-248759 IRAK3 protein Q9Y616 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates activity 10090 BTO:0000801 12150927 NO IRAK-M(-/-) cells exhibited increased cytokine production upon TLR/IL-1 stimulation and bacterial challenge, and IRAK-M(-/-) mice showed increased inflammatory responses to bacterial infection. 0.7 SIGNOR-259288 IGF1 protein P05019 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates 10090 10448861 NO lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. 0.264 SIGNOR-235825 SNAPIN protein O95295 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000793 18167355 YES miannu In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA. 0.583 SIGNOR-261171 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser394 TRQTPVDsPDDSTLS 9606 9271440 YES gcesareni Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1. 0.385 SIGNOR-50603 JAK2 protein O60674 UNIPROT PRMT5 protein O14744 UNIPROT down-regulates phosphorylation Tyr297 NRPPPNAyELFAKGY 9606 21316606 YES llicata Oncogenic jak2 kinases phosphorylate prmt5 in_vivo phosphorylation of prmt5 by jak2v617f greatly impairs its methyltransferase activity 0.692 SIGNOR-171994 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Tyr198 AQRCTISyRAPELFS -1 18184589 YES Manara Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition. 0.2 SIGNOR-260805 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process 0.738 SIGNOR-171042 NFYA protein P23511 UNIPROT NFY complex SIGNOR-C1 SIGNOR form complex binding 9606 9885213 YES lperfetto Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding. 0.963 SIGNOR-63013 PCDH10 protein Q9P2E7 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-269034 EP300 protein Q09472 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 NO lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. 0.2 SIGNOR-254097 NFKBIA protein P25963 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity binding 9606 SIGNOR-C13 1340770 YES lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b 0.74 SIGNOR-17688 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.762 SIGNOR-252747 KHK protein P50053 UNIPROT PRPS1 protein P60891 UNIPROT up-regulates activity phosphorylation Thr225 LVDDMADtCGTICHA 29074724 YES lperfetto Ketohexokinase-A (KHK-A; also known as fructokinase-A) phosphorylates PRPS1 T225 and activates PRPS1 by blocking the binding of ADP, AMP, and GDP, which is required for hepatocellular carcinoma development 0.349 SIGNOR-265735 CDK2 protein P24941 UNIPROT RNF138 protein Q8WVD3 UNIPROT up-regulates activity phosphorylation Thr27 VCQEVLKtPVRTTAC 9606 BTO:0000007 38309501 YES miannu Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner.Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner. 0.2 SIGNOR-277831 pravastatin chemical CHEBI:63618 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 1597859 YES miannu A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). 0.8 SIGNOR-258350 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267123 SWI/SNF complex complex SIGNOR-C92 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16452181 NO irozzo C-myc is a direct target of SWI/SNF complex–dependent promoter repression. These results indicate that repression of c-myc is indeed dependent on the activity of SWI/SNF–related complexes and specifically on complexes that contain ARID1A. 0.402 SIGNOR-256292 TAF2 protein Q6P1X5 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.551 SIGNOR-269574 MMP24 protein Q9Y5R2 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272368 PKN1 protein Q16512 UNIPROT PGM1 protein P36871 UNIPROT up-regulates phosphorylation Thr467 SANDKVYtVEKADNF 9606 BTO:0001271 15378030 YES llicata Pak1-mediated phosphorylation of pgm selectively on threonine 466 significantly increased pgm enzymatic activity 0.2 SIGNOR-128722 LAMC1 protein P11047 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR form complex binding 10809728 YES lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 0.547 SIGNOR-253225 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser14 MGAELPSsPLAIEYV 9606 BTO:0000567 11416124 YES lperfetto These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription. 0.335 SIGNOR-108560 CEBPA protein P49715 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004408 19620402 NO miannu The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPalpha, documenting the role of LEF1 in the diminished ELA2 expression. 0.308 SIGNOR-253769 LRIG1 protein Q96JA1 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates 9606 23723069 NO miannu Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation. 0.607 SIGNOR-202146 PRKACA protein P17612 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates phosphorylation 9606 16481469 YES lperfetto Mutation of either the three pka sites or pka-primed cki sites prevents phosphorylation of ci by cki in vitro and blocks ci cleavage in embryos 0.389 SIGNOR-144557 CGB Family proteinfamily SIGNOR-PF108 SIGNOR LHCGR protein P22888 UNIPROT up-regulates binding 9606 10446903 YES gcesareni The ?-Subunit of human choriogonadotropin interacts with the exodomain of the luteinizing hormone/choriogonadotropin receptor 0.2 SIGNOR-69400 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 SIGNOR-C110 9734785 YES lperfetto Interaction with beta-catenin and GSK-3beta was required for the Axin-mediated beta-catenin reduction. 0.92 SIGNOR-60046 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr371 LLAKLEEtKEYQEPE -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276210 SIRT7 protein Q9NRC8 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275882 NR0B2 protein Q15466 UNIPROT NR1H2 protein P55055 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000195 12198243 NO gcesareni Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter. T 0.46 SIGNOR-91901 FBLIM1 protein Q8WUP2 UNIPROT FLNA protein P21333 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 YES miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 0.888 SIGNOR-266105 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys70 GKAVRGAkGHHHPHP 9606 17098745 YES gcesareni Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells. 0.442 SIGNOR-150599 KSR2 protein Q6VAB6 UNIPROT ARAF protein P10398 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 YES miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 0.552 SIGNOR-273875 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage -1 10978167 YES lperfetto Thrombin selectively cleaves PAR1, PAR3, and PAR4 to induce activation of platelets and vascular cells, 0.887 SIGNOR-263608 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 SIGNOR-C15 19933840 YES lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction 0.2 SIGNOR-161810 FAM83G protein A6ND36 UNIPROT CD2AP protein Q9Y5K6 UNIPROT up-regulates activity binding 9606 BTO:0001938 29175910 YES lperfetto PAWS1 interacts in a dynamic fashion with the actin/cytoskeletal regulator CD2AP at lamellae|Loss of PAWS1 causes severe defects in F-actin organization and distribution as well as in lamellipodial organization, resulting in impaired cell migration. 0.346 SIGNOR-264768 CHUK protein O15111 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 SIGNOR-C14 15084260 YES gcesareni Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. 0.571 SIGNOR-252893 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. 0.382 SIGNOR-216809 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.497 SIGNOR-248312 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. 0.75 SIGNOR-236671 RNF123 protein Q5XPI4 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25860612 YES miannu  Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. 0.398 SIGNOR-272221 AKT1 protein P31749 UNIPROT ILF3 protein Q12906 UNIPROT up-regulates activity phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 YES llicata Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. 0.367 SIGNOR-252512 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 18650425 YES gcesareni Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun. 0.37 SIGNOR-179551 PGAM2 protein P15259 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI down-regulates quantity chemical modification 9606 24786789 YES miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. 0.8 SIGNOR-266512 lapatinib chemical CHEBI:49603 ChEBI CSK protein P41240 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 YES Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. 0.8 SIGNOR-257900 KIT protein P10721 UNIPROT STAP1 protein Q9ULZ2 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10679268 YES miannu STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells. 0.506 SIGNOR-261820 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257981 CAMK2B protein Q13554 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL BTO:0003036 8940188 YES llicata By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons. 0.605 SIGNOR-250688 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 10864927 YES lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.844 SIGNOR-216773 AGTR2 protein P50052 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 32201502 NO MIANNU AT2 receptor stimulation has been associated, for instance, with protection of the brain against ischemia [94]. In essence, AT2 receptors are linked to vasodilatation, release of nitric oxide, tissue development and remodeling, by stimulating apoptosis and inhibition of cell growth 0.7 SIGNOR-260232 serotonin smallmolecule CHEBI:28790 ChEBI HTR2B protein P41595 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264286 ASXL1 protein Q8IXJ9 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 29967380 YES miannu Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice. 0.301 SIGNOR-260119 APLNR protein P35414 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.436 SIGNOR-256681 bethanechol chemical CHEBI:3084 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258625 CSNK1A1 protein P48729 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser9 LTFMASDsEEEVCDE -1 8972483 YES llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  0.392 SIGNOR-250792 PAK proteinfamily SIGNOR-PF13 SIGNOR SYN1 protein P17600 UNIPROT unknown phosphorylation 10116 12237306 YES inferred from 70% family members miannu Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues. 0.2 SIGNOR-269974 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 HNSSQMKsMSTFIEE 9606 BTO:0000567 25670858 YES lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 0.587 SIGNOR-265232 GTP(4-) chemical CHEBI:37565 ChEBI 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI up-regulates quantity precursor of 23258413 YES lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. 0.8 SIGNOR-276595 OCRL protein Q01968 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI down-regulates quantity chemical modification 9606 33722976 YES miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis. These observations raised the possibility that PtdIns(4,5)P2 depletion is in fact required for the completion of macropinocytosis or to prevent macropinosome back-fusion with the plasmalemma. 0.8 SIGNOR-277773 PRKCG protein P05129 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 YES lperfetto Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. 0.2 SIGNOR-249060 AKT proteinfamily SIGNOR-PF24 SIGNOR FANCA protein O15360 UNIPROT unknown phosphorylation Ser1149 CLRSRDPsLMVDFIL -1 11855836 YES FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time. 0.2 SIGNOR-251476 MLN protein P12872 UNIPROT MLNR protein O43193 UNIPROT up-regulates binding 9606 BTO:0000938 10381885 YES gcesareni A heterotrimeric guanosine triphosphate-binding protein (g protein)-coupled receptor for motilin was isolated from human stomach 0.769 SIGNOR-68721 RPA4 protein Q13156 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 NO lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.7 SIGNOR-275708 ATM protein Q13315 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT unknown phosphorylation Ser251 ASLQGIDsQCVNQPE 9606 18644470 YES lperfetto Here, we have identified two major in vitro dna-pk phosphorylation sites in the c-terminal region of xlf, serines 245 and 251. We show that these represent the major phosphorylation sites in xlf in vivo and that serine 245 is phosphorylated in vivo by dna-pk, while serine 251 is phosphorylated by ataxia-telangiectasia mutated (atm). 0.588 SIGNOR-179528 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser102 LQTVIRTsPSSLVAF 26190112 YES Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. 0.297 SIGNOR-253542 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser674 QSPKRPRsPGSNSKV 9606 10648599 YES lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. 0.365 SIGNOR-74300 USP2 protein O75604 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity deubiquitination Lys502 LSQQEGIkM -1 29490279 YES miannu Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. 0.2 SIGNOR-273605 ARPC4 protein P59998 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 YES The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc 0.965 SIGNOR-251517 CHD8 protein Q9HCK8 UNIPROT NEUROD4 protein Q9HD90 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.2 SIGNOR-268918 NANOG protein Q9H9S0 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 NO miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 0.442 SIGNOR-254626 SNAI1 protein O95863 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 BTO:0000452;BTO:0002625 22223884 YES alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin 0.43 SIGNOR-254526 GPHA2 protein Q96T91 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 YES gcesareni Recombinant a2/b5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human tsh receptors, but not lh and fsh receptors, and showed high affinity to tsh receptors in a radioligand receptor assay 0.545 SIGNOR-88614 MITF protein O75030 UNIPROT PMEL protein P40967 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12819038 NO miannu The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels. 0.434 SIGNOR-254589 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 15221015 YES gcesareni Wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. 0.731 SIGNOR-126128 CSNK2B protein P67870 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 YES llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 0.327 SIGNOR-251064 (E)-3-tosylacrylonitrile chemical CHEBI:85928 ChEBI PTPN1 protein P18031 UNIPROT down-regulates chemical inhibition 9606 Other YES The anti-inflammatory compound BAY 11-7082 is a potent inhibitor of Protein Tyrosine Phosphatases. gcesareni 0.8 SIGNOR-190254 MSH2 protein P43246 UNIPROT BLM protein P54132 UNIPROT up-regulates binding 9606 SIGNOR-C60 15064730 YES miannu We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro 0.584 SIGNOR-123699 RNF4 protein P78317 UNIPROT NFYA protein P23511 UNIPROT up-regulates activity binding 9606 15496512 YES miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. 0.2 SIGNOR-252229 IRX5 protein P78411 UNIPROT KCND2 protein Q9NZV8 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000387 16239150 YES Luana Irx5 Directly Represses the Kcnd2 Promoter 0.487 SIGNOR-266045 NUP214 protein P35658 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.663 SIGNOR-262075 RAD23B protein P54727 UNIPROT RPA3 protein P35244 UNIPROT up-regulates activity binding 24086043 YES lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.521 SIGNOR-275700 WNK2 protein Q9Y3S1 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates activity phosphorylation Ser382 KRASFAKsVIGTPEF 9606 22032326 YES Manara WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). | We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro. 0.547 SIGNOR-260790 ATF2 protein P15336 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16149046 NO miannu Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2. 0.2 SIGNOR-252226 ADORA2A protein P29274 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257413 NOG protein Q13253 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR down-regulates binding 9606 BTO:0000142 12478285 YES Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmpby blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors 0.598 SIGNOR-217541 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser397 TYHSRDEsTDSGLSM 9606 BTO:0000007 20048001 YES lperfetto We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition 0.839 SIGNOR-218034 RPSA protein P08865 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.847 SIGNOR-262414 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 YES gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. 0.681 SIGNOR-252998 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 NO lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enancers. 0.7 SIGNOR-37461 SOD1 protein P00441 UNIPROT KARS1 protein Q15046 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0004055 18715867 YES P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction) In the presence of mutant SOD1, mitoKARS displays a high propensity to misfold and aggregate prior to its import into mitochondria, becoming a target for proteasome degradation. 0.2 SIGNOR-262800 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 YES miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. 0.8 SIGNOR-268757 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1738 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248813 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 YES lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). 0.894 SIGNOR-227905 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Thr43 VNLSAAQtLRAAFIK 9606 19370760 YES llicata Stk25 phosphorylates ccm3 at serine 39 and threonine 43 0.767 SIGNOR-185392 RNF13 protein O43567 UNIPROT SNAPIN protein O95295 UNIPROT up-regulates activity polyubiquitination 9534 BTO:0000298 22890573 YES miannu  RNF13 directly interacted with snapin, a SNAP-25-interacting protein. Interestingly, snapin was ubiquitinated by RNF13 via the lysine-29 conjugated polyubiquitin chain, which in turn promoted the association of snapin with SNAP-25. Consistently, we found an attenuated interaction between snapin and SNAP-25 in the RNF13-null mice. Therefore, these results suggest that RNF13 is involved in the regulation of the SNARE complex, which thereby controls synaptic function. 0.522 SIGNOR-272044 ARNTL protein O00327 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.933 SIGNOR-253626 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp78 PNVVAARdVPEGMQN 9606 11741536 YES gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. 0.365 SIGNOR-256434 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.411 SIGNOR-252883 sorafenib tosylate chemical CHEBI:50928 ChEBI RAF1 protein P04049 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). 0.8 SIGNOR-259228 AMPK complex SIGNOR-C15 SIGNOR CPS1 protein P31327 UNIPROT down-regulates quantity 9606 28538732 NO Luana In KL cells, pharmacological activation of AMPK or expression of constitutively active AMPK reduced CPS1 mRNA and protein, and silencing AMPK increased CPS1 expression even in the presence of LKB1 0.271 SIGNOR-267920 FBXW11 protein Q9UKB1 UNIPROT Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR up-regulates activity binding 9606 BTO:0000007 31092637 YES miannu  Further analysis indicated that CUL7 mediated AID ubiquitination by forming a complex with FBXW11. In a CUL7 fl/fl CD19 cre+ mouse model, we demonstrated that CUL7 knockout significantly enhanced AID protein levels in B cells in the germinal center and increased both the IgG1 and IgA class switching. Collectively, our results reveal a subtle regulation mechanism for tightly controlling AID protein levels. F-box proteins are components of SCF ubiquitin-ligase complexes that contain Skp1, CUL1, or CUL7, and an F-box protein 0.712 SIGNOR-272025 HDAC4 protein P56524 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 10737771 YES gcesareni We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2. 0.691 SIGNOR-76237 ivacaftor chemical CHEBI:66901 ChEBI CFTR protein P13569 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;potentiator gcesareni 0.8 SIGNOR-193495 IYD protein Q6PHW0 UNIPROT 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI down-regulates quantity chemical modification 9606 28153798 YES scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. 0.8 SIGNOR-267036 GATAD2B protein Q8WXI9 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.775 SIGNOR-263845 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser466 DEDDGEFsDDSGADQ 9606 BTO:0000007 11500362 YES llicata The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo. 0.324 SIGNOR-250787 STAT5A protein P42229 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 YES FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells 0.263 SIGNOR-261552 BRSK1 protein Q8TDC3 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567 15150265 YES lperfetto Overexpression of hssad1 resulted in an increased phosphorylation of cdc25c on ser-216 in vivo. Phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.484 SIGNOR-107408 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser248 SVQSDIWsMGLSLVE -1 8413257 YES lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. 0.789 SIGNOR-39058 PSMD4 protein P55036 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.904 SIGNOR-263347 CD28 protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 24098653 YES fspada Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation 0.701 SIGNOR-202706 HDAC1 protein Q13547 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR form complex binding 9606 BTO:0000007 21041482 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.795 SIGNOR-266968 MED9 protein Q9NWA0 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.668 SIGNOR-266680 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr519 EDPYAGStDENTDSE 9606 BTO:0000567 15367657 YES lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 0.396 SIGNOR-128897 SGK1 protein O00141 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates activity phosphorylation Ser352 SEAKDLIsKLLVRDA -1 28545025 YES miannu We show that SGK1 phosphorylates MNK1 at a conserved site, which represses its activity.  0.2 SIGNOR-277357  CDX2 protein Q99626 UNIPROT VIL1 protein P09327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19371634 NO miannu We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter. 0.34 SIGNOR-185486 FLT3 protein P36888 UNIPROT USP22 protein Q9UPT9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26049753 NO USP22 deubiquitinase was overexpressed in FLT3-ITD positive AML CD34+ cells.USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells. 0.2 SIGNOR-261559 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Ser204 KNSRVTFsEDDEIIN -1 9407077 YES llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. 0.475 SIGNOR-251023 ATF4 protein P18848 UNIPROT CARS1 protein P49589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269416 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr80 DQHSISYtLSRAQTV -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.767 SIGNOR-276138 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 16101282 YES gcesareni Ptp1b and shp-2 are bound to the c-met receptor to control its activity. Although the binding of ptp1b increases when there is a decrease in c-met activation and acts as a negative regulator of the receptor, the increased binding and phosphorylation of shp-2 coincide with maximal stimulation of c-met, acting as a positive regulator. 0.365 SIGNOR-139560 SKP1 protein P63208 UNIPROT CUL1 protein Q13616 UNIPROT up-regulates binding 9606 10023660 YES gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. 0.959 SIGNOR-64511 AKT3 protein Q9Y243 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 YES lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 0.736 SIGNOR-245424 SCF-SKP2 complex SIGNOR-C136 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 25733682 YES miannu  MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding.  0.289 SIGNOR-276889 KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 7744823 YES fstefani Mitogen-activated protein kinase kinase kinase (mekk1) is a serine-threonine kinase that regulates sequential protein kinase pathways involving stress-activated protein kinases and mitogen-activated protein kinases. Mekk1 is activated in response to growth factor stimulation of cells and by expression of activated ras. mekk1 directly binds ras.GTP. Thus, ras interacts with protein kinases of both the raf and mekk families. 0.366 SIGNOR-32620 YAP1 protein P46937 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 BTO:0000562 23607968 YES gcesareni Additionally, the hippo and wnts also cooperate in the nucleus, where yap interacts with beta-catenin and induces the expression of canonical wnt target genes, such as sox2 and snai2 in mouse heart tissue. 0.532 SIGNOR-201939 TLK2 protein Q86UE8 UNIPROT ASF1A protein Q9Y294 UNIPROT up-regulates quantity by stabilization phosphorylation Ser192 GWSTSENsLNVMLES 9606 20016786 YES Manara We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | Consistent 0.67 SIGNOR-260787 WNT3A protein P56704 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 YES gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes. 0.795 SIGNOR-169651 PCSK6 protein P29122 UNIPROT INSR protein P06213 UNIPROT up-regulates activity cleavage 9606 BTO:0000666 25527501 YES Giorgia Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. 0.2 SIGNOR-260366 N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine chemical CHEBI:91340 ChEBI CHUK protein O15111 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258085 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr775 SSNYMAPyDNYVPSA -1 8940081 YES miannu The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues. 0.2 SIGNOR-250259 CALM3 protein P0DP25 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 BTO:0001009 14701738 YES miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. 0.2 SIGNOR-266341 CCL2 protein P13500 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 NO miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection 0.7 SIGNOR-261032 pazopanib chemical CHEBI:71219 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258260 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation 9606 14532121 YES inferred from 70% family members gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. 0.2 SIGNOR-270063 TGFB1 protein P01137 UNIPROT OMD protein Q99983 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16970923 NO miannu We found tgf-beta1 to down regulate osad 0.269 SIGNOR-149565 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Ser230 PEGATPTsPVGHFAK 9606 BTO:0000848 BTO:0001253 20959475 YES lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). 0.2 SIGNOR-168754 MMP23B protein O75900 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272390 DRD1 protein P21728 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.265 SIGNOR-257391 WNT11 protein O96014 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 YES gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. 0.711 SIGNOR-253127 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser239 GAKLRKVsKQEEASG 9606 14679200 YES lperfetto Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro 0.734 SIGNOR-120351 PPARA protein Q07869 UNIPROT LPL protein P06858 UNIPROT up-regulates activity 9606 16511610 NO Regulation miannu The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha-dependent stimulation of lipoprotein lipase and of apolipoprotein (apo)A-V and to an inhibition of apoC-III expression, whereas the increase in plasma HDL-cholesterol depends partly on an overexpression of apoA-I and apoA-II.  0.59 SIGNOR-251849 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 BTO:0000246 12907755 YES PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 0.295 SIGNOR-248393 PKNOX1 protein P55347 UNIPROT HOXA1 protein P49639 UNIPROT up-regulates activity binding 9606 BTO:0000007 9582372 YES miannu Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding. 0.587 SIGNOR-220242 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser677 QMQPDTTsVVKDSQV 9606 19120698 YES llicata Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity 0.2 SIGNOR-183022 SUN2 protein Q9UH99 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.539 SIGNOR-263286 clozapine chemical CHEBI:3766 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258368 SP1 protein P08047 UNIPROT PDGFC protein Q9NRA1 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001685 15247255 NO The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter 0.2 SIGNOR-254272 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Thr203 VRAMAVLtDHPYASL 33850055 YES lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o 0.2 SIGNOR-275645 CHAMP1 protein Q96JM3 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 21063390 NO miannu Proper attachment of microtubules to kinetochores is essential for accurate chromosome segregation. These data suggest that CAMP is required for maintaining kinetochore-microtubule attachment during biorientation. 0.7 SIGNOR-264901 FNIP2 protein Q9P278 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 YES miannu FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. 0.412 SIGNOR-261414 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser440 NGTSGKDsATTSTLS 9606 BTO:0000567 34198826 YES miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. 0.25 SIGNOR-276662 KDM1A protein O60341 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 28720390 NO gianni The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. 0.7 SIGNOR-268728 ZWINT protein O95229 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 BTO:0000567 20462495 YES lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. 0.651 SIGNOR-265013 SLBP protein Q14493 UNIPROT H2BW1 protein Q7Z2G1 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265387 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 10116 7535768 YES We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively 0.786 SIGNOR-248463 PRKCA protein P17252 UNIPROT RALBP1 protein Q15311 UNIPROT up-regulates activity phosphorylation Thr297 ACGRTTEtEKVQEFQ -1 16087181 YES miannu In deletion mutant analyses of potential phosphorylation sites in RLIP76, we identified T297 and S509 as targets for phosphorylation by PKCalpha. Phosphorylation at T297 increased doxorubicin (DOX)-transport activity approximately 2-fold for RLIP76 purified from recombinant source 0.39 SIGNOR-263164 TOX2 protein Q96NM4 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 25352127 YES Luana We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). 0.294 SIGNOR-266097 SCAP protein Q12770 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates activity relocalization 10029 BTO:0000246 12202038 YES SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function 0.901 SIGNOR-267502 abiraterone acetate chemical CHEBI:68639 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205573 USH1C protein Q9Y6N9 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 YES lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. 0.688 SIGNOR-262576 MMP9 protein P14780 UNIPROT PZP protein P20742 UNIPROT down-regulates quantity by destabilization cleavage Leu778 WKAGAFClSEDAGLG -1 9344465 YES lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.35 SIGNOR-261785 MMP19 protein Q99542 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE -1 10922468 YES lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development. 0.4 SIGNOR-266978 SCF-SKP2 complex SIGNOR-C136 SIGNOR RBL2 protein Q08999 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 phosphorylation:Ser672 TLYDRYSsPPASTTR 12435635 YES miannu  The activity of the ubiquitin ligase complex Skp1-Cul1/Cdc53-F-box protein Skp2 (SCF(Skp2)) and the proteasome were necessary for p130 degradation. In vitro, recombinant Skp2 was able to bind hyperphosphorylated but not dephosphorylated p130. Furthermore, in vitro polyubiquitination of p130 by SCF(Skp2) was specifically dependent on phosphorylation of p130 on Serine 672.  0.563 SIGNOR-272598 (R)-5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin chemical CID:11957727 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258867 GDF5 protein P43026 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates activity binding 10090 15890363 YES In contrast to other members of the TGF-beta superfamily, GDF-5 shows a pronounced specificity in type I receptor interaction in cross-link experiments binding only to BMP receptor IB (BMPR-IB). In mice, deletion of either GDF-5 or BMPR-IB results in a similar phenotype, indicating that GDF-5 signaling is highly dependent on BMPR-IB. 0.774 SIGNOR-256483 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 YES miannu Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. 0.2 SIGNOR-260131 Dinaciclib chemical CID:46926350 PUBCHEM CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191328 rep protein P0C6X7 UNIPROT DDX5 protein P17844 UNIPROT up-regulates activity binding 9606 19224332 YES lperfetto To our knowledge, this is the first report to show that SARS-CoV helicase can interact directly with multifunctional protein Ddx5 in cell culture and that inhibition of Ddx5 results in the suppression of viral replication. We speculate that Ddx5 may act as a coactivator by direct binding to the SARS-CoV helicase, resulting in enhanced viral genome transcription and virus proliferation. SIGNOR-260250 ramucirumab antibody DB05578 DRUGBANK KDR protein P35968 UNIPROT down-regulates activity binding 9606 28395526 YES miannu Ramucirumab (Cyramza), an anti-angionenic agent was approved in 2014 for treatment of several malignancies, including second-line treatment of patients with NSCLC with disease progression on or after platinum-based chemotherapy. Ramucirumab, an anti-VEGFR2 agent, combined with docetaxel, was FDA-approved for NSCLC patients. 0.4 SIGNOR-259901 PRKACA protein P17612 UNIPROT DYNLRB1 protein Q9NP97 UNIPROT up-regulates phosphorylation Ser73 LTFLRIRsKKNEIMV 9606 23333499 YES llicata Our results show that km23-1 is required for camp-responsive element (cre) transcriptional activation by tgf_, with s73-km23-1 being required for the cre-dependent tgf_ stimulation of fibronectin (fn) transcription. 0.2 SIGNOR-200456 MAPK1 protein P28482 UNIPROT DAZAP1 protein Q96EP5 UNIPROT down-regulates activity phosphorylation Thr315 GVPPPPAtPGAAPLA 9606 BTO:0000007 16848763 YES miannu Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ 0.2 SIGNOR-262971 CKM complex complex SIGNOR-C406 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. 0.2 SIGNOR-273174 DVL3 protein Q92997 UNIPROT PIP5K1A protein Q99755 UNIPROT up-regulates binding 9606 18772438 YES gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. 0.2 SIGNOR-180788 PD173955 chemical CHEBI:49791 ChEBI SRC protein P12931 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258264 MAPK8 protein P45983 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation 9606 17525747 YES gcesareni Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6. 0.592 SIGNOR-155205 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.91 SIGNOR-252855 Fe2S2 iron-sulfur cluster chemical CHEBI:49601 ChEBI Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. 0.8 SIGNOR-267735 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu65 MEETCSYeEAREVFE -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263670 JAK1 protein P23458 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. 0.68 SIGNOR-249492 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 BTO:0004553 24614225 YES gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. 0.307 SIGNOR-266434 NADPH(4-) smallmolecule CHEBI:57783 ChEBI PGD protein P52209 UNIPROT down-regulates activity binding 9606 34765544 YES miannu We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. PGDH is the onl yrate-limiting unidirectional enzyme susceptible to allosteric inhibition by NADPH 0.8 SIGNOR-267372 AKT proteinfamily SIGNOR-PF24 SIGNOR PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser318 CKIFRRPsLPCISRE 10090 BTO:0000011 10454575 YES gcesareni PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B. 0.2 SIGNOR-248027 DUOX1 protein Q9NRD9 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.7 SIGNOR-264719 APP protein P05067 UNIPROT GSK3A protein P49840 UNIPROT up-regulates 9606 BTO:0000938 16446437 NO gcesareni These results suggest a direct relationship between app proteolytic processing, but not amyloid-_, in gsk-3_ activation and tau phosphorylation in human neurons. 0.41 SIGNOR-144057 SMAD6 protein O43541 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity binding 9606 BTO:0000007 19561075 YES miannu Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. 0.83 SIGNOR-272786 NPFFR2 protein Q9Y5X5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257104 RPS6KA1 protein Q15418 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 10558990 YES lperfetto The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival. 0.746 SIGNOR-72117 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr81 APAPAAPtPAAPAPA 9606 BTO:0000007 11283254 YES lperfetto Jnk phosphorylated p53 at t81 in response to dna damage and stress-inducing agents, as determined by phospho-specific antibodies to t81 . Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress. 0.796 SIGNOR-106542 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. 0.64 SIGNOR-164404 MRGPRD protein Q8TDS7 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 10116 23446738 NO Luana Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. 0.7 SIGNOR-262309 FOXO3 protein O43524 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates activity transcriptional regulation 10090 15031210 YES We then characterized the human gilz promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal 0.396 SIGNOR-256094 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser283 RSVPEPLsPVSSLQA 9606 16027724 YES miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation 0.415 SIGNOR-250092 yohimbine chemical CHEBI:10093 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258682 CAMK2A protein Q9UQM7 UNIPROT DAGLA protein Q9Y4D2 UNIPROT down-regulates activity phosphorylation Ser782 APLATMEsLSDTESL 23502535 YES lperfetto Activated CaMKII interacted with the C-terminal domain of DGLalpha, phosphorylated two serine residues and inhibited DGLalpha activity. |CaMKIIalpha phosphorylates DGLalpha at Ser808 and Ser782 0.2 SIGNOR-275539 CAMK4 protein Q16566 UNIPROT NOVA2 protein Q9UNW9 UNIPROT up-regulates quantity phosphorylation Thr27 VCTKRSNtGEEGEYF 9606 BTO:0000007 32492405 YES miannu CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. Conversely, Nova-2 with single or double mutations to alanine (2A and 1A2A) was predominantly nuclear, like the WT (Figures 5H and ​and5I).5I). In contrast, glutamate mutations at site 3 had no effect on Nova-2 localization (Figures 5H and ​and5I)5I) or on Nova-2 binding to RNA (Figure S5E). These results showed that active CaMKIV reduces Nova-2 nuclear localization by phosphorylating sites 1 and 2 (S25, T27). 0.255 SIGNOR-273520 MLL1 complex complex SIGNOR-C89 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.2 SIGNOR-268802 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys262 DSDDALLkMTISQQE -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 0.464 SIGNOR-272744 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18521620 YES gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). 0.787 SIGNOR-178803 TP53 protein P04637 UNIPROT ANKRD11 protein Q6UB99 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 18840648 YES miannu Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53. 0.308 SIGNOR-266735 ELOVL3 protein Q9HB03 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267886 RPS6KA5 protein O75582 UNIPROT H2AW protein Q7L7L0 UNIPROT up-regulates activity phosphorylation Ser2 sGRGKQGG -1 15010469 YES miannu We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1. Furthermore, we found that acetylation of histone H3 by the p300 and CREB-binding protein associated factor, PCAF, suppressed the kinase-dependent inhibition of transcription. These results suggest that acetylation of histones may stimulate transcription by suppressing an inhibitory phosphorylation by a kinase as MSK1. 0.2 SIGNOR-262942 CDK1 protein P06493 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 SIGNOR-C17 19737929 YES lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity 0.761 SIGNOR-187880 CRK protein P46108 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates binding 9606 7806500 YES gcesareni The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo. 0.901 SIGNOR-33732 HSP90AB1 protein P08238 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 9580552 YES miannu Here we show that Hsp90 associates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists that stimulate production of nitric oxide, namely vascular endothelial growth factor, histamine and fluid shear stress. Moreover, the binding of Hsp90 to eNOS enhances the activation of eNOS. 0.545 SIGNOR-252214 KAT2B protein Q92831 UNIPROT H3Y2 protein P0DPK5 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269615 GNB3 protein P16520 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14668344 YES gcesareni Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein. 0.4 SIGNOR-252680 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Ser672 CVMSGTDsQPKPDLE 9606 15194694 YES lperfetto Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability. 0.807 SIGNOR-125873 CHEK1 protein O14757 UNIPROT SETMAR protein Q53H47 UNIPROT down-regulates activity phosphorylation Ser508 LYDNRRRsAQWLDQE 9606 BTO:0000007 25024738 YES miannu We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination.  0.491 SIGNOR-273610 AURKB protein Q96GD4 UNIPROT PLEKHG6 protein Q3KR16 UNIPROT up-regulates phosphorylation Thr544 SPSTRPStPSLEGSQ 9606 24482237 YES lperfetto In this study we report that aurora b-mediated phosphorylation of myogef at thr-544 creates a docking site for plk1, leading to the localization and activation of myogef at the central spindle. 0.254 SIGNOR-204534 PRKCZ protein Q05513 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates activity phosphorylation Thr50 QLPVLDKtKFLVPDH -1 31857374 YES done miannu LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). 0.2 SIGNOR-273906 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 11604500 YES lperfetto The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding. 0.802 SIGNOR-111056 ATG4B protein Q9Y4P1 UNIPROT MAP1LC3C protein Q9BXW4 UNIPROT up-regulates activity cleavage 9606 BTO:0000007;BTO:0000567 15187094 YES lperfetto Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16. 0.756 SIGNOR-125489 BBS9 protein Q3SYG4 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 YES lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 0.792 SIGNOR-262555 PELI1 protein Q96FA3 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000815 36841821 YES miannu EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse. 0.2 SIGNOR-277875 FLT4 protein P35916 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276180 OAT protein P04181 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI down-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) 0.8 SIGNOR-256032 TLR2 protein O60603 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 10090 22664090 YES scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.725 SIGNOR-266745 androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of 9606 BTO:0000975 27702664 YES lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively 0.8 SIGNOR-268668 Ub:E2 complex SIGNOR-C497 SIGNOR VPS11 protein Q9H270 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271125 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Ser686 LEELHEKsQEVIWGL -1 12852856 YES lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction 0.699 SIGNOR-103348 PTEN protein P60484 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates activity dephosphorylation 9606 19436944 NO miannu Expression of WT-PTEN also caused decreased activation of Akt, p70 S6K, and Erk signaling pathways.|This may potentially be a result of PTEN inhibition of p70 S6K phosphorylation and may explain the mechanism by which PTEN inhibits proliferation of HSCs. 0.532 SIGNOR-277080 SRGAP3 protein O43295 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 12447388 YES miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. 0.554 SIGNOR-95967 NLGN1 protein Q8N2Q7 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.828 SIGNOR-264164 FZD3 protein Q9NPG1 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 14977528 YES gcesareni Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. 0.244 SIGNOR-122892 risperidone chemical CHEBI:8871 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258527 BRAF protein P15056 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser614 SHQFEQLsGSILWMA 9606 BTO:0002181 27345148 YES miannu The phosphorylation of S614 is mitogen inducible and the result of autophosphorylation. These data suggest that phosphorylation at this site is inhibitory, and part of the physiological shut-down mechanism of BRAF signalling. 0.2 SIGNOR-277255 CDK1 protein P06493 UNIPROT TEX14 protein Q8IWB6 UNIPROT down-regulates quantity by destabilization phosphorylation Thr618 EEASSPStGQPSLCS 9606 BTO:0000007 22405274 YES miannu Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction 0.334 SIGNOR-273523 TFIIE complex SIGNOR-C458 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR up-regulates activity relocalization 9606 31064989 YES lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. 0.737 SIGNOR-269363 RAB38 protein P57729 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR up-regulates activity relocalization 9606 23247405 YES miannu Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. 0.278 SIGNOR-268526 PPP1R8 protein Q12972 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity binding -1 1322907 YES We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity. 0.623 SIGNOR-255657 CLU protein P10909 UNIPROT COMMD1 protein Q8N668 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001321 20068069 YES miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. 0.393 SIGNOR-271432 PSMA3 protein P25788 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.854 SIGNOR-263362 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002548 27572267 YES miannu We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. 0.2 SIGNOR-277277 Y-27632 chemical CHEBI:75393 ChEBI ROCK2 protein O75116 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207893 MAPK11 protein Q15759 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 YES lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 0.2 SIGNOR-264447 TRIM31 protein Q9BZY9 UNIPROT KIF21B protein O75037 UNIPROT up-regulates activity binding 24086586 YES Here we show that the ubiquitin E3 ligase TRIM3, also known as BERP, interacts with KIF21B via its RBCC domain ||he E3-ligase function of TRIM3 is not involved in KIF21B degradation, however TRIM3 depletion reduces the motility of the motor. Together, our data suggest that TRIM3 is a regulator in the modulation of KIF21B motor function 0.2 SIGNOR-272479 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT down-regulates binding 9606 9311920 YES gcesareni Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r,. 0.774 SIGNOR-51104 GRIN1 protein Q05586 UNIPROT NMDA receptor_2D complex SIGNOR-C350 SIGNOR form complex binding 9606 BTO:0000938 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits 0.663 SIGNOR-264126 NEDD4 protein P46934 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 0.452 SIGNOR-272753 CSNK1A1 protein P48729 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by destabilization phosphorylation Ser243 GSDTDTDsGYGGESE 9606 BTO:0002181 25202122 YES miannu CK1α-mediated phosphorylation of DEC1 on a conserved degron is required for DEC1 degradation.  0.2 SIGNOR-276851 NSD2 protein O96028 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19481544 YES miannu In this study, we discovered that nsd2 specifically interacts with the dna-binding domain of androgen receptor (ar) via its hmg domain, and the nuclear translocation of both nsd2 and ar is enhanced in the presence of ligand / the histone methyltransferase, nsd2, enhances androgen receptor-mediated transcription. 0.2 SIGNOR-186045 GSK3B protein P49841 UNIPROT PAX3 protein P23760 UNIPROT up-regulates quantity phosphorylation Ser201 ERASAPQsDEGSDID 9606 22679108 YES miannu The ubiquitously expressed CK2 often provides the priming phosphorylation for GSK-3, however, we found that GSK-3beta alone was sufficient to phosphorylate PAX3 at both Ser205 and Ser197 and Ser201 in-vitro. 0.334 SIGNOR-278481 KAR proteinfamily SIGNOR-PF57 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 15919192 NO miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. 0.7 SIGNOR-264693 ibrutinib chemical CHEBI:76612 ChEBI BTK protein Q06187 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189641 KLHL7 protein Q8IXQ5 UNIPROT TUT1 protein Q9H6E5 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000675 29032201 YES miannu Kelch-like protein 7 (KLHL7) is a component of Cul3-based Cullin-RING ubiquitin ligase. In this study, we report that KLHL7 increases terminal uridylyl transferase 1 (TUT1) ubiquitination involved in nucleolar integrity. 0.2 SIGNOR-272318 NRAS protein P01111 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. It was also described that ras interacts with pi3k in a direct manner.llysine residue 227 is essential for the interaction of ras with pi3k 0.721 SIGNOR-175228 midostaurin chemical CHEBI:63452 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition 16969355 YES lperfetto Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases 0.8 SIGNOR-261982 PPARGC1A protein Q9UBK2 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001103 SIGNOR-C13 20404331 NO lperfetto In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB 0.353 SIGNOR-217969 MSL1 protein Q68DK7 UNIPROT MSL acetyltransferase complex SIGNOR-C344 SIGNOR form complex binding 9606 BTO:0000567 16227571 YES miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 0.856 SIGNOR-263942 PKA proteinfamily SIGNOR-PF17 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser950 EGFHPRRsSQGATQM 19018281 YES miannu  Our results demonstrate that PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650.  0.2 SIGNOR-276174 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270364 HBA1 protein P69905 UNIPROT ADAMTS13 protein Q76LX8 UNIPROT down-regulates activity 9606 15367436 NO Regulation of binding miannu Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher. 0.2 SIGNOR-251749 PRKCD protein Q05655 UNIPROT SMPD1 protein P17405 UNIPROT up-regulates phosphorylation Ser510 DGNYSGSsHVVLDHE 9606 17303575 YES lperfetto Activation of acid sphingomyelinase by protein kinase cdelta-mediated phosphorylation. Phosphorylation of ser(508) proved to be an indispensable step for asmase activation and membrane translocation in response to pma 0.256 SIGNOR-153276 PRKACA protein P17612 UNIPROT PDE3B protein Q13370 UNIPROT unknown phosphorylation Ser442 TPQLRRSsGTSGLLP -1 8163498 YES miannu Serine 427 is the target for cAMP-PK phosphorylation of the rat adipocyte cGI-PDE in vitro 0.473 SIGNOR-250023 prostaglandin F2alpha(1-) smallmolecule CHEBI:57404 ChEBI PTGFR protein P43088 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257573 (-)-anisomycin chemical CHEBI:338412 ChEBI PCSK7 protein Q16549 UNIPROT up-regulates chemical activation 9606 BTO:0000142 16581040 YES gcesareni These results indicate that activation of p38 mapk by anisomycin induces ltd and subsequently occludes electrically induced ltd 0.8 SIGNOR-145496 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser567 VLSDNDRsLLERWTR 9606 BTO:0000567 20667468 YES miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. 0.2 SIGNOR-259823 CSNK2B protein P67870 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.286 SIGNOR-251053 FYN protein P06241 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 YES lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. 0.532 SIGNOR-249337 HCRTR1 protein O43613 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257012 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr1969 DKASLTRtLQHRIAL 9606 BTO:0000938 19824698 YES lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. Substitution of thr1967, an autophosphorylation site located within the kinase domain, to ala caused a significant decrease in the kinase activity 0.2 SIGNOR-188421 TOMM22 protein Q9NS69 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 YES lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. 0.779 SIGNOR-267679 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser129 VNTRAGPsQHSSPAV 9606 BTO:0000671 12628002 YES lperfetto Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149) 0.702 SIGNOR-99127 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UHRF1 protein Q96T88 UNIPROT down-regulates quantity by destabilization phosphorylation Ser639 QQEGGFAsPRTGKGK -1 22411829 YES miannu Importantly, the S652ph antibody identifies phosphorylated UHRF1 in mitotic cells and consistently S652 can be phosphorylated by the M phase-specific kinase CDK1-cyclin B in vitro. UHRF1 S652 phosphorylation significantly reduces UHRF1 interaction with USP7 in vitro and in vivo, which is correlated with a decreased UHRF1 stability in the M phase of the cell cycle. In contrast, UHRF1 carrying the S652A mutation, which renders UHRF1 resistant to phosphorylation at S652, is more stable.  0.318 SIGNOR-276408 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 NO Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits 0.608 SIGNOR-254955 EZR protein P15311 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001802 16488997 NO Ezrin is indispensable for Six1-induced metastasis and highly expressed in a panel of representative pediatric cancers. 0.7 SIGNOR-259375 THRB protein P10828 UNIPROT GATA2 protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 YES scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. 0.2 SIGNOR-267256 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr280 LKKTDRIyAMKVVKK 9606 11713277 YES llicata Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. 0.532 SIGNOR-111924 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 YES llicata Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. 0.2 SIGNOR-188131 PTPN11 protein Q06124 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 YES Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B 0.652 SIGNOR-248671 MYC protein P01106 UNIPROT ST3GAL1 protein Q11201 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 NO We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 0.2 SIGNOR-253961 GSK3B protein P49841 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization phosphorylation Ser13 ELKQMVMsLRVSELQ 10090 BTO:0002268 26157031 YES miannu We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting.  0.333 SIGNOR-276924 S1PR2 protein O95136 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.385 SIGNOR-256871 CHEK2 protein O96017 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates activity phosphorylation Ser100 VSYARPSsEVIKDAN 9606 21745814 YES miannu Taken together, these findings indicate that phosphorylation at residue S100 by Chk2 enhances HuR-binding to the occludin mRNA, while phosphorylation at S88 and T118 reduces this interaction; these modifications in turn regulate occludin translation. 0.551 SIGNOR-278161 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRNB3 protein Q05901 UNIPROT up-regulates activity chemical activation 9606 BTO:0000227 28901280 YES miannu Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. 0.8 SIGNOR-264258 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 YES gcesareni ...expression of GRK4ƒŽ‚ drastically increased the basal level of32P incorporation into B2R.[ƒ‚€‚]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. 0.289 SIGNOR-249674 WWP2 protein O00308 UNIPROT SOX2 protein P48431 UNIPROT down-regulates quantity ubiquitination 9606 34732716 YES miannu Among the four E3 ligases, only WWP2 knockdown was found to increase SOX2 protein levels in GSCs (Fig.\u00a04A).|We first verified that WWP2 ubiquitinates SOX2 in vitro. 0.362 SIGNOR-278798 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 19118012 YES gcesareni Phosphorylation by activated jnk protects c-jun from ubiquitination;phosphorylation of c-jun on ser73 by jnk is sufficient to protect c-jun from ubiquitination c-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk). Phosphorylation by activated jnk protects c-jun from ubiquitination, thus by prolonging its half-life targets of the jnk signal transduction pathway include the transcription factors atf2 and c-jun apoptosis, altered;apoptosis, induced;transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts) transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts) 0.884 SIGNOR-183017 ADSS1 protein Q8N142 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-267344 KIF5B protein P33176 UNIPROT SYBU protein Q9NX95 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 15459722 YES miannu Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes. 0.561 SIGNOR-264811 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0000007 32989218 YES miannu The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. 0.2 SIGNOR-266376 FBXL5 protein Q9UKA1 UNIPROT NABP2 protein Q9BQ15 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25249620 YES miannu Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation.  0.344 SIGNOR-272460 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser5 sPPLRDVD 9606 SIGNOR-C17 14749395 YES lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. 0.365 SIGNOR-121605 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206124 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT up-regulates activity phosphorylation Ser83 EEGTFRSsIRRLSTR -1 15621037 YES miannu PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA. 0.449 SIGNOR-263117 CHRM3 protein P20309 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.277 SIGNOR-256739 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 10090 BTO:0000165 11226752 YES gcesareni Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis 0.78 SIGNOR-236870 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 YES lperfetto Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised 0.398 SIGNOR-146585 HNRNPU protein Q00839 UNIPROT NHLH2 protein Q02577 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 NO lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. 0.295 SIGNOR-262286 EYA3 protein Q99504 UNIPROT Six1/Dach complex SIGNOR-C122 SIGNOR up-regulates activity dephosphorylation 10090 14628042 YES llicata The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, 0.567 SIGNOR-238032 RPS6KB1 protein P23443 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates activity phosphorylation Ser549 VWRQRYQsHPDAAVQ 9606 35318320 YES miannu Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. 0.727 SIGNOR-273844 AATF protein Q9NY61 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 23146908 YES Chromatin immunoprecipitation in combination with siRNA-mediated knockdown revealed that recruitment of AATF and ZIPK to the PSA enhancer was dependent on AR, whereas recruitment of TSG101 was dependent on AATF. 0.2 SIGNOR-253669 Flesinoxan chemical CID:57347 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). 0.8 SIGNOR-258950 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT down-regulates activity phosphorylation Ser189 LLGVDLGsMDEEEEI 10090 BTO:0000944 14754904 YES miannu Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. 0.265 SIGNOR-262729 HIPK2 protein Q9H2X6 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 17210684 YES llicata Based on all these observations, it is legitimate to suggest that axin and daxx seem to adopt both parallel routes and a convergent means to activate p53. In either case, hipk2 seems to be the protein kinase that catalyzes the ser46 phosphorylation. 0.796 SIGNOR-151930 MARK4 protein Q96L34 UNIPROT MAPT protein P10636-5 UNIPROT down-regulates activity phosphorylation Thr231 KKVAVVRtPPKSPSS -1 21204788 YES miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.42 SIGNOR-273932 GDNF protein P39905 UNIPROT DNM2 protein P50570 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. 0.2 SIGNOR-252173 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT up-regulates quantity by stabilization phosphorylation Ser1424 SYELPARsQIGQKSP 10090 29301787 YES lperfetto Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466 0.261 SIGNOR-272269 BTRC protein Q9Y297 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates ubiquitination 9606 10228155 YES gcesareni Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels. 0.872 SIGNOR-67374 DRAM2 protein Q6UX65 UNIPROT RHOB protein P62745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 NO irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. 0.2 SIGNOR-259145 PRKACA protein P17612 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 YES miannu HTH1 was phosphorylated at Ser40 by PKA. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. phosphorylationof hTH1‚4 at Ser40, to a stoichiometry of up to 1.0 molphosphate per mol TH subunit, dramatically increases their binding to 14-3-3 proteins. 0.369 SIGNOR-250061 FBXO6 protein Q9NRD1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 19716789 YES miannu  Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. 0.677 SIGNOR-271881 CEBPA protein P49715 UNIPROT S100A9 protein P06702 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001370 9706399 YES Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells. 0.227 SIGNOR-254041 MTF1 protein Q14872 UNIPROT MCAT protein Q8IVS2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15378601 NO miannu MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase. 0.2 SIGNOR-254600 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser54 QPLPPRPsPAALPGG 23871434 YES lperfetto WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85 0.42 SIGNOR-275480 SLC25A13 protein Q9UJS0 UNIPROT aspartic acid smallmolecule CHEBI:22660 ChEBI up-regulates quantity relocalization 9606 12084073 YES miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 0.8 SIGNOR-265157 NOTCH1 protein P46531 UNIPROT ZMIZ1 protein Q9ULJ6 UNIPROT up-regulates activity binding 10090 BTO:0001825 26522984 YES miannu The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions 0.452 SIGNOR-263937 COL21A1 protein Q96P44 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 35267698 YES lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. 0.379 SIGNOR-272347 EEF1A2 protein Q05639 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269529 ISGF3 complex complex SIGNOR-C124 SIGNOR EIF2AK2 protein P19525 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27712625 NO miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. 0.489 SIGNOR-260158 DMD protein P11532 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.684 SIGNOR-255998 SLBP protein Q14493 UNIPROT H3-3A protein P84243 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265418 ABL1 protein P00519 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation Tyr261 GLVTTLHyPAPKCNK 9606 15735735 YES lperfetto The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization 0.516 SIGNOR-134396 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000007 16461343 YES In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22. 0.448 SIGNOR-248837 sorafenib tosylate chemical CHEBI:50928 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 0.8 SIGNOR-259224 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR FBXL7 protein Q9UJT9 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys109 RLASRPQkEQASIDR 10090 BTO:0002268 25654763 YES miannu F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18. 0.628 SIGNOR-272450 mir-133a1 mirna URS00005EB596_9606 RNAcentral IGF1R protein P08069 UNIPROT down-regulates quantity post transcriptional regulation 9606 17996649 NO miannu Here, we show that miR-223 is a direct transcriptional target of AML1/ETO. By recruiting chromatin remodeling enzymes at an AML1-binding site on the pre-miR-223 gene, AML1/ETO induces heterochromatic silencing of miR-223. Ectopic miR-223 expression, RNAi against AML1/ETO, or demethylating treatment enhances miR-223 levels and restores cell differentiation. 0.4 SIGNOR-261973 NKX2-5 protein P52952 UNIPROT NPPB protein P16860 UNIPROT unknown transcriptional regulation 15837525 NO In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription. 0.327 SIGNOR-253649 sertindole chemical CHEBI:9122 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258548 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763;BTO:0000149 10197981 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-66763 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser72 SKVQTTPsKPGGDRY 9606 BTO:0000567 15525512 YES llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  0.992 SIGNOR-250607 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation 9606 20230789 YES inferred from 70% family members lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity 0.2 SIGNOR-270203 SRF protein P11831 UNIPROT NKX3-1/SRF complex SIGNOR-C25 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001260 10993896 YES lperfetto A novel complex element containing a juxtaposed nkx-binding site (nke) and an srf-binding element (sre) in the proximal promoter region was found to be necessary for the nkx3-1/srf coactivation of smga transcription. 0.397 SIGNOR-82090 GAMT protein Q14353 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR up-regulates -1 26319512 NO Luana GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system 0.7 SIGNOR-265794 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12771128 YES gcesareni A dominant-negative mutant of high cell density-enhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. 0.407 SIGNOR-101279 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257500 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 BTO:0001938;BTO:0000567 25784705 YES SARA PKR directly interacts with G3BP1 through the NTF2-like and PXXP domains of G3BP1. The recruitment of inactive PKR to SGs through this interaction correlates with its activation 0.307 SIGNOR-260981 P2RY11 protein Q96G91 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256931 DIP2A protein Q14689 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity binding 10090 BTO:0003102 33622779 YES miannu Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. 0.2 SIGNOR-266593 GRK2 protein P25098 UNIPROT OXTR protein P30559 UNIPROT down-regulates activity phosphorylation 9534 BTO:0000298 16179383 YES miannu Recent experiments in COS-7 cells transfected with OTR have demonstrated that a rapid GRK2-mediated phosphorylation of the agonist-occupied OTR is a key first step leading to its desensitization, and that it precedes and is required for β-arrestin-dependent internalization 0.2 SIGNOR-270329 WASL protein O00401 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 YES lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. 0.789 SIGNOR-261003 PPP2CB protein P62714 UNIPROT MYC protein P01106 UNIPROT down-regulates dephosphorylation Ser62 LLPTPPLsPSRRSGL 9606 16987807 YES esanto Phosphorylation at ser-62 by pro-directed kinases (p-k) is a prerequisite for gsk3-dependent phosphorylation of thr-58. This triggers binding of pin1, subsequently protein phosphatase 2a (pp2a)-dependent dephosphorylation of ser-62, and then recruitment of scf-fbw7 to the thr-58-phosphorylated myc. Scf-fbw7 polyubiquitinylates myc (branching through lys-48), leading to its proteasomal degradation. 0.276 SIGNOR-149726 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser282 NSLQRVPsYDSFDSE BTO:0003637 12475968 YES llicata Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1  0.31 SIGNOR-250686 PRKCA protein P17252 UNIPROT MET protein P08581 UNIPROT down-regulates phosphorylation Ser985 PHLDRLVsARSVSPT 9606 8294430 YES fstefani These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor. 0.256 SIGNOR-37718 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity chemical inhibition 25309440 YES inferred from 70% of family members lperfetto Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway. 0.8 SIGNOR-269849 CAMK2G protein Q13555 UNIPROT SPR protein P35270 UNIPROT unknown phosphorylation Ser213 QQLARETsVDPDMRK 11825621 YES llicata Phosphorylation sites of rat sepiapterin reductase (rSPR) by Ca2+/calmodulin-dependent protein kinase II were determined in the present study. Using specific monoclonal anti-phospho-Ser and -Thr antibodies, we found that only Ser residues of rSPR were phosphorylated. We constructed several point mutants of SPR by systematically replacing the three Ser residues by Ala ones. These mutants showed that all three Ser residues, i.e. S46, S196, and S214, of rSPR were phosphorylated. We also recognized that only Ser-213 of human SPR was phosphorylated.  0.307 SIGNOR-250705 GART protein P22102 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI down-regulates quantity chemical modification 9606 34283828 YES miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 0.8 SIGNOR-267298 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 11108261 YES lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. 0.2 SIGNOR-244251 Ub:E2 complex SIGNOR-C497 SIGNOR UBR5 protein O95071 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271299 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity phosphorylation Ser1773 AAHGKRPsIGNLEHV -1 19074150 YES miannu We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry. 0.395 SIGNOR-263109 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.2 SIGNOR-159365 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 12670868 YES miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. 0.2 SIGNOR-264483 CEBPB protein P17676 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 15044620 NO miannu C/EBPbeta activates the endogenous MDR1 gene of MCF-7 cells, and this activation was associated with a novel C/EBPbeta interaction region within the proximal MDR1 promoter (-128 to -75). 0.444 SIGNOR-253771 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268783 XBP1 protein P17861 UNIPROT XBP1 protein P17861 UNIPROT up-regulates activity binding -1 12805554 YES miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins 0.2 SIGNOR-224199 MTA1 protein Q13330 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001938 19805145 YES miannu MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism 0.2 SIGNOR-271892 NR0B2 protein Q15466 UNIPROT CEBPA protein P49715 UNIPROT down-regulates activity binding 9606 17094771 YES miannu SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. 0.269 SIGNOR-254831 EIF2AK4 protein Q9P2K8 UNIPROT MARS1 protein P56192 UNIPROT down-regulates phosphorylation Ser662 NRAGMFVsKFFGGYV 9606 22106287 YES lperfetto Here we demonstrate that aimp3 is released from mrs by uv irradiation-induced stress. Dissociation was induced by phosphorylation of mrs at ser662 by general control nonrepressed-2 (gcn2) following uv irradiation. Substitution of ser662 to asp (s662d) induced a conformational change in mrs and significantly reduced its interaction with aimp3. This mutant possessed significantly reduced mrs catalytic activity because of loss of trna(met) binding, resulting in down-regulation of global translation. 0.2 SIGNOR-177648 RPS12 protein P25398 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.776 SIGNOR-262440 BIRC5 protein O15392 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 YES miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). 0.801 SIGNOR-275424 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser523 MEKEDYHsLYQSHL 9606 10347209 YES llicata We conclude that pkc-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein. our results strongly suggest that direct phosphorylation of tyrosinase by pkc-_ leads to its activation. 0.44 SIGNOR-67866 PTAFR protein P25105 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-257387 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2D3 protein P61077 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.734 SIGNOR-271348 INSR protein P06213 UNIPROT IRS4 protein O14654 UNIPROT up-regulates activity phosphorylation 10090 25905389 YES lperfetto The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok. 0.517 SIGNOR-217897 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 SIGNOR-C110 11955436 YES gcesareni Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). 0.86 SIGNOR-116524 AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser1261 PMKKLHVsTINLQKA 10090 BTO:0002572 31186373 YES miannu AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. AMPK associates with and phosphorylates mTOR within mTORC2., these data indicate that AMPK phosphorylates mTOR on Ser1261 within mTORC2, an event that correlates with increased mTORC2 autophosphorylation and downstream signaling. 0.566 SIGNOR-262535 USP45 protein Q70EL2 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR up-regulates activity deubiquitination 9606 BTO:0001938 25538220 YES miannu USP45 associates with the ERCC1–XPF endonuclease. USP45 interacts specifically with ERCC1–XPF via its N-terminal 61 residues. USP45 deubiquitylates ERCC1. USP45 promotes survival of cells exposed to agents that induce DNA damage responses controlled by ERCC1–XPF endonuclease 0.543 SIGNOR-268504 prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 20219869 NO apalma Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle 0.7 SIGNOR-256213 N protein P59595 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates quantity binding 9606 BTO:0000763 18055455 YES miannu In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis. 0.2 SIGNOR-260427 UBE2D2 protein P62837 UNIPROT TRIM9 protein Q9C026 UNIPROT up-regulates activity binding 9606 BTO:0000142 20085810 YES miannu Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N 0.423 SIGNOR-271420 CHEVI complex complex SIGNOR-C269 SIGNOR SEC22B protein O75396 UNIPROT up-regulates activity relocalization 9606 27319744 YES lperfetto VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles 0.376 SIGNOR-261832 STX11 protein O75558 UNIPROT STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR form complex binding 9606 BTO:0000132 22767500 YES lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  0.732 SIGNOR-261894 HRH1 protein P35367 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257050 CADPS protein Q9ULU8 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 YES miannu CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1 0.368 SIGNOR-264338 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 17609368 YES lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. 0.502 SIGNOR-216651 FABP4 protein P15090 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264458 belinostat chemical CHEBI:61076 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257744 SRC protein P12931 UNIPROT SH3GL1 protein Q99961 UNIPROT unknown phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 YES llicata These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. 0.637 SIGNOR-139154 ESRRA protein P11474 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.252 SIGNOR-253790 SMO protein Q99835 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 10090 BTO:0002572 16885213 YES gcesareni We found that Smo, by virtue of what appears to be constitutive activity, activates all members of the G(i) family but does not activate members of the G(s), G(q), and G(12) families. The activation is suppressed by cyclopamine and other inhibitors of Hedgehog signaling and is enhanced by the Smo agonist purmorphamine. 0.515 SIGNOR-148487 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 15621017 NO It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK. 0.7 SIGNOR-255481 regorafenib chemical CHEBI:68647 ChEBI ABCB1 protein P08183 UNIPROT down-regulates activity chemical inhibition 9606 26254357 YES miannu It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG2 0.8 SIGNOR-259182 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 YES gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. 0.791 SIGNOR-184198 PCDHA6 protein Q9UN73 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265666 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT down-regulates activity phosphorylation Tyr731 PYDTLHIyGYEGSES 10029 BTO:0000246 16027153 YES lperfetto cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity. 0.568 SIGNOR-246466 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser540 KVMARSLsPPPELEE 10090 BTO:0000944 15851026 YES lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. 0.68 SIGNOR-249454 FERMT2 protein Q96AC1 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 YES miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 0.782 SIGNOR-266102 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNJ1 protein P48048 UNIPROT up-regulates activity phosphorylation Ser4 sSRNVFDT -1 12221079 YES miannu We conclude that ROMK1 is a substrate of PKC and that serine residues 4 and 201 are the two main PKC phosphorylation sites that are essential for the expression of ROMK1 in the cell surface. 0.2 SIGNOR-275989 ZNF239 protein Q16600 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12409453 NO miannu We have demonstrated that MOK2 can bind to the 8 bp present in the IRBP promoter and repress transcription from this promoter by competing with the CRX activator for DNA binding. 0.308 SIGNOR-255629 SRC protein P12931 UNIPROT PIP5K1C protein O60331 UNIPROT up-regulates phosphorylation Tyr649 TDERSWVySPLHYSA 9606 15738269 YES lperfetto Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation. 0.285 SIGNOR-134459 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.774 SIGNOR-268709 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser231 KSNIVLLsAEEKKEQ 9606 7678037 YES llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells. 0.307 SIGNOR-250915 ACTL6B protein O94805 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.682 SIGNOR-270749 METTL3 protein Q86U44 UNIPROT USP13 protein Q92995 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 36528756 YES lperfetto Furthermore, N6-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m6A reader IGF2BP2. 0.2 SIGNOR-275839 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser188 QNRYSFYsTCSGQKA -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273490 RNF125 protein Q96EQ8 UNIPROT DDX58 protein O95786 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0005029 17460044 YES miannu Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production. 0.67 SIGNOR-271647 STRN4 protein Q9NRL3 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 YES miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms 0.572 SIGNOR-261697 PRKCD protein Q05655 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 YES miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 0.2 SIGNOR-276048 NR3C1 protein P04150 UNIPROT TIMELESS protein Q9UNS1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19805059 YES miannu GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription 0.252 SIGNOR-268052 FN1 protein P02751 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 15721307 YES lperfetto Integrin alpha8beta1-fibronectin interactions promote cell survival via PI3 kinase pathway. 0.681 SIGNOR-253304 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12393875 YES inferred from 70% family members gcesareni We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac. 0.2 SIGNOR-269964 PRKCG protein P05129 UNIPROT NRGN protein Q92686 UNIPROT up-regulates activity phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 YES lperfetto Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM. 0.43 SIGNOR-248915 eIF4F_complex complex SIGNOR-C44 SIGNOR Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 30459806 NO gianni The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation 0.7 SIGNOR-268530 TRIM13 protein O60858 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21333377 YES miannu Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. 0.374 SIGNOR-271851 SMARCA4 protein P51532 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.915 SIGNOR-132922 E protein P59637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000661 16048439 NO Luana Overexpression of SARS-CoV E protein in T-cells promoted apoptosis 0.7 SIGNOR-260208 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000007 15466476 YES lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. 0.573 SIGNOR-129690 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 SIGNOR-C110 16293724 YES gcesareni This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. 0.86 SIGNOR-141803 PRKCZ protein Q05513 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 YES lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. 0.277 SIGNOR-249261 PLK2 protein Q9NYY3 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 YES lperfetto Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein. 0.479 SIGNOR-182155 CC2D1A protein Q6P1N0 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 20171170 YES nucleus lperfetto Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor. 0.371 SIGNOR-268295 MAPK1 protein P28482 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 YES gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3 0.372 SIGNOR-169875 WNT11 protein O96014 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 22309736 YES gcesareni We provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase 0.457 SIGNOR-195966 8a protein Q7TFA0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001950 17597455 NO Luana Open Reading Frame 8a of the Human Severe Acute Respiratory Syndrome Coronavirus Not Only Promotes Viral Replication but Also Induces Apoptosis 0.7 SIGNOR-260206 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257979 procaterol chemical CHEBI:135209 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257864 SNIP1 protein Q8TAD8 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR down-regulates binding 9606 10887155 YES lperfetto In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4 0.605 SIGNOR-217661 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr699 DPEGGVDyKNIHLEK 9606 15297464 YES lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. 0.2 SIGNOR-127536 CBX5 protein P45973 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-264489 CASP3 protein P42574 UNIPROT GRIPAP1 protein Q4V328 UNIPROT up-regulates activity cleavage 9606 17761173 YES Giorgia These results suggest that the region of GRASP‐1 downstream of the Caspase‐3‐cleavage site is capable of activating the JNK signaling pathway by enhancing the phosphorylation of JNK. these results suggest that full length GRASP‐1 does not enhance JNK pathway activity, possibly due to the inhibitory effect of the N‐terminal fragment on the C‐terminal fragment. In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein. 0.414 SIGNOR-260641 RRAGD protein Q9NQL2 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates binding 9606 SIGNOR-C3 20006481 YES gcesareni Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor 0.905 SIGNOR-162093 DCAF1 protein Q9Y4B6 UNIPROT NF2 protein P35240 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 18332868 YES miannu VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation. 0.2 SIGNOR-271673 ACP1 protein P24666 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr857 DIMRDSNyISKGSTF 9606 12149261 YES Insight into the role of low molecular weight phosphotyrosine phosphatase (LMW-PTP) on platelet-derived growth factor receptor (PDGF-r) signaling. LMW-PTP controls PDGF-r kinase activity through TYR-857 dephosphorylation|On the basis of these results, we propose a key role for LMW-PTP in PDGF-r down-regulation through the dephosphorylation of the activation loop Tyr-857, thus determining a general negative regulation of all downstream signals, with the exception of those elicited by internalized receptors. 0.308 SIGNOR-248452 NMDA receptor_2C complex SIGNOR-C349 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 YES miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. 0.288 SIGNOR-266601 Ub:E2 complex SIGNOR-C497 SIGNOR LONRF1 protein Q17RB8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271156 ULK1 protein O75385 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser490 ELAPRNSsLRLTDTA 9606 25925668 YES lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. 0.433 SIGNOR-264731 IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 10090 BTO:0000944 11416002 YES lperfetto To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1 0.722 SIGNOR-235487 IFNG protein P01579 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates binding 9606 7673114 YES gcesareni Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (43 45) is required for signal transduction 0.647 SIGNOR-31013 PTPN12 protein Q05209 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 18482983 YES we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin 0.541 SIGNOR-248659 EGFR protein P00533 UNIPROT PKIA protein P61925 UNIPROT up-regulates phosphorylation Tyr8 MTDVETTyADFIASG 9606 1956339 YES lperfetto The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency. 0.307 SIGNOR-22455 MSX2 protein P35548 UNIPROT DLX2 protein Q07687 UNIPROT down-regulates activity binding 10090 BTO:0000945 9111364 YES 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. 0.392 SIGNOR-240932 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 SIGNOR-C3 20516213 YES fstefani The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. 0.711 SIGNOR-165795 SREBF2 protein Q12772 UNIPROT LDLR protein P01130 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21123766 YES miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. 0.772 SIGNOR-254453 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120128 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser173 MLETLSQsPPKGVTI 10090 BTO:0000664 17475908 YES miannu All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells. 0.2 SIGNOR-262668 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 YES gcesareni Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase. 0.678 SIGNOR-33141 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser53 LPPFEDEsEGLLGTE 9606 19647517 YES lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry 0.962 SIGNOR-187400 IQSEC2 protein Q5JU85 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0000142 18164504 YES miannu Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6. 0.458 SIGNOR-264906 RAB4A protein P20338 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity binding 9606 20534812 YES Giulio Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4 0.679 SIGNOR-261280 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser181 NPLLRKEsAPPSLRR -1 15738054 YES lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. 0.479 SIGNOR-249273 WNT5B protein Q9H1J7 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.587 SIGNOR-131885 RGCC protein Q9H4X1 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity binding 9606 BTO:0001685 11687586 YES miannu RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity. 0.531 SIGNOR-262726 MAD2L1BP protein Q15013 UNIPROT TRIP13 protein Q15645 UNIPROT up-regulates activity binding 9606 BTO:0000567 25092294 YES miannu We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). 0.47 SIGNOR-265971 MYCBP2 protein O75592 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 YES miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 0.416 SIGNOR-267147 MTOR protein P42345 UNIPROT ISCU protein Q9H1K1 UNIPROT up-regulates phosphorylation Ser14 FRLRRAAsALLLRSP 9606 SIGNOR-C3 23508953 YES llicata Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein. 0.2 SIGNOR-201595 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0001271 8622703 YES lperfetto We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr. 0.2 SIGNOR-40615 ERBB3 protein P21860 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 14967450 YES gcesareni All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3. 0.838 SIGNOR-121971 PRKCA protein P17252 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 10116 BTO:0002320 15367659 YES lperfetto We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E 0.2 SIGNOR-249268 NTN4 protein Q9HB63 UNIPROT NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 28245592 YES miannu Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins. 0.537 SIGNOR-268170 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu50 RANTFLEeVRKGNLE -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263676 CILK1 protein Q9UPZ9 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 22356909 YES lperfetto Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division. 0.2 SIGNOR-217562 NMDA receptor_2D complex SIGNOR-C350 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 YES miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. 0.288 SIGNOR-266602 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000586 16293724 NO lperfetto We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein;G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt 0.816 SIGNOR-235914 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1C protein Q8TCG5 UNIPROT down-regulates activity binding 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267116 DNAJB9 protein Q9UBS3 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates activity binding -1 12356756 YES miannu When BAP was added to BiP (2:1 molar ratio of BAP:BiP), it increased the ATPase activity of BiP by about 2-fold, which was similar to the increase observed when the J domain of ERdj4 was added to BiP (Fig.5). When both BAP and the J domain were added to BiP, the rate of ATP hydrolysis by BiP was stimulated by about 4-fold over basal levels, indicating that both BAP and ERdj4 positively regulate the ATPase activity of BiP 0.543 SIGNOR-261044 HTR1B protein P28222 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.479 SIGNOR-256999 PRKCI protein P41743 UNIPROT NUMB protein P49757 UNIPROT down-regulates phosphorylation 9606 17609107 YES esanto Numb is regulated by phosphorylation since the protein is released from ccss and no longer binds integrins when phosphorylated by atypical protein kinase c (apkc). 0.77 SIGNOR-156765 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser381 CIPTAGMsPSRSNTI 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.601 SIGNOR-249395 Ub:E2 complex SIGNOR-C497 SIGNOR PDZRN4 protein Q6ZMN7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271036 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.271 SIGNOR-265803 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9335504 YES llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. 0.642 SIGNOR-52670 GBAF complex SIGNOR-C467 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 NO miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.7 SIGNOR-269790 SAGA complex complex SIGNOR-C465 SIGNOR H3Y1 protein P0DPK2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269631 Ub:E2 complex SIGNOR-C497 SIGNOR HECTD1 protein Q9ULT8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271294 SIRT6 protein Q8N6T7 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity binding 9606 BTO:0000007 25083875 YES miannu SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids. 0.371 SIGNOR-268158 ETV4 protein P43268 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24983502 NO miannu Transcriptional activation of oct4 by the ets transcription factor pea3 in nccit human embryonic carcinoma cells 0.378 SIGNOR-205173 KDM4B protein O94953 UNIPROT BBC3 protein Q9BXH1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 NO miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. 0.2 SIGNOR-263732 WNT3A protein P56704 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 BTO:0000222 10601008 YES gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes. 0.795 SIGNOR-73036 ALDOB protein P05062 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266484 PSMA2 protein P25787 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.854 SIGNOR-263367 CADPS protein Q9ULU8 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 YES miannu CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly. 0.429 SIGNOR-264340 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser192 VNSVRRKsCLVKEVE 9606 17567953 YES lperfetto Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres. 0.73 SIGNOR-155898 3b protein P59633 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21561061 NO Luana 3b Augments c-Fos Levels by Activating the ERK Pathway. | An increase of∼2.0-fold inphospho ERK (Thr-202/Tyr-204) levels in 3b-expressing Huh7cells as compared to GFP-transfected control cells (Figure 4a)was observed. This increase in phospho ERK levels was also 0.2 SIGNOR-260763 PPP3CA protein Q08209 UNIPROT NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 YES gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. 0.536 SIGNOR-176376 C25H27N5O4S chemical CID:66577011 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189711 CENP-A nucleosome complex SIGNOR-C321 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000567 20566683 NO miannu Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity. 0.7 SIGNOR-263703 MAPKAPK2 protein P49137 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates phosphorylation Ser323 KDLGRSEsLRVVCRP 9606 16456544 YES lperfetto Mk2 activated limk1 by phosphorylation at ser-323. 0.36 SIGNOR-144333 PKG proteinfamily SIGNOR-PF77 SIGNOR 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. 0.8 SIGNOR-266507 WNK1 protein Q9H4A3 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates activity phosphorylation Thr1023 QKKQGKNtIDVWWLF 9606 BTO:0000007 36318922 YES miannu Combining these biochemical studies with the live cell imaging data, these results collectively suggest that the entire CTD is necessary for WNK1 to drive optimal SPAK/OSR1 activation and downstream NKCC1/KCC phosphorylation via PS. 0.492 SIGNOR-277859 PRKAA1 protein Q13131 UNIPROT SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation Ser9 NYLRRRLsDSNFMAN 9606 10880969 YES lperfetto It has been reported that site 1 of syn i can be phosphorylated by pka. Pka-mediated synapsin i ser9 phosphorylation occurs in response to cgs 21680 treatment. Results show that the adenosine a2a receptor agonist, cgs 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase a activation, which in turn increased synapsin i phosphorylation 0.2 SIGNOR-78891 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268586 MAP4K1 protein Q92918 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser556 TKMQPPRsRSSIMSI -1 19706536 YES miannu HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. 0.493 SIGNOR-276259 ADRB2 protein P07550 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.314 SIGNOR-257192 MRAP protein Q8TCY5 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. 0.397 SIGNOR-252368 EFR3A protein Q14156 UNIPROT PI4KA protein P42356 UNIPROT up-regulates quantity binding 9606 BTO:0000007 34504076 YES miannu PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B 0.47 SIGNOR-269092 FFAR1 protein O14842 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257184 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 22975381 YES lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.772 SIGNOR-192057 Ub:E2 complex SIGNOR-C497 SIGNOR RNF169 protein Q8NCN4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271202 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS2 protein Q9NRM7 UNIPROT up-regulates 9606 23075495 NO gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. 0.8 SIGNOR-199199 STOML2 protein Q9UJZ1 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 18641330 YES Giorgia In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. 0.2 SIGNOR-260378 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270414 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser365 KDCERRFsRSDQLKR 9606 9366517 YES llicata Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo. 0.341 SIGNOR-53172 SPI1 protein P17947 UNIPROT miR-146a mirna URS000075D8A0_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 10090 21730352 NO miannu We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation. 0.4 SIGNOR-256243 DDX5 protein P17844 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 18829551 YES miannu P68 is a nuclear protein and interacts with ar / p68 co-occupies the active psa promoter at are regions and enhances ar transcriptional activity 0.32 SIGNOR-181456 LMP1 protein P03230 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9606 26428373 NO scontino AP1 is a dimeric transcription factor composed of members of the Jun and Fos protooncoprotein families. AP1 was found induced by LMP1 through the JNK signaling cascade, involving JNK1-mediated phosphorylation and activation of c-Jun. JNK1 activation critically relies on CTAR2 and its P379VQLSYY motif. It has long been unclear which signaling mediators at CTAR2 are involved in JNK activation. 0.2 SIGNOR-267617 N protein P59595 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9534 15294014 NO Luana Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways. 0.2 SIGNOR-261131 3b protein P59633 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9606 21561061 NO Luana An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP 0.2 SIGNOR-260760 ERG protein P11308 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22140532 NO miannu ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability. 0.2 SIGNOR-254065 CPSF3 protein Q9UKF6 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 30507380 NO lperfetto Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes. 0.7 SIGNOR-268336 AKT1 protein P31749 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr39 LKKIRLDtETEGVPS 9606 18354084 YES lperfetto Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity. 0.329 SIGNOR-178058 PTPN14 protein Q15678 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 BTO:0000586 22710723 YES lperfetto We show that p130 crk-associated substrate (p130cas) is a direct substrate of ptpn14 and that ptpn14 specifically regulates p130cas phosphorylation at tyrosine residue 128 (y128) in colorectal cancer (crc) cells. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation 0.394 SIGNOR-197923 CAST protein P20810 UNIPROT CAPN2 protein P17655 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 YES lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain 0.903 SIGNOR-251609 RUNX3 protein Q13761 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 19800882 YES gcesareni To investigate the possible mechanism of the down-regulation of hes-1 by runx3, we performed western blot and reporter assay and found that runx3 suppressed intracellular domain of notch1 (icn1)-mediated transactivation of notch signaling while it did not alter the expression of icn1 and recombination signal binding protein-j kappa (rbp-j) in smmc7721 cells. 0.689 SIGNOR-188338 RELA protein Q04206 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR form complex binding 9606 BTO:0000671 9056676 YES miannu Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel. 0.675 SIGNOR-46948 N protein P59595 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 BTO:0000298 15294014 NO Luana Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways. 0.2 SIGNOR-261132 3a protein P59632 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0001950 18632968 NO Luana Severe Acute Respiratory Syndrome Coronavirus 3a Protein Activates the Mitochondrial Death Pathway Through p38 MAP Kinase Activation 0.2 SIGNOR-260193 7a protein P59635 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0000007 16378980 NO Luana While there is a low level of activated p38 normally found in 293T cells, expression of 7a-protein stimulated larger amounts of activated p38 during the 24-h time course.  0.2 SIGNOR-260754 E protein P59637 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 10090 BTO:0000763 25122212 NO Luana Interestingly, an increase in p38 MAPK activation was observed during infection with viruses containing E protein PBM, similarly to what was observed in the lungs of SARS-CoV-infected mice. These results indicated that the E protein PBM is involved in p38 MAPK activation in response to SARS-CoV infection. 0.2 SIGNOR-260751 CDK1 protein P06493 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates phosphorylation Ser552 DLEVLTSsPTRNLNG 9606 24013421 YES llicata Here, we report that cyclin-dependent kinase 1 (cdk1) phosphorylates the histone h2a deubiquitinase ubp-m at serine 552 (s552p), and, importantly, this phosphorylation is required for cell cycle progression. 0.455 SIGNOR-202678 chelerythrine chemical CHEBI:78373 ChEBI MAPK8 protein P45983 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-190964 NLRC4 protein Q9NPP4 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.75 SIGNOR-256404 CDX2 protein Q99626 UNIPROT MEP1A protein Q16819 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22326557 YES TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis| 0.472 SIGNOR-253965 E2F1 protein Q01094 UNIPROT TLR3 protein O15455 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 22310660 NO lperfetto Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is upregulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells. 0.2 SIGNOR-254136 SLBP protein Q14493 UNIPROT H2AZ1 protein P0C0S5 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265408 TH protein P07101 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI up-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). 0.8 SIGNOR-263991 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR up-regulates activity chemical activation 26083061 YES lperfetto Respiratory chain complexes I–III depend on Fe-S clusters for function 0.8 SIGNOR-262136 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 14579029 YES gcesareni Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632 0.705 SIGNOR-118877 NR3C1 protein P04150 UNIPROT ATP1B1 protein P05026 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9694812 YES miannu Together these data indicate that the 21-base pair sequence represents a true MRE/GRE and that optimal activation of the human Na/K-ATPase beta1 promoter is controlled by mineralocorticoid and glucocorticoid hormones. It appears that an interaction of MR with GR on the beta1 promoter effectively down-regulates transcription. 0.2 SIGNOR-254864 MAPKAPK2 protein P49137 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser326 LTIPPRFsIAPSSLD 9606 18695677 YES llicata Here, we have identified mk2 as a major plk1 kinase toward ser326, whose phosphorylation is critical to recruit ?-Tubulin to centrosomes and subsequent establishment of functional bipolar spindles. To our knowledge, this is the first direct evidence to demonstrate that the essential function of plk1 in centrosome maturation and bipolar spindle formation is controlled by its upstream kinase. 0.35 SIGNOR-179968 RORA protein P35398 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates quantity by expression transcriptional regulation 28608249 YES lperfetto Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005). 0.266 SIGNOR-265137 CFL1 protein P23528 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR down-regulates quantity binding 9606 BTO:0000132 27871158 YES lperfetto Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. 0.7 SIGNOR-261836 PTEN protein P60484 UNIPROT ABTB1 protein Q969K4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 NO miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 0.357 SIGNOR-260050 P2RY10 protein O00398 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257348 PAX6 protein P26367 UNIPROT GCG protein P01275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000120 12783165 NO miannu In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. 0.61 SIGNOR-254905 MEF2D protein Q14814 UNIPROT ASH2L protein Q9UBL3 UNIPROT up-regulates 9606 BTO:0000887 18026121 NO gcesareni Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d. 0.466 SIGNOR-159334 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser637 HSLLERYsVNEGLVA 9606 BTO:0000567 phosphorylation:Thr550 PPINGSStPNPKIAS 19509060 YES lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. 0.617 SIGNOR-272991 LPCAT4 protein Q643R3 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272771 MBL2 protein P11226 UNIPROT MASP2 protein O00187 UNIPROT up-regulates activity binding 9606 9087411 YES lperfetto The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). 0.739 SIGNOR-263415 NMBR protein P28336 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 YES gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways. 0.282 SIGNOR-107025 MC5R protein P33032 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.458 SIGNOR-268712 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 10567431 YES lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.755 SIGNOR-217056 PTPN1 protein P18031 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation 9606 23521888 YES lperfetto Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well.|The results indicate that PTP1B completely dephosphorylated Gab1 and the mutant protein failed to dephosphorylate Gab1 (Figure\u00a0 xref C). 0.381 SIGNOR-276965 HTR1A protein P08908 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.569 SIGNOR-256836 bisphenol F chemical CHEBI:34575 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 31995776 YES miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 0.8 SIGNOR-268734 trimipramine chemical CHEBI:9738 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 9537821 YES miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  0.8 SIGNOR-258742 PPP1CA protein P62136 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 YES Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. 0.314 SIGNOR-248557 RPS6KA2 protein Q15349 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 20385620 YES gcesareni Rsk2 is activated by treatment with tumor necrosis factor-alfa (tnf-alfa) and directly phosphorylates ikbalfa at ser-32, leading to ikbalfa degradation. 0.267 SIGNOR-164790 M protein P59596 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0005029 25271362 NO Luana Consistent with our previous result, we detected a reduced phosphorylated PKB/Akt level and diminished PKB/Akt activity in mammalian cells expressing M-protein. 0.2 SIGNOR-260200 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9534 12387817 YES lperfetto Thus, it was suggested that NHERF2 mediates the activation and phosphorylation of SGK1 by PDK1 through its first PDZ domain and PIF motif, as a novel SGK1 activation mechanism. 0.649 SIGNOR-236800 amisulpride chemical CHEBI:64045 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258364 QARS1 protein P47897 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.2 SIGNOR-270358 HSPB1 protein P04792 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 12855565 NO gcesareni These data demonstrate that hsp27 inhibits the release of smac 0.328 SIGNOR-103539 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11085989 NO miannu We also show for the first time that leptin rapidly stimulates the mRNA expression of the zinc finger transcription factor, Egr-1, in the hypothalamus of mice. Our transfection results suggest that this regulation by leptin occurs by activation of theegr-1 promoter via activation of SHP-2 and of the ERK pathway.  0.2 SIGNOR-263507 IL23R protein Q5VWK5 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 YES gcesareni Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12. 0.7 SIGNOR-87808 PALB2 protein Q86YC2 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates binding 9606 BTO:0000150 16793542 YES miannu Palb2 colocalizes with brca2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. 0.941 SIGNOR-147217 MAPK9 protein P45984 UNIPROT MFN2 protein O95140 UNIPROT down-regulates phosphorylation Ser27 HMAEVNAsPLKHFVT 9606 22748923 YES lperfetto Jnk phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (e3) huwe1/mule/arf-bp1/hecth9/e3histone/lasu1 to mitofusin 2, with the bh3 domain of huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2these data establish that mfn2 is phosphorylated on ser27 in response to a variety of cellular stresses and implicate jnk in this process 0.352 SIGNOR-198054 MAPK3 protein P27361 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 YES lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. 0.2 SIGNOR-184180 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273050 ATP smallmolecule CHEBI:15422 ChEBI P2RX7 protein Q99572 UNIPROT up-regulates chemical activation 9606 18827222 YES mrosina Pericellular ATP activates P2XRs on the T cell in an autocrine fashion (step 4) and perhaps also P2X7 receptors on the APC in a paracrine fashion resulting in IL-1beta processing and release (step 5). 0.8 SIGNOR-254965 NCF2 protein P19878 UNIPROT Phagocyte NADPH oxidase complex complex SIGNOR-C557 SIGNOR form complex binding 9606 37263099 YES miannu NADPH oxidase is composed of essential protein components in its active state: membranous subunits, including p22-phox and gp91-phox, and cytoplasmic subunits, including p47-phox, p67-phox, p40-phox, and RAC2 (in neutrophils), among which NCF4 encodes the cytoplasmic subunit p40-phox 0.748 SIGNOR-277632 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT down-regulates activity phosphorylation Ser941 NVRSKVGsTENIKHQ -1 8631898 YES miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 0.438 SIGNOR-250171 HOXA11 protein P31270 UNIPROT PRL protein P01236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003697 19727442 YES Luana HoxA-11 enhanced upregulation of PRL only in differentiated cells. 0.351 SIGNOR-261630 SNTB1 protein Q13884 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates 10090 BTO:0002314 BTO:0001103 29681515 YES apalma [...] suggesting that, during an asymmetric cell division, p38gamma localization would be basally restricted by the DGC complex via its interaction with beta-1-syntrophin. 0.369 SIGNOR-255903 TRAF6 protein Q9Y4K3 UNIPROT LGMN protein Q99538 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000815 24610907 YES miannu We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. We now present evidence that AEP is a substrate for TRAF6 ubiquitination, resulting in AEP/TRAF6/HSP90α complex formation. 0.308 SIGNOR-272853 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.394 SIGNOR-89264 DOK1 protein Q99704 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257671 NR0B2 protein Q15466 UNIPROT NR5A2 protein O00482 UNIPROT down-regulates binding 9606 12198243 YES gcesareni Here we show that shp can interact with the liver x receptors lxralpha (nr1h3) and lxrbeta (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter 0.564 SIGNOR-92060 CAV1 protein Q03135 UNIPROT HMGA1 protein P17096 UNIPROT up-regulates activity relocalization 9606 22706202 YES miannu CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. 0.265 SIGNOR-254428 Core Binding Factor complex complex SIGNOR-C214 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 19813271 NO The core binding factor (CBF), consisting of a Runx protein and the CBFβ protein, is a transcription factor complex that is essential for emergence of the hematopoietic stem cell (HSC) from an endothelial cell stage. The hematopoietic defects observed in either Runx1 or CBFβ knockout mice underscore the necessity of this complex for definitive hematopoiesis. 0.7 SIGNOR-255740 IKBKE protein Q14164 UNIPROT CDK2AP1 protein O14519 UNIPROT unknown phosphorylation Ser46 LSDYGPPsLGYTQGT -1 22427660 YES lperfetto CDK2AP1 is phosphorylated at a conserved Ser-46 site in the N-terminal "intrinsically disordered" region by IkappaB kinase epsilon. 0.2 SIGNOR-264780 WDR62 protein O43379 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity relocalization 10090 30566428 YES lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis 0.2 SIGNOR-271715 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR MECOM protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 YES miannu We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. 0.2 SIGNOR-260107 F2 protein P00734 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 YES lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. 0.578 SIGNOR-261859 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by stabilization phosphorylation Ser419 S-->N 9606 25605940 YES miannu We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. 0.436 SIGNOR-276476 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation Tyr261 GLVTTLHyPAPKCNK 9606 15735735 YES lperfetto The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization 0.2 SIGNOR-134400 APC-c complex SIGNOR-C150 SIGNOR AURKA protein O14965 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0004055 12023018 YES miannu We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity. 0.443 SIGNOR-272612 SIRT2 protein Q8IXJ6 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by stabilization 9606 23175188 NO miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. 0.376 SIGNOR-255147 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0001538 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.718 SIGNOR-219337 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB3 protein Q9Y5G1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265685 KATNB1 protein Q9BVA0 UNIPROT KATNA1 protein O75449 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 10751153 YES miannu In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer 0.755 SIGNOR-267173 YWHAZ protein P63104 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 14701738 YES miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase 0.303 SIGNOR-261725 DUSP5 protein Q16690 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 10224087 YES gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway 0.781 SIGNOR-67355 INTS4 protein Q96HW7 UNIPROT DYNC1H1 protein Q14204 UNIPROT up-regulates quantity 9606 BTO:0000567 23904267 NO Monia We propose a model in which nuclear localized Integrator complex, including ASUN, mediates 3′-end processing of snRNA, which in turn is required for normal processing of mRNA encoding a key regulator(s) of cytoplasmic dynein localization. When Integrator activity is compromised (e.g., by knockdown of an essential subunit), production of critical transcript(s) during interphase is impaired, leading to reduction of perinuclear dynein at G2/M. 0.2 SIGNOR-261186 UBE2D2 protein P62837 UNIPROT PEX5 protein P50542 UNIPROT down-regulates quantity by destabilization ubiquitination -1 19687296 YES miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 0.416 SIGNOR-253023 CCT365623 (hydrochloride) chemical CID:139266765 PUBCHEM LOX protein P28300 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000195 31070916 YES Simone Vumbaca Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy. 0.8 SIGNOR-261121 MAPK8 protein P45983 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity phosphorylation Ser27 HMAEVNASPLKHFVT 9606 BTO:0001938 22748923 YES Barakat We demonstrate that a critical component of the mitochondrial fusion apparatus, the mitofusin Mfn2, is a target for phosphorylation in response to a variety of cellular stresses. We provide direct evidence that JNK mediates this phosphorylation. 0.428 SIGNOR-274138 ITGB1 protein P05556 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates activity binding 9606 35442831 YES miannu One such mechanism is operant in colorectal cancer (CRC) cells. On integrin-dependent CRC cell adhesion, the Kv11.1/β1 integrin complex recruits the PI3K p85 subunit, which stimulates AKT phosphorylation and thus regulates autophagy 0.2 SIGNOR-277614 HRH1 protein P35367 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257318 CDKN2AIP protein Q9NXV6 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18292944 NO fstefani Carf interacts with hdm2 and undergoes degradation by an hdm2-dependent proteasome pathway, and ii) it acts as a transcriptional repressor of hdm2. 0.371 SIGNOR-160971 SP1 protein P08047 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 NO miannu We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. 0.2 SIGNOR-254812 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu612 IKTEEISeVKMDAEF -1 8943232 YES lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261766 PTPRB protein P23467 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 YES gcesareni Inally, mrna tissue distribution of these ptps by rt-pcr analysis and coexpression of the wild-type ptps to test their ability to dephosphorylate ligand-activated ghr suggest ptp-h1 and ptp1b as potential candidates involved in ghr signaling. 0.295 SIGNOR-104580 WARS1 protein P23381 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 0.8 SIGNOR-270512 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr131 KENLIREyVKQTWNL 9606 BTO:0000776 9820500 YES lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 0.2 SIGNOR-246601 imiquimod chemical CHEBI:36704 ChEBI TLR7 protein Q9NYK1 UNIPROT up-regulates activity chemical activation 9606 15661881 YES miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. 0.8 SIGNOR-259244 CDK1 protein P06493 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation 9606 16682949 YES gcesareni We found that nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative cdc2 phosphorylation sites in nde1 and found that alteration of these sites diminishes phosphorylation by cdc2 in vitro and affects the stability of su48-nde1 interactions and the centrosomal localization of nde1. 0.653 SIGNOR-146734 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser679 SPDSMNAsRLSQPGQ 9606 BTO:0000007 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251277 AKT2 protein P31751 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 YES gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. 0.261 SIGNOR-164302 DAB2IP protein Q5VWQ8 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity gtpase-activating protein 9606 27858941 YES miannu The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP. 0.598 SIGNOR-254745 COL1A1 protein P02452 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 NO Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I 0.7 SIGNOR-254662 ERG protein P11308 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 NO miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. 0.2 SIGNOR-253925 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe709 ENPTYKFfEQMQN 9606 10931940 YES lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform. 0.545 SIGNOR-261779 PTP4A3 protein O75365 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity dephosphorylation Tyr783 DTGENPIyKSAVTTV 9606 23092334 YES miannu In this study, we demonstrate that PRL-3 directly binds to integrin \u03b21 and dephosphorylates integrin \u03b21-Y783, a key residue for integrin \u03b21 function [ ].|These results indicate that PRL-3 dephosphorylates integrin \u03b21 in vitro and in vivo. 0.525 SIGNOR-277050 HHAT protein Q5VTY9 UNIPROT SHH protein Q15465 UNIPROT up-regulates palmitoylation 9606 18534984 YES gcesareni Both the shh precursor and mature protein are n-palmitoylated by hhatn-palmitoylation of cys-24 by hhat is required for n-product multimerization and full activity 0.682 SIGNOR-161548 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 9606 15952796 YES lperfetto We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling. 0.374 SIGNOR-138167 IGF1R protein P08069 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity binding -1 7541045 YES lperfetto In our present work, we show that both IRS-1 and SHC interact directly with the juxtamembrane region of the IGFIR in a phosphotyrosine-dependent manner. |We propose a model in which IGFIR autophosphorylation of Tyr-950 forms a direct binding site for the amino-terminal receptor binding domains of SHC and IRS-1. This interaction is presumed to facilitate tyrosine phosphorylation of SHC on Tyr-317 leading to GRB2/SOS interaction 0.735 SIGNOR-262587 CDK1 protein P06493 UNIPROT ERCC6L protein Q2NKX8 UNIPROT up-regulates phosphorylation Thr1063 VKQFDAStPKNDISP 9606 17218258 YES lperfetto Following phosphorylation of pich on the cdk1 site t1063, plk1 is recruited to pich and controls its localization. Starting in prometaphase, pich accumulates at kinetochores and inner centromeres. 0.578 SIGNOR-152133 MAP3K7 protein O43318 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9278437 YES lperfetto Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway. 0.71 SIGNOR-50618 KNG1 protein P01042 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates activity binding 9606 cleavage:Arg381;Arg389 GMISLMKrPPGFSPF;PPGFSPFrSSRIGEI 28966616 YES lperfetto BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis. 0.856 SIGNOR-263554 p38 proteinfamily SIGNOR-PF16 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 YES inferred from 70% family members gcesareni Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target 0.2 SIGNOR-270124 Gbeta proteinfamily SIGNOR-PF4 SIGNOR WWC1 protein Q8IX03 UNIPROT unknown phosphorylation 9606 BTO:0000149 24269383 YES inferred from 70% family members llicata We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro. 0.2 SIGNOR-270121 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates quantity by destabilization ubiquitination Lys212 LDGEMDPkVPAIEEN 9606 BTO:0000007 17805301 YES miannu  In the presence of relevant cofactors (DDB1, DET1), COP1 promoted the ubiquitination of wild-type but not COP1-interaction defective VP/AA TORC2 (Fig. 3e). COP1 also stimulated the ubiquitination of TORC2(K213R) but had no effect on TORC2(K628R), suggesting an important role for Lys 628 in this regard (Fig. 3e). We performed mass spectrometry studies to characterize residues in TORC2 that undergo COP1-mediated ubiquitination. This analysis revealed one major (Lys 628) and one minor (Lys 213) site on TORC2 0.2 SIGNOR-271666 FBXO3 protein Q9UK99 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25721664 YES miannu F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway. 0.2 SIGNOR-272444 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr568 EEINGNNyVYIDPTQ 9606 BTO:0001271 12824176 YES lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated 0.2 SIGNOR-102633 GRB2 protein P62993 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 BTO:0001271 8402896 YES GRB2 binds BCR-ABL with SH2 domain gcesareni We demonstrate that bcr-abl exists in a complex with grb-2 in vivo. Binding of grb-2 to bcr-abl is mediated by the direct interaction of the grb-2 sh2 domain with a phosphorylated tyrosine, y177, within the bcr first exon. 0.579 SIGNOR-39049 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser633 SFDTHFRsPSSSVGS 9606 12620228 YES llicata Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth. 0.2 SIGNOR-98980 PRKCB protein P05771 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 YES lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. 0.364 SIGNOR-249087 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser146 RPSQRHGsKYLATAS -1 2413024 YES lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 0.49 SIGNOR-248870 MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 7839144 YES lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. 0.59 SIGNOR-34121 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr853 HLGRVLGyGAFGKVV 9606 20431062 YES lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. 0.511 SIGNOR-165055 PPARGC1A protein Q9UBK2 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20089851 NO Regulation miannu PGC-1α has been reported to induce Mn-SOD expression 0.373 SIGNOR-251762 CPSF7 protein Q8N684 UNIPROT CFI complex complex SIGNOR-C388 SIGNOR form complex binding 9606 BTO:0000567 8626397 YES lperfetto We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity. 0.789 SIGNOR-266124 ARRB2 protein P32121 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity relocalization 21296876 YES lperfetto Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs) 0.398 SIGNOR-275506 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 19573809 NO lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth 0.816 SIGNOR-252634 CDT1 protein Q9H211 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity binding 9606 BTO:0000007 14672932 YES Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1. 0.812 SIGNOR-261681 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 21205641 YES lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.49 SIGNOR-216453 DLG4 protein P78352 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 19075115 NO miannu Postsynaptic density 95 (PSD-95) is an important regulator of synaptic structure and plasticity. 0.7 SIGNOR-264053 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270398 PIM1 protein P11309 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 16146838 NO lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. 0.7 SIGNOR-249623 NFYA protein P23511 UNIPROT SOX18 protein P35713 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 18496767 NO miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells 0.2 SIGNOR-254818 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr136 AEDAKAIyDFTDTVI 9606 22195962 YES llicata Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1 0.347 SIGNOR-191719 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR CDH1 protein P12830 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 YES miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 0.2 SIGNOR-265817 OGT protein O15294 UNIPROT PFKP protein Q01813 UNIPROT down-regulates activity glycosylation Ser540 VMVPATVsNNVPGSD 9606 BTO:0000018 26399441 YES lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 0.257 SIGNOR-267583 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr217 MAEEKKAyKKAKERE 9606 BTO:0000567 19059208 YES miannu We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. 0.416 SIGNOR-262850 DCK protein P27707 UNIPROT CDK1 protein P06493 UNIPROT down-regulates activity binding 22850745 YES lperfetto We demonstrate that dCK interacts with cyclin-dependent kinase 1 (Cdk1) after IR and that the interaction inhibits Cdk1 activity both in vitro and in vivo. 0.378 SIGNOR-275805 Fanconi anemia core complex complex SIGNOR-C300 SIGNOR FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 17396147 YES lperfetto Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.77 SIGNOR-263249 MAPK3 protein P27361 UNIPROT ETS1 protein P14921 UNIPROT up-regulates phosphorylation Thr38 CADVPLLtPSSKEMM 9606 11948414 YES gcesareni We found that hgf/sf activates the erk1 map kinase, leading to the phosphorylation of the threonine 38 residue of ets1 0.671 SIGNOR-116494 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.822 SIGNOR-178411 CHEK2 protein O96017 UNIPROT CDC5L protein Q99459 UNIPROT down-regulates activity phosphorylation 9606 32059558 YES miannu Remarkably, however, the activation of the DDC triggers a Rad53-dependent phosphorylation of Cdc5 that inhibits the polo-like kinase, thus favoring Cdh1 activity and subsequently also restraining spindle elongation and anaphase progression [34,54] (Figure 1). 0.305 SIGNOR-279694 MLEC protein Q14165 UNIPROT OST-B complex complex SIGNOR-C536 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.356 SIGNOR-272066 CDK4 protein P11802 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 YES lperfetto Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown). 0.226 SIGNOR-87105 MAPK3 protein P27361 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 9606 15486195 YES lperfetto In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel 0.73 SIGNOR-129878 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr760 LFKSATTtVMNPKFA 9606 BTO:0000751 11700305 YES lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | 0.341 SIGNOR-249125 RIPK3 protein Q9Y572 UNIPROT DLD protein P09622 UNIPROT up-regulates activity phosphorylation Thr135 STAVKALtGGIAHLF -1 29358703 YES miannu Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. 0.2 SIGNOR-266372 baicalein chemical CHEBI:2979 ChEBI CYP2C9 protein P11712 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190236 COPS4 protein Q9BT78 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.943 SIGNOR-270773 DNMT3A protein Q9Y6K1 UNIPROT CDKN2B protein P42772 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 NO miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family 0.347 SIGNOR-261509 CD40 protein P25942 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 12324477 NO gcesareni Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively. 0.427 SIGNOR-93387 MRPL37 protein Q9BZE1 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.697 SIGNOR-262360 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 YES gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function 0.742 SIGNOR-126740 AURKA protein O14965 UNIPROT NSD2 protein O96028 UNIPROT up-regulates quantity by stabilization phosphorylation Ser56 SKAQLSSsLQEGVMQ 35389552 YES lperfetto Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop. 0.2 SIGNOR-275512 FYN protein P06241 UNIPROT CNN1 protein P51911 UNIPROT down-regulates activity phosphorylation Tyr182 SQQGMTAyGTRRHLY 9534 15206927 YES We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin 0.334 SIGNOR-251157 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 YES lperfetto Although AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that AKT-dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70S6K activation in HEK cells. 0.929 SIGNOR-251099 USP7 protein Q93009 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.786 SIGNOR-270837 ADORA3 protein P0DMS8 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.451 SIGNOR-256814 mTORC2 complex SIGNOR-C2 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 NO miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity 0.353 SIGNOR-256171 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 10512765 YES gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. 0.8 SIGNOR-71024 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr163 YEHKEIEyVETVTSR -1 21840312 YES miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. 0.389 SIGNOR-263038 CHEK2 protein O96017 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates activity phosphorylation Ser91 RRLSRRKsRSSQLSS 9606 33355621 YES miannu Also, inhibition of Chk2 by Chk2 inhibitor II in cytokinesis after release of cells from a nocodazole-induced prometaphase block diminished INCENP localization to the midbody center in late midbodies (Fig. 1, M and N).|In turn, active Chk2 phosphorylates human INCENP at the newly identified site Ser91 to promote INCENP binding to Mklp2, resulting in recruitment of the INCENP\u2013Mklp2 complex to the midbody center through Mklp2\u2019s interaction with the midbody protein Cep55 to delay abscission. 0.261 SIGNOR-279695 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition 9606 26254357 YES miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF 0.8 SIGNOR-259452 Ub:E2 complex SIGNOR-C497 SIGNOR RNF150 protein Q9ULK6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271070 MAPK14 protein Q16539 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates activity phosphorylation Thr1392 CSAKNALtPSSKKPV 10090 BTO:0002572 16138080 YES lperfetto We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes 0.459 SIGNOR-140082 MAPK3 protein P27361 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr507 GLGENLLtHLPEEIG 9606 BTO:0000007 30865892 YES miannu Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. 0.335 SIGNOR-277443 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CDT1 protein Q9H211 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 10790373 YES miannu  Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3. 0.435 SIGNOR-272568 WDR61 protein Q9GZS3 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 YES miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  0.85 SIGNOR-269831 prazosin chemical CHEBI:8364 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258473 POLR1H protein Q9P1U0 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16373708 NO miannu ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. 0.2 SIGNOR-259907 MECP2 protein P51608 UNIPROT FKBP5 protein Q13451 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16002417 YES Luana These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress. 0.306 SIGNOR-264542 DYRK1A protein Q13627 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser329 STISGRLsPIMTEQD 9606 BTO:0000887;BTO:0001103 11311120 YES lperfetto The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus 0.507 SIGNOR-106829 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr46 NKISADTtDNSGTVN -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276218 UCHL1 protein P09936 UNIPROT UBC protein P0CG48 UNIPROT up-regulates quantity cleavage 9606 9521656 YES lperfetto These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains 0.864 SIGNOR-249693 ATAT1 protein Q5SQI0 UNIPROT TUBA3C protein P0DPH7 UNIPROT up-regulates quantity by stabilization acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 YES lperfetto Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules 0.242 SIGNOR-272244 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 YES Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs 0.758 SIGNOR-258989 MAPK8 protein P45983 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 15192708 YES The effect has been demonstrated using Q43561-2 gcesareni Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway.Mutational analysis revealed that t155 but not t94 or t140 is the site of jnk-mediated phosphorylation (figure 2b). Erk also phosphorylated lat at t155 (figure 2c), whereas p38, which was able to phosphorylate atf2, failed to induce threonine phosphorylation of lat (figure 2d). These results indicate that lat is directly phosphorylated by erk and jnk at the same site, t155. 0.308 SIGNOR-125774 SHH protein Q15465 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887 17688959 NO lperfetto Most importantly, we report that shh induces mapk/erk and phosphoinositide 3-kinase (pi3k)-dependent akt phosphorylation and that activation of both signaling pathways is essential for shh's signaling in muscle cells. However, the effect of shh on akt phosphorylation is more robust than that on mapk/erk, and data suggest that shh influences these pathways in a manner similar to igf-i. 0.47 SIGNOR-244446 TBX3 protein O15119 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 YES lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS 0.395 SIGNOR-249603 HES5 protein Q5TA89 UNIPROT ATOH1 protein Q92858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 NO lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 0.406 SIGNOR-265145 AP-3 complex complex SIGNOR-C247 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.346 SIGNOR-260668 ARHGAP5 protein Q13017 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.828 SIGNOR-260461 DEAF1 protein O75398 UNIPROT EN1 protein Q05925 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000375 31145909 YES Gianni Deaf1 is the first transcription factor implicated in the regulation of En1, a critical determinant of eccrine fate, within keratinocytes. 0.2 SIGNOR-269062 protriptyline chemical CHEBI:8597 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 9537821 YES miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. 0.8 SIGNOR-258736 MAPK1 protein P28482 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates phosphorylation Ser250 SSSGVPYsPAIPNKR 9606 22595671 YES lperfetto Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling. 0.331 SIGNOR-197543 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 20626350 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. 0.809 SIGNOR-166633 trichostatin A chemical CHEBI:46024 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257936 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9694870 NO lperfetto Here we report the identification of Smad Binding Elements (SBEs) composed of the sequence CAGACA in the promoter of the JunB gene, an immediate early gene that is potently induced by TGF-beta, activin, and bone morphogenetic protein (BMP) 2. Two JunB SBEs are arranged as an inverted repeat that is transactivated in response to Smad3 and Smad4 co-overexpression and shows inducible binding of a Smad3- and Smad4-containing complex in nuclear extracts from TGF-beta-treated cells. 0.576 SIGNOR-59476 SREBF1 protein P36956 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 YES inferred from family member gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) 0.333 SIGNOR-270288 miR-495 mirna URS000075C517_9606 RNAcentral Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 26055960 NO miannu Our results suggest that activating mutation of FLT3 in AML can lead, through the induction of JUN, to an increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently may causes block of myeloid differentiation. 0.4 SIGNOR-255801 protriptyline chemical CHEBI:8597 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258737 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Ser1035 DHQTPPTsPVQGTTP 9606 24089523 YES lperfetto Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1 0.427 SIGNOR-202698 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 15225553 YES lperfetto Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174. 0.609 SIGNOR-126654 ZFX protein P17010 UNIPROT FBP1 protein P09467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003081;BTO:0000849 30616754 YES lperfetto For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma 0.2 SIGNOR-267595 CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR AR protein P10275 UNIPROT down-regulates quantity by destabilization phosphorylation Ser310 TEDTAEYsPFKGGYT 9534 17698582 YES phosphorylation site remapping based on Fig 7D lperfetto We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1). 0.51 SIGNOR-273125 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser155 FPLRKTVsEPNLKLR -1 15738054 YES lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. 0.479 SIGNOR-249275 PRKCD protein Q05655 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Ser221 QAQRFRFsPMGVDHM 9606 20086103 YES lperfetto Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur. 0.636 SIGNOR-163524 CD3E protein P07766 UNIPROT NCK1 protein P16333 UNIPROT up-regulates activity relocalization 9606 BTO:0000661 12110186 YES We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck. 0.372 SIGNOR-259934 etorphine chemical CHEBI:4912 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258803 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser391 GAATPRTsQFTKYWT 9606 16216881 YES lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. 0.2 SIGNOR-141002 PRKCA protein P17252 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Ser1064 NRKVTIYsFTGNQRN -1 36040231 YES miannu PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. 0.2 SIGNOR-276866 SNAI2 protein O43623 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 20509143 NO miannu SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. 0.421 SIGNOR-255154 CAMK2A protein Q9UQM7 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Thr154 ICLEDIHtSRVVAHV 9606 17568776 YES lperfetto Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53 0.297 SIGNOR-156068 CYLD protein Q9NQC7 UNIPROT BCL3 protein P20749 UNIPROT down-regulates deubiquitination 9606 BTO:0001286 16713561 YES gcesareni Cyld binds and deubiquitinates bcl-3in cyld+/+ keratinocytes, tpa or uv light triggers the translocation of cyld from the cytoplasm to the perinuclear region, where cyld binds and deubiquitinates bcl-3, thereby preventing nuclear accumulation of bcl-3 and p50/bcl-3- or p52/bcl-3-dependent proliferation. 0.513 SIGNOR-146774 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser6 sQLDSDFS 9606 12697768 YES llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 0.873 SIGNOR-100649 GSK3B protein P49841 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr265 ATYHHNStTTWTGSR 10090 BTO:0000944 25373906 YES miannu In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.  0.398 SIGNOR-276442 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258005 lurasidone chemical CHEBI:70735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10030 20404009 YES Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. 0.8 SIGNOR-257839 ETNK2 protein Q9NVF9 UNIPROT ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI down-regulates quantity chemical modification 36866238 YES lperfetto Ethanolamine kinase 2 (ETNK2) is a protein-coding gene. Spondylometaphyseal dysplasia with cone-rod dystrophy is one of the diseases linked to the ETNKT2 gene. Glycerophospholipid biosynthesis and nuclear receptor meta-pathways are two of the ETNK2-related pathways. 0.8 SIGNOR-275644 FBXO6 protein Q9NRD1 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 19716789 YES miannu  Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. 0.497 SIGNOR-271879 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser85 PLPDAGAsPAPSRCC 23871434 YES lperfetto WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85 0.42 SIGNOR-275481 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEYL protein Q9NQ87 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 11044625 NO gcesareni The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j. 0.2 SIGNOR-254339 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A2-B2 complex SIGNOR-C137 SIGNOR up-regulates activity chemical activation 9606 15036565 YES gcesareni One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP) 0.8 SIGNOR-243961 EGR1 protein P18146 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9867871 NO miannu The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments. 0.291 SIGNOR-253897 all-cis-5,8,11,14,17-icosapentaenoic acid smallmolecule CHEBI:28364 ChEBI FBN1 protein P35555 UNIPROT up-regulates quantity by expression 9606 16467281 NO Regulation of expression miannu It was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin. 0.8 SIGNOR-251910 MAPK3 protein P27361 UNIPROT DEPTOR protein Q8TB45 UNIPROT up-regulates quantity by stabilization phosphorylation Ser235 MELLNEKsPSSQETH -1 35216969 YES miannu Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay. 0.282 SIGNOR-277587 PXN protein P49023 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity 9606 BTO:0000182 phosphorylation:Tyr88 PQSSSPVyGSSAKTS 27447856 NO lperfetto Together, our data suggest that phosphorylation of paxillin Y88 activates AKT through the paxillin-p130Cas-p85/PI3K-AKT signaling axis and promotes colorectal tumorigenesis 0.919 SIGNOR-263979 NEU1 protein Q99519 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR down-regulates activity binding 9606 BTO:0003554 32164705 YES miannu NEU1 disrupts FN/ α5β1 interaction. taken together, strongly indicate that overexpressed NEU1 inhibits the Akt pathway by disrupting FN-integrin α5β1 interaction. 0.2 SIGNOR-260658 DYRK2 protein Q92630 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000150 22307329 YES lperfetto Degradation of c-jun/c-myc is a critical process for the g(1)/s transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 ? (gsk3?). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this gsk3? Modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase dyrk2 functions as a priming kinase of c-jun and c-myc.The finding that kinase-active dyrk2 phosphorylated gst_c-jun210_310-wt by detection with an anti_phospho_c-jun(ser243) antibody demonstrated that dyrk2 is a ser243 kinase in vitro 0.256 SIGNOR-195771 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.554 SIGNOR-270912 GOT2 protein P00505 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 31422819 YES miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-268059 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT up-regulates activity phosphorylation Ser299 FLELVVSsDKREARQ 9606 17006539 YES gcesareni A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK. 0.2 SIGNOR-149948 CSNK2A1 protein P68400 UNIPROT F5 protein P12259 UNIPROT down-regulates activity phosphorylation Ser692 IPDDDEDsYEIFEPP -1 9525959 YES llicata Factor Va, the essential cofactor for prothrombinase, is phosphorylated on the acidic COOH terminus of the heavy chain of the cofactor, at Ser692, by a platelet membrane-associated casein kinase II (CKII). | The phosphorylated cofactor has increased susceptibility to inactivation by activated protein C, since phosphorylated factor Va was found to be inactivated approximately 3-fold faster than its native counterpart. 0.307 SIGNOR-250862 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.777 SIGNOR-273914 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 19029298 YES llicata We show that pkd1-ser916 autophosphorylation does not necessarily correlate with pkd1 activity. Rather, autophosphorylation at ser916 is required for subsequent autophosphorylation at ser748. 0.2 SIGNOR-182480 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763 12193595 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-91738 PRKAA2 protein P54646 UNIPROT HNF4A protein P41235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser313 GKIKRLRsQVQVSLE 10029 BTO:0000246 12740371 YES miannu AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. Phosphorylation of HNF4α on Ser-304 reduces protein stability. 0.368 SIGNOR-250322 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.417 SIGNOR-249278 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM64C protein A6NLI5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271272 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 20610653 NO miannu Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. 0.2 SIGNOR-260329 EXOSC8 protein Q96B26 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.914 SIGNOR-261384 ARHGAP35 protein Q9NRY4 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.892 SIGNOR-260492 LCK protein P06239 UNIPROT LAX1 protein Q8IWV1 UNIPROT up-regulates activity phosphorylation Tyr193 SSEDSHDyVNVPTAE 9606 BTO:0000007 12359715 YES miannu Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85.  0.4 SIGNOR-273525 ACACB protein O00763 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 20952656 YES miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA 0.8 SIGNOR-267106 MFGE8 protein Q08431 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 10116 31958465 NO miannu We demonstrated that Milk fat globule-EGF factor8 (MFGE8) is protective against Ang-II-induced atrial fibrosis and atrial fibrillation. In vitro, silencing of MFGE8 by small interfering RNA significantly increased Ang-II-induced atrial fibrosis, whereas administration of recombinant human MFGE8 (rhMFGE8) attenuated the atrial fibrosis. 0.7 SIGNOR-260646 CAPN1 protein P07384 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity cleavage 9606 BTO:0000590 25969760 YES lperfetto Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains 0.334 SIGNOR-251584 Late macropinosomes phenotype SIGNOR-PH229 SIGNOR Lysosome fusion phenotype SIGNOR-PH231 SIGNOR up-regulates 9606 39000072 NO miannu The fusion of matured macropinosomes with lysosomes is promoted by TRPML1, and degradation of macropinosomes is inhibited by mTORC1. 0.7 SIGNOR-277787 MMP14 protein P50281 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 28709001 NO MMP14 Promotes Adipogenesis Downstream of or in Parallel to TIMP3 0.7 SIGNOR-255909 GSK3B protein P49841 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser184 NLLQSPSsILSTLDV 9606 BTO:0000567 21757741 YES miannu Here, we demonstrate that glycogen synthase kinase-3β (GSK3β) phosphorylates securin to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase. 0.2 SIGNOR-276344 MARCHF9 protein Q86YJ5 UNIPROT CEMIP2 protein Q9UHN6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271533 UDP-D-galactose smallmolecule CHEBI:18307 ChEBI lactose smallmolecule CHEBI:17716 ChEBI up-regulates quantity precursor of 9606 16157350 YES miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 0.8 SIGNOR-268471 topotecan chemical CHEBI:63632 ChEBI TOP1 protein P11387 UNIPROT down-regulates activity chemical inhibition 9606 11166732 YES miannu Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma. 0.8 SIGNOR-259317 N protein P59595 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR down-regulates quantity by repression transcriptional regulation 17108024 NO miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. 0.2 SIGNOR-260342 3b protein P59633 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR down-regulates quantity by repression transcriptional regulation 17108024 NO miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. 0.2 SIGNOR-260343 6 protein P59634 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR down-regulates quantity by repression transcriptional regulation 17108024 NO miannu The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling. 0.2 SIGNOR-260344 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT unknown phosphorylation Ser696 PNKELPPsPEKKTKP 9606 BTO:0000567 10791892 YES miannu We have shown that MAP4 is phosphorylated in vivo in mitotic HeLa cells at eight sites. Five of these were phosphorylated by p34cdc2 kinase. Two of the five p34cdc2 kinase phosphorylation sites were shown to be Ser696 and Ser787 in the proline-rich region 0.498 SIGNOR-277461 NFIA protein Q12857 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268893 ITGB8 protein P26012 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.468 SIGNOR-257729 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 30230471 NO lperfetto In keeping with the overall improvement in insulin sensitivity we found that insulin-induced IR Y1162/Y1163 tyrosine phosphorylation and activation and downstream PI3K/AKT signaling in the liver (as monitored by AKT Ser-473 phosphorylation) were dramatically enhanced by POMC TCPTP deficiency (Figure 4h).|This would suggest that TCPTP deletion, or decreased TCPTP in POMC neurons in response to feeding, represses HGP by enhancing IR signaling and permitting POMC neurons to be activated by insulin. 0.622 SIGNOR-276956 NDFIP2 protein Q9NV92 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity relocalization 9606 BTO:0002181 26363003 YES SARA Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. 0.57 SIGNOR-260996 CYP1B1 protein Q16678 UNIPROT 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI up-regulates quantity chemical modification 9606 BTO:0000093 8790407 YES Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. 0.8 SIGNOR-269754 TRIM13 protein O60858 UNIPROT TRIM13 protein O60858 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 31744379 YES miannu  In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1).  0.2 SIGNOR-272219 GSK3B protein P49841 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr171 ETSKSFVtPPQSHFV 9606 BTO:0002181 26028025 YES miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. 0.259 SIGNOR-276906 IL12A protein P29459 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 NO miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12 0.365 SIGNOR-260861 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding -1 BTO:0000567 16729043 YES lperfetto We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. 0.923 SIGNOR-236327 CD40LG protein P29965 UNIPROT IGSF6 protein O95976 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9809579 NO miannu CD40L activation of dendritic cells down-regulates DORA, a novel member of the immunoglobulin superfamily 0.325 SIGNOR-261727 SRC protein P12931 UNIPROT KRAS protein P01116 UNIPROT up-regulates phosphorylation 9606 9096340 YES gcesareni Expression of v-src, a transforming nonreceptor tyrosine kinase, results in ras activation, and ras function in nih 3t3 cells suppresses transformation by v-src, indicating that in these cells ras-dependent signaling pathways are required for v-src to exert its biological effects. 0.657 SIGNOR-47152 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 NO gcesareni These findings suggest that c-src mediated bmk1 activation by h(2)o(2) may counteract ischemic cellular damage probably through the activation of mef2c transcription factor. 0.8 SIGNOR-113758 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR BIRC5 protein O15392 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys90 GCAFLSVkKQFEELT 10090 BTO:0002268 25778398 YES miannu Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation. 0.331 SIGNOR-272438 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser51 ADGHRGPsAAFAPAA 9606 33388549 YES miannu P -Ser9 GSK-3\u03b2 phosphorylates Ser43, Ser51, and Ser493 residues of src, regulating src activity. 0.383 SIGNOR-278443 AURKA protein O14965 UNIPROT SOX8 protein P57073 UNIPROT up-regulates activity phosphorylation Ser327 SAPSASAsPTETGPP 9606 BTO:0000410 32550913 YES miannu We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance. 0.2 SIGNOR-273548 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 21658387 YES lperfetto Lrrk2 directly phosphorylates akt1 as a possible physiological substrate. These data establish that lrrk2 can protect neurons from apoptotic insult through a survival pathway in which lrrk2 signals to activate akt. Lrrk2-mediated phosphorylation of akt1 (ser473) 0.38 SIGNOR-244410 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499-2 UNIPROT down-regulates phosphorylation Ser579 YQSTIPQsPSPAPDD 9606 10828059 YES The effect has been demonstrated using Q08499-5 llicata The pde4d2 isoform is inhibited by erk2 phosphorylation 0.353 SIGNOR-77563 EDNRA protein P25101 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0000671 10199825 YES gcesareni We studied the ability of et receptors to activate galfa13 using an assay for g protein alfa-chain activation that is based on the fact that an activated (gtp-bound) alfa-chain is resistant to trypsinization compared with an inactive (gdp-bound) alfa-chain. 0.556 SIGNOR-66856 FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 NO lperfetto Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity 0.405 SIGNOR-235367 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr74 SVLTGKLtTVFLPIV -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.395 SIGNOR-263587 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser338 KGKRGGHsSVSTESE 9606 10521508 YES Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. 0.2 SIGNOR-260900 MMP15 protein P51511 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272360 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 12576312 YES lperfetto Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of rhoa and is inhibited by cgmp-dependent protein kinase phosphorylation. Three phosphorylation sites have been identified in vasp: ser157, ser239, and thr278, all of which can be phosphorylated by either pka or pkg in vitro 0.734 SIGNOR-98139 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 16782899 YES llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain 0.496 SIGNOR-147183 S1PR3 protein Q99500 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257330 IKBKE protein Q14164 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 YES miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. 0.422 SIGNOR-217379 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. 0.616 SIGNOR-252692 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCE protein Q02156 UNIPROT down-regulates chemical inhibition 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-190353 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000007 12475979 YES When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365)), 0.607 SIGNOR-248703 PLCB3 protein Q01970 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity 23994464 NO apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release 0.8 SIGNOR-255014 NOD1 protein Q9Y239 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000567 19898471 NO miannu Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. 0.7 SIGNOR-252404 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.43 SIGNOR-154261 PTPRG protein P23470 UNIPROT DAB1 protein O75553 UNIPROT down-regulates activity dephosphorylation Tyr198 EDVEDPVyQYIVFEA -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254697 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 29440413 YES miannu We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex. 0.474 SIGNOR-277385 YAP1 protein P46937 UNIPROT BMP4 protein P12644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 NO gcesareni In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression. 0.319 SIGNOR-199066 FOXJ1 protein Q92949 UNIPROT TEKT2 protein Q9UIF3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.324 SIGNOR-266937 SLBP protein Q14493 UNIPROT H2AW protein Q7L7L0 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265409 glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates activity chemical inhibition 9606 32745890 YES miannu Glucose deprivation, activates the glucose level–sensing kinase, AMPK, which in turn influences Rac1-dependent macropinocytosis. In this context macropinosomes take up necrotic cell debris as a rich nutrient source to fuel tumor cell growth 0.8 SIGNOR-277765 UTS2R protein Q9UKP6 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257377 SLC6A3 protein Q01959 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 YES miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. 0.8 SIGNOR-269189 AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR Early Endosome complex SIGNOR-C246 SIGNOR up-regulates activity relocalization 9606 23144738 YES lperfetto Rabip4' colocalized with AP-3 on a tubular subdomain of early endosomes and the extent of colocalization was increased by a dominant negative rab4 mutant. Knock-down of AP-3 had an ever more dramatic effect and caused accumulation of lysosomes in protrusions at the plasma membrane. The most peripheral lysosomes were localized beyond microtubules, within the cortical actin network. Our results uncover a novel function for AP-3 and rabip4' in regulating lysosome positioning through an interorganellar pathway. 0.2 SIGNOR-260712 PIK3R1 protein P27986 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates activity binding 9534 14665640 YES lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.828 SIGNOR-242643 KLHL9 protein Q9P2J3 UNIPROT CEBPD protein P49716 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000527 25303533 YES miannu KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ. 0.251 SIGNOR-272459 TFE3 protein P19532 UNIPROT LAMP1 protein P11279 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.357 SIGNOR-276825 TNFRSF10B protein O14763 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 YES amattioni Fadd binds to ligated trailr1 or trail-r2 0.849 SIGNOR-98565 YAP1 protein P46937 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23075495 NO gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. 0.7 SIGNOR-256669 MDM2 protein Q00987 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 BTO:0001938 12646252 YES gcesareni These data strongly suggest thatmdm2functions as the ubiquitin ligase toward hnumb and that it induces its degradation in intact cells. 0.445 SIGNOR-99497 MAPK8 protein P45983 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 12591950 YES miannu Activated JNK causes BimL and Bmf phosphorylation in vivo. It is known that UV radiation causes the release of Bim and Bmf from dynein and myosin V motor complexes and that these proteins cause Bax/Bak-dependent apoptosis . The results of this study demonstrate that JNK can engage this apoptotic pathway by phosphorylation of BH3-only proteins, including Bim and Bmf. 0.689 SIGNOR-250116 RBX1 protein P62877 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 YES miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro 0.598 SIGNOR-271439 CDK1 protein P06493 UNIPROT PPP1R13L protein Q8WUF5 UNIPROT up-regulates activity phosphorylation Ser113 LHPYSPLsPKGRPSS 9606 30105797 YES done miannu Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53.  0.506 SIGNOR-273586 RPS6KA1 protein Q15418 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 7838153 YES gcesareni Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii. 0.494 SIGNOR-34113 SLC38A9 protein Q8NBW4 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 25567906 NO Luana SLC38A9 is a Lysosomal Membrane Protein Required for mTORC1 Activation 0.483 SIGNOR-268014 HP protein P00738 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity binding 9606 9315856 YES Regulation of binding miannu Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers. 0.774 SIGNOR-251815 MTOR protein P42345 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 29789464 NO Luana The mTOR complexes are essential to neurogenesis and the establishment of neural circuits. | Activation of mTOR complexes exerts profound effects on all the processes of neurogenesis, including dendrite formation. 0.7 SIGNOR-265771 TCF7L1 protein Q9HCS4 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001581 16894029 YES Luana These experiments showed that Tcf3 is associated with chromatin in the Nanog promoter regions and that the DNA-binding activity of Tcf3 was required for repression. 0.341 SIGNOR-266081 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 BTO:0000017 28192398 YES miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  0.627 SIGNOR-277341 EID1 protein Q9Y6B2 UNIPROT EP300 protein Q09472 UNIPROT down-regulates activity binding 11073990 YES lperfetto Inhibition of MyoD may be explained by EID-1's ability to bind and inhibit p300's histone acetylase activity, an essential MyoD coactivator. 0.422 SIGNOR-253377 TFE3 protein P19532 UNIPROT ATP6V1C1 protein P21283 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.2 SIGNOR-276811 CRYGD protein P07320 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 10521291 NO The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. 0.7 SIGNOR-253620 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr218 PPRDFAAyRS 9606 BTO:0000782;BTO:0001271 8992971 YES lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail 0.689 SIGNOR-45520 SPEN protein Q96T58 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 12374742 YES gcesareni We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen. 0.702 SIGNOR-94201 NOG protein Q13253 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates activity binding 9031 SIGNOR-C29 12478285 YES Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955). Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors 0.586 SIGNOR-219225 TNF protein P01375 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18647246 NO miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. 0.416 SIGNOR-252407 SMARCD3 protein Q6STE5 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.759 SIGNOR-270705 SSTR4 protein P31391 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256959 STUB1 protein Q9UNE7 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding -1 12150907 YES miannu In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6).  0.2 SIGNOR-272888 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 BTO:0000142 16401070 YES lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. 0.554 SIGNOR-143477 SYK protein P43405 UNIPROT LAX1 protein Q8IWV1 UNIPROT up-regulates activity phosphorylation Tyr373 SNEDSSDyENVLTAK 9606 BTO:0000007 12359715 YES miannu Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85.  0.378 SIGNOR-273535 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 YES lperfetto Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a. 0.2 SIGNOR-244685 STAT3 protein P40763 UNIPROT S100A9 protein P06702 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18809714 NO miannu Accumulation of myeloid-derived suppressor cells (MDSCs) associated with inhibition of dendritic cell (DC) differentiation is one of the major immunological abnormalities in cancer and leads to suppression of antitumor immune responses. The molecular mechanism of this phenomenon remains unclear. We report here that STAT3-inducible up-regulation of the myeloid-related protein S100A9 enhances MDSC production in cancer. 0.374 SIGNOR-261931 NR1I2 protein O75469 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000003 18540626 NO miannu Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals. 0.458 SIGNOR-254834 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser114 HISPAQGsPKPPPAA -1 29945972 YES miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. 0.2 SIGNOR-277880 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 YES lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.2 SIGNOR-244647 FOXO1 protein Q12778 UNIPROT POMC protein P01189 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000614 28270795 NO miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. 0.405 SIGNOR-263503 WNT5A protein P41221 UNIPROT FZD4 protein Q9ULV1 UNIPROT up-regulates activity binding 9606 16602827 YES areggio We show that in addition to its inhibitory function, Wnt5a can also activate beta-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4. 0.737 SIGNOR-258954 PTH1R protein Q03431 UNIPROT CYP24A1 protein Q07973 UNIPROT up-regulates quantity 28363951 NO lperfetto These PTH actions are mainly mediated by Gsalpha signaling, which induces the expression of the gene encoding 25-hydroxyvitamin D 1alpha-hydroxylase (Cyp27b1) and destabilizes the transcript encoding vitamin D 24-hydroxylase (Cyp24a1) 0.288 SIGNOR-270555 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser467 SVRCSSMs 9534 9346908 YES lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. 0.824 SIGNOR-235995 8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid chemical CID:92577 PUBCHEM PTPN11 protein Q06124 UNIPROT down-regulates activity chemical inhibition -1 19233143 YES lperfetto In this study, we screened protein tyrosine phosphatases (PTPs) by in vitro phosphatase assays to identify PTPs that are inhibited by 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), a potent inhibitor of SHP-1 and SHP-2 PTPs. 0.8 SIGNOR-261977 CYCS protein P99999 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 YES lperfetto Caspase-9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cytochrome c and datp, an event that leads to caspase-9 activation. 0.879 SIGNOR-53585 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RHOA protein P61586 UNIPROT up-regulates activity phosphorylation Ser88 LMCFSIDsPDSLENI 9534 BTO:0000298 26816343 YES miannu We have recently reported that Rac1 is phosphorylated on threonine 108 (108T) by extracellular signal-regulated kinases (ERK) in response to epidermal growth factor (EGF) stimulation. Here, we provide evidence that RhoA is phosphorylated by ERK on 88S and 100T in response to EGF stimulation. 0.2 SIGNOR-277202 PRKAA1 protein Q13131 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser486 DDEITEAKsGTATPQRS -1 17023420 YES We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators 0.2 SIGNOR-256114 SRF protein P11831 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates 9606 22225874 YES FFerrentino Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy. 0.252 SIGNOR-255965 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT up-regulates activity phosphorylation Ser45 LGIRSSKsAGALEEG 9606 BTO:0002524 30631047 YES miannu Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Function assay of ARMC10 and ARMC10 phosphorylation at S45. 0.2 SIGNOR-277792 KLHL22 protein Q53GT1 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity binding -1 23455478 YES miannu Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors.  0.446 SIGNOR-272108 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 7925415 YES lperfetto Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. 0.405 SIGNOR-34691 PHLPP1 protein O60346 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity dephosphorylation Ser338 RPRGQRDsSYYWEIE 10090 24530606 YES gcesareni PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression. 0.272 SIGNOR-237449 AMOT protein Q4VCS5 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates relocalization 9606 BTO:0000567 21205866 YES AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity. gcesareni Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition. 0.677 SIGNOR-175776 LRRC4 protein Q9HBW1 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 9606 BTO:0000142 25526788 NO miannu The overexpression of LRRC4/NGL-2 suppresses glioma cell growth, angiogenesis and invasion through complicated signaling regulation networks. 0.7 SIGNOR-264060 AXIN1 protein O15169 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR form complex binding 9606 BTO:0000586 9734785 YES lperfetto Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level. 0.932 SIGNOR-227292 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264922 ZNF304 protein Q9HCX3 UNIPROT CDKN2B protein P42772 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000391 24623306 YES Luana Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells. 0.281 SIGNOR-266099 CIITA protein P33076 UNIPROT HLA-DOB protein P13765 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11823510 NO Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. 0.311 SIGNOR-254015 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Ser253 QEALQKLsDVTLVPV 33850055 YES lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o 0.2 SIGNOR-275646 SEC23A protein Q15436 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.795 SIGNOR-265289 P4HB protein P07237 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity binding 32149426 YES lperfetto The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. 0.428 SIGNOR-275573 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 YES lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. 0.805 SIGNOR-109719 GNG2 protein P59768 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR form complex binding 9606 23994464 YES apalma Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit 0.94 SIGNOR-255005 WWTR1 protein Q9GZV5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 21084559 YES gcesareni Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. 0.592 SIGNOR-169835 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 9606 20626350 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. 0.809 SIGNOR-166629 SWI/SNF complex complex SIGNOR-C92 SIGNOR TP53 protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0002181 11950834 YES irozzo Using genetic and biochemical approaches, we show that several subunits of the human SWI/SNF complex bind to the tumor suppressor protein p53 in vivo and in vitro.Molecular connection between p53 and the SWI/SNF complex implicates that (i) the SWI/SNF complex is necessary for p53-driven transcriptional activation, and (ii) the SWI/SNF complex plays an important role in p53-mediated cell cycle control. 0.433 SIGNOR-256285 SETDB1 protein Q15047 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR form complex binding 10090 21952300 YES FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43. 0.545 SIGNOR-253522 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001289 21489980 NO miannu Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. We propose that methylation of the TM promoter is responsible for silencing of TM expression in MM tissue, a process that is regulated by PARP1. 0.2 SIGNOR-254893 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1242 ATSMFDDyQGDSSTL 9606 9722576 YES lperfetto Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor. 0.2 SIGNOR-59754 MARCHF8 protein Q5T0T0 UNIPROT SLC3A2 protein P08195 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 21757542 YES miannu Taken together, these findings demonstrate that MARCH8 directly ubiquitinates CD98, and this likely leads to its routing to late endosomes for degradation. 0.2 SIGNOR-272755 CAMK2G protein Q13555 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.271 SIGNOR-275795 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF6 protein O60337 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271248 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD -1 19661060 YES miannu We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.2 SIGNOR-276231 NEFM protein P07197 UNIPROT Neurofilament L/M complex SIGNOR-C207 SIGNOR form complex binding 9606 19468066 YES miannu Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H 0.523 SIGNOR-255271 CPT1B protein Q92523 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267127 ATM protein Q13315 UNIPROT KHSRP protein Q92945 UNIPROT up-regulates phosphorylation Ser670 GPGAPPGsQPDYSAA 9606 21329876 YES lperfetto The atm kinase directly binds to and phosphorylates ksrp, leading to enhanced interaction between ksrp and pri-mirnas and increased ksrp activity in mirna processing 0.423 SIGNOR-172127 bis(2-ethylhexyl) phthalate chemical CHEBI:17747 ChEBI HCAR2 protein Q8TDS4 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). 0.8 SIGNOR-268772 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser83 YSGSEGDsESGEEEE -1 2046671 YES llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro. We report here that serine 83 appears to be the residue phosphorylated by CKII but that three other serines in this region can also be involved in phosphorylation and the enhancement of DNA-binding activity. 0.551 SIGNOR-250958 SNRPD3 protein P62318 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.74 SIGNOR-270662 BCR protein P11274 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.6 SIGNOR-260526 S1PR3 protein Q99500 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.423 SIGNOR-257175 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser487 GQPTSMLsPRHRMSP 9606 BTO:0000801 29170386 YES Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. 0.246 SIGNOR-256097 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 11133764 YES gcesareni Jab/socs1/ssi-1 is an il-2 induced inhibitor of il-2 signaling that functions by inhibiting jak kinase activity 0.731 SIGNOR-85352 CSNK2A1 protein P68400 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser66 KAARVLGsEGEEEDE 9606 BTO:0000567 12851383 YES lperfetto Moreover, these data confirmed the occurrence of Ser66 phosphorylation, which was previously studied with a specific monoclonal antibody (23). 0.34 SIGNOR-103258 STAT5A protein P42229 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 YES FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells 0.652 SIGNOR-261551 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization 10090 17548510 NO Simone Vumbaca Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability 0.598 SIGNOR-255637 PRKCD protein Q05655 UNIPROT TBL1XR1 protein Q9BZK7 UNIPROT up-regulates activity phosphorylation Ser123 AAASQQGsAKNGENT 9606 18374649 YES Manara In addition, we describe that the functions and the specificity of these two highly- related exchange factors is tightly regulated by signal-induced phosphorylation events at the level of target gene promoters, as exemplified by the role of TBLR1 phosphorylation at Ser 123 by PKCδ upon retinoic acid or estrogen stimulation. 0.2 SIGNOR-260903 VWF protein P04275 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 YES lperfetto Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury 0.681 SIGNOR-261854 Ub:E2 complex SIGNOR-C497 SIGNOR KCMF1 protein Q9P0J7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271242 WNK4 protein Q96J92 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Ser371 VRRVPGSsGHLHKTE 16990453 YES lperfetto Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1 0.508 SIGNOR-264641 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 NO gcesareni In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. 0.506 SIGNOR-178639 metaproterenol chemical CHEBI:6792 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) 0.8 SIGNOR-257873 TRAF6 protein Q9Y4K3 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates activity ubiquitination 9606 25340740 YES miannu TRAF6 likely directly ubiquitinates MCL-1 since purified TRAF6 promoted the ubiquitination of recombinant GST-MCL-1 and co-expression of Tax with TRAF6 further enhanced MCL-1 ubiquitination .|Therefore, TRAF6 mediated MCL-1 stabilization appears to be a common mechanism of cell survival usurped by both viral and non viral cancers. 0.396 SIGNOR-278726 RPS6KB1 protein P23443 UNIPROT PIP5K1C protein O60331 UNIPROT down-regulates quantity by destabilization phosphorylation Thr553 QPRYRRRtQSSGQDG 27780861 YES miannu Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation. 0.2 SIGNOR-277282 AKT1 protein P31749 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates phosphorylation Ser159 LLRERKSsAPSHSSQ 9606 11782427 YES lperfetto Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation. 0.698 SIGNOR-252468 AKT proteinfamily SIGNOR-PF24 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates activity phosphorylation 9606 BTO:0003324 25323588 YES miannu Earlier studies found that expression of active Akt increases mitochondrial HK activity and the anti-apoptotic effect of Akt required mitoHK 0.484 SIGNOR-267577 FBXW7 protein Q969H0 UNIPROT CCDC6 protein Q16204 UNIPROT down-regulates binding 9606 BTO:0000551 23108047 YES miannu Fbxw7 interacts with and targets ccdc6 for ubiquitin-mediated proteasomal degradation 0.367 SIGNOR-199279 Ub:E2 complex SIGNOR-C497 SIGNOR TRIML1 protein Q8N9V2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271200 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation -1 9865727 YES Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. 0.682 SIGNOR-253639 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr371 TQEQYELyCEMGSTF 10090 BTO:0000944 11997497 YES Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation. 0.526 SIGNOR-251304 QRICH1 protein Q2TAL8 UNIPROT FARS2 protein O95363 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269403 ARNTL protein O00327 UNIPROT MAGEL2 protein Q9UJ55 UNIPROT down-regulates activity binding 9606 BTO:0000007 22208286 YES miannu Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. 0.369 SIGNOR-253517 RET protein P07949 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000944 15994200 YES lperfetto The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity 0.323 SIGNOR-252619 axitinib chemical CHEBI:66910 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 YES gcesareni Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine. 0.8 SIGNOR-171857 FLT3 protein P36888 UNIPROT XRCC5 protein P13010 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21228325 NO fcortellessa We detected an approximately 5-fold decrease in Ku86 expression in early pro-B cells from FLT3/ITD mice compared with the wild-type controls. These data support the finding that FLT3/ITD mutations exert a suppressive role on Ku86 expression. 0.2 SIGNOR-261684 7a protein P59635 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 16303160 NO Luana Expression of SARS-CoV ORF7a block cell cycle arrest in G0/G1 0.7 SIGNOR-260207 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12857757 YES gcesareni We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch). 0.967 SIGNOR-103611 DPYD protein Q12882 UNIPROT 5-fluorouracil chemical CHEBI:46345 ChEBI down-regulates quantity chemical modification 9606 10499634 YES miannu Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil. 0.8 SIGNOR-253987 NEUROD1 protein Q13562 UNIPROT MGAT5B protein Q3V5L5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 21771782 NO miannu By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression. 0.251 SIGNOR-253825 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr692 HEELTVLySELKKTH -1 12051764 YES miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. 0.2 SIGNOR-274007 PTGER1 protein P34995 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.455 SIGNOR-256811 NEDD4L protein Q96PU5 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 YES miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 0.335 SIGNOR-253458 KLHL8 protein Q9P2G9 UNIPROT RAPSN protein Q13702 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000944 19158078 YES miannu We found that rapsyn was polyubiquitinated by KLHL8-containing E3 ligase, but not by KEAP1-containing E3 ligase, clearly indicating that rapsyn is a direct substrate of KLHL8-containing E3 ligase in mammals. We next examined the effect of KLHL-8 depletion on the ubiquitination of rapsyn by performing RNAi experiments in mammalian cells. We found that knockdown of KLHL8 in 3T3 cells reduced the level of rapsyn ubiquitination (Fig. 5C), again indicating that the maintenance mechanism for rapsyn stability is conserved in mammals.The in vitro ubiquitination of mammalian rapsyn by CUL3-containing E3 ligase and the effect of KLHL8 knockdown on the ubiquitination of rapsyn. 0.483 SIGNOR-271781 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 31422819 YES miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-267512 BRD7 protein Q9NPI1 UNIPROT BRD2 protein P25440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000192 12600283 NO miannu BRD7 protein could respectively interact with proteins, BRD2 and BRD3, and BRD7 could up-regulate the expression levels of BRD2 and BRD3 genes in mRNA level to some extent. 0.412 SIGNOR-253763 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT up-regulates activity cleavage Arg1708 EDENQSPrSFQKKTR -1 10350471 YES lperfetto Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689. 0.754 SIGNOR-263639 CAD protein P27708 UNIPROT (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI up-regulates quantity chemical modification 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267420 AL/b2 integrin complex SIGNOR-C169 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.458 SIGNOR-257712 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr426 ASAASFEyTILDPSS 12441334 YES JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 0.811 SIGNOR-251349 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20584981 NO fspada Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program. 0.291 SIGNOR-166426 RPS6KA5 protein O75582 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 12213813 YES lperfetto Phosphorylation of Bad at Ser112 in response to growth factors or cytokines is generally linked to cell survival. Knockdown of MSK1 suppressed Bad phosphorylation after calcium ionophore A23187 treatment in neuronal cells 0.345 SIGNOR-262990 FOXO3 protein O43524 UNIPROT CITED2 protein Q99967 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18158893 NO gcesareni Foxo3a induces expression of cited2 0.471 SIGNOR-160127 SCN5A protein Q14524 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 YES miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. 0.8 SIGNOR-253401 DVL1 protein O14640 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity 9606 19279717 YES areggio Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin 0.275 SIGNOR-258978 DAPK1 protein P53355 UNIPROT TPM1 protein P09493 UNIPROT up-regulates activity phosphorylation Ser283 HALNDMTsI 9606 BTO:0000007 17895359 YES miannu We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling. 0.277 SIGNOR-262845 HOXC13 protein P31276 UNIPROT DSG4 protein Q86SJ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19683850 NO miannu we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle. 0.385 SIGNOR-254184 PRKACA protein P17612 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Thr138 GGFIRRVtNDARENE 10116 BTO:0001009 12459461 YES miannu Thr138 as the exclusive site of SNAP-25 phosphorylation by protein kinase A in vivo. PMA or forskolin treatment alone resulted in dramatic phosphorylation of SNAP-25 Ser187 and/or Thr138 without appreciable neurotransmitter release. 0.326 SIGNOR-250052 RAB1A protein P62820 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 BTO:0000007 27479033 YES Giulio Hemagglutinin (HA)-Rab1A is associated with mTOR and Raptor, not Rictor (Figure S2A), and is bound more with Myc-Raptor than Myc-mTOR (Figures S2B and S2C).|Rab1A Is an mTORC1 Activator and a Colorectal Oncogene 0.316 SIGNOR-261286 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM59 protein Q8IWR1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271123 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9657565 YES allergic rhinitis gcesareni 0.8 SIGNOR-251689 PRKACA protein P17612 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation 10090 23644383 YES milica Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381. 0.2 SIGNOR-236991 GAST protein P01350 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000269 22228178 NO Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation. 0.343 SIGNOR-254252 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser539 GLITINSsQEHLTVQ 9606 22123827 YES lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. 0.376 SIGNOR-177797 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr22 GVLPSHYyESFLEKK 9606 12540842 YES lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src. 0.407 SIGNOR-247333 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Thr527 PPKAKDPtVS -1 35080342 YES miannu Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. 0.405 SIGNOR-277578 TLN1 protein Q9Y490 UNIPROT ITGB7 protein P26010 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.585 SIGNOR-257633 AKT proteinfamily SIGNOR-PF24 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT down-regulates activity phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 BTO:0000759 17554339 YES lperfetto Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin. 0.2 SIGNOR-155532 Calcineurin complex SIGNOR-C155 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 YES When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. 0.272 SIGNOR-252315 IL1B protein P01584 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 NO doi: 10.1016/j.cytogfr.2020.05.003 miannu Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α) 0.512 SIGNOR-260855 DGC complex SIGNOR-C217 SIGNOR NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 YES miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. 0.36 SIGNOR-265447 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR up-regulates 25901680 NO lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.7 SIGNOR-262602 AURKA protein O14965 UNIPROT CETN2 protein P41208 UNIPROT up-regulates phosphorylation Ser170 LRIMKKTsLY 9606 BTO:0000150 21731694 YES llicata Our studies show that aurora a phosphorylates centrin at serine 170 in vitro and that the serine 170 phosphorylation affects the stability of centrin by regulating its interaction with apc/c. finally we demonstrated that phosphorylation of centrin serine 170 is an absolute requirement for aurora a-mediated centriole amplification. 0.514 SIGNOR-174686 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 19282669 YES lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.594 SIGNOR-252961 CDK1 protein P06493 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 YES lperfetto Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20) 0.348 SIGNOR-275489 APC-c complex SIGNOR-C150 SIGNOR CCNB1 protein P14635 UNIPROT down-regulates quantity by destabilization ubiquitination 21596315 YES lperfetto Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B. 0.621 SIGNOR-265051 dactolisib chemical CHEBI:71952 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 YES ATP-competitive inhibitor of PI3K and mTOR gcesareni While the pi3k inhibitors, ly294002 or wortmannin, in the presence of plx4032 were individually inactive against pprm cell lines (fig. S4), the dual pi3k and mtorc1/2 inhibitor bez235 was highly specific (vs. parental lines) and potent in growth-inhibiting pprm cell lines 0.8 SIGNOR-175709 CDK5RAP2 protein Q96SN8 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates activity binding 9606 BTO:0002181 17959831 YES Giulio Immunoprecipitation of CDK5RAP2 specifically coprecipitated _TuRC components, as detected on immunoblots of _-tubulin and GCP3 (Figure 3A).| Perturbing CDK5RAP2 function delocalized gamma-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in gammaTuRC attachment and therefore in the microtubule organizing function of the centrosome. 0.651 SIGNOR-260310 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9534 7791754 YES fspada Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. 0.63 SIGNOR-33440 PAK1 protein Q13153 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation 9606 15037762 YES gcesareni Kinases targeted sequentially to the neck, cla4/pak and cdc5/polo, are responsible for stepwise phosphorylation and down-regulation of swe1. 0.3 SIGNOR-123528 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser44 PGTALVGsQKEPSEV 9606 10617144 YES fspada In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64 0.263 SIGNOR-73606 PFDN2 protein Q9UHV9 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 YES miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR96 0.713 SIGNOR-270919 KDM6B protein O15054 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 NO lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. 0.7 SIGNOR-249563 PRKCG protein P05129 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 YES lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. 0.2 SIGNOR-202788 MASP2 protein O00187 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 YES lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase 0.434 SIGNOR-263416 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 15541388 YES lperfetto Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles. 0.553 SIGNOR-216896 Zalospirone chemical CID:163925 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258864 Spike protein-ACE2 complex SIGNOR-C240 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 18554741 NO miannu Endocytosis of the Receptor-Binding Domain of SARS-CoV Spike Protein Together With Virus Receptor ACE2. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. 0.7 SIGNOR-260289 CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 32221306 NO miannu We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease. 0.7 SIGNOR-260743 CoV2 spike protein-NRP1 complex SIGNOR-C267 SIGNOR Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 10090 BTO:0000108 33082293 YES Luana NRP mediates entry of nanoparticles coated with SARS-CoV-2 (SARS-2) S–derived CendR peptides into cultured cells, olfactory epithelium, and the central nervous system of mice. 0.7 SIGNOR-262316 CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32231345 NO doi.org/10.1101/2020.03.09.983247 miannu Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell-cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity. 0.7 SIGNOR-260741 CoV2 Spike protein-ACE2 complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32221306 NO miannu We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease. 0.7 SIGNOR-260744 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser51 GVVSESDsPVKRPGR 9606 BTO:0000567 12851383 YES lperfetto Thus, phosphorylation of serine 51 on hligi plays a critical role in regulating the interaction between hligi and rfc, which is required for efficient dna replication and repair. 0.457 SIGNOR-103246 CSNK2A1 protein P68400 UNIPROT CERS4 protein Q9HA82 UNIPROT up-regulates activity phosphorylation Ser347 IRSDVEEsDSSEEAA 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273983 bortezomib chemical CHEBI:52717 ChEBI PSMB1 protein P20618 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 YES miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. 0.8 SIGNOR-259306 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.791 SIGNOR-262996 ER stress stimulus SIGNOR-ST9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates 9606 22492984 NO gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins 0.7 SIGNOR-196941 PRKACA protein P17612 UNIPROT PIM1 protein P11309 UNIPROT up-regulates activity phosphorylation Ser65 HSHSPRHsLRHSPGS 9606 30017192 YES miannu In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia. 0.267 SIGNOR-256153 RPS3A protein P61247 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.854 SIGNOR-262420 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 10090 BTO:0000944 SIGNOR-C3 17510057 YES lperfetto mTORC1 catalyzes the phosphorylation of eIF4E binding protein-1 (4EBP1, also known as PHAS-I) and p70 S6 kinase 1 (S6K1)Phosphorylation of S6K1 at Thr-389 0.96 SIGNOR-235507 NOTCH1 protein P46531 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 16554461 NO gcesareni Notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes. 0.495 SIGNOR-145322 STAT5A protein P42229 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 23132946 NO irozzo We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells. 0.4 SIGNOR-255885 KANSL1 protein Q7Z3B3 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 26243146 NO miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. 0.7 SIGNOR-267172 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 23028682 YES lperfetto The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program. 0.401 SIGNOR-217268 CYP26A1 protein O43174 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI down-regulates activity chemical inhibition 9606 9716180 YES Gianni The RA-induced CYP26 was shown to be highly specific for the hydroxylation of all-trans-RA and did not recognize the 13-cis and 9-cis isomers. This substrate specificity is promising for finding retinoids that are not recognized by this enzyme and, therefore, could be more effective in growth inhibition of susceptible cancer cells. 0.8 SIGNOR-266425 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity phosphorylation Tyr398 HLGADGVyLDDLTDM 9606 BTO:0002181 33203880 YES miannu Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. 0.2 SIGNOR-277292 CGA protein P01215 UNIPROT TSH complex SIGNOR-C412 SIGNOR form complex binding 9606 BTO:0001379 8196184 YES scontino TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors. 0.68 SIGNOR-267046 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.764 SIGNOR-252865 C7 protein P10643 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 YES lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer 0.469 SIGNOR-263443 EFNA5 protein P52803 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.896 SIGNOR-52476 HSPA1A protein P0DMV8 UNIPROT PACRG protein Q96M98 UNIPROT up-regulates quantity by stabilization binding -1 12150907 YES miannu Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo. 0.2 SIGNOR-272890 UFL1 protein O94874 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 30886146 YES lperfetto UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage. 0.2 SIGNOR-265073 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Thr663 IATVIVItLVMLKKK -1 10605825 YES lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. 0.489 SIGNOR-261793 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Pro) smallmolecule CHEBI:29177 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269493 ANK2 protein Q01484 UNIPROT PPP2R5A protein Q15172 UNIPROT up-regulates quantity relocalization 9606 BTO:0003324 19840192 YES miannu Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. 0.283 SIGNOR-266729 CRP protein P02741 UNIPROT NOS3 protein P29474 UNIPROT down-regulates quantity by destabilization 17942113 NO miannu C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. we found that CRP decreased the eNOS dimer/monomer ratio further supporting eNOS uncoupling. 0.463 SIGNOR-252217 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248515 NMUR2 protein Q9GZQ4 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257010 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding 9606 27629041 YES miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival 0.697 SIGNOR-260174 FOXJ1 protein Q92949 UNIPROT SPAG6 protein O75602 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.447 SIGNOR-266935 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 YES lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor 0.689 SIGNOR-198747 DCAF11 protein Q8TEB1 UNIPROT GEN1 protein Q17RS7 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 31409866 YES miannu (WDR23) isoforms differentially ubiquitinate (GEN1). In the presence of the necessary components for a successful ubiquitination reaction (CUL4A-DDB1-WDR23 complex, UBE1, UBE2D1, ubiquitin, and ATP) GEN1 receives the addition of ubiquitin in a time dependent manner. 0.2 SIGNOR-272258 INTS6 protein Q9UL03 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.848 SIGNOR-261463 Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 NO lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell 0.7 SIGNOR-266029 FBXO3 protein Q9UK99 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0004573 18809579 YES miannu O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.  0.464 SIGNOR-271744 C1QBP protein Q07021 UNIPROT C1QA protein P02745 UNIPROT down-regulates activity binding SIGNOR-C308 28018340 YES lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. 0.384 SIGNOR-263402 PIK-90 chemical CID:6857685 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206226 FLT3 protein P36888 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001545 17851558 YES miannu Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML. 0.409 SIGNOR-260124 DBP protein Q10586 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8383844 NO inferred from family member miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators 0.2 SIGNOR-270225 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates activity phosphorylation Ser173 VKKNPHHsQWGDMKL 9606 BTO:0000018 16540648 YES llicata Defects in ATR-dependent XPA phosphorylation increases the cell sensitivity to UV irradiation. | The XPA-deficient cells complemented with XPA-S196A mutant, in which Ser196 was substituted with an alanine, displayed significantly higher UV sensitivity compared with the XPA cells complemented with wild-type XPA. Moreover, substitution of Ser196 with aspartic acid for mimicking the phosphorylation of XPA increased the cell survival to UV irradiation. 0.493 SIGNOR-250584 KLHL12 protein Q53G59 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000567 22358839 YES miannu By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division. 0.532 SIGNOR-272011 bufexamac chemical CHEBI:31317 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 21258344 YES Luana  We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. 0.8 SIGNOR-257892 LAMTOR3 protein Q9UHA4 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates binding 9606 15547943 YES gcesareni We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations. 0.614 SIGNOR-130924 SEMA3C protein Q99985 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates activity binding 19666519 YES lperfetto Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. 0.509 SIGNOR-253151 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 YES lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins 0.2 SIGNOR-244144 CCNE2 protein O96020 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR form complex binding 9606 19665013 YES lperfetto The eukaryotic cell cycle is controlled by different cyclins and their associated kinases (murray and hunt, 1993). In mammalian cells, levels of cycline and its associated kinase, cdk2, rise in late g1/early s-phase when dna replication is initiated 0.933 SIGNOR-187454 EEF1A2 protein Q05639 UNIPROT Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269522 MATK protein P42679 UNIPROT LYN protein P07948 UNIPROT down-regulates activity phosphorylation Tyr508 YTATEGQyQQQP -1 9171348 YES miannu In vitro phosphorylation assays showed that Chk suppressed Lyn activity by phosphorylating its C-terminal negative regulatory tyrosine. 0.334 SIGNOR-250177 IFNW1 protein P05000 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 YES miannu Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.743 SIGNOR-260336 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Ser38 YVVKRRDsATSFSLD 9606 BTO:0000776 18417471 YES llicata We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43 0.325 SIGNOR-178244 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 YES llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo. 0.757 SIGNOR-250767 L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 24657844 YES miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. 0.8 SIGNOR-267536 AKT1 protein P31749 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 YES lperfetto Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor. 0.741 SIGNOR-252542 MAPK3 protein P27361 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 YES gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. 0.6 SIGNOR-118550 Food intake phenotype SIGNOR-PH152 SIGNOR vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity 9606 30080183 NO lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin. Vitamin D can also be obtained from nutrition. 0.7 SIGNOR-270565 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CHEK1 protein O14757 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 19716789 YES miannu  Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. 0.446 SIGNOR-271880 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr310 LPNQEENyVTPIGDG BTO:0000007 12540842 YES lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2. 0.343 SIGNOR-249372 MECP2 protein P51608 UNIPROT BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 14593183 YES Luana We find that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene. 0.471 SIGNOR-264540 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24877152 NO Conversely, a reduced amount of IGF-1R diminished the levels of P-AKT, allowing dissociation and nuclear translocation of Smad3 and enhancement of the TGFŒ≤1 signaling pathway and fibrosis 0.7 SIGNOR-254375 HNF4A protein P41235 UNIPROT NPC1L1 protein Q9UHC9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21123766 NO miannu Our results showed a positive correlation between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA expression, a finding that supports the notion that these transcription factors stimulate intestinal NPC1L1 expression. 0.26 SIGNOR-254460 LE-TGN SNARE complex SIGNOR-C157 SIGNOR M6PR protein P20645 UNIPROT up-regulates activity relocalization 9606 18195106 YES lperfetto These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function. 0.534 SIGNOR-253084 IFI30 protein P13284 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 31810556 YES scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. 0.8 SIGNOR-267864 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 12777400 YES Manara These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386 0.34 SIGNOR-260771 TOM40 complex complex SIGNOR-C421 SIGNOR ATF5 protein Q9Y2D1 UNIPROT down-regulates activity relocalization 31387448 YES lperfetto Central to the mtUPR is the transcription factor ATF5. When stress causes protein import and/or electron transport chain dysfunction ATF5 accumulates in the nucleus to transcribe mitochondrial chaperones and protease genes |Under normal conditions, ATF5 is imported into and sequestered within mitochondria. 0.2 SIGNOR-267685 HNF4G protein Q14541 UNIPROT HAS2 protein Q92819 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003723 23896584 YES Luana Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G. 0.337 SIGNOR-261626 cabazitaxel chemical CHEBI:63584 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 21770474 YES miannu Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization 0.8 SIGNOR-259340 HERC2 protein O95714 UNIPROT XPA protein P23025 UNIPROT down-regulates ubiquitination 9606 20304803 YES miannu Herc2 may ubiquitinate xpa and thus target it for proteolytic degradation 0.386 SIGNOR-164595 IL3RA protein P26951 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 15795318 NO gcesareni We previously demonstrated that integrin-dependent adhesion activates stat5a, a well known target of il-3-mediated signaling 0.572 SIGNOR-134862 UV stress stimulus SIGNOR-ST7 SIGNOR CDKN2A protein P42771 UNIPROT up-regulates 9606 11830546 NO miannu The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. The increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor. 0.7 SIGNOR-252376 PLG protein P00747 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR up-regulates 9606 1447176 NO lperfetto The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme 0.7 SIGNOR-263535 P2RY6 protein Q15077 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257398 BRAF protein P15056 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 NO miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 0.2 SIGNOR-267362 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Ser29 VSHWQQQsYLDSGIH -1 12432063 YES miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  0.47 SIGNOR-275995 HMGCS2 protein P54868 UNIPROT acetoacetyl-CoA smallmolecule CHEBI:15345 ChEBI down-regulates quantity chemical modification 29597274 YES lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis 0.8 SIGNOR-267659 FOXP3 protein Q9BZS1 UNIPROT T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR up-regulates 9606 15785758 NO mrosina Viewed as a whole, the available data demonstrate essential involvement of Foxp3 in the development and function of CD4 + CD25 + T reg cells. 0.7 SIGNOR-254970 PKA proteinfamily SIGNOR-PF17 SIGNOR AQP5 protein P55064 UNIPROT up-regulates activity phosphorylation Ser156 STDSRRTsPVGSPAL 9606 BTO:0000007 26569106 YES lperfetto AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation. 0.2 SIGNOR-272087 SRP54 protein P61011 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity binding -1 8816452 YES Monia We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65). 0.299 SIGNOR-261161 XIAP protein P98170 UNIPROT SEPTIN4 protein O43236 UNIPROT down-regulates quantity ubiquitination 9606 22185822 YES miannu Fig. 1 D revealed that co-transfection of ARTS and full length XIAP strongly reduces the levels of ARTS, while co-transfection of ARTS and XIAPdelRING does not change ARTS protein levels.|In this study we show that XIAP also promotes the ubiquitination and degradation of its antagonist ARTS. 0.2 SIGNOR-278801 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 YES lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A 0.778 SIGNOR-120836 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 YES lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively 0.246 SIGNOR-180767 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser212 DETERAYsFCGTIEY 9606 15568999 YES lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. 0.2 SIGNOR-131387 H2AZ1 protein P0C0S5 UNIPROT Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR form complex binding -1 24311584 YES miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. 0.2 SIGNOR-263715 TNF protein P01375 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity transcriptional regulation 9606 BTO:0000847 9767234 NO miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. 0.289 SIGNOR-252381 17beta-estradiol smallmolecule CHEBI:16469 ChEBI 17beta-estradiol 3-sulfate(1-) smallmolecule CHEBI:136582 ChEBI up-regulates quantity precursor of -1 7779757 YES Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. 0.8 SIGNOR-269750 GRM6 protein O15303 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 YES miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. 0.338 SIGNOR-264084 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Ser409 LRLDPTLsVDDLANS 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 YES lperfetto Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function. 0.2 SIGNOR-246743 PRKACA protein P17612 UNIPROT DSP protein P15924 UNIPROT down-regulates activity phosphorylation Ser2849 RSGSRRGsFDATGNS 9606 BTO:0000567 7525582 YES miannu HeLa cells treated with forskolin indicated that stimulation of protein kinase A in transfected cells could decrease the interaction of DP.AN.SerC23 with keratin IF networks. phosphorylation of Ser-C23 could destabilize interactions that occur either directly through this 20 residue sequence or that are dependent on its correct conformation 0.329 SIGNOR-250353 SRC protein P12931 UNIPROT TGFA protein P01135 UNIPROT up-regulates activity 9606 17251915 NO lperfetto Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network. 0.3 SIGNOR-236534 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000567 10653583 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. 0.2 SIGNOR-236487 GREB1 protein Q4ZG55 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 BTO:0000599 31462641 YES miannu GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription 0.2 SIGNOR-265884 DNM2 protein P50570 UNIPROT GJB2 protein P29033 UNIPROT down-regulates binding 9606 25263585 YES miannu This study identifies dynamin 2 (dyn2) as a cx26 interactor in yeast and mammalian cells / we demonstrate that dyn2 regulates cx26 endocytosis and ubiquitination 0.328 SIGNOR-205372 PRKCZ protein Q05513 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 YES lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) 0.497 SIGNOR-217370 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190206 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 YES lperfetto Recently, Liu et al. [3] identified CyclinE/CDK2 to be the kinase phosphorylating OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) by elegantly combining genetics and biochemistry. Knockout of all five G1 cyclins (D1, D2, D3, E1 and E2) in mESCs (coined Q-KO cells) and consequent inactivation of CDK2/4/ 6 leads to perturbation of the pluripotent state and to the adaption of the trophectoderm cell fate. This was attributed to reduced phosphorylation of OCT4 (as well as SOX2 and NANOG) leading to an increase of protein turnover [3]. 0.319 SIGNOR-264437 LCK protein P06239 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Tyr194 DVQKSKEyFSKQK -1 20178744 YES miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. 0.2 SIGNOR-276277 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR NUDT1 protein P36639 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0005713 28947420 YES miannu Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination.  0.2 SIGNOR-272791 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr130 PAQLLCStPNGLDRG 9606 SIGNOR-C17 10864927 YES gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.858 SIGNOR-78424 VARS1 protein P26640 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270797 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr407 SRIPASQtSVPFDHL 9606 BTO:0000007 10542239 YES llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T 0.2 SIGNOR-250814 GRK2 protein P25098 UNIPROT PDE6G protein P18545 UNIPROT up-regulates activity phosphorylation Thr62 PGMEGLGtDITVICP 9606 BTO:0000007 11502744 YES Rod PDEγ is predominantly phosphorylated by GRK2 at the Thr-62. GRK2 is required for the stimulatory effect of rod PDEγ on both the EGF- and thrombin-dependent activation of p42/p44 MAPK 0.2 SIGNOR-251459 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR SMURF1 protein Q9HCE7-2 UNIPROT down-regulates quantity by destabilization polyubiquitination LYS357 RDLVQKLkVLRHELS 9606 BTO:0000007 21572392 YES miannu Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation.  FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells. 0.502 SIGNOR-271912 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Thr495 LLSLFEDtLDPT 9606 12738781 YES lperfetto These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site.  0.72 SIGNOR-249208 FER protein P16591 UNIPROT FER protein P16591 UNIPROT up-regulates activity phosphorylation Tyr714 RQEDGGVySSSGLKQ 9534 10998246 YES P94fer undergoes autophosphorylation in-trans in vivo and that oligomerization mediates this process. the N-terminal sequences of the FER tyrosine kinases direct their different cellular autophosphorylation states, thereby dictating their different cellular functions. 0.2 SIGNOR-251133 Ub:E2 complex SIGNOR-C497 SIGNOR RNF31 protein Q96EP0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270985 NLGN2 protein Q8NFZ4 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.824 SIGNOR-264166 IDH3G protein P51553 UNIPROT IDH complex SIGNOR-C396 SIGNOR form complex binding 9606 28139779 YES miannu Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 0.702 SIGNOR-266247 WNT1 protein P04628 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.626 SIGNOR-131571 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273070 MRPS15 protein P82914 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.742 SIGNOR-261455 Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR protein polypeptide chain smallmolecule CHEBI:16541 ChEBI up-regulates quantity chemical modification 9606 29735640 YES miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide.  0.8 SIGNOR-270818 PHF10 protein Q8WUB8 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.688 SIGNOR-270598 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 SIGNOR-C110 16293724 YES gcesareni This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. 0.86 SIGNOR-141799 TGFB1 protein P01137 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression 9606 17283133 NO gcesareni In normal primary endometrial epithelial cells (eecs), tgfbeta directly induced a dose-dependent increase in p27 protein levels and its nuclear localization 0.289 SIGNOR-152945 ABL1 protein P00519 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 12445832 YES Manara In this report we describe for the first time that ABL1 and Btk physically interact and that ABL1 can phosphorylate tyrosine 223 in the SH3 domain of Btk. | This is presumably due to the negative regulatory effectof Btk SH3 domain phosphorylation caused by ABL1,which would result in a decreased catalytic activity ofBtk resulting in impaired autophosphorylation. 0.336 SIGNOR-260801 belinostat chemical CHEBI:61076 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257957 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1143 PMGSSHAsQVCSETP 9606 BTO:0002181 11114888 YES llicata Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. 0.8 SIGNOR-250581 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273097 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 18936167 YES gcesareni The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2. 0.698 SIGNOR-181672 RELA protein Q04206 UNIPROT SP1 protein P08047 UNIPROT up-regulates binding 9606 SIGNOR-C13 10671503 YES gcesareni Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1. 0.629 SIGNOR-75004 teniposide chemical CHEBI:75988 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 1329225 YES miannu Recognition of transient DNA breaks induced by teniposide, etoposide, and other podophyllotoxin analogues established not only that their site of activity was DNA but also that their cytotoxic effect was dose-dependent. Extensive investigation has further indicated that a primary mechanism of action of these agents involves inhibition of the catalytic activity of eukaryote topoisomerase II and, more important, the consequent stabilization of the normally transient covalent intermediate formed between the DNA substrate and the enzyme. 0.8 SIGNOR-259329 Ub:E2 complex SIGNOR-C497 SIGNOR RNF166 protein Q96A37 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271065 IKBKB protein O14920 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 9606 20300203 YES gcesareni The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta. 0.816 SIGNOR-164509 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity chemical inhibition 9606 26347206 YES miannu Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation. 0.8 SIGNOR-259446 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Thr202 HDHTGFLtEYVATRW 10116 7535768 YES We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively 0.786 SIGNOR-248462 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 10090 BTO:0004052 23996074 YES irozzo In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL.The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1 0.2 SIGNOR-255869 TTL protein Q8NG68 UNIPROT TUBA1B protein P68363 UNIPROT down-regulates tyrosination 9606 22020298 YES miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization 0.458 SIGNOR-176915 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 YES lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. 0.794 SIGNOR-109551 TGFBI protein Q15582 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR up-regulates activity binding 26387839 YES lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers 0.44 SIGNOR-253266 PIP5K1A protein Q99755 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 18772438 NO gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490 0.273 SIGNOR-180800 ARVCF protein O00192 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.467 SIGNOR-252128 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr115 GTIAKSGtKAFMEAL 9606 24117238 YES lperfetto Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity. 0.258 SIGNOR-202812 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates activity ubiquitination 9606 15221015 YES lperfetto Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor. 0.731 SIGNOR-227466 RSPO3 protein Q9BXY4 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 YES gcesareni Here, we show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling. 0.423 SIGNOR-172756 CREB1 protein P16220 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11557984 YES CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo 0.552 SIGNOR-256150 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of -1 18772128 YES miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. 0.8 SIGNOR-268105 FBXO45 protein P0C2W1 UNIPROT ZEB2 protein O60315 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.363 SIGNOR-272180 AKT proteinfamily SIGNOR-PF24 SIGNOR ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser345 ELLCLRRsSLKAYGN 9606 11809767 YES lperfetto Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation. 0.2 SIGNOR-114466 OPRL1 protein P41146 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.462 SIGNOR-256722 EZH2 protein Q15910 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates activity 10090 15520282 NO We report that Ezh2 expression was developmentally regulated in the myotome compartment of mouse somites and that its down-regulation coincided with activation of muscle gene expression and differentiation of satellite-cell-derived myoblasts 0.7 SIGNOR-255719 PRKCA protein P17252 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization phosphorylation Ser423 GRAGPFSsSRCGASV -1 35931119 YES miannu Through mass spectrometry, we identified that ULK1 is O-GlcNAcylated at Ser409, which is distinct from the previously reported Thr635/Thr754 sites. It has been demonstrated that PKCα mediates phosphorylation of ULK1 at Ser423, which attenuates its stability by shunting ULK1 to the chaperone-mediated autophagy (CMA) pathway.  0.2 SIGNOR-277900 SYK protein P43405 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates phosphorylation Tyr397 EDEPEGDyEEVLEPE 9606 BTO:0000776 9104825 YES llicata Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis. 0.666 SIGNOR-47342 CDK5 protein Q00535 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates phosphorylation Ser13 ARKNAQPsPARAPAE 9606 BTO:0001271 21145489 YES llicata We show that noxa is phosphorylated on a serine residue (s(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify cdk5 as the noxa kinase 0.357 SIGNOR-170357 MPG protein P29372 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 25207814 YES miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. 0.2 SIGNOR-271930 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:HECT_E3 complex SIGNOR-C518 SIGNOR form complex binding 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 0.2 SIGNOR-271379 PKC proteinfamily SIGNOR-PF53 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates activity phosphorylation Thr193 VKLSNIPtIKRFLEP 9534 12646569 YES lperfetto Mutational analysis show that the putative mitochondrial targeting signal resides within the C-terminal 20 amino acid residues of the protein and that the targeting signal requires activation by phosphorylation at the C-terminal-most protein kinase A (PKA) site at Ser-189 or protein kinase C (PKC) site at Thr-193. 0.2 SIGNOR-264795 LETM1 protein O95202 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 10090 29123128 YES lperfetto Others have suggested that LETM1 plays an essential role in mitochondrial K+ homeostasis by mediating the mitochondrial K+/H+ exchange 0.8 SIGNOR-262542 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 14981546 NO These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. 0.292 SIGNOR-261521 clenbuterol chemical CHEBI:174690 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257861 SWI/SNF complex complex SIGNOR-C92 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 33941852 NO Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription.  0.7 SIGNOR-268623 MAT2B protein Q9NZL9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001938 30942439 NO miannu MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen 0.7 SIGNOR-261242 AKT1 protein P31749 UNIPROT ARFIP2 protein P53365 UNIPROT unknown phosphorylation Ser260 GTRGRLEsAQATFQA 9606 BTO:0000938 15809304 YES llicata Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells. 0.46 SIGNOR-252476 FBXW7 protein Q969H0 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 14739463 YES miannu  We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCF(Fbw7), which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.  0.496 SIGNOR-272950 HIF1A protein Q16665 UNIPROT PGK1 protein P00558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0000972 8089148 NO miannu Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine). Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. 0.47 SIGNOR-254424 PRDM16 protein Q9HAZ2 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 NO fspada Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells. 0.7 SIGNOR-180295 MMP10 protein P09238 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 YES miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. 0.324 SIGNOR-256332 pazopanib chemical CHEBI:71219 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258262 BGJ-398 chemical CHEBI:63451 ChEBI FGFR4 protein P22455 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190272 Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 YES lperfetto The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate 0.7 SIGNOR-249584 MMP13 protein P45452 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272381 GSK3B protein P49841 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates activity phosphorylation Thr586 HNTPVDVtPCMSPLP -1 24879152 YES lperfetto The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. 0.429 SIGNOR-261795 CALM3 protein P0DP25 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 YES miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.527 SIGNOR-266340 DDX39B protein Q13838 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 YES miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. 0.906 SIGNOR-268512 LPAR3 protein Q9UBY5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.456 SIGNOR-256890 RXR proteinfamily SIGNOR-PF44 SIGNOR PPARG protein P37231 UNIPROT up-regulates activity binding 9606 11237216 YES miannu Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology 0.2 SIGNOR-259057 PPP1R3B protein Q86XI6 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates binding 9606 BTO:0000759 36551183 YES miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) 0.71 SIGNOR-271736 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 20590599 YES Luana Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3). 0.8 SIGNOR-257855 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GPHN protein Q9NQX3 UNIPROT down-regulates phosphorylation Ser268 ASLSTTPsESPRAQA 9606 BTO:0000142 23408424 YES miannu Erk phosphorylates gephyrin at ser-268 to regulate size of gephyrin postsynaptic scaffold and strength of gabaergic transmission./ Ser-268 phosphorylation restricts gephyrin cluster size via calpain 1 proteolysis 0.2 SIGNOR-200953 PTPMT1 protein Q8WUK0 UNIPROT 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) smallmolecule CHEBI:60110 ChEBI down-regulates quantity chemical modification 10090 21641550 YES lperfetto PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. 0.8 SIGNOR-267026 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 22123909 YES gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) 0.341 SIGNOR-177818 CSN1S1 protein P47710 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser529 GLPNGLLsGDEDFSS 9606 21232017 YES gcesareni Phosphorylation of serine 529 of p65 is mediated by casein kinase ii, but is prevented in nonstimulated cells by the interaction with ikba 0.2 SIGNOR-171222 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9534 BTO:0001538 11163210 YES miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  0.87 SIGNOR-272937 CREBBP protein Q92793 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR form complex binding 9606 21131905 YES lperfetto Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators. 0.653 SIGNOR-170262 PRKACA protein P17612 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates activity phosphorylation Ser1444 NIKARASsSPVILVG -1 24351927 YES gcesareni Furthermore, our work establishes S1444 as a PKA-regulated 14-3-3 docking site€.Strikingly, 14-3-3 binding to phospho-S1444 decreased LRRK2 kinase activity in vitro. 0.407 SIGNOR-237444 Compound A [PMID:15866883] chemical CID:51529932 PUBCHEM LTB4R2 protein Q9NPC1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257535 zotepine chemical CHEBI:32316 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258557 S protein P59594 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 16310778 NO Luana We demonstrated that the adenovirus-mediated over-expression of SARS-CoV spike (S) protein and its C-terminal domain (S2) induce apoptosis in Vero E6 cells in a time- and dosage-dependent manner 0.7 SIGNOR-260219 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 15294014 NO Luana In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors. 0.7 SIGNOR-260204 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 17453707 NO Luana SARS-CoV Nucleocapsid Protein Induced Apoptosis of COS-1 Mediated by the Mitochondrial Pathway 0.7 SIGNOR-260205 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 NO Luana Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells. 0.7 SIGNOR-260199 M protein P59596 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 NO Luana Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells. 0.7 SIGNOR-260198 3a protein P59632 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates activity 9534 15958670 NO Luana These results indicated that the 3a protein induced apoptosis in Vero E6 cells. 0.7 SIGNOR-260195 3b protein P59633 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates activity 9534 16965829 NO Luana Over-expression of severe acute respiratory syndrome coronavirus 3b protein induces both apoptosis and necrosis in Vero E6 cells 0.7 SIGNOR-260194 6 protein P59634 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 18708124 NO Luana A SARS-CoV protein, ORF-6, induces caspase-3 mediated, ER stress and JNK-dependent apoptosis 0.7 SIGNOR-260203 7a protein P59635 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000018 15564512 NO Luana 7a induces apoptosis via a caspase-dependent pathway and in cell lines derived from different organs, including lung, kidney, and liver. | The overexpression of HA-tagged 7a (7a-HA) induces apoptosis in 293T (human kidney epithelial) cells, as evidenced by an increase in caspase-3 protease activity, a hallmark of apoptosis, which is comparable to that caused by the overexpression of BAX, a proapoptotic member of the Bcl-2 family 0.7 SIGNOR-260197 7a protein P59635 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 NO Luana Cells expressing the ORF7a or ORF7b protein undergo apoptosis. 0.7 SIGNOR-260209 MYC protein P01106 UNIPROT FUT3 protein P21217 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 NO miannu We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 0.253 SIGNOR-254612 HIF1A protein Q16665 UNIPROT KDM1A protein O60341 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.265 SIGNOR-271573 CSNK1G2 protein P78368 UNIPROT LYN protein P07948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser13 SKGKDSLsDDGVDLK 9606 BTO:0000007 33004926 YES miannu Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane. 0.2 SIGNOR-275397 MAPK1 protein P28482 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation Ser982 KKKSEPSsPDHGSST -1 11287604 YES lperfetto coimmunoprecipitation detected a specific association between the activated erk and plc beta1 within the nucleus. In vitro studies revealed that recombinant plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 this result suggests that erk-evoked phosphorylation of plc beta1 at serine 982 plays a critical role in the activation of the nuclear pi cycle and is also crucial to the mitogenic action of igf-i. 0.398 SIGNOR-106561 STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000782 22767500 NO lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. 0.7 SIGNOR-261899 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser29 VSHWQQQsYLDSGIH 9606 BTO:0000007 12432063 YES llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin 0.6 SIGNOR-251065 7b protein Q7TFA1 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 NO Luana Cells expressing the ORF7a or ORF7b protein undergo apoptosis. 0.7 SIGNOR-260210 MAPKAPK2 protein P49137 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 20626350 YES gcesareni Mk2 and mk3 participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating the are-binding proteins ttp and hur, and by regulating eef2k 0.303 SIGNOR-166622 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization ubiquitination Lys572 VVRPKLPkPPTDPLG 10090 35670107 YES lperfetto TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels 0.2 SIGNOR-272541 A9/b1 integrin complex SIGNOR-C166 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269015 DGCR8 protein Q8WYQ5 UNIPROT RNF168 protein Q8IYW5 UNIPROT up-regulates activity binding 9606 BTO:0002181 34188037 YES miannu  Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.  0.2 SIGNOR-277309 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 18326031 YES lperfetto Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation. 0.619 SIGNOR-161278 PTGS2 protein P35354 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 20219869 YES apalma Furthermore, COX-2 inhibition reduced MyoD expression in regenerating muscle, suggesting a role for COX-2 in modulating muscle differentiation, as well as growth 0.264 SIGNOR-256214 HSPA2 protein P54652 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 12391142 YES gcesareni Coimmunoprecipitation analysis revealed a physical interaction between endogenous hsp72 and ask1 in nih 3t3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ask1 and ask1-dependent apoptosis. 0.2 SIGNOR-94565 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser377 PPFNPNVsGPNDLRH -1 12023960 YES miannu The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6. 0.339 SIGNOR-250296 SREBF1 protein P36956 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 YES gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) 0.29 SIGNOR-166381 NPTX1 protein Q15818 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 NO lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control 0.2 SIGNOR-260411 EIF5B protein O60841 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR down-regulates activity binding 9606 30211544 YES lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. 0.676 SIGNOR-269120 Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR AICDA protein Q9GZX7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 31092637 YES miannu  Further analysis indicated that CUL7 mediated AID ubiquitination by forming a complex with FBXW11. In a CUL7 fl/fl CD19 cre+ mouse model, we demonstrated that CUL7 knockout significantly enhanced AID protein levels in B cells in the germinal center and increased both the IgG1 and IgA class switching. Collectively, our results reveal a subtle regulation mechanism for tightly controlling AID protein levels. F-box proteins are components of SCF ubiquitin-ligase complexes that contain Skp1, CUL1, or CUL7, and an F-box protein 0.249 SIGNOR-272026 PGAM proteinfamily SIGNOR-PF78 SIGNOR 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity chemical modification 9606 24786789 YES miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. 0.8 SIGNOR-266516 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation 9606 BTO:0000149 24342355 YES inferred from 70% family members lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity 0.2 SIGNOR-270118 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Thermogenesis phenotype SIGNOR-PH192 SIGNOR up-regulates 9606 24692351 NO scontino TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight. 0.7 SIGNOR-267491 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 21993628 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-176748 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates activity 9606 25910399 NO Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. 0.7 SIGNOR-266901 CEBPD protein P49716 UNIPROT TNFAIP6 protein P98066 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 NO CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. 0.259 SIGNOR-254057 PRKAA1 protein Q13131 UNIPROT EGLN1 protein Q9GZT9 UNIPROT down-regulates activity phosphorylation Ser136 AAAGGQGsAVAAEAE 9606 BTO:0000599 35538889 YES miannu Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling. 0.373 SIGNOR-277593 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS -1 10605825 YES lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. 0.489 SIGNOR-261771 mTORC1 complex SIGNOR-C3 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates 9606 20670887 NO gcesareni Hif1alfa is the transcription factor downstream of mtorc1 in the control of glycolytic genes. 0.361 SIGNOR-167187 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT down-regulates activity phosphorylation Ser745 PEYLEQPsRSDFSKH 9606 BTO:0000007 25755282 YES miannu Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.  0.294 SIGNOR-273579 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.307 SIGNOR-254726 ATF4 protein P18848 UNIPROT LARS1 protein Q9P2J5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269420 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190176 RET protein P07949 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 16153436 YES gcesareni We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1). 0.424 SIGNOR-140294 MAPK14 protein Q16539 UNIPROT H3-3A protein P84243 UNIPROT unknown phosphorylation 9606 10806218 YES gcesareni More importantly, incubation of active erk2 or p38 kinase with h3 protein resulted in phosphorylation of h3 at serine 10 in vitro. These results suggest that erk and p38 kinase are at least two important mediators of phosphorylation of h3 at serine 10. 0.2 SIGNOR-77224 DDX21 protein Q9NR30 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 YES miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 0.435 SIGNOR-268824 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr286 EELAMDVyDEVDRRE 9606 16317044 YES fspada Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest. 0.344 SIGNOR-142711 Caspase 3 complex complex SIGNOR-C221 SIGNOR STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp349 RVASTMTdGANTMIE 9534 BTO:0004055 11517310 YES lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. 0.616 SIGNOR-256445 GRK2 protein P25098 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15843435 YES llicata Grk2 phosphorylates glutathione s-transferase (gst)-ezrin, but not an ezrin fusion protein lacking threonine 567 (t567), in vitro. These results suggest that t567, the regulatory phosphorylation site responsible for maintaining ezrin in its active conformation, represents the principle site of grk2-mediated phosphorylation. 0.2 SIGNOR-135622 FOXO proteinfamily SIGNOR-PF27 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 NO gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. 0.2 SIGNOR-252937 ERG protein P11308 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21669963 NO miannu Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt -115 to -118) in the OPN promoter. 0.2 SIGNOR-254066 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 24265311 YES lperfetto Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit. 0.2 SIGNOR-203281 ATG13 protein O75143 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR form complex binding 9606 23863160 YES lperfetto In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. 0.918 SIGNOR-209884 FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 11717445 YES amattioni Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains. 0.931 SIGNOR-112061 MUC1 protein P15941 UNIPROT KLF4 protein O43474 UNIPROT up-regulates activity binding 17308127 YES lperfetto Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. Our results show that MUC1-C binds constitutively to KLF4, occupies PE21 with KLF4, and enhances the KLF4 occupancy of PE21.  0.281 SIGNOR-270543 Caspase 3 complex complex SIGNOR-C221 SIGNOR RAD51 protein Q06609 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0002882 11684015 YES lperfetto The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin 0.467 SIGNOR-271708 SRP54 protein P61011 UNIPROT SRPRB protein Q9Y5M8 UNIPROT up-regulates activity binding -1 30649417 YES miannu The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site. 0.819 SIGNOR-261165 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser14 LNVIKMKsSDFLESA -1 18408713 YES miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) 0.2 SIGNOR-276161 CSNK2A1 protein P68400 UNIPROT FUNDC1 protein Q8IVP5 UNIPROT down-regulates activity phosphorylation Ser13 PPPQDYEsDDDSYEV 9606 BTO:0000567 24746696 YES miannu Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation.  0.426 SIGNOR-273622 P4HB protein P07237 UNIPROT Collagen proteinfamily SIGNOR-PF103 SIGNOR up-regulates quantity by stabilization binding 9606 9545296 YES miannu We also show that PDI associates independently with the C-propeptide of monomeric procollagen chains prior to trimer formation, indicating a role for this protein in coordinating the assembly of heterotrimeric molecules. This demonstrates that PDI has multiple functions in the folding of the same protein, that is, as a catalyst for disulfide bond formation, as a subunit of P4-H during proline hydroxylation, and independently as a molecular chaperone during chain assembly. 0.2 SIGNOR-269731 KLHL13 protein Q9P2N7 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates activity binding 9606 BTO:0000567 17543862 YES miannu Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis. 0.741 SIGNOR-271657 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser616 PSVASSVsEEYFEVR -1 24554596 YES lperfetto These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. 0.374 SIGNOR-264767 SMAD6 protein O43541 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 22298955 YES Create a non-functional complex with smad4 and competes with R-smad. lperfetto On the other hand, Smad6 competes with R-Smad and forms a non-functional complex with Smad4, which will inhibit BMP signaling in bone formation. Smad6 is involved in a negative feedback loop regulating BMP signaling and is required to limit BMP signaling during endochondral bone formation. 0.573 SIGNOR-195648 TGFBI protein Q15582 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 26387839 YES lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers 0.452 SIGNOR-253267 DDHD2 protein O94830 UNIPROT 1-acyl-sn-glycerol 3-phosphate smallmolecule CHEBI:16975 ChEBI up-regulates quantity chemical modification 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269655 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-267934 FAM83A protein Q86UY5 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273748 NME1 protein P15531 UNIPROT LPAR1 protein Q92633 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 NO miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 0.405 SIGNOR-255163 SRC protein P12931 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates activity phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000132 19718473 YES lperfetto Integrin-dependent translocation of LASP-1 to the cytoskeleton of activated platelets correlates with LASP-1 phosphorylation at tyrosine 171 by Src-kinase 0.253 SIGNOR-271706 MED25 protein Q71SY5 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.591 SIGNOR-266681 frovatriptan chemical CHEBI:134991 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation -1 9986723 YES miannu As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold). 0.8 SIGNOR-259073 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser8 MESEMLQsPLLGLGE 9606 BTO:0000007 SIGNOR-C3 21071439 YES lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.469 SIGNOR-169530 CASP3 protein P42574 UNIPROT Caspase 3 complex complex SIGNOR-C221 SIGNOR form complex binding cleavage:Asp28 IHGSESMdSGISLDN 15115390 YES lperfetto Caspases are expressed as inactive proenzymes of 30−50 kDa that include an amino-terminal domain of variable length and sequence that is followed by two domains of conserved sequences:  a large subunit (approximately 20 kDa, designated p17 in caspase-3) and a small carboxy-terminal subunit (approximately 10 kDa, designated p12 in caspase-3). Activation is accomplished by proteolytic cleavage between these domains and subsequent assembly of heterotetramers that contain two copies each of the large and small subunits but lack the amino-terminal domains. 0.2 SIGNOR-256387 LRP4 protein O75096 UNIPROT MUSK protein O15146 UNIPROT up-regulates activity binding 9606 BTO:0000887 23458718 YES miannu AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer. 0.729 SIGNOR-273850 HIF1A protein Q16665 UNIPROT PKG proteinfamily SIGNOR-PF77 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0000972 8089148 NO inferred from family member miannu Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine). Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. 0.47 SIGNOR-270291 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.286 SIGNOR-129292 NCF4 protein Q15080 UNIPROT Phagocyte NADPH oxidase complex complex SIGNOR-C557 SIGNOR form complex binding 9606 37263099 YES miannu NADPH oxidase is composed of essential protein components in its active state: membranous subunits, including p22-phox and gp91-phox, and cytoplasmic subunits, including p47-phox, p67-phox, p40-phox, and RAC2 (in neutrophils), among which NCF4 encodes the cytoplasmic subunit p40-phox 0.648 SIGNOR-277629 PKC proteinfamily SIGNOR-PF53 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD -1 19661060 YES miannu Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.2 SIGNOR-276228 EEF2 protein P13639 UNIPROT 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR up-regulates activity binding 9606 14709557 YES lperfetto In mammalian cells, peptide chain elongation requires two main elongation factors, eEF1A and eEF2. The latter mediates the translocation step of elongation in which the ribosome moves by the equivalent of one codon relative to the mRNA, and the peptidyl-tRNA shifts from the A- into the P-site on the ribosomend eEF2. 0.2 SIGNOR-269397 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 20663871 YES lperfetto The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. 0.788 SIGNOR-167163 SRC protein P12931 UNIPROT WASL protein O00401 UNIPROT up-regulates activity phosphorylation 9606 15791211 YES miannu An Src family tyrosine kinase, v-Src, phosphorylates and activates N-WASP. 0.758 SIGNOR-279487 NEK1 protein Q96PY6 UNIPROT VHL protein P40337 UNIPROT down-regulates quantity by destabilization phosphorylation Ser168 RCLQVVRsLVKPENY 9606 BTO:0000007 23255108 YES miannu Nek1 phosphorylates Von Hippel-Lindau tumor suppressor to promote its proteasomal degradation and ciliary destabilization. Mutation of pVHL at S-168 increases protein stability. 0.257 SIGNOR-276434 ABL2 protein P42684 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Tyr78 RAIDFSPyLEPLGAP 9606 BTO:0000007 19563810 YES gcesareni The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells 0.275 SIGNOR-186427 RIMBP3 protein Q9UFD9 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.342 SIGNOR-264360 AUTS2 protein Q8WXX7 UNIPROT DOCK1 protein Q14185 UNIPROT up-regulates activity binding 10090 BTO:0001909 25533347 YES miannu Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells. 0.2 SIGNOR-266820 spermine smallmolecule CHEBI:15746 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 NO apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism 0.7 SIGNOR-255552 NLGN3 protein Q9NZ94 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.83 SIGNOR-264152 AKT proteinfamily SIGNOR-PF24 SIGNOR ILF3 protein Q12906 UNIPROT up-regulates activity phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 YES llicata Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. 0.2 SIGNOR-168169 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser860 NRAVSLDsPVSVGSS 9606 BTO:0000093 15383283 YES miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. 0.525 SIGNOR-250105 TOPBP1 protein Q92547 UNIPROT BRCA1-B complex complex SIGNOR-C298 SIGNOR form complex binding 25400280 YES lperfetto Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation 0.674 SIGNOR-263218 SMAD3 protein P84022 UNIPROT FOXA1 protein P55317 UNIPROT down-regulates activity binding 9606 18003659 YES miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. In this study, we found that SMAD3 interacts through its MAD domains, MH1 and MH2 with NKX2.1 and FOXA1 proteins. The sites of interaction on NKX2.1 are located within the NH2 and COOH domains, known to be involved in transactivation function. 0.331 SIGNOR-254168 RPS6KA1 protein Q15418 UNIPROT L1CAM protein P32004 UNIPROT up-regulates activity phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 YES lperfetto Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152. 0.505 SIGNOR-248948 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.708 SIGNOR-252874 TAF4 protein O00268 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.884 SIGNOR-263921 MEN1 protein O00255 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates binding 9606 12874027 YES miannu Menin interacts with fancd2 / loss of menin expression in mouse embryonic fibroblasts leads to increased sensitivity to dna damage. Furthermore, menin is localized to chromatin and nuclear matrix, and the association with nuclear matrix is enhanced by gamma-irradiation. Together, these results suggest that menin plays a critical role in repair of dna damage in concert with fancd2. 0.442 SIGNOR-103947 EIF2B2 protein P49770 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.75 SIGNOR-269130 SP1 protein P08047 UNIPROT LORICRIN protein P23490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 12200429 NO miannu Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. 0.2 SIGNOR-254538 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr380 YAGGRGSyGDLGGPI 9606 12052863 YES lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). 0.603 SIGNOR-88915 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL 9606 19661060 YES Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.2 SIGNOR-260885 CSNK2A1 protein P68400 UNIPROT KIF1C protein O43896 UNIPROT unknown phosphorylation Ser1092 PRMRRQRsAPDLKES -1 10559254 YES llicata Serine 1092 was a substrate for the protein kinase casein kinase II in vitro, and inhibition of casein kinase II in cells diminished the association of KIF1C with 14-3-3gamma. Our data thus suggest that KIF1C can form dimers and is associated with proteins of the 14-3-3 family. 0.31 SIGNOR-250912 WNT10B protein O00744 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.615 SIGNOR-131625 PPP1R3C protein Q9UQK1 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates binding 9606 BTO:0000759 36551183 YES miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) 0.678 SIGNOR-271735 hsa-miR-150-3p mirna URS00005EAAAD_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002745 26622579 YES These results suggested that miRNA-150 may negatively regulate the expression of CXCR4 by directly targeting the 3′UTR of CXCR4 mRNA. 0.4 SIGNOR-277940 PAX7/MLL2 complex complex SIGNOR-C91 SIGNOR MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 NO miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.492 SIGNOR-198641 Gbeta proteinfamily SIGNOR-PF4 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation 9606 25846811 YES inferred from 70% family members lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. 0.2 SIGNOR-270071 RNF149 protein Q8NC42 UNIPROT BRAF protein P15056 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001109 22628551 YES miannu We showed that RNF149 bound directly to the C-terminal kinase-containing domain of wild-type BRAF and induced ubiquitination, followed by proteasome-dependent degradation, of the latter protein. Functionally, RNF149 attenuated the increase in cell growth induced by wild-type BRAF.  0.338 SIGNOR-272043 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 YES The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. 0.2 SIGNOR-270174 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 17259970 YES milica Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity. 0.535 SIGNOR-152917 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser119 GAAAAPPsPAWSEPE 10090 37029927 YES miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. 0.2 SIGNOR-277796 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr86 AASASPYtPEHAASV 9606 12676926 YES lperfetto Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. 0.534 SIGNOR-216702 PLK2 protein Q9NYY3 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation Ser48 VVGGTDSsMDVFHLE 9606 26625870 YES miannu PLK2 inhibits TAp73 translocation to the nucleus.|PLK2 phosphorylated TAp73 at residue Ser48 within the TA domain; phosphorylation of TAp73 was abolished by mutating this residue. 0.275 SIGNOR-278218 COL18A1 protein P39060 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 NO lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 0.7 SIGNOR-252269 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates activity phosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 11870224 YES Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3 0.2 SIGNOR-251117 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation -1 16226275 YES inferred from 70% family members lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| 0.2 SIGNOR-270202 CBX5 protein P45973 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity binding 9606 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-265325 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.289 SIGNOR-251207 TGFB1 protein P01137 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates 10090 14739161 NO lperfetto Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12. 0.2 SIGNOR-235602 CD79A protein P11912 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323266 YES scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. 0.656 SIGNOR-268188 CTCFL protein Q8NI51 UNIPROT BAG1 protein Q99933 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003293 18413740 YES lperfetto DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation 0.28 SIGNOR-254107 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB1 protein Q9Y5G3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265703 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2V1 protein Q13404 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.578 SIGNOR-271321 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD86 protein P42081 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 NO miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. 0.291 SIGNOR-254782 MTCP1 protein P56278 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.363 SIGNOR-81677 F2R protein P25116 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.581 SIGNOR-257219 SHMT1 protein P34896 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity chemical modification 9606 32439610 YES lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 0.8 SIGNOR-268223 GRPEL2 protein Q8TAA5 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.514 SIGNOR-267700 PTPN2 protein P17706 UNIPROT SRC protein P12931 UNIPROT down-regulates dephosphorylation 9606 22080863 YES gcesareni We found that tcptp dephosphorylates and inactivates src family kinases to regulate t cell responses._ 0.72 SIGNOR-177116 GRIA1 protein P42261 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264947 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 YES The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.614 SIGNOR-138961 RNA Polymerase II complex SIGNOR-C391 SIGNOR precursor messenger RNA smallmolecule CHEBI:139356 ChEBI up-regulates quantity chemical modification 9606 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. 0.8 SIGNOR-266176 PTPN1 protein P18031 UNIPROT ABL1 protein P00519 UNIPROT down-regulates dephosphorylation 9606 9566916 YES gcesareni These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo. 0.611 SIGNOR-56815 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257907 PTEN protein P60484 UNIPROT AR protein P10275 UNIPROT up-regulates activity dephosphorylation Ser83 QQQQQETsPRQQQQQ 9606 24480624 NO miannu Furthermore, PTEN depletion increased AR protein instability, and this effect was further enhanced by p300 silencing in LAPC4 cells .|Our data demonstrate that loss of PTEN increases AR phosphorylation at Ser81 and that Ser81 phosphorylation acts as a molecular beacon that is required for the binding of p300, a key event that subsequently leads to AR acetylation, inhibition of AR ubiquitination and AR stabilization (XREF_FIG). 0.58 SIGNOR-277077 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 BTO:0000007 18204439 YES lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. 0.716 SIGNOR-252958 SP1 protein P08047 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR form complex binding 9606 19723038 YES miannu Sp1 and stat3 seem to synergistically augment renalase transcription. 0.456 SIGNOR-187790 ERBB2 protein P04626 UNIPROT BBC3 protein Q9BXH1 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr58 PTLLPAAyLCAPTAP 9606 BTO:0000093 24236056 YES miannu HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. 0.281 SIGNOR-276473 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser268 SDEFRPRsKSQSSSN -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251288 CSNK1A1 protein P48729 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Ser38 TEMTASSsSDYGQTS -1 26344095 YES miannu Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites. 0.2 SIGNOR-276936 CSNK2A2 protein P19784 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser718 KEAEEESsEDD 9606 11500362 YES llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  0.37 SIGNOR-250990 MAPK1 protein P28482 UNIPROT NCOA6 protein Q14686 UNIPROT up-regulates activity phosphorylation Ser884 NKDVTLTsPLLVNLL -1 11773444 YES miannu In vitro phosphorylation studies with His-tagged TRBP (795–931) suggested that S884 can be phosphorylated by MAPK (ERK2) in vitro (Fig. 10A).Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERβ, TR, and RXR vs. ERα. 0.2 SIGNOR-265882 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 18467333 YES gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. 0.389 SIGNOR-178615 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763 12193595 YES gcesareni We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity. 0.721 SIGNOR-91714 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr86 YTLSRAQtVVVEYTH -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.657 SIGNOR-276128 NLGN2 protein Q8NFZ4 UNIPROT MAGI2 protein Q86UL8 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 YES miannu S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 0.403 SIGNOR-265444 CASP8 protein Q14790 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 YES lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. 0.369 SIGNOR-261760 HBA1 protein P69905 UNIPROT Hemoglobin complex SIGNOR-C209 SIGNOR form complex binding 9606 18179859 YES miannu AHSP does not bind to β-hemoglobin (βHb) or the hemoglobin tetramer, instead, it specifically binds to free αHb, avoiding its precipitation and its pro-oxidant activity. In the presence of βHb, the αHb-AHSP complex is dismembered and βHb displaces AHSP to generate the quaternary structure of hemoglobin 0.709 SIGNOR-255274 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. 0.91 SIGNOR-252857 PGAM2 protein P15259 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity chemical modification 9606 24786789 YES miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. 0.8 SIGNOR-266515 PRKCD protein Q05655 UNIPROT FGF1 protein P05230 UNIPROT up-regulates quantity phosphorylation Ser131 VGLKKNGsCKRGPRT 9606 24595027 YES miannu Translocated FGF1 can be phosphorylated by PKC\u03b4 on serine 130. 0.2 SIGNOR-278451 P2RY14 protein Q15391 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.401 SIGNOR-256723 STK24 protein Q9Y6E0 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 YES lperfetto In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease 0.275 SIGNOR-260265 ELF1 protein P32519 UNIPROT IL2RA protein P01589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 7862168 NO 2 miannu The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells. 0.2 SIGNOR-240193 PIK3CB protein P42338 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 NO lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.7 SIGNOR-242652 CUDC-907 chemical CID:54575456 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191157 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263808 TIMP1 protein P01033 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 NO lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 0.7 SIGNOR-252272 PTPN13 protein Q12923 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation 9606 19734941 YES miannu Since a previous report showed PTPN13 may dephosphorylate ErbB2 directly, we also examined levels of phospho-ErbB2 (tyr 1248), and we also observed a small effect in the presence of wild-type PTPN13 (XREF_FIG).|The fact that both ErbB2 and H-RasV12 were potentiated by PTPN13 loss and PTPN13 inhibited MAP kinase signaling downstream of multiple oncogenes (ErbB2, EGFR, H-RasV12), suggest that the phosphatase target that inhibits MAP kinase signaling may not only be limited to ErbB2 tyrosine 1248. 0.333 SIGNOR-277087 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 21098032 YES gcesareni Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro. 0.2 SIGNOR-170008 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1665 SPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248819 RPS6KA6 protein Q9UK32 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 32396532 YES lperfetto Moreover, RSK4 stabilized Beta-catenin in the presence of GSK-3Beta WT but not RSK4 stabilizes Beta-catenin through phosphorylation of GSK-3Beta (Ser9) in ESCC cells|GSK-3Beta S9A in ESCC cells, which was similar to overexpression of GSK3Beta S9D| 0.2 SIGNOR-275801 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 15486195 YES inferred from 70% family members lperfetto In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel 0.2 SIGNOR-270031 CDK5 protein Q00535 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates activity phosphorylation Ser778 GRRSPTSsPTPQRRA -1 12855954 YES llicata Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE.  0.517 SIGNOR-250662 HOXB6 protein P17509 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 15269212 YES Luana HOXB6 protein represses globin transcript levels in stably transfected K562 cells in a DNA-binding dependent fashion. 0.2 SIGNOR-261637 SMURF1 protein Q9HCE7 UNIPROT IMPACT protein Q9P2X3 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272686 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257470 ELOVL7 protein A1L3X0 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267895 Ub:E2 complex SIGNOR-C497 SIGNOR TOPORS protein Q9NS56 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271118 AKT1 protein P31749 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser283 ILSLRSCsLGSLGAL -1 27407113 YES miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. In vitro kinase assays demonstrated that TRBP-D3 can be phosphorylated by S6K1, S6K2, but also AKT1 (Figure ​(Figure1C),1C), 0.2 SIGNOR-274064 ANKS1B protein Q7Z6G8 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 26356309 YES miannu The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95. 0.451 SIGNOR-264228 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 24714526 YES miannu HRI is an intracellular heme sensor that coordinates heme and globin synthesis in erythropoiesis by inhibiting protein synthesis of globins and heme biosynthetic enzymes during heme deficiency. HRI is a heme-regulated kinase that phosphorylates the α-subunit of eIF2 in heme deficiency, impairing another round of translational initiation and thereby inhibiting translation. 0.89 SIGNOR-251817 Gbeta proteinfamily SIGNOR-PF4 SIGNOR POLR2A protein P24928 UNIPROT down-regulates phosphorylation 9606 14662762 YES inferred from 70% family members lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.2 SIGNOR-270039 PGM1 protein P36871 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI down-regulates quantity chemical modification 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-267931 ABL1 protein P00519 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Tyr143 SPAGRSIyNSFYVYC 9606 BTO:0000142 20823226 YES llicata Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function. 0.2 SIGNOR-167853 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 18265945 YES lperfetto More recently, Shreeram et al.  have also shown that Wip1 dephosphorylates human ATM at Ser367 as well as Ser1981.|Thus, overexpression of Wip1 in an oncogenic context could contribute to tumor promotion by inhibiting both p53 and ATM functions. 0.488 SIGNOR-276954 GNAI1 protein P63096 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 19703466 YES GTP-bound, active WT Gαi1 acts to inhibit AC, resulting in a decreased concentration of intracellular cAMP. 0.55 SIGNOR-256498 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 16885213 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.383 SIGNOR-148595 SS18 protein Q15532 UNIPROT SS18/MLLT10 complex SIGNOR-C75 SIGNOR form complex binding 9606 BTO:0001271 11423977 YES miannu Based on these results, a model is proposed in which the syt and af10 proteins act in concert as bipartite transcription factors 0.427 SIGNOR-108927 NFIB protein O00712 UNIPROT NFIC protein P08651 UNIPROT down-regulates activity binding 9606 BTO:0000567 9099724 YES 2 miannu Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function. 0.362 SIGNOR-240880 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR IGFBP5 protein P24593 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.311 SIGNOR-136601 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition 9606 17868033 YES Simone Vumbaca Apicidin inhibited rhHDACs 2 and 3 in the nanomolar range. 0.8 SIGNOR-261128 N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine chemical CHEBI:91340 ChEBI IKBKB protein O14920 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258190 CDK16 protein Q00536 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity phosphorylation Ser10 NVRVSNGsPSLERMD 9606 25205104 YES miannu Experimentally overexpressing PCTAIRE1 in these cells caused p27 Ser10 phosphorylation , and reduced p27 protein levels in a proteasome dependent manner .|PCTAIRE1 phosphorylates p27 at Ser 10. 0.333 SIGNOR-278214 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 22944199 NO gcesareni In explant cultures of mouse paraxial mesoderm, Wnt1 induced expression of the MRF Myf5, whereas Wnt7a or Wnt6 preferentially activated the MRF MyoD 0.337 SIGNOR-198849 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr317 PPTPGNTyQIPRTFP 9606 BTO:0000007 19881549 YES lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis 0.703 SIGNOR-236306 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser183 PTQQYAKsLPVSVPV -1 SIGNOR-C3 SIGNOR-C3 18372248 YES lperfetto Pras40 functions as a negative regulator when bound to mtorc1, and it dissociates from mtorc1 in response to insulin. Pras40 has been demonstrated to be a substrate of mtorc1, and one phosphorylation site, ser-183, has been identified. 0.904 SIGNOR-178120 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr201 DQTPLAIyNSISYKT 9534 BTO:0000298 17027227 YES Site of Jak2 tyrosine autophosphorylation; namely, tyrosine 201. Jak2 tyrosine residue 201 was the principal mediator of SHP-2 binding as conversion of this tyrosine residue to phenylalanine abolished this interaction 0.2 SIGNOR-251360 PPBP protein P02775 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.383 SIGNOR-258413 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.732 SIGNOR-253681 hsa-mir-223 mirna URS000037EC34_9606 RNAcentral CARM1 protein Q86X55 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 24332853 YES miannu PRMT4 is downregulated by miR-223 during normal myeloid differentiation 0.4 SIGNOR-261970 2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester chemical CHEBI:95001 ChEBI CETP protein P11597 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191265 TLRs proteinfamily SIGNOR-PF20 SIGNOR TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 YES gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.2 SIGNOR-252095 Ub:E2 complex SIGNOR-C497 SIGNOR MEX3C protein Q5U5Q3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271030 CAPRIN2 protein Q6IMN6 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 19619488 YES gcesareni A cytoplasmic protein in vertebrates, referred to as caprin-2, binds to lrp6 and facilitates lrp6 phosphorylation by gsk3 0.358 SIGNOR-187177 ISCU protein Q9H1K1 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 YES lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. 0.699 SIGNOR-262128 Ub:E2 complex SIGNOR-C497 SIGNOR ZNF598 protein Q86UK7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271185 PTGER2 protein P43116 UNIPROT GNAS protein P63092 UNIPROT up-regulates binding 9606 16293724 YES gcesareni Pge2 receptors are coupled to the g protein gs, which causes accumulation of cyclic adenosine monophosphate (camp) and activates protein kinase a (pka), we confirmed that pge2 treatment or transfection of cells with the active catalytic subunit of pka also stimulated the activity of a camp-responsive-elementdriven reporter gene (cre-luc). 0.433 SIGNOR-141597 SRC protein P12931 UNIPROT DNM2 protein P50570 UNIPROT down-regulates activity phosphorylation Tyr597 NTEQRNVyKDLRQIE 10090 BTO:0000944 33113375 YES miannu We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G). 0.558 SIGNOR-277539 SLBP protein Q14493 UNIPROT H2BE1 protein A0A2R8Y619 UNIPROT up-regulates quantity by expression translation regulation 9606 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265380 ZBTB20 protein Q9HC78 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23776228 YES miannu ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to IκBα gene promoter (+1 to +60 region) after TLR activation. ZBTB20 could inhibit IκBα gene transcription, govern IκBα protein expression, and then promote NF-κB activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor IκBα gene transcription. 0.259 SIGNOR-266868 LATS1 protein O95835 UNIPROT CDC26 protein Q8NHZ8 UNIPROT up-regulates activity phosphorylation Thr7 tRLELKLD 25723520 YES lperfetto LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C|Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly 0.466 SIGNOR-275472 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 10090 BTO:0000887 24145169 NO The BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling 0.2 SIGNOR-256487 PTK2B protein Q14289 UNIPROT ASAP2 protein O43150 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10022920 YES miannu Tyrosine phosphorylation of Pap by Pyk2 or Src kinases. We have identified a new Pyk2 binding protein designated Pap. Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. We demonstrate that Pap forms a stable complex with Pyk2 and that activation of Pyk2 leads to tyrosine phosphorylation of Pap in living cells. 0.526 SIGNOR-269704 RPS6KA4 protein O75676 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19797274 NO gcesareni Mitogen- and stress-activated kinase 2 (msk2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, msk2 selectively suppressed the expression of a subset of p53 target genes.Msk2 can also control the the transcriptional activity of p53 in a kinase-indipendent mannermsk2 can also control the the transcriptional activity of p53 in a kinase-indipendent manner 0.249 SIGNOR-188334 CALM3 protein P0DP25 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 YES miannu The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases 0.609 SIGNOR-266344 AMPK complex SIGNOR-C15 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr101 IVLNKGKtIFRFSAT 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.318 SIGNOR-275769 WKYMVm chemical CID:457933 PUBCHEM FPR2 protein P25090 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257493 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.497 SIGNOR-248798 ABCA1 protein O95477 UNIPROT APOA1 protein P02647 UNIPROT up-regulates activity binding 9606 15347662 YES miannu The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 forms a high affinity complex with apoA-I by binding amphipathic helices within the apolipoprotein. VFVNFA sequence is required for ABCA1 to form a complex with apoA-I and to transfer cholesterol to the apolipoprotein. 0.789 SIGNOR-252100 MAPK1 protein P28482 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0001260 10514499 YES lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. 0.538 SIGNOR-71033 ITGB6 protein P18564 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.869 SIGNOR-253210 DTX1 protein Q86Y01 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 11564735 YES gcesareni We found that a significant fraction of dtx1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300. 0.381 SIGNOR-110629 CDON protein Q4KMG0 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR form complex binding 10090 21664576 YES lperfetto Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands. 0.569 SIGNOR-209596 PDZD11 protein Q5EBL8 UNIPROT TSPAN33 protein Q86UF1 UNIPROT up-regulates activity binding 10116 BTO:0003618 30463011 YES Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33 0.329 SIGNOR-261252 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 16293724 YES lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. 0.894 SIGNOR-227889 DDHD1 protein Q8NEL9 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269653 ARFGAP1 protein Q8N6T3 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 22363216 YES The effect has been demonstrated using Q8N6T3-2 flangone The gtp hydrolysis activity of lrrk2 is markedly enhanced by arfgap1 supporting a role for arfgap1 as a gtpase-activating protein for lrrk2.Lrrk2 and arfgap1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at golgi membranes 0.58 SIGNOR-196264 PRKACA protein P17612 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT down-regulates activity phosphorylation Thr108 SPRAWRRPtIESHHVAI 10116 10187789 YES In vitro, CaMKK is phosphorylated by PKA and this is associated with inhibition of enzyme activity. The major site of phosphorylation is threonine 108, although additional sites are phosphorylated with lower efficiency. 0.2 SIGNOR-256115 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-268072 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Thr516 GASKRLQtICMSGTG 9606 20448038 YES lperfetto Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation. 0.372 SIGNOR-165237 GATA6 protein Q92908 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression 9606 BTO:0000195 24317510 NO lperfetto Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. 0.278 SIGNOR-253153 MAPK3 protein P27361 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 YES lperfetto The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity. 0.289 SIGNOR-133276 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 12591950 YES lperfetto Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58) 0.2 SIGNOR-98392 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr327 PLLREETyDVPPAFA 9606 12601080 YES lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. 0.256 SIGNOR-98500 POU3F2 protein P20265 UNIPROT POU3F2 protein P20265 UNIPROT up-regulates activity binding 9606 11029584 YES miannu These experiments lead to the conclusion that the full-length Brn-2 protein can interact with full-length Brn-2. Assay of homodimerization properties of Brn-2 protein on the b2s1 dimer recognition sequence also demonstrated cooperativity, indicating that protein-protein contacts would be important for synergistic interactions between the Brn-2 subunits. 0.2 SIGNOR-221824 MAD2L2 protein Q9UI95 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity binding -1 11459826 YES miannu The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1 0.543 SIGNOR-264902 AURKB protein Q96GD4 UNIPROT SSU72 protein Q9NP77 UNIPROT down-regulates quantity by destabilization phosphorylation Ser19 CSSNQNRsMEAHNIL 24149858 YES lperfetto Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. 0.254 SIGNOR-275529 PRKCD protein Q05655 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 YES gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). 0.588 SIGNOR-154791 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 YES lperfetto Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.547 SIGNOR-204716 DEF6 protein Q9H4E7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 18976935 YES lperfetto Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. 0.392 SIGNOR-253369 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.552 SIGNOR-89166 MLNR protein O43193 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257132 LMO3 protein Q8TAP4 UNIPROT ASCL1 protein P50553 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21573214 NO miannu Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1. 0.361 SIGNOR-254825 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR2B protein P31323 UNIPROT down-regulates activity chemical inhibition 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.8 SIGNOR-258762 ATR protein Q13535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation Ser179 FRPEYSAsQLKGFSL 9606 BTO:0000018 33811702 YES miannu Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site-specific phosphorylation inactivates PARP1, inhibiting ionophore-induced necrosis. 0.357 SIGNOR-277551 FOXL2 protein P58012 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000975 16153597 NO miannu We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2 0.7 SIGNOR-140391 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BCL6 protein P41182 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0000785 9649500 YES inferred from 70% family members gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. 0.2 SIGNOR-270011 ZNF165 protein P49910 UNIPROT SMURF2 protein Q9HAU4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 26567849 YES Luana ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1. 0.268 SIGNOR-266095 MAP2K6 protein P52564 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9534 9430721 YES Luana The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms 0.744 SIGNOR-260721 mTORC1 complex SIGNOR-C3 SIGNOR PPARG protein P37231 UNIPROT up-regulates quantity by expression 10090 19593385 NO lperfetto Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation. 0.446 SIGNOR-235343 ATR protein Q13535 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates phosphorylation Ser516 VHPPLPIsQSPENES 9606 4709074 YES lperfetto Mll is phosphorylated at serine 516 by atr in response to genotoxic stress in the s phase, which disrupts its interaction with, and hence its degradation by, the scf(skp2) e3 ligase, leading to its accumulation. 0.281 SIGNOR-25151 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SCNN1B protein P51168 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 YES inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. 0.2 SIGNOR-270050 AKT2 protein P31751 UNIPROT YBX2 protein Q9Y2T7 UNIPROT up-regulates quantity by stabilization phosphorylation Ser137 NPRKFLRsVGDGETV 10090 BTO:0006430 37860762 YES miannu In this context, YBX2 is a dual substrate for both AMPK and Akt2. The phosphorylation at Thr115 by AMPK or at Ser137 by Akt2 facilitates YBX2 accumulation in brown adipocytes by decreasing ubiquitination-mediated degradation.  0.2 SIGNOR-277869 GFI1 protein Q99684 UNIPROT EGR2 protein P11161 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 NO irozzo Importantly, overexpression of Gfi-1 in these cells resulted in the attenuation of both Egr-1 and Egr-2 expression, but not Nab-2. 0.31 SIGNOR-256133 sertindole chemical CHEBI:9122 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258843 SRC protein P12931 UNIPROT DLG4 protein P78352 UNIPROT up-regulates phosphorylation Tyr523 REDSVLSyETVTQME 9606 24981431 YES llicata These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission. 0.566 SIGNOR-205120 BAG4 protein O95429 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity binding 10090 BTO:0000801 12748303 YES gcesareni It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation 0.646 SIGNOR-245022 NOX3 protein Q9HBY0 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.7 SIGNOR-264715 mTORC1 complex SIGNOR-C3 SIGNOR PIP4K2C protein Q8TBX8 UNIPROT up-regulates quantity phosphorylation Ser328 LVGSYGTsPEGIGGY 9606 BTO:0000567 25372051 YES miannu  PIP4kγ was phosphorylated by mTORC1 and associated with the complex. Phosphorylated PIP4kγ was enriched in light microsomal vesicles, whereas the unphosphorylated form was enriched in heavy microsomal vesicles associated with the Golgi.  0.284 SIGNOR-273681 KLHL6 protein Q8WZ60 UNIPROT CDK2 protein P24941 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000775 29720484 YES miannu We confirmed the formation of ubiquitin and CDK2 by different systems and further identified the E3 ligase KLHL6 as a mediator of the ubiquitination and degradation of CDK2.  0.2 SIGNOR-272310 GCK protein P35557 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266448 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr771 ADIESSNyMAPYDNY -1 7545675 YES Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides 0.749 SIGNOR-248669 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Thr260 QPWNSDStLNSRQLE 9606 19468302 YES llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. 0.639 SIGNOR-185758 S100G protein P29377 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 31731478 YES miannu Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. 0.8 SIGNOR-268517 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266466 clofarabine chemical CHEBI:681569 ChEBI POLB protein P06746 UNIPROT down-regulates activity chemical inhibition 9606 1707752 YES miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. 0.8 SIGNOR-258358 Histone H2B proteinfamily SIGNOR-PF68 SIGNOR RNF168 protein Q8IYW5 UNIPROT up-regulates binding 9606 19203578 YES gcesareni Rnf168 is recruited to sites of dna damage by binding to ubiquitylated histone h2a. 0.2 SIGNOR-265372 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9534 BTO:0000298 8557118 YES lperfetto PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. 0.365 SIGNOR-248938 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser8 MPLNRTLsMSSLPGL -1 6263629 YES A reinvestigation of the phosphorylation of Rabbit Skeletal-muscle glycogen synthase by cyclic AMP dependent Protein Kinase: identification of the third site of phosphorylation at Serine-7 0.507 SIGNOR-253008 RAP1GAP protein P47736 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity binding 9606 BTO:0001949 22173489 YES Marta Tosoni Overexpression of Rap1GAP significantly inhibited Rap1 activation, ERK and Akt phosphorylation of HUVECs compared with pcDNA transfection controls 0.306 SIGNOR-278056 naloxone chemical CHEBI:7459 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258770 PRCP protein P42785 UNIPROT POMC protein P01189 UNIPROT down-regulates activity 10090 20694162 NO miannu Prolylcarboxypeptidase (PRCP) was found to be responsible for the control of food intake and energy expenditure at a central level. The molecular mechanisms underlying the suppression of food intake in PRCP-deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of α-MSH 0.298 SIGNOR-252372 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser345 ELLCLRRsSLKAYGN -1 1848190 YES lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. 0.352 SIGNOR-248857 CKMT1A protein P12532 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265790 HERC2 protein O95714 UNIPROT USP20 protein Q9Y2K6 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 25355518 YES miannu USP20 is regulated by HERC2 following DNA damage or replication stress.The HECT domain of WT HERC but not the catalytic inactive mutant (CA) ubiquitinated USP20 in vitro (Figure ​(Figure4G).4G). Taken together, these results suggested that HERC2 functions as an E3 ligase of USP20 and negatively regulates USP20 in unstressed cells. 0.373 SIGNOR-272820 SQSTM1 protein Q13501 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 19765191 YES P00441:p.Ala5Val (mutation causing interaction)  This study provides a novel molecular mechanism by which mutant SOD1 can be recognized by p62 in an ubiquitin-independent fashion and targeted for the autophagy-lysosome degradation pathway. 0.514 SIGNOR-262801 EIF3_complex complex SIGNOR-C401 SIGNOR EIF1 protein P41567 UNIPROT up-regulates activity stabilization 9606 17581632 YES lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 0.604 SIGNOR-269152 PRKAA1 protein Q13131 UNIPROT G6PC1 protein P35575 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21892142 NO gcesareni Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation 0.2 SIGNOR-176475 GPR35 protein Q9HC97 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257112 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270400 mTORC1 complex SIGNOR-C3 SIGNOR Lysosome fusion phenotype SIGNOR-PH231 SIGNOR down-regulates activity 9606 39000072 NO miannu The fusion of matured macropinosomes with lysosomes is promoted by TRPML1, and degradation of macropinosomes is inhibited by mTORC1. 0.7 SIGNOR-277786 WNK4 protein Q96J92 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates activity phosphorylation Thr50 SHLTHSStFCMRTFG -1 22342722 YES Q9BYP7:p.Glu562Lys (mutation causing interaction);Q9BYP7:p.Asp564Ala (mutation causing interaction);Q9BYP7:p.Gln565Glu (mutation causing interaction) lperfetto Threonine 48 was identified as the WNK4 phosphorylation site at mouse NCC|. Thus, WNK4 stimulates NCC in three ways: (1) direct phosphorylation and in turn increasing NCC protein abundance; (2) facilitating the phosphorylation of NCC by SPAK/OSR1 indirectly, and (3) phosphorylating and activating SPAK/OSR1.|Evidences from early studies using Xenopus oocytes and mammalian cells indicate that WNK4 inhibits NCC and PHAII-causing mutations relieve the inhibition 0.58 SIGNOR-264631 NPLOC4 protein Q8TAT6 UNIPROT UFD1 protein Q92890 UNIPROT up-regulates activity binding 9606 20442859 YES miannu These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes. 0.2 SIGNOR-252422 GALR3 protein O60755 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.289 SIGNOR-257206 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT up-regulates activity phosphorylation Ser25 PELLVVGsRPELGRW 9606 BTO:0000007 21728993 YES miannu We demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser(25) as the residue involved in this modification. We also show that Ser(25) is phosphorylated both in vitro and in vivo by AMPK. Lastly, we demonstrate that this residue plays a critical role for both the phosphatase activity and the ability of laforin to interact with itself and with previously established binding partners. 0.351 SIGNOR-277830 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0000222 BTO:0000887;BTO:0001103 18676376 YES gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.703 SIGNOR-179796 ITGB1BP1 protein O14713 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257644 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000527;BTO:0000017 9890893 YES lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). 0.76 SIGNOR-236392 TWIST2 protein Q8WVJ9 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255499 BMP7 protein P18075 UNIPROT ACTR2 protein P61160 UNIPROT up-regulates binding 9606 16446785 YES acerquone The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2 0.289 SIGNOR-144144 PI-103 chemical CHEBI:90524 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206172 (S)-duloxetine chemical CHEBI:36795 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 18387300 YES Luana Selective inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake (SNRI) has been shown to be an attractive dual pharmacology approach for the treatment of a number of diseases.1,2 For example, dual 5- HT/NA reuptake inhibitor duloxetine (1) has shown clinical efficacy in the treatment of depression, pain, and urinary incontinence. 0.8 SIGNOR-257776 TACR1 protein P25103 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.431 SIGNOR-257423 eribulin mesylate chemical CHEBI:70710 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 16940412 YES miannu The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. 0.8 SIGNOR-259345 CTNNB1 protein P35222 UNIPROT SCRIB protein Q14160 UNIPROT up-regulates activity binding 9606 BTO:0000938 21255999 YES miannu Cadherins mediate the localization of vesicles to presynaptic compartments through multiple mechanisms. Cadherin-bound β-catenin then recruits scribble (Scrib) which acts as a scaffold for the further recruitment of proteins that mediate the localization of SVs. 0.434 SIGNOR-265826 Dinaciclib chemical CID:46926350 PUBCHEM CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191331 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.2 SIGNOR-269171 Stress_granules phenotype SIGNOR-PH124 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 27920254 NO miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. 0.7 SIGNOR-260865 CSNK1A1 protein P48729 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Ser12 FSLHDALsGSGNPNP -1 8253806 YES llicata L-29, a soluble lactose-binding lectin, is phosphorylated on serine 6 and serine 12 in vivo and by casein kinase I. 0.309 SIGNOR-250789 WNT11 protein O96014 UNIPROT FZD6 protein O60353 UNIPROT up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 YES gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. 0.671 SIGNOR-141431 PAK2 protein Q13177 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity phosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 YES miannu P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. 0.36 SIGNOR-277182 STUB1 protein Q9UNE7 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19536328 YES miannu CHIP can ubiquitinate LRRK2.|These results indicate that both the chaperone interaction and the ubiquitin ligase activity of CHIP are required for CHIP mediated degradation of LRRK2 protein. 0.434 SIGNOR-278615 REST protein Q13127 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 10449787 NO miannu We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity. 0.293 SIGNOR-220698 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000017 28192398 YES miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  0.48 SIGNOR-277344 EIF4B protein P23588 UNIPROT 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.2 SIGNOR-269165 Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 NO lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). 0.7 SIGNOR-262138 TNF protein P01375 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 17350185 NO Luana TNF-alpha represses the activity of a human Bmp4 promoter-luciferase construct, transfected into A549 and H441 cells. 0.315 SIGNOR-266085 MAPK1 protein P28482 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 YES llicata Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. 0.407 SIGNOR-80092 TACR3 protein P29371 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.283 SIGNOR-257389 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 18550549 YES gcesareni Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144. 0.272 SIGNOR-178888 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10116 9428795 YES We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU) 0.46 SIGNOR-251655 CSK protein P41240 UNIPROT EEF2 protein P13639 UNIPROT down-regulates quantity phosphorylation 9606 24648518 YES miannu C-terminal Src kinase (Csk)-mediated phosphorylation of eukaryotic elongation factor 2 (eEF2) promotes proteolytic cleavage and nuclear translocation of eEF2.|In this report, we show that eukaryotic elongation factor 2 (eEF2) is a new protein substrate of Csk and could locate in the nucleus. 0.264 SIGNOR-279698 CCR4-NOT complex complex SIGNOR-C439 SIGNOR PUM1 protein Q14671 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 YES lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins 0.366 SIGNOR-268351 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates activity phosphorylation Ser715 MQLEEQAsRQISSKK 9606 BTO:0002181 26206521 YES miannu Active PLK1, in turn, phosphorylates MCAK at Ser715 which promotes its microtubule depolymerase activity essential for faithful chromosome segregation. 0.811 SIGNOR-276931 PRKAG1 protein P54619 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates binding 9606 16054041 YES gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. 0.897 SIGNOR-139173 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 YES apalma Numb is an inhibitor of Notch signaling that interacts with the intracellular portion of Notch and antagonizes its activity by preventing nuclear translocation 0.797 SIGNOR-255374 AKT proteinfamily SIGNOR-PF24 SIGNOR PALLD protein Q8WX93 UNIPROT unknown phosphorylation Ser1118 VRRPRSRsRDSGDEN 9606 20471940 YES llicata Akt1, but not akt2, phosphorylates palladin at ser507 in a domain that is critical for f-actin bundling. 0.2 SIGNOR-165497 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 YES lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins 0.2 SIGNOR-244148 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000975 11018021 YES lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. 0.748 SIGNOR-244945 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 2155236 YES miannu GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments. 0.283 SIGNOR-249713 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser126 NPEAESSsKEGELDA -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.628 SIGNOR-276123 POMC protein P01189 UNIPROT MC3R protein P41968 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.758 SIGNOR-268705 Aldolase proteinfamily SIGNOR-PF75 SIGNOR glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266486 AKT1 protein P31749 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 YES lperfetto The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate 0.437 SIGNOR-252559 G3BP2 protein Q9UN86 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity binding 9606 BTO:0002181 17297477 YES miannu G3BP2 binds to MDM2 and decreases its E3 ligase activity. The G3BP2 isoform additionally associated with murine double minute 2 (MDM2), a negative regulator of p53. G3BP2 expression resulted in significant reduction in MDM2-mediated p53 ubiquitylation and degradation. 0.3 SIGNOR-278892 PTCHD1 protein Q96NR3 UNIPROT VPS35 protein Q96QK1 UNIPROT up-regulates quantity binding 10090 BTO:0000142 29118110 YES miannu Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus 0.2 SIGNOR-266653 CDK1 protein P06493 UNIPROT VHL protein P40337 UNIPROT down-regulates quantity by destabilization phosphorylation Ser80 QVIFCNRsPRVVLPV 9606 BTO:0000815 36813923 YES miannu  Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1. PIN1 then binds to phosphorylated pVHL and facilitates the recruitment of the E3 ligase WSB1, therefore targeting pVHL for ubiquitination and degradation.  0.2 SIGNOR-277836 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser748 DSEGFEDsFEEEEEE 9606 BTO:0000599 23287549 YES lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. 0.2 SIGNOR-265272 PRKCD protein Q05655 UNIPROT PTPRA protein P18433 UNIPROT up-regulates activity phosphorylation Ser213 PLLARSPsTNRKYPP 9606 11676480 YES lperfetto In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232. 0.329 SIGNOR-249114 p38 proteinfamily SIGNOR-PF16 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10116 15486195 YES miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. 0.2 SIGNOR-260443 KLF4 protein O43474 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002104 23370975 NO miannu The expression of superoxide dismutase (SOD) 1 in both mRNA and protein levels was found to be decreased by overexpressing KLF4, while increased by knockdown of KLF4 0.291 SIGNOR-254545 PRKDC protein P78527 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR form complex binding 9606 17308091 YES miannu Complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established 0.935 SIGNOR-226026 PPP3CB protein P16298 UNIPROT FLNA protein P21333 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 YES Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation. 0.2 SIGNOR-248362 pipamperone chemical CHEBI:78549 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258572 STAT6 protein P42226 UNIPROT ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 NO apalma Cytokines like IL-4 or IL-13 lead to STAT6 phosphorylation with consecutive arginase expression and varying further aspects of M2 polarization (mannose receptor, Ym1, Fizz1) 0.407 SIGNOR-255557 CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 NO fspada Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma). 0.539 SIGNOR-80592 RARB protein P10826 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. 0.681 SIGNOR-16519 PRKAA1 protein Q13131 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 SIGNOR-C15 21892142 YES gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). 0.274 SIGNOR-176487 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.564 SIGNOR-161553 CSF1 protein P09603 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 YES gcesareni A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (gcsf) and a ligand binding region of gcsf receptor (gcsf-r), has been determined to 2.8 a resolution 0.321 SIGNOR-144737 SETBP1 protein Q9Y6X0 UNIPROT SET protein Q01105 UNIPROT up-regulates binding 9606 22566606 YES miannu Setbp1 was shown to form a complex with set and pp2a, enhancing the stability of set and its inhibition of pp2a. 0.479 SIGNOR-197324 CAMK2A protein Q9UQM7 UNIPROT ITGB1BP1 protein O14713 UNIPROT up-regulates activity phosphorylation Thr38 GGLSRSStVASLDTD 9813144 YES llicata The point mutation T38D localized within the optimal CaMKII recognition motif of ICAP-1alpha results in a strong defect in cell spreading which cannot be overcome by the inhibition of the endogenous CaMKII. This fact strongly suggests that the phosphorylation of Threonine 38 by CaMKII modulates the alpha5beta1 integrin function. Conversely, the mutation T38A produces an analog of ICAP-1alpha that cannot be phosphorylated and that stimulates cell spreading on fibronectin to a similar extent when CaMKII is inhibited. 0.307 SIGNOR-250632 DGC complex SIGNOR-C217 SIGNOR GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates quantity binding 9606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265441 MIB1 protein Q86YT6 UNIPROT SMN1 protein Q16637 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23615451 YES miannu In this study, we show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. Knocking down Mib1 levels increases SMN protein levels in cultured cells.  0.324 SIGNOR-272664 MAPK10 protein P53779 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 24610780 YES lperfetto Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. is regulated by jnk3 via phosphorylation of app at thr668 0.58 SIGNOR-204671 TCF3 protein P15923 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887 1649701 YES E12/E47-like proteins interact in vivo with the myogenic HLH proteins MyoD and myogenin lperfetto In addition we demonstrate that myod, in conjunction with e12/e47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators. 0.805 SIGNOR-20540 HAND2 protein P61296 UNIPROT HAND2 protein P61296 UNIPROT up-regulates activity binding -1 11812799 YES miannu The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer 0.2 SIGNOR-223476 GHSR protein Q92847 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257255 CSNK2A1 protein P68400 UNIPROT PSMA3 protein P25788 UNIPROT unknown phosphorylation Ser243 AEKYAKEsLKEEDES -1 8619999 YES llicata Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery. 0.382 SIGNOR-250938 INPPL1 protein O15357 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates 9606 18486448 NO gcesareni Ship2 positively modulated the mlk3/jip1-mediated jnk1 activation 0.2 SIGNOR-178652 DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates 9606 26527132 NO lperfetto Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair. 0.7 SIGNOR-242616 MAPK8 protein P45983 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD 9606 12351702 YES gcesareni Taken together, these findings suggest that jnk-mediated phosphorylation of the gr-ser226 enhances gr nuclear export and may contribute to termination of gr-mediated transcription. 0.637 SIGNOR-93558 RIMBP3B protein A6NNM3 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.345 SIGNOR-264364 H3-4 protein Q16695 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 YES miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 0.2 SIGNOR-263725 MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Ser474 RTHFPQFsYSASIRE 9606 12181443 NO lperfetto We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek. 0.426 SIGNOR-91408 CSNK2A1 protein P68400 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.286 SIGNOR-250831 DKK1 protein O94907 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 NO Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass. 0.733 SIGNOR-195573 AMBRA1 protein Q9C0C7 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity binding 9606 BTO:0000567 25438055 YES phosphorylation site remapping based on mass spec table lperfetto We found that AMBRA1 favours the interaction between c-Myc and its phosphatase PP2A and that, when mTOR is inhibited, it enhances PP2A activity on this specific target, thereby reducing the cell division rate. As expected, such a de-regulation of c-Myc correlates with increased tumorigenesis in AMBRA1-defective systems, thus supporting a role for AMBRA1 as a haploinsufficient tumour suppressor gene. 0.2 SIGNOR-272964 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr288 IDDNEYAyLKAIIFF 9606 22308320 YES lperfetto Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function. 0.365 SIGNOR-195900 MKRN1 protein Q9UHC7 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys291 TEEENLRkKGEPHHE 9606 BTO:0002552 19536131 YES miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53 0.432 SIGNOR-271846 RHOA protein P61586 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates binding 9606 11102529 YES gcesareni Our results demonstrate that direct stimulation of pld1 in vivo by rhoa 0.696 SIGNOR-84953 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 10660534 YES lperfetto Rlk phosphorylated the N-terminal region of SLP-76, a region that has been previously shown to serve as a target for ZAP-70. Loss of N-terminal YESP/YEPP sites of SLP-76 or the Rlk kinase activity attenuated cooperativity between Rlk and SLP-76 0.727 SIGNOR-246929 CEP76 protein Q8TAP6 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity binding 9606 BTO:0001938 27065329 YES miannu Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. 0.431 SIGNOR-262731 SERPINC1 protein P01008 UNIPROT F9 protein P00740 UNIPROT down-regulates activity cleavage 31030036 YES lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 0.897 SIGNOR-264140 RNF7 protein Q9UBF6 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates activity ubiquitination 9606 23136067 YES miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 0.299 SIGNOR-271449 MED7 protein O43513 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.852 SIGNOR-266657 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Thr345 GADSDVEtPSNFGKY 9606 BTO:0000007 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.301 SIGNOR-262984 NF1 protein P21359 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 7549116 NO miannu Our results pointed to a key role that NF1 might play in the functioning of the AFP promoter. Indeed, overexpression of NF1 induced a specific decrease in the activity of the AFP promoter. Competition between NF1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter would be critical for modulating its activity. 0.271 SIGNOR-254636 WNT7A protein O00755 UNIPROT SPRY4 protein Q9C004 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002058 15705594 NO miannu In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity. 0.275 SIGNOR-253034 MAPK8 protein P45983 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 15538382 YES lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. 0.713 SIGNOR-252964 SS18L1 protein O75177 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates relocalization 9606 BTO:0000938 15488321 YES miannu The calcium-responsive transactivator recruits creb binding protein to nuclear bodies. 0.398 SIGNOR-129926 1-naphthol chemical CHEBI:10319 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258163 BLM protein P54132 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 28912125 NO miannu The BLM gene product, BLM, is a RECQ helicase that is involved in DNA replication and repair of DNA double-strand breaks by the homologous recombination (HR) pathway. During HR, BLM has both pro- and anti-recombinogenic activities, either of which may contribute to maintenance of genomic integrity. 0.7 SIGNOR-261824 IL2RB protein P14784 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 YES milica In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain 0.63 SIGNOR-204972 YES1 protein P07947 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 BTO:0000578 35041461 YES miannu Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). 0.72 SIGNOR-277653 WNT9A protein O14904 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.621 SIGNOR-132070 SMARCD2 protein Q92925 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.749 SIGNOR-270733 MAP1LC3C protein Q9BXW4 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates binding 9606 BTO:0000007 19250911 YES gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. . downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1. 0.531 SIGNOR-184258 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser36 AQQVSSLsESEESQD 9606 20730097 YES lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf1 0.2 SIGNOR-167560 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Thr114 TMPDDLLtTLDDTCD 9606 BTO:0002181 25795775 YES miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA.  0.2 SIGNOR-276449 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation 9606 18694962 YES Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. 0.2 SIGNOR-269996 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 NO miannu Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton 0.7 SIGNOR-266597 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258252 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 12172553 YES gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. 0.728 SIGNOR-91388 METTL3 protein Q86U44 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000567 27117702 YES miannu Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.  0.2 SIGNOR-265955 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763 12193595 YES miannu Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction. 0.721 SIGNOR-91722 NEK2 protein P51955 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 24695856 YES lperfetto Our data support a model in which centrosome disjunction is triggered by the hyperphosphorylation of c-nap1, a major linker component. This occurs in response to a shift in the balance of activities of the nek2?_Pp1 bi-stable switch. C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro. 0.773 SIGNOR-204833 MRPL48 protein Q96GC5 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.681 SIGNOR-262348 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR ERO1A protein Q96HE7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 27855403 YES miannu Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex 0.2 SIGNOR-272332 ODC1 protein P11926 UNIPROT putrescine smallmolecule CHEBI:17148 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) 0.8 SIGNOR-256034 DDIT3 protein P35638 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 YES miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. 0.455 SIGNOR-260173 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys673 KFDVEVLkQLLKLLP 9606 BTO:0000007 28448495 YES miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 0.2 SIGNOR-272804 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCE protein Q02156 UNIPROT up-regulates activity binding 9606 14967450 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. 0.8 SIGNOR-242590 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 10660596 YES gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. 0.897 SIGNOR-74860 PTK2 protein Q05397 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates activity phosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0004055 11369769 YES lperfetto The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (fak).Tyrosine phosphorylation reduced the amount of alpha-actinin that cosedimented with actin filaments. 0.573 SIGNOR-108329 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 9606 BTO:0000887 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.274 SIGNOR-163768 PLRG1 protein O43660 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR form complex binding 9606 BTO:0000567 20176811 YES miannu In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27. 0.801 SIGNOR-271969 DCAF7 protein P61962 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates activity binding 9534 BTO:0000298 14593110 YES miannu Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions. 0.73 SIGNOR-260631 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 15766588 YES gcesareni Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22. 0.934 SIGNOR-134524 MAPK10 protein P53779 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 YES Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191 0.2 SIGNOR-124005 SMARCB1 protein Q12824 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.849 SIGNOR-270737 PLCG1 protein P19174 UNIPROT ITPRIPL1 protein Q6GPH6 UNIPROT up-regulates 9606 BTO:0000938 21368195 NO gcesareni Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores 0.2 SIGNOR-172500 FCRL3 protein Q96P31 UNIPROT SYK protein P43405 UNIPROT up-regulates activity binding -1 12051764 YES miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. 0.353 SIGNOR-274011 FZD7 protein O75084 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 23290138 NO Simone Vumbaca We observed that overexpression of Fzd7 or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts 0.453 SIGNOR-255647 AMPK complex SIGNOR-C15 SIGNOR WDR45 protein Q9Y484 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 28561066 YES miannu WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes. 0.314 SIGNOR-268480 Ub:E2 complex SIGNOR-C497 SIGNOR RNF186 protein Q9NXI6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271074 TCOF1 protein Q13428 UNIPROT NBN protein O60934 UNIPROT up-regulates activity relocalization 9606 25064736 YES lperfetto We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent. 0.319 SIGNOR-265085 KRAS protein P01116 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000797 27340238 NO These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein. 0.7 SIGNOR-259372 PTPN11 protein Q06124 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 YES Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. 0.68 SIGNOR-252094 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257968 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii 0.777 SIGNOR-203544 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0000567 10806207 YES llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. 0.603 SIGNOR-77204 MYOD1 protein P15172 UNIPROT SMARCA4 protein P51532 UNIPROT up-regulates binding 9606 SIGNOR-C92 17194702 YES miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes 0.529 SIGNOR-151685 PIM1 protein P11309 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation 9606 25280219 YES FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells 0.696 SIGNOR-261557 BAG3 protein O95817 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates activity binding -1 27474740 YES lperfetto Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70. 0.788 SIGNOR-254116 MARK2 protein Q7KZI7 UNIPROT UTRN protein P46939 UNIPROT up-regulates phosphorylation Ser1258 TLEERMKsTEVLPEK 9606 BTO:0000887;BTO:0001103 19945424 YES lperfetto Par-1b, interacts with the utrophin-dg complex, and positively regulates the interaction between utrophin and dg. Ser1258 within r9 is specifically phosphorylated by par-1b. 0.425 SIGNOR-161915 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity dephosphorylation Thr387 TMKRRDEtMQPAKPS 9606 20513427 YES PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. 0.295 SIGNOR-248329 GSK3A protein P49840 UNIPROT PKD2 protein Q13563 UNIPROT unknown phosphorylation Ser76 AGAAASPsPPLSSCS 9606 BTO:0000007 BTO:0000671 16551655 YES llicata We report the identification of a new phosphorylation site for pc2 within its n-terminal domain (ser(76)) and demonstrate that this residue is phosphorylated by glycogen synthase kinase 3 (gsk3). 0.2 SIGNOR-145306 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser327 DPEMEEDsYDSFGEP -1 9558331 YES llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. 0.365 SIGNOR-250800 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Thr178 NHNHRIRtNPAIVKT 10090 BTO:0001103 17609368 YES gcesareni AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter 0.502 SIGNOR-228642 ETF1 protein P62495 UNIPROT Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR form complex binding 9606 29735640 YES miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. 0.973 SIGNOR-270813 ARF6 protein P62330 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 14973189 NO lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface 0.7 SIGNOR-272154 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 YES lperfetto Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation. 0.805 SIGNOR-235709 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser464 DKEGLSEsVRSSCTL 9606 20643644 YES Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. 0.2 SIGNOR-260796 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM71 protein Q2Q1W2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271014 BDKRB2 protein P30411 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256974 FGF4 protein P08620 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 YES gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. 0.671 SIGNOR-18567 PRKAB1 protein Q9Y478 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 21460634 YES gcesareni Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition 0.536 SIGNOR-173044 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-252815 vinorelbine L-tartrate chemical CHEBI:32296 ChEBI TUBB protein P07437 UNIPROT down-regulates activity chemical inhibition 9606 7740336 YES miannu Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) and paclitaxel (Taxol; Bristol-Myers Oncology, Princeton, NJ) as single-agent therapy exhibit good activity in breast and lung cancers. Because these agents bind to distinct sites on tubulin and affect microtubules in opposite ways, a pilot study was conducted of the combination of vinorelbine and paclitaxel in patients with metastatic breast cancer or lung cancer who were refractory to first-line chemotherapy. 0.8 SIGNOR-259348 STAT6 protein P42226 UNIPROT RETN protein Q9HD89 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 NO lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. 0.313 SIGNOR-249536 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 YES miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. 0.276 SIGNOR-262868 TNF protein P01375 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.252 SIGNOR-253479 AURKA protein O14965 UNIPROT PIN1 protein Q13526 UNIPROT down-regulates activity phosphorylation Ser16 PGWEKRMsRSSGRVY 9606 23970419 YES llicata Here, we found that aurora a can interact with and phosphorylate pin1 at ser16, which suppresses the g2/m function of pin1 by disrupting its binding ability and mitotic entry. 0.254 SIGNOR-202487 atomoxetine chemical CHEBI:127342 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 9871604 YES miannu The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. 0.8 SIGNOR-259067 MCHR2 protein Q969V1 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257334 naltrexone chemical CHEBI:7465 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258936 MCU protein Q8NE86 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.706 SIGNOR-270874 SRC protein P12931 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT 9606 BTO:0000776 10880360 YES lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell linesyrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. 0.585 SIGNOR-247119 ATG5 protein Q9H1Y0 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR form complex binding 9606 BTO:0000007 18321988 YES lperfetto Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex). 0.949 SIGNOR-226693 SOX9 protein P48436 UNIPROT OTX2 protein P32243 UNIPROT up-regulates activity binding 10090 20530484 YES miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. 0.349 SIGNOR-255184 TUT7 protein Q5VYS8 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 NO lperfetto Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. 0.7 SIGNOR-268345 PIK3R1 protein P27986 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 YES lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.722 SIGNOR-242646 SNCA protein P37840 UNIPROT VAMP2 protein P63027 UNIPROT down-regulates quantity binding 9606 BTO:0000938 31110017 YES miannu The normal function of the small presynaptic protein α-synuclein (α-syn) is of exceptional interest, not only in the context of neurodegeneration, but also as a cytosolic regulator of neurotransmission. we show that α-syn-VAMP2 interactions are necessary for α-syn-induced synaptic attenuation. Our data connect divergent views and suggest a unified model of α-syn function. the data indicate that α-syn–VAMP2 binding is essential for α-syn function and advocate an “interlocking model” where α-syn multimers on the SV surface interact with VAMP2 on adjacent SVs, helping to maintain physiologic SV clustering. 0.401 SIGNOR-264104 Enolase proteinfamily SIGNOR-PF74 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 BTO:0000318 2005901 YES inferred from family member Luana This result suggests that MBP-1 in vivo acts as a sequence-specific repressor. 0.2 SIGNOR-270308 HCRTR1 protein O43613 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257128 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 YES miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. 0.2 SIGNOR-159476 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1125 APSRDPHyQDPHSTA 9606 8845374 YES lperfetto The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site 0.624 SIGNOR-44247 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10980595 YES llicata We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway 0.729 SIGNOR-81460 MC4R protein P32245 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257336 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr720 IPKEPSNyDFVYDCN 9606 15952790 YES llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. 0.605 SIGNOR-138158 ACTL6A protein O96019 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.827 SIGNOR-270712 FGR protein P09769 UNIPROT FGR protein P09769 UNIPROT up-regulates activity phosphorylation Tyr412 RLIKDDEyNPCQGSK -1 8612628 YES Autophosphorylation of c-Fgr under basal conditions involves Tyr-400 (homologous of c-Src Tyr-416) but not, to any appreciable extent, Tyr-511. Both Tyr-511 and Tyr-400, however, incorporate phosphate if autophosphorylation is performed in the presence of polycationic peptides, such as polylysine, histones H1 and protamines. Such a double phosphorylation induced by polylysine gives rise to an upshifted form of c-Fgr on SDS-PAGE and correlates with a stimulation of catalytic activity instead of a down-regulation 0.2 SIGNOR-251143 IC-87114 chemical CHEBI:90686 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206187 PARVA protein Q9NVD7 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 YES lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. 0.73 SIGNOR-265761 TGFB1 protein P01137 UNIPROT TAGLN protein Q01995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20846954 NO Regulation miannu We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. 0.338 SIGNOR-251924 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120012 SLBP protein Q14493 UNIPROT H2AC18 protein Q6FI13 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265396 PRKCA protein P17252 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation Ser657 QSDFEGFsYVNPQFV 9606 15277524 YES lperfetto Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function 0.2 SIGNOR-127253 GLI2 protein P10070 UNIPROT GLI1 protein P08151 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 NO lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. 0.456 SIGNOR-209629 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates phosphorylation 9606 18596912 YES lbriganti The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform 0.458 SIGNOR-210182 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 9606 23817177 YES irozzo RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity. 0.566 SIGNOR-255708 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 19933840 YES lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction 0.2 SIGNOR-216572 SOSTDC1 protein Q6X4U4 UNIPROT WNT3 protein P56703 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.278 SIGNOR-242730 WNT8A protein Q9H1J5 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.632 SIGNOR-131987 EEF2K protein O00418 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser445 SGDSGYPsEKRGELD 9606 22669845 YES gcesareni The combination of eef2k autophosphorylation (targeting ser445) and a yet to be identified kinase (targeting ser441) would be needed to generate the eef2k phosphodegron specifically in response to dna damage. 0.2 SIGNOR-197725 GATA3 protein P23771 UNIPROT CD8A protein P01732 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8413295 NO miannu Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity. 0.306 SIGNOR-254079 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr525 ALRADENyYKAQTHG 9606 9820500 YES lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 0.2 SIGNOR-246617 ATG9A protein Q7Z3C6 UNIPROT YWHAE protein P62258 UNIPROT up-regulates activity binding 9606 25266655 YES miannu Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. 0.2 SIGNOR-266368 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257925 MARCHF9 protein Q86YJ5 UNIPROT PTPRJ protein Q12913 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271535 sapropterin smallmolecule CHEBI:59560 ChEBI GCHFR protein P30047 UNIPROT up-regulates activity chemical activation 9606 11361142 YES miannu The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine 0.8 SIGNOR-252204 STAT1 protein P42224 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR form complex binding -1 8943351 YES 2 miannu The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3 0.684 SIGNOR-240606 SMURF1 protein Q9HCE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 YES Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps 0.707 SIGNOR-195660 nintedanib chemical CHEBI:85164 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 18559524 YES Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. 0.8 SIGNOR-257802 PLEKHG3 protein A1L390 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.355 SIGNOR-260585 GSDMD protein P57764 UNIPROT Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates cleavage:Asp275 CLHNFLTdGVPAEGA 26375003 NO lperfetto These results establish that proteolytic cleavage at Asp275 in GSDMDis sufficient to instructmammalian cells to undergo pyroptosis 0.7 SIGNOR-256416 CHUK protein O15111 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 9606 20300203 YES gcesareni The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta. 0.784 SIGNOR-164506 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM JAK3 protein P52333 UNIPROT down-regulates activity chemical inhibition -1 24556163 YES miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 0.8 SIGNOR-262234 RXRA protein P19793 UNIPROT PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR up-regulates activity binding 10090 17613434 YES irozzo RXR Binding Increases the DNA-Binding Affinity of PML/RARA. Here, we demonstrate that the presence of the RARA heterodimeric partner RXR in the PML/RARA complex is required for leukemogenesis in transgenic mice. RXR greatly facilitates the binding of PML/RARA to DNA, but titration of RXR by PML/RARA could also contribute to transformation. 0.2 SIGNOR-255804 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 YES The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5. Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD. 0.41 SIGNOR-261543 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 9606 15379552 YES lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) 0.2 SIGNOR-129196 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT up-regulates activity phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 BTO:0000452 8702790 YES lperfetto These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation. 0.2 SIGNOR-43088 SRC protein P12931 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000763 14978237 YES lperfetto The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation. 0.56 SIGNOR-235696 PLK1 protein P53350 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19473992 NO lperfetto Plk1-mediated phosphorylation of topors regulates p53 stability. Herein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. 0.577 SIGNOR-185841 AURKB protein Q96GD4 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates phosphorylation Ser109 KETNRRKsLHPIHQG 9606 20471944 YES lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). 0.651 SIGNOR-165550 SKA complex complex SIGNOR-C364 SIGNOR Ndc80 complex complex SIGNOR-C361 SIGNOR up-regulates activity relocalization -1 22483620 YES lperfetto The Ska complex is an essential mitotic component required for accurate cell division in human cells. It is composed of three subunits that function together to establish stable kinetochore-microtubule interactions in concert with the Ndc80 network. |We discuss how this symmetric architecture might complement and stabilize the Ndc80-microtubule attachments 0.554 SIGNOR-265225 GNB5 protein O14775 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity binding 9606 BTO:0004032 21303898 YES miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC 0.479 SIGNOR-267850 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.762 SIGNOR-252485 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Ser2070 DEYNVTPsPPGTVLT 9606 BTO:0000007 12794074 YES Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes. 0.482 SIGNOR-251254 TNFAIP1 protein Q13829 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity binding 9606 19782033 YES miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. 0.35 SIGNOR-264235 CDK1 protein P06493 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Thr92 EVPDVTAtPARLLFF 9606 SIGNOR-C17 20526282 YES gcesareni Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons. 0.461 SIGNOR-165867 MAPK1 protein P28482 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 YES lperfetto Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity 0.37 SIGNOR-161851 EEF1A1P5 protein Q5VTE0 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269552 CRP protein P02741 UNIPROT GCH1 protein P30793 UNIPROT down-regulates activity 9606 BTO:0004602 17942113 NO miannu The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP-mediated pathway. In the present study, CRP-mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues. 0.278 SIGNOR-252215 S1PR5 protein Q9H228 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.49 SIGNOR-256676 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18854138 NO lperfetto Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. 0.598 SIGNOR-181624 MRPL47 protein Q9HD33 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.728 SIGNOR-262349 CREB1 protein P16220 UNIPROT GDA protein Q9Y2T3 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0000938 BTO:0000142 21715638 YES lperfetto In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches. 0.2 SIGNOR-268968 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 12167717 NO lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, 0.791 SIGNOR-252710 NTNG2 protein Q96CW9 UNIPROT LRRC4 protein Q9HBW1 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 YES miannu The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. 0.73 SIGNOR-264048 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 YES gcesareni The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation. 0.323 SIGNOR-70603 EGFR protein P00533 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Tyr228 YPGGSDNyGSLSRVT 9606 BTO:0000017 14996911 YES llicata In A431 cells, epidermal growth factor induced striking p120 phosphorylation at Y228. Y228-phosphorylated p120 localized to adherens junctions and lamellipodia, and was significantly enhanced in cells around the colony periphery. 0.64 SIGNOR-251092 ECSIT protein Q9BQ95 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 22588174 YES Giorgia ECSIT interacts with IPS-1|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation 0.429 SIGNOR-260371 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 12438563 YES gcesareni Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (4345) is required for signal transduction 0.886 SIGNOR-95626 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000150 10550055 YES gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. 0.497 SIGNOR-72083 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST -1 17711846 YES done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). 0.41 SIGNOR-274096 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 YES gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 0.751 SIGNOR-249654 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT up-regulates activity deacetylation Lys63 TGGMANVkAAPKIID 9606 BTO:0002806 30327428 YES miannu SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR 0.512 SIGNOR-262293 AKAP12 protein Q02952 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity relocalization 14657015 YES lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. 0.2 SIGNOR-271835 SCN3A protein Q9NY46 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 NO miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. 0.7 SIGNOR-253455 AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity relocalization 9606 25720354 YES scontino APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place. 0.8 SIGNOR-267862 ING2 protein Q9H160 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001913 19437536 NO miannu ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression. 0.385 SIGNOR-254491 GSK3B protein P49841 UNIPROT DPYSL5 protein Q9BPU6 UNIPROT up-regulates activity phosphorylation Thr516 TPLADTPtRPVTRHG 9606 BTO:0000938 25040932 YES lperfetto The T516 phosphorylation was achieved by the glycogen synthase kinase-3beta (GSK-3beta), which can phosphorylate the wildtype protein but not the non-phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin-binding property of CRMP5. Therefore, CRMP5-induced growth inhibition is dependent on T516 phosphorylation through the GSK-3beta pathway. 0.43 SIGNOR-264835 FBXO15 protein Q8NCQ5 UNIPROT CRLS1 protein Q9UJA2 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0005816 24703837 YES miannu Fbxo15 Targets CLS1 Protein for Ubiquitination and Degradation to Disrupt Mitochondrial Function. S. aureus infection induces expression of a kinase, PINK1, that phosphorylates an indispensable protein CLS1, which in turn triggers CLS1 ubiquitination and degradation by the F box protein (SCFFbxo15). 0.334 SIGNOR-272170 IL22 protein Q9GZX6 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 17208301 YES gcesareni See table 2 0.695 SIGNOR-151880 G6PD protein P11413 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI up-regulates quantity chemical modification 9606 24769394 YES miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress 0.8 SIGNOR-267051 CHD2 protein O14647 UNIPROT XRCC4 protein Q13426 UNIPROT up-regulates quantity relocalization 9606 BTO:0001938 26895424 YES miannu CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs. 0.2 SIGNOR-264528 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser408 GPLPRAPsISTVEPK 26843621 YES Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. 0.297 SIGNOR-253540 ITK protein Q08881 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 YES lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2 0.2 SIGNOR-112475 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203588 MRGPRX1 protein Q96LB2 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257433 FRG1 protein Q14331 UNIPROT KMT5B protein Q4FZB7 UNIPROT down-regulates activity binding 10090 BTO:0000165 23720823 YES miannu Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. 0.2 SIGNOR-266639 RXRB protein P28702 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. 0.714 SIGNOR-16683 SAICAR(4-) smallmolecule CHEBI:58443 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 22812634 YES miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case 0.8 SIGNOR-268068 ASXL1 protein Q8IXJ9 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 YES irozzo In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells. 0.285 SIGNOR-255911 PCSK5 protein Q92824 UNIPROT Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 YES miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. 0.2 SIGNOR-270336 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 10976919 YES inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr 0.653 SIGNOR-267805 MC3R protein P41968 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257298 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 9748228 YES fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 0.702 SIGNOR-60174 CXCL8 protein P10145 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252288 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 YES milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). 0.675 SIGNOR-204841 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA7 protein Q9Y5G6 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265687 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 YES gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.613 SIGNOR-84050 VEGFD protein O43915 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252278 MET protein P08581 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 22128289 YES irozzo For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS. 0.694 SIGNOR-256261 PRKCB protein P05771 UNIPROT protein Q5T7P8 UNIPROT up-regulates activity phosphorylation Thr417 RRLKKKKtTIKKNTL 9606 BTO:0001277 16111671 YES miannu We have previously reported that synaptotagmin VI is present in human sperm cells and that a recombinant protein containing the C2A and C2B domains abrogates acrosomal exocytosis in permeabilized spermatozoa, an effect that was regulated by phosphorylation. We found by site-directed mutagenesis that Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain--a key region for the function of synaptotagmins--are the PKC target that regulates its inhibitory effect on acrosomal exocytosis. Similarly, we showed that Thr284 in the polybasic region of C2A (KCKLQTR) is the target for PKC-mediated phosphorylation in this domain. 0.2 SIGNOR-273564 DUSP9 protein Q99956 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 21908610 YES gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. 0.698 SIGNOR-176583 CSNK1E protein P49674 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation 9606 11524435 YES gcesareni Tcf3 is a substrate for both glycogen synthase kinase (gsk) 3 and casein kinase (ck) 1epsilon, and phosphorylation of tcf3 by ckiepsilon stimulates its binding to beta-catenin, an effect reversed by gsk3. 0.2 SIGNOR-110056 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation 10029 BTO:0000246 15379552 YES inferred from 70% family members lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.2 SIGNOR-270060 GAB2 protein Q9UQC2 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12819203 YES gcesareni Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2we propose that gab1 and gab2 in cooperation with other adapter molecules might regulate the cellular localization of gc-gap under specific stimuli. 0.375 SIGNOR-102628 FGF2 protein P09038 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004473 19049325 NO miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. 0.257 SIGNOR-252191 ELOVL4 protein Q9GZR5 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267899 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR VEPH1 protein Q14D04 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 NO In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 0.2 SIGNOR-269959 MAPK14 protein Q16539 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Thr311 NSLALSLtADQMVSA 9606 12138194 YES gcesareni P38 mitogen-activated protein kinase was involved in estrogen receptor activation by estrogens and mekk1. Here, we report estrogen receptor-dependent p38 activation by estrogens in endometrial adenocarcinoma cells and in vitro and in vivo phosphorylation of the estrogen receptor alpha mediated through p38. The phosphorylation site was identified as threonine-311 (thr(311)), located in helix 1 of the hormone-binding domain. 0.624 SIGNOR-90823 PTPRG protein P23470 UNIPROT PTPRG protein P23470 UNIPROT down-regulates activity binding 9606 25624455 YES miannu The main regulatory mechanism of RPTP activity consists of the reversible transition from a homodimeric inactive form to a monomeric active form. PTPRG is constitutively expressed on monocyte plasma membrane as a homodimer with the WD involved in catalytic domain blockade. 0.2 SIGNOR-254737 NFATC4 protein Q14934 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21871017 YES miannu NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration 0.282 SIGNOR-264027 CAMK2A protein Q9UQM7 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT down-regulates activity phosphorylation Thr591 LKQGYNKtLLRLRLR -1 37193065 YES miannu CaM inhibits the function of TRPP3 through promoting CaMK2's phosphorylation towards T591 on TRPP3. 0.2 SIGNOR-277798 PTH1R protein Q03431 UNIPROT SLC34A3 protein Q8N130 UNIPROT down-regulates quantity 28363951 NO lperfetto PTH inhibits reabsorption of phosphate from the glomerular filtrate in RPT by decreasing the abundance of sodium-phosphate co-transporters NPT2a and NPT2c on the apical membrane, thus enhancing renal phosphate excretion 0.343 SIGNOR-270557 SRC protein P12931 UNIPROT ARHGEF4 protein Q9NR80 UNIPROT up-regulates phosphorylation Tyr165 VGSEEDLyDDLHSSS 9606 BTO:0000017 18653540 YES llicata This observation strongly argues for the positive role of tyr94 phosphorylation in egf-induced asef activation following the activation of rac1. 0.312 SIGNOR-179601 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9009272 YES miannu For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system. 0.8 SIGNOR-258580 SMARCA2 protein P51531 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates binding 9606 10078207 YES miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. 0.911 SIGNOR-65432 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2G1 protein P62253 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.762 SIGNOR-271315 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr141 EDEAKFPtMNRRGAI 9606 19366211 YES llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. a t141d substitution markedly increases basal lipid-independent pkcdelta activity; 0.2 SIGNOR-185279 bromocriptine chemical CHEBI:3181 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258722 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 9545235 YES lperfetto IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspasesThese findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis 0.922 SIGNOR-56484 NFYC protein Q13952 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 NO miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 0.301 SIGNOR-254433 Ub:E2 complex SIGNOR-C497 SIGNOR SIAH2 protein O43255 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271121 DAGLA protein Q9Y4D2 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI down-regulates quantity chemical modification 9606 26787883 YES miannu Diacylglycerol lipases (DAGL√鬱 and DAGL√é¬≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. 0.8 SIGNOR-264262 NFIL3 protein Q16649 UNIPROT IL3 protein P08700 UNIPROT up-regulates quantity by expression transcriptional regulation 9580 7565758 YES Luana NF-IL3A transactivates the IL-3 promoter through the A region sequences. 0.528 SIGNOR-266222 VTN protein P04004 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 BTO:0000007 7559467 YES lperfetto The human integrin alpha 8 beta 1 functions as a receptor for tenascin, fibronectin, and vitronectin. 0.577 SIGNOR-253307 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates chemical activation 9606 16014605 YES gcesareni Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors. 0.8 SIGNOR-138585 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.4 SIGNOR-259015 FYN protein P06241 UNIPROT PTPRF protein P10586 UNIPROT up-regulates activity phosphorylation 9534 12496362 YES LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. we confirmed that LAR dephosphorylated the phosphorylated tyrosine residues of Lck and Fyn, and tyrosine residue(s) in LAR PTPase D2 was phosphorylated by Fyn to supply Fyn SH2 binding site. 0.397 SIGNOR-251180 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 YES llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  0.365 SIGNOR-250803 NARS1 protein O43776 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270457 PPARG protein P37231 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 32991581 YES brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, 0.903 SIGNOR-263984 LTN1 protein O94822 UNIPROT RQC complex complex SIGNOR-C559 SIGNOR form complex binding 28528489 YES lperfetto The ribosome-bound quality control (RQC) complex is a multi-protein complex conserved throughout eukaryotes and composed of the E3 ubiquitin ligase Ltn1/Listerin, the ATPase Cdc48/p97 with its co-factors Ufd1/UFD1L and Npl4/NPLOC4, as well as the factors Rqc1/TCF25 and Rqc2/NEMF (Fig. 1). 0.496 SIGNOR-277694 RPL27 protein P61353 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.851 SIGNOR-262474 FOS protein P01100 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 YES miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.259 SIGNOR-254878 MAPK14 protein Q16539 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation 9606 7479834 YES gcesareni Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression. 0.626 SIGNOR-26511 IFNG protein P01579 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000801 2114181 NO Regulation miannu Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. The data indicate that IFN-gamma is inhibiting macrophage LPL at least in part via a reduction of LPL synthesis 0.355 SIGNOR-251848 AIRE protein O43918 UNIPROT ICA1 protein Q05084 UNIPROT down-regulates quantity by repression transcriptional regulation 22447927 YES lperfetto Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression. 0.362 SIGNOR-268973 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT up-regulates quantity transcriptional regulation 9606 31257023 NO Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. 0.678 SIGNOR-259334 Ast-487 chemical CID:11409972 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259693 PGK1 protein P00558 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. 0.8 SIGNOR-266502 GCSAM protein Q8N6F7 UNIPROT GRB2 protein P62993 UNIPROT down-regulates activity binding 9606 31362927 YES miannu Herein, we demonstrate that the adaptor protein HGAL, specifically expressed in GC lymphocytes and GC-derived lymphomas, directly binds to Grb2 upon BCR activation and negates the inhibitory effects of Grb2 on the BCR-induced biochemical signaling cascade.  0.2 SIGNOR-273608 MAPK1 protein P28482 UNIPROT DYNC1LI1 protein Q9Y6G9 UNIPROT unknown phosphorylation Ser516 VSPTTPTsPTEGEAS 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.255 SIGNOR-262773 FOXA1 protein P55317 UNIPROT SFTPB protein P07988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 18003659 NO miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. 0.283 SIGNOR-254171 MARCHF5 protein Q9NX47 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 20103533 YES lperfetto MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. 0.2 SIGNOR-272981 BMI1 protein P35226 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20551323 NO gcesareni One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf 0.456 SIGNOR-259359 ROCK1 protein Q13464 UNIPROT RDX protein P35241 UNIPROT up-regulates activity phosphorylation Thr564 AGRDKYKtLRQIRQG 10090 BTO:0005065 9456324 YES lperfetto  A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad. | In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active. 0.679 SIGNOR-248994 MED10 protein Q9BTT4 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.849 SIGNOR-266656 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys22 GPRDGLKkERLLDDR 9606 7479976 YES gcesareni Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. 0.541 SIGNOR-26577 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 10197981 YES llicata Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain. 0.745 SIGNOR-66746 PLK1 protein P53350 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Ser1618 LTKAADIsLDNLVEG -1 24703952 YES lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Addition of the inhibitors for PLK1 and the p38 MAPK leads to a complete loss of pT1609/pS1618 signal within 3 hr in mitotic cells 0.597 SIGNOR-264413 CEP72 protein Q9P209 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 YES lperfetto By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically. 0.662 SIGNOR-271720 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr106 EDPVTVEyITRYIAS 9606 25620702 YES Manara PSMA7 degradation is suppressed by c-Abl-mediated tyrosine phosphorylation at Y106 0.398 SIGNOR-260937 RORA protein P35398 UNIPROT SLC1A6 protein P48664 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 YES miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 0.251 SIGNOR-266850 PLK1 protein P53350 UNIPROT WDCP protein Q9H6R7 UNIPROT up-regulates activity phosphorylation Ser695 SHSPGAVsSLKVFTG 9606 BTO:0000007 30297404 YES miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. we performed in vitro kinase assays followed by mass spectrometry and found that two sites (S686 and S695) in this cluster were phosphorylated. Thus, all of these results are in agreement that this cluster is phosphorylated by PLK1. 0.2 SIGNOR-273731 AKT proteinfamily SIGNOR-PF24 SIGNOR TP53RK protein Q96S44 UNIPROT up-regulates phosphorylation Ser250 RLRGRKRsMVG 9606 17712528 YES gcesareni Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250. 0.2 SIGNOR-157467 TGFB1 protein P01137 UNIPROT TSHB protein P01222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14623893 YES miannu TGF-β inhibits thyroid-stimulated hormone (TSH)-induced NIS mRNA and protein levels in a dose-dependent manner. This effect takes place at the transcriptional level, as TGF-β inhibits TSH-induced transcription 0.2 SIGNOR-251991 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 11777359 YES rheumatoid arthritis gcesareni 0.8 SIGNOR-251699 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.604 SIGNOR-263435 GSK3B protein P49841 UNIPROT OGT protein O15294 UNIPROT up-regulates activity phosphorylation Ser3 sSVGNVAD 10090 BTO:0000142 23395175 YES miannu We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation. 0.516 SIGNOR-276482 PI4KA protein P42356 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269096 TGFb proteinfamily SIGNOR-PF5 SIGNOR SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 30017632 NO miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. 0.629 SIGNOR-260428 FGFR2 protein P21802 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates 10090 BTO:0000011 12270934 NO lperfetto  Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors 0.302 SIGNOR-235337 IRF9 protein Q00978 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR form complex binding -1 8943351 YES 2 miannu The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3 0.868 SIGNOR-240600 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 19346248 YES lperfetto The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo. 0.384 SIGNOR-217556 ATAT1 protein Q5SQI0 UNIPROT TUBA3E protein Q6PEY2 UNIPROT up-regulates quantity by stabilization acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 YES lperfetto Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules 0.267 SIGNOR-272248 SH3RF1 protein Q7Z6J0 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 9482736 YES gcesareni Posh activates jnk1 in cos-1 cells. 0.371 SIGNOR-55759 MDM2 protein Q00987 UNIPROT POLQ protein O75417 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001890 22056306 YES miannu DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation 0.2 SIGNOR-272729 PRKAA1 protein Q13131 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 SIGNOR-C15 21892142 YES gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). 0.274 SIGNOR-176491 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 9606 16874298 YES lperfetto The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo 0.618 SIGNOR-148319 PPP1CC protein P36873 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 21750978 YES miannu Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway 0.33 SIGNOR-174865 COX7A2 protein P14406 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.487 SIGNOR-267741 CDK5 protein Q00535 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr514 TTTPKGGtPAGSARG 9606 16611631 YES lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.602 SIGNOR-145971 ULK1 protein O75385 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation 9606 29671878 YES miannu In the nucleation step of autophagy, The ULK1 complex phosphorylates and activates the Beclin-1-VPS34 complex. 0.77 SIGNOR-278503 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process 0.43 SIGNOR-171050 PPP1CA protein P62136 UNIPROT PREX1 protein Q8TCU6 UNIPROT up-regulates activity dephosphorylation Ser1165 DSGHDTMsYRDSYSE 9606 22242915 YES lperfetto MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation. 0.2 SIGNOR-277023 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 YES miannu Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). 0.2 SIGNOR-260084 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT down-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 452646 11551945 YES miannu MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription 0.611 SIGNOR-250146 TNK1 protein Q13470 UNIPROT TNK1 protein Q13470 UNIPROT up-regulates activity phosphorylation Tyr277 LGGARGRyVMGGPRP -1 36334623 YES done miannu  We found a similar reduction in the levels of phosphorylation of Tyr277, which corresponds to the predicted major site of autophosphorylation within the activation loop of Tnk1 (Fig. 3C).  0.2 SIGNOR-274126 CDK5 protein Q00535 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Thr135 TVQQHPStPKRHTVL 9606 BTO:0000007 21209322 YES lperfetto High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. n hek293 cells, mass spectrometry shows phosphorylation of tonebp/orebp-s120, -s134, -t135, and -s155. 0.2 SIGNOR-170886 MAPK1 protein P28482 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr201 DIPEKPKtPQQLWYT 9606 11741541 YES lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna 0.394 SIGNOR-112809 IL33 protein O95760 UNIPROT IL1RL1 protein Q01638 UNIPROT up-regulates activity binding 9606 BTO:0001679 16286016 YES miannu We report a member of the IL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs.The binding of IL-33 to cells that express ST2 results in the activation of NF-κB and MAP kinases. Administration of purified IL-33 either in vitro or in vivo leads to the production of TH2-associated cytokines. 0.925 SIGNOR-277711 SMURF1 protein Q9HCE7 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity ubiquitination 9606 22298955 YES lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. 0.614 SIGNOR-195672 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 15549093 NO lperfetto The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary 0.7 SIGNOR-251496 PPARA protein Q07869 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16556735 YES miannu We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. 0.595 SIGNOR-268024 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation 9606 16456541 YES inferred from 70% family members gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. 0.2 SIGNOR-270196 GABRB3 protein P28472 UNIPROT GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR form complex binding 9606 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.465 SIGNOR-263747 DYNLL1 protein P63167 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates binding 9606 20921139 YES gcesareni The beclin 1vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1interacting protein ambra1 and dynein light chains 1/2. 0.55 SIGNOR-168255 DDB1 protein Q16531 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 BTO:0000567 9418871 YES miannu We show that ddb, a putative dna repair protein, associates with the activation domain of e2f1 / expression of ddb specifically stimulated e2f1-activated transcription 0.352 SIGNOR-54096 LAMTOR5 protein O43504 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 22740693 NO miannu It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. 0.364 SIGNOR-255248 SLBP protein Q14493 UNIPROT H4C1 protein P62805 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265376 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT2 protein P31751 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000782 25336630 YES miannu stimulations were performed in the presence or absence of Akt inhibitor VIII, which selectively inhibits Akt1/Akt2 activity. 0.8 SIGNOR-262228 SOX9 protein P48436 UNIPROT COL9A2 protein Q14055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 NO miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. 0.355 SIGNOR-251757 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 YES miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation. 0.765 SIGNOR-260165 sorafenib tosylate chemical CHEBI:50928 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 0.8 SIGNOR-259221 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Ser246 CPRLRIFsHPNVLPV 9606 17420447 YES lperfetto We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin. 0.41 SIGNOR-154303 BRAP protein Q7Z569 UNIPROT BRAP protein Q7Z569 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23105109 YES miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. 0.2 SIGNOR-272027 LSM8 protein O95777 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.83 SIGNOR-270626 AKT1 protein P31749 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 YES lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta 0.658 SIGNOR-217460 MDN1 protein Q9NU22 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 27814492 YES miannu MDN1 Is Physically and Functionally Associated with the Mammalian PELP1 Complex. To more specifically determine a function of mammalian MDN1 in the subnuclear distribution of PELP1-containing pre-60S-particles, we examined PELP1 localization in control cells or cells depleted from MDN1. Importantly, in the absence of MDN1, PELP1 became sequestered in enlarged nucleoli, indicating that MDN1 is involved in the nucleolar release of PELP1-containing pre-60S ribosomes 0.378 SIGNOR-261357 STAT3 protein P40763 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 10090 11426647 NO Constitutive activation of Stat3 signaling is accompanied by upregulation of cyclin D1, c-Myc, and Bcl-x, changes consistent with subversion of normal cellular growth and survival control mechanisms. 0.7 SIGNOR-252090 EGR2 protein P11161 UNIPROT NAB2 protein Q15742 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 20506119 NO miannu In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression. 0.577 SIGNOR-253885 GATA1 protein P15976 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12359731 NO miannu Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter. 0.281 SIGNOR-254158 APOC2 protein P02655 UNIPROT LPL protein P06858 UNIPROT up-regulates activity 9606 19956660 NO Regulation miannu Triglycerides in VLDL are hydrolyzed by lipoprotein lipase, which in turn is activated by apolipoprotein CII on the surface but inhibited by apolipoprotein CIII. 0.763 SIGNOR-251846 SMARCC1 protein Q92922 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.82 SIGNOR-270736 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser144 NSDESNFsEKLRAST 9606 BTO:0000007 16818229 YES miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. 0.772 SIGNOR-276289 STAT1 protein P42224 UNIPROT TAP1 protein Q03518 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15778351 NO miannu We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. 0.273 SIGNOR-254531 DAPK3 protein O43293 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 16219639 YES miannu ZIPK phosphorylated STAT3 on serine 727 (Ser727) and enhanced STAT3 transcriptional activity. 0.402 SIGNOR-279702 HTR2C protein P28335 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257129 AS-605240 chemical CID:5289247 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189921 UGP2 protein Q16851 UNIPROT UTP(4-) smallmolecule CHEBI:46398 ChEBI down-regulates quantity chemical modification 9606 8631325 YES miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. 0.8 SIGNOR-267927 STAT1 protein P42224 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 NO T-bet is a transcription factor detected in Th1, but not in Th0 or Th2 cells. Its expression is up-regulated by IFN-gamma, through a STAT-1-dependent mechanism 0.491 SIGNOR-254293 MAPK1 protein P28482 UNIPROT TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000567 21617040 YES gcesareni Evidence for ERK2-mediated TFEB phosphorylation came from ERK2-TFEB coimmuno-precipitation (fig. S12C) in normal but not in starved medium and from a peptide-based kinase assay showing that mutation of Ser142 to alanine abolished ERK2-mediated phosphorylation ( 0.414 SIGNOR-248279 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr732 CSSAQAQyDTPKAGK -1 23770091 YES done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. 0.351 SIGNOR-273947 LZTR1 protein Q8N653 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity ubiquitination Lys170 IRQYRLKkISKEEKT 9606 BTO:0000007 30442762 YES Gianni By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. 0.25 SIGNOR-269068 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 YES lperfetto Erk phosphorylates threonine 42 residue of ribosomal protein s3. 0.2 SIGNOR-137955 LAMA3 protein Q16787 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR form complex binding 9211848 YES lperfetto Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2. 0.576 SIGNOR-253235 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu59 HLERECMeETCSYEE -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263668 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 16508002 YES gcesareni Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. 0.644 SIGNOR-144827 PSMD11 protein O00231 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.904 SIGNOR-263351 SRC protein P12931 UNIPROT CEACAM1 protein P13688 UNIPROT up-regulates activity phosphorylation Tyr520 LTATEIIySEVKKQ 9606 BTO:0000007 9867848 YES lperfetto Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515 0.426 SIGNOR-246475 LATS1 protein O95835 UNIPROT AMOT protein Q4VCS5 UNIPROT up-regulates quantity by stabilization phosphorylation Ser175 QGHVRSLsERLMQMS 24101513 YES lperfetto Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130 0.523 SIGNOR-275843 DUSP16 protein Q9BY84 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 11359773 YES gcesareni Mkp-7 binds to and inactivates p38 mapk and jnk/sapk, but not erk inhibited by dual specificity phosphatases, such as dusp1, dusp10, and dusp16(uniprot) 0.804 SIGNOR-108233 DYRK1A protein Q13627 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity phosphorylation Thr163 TDGSLPStPPPAEEE 9606 32587776 YES miannu Furthermore, DYRK1A likely directly bound and phosphorylated Mcl-1, thereby enhancing Mcl-1 protein stability and contributing to the development of acquired resistance to Bcl-2 inhibitors.|DYRK1A upregulates Mcl-1 expression in NSCLC cells.|We demonstrated that DYRK1A suppression by siRNA or harmine decreased the phosphorylation of Mcl-1 at Ser159/Thr163. 0.2 SIGNOR-279703 ATM protein Q13315 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 9606 18769144 YES lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively 0.403 SIGNOR-180747 MAPK3 protein P27361 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser674 QSPKRPRsPGSNSKV 9606 10648599 YES lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. 0.375 SIGNOR-74308 LRRK2 protein Q5S007 UNIPROT ARFGAP1 protein Q8N6T3 UNIPROT down-regulates phosphorylation 9606 22423108 YES gcesareni Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid. 0.58 SIGNOR-196732 trichostatin A chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258015 PAK6 protein Q9NQU5 UNIPROT PACSIN1 protein Q9BY11 UNIPROT up-regulates activity phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 YES miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 0.2 SIGNOR-263021 MLF1 protein P58340 UNIPROT COPS3 protein Q9UNS2 UNIPROT up-regulates binding 9606 15861129 YES miannu As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53 0.403 SIGNOR-135937 RFWD3 protein Q6PCD5 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity ubiquitination 9606 33842359 YES miannu Rad51 directly interacts with the N-terminal of RFWD3 and is ubiquitinated by RFWD3. 0.402 SIGNOR-278543 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation 9606 22094256 YES tpavlidou We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1, thereby maintain expression of g1/s phase genes, suppress the levels of reactive oxygen species (ros), and protect cancer cells from senescence. 0.623 SIGNOR-177266 α-D-glucose smallmolecule CHEBI:17925 ChEBI alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266450 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.2 SIGNOR-251444 AURKB protein Q96GD4 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates phosphorylation Ser100 RQSWRRAsMKETNRR 9606 20471944 YES lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). 0.651 SIGNOR-165546 PAMPs stimulus SIGNOR-ST11 SIGNOR COLEC11 protein Q9BWP8 UNIPROT up-regulates activity binding -1 20956340 YES lperfetto We finally show that CL-11 binds to intact bacteria, fungi, and viruses and that CL-11 decreases influenza A virus infectivity and forms complexes with DNA|it is conceivable that CL-11 plays a role in activation of the complement system and in the defense against invading microorganisms. 0.7 SIGNOR-263408 MIF protein P14174 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 10090 17435771 YES gcesareni We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. 0.382 SIGNOR-252061 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr382 DHYRYSDtTDSDPEN 9606 21779440 YES gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity 0.605 SIGNOR-161122 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 20640476 YES lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 0.502 SIGNOR-209940 JUN protein P05412 UNIPROT SPI1 protein P17947 UNIPROT up-regulates activity binding 9606 BTO:0004136 12393465 YES apalma These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1. 0.556 SIGNOR-255660 tiagabine chemical CHEBI:9586 ChEBI SLC6A1 protein P30531 UNIPROT down-regulates activity chemical inhibition -1 7851497 YES miannu Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. 0.8 SIGNOR-258477 DDX23 protein Q9BUQ8 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.728 SIGNOR-270646 PLEKHG4B protein Q96PX9 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.285 SIGNOR-260565 PLK1 protein P53350 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 24413556 YES miannu Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis. 0.2 SIGNOR-275421 MRPS9 protein P82933 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.78 SIGNOR-261438 HIF1A protein Q16665 UNIPROT FAM162A protein Q96A26 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15082785 YES Giulio In this work, we report the identification of an HIF-1 alpha-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1 alpha through a hypoxia-responsive element on the HGTD-P promoter region. 0.282 SIGNOR-260292 MMP9 protein P14780 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272399 CACNA1A protein O00555 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 YES miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). 0.8 SIGNOR-264323 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR RBBP8 protein Q99708 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 27561354 YES miannu  Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. 0.281 SIGNOR-272412 CSNK1A1 protein P48729 UNIPROT CBX4 protein O00257 UNIPROT down-regulates quantity by destabilization phosphorylation Thr437 ARSISTPtCLGGSPA 9606 BTO:0002181 32111827 YES miannu The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.  0.2 SIGNOR-277512 AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSSN 10116 11069105 YES AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. AMPK-mediated PFK-2 activation is likely to be involved in the stimulation of heart glycolysis during ischaemia. 0.405 SIGNOR-260011 SRC protein P12931 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates activity phosphorylation Tyr14 VDSEGHLyTVPIREQ 9606 12921535 YES lperfetto Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn 0.763 SIGNOR-118007 STAT5A protein P42229 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 10050749 YES lperfetto Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α 0.433 SIGNOR-251743 CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22198637 YES lperfetto Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 0.516 SIGNOR-253713 PPP2CB protein P62714 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.507 SIGNOR-248614 MAPK3 protein P27361 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Ser780 DSLDSRLsPPAGLFT 9606 BTO:0000975 10194762 YES gcesareni Serine 780 is the only substrate in full-length stat5a for active erk 0.705 SIGNOR-66247 PPP1R14B protein Q96C90 UNIPROT PPP1CB protein P62140 UNIPROT down-regulates activity binding -1 12144526 YES lperfetto We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin 0.286 SIGNOR-265743 sertindole chemical CHEBI:9122 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258545 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0001260 10514499 YES lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. 0.476 SIGNOR-71041 DUSP22 protein Q9NRW4 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9606 16636663 NO miannu IL-6 and LIF-induced LMW-DSP2 expression in murine testicular or hepatoma cell lines, while LMW-DSP2 overexpression in 293T cells suppressed IL-6-induced phosphorylation and activation of STAT3.|These results strongly suggest that LMW-DSP2 acts as a negative regulator of the IL-6/LIF/STAT3-mediated signaling pathway. 0.358 SIGNOR-277149 hexestrol chemical CHEBI:31669 ChEBI AKR1C1 protein Q04828 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193230 MT-CO3 protein P00414 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.683 SIGNOR-267743 3-(4-Methylphenyl)-5-(1-propyl-3,6-dihydro-2H-pyridin-5-yl)-1,2-oxazole chemical CID:9817231 PUBCHEM SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 10090 9144641 YES Federica PD144418 exhibited an affinity for ơ1 of 0.08nM(Ki) versusa Ki of 1377nM for ơ2 site. 0.8 SIGNOR-261114 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH6 protein P55285 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265846 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002417 15358865 YES gcesareni Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch. 0.654 SIGNOR-245315 PPM1A protein P35813 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 27419230 YES miannu In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG). 0.248 SIGNOR-277152 PRKACG protein P22612 UNIPROT PHKA2 protein P46019 UNIPROT down-regulates activity phosphorylation 9606 10487978 YES Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. 0.324 SIGNOR-267414 CARD9 protein Q9H257 UNIPROT BCL10 protein O95999 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 11053425 YES To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB. 0.759 SIGNOR-257602 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. 0.2 SIGNOR-238625 Raltegravir chemical CID:54671008 PUBCHEM UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258162 IGF1 protein P05019 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 17200203 NO Regulation of expression miannu Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts 0.291 SIGNOR-251862 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1333 ARGGQVFyNSEYGEL 9606 BTO:0000394 12881528 YES lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. 0.2 SIGNOR-104084 NOS1 protein P29475 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.362 SIGNOR-255996 AHCYL1 protein O43865 UNIPROT PAPOLB protein Q9NRJ5 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 YES lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. 0.2 SIGNOR-268331 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.459 SIGNOR-257345 MC3R protein P41968 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257026 Ub:E2 complex SIGNOR-C497 SIGNOR HERC2 protein O95714 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271292 GCG protein P01275 UNIPROT GCGR protein P47871 UNIPROT up-regulates binding 9606 BTO:0000007 22863277 YES milica In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function. 0.776 SIGNOR-198504 SOD1 protein P00441 UNIPROT ER stress stimulus SIGNOR-ST9 SIGNOR up-regulates 10090 18519638 NO P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK 0.7 SIGNOR-262788 CSNK1A1L protein Q8N752 UNIPROT GLI2 protein P10070 UNIPROT up-regulates phosphorylation 9606 18698484 YES gcesareni Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed 0.333 SIGNOR-179972 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA11 protein Q9Y5H2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265690 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser285 NHTLAPAsPAPARPR -1 11113134 YES llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  0.522 SIGNOR-250650 PRTN3 protein P24158 UNIPROT Pr3-ANCA complex SIGNOR-C475 SIGNOR up-regulates activity binding 9606 BTO:0000133 15972951 YES lperfetto ANCAs comprise a group of autoantibodies directed against proteins contained in the lysosomal compartments of neutrophils and monocytes. The primary target antigens have been identified as proteinase 3 (Pr3), a 29-kd neutral serine proteinase, and myeloperoxidase (MPO), a 140-kd protein involved in the generation of reactive oxygen species.2 To date, detection of ANCAs has proven to be a helpful diagnostic tool and many clinical studies have confirmed that Pr3-ANCA and MPO-ANCA are highly specific for Wegener's granulomatosis and microscopic polyangiitis, respectively 0.2 SIGNOR-270581 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser25 KRRSARLsAKPPAKV 9606 10739259 YES lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. 0.307 SIGNOR-76286 GCG protein P01275 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates 9606 23075495 NO inferred from 70% of family members gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. 0.272 SIGNOR-269857 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser385 RYSDTTDsDPENEPF -1 12297295 YES llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  0.704 SIGNOR-251027 FYN protein P06241 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr731 QQIDSCTyEAMYNIQ 9606 9890970 YES lperfetto Fyn associates with cbl and phosphorylates tyrosine 731 in cbl, a binding site for phosphatidylinositol 3-kinasecbl represents a substrate for src-like kinases that are activated in response to the engagement of cell surface receptors, and that src-like kinases are responsible for the phosphorylation of a tyrosine residue in cbl that may regulate activation of phosphatidylinositol 3-kinase 0.812 SIGNOR-63968 PRKACA protein P17612 UNIPROT PDE10A protein Q9Y233 UNIPROT unknown phosphorylation Thr15 SQHLTGLtDEKVKAY 9606 BTO:0000007 20610737 YES llicata When coexpressed with the catalytic subunit of pka in transfected hek293 cells, wild-type (wt) pde10a2 (pde10a2wt) was phosphorylated at thr-16 these data confirm the previously reported findings that pka phosphorylation of pde10a2 on thr-16 results in a cytosolic localization 0.369 SIGNOR-166559 BMP7 protein P18075 UNIPROT UCP1 protein P25874 UNIPROT up-regulates transcriptional regulation 9606 18719589 NO fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways 0.428 SIGNOR-210059 RNF146 protein Q9NTX7 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 YES By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. 0.67 SIGNOR-259997 GTF2H5 protein Q6ZYL4 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 YES lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.875 SIGNOR-269310 CAMK2A protein Q9UQM7 UNIPROT FBXO43 protein Q4G163 UNIPROT up-regulates activity phosphorylation Ser192 NLEKNIPsSASGFSR -1 16407128 YES Manara CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. | these results implicate the 192RSST motif of Emi2 as a critical molecular target of CaMKII during CSF release 0.402 SIGNOR-260907 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Ser372 EEIYGANsPIWESGF 24870244 YES lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) 0.41 SIGNOR-275496 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr230 QPYDPNFyDETYDYG 9606 12052863 YES lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). 0.603 SIGNOR-88903 SP1 protein P08047 UNIPROT CACNA1G protein O43497 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23868804 YES miannu Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression. 0.261 SIGNOR-264034 PPP1R9B protein Q96SB3 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 10090 BTO:0001976 15996550 NO miannu Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc 0.7 SIGNOR-269179 BDNF protein P23560 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates binding 9606 7679912 YES gcesareni Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb 0.816 SIGNOR-31597 GLS protein O94925 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 22049910 YES miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. 0.8 SIGNOR-266910 KSR2 protein Q6VAB6 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 YES miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 0.616 SIGNOR-273877 MAPK3 protein P27361 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser455 SIDSEPGsPLLDDAK 9606 14988395 YES lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. 0.392 SIGNOR-123053 MAPK10 protein P53779 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 YES gcesareni Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset. 0.245 SIGNOR-164085 IKZF5 protein Q9H5V7 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 NO miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 0.2 SIGNOR-255407 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 12023960 YES miannu The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6. 0.339 SIGNOR-250297 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr169 TEAPAVVtEEEDDDE 9606 BTO:0004828 32483448 YES lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway 0.2 SIGNOR-273112 CD27 protein P26842 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 12324477 NO gcesareni Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively. 0.322 SIGNOR-93320 RPS6KA1 protein Q15418 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT up-regulates quantity phosphorylation Ser57 HGTGHPEsAGEHALE 9606 BTO:0000007 18280241 YES miannu RSK phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo.RanBP3 phosphorylation increases its affinity towards Ran 0.319 SIGNOR-276149 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258717 POU2F1 protein P14859 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.2 SIGNOR-238760 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 YES Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells 0.426 SIGNOR-248559 KIF2A protein O00139 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272533 HTR7 protein P34969 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.281 SIGNOR-257055 SP1 protein P08047 UNIPROT ENG protein P17813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002741 21146604 NO miannu In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor. 0.2 SIGNOR-255201 SMARCA4 protein P51532 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.835 SIGNOR-270608 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB6 protein Q9Y5F9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265684 NKX3-1 protein Q99801 UNIPROT NKX3-1/SRF complex SIGNOR-C25 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001260 10993896 YES lperfetto A novel complex element containing a juxtaposed nkx-binding site (nke) and an srf-binding element (sre) in the proximal promoter region was found to be necessary for the nkx3-1/srf coactivation of smga transcription. 0.397 SIGNOR-82087 POLR2M protein Q6EEV4 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.454 SIGNOR-266175 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser346 LLCLRRSsLKAYGNG -1 1848190 YES lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. 0.352 SIGNOR-248856 CHEK1 protein O14757 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation Thr309 LRKGRGEtRICKIYD 9606 15665856 YES gcesareni We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner 0.842 SIGNOR-133375 TLE1 protein Q04724 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates activity binding -1 19460168 YES Our data shows that Groucho/TLE repression requires two sites of interaction in LEF-1 and that a central, conserved amino acid sequence within the primary region (F S/T/P/xx y I/L/V) is critical. 0.689 SIGNOR-260109 NARS1 protein O43776 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270455 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr590 PALLEHRtGRYAPTI 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.2 SIGNOR-262927 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr145 PVEDDADyEPPPSND 9606 12817019 YES lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. 0.804 SIGNOR-102515 ATM protein Q13315 UNIPROT RNF20 protein Q5VTR2 UNIPROT up-regulates phosphorylation 9606 21763684 YES gcesareni E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm. 0.522 SIGNOR-174949 CUL3 protein Q13618 UNIPROT KCTD13 protein Q8WZ19 UNIPROT up-regulates activity binding 9606 19782033 YES miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. 0.537 SIGNOR-264233 HOOK1 protein Q9UJC3 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 9606 BTO:0000018 25331952 NO miannu The epithelial-mesenchymal transition (EMT) is an essential process for embryogenesis. It also plays a critical role in the initiation of tumor metastasis.Overexpression of Hook1 inhibited EMT while knockdown of Hook1 promoted EMT. 0.7 SIGNOR-260643 MDFI protein Q99750 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000944 8797820 YES 2 miannu We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals. 0.498 SIGNOR-240436 ANGPT1 protein Q15389 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 NO lperfetto Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. 0.2 SIGNOR-241560 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 15735019 YES miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates 0.648 SIGNOR-150492 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 9606 10359597 YES lperfetto Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. 0.748 SIGNOR-235987 DCC-2036 chemical CHEBI:62166 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191313 INS protein P01308 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity 9606 10358076 NO lperfetto Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect. 0.479 SIGNOR-252952 YWHAH protein Q04917 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 12042314 YES miannu 14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue. 0.5 SIGNOR-109771 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR CDC6 protein Q99741 UNIPROT up-regulates quantity by expression transcriptional regulation 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276576 LDHB protein P07195 UNIPROT (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity chemical modification 9606 24929216 YES lperfetto Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. 0.8 SIGNOR-267657 KPNA6 protein O60684 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 YES gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling. 0.2 SIGNOR-254332 AKAP8 protein O43823 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity binding 9606 BTO:0000007 19531803 YES Giulio To determine whether AKAP95 and p105 were present in a complex in mammalian cells, FLAG-tagged AKAP95 wascoexpressed with Myc-tagged p105 in human embryonic kidney (HEK) 293 cells. Immunoprecipitation of either protein pulled down a complex containing AKAP95, p105, and PKA-Ca (Fig. 6D).|The identification of a PKA phosphorylation site in the C-terminal region of p105 suggests that p105 is a candidate substrate for AKAP95-targeted PKA. 0.295 SIGNOR-260302 PRKAA1 protein Q13131 UNIPROT NR0B2 protein Q15466 UNIPROT up-regulates 9606 17909097 NO gcesareni We have concluded that metformin inhibits hepatic gluconeogenesis through ampk-dependent regulation of shp 0.2 SIGNOR-158071 RPS6KB1 protein P23443 UNIPROT MRE11 protein P49959 UNIPROT down-regulates quantity by destabilization phosphorylation Thr597 SQRGRADtGLETSTR -1 28967905 YES miannu MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. 0.2 SIGNOR-265944 CHEK2 protein O96017 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser342 SKLTHSLsTSDITAI 9606 16163388 YES lperfetto Phosphorylation of s342 and s367 in vivo require the chk2 kinase. Chk2 also stimulates mdmx ubiquitination and degradation by mdm2 0.722 SIGNOR-140417 PAK4 protein O96013 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by stabilization phosphorylation Ser158 CDAQSRKsFSCKYCD -1 29849120 YES miannu PAK4 bound and directly phosphorylated Slug at two previously unknown sites, S158 and S254, which resulted in its stabilization.  0.2 SIGNOR-277393 NEDD4 protein P46934 UNIPROT KIF26B protein Q2KJY2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 phosphorylation:Thr1855 PSPYSKItPPRRPHR 22768111 YES miannu We find that Kif26b interacts with an E3 ubiquitin ligase, neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) in developing kidney. Phosphorylation of Kif26b at Thr-1859 and Ser-1962 by the cyclin-dependent kinases (CDKs) enhances the interaction of Kif26b with Nedd4. Nedd4 polyubiquitinates Kif26b and thereby promotes degradation of Kif26b via the ubiquitin-proteasome pathway.  0.316 SIGNOR-272906 IL22RA1 protein Q8N6P7 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 YES gcesareni Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain. 0.522 SIGNOR-124489 SMURF2 protein Q9HAU4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11016919 YES lperfetto The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway. 0.778 SIGNOR-236133 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 YES Manara We conclude that Chk2-dependent phosphorylation of Cdc25A on Ser 123 represents a critical step in promoting its rapid destruction in response to IR-induced DNA damage. 0.842 SIGNOR-260778 BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 YES gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax bax/bak are kept in check by the pro-survival bcl-2 family members and also proposes that for apoptotic death to occur, all pro-survival bcl-2-like proteins present within a given cell need to be neutralised by bh3-only proteins, thereby derepressing bax/bak 0.676 SIGNOR-152980 ESCRT-III complex SIGNOR-C379 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 26775243 NO miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. 0.7 SIGNOR-265536 PSPH protein P78330 UNIPROT O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI down-regulates quantity chemical modification 9606 BTO:0000142 12213811 YES lperfetto Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP 0.8 SIGNOR-268570 PPARGC1A protein Q9UBK2 UNIPROT APOA5 protein Q6Q788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.281 SIGNOR-255058 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 YES gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.747 SIGNOR-26251 ACTB protein P60709 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.507 SIGNOR-269826 MAPK3 protein P27361 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 22344252 YES llicata Our data suggested a close relationship between k8(s431) phosphorylation and keratin reorganization in epithelial tumor cells. 0.42 SIGNOR-196141 SRC protein P12931 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Tyr21 VSSDAEEyQPPIWKS 9606 17560670 YES llicata Here we report that beta2-chimaerin is tyrosine-phosphorylated by src-family kinases (sfks) upon cell stimulation with epidermal growth factor (egf). Mutational analysis identified tyr-21 in the n-terminal regulatory region as a major phosphorylation site. these results suggest tyr-21 phosphorylation as a novel, sfk-dependent mechanism that negatively regulates beta2-chimaerin rac-gap activity. 0.2 SIGNOR-155713 SLBP protein Q14493 UNIPROT H2BC12 protein O60814 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265383 HRH2 protein P25021 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257375 DKK1 protein O94907 UNIPROT KREMEN2 protein Q8NCW0 UNIPROT up-regulates binding 9606 12050670 YES gcesareni Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/beta-catenin . Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membranekremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane 0.604 SIGNOR-88882 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16239230 YES gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. 0.521 SIGNOR-243534 Osmotic_stress stimulus SIGNOR-ST28 SIGNOR HNRNPA1 protein P09651 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 NO We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne 0.7 SIGNOR-262816 ponatinib chemical CHEBI:78543 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001056 23409026 YES miannu Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. 0.8 SIGNOR-259268 GAPDHS protein O14556 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 11724794 YES miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion 0.8 SIGNOR-266498 BKM120 chemical CHEBI:71954 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190392 GABRB1 protein P18505 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR form complex binding 9606 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.644 SIGNOR-263766 DAPK3 protein O43293 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 YES lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. 0.487 SIGNOR-188793 PRKCG protein P05129 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.416 SIGNOR-249282 INSR protein P06213 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 YES lperfetto The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. 0.404 SIGNOR-24782 CD79A protein P11912 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323266 YES scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. 0.656 SIGNOR-268192 PRKACA protein P17612 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation Thr131 LERAKRAtIMSLEDF 9606 BTO:0000142 21677187 YES lperfetto Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple 0.398 SIGNOR-174410 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 EPLSPVSsLQASVPG 9606 16027724 YES miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation 0.415 SIGNOR-250093 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser312 SKSHRRTsLPCIPRE 9606 19261611 YES gcesareni Phosphorylation and activation of pde3a required the activation of pkc 0.2 SIGNOR-184448 PRKCA protein P17252 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates activity phosphorylation Ser153 SMTDFYHsKRRLIFS 9606 16055744 YES lperfetto Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase c-mediated phosphorylation of ser153| When phosphorylated at Ser153, p21 is located at the cytoplasm and disrupts stress fibers. 0.376 SIGNOR-139302 OPRK1 protein P41145 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.348 SIGNOR-256989 CDK14 protein O94921 UNIPROT CyclinY/CDK14 complex SIGNOR-C541 SIGNOR form complex binding 19524571 YES lperfetto A novel cyclin, CCNY, was identified as a PFTK1 interacting protein in a yeast two-hybrid screen. The cyclin box in CCNY and the PFTAIRE motif in PFTK1 are both required for the interaction which was confirmed by in vivo and in vitro assays. 0.829 SIGNOR-273005 UNC5A protein Q6ZN44 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 YES miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. 0.66 SIGNOR-268164 MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin 0.7 SIGNOR-255466 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 12145304 YES gcesareni Oxidative stress-responsive kinase-1 (osr1) is a known upstream regulator of n(k)ccs. these results suggest that, globally, osr1 is involved in the regulation of bp and renal tubular na(+) reabsorption mainly via the activation of nkcc1 and nkcc2. 0.525 SIGNOR-90931 DZIP3 protein Q86Y13 UNIPROT H2AC14 protein Q99878 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271762 PRKCD protein Q05655 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr678 RHIVRKRtLRRLLQE 10090 1860884 YES lperfetto These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling. 0.369 SIGNOR-248858 CSNK2A1 protein P68400 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 YES lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. 0.269 SIGNOR-275738 TRIP13 protein Q15645 UNIPROT MCC complex SIGNOR-C382 SIGNOR down-regulates quantity by destabilization binding 9606 BTO:0000567 25092294 YES miannu We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). 0.518 SIGNOR-265972 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser502 FSTDNSGsQPKQKSD 9606 22123827 YES lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. 0.376 SIGNOR-177793 TNKS protein O95271 UNIPROT PSMF1 protein Q92530 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 23622245 YES lperfetto We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31. 0.5 SIGNOR-263387 ACSS1 protein Q9NUB1 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271831 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207830 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity relocalization 9606 19352540 YES lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. 0.882 SIGNOR-185131 dopamine smallmolecule CHEBI:18243 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). 0.8 SIGNOR-264180 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.291 SIGNOR-275781 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR MASTL protein Q96GX5 UNIPROT down-regulates activity dephosphorylation Thr194 NMMDILTtPSMAKPR 9606 BTO:0002181 24391510 YES miannu We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194.Gwl phosphorylation by CycA/Cdk2 in vitro. Flag WT and Thr194A Gwl was transiently expressed and purified from asynchronous HEK 293T cells and incubated with recombinant CycA/Cdk2, following treatment with alkaline phosphatase (aPh) in the indicated samples. The proteins were analysed by immuno-blotting with anti-Gwl and Gwl pThr194 antibodies 0.49 SIGNOR-276615 PP1 proteinfamily SIGNOR-PF54 SIGNOR NOS3 protein P29474 UNIPROT up-regulates activity dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 YES lperfetto The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation 0.2 SIGNOR-264668 INCENP protein Q9NQS7 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 7227 16824953 YES lperfetto INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop 0.694 SIGNOR-252048 PTEN protein P60484 UNIPROT CREB1 protein P16220 UNIPROT down-regulates activity dephosphorylation Ser119 EILSRRPsYRKILND 10090 BTO:0002572 21385900 YES Our study demonstrates that PTEN can dephosphorylate CREB at Ser133 and that PTEN protein phosphatase activity is required for CREB dephosphoryation.|Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. 0.436 SIGNOR-248543 motesanib chemical CHEBI:51098 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194566 AXIN2 protein Q9Y2T1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 YES gcesareni It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. 0.848 SIGNOR-79947 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Tyr69 NLTKSERySSSGSPA 9606 BTO:0000093 35513296 YES miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings 0.342 SIGNOR-277909 ZBED1 protein O96006 UNIPROT RPS12 protein P25398 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 17220279 YES Luana HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid. 0.2 SIGNOR-266084 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser626 DQTNVLSsTFLSPQC 9606 BTO:0000007 16141410 YES In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity 0.398 SIGNOR-251247 NOTCH proteinfamily SIGNOR-PF30 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11486031 NO gcesareni Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo 0.2 SIGNOR-254349 NAA25 protein Q14CX7 UNIPROT NatB complex SIGNOR-C416 SIGNOR form complex binding 9606 18570629 YES miannu In the present study we present the components of hNatB (human NatB complex). It consists of the Nat3p homologue hNAT3 (human N-acetyltransferase 3) and the Mdm20p homologue hMDM20 (human mitochondrial distribution and morphology 20). They form a stable complex and in vitro display sequence-specific N(alpha)-acetyltransferase activity on a peptide with the N-terminus Met-Asp-. 0.89 SIGNOR-267231 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 30519351 YES miannu One of the most well studied activators of CCND1 transcription is β-catenin, which could be actived by AKT signalling to inducing G1/S transition. When β-catenin is translocated from the cytoplasm to the nucleus, it forms a complex with the ternary complex factor (TCF) and/or lymphoid enhancer-binding factor (LEF) and stimulates cyclin D1 gene transcription (Fig. 4C).In agreement with the data described above, a chromatin immunoprecipitation (ChIP) assay confirmed that TNC regulates the binding of β-catenin to the TCF/LEF-binding site in the CCND1 promoter (Fig. 4C). Additionally, the β-cateninbinding activity with respect to the CCND1 promoter was much higher in TNC-overexpression PANC-1 cells than in the vector controls. 0.8 SIGNOR-277738 SEC23IP protein Q9Y6Y8 UNIPROT 1-acyl-sn-glycerol 3-phosphate smallmolecule CHEBI:16975 ChEBI up-regulates quantity chemical modification 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269657 MRAP protein Q8TCY5 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. 0.49 SIGNOR-252362 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation 9606 18394876 YES gcesareni The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1 0.681 SIGNOR-253002 CSNK2A1 protein P68400 UNIPROT STARD10 protein Q9Y365 UNIPROT down-regulates phosphorylation Ser284 GGAGGEGsDDDTSLT 9606 BTO:0002181 17561512 YES gcesareni Interestingly, hypotonic extracts prepared from hek293t cells expressing the serine to alanine mutant exhibited increased lipid transfer activity compared with those from wild-type stard10-expressing cells, suggesting that, in a cellular context, phosphorylation on serine 284 negatively regulates stard10 activity 0.408 SIGNOR-155740 propionic acid chemical CHEBI:30768 ChEBI FFAR3 protein O14843 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257490 CRYBB2 protein P43320 UNIPROT CRYBB3 protein P26998 UNIPROT up-regulates activity binding 9606 16319073 YES miannu At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency. 0.454 SIGNOR-252152 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT up-regulates activity phosphorylation Ser964 MMDAPPLsPFPHIKQ 9606 12006580 YES llicata Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.  0.806 SIGNOR-250764 FUBP1 protein Q96AE4 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 NO irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In particular, elevated expression of the Bcl-2 family members Bik and Noxa was detected. 0.2 SIGNOR-259128 2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine chemical CHEBI:91330 ChEBI ATM protein Q13315 UNIPROT down-regulates activity chemical inhibition -1 18794134 YES Gianni A targeted compound library was screened for potential inhibitors of the ATM kinase, and CP466722 was identified. 0.8 SIGNOR-261975 CCND1 protein P24385 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates 9606 BTO:0000150 BTO:0000149 20443831 NO gcesareni The mechanism by which cyclin d1 enhances notch1 activity in different cell types remains to be determined;the current studies demonstrate for the first time that notch1 activity is induced by cyclin d1. The expression of cyclin d1 sirna reduced notch1 activity. 0.636 SIGNOR-165189 CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR GCG protein P01275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10506141 NO miannu Pax-6 and cdx-2 also directly interacted with one another at the protein level. pax-6, bound to its dna recognition site in the glucagon g1 promoter element, tethered cdx-2 to the molecular complex of pax-6 and p300. Further, we found that the presence of cdx-2 enhanced the interaction of pax-6 with p300, thus establishing a molecular complex of transcription factors implicated in tissue-specific glucagon gene expression with the basal transcriptional machinery. 0.462 SIGNOR-70957 PSMB3 protein P49720 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.866 SIGNOR-263359 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr279 TDGEDADyTHFTNQQ 9606 BTO:0000567 19059208 YES miannu We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. 0.2 SIGNOR-262854 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr31 SNYRAYAtEPHAKKK 9606 BTO:0000671 18986304 YES llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). 0.2 SIGNOR-182057 MRGPRX1 protein Q96LB2 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257259 TAF6 protein P49848 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.912 SIGNOR-263922 JUN protein P05412 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 24708856 YES miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. 0.4 SIGNOR-255767 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr643 GVHHIDYyKKTSNGR 9606 BTO:0001130 18670643 YES lperfetto Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4. 0.2 SIGNOR-179780 CTCF protein P49711 UNIPROT RARRES1 protein P49788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 22615834 NO miannu Epigenetic repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding. knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state. 0.346 SIGNOR-253831 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 10116 BTO:0001009 12064478 YES llicata  the present study it is shown that in apoptotic PC12 cells the levels of p53 and Cdk5 increase concomitantly. Further, Cdk5/p25 effectively phosphorylates recombinant p53 in vitro. Transient transfection of Cdk5/p25 into cells results in an increase in p53 levels, as well as the expression of the p53-responsive genes p21 and Bax. Furthermore, evidence is provided that increased Cdk5 activity increases p53 transcriptional activity significantly, suggesting that p53 is modulated in situ by Cdk5.  0.586 SIGNOR-250674 Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 NO lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. 0.7 SIGNOR-273458 GRM4 protein Q14833 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 YES miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. 0.343 SIGNOR-264082 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser369 RPSSRASsRASSRPR 9606 16474210 YES lperfetto We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity. 0.44 SIGNOR-144469 HDAC1 protein Q13547 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity deacetylation 20081843 YES Here, we identify a mechanism whereby Hh signalling is regulated, in which acetylation of Gli1 at Lys 518 represents a transcriptional inhibitory switch, while its HDAC1-mediated deacetylation is responsible for transcriptional activation. 0.593 SIGNOR-253544 HNRNPU protein Q00839 UNIPROT HEXIM1 protein O94992 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 NO lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. 0.247 SIGNOR-262283 Ub:E2 complex SIGNOR-C497 SIGNOR HERC5 protein Q9UII4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271297 IFNB1 protein P01574 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 YES miannu Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.77 SIGNOR-260335 CBL protein P22681 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000944 10347229 YES miannu  Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha. 0.628 SIGNOR-272549 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser396 GHQGTVPsDNIDSQG -1 8662852 YES we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 0.693 SIGNOR-251195 TGFB1 protein P01137 UNIPROT TFAP4 protein Q01664 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 21228219 NO miannu TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts. 0.2 SIGNOR-255428 RXRA protein P19793 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 10976919 YES inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr). 0.723 SIGNOR-267800 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251596 SMURF1 protein Q9HCE7 UNIPROT NFIC protein P08651 UNIPROT down-regulates quantity ubiquitination 9606 22195013 YES miannu In addition, Smurf1 knockdown also blocked the degradation of endogenous NFI-C in response to TGF-beta1 (XREF_FIG).|In particular, Smurf1 and Smurf2 markedly increased the polyubiquitination of NFI-C in the presence of TGF-beta1 (XREF_FIG and XREF_SUPPLEMENTARY). 0.33 SIGNOR-278753 ADIPOQ protein Q15848 UNIPROT ADIPOR2 protein Q86V24 UNIPROT up-regulates binding 9606 16622416 YES milica Two adiponectin receptors, adipor1 and adipor2, have recently been identified. 0.772 SIGNOR-146173 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 YES gcesareni Akt activation is achieved through a series of phosphorylation steps, the first being akt phosphorylation at thr-450 by jnk kinases. Pp-1 acts as a major phosphatase to dephosphorylate akt at thr-450 and thus modulate its functions. 0.387 SIGNOR-163965 125-L-serine-2-133-interleukin 2 (human reduced) smallmolecule SID:46508054 PUBCHEM IL2RA protein P01589 UNIPROT up-regulates activity chemical activation 9606 18031103 YES miannu Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. 0.8 SIGNOR-259388 PLK2 protein Q9NYY3 UNIPROT NPM1 protein P06748 UNIPROT up-regulates phosphorylation Ser4 sMDMDMSP 9606 BTO:0000567 15190079 YES gcesareni Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis. 0.535 SIGNOR-125720 GSK3B protein P49841 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000812 phosphorylation:Ser64 EPGTPPSsPLSAEQL 27875297 YES lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation 0.2 SIGNOR-264885 PCDH19 protein Q8TAB3 UNIPROT GABRA2 protein P47869 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C331 29360992 YES miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  0.2 SIGNOR-267218 NFE2L3 protein Q9Y4A8 UNIPROT PLA2G7 protein Q13093 UNIPROT up-regulates quantity by expression transcriptional regulation 22247257 YES lperfetto Moreover, we demonstrated that nuclear factor erythroid 2-related factor 3 (Nrf3) regulates Pla2g7 gene expression through direct binding to the promoter regions of Pla2g7 gene. 0.363 SIGNOR-268979 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.383 SIGNOR-189129 ERN1 protein O75460 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 18519638 YES P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) Activated IRE1 has been demonstrated to recruit TRAF2 and ASK1 on the ER membrane and thus to activate ASK1|ASK1 was found to associate with IRE1 only in the presence of TRAF2 and SOD1mut (Fig. 4B), suggesting that SOD1mut induces formation of an IRE1–TRAF2–ASK1 complex on the ER membrane and thus activates ASK1 by triggering ER stress-induced IRE1 activation. 0.676 SIGNOR-262790 WNT5A protein P41221 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates 9606 SIGNOR-C110 21078818 NO gcesareni We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3). 0.475 SIGNOR-169663 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR RASSF1 protein Q9NS23 UNIPROT down-regulates binding 9606 21776416 YES gcesareni Basal inactivation of rassf1a is achieved by rassf1a self association and via 14-3-3 interactions (to isoforms s and e) at serine 175/178/179 of rassf1a. 0.2 SIGNOR-175121 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 NO miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. CD44 is also upregulated by NUP98‐HOXA9. 0.2 SIGNOR-261502 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR4 protein P31391 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257584 NOTCH1 protein P46531 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9528780 NO gcesareni In transient-transfection assays we show that truncated notch-1 strongly induces nf-kappab2 promoter activity. 0.289 SIGNOR-56097 ATP6V1H protein Q9UI12 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 10090 BTO:0004122 29782852 YES miannu ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs. 0.2 SIGNOR-266886 FFAR4 protein Q5NUL3 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257313 RNF139 protein Q8WU17 UNIPROT INSIG1 protein O15503 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 YES miannu TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Thus, we conclude that INSIG-1 and 2 physically interact with TRC8, and that TRC8 enhances ubiquitylation of INSIG-1 in a RING-dependent manner 0.478 SIGNOR-271955 ATG16L1 protein Q676U5 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR form complex binding 9606 BTO:0000007 18321988 YES lperfetto Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex). 0.885 SIGNOR-226696 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL 26933062 YES lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. 0.425 SIGNOR-276587 CXCL1 protein P09341 UNIPROT Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000130 35022267 NO miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. 0.7 SIGNOR-277721 Gbeta proteinfamily SIGNOR-PF4 SIGNOR EWSR1 protein Q01844 UNIPROT unknown phosphorylation 9606 19076070 YES inferred from 70% family members lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2. 0.2 SIGNOR-270062 DUSP1 protein P28562 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 YES fstefani We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively. 0.68 SIGNOR-40879 MAP3K5 protein Q99683 UNIPROT ZNF622 protein Q969S3 UNIPROT up-regulates phosphorylation Thr318 KGKSFYStEAVQAHM 9606 21771788 YES gcesareni Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis. 0.488 SIGNOR-175117 FZD2 protein Q14332 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR up-regulates activity 21952300 YES FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43. 0.391 SIGNOR-253521 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR unknown phosphorylation 9606 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. 0.869 SIGNOR-217376 atropine chemical CHEBI:16684 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258392 INS protein P01308 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 NO lperfetto The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.488 SIGNOR-235619 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 BTO:0000567 16371512 YES gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell 0.503 SIGNOR-143368 DRD4 protein P21917 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.278 SIGNOR-257098 Isoetharine chemical CHEBI:6005 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 YES miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. 0.8 SIGNOR-258433 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR BACE1 protein P56817 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000938 20854419 YES miannu SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production. 0.258 SIGNOR-271903 Ub:E2 complex SIGNOR-C497 SIGNOR RNF38 protein Q9H0F5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271222 GART protein P22102 UNIPROT N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity chemical modification 9606 33179964 YES miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. 0.8 SIGNOR-267305 PRKAR1A protein P10644 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.863 SIGNOR-258755 IFNAR complex SIGNOR-C243 SIGNOR CCL2 protein P13500 UNIPROT up-regulates quantity by expression 10090 32283152 NO miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. 0.315 SIGNOR-260851 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 YES miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. 0.2 SIGNOR-277853 NFIL3 protein Q16649 UNIPROT SOSTDC1 protein Q6X4U4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 25338303 NO lperfetto E4BP4 is a repressor of epigenetically regulated SOSTDC1 expression in breast cancer cells. 0.2 SIGNOR-242767 CDK1 protein P06493 UNIPROT DCTN6 protein O00399 UNIPROT up-regulates activity phosphorylation Thr186 KTMKGSStPVKN -1 23455152 YES lperfetto Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores. 0.307 SIGNOR-264777 PPP1CC protein P36873 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 YES Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells 0.383 SIGNOR-248502 THOC7 protein Q6I9Y2 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 YES miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. 0.913 SIGNOR-268507 WWTR1 protein Q9GZV5 UNIPROT TEAD proteinfamily SIGNOR-PF22 SIGNOR up-regulates activity binding 9606 23431053 YES miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death 0.898 SIGNOR-230722 GlyR proteinfamily SIGNOR-PF62 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18721822 YES miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 0.8 SIGNOR-264984 ADORA1 protein P30542 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.391 SIGNOR-256976 GNG3 protein P63215 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. 0.2 SIGNOR-199141 IL1B protein P01584 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 NO scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. 0.2 SIGNOR-267486 PITX1 protein P78337 UNIPROT LHB protein P01229 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19106114 NO miannu GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. 0.349 SIGNOR-254920 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 9155017 YES gcesareni We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2. 0.575 SIGNOR-48352 CD19 protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000776 25673924 YES lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. 0.521 SIGNOR-252670 SRGAP2 protein O75044 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.602 SIGNOR-260517 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 1840554 YES The expression levels of both C/EBPB and C/EBPD are increased dramatically during the time of hormonal stimulation (see Fig. 8). Furthermore, the C/EBPB- and C/EBPD encoding genes are activated directly by adipogenic hormones 0.315 SIGNOR-251648 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr334 DSTQTSDtATNSTLP -1 7836371 YES Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation. 0.2 SIGNOR-251451 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA2 protein Q9Y5H1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265691 PHLPP1 protein O60346 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 19261608 YES The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. 0.759 SIGNOR-248331 THBS1 protein P07996 UNIPROT NGF protein P01138 UNIPROT up-regulates binding 9606 10708953 YES lpetrilli We have identified a mechanism for the activation of latent tgf-beta that involves binding of the secreted and extracellular matrix protein, thrombospondin-1 (tsp-1), to the latent precursor. 0.278 SIGNOR-75624 GRIN2C protein Q14957 UNIPROT NMDA receptor_2C complex SIGNOR-C349 SIGNOR form complex binding 9606 BTO:0000938 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits 0.611 SIGNOR-264125 REST protein Q13127 UNIPROT HCN1 protein O60741 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0000938 21905079 YES lperfetto Levels of NRSF and its physical binding to the Hcn1 gene were augmented after SE, resulting in repression of HCN1 expression and HCN1-mediated currents (I(h) ), and reduced I(h) -dependent resonance in hippocampal CA1 pyramidal cell dendrites. 0.2 SIGNOR-268970 SRC protein P12931 UNIPROT KLF16 protein Q9BXK1 UNIPROT up-regulates activity phosphorylation Tyr10 AAVACVDyFAADVLM 9606 BTO:0003041 22203677 YES miannu We further confirmed that the Tyr-10 residue of KLF16 is phosphorylated in uterine cells (Fig. 7c). Additional experiments using both pharmacological and dominant negative inhibitors of Src further supported a role for this tyrosine kinase in modulating the activity of KLF16 (Fig. 7, d and f).  0.245 SIGNOR-276398 RAB33B protein Q9H082 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates binding 9606 18448665 YES gcesareni Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation. 0.75 SIGNOR-178542 TNF protein P01375 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005760 16877633 NO Regulation of expression miannu TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na(+) channel (ENaC) by approximately 70% in alveolar epithelial cells. 0.305 SIGNOR-251954 bepotastine chemical CHEBI:71204 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257781 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.383 SIGNOR-189133 TFIID complex SIGNOR-C343 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity binding 9606 27096372 YES miannu Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation. 0.543 SIGNOR-263934 HSPA5 protein P11021 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity binding 9606 31226023 YES miannu Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain 0.82 SIGNOR-260176 MET protein P08581 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001033 22035268 NO miannu C-Met expression and activation appears to be one of the common mechanisms of resistance to other targeted therapies. Given these multiple roles of c-Met in prostate cancer, several c-Met inhibitors have been developed. Evidence to date suggests that aberrant activation of the HGF/c-Met axis in prostate cancer epithelial cells appears to be a relatively late event in tumor progression. C-Met expression increases in advanced stages of the disease, with the highest expression observed in bone metastases. 0.7 SIGNOR-263658 DOT1L protein Q8TEK3 UNIPROT H3-4 protein Q16695 UNIPROT unknown methylation Lys80 REIAQDFkTDLRFQS 9606 12123582 YES miannu HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase. 0.2 SIGNOR-267142 CDK2AP1 protein O14519 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity binding 22427660 YES lperfetto The ubiquitously expressed CDK2AP1 protein is the only known specific inhibitor of CDK2, making it an important component of cell cycle regulation during G1-to-S phase transition. 0.442 SIGNOR-264781 ERN1 protein O75460 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity phosphorylation Tyr628 EHPNVIRyFCTEKDR -1 25968568 YES miannu IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures.  0.2 SIGNOR-275417 ATF3 protein P18847 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15670751 YES lperfetto In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells. 0.426 SIGNOR-253725 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.4 SIGNOR-259020 PTBP2 protein Q9UKA9 UNIPROT HNRNPH1 protein P31943 UNIPROT up-regulates activity binding 9606 BTO:0000567 11003644 YES lperfetto Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA. 0.389 SIGNOR-261269 NMBR protein P28336 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257248 SYK protein P43405 UNIPROT LAX1 protein Q8IWV1 UNIPROT up-regulates activity phosphorylation Tyr268 SSQISNDyVNMTGLD 9606 BTO:0000007 12359715 YES miannu Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85.  0.378 SIGNOR-273533 CREBBP protein Q92793 UNIPROT MYBL1 protein P10243 UNIPROT up-regulates activity binding 9534 9210395 YES 2 miannu CBP co-operates functionally with A-Myb 0.482 SIGNOR-240984 FAS protein P25445 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates 9606 9743501 NO gcesareni Fas activation induced daxx to interact with ask1 0.703 SIGNOR-60167 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.2 SIGNOR-269249 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10090 15486195 YES miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. 0.758 SIGNOR-250132 VRK2 protein Q86Y07 UNIPROT DTNBP1 protein Q96EV8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser299 RAKPPSSsSTCTDSA -1 30062698 YES miannu  We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting.  0.2 SIGNOR-277404 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 YES lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity 0.742 SIGNOR-232134 KLF11 protein O14901 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 YES miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. 0.488 SIGNOR-222344 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.432 SIGNOR-81153 FGF2 protein P09038 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 NO gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/ fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts 0.447 SIGNOR-134791 tacedinaline chemical CHEBI:90195 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258007 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273099 MYC protein P01106 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates quantity transcriptional regulation 10116 10823814 YES inferred from family member C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. 0.412 SIGNOR-270247 PRKCA protein P17252 UNIPROT RAB11A protein P62491 UNIPROT unknown phosphorylation Ser177 TEIYRIVsQKQMSDR -1 22188018 YES miannu This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. 0.2 SIGNOR-263168 JAK2 protein O60674 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Tyr643 TSDEKVDyVQVDKEK 9606 BTO:0000130 18644434 YES lperfetto In vitro, activated jak2 directly phosphorylated specific gab2 tyrosine residues. Mutagenesis studies revealed that gab2 tyrosine 643 (y643) was a major target of jak2 in vitro, and a key residue for jak2-dependent phosphorylation in intact cells. Mutation of gab2 y643 inhibited g-csf-stimulated erk1/2 activation and shp2 binding to gab2. 0.513 SIGNOR-179488 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.278 SIGNOR-276084 CDK5 protein Q00535 UNIPROT CORO1A protein P31146 UNIPROT up-regulates activity phosphorylation Thr424 AAPEASGtPSSDAVS 9606 BTO:0001588 26823173 YES lperfetto We here show that phosphorylation of coronin 1 on Thr(418/424) by cyclin-dependent kinase (CDK) 5 activity was responsible for coronin 1-G_s association and the modulation of cAMP production. Together these results show an essential role for CDK5 activity in promoting the coronin 1-dependent cAMP/PKA pathway. 0.288 SIGNOR-245187 KPNA3 protein O00505 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 YES gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. 0.325 SIGNOR-165280 ATP6V1F protein Q16864 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.767 SIGNOR-277755 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates activity phosphorylation Ser521 WTNRLYEsFKASDPL -1 21642394 YES miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. 0.2 SIGNOR-276329 CLTB protein P09497 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 YES lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  0.769 SIGNOR-260666 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH2 protein Q04721 UNIPROT up-regulates activity cleavage 9606 25610395 YES lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins. 0.588 SIGNOR-209723 MTNR1B protein P49286 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.47 SIGNOR-256707 HDAC1 protein Q13547 UNIPROT CEBPA protein P49715 UNIPROT down-regulates transcriptional regulation 9606 16431920 YES fspada These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome 0.436 SIGNOR-210013 FBXO22 protein Q8NEZ5 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000356 29945959 YES lperfetto FBXO22 elicits its antimetastatic effects by targeting SNAIL, a master regulator of EMT and breast cancer metastasis, for ubiquitin-mediated proteasomal degradation in a glycogen synthase kinase 3β phosphorylation-dependent manner.  0.2 SIGNOR-273446 Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity ubiquitination 9606 25519132 YES miannu Mechanism of transcriptional activation. PRC1 can monoubiquitinate H2AK119 through its RING1B component.  0.2 SIGNOR-266815 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248689 EIF2AK2 protein P19525 UNIPROT PPP2R5A protein Q15172 UNIPROT up-regulates phosphorylation Ser28 VDGFTRKsVRKAQRQ 9606 18957415 YES llicata Phosphorylation of serine 28 by pkr promotes mitochondrial localization of b56alpha, because wild-type but not mutant s28a b56alpha promoted mitochondrial pp2a activity. 0.328 SIGNOR-181793 ESRRA protein P11474 UNIPROT RNF208 protein Q9H0X6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 31862882 YES Gianni Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner 0.2 SIGNOR-269052 CSNK1D protein P48730 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization phosphorylation Ser35 LGPSPGPsPGSAHSM 9606 BTO:0001225 30177679 YES miannu  We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.  0.2 SIGNOR-277407 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr88 QALEEAAtADLDITE 9606 19530738 YES lperfetto First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form. 0.462 SIGNOR-186151 PRKCB protein P05771 UNIPROT EIF6 protein P56537 UNIPROT down-regulates activity phosphorylation Ser235 QPSTIATsMRDSLID 9606 14654845 YES lperfetto Our results show that release of eIF6 from 60S subunits may operate, in mammalian cells, through a RACK1–PKC betaII pathway. |Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. |S235A eIF6 inhibits ribosomal joining in the presence of RACK1–PKCbetaII 0.307 SIGNOR-249245 Jervine chemical CHEBI:6088 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 BTO:0000149 16112412 YES gcesareni Here, we demonstrate that cyclopamine and jervine, two structurally related inhibitors of smo, force ciliary translocation of smo. 0.8 SIGNOR-139865 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 YES gcesareni These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis. 0.474 SIGNOR-138437 IRX1 protein P78414 UNIPROT ERMAP protein Q96PL5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. 0.2 SIGNOR-261667 PEA15 protein Q15121 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates 9606 11702783 NO inferred from 70% of family members gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. 0.2 SIGNOR-269904 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr2035 GIKTSEGtPGFRAPE 9606 BTO:0000938 20595391 YES lperfetto Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2. 0.2 SIGNOR-166474 NAALAD2 protein Q9Y3Q0 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 10085079 YES miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. 0.8 SIGNOR-267542 BIK protein Q13323 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 7478623 YES gcesareni We have identified a novel cellular protein, bik, that interacts with the cellular survival-promoting proteins, bcl-2 and bcl-xl in transient transfection assays, bik promotes cell death in a manner similar to the death-promoting members of the bcl-2 family, bax and bak. 0.807 SIGNOR-26453 SETD2 protein Q9BYW2 UNIPROT Iws1:Spt6:CTD complex complex SIGNOR-C548 SIGNOR form complex binding 9606 19141475 YES miannu We showed recently that Spt6, a transcription elongation factor and histone H3 chaperone, binds to the Ser2P CTD and recruits Iws1 and the REF1/Aly mRNA export adaptor to facilitate mRNA export.In vitro, recombinant Spt6 binds selectively to a stretch of uninterrupted consensus repeats located in the N-terminal half of the CTD and recruits Iws1. Thus Iws1 connects two distinct CTD-binding proteins, Spt6 and HYPB/Setd2, in a megacomplex that affects mRNA export as well as the histone modification state of active genes. 0.562 SIGNOR-273499 COL4A5 protein P29400 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 YES Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) 0.7 SIGNOR-254669 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 16885213 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp 0.2 SIGNOR-148592 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267881 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser287 WEPPGRAsPSQGSSP 9606 14697653 YES lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.268 SIGNOR-120475 CRTC2 protein Q53ET0 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 YES Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB 0.2 SIGNOR-256103 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001487 21966368 NO Regulation miannu Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms 0.464 SIGNOR-251857 ACP1 protein P24666 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation 9606 12815062 YES miannu Lymphocyte function-associated antigen-1-mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity.  4000254={CellProcess=4107155 CellType=10000184}}|Moreover, in these conditions LMW-PTP causes FAK dephosphorylation, thus preventing the activation of FAK downstream pathways. 0.276 SIGNOR-277064 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.759 SIGNOR-219320 CAMK2B protein Q13554 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 YES miannu ERK1/2 and CaMKIIβ mediated phosphorylation of GABAB1 at serine 867 (S867) and threonine 872 (T872). We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. 0.2 SIGNOR-277850 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 YES miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. 0.2 SIGNOR-277852 CDK2 protein P24941 UNIPROT MCM3AP protein O60318 UNIPROT up-regulates activity phosphorylation Ser508 FWHRKKIsPNKKPFS 10090 BTO:0000776 11526238 YES miannu To study the inducible regulation of GANP DNA-primase during cell activation, we examined phosphorylation induced by various kinds of kinases.We observed that the cell cycle-associated kinase Cdks induced phosphorylation of GANP in vitro. Examination of immunoprecipitates of Cdk2 from B cells revealed phosphorylation of GANP-PD at a consensus sequence of Cdk phosphorylation at Ser502 (S/T-P-X-K/R) (Fig. ​(Fig.1C1C Left; ref. 22). 0.2 SIGNOR-262734 LEF1 protein Q9UJU2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 NO amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. 0.7 SIGNOR-229764 CDH1 protein P12830 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20940130 YES gcesareni P12Beta-catenin_ also associates to the_ wnt_ co-receptor lrp5/6, an interaction mediated by e-cadherin. 0.364 SIGNOR-168464 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates activity binding 9606 BTO:0000130 35022267 YES miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. 0.905 SIGNOR-277720 IKBKB protein O14920 UNIPROT TARDBP protein Q13148 UNIPROT down-regulates quantity by destabilization phosphorylation Ser92 MDETDASsAVKVKRA 9606 BTO:0002181 38197897 YES miannu IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. 0.2 SIGNOR-277860 RPS6KB1 protein P23443 UNIPROT SRPK2 protein P78362 UNIPROT up-regulates activity phosphorylation Ser494 HDRSRTVsASSTGDL 9606 BTO:0000007 29153836 YES no miannu  Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. 0.356 SIGNOR-275459 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 YES inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. 0.2 SIGNOR-270171 JNK proteinfamily SIGNOR-PF15 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18931691 NO miannu JNKs activate apoptotic signaling by the upregulation pro-apoptotic genes via the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and anti-apoptotic proteins through distinct phosphorylation events. 0.7 SIGNOR-260178 DAPK1 protein P53355 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Ser19 KRPQRATsNVFAMFD 9606 BTO:0000567 11485996 YES miannu DAPK Phosphorylates Myosin II RLC in Vitro and in Vivo. Together these results show that similar to the conventional MLCKs, Ser-19 is the primary RLC residue phosphorylated by DAPK and that phosphorylation of Thr-18 is also possible. 0.275 SIGNOR-262842 KLHL20 protein Q9Y2M5 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 26687681 YES miannu Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1 0.277 SIGNOR-272415 TWIST2 protein Q8WVJ9 UNIPROT RAP1A protein P62834 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255508 DHFR2 protein Q86XF0 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI down-regulates quantity chemical modification 9606 21876184 YES lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. |We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR. 0.8 SIGNOR-268260 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr353 AQQCNGIyIWKIGNF 9606 BTO:0002181 37977223 YES miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. 0.566 SIGNOR-277864 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 8692915 YES Manara The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites. 0.414 SIGNOR-260821 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 YES lperfetto Thus, serine 418 is phosphorylated in vivo. Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.542 SIGNOR-204688 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser15 FSFGTLSsWELEAWY 9606 BTO:0000567 12876286 YES llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites 0.345 SIGNOR-250851 DAPK1 protein P53355 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Thr18 KKRPQRAtSNVFAMF 9606 BTO:0000567 11485996 YES miannu DAPK Phosphorylates Myosin II RLC in Vitro and in Vivo. Together these results show that similar to the conventional MLCKs, Ser-19 is the primary RLC residue phosphorylated by DAPK and that phosphorylation of Thr-18 is also possible. 0.275 SIGNOR-262843 SIK2 protein Q9H0K1 UNIPROT SIK2 protein Q9H0K1 UNIPROT up-regulates activity phosphorylation Ser343 RLKSHRSsFPVEQRL -1 27478041 YES miannu SIK2 S358 Autophosphorylation Is a Marker of SIK2 Activity 0.2 SIGNOR-277268 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Thr203 SSLATPPtLSSTVLI 9606 12815053 YES lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 0.54 SIGNOR-102498 RELA protein Q04206 UNIPROT EGR1 protein P18146 UNIPROT up-regulates binding 9606 SIGNOR-C13 10671503 YES gcesareni The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo 0.433 SIGNOR-75001 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT down-regulates activity phosphorylation Ser109 KERRRTEsINSAFAE 10116 BTO:0001556 14636580 YES miannu In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function. 0.296 SIGNOR-249989 WT1 protein P19544 UNIPROT PAX2 protein Q02962 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000671 7720589 YES A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis 0.599 SIGNOR-252298 EGFR protein P00533 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates phosphorylation Tyr1276 GGGPGGDyAAMGACP 9606 BTO:0000150 7929151 YES lperfetto The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism. 0.67 SIGNOR-34748 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser740 SFTALDWsWLQTEEE 9606 18957422 YES lperfetto Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma 0.343 SIGNOR-181802 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 YES PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. 0.308 SIGNOR-248487 SULT1E1 protein P49888 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification -1 7779757 YES Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. 0.8 SIGNOR-269749 FGG protein P02679 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 NO lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. 0.7 SIGNOR-253373 CSNK1G2 protein P78368 UNIPROT PER1 protein O15534 UNIPROT down-regulates phosphorylation 9606 15917222 YES miannu Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1. 0.394 SIGNOR-137751 2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid chemical CHEBI:95066 ChEBI SGK3 protein Q96BR1 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003136 25458846 YES lperfetto A catalytic small molecule pan-SGK inhibitor, GSK650394 (Sherk et al., 2008) also significantly blocks MCF7, ZR-75-1, and T47D cell migration (Figure 5C, Figures S4B–C). Finally, ectopic expression of SGK3 also promotes invasive migration through Matrigel (Figure 5D). Therefore, SGK3 protein kinase activity promotes migration of breast cancer cells that display elevated levels of INPP4B. 0.8 SIGNOR-262019 CCT137690 chemical CID:25154041 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190895 SPOP protein O43791 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000783 20811152 YES Gianni Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. 0.327 SIGNOR-268859 IL9 protein P15248 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 YES gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex 0.579 SIGNOR-108867 Neuropeptide W-30 smallmolecule CHEBI:80256 ChEBI NPBWR1 protein P48145 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257548 ATM protein Q13315 UNIPROT KIFC1 protein Q9BW19 UNIPROT up-regulates quantity by stabilization phosphorylation Ser26 RPLIKAPsQLPLSGS 9606 BTO:0000815 33397932 YES miannu  ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro. 0.2 SIGNOR-277295 LYN protein P07948 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr359 AKPDSSFyKGLDLNG -1 10942405 YES Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport. 0.338 SIGNOR-251412 GOT2 protein P00505 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 31422819 YES miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-267518 SMO protein Q99835 UNIPROT GNB2 protein P62879 UNIPROT up-regulates binding 9606 16885213 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.2 SIGNOR-148589 SMAD4 protein Q13485 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 YES lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. 0.711 SIGNOR-229560 oxotremorine M chemical CHEBI:38322 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258657 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1132 TLPHGPRsASVSSIS 9606 8816480 YES lperfetto In this report, we describe the identification of five MAP kinase sites (S-1137, S-1167, S-1178, S-1193, and S-1197) on hSos1.Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 0.634 SIGNOR-43939 FUBP1 protein Q96AE4 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 NO irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In addition, mRNA levels of the death ligands tumor necrosis factor (TNF) α and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were significantly increased. 0.2 SIGNOR-259129 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser731 DPLPPVFsGTPKGSG 9606 BTO:0000567 20667468 YES miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. 0.2 SIGNOR-259821 N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91439 ChEBI TBK1 protein Q9UHD2 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190795 MAPK3 protein P27361 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser62 ELILKPPsPISEAPR 10116 BTO:0000142 9525956 YES lperfetto SCG10, a growth cone-enriched MT-destabilizing protein, has been recently characterized as an in vitro substrate for various serine/threonine kinases including PKA, MAP kinase, and CDK (19). We have found that SCG10 is phosphorylated in vivo in developing rat brain.| The sites for MAP kinase phosphorylation were identified as Ser-62 and Ser-73 of SCG10|By expressing a series of phosphorylation site mutants, we showed that the MT-destabilizing effect of SCG10 could be modulated. While the nonphosphorylatable mutant showed higher activity than the wild-type protein, the activity of the mutant in which phosphorylation on all four sites was mimicked by an aspartate residue was greatly reduced. These data suggest that the nonphosphorylated state of SCG10 represents the most active form of the protein. 0.353 SIGNOR-249115 EIF3M protein Q7L2H7 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.936 SIGNOR-266388 FUBP1 protein Q96AE4 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 NO irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In addition, mRNA levels of the death ligands tumor necrosis factor (TNF) α and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were significantly increased. 0.2 SIGNOR-259130 GABRD protein O14764 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.41 SIGNOR-263770 GDNF protein P39905 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.2 SIGNOR-252176 MITF protein O75030 UNIPROT SERPINF1 protein P36955 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001177 22115973 NO miannu Here we show that the basic-helix-loop-helix-leucine zipper microphthalmia-associated transcription factor (MITF), which plays central roles in the development and function of a variety of cell types including RPE cells, upregulates the expression of a multifunctional factor PEDF in RPE cells. 0.306 SIGNOR-254587 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser348 PSLQSSLsNPNLQAS 9606 BTO:0000567 16306228 YES lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 0.643 SIGNOR-249168 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk. 0.309 SIGNOR-186951 MAPK14 protein Q16539 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates quantity by destabilization phosphorylation Ser301 S-->T -1 30301786 YES miannu P38α phosphorylates and destabilizes p63. 0.308 SIGNOR-277414 NUP58 protein Q9BVL2 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.2 SIGNOR-262077 POU5F1 protein Q01860 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.472 SIGNOR-254932 NMDA receptor_2D complex SIGNOR-C350 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor 0.74 SIGNOR-264225 LEF1 protein Q9UJU2 UNIPROT NCAM1 protein P13591 UNIPROT up-regulates activity transcriptional regulation 10090 BTO:0003952 11696550 NO miannu Consistent with our observation that expression of exogenous LEF-1 causes transactivation of the N-CAM promoter, a recent study demonstrated that noggin-dependent induction of LEF-1 coincidentally increased N-CAM expression (50). Ectopic noggin added to skin cultures up-regulates LEF-1 expression and stimulates hair induction. Based on promoter assays and EMSAs, our results further support the notion that N-CAM is a direct target of LEF-1. 0.275 SIGNOR-254549 GRK2 protein P25098 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1278 EPGFREVsFYYSEEN -1 22509025 YES miannu GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation 0.2 SIGNOR-276413 CDC25A protein P30304 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000007 23429262 YES lperfetto We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases’ activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1. 0.65 SIGNOR-245456 CXCL5 protein P42830 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 BTO:0000584 38339310 YES miannu CXCL5 is another ELR+ CXC chemokine and, thus, also potently attracts neutrophils. Just like CXCL1, CXCL5 also signals through CXCR2, explaining why, often, CXCL5 and CXCL1 are seen to function in parallel in PDAC. CXCL5 was increased in human pancreatic tissue compared to the normal pancreas, and the knockdown of CXCL5 in pancreatic cancer cell lines reduced the proliferation and migration ability of cells 0.751 SIGNOR-277730 PKA proteinfamily SIGNOR-PF17 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 10230396 YES inferred from 70% family members gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.2 SIGNOR-270129 ACSS2 protein Q9NR19 UNIPROT LAMP1 protein P11279 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants 0.2 SIGNOR-276556 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation 9606 15568999 YES inferred from 70% family members gcesareni In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. 0.2 SIGNOR-270076 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 YES lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 0.2 SIGNOR-244580 NR1I2 protein O75469 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 NO miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. 0.455 SIGNOR-254440 IQSEC2 protein Q5JU85 UNIPROT GRIA3 protein P42263 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 27009485 YES miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. 0.2 SIGNOR-264914 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 14732063 YES [...] two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b) 0.93 SIGNOR-253594 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr730 SNCTNELyMMMRDCW 10116 BTO:0002809;BTO:0001009 8622701 YES lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 0.2 SIGNOR-235686 PTEN protein P60484 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity 9606 BTO:0000938 18794881 NO lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). 0.716 SIGNOR-252725 bromocriptine chemical CHEBI:3181 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258723 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.453 SIGNOR-270892 FYN protein P06241 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Tyr18 MEDHAGTyGLGDRKD 9606 14999081 YES lperfetto In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn. 0.536 SIGNOR-123099 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257579 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273059 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 YES lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform. 0.2 SIGNOR-244971 MAPKAPK2 protein P49137 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser179 RRFRRSQsDCGELGD -1 15850461 YES miannu Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.478 SIGNOR-263079 MAPK9 protein P45984 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 BTO:0000782 14517246 YES gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin 0.542 SIGNOR-118223 CERS6 protein Q6ZMG9 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 YES done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  0.8 SIGNOR-273997 NKRF protein O15226 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0005065 10562553 YES Luana Constitutive silencing of IFN-beta promoter is mediated by NRF (NF-kappaB-repressing factor), a nuclear inhibitor of NF-kappaB 0.359 SIGNOR-266227 CASP1 protein P29466 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.321 SIGNOR-261748 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Phe59 GVTVETVfSVDEFSA -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.526 SIGNOR-263585 IL1RL1 protein Q01638 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 35238669 YES miannu The activated heterodimer complex recruits downstream signaling components, including myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor (IL-1R)–associated kinase, tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), and transforming growth factor (TGF)-β–activated kinase 1 (TAK1) complex, resulting in TAK1 activation. TAK1 subsequently activates downstream kinases inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) and IKKβ, which phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor (IκB) proteins. These events ultimately lead to activation of the transcription factor NF-κB and induction of downstream effector genes 0.2 SIGNOR-277716 AKT proteinfamily SIGNOR-PF24 SIGNOR CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 9606 BTO:0000567 20682768 YES lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva 0.2 SIGNOR-244214 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-98297 ACTB protein P60709 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR up-regulates 9606 BTO:0000007 19121306 NO lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. 0.306 SIGNOR-260610 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 21818122 YES miannuccelli Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. 0.428 SIGNOR-279752 PIM1 protein P11309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 18593906 YES gcesareni We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels. 0.383 SIGNOR-179300 DNA polymerase alpha:primase complex complex SIGNOR-C262 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 24043831 NO lperfetto At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation  0.7 SIGNOR-261344 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258467 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 11839802 YES gcesareni Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta 0.893 SIGNOR-114767 UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR form complex binding 9606 22160681 YES miannu Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis.  0.8 SIGNOR-267923 CDK2 protein P24941 UNIPROT RNF4 protein P78317 UNIPROT up-regulates activity phosphorylation Thr112 DVYVTTHtPRNARDE 9606 BTO:0002181 25948581 YES miannu Here we reported that CDK2 could phosphorylate RNF4 on T26 and T112 and enhance RNF4 E3 ligase activity, which is important for MDC1 degradation and proper HR repair during S phase.  0.2 SIGNOR-276901 PLK1 protein P53350 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 15849359 YES lperfetto Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinase| irs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin. 0.267 SIGNOR-135688 CDK1 protein P06493 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser373 SSRSAPAsPNHAGVL 9606 20810654 YES gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. 0.373 SIGNOR-167822 CSNK2A1 protein P68400 UNIPROT GGA1 protein Q9UJY5 UNIPROT down-regulates activity phosphorylation Ser355 EQPSASVsLLDDELM 9534 BTO:0000298 12060753 YES miannu Serine-355 of GGA1 is phosphorylated in vivo and in vitro. This inhibition is caused by the binding of an AC-LL sequence present in the hinge segment to the ligand-binding site in the VHS domain. The inhibition depends on the phosphorylation of a serine located three residues upstream of the AC-LL motif. The serine is phosphorylated by casein kinase 2 in in vitro assays.  0.504 SIGNOR-273623 sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 19401148 YES miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 0.8 SIGNOR-268133 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000669 15568017 YES gcesareni Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. 0.58 SIGNOR-131307 PPP2R5C protein Q13362 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 7592815 YES We have identified by two-hybrid interaction a new human gene family encoding PP2A B subunits. This family, denoted B56, contains three distinct genes, one of which is differentially spliced. 0.864 SIGNOR-268155 TGFB1 protein P01137 UNIPROT SALL2 protein Q9Y467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 21228219 NO miannu TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts. 0.2 SIGNOR-255427 PIK3C3 protein Q8NEB9 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 YES lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.894 SIGNOR-260320 CDK1 protein P06493 UNIPROT NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr120 HKFNVTGtPEQYVPY 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275588 MYC protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 YES gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a 0.778 SIGNOR-102740 Obatoclax mesylate chemical CID:46930996 PUBCHEM MCL1 protein Q07820 UNIPROT down-regulates activity chemical inhibition -1 23515850 YES lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro|The ability of obatoclax to inhibit MCL-1 may be particularly important, given that several hematological malignancies appear to depend on this protein for survival, such as acute lymphoblastic leukemia (ALL),44 CLL,44 multiple myeloma,45 and diffuse large B-cell lymphoma (DLBCL) 0.8 SIGNOR-262025 COX4I1 protein P13073 UNIPROT Oxidative_phosphorylation phenotype SIGNOR-PH78 SIGNOR up-regulates 10090 23021218 NO lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 0.7 SIGNOR-253101 KIF1B protein O60333 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272519 FGFR2 protein P21802 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates activity phosphorylation 10116 BTO:0002809 9182757 YES fspada In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. 0.777 SIGNOR-236950 AMPK complex SIGNOR-C15 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 15866171 YES lperfetto Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest 0.443 SIGNOR-216475 RPS6K proteinfamily SIGNOR-PF26 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 10464286 YES gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-265345 TGFBI protein Q15582 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates activity 10090 BTO:0004093 25786978 YES lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. 0.349 SIGNOR-253283 BTF3 protein P20290 UNIPROT SSPN protein Q14714 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 17312387 NO In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. 0.2 SIGNOR-253951 NTN4 protein Q9HB63 UNIPROT UNC5A protein Q6ZN44 UNIPROT up-regulates binding 9606 12598531 YES gcesareni The unc5hs are axon guidance receptors that mediate netrin-1-dependent chemorepulsion, and dependence receptors that mediate netrin-1-independent apoptosis. 0.608 SIGNOR-98483 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 YES lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins 0.823 SIGNOR-52859 GDNF protein P39905 UNIPROT GCH1 protein P30793 UNIPROT up-regulates activity 9606 12358777 NO miannu GDNF can support the function of primary dopaminergic neurones by triggering activation of GTP-cyclohydrolase I (GTPCH I), a key enzyme in catecholamine biosynthesis. GTPCH I mRNA levels in primary dopaminergic neurones were not altered by GDNF treatment, suggesting that the mode of action for that up-regulation is not directly connected to the regulation of GTPCH I transcription 0.277 SIGNOR-252221 STC2 protein O76061 UNIPROT STC2/HMOX1 complex SIGNOR-C244 SIGNOR form complex binding BTO:0000298 22503972 YES Giorgia Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme. 0.344 SIGNOR-260387 PTK2B protein Q14289 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity phosphorylation Tyr470 AYATEAVyESAEAPG 9606 29133485 YES miannu In conclusion, these data suggest that Pyk2 phosphorylates cortactin on tyrosine residues Y421, Y466, and Y482.|To confirm the direct and indirect effects of Pyk2 on cortactin phosphorylation, we used cells overexpressing Arg YFP and treated with Pyk2 siRNA or a nonsilencing siRNA. 0.366 SIGNOR-278344 GCM2 protein O75603 UNIPROT PTH protein P01270 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004712 20558332 NO miannu We found that GCMB binds to the PTH gene 5'-promoter (-390/-383 bp) and positively regulates its transcription. 0.408 SIGNOR-254200 AKT proteinfamily SIGNOR-PF24 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 YES lperfetto Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. 0.2 SIGNOR-244322 azelastine chemical CHEBI:2950 ChEBI HRH3 protein Q9Y5N1 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 21381763 YES Luana Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively.  0.8 SIGNOR-257895 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257518 TNF protein P01375 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 NO miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection 0.7 SIGNOR-261034 ULK2 protein Q8IYT8 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 YES miannu We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I 0.305 SIGNOR-173089 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 8621729 YES lperfetto Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling. 0.753 SIGNOR-244813 ribosomal RNA smallmolecule CHEBI:18111 ChEBI B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 YES miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 0.8 SIGNOR-269470 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Thr221 AGTSFMMtPYVVTRY 9606 BTO:0000007 17761173 YES lperfetto We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3 0.743 SIGNOR-260614 MELK protein Q14680 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity phosphorylation 9606 29212029 YES miannu Consistent with our SILAC experiments, MELK directly phosphorylated SQSTM1 (XREF_FIG).|Furthermore, we show that MELK promotes melanoma growth by activating NF-kappaB pathway activity via Sequestosome 1 (SQSTM1 and p62). 0.2 SIGNOR-279544 MAP2K7 protein O14733 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG 9606 BTO:0000975 17360977 YES lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 Ser312 can be phosphorylated by kinases, such as c-jun NH2-terminal kinase and inhibitor of _B kinase 0.369 SIGNOR-217920 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser295 VIRPRRRsSCVSLGE 10090 BTO:0000944 10454575 YES PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B 0.687 SIGNOR-252573 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. 0.2 SIGNOR-252347 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT up-regulates quantity by stabilization deubiquitination Lys501 ADDISLLk 9606 BTO:0003704 27302062 YES irozzo Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501. 0.451 SIGNOR-259101 TBKBP1 protein A7MCY6 UNIPROT CARD10 protein Q9BWT7 UNIPROT up-regulates activity relocalization 9606 31792381 YES TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation 0.2 SIGNOR-272470 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 YES Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels 0.2 SIGNOR-262522 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 YES lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination 0.755 SIGNOR-188412 TGFB1 protein P01137 UNIPROT ANKH protein Q9HCJ1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20930330 NO miannu TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line. 0.2 SIGNOR-252201 Monobutylphthalate chemical CHEBI:88522 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9606 BTO:0000816 16326050 YES miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast 0.8 SIGNOR-268752 PTPN22 protein Q9Y2R2 UNIPROT CBL protein P22681 UNIPROT down-regulates dephosphorylation Ser798 SDISNASsSFGWLSL 9606 BTO:0000782 10068674 YES amattioni The tyrosine phosphatase lyp1 was found to be constitutively associated with the proto-oncogene c-cbl in thymocytes and t cells. Overexpression of lyp1 reduces cbl tyrosine phosphorylation. It is known that cbl is heavily tyrosine phosphorylated after tcr stimulation and can associate with the syk and zap tyrosine kinases, negatively regulating their activities. Tyrosine phosphatases keep cbl in a basally dephosphorylated state. 0.387 SIGNOR-65405 CHUK protein O15111 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser1415 PTPAILEsLISINNK 9606 BTO:0002181 24990947 YES miannu  Importantly, IKKα is shown to phosphorylate mTOR at serine 1415 in a manner dependent on Akt to promote mTORC1 activity. These results demonstrate that IKKα is an effector of Akt in promoting mTORC1 activity. 0.512 SIGNOR-276646 PRKCD protein Q05655 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 YES lperfetto Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. 0.2 SIGNOR-249059 PTPRF protein P10586 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 11121408 YES gcesareni Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b 0.426 SIGNOR-85170 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates ubiquitination 9606 22575959 YES gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6. 0.292 SIGNOR-197417 AURKA protein O14965 UNIPROT SKI protein P12755 UNIPROT down-regulates quantity by destabilization phosphorylation Ser326 RRVPRVSsEPPASIR -1 26138431 YES miannu Here we show that AURKA phosphorylates in vitro the transcripcional co-repressor Ski on aminoacids Ser326 and Ser383. Phosphorylations on these aminoacids decreased Ski protein half-life 0.2 SIGNOR-276918 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation 0.889 SIGNOR-209773 HNF4A protein P41235 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 NO inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.257 SIGNOR-267790 RPIA protein P49247 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 34775382 YES miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. 0.8 SIGNOR-267070 RNF111 protein Q6ZNA4 UNIPROT PML protein P29590 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23530056 YES miannu Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4. 0.355 SIGNOR-272883 NMDA receptor_2B complex SIGNOR-C348 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 YES miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. 0.3 SIGNOR-266600 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser156 KKPVRPVsRGCLHSH 9606 BTO:0002181 34363019 YES miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  0.2 SIGNOR-276740 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CALD1 protein Q05682 UNIPROT down-regulates phosphorylation 9606 BTO:0001260 10514499 YES inferred from 70% family members lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. 0.2 SIGNOR-270162 CHEK1 protein O14757 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser230 AFAQRPSsAPDLMCL 9606 17003105 YES lperfetto Here, we show that cdc25b is phosphorylated by chk1 in vitro on multiple residues, including s230 and s563.We show that the s230-phosphorylated form of cdc25b is located at the centrosome from early s phase until mitosis. Furthermore, mutation of s230 to alanine increases the mitotic-inducing activity of cdc25b 0.784 SIGNOR-149898 CBL protein P22681 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates ubiquitination 9606 BTO:0000782 11526404 YES lperfetto Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner. 0.611 SIGNOR-252668 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT up-regulates 9606 9362449 NO Nck interacts witn ErbB1 through SH2 and SH3 domains gcesareni We found that nck does not directly bind to egf receptor, instead it binds via its sh2 domain to a 62 kda phosphotyrosine protein 0.577 SIGNOR-52954 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Thr66 ATRKALGtVNRATEK 9606 BTO:0000567 24781523 YES miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase 0.31 SIGNOR-276377 RPS6KA3 protein P51812 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002181 23608533 YES miannu We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. 0.2 SIGNOR-276464 RNF152 protein Q8N8N0 UNIPROT RRAGA protein Q7L523 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0000007 25936802 YES miannu  Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases.  0.739 SIGNOR-272222 SHOC2 protein Q9UQ13 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates activity binding 9606 BTO:0000007 16630891 YES Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site 0.595 SIGNOR-251647 PEX1 protein O43933 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity binding 10029 16314507 YES Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner. 0.549 SIGNOR-253618 RNF8 protein O76064 UNIPROT H2AX protein P16104 UNIPROT up-regulates ubiquitination 9606 18001824 YES gcesareni Rnf8 can ubiquitylate histone h2a and h2ax, 0.2 SIGNOR-159309 PIK3R1 protein P27986 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity 10116 21798082 NO lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). 0.8 SIGNOR-175678 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser535 ESEQSMDsEEPDSRG -1 12133000 YES The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535). 0.578 SIGNOR-251236 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA2 protein Q9Y5H1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265713 SF3B1 protein O75533 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 25428262 NO irozzo We have shown that SF3B1 knockdown in four myeloid cell lines resulted in inhibition of cell growth and disruption of the cell cycle.Taken together, these data show that SF3B1 knockdown results in inhibition of cell growth, induction of cell cycle arrest and impairment of erythroid differentiation in myeloid cell lines. 0.7 SIGNOR-256003 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 15831498 YES gcesareni Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300 0.464 SIGNOR-135469 CSNK2A1 protein P68400 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser282 EGRGEVGsAGDMRAA 9606 BTO:0000150;BTO:0000567 20043841 YES lperfetto Additionally protein kinase ck2 was identified as a kinase that phosphorylated eralpha at s282 and s559 s282 and s559 represent the second and third sites of er_ regulation by ck2. Remarkably, mutation of s282 or s559 to alanine resulted in near opposite functional effects on er_ as compared to mutation of s167 to alanine. Er_ ligand independent transcriptional activity was markedly enhanced upon mutation of s282 and s559 to alanine 0.246 SIGNOR-162653 GABRG2 protein P18507 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.641 SIGNOR-263764 midostaurin chemical CHEBI:63452 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258247 UBE2D1 protein P51668 UNIPROT MGRN1 protein O60291 UNIPROT up-regulates activity binding 9606 BTO:0000567 17229889 YES miannu Our in vivo and in vitro ubiquitylation studies demonstrate that the binding of TSG101 to Mahogunin targets the substrate TSG101 for ubiquitylation by Mahogunin E3 ligase in cooperation with its cognate E2 enzyme Ubc5a 0.494 SIGNOR-271637 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser746 RRSVRIGsYIERDVT 9606 7539802 YES miannu Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity 0.53 SIGNOR-28605 SMARCD3 protein Q6STE5 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 NO lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by MyoD and other regulatory proteins. 0.353 SIGNOR-136945 KCTD17 protein Q8N5Z5 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0004910 25270598 YES miannu We have identified KCTD17 as a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of KCTD17 specifically arrests ciliogenesis at the initial step of axoneme extension through aberrant trichoplein-Aurora-A activity. Thus, CRL3-KCTD17 targets trichoplein to proteolysis to initiate the axoneme extension during ciliogenesis. 0.433 SIGNOR-272464 KDM4C protein Q9H3R0 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 BTO:0001033 29207681 YES miannu JMJD2C was found to be co-localized with AR and LSD1 in the epithelium of prostate carcinoma and normal prostate cells. For the detailed mechanism, JMJD2C, AR and LSD1 assembled on the chromatin to remove the methyl groups from mono-, di- and trimethylated H3K9. Importantly, JMJD2C specifically removed the demethylation of the trimethyl H3K9 marks and modulated the transcriptional activity of AR. Moreover, JMJD2C cooperated with LSD1 and activated AR-mediated gene expression via decreasing H3K9me3 at the promoter of AR targeting genes KLK2 and PSA. 0.2 SIGNOR-263879 FRAT1 protein Q92837 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 9635432 YES lperfetto The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway 0.642 SIGNOR-227994 UBA6 protein A0AVT1 UNIPROT Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR form complex binding 9606 24816100 YES miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. 0.2 SIGNOR-270835 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1B protein P49286 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257546 PLK1 protein P53350 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity phosphorylation Thr680 SKMQLLEtEFSHTVG -1 18922800 YES miannu These findings indicate mechanistic roles contributed by protein phosphorylation and Plk1 to the SAC activity of Mad1.Here, we have studied the phosphorylation of Mad1 and mapped using liquid chromatography-tandem mass spectrometry several phosphorylated amino acids in this protein. One phosphorylated residue, Thr680, was characterized to be important for the kinetochore localization of Mad1 and its SAC function. 0.463 SIGNOR-276173 PLK1 protein P53350 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1791 REPLGEDsVGLKPLK 9606 BTO:0000552 31597699 YES miannu As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F). 0.402 SIGNOR-277491 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT down-regulates activity phosphorylation Tyr273 SFFSSPPyFED 9534 BTO:0001538 24284075 YES miannu Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity 0.2 SIGNOR-263142 TP53 protein P04637 UNIPROT RLIM protein Q9NVW2 UNIPROT down-regulates quantity by repression transcriptional regulation 23650532 NO lperfetto In the present study, we identified RLIM as a novel target of p53 and demonstrated that p53 repressed both mRNA and protein levels of RLIM. 0.2 SIGNOR-268981 LMO2 protein P25791 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 NO miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. 0.331 SIGNOR-198249 Ub:E2 complex SIGNOR-C497 SIGNOR MIB2 protein Q96AX9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270989 PRKACA protein P17612 UNIPROT APC protein P25054 UNIPROT down-regulates activity phosphorylation Ser2054 MPKKKKPsRLKGDNE 9606 11050185 YES miannu Changing a serine residue (Ser(2054)) to aspartic acid mutated the potential protein kinase A site adjacent to NLS2(APC), resulting in both inhibition of the NLS2(APC)-mediated nuclear import of a chimeric beta-galactosidase fusion protein and a reduction of full-length APC nuclear localization. 0.307 SIGNOR-250335 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates activity phosphorylation Ser467 RPLGRTQsAPLPQNA BTO:0001938 11470791 YES llicata CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus. 0.619 SIGNOR-250711 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser168 QGGGAFFsPSPGSSS 9606 11997522 YES lperfetto Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity. 0.2 SIGNOR-87393 CBL protein P22681 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates ubiquitination 9606 BTO:0000782 11526404 YES lperfetto Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner. 0.694 SIGNOR-110060 PRKACA protein P17612 UNIPROT ASIC1 protein P78348 UNIPROT unknown phosphorylation Ser479 QKEAKRSsADKGVAL 9606 BTO:0000142 12578970 YES llicata We found that protein kinase a phosphorylation of ser-479 in the asic1 c terminus interfered with pick1 binding. 0.327 SIGNOR-98196 SMOC1 protein Q9H4F8 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 NO lperfetto The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells 0.2 SIGNOR-260400 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR down-regulates 9606 BTO:0000132 23805129 NO lperfetto Inhibition of actin polymerization also augments the kinetics and degree of alpha-granule release (Flaumenhaft et al., 2005). These results suggest that F-actin disassembly might actually be required for normal granule secretion and that activation-mediated granule release is related to actin. 0.7 SIGNOR-266000 SRC protein P12931 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 YES lperfetto Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir. 0.448 SIGNOR-78706 PTEN protein P60484 UNIPROT NCL protein P19338 UNIPROT up-regulates activity dephosphorylation Thr84 PAKKAAVtPGKKAAA 9606 28332494 YES miannu The fact that PTEN\u03b2 interacts with nucleolin and dephosphorylates nucleolin at Thr84 raised a question as to whether nucleolin mediates PTEN\u03b2 regulation of rDNA transcription, and thus represents a direct mechanism by which PTEN\u03b2 controls ribosomal biogenesis. 0.27 SIGNOR-277166 MMP16 protein P51512 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272361 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120076 EIF2AK2 protein P19525 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 YES miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. 0.314 SIGNOR-263120 MAPK8 protein P45983 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10116 BTO:0003324 16306447 YES gcesareni We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase. 0.428 SIGNOR-252426 Ub:E2 complex SIGNOR-C497 SIGNOR RNF115 protein Q9Y4L5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271000 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser66 GVYATRSsAVRLRSS -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248884 DLG4 protein P78352 UNIPROT LRFN2 protein Q9ULH4 UNIPROT up-regulates activity binding 9606 BTO:0000938 21736948 YES miannu SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses. 0.748 SIGNOR-264094 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr1097 SMIRTGEtPTKKRGI 9606 BTO:0001938 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104695 MC3R protein P41968 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.272 SIGNOR-257358 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser203 PRLQHSFsFAGFPSA 9606 18326031 YES lperfetto Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation. 0.619 SIGNOR-161270 SH2B3 protein Q9UQQ2 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 10090 BTO:0002882 18618018 YES miannu we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. we identify a direct interaction between Lnk and the Mpl/JAK2 complex that regulates various HSC functions. 0.642 SIGNOR-260075 NLGN1 protein Q8N2Q7 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.839 SIGNOR-264149 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr287 RDPLLEVyDVPPSVE 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246405 AKT proteinfamily SIGNOR-PF24 SIGNOR WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Thr60 EYRRRRHtMDKDSRG 9606 16081417 YES llicata Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt. 0.2 SIGNOR-139391 UVB radiation stimulus SIGNOR-ST17 SIGNOR MC1R protein Q01726 UNIPROT up-regulates 9606 9767234 NO miannu Melanocyte-stimulating hormone (MSH) receptor binding activity and melanocortin-1 receptor (MC1-R) gene expression on normal human melanocytes have been studied as responses to the effects of ultraviolet B (UVB), interleukin-1 (IL-1), endothelin-1 (ET-1) and tumour necrosis factor-alpha (TNF-alpha), which are known as UV sensitive regulators of melanocytic function. MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. 0.7 SIGNOR-252388 PPARD protein Q03181 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001951 18048767 NO miannu Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. 0.266 SIGNOR-255053 HDAC1 protein Q13547 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity deacetylation 10090 24463822 YES The ability of HDAC1 to cause muscle atrophy required its deacetylase activity and was linked to the induction of several atrophy genes by HDAC1, including atrogin-1, which required deacetylation of FoxO3a 0.368 SIGNOR-256486 CHEK1 protein O14757 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity phosphorylation Ser331 KSKGRASsSGNQESS 9606 BTO:0000567 19861535 YES lperfetto In vitro and in vivo experiments show that phosphorylation of s331 is mediated by chk1, the s-phase checkpoint kinase implicated in the fanconi anemia dna repair pathway. phosphorylation at this site is dependent on chk1, signifying the importance of the s-phase checkpoint in the activation of fanconi anemia pathway. 0.586 SIGNOR-107042 CSNK1G3 protein Q9Y6M4 UNIPROT LYN protein P07948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser13 SKGKDSLsDDGVDLK 9606 BTO:0000007 33004926 YES miannu Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane. 0.2 SIGNOR-275395 LRRK2 protein Q5S007 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Thr595 NWRGMLKtSKAEELL 9606 BTO:0002181 23813973 YES miannu LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy 0.569 SIGNOR-276495 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007;BTO:0000443 SIGNOR-C3 17510057 YES lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. 0.926 SIGNOR-154814 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 14707117 YES gcesareni Furthermore, we demonstrate that pstpip serves as a scaffold protein between ptp-pest and wasp and allows ptp-pest to dephosphorylate wasp. This finding suggests a possible mechanism for ptp-pest to directly modulate actin remodeling through the pstpip-wasp interaction. 0.445 SIGNOR-121136 FBXW7 protein Q969H0 UNIPROT CCNE2 protein O96020 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002524 17298674 YES miannu Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme 0.437 SIGNOR-271642 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation 9606 15356145 YES inferred from 70% family members lperfetto Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623. 0.2 SIGNOR-270133 PIAS3 protein Q9Y6X2 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 SIGNOR-C9 14691252 YES gcesareni Taken together, our studies indicate that on tgf-beta treatment, pias3 can form a complex with smads and p300/cbp and activate smad transcriptional activity. 0.596 SIGNOR-120359 okadaic acid chemical CHEBI:44658 ChEBI STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates 9606 23493077 NO inferred from 70% of family members gcesareni Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway. 0.8 SIGNOR-269947 TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 15340059 YES lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. 0.916 SIGNOR-235895 ZNF165 protein P49910 UNIPROT PMEPA1 protein Q969W9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 26567849 YES Luana ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1. 0.271 SIGNOR-266094 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. 0.8 SIGNOR-268094 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203540 AURKB protein Q96GD4 UNIPROT NSUN2 protein Q08J23 UNIPROT down-regulates phosphorylation Ser139 SRKILRKsPHLEKFH 9606 17215513 YES lperfetto Aurora-b phosphorylated nsun2 at ser139. Aurora-b-phosphorylation and the phosphorylation-mimic mutation (s139e) suppressed methyltransferase activities of nsun2. 0.719 SIGNOR-152001 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1176 ISLGESVsDMAPARP -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262904 ACSS2 protein Q9NR19 UNIPROT PPM1D protein O15297 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; 0.2 SIGNOR-276560 PPP2CA protein P67775 UNIPROT DOCK6 protein Q96HP0 UNIPROT down-regulates activity phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 YES lperfetto Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching 0.2 SIGNOR-275669 IL4R protein P24394 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 YES lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. 0.623 SIGNOR-249530 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser621 PKINRSAsEPSLHRA 9606 11971957 YES gcesareni We have mapped all camp-induced phosphorylation sites in raf-1, showing that serines 43, 259, and 621 are phosphorylated by pka in vitro and induced by camp in vivo 0.499 SIGNOR-86137 AIM2 protein O14862 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.748 SIGNOR-256399 CSNK1D protein P48730 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Ser159 GIPVRCYsAEVVTLW -1 10500146 YES llicata We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. 0.554 SIGNOR-250798 MAPK8IP2 protein Q13387 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 10490659 YES gcesareni Deletion analysis demonstrated that the cooh-terminal regions of jip1 and jip2 were sufficient for the formation of hetero-oligomeric complexes 0.655 SIGNOR-70863 CHRNB3 protein Q05901 UNIPROT APC protein P25054 UNIPROT up-regulates activity binding 9606 BTO:0002916 14502292 YES miannu Treatment of muscle cells with neural agrin causes tyrosine phosphorylation of the AChR β subunit and induces AChR clustering by promoting anchoring of the receptor protein to postsynaptic cytoskeleton. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. By showing a direct requirement for APC in AChR clustering, our present study suggests that the Wnt/β-catenin pathway may crosstalk with the agrin signaling cascade during the formation of mammalian neuromuscular junction. 0.2 SIGNOR-264261 RPS6KA1 protein Q15418 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 17360704 NO gianni Mutation of rpS6 at Ser(235/236) reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery. 0.7 SIGNOR-268528 NDUFA10 protein O95299 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 0.826 SIGNOR-262151 HMGB1 protein P09429 UNIPROT TLR4 protein O00206 UNIPROT up-regulates activity binding 9606 20547845 YES gcesareni Here we show that Toll-like receptor 4 (TLR4), a pivotal receptor for activation of innate immunity and cytokine release, is required for HMGB1-dependent activation of macrophage TNF release. 0.802 SIGNOR-252057 CAV1 protein Q03135 UNIPROT SLC1A6 protein P48664 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 YES miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. 0.2 SIGNOR-264810 MYT1L protein Q9UL68 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR down-regulates 9606 29397565 NO miannu Myt1L (myelin transcription factor 1-like), mainly expressed in neurons, has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1L was expressed in oligodendrocyte lineage cells during myelination and remyelination. 0.7 SIGNOR-266779 ATM protein Q13315 UNIPROT RIF1 protein Q5UIP0 UNIPROT up-regulates activity binding 9606 15342490 YES miannu Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. After induction of double-strand breaks (DSBs), Rif1 formed foci that colocalized with other DNA-damage-response factors. This response was strictly dependent on ATM (ataxia telangiectasia mutated) and 53BP1, but not affected by diminished function of ATR (ATM- and Rad3-related kinase), BRCA1, Chk2, Nbs1, and Mre11. 0.497 SIGNOR-259059 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr92 FYEEIKKyEKLETEE 16725308 YES miannu Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.  0.2 SIGNOR-266293 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFKM protein P08237 UNIPROT up-regulates activity binding 9606 19454274 YES The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux 0.8 SIGNOR-267267 CyclinA2/CDK18 complex SIGNOR-C547 SIGNOR AQP2 protein P41181 UNIPROT down-regulates quantity by destabilization phosphorylation Ser261 RQSVELHsPQSLPRG 9606 BTO:0000007 32164329 YES lperfetto CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. |We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance 0.26 SIGNOR-273438 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI GSN protein P06396 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 12788695 YES lperfetto We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations. 0.8 SIGNOR-261840 PEX3 protein P56589 UNIPROT PEX19 protein P40855 UNIPROT up-regulates activity binding -1 15007061 YES miannu PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes. 0.954 SIGNOR-253026 SCF-FBW7 complex SIGNOR-C135 SIGNOR PDCD1 protein Q15116 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys233 LDFQWREkTPEPPVP 9606 BTO:0000007 36104103 YES miannu We identified FBW7 as a E3 ubiquitin ligase for PD-1 protein, in which FBW7 promotes the K48-linked polyubiquitination of PD-1 protein at Lys233 residue. 0.2 SIGNOR-277606 FOXO1 protein Q12778 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 18391974 NO Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism. 0.7 SIGNOR-253010 ATP6V1A protein P38606 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.765 SIGNOR-277757 NFKB1 protein P19838 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001321 11909978 YES NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. 0.2 SIGNOR-253668 ABL1 protein P00519 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 16943190 YES gcesareni We show that activated abl phosphorylates the egfr primarily on tyrosine 1173. 0.42 SIGNOR-149273 CORT protein O00230 UNIPROT MRGPRX2 protein Q96LB1 UNIPROT up-regulates binding 9606 BTO:0000938 16111673 YES gcesareni The mrgx2 receptor has been shown to be activated by the peptides cortistatin and proadrenomedullin n-terminal peptides (pamp) 0.512 SIGNOR-139855 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 YES gcesareni Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo. 0.559 SIGNOR-74939 MEGF10 protein Q96KG7 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 9606 28526325 NO miannu Our results indicate that MEGF10 may be responsible for phagocytic activity targeted toward unwanted substances such as amyloid in cholinergic and glutamatergic neurons. 0.7 SIGNOR-265166 CASP8 protein Q14790 UNIPROT Caspase 8 complex complex SIGNOR-C231 SIGNOR form complex binding cleavage:Asp216 SDSPREQdSESQTLD 10508785 YES lperfetto Activated caspase-8 (an alpha2beta2 heterotetramer) activates other downstream caspases that are incapable of autocatalytic processing and activation. |The alphabeta dimeric protein associates further to form an alpha2beta2 heterotetramer that appears to be required for catalytic activity. 0.2 SIGNOR-256395 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120144 GATA6 protein Q92908 UNIPROT SEMA3C protein Q99985 UNIPROT up-regulates quantity by expression transcriptional regulation 19666519 NO lperfetto Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. 0.398 SIGNOR-253150 ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation 9606 15068801 YES gcesareni Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter. 0.296 SIGNOR-123717 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1623 SPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248816 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002423 21489980 NO miannu Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. 0.2 SIGNOR-254892 MAPK1 protein P28482 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10906323 YES gcesareni Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function. 0.353 SIGNOR-79515 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 19933846 YES gcesareni Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. 0.644 SIGNOR-161819 BMP10 protein O95393 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000562 16049014 YES acerquone We showed that three orphan ligands known to be important for joint and cartilage formation (gdf6) (10), interneuron, sensory neurons, and seminal vesicle formation (gdf7) (11_13), and heart development (bmp10) (14) used the type i receptors alk3 or alk6 and the type ii receptors bmprii or actriia to activate the smad1/5/8 proteins. 0.631 SIGNOR-139052 SMO protein Q99835 UNIPROT GPR161 protein Q8N6U8 UNIPROT down-regulates activity relocalization 10090 23332756 NO Constitutive Gpr161 activity increases cAMP levels, which is reduced upon knockdown of Gαs, suggesting it to be a Gαs-coupled receptor. 0.318 SIGNOR-259937 RNF138 protein Q8WVD3 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16714285 YES miannu Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome. 0.326 SIGNOR-271593 TGFB2 protein P61812 UNIPROT Activated PSC phenotype SIGNOR-PH224 SIGNOR up-regulates 9606 BTO:0000988 38540204 YES miannu Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction 0.7 SIGNOR-277680 SPI1 protein P17947 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20861919 NO apalma In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation. 0.7 SIGNOR-256372 LRRC4 protein Q9HBW1 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25526788 NO miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. 0.2 SIGNOR-264055 PPP1CA protein P62136 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000599;BTO:0001594 19440292 YES Avicins dephosphorylate Stat3 in a variety of human tumor cell lines, leading to a decrease in the transcriptional activity of Stat3.| However, PD98059, an inhibitor of MEK1/2, had no significant effects on avicin-induced dephosphorylation of Stat3 (Ser 727) 0.33 SIGNOR-248563 TET2 protein Q6N021 UNIPROT WT1 protein P19544 UNIPROT up-regulates activity binding 9606 BTO:0000670;BTO:0000738 25601757 YES irozzo  In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes. 0.448 SIGNOR-255703 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE 9606 10702308 YES lperfetto A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192. 0.2 SIGNOR-235758 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser469 NYALKMNsPSQSSPG 9606 BTO:0000801 29170386 YES Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. 0.246 SIGNOR-256096 pirenzepine chemical CHEBI:8247 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258395 PPP2CA protein P67775 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation Thr202 HDHTGFLtEYVATRW 9606 phosphorylation:Thr202 HDHTGFLtEYVATRW 16456541 YES gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk 0.646 SIGNOR-144322 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr507 FGESRAStFCGTPDY 9606 19366211 YES llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. studies reported herein show that a t505a substitution reduces pkcdelta-thr(295) autophosphorylation 0.2 SIGNOR-185287 SEPTIN7 protein Q16181 UNIPROT SEPT6/SEPT7 complex SIGNOR-C72 SIGNOR form complex binding 9606 16914550 YES miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. 0.2 SIGNOR-148898 pralatrexate chemical CHEBI:71223 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 23409799 YES miannu Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. 0.8 SIGNOR-259353 RPS6K proteinfamily SIGNOR-PF26 SIGNOR NR4A3 protein Q92570 UNIPROT down-regulates activity phosphorylation Ser376 GRRGRLPsKPKSPLQ 9606 BTO:0000007 16223362 YES lperfetto Phosphorylation of Nur77 on Ser354 has been suggested to reduce ability of Nur77 to bind DNA; however, the kinase responsible for this phosphorylation in cells has not been clearly established. In the present study, we show that Nur77 is phosphorylated on this site by RSK (ribosomal S6 kinase) 0.2 SIGNOR-252771 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates activity relocalization 9606 BTO:0000661 9632809 NO The polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor (CBF) is a transcription factor composed of two subunits, α and β. The gene encoding the β subunit is disrupted by inv(16), resulting in the formation of a chimeric protein, β-SMMHC, which is associated with acute myelogenous leukemia.Thus, the result suggess that β-SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the α subunit. 0.2 SIGNOR-255741 GSK3A protein P49840 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 19214430 YES gcesareni Taken together, our results indicate that gsk-3alfa is a negative regulator of notch1/nicd. 0.32 SIGNOR-183969 SLC36A4 protein Q6YBV0 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity relocalization 8355 21097500 YES lperfetto HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM). 0.8 SIGNOR-264736 CSNK2A2 protein P19784 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity phosphorylation Thr770 DSILRLQtWDEAVFR 9606 BTO:0000007 21068236 YES miannu Phosphorylation of RIG-I by casein kinase II inhibits its antiviral response.Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of RIG-I are phosphorylated by casein kinase II (CK2) in the resting state of the cell and dephosphorylated when cells are infected by RNA virus. 0.2 SIGNOR-276285 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120168 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation 9606 18694962 YES Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. 0.2 SIGNOR-270131 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 20138985 YES lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. 0.729 SIGNOR-252539 MAPK1 protein P28482 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr292 ETPPRPRtPGRPLSS 9534 BTO:0004055 14993270 YES lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. 0.75 SIGNOR-236335 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268760 RPS6KA1 protein Q15418 UNIPROT METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 YES gcesareni Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro. 0.324 SIGNOR-135948 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr272 KCNKPTVyGVSPIHD -1 34144039 YES miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. 0.303 SIGNOR-277305 glycine smallmolecule CHEBI:15428 ChEBI GLRB protein P48167 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 YES miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 0.8 SIGNOR-264983 PRKCA protein P17252 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Thr1075 NQRNRCStFRVKRNQ -1 36040231 YES miannu PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. 0.2 SIGNOR-276865 PHKA2 protein P46019 UNIPROT PHKG2 protein P15735 UNIPROT down-regulates activity binding 9606 10487978 YES Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. 0.916 SIGNOR-267406 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 16537444 YES gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. 0.636 SIGNOR-145145 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity precursor of 9606 24786789 YES miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. 0.8 SIGNOR-266510 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18936167 YES gcesareni The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2. 0.698 SIGNOR-181676 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys682 LLKLLPEkHEIENLR 9606 BTO:0000007 28448495 YES miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 0.2 SIGNOR-272805 CDK2 protein P24941 UNIPROT UHRF1 protein Q96T88 UNIPROT down-regulates quantity by destabilization phosphorylation Ser675 KTKVEPYsLTAQQSS -1 26727879 YES miannu UHRF1 is phosphorylated by CDK2/cyclin A. In vitro kinase assay was performed with CDK2/cyclin A using recombinant wild-type UHRF1 or UHRF1-S674A mutant  0.303 SIGNOR-277192 KDM4C protein Q9H3R0 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys37 APSTGGVkKPHRYRP 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-263868 MLST8 protein Q9BVC4 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.832 SIGNOR-205612 KAT2B protein Q92831 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269617 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR HJURP protein Q8NCD3 UNIPROT up-regulates activity binding -1 17256767 YES miannu These data define a new protein complex in mammalian cells where 14‐3‐3 associates with FAKTS through phosphorylated S479. Our research identifies a widely expressed eukaryotic protein FAKTS, as a new Akt/PKB substrate localized in the nucleus. Akt/PKB promotes FAKTS association with 14‐3‐3, placing FAKTS under the control of 14‐3‐3 proteins. FAKTS may play an important role in transmitting Akt/PKB‐mediated signals in the complex network of intracellular signal transduction. 0.2 SIGNOR-262624 IL17A protein Q16552 UNIPROT KLF15 protein Q9UIH9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23332504 NO fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. 0.2 SIGNOR-192474 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 7515062 YES gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. 0.897 SIGNOR-27028 IFI30 protein P13284 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 31810556 YES scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. 0.8 SIGNOR-267865 ASNS protein P08243 UNIPROT L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI up-regulates quantity chemical modification 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-267533 MAPK3 protein P27361 UNIPROT EPS8 protein Q12929 UNIPROT down-regulates activity phosphorylation Ser625 ADTPPAPsPPPTPAP -1 19564905 YES miannu We further show that the actin barbed-end capping activity of Eps8 is inhibited by brain-derived neurotrophic factor (BDNF) treatment through MAPK-dependent phosphorylation of Eps8 residues S624 and T628. Additionally, an Eps8 mutant, impaired in the MAPK target sites (S624A/T628A), displays increased association to actin-rich structures, is resistant to BDNF-mediated release from microfilaments, and inhibits BDNF-induced filopodia. The opposite is observed for a phosphomimetic Eps8 (S624E/T628E) mutant. Thus, collectively, our data identify Eps8 as a critical capping protein in the regulation of axonal filopodia and delineate a molecular pathway by which BDNF, through MAPK-dependent phosphorylation of Eps8, stimulates axonal filopodia formation, a process with crucial impacts on neuronal development and synapse formation. 0.324 SIGNOR-263058 methoxamine chemical CHEBI:6839 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258448 Ub:E2 complex SIGNOR-C497 SIGNOR PHRF1 protein Q9P1Y6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271075 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDK7 protein P50613 UNIPROT up-regulates activity phosphorylation Ser164 GLAKSFGsPNRAYTH -1 11113184 YES lperfetto Activating phosphorylation of CDK7 by CDC2 and CDK2. The ability of pure CDK2-cyclin A to activate CDK7 in T170-dependent fashion (Fig. ​(Fig.3C,3C, lane 2) strongly suggested a direct phosphorylation mechanism. Tryptic phosphopeptide mapping confirmed that both CDK2-cyclin A (Fig. ​(Fig.4A)4A) and CDC2-cyclin B (Fig. ​(Fig.4D)4D) phosphorylated CDK7 on both S164 and T170. 0.644 SIGNOR-270807 BMPR1A protein P36894 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates activity phosphorylation 9606 19620713 YES ggiuliani To ascertain whether overexpression of BMPr1A can initiate adipocyte lineage commitment in the absence of its BMP ligand, constitutively active (CA)-BMPr1A and CA-BMPr1B were expressed in C3H10T1/2 stem cells using a mouse stem cell virus (MSCV) retroviral system. […]Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway. 0.705 SIGNOR-255772 PHRF1 protein Q9P1Y6 UNIPROT PARP1 protein P09874 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25855964 YES miannu Furthermore, PHRF1 mediates PARP1 polyubiquitination for proteasomal degradation. 0.2 SIGNOR-278774 E2F4 protein Q16254 UNIPROT PPARG protein P37231 UNIPROT down-regulates transcriptional regulation 9606 12110166 NO During terminal adipocyte differentiation fspada we show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation 0.46 SIGNOR-210050 NOTCH1 protein P46531 UNIPROT HOXA5 protein P20719 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 NO gcesareni Other than a role in t-cell development, the hox genes may be involved in alternative notchregulated processes in hematopoietic stem cells. Notch signaling is clearly important for self-renewal of hematopoietic progenitors (reviewed by radkte et al. 57). Interestingly, hoxa5, a9 and a10 were found to be part of the stem cell profile' 0.317 SIGNOR-149770 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 12042314 YES lperfetto Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation. 0.2 SIGNOR-244194 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates activity phosphorylation Thr383 PSVAYVHtTPGLPSG -1 12911626 YES miannu Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1. 0.787 SIGNOR-263076 IGF1 protein P05019 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates 10090 10448861 NO lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. 0.265 SIGNOR-252306 CEBPB protein P17676 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 24086573 YES Promoter analysis and chromatin immunoprecipitation analysis revealed that CEBPB could contribute to K7174-mediated transcriptional activation of GDF15. 0.276 SIGNOR-254050 HDAC1 protein Q13547 UNIPROT RELN protein P78509 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 NO miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 0.278 SIGNOR-254577 AR protein P10275 UNIPROT BTG1 protein P62324 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16281084 NO After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. 0.2 SIGNOR-253673 AMPA proteinfamily SIGNOR-PF58 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 NO inferred from family member Luana AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by na√Øve ones. 0.7 SIGNOR-270304 KRT14 protein P02533 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity binding 9606 11684708 YES Regulation miannu TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD. 0.265 SIGNOR-251906 GTP smallmolecule CHEBI:15996 ChEBI GNAI1 protein P63096 UNIPROT up-regulates chemical activation 9606 12040175 YES gcesareni Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of gdp from the alfa subunit followed by gtp-binding to galfa and the dissociation of galfa from gbetagamma subunits1. The alfa subunits of g proteins are divided into four subfamilies: galfas, galfai, galfaq and galfa12, and a single gpcr can couple to either one or more families of galfa proteins. 0.8 SIGNOR-88238 SET protein Q01105 UNIPROT NME1 protein P15531 UNIPROT down-regulates binding 9606 12628186 YES miannu Tumor suppressor nm23-h1 is a granzyme a-activated dnase during ctl-mediated apoptosis, and the nucleosome assembly protein set is its inhibitor. / nm23-h1 binds to set and is released from inhibition by gzma cleavage of set. 0.727 SIGNOR-99205 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 10581361 YES lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function 0.507 SIGNOR-72712 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 18593525 YES gcesareni The hrh1 predominantly couples to g?q/11 proteins, leading to the activation of phospholipase c (plc) and subsequent release of the second messengers inositol trisphosphate (ip3) and diacylglycerol (dag) followed by the activation of pkc and the release of [ca2+]i. 0.8 SIGNOR-179291 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates phosphorylation Tyr321 LGQRIYQyIQSRFYR 9606 10910078 YES lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site 0.2 SIGNOR-79764 MC3R protein P41968 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257407 HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19129776 YES gcesareni HES1 binding to the promoter of the NC3C1 gene inhibits its expression and results in insufficient production of the encoded glucocorticoid receptor- rendering these cells resistant to treatment with dexamethasone 0.2 SIGNOR-251674 IFNG protein P01579 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 NO scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. 0.2 SIGNOR-267487 DDX3X protein O00571 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 21883093 YES miannu In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival. 0.571 SIGNOR-269194 PDGFRB protein P09619 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 8195171 YES gcesareni In this study, we have characterized the interaction between the pdgf beta-receptor and shc. multiple autophosphorylation sites in the pdgf beta-receptor are responsible for the binding of shc. 0.659 SIGNOR-36906 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN2A protein Q99250 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 32599005 YES lperfetto For example, protein kinase A (PKA) and protein kinase C (PKC) have been shown to phosphorylate multiple serine residues on the interdomain I-II and III-IV linkers of Nav1.2, significantly reducing current and increasing firing thresholds 0.2 SIGNOR-275749 MAPK9 protein P45984 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates activity phosphorylation Thr103 LIDATGDtPGAEDDE 9606 BTO:0000298 12756254 YES lperfetto Recruitment of jnk to jip1 and jnk-dependent jip1 phosphorylation regulates jnk module dynamics and activation it was observed that phosphorylation by jnk of jip1 on thr-103 and not other phosphorylated jip1 residues is necessary for the regulation of dlk association with jip1, dlk activation, and subsequent module activation. 0.769 SIGNOR-101201 UBE2I protein P63279 UNIPROT FOS protein P01100 UNIPROT down-regulates activity sumoylation Lys265 SISSMELkTEPFDDF 9606 SIGNOR-C154 16055711 YES lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 0.366 SIGNOR-263013 PIGBOS1 protein A0A0B4J2F0 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 31653868 NO miannu We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels 0.2 SIGNOR-261043 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.893 SIGNOR-248628 BMP7 protein P18075 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 18719589 NO fspada Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (bmps) support white adipocyte differentiation, bmp7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. 0.7 SIGNOR-180305 GSK3B protein P49841 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Ser175 SFVTPPQsHFVRVST 9606 BTO:0002181 26028025 YES miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. 0.259 SIGNOR-276911 FZD4 protein Q9ULV1 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 18077588 YES areggio Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. 0.648 SIGNOR-258964 SP3 protein Q02447 UNIPROT CYP27A1 protein Q02318 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11867220 NO miannu Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells. 0.2 SIGNOR-255197 NCOA2 protein Q15596 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 12503607 YES gcesareni Transcriptional coactivator for steroid receptors and nuclear receptors.nteracts with casp8ap2 and ttll5/stamp. Interacts with esr1, rara and rxra. 0.63 SIGNOR-96827 MSL2 protein Q9HCI7 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271976 Ub:HECT_E3 complex SIGNOR-C518 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 NO miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 0.7 SIGNOR-271382 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000007 14761950 YES The effect has been demonstrated using P10636-8 lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. 0.374 SIGNOR-121717 CPSF3 protein Q9UKF6 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 30507380 NO lperfetto Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes. 0.7 SIGNOR-268337 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser78 NKDQHSIsYTLSRAQ 9606 BTO:0000007 12496252 YES lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation 0.767 SIGNOR-96743 CSTF1 protein Q05048 UNIPROT CSTF complex complex SIGNOR-C441 SIGNOR form complex binding 9606 10669729 YES lperfetto We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other.  0.936 SIGNOR-268365 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269371 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS -1 9199504 YES miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. 0.524 SIGNOR-250088 CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 NO gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) β plays an essential role. 0.7 SIGNOR-238297 PRKN protein O60260 UNIPROT GRIK2 protein Q13002 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25316086 YES miannu Parkin interacts with and ubiquitinates the GluK2 KAR subunit and regulates GluK2 levels and KAR currents.|The loss of parkin function increases surface and total GluK2 levels, and consistently increases KAR currents. 0.2 SIGNOR-278541 RPS6KB1 protein P23443 UNIPROT MAPKAP1 protein Q9BPZ7 UNIPROT down-regulates activity phosphorylation 9606 24161930 YES miannu Consistently, we detected in vivo Sin1 phosphorylation triggered by S6K1 and to a lesser extent, Akt1, but not other characterized AGC kinases (XREF_FIG and XREF_SUPPLEMENTARY).|Here we report that phosphorylation of Sin1 at Thr 86 and Thr 398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2. 0.566 SIGNOR-279568 SIK3 protein Q9Y2K2 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 29227248 YES miannu In the current study, we found that SIK3 promotes phosphorylation of PER2 and regulates the abundance of the protein by accelerating its degradation. 0.2 SIGNOR-279570 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 YES gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. 0.681 SIGNOR-252999 FZD1 protein Q9UP38 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates activity binding 9606 23151663 YES areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  0.656 SIGNOR-258953 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 18593525 YES gcesareni The increases in the membrane levels of nacholeate itself and of dag induce a translocation and overexpression of protein kinase c (pkc) and subsequent reductions of cyclin d, cyclin-dependent kinases 4 and 6 (cdks 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of e2f1 and knockdown of dihydrofolate reductase (dhfr) impairing dna synthesis. 0.8 SIGNOR-179279 8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid chemical CHEBI:95064 ChEBI PTPN6 protein P29350 UNIPROT down-regulates activity chemical inhibition 9606 20337577 YES NSC-87877 (1, Fig. (7)) was identified as a Shp2 PTP inhibitor with an IC50 of 0.33 μM [83]. NSC-87877 inhibits Shp1 with the same potency. 0.8 SIGNOR-261913 CDK1 protein P06493 UNIPROT SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser334 FLLLAGLsLRGQGNF 9606 25482198 YES miannu Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. 0.358 SIGNOR-263100 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT up-regulates activity phosphorylation Ser297 PQKTSAKsPGPMRRS 9606 14741103 YES llicata We identified that Ser297 is the major phosphorylation site by Cdk5. Phosphorylation of this site occurs in human. | Mutation of Ser297 blocks the effect of Dcx on migration in a fashion similar to pharmacological inhibition of Cdk5 activity. 0.405 SIGNOR-250657 Ub:E2 complex SIGNOR-C497 SIGNOR VPS18 protein Q9P253 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271231 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR G2/M_transition phenotype SIGNOR-PH52 SIGNOR up-regulates 15549093 NO lperfetto The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary 0.7 SIGNOR-251497 SRC protein P12931 UNIPROT ARHGEF5 protein Q12774 UNIPROT up-regulates activity phosphorylation 9606 21525037 YES miannu Arhgef5 was tyrosine-phosphorylated by Src and bound to Src to positively regulate its activity.|Using an inducible system for Src activation, we found that Src induced podosome formation depends upon the Src SH3 domain, and identified Arhgef5 as a Src SH3 binding protein. 0.465 SIGNOR-279571 MTCP1 protein P56278 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.477 SIGNOR-81671 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 17997719 YES gcesareni Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity. 0.728 SIGNOR-159052 IMPDH2 protein P12268 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity binding 9606 BTO:0001616 30518405 YES miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. There is evidence that IMPDH2 interacts with the pleckstrin homology domain of PKB/AKT in the regulation of GTP biosynthesis. 0.387 SIGNOR-260961 CSNK1D protein P48730 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 YES gcesareni However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo. 0.625 SIGNOR-87441 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR G3BP1 protein Q13283 UNIPROT up-regulates activity binding 30804210 YES SARA The RGG domain of G3BP1 could mediate the direct binding of HCV-dsRNA and poly(IC) 0.7 SIGNOR-260979 NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 YES lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. 0.854 SIGNOR-175219 FGFR2 protein P21802 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates activity phosphorylation Tyr769 TLTTNEEyLDLSQPL 9606 BTO:0000567 15629145 YES miannu Our data also show that tyrosine 769 is not involved in the regulation of the endocytic process of KGFR.Following ligand binding, KGFR is rapidly autophosphorylated on specific tyrosine residues 0.2 SIGNOR-276026 SRC protein P12931 UNIPROT CNTNAP1 protein P78357 UNIPROT down-regulates activity phosphorylation 9606 11672527 YES miannu If that is the case, then our genetic results support the notion that p190 is negatively regulated by both Src and integrin.|The Src family of tyrosine kinases phosphorylate mammalian p190. 0.337 SIGNOR-279572 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation 9606 34216621 YES miannu Furthermore, LKB1-mediated Sirt1 activation may also play physiological roles in the context of antiaging and anticancer.|Together, these results suggest that LKB1-dependent phosphorylation of Sirt1 is crucial for mitochondrial biogenesis and respiration through the activation of PGC-1\u03b1. 0.574 SIGNOR-279573 MC5R protein P33032 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257070 miR221 mirna URS0000245997_9606 RNAcentral ZEB2 protein O60315 UNIPROT down-regulates quantity by repression destabilization 10090 26762731 YES We identified miR-143 as a regulator of the insulin growth factor-binding protein 5 (Igfbp5) in primary myoblasts and show that the expression of miR-143 and its target gene is disrupted in satellite cells from old mice. 0.4 SIGNOR-255939 Raf265 derivative chemical CID:23654923 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206394 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates activity phosphorylation Ser633 ELSSQMSsFNEAMTQ 9606 BTO:0000567 25504441 YES miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. 0.811 SIGNOR-276861 BDKRB1 protein P46663 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.25 SIGNOR-256764 PSME1 protein Q06323 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 35932807 YES lperfetto While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. 0.606 SIGNOR-275867 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser465 HNPISSVs 9606 9136927 YES lperfetto Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro 0.664 SIGNOR-217989 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 16403219 YES miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. 0.347 SIGNOR-250396 POU2F1 protein P14859 UNIPROT MYH10 protein P35580 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.2 SIGNOR-238772 PTH1R protein Q03431 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 28363951 YES lperfetto This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11. 0.504 SIGNOR-270551 PCDH19 protein Q8TAB3 UNIPROT GABRA3 protein P34903 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C334 29360992 YES miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  0.2 SIGNOR-267222 STAT2 protein P52630 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 17923090 YES lperfetto We then examined STAT2 acetylation within the b-barrel DBD. A direct interaction between the STAT2-DBD (315485) and STAT1 was detected (Figure 6E) (Li et al., 1997). 0.553 SIGNOR-217957 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT down-regulates activity phosphorylation Ser220 KAKPSLLsRVGALTN 10090 11751901 YES miannu PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276) 0.503 SIGNOR-250028 SRF protein P11831 UNIPROT TAGLN protein Q01995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21673106 NO gcesareni The contractile phenotype of smooth muscle (sm) cells is controlled by serum response factor (srf), which drives the expression of sm-specific genes including sm alpha-actin, sm22, and others. 0.411 SIGNOR-174393 MOB1B protein Q7L9L4 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 YES Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. 0.921 SIGNOR-169795 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Ser75 LGYEPEGsASPTPPY -1 17318175 YES lperfetto Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling. 0.784 SIGNOR-249189 IL23R protein Q5VWK5 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates 9606 BTO:0000782 12023369 NO gcesareni Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12. 0.589 SIGNOR-87838 USP6 protein P35125 UNIPROT ARF6 protein P62330 UNIPROT up-regulates relocalization 9606 15509780 YES miannu Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs). 0.659 SIGNOR-130019 AGTR1 protein P30556 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 11313903 YES gcesareni These neuropeptide gpcrs are coupled to the activation of phospholipase c, and therefore to calcium ele- vation and protein kinase c (pkc) activation, through g proteins of the alfaq family. 0.642 SIGNOR-106932 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 YES lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | 0.345 SIGNOR-249123 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PGR protein P06401 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 10655479 YES inferred from 70% family members gcesareni Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation. 0.2 SIGNOR-270040 YWHAB protein P31946 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 YES miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. 0.254 SIGNOR-252396 SLBP protein Q14493 UNIPROT H2AX protein P16104 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265405 PTK2 protein Q05397 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 21454698 YES llicata Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed. 0.638 SIGNOR-173009 RAPH1 protein Q70E73 UNIPROT VASP protein P50552 UNIPROT up-regulates activity binding 9606 20417104 YES miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. 0.579 SIGNOR-268426 TRPC4AP protein Q8TEL6 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 20551172 YES miannu We characterize a new Myc-interacting factor, TRPC4AP (transient receptor potential cation channel, subfamily C, member 4-associated protein)/TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein), which is the receptor for a DDB1 (damage-specific DNA-binding protein 1)-CUL4 (Cullin 4) E3 ligase complex for selective Myc degradation through the proteasome. TRPC4AP/TRUSS binds specifically to the Myc C terminus and promotes its ubiquitination and destruction through the recognition of evolutionarily conserved domains in the Myc N terminus.  0.351 SIGNOR-271963 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys68 ETSAAKLkRKYWWKN 9606 BTO:0000007 23353890 YES miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. 0.329 SIGNOR-272094 IFNAR2 protein P48551 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR form complex binding 9606 11278538 YES miannu The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. 0.906 SIGNOR-260333 OPTN protein Q96CV9 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 27181519 NO lperfetto Optineurin and TBK1 have also been discovered co-localizing in protein aggregates, and the phosphorylation of optineurin at serine 177 has been shown to be critical to its function in mediating clearance of aggregated proteins via autophagy 0.7 SIGNOR-262275 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 15356634 YES lperfetto Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. 0.548 SIGNOR-128738 STK4 protein Q13043 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates phosphorylation 9606 21808241 YES inferred from 70% of family members gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. 0.641 SIGNOR-269859 (2S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide chemical CHEBI:94760 ChEBI AR protein P10275 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189623 IQSEC2 protein Q5JU85 UNIPROT GRIA2 protein P42262 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 27009485 YES miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. 0.2 SIGNOR-264913 copper(1+) smallmolecule CHEBI:49552 ChEBI SOD3 protein P08294 UNIPROT up-regulates activity chemical activation 1542024 YES lperfetto Copper as a cofactor and regulator of copper,zinc superoxide dismutase 0.8 SIGNOR-272301 PRRX1 protein P54821 UNIPROT MAFG protein O15525 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.339 SIGNOR-221961 NR5A1 protein Q13285 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 NO miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.409 SIGNOR-254868 MAPK1 protein P28482 UNIPROT TNKS1BP1 protein Q9C0C2 UNIPROT unknown phosphorylation Thr131 KEEPPPLtPPARCAA 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262782 PTPN6 protein P29350 UNIPROT PKM protein P14618 UNIPROT down-regulates activity dephosphorylation Tyr105 FASDPILyRPVAVAL 9606 26959741 YES lperfetto SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs.|SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated hepatocellular carcinoma cells.|SHP-1 dephosphorylates p-PKM2Y105 and further affects the nucleus-related cell proliferation. 0.2 SIGNOR-276997 IGFBP3 protein P17936 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR down-regulates 10090 BTO:0000142 17278996 NO Luana IGFBP3 overexpression due to lack of MeCP2 may lead to delayed brain maturation. 0.7 SIGNOR-265774 GABRB1 protein P18505 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR form complex binding 9606 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.621 SIGNOR-263760 AIM2 inflammasome complex SIGNOR-C222 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 NO miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. 0.7 SIGNOR-263123 NOXA1 protein Q86UR1 UNIPROT NOX1 protein Q9Y5S8 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 YES lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation 0.75 SIGNOR-264710 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 SIGNOR-C14 17977820 YES lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I 0.962 SIGNOR-158663 CAY10505 chemical CID:1204893 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190859 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr165 PSPATDLyQVPPGPG 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246385 FBXO6 protein Q9NRD1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 27855403 YES miannu Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex 0.677 SIGNOR-272331 LCK protein P06239 UNIPROT CD33 protein P20138 UNIPROT up-regulates phosphorylation Tyr340 EMDEELHyASLNFHG 9606 10887109 YES lperfetto Human cd33 has two tyrosine residues in its cytoplasmic domain (y340 and y358). When phosphorylated, these tyrosines could function as docking sites for the phosphatases, shp-1 and/or shp-2, enabling cd33 to function as an inhibitory receptor. Lck is effective at phosphorylating y340 0.271 SIGNOR-78960 BRCA1 protein P38398 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 18776923 NO miannu We report here that glucose-regulated protein (GRP)-78, a critical regulator of the unfolded protein response (UPR), is a novel downstream target of BRCA1. We showed that overexpression of wild-type BRCA1 suppressed the expression of GRP78, whereas expression of mutant BRCA1 gene or targeted inhibition of endogenous BRCA1 using small-interfering RNA (siRNA) enhanced GRP78 expression. 0.2 SIGNOR-253761 trichostatin A chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257942 SMURF2 protein Q9HAU4 UNIPROT YY1 protein P25490 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24803334 YES miannu In addition, Smurf2 decreased the protein half-life and transcriptional activity of YY1.|Wild type Smurf2, but not the E3 ubiquitin ligase defective mutant, increased the poly-ubiquitination of YY1. 0.365 SIGNOR-278544 MARK2 protein Q7KZI7 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser267 RVQSKIGsLDNITHV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.706 SIGNOR-275435 ABL1 protein P00519 UNIPROT CLASP2 protein O75122 UNIPROT up-regulates quantity phosphorylation 9606 24520051 YES miannu We find that Abl binds to and phosphorylates CLASP2 in response to extracellular signals such as serum or PDGF. 0.5 SIGNOR-279580 ABL1 protein P00519 UNIPROT MLH1 protein P40692 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 36338985 YES miannu We also observed phosphorylation of MLH1 by ABL1 in an in vitro kinase assay with purified recombinant ABL1 and MLH1, confirming there is a direct phosphorylation between ABL1 and the MLH1 component of the MLH1-PMS2 heterodimer.|we propose that ABL1 prevents MLH1 from being targeted for degradation by the chaperone Hsp70 and that in the absence of ABL1 activity at least a portion of MLH1 is degraded. 0.345 SIGNOR-279581 AKT1 protein P31749 UNIPROT HIRA protein P54198 UNIPROT up-regulates activity phosphorylation 9606 27515126 YES miannu Consistently, HIRA phosphorylation was effectively decreased by Akt1 knockdown and was completely eliminated by the depletion of both Akt1 and Akt2, suggesting that HIRA is phosphorylated primarily by Akt1 and that Akt2 seemed to contribute to HIRA phosphorylation as a supplementary kinase in myoblasts (XREF_FIG).|In this study, HIRA was more efficiently targeted by Akt1 in myoblasts. 0.2 SIGNOR-279584 clotrimazole chemical CHEBI:3764 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9606 9770465 YES miannu In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR. 0.8 SIGNOR-259065 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263793 BCOR protein Q6W2J9 UNIPROT RNF2 protein Q99496 UNIPROT up-regulates activity binding 9606 17296600 YES miannu BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. In summary, we have widened the set of multiprotein complexes containing the Polycomb group protein Ring1B/Rnf2. The new interactors contain protein motifs whose enzymatic activities and binding properties would expand the regulatory potential and gene target diversity of Ring1B/Rnf2 complexes in terms of recruitment to and modification of chromatin 0.546 SIGNOR-252241 HOXD9 protein P28356 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding 9606 10523646 YES miannu We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9 0.509 SIGNOR-220721 DLGAP3 protein O95886 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.799 SIGNOR-264592 fingolimod chemical CHEBI:63115 ChEBI S1PR1 protein P21453 UNIPROT down-regulates chemical inhibition 9606 22225501 YES gcesareni Sphingosine-1-phosphate (s1p(1)) receptor agonists such as fingolimod (fty-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. 0.8 SIGNOR-195343 GAPDH protein P04406 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 11724794 YES miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion 0.8 SIGNOR-266495 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 YES lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). 0.914 SIGNOR-235979 SYP protein P08247 UNIPROT Synaptic_vesicle_recycling phenotype SIGNOR-PH161 SIGNOR up-regulates 9606 BTO:0000938 33769286 NO miannu This study reveals that Syp has a single physiological role in SV recycling, the accurate trafficking, and retrieval of SybII. 0.7 SIGNOR-264111 HTR2C protein P28335 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.277 SIGNOR-257405 Vps34 Complex II complex SIGNOR-C241 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 NO lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.7 SIGNOR-260326 TBK1 protein Q9UHD2 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 23023393 YES miannuccelli TBK1 induces NIK phosphorylation and degradation. 0.371 SIGNOR-279767 MAPKAPK2 protein P49137 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 20626350 YES gcesareni Mk2 was found to phopsphorylate in vitro the ago2 protein in ser387, which was identified as the major ago2 phosphorylation site in cells.and mutation of ser387 to alanineimpairsago2 localization to therna-containing granules termedprocessing bodies 0.437 SIGNOR-166615 Ub:E2 complex SIGNOR-C497 SIGNOR RNF187 protein Q5TA31 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271165 MAP2K6 protein P52564 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation Tyr185 ADSEMTGyVVTRWYR 9606 19230643 YES gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases 0.658 SIGNOR-184138 CSNK2A1 protein P68400 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser133 NAIRYIEsLQELLRE -1 9461343 YES llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  0.307 SIGNOR-250922 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 YES Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform 0.469 SIGNOR-248586 EXOSC9 protein Q06265 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.921 SIGNOR-261388 lanreotide chemical CHEBI:135901 ChEBI SSTR2 protein P30874 UNIPROT up-regulates activity chemical activation 9606 25060168 YES miannu Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2. 0.8 SIGNOR-259242 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR ACLY protein P53396 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002552 27664236 YES miannu Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells.  0.288 SIGNOR-272335 pregnenolone smallmolecule CHEBI:16581 ChEBI 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268648 IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 9716487 YES lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. 0.638 SIGNOR-238630 UBXN8 protein O00124 UNIPROT VCP protein P55072 UNIPROT down-regulates quantity relocalization 9606 21949850 YES SARA The human protein named Rep8 or Ubxd6 as a new cofactor of p97. Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation. 0.522 SIGNOR-261002 TRIM27 protein P14373 UNIPROT PIK3C2B protein O00750 UNIPROT down-regulates ubiquitination 9606 22128329 YES miannu We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity. 0.402 SIGNOR-177935 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser950 EGFHPRRsSQGATQM 10090 BTO:0000944 11581251 YES lperfetto HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme 0.601 SIGNOR-249203 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 YES Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells 0.426 SIGNOR-252603 RNF8 protein O76064 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR up-regulates ubiquitination 9606 20551964 YES gcesareni Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist. 0.2 SIGNOR-265313 MIB1 protein Q86YT6 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24239288 YES miannu BLM is Ubiquitinated by E3 Ligase MIB1.|Moreover, MIB1 mediated BLM degradation in G1 phase appears to be important for DNA double-strand break repair. 0.281 SIGNOR-278548 MID2 protein Q9UJV3 UNIPROT SPAG5 protein Q96R06 UNIPROT down-regulates quantity by destabilization ubiquitination Lys409 QTGLVGTkHSTSETE 9606 26748699 YES miannu These data indicated that Mid2 was ubiquitinating Astrin at K409 and targeting Astrin for degradation during cytokinesis. 0.31 SIGNOR-278549 axitinib chemical CHEBI:66910 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 YES gcesareni Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine. 0.8 SIGNOR-171863 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser123 EEEEESEsEDSEDSG 9606 16308564 YES lperfetto Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. 0.2 SIGNOR-142347 PRMT1 protein Q99873 UNIPROT TAF15 protein Q92804 UNIPROT up-regulates methylation 9606 19124016 YES miannu The methylation of taf15 by prmt1 is required for the ability of taf15 to positively regulate the expression of the studied endogenous taf15-target genes. 0.432 SIGNOR-183137 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.29 SIGNOR-249246 ELOVL proteinfamily SIGNOR-PF93 SIGNOR palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267901 EPM2A protein O95278 UNIPROT PPP1R3C protein Q9UQK1 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 BTO:0000007 19171932 YES miannu We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.  0.748 SIGNOR-276239 NR0B2 protein Q15466 UNIPROT PCK2 protein Q16822 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17094771 NO miannu SHP repressed C/EBPalpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBPalpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBPalpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. 0.386 SIGNOR-254832 LIMS4 protein P0CW20 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 YES lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. 0.2 SIGNOR-265766 AKT2 protein P31751 UNIPROT C2CD5 protein Q86YS7 UNIPROT up-regulates activity phosphorylation Ser197 EARQRLIsLMSGELQ 9606 21907143 YES miannu MS analysis of an HA-CDP138 sample from the in vitro kinase assay revealed that active Akt2 induces CDP138 phosphorylation at serine (Ser)197, which lies within a consensus Akt substrate motif RQRLIS 197 ( xref ). 0.511 SIGNOR-279585 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 14633703 YES Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells 0.387 SIGNOR-252604 DYRK1A protein Q13627 UNIPROT DNM1 protein Q05193 UNIPROT down-regulates phosphorylation Ser795 VPPARPGsRGPAPGP 9606 BTO:0000142 15287745 YES lperfetto Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation. 0.417 SIGNOR-127440 CFII complex complex SIGNOR-C387 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity cleavage 9606 30139799 YES lperfetto Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. The heterodimer is active in partially reconstituted cleavage reactions 0.8 SIGNOR-266121 PAX7 protein P23759 UNIPROT MLL2 complex complex SIGNOR-C88 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 YES lperfetto Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.304 SIGNOR-217712 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser170 ESLDWDSsLVKTFKL 9606 19468302 YES llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. 0.639 SIGNOR-185750 ITGB1 protein P05556 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.709 SIGNOR-257700 ATM protein Q13315 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity phosphorylation Ser734 S-->L 9606 24162653 YES miannu Enhancer of zeste homolog 2 (EZH2), a core catalytic component of polycomb repressive complex 2, is a new ATM kinase target, and ATM-mediated phosphorylation of EZH2 on Ser734 reduces protein stability.|We verified that S734 is the predominant ATM site on EZH2 by performing ATM in vitro kinase assays using GST-EZH2 fusion proteins as substrates (Fig. 2b). The phosphorylation signal was nearly lost when the EZH2-S734A mutant was used as substrate 0.459 SIGNOR-279586 NFIA protein Q12857 UNIPROT NFIX protein Q14938 UNIPROT up-regulates quantity transcriptional regulation 10090 29106906 YES Gianni We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. 0.2 SIGNOR-268871 JARID2 protein Q92833 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 23435416 YES lperfetto JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells|Addition of Differentiation Media (DM) to human myoblasts was associated with the induction of MYOG, MYOD and MYL1 and a decrease in JARID2 RNA expression|Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent upon EED, a core component of the Polycomb Repressive Complex 2 (PRC2). Therefore JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS 0.2 SIGNOR-249599 KLKB1 protein P03952 UNIPROT F12 protein P00748 UNIPROT up-regulates activity cleavage Arg353 EQPPSLTrNGPLSCG 9606 BTO:0000131 28966616 YES lperfetto FXIIa converts PK to the active protease PKa, which reciprocally activates more FXII|In addition, PKa can initiate a further proteolysis of FXIIa into a ~30 kDa light chain fragment, termed β-FXIIa. The cleavage takes place at the peptide bond Arg353–Val354 and consequently, the active site released from the heavy chain and thus from surfaces. 0.605 SIGNOR-263520 CELF1 protein Q92879 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity binding 10090 BTO:0000759 16931514 YES miannu These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein. 0.251 SIGNOR-262736 trichostatin A chemical CHEBI:46024 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258018 L-thyroxine smallmolecule CHEBI:18332 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 10116 BTO:0000759 2158622 YES inferred from family member miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 0.8 SIGNOR-270300 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Thr739 SEGSGTAtPSALITT 9606 14744793 YES lperfetto Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. 0.652 SIGNOR-249481 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT down-regulates activity phosphorylation Tyr658 GEMDTTSyDVSVLNS 10029 BTO:0000246 16027153 YES lperfetto cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity. 0.568 SIGNOR-246462 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 8940173 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.581 SIGNOR-247197 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.54 SIGNOR-270887 SIK2 protein Q9H0K1 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser154 STLYRTQsSSNLAEL -1 27478041 YES miannu The Regulatory Subunit of PI3K Is a Direct Catalytic Target of SIK2. These data confirm that p85α is a direct catalytic substrate of SIK2 and that SIK2 S154 phosphorylation significantly increases the activity of the PI3K/AKT pathway in ovarian cancer cells. 0.323 SIGNOR-277269 KDM1A protein O60341 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 YES miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. 0.741 SIGNOR-222121 AURKA protein O14965 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Ser1070 DSFLQRYsSDPTGAL 9606 23520446 YES miannu Because AURKA associated with EGFR, we next investigated whether AURKA phosphorylates EGFR at Thr654 and Ser1046.|Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells. 0.394 SIGNOR-279589 AURKB protein Q96GD4 UNIPROT MAPRE2 protein Q15555 UNIPROT up-regulates activity phosphorylation 9606 27030108 YES miannu Together, these data indicate that Aurora B and CDK1 phosphorylate EB2 at distinct sites and maintain the hyperphosphorylation of EB2 and its binding affinity to MTs while SAC activity is sustained. 0.537 SIGNOR-279591 ATG16L1 protein Q676U5 UNIPROT CLTCL1 protein P53675 UNIPROT up-regulates binding 9606 20639872 YES gcesareni Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors 0.304 SIGNOR-166705 CSNK2B protein P67870 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275752 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 YES lperfetto Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo 0.346 SIGNOR-158418 IL10 protein P22301 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 BTO:0000671 11035029 YES fspada The il-10r2 chain is ubiquitously expressed, whereas the il-10 activity is restricted mainly to cells of hematopoietic origin (35, 36). This raised the question of why the second chain of the il-10 receptor complex is widely expressed when its function was required only in limited cellular subsets. One hypothesis is that the il-10r2 chain is shared by receptors for ligands other than il-10 0.714 SIGNOR-83191 canertinib chemical CHEBI:61399 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258095 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 8702756 YES miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. 0.646 SIGNOR-261718 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr187 FSEEIRFyQLGEEAM 9606 11812778 YES gcesareni The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties. 0.311 SIGNOR-114641 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.91 SIGNOR-252523 GBF1 protein Q92538 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 15616190 YES miannu GBF1 Stimulates Production of Arf-GTP In Vivo 0.718 SIGNOR-277400 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser113 GQKFARKsTRRSIRL 9606 7559487 YES miannu Pleckstrin is a substrate for protein kinase c / a combination of phosphopeptide analysis and site-directed mutagenesis shows that three residues in the intervening sequence between the two pleckstrin ph domains become phosphorylated: ser113, thr114, and ser117. /these results suggest that the phosphorylation of at least two of the sites is required for maximal pleckstrin activity 0.28 SIGNOR-28880 ADRA1A protein P35348 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.584 SIGNOR-257084 MAP4K5 protein Q9Y4K4 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000776 16914735 YES lperfetto Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3_ and enhance the in vivo phosphorylation of gsk3_ on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3_ at serine 9 and decreases the accumulation of cytosolic _-catenin. 0.2 SIGNOR-148908 Guanabenz chemical CHEBI:5553 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258910 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates dephosphorylation 9606 19360021 YES gcesareni The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity. 0.488 SIGNOR-185135 alvimopan chemical CHEBI:135686 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition -1 18313920 YES Luana A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors. 0.8 SIGNOR-257772 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser214 TVLTAQEsFSGSLGH -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276216 TRIM71 protein Q2Q1W2 UNIPROT LIN28B protein Q6ZN17 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001950 24602972 YES miannu In cells, TRIM71 negatively regulates Lin28B protein stability by catalyzing polyubiquitination.  0.528 SIGNOR-272054 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Ser197 SFGLSAMsPTKAAVD 9606 BTO:0001271 18246121 YES llicata Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects. 0.282 SIGNOR-160626 GLI3 protein P10071 UNIPROT MED12 protein Q93074 UNIPROT down-regulates binding 9606 17000779 YES gcesareni We propose that activated gli3 physically targets med12 in mediator to reverse mediator-dependent suppression of shh target gene (i.e., Gli1 or cyclin d1) transcription. 0.505 SIGNOR-149876 TSSK1B protein Q9BXA7 UNIPROT TSSK1B protein Q9BXA7 UNIPROT up-regulates activity phosphorylation Thr174 GRMALSKtFCGSPAY -1 15733851 YES Manara Electrospray Q‐TOF2 mass spectroscopy analysis of a trypsin digested TSSK1 purified from E. coli, revealed that it was phosphorylated at its T‐loop residue (Fig. 2D), indicating that TSSK1 as was previously shown for MELK [18], can autophosphorylate its T‐loop Thr residue. 0.2 SIGNOR-260823 NEK2 protein P51955 UNIPROT KIF24 protein Q5T7B8 UNIPROT up-regulates activity phosphorylation 9606 26290419 YES miannu Nek2 binds and phosphorylates Kif24.|We also provide evidence that Nek2 dependent phosphorylation induces a conformational change in Kif24 that promotes its activity. 0.694 SIGNOR-278413 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser79 AGALYSGsEGDSESG -1 2046671 YES llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated. 0.551 SIGNOR-250956 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 YES gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. 0.697 SIGNOR-32433 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 YES lperfetto PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. 0.559 SIGNOR-135980 PLK1 protein P53350 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by stabilization phosphorylation Ser234 GKFVLKAsLSAPGSE 9606 BTO:0002181 31281496 YES miannu We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. 0.249 SIGNOR-277463 PIAS1 protein O75925 UNIPROT DDX5 protein P17844 UNIPROT up-regulates sumoylation Lys53 WNLDELPkFEKNFYQ 9606 17369852 YES miannu We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53. 0.545 SIGNOR-153719 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH22 protein Q9UJ99 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265838 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 YES lperfetto The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. 0.372 SIGNOR-105247 PHA-767491 chemical CID:11715767 PUBCHEM CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206115 COP1 protein Q8NHY2 UNIPROT ACACA protein Q13085 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16794074 YES miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). 0.2 SIGNOR-271598 SSTR2 protein P30874 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-256827 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT up-regulates activity phosphorylation Thr181 PANSFVGtPYWMAPE 9534 BTO:0004055 10559204 YES lperfetto These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK. 0.2 SIGNOR-246298 CAST protein P20810 UNIPROT CAPN1 protein P07384 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 YES lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain 0.915 SIGNOR-251582 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000567 16825193 YES lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding 0.486 SIGNOR-236649 RPS16 protein P62249 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.877 SIGNOR-262435 TRAF6 protein Q9Y4K3 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. 0.865 SIGNOR-205455 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 YES lperfetto Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20) 0.334 SIGNOR-275490 AKT2 protein P31751 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity 9606 16293724 NO gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. 0.569 SIGNOR-141655 KCNJ10 protein P78508 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 24561201 YES miannu KCNJ10 encodes Kir4.1, a member of the K+ channel family known as inwardly rectifying K+ (Kir) channels. Kir4.1 channels may comprise either Kir4.1 homomers or Kir4.1/Kir5.1 heteromers 0.8 SIGNOR-269446 metformin chemical CHEBI:6801 ChEBI NDUFS1 protein P28331 UNIPROT down-regulates activity chemical inhibition 9606 24843020 YES Federica In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration 0.8 SIGNOR-261080 CHUK protein O15111 UNIPROT TRAF4 protein Q9BUZ4 UNIPROT down-regulates phosphorylation Ser426 KPGTWRGsLDESSLG 9606 22547678 YES llicata Traf4 is atypical within its family because it is the only traf family member to negatively regulate innate immune signaling. Ikk_'s phosphorylation of serine-426 on traf4 was required for this negative regulation. 0.384 SIGNOR-197253 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10029 17510057 YES lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. 0.755 SIGNOR-235748 ETV2 protein O00321 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24583263 NO irozzo We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression. 0.259 SIGNOR-256006 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 YES gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. 0.706 SIGNOR-165216 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 YES gcesareni Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 0.2 SIGNOR-242578 PRKCE protein Q02156 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Ser779 PLDQYSPsFPDTRSS 9606 BTO:0000938 23564461 YES lperfetto Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiationour findings show that in addition to fgfr tyrosine phosphorylation, the phosphorylation of a conserved serine residue, ser(779), can quantitatively control ras/mapk signaling to promote specific cellular responses. 0.2 SIGNOR-201671 SMAD2 protein Q15796 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. 0.555 SIGNOR-255023 NEK9 protein Q8TD19 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates activity phosphorylation Thr50 QLPVLDKtKFLVPDH -1 31857374 YES done miannu LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). 0.2 SIGNOR-273904 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 YES lperfetto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. 0.2 SIGNOR-244673 FOXQ1 protein Q9C009 UNIPROT MYLK protein Q15746 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 10896677 YES Luana Results from this analysis revealed that the inhibitory activity of HFH-1 was contained within the forkhead DNA-binding domain. Truncated HFH-1 proteins that lack the entire forkhead domain were unable to repress telokin promoter activity, in contrast expression of the forkhead domain alone was able to repress promoter activity 0.2 SIGNOR-261609 PRKAA1 protein Q13131 UNIPROT FANCA protein O15360 UNIPROT up-regulates activity phosphorylation Ser347 VQMQREWsFARTHPL 9606 BTO:0001938 27449087 YES miannu FANCA was phosphorylated by AMPK at S347 and phosphorylation increased with MMC treatment. MMC-induced FANCD2 monoubiquitination and nuclear foci formation were compromised in a U2OS cell line that stably overexpressed the S347A mutant form of FANCA compared to wild-type FANCA-overexpressing cells, indicating a requirement for FANCA phosphorylation at S347 for proper activation of the FA/BRCA pathway.  0.333 SIGNOR-277264 CDK1 protein P06493 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser613 EKKQITTsPITVRKN 9606 SIGNOR-C17 12372621 YES lperfetto Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition. 0.39 SIGNOR-94160 EIF2AK2 protein P19525 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27712625 NO miannu The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum. 0.7 SIGNOR-260159 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 10635327 YES llicata Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR. 0.2 SIGNOR-251093 TTK protein P33981 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Thr927 LSRLATNtSAPDLKN 9606 BTO:0000567 31253867 YES miannu We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation.  0.2 SIGNOR-277462 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser208 DINRGAPsITSVTPR 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.742 SIGNOR-262717 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT down-regulates activity dephosphorylation Thr1109 MWLSREQtLHTPVMM 9606 BTO:0000567 15737063 YES lperfetto Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase 0.737 SIGNOR-275533 MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP -1 9162092 YES Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4. 0.2 SIGNOR-251421 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 YES irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. 0.2 SIGNOR-255876 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 11971971 YES lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. 0.2 SIGNOR-244788 Microprocessor complex complex SIGNOR-C356 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 24581491 NO lperfetto Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA. 0.7 SIGNOR-264850 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys137 KNGETSLkPEDFDFT 31476572 YES lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. 0.2 SIGNOR-275676 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-181195 PRKCD protein Q05655 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Thr1224 RYVPPSStDRSPYEK 9606 11877440 YES gcesareni We show that phosphorylation of muc1 by pkcdelta increases binding of muc1 and beta-catenin in vitro and in vivo. The functional significance of the muc1-pkcdelta interaction is further supported by the demonstration that mutation of the pkcdelta phosphorylation site abrogates muc1-mediated decreases in binding of beta-catenin to e-cadherin 0.337 SIGNOR-115501 CLK2 protein P49760 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser142 HSSRRAKsVEDDAEG 9606 BTO:0000567 20682768 YES lperfetto Clk2 was reported to regulate its nuclear localization by autophosphorylating serine 141 0.2 SIGNOR-167344 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.564 SIGNOR-89213 SMURF2 protein Q9HAU4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11163210 YES miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  0.87 SIGNOR-272940 EGLN2 protein Q96KS0 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization hydroxylation 9606 24990963 YES lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization 0.856 SIGNOR-261999 MAPK12 protein P53778 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser108 LPGASPKsPGLKAMV -1 15850461 YES miannu Peptide T2 was sequenced and shown to comprise residues 79–112 of CapZIP, phosphorylated at Ser-108 (Figure 2B). The identity of peptide T1 is unknown. These experiments established that the SAPK3/p38γ substrate was CapZIP. Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown). An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.504 SIGNOR-263083 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Thr830 DSAEGSHtSGQSNGR 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.328 SIGNOR-276515 MAPK3 protein P27361 UNIPROT THRB protein P10828 UNIPROT down-regulates activity phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 YES llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. 0.427 SIGNOR-102224 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates cleavage 9606 22972936 YES Thrombin acts on protease-activated receptors (PARs), a subfamily of G protein-coupled receptors (GPCR) that participate in a variety of biological process, including chemokine and cytokine release, tissue remodeling, inflammation, proliferation, and angiogenesis. gcesareni The par1 receptor subtype is activated when the n terminus is proteolytically cleaved by the serine protease thrombin, resulting in an irreversible activation of the receptor. Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4). 0.887 SIGNOR-199007 HPS3 protein Q969F9 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR form complex binding 9606 15030569 YES lperfetto Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6 0.708 SIGNOR-260688 PDIA6 protein Q15084 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 10090 BTO:0004086 17420453 NO Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells. 0.7 SIGNOR-256533 AKT proteinfamily SIGNOR-PF24 SIGNOR LARP6 protein Q9BRS8 UNIPROT up-regulates activity phosphorylation Ser451 QEKSPGTsPLLSRKM 9606 BTO:0000007 26932461 YES miannu This strongly suggested that Akt dependent phosphorylation of LARP6 targets S451.S451A mutant of LARP6 acts as dominant negative protein in collagen synthesis. these results support the hypothesis that phosphorylation of S451 by Akt is a necessary step to activate productive synthesis type I collagen and suggests that secretion and modifications of type I collagen are impaired if LARP6 is not phosphorylated on S451. 0.2 SIGNOR-273539 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18621737 YES lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. 0.895 SIGNOR-179456 DGC complex SIGNOR-C217 SIGNOR NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 YES miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. 0.301 SIGNOR-265451 METTL3 protein Q86U44 UNIPROT UCK2 protein Q9BZX2 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 34430596 YES lperfetto Furthermore, the m6A modification regulated by METTL3 led to UCK2 increased messenger RNA (mRNA) stability in melanoma cancer. Functional and mechanistic experiments indicated that UCK2 enhanced the metastasis of melanoma cancer cells through the WNT/β-catenin pathway. 0.2 SIGNOR-275862 MAPK3 protein P27361 UNIPROT BRD4 protein O60885 UNIPROT down-regulates activity 9606 32482868 YES lperfetto The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity. 0.312 SIGNOR-262048 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 YES gcesareni Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death 0.432 SIGNOR-67400 ACSS3 protein Q9H6R3 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271834 L-serine chemical CHEBI:17115 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 10090 BTO:0000142 12393813 YES lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. 0.8 SIGNOR-268269 CDC42 protein P60953 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR up-regulates activity binding 10090 BTO:0000142 8107774 YES gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. 0.942 SIGNOR-248259 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 YES Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. 0.2 SIGNOR-248603 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 YES lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. 0.675 SIGNOR-248923 E2F1 protein Q01094 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8649818 NO lperfetto We have found that cell cycle regulation of cyclin E transcription is mediated by E2F binding sites present in the promoter. The activity of this promoter can be regulated negatively by pRB. 0.682 SIGNOR-245474 PAK1 protein Q13153 UNIPROT TBCB protein Q99426 UNIPROT up-regulates phosphorylation Ser65 GVDDKFYsKLDQEDA 9606 BTO:0000150 15831477 YES lperfetto P21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor b. Pak1 directly phosphorylated tcob in vitro and in vivo on serines 65 and 128 and colocalized with tcob on newly polymerized microtubules and on centrosomes. Pak1 phosphorylation is necessary for normal tcob function 0.449 SIGNOR-135464 AKT1 protein P31749 UNIPROT RAB3IP protein Q96QF0 UNIPROT up-regulates activity phosphorylation Ser165 LSRLRSPsVLEVREK 9606 BTO:0001950 36797475 YES miannu Rabin8 is phosphorylated and activated by Akt in cells grown on stiff ECM. 0.2 SIGNOR-277816 FHIT protein P49789 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 NO miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. 0.271 SIGNOR-159867 AKT1 protein P31749 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 NO PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype. 0.7 SIGNOR-254371 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.601 SIGNOR-249399 TEK protein Q02763 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 NO lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. 0.2 SIGNOR-241541 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 16440056 NO lperfetto The most abundant cytoplasmic dynein complex, cytoplasmic dynein 1, is involved in functions as diverse as spindle-pole organization and nuclear migration during mitosis, the positioning and functioning of the endoplasmic reticulum, the Golgi apparatus, and the nucleus, and also the minus-end-directed transport of vesicles, including endosomes and lysosomes, along microtubules and retrograde axonal transport in neurons. 0.7 SIGNOR-265058 SEC13 protein P55735 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.845 SIGNOR-265296 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000876 7964161 YES lperfetto Interleukin-1 receptor (il-1r) is a cytokine receptor which binds interleukin 1. 0.766 SIGNOR-35077 GNB1 protein P62873 UNIPROT PLCB1 protein Q9NQ66 UNIPROT down-regulates binding 9606 8870665 YES gcesareni These results indicate that g-protein beta gamma subunits constitute a mechanism by which g-protein mediate a rapid and transient plc- beta 1. 0.481 SIGNOR-44369 GCK protein P35557 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266458 BCL2L11 protein O43521 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 22492984 YES gcesareni Bim, and puma bind with high affinity to all pro-survival proteins 0.837 SIGNOR-196932 GATA1 protein P15976 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10523830 NO irozzo Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression. 0.519 SIGNOR-256053 PPP2R5B protein Q15173 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 YES gcesareni Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt. 0.66 SIGNOR-252615 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser176 TNAENTAsQSPRTRG 9606 19789335 YES gcesareni Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha. 0.841 SIGNOR-188321 CLTCL1 protein P53675 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 YES lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  0.73 SIGNOR-260662 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT down-regulates activity dephosphorylation Ser74 TVNQSLLsPLVLEVD 9606 BTO:0000586 19115206 YES the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431|The site-specific phosphorylation of keratins induces the disassembly of these filaments, and the balance between their phosphorylation and dephosphorylation controls the continuous exchange of intermediate filament subunits between a soluble pool and polymerized filaments 0.272 SIGNOR-248340 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1231 HSLAARYyNWVSFPG 9606 12881528 YES lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. 0.2 SIGNOR-104076 XL765 chemical CHEBI:71958 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252660 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 15774499 YES gcesareni The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. 0.595 SIGNOR-134658 CEBPA protein P49715 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 NO lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. 0.7 SIGNOR-249632 INO80B protein Q9C086 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.65 SIGNOR-270846 CYP2D6 protein P10635 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† 0.8 SIGNOR-263996 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 YES lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling 0.2 SIGNOR-244541 TFEB protein P19484 UNIPROT GNS protein P15586 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.312 SIGNOR-276540 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr34 KDQFPEVyVPTVFEN 9606 BTO:0000567 23027962 YES lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity 0.2 SIGNOR-271700 PRKCA protein P17252 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates phosphorylation Ser312 ASLKRSPsASSLSSM 9606 20519438 YES lperfetto Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively 0.2 SIGNOR-165857 GART protein P22102 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI down-regulates quantity chemical modification 9606 11381136 YES miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. 0.8 SIGNOR-267303 CAD protein P27708 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267424 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 10617468 YES lperfetto The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1 0.805 SIGNOR-73614 DR1 protein Q01658 UNIPROT NC2 complex complex SIGNOR-C108 SIGNOR form complex binding 9606 BTO:0000567 18838386 YES miannu NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex 0.751 SIGNOR-226405 AKT proteinfamily SIGNOR-PF24 SIGNOR ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 YES Threonine phosphorylation of the beta 3 integrin cytoplasmic tail, at a site recognized by PDK1 and Akt/PKB in vitro, regulates Shc binding.|We recently observed that phosphorylation of a threonine (Thr-753), six amino acids proximal to tyrosine 759 in beta(3) of the platelet specific integrin alpha(IIb)beta(3), inhibits outside-in signaling through this receptor.| A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. 0.2 SIGNOR-251479 TNRC6B protein Q9UPQ9 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity binding -1 17891150 YES miannu The assay showed that full-length TNRC6B binds full-length human AGO2. We have identified and molecularly dissected important sequence and structure features in the conserved Ago hooks of S. pombe Tas3 and human TNRC6B. The effect of Ago hook peptides from the shuttling P-body component TNRC6B in our miRNA-mediated translational repression assay (Fig. 5b), in particular, hints at a novel regulatory role of Ago hooks in miRNA-mediated gene repression mechanisms. 0.795 SIGNOR-269680 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 SIGNOR-C3 10942774 YES lperfetto Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies. 0.926 SIGNOR-80797 Diprenorphine chemical CHEBI:4650 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258789 CSNK2A2 protein P19784 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 YES llicata In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro. 0.342 SIGNOR-251028 CUL9 protein Q8IWT3 UNIPROT FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 35469017 YES miannu M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2. 0.2 SIGNOR-276717 C8B protein P07358 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 YES lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer 0.591 SIGNOR-263444 CEBPE protein Q15744 UNIPROT CEBPG protein P53567 UNIPROT up-regulates activity binding 9606 BTO:0000007 15588942 YES miannu C/EBP-epsilon interacts with C/EBP-gamma through the leucine-zipper containing domain. C/EBP-epsilon and C/EBP-gamma synergistically activate transcription of lactoferrin promoter 0.374 SIGNOR-224900 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 YES gcesareni Although sh2 domains have not been reported previously to be phosphorylated, the tensin-3 sh2 domain is a physiologic substrate for src. Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. 0.409 SIGNOR-187854 DUSP9 protein Q99956 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates binding 9606 21908610 YES gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. 0.703 SIGNOR-176589 NKX3-1 protein Q99801 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates activity binding 9606 16697957 YES miannu NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity. 0.37 SIGNOR-251549 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates quantity by destabilization phosphorylation Ser98 KGFNGCDsPEPDGED 10090 BTO:0000944 25733682 YES miannu  MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding.  0.265 SIGNOR-276887 ASXL3 protein Q9C0F0 UNIPROT BRD4 protein O60885 UNIPROT up-regulates activity binding 9606 BTO:0000189 32669118 YES miannu We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. 0.2 SIGNOR-266762 STAT3 protein P40763 UNIPROT IL1RN protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000876 20032313 NO miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. our findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB. 0.504 SIGNOR-254795 ATM protein Q13315 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser696 NVLSVALsQRTTVPE 9606 21095582 YES lperfetto Here we show that hypoxia results in ataxia telangiectasia mutated (atm)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (hif-1_) on serine(696) and mediates downregulation of mtorc1 signaling. phosphorylation of hif-1_ by atm is required for its stability 0.433 SIGNOR-169999 CSDE1 protein O75534 UNIPROT FOS protein P01100 UNIPROT down-regulates quantity post transcriptional regulation 10090 BTO:0000944 15314026 YES By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv 0.295 SIGNOR-261145 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser696 PNKELPPsPEKKTKP 9606 BTO:0000567 9398320 YES lperfetto Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)]. 0.498 SIGNOR-53735 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10029 15069075 YES lperfetto Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results. 0.722 SIGNOR-236760 KPNB1 protein Q14974 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity relocalization 9534 17596301 YES lperfetto Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization. 0.27 SIGNOR-260274 ARHGAP31 protein Q2M1Z3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.527 SIGNOR-260488 INS protein P01308 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates activity 9606 BTO:0000887 9415393 NO lperfetto Studies in adipose cells have demonstrated that insulin stimulates its receptor to phosphorylate tyrosine residues in irs-1, leading to activation of phosphatidylinositol 3-kinase, which plays a necessary role in mediating the translocation of the insulin-responsive glucose transporter glut4 to the cell surface. 0.496 SIGNOR-236781 ALDH5A1 protein P51649 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 19300440 YES miannu Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. 0.8 SIGNOR-266617 GMPS protein P49915 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI down-regulates quantity chemical modification 9606 6698284 YES miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). 0.8 SIGNOR-267337 DVL1P1 protein P54792 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells. 0.2 SIGNOR-199451 MAPK8 protein P45983 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation Ser198 GKTKTCEsPVSPIKM -1 28943315 YES miannu JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. 0.369 SIGNOR-277324 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser184 HPPVLRQsISFSGLP -1 14688255 YES miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. 0.698 SIGNOR-250153 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RXRA protein P19793 UNIPROT down-regulates activity phosphorylation 9606 17604322 YES inferred from 70% family members lperfetto In colon cancer cells, the Ras/mitogen‚Äêactivated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‚Äêmutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 0.2 SIGNOR-269995 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258459 MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 NO apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction 0.7 SIGNOR-255108 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR GATA2 protein P23769 UNIPROT up-regulates activity binding 10090 BTO:0001516 10938104 YES We provide evidence that GATA-2 can physically associate with PML-RARα. Functional experiments further demonstrated that this interaction has the capacity to render GATA-dependent transcription inducible by retinoic acid, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL. 0.2 SIGNOR-259941 DDIT3 protein P35638 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31226023 NO miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. 0.7 SIGNOR-260171 ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 YES lperfetto We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm. 0.52 SIGNOR-119546 RXRA protein P19793 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.686 SIGNOR-16671 DAXX protein Q9UER7 UNIPROT AIRE protein O43918 UNIPROT down-regulates activity binding 9606 BTO:0000567 20185822 YES 1 miannu The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells. The interaction has been further confirmed by showing in transactivation assays that DAXX exerts a strong repressive role on the transcriptional activity of AIRE. 0.335 SIGNOR-239287 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser576 CAEMREDsARVYENV 9606 11781100 YES lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. 0.331 SIGNOR-249136 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 16729043 YES gcesareni We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5. 0.821 SIGNOR-146852 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 YES lperfetto Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. 0.263 SIGNOR-216445 FUBP1 protein Q96AE4 UNIPROT CCND2 protein P30279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19637194 NO irozzo A positive cell cycle regulator that we found down-regulated in Hep3B cells upon FBP1 inactivation was cyclin D2. In addition, Cyclin D2 mRNA levels were diminished in the FBP1 knockdown cells, whereas the amount of Cyclin D1 mRNA remained unaffected. Numerous studies have classified D-type cyclins as cell cycle–promoting oncoproteins important for cellular transformation, and our results suggest that cyclin D2 is a candidate FBP1-regulated oncoprotein in HCC. 0.2 SIGNOR-259124 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr504 AEPLPPSyVACS 12441334 YES JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 0.811 SIGNOR-251355 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 17389604 YES lperfetto Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1 0.335 SIGNOR-216880 TEAD1 protein P28347 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20153295 NO lperfetto We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. 0.32 SIGNOR-235599 AP1 complex SIGNOR-C154 SIGNOR CCND1 protein P24385 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000762 12509763 NO lperfetto Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers.|As a result of stimulating these transcriptional regulators, key cell-cycle regulatory proteins, such as D-type cyclins, are expressed, which enables the cell to progress through the G1 phase of the cell-cycle. 0.619 SIGNOR-253215 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1173 QDTSKFWyKADISRE 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 YES llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate 0.409 SIGNOR-187843 EGFR protein P00533 UNIPROT LRRK1 protein Q38SD2 UNIPROT down-regulates activity phosphorylation Tyr971 TQQTEEQyFQFLAKF 9534 BTO:0000298 22337768 YES miannu In this study, we demonstrate that EGFR regulates the kinase activity of LRRK1 via tyrosine phosphorylation and that this is required for proper endosomal trafficking of EGFR. Phosphorylation of LRRK1 at Tyr-944 results in reduced LRRK1 kinase activity. 0.343 SIGNOR-262856 ZM447439 chemical CHEBI:91376 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207926 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 9892110 YES lperfetto SMAD7 functions as an antagonist to TGFB by binding to the TBRI and thus inhibiting activation of SMAD2 and SMAD3. 0.788 SIGNOR-64088 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 10090 BTO:0002572 14966296 YES The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP. 0.563 SIGNOR-248390 PRRX1 protein P54821 UNIPROT MAFF protein Q9ULX9 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.354 SIGNOR-221890 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Thr235 SSSSPPGtPSPADAK 10090 BTO:0001169 22355693 YES We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188 0.458 SIGNOR-251644 ginkgolide B chemical CHEBI:5356 ChEBI PTAFR protein P25105 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192684 NODAL protein Q96S42 UNIPROT ACVR1C protein Q8NER5 UNIPROT up-regulates activity binding 9606 BTO:0004094 15531507 YES Indirect_regulation of expression miannu Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation. 0.635 SIGNOR-251936 IRF3 protein Q14653 UNIPROT IFNB1 protein P01574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16699525 YES lperfetto Similarly, exogenous expression of wild-type Pin1 suppressed TLR3-mediated, IRF3-dependent activation of the IFN-beta promoter and reduced IFN-beta secretion in culture supernatants 0.664 SIGNOR-252257 MAGOH protein P61326 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 YES miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. 0.951 SIGNOR-265243 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273037 CNP protein P09543 UNIPROT MBP protein P02686 UNIPROT down-regulates activity 28076777 YES SimoneGraziosi We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP). 0.455 SIGNOR-269269 MECP2 protein P51608 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates activity binding 9606 BTO:0000007 12473678 YES Luana Thus, these results indicate that MeCP2-interacting Dnmt1 has significant maintenance DNA methyltransferase activity and that MeCP2 does not vanish Dnmt1 enzymatic activity. 0.529 SIGNOR-264541 ABI1 protein Q8IZP0 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 YES miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems 0.846 SIGNOR-253571 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI SDHB protein P21912 UNIPROT up-regulates activity chemical activation 26083061 YES lperfetto Succinate dehydrogenase subunit B contains three Fe-S clusters |The enzymatic activity of both proteins depends on the presence of intact Fe-S clusters 0.8 SIGNOR-262133 CTDSPL2 protein Q05D32 UNIPROT STK35 protein Q8TDR2 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser413 NVNKYWLsSACGSDF 9606 BTO:0002181 35021089 YES miannu  We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D). 0.282 SIGNOR-273776 SPOP protein O43791 UNIPROT HDAC6 protein Q9UBN7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 28599312 YES Gianni Cullin3 SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6 0.2 SIGNOR-268862 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.272 SIGNOR-275788 ZFYVE26 protein Q68DK2 UNIPROT TTC19 protein Q6DKK2 UNIPROT up-regulates activity binding 9606 BTO:0000567 20208530 YES miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. FYVE-CENT interacts with KIF13A and TTC19 0.462 SIGNOR-265538 SLC16A3 protein O15427 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 NO lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. 0.7 SIGNOR-256581 EP300 protein Q09472 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12954631 NO miannu these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter. 0.2 SIGNOR-253904 1-phosphatidyl-1D-myo-inositol 3-phosphate(3-) smallmolecule CHEBI:58088 ChEBI 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity precursor of 9606 18429927 YES miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 0.8 SIGNOR-269809 GABA-B receptor complex SIGNOR-C336 SIGNOR GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 30541966 YES miannu GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. 0.478 SIGNOR-265064 NARS1 protein O43776 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270456 RAB23 protein Q9ULC3 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates 9606 16364285 NO gcesareni Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization. 0.2 SIGNOR-143163 XPA protein P23025 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 NO lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.7 SIGNOR-275704 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG -1 17711846 YES done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). 0.41 SIGNOR-274095 DLGAP4 protein Q9Y2H0 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 YES miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. 0.803 SIGNOR-264212 TCF4 protein P15884 UNIPROT SSTR2 protein P30874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 10207097 YES Luana Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain. 0.358 SIGNOR-261618 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 BTO:0002035 11948419 YES miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). 0.374 SIGNOR-275983 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 YES miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 0.2 SIGNOR-256322 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 11041858 YES lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex 0.89 SIGNOR-83226 FAD(3-) chemical CHEBI:57692 ChEBI ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 YES miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. 0.8 SIGNOR-269469 DAXX protein Q9UER7 UNIPROT FAS protein P25445 UNIPROT down-regulates binding 9606 9215629 YES gcesareni A c-terminal portion of daxx interacts with the fas death domain. The fas-binding domain of daxx is a dominant-negative inhibitor of both fas-induced apoptosis and jnk activation. 0.703 SIGNOR-49473 AKT proteinfamily SIGNOR-PF24 SIGNOR PTPN1 protein P18031 UNIPROT down-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 YES lperfetto Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor. 0.2 SIGNOR-235411 VPS33A protein Q96AX1 UNIPROT CORVET tethering complex complex SIGNOR-C550 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.834 SIGNOR-273697 hsa-mir-494-3p mirna URS0000535FDD_9606 RNAcentral VIM protein P08670 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000150 25955111 YES In the present study, significant upregulation of E-cadherin and downregulation of N-cadherin, vimentin and α-SMA were observed in the miR-494 mimic-transfected cells compared to the control cells, indicating suppression of EMT following miR-494 transfection in breast cancer cells. 0.4 SIGNOR-277946 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 23729744 YES apalma The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes 0.95 SIGNOR-255377 MAPK1 protein P28482 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser425 NREKVAAsPKSPTAA 9606 16198290 YES lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. 0.367 SIGNOR-140890 SRC protein P12931 UNIPROT VCL protein P18206 UNIPROT down-regulates activity phosphorylation Tyr100 QMLQSDPySVPARDY 9534 15229287 YES lperfetto The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail. 0.759 SIGNOR-247424 ADORA3 protein P0DMS8 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.46 SIGNOR-256671 AMPK complex SIGNOR-C15 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 17728241 YES lperfetto Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by ampk 0.803 SIGNOR-216411 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 BTO:0002320 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.289 SIGNOR-249002 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2137 EDRTVPStPTLVVPH 9606 18794356 YES miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. 0.375 SIGNOR-181022 ARID1A protein O14497 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.806 SIGNOR-270689 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 15647376 YES llicata N this study we have demonstrated that ezrin y145 is a direct target for phosphorylation by the tyrosine kinase src evidence from this study suggests that a positive feedback loop exists whereby src-mediated ezrin y145 phosphorylation sustains src activity._ 0.647 SIGNOR-133227 CTNND2 protein Q9UQB3 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.448 SIGNOR-252134 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 10398585 YES lperfetto Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation 0.58 SIGNOR-249333 biphenyl-4,4'-diol chemical CHEBI:34367 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9751507 YES miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings. 0.8 SIGNOR-268740 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.34 SIGNOR-273148 CDK2 protein P24941 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR form complex binding 9606 19056339 YES lperfetto We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2. 0.977 SIGNOR-182569 ESR2 protein Q92731 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 NO ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression 0.291 SIGNOR-253943 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 NO lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS 0.7 SIGNOR-260258 SRC protein P12931 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Tyr156 YGPRAEEyEFLTPVE 9606 16943322 YES llicata We show here that src kinase binds and phosphorylates rhogdi both in vitro and in vivo at tyr156. analysis of rho gtpase-rhogdi complexes using in vitro assays of complexation and in vivo by coimmunoprecipitation analysis indicates that src-mediated phosphorylation of tyr156 causes a dramatic decrease in the ability of rhogdi to form a complex with rhoa, rac1, or cdc42. 0.4 SIGNOR-149282 IKBKG protein Q9Y6K9 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 9606 SIGNOR-C14 12192055 YES lperfetto The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation 0.93 SIGNOR-217436 PRKCA protein P17252 UNIPROT PPP1R16B protein Q96T49 UNIPROT down-regulates activity phosphorylation Ser331 SQLRHKSsLSRRTSS -1 27939168 YES done miannu PKCα phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function. 0.2 SIGNOR-273802 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR BCOR protein Q6W2J9 UNIPROT up-regulates activity binding 10090 BTO:0000944 12776190 YES irozzo As BCoR binds the C-terminus of AF9, it seems likely that BCoR will also bind chimeric MLL–AF9 proteins. As transcriptional repressors, BCoR or Pc3 bound to MLL–AF9 might interfere with the expression of genes required for normal hematopoiesis. 0.2 SIGNOR-256142 EPAS1 protein Q99814 UNIPROT KDM5C protein P41229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.278 SIGNOR-271579 Ub:E2 complex SIGNOR-C497 SIGNOR HECTD4 protein Q9Y4D8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271303 NF90-NF45 complex SIGNOR-C443 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by repression 10116 25566957 NO miannu In the present study, we investigated the expression profiles of NF45 in the sciatic nerve of adult rats following crush injury.  in the TNF-α-induced Schwann cell proliferation assay, protein level of NF45 and cyclin E was elevated while expression of p21 was down-regulated. Further, when NF45 was knocked down, Schwann cell proliferation was interrupted and the expression of cyclin E was attenuated, while the expression of p21 was up-regulated. To repress the expression of p21 is one of the basic mechanisms for NF45-regulated cell proliferation. 0.248 SIGNOR-268491 LPAR5 protein Q9H1C0 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256997 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 YES lperfetto Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2. 0.69 SIGNOR-153944 HBA1 protein P69905 UNIPROT EDN1 protein P05305 UNIPROT down-regulates activity 9606 8573884 NO Regulation of localization miannu Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury. 0.261 SIGNOR-251767 GAS6 protein Q14393 UNIPROT MERTK protein Q12866 UNIPROT up-regulates binding 9606 BTO:0000975 8939948 YES gcesareni We also found that gas6 stimulated tyrosine phosphorylation of axl, sky, and mer receptors ectopically expressed in chinese hamster ovary cells. Taken together, these findings suggest that gas6 is a common ligand for axl, sky, and mer, all known members of an axl/sky receptor subfamily. 0.761 SIGNOR-44953 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 YES flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. 0.36 SIGNOR-75934 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr326 TSSSQLStPKSKQSP 9606 14741103 YES llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. 0.405 SIGNOR-250659 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser181 RAKGPSEsSKERNTP -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.285 SIGNOR-273977 PRKCZ protein Q05513 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 17525161 YES lperfetto Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184. 0.2 SIGNOR-155111 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity dephosphorylation Tyr576 RYMEDSTyYKASKGK -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.244 SIGNOR-254719 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 YES lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. 0.871 SIGNOR-109609 BLOC-2 complex SIGNOR-C252 SIGNOR KIF13A protein Q9H1H9 UNIPROT up-regulates activity binding 9606 30404817 YES lperfetto Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. 0.257 SIGNOR-260702 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR CCL7 protein P80098 UNIPROT up-regulates quantity 10090 32283152 NO miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. 0.7 SIGNOR-260963 KCNS3 protein Q9BQ31 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 10029 BTO:0000246 10484328 YES miannu We describe the cloning and characterization of the first human members, hKv9.1 and hKv9.3, of the electrically silent delayed-rectifying-like K+ channel subfamily. 0.8 SIGNOR-269448 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 8266078 YES gcesareni Il-2r gamma was demonstrated to be a component of the il-4 receptor on the basis of chemical cross-linking data, the ability of il-2r gamma to augment il-4 binding affinity, and the requirement for il-2r gamma in il-4-mediated phosphorylation of insulin receptor substrate-1. 0.83 SIGNOR-37362 pemetrexed chemical CHEBI:63616 ChEBI DHFR protein P00374 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205819 CDK1 protein P06493 UNIPROT FANCG protein O15287 UNIPROT up-regulates phosphorylation Ser387 PRFSPPPsPPGPCMP 9606 15367677 YES gcesareni S387a mutant abolished fancg fusion protein phosphorylation by cdc2. 0.355 SIGNOR-129061 MARCHF9 protein Q86YJ5 UNIPROT LILRB1 protein Q8NHL6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271534 PDPK1 protein O15530 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Thr507 FGESRAStFCGTPDY 9606 BTO:0000007 9748166 YES miannu PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. PKCδ was also phosphorylated in the activation loop site (T505) 0.576 SIGNOR-250269 leuprolide acetate chemical CHEBI:63597 ChEBI GNRHR protein P30968 UNIPROT up-regulates activity chemical activation 9606 22416801 YES miannu Clinical data have shown that the GnRH antagonist, degarelix, is associated with more rapid PSA suppression and improved PSA PFS compared with the GnRH agonist, leuprolide. 0.8 SIGNOR-259163 DUSP9 protein Q99956 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates binding 9606 21908610 YES inferred from 70% of family members gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. 0.725 SIGNOR-269924 C5AR1 protein P21730 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.7 SIGNOR-263462 MAP2K6 protein P52564 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates phosphorylation 9606 9430721 YES gcesareni The p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms. 0.701 SIGNOR-54947 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 15664191 YES gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk 0.636 SIGNOR-133345 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr155 LNDSAAYyLNDLDRI -1 33139573 YES miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. 0.462 SIGNOR-277226 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 YES lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. 0.716 SIGNOR-118027 AKT1 protein P31749 UNIPROT TIFA protein Q96CG3 UNIPROT up-regulates activity phosphorylation Thr9 TSFEDADtEETVTCL 9606 BTO:0000007 27965388 YES miannu For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs. 0.2 SIGNOR-273542 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258626 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 BTO:0000222 14749395 YES lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. 0.319 SIGNOR-216920 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser283 RSVPEPLsPVSSLQA -1 16027724 YES GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) 0.381 SIGNOR-251227 CDK1 protein P06493 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Thr412 DTEIANStPNPKPAA 9606 16378098 YES gcesareni Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase. 0.758 SIGNOR-143387 FER protein P16591 UNIPROT JUP protein P14923 UNIPROT up-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 YES The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin) 0.525 SIGNOR-251134 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser392 ERLRLSPsPTSQRSR 9606 18815303 YES gcesareni Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm 0.537 SIGNOR-181318 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 12832520 YES gcesareni Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity. 0.498 SIGNOR-102652 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser231 FGDDEDDsGTEES 9606 BTO:0000567 11546811 YES lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. 0.395 SIGNOR-110399 EP300 protein Q09472 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 NO Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. 0.2 SIGNOR-254260 SMARCB1 protein Q12824 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates 9606 12226744 NO miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. 0.314 SIGNOR-92785 CDK9 protein P50750 UNIPROT XRN2 protein Q9H0D6 UNIPROT up-regulates activity phosphorylation Thr439 FTPSGILtPHALGSR -1 26728557 YES miannu Among the RNA processing factors phosphorylated by Cdk9 was the 5'-to-3' "torpedo" exoribonuclease Xrn2, required in transcription termination by Pol II, which we validated as a bona fide P-TEFb substrate in vivo and in vitro. Phosphorylation by Cdk9 or phosphomimetic substitution of its target residue, Thr439, enhanced enzymatic activity of Xrn2 on synthetic substrates in vitro.  0.278 SIGNOR-277194 NFKB1 protein P19838 UNIPROT CD80 protein P33681 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000776 12860928 NO Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. 0.298 SIGNOR-253934 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 11390389 YES lperfetto C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1 0.385 SIGNOR-86013 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 ChEBI up-regulates quantity precursor of -1 18772128 YES miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. 0.8 SIGNOR-267245 TRIM62 protein Q9BVG3 UNIPROT CARD9 protein Q9H257 UNIPROT up-regulates activity ubiquitination Lys125 LLMTEVMkLQKKVQD 9606 26488816 YES miannu Importantly, using in vitro ubiquitination assays with purified proteins, we verified that CARD9 is directly ubiquitinated by TRIM62 at residue K125; this ubiquitination is dependent on the ligase activity of TRIM62 and does not occur in CARD9 Delta11 (XREF_FIG). 0.51 SIGNOR-278552 PRLHR protein P49683 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.264 SIGNOR-257280 CHD8 protein Q9HCK8 UNIPROT SOX7 protein Q9BT81 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.2 SIGNOR-268922 ID3 protein Q02535 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.531 SIGNOR-241134 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr94 SSLPEGYyEEAVPLS 9534 9655255 YES lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. 0.573 SIGNOR-246363 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR BIN1 protein O00499 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.277 SIGNOR-136399 RCSD1 protein Q6JBY9 UNIPROT CAPZA1 protein P52907 UNIPROT up-regulates binding -1 15850461 YES miannu An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B). Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.668 SIGNOR-263088 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258775 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr37 EECDQNWyKAELNGK 9606 20554525 YES lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. 0.2 SIGNOR-246289 MAPK1 protein P28482 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Thr891 NSETSSDtPEMSLSA 10090 BTO:0000944 11581251 YES lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. 0.369 SIGNOR-249413 APH1B protein Q8WW43 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12522139 YES gcesareni Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity. 0.911 SIGNOR-97107 NTN1 protein O95631 UNIPROT UNC5C protein O95185 UNIPROT up-regulates binding 9606 10399920 YES gcesareni We provide evidence that netrin-1 triggers the formation of a receptor complex of dcc and unc5 proteins and simultaneously derepresses the interaction between their cytoplasmic domains, thereby converting dcc-mediated attraction to unc5/dcc-mediated repulsion. 0.831 SIGNOR-69047 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Thr120 QGSPRTStPFGSGRV 9606 17310276 YES lperfetto Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1 0.341 SIGNOR-153308 PRKDC protein P78527 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 YES gcesareni DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform 0.753 SIGNOR-252447 EGFR protein P00533 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates activity phosphorylation Tyr433 AALDTIQySKHPPPL 9606 31931029 YES miannu Here we found that EGFR-stimulated phosphorylation of SQSTM1 at tyrosine 433 induces dimerization of its UBA domain, which disturbs the sequestration function of SQSTM1 and causes autophagic flux blocking. 0.33 SIGNOR-277500 NCK1 protein P16333 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10029 BTO:0000246 7862111 YES lperfetto We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located. 0.614 SIGNOR-236321 TYMS protein P04818 UNIPROT dUMP(2-) smallmolecule CHEBI:246422 ChEBI down-regulates quantity chemical modification 9606 21876188 YES lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. 0.8 SIGNOR-268234 EGFR protein P00533 UNIPROT HDAC6 protein Q9UBN7 UNIPROT down-regulates phosphorylation Tyr570 SSNFDSIyICPSTFA 9606 20029029 YES gcesareni A negative feedback loop consisting of egfr-mediated phosphorylation of hdac6 tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin. 0.441 SIGNOR-162431 TICAM1 protein Q8IUC6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 14530355 YES lperfetto Toll/il-1 receptor domain-containing adaptor inducing ifn-beta (trif) associates with tnf receptor-associated factor 6 and tank-binding kinase 1, and activates two distinct transcription factors, nf-kappa b and ifn-regulatory factor-3, in the toll-like receptor signaling 0.821 SIGNOR-118458 IGF1R protein P08069 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 15829723 NO apalma Mechanical loading increases IGF-I release, and IGF-I can stimulate Ca2+ influx and thereby activate calcineurin 0.8 SIGNOR-255100 PRKCZ protein Q05513 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Thr110 SHSRQAStDAGTAGA 9606 BTO:0002181 25660024 YES miannu  Yap and β-catenin are direct substrates of PKCζ.We show here that PKCζ suppresses intestinal stem cell function by promoting the downregulation of β-catenin and Yap through direct phosphorylation.Consistent with MS/MS analysis, mutation to alanine of these two sites completely abolished Yap phosphorylation by PKCζ. Interestingly, S109 and T110 sites were highly conserved among species (Figure S3B), which suggested an important role in Yap regulation. 0.277 SIGNOR-276877 ELOVL5 protein Q9NYP7 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267898 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 12582165 YES lperfetto Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not 0.869 SIGNOR-236424 BMPR1A protein P36894 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 YES lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). 0.563 SIGNOR-255257 PELI1 protein Q96FA3 UNIPROT HPD protein P32754 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0003036 31537781 YES lperfetto Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. 0.2 SIGNOR-272959 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr317 PTQRMTItEFMNHPW -1 7592979 YES miannu In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction 0.769 SIGNOR-250102 MST1R protein Q04912 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation 35569509 YES lperfetto This suggests that by interacting with Sdc4, either directly or indirectly, RON is activated via transphosphorylation when clustered, engages the ABL1 SH2 domain, and activates ABL1 by phosphorylation. 0.273 SIGNOR-272999 CCL3 protein P10147 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  0.744 SIGNOR-255115 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser717 VYKSPVVsGDTSPRH 9606 BTO:0000590 12387894 YES lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. 0.738 SIGNOR-249355 PCSK2 protein P16519 UNIPROT OXT protein P01178 UNIPROT down-regulates quantity cleavage 9606 BTO:0001073 11690596 YES miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. 0.265 SIGNOR-270328 APH1A protein Q96BI3 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 YES gcesareni Gamma secretase subunit. Leads to ps1/ps2 eterodimer complex stabilisation. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. 0.923 SIGNOR-93265 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12950161 YES lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases 0.34 SIGNOR-86684 E2F1 protein Q01094 UNIPROT LRBA protein P50851 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15064745 NO miannu We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA. 0.2 SIGNOR-253846 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.2 SIGNOR-262995 RUNX1 protein Q01196 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30500954 NO irozzo Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. 0.334 SIGNOR-259133 TGFA protein P01135 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 BTO:0000584 16585207 YES Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines gcesareni Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo. 0.899 SIGNOR-93199 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser518 LSASPRMsGFIYQGK 9606 25009260 YES lperfetto Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome 0.2 SIGNOR-205234 haloperidol chemical CHEBI:5613 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258522 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT up-regulates activity phosphorylation Ser532 KSPAEAKsPEKEEAK 10116 9592082 YES lperfetto The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. 0.368 SIGNOR-249425 STUB1 protein Q9UNE7 UNIPROT S100A2 protein P29034 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 23344957 YES miannu S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway. 0.318 SIGNOR-272918 PRKAA1 protein Q13131 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser99 GGIKRTVsEPSLSGLL 9606 BTO:0001025 30022161 YES We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo 0.2 SIGNOR-256134 MTA1 protein Q13330 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.807 SIGNOR-263842 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT up-regulates activity phosphorylation Tyr183 NSFVGTPyWMAPEVI 9534 BTO:0004055 10559204 YES lperfetto These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK. 0.2 SIGNOR-246302 dopamine smallmolecule CHEBI:18243 ChEBI 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-264177 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 YES lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. 0.79 SIGNOR-252358 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser101 AAPEAGAsPVEKEAP -1 8034575 YES lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites. 0.729 SIGNOR-248909 SSTR5 protein P35346 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.495 SIGNOR-256690 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 16280325 YES lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. 0.34 SIGNOR-216868 AKT2 protein P31751 UNIPROT ANKRD2 protein Q9GZV1 UNIPROT up-regulates phosphorylation Ser99 QERVRKTsLDLRREI 10090 BTO:0000165;BTO:0000222 21737686 YES llicata In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions. 0.414 SIGNOR-236978 LRIG1 protein Q96JA1 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates ubiquitination 9606 16123311 YES gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. 0.607 SIGNOR-139954 ECM stimulus SIGNOR-ST20 SIGNOR A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259047 CSF1R protein P07333 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24890514 NO apalma The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation 0.286 SIGNOR-255572 CDK1 protein P06493 UNIPROT PIK3C2A protein O00443 UNIPROT down-regulates activity phosphorylation Ser259 KVSNLQVsPKSEDIS 9606 12719431 YES lperfetto Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk 0.281 SIGNOR-100903 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser689 KGVDFESsEDDDDDP -1 28436950 YES miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. 0.2 SIGNOR-265895 PAK1 protein Q13153 UNIPROT MORC2 protein Q9Y6X9 UNIPROT up-regulates activity phosphorylation Ser739 ATPSRKRsVAVSDEE 9606 BTO:0003878 25888627 YES done miannu We demonstrate that PAK1-mediated MORC2 phosphorylation promotes cell cycle progression, defective phosphorylation of MORC2-S677A results in attenuated cell proliferation and tumorigenicity of gastric cancer cells, which is significantly enhanced in overexpression of phospho-mimic MORC2-S677E form, suggesting the importance of MORC2 phosphorylation in tumorigenesis.  0.366 SIGNOR-273714 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000590 9832145 YES lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. 0.738 SIGNOR-249354 PI3K complex SIGNOR-C156 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 NO apalma Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation. 0.7 SIGNOR-255577 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 YES amattioni Crk can interact directly with tyrosine kinase receptors and can transmit signals downstream 0.608 SIGNOR-185667 CHKA protein P35790 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates quantity by destabilization phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017875 YES miannu DEPTOR phosphorylation by mTOR in response to growth signals, and in collaboration with casein kinase I (CKI), generates a phosphodegron that binds Œ≤TrCP.|These data suggests that CKI overexpression may overcome a requirement for phosphorylation at the major mTOR sites in DEPTOR for formation of the degron and are consistent with our finding that CKI can phosphorylate S286 and S287 in DEPTOR in vitro in the absence of mTOR. 0.2 SIGNOR-279604 CHKA protein P35790 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017875 YES miannu These data suggests that CKI overexpression may overcome a requirement for phosphorylation at the major mTOR sites in DEPTOR for formation of the degron and are consistent with our finding that CKI can phosphorylate S286 and S287 in DEPTOR in vitro in the absence of mTOR. 0.2 SIGNOR-279605 MC3R protein P41968 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity 9606 22215617 YES lperfetto We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus. 0.546 SIGNOR-253068 imatinib chemical CHEBI:45783 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258227 UCHL3 protein P15374 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.871 SIGNOR-270832 MAS1 protein P04201 UNIPROT AGTR1 protein P30556 UNIPROT down-regulates activity binding 9606 BTO:0000007 15809376 YES miannu our findings demonstrate that the protein encoded by the Mas proto-oncogene exhibits direct antagonistic properties on the AT1 receptor in vitro and that this oligomeric interaction may represent a natural state for these receptors in vivo in some tissues. the present findings in native tissues suggest that the Mas receptor can act as an in vivo functional antagonist of the AT1 receptor owing to formation of a hetero-oligomeric complex 0.276 SIGNOR-260626 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 YES llicata Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. 0.2 SIGNOR-188135 PI4KA protein P42356 UNIPROT 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI up-regulates quantity chemical modification 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269103 SRC protein P12931 UNIPROT PLEKHG2 protein Q9H7P9 UNIPROT up-regulates activity phosphorylation Tyr489 SEPVKDPyVMFPQNA 9606 BTO:0000007 24378532 YES done miannu Through deletion and base substitution mutagenesis we have identified Tyr489 of PLEKHG2 as the site phosphorylated by cSrc.The interaction between PLEKHG2 and the full-length of PIK3R3, but not ABL1, occurs in a tyrosine-phosphorylation-dependent manner. 0.2 SIGNOR-273808 CDK5RAP2 protein Q96SN8 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity binding 9606 BTO:0000567 19282672 YES Giulio We show here that inhibition of CDK5RAP2 expression causes chromosome mis-segregation, fails to maintain the spindle checkpoint, and is associated with reduced expression of the spindle checkpoint proteins BUBR1 and MAD2 and an increase in chromatin-associated CDC20.|We found that the APC activator CDC20, but not others we exam-ined, was present in the CDK5RAP2 immunocomplex in HeLa cell extracts (Fig. 3A). CDK5RAP2 was detected in the CDC20 immunocomplex as well (Fig. 3B). 0.313 SIGNOR-260311 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 YES gcesareni Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis. 0.746 SIGNOR-173331 CSNK1G1 protein Q9HCP0 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser322 PRTSSNAsTISGRLS -1 11980723 YES llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR 0.493 SIGNOR-250822 ADAM17 protein P78536 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 10882063 YES gcesareni ... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases. 0.738 SIGNOR-78903 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1005 EHDSDESsDDDSDSE 9606 10066810 YES gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, 0.442 SIGNOR-65273 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr381 VIHSPGFyTGKPGYK 9606 BTO:0002181 37977223 YES miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. 0.566 SIGNOR-277866 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser758 PVVFTVGsPPSGSTP 9606 BTO:0001938 21383122 YES lperfetto When cells are replenished with rich medium, mtor is activated;it phosphorylates serine 638 and serine 758. The phosphorylation of ulk1 at serine 758 then leads to reassociation between ulk1 and ampk. 0.849 SIGNOR-172541 STAT3 protein P40763 UNIPROT HAMP protein P81172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001950 18671304 NO miannu HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter. 0.427 SIGNOR-255239 FPR1 protein P21462 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256682 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2C complex SIGNOR-C349 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 YES lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically 0.8 SIGNOR-268279 MMP17 protein Q9ULZ9 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272362 PAK1 protein Q13153 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity phosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 YES miannu P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. 0.368 SIGNOR-277181 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 YES lperfetto We have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl 0.2 SIGNOR-99215 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 10581258 YES lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.772 SIGNOR-72695 PPP2R2A protein P63151 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity binding 10090 18042541 YES gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). 0.483 SIGNOR-252637 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 YES Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. 0.318 SIGNOR-248646 AKT1 protein P31749 UNIPROT ACOT4 protein Q8N9L9 UNIPROT up-regulates quantity by stabilization phosphorylation Ser392 GGEPRAHsKAQEDAW 9606 BTO:0001861 33148467 YES lperfetto HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. |AKT phosphorylates ACOT4 at S392 and promotes ACOT4 stability 0.2 SIGNOR-271820 MYC protein P01106 UNIPROT ST3GAL3 protein Q11203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 NO We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 0.2 SIGNOR-253962 KDM5A protein P29375 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-265334 CAV3 protein P56539 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.506 SIGNOR-255997 PRKCB protein P05771 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 YES lperfetto Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E . 0.349 SIGNOR-248946 STRADA protein Q7RTN6 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity binding 9606 12805220 YES Gianni Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419 0.939 SIGNOR-247560 MAPK3 protein P27361 UNIPROT TRPV3 protein Q8NET8 UNIPROT up-regulates activity phosphorylation Thr264 EGFYFGEtPLALAAC 9606 BTO:0000552 29084846 YES done miannu We observed that ERK-mediated phosphorylation of TRPV3 alters its responsiveness to repeated chemical stimuli. Among several putative ERK phosphorylation sites, we identified threonine 264 in the N-terminal ankyrin repeat domain as the most critical site for the ERK-dependent modulation of TRPV3 channel activity. Of note, Thr264 is in close vicinity to a structurally and functionally important TRPV3 region comprising an atypical finger 3 and oxygen-dependent hydroxylation site. In summary, our findings indicate that Thr264 in TRPV3 is a key ERK phosphorylation site mediating EGFR-induced sensitization of the channel to stimulate signaling pathways involved in regulating skin homeostasis. 0.2 SIGNOR-273672 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates phosphorylation 9606 16469705 YES gcesareni Here we show that tnfalpha-mediated jnk activation accelerates turnover of the nf-kappab-induced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activation of the e3 ubiquitin ligase itch, which specifically ubiquitinates c-flip and induces its proteasomal degradation. 0.654 SIGNOR-144456 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.764 SIGNOR-252863 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10644769 NO miannu these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation. 0.383 SIGNOR-253873 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 YES lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | 0.33 SIGNOR-249120 IFITM3 protein Q01628 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates activity binding 10090 32879487 YES miannu IFITM3 directly binds to γ-secretase. IFITM3 KO reduced γ-secretase activity for both Aβ40 and Aβ42 cleavages as compared to the EV (empty vector guide RNA) cell line by 36% and 27%, respectively (Fig. 2d, bar 1 and 3). 0.2 SIGNOR-266303 RTKs proteinfamily SIGNOR-PF38 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation 9606 30889378 YES miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. 0.2 SIGNOR-259030 USP17L2 protein Q6R6M4 UNIPROT LGMN protein Q99538 UNIPROT down-regulates quantity by destabilization deubiquitination 9606 BTO:0000815 24610907 YES miannu We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. We now present evidence that AEP is a substrate for TRAF6 ubiquitination, resulting in AEP/TRAF6/HSP90α complex formation. 0.309 SIGNOR-272854 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000776 25673924 YES lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. 0.772 SIGNOR-242891 F2RL1 protein P55085 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256895 FGF14 protein Q92915 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.244 SIGNOR-253445 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.2 SIGNOR-249647 CDK2 protein P24941 UNIPROT CCNO protein P22674 UNIPROT up-regulates activity phosphorylation Ser81 PSAARGGsPLPGPAQ 9606 BTO:0000007 25364462 YES lperfetto Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O|CKD2 phosphorylates the 81st serine residue of cyclin O 0.454 SIGNOR-275615 SMARCC1 protein Q92922 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.798 SIGNOR-270606 CTNNB1 protein P35222 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity 9606 16510874 NO Luana Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. 0.2 SIGNOR-265358 BST1 protein Q10588 UNIPROT nicotinic acid-adenine dinucleotide phosphate smallmolecule CHEBI:76072 ChEBI up-regulates quantity chemical modification 9606 18626062 YES miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. 0.8 SIGNOR-264249 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr988 RVDSDNAyIGVTYKN 9823 BTO:0004007 7535778 YES miannu We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ. 0.2 SIGNOR-250252 quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206331 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 YES gcesareni It has been shown that the c-terminal domains of ck2? Are phosphorylated by cdc2 and interact with the peptidyl-prolyl isomerase pin1 in a cell cycle-dependent manner 0.355 SIGNOR-161843 chlorpromazine chemical CHEBI:3647 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258370 MMP3 protein P08254 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE 9606 BTO:0000206 9202061 YES lperfetto Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374 0.737 SIGNOR-266986 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Thr658 VGGVVIAtVIVITLV -1 10605825 YES lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. 0.489 SIGNOR-261792 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser31 EILGRGVsSVVRRCI -1 7935360 YES miannu Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81. 0.2 SIGNOR-250388 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 10929711 YES amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. 0.914 SIGNOR-171770 PRKCQ protein Q04759 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates activity phosphorylation Thr227 LEPEALHtPTLMTTP 9606 27816489 YES Manara PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors. 0.2 SIGNOR-260879 PHF12 protein Q96QT6 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 YES miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. 0.2 SIGNOR-266994 FYN protein P06241 UNIPROT CD79A protein P11912 UNIPROT up-regulates activity phosphorylation Tyr199 NLDDCSMyEDISRGL -1 9531288 YES Lyn and Fyn phosphorylated the CD79a cytoplasmic portion of the fusion proteins well, with >80% of phosphorylation occurring at Y182. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). 0.594 SIGNOR-251153 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr585 PPGLEYCyNPSHNPE 10116 19224897 YES lperfetto Autophosphorylation of Y653 is followed by the ordered autophosphorylation of several key tyrosine residues within binding sites for the SH2 or PTB domains of signaling proteins that bind to and are phosphorylated by activated FGFR1. This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region 0.2 SIGNOR-235682 PTGDR protein Q13258 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.592 SIGNOR-256755 RPS6KB1 protein P23443 UNIPROT MXI1 protein P50539 UNIPROT down-regulates activity phosphorylation Ser160 MERIRMDsIGSTISS 9606 29507620 YES miannu Phosphorylation of Mxi1 by S6K1 at S160 site promotes its binding to beta-Trcp and ubiquitin mediated degradation.|The above findings demonstrate that S6K1 and beta-Trcp negatively regulates the stability of Mxi1 through ubiquitin proteasome pathway. 0.352 SIGNOR-278231 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 YES gcesareni Mcl-1 can be rapidly degraded by certain death-inducing signals, but it is able to be readily induced by diverse survival cytokines such as epidermal growth factor, vascular endothelial growth factor, granulocyt-macrophage colony-stimulating factor, and interleukin 3 through phosphatidy-linositol-3-oh kinase/akt, mek/mapk, or janus-activated kinase/stat signaling cascades 0.527 SIGNOR-179816 (8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol chemical CHEBI:92234 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258730 SREBF1 protein P36956 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 9539737 NO gcesareni Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands 0.448 SIGNOR-170607 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) 0.8 SIGNOR-257877 HRH1 protein P35367 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.426 SIGNOR-257376 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser170 RDSEGFNsPKQCDSS -1 12361598 YES miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) 0.516 SIGNOR-265958 RNF4 protein P78317 UNIPROT KDM5C protein P41229 UNIPROT up-regulates activity sumoylation 9606 33859667 YES SaraGualdi Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015). 0.2 SIGNOR-271576 FBXO11 protein Q86XK2 UNIPROT DTL protein Q9NZJ0 UNIPROT down-regulates binding 9606 23478441 YES miannu We determined that the f-box protein fbxo11 interacts with cdt2,a dcaf protein that controls cell-cycle progression, and recruits cdt2 to the scf(fbxo11)complex to promote its proteasomal degradation. 0.544 SIGNOR-192325 p38 proteinfamily SIGNOR-PF16 SIGNOR CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser391 LRSAAPSsPGSPRPA 9606 BTO:0000567 21930785 YES miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  0.2 SIGNOR-276362 ACVR1 protein Q04771 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 18801898 NO gcesareni Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle. 0.248 SIGNOR-243185 PLK1 protein P53350 UNIPROT STARD9 protein Q9P2P6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser312 SVSNGGDsGILSSPS 9606 25501367 YES miannuccelli NI indicates the noninduced control. (B) Plk1 phosphorylates STARD9-motor domain at serine 312. 0.31 SIGNOR-279806 NPTX1 protein Q15818 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 NO lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control 0.2 SIGNOR-260413 IL1B protein P01584 UNIPROT ITGA2 protein P17301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001596 1744142 NO lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. 0.274 SIGNOR-253356 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 YES lperfetto The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival 0.965 SIGNOR-236236 SMARCC2 protein Q8TAQ2 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.835 SIGNOR-270735 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L5 protein A0A1B0GUS4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271331 SOX9 protein P48436 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15240568 NO SOX9 represses the expression of the CDX2 transcription factor, known to be mostly active in villus cells. 0.381 SIGNOR-253322 FYN protein P06241 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 YES miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  0.357 SIGNOR-276371 SOST protein Q9BQB4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 NO Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass 0.582 SIGNOR-195684 NFATC4 protein Q14934 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 YES miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. 0.2 SIGNOR-264023 TMPRSS2 protein O15393 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25122198 YES miannu we identified pro-hepatocyte growth factor (HGF) as a TMPRSS2 substrate and confirmed that HGF and it’s cognate receptor c-Met are activated in prostate cancers expressing TMPRSS2, a finding that also associated with the acquisition of a pro-invasive mesenchymal gene expression program. 0.2 SIGNOR-263657 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI TYRO3 protein Q06418 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190410 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser182 AKGPSESsKERNTPR -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.321 SIGNOR-273967 ITCH protein Q96J02 UNIPROT BID protein P55957 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20392206 YES miannu The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid 0.353 SIGNOR-271415 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193627 COL1A2 protein P08123 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 10090 BTO:0000165 12496264 YES lperfetto Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins. 0.476 SIGNOR-253346 Erythrocytic spectrin complex SIGNOR-C384 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 NO lperfetto Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes. 0.7 SIGNOR-266028 AKT2 protein P31751 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 YES lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis 0.677 SIGNOR-235852 ARHGEF6 protein Q15052 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 BTO:0000599 23776207 NO lperfetto Activation of ARF6 promotes cortical actin assembly (9) and plasma membrane remodeling  0.7 SIGNOR-272236 GSK3A protein P49840 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 YES We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B 0.368 SIGNOR-251215 PDGFRB protein P09619 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 11896619 YES miannu The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway 0.579 SIGNOR-115843 BMI1 protein P35226 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24392140 YES lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, 0.456 SIGNOR-253385 TTL protein Q8NG68 UNIPROT TUBA3E protein Q6PEY2 UNIPROT down-regulates tyrosination 9606 22020298 YES miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization 0.458 SIGNOR-176924 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Ser1255 CLTERAMsWQDRARQ -1 27292631 YES miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. 0.304 SIGNOR-274059 EEF1A1P5 protein Q5VTE0 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269559 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp242 VRQKSEVdIVVSEDL 9606 11741536 YES gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. 0.365 SIGNOR-256441 DLX2 protein Q07687 UNIPROT MSX2 protein P35548 UNIPROT down-regulates activity binding 10090 9111364 YES 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. 0.392 SIGNOR-240911 FANCF protein Q9NPI8 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.908 SIGNOR-263242 TUBG1 protein P23258 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 19029337 NO miannu It has been reported that NEDD1 directly interacts with and recruits the γ-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly 0.7 SIGNOR-261423 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT down-regulates activity cleavage Pro21 FLLSYAVpSCGRSVE -1 8753751 YES lperfetto Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments. 0.422 SIGNOR-270546 DSN1 protein Q9H410 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR form complex binding -1 27881301 YES lperfetto Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits 0.901 SIGNOR-265189 ULK3 protein Q6PHR2 UNIPROT IST1 protein P53990 UNIPROT down-regulates activity phosphorylation 9606 26011858 YES miannu ULK3 phosphorylation of IST1 is required to sustain the abscission checkpoint and inhibits IST1 function in abscission. 0.625 SIGNOR-278205 SLC6A8 protein P48029 UNIPROT creatine smallmolecule CHEBI:16919 ChEBI up-regulates quantity relocalization 9606 18652074 YES miannu CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour. 0.8 SIGNOR-265782 LEF1 protein Q9UJU2 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 NO irozzo Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation 0.598 SIGNOR-256281 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.557 SIGNOR-270907 fentanyl chemical CHEBI:119915 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258939 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 YES lperfetto To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells 0.2 SIGNOR-252784 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR LEFTY2 protein O00292 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.42 SIGNOR-269251 POU2F1 protein P14859 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 23836662 NO miannu This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. 0.257 SIGNOR-254152 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1035 NMDAPPLsPYPFVRT 9606 BTO:0001938 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus) 0.679 SIGNOR-104711 MAP3K11 protein Q16584 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Ser281 WHKTTQMsAAGTYAW 9606 11053428 YES gcesareni These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites. 0.2 SIGNOR-83407 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Ser452 PVKTLPFsPSQFLNF BTO:0000007 10593981 YES llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 0.718 SIGNOR-250735 METTL3 protein Q86U44 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000567 27117702 YES miannu Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.  0.331 SIGNOR-265954 H2AX protein P16104 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 15635255 YES esanto Nbs1 physically interacts with ?-H2ax to form nuclear foci at dna damage sites. The inhibition of this interaction by introduction of anti-?-H2ax antibody into cells abolishes nbs1 foci formation in response to dna damage. 0.2 SIGNOR-133020 MAPK8 protein P45983 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 YES JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8 gcesareni Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-187. 0.338 SIGNOR-124016 CHUK protein O15111 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation 9606 27027448 YES miannu In those studies, we found that IKKalpha interacts with and phosphorylates mTOR in the mTORC1 complex to activate mTORC1, and that Akt signaling drives the IKKalpha-mTORC1 interaction.|We then studied whether IKKalpha promotes Akt and mTOR activity in other mammalian cancer cell lines. 0.512 SIGNOR-279607 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser867 SPVSVGSsPPVKNIS 9606 BTO:0000093 15383283 YES miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. 0.525 SIGNOR-250106 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 16669787 YES miannu We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1 0.525 SIGNOR-146521 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 16046550 YES The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. 0.342 SIGNOR-138912 sertindole chemical CHEBI:9122 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258542 CDK1 protein P06493 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser540 HVSEDSSsPERTSPP 9606 SIGNOR-C17 19107194 YES gcesareni We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells 0.529 SIGNOR-182863 SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16729043 YES gcesareni In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation. 0.819 SIGNOR-146897 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr41 GIHSGATtTAPSLSG 9606 19667122 YES lperfetto Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta. 0.2 SIGNOR-187582 CSNK2A1 protein P68400 UNIPROT SLC29A1 protein Q99808 UNIPROT up-regulates activity phosphorylation Ser254 ETKLDLIsKGEEPRA -1 17520485 YES miannu These data suggest that inhibition of CK2-mediated phosphorylation at Ser254 had the same effect on transporter function as the actual loss of Ser254 in mENT1a, implying that this site is constitutively phosphorylated by CK2.  0.2 SIGNOR-276063 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 1846781 YES lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. 0.331 SIGNOR-21776 CLK1 protein P49759 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation 9606 23707382 YES miannu In a previous study, we showed that CLK1 phosphorylates SRSF1 to a greater extent than SRPK1, inducing a hyper-phosphorylated state that can be readily detected by a gel shift on SDS-PAGE. xref In xref , the phosphorylation of SRSF1 in single turnover experiments using SRPK1 and CLK1 is shown.|Unlike SRPK1, CLK1 induces a unique structural form of SRSF1 observed by SDS-PAGE that is exclusively the result of Ser-Pro rather than Arg-Ser phosphorylation. 0.675 SIGNOR-279608 DYRK1A protein Q13627 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity phosphorylation Ser62 S-->E 9606 24901999 YES miannu We also found that DYRK1A phosphorylated c-Myc on Ser62, priming phosphorylation on Thr58 by GSK3\u03b2 and subsequent degradation.|c-Myc expression is down-regulated by DYRK1A. 0.374 SIGNOR-279609 PHF12 protein Q96QT6 UNIPROT TLE4 protein Q04727 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 YES miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. 0.2 SIGNOR-266989 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257927 PRKCA protein P17252 UNIPROT RAB37 protein Q96AX2 UNIPROT down-regulates activity phosphorylation Thr172 YGVPFLEtSAKTGMN 9606 BTO:0002877 29312551 YES done miannu We also show that Rab37 is phosphorylated by protein kinase Cα (PKCα) at threonine 172 (T172), leading to attenuation of its GTP-bound state, and impairment of the Rab37-mediated exocytosis of TIMP1, and thus reduces its suppression activity on lung cancer cell motility.  0.2 SIGNOR-273803 PTPN2 protein P17706 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity dephosphorylation 9606 33122197 YES miannu Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. 0.276 SIGNOR-277039 Upadacitinib chemical CID:58557659 PUBCHEM JAK1 protein P23458 UNIPROT down-regulates activity binding 9606 33240390 YES Upadacitinib (ABT-494) is another selective inhibitor of JAK1 undergoing clinical trials to determine its benefit for several inflammatory diseases 0.8 SIGNOR-272504 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269335 TFAP2A protein P05549 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 YES miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 0.259 SIGNOR-253636 LFNG protein Q8NES3 UNIPROT DLL1 protein O00548 UNIPROT up-regulates binding 9606 11346656 YES gcesareni The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng 0.447 SIGNOR-107699 desipramine chemical CHEBI:47781 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 9400006 YES miannu In the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.in the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.Thus, amitriptyline, imipramine, nortriptyline and desipramine showed high affinity for the SERT, particularly the human version, and for the NET in which the secondary amines were more potent. 0.8 SIGNOR-258679 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 YES Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. 0.2 SIGNOR-251470 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT down-regulates dephosphorylation 9606 12857726 YES gcesareni Our results demonstrate that ptp1b plays an important role in the integrin-mediated dephosphorylation of lat in human platelets and is involved in the control of irreversible aggregation upon fcgammariia stimulation. 0.503 SIGNOR-103599 ASB3 protein Q9Y575 UNIPROT TNFRSF1B protein P20333 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 15899873 YES miannu While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-alpha by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation 0.398 SIGNOR-271546 RAPGEF3 protein O95398 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 YES miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. 0.709 SIGNOR-263956 KLF10 protein Q13118 UNIPROT TGFBI protein Q15582 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 18359287 YES lperfetto Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia. 0.242 SIGNOR-253212 EIF2AK2 protein P19525 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 25360179 YES miannu Silencing PKR gene expression in HepG2 cells with siRNA reduced STAT3 phosphorylation at Tyr705 and Ser727 (XREF_FIG).|The results also revealed that PKR activates STAT3, a transcription factor associated with primary liver tumors, which is suggested to promote tumor cell proliferation. 0.611 SIGNOR-279613 DLC1 protein Q96QB1 UNIPROT MYH9 protein P35579 UNIPROT down-regulates activity binding 9606 BTO:0004006 phosphorylation:Ser1943 RKGAGDGsDEEVDGK 26977077 YES miannu Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9), plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. Dlc1 interacts with phosphorylated Myh9 (Ser-1943). This association of Dlc1 with S1943 phosphorylated Myh9, suggests that Dlc1 may be involved in reduced Myh9 filament stability. 0.2 SIGNOR-269283 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates activity binding 9606 14967450 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. 0.8 SIGNOR-242599 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.264 SIGNOR-276099 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR TFCP2 protein Q12800 UNIPROT down-regulates activity phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 YES lperfetto In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression 0.266 SIGNOR-273180 KLHL20 protein Q9Y2M5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 26687681 YES miannu Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1 0.295 SIGNOR-272414 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 20145185 YES gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. 0.8 SIGNOR-163730 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 11948419 YES gcesareni Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo. 0.374 SIGNOR-116499 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR KDM5B protein Q9UGL1 UNIPROT down-regulates activity 9606 35217626 YES SaraGualdi Our transcriptomic profiling in AML further identified Kdm5b (also known as Jarid1b, Plu-1, or RBP2-H1), a multifunctional demethylase that can remove histone H3 lysine 4 tri/di-methylation (H3K4me3/2), to be a critical downstream target repressed by PRC2. 0.362 SIGNOR-271577 OGA protein O60502 UNIPROT PFKL protein P17858 UNIPROT up-regulates activity deglycosylation Ser529 CVIPATIsNNVPGTD 9606 26399441 YES lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 0.2 SIGNOR-267608 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid chemical CHEBI:94640 ChEBI GRM2 protein Q14416 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193728 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser322 PRTSSNAsTISGRLS -1 11980723 YES llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR 0.493 SIGNOR-252901 CIITA protein P33076 UNIPROT HLA-DRB3 protein P79483 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10886240 NO These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. 0.2 SIGNOR-254011 MXI1 protein P50539 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002036 11875718 YES Luana Mxi1 inhibits the proliferation of U87 glioma cells through down-regulation of cyclin B1 gene expression | Mxi1 inhibits the promoter activity of the cyclin B1 gene. 0.266 SIGNOR-266064 MKNK1 protein Q9BUB5 UNIPROT PNPLA8 protein Q9NP80 UNIPROT up-regulates activity phosphorylation Ser511 ELYRKLGsDVFSQNV 9534 BTO:0000298 23258543 YES done miannu Constitutively active MNK1 activates and phosphorylates iPLA2γ. Thus, complement-mediated activation of iPLA(2)γ is mediated via ERK and p38 pathways, and phosphorylation of Ser-511 and/or Ser-515 plays a key role in the catalytic activity and signaling of iPLA(2)γ. 0.2 SIGNOR-273677 PDK1 protein Q15118 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 YES miannu PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3. 0.306 SIGNOR-250264 TLR4 protein O00206 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 YES gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.85 SIGNOR-252067 KLHL21 protein Q9UJP4 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000567 27641145 YES miannu Indeed, KLHL21 localizes to FA structures preferentially at the leading edge, and in complex with Cul3, ubiquitylates EB1 within its microtubule-interacting CH-domain. Cells lacking CRL3(KLHL21) activity or expressing a non-ubiquitylatable EB1 mutant protein are unable to migrate and exhibit strong defects in FA dynamics, lamellipodia formation and cortical plasticity. Our study thus reveals an important mechanism to regulate cortical dynamics during cell migration that involves ubiquitylation of EB1 at focal adhesions. 0.568 SIGNOR-272408 GRIA4 protein P48058 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264950 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser789 VSAGPRPsPLPSPQP 9606 20005250 YES miannu Further, investigation revealed that MLK3 was phosphorylated at two residues Ser789 and Ser793 by GSK3beta.|When, these two sites on MLK3 were mutated to non-phosphorable Ala, the activation of MLK3 by GSK3\u03b2 was blocked, and neuronal cell death upon NGF withdrawal also prevented ( xref ). 0.336 SIGNOR-279616 GTF3C4 protein Q9UKN8 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 YES lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains 0.888 SIGNOR-266185 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT down-regulates activity binding 9606 19956691 YES Regulation miannu We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. 0.688 SIGNOR-251865 JAKMIP1 protein Q96N16 UNIPROT TUBB protein P07437 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000661 15277531 YES SARA In Jamip1, the N-terminal region mediates the association with microtubules, when highly expressed, N-ter drastically affects the organization of microtubules that appear to be bundled, stabilized against the depolymerizing effect of nocodazole, and enriched in acetylated tubulin. 0.2 SIGNOR-260987 GDAP1 protein Q8TB36 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 NO lperfetto However, it remains elusive if additional proteins are involved in the regulation of mitochondrial fission, such as proposed fission factor GDAP1 0.7 SIGNOR-272977 GLI1 protein P08151 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 3563490 NO gcesareni The gli gene is a member of a select group of cellular genes that are genetically altered in primary human tumors. 0.7 SIGNOR-235196 CREB5 protein Q02930 UNIPROT MAPKAPK3 protein Q16644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002814 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.25 SIGNOR-253807 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 10090 BTO:0000944 7889942 YES lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency. 0.562 SIGNOR-235467 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 9606 15568999 YES lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. 0.2 SIGNOR-131403 lofexidine chemical CHEBI:51368 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 22341244 YES Luana Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism.  0.8 SIGNOR-258331 AURKC protein Q9UQB9 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates activity phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 29050234 YES miannu AURKC directly induces IkappaBalpha activation via an interaction between the two proteins, leading to phosphorylation of IkappaBalpha.|AURKC phosphorylates IkappaBalpha on S32 and binds its ankyrin repeat domain. 0.2 SIGNOR-278470 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 29953871 NO miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. 0.7 SIGNOR-264954 JUN protein P05412 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 22944199 NO gcesareni Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements 0.7 SIGNOR-198834 ARAF protein P10398 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000567 8621729 YES lperfetto Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222. 0.739 SIGNOR-236451 MDH2 protein P40926 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-266288 ZFP36 protein P26651 UNIPROT EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR up-regulates activity relocalization 9606 30917308 YES lperfetto A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs 0.2 SIGNOR-261014 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates activity phosphorylation Thr208 TFGNKLDtFCGSPPY -1 18424437 YES miannu MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. 0.587 SIGNOR-276165 YWHAG protein P61981 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 14701738 YES miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase 0.267 SIGNOR-261723 EGR1 protein P18146 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 20506119 NO miannu In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2. 0.594 SIGNOR-253881 CDK4 protein P11802 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity phosphorylation Ser430 KYTYGQSsMSPLPQM 9606 23469153 YES miannu In summary, our study showed that Cdk4 phosphorylates and activates PAX3-FOXO1, thereby promoting its oncogenic function.|These findings suggest that Cdk4 phosphorylates the Ser 430 residue of PAX3-FOXO1 in vitro . 0.461 SIGNOR-278377 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR CREB3L2 protein Q70SY1 UNIPROT up-regulates 9606 17178827 NO miannu Although bbf2h7 protein is not expressed under normal conditions, it is markedly induced at the translational level during er stress, suggesting that bbf2h7 might contribute to only the late phase of unfolded protein response signaling. 0.7 SIGNOR-151312 ADRA1A protein P35348 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.278 SIGNOR-256955 ATM protein Q13315 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by destabilization phosphorylation Thr134 SRAAFSHtQVIELER 9606 BTO:0002181 23890999 YES miannu ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction. 0.362 SIGNOR-276499 PI3K complex SIGNOR-C156 SIGNOR PIK3CG protein P48736 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 YES lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.601 SIGNOR-252721 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10611223 YES lperfetto Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau. 0.336 SIGNOR-73533 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 10428798 YES lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. 0.419 SIGNOR-217284 COL4A3 protein Q01955 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.452 SIGNOR-253244 SARS1 protein P49591 UNIPROT tRNA(Ser) smallmolecule CHEBI:29179 ChEBI down-regulates quantity chemical modification 9606 24095058 YES miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis 0.8 SIGNOR-270493 DAPK1 protein P53355 UNIPROT PELI1 protein Q96FA3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser39 GDRGRRKsRFALFKR 9606 BTO:0003575 33052227 YES miannu DAPK1, which directly binds to and phosphorylates Pellino1 at Ser39, leading to Pellino1 poly-ubiquitination and turnover. 0.2 SIGNOR-277531 NFYC protein Q13952 UNIPROT SOX18 protein P35713 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 18496767 NO miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells 0.2 SIGNOR-254822 CDK1 protein P06493 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 SIGNOR-C17 20150555 YES gcesareni Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis. 0.464 SIGNOR-163738 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.572 SIGNOR-270883 NDN protein Q99608 UNIPROT EID1 protein Q9Y6B2 UNIPROT up-regulates activity binding 10090 BTO:0000165 18557765 YES llicata The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation. 0.375 SIGNOR-237614 SEC61B protein P60468 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 YES lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER 0.909 SIGNOR-265277 DHCR7 protein Q9UBM7 UNIPROT cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI down-regulates quantity chemical modification 9606 9634533 YES miannu In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol. 0.8 SIGNOR-267251 methylnaltrexone chemical CHEBI:136007 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10030 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258148 RARA protein P10276 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10772826 NO lperfetto Retinoic acid and its receptors repress the expression and transactivation functions of nur77 0.292 SIGNOR-76980 LUBAC complex SIGNOR-C527 SIGNOR PRKCA protein P17252 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 17069764 YES miannu In this report, we demonstrated that LUBAC, a ubiquitin ligase complex, is an E3 of activated cPKCs. LUBAC preferentially bound PMA-activated PKCa and PKCbII and their constitutively active mutants (Fig. 2). degradation of PMA-activated PKCa was delayed in HOIL-1L/-MEF (Fig. 3F). These results indicate that LUBAC is the ubiquitin ligase that induces ubiquitination and degradation of activated cPKCs. 0.393 SIGNOR-271618 Prolactin-releasing peptide-20 smallmolecule CHEBI:80301 ChEBI PRLHR protein P49683 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257566 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser435 TLASERSsPQRKSQR -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414. An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.286 SIGNOR-262747 ESR2 protein Q92731 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 NO lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. 0.477 SIGNOR-268547 BRCA1 protein P38398 UNIPROT FOXC2 protein Q99958 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 22120723 NO miannu We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. 0.26 SIGNOR-253760 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 BTO:0002181 19797085 YES miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  0.354 SIGNOR-276263 MAML1 protein Q92585 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11101851 YES gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. 0.808 SIGNOR-84835 ALG2 protein Q9H553 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI up-regulates quantity chemical modification 9606 28575298 YES lperfetto The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. 0.8 SIGNOR-260419 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser567 SSSRRRRsSSTAPPT 9606 16513649 YES llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization 0.2 SIGNOR-145032 TADA2B protein Q86TJ2 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.77 SIGNOR-269571 PABPC1 protein P11940 UNIPROT EIF4E protein P06730 UNIPROT up-regulates activity binding 9606 30209168 YES miannu The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling 0.805 SIGNOR-260968 PTPRA protein P18433 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 YES We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI 0.3 SIGNOR-248436 sorafenib tosylate chemical CHEBI:50928 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 0.8 SIGNOR-259222 CSNK2A1 protein P68400 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 7598724 YES llicata We report that recombinant glia maturation factor (GMF), a 17-kD brain protein, can be phosphorylated in vitro at the serine residue by protein kinase C (PKC), protein kinase A (PKA), and casein kinase II (CKII), and at the threonine residue by p90 ribosomal S6 kinase (RSK).  0.331 SIGNOR-250868 PRKACA protein P17612 UNIPROT SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser1445 PSPTSRQsPASPPPL 9606 BTO:0000007 20622900 YES miannu HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further. 0.25 SIGNOR-263066 SRC protein P12931 UNIPROT DMAP1 protein Q9NPF5 UNIPROT down-regulates activity phosphorylation Tyr246 EQVAEEEyLLQELRK 9606 30553276 YES miannu C-Src phosphorylates DMAP1 at Tyr246 and disrupts Bub3/DMAP1 complex formation. 0.2 SIGNOR-279431 AKT1 protein P31749 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates activity phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 BTO:0000759 17554339 YES lperfetto Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin. 0.448 SIGNOR-252502 CASP6 protein P55212 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.363 SIGNOR-261750 ILK protein Q13418 UNIPROT SYNPO2 protein Q9UMS6 UNIPROT up-regulates activity phosphorylation 9606 21643011 YES miannu Fourth, ILK dependent phosphorylation of myopodin is found both in vivo and in vitro.|The ILK dependent activation of myopodin provides a novel link between extracellular matrix-integrin-ILK signaling and myopodin tumor suppression. 0.504 SIGNOR-279622 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.336 SIGNOR-262755 FFAR2 protein O15552 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256803 MAGEL2 protein Q9UJ55 UNIPROT WASHC1 protein A8K0Z3 UNIPROT up-regulates activity binding 9606 23452853 YES miannu Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport. 0.2 SIGNOR-253515 CSAG2 protein Q9Y5P2 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity binding 9606 32761762 YES miannu Here, we show that the previously undescribed CSAG2 protein is a direct activator of SIRT1.  Biochemical studies revealed that CSAG2 directly binds to and stimulates SIRT1 activity toward multiple substrates. Importantly, CSAG2 enhances SIRT1‐mediated deacetylation of p53, inhibits p53 transcriptional activity, and improves cell survival in response to genotoxic stress. 0.2 SIGNOR-261670 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 10116 BTO:0000452 1749429 YES lperfetto Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation. 0.501 SIGNOR-236686 ITK protein Q08881 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity phosphorylation 9606 23454662 YES miannu This ability of Itk to phosphorylate Galpha13 was abolished in Itk mutants R29C (no longer able to interact with the membrane, and thus unable to interact with Galpha13) and K391M (no kinase activity) (XREF_FIG).|To determine whether Itk is a downstream mediator of Galpha13, we examined whether Galpha13 could interact with Itk when locked in the GDP bound or GTP bound state. 0.2 SIGNOR-279623 CDKL5 protein O76039 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 10090 23651931 YES gcesareni This 120-kDa protein was identified as amphiphysin 1 (Amph1) by LC-MS/MS analysis, and the site of phosphorylation by CDKL5 was determined to be Ser-293.| The phosphorylation mimic mutants, Amph1(S293E) and Amph1(S293D), showed significantly reduced affinity for endophilin, a protein involved in synaptic vesicle endocytosis 0.361 SIGNOR-245881 JAK1 protein P23458 UNIPROT SNX8 protein Q9Y5X2 UNIPROT up-regulates activity phosphorylation Tyr95 LFLKHVEyEVSSQRF 9606 BTO:0000007 29180417 YES miannu IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKβ to the JAK1 complex.  0.342 SIGNOR-273647 PTPRF protein P10586 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 NO miannu LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance 0.7 SIGNOR-264090 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser485 QPDNSSDsDYDLHGA 9606 9834084 YES lperfetto In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461) 0.343 SIGNOR-62311 OGT protein O15294 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity glycosylation Ser530 VVIPATVsNNVPGSD 9606 26399441 YES lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 0.346 SIGNOR-267584 SNRPE protein P62304 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.944 SIGNOR-270681 CCL3 protein P10147 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity binding 10090 15075201 YES lperfetto The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. 0.554 SIGNOR-251723 CASP8 protein Q14790 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp348 GTGGLEPdLARGRWA 9606 BTO:0005111 32122970 YES miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. 0.315 SIGNOR-272194 RNF180 protein Q86T96 UNIPROT ZIC2 protein O95409 UNIPROT down-regulates quantity by destabilization ubiquitination 10116 18363970 YES miannu Rinescan directly interact with Zic2. the ubiquitination of endogenous Zic2 was enhanced by Myc-Rines in rat neural stem cellline MNS70 cells. Rines-induced degradation of Zic2 0.374 SIGNOR-226303 RPL35A protein P18077 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.856 SIGNOR-262465 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257982 TRAF6 protein Q9Y4K3 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity ubiquitination 9606 23911927 YES miannu Together, these results demonstrate that mTOR polyubiquitination by TRAF6 modulates its activation in response to amino acids and point to a role for K63 ubiquitin modification as a sensor of nutrient status. 0.439 SIGNOR-278789 NOTCH4 protein Q99466 UNIPROT MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 12386158 YES gcesareni We show here identification of two new members of human mam family (human mastermind-2 (hmam-2) and human mastermind-3 (hmam-3)), which retain characteristics similar to human mastermind-1 (hmam-1) and drosophila mastermind. Both hmam-2 and hmam-3 stabilize and participate in the dna-binding complex rbp-j/cbf-1 protein and the notch intracellular domains that serve as intermediates of the signaling. Both hmam-2 and hmam-3 enhanced the activation of transcription from a target promoter by notch signaling. However, we also show evidence that the activation of the target promoter by notch3 and notch4 is more efficiently potentiated by hmam-2 than by hmam-1 or -3. 0.86 SIGNOR-94279 SMAD7 protein O15105 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates binding 9606 BTO:0001253 17384642 YES lperfetto The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling 0.568 SIGNOR-153917 Ub:E2 complex SIGNOR-C497 SIGNOR RNF213 protein Q63HN8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271097 bortezomib chemical CHEBI:52717 ChEBI PSMD1 protein Q99460 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 YES miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. 0.8 SIGNOR-259312 CTBP1 protein Q13363 UNIPROT ZEB2 protein O60315 UNIPROT up-regulates activity binding 9606 16061479 YES miannu Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP 0.475 SIGNOR-225484 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 YES lperfetto The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane. 0.935 SIGNOR-236656 Ub:E2 complex SIGNOR-C497 SIGNOR HERC4 protein Q5GLZ8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271307 RAF1 protein P04049 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 YES miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  0.2 SIGNOR-276407 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Thr312 RSQELRKtFKEIICC 9606 12639913 YES miannu Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA 0.309 SIGNOR-250017 Ub:E2 complex SIGNOR-C497 SIGNOR RNFT1 protein Q5M7Z0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271262 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates activity phosphorylation 9606 23431053 YES miannu Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity 0.9 SIGNOR-256185 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887;BTO:0001103 12058061 YES lperfetto Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. 0.509 SIGNOR-236575 Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR SIGLEC7 protein Q9Y286 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001516 17138568 YES miannu SOCS proteins can act as E3 ligases by forming a complex with Elongin B/C and Cul5/Rbx1/2.SOCS3 targets Siglec 7 for degradation 0.2 SIGNOR-272644 HOPS tethering complex complex SIGNOR-C549 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.32 SIGNOR-273692 CASP3 protein P42574 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 YES lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. 0.454 SIGNOR-261756 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000007 17035229 YES SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.514 SIGNOR-248796 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.551 SIGNOR-270880 ADSL protein P30566 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression 9606 31729379 NO miannu An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels 0.2 SIGNOR-266614 MAPK9 protein P45984 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 YES gcesareni Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells. 0.2 SIGNOR-178934 TP53 protein P04637 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 YES miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 0.471 SIGNOR-253638 CDK5 protein Q00535 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr75 RPNPCAYtPPSLKAV 10116 BTO:0000142 10604473 YES llicata We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. 0.776 SIGNOR-250671 HSP90AB1 protein P08238 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 10944114 YES gcesareni The present studies demonstrate that heat shock protein 90 (hsp90) forms a cytosolic complex with apaf-1 and thereby inhibits the formation of the active complex. 0.389 SIGNOR-81043 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser718 KEAEEESsEDD 9606 BTO:0000007 11500362 YES llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  0.386 SIGNOR-250860 CDK2 protein P24941 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by destabilization phosphorylation Thr156 HLFTFPPtPPKDVSP 9606 BTO:0000567 24820417 YES miannu Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156. 0.363 SIGNOR-276634 SP3 protein Q02447 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 YES lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. 0.2 SIGNOR-251741 GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. 0.448 SIGNOR-252683 CAMK1 protein Q14012 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD -1 8663317 YES llicata Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site. 0.511 SIGNOR-250611 daunorubicin chemical CHEBI:41977 ChEBI ABCC1 protein P33527 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002206 9647783 YES Simone Vumbaca Unconjugated Dox and Dau failed to inhibit the transport of LTC4, whereas 30 microM GS-Dox or GS-Dau conjugates completely inhibited the transport. 0.8 SIGNOR-261086 ANK3 protein Q12955 UNIPROT GABARAP protein O95166 UNIPROT up-regulates activity binding 10090 BTO:0003102 30504823 YES miannu Importantly, the 480 kDa ankyrin-G isoform has also been shown to stabilize GABAergic synapses on the soma and AIS of excitatory pyramidal neurons by interacting with the GABAA receptor-associated protein (GABARAP) to inhibit GABAA receptor endocytosis 0.446 SIGNOR-266709 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 YES gcesareni MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt 0.642 SIGNOR-252448 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 10551811 YES gcesareni The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. 0.359 SIGNOR-72108 CCKAR protein P32238 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.252 SIGNOR-257236 BCL7A protein Q4VC05 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.491 SIGNOR-269784 AFDN protein P55196 UNIPROT RIT1 protein Q92963 UNIPROT up-regulates activity binding 9606 10545207 YES miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. 0.2 SIGNOR-220917 CDK1 protein P06493 UNIPROT NDUFV1 protein P49821 UNIPROT up-regulates activity phosphorylation Thr383 HESCGQCtPCREGVD 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275594 STARD8 protein Q92502 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.555 SIGNOR-260519 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD 9606 19661060 YES Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.2 SIGNOR-260881 DTX1 protein Q86Y01 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity ubiquitination 7227 22162134 YES lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch 0.78 SIGNOR-254317 SYVN1 protein Q86TM6 UNIPROT HMGCR protein P04035 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000944 14593114 YES miannu In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols. 0.563 SIGNOR-272594 BRCA1-C complex complex SIGNOR-C299 SIGNOR G2/M_transition-checkpoint phenotype SIGNOR-PH146 SIGNOR up-regulates 9606 BTO:0000567 16391231 NO lperfetto This result implies that the BRCA1/BARD1–RMN–CtIP complex is required for activation of the G2/M checkpoint. 0.7 SIGNOR-263229 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Thr254 RQVAIVFRtPPYADPS 10090 BTO:0000249 22761446 YES Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation 0.358 SIGNOR-255828 NCS1 protein P62166 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates activity 10116 21104311 NO miannu In chromaffin and PC12 cells, NCS-1 can enhance secretion via its activation of PI4 kinaseIIIb with the subsequent increase in PIP2 levels. PIP2 has been shown to be an important requirement for exocytosis 0.65 SIGNOR-263963 RUNX1 protein Q01196 UNIPROT MECOM protein Q03112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22689058 NO irozzo Our results suggest that RUNX1 and EVI1 could be regulating each other. RUNX1 would activate EVI1 transcription, and when highly expressed, EVI1 could bind to RUNX1 at protein level, inhibiting its activity as a transcription factor, acting in a negative feedback. 0.523 SIGNOR-255715 PPP1CC protein P36873 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity dephosphorylation 9606 27629041 YES miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival 0.413 SIGNOR-254119 ATM protein Q13315 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser106 GPGQVMAsQAQQSSP 9606 20471956 YES lperfetto Atm mediates phosphorylation of p300 in response to dna damageexpression of nonphosphorylatable serine to alanine form of p300 (s106a) destabilized both p300 and nbs1 proteins, after dna damage 0.4 SIGNOR-165567 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Thr356 FREFCIPtSSNIEQQ 9606 BTO:0000007 12123746 YES gcesareni These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells 0.2 SIGNOR-247782 LIMK2 protein P53671 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates activity phosphorylation 9606 32859889 YES miannu In vitro kinase assays revealed that LIMK2 phosphorylates SRPK1 (Fig. xref ).|LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1. 0.2 SIGNOR-279625 SRC protein P12931 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity phosphorylation Tyr251 LQFPGAVyGTDGCPV 29844931 YES lperfetto As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity. 0.374 SIGNOR-272998 LRRK1 protein Q38SD2 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity phosphorylation 9606 27600824 YES miannu In vitro kinase assays confirmed that recombinant Lrrk1 phosphorylated RAC1-GST protein, and immunoprecipitation showed that the interaction of Lrrk1 with RAC1 occurred within 10 min after RANKL treatment.|Lrrk1 phosphorylates and activates RAC1 and Cdc42 small GTPase proteins in osteoclasts. 0.292 SIGNOR-279626 Naltriben chemical CID:5486827 PUBCHEM OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258425 sitagliptin chemical CHEBI:40237 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 20927248 YES Luana Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor 0.8 SIGNOR-257883 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 22369944 YES lperfetto Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. 0.337 SIGNOR-217316 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1616 NSHSPAGsAAISQQD 9606 BTO:0000018 27991932 YES lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. 0.258 SIGNOR-275611 zotepine chemical CHEBI:32316 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 20223878 YES Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. 0.8 SIGNOR-257829 TBK1 protein Q9UHD2 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser403 ESLSQMLsMGFSDEG 9606 BTO:0000801 22921120 YES llicata Tbk-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on ser-403, a residue essential for its role in autophagic clearance. 0.708 SIGNOR-191944 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr592 NSTPESDyDNTPNDM 9606 16317044 YES fspada Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest. 0.344 SIGNOR-142719 KDM5C protein P41229 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264305 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity binding 9606 BTO:0000007 28195531 YES While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. 0.422 SIGNOR-252029 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10090 15306821 YES lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. 0.787 SIGNOR-127908 PINK1 protein Q9BXM7 UNIPROT UBC protein P0CG48 UNIPROT up-regulates activity phosphorylation Ser65 DYNIQKEsTLHLVLR 9606 BTO:0000938 24784582 YES lperfetto Ubiquitin is phosphorylated by PINK1 to activate parkin|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells 0.603 SIGNOR-249691 RCOR1 protein Q9UKL0 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 YES miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. 0.754 SIGNOR-222115 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Thr10 SKRAKAKtTKKRPQR 9606 22136066 YES lperfetto Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity 0.278 SIGNOR-191536 POU5F1 protein Q01860 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.56 SIGNOR-254933 PAH protein P00439 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors 0.8 SIGNOR-263989 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 YES miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). 0.503 SIGNOR-276312 CFH protein P08603 UNIPROT CFB protein P00751 UNIPROT down-regulates activity binding 9606 19050261 YES miannu As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity) 0.516 SIGNOR-252142 NMUR1 protein Q9HB89 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.491 SIGNOR-256751 TPSAB1 protein Q15661 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity binding 10116 21999702 YES lperfetto Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2).|Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2. 0.251 SIGNOR-251744 Ub:E2 complex SIGNOR-C497 SIGNOR PEX12 protein O00623 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271023 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1735 SPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248788 TALDO1 protein P37837 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 19401148 YES miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 0.8 SIGNOR-267090 ASXL3 protein Q9C0F0 UNIPROT CBX5 protein P45973 UNIPROT down-regulates activity binding 9606 BTO:0000972 25450400 YES miannu Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. 0.252 SIGNOR-266763 CDKN2A protein P42771 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 SIGNOR-C18 8891723 YES miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks, cdk4 and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. 0.905 SIGNOR-44554 PRSS2 protein P07478 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.2 SIGNOR-263606 LATS2 protein Q9NRM7 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by stabilization phosphorylation -1 24157836 YES miannu FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. 0.529 SIGNOR-272138 PPP2CB protein P62714 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 8650155 YES gcesareni These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity 0.479 SIGNOR-42123 PRKCA protein P17252 UNIPROT LMNA protein P02545 UNIPROT up-regulates activity phosphorylation Ser403 QRSRGRAsSHSSQTQ -1 7925482 YES lperfetto Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence. 0.362 SIGNOR-248903 BTRC protein Q9Y297 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 16421275 YES lperfetto Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, D(N) and D(C), and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals.Levels of _TrCP appeared to be limiting for Gli1 degradation, as increasing the levels of _TrCP protein significantly decreased steady-state levels of Gli1 protein 0.663 SIGNOR-235631 Ub:E2 complex SIGNOR-C497 SIGNOR WWP1 protein Q9H0M0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271293 Ub:E2 complex SIGNOR-C497 SIGNOR WDSUB1 protein Q8N9V3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271276 MRTFB protein Q9ULH7 UNIPROT SRF protein P11831 UNIPROT up-regulates activity binding 9606 BTO:0000567 14565952 YES llicata MKL2 binds to and activates SRF similar to myocardin and MKL1. 0.2 SIGNOR-237671 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 YES gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.744 SIGNOR-134529 ADNP protein Q9H2P0 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 32533114 YES miannu Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. 0.249 SIGNOR-266756 AKT1 protein P31749 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT down-regulates quantity by destabilization phosphorylation Thr181 LIRDRLKtEPFEENS 9606 BTO:0000567 25661488 YES miannu Akt1 phosphorylates XLF at T181 Here, we report that Akt phosphorylates XLF at Thr181 to trigger its dissociation from the DNA ligase IV/XRCC4 complex, and promotes its interaction with 14-3-3β leading to XLF cytoplasmic retention, where cytosolic XLF is subsequently degraded by SCF(β-TRCP) in a CKI-dependent manner.  0.358 SIGNOR-276881 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2I protein P63279 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.532 SIGNOR-271312 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC13 protein Q99880 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271995 proline smallmolecule CHEBI:26271 ChEBI Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270434 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248679 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR PYGO2 protein Q9BRQ0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 26170450 YES miannu Here we report that Pygo2 protein is degraded through the ubiquitin/proteasome pathway and is posttranslationally stabilized through phosphorylation by activated phosphatidylinositol 3-kinase/Akt signaling. Specifically, Pygo2 is stabilized upon inhibition of the proteasome, and its intracellular level is regulated by Cullin 4 (Cul4) and DNA damage-binding protein 1 (DDB1), components of the Cul4-DDB1 E3 ubiquitin ligase complex. 0.296 SIGNOR-273501 MAPK1 protein P28482 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 23405013 YES lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling 0.309 SIGNOR-200880 MAP4K1 protein Q92918 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 YES done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  0.2 SIGNOR-273899 CSNK1A1 protein P48729 UNIPROT JADE1 protein Q6IE81 UNIPROT down-regulates activity phosphorylation Ser18 EDSDDNGsLSTTWSQ 9606 BTO:0000007 25100726 YES done miannu We demonstrate that the destruction complex component casein kinase 1α (CK1α) phosphorylates Jade-1 at a conserved SLS motif and reduces the ability of Jade-1 to inhibit β-catenin signaling.  0.277 SIGNOR-273618 PTPN1 protein P18031 UNIPROT EPHA3 protein P29320 UNIPROT down-regulates activity dephosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 21135139 YES Nevertheless, the finding that phosphorylation of the activation loop tyrosine (EphA3-Y779), a recently identified PTP1B substrate (Mertins et al., 2008), is essential for ligand-induced endocytosis (Janes et al., 2009) 0.417 SIGNOR-248426 PHLPP1 protein O60346 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 BTO:0001544 19261608 YES The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. 0.646 SIGNOR-248330 CDK7 protein P50613 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG 9606 BTO:0001086 31306665 YES lperfetto Here, we combined molecular and cellular biology with CRISPR/Cas9-mediated genome engineering to pinpoint the function of serine 12 of OCT4 in ESCs. Using chemical inhibitors and an antibody specific to OCT4 phosphorylated on S12, we identified cyclin-dependent kinase (CDK) 7 as upstream kinase. |Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2. 0.2 SIGNOR-264404 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRC4 inflammasome complex SIGNOR-C223 SIGNOR up-regulates activity 16037825 NO miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-263124 GPC6 protein Q9Y625 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates activity binding 9606 31756413 YES miannu Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction. 0.351 SIGNOR-264031 IWS1 protein Q96ST2 UNIPROT Iws1:Spt6:CTD complex complex SIGNOR-C548 SIGNOR form complex binding 9606 19141475 YES miannu We showed recently that Spt6, a transcription elongation factor and histone H3 chaperone, binds to the Ser2P CTD and recruits Iws1 and the REF1/Aly mRNA export adaptor to facilitate mRNA export.In vitro, recombinant Spt6 binds selectively to a stretch of uninterrupted consensus repeats located in the N-terminal half of the CTD and recruits Iws1. Thus Iws1 connects two distinct CTD-binding proteins, Spt6 and HYPB/Setd2, in a megacomplex that affects mRNA export as well as the histone modification state of active genes. 0.769 SIGNOR-273497 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 SIGNOR-C9 15241418 YES llicata We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase 0.745 SIGNOR-126748 JUN protein P05412 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 NO miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.27 SIGNOR-254874 FGFR4 protein P22455 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 10918587 YES Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. 0.402 SIGNOR-251142 PKA proteinfamily SIGNOR-PF17 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1548 YAPSRRMtSVATAKG -1 21406690 YES miannu PKA phosphorylated LRP6, which enhanced the binding of Gα(s) to LRP6, its localization to the plasma membrane, and the production of cAMP in response to PTH. Only alteration of Thr1548 abolished the phosphorylation of LRP6C by PKA (Fig. 6B), and mass spectrometry analysis confirmed that Thr1548 was the PKA phosphorylation site in LRP6C (fig. S1). 0.2 SIGNOR-275416 ACOT4 protein Q8N9L9 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271807 DLL4 protein Q9NR61 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 YES lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. 0.2 SIGNOR-209744 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203604 WDFY3 protein Q8IZQ1 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 22653340 NO miannu ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. 0.7 SIGNOR-266794 MAP3K2 protein Q9Y2U5 UNIPROT STK38 protein Q15208 UNIPROT up-regulates quantity by stabilization phosphorylation Ser91 LGLEDFEsLKVIGRG 9606 31690749 YES miannu Our data suggest that Ser91 phosphorylation of STK38 by MEKK2 possibly blocks the interaction of calpain with STK38 or disrupts proper conformation for cleaving, thereby protecting STK38 from calpain-dependent degradation. 0.403 SIGNOR-279066 FGF1 protein P05230 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates activity binding 9606 BTO:0001487 18940940 YES fspada Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity. 0.914 SIGNOR-236936 PRKCA protein P17252 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC -1 27784766 YES miannu Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. 0.2 SIGNOR-276459 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation 0.312 SIGNOR-129308 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM11 protein Q96F44 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271083 AKT1 protein P31749 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C7 17964260 YES gcesareni Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. 0.696 SIGNOR-158624 Ub:E2 complex SIGNOR-C497 SIGNOR PJA1 protein Q8NG27 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270990 PDX1 protein P52945 UNIPROT INS protein P01308 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11309388 YES In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. 0.642 SIGNOR-255541 CYLD protein Q9NQC7 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity deubiquitination 10090 29291351 YES gianni Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. 0.635 SIGNOR-266437 GRIN2B protein Q13224 UNIPROT NMDA receptor_2B complex SIGNOR-C348 SIGNOR form complex binding 9606 BTO:0000938 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits 0.728 SIGNOR-264123 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.261 SIGNOR-268607 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120140 MBD1 protein Q9UIS9 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001412 19781662 NO Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. 0.2 SIGNOR-254030 STUB1 protein Q9UNE7 UNIPROT CIP2A protein Q8TCG1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24293411 YES miannu CHIP is the ubiquitin E3 ligase mediating celastrol-triggered CIP2A degradation. 0.2 SIGNOR-272877 PRKACA protein P17612 UNIPROT ARPP21 protein Q9UBL0 UNIPROT up-regulates activity phosphorylation Ser58 QERRKSKsGAGKGKL -1 10854908 YES miannu The specificity of antibody G534 was examined using recombinant full-length rat ARPP-21 phosphorylated by PKA. Radiolabeled ARPP-21 from a reaction containing [γ32P]ATP correlated with the detection of phospho-Ser55-ARPP-21 by immunoblotting (Fig. 1A, left and middle panels). 0.2 SIGNOR-263107 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser117 SFSLEEKsKISKNRV 9606 20573420 YES lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. 0.362 SIGNOR-166321 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17548584 YES svumbaca The loss of macrophage expression of HIF-1 led to significant decreases in the production of TNF-a, IL-1a, IL-1b, and IL-12 0.336 SIGNOR-256235 IL1A protein P01583 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 19005488 NO miannu UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts. 0.492 SIGNOR-252209 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 YES Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 0.686 SIGNOR-256255 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 YES gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway 0.691 SIGNOR-252948 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HERPUD1 protein Q15011 UNIPROT up-regulates quantity by expression 9606 10922362 NO miannu We demonstrate a new target gene for upr-induced transcription, herp. 0.7 SIGNOR-80156 SGO1 protein Q5FBB7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000567 24055156 YES lperfetto The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl. 0.2 SIGNOR-265264 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser242 SSLRASTsKSESSQK -1 1985906 YES miannu The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide. 0.31 SIGNOR-250234 HNF1B protein P35680 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity binding 9606 BTO:0000007 9671480 YES 2 miannu The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays. 0.373 SIGNOR-241323 RPS6KB1 protein P23443 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 11500364 YES lperfetto We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity 0.735 SIGNOR-109712 GRK2 protein P25098 UNIPROT SNCG protein O76070 UNIPROT down-regulates activity phosphorylation Ser124 EVAEEAQsGGD -1 10852916 YES GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser124 dramatically inhibits γ-synuclein phosphorylation by GRK2 0.2 SIGNOR-251204 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser374 GLEQAILsPGQNSGN 9606 22966201 YES llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. 0.322 SIGNOR-198988 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 31226023 YES miannu Also, SARS-CoVPLPro catalyzed deubiquitination ofTNF-receptor-associatedfactor3(TRAF3)and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist 0.2 SIGNOR-260248 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9606 16291744 YES gcesareni Here we report that protein-tyrosine phosphatase 1b (ptp 1b) is an ?-Actinin phosphatase. 0.335 SIGNOR-141634 RNF7 protein Q9UBF6 UNIPROT NF1 protein P21359 UNIPROT down-regulates activity ubiquitination 9606 23136067 YES miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 0.249 SIGNOR-271453 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270407 CBP/p300 complex SIGNOR-C6 SIGNOR YY1 protein P25490 UNIPROT up-regulates activity acetylation -1 11486036 YES miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. 0.651 SIGNOR-268834 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257967 SOCS1 protein O15524 UNIPROT JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 14522994 YES lperfetto Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor 0.794 SIGNOR-118407 SOX6 protein P35712 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 NO miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1 0.419 SIGNOR-251760 PHGDH protein O43175 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates activity chemical modification 9606 25406093 YES lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. 0.8 SIGNOR-268567 PTAFR protein P25105 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256932 SH3GL2 protein Q99962 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 NO miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 0.7 SIGNOR-263883 EPHB2 protein P29323 UNIPROT ARHGEF15 protein O94989 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr353 PLQDEPLyQTYRAAV 9606 BTO:0000007 21029865 YES miannu We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. EphB2 mediates phosphorylation of Ephexin5 at tyrosine-361 0.485 SIGNOR-262864 DRAM2 protein Q6UX65 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 NO irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. 0.2 SIGNOR-259144 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser164 TSTPGRRsCFGFEGL -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.71 SIGNOR-276120 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7834749 YES Nuclear p53 amattioni Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis 0.752 SIGNOR-33922 ACIN1 protein Q9UKV3 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 10490026 NO Cleaved by CASP3 amattioni Acinus induces apoptotic chromatin condensation after cleavage by caspase-3 without inducing dna fragmentation. 0.7 SIGNOR-70797 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser313 TALHRSKsHEFQLGH 10090 19560418 YES These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 0.26 SIGNOR-248527 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-268070 SYN3 protein O14994 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 YES miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 0.2 SIGNOR-269183 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr420 RLIEDNEyTARQGAK -1 9425276 YES Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. 0.2 SIGNOR-251167 Ub:E2 complex SIGNOR-C497 SIGNOR PLAG1 protein Q6DJT9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271068 FBXW11 protein Q9UKB1 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates ubiquitination 9606 11359933 YES gcesareni Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3. 0.261 SIGNOR-108240 HLA2 alpha chain proteinfamily SIGNOR-PF91 SIGNOR Class II MHC complex SIGNOR-C428 SIGNOR form complex binding 9606 1311249 YES scontino The biosynthesis of MHC Class II molecules starts with the assembly of the alpha and beta subunits. 0.2 SIGNOR-267870 PLK1 protein P53350 UNIPROT RSF1 protein Q96T23 UNIPROT up-regulates activity phosphorylation Ser1359 ENVGKVGsPLDYSLV 9606 BTO:0000567 26259146 YES done miannu Moreover, CDK1 phosphorylates RSF1 at Ser1375, and this phosphorylation is necessary for PLK1 recruitment. Subsequently, PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition.  0.352 SIGNOR-273590 F2RL3 protein Q96RI0 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.322 SIGNOR-256772 LYN protein P07948 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr381 SESSDDDyDDVDIPT 9534 11514608 YES BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. Tyr-379 within HPK1 is essential for binding to BASH and thus strongly suggest that the DDDYDDV sequence containing the phosphorylated Tyr-379 is the binding site for the BASH SH2 domain. 0.381 SIGNOR-251403 PTPN11 protein Q06124 UNIPROT FGFR2 protein P21802 UNIPROT down-regulates activity dephosphorylation 9606 23420874 YES miannu In forming this heterotetrameric complex Grb2 inhibits both the dephosphorylation of FGFR2 by Shp2 and the phosphorylation of Shp2 by FGFR2 (XREF_FIG, respectively).|Knockdown of Grb2 elevates Shp2 phosphorylation (XREF_FIG), strongly suggesting that the inability of Shp2 to interact directly with the receptor in the presence of Grb2 prevents FGFR2 kinase activity toward Shp2. 0.621 SIGNOR-277030 PI3K complex SIGNOR-C156 SIGNOR PIK3CD protein O00329 UNIPROT up-regulates activity binding 9534 14665640 YES lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.622 SIGNOR-252720 Naltrindole chemical CHEBI:81528 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258818 FOXP1 protein Q9H334 UNIPROT CSF1R protein P07333 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000738 15286807 YES Gianni Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation. 0.297 SIGNOR-269048 RPL35 protein P42766 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.863 SIGNOR-262466 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 YES amattioni Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation. 0.342 SIGNOR-85183 EDNRA protein P25101 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.469 SIGNOR-257427 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNT3 protein P45378 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.306 SIGNOR-136942 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr471 PIKPLIStPPVSSQP 9606 BTO:0000567 30021153 YES lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. 0.2 SIGNOR-265034 LAT protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 YES lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. 0.808 SIGNOR-246060 SSTR3 protein P32745 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.451 SIGNOR-256820 CYP21A2 protein P08686 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 25855791 YES lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively 0.8 SIGNOR-268646 perifosine chemical CHEBI:67272 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 BTO:0001130 14617782 YES Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation gcesareni Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.| Our results demonstrate that Akt is an important cellular target of perifosine action. In addition, these studies show that the membrane translocation of certain PH domain-containing molecules can be greatly perturbed by the alkylphospholipid class of drugs and imply further that the PI3K/Akt pathway contributes to regulation of p21(WAF1/CIP1) expression. 0.8 SIGNOR-119189 lenvatinib chemical CHEBI:85994 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191454 CBL protein P22681 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19450681 YES lperfetto Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation 0.732 SIGNOR-185680 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg25 PLLSARTrARRPESK -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus 0.887 SIGNOR-263568 PPP2R2C protein Q9Y2T4 UNIPROT SRC protein P12931 UNIPROT down-regulates activity binding 9606 BTO:0001938 18069897 YES gcesareni We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC 0.2 SIGNOR-247966 WDR83 protein Q9BRX9 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15118098 YES gcesareni Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. 0.524 SIGNOR-124476 TOP2A protein P11388 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 20562910 NO lperfetto Topoisomerase IIalpha (topoIIalpha) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis. 0.7 SIGNOR-242530 FOXL2 protein P58012 UNIPROT STAR protein P49675 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 NO miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. 0.36 SIGNOR-254180 Ast-487 chemical CID:11409972 PUBCHEM KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258070 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. 0.87 SIGNOR-236209 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser339 SPISTPTsPGSLRKH 9606 14741103 YES llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. 0.405 SIGNOR-250673 PHLPP2 protein Q6ZVD8 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 YES gcesareni Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle 0.329 SIGNOR-237039 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser281 DGTGDTSsEEDEDEE -1 11278496 YES llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. 0.38 SIGNOR-250875 CAPN3 protein P20807 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 25969760 YES lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain 0.324 SIGNOR-251602 MAPKAPK2 protein P49137 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 15688025 YES gcesareni Hdm2 phosphorylation by mapkap kinase 2 enhances hdm2 activity and promote the degradation of p53. 0.364 SIGNOR-133560 progesterone smallmolecule CHEBI:17026 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268649 ABL2 protein P42684 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Tyr118 AGPLIVPyNLPLPGG 9606 20150913 YES llicata The sh (src homology)3 domains of c-abl/arg bind to a p(80)gppsgp motif of gal3, and tyr79 and tyr118 are the major tyrosine phosphorylation sites. A consequence of this interaction and phosphorylation is the significant impairment of chaperone-mediated autophagy of gal3. 0.2 SIGNOR-163743 CDC42BPA protein Q5VT25 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 YES lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. 0.517 SIGNOR-188781 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257963 RASGRF2 protein O14827 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.552 SIGNOR-260575 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 YES gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation 0.715 SIGNOR-67634 STAT1 protein P42224 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19643666 YES lperfetto Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways. 0.676 SIGNOR-249565 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 YES miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. 0.673 SIGNOR-250290 PRKACA protein P17612 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation 9606 10487978 YES miannu Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. 0.431 SIGNOR-267411 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 12747827 YES lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. 0.755 SIGNOR-235964 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ubiquitinated-Viral_Protein complex SIGNOR-C427 SIGNOR form complex binding 9606 25688236 YES scontino MHC class I antigen presentation pathway. Proteins with ubiquitin tags (red spheres) are degraded by proteasomes and the resulting peptides are transported into the endoplasmic reticulum (ER) by TAP|Many viruses have mechanisms of interfering with MHC class I processing, including direct interaction of viral proteins with immunoproteasome subunits. 0.2 SIGNOR-267766 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1064 SCPIKEDsFLQRYSS 9606 BTO:0000007 10347170 YES llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  0.371 SIGNOR-250619 HIF-1 complex complex SIGNOR-C418 SIGNOR SLC2A1 protein P11166 UNIPROT up-regulates quantity transcriptional regulation 10116 11120745 YES Collectively these results indicate that H-Ras up-regulates the glut1 promoter, at least in part, by increasing HIF-1alpha protein levels leading to transactivation of promoter through the HIF-1 binding site. 0.411 SIGNOR-267478 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 YES llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. 0.2 SIGNOR-203306 NEIL2 protein Q969S2 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275719 SLC16A4 protein O15374 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 NO lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. 0.7 SIGNOR-242519 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 YES gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop 0.529 SIGNOR-249652 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr274 SNVVRKDyDTLSKCS -1 21840312 YES miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. 0.389 SIGNOR-263039 PRKCH protein P24723 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276014 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR HIRA protein P54198 UNIPROT up-regulates phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 11238922 YES lperfetto Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle. 0.326 SIGNOR-216670 ACTR3 protein P61158 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 YES The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc 0.92 SIGNOR-251513 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12217858 YES gcesareni Addition of active c-src and [32p]atp to the purified romk1 protein resulted in the phosphorylation of the romk1 protein. However, c-src did not phosphorylate r1y337a in which tyrosine residue 337 was mutated to alanine. Furthermore, phosphopeptide mapping identified two phosphopeptides from the trypsin-digested romk1 protein. 0.313 SIGNOR-92513 AP-2 complex complex SIGNOR-C245 SIGNOR GABA-A proteinfamily SIGNOR-PF61 SIGNOR down-regulates quantity relocalization 9606 BTO:0000938 25600368 YES miannu The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface. 0.2 SIGNOR-264990 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Ser245 GGGDLPNsQEALQKL 33850055 YES lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o 0.2 SIGNOR-275648 TFEB protein P19484 UNIPROT GBA protein P04062 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants 0.325 SIGNOR-276551 PRKCB protein P05771 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.29 SIGNOR-249247 RPGRIP1L protein Q68CZ1 UNIPROT RELA protein Q04206 UNIPROT down-regulates demethylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 YES miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. 0.2 SIGNOR-163320 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser673 RVQSKIGsLDNITHV -1 12435421 YES miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly 0.434 SIGNOR-250007 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1206 SHSFRGAyGLAMKVA 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 YES llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate 0.409 SIGNOR-187847 Sincalide smallmolecule CID:9833444 PUBCHEM CCKAR protein P32238 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257466 HSP90AA1 protein P07900 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 18591668 YES lpetrilli The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs. 0.416 SIGNOR-179268 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 9606 12414794 YES lperfetto We find that activation of the c-jun promoter through the atf1 site requires phosphorylation of atf1 at serine 63. atf1 can be phosphorylated by mitogen- and stress-activated protein kinase 1 (msk1), which is activated by egf and erk1/2. 0.689 SIGNOR-95318 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268598 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 YES lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. 0.613 SIGNOR-233438 NR3C1 protein P04150 UNIPROT LCK protein P06239 UNIPROT up-regulates binding 9606 16888650 YES gcesareni The present study shows that the GC receptor is part of a TCR-linked multiprotein complex containing heat-shock protein (HSP)90, LCK and FYN, which is essential for TCR-dependent LCK/FYN activation. 0.356 SIGNOR-251685 IKBKE protein Q14164 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000801 20717897 YES lperfetto The activated ikk complex then phosphorylates ikbalfa (an inhibitor of nf-kb) thereby targeting it for ubiquitination and proteasomal degradation. 0.485 SIGNOR-167524 GPR84 protein Q9NQS5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256983 AKT1 protein P31749 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 18836482 YES gcesareni Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b. 0.394 SIGNOR-252520 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15743829 YES lperfetto 3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt), 0.748 SIGNOR-244469 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT down-regulates activity sumoylation Lys417 TSPVTQkVkDEAAAQP 9606 16442531 YES We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity. 0.367 SIGNOR-256130 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg707 ESTVMATrKMHDRLE -1 10026263 YES lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 0.499 SIGNOR-263647 peptide antigen smallmolecule CHEBI:166824 ChEBI Class II MHC:Antigen complex SIGNOR-C429 SIGNOR form complex binding 9606 33374673 YES scontino The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). 0.8 SIGNOR-267871 HLA1 proteinfamily SIGNOR-PF87 SIGNOR Class I MHC complex SIGNOR-C425 SIGNOR form complex binding -1 28367149 YES scontino One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER) 0.966 SIGNOR-267776 ABL1 protein P00519 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr508 EDMRGILyAAPQLRS 10090 11120811 YES gcesareni The results revealed that only tyrosine (Y)490 of CD19 was phosphorylated by c-Abl. 0.534 SIGNOR-245283 FBXL2 protein Q9UKC9 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates binding 9606 BTO:0000007 23604317 YES miannu FBXL2 binds p85α and p85β. p85β is targeted for ubiquitylation and degradation by SCF FBXL2. 0.498 SIGNOR-272112 PER2 protein O15055 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. 0.762 SIGNOR-267977 GNG2 protein P59768 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. 0.2 SIGNOR-199138 PSENEN protein Q9NZ42 UNIPROT RYK protein P34925 UNIPROT up-regulates cleavage 9606 19000841 YES gcesareni Ryk activity is modulated through cleavage of its icd by gamma-secretase 0.2 SIGNOR-182145 STAT6 protein P42226 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates 9606 BTO:0000018 12517954 NO lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. 0.328 SIGNOR-254101 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259441 RPS6K proteinfamily SIGNOR-PF26 SIGNOR L1CAM protein P32004 UNIPROT up-regulates activity phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 YES lperfetto Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152. 0.2 SIGNOR-252766 antigen smallmolecule CHEBI:59132 ChEBI BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 YES scontino The recognition of antigen by the BCR initiates BCR signaling cascade. 0.8 SIGNOR-268205 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248749 FBXW7 protein Q969H0 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27858941 YES miannu DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1 0.327 SIGNOR-254774 GATA3 protein P23771 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 12876556 NO Initiation of transcription of the gene encoding IL-4 in naive T(H) cells is regulated by the T(H) 2-specific transcription factor GATA3 0.487 SIGNOR-254500 NEK3 protein P51956 UNIPROT SNAP29 protein O95721 UNIPROT up-regulates activity phosphorylation Ser105 MDQDLKIsQKHINSI 9606 BTO:0000007 29454964 YES miannu In the present study, we show that NEK3 (NIMA-never in mitosis gene A-related kinase 3)-mediated serine 105 (S105) phosphorylation of SNAP29 directs its membrane association, without which cells present defective focal adhesion formation, impaired Golgi structure and attenuated cellular recycling. Our results highlight the importance of NEK3-mediated S105 phosphorylation of SNAP29 for its membrane localization and for membrane fusion dependent processes. 0.2 SIGNOR-273708 LZTR1 protein Q8N653 UNIPROT KRAS protein P01116 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 31337872 YES Gianni We demonstrate that LZTR1 facilitates the polyubiquitination and degradation of RAS via the ubiquitin-proteasome pathway, leading to the inhibition of the RAS/MAPK signaling. 0.25 SIGNOR-269069 OSTC protein Q9NRP0 UNIPROT OST-A complex complex SIGNOR-C535 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.577 SIGNOR-272058 CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 YES lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity 0.827 SIGNOR-245459 MAOA protein P21397 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). 0.8 SIGNOR-264001 PRKCB protein P05771 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 YES lperfetto Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization 0.2 SIGNOR-151011 LMX1A protein Q8TE12 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR form complex binding 9606 BTO:0000007 9452425 YES lperfetto Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas. 0.34 SIGNOR-236812 MECOM protein Q03112 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15889140 YES Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  0.2 SIGNOR-266060 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr814 PLHDGSRtPAQSGAW 9606 16427012 YES lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif 0.776 SIGNOR-143943 MAPK1 protein P28482 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr693 RELVEPLtPSGEAPN -1 1651322 YES lperfetto A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase 0.638 SIGNOR-20545 peptide smallmolecule CHEBI:16670 ChEBI Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR up-regulates activity binding 9606 29735640 YES miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide.  0.8 SIGNOR-270815 PAX7 protein P23759 UNIPROT PAX7/MLL2 complex complex SIGNOR-C91 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 YES miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.304 SIGNOR-198635 CDK1 protein P06493 UNIPROT KIF20B protein Q96Q89 UNIPROT up-regulates activity phosphorylation Thr1644 VKHPGCTtPVTVKIP 9606 11470801 YES miannu Here we report the identification of a novel KRP, termed KRMP1, which undergoes in vivo phosphorylation. The carboxyl-terminal globular tail domain is strongly phosphorylated by mitotic kinase activities almost attributed to cdc2 kinase, which is responsible for phosphorylation on residue Thr-1604 of KRMP1. 0.41 SIGNOR-262695 ELF2 protein Q15723 UNIPROT VCP protein P55072 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 18544453 NO These findings indicate that ELF2 transactivates VCP promoter through binding to two motifs, with a predominant contribution of the upstream one. 0.361 SIGNOR-254283 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT up-regulates phosphorylation Ser2733 SVSPKRNsISRTHKD 9606 15383279 YES llicata Using a combination of biochemical, enzymatic, and immunofluorescence techniques, we show that the anchoring protein contributes to pkd activation in two ways: it recruits an upstream kinase pkceta and coordinates pka phosphorylation events that release activated protein kinase d. Thus, akap-lbc synchronizes pka and pkc activities in a manner that leads to the activation of a third kinase. 0.332 SIGNOR-129345 GNAI1 protein P63096 UNIPROT PLD2 protein O14939 UNIPROT down-regulates binding 9606 9148895 YES gcesareni The results of this study suggest that membrane phospholipase d activity can be negatively regulated via gi 0.307 SIGNOR-48256 ORC1 protein Q13415 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 YES lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA 0.945 SIGNOR-267567 HECTD4 protein Q9Y4D8 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 YES miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 0.2 SIGNOR-267146 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Thr312 RSQELRKtFKEIICC 9606 12639913 YES gcesareni Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor. 0.2 SIGNOR-247770 MYO9B protein Q13459 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.539 SIGNOR-260510 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 21757781 YES gcesareni Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian ta rget of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin. 0.8 SIGNOR-174886 MMUT protein P22033 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity chemical modification 9606 1978672 YES miannu Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). 0.8 SIGNOR-269109 FN1 protein P02751 UNIPROT SDC4 protein P31431 UNIPROT up-regulates activity binding 9606 23290138 YES apalma Sdc4 is a high affinity receptor for fibronectin (FN) […] Therefore, we conclude that Sdc4 binds FN on activated satellite cells. 0.71 SIGNOR-255846 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp 0.2 SIGNOR-199180 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000007 23287467 YES miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. 0.877 SIGNOR-272896 PKNOX1 protein P55347 UNIPROT HOXB1 protein P14653 UNIPROT up-regulates activity binding -1 9482740 YES 2 miannu we observe the formation of a ternary Prep1-Pbx1-HOXB1 complex on a HOXB1-responsive target in vitro. Interaction with Prep1 enhances the ability of the HOXB1-Pbx1 complex to activate transcription in a cooperative fashion from the same target. 0.612 SIGNOR-241215 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 9677429 YES MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. gcesareni The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. 0.752 SIGNOR-59157 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates activity phosphorylation Ser533 KKSQHRSsSSAPHHN 10441130 YES miannu Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation 0.429 SIGNOR-250340 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.462 SIGNOR-269240 UBTF protein P17480 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR up-regulates activity binding 9606 15970593 YES lperfetto Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. 0.504 SIGNOR-269568 TBX2 protein Q13207 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 25211658 YES lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS 0.345 SIGNOR-249593 FAM83B protein Q5T0W9 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273754 GSK3A protein P49840 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 BTO:0000567 16543145 YES  MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). Glycogen Synthase Kinase-3 Regulates Mitochondrial Outer Membrane Permeabilization and Apoptosis by Destabilization of MCL-1. threonine 163, which represents the GSK-3 priming phosphorylation in this protein 0.457 SIGNOR-251217 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT up-regulates phosphorylation 9606 18042454 YES miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. 0.26 SIGNOR-159435 IKBKE protein Q14164 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser556 EREAIRLsLEQALPP 9606 BTO:0002181 30472208 YES miannu Upon virus infection, the kinase IKKɛ directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1-dependent suppression of MAVS. 0.283 SIGNOR-277618 STAP1 protein Q9ULZ2 UNIPROT TEC protein P42680 UNIPROT up-regulates activity binding 9606 BTO:0000007 10518561 YES miannu In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. BRDG1 may activate Tec by disrupting an intramolecular interaction. 0.392 SIGNOR-261819 GNAI2 protein P04899 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates binding 9606 8327893 YES gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required 0.633 SIGNOR-267849 ITGB1BP1 protein O14713 UNIPROT ITGB6 protein P18564 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.288 SIGNOR-257662 PTMS protein P20962 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates activity binding 9606 BTO:0000567 16150697 YES miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells. 0.2 SIGNOR-268462 SPAG5 protein Q96R06 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity 9606 BTO:0000567 17664331 NO lperfetto Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F. 0.379 SIGNOR-252041 WWP2 protein O00308 UNIPROT EGR2 protein P11161 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 19651900 YES lperfetto The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination|AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death. 0.373 SIGNOR-268849 PTPN5 protein P54829 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000938 BTO:0000671 11983687 YES lperfetto Wild-type step(61) dephosphorylates fyn at tyr(420) but not at tyr(531). These results suggest that step regulates the activity of fyn by specifically dephosphorylating the regulatory tyr(420) and may be one mechanism by which fyn activity is decreased within psds. 0.528 SIGNOR-86791 CAV1 protein Q03135 UNIPROT SLC1A2 protein P43004 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 YES miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. 0.248 SIGNOR-264809 CHUK protein O15111 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 16103118 YES gcesareni Ikkalpha regulates subcellular localization and proteolysis of cyclin d1 by phosphorylation of cyclin d1 at thr286. 0.379 SIGNOR-139570 BMX protein P51813 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates quantity phosphorylation Tyr12 NVLAKALyDNVAESP 10090 BTO:0002572 21937722 YES miannu Recombinant Bmx kinase was found to effectively phosphorylate the wt CAS SH3 domain on Tyr-12 (Figure 2B). A novel phosphorylation site on CAS, Tyr-12 (Y12) within the ligand-binding hydrophobic pocket of the CAS SH3 domain, was identified and found to be enriched in Src-transformed cells and invasive human carcinoma cells.  0.507 SIGNOR-276384 CCT5 protein P48643 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.755 SIGNOR-272861 TBK1 protein Q9UHD2 UNIPROT STAT6 protein P42226 UNIPROT up-regulates phosphorylation Tyr641 MGKDGRGyVPATIKM 9606 22000020 YES gcesareni We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing. 0.673 SIGNOR-176775 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2Z protein Q9H832 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.778 SIGNOR-271347 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 NO miannu Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes 0.7 SIGNOR-260440 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 11325528 YES lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. 0.431 SIGNOR-249089 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1009 DESSDDDsDSEEPSK 9606 10066810 YES gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, 0.442 SIGNOR-65277 ATF4 protein P18848 UNIPROT DARS2 protein Q6PI48 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269418 QRICH1 protein Q2TAL8 UNIPROT TARS2 protein Q9BW92 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269407 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser539 LTAQRRAsTVSSVTQ -1 15684429 YES miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. 0.249 SIGNOR-263018 HES1 protein Q14469 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 NO lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 0.441 SIGNOR-265146 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser2 sDNDDIEV 9606 8018564 YES gcesareni Here, we have mapped the nh2-terminal in vivo phosphorylation sites of max to ser2 and ser11[...] 0.362 SIGNOR-35772 CDK1 protein P06493 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 SIGNOR-C17 17466630 YES gcesareni Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. 0.429 SIGNOR-154626 PPP2CB protein P62714 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity dephosphorylation Thr68 SSLETVStQELYSIP 9606 16596250 YES Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. 0.309 SIGNOR-248582 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1474 GSSNGHVyEKLSSIE 11483655 YES lperfetto We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src and Fyn and compared this to phosphorylation by tyrosine kinases associated with the postsynaptic density (PSD)|Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases 0.767 SIGNOR-249338 U1 snRNP complex complex SIGNOR-C480 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 NO lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.7 SIGNOR-270687 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 24376897 YES The effect has been demonstrated using Q9UKI8-2 llicata Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue. 0.448 SIGNOR-203499 glycine smallmolecule CHEBI:15428 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity precursor of 9606 16051266 YES lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. 0.8 SIGNOR-268237 fenoterol chemical CHEBI:149226 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1).  0.8 SIGNOR-257868 calcium(2+) smallmolecule CHEBI:29108 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 29953871 NO miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. 0.7 SIGNOR-264953 FBXW2 protein Q9UKT8 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 31548378 YES miannu  Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase.  Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation. 0.684 SIGNOR-272260 RETREG3 protein Q86VR2 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000934 23939472 NO lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  0.7 SIGNOR-261490 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr136 SEEGYQDyEPEA 9606 BTO:0000975;BTO:0000142 11744621 YES llicata Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers. 0.53 SIGNOR-113069 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation 9606 7816602 YES inferred from 70% family members lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. 0.2 SIGNOR-270105 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser418 VEEDPLNsGDDVSEQ -1 12107178 YES llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. 0.415 SIGNOR-250993 CDK1 protein P06493 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 YES gcesareni Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. 0.574 SIGNOR-151799 CSNK2A1 protein P68400 UNIPROT SEPTIN2 protein Q15019 UNIPROT down-regulates phosphorylation Ser218 YHLPDAEsDEDEDFK 9606 16857012 YES lperfetto Here we show that human septin 2 is phosphorylated in vivo at ser218 by casein kinase ii. Septin 2 binds and hydrolyses gtp. The purified protein has the capacity to polymerize into long filaments when loaded with gtp or gdp. Moreover, we show that the endogenous protein in hela cells, like that produced in insect cells, is phosphorylated by casein kinase ii and that this phosphorylation alters nucleotide binding. 0.2 SIGNOR-148010 PRKCD protein Q05655 UNIPROT HVCN1 protein Q96D96 UNIPROT up-regulates activity phosphorylation Thr10 TWDEKAVtRRAKVAP 9606 25425665 YES done miannu HVCN1S is phosphorylated more by PKC-δ than HVCN1L. PKC-δ in vitro kinase assay showing phosphorylation of HVCN1 0.2 SIGNOR-273827 CSNK1A1 protein P48729 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Ser269 QVRVGGSsVDLHRFH 9606 24412065 YES miannu Moreover, CK1α phosphorylates p120-catenin on Ser268 and Ser269, releasing this protein from the signalosome and facilitating the subsequent phosphorylation of cadherin and the disruption of this cadherin interaction with LRP5/6 0.2 SIGNOR-277893 NLGN2 protein Q8NFZ4 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 NO miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. 0.7 SIGNOR-264977 AKT2 protein P31751 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation 9606 16023596 YES gcesareni Activated pi3k/akt pathway results in inhibitory phosphorylation of gsk3 0.556 SIGNOR-138179 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT up-regulates 9606 BTO:0000934 23939472 NO lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  0.265 SIGNOR-261451 CYP17A1 protein P05093 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268657 ATM protein Q13315 UNIPROT USP10 protein Q14694 UNIPROT up-regulates quantity by stabilization phosphorylation Ser337 ASGTLPVsQPKSWAS 9606 BTO:0001109 20096447 YES miannu The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337.  0.252 SIGNOR-276276 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 9606 BTO:0000568 10747897 YES llicata Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities. 0.667 SIGNOR-250967 CDK5RAP2 protein Q96SN8 UNIPROT CEP63 protein Q96MT8 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 YES lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. 0.691 SIGNOR-271722 JAK1 protein P23458 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity phosphorylation Tyr619 NKVDDCNyAIKRIRL 10090 BTO:0000099 25113558 YES miannu JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3. 0.2 SIGNOR-276677 WNT6 protein Q9Y6F9 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.627 SIGNOR-131891 PDP2 protein Q9P2J9 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation 9606 20208177 YES Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation 0.657 SIGNOR-251665 CKM complex complex SIGNOR-C406 SIGNOR Core mediator complex complex SIGNOR-C405 SIGNOR down-regulates activity binding -1 23563140 YES miannu We found that interaction of the CKM with Mediator's middle module interferes with CTD-dependent RNAPII binding to a previously unknown middle-module CTD-binding site and with the holoenzyme formation process. Taken together, our results reveal the basis for CKM repression, clarify the origin of the connection between CKM subunits and the CTD and suggest that a combination of competitive interactions and conformational changes that facilitate holoenzyme formation underlie the mechanism of transcription regulation by Mediator. 0.762 SIGNOR-266687 MAPK3 protein P27361 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates activity phosphorylation Thr906 SLDNNYStPNERGDH 9615 BTO:0000837 32010791 YES miannu  Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. 0.294 SIGNOR-277506 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA9 protein Q9Y5G4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265700 zotepine chemical CHEBI:32316 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258558 PPP2CA protein P67775 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 BTO:0002181 15988018 YES lperfetto In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif. 0.2 SIGNOR-138428 ASIP protein P42127 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.738 SIGNOR-268698 monoisononyl phthalate chemical CHEBI:132593 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268779 CASZ1 protein Q86V15 UNIPROT EGFL7 protein Q9UHF1 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001176 24150064 YES miannu We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis. 0.425 SIGNOR-266858 MAX protein P61244 UNIPROT MGA protein Q8IWI9 UNIPROT up-regulates activity binding 9606 7954804 YES 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. 0.569 SIGNOR-240261 AKT proteinfamily SIGNOR-PF24 SIGNOR GATA2 protein P23769 UNIPROT down-regulates activity phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 YES PI-3K/Akt-dependent manner. lperfetto We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity 0.2 SIGNOR-244271 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR CEP97 protein Q8IW35 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0004790 30404837 YES miannu Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation. we identified the cullin-3-RBX1-KCTD10 complex as the E3 ligase that mediates CEP97 degradation and removal from the mother centriole. 0.269 SIGNOR-272925 clofarabine chemical CHEBI:681569 ChEBI RRM1 protein P23921 UNIPROT down-regulates activity chemical inhibition 9606 1707752 YES miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate 0.8 SIGNOR-258357 CDC7 protein O00311 UNIPROT RAD18 protein Q9NS91 UNIPROT unknown phosphorylation Ser434 IQEVLSSsESDSCNS 9606 21098111 YES llicata Although the cdc7/rad18 interaction and phosphorylation at s434 are induced by dna damage, s434 was also observed to be phosphorylated basally 0.49 SIGNOR-170049 USP6 protein P35125 UNIPROT MMP10 protein P09238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20418905 NO miannu In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock. 0.2 SIGNOR-164943 ARNT protein P27540 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 21544813 NO lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC 0.572 SIGNOR-253697 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates quantity transcriptional regulation 10090 10783894 YES gcesareni AFX transcriptionally activates p27kip1, resulting in increased protein levels. 0.2 SIGNOR-252928 NMUR2 protein Q9GZQ4 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256731 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser689 SQPGQLMsQPSTASN 9606 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251279 AMPK complex SIGNOR-C15 SIGNOR PAK2 protein Q13177 UNIPROT unknown phosphorylation Ser20 APPVRMSsTIFSTGG 9606 22137581 YES lperfetto Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells. 0.242 SIGNOR-216612 Papain-like proteinase protein P0C6X9-PRO_0000037340 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression 9606 BTO:0000007 17761676 NO lperfetto SARS-CoV PLpro domain inhibits activation of IFN-β promoter following engagement of TLR3 or RIG-I pathways independent of its protease activity 0.2 SIGNOR-260277 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 12612081 YES In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin 0.622 SIGNOR-248385 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp683 HHGVVEVdAAVTPEE -1 8943232 YES lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261765 trichostatin A chemical CHEBI:46024 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258014 FOXA1 protein P55317 UNIPROT KRT7 protein P08729 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 20043065 NO miannu These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes. FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells. 0.28 SIGNOR-254167 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT up-regulates activity phosphorylation Ser551 CVMRFLVsKRKFKES 10029 BTO:0000246 12754513 YES lperfetto Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process. 0.325 SIGNOR-249209 OPRL1 protein P41146 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.348 SIGNOR-257001 CNOT8 protein Q9UFF9 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.792 SIGNOR-268310 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 9315650 YES llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. 0.459 SIGNOR-51292 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120172 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Lys) smallmolecule CHEBI:29185 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270403 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 12496362 YES lperfetto Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule. 0.397 SIGNOR-96768 MBD2 protein Q9UBB5 UNIPROT CHD4 protein Q14839 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000776 23071088 NO lperfetto MBD2 and multiple domains of CHD4 are required for transcriptional repression by Mi-2/NuRD complexes 0.63 SIGNOR-254102 porfimer chemical CHEBI:60652 ChEBI FCGR1A protein P12314 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000876 2544592 YES miannu Inhibition of the high affinity Fc receptor (Fc gamma RI) on human monocytes by porphyrin photosensitization is highly specific and mediated by the generation of superoxide radicals. 0.8 SIGNOR-259303 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Thr650 HLKAPNLtNVNKISN 9606 15194694 YES lperfetto Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability. 0.807 SIGNOR-125877 PPARA protein Q07869 UNIPROT CPT1A protein P50416 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 NO miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. 0.628 SIGNOR-255047 PHF5A protein Q7RTV0 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 YES lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). 0.91 SIGNOR-268409 AIMP2 protein Q13155 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.921 SIGNOR-270361 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates quantity by destabilization phosphorylation Ser197 SATDSDGsPLSNSQP 9606 15632084 YES gcesareni In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. 0.904 SIGNOR-132971 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 16782899 YES llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain 0.496 SIGNOR-147203 RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT up-regulates activity phosphorylation Ser236 AKRRRLSsLRASTSK 10090 15809305 YES lperfetto A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size. 0.937 SIGNOR-135176 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 YES gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2). 0.676 SIGNOR-59647 PER2 protein O15055 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 22260161 NO apalma We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML) 0.7 SIGNOR-256370 dicyclomine chemical CHEBI:4514 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258388 KLF2 protein Q9Y5W3 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15947087 NO Regulation of expression miannu Our results show that KLF2 positively regulates the human (ε) and murine (Ey and βh1) embryonic globin genes at both E10.5 and E12.5, in the yolk sac, which is the site of primitive erythropoiesis. 0.243 SIGNOR-251830 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 YES milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity 0.851 SIGNOR-201318 EGR1 protein P18146 UNIPROT TBXA2R protein P21731 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19747485 NO Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein. 0.26 SIGNOR-254253 DNMT3A protein Q9Y6K1 UNIPROT CDKN2C protein P42773 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 NO miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family 0.339 SIGNOR-261508 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 11864573 YES The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX. 0.391 SIGNOR-248530 RET protein P07949 UNIPROT DOK6 protein Q6PKX4 UNIPROT up-regulates binding 9606 BTO:0000671 15286081 YES gcesareni These data identify dok-6 as a novel dok-4/5-related adaptor molecule that may function in vivo to transduce signals that regulate ret-mediated processes such as axonal projection. 0.646 SIGNOR-127382 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser126 RKETSARsLGSPLLH 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.742 SIGNOR-262715 Ub:E2 complex SIGNOR-C497 SIGNOR RNF40 protein O75150 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271109 LEF1 protein Q9UJU2 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 24344199 YES lperfetto We further demonstrate that Fst is a direct target of the WNT/β-catenin pathway. Activation and inactivation of β-catenin induced and inhibited Fst expression, respectively, in both C2C12 cells and mouse embryos. Specific TCF/LEF1 binding sites within the promoter and intron 1 region of the Fst gene were required for RSPO2 and WNT/β-catenin-induced Fst expression. 0.28 SIGNOR-251722 RAB12 protein Q6IQ22 UNIPROT SLC36A4 protein Q6YBV0 UNIPROT down-regulates quantity by destabilization relocalization 10090 BTO:0002572 23478338 YES lperfetto We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters. 0.446 SIGNOR-264763 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 FGLSRLMtGDTYTAH 9606 10964922 YES Manara We demonstrate here that autophosphorylation of ABL1 is intermolecular and stimulates Abl catalytic activity. 0.2 SIGNOR-260781 MCHR1 protein Q99705 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.528 SIGNOR-257302 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr292 ETPPRPRtPGRPLSS 9534 BTO:0004055 14993270 YES lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. 0.2 SIGNOR-244557 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser347 TFPAQSLsPEPLPQE 9606 14697653 YES lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.268 SIGNOR-120479 HBA1 protein P69905 UNIPROT APOB protein P04114 UNIPROT up-regulates quantity by stabilization 9606 8611031 NO Regulation of binding miannu Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Crosslinked apo B was shown to resist lysosomal degradation, thereby causing accumulation of oxidized LDL in macrophages 0.32 SIGNOR-251755 FBXW7 protein Q969H0 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 10090 BTO:0002572 22388891 YES miannu Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α 0.891 SIGNOR-272908 DAPK3 protein O43293 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 15001356 YES gcesareni Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein. 0.342 SIGNOR-123159 PTPN1 protein P18031 UNIPROT IGF1R protein P08069 UNIPROT down-regulates activity dephosphorylation 9606 11884589 YES lperfetto Ptp-1b can regulate igf-ir kinase activity and function and that loss of ptp-1b can enhance igf-i-mediated cell survival, growth, and motility in transformed cells. 0.861 SIGNOR-115709 CSNK2A1 protein P68400 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser263 GEDTLSDsDDEDDEE -1 1425701 YES llicata Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263. 0.447 SIGNOR-250921 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser539 RPKRTKAsMSEFLES 25855382 YES lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro 0.362 SIGNOR-275557 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.422 SIGNOR-248308 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr334 RLFFVIEyVNGGDLM 9606 11713277 YES llicata Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. 0.532 SIGNOR-111928 PNMT protein P11086 UNIPROT adrenaline smallmolecule CHEBI:33568 ChEBI up-regulates quantity chemical modification 9606 7961964 YES brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). 0.8 SIGNOR-264007 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CCNE2 protein O96020 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002524 17298674 YES miannu Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme 0.511 SIGNOR-271638 ECM stimulus SIGNOR-ST20 SIGNOR A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259049 XAF1 protein Q6GPH4 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates binding 9606 17613533 YES gcesareni Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3. 0.416 SIGNOR-156843 KX2-391 chemical CID:23635314 PUBCHEM SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193624 EIF4E protein P06730 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 30459806 NO gianni The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation 0.7 SIGNOR-268529 SKI protein P12755 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 YES lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway 0.781 SIGNOR-253300 PSMA5 protein P28066 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.87 SIGNOR-263364 CSNK2A2 protein P19784 UNIPROT CDC37 protein Q16543 UNIPROT up-regulates activity phosphorylation Ser13 VWDHIEVsDDEDETH -1 12930845 YES llicata Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site. 0.49 SIGNOR-250982 MYC protein P01106 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR up-regulates quantity by expression transcriptional regulation 10116 10823814 YES C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. 0.33 SIGNOR-267587 IL20 protein Q9NYY1 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT up-regulates binding 9606 11163236 YES gcesareni An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis. 0.605 SIGNOR-151877 AKT proteinfamily SIGNOR-PF24 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates activity phosphorylation Ser87 FIFMRRSsLLSRSSS 9606 16282323 YES lperfetto Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL). 0.2 SIGNOR-141581 MXD1 protein Q05195 UNIPROT UBTF protein P17480 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000539 15282543 YES lperfetto MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter. 0.36 SIGNOR-269646 CSNK1A1 protein P48729 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 YES lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. 0.2 SIGNOR-264877 CTH protein P32929 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275820 serotonin smallmolecule CHEBI:28790 ChEBI HTR2A protein P28223 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264293 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT down-regulates activity phosphorylation Ser70 QNNSFQRsKRRYFKL 9534 15228384 YES lperfetto The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain. 0.366 SIGNOR-249266 TFEB protein P19484 UNIPROT HPS3 protein Q969F9 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 NO lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) 0.2 SIGNOR-276794 MAPK1 protein P28482 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates activity phosphorylation Ser203 EYPEPYAsPPQPGLP 9534 BTO:0004055 10230405 YES lperfetto Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway. 0.463 SIGNOR-249431 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 16440056 NO lperfetto The most abundant cytoplasmic dynein complex, cytoplasmic dynein 1, is involved in functions as diverse as spindle-pole organization and nuclear migration during mitosis, the positioning and functioning of the endoplasmic reticulum, the Golgi apparatus, and the nucleus, and also the minus-end-directed transport of vesicles, including endosomes and lysosomes, along microtubules and retrograde axonal transport in neurons. 0.7 SIGNOR-265059 MAPK8 protein P45983 UNIPROT NFE2 protein Q16621 UNIPROT down-regulates quantity by destabilization phosphorylation Ser157 LNYSDAEsLELEGTE 19966288 YES lperfetto Through use of different approaches including nano-scale proteomics, we show that activated-JNK, or Phospho-JNK (P-JNK), physically interacts with p45/NF-E2 and phosphorylates its Ser157 residue. This reaction leads to the poly-ubiquitination of p45/NF-E2 at one or more of six Lys residues, one of which being also a sumoylation site, and its degradation through the proteasome pathway. 0.411 SIGNOR-275552 BMP4 protein P12644 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7673243 YES acerquone We have isolated a cdna encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type ii receptor that binds bmp-4. This receptor (brk-3) is distantly related to other known type ii receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain. 0.78 SIGNOR-30697 KDM6A protein O15550 UNIPROT ETV6 protein P41212 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 YES miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase 0.301 SIGNOR-260032 RNA Polymerase III complex SIGNOR-C389 SIGNOR transfer RNA smallmolecule CHEBI:17843 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-266143 POLD3 protein Q15054 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR form complex binding -1 12403614 YES lperfetto Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme. 0.933 SIGNOR-265515 CDC25C protein P30307 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 BTO:0001938 10913154 YES lperfetto Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition 0.844 SIGNOR-255037 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 YES gcesareni Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization. 0.85 SIGNOR-179109 ADORA1 protein P30542 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.457 SIGNOR-256697 AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity 9606 30274374 NO miannu AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy. 0.566 SIGNOR-260096 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr710 DLQEAEKtIGRSRST 9606 12030846 YES lperfetto Mypt1 was phosphorylated by ilk and phosphorylation sites in the n- and c-terminal fragments of mypt1 were detected. From sequence analyses, three sites were identified: a primary site at thr(709), and two other sites at thr(695) and thr(495). phosphorylation of the various sites indicated that thr695 was the major inhibitory site, thr709 had only a slight inhibitory effect 0.583 SIGNOR-87928 RAP1B protein P61224 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 10090 BTO:0003104 12808052 YES lperfetto The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. 0.441 SIGNOR-253363 SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 9606 27563484 NO ggiuliani Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression. 0.48 SIGNOR-255784 NEDD4L protein Q96PU5 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 YES miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 0.464 SIGNOR-253456 FBXL2 protein Q9UKC9 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 10090 BTO:0002268 22323446 YES miannu F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation. Purified SCF complex components were incubated with V5-cyclin D2 and the full complement of ubiquitination reaction components (second lane from left) showing polyubiquitinated cyclin D2. 0.622 SIGNOR-272008 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 NO miannu YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. 0.7 SIGNOR-277639 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity binding 9606 25520508 YES miannu We show that G3BP1 can activate effectors of the innate immune transcriptional program, culminating in enhanced expression of a set of cytokines. We demonstrate that a subset of PKR is recruited to SGs, that close-proximity interactions between G3BP1 and PKR complexes increase in response to stress and PKR activation, that once activated PKR no longer associates with SGs, and that the PXXP domain of G3BP1 is essential for PKR recruitment to SGs and PKR activation in cells. Together, these findings suggest that G3BP1 plays an important role in the recruitment of PKR to SGs and suggest that activation of PKR can take place at the SG. 0.307 SIGNOR-260750 COL4A4 protein P53420 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 YES Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) 0.7 SIGNOR-254668 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 15579115 YES miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 0.8 SIGNOR-259260 RUNX1 protein Q01196 UNIPROT ELF4/RUNX1 complex SIGNOR-C47 SIGNOR form complex binding 9606 BTO:0001271 10207087 YES miannu We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function 0.352 SIGNOR-66963 STON2 protein Q8WXE9 UNIPROT SYT1 protein P21579 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 YES miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. 0.777 SIGNOR-264115 PFKP protein Q01813 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266469 MAPKAPK2 protein P49137 UNIPROT LSP1 protein P33241 UNIPROT unknown phosphorylation Ser204 KLIDRTEsLNRSIEK -1 8995217 YES miannu LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils 0.637 SIGNOR-250147 dexmedetomidine chemical CHEBI:4466 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258908 WEE1 protein P30291 UNIPROT CDK2 protein P24941 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 BTO:0000567 11029659 YES gcesareni Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases. 0.665 SIGNOR-83139 CRH protein P06850 UNIPROT CRHR2 protein Q13324 UNIPROT up-regulates activity binding 9606 23504413 YES lperfetto The actions of CRH are transduced through CRH receptors, which belong to the class II/secretin-like family of the G-protein coupled receptor (GPCR) superfamily (Martin et al. 2005). There are three types of CRH receptors – type 1 (CRHR1), type 2 (CRHR2) and type 3 (CRHR3). Among these, CRHR3 has not been identified in mammals. |CRH is a high-affinity ligand of CRHR1. It also binds to CRHR2, but with lower affinity 0.917 SIGNOR-268611 CDC25B protein P30305 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates dephosphorylation 9606 7880537 YES lperfetto Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex 0.767 SIGNOR-217511 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIFC1 protein Q9BW19 UNIPROT up-regulates quantity by stabilization phosphorylation Ser6 sPLLEVKG -1 24510915 YES miannu Tryptic digests of KIFC1 treated with CDK1/CYCLIN B were analyzed by LC-MS/MS revealing phosphorylation at Ser6 (Supplementary Fig S5B). These data indicate that phosphorylation by CDK1/CYLCIN B contributes to KIFC1 stability by protecting KIFC1 from APC/C-mediated ubiquitination and subsequent proteasomal degradation. 0.423 SIGNOR-266113 PRKACA protein P17612 UNIPROT RET protein P07949 UNIPROT down-regulates phosphorylation Ser696 SSGARRPsLDSMENQ 9606 BTO:0000938 20682772 YES llicata Furthermore, we find that activation of protein kinase a (pka) by forskolin reduces the recruitment of shp2 to ret and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of ser(696), a known pka phosphorylation site in ret, enhances shp2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. 0.399 SIGNOR-167349 NTRK1 protein P04629 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.777 SIGNOR-273923 Vps34 Complex I complex SIGNOR-C242 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 30397185 NO lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.7 SIGNOR-260323 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248755 ADAM17 protein P78536 UNIPROT GP1BA protein P07359 UNIPROT down-regulates activity cleavage Val466 ATSPTILvSATSLIT 9606 BTO:0000132 25297919 YES lperfetto GPIbα is shed by metalloproteases such as ADAM17, a process that releases a soluble GPIbα fragment termed glycocalicin. ADAM17 cleaves within the GPIbα-based peptide (LRGV465LK) through a mechanism that is only partially understood [42]. GPIbα shedding has been shown to be constitutive but it can be increased by activation of protein kinases C (PKC) or inhibition of calmodulin [42, 43]. Shedding leads to decreased receptor density 0.284 SIGNOR-261861 CRP protein P02741 UNIPROT CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004910 26961257 NO miannu In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. 0.477 SIGNOR-252143 atenolol chemical CHEBI:2904 ChEBI ADRB2 protein P07550 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 10079020 YES Luana In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue 0.8 SIGNOR-258335 SF3B4 protein Q15427 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.768 SIGNOR-270666 DOT1L protein Q8TEK3 UNIPROT H3C1 protein P68431 UNIPROT unknown methylation Lys80 REIAQDFkTDLRFQS 9606 12123582 YES miannu HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase. 0.2 SIGNOR-267141 KAT2A protein Q92830 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.735 SIGNOR-269588 PRKCH protein P24723 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 YES miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 0.2 SIGNOR-276049 MAPK14 protein Q16539 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 YES llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro 0.269 SIGNOR-173409 bosutinib chemical CHEBI:39112 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190696 SEC63 protein Q9UGP8 UNIPROT SEC62 protein Q99442 UNIPROT up-regulates activity binding 9606 BTO:0000599 23287549 YES lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. 0.96 SIGNOR-265273 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity 9606 BTO:0000007 17715225 NO miannu We mapped a strong inhibitory activity to SARS-CoV nonstructural protein 1 (nsp1) and show that expression of nsp1 significantly inhibited the activation of all three virus-dependent signaling pathways. We show that expression of nsp1 significantly inhibited IFN-dependent signaling by decreasing the phosphorylation levels of STAT1 while having little effect on those of STAT2, JAK1, and TYK2. 0.2 SIGNOR-262502 ITGB1 protein P05556 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.819 SIGNOR-253180 NSFL1C protein Q9UNZ2 UNIPROT CTSL protein P07711 UNIPROT down-regulates activity binding -1 15498563 YES lperfetto The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L. 0.2 SIGNOR-265043 KLF6 protein Q99612 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 15917248 NO fspada We have identified kr?ppel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. 0.7 SIGNOR-137807 EFNA1 protein P20827 UNIPROT EPHA1 protein P21709 UNIPROT up-regulates binding 9606 9330863 YES gcesareni The eph family receptors and ligands. 0.83 SIGNOR-51932 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser437 SGIVTNGsFSSSNAE 9606 BTO:0000007 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249305 PRKCA protein P17252 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 BTO:0000938 BTO:0000671 9679146 YES gcesareni These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc. 0.2 SIGNOR-59229 PRKAA1 protein Q13131 UNIPROT GFPT1 protein Q06210 UNIPROT up-regulates phosphorylation Ser261 CNLSRVDsTTCLFPV 9606 17941647 YES gcesareni Amp-activated protein kinase and calcium/calmodulin-dependent kinase ii were identified to phosphorylate specifically ser243 in vitro. Phosphorylation by these two kinases results in an increase of enzymatic activity by 1.4-fold. These findings suggest for the first time that hgfat1 may be regulated by kinases other than pka. 0.2 SIGNOR-158490 EEF1A1 protein P68104 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269511 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 YES In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. 0.2 SIGNOR-251330 C9orf72 protein Q96LT7 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity binding 9606 27334615 YES lperfetto C9orf72 interacts with the ULK1 initiation complex|C9orf72 regulates translocation of the ULK1 complex to the phagophore via Rab1a 0.419 SIGNOR-261281 SRC protein P12931 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276189 HIF1A protein Q16665 UNIPROT EPO protein P01588 UNIPROT up-regulates quantity by expression transcriptional regulation 8663540 YES lperfetto Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene. 0.642 SIGNOR-253695 FBXL2 protein Q9UKC9 UNIPROT CCND3 protein P30281 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000018 22024926 YES miannu Here, we show that a relatively new E3 ligase component belonging to the SCF (Skip-Cullin1-F-box protein) E3 ligase family, SCF (FBXL2) , impairs cell proliferation by mediating cyclin D3 polyubiquitination and degradation.  0.484 SIGNOR-271887 AM/b2 integrin complex SIGNOR-C170 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.47 SIGNOR-257713 GPR35 protein Q9HC97 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256860 MAGED1 protein Q9Y5V3 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000222 BTO:0000887 20646279 NO gcesareni These data demonstrate for the first time that maged1 is an important factor required for proper skeletal myoblast differentiation and muscle healing. 0.7 SIGNOR-166896 ELOVL7 protein A1L3X0 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267888 bosutinib chemical CHEBI:39112 ChEBI SRC protein P12931 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258089 GNB3 protein P16520 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 14668344 YES gcesareni Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein. 0.398 SIGNOR-120264 BMS 794833 chemical CID:44155856 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190422 PTPN6 protein P29350 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 9261115 YES To determine whether the COOH-terminal or other phosphotyrosine residues within Src are subject to dephosphorylation by SHP-1, the effects of this phosphatase on Src tyrosine phosphorylation were initially examined using CNBr cleavage analysis. As illustrated in Fig.1 A, CNBr treatment of 32P-labeled human Src has been shown previously to yield phosphorylated cleavage fragments of about 31, 9.7, and 4.7 kDa, which, respectively, contain the Src NH2-terminal region encompassing the major sites for serine phosphorylation on Src, Ser-12 and Ser-17 (31-kDa fragment), the inhibitory tyrosine phosphorylation site, Tyr-530 (4.7-kDa fragment), and a key site for autophosphorylation on activated Src, Tyr-419 [} These observations, together with the finding of reduced Src activity in HEY cells expressing a dominant negative form of SHP-1, provide compelling evidence that SHP-1 functions include the positive regulation of Src activation. 0.528 SIGNOR-248473 Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR NANOS2 protein P60321 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 20603330 YES miannu We have identified SPRY domain-containing SOCS (suppressor of cytokine signaling) box protein 2 (SPSB2) as a novel negative regulator that recruits an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in its proteasomal degradation. A cell-free ubiquitination assay was established to demonstrate SPSB2-dependent ubiquitination of iNOS. LPS/IFN-γ–stimulated macrophage lysates from Spsb2−/− mice were used as a source of iNOS and incubated with ubiquitin and a trimeric SPSB2/elongin BC complex in the presence of E1 and E2 (UbcH5a) enzymes, Rbx2, and Cullin5 for various times. 0.2 SIGNOR-271900 naratriptan chemical CHEBI:7478 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 10193663 YES Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  0.8 SIGNOR-258338 RFX complex complex SIGNOR-C104 SIGNOR HLA-DPB1 protein P04440 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.287 SIGNOR-253990 PDXP protein Q96GD0 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity dephosphorylation Ser166 SSRRRAIsETEENSD 9606 33414453 YES miannu Considering the roles of NF2 in actin dynamics and Mdm2 regulation  - , , , it is noteworthy to elucidate whether interaction of PLPP and CIN with NF2 modulates actin dynamics and Mdm2 degradation in neuronal excitability.|Recently, we have reported that PLPP and CIN dephosphorylates Mdm2 at S166 site in activity dependent manners, which inhibits Mdm2 mediated PSD95 degradation by facilitating Mdm2 ubiquitination 38. 0.2 SIGNOR-277151 monoisononyl phthalate chemical CHEBI:132593 ChEBI OXER1 protein Q8TDS5 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268778 DNA_damage stimulus SIGNOR-ST1 SIGNOR PALB2 protein Q86YC2 UNIPROT up-regulates activity 9606 BTO:0001938 19369211 NO lperfetto Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations. 0.7 SIGNOR-244490 PLPPR1 protein Q8TBJ4 UNIPROT RASGEF1B protein Q0VAM2 UNIPROT up-regulates activity binding 9606 27058420 YES miannu Oncogenic effects of imbalanced PRG3 are mediated via PRG3-RasGEF1 interaction and Ras activation. PRG3 interacts with RasGEF1 in vivo.We could further show that PRG3 executes the binding to RasGEF1 predominantly via its C-terminal domain (CT) and in the consequence causes Ras activation. 0.2 SIGNOR-261806 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2B complex SIGNOR-C348 SIGNOR up-regulates activity chemical activation 9606 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate 0.8 SIGNOR-264129 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser99 KEEEEGIsQESSEEE -1 2806554 YES llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol. 0.328 SIGNOR-251006 PDHX protein O00330 UNIPROT GCG protein P01275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001731 12783165 NO miannu In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%. 0.2 SIGNOR-254901 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 BTO:0002035 11948419 YES miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). 0.537 SIGNOR-275981 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 BTO:0000567 9687510 YES gcesareni Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha 0.614 SIGNOR-59447 EDNRA protein P25101 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 15475516 YES gcesareni The response to endothelin-1 (et-1) consisted of two phases in both cell types. The initial, transient phase of contraction and phosphorylation of 20-kda myosin light chain (mlc20) was mediated additively by eta and etb receptors and initiated by galphaq-, ca2+/calmodulin-dependent activation of mlc kinase. 0.541 SIGNOR-129817 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr487 SLSNIDFyAQVSDIT 10029 BTO:0000246 12907755 YES PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 0.295 SIGNOR-248392 KAT2A protein Q92830 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 BTO:0000150 SIGNOR-C7 15009097 YES gcesareni Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo. 0.337 SIGNOR-123315 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1189 RDIYETDyYRKGGKG -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; 0.2 SIGNOR-106514 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser138 SLQLGAVsPGTLTPT 26933062 YES lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. 0.389 SIGNOR-276592 clofarabine chemical CHEBI:681569 ChEBI POLG2 protein Q9UHN1 UNIPROT down-regulates activity chemical inhibition 9606 1707752 YES miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. 0.8 SIGNOR-258362 ZNF76 protein P36508 UNIPROT TCP1 protein P17987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10893243 YES Luana The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription. 0.347 SIGNOR-266221 carfilzomib chemical CHEBI:65347 ChEBI PSMB8 protein P28062 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000873 19348473 YES Luana Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes. 0.8 SIGNOR-257819 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32195003 NO Notch signaling is initiated by the interaction of Notch ligands and receptors on adjacent cells, which further triggers two proteolytic cleavage events. The first cleavage releases a functional extracellular domain (NECD); the second cleavage, mediated by γ-secretase, releases the intracellular domain (NICD) into the cytoplasm. The NICD then translocates to the nucleus, binds to the transcription factor CBF/Su (H)/LAG-2 (CSL), and recruits Mastermind-like protein 1 and p300/CBP to induce transcription of Notch target genes, including Hes1, p21, Akt, cyclin D1, and mTOR 0.2 SIGNOR-261534 RIMBP2 protein O15034 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.502 SIGNOR-264361 Oxotremorine chemical CHEBI:7851 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258653 Condensin I complex SIGNOR-C341 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 32445620 NO miannu Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.7 SIGNOR-263907 EPAS1 protein Q99814 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271586 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser9 STRSVSSsSYRRMFG -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248876 RPS6KA4 protein O75676 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 10090 12773393 YES lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 0.2 SIGNOR-265355 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity phosphorylation Ser272 LSASPQPsSVAPRRP 10090 BTO:0002284 19833727 YES We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose 0.2 SIGNOR-255567 CAD protein P27708 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI down-regulates quantity chemical modification 9606 24332717 YES In animals, the first three reactions of the pathway are catalyzed by CAD, an 240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities 0.8 SIGNOR-267199 UBR4 protein Q5T4S7 UNIPROT TRPV5 protein Q9NQA5 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0003913 23747339 YES miannu Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5.  UBR4/p600 ubiquitin ligase is responsible for TRPV5 ubiquitination and proteasomal degradation in response to cytomix 0.246 SIGNOR-272117 BMP7 protein P18075 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7644468 YES acerquone In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7. 0.803 SIGNOR-30512 CCNA2 protein P20248 UNIPROT CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR form complex binding 9606 29870721 YES lperfetto Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. 0.922 SIGNOR-267571 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1267 PATGEQVyQQDWAQN -1 10195142 YES lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. 0.733 SIGNOR-247155 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser179 TASGSSVsPGLYSKT 9606 BTO:0000567 35469017 YES miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. 0.2 SIGNOR-276721 PRKCA protein P17252 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates phosphorylation Ser435 KKLERNLsFEIKKVP 9606 7520867 YES llicata Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435. our results suggest that both pkc and pka are capable of phosphorylating, and therefore inhibiting, ptp-pest in vivo 0.322 SIGNOR-27304 PF-03814735 chemical CID:49830590 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205950 PSTPIP1 protein O43586 UNIPROT ABL1 protein P00519 UNIPROT down-regulates 9606 11163214 NO lperfetto Cytoskeletal protein pstpip1 directs the pest-type protein tyrosine phosphatase to the c-abl kinase to mediate abl dephosphorylationSeveral experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity 0.598 SIGNOR-105035 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LCK protein P06239 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 8618896 YES inferred from 70% family members lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. 0.2 SIGNOR-270177 GSK3A protein P49840 UNIPROT IL17RA protein Q96F46 UNIPROT down-regulates quantity by destabilization phosphorylation Thr780 MVLTDPHtPYEEEQR 9606 BTO:0000007 26871944 YES miannu Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.  0.2 SIGNOR-277206 PAX7 protein P23759 UNIPROT MLL1 complex complex SIGNOR-C89 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 YES lperfetto Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.2 SIGNOR-217716 GTF2F2 protein P13984 UNIPROT GTF2F1 protein P35269 UNIPROT up-regulates activity binding 9534 11278533 YES miannu Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30. 0.962 SIGNOR-261180 IKBKE protein Q14164 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser151 VLPSSKRsPSTATLS 9606 BTO:0001061 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.2 SIGNOR-276778 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs 0.87 SIGNOR-209647 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207087 TNF protein P01375 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 10485710 NO lperfetto Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). 0.317 SIGNOR-252733 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr307 IGPDNLPyVQILKTA 9606 8443592 YES lperfetto Tyrosine residues 154 and 307, which are in the extracellular domain of transmembrane receptor isoforms and are in an unusual sequence context for tyrosine phosphorylation, were also phosphorylated. 0.2 SIGNOR-98630 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu86 ENTERTTeFWKQYVD 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263696 COLGALT1 protein Q8NBJ5 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates activity glycosylation -1 19075007 YES Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. 0.4 SIGNOR-261155 Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 9606 27487822 YES miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. 0.8 SIGNOR-266268 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates relocalization 9606 11238441 YES lperfetto Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels 0.378 SIGNOR-105491 CSNK1A1 protein P48729 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 11955435 YES gcesareni In principle, pka, ck-1 and gsk3 can phosphorylate as many as 19 serine residues in gli3: fourpkasites, three primarygsk3sites, four primary ck-1 sites and eight secondary gsk3 and ck-1 sites 0.599 SIGNOR-116512 HBA1 protein P69905 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000876 11901318 NO Regulation of expression miannu Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes. 0.2 SIGNOR-251753 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 YES miannu Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome 0.442 SIGNOR-74708 CYP21A2 protein P08686 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 25855791 YES lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively 0.8 SIGNOR-268645 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 YES gcesareni Ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. 0.305 SIGNOR-76096 ME1 protein P48163 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 YES miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle 0.8 SIGNOR-267055 YY1 protein P25490 UNIPROT TNFRSF10B protein O14763 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 34589486 YES miannu Depletion of FKBP51 impairs the acetylation status of YY1 and interferes with its binding on the DR5 promoter. The lack of the repressor activity of YY1 increases DR5 transcription and sensitizes melanoma cell to TRAIL-induced apoptosis. 0.404 SIGNOR-268793 CCND1 protein P24385 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR form complex binding 9606 8114739 YES lperfetto Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. 0.951 SIGNOR-250680 MAPK14 protein Q16539 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 SIGNOR up-regulates phosphorylation 9606 21902831 YES lperfetto P38 can phosphorylate the histone-lysine n-methyltransferase ezh2, the catalytic subunit of the polycomb repressive complex 2 (prc2), with phosphorylation of ezh2 necessary for prc2s association with the transcriptional repressor yy1 and subsequent chromatin remodelling. 0.372 SIGNOR-217676 MAPK14 protein Q16539 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates activity phosphorylation Thr735 KPFPAPQtPGRLQPA 10029 BTO:0000246 20188673 YES gcesareni We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that is also known as ADAM17 and effects shedding in response to growth factors and Erk MAP kinase activation. p38alpha MAP kinase interacts with the cytoplasmic domain of TACE and phosphorylates it on Thr(735), which is required for TACE-mediated ectodomain shedding 0.405 SIGNOR-163970 MAPK1 protein P28482 UNIPROT SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation Thr622 LGTQVPGtPPPKYNT -1 11805112 YES lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. 0.361 SIGNOR-249448 SDHAF2 protein Q9NX18 UNIPROT SDHB protein P21912 UNIPROT up-regulates binding 9606 19628817 YES miannu Sdh5 is required for sdh activity and stability / the sdh1-sdh5 interaction is likely to be functionally important because the sdh5_ mutant lacks sdh activity 0.618 SIGNOR-187239 TRIM39 protein Q9HCM9 UNIPROT MOAP1 protein Q96BY2 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 19100260 YES miannu  TRIM39 stabilizes MOAP-1 by inhibiting the poly-ubiquitination process of MOAP-1.In this study, we report the identification and characterization of TRIM39 as a binding partner of MOAP-1. TRIM39 is the first regulator of MOAP-1 protein stability identified. 0.484 SIGNOR-272911 E2F3 protein O00716 UNIPROT TFDP1 protein Q14186 UNIPROT up-regulates activity binding 10029 BTO:0000246 8832394 YES 2 miannu The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3. 0.739 SIGNOR-240553 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 12244043 NO azuccotti Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes 0.7 SIGNOR-254989 NUMA1 protein Q14980 UNIPROT TUBD1 protein Q9UJT1 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.2 SIGNOR-117159 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F10 protein P00742 UNIPROT up-regulates activity binding 9606 BTO:0000131 32665005 YES lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. 0.651 SIGNOR-263543 HNF1A protein P20823 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10050749 YES lperfetto Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α 0.301 SIGNOR-251720 NBEAL2 protein Q6ZNJ1 UNIPROT Platelet_morphogenesis phenotype SIGNOR-PH135 SIGNOR up-regulates 9606 BTO:0000132 28082341 NO lperfetto We compared platelet size and number of α-granules for two NBEAL2 and two GATA1-deficient patients and found reduced numbers of α-granules for all, with the defect being more pronounced for NBEAL2 deficiency.  0.7 SIGNOR-261882 LRAT protein O95237 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI down-regulates quantity chemical modification 10090 18093970 YES lperfetto We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis 0.8 SIGNOR-265110 STMN3 protein Q9NZ72 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates quantity by destabilization binding 22577147 YES lperfetto  Stathmins can thus sequester free tubulin that may result in inhibiting microtubule growth and/or promoting microtubule collapse 0.7 SIGNOR-264896 SERPINC1 protein P01008 UNIPROT F12 protein P00748 UNIPROT down-regulates activity cleavage 31030036 YES lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 0.599 SIGNOR-264139 CNTF protein P26441 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 10966616 YES gcesareni Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr) 0.741 SIGNOR-81382 BMPR1A protein P36894 UNIPROT SOST protein Q9BQB4 UNIPROT up-regulates 9606 19874086 NO gcesareni These results demonstrate that bmpria in osteoblasts negatively regulates endogenous bone mass and wnt/beta-catenin signaling and that this regulation may be mediated by the activities of sost and dkk1. 0.33 SIGNOR-188958 CDK4 protein P11802 UNIPROT KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Ser372 EEIYGANsPIWESGF 24870244 YES lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) 0.361 SIGNOR-275494 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 23074268 YES gcesareni We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins 0.2 SIGNOR-199104 MAPK9 protein P45984 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Thr200 IARYVPStPWFLMPI 9606 15805466 YES llicata Inactivation is due to phosphorylation of tif-ia by c-jun n-terminal kinase (jnk) at a single threonine residue (thr 200). Phosphorylation at thr 200 impairs the interaction of tif-ia with pol i and the tbp-containing factor tif-ib/sl1, thereby abrogating initiation complex formation. 0.472 SIGNOR-134878 MMP2 protein P08253 UNIPROT LAMC2 protein Q13753 UNIPROT up-regulates activity cleavage 9211848 YES lperfetto Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling. 0.47 SIGNOR-253240 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCB protein P05771 UNIPROT up-regulates activity binding 9606 14967450 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. 0.8 SIGNOR-242584 STOX1 protein Q6ZVD7 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000601 22728895 YES Gianni In this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A. 0.2 SIGNOR-269065 PHGDH protein O43175 UNIPROT (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI up-regulates activity chemical modification 25406093 YES lperfetto Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG). 0.8 SIGNOR-268572 PKA proteinfamily SIGNOR-PF17 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 26088133 YES lperfetto Interestingly, GSK3beta can be released from the multienzyme complex in response to PKA phosphorylation on serine 9, which suppresses GSK3beta activity. 0.2 SIGNOR-264819 ESPL1 protein Q14674 UNIPROT RAD21 protein O60216 UNIPROT down-regulates quantity by destabilization cleavage 9606 15737063 YES lperfetto In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase 0.779 SIGNOR-275537 MSX1 protein P28360 UNIPROT TBP protein P20226 UNIPROT down-regulates activity binding -1 8700832 YES 2 miannu Msx-1 is a potent transcriptional repressor and that this activity is independent of its DNA binding function. Here we show that Msx-1 interacts directly with the TATA binding protein (TBP) but not with several other general transcription factors. This interaction is mediated by the Msx-1 homeodomain, specifically through residues in the N-terminal arm. These same N-terminal arm residues are required for repression by Msx-1, suggesting a functional relationship between TBP association and transcriptional repression. 0.398 SIGNOR-240401 NEU1 protein Q99519 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates activity 9606 BTO:0000182 19151752 NO Giorgia In HT-29 cells cultured with 10% fetal bovine serum (FBS), the phosphorylation of integrin β4 was significantly decreased in NEU1-overexpressing cells and the level seemed to be inversely correlated with the sialidase activity. These results suggest that NEU1 is involved in the regulation of integrin β4 phosphorylation probably through desialylation in colon cancer cells. 0.2 SIGNOR-260655 ELANE protein P08246 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 YES miannu Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen. 0.275 SIGNOR-256313 RNF111 protein Q6ZNA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity ubiquitination 10090 17341133 YES lperfetto Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. 0.653 SIGNOR-235388 SEC23IP protein Q9Y6Y8 UNIPROT SEC23B protein Q15437 UNIPROT up-regulates activity binding 10090 BTO:0000142 10400679 YES lperfetto The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway. 0.347 SIGNOR-265306 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr47 GTESEMEtPSAINGN 9606 10617621 YES lperfetto Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis 0.2 SIGNOR-73642 SIRT7 protein Q9NRC8 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity deacetylation Lys37 APATGGVkKPHRYRP 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275877 DGC complex SIGNOR-C217 SIGNOR NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 YES miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. 0.281 SIGNOR-265449 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR up-regulates activity phosphorylation 10090 19620713 YES ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). 0.69 SIGNOR-255788 SAGA complex complex SIGNOR-C465 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269629 PAK proteinfamily SIGNOR-PF13 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 16129686 YES lperfetto Inhibition of pak kinase activity dramatically decreased phosphorylation of mek1 at ser(298) in response to either pdgf or egf. 0.581 SIGNOR-244920 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates activity binding 9031 BTO:0000140 12478285 YES lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955).Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors. 0.61 SIGNOR-219221 PRKCZ protein Q05513 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276017 PPP2CA protein P67775 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates dephosphorylation Ser23 PAPIRRRsSNYRAYA 9606 BTO:0000887 15769444 YES lperfetto The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2. 0.4 SIGNOR-134597 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.637 SIGNOR-269236 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 10037602 YES gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. 0.858 SIGNOR-64964 AKT1 protein P31749 UNIPROT SCYL1 protein Q96KG9 UNIPROT up-regulates activity phosphorylation Thr469 STRHRVLtSAFSRAT 9606 BTO:0000567 24769208 YES lperfetto In previous work, we demonstrated that TEIF (transcriptional element-interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions.|A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification. 0.255 SIGNOR-265496 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr456 PPHLKYLyLVVSDSG 12441334 YES JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 0.811 SIGNOR-251351 PKA proteinfamily SIGNOR-PF17 SIGNOR PHKA2 protein P46019 UNIPROT down-regulates activity phosphorylation 9606 10487978 YES Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. 0.2 SIGNOR-267408 PLK1 protein P53350 UNIPROT SUZ12 protein Q15022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser541 KRTKASMsEFLESED 25855382 YES lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|In SUZ12, residues 539, 541 and 546 phosphorylated by Plk1 in vitro 0.362 SIGNOR-275555 SHH protein Q15465 UNIPROT GLI2 protein P10070 UNIPROT up-regulates activity 9606 BTO:0001593 16880529 NO lperfetto Finally, Sonic hedgehog (Shh) stimulates BMP-2 promoter activity and osteoblast differentiation, and the effects of Shh are mediated by Gli2. 0.728 SIGNOR-148349 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Thr263 PSRPPPPtPRRPASV 9606 BTO:0000007 16446428 YES gcesareni Itch undergoes JNK1-mediated phosphorylation that greatly enhances its enzymatic activity. To investigate how phosphorylation activates an E3 Ub ligase we have identified the JNK1 phosphorylation sites within Itch as S199, S232, and T222 0.654 SIGNOR-249579 USP24 protein Q9UPU5 UNIPROT DDB2 protein Q92466 UNIPROT up-regulates deubiquitination 9606 23159851 YES miannu Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation 0.702 SIGNOR-199731 CSNK2A1 protein P68400 UNIPROT TERF1 protein P54274 UNIPROT up-regulates phosphorylation Thr122 LTACQLRtIYICQFL 9606 18347021 YES lperfetto Regulation of telomeric repeat binding factor 1 binding to telomeres by casein kinase 2-mediated phosphorylation. Mapping of the ck2 target site identified threonine 122 as a substrate in trf1. A threonine to alanine change at this position led to a diminished dna binding due to reduced dimerization of trf1. 0.2 SIGNOR-178034 DUSP4 protein Q13115 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates activity dephosphorylation 10116 7535768 YES inferred from 70% of family members Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK 0.2 SIGNOR-269914 Factor VIIIa-IXa complex SIGNOR-C320 SIGNOR F10 protein P00742 UNIPROT up-regulates activity cleavage 10090 BTO:0000131 25769543 YES lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. 0.57 SIGNOR-263538 PRKCB protein P05771 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.309 SIGNOR-251630 SNRPD3 protein P62318 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.927 SIGNOR-270686 GSK3A protein P49840 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation 9606 20932480 YES miannu Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687 0.2 SIGNOR-168385 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates activity phosphorylation -1 12556484 YES done miannu We found that Nudel and NudE were also phosphorylated in M phase (Fig. ​(Fig.22 and ​and3).3). First, Nudel and NudE were specifically phosphorylated in M phase. Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro.Due to conservation of the S/TP motifs, NudE may also be phosphorylated at similar sites by these kinases, though it contains an additional potential Cdk site at S282 (SPNR). 0.375 SIGNOR-274078 MITF protein O75030 UNIPROT TYRP1 protein P17643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 22371403 NO miannu MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription. 0.487 SIGNOR-254591 KLF6 protein Q99612 UNIPROT DLK1 protein P80370 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15917248 NO Repression of Dlk1 requires HDAC3 deacetylase activity fspada We have identified kr?ppel-like factor-6 (klf6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene delta-like 1 (dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. 0.282 SIGNOR-137836 ITCH protein Q96J02 UNIPROT TRPV4 protein Q9HBA0 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 17110928 YES miannu AIP4 ubiquitin ligase is involved in the ubiquitination of both TRPV4 and TRPC4.Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. 0.377 SIGNOR-272625 POLR3G protein O15318 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.697 SIGNOR-266127 LRIG1 protein Q96JA1 UNIPROT ERBB3 protein P21860 UNIPROT down-regulates ubiquitination 9606 16123311 YES gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. 0.435 SIGNOR-139951 PRMT1 protein Q99873 UNIPROT FUS protein P35637 UNIPROT down-regulates activity methylation 9606 BTO:0000567 30354839 YES lperfetto PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis. 0.486 SIGNOR-262274 BMP7 protein P18075 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates activity binding 9606 7791754 YES fspada  BMPR-II is a transmembrane serine/threonine kinase that binds BMP-2 and BMP-7 in association with multiple type I receptors, including BMPR-IA/Brk1, BMPR-IB, and ActR-I, which is also an activin type I receptor.  0.778 SIGNOR-232216 DBH protein P09172 UNIPROT noradrenaline smallmolecule CHEBI:33569 ChEBI up-regulates quantity chemical modification 10090 7961964 YES brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. 0.8 SIGNOR-264006 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates ubiquitination 9606 10023660 YES lperfetto These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin. 0.728 SIGNOR-217181 H2BC11 protein P06899 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 YES miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 0.2 SIGNOR-263727 HLA2 beta chain proteinfamily SIGNOR-PF90 SIGNOR Class II MHC complex SIGNOR-C428 SIGNOR form complex binding 9606 1311249 YES scontino The biosynthesis of MHC Class II molecules starts with the assembly of the alpha and beta subunits. 0.2 SIGNOR-267869 MYCN protein P04198 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000793;BTO:0002104 7923112 NO miannu Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. 0.369 SIGNOR-254616 LRRK2 protein Q5S007 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 YES lperfetto In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease 0.331 SIGNOR-260267 ZNF322 protein Q6U7Q0 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24550733 YES lperfetto Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays revealed that Zfp322a binds to Pou5f1 and Nanog promoters and regulates their transcription. 0.2 SIGNOR-264900 CAMK2B protein Q13554 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 15980064 YES gcesareni These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. 0.2 SIGNOR-138360 CHEK1 protein O14757 UNIPROT TLK1 protein Q9UKI8 UNIPROT down-regulates phosphorylation Ser743 PHMRRSNsSGNLHMA 9606 12660173 YES llicata Chk1 phosphorylates tlk1 on serine 695 (s695) these findings identify an unprecedented functional co- operation between atm and chk1 in propagation of a checkpoint response during s phase and suggest that, through transient inhibition of tlk kinases, the atm_chk1_tlk pathway may regulate processes involved in chromatin assembly. 0.432 SIGNOR-99653 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FGFR1 protein P11362 UNIPROT down-regulates phosphorylation 9606 23405013 YES inferred from 70% family members lperfetto Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling 0.2 SIGNOR-270013 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 19115199 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-183000 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16899510 YES Luana Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2. 0.299 SIGNOR-259849 SMC3 protein Q9UQE7 UNIPROT RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR form complex binding 10090 BTO:0000534 21242291 YES miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. 0.82 SIGNOR-264537 RPS6KA3 protein P51812 UNIPROT GSK3A protein P49840 UNIPROT down-regulates activity phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000130 11583116 YES lperfetto P90-rsk and akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. These reactions were monitored with a phosphospecific antibody that only recognized the alpha- or beta-isoforms of GSK-3 when these proteins were phosphorylated on serine residues 21 and 9, respectively. 0.265 SIGNOR-110827 LATS1 protein O95835 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 YES Together,the YAP/TAZ-TEAD complex promotes proliferative and survival programs. milica In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. 0.79 SIGNOR-197643 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates phosphorylation Ser95 IQKQKRRsVNSKIPA 9606 17567953 YES lperfetto Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres. 0.73 SIGNOR-155890 oxymetazoline chemical CHEBI:7862 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9913 BTO:0000142 9632357 YES miannu Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives. 0.8 SIGNOR-258927 DOT1L protein Q8TEK3 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20854876 NO irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. 0.401 SIGNOR-256143 RFX complex complex SIGNOR-C104 SIGNOR HLA-DOA protein P06340 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.328 SIGNOR-253994 PLCB3 protein Q01970 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate(6-) smallmolecule CHEBI:203600 ChEBI up-regulates quantity chemical modification 9606 23994464 YES apalma The first phase of this signal is likely mediated by phospholipase C≈í‚⧠(PLC≈í‚â§) enzymes leading to the generation of IP3 and concomitant release of Ca2+ from intracellular stores 0.8 SIGNOR-255018 DIO3 protein P55073 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity chemical modification 9606 12746313 YES scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. 0.8 SIGNOR-266941 PRKDC protein P78527 UNIPROT USF1 protein P22415 UNIPROT up-regulates phosphorylation 9606 19303849 YES miannu Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation. 0.293 SIGNOR-184849 BCL2L1 protein Q07817 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 9670005 YES amattioni The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal. 0.744 SIGNOR-59141 CAMKK2 protein Q96RR4 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates phosphorylation Thr483 KHIPSLAtVILVKTM 9606 22778263 YES lperfetto It has been proposed that a major consequence of relief from autoinhibition is autophosphorylation of thr-482, a post-translational change that likely contributes to the increased autonomous activity of camkk2 0.2 SIGNOR-198107 CTSE protein P14091 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Phe834 QLEASPAfLAVPVEK -1 12631277 YES lperfetto Disruption of structural and functional integrity of alpha 2-macroglobulin by cathepsin E|Analysis of the N-terminal amino-acid sequences of these proteins revealed that alpha 2M was selectively cleaved at the Phe811-Leu812 bond in about 100mer downstream of the bait region. 0.381 SIGNOR-266977 MAPK9 protein P45984 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 18158901 YES gcesareni H2ax interacts with numerous proteins required for dna damage signaling and repair when phosphorylated on ser-140. Phosphorylation of ser-140 (h2ax139ph) in response to ionizing radiation is mediated by both atm and prkdc. Our data showed that h2ax is phosphorylated by uva-activated jnk. 0.2 SIGNOR-160210 INSR protein P06213 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Tyr291 LAEEIQKyCCSRK 15870194 YES lperfetto Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK 0.479 SIGNOR-275516 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates activity chemical inhibition -1 20565110 YES We report two crystal structures of the PARP domain of human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling. 0.8 SIGNOR-259995 SIRT1 protein Q96EB6 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20089851 NO Regulation miannu SIRT1 deacetylates and activates the FOXOs under oxidative stress, thereby inducing Mn-SOD expression 0.491 SIGNOR-251763 miR-27a mirna URS0000233054_9606 RNAcentral PPARG protein P37231 UNIPROT down-regulates quantity post transcriptional regulation 10090 26344767 NO Luana We also found that miR-199a expression and blockade (see below for details) potentiated and attenuated, respectively, the phosphorylation levels in neurons of S6 ribosomal protein, which signify the activation of mTOR signaling, indicating that miR-199a positively regulates mTOR signaling activity 0.4 SIGNOR-265770 DNMT1 protein P26358 UNIPROT DNMT1/DNMT3B complex SIGNOR-C43 SIGNOR form complex binding 9606 12145218 YES miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation 0.789 SIGNOR-90839 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Thr306 LKGAILTtMLATRNF 9606 1324926 YES lperfetto After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314 0.2 SIGNOR-17316 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates phosphorylation Tyr619 NKVDDCNyAIKRIRL 9606 17998206 YES lperfetto We show that perk is capable of autophosphorylating on tyrosine residues in vitro and in vivo. We further show that tyrosine 615, which is embedded in a highly conserved region of the kinase domain of perk, is essential for autocatalytic activity. 0.2 SIGNOR-159156 CCR1 protein P32246 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. 0.311 SIGNOR-255118 PSAT1 protein Q9Y617 UNIPROT O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI up-regulates activity chemical modification 3702 30034403 YES lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. 0.8 SIGNOR-268560 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser83 NKEKKAVsPLLLTTT 9606 11152499 YES tpavlidou Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites. 0.2 SIGNOR-85769 PIAS1 protein O75925 UNIPROT SATB2 protein Q9UPW6 UNIPROT down-regulates activity sumoylation Lys350 PPIPRAVkPEPTNSS 9606 BTO:0000007 14701874 YES gianni We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1. 0.581 SIGNOR-269112 PDK3 protein Q15120 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 YES miannu Pdh2 was found to be very similar to pdh1 / in the mechanism of inactivation by phosphorylation of three sites;and (iv) in the phosphorylation of sites 1 and 2 by pdk3 / (ser-264 (site 1), ser-271 (site 2), and ser-203 (site 3) 0.562 SIGNOR-143974 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 16046550 YES The effect has been demonstrated using Q01196-8 miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 0.2 SIGNOR-138969 UBE3A protein Q05086 UNIPROT RAD23B protein P54727 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 10373495 YES miannu  Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B. 0.405 SIGNOR-272551 Niflumic acid chemical CHEBI:34888 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258062 AIP protein O00170 UNIPROT TFF1 protein P04155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21984905 YES miannu We show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. 0.2 SIGNOR-259911 FLT3 protein P36888 UNIPROT CISH protein Q9NSE2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 NO The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD 0.299 SIGNOR-261542 DRD2 protein P14416 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.556 SIGNOR-256844 ZNF76 protein P36508 UNIPROT TBP protein P20226 UNIPROT down-regulates activity binding 9606 15280358 YES miannu We identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini. ZNF76 targets TBP for transcriptional repression. 0.4 SIGNOR-224650 MRPS34 protein P82930 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.667 SIGNOR-261443 SHANK2 protein Q9UPX8 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 NO miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. 0.7 SIGNOR-264606 TGFB1 protein P01137 UNIPROT KRT1 protein P04264 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16258965 NO Regulation miannu TGFβ1 and TGFβ2 induce loss of epithelial morphology, cytokeratin, and membrane-associated Zonula Occludens-1 and increase the smooth muscle markers calponin and caldesmon 0.2 SIGNOR-251884 RPS6KA1 protein Q15418 UNIPROT PPP1R3A protein Q16821 UNIPROT up-regulates activity phosphorylation Ser46 PQPSRRGsDSSEDIY -1 10648825 YES lperfetto The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates.  0.429 SIGNOR-249036 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 YES Manara Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A 0.842 SIGNOR-260833 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI L-alanine zwitterion smallmolecule CHEBI:57972 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. 0.8 SIGNOR-268123 FANCD2 protein Q9BXW9 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 YES lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  0.744 SIGNOR-263255 BUB3 protein O43684 UNIPROT MCC complex SIGNOR-C382 SIGNOR form complex binding 9606 BTO:0000567 25092294 YES miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 0.966 SIGNOR-265975 pazopanib chemical CHEBI:71219 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258261 MSX1 protein P28360 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001103 15192231 NO gcesareni We found that msx1 and h1b bind to a key regulatory element of myod, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin. 0.425 SIGNOR-125765 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001938 15254178 YES lperfetto Although the stabilization of p53 was apparently concordant with its phosphorylation on N-terminal serine residues in HFFF-2 cells, it did not require the phosphorylation of Ser15 or Ser20 by ATM, a cellular kinase known to phosphorylate and promote the stabilization of p53 in response to DNA damage. 0.843 SIGNOR-126757 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 YES milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) 0.42 SIGNOR-230733 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser465 VRRDRSTsIKLQEAP 9606 19261611 YES llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. 0.2 SIGNOR-184460 DOK1 protein Q99704 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.295 SIGNOR-257692 SARS1 protein P49591 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 24095058 YES miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis 0.8 SIGNOR-270496 CDC25A protein P30304 UNIPROT CDK4 protein P11802 UNIPROT up-regulates activity dephosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 27485204 YES miannu Cdc25A mainly promotes G1-S transition by dephosphorylating CDK4 (Y17)-cyclin D, CDK6 (Y24)-cyclin D and CDK2 (T14 and Y15)-cyclin E/A complexes and G2-M progression by dephosphorylating CDK1 (T14 and Y15)-cyclin A/B    .|Cdc25A mainly promotes G1-S transition by dephosphorylating CDK4 (Y17)-cyclin D, CDK6 (Y24)-cyclin D and CDK2 (T14/Y15)-cyclin E/A complexes and G2-M progression by dephosphorylating CDK1 (T14/Y15)-cyclin A/B . 0.704 SIGNOR-277138 TNFRSF10A protein O00220 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 YES amattioni Fadd binds to ligated trailr1 or trail-r2 0.83 SIGNOR-97869 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA9 protein Q9Y5G4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265678 MAPKAPK5 protein Q8IW41 UNIPROT MAPK4 protein P31152 UNIPROT up-regulates phosphorylation Ser186 YSHKGYLsEGLVTKW 9606 1319925 YES lperfetto This is due to mk5-dependent phosphorylation and only this retarded erk4 species is both phosphorylated on ser(186) and co-immunoprecipitates with wild-type mk5. We conclude that binding between erk4 and mk5 facilitates phosphorylation of ser(186) and stabilization of the erk4-mk5 complex. 0.629 SIGNOR-17069 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203524 BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 15694340 YES gcesareni Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly. 0.956 SIGNOR-133829 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Thr305 KLKGAILtTMLATRN 9606 1324926 YES lperfetto After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314 0.2 SIGNOR-17312 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1337 QVFYNSEyGELSEPS 9606 20431062 YES lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. 0.511 SIGNOR-165043 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione chemical CHEBI:74947 ChEBI CRBN protein Q96SW2 UNIPROT up-regulates activity chemical activation 9606 20223979 YES gcesareni We identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks 0.8 SIGNOR-234786 GATA1 protein P15976 UNIPROT SPTA1 protein P02549 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10037687 NO Regulation of expression miannu GATA-1 and CACCC-related Proteins Are Both Major Activators of the Human Erythroid β-Spectrin Gene Promoter 0.378 SIGNOR-251928 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity acetylation 9606 22298955 YES gcesareni Bmp-induced non-smad erk signaling pathway cooperatively regulates osteoblast differentiation, in part, through increasing the stability and transcriptional activity of runx2 or increasing runx2 acetylation by p300. 0.453 SIGNOR-195579 HTR2C protein P28335 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257295 ECM stimulus SIGNOR-ST20 SIGNOR Av/b2 integrin complex SIGNOR-C176 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259054 HTR1A protein P08908 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.493 SIGNOR-256693 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120180 MITF protein O75030 UNIPROT DCT protein P40126 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22371403 NO miannu MITF transcription factor regulates melanogenesis by activation of tyrosinase, TRP1 and TRP2 transcription. 0.461 SIGNOR-254592 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.708 SIGNOR-249643 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser60 RLPGRSTsLVEGRSC -1 14688255 YES miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. 0.698 SIGNOR-250155 PKA proteinfamily SIGNOR-PF17 SIGNOR SEC14L2 protein O76054 UNIPROT up-regulates activity phosphorylation Ser289 VQISRGSsHQVEYEI -1 15680919 YES miannu These results suggest that phosphorylation of SPF by PKA is a dynamic process and that, in the absence of PKA activity, SPF is rapidly inactivated.Thus, phosphorylation of SPF at Ser-289 appears necessary for maximal stimulation of squalene monooxygenase activity in vitro and absolutely required for the stimulation of cholesterol synthesis in cell culture. 0.2 SIGNOR-276028 RPL31 protein P62899 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.865 SIGNOR-262469 ACVR1B protein P36896 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 14517293 YES gcesareni ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway 0.74 SIGNOR-235160 KDM2A protein Q9Y2K7 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates demethylation 9606 20080798 YES lperfetto Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. 0.46 SIGNOR-217415 SOX17 protein Q9H6I2 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity 10090 33083751 NO SimoneGraziosi Sox17 prevents beta-catenin activation by increasing its phosphorylation, particularly in WM lesions 0.685 SIGNOR-269268 SKP2 protein Q13309 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 10790373 YES miannu  Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3. 0.92 SIGNOR-272567 TTK protein P33981 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 15618221 YES lperfetto Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage 0.292 SIGNOR-132665 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser518 GEDPYAGsTDENTDS 9606 20471329 YES lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 0.396 SIGNOR-165423 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 24614225 YES lperfetto Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity. 0.2 SIGNOR-25334 MYOG protein P15173 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates binding 9606 BTO:0001103 17194702 YES lperfetto Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle 0.321 SIGNOR-217740 PHLPP2 protein Q6ZVD8 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001544 19261608 YES The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. 0.772 SIGNOR-248728 CHUK protein O15111 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 BTO:0000567 SIGNOR-C14 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation 0.896 SIGNOR-52875 NEDD4 protein P46934 UNIPROT N4BP1 protein O75113 UNIPROT up-regulates activity monoubiquitination 9606 17114934 YES miannu This observation, together with the monoubiquitination of Nedd4-BP1 by the ubiquitin ligase Nedd4 suggests that the NYN domain proteins of eukaryotes are regulated by monoubiquitination. Given the localization of Nedd4-BP1 to punctuate nuclear bodies, it is likely that they are parts of nuclear RNA-processing complexes that are dependent on monoubiquitination for their assembly. 0.448 SIGNOR-272626 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 YES gcesareni These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor. 0.653 SIGNOR-252555 MACF1 protein Q9UPN3 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity 9606 BTO:0000938 16815997 NO lperfetto In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes. 0.402 SIGNOR-228000 IRS1 protein P35568 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 10116 BTO:0001103 21798082 YES lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2). 0.813 SIGNOR-175668 IFNB1 protein P01574 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates activity binding 9534 BTO:0004055 11278538 YES lperfetto Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.866 SIGNOR-219301 ELP3 protein Q9H9T3 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 YES miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. 0.807 SIGNOR-269710 NEK6 protein Q9HC98 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Ser608 VLKNLNNsNLFSPVN -1 21335236 YES done miannu To elucidate which of the identified sites can be targeted by CDK1/cyclin B1 and Nek6 in vitro (Figure S1D), we performed phosphorylation reactions using recombinant kinases and unlabeled ATP followed by phosphopeptide mapping (Table S1). MS analysis confirmed phosphorylation of S591 and S822 by Nek6 as well as phosphorylation of T529, T536, S595, S606, and T653 by CDK1. Phosphomimetic Mutants of Nup98 Show Defects in NPC Localization 0.315 SIGNOR-273892 RUNX2 protein Q13950 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 20740684 YES Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1-IC-RBP-Jk complex gcesareni Runx2 is an inhibitor of the notch1 signaling pathway during normal osteoblast differentiation. The n-terminal domain of runx2 was crucial to the binding and inhibition of the the n-terminus of the notch1 intracellular domain. 0.381 SIGNOR-167627 WNT9A protein O14904 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 YES gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. 0.2 SIGNOR-195972 RBCK1 protein Q9BYM8 UNIPROT BACH1 protein O14867 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 17682061 YES miannu HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process. 0.345 SIGNOR-236971 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr252 EAYPEEAyIADLDAK 9606 BTO:0000007 32420483 YES done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. 0.265 SIGNOR-274109 Av/b8 integrin complex SIGNOR-C185 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.584 SIGNOR-257730 CSNK2A1 protein P68400 UNIPROT NOL3 protein O60936 UNIPROT up-regulates activity phosphorylation Thr149 SEAVQSGtPEEPEPE 9606 BTO:0000007 12191471 YES miannu Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm. 0.324 SIGNOR-262837 PAS complex complex SIGNOR-C190 SIGNOR 1,2-dioctanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-bisphosphate)(5-) smallmolecule CHEBI:85342 ChEBI up-regulates quantity chemical modification -1 17556371 YES miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. we demonstrate a central function for each component of the core protein machinery for PtdIns(3,5)P2 synthesis and turnover in the formation/detachment (or maturation) of transport vesicle intermediates from early endosomes. 0.8 SIGNOR-253531 MLH1 protein P40692 UNIPROT MLH1/PMS2 complex SIGNOR-C59 SIGNOR form complex binding 9606 10542278 YES miannu Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_ 0.758 SIGNOR-71771 Ub:E2 complex SIGNOR-C497 SIGNOR HERC6 protein Q8IVU3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271295 gemfibrozil chemical CHEBI:5296 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 21889235 YES Luana  The combination of stilbene scaffold and gemfibrozil enhances the PPARα agonistic activity. 0.8 SIGNOR-258318 DAB2IP protein Q5VWQ8 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates activity binding 9606 27858941 YES miannu DAB2IP binds the p85 subunit of PI3K through its PR domain and prevents PI3K-p85 relocation from the cytoplasm to the membrane, a necessary step for PI3K activation and signaling to AKT. Notably, DAB2IP reinforces this inhibitory effect by directly binding AKT.2 0.283 SIGNOR-254757 IL4R protein P24394 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 YES milica Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2. 0.591 SIGNOR-100771 PPP2R5A protein Q15172 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 9774674 YES gcesareni In this report, we show that another wd-40 repeat protein, the balpha subunit of protein phosphatase 2a, associates with the cytoplasmic domain of type i tgf-beta receptors..[..] Furthermore, balpha enhances the growth inhibition activity of tgf-beta in a receptor-dependent manner 0.262 SIGNOR-60743 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 19914168 YES lpetrilli In contrast, ERK2 phosphorylated all four Smad1 residues almost evenly, while showing a preference for S204 over S208 and S213 in Smad3 0.745 SIGNOR-161698 MAPK8 protein P45983 UNIPROT STAT6 protein P42226 UNIPROT down-regulates phosphorylation Ser707 IPPYQGLsPEESVNV 9606 21123173 YES llicata Deactivation of stat6 through serine 707 phosphorylation by jnk. 0.353 SIGNOR-170153 HCRTR2 protein O43614 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257124 UBXN2B protein Q14CS0 UNIPROT AURKA protein O14965 UNIPROT down-regulates activity binding 6239 23649807 YES lperfetto The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts 0.305 SIGNOR-265042 SAGA complex complex SIGNOR-C465 SIGNOR H3Y2 protein P0DPK5 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269632 PIM2 protein Q9P1W9 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by stabilization phosphorylation Thr454 RAPIIAVtRNPQTAR 9606 24142698 YES Manara Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. 0.371 SIGNOR-260905 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR IREB2 protein P48200 UNIPROT down-regulates phosphorylation Ser157 LQKAGKLsPVKVQPK 9606 18574241 YES lperfetto Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity 0.353 SIGNOR-216888 TFE3 protein P19532 UNIPROT CTSA protein P10619 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.2 SIGNOR-276815 PFDN6 protein O15212 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 YES miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) 0.942 SIGNOR-270930 SHH protein Q15465 UNIPROT PTCH2 protein Q9Y6C5 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 YES lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. 0.802 SIGNOR-217776 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 18758450 YES lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. 0.429 SIGNOR-236119 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR WNK1 protein Q9H4A3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23838290 YES miannu We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body. 0.321 SIGNOR-272124 FGD5 protein Q6ZNL6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.2 SIGNOR-260555 GCG protein P01275 UNIPROT GLP1R protein P43220 UNIPROT up-regulates binding 9606 BTO:0000776 7937318 YES gcesareni In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin 0.782 SIGNOR-34855 RRAGB protein Q5VZM2 UNIPROT RAGBC complex SIGNOR-C115 SIGNOR form complex binding 9606 20381137 YES gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant 0.792 SIGNOR-228176 CHKA protein P35790 UNIPROT choline phosphate(1-) smallmolecule CHEBI:295975 ChEBI up-regulates quantity chemical modification 27149373 YES lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes 0.8 SIGNOR-275636 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GTF2I protein P78347 UNIPROT up-regulates phosphorylation 9606 10648599 YES inferred from 70% family members lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. 0.2 SIGNOR-270169 acetylsalicylic acid chemical CHEBI:15365 ChEBI PTGS1 protein P23219 UNIPROT down-regulates chemical inhibition 9606 11809688 YES gcesareni Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects. 0.8 SIGNOR-114377 FBXO22 protein Q8NEZ5 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates binding 9606 BTO:0000007 28117675 YES miannu FBXO22 mediates poly-ubiquitination and degradation of CD147. Classically, F-box protein together with Skp1 and Cullin 1 constitute Skp-Cullin-F box ubiquitin E3 ligase (SCFs) 0.585 SIGNOR-272788 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 12421349 YES The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax 0.267 SIGNOR-95487 NFIX protein Q14938 UNIPROT NEUROD4 protein Q9HD90 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268905 SRGAP1 protein Q7Z6B7 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.559 SIGNOR-260515 HNF1B protein P35680 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity binding 9606 BTO:0000007 9671480 YES 2 miannu The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays. 0.307 SIGNOR-241320 HSP90AA1 protein P07900 UNIPROT PAFAH1B1 protein P43034 UNIPROT up-regulates quantity by stabilization binding 9606 20133715 YES miannu The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability. 0.521 SIGNOR-252168 DPYD protein Q12882 UNIPROT uracil smallmolecule CHEBI:17568 ChEBI down-regulates quantity chemical modification 10499634 YES Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil. 0.8 SIGNOR-253988 CDK3 protein Q00526 UNIPROT CyclinC/CDK3 complex SIGNOR-C545 SIGNOR form complex binding 9606 BTO:0004173 25344755 YES lperfetto Cyclin C was cloned as a growth-promoting G1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumor suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase, as well as CDK8 and CDK3. 0.68 SIGNOR-273157 STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 10090 24948596 NO IL-4 was shown to inhibit lipid accumulation in adipose tissue by a mechanism that includes activation of Stat6, which suppresses PPARα transcriptional activity 0.515 SIGNOR-254682 CyclinY/CDK16 complex SIGNOR-C540 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 NVRVSNGsPSLERMD 9606 BTO:0000567 25205104 YES lperfetto In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells.|Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target. 0.333 SIGNOR-273012 NFATC2 protein Q13469 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000776 11163226 NO scontino In this study, the roles of NFATc1 and NFATc2 in T and B cells were examined. These results further characterize NFAT as a transcription factor family that plays a critical role in the regulation of lymphocyte effector differentiation. 0.7 SIGNOR-270538 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 YES gcesareni Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase. 0.685 SIGNOR-33197 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1152 SERLKRTsQKVDLAL 9606 15590641 YES gcesareni Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites. 0.2 SIGNOR-132247 IFIH1 protein Q9BYX4 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 YES miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. 0.813 SIGNOR-260140 PTPRJ protein Q12913 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity dephosphorylation 9606 21262971 YES miannu Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation. 0.491 SIGNOR-277092 TGFBR1 protein P36897 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity 9606 19726546 YES lperfetto Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity. 0.638 SIGNOR-227499 RPS6KA3 protein P51812 UNIPROT KCNK3 protein O14649 UNIPROT up-regulates activity phosphorylation Ser393 GLMKRRSsV 9606 21357689 YES gcesareni The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c. 0.2 SIGNOR-172470 MAPK1 protein P28482 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr386 IGLNQPStPTHAAGV 9606 10567369 YES lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 0.75 SIGNOR-236498 CDK5 protein Q00535 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates phosphorylation Ser400 IHKVILGsPAHRAGL 9606 21701498 YES lperfetto Here we report that cyclin-dependent kinase-5 (cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating htra2 at s400.We have shown previously that phosphomimetic mutants of htra2 at s400 result in increased proteolytic activity and contribute to enhanced resistance to mitochondrial stress 0.457 SIGNOR-174598 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10673501 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-75025 wortmannin chemical CHEBI:52289 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates chemical inhibition 9534 BTO:0001444 22253445 YES lperfetto From these results, we conclude that LY294002 and wortmannin inhibit SARS pseudovirus entry by targeting PI4KB and that PI4KB is involved in SARS-CoV S-mediated entry into VeroE6 cells. 0.8 SIGNOR-260730 PIK3CG protein P48736 UNIPROT TPM2 protein P07951 UNIPROT up-regulates activity phosphorylation Ser61 EDEVEKYsESVKEAQ -1 16094730 YES miannu Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization. 0.335 SIGNOR-263028 CSNK2A1 protein P68400 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser358 AKVLASLsDDEDEEE 9606 16428860 YES lperfetto Phosphorylation of rangap1 stabilizes its interaction with ran and ranbp1. Serine-358 (358s) was identified as the major phosphorylation site. Experiments using purified recombinant kinase and specific inhibitors such as drb and apigenin strongly suggest that casein kinase ii (ck2) is the responsible kinase 0.311 SIGNOR-143948 EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 23584478 YES lperfetto The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1). 0.939 SIGNOR-167176 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 15952796 YES inferred from 70% family members lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation 0.2 SIGNOR-270178 DCAF4 protein Q8WV16 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0004297 30945288 YES miannu We found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). 0.564 SIGNOR-272308 bradykinin smallmolecule CHEBI:3165 ChEBI BDKRB1 protein P46663 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257464 CSNK1E protein P49674 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser314 SREQSTDsGLGLGCY 9606 24715453 YES milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) 0.364 SIGNOR-230747 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR PIK3R2 protein O00459 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23604317 YES miannu  FBXL2 interacts with the pool of p85β that is free of p110 PI(3)K catalytic subunits and targets this pool for ubiquitylation and subsequent proteasomal degradation.This result suggests that FBXL2 localization to cell membranes facilitates substrate binding, which in turn stimulates CUL1 neddylation and activation of ubiquitin ligase activity. 0.25 SIGNOR-271938 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.2 SIGNOR-262980 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr154 QLNDSAAyYLNDLDR -1 33139573 YES miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. 0.462 SIGNOR-277227 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 24449215 NO miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 0.2 SIGNOR-255970 SF3A3 protein Q12874 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 YES miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. 0.974 SIGNOR-263949 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.748 SIGNOR-248632 DOK1 protein Q99704 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.297 SIGNOR-257685 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser358 ELRKTQTsMSLGTTR -1 24012422 YES gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays 0.753 SIGNOR-266439 C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg751 HKDMQLGrLHMKTLL 9606 BTO:0000089 26489954 YES lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). 0.557 SIGNOR-263482 BMP7 protein P18075 UNIPROT UCP1 protein P25874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18719589 NO fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways 0.428 SIGNOR-180354 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR ELK1 protein P19419 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23940030 YES miannu The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1 protein. FBXO25 is one of the 69 known human F-box proteins that serve as specificity factors for a family of ubiquitin ligases composed of SKP1, Rbx1, Cullin1, and F-box protein (SCF1) that are involved in targeting proteins for degradation across the ubiquitin proteasome system. FBXO25 interacted with and mediated the ubiquitination and proteasomal degradation of ELK-1 in HEK293T cells. 0.2 SIGNOR-272129 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC3R protein P41968 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257537 TRiC complex SIGNOR-C539 SIGNOR Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.2 SIGNOR-272868 STX16 protein O14662 UNIPROT LE-TGN SNARE complex SIGNOR-C157 SIGNOR form complex binding 9606 BTO:0000567 18195106 YES lperfetto We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport 0.805 SIGNOR-253079 STUB1 protein Q9UNE7 UNIPROT NRK protein Q7Z2Y5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 32162334 YES miannu Our results indicate that Nrk is ubiquitinated by CHIP in a chaperone-dependent manner, resulting in its proteasomal degradation. 0.2 SIGNOR-274110 tolazoline chemical CHEBI:28502 ChEBI ADRA2B protein P18089 UNIPROT down-regulates activity chemical inhibition 9606 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258913 ARHGAP40 protein Q5TG30 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.408 SIGNOR-260497 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 YES gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required 0.594 SIGNOR-38029 TPH2 protein Q8IWU9 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity chemical modification 9606 31024440 YES brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. 0.8 SIGNOR-264012 ID3 protein Q02535 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR down-regulates activity binding 10090 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.447 SIGNOR-241155 PTPRZ1 protein P23471 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity dephosphorylation Tyr1105 RNEEENIySVPHDST 10090 BTO:0000601 16513268 YES Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP| Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo. 0.417 SIGNOR-248451 FLT3 protein P36888 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15498859 NO Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. 0.42 SIGNOR-261519 PPARGC1A protein Q9UBK2 UNIPROT PCK2 protein Q16822 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.395 SIGNOR-255060 CSNK1G3 protein Q9Y6M4 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1493 NPPPSPAtERSHYTM 9606 35487243 YES miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 0.288 SIGNOR-275401 GRPR protein P30550 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257247 HMGB1 protein P09429 UNIPROT HOXB1 protein P14653 UNIPROT up-regulates activity binding -1 8890171 YES miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. 0.298 SIGNOR-219853 ROCK1 protein Q13464 UNIPROT MPRIP protein Q6WCQ1 UNIPROT down-regulates phosphorylation 9606 17761936 YES gcesareni Enhanced rho kinase activity induces endothelial barrier dysfunction by a contractile mechanism via inactivation of myosin phosphatase (mp).. 0.296 SIGNOR-157593 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser746 AMRFARRsVSDNDIR 9606 BTO:0000150 16551632 YES llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I 0.2 SIGNOR-145288 AKT2 protein P31751 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15531580 YES llicata Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression 0.375 SIGNOR-130260 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr713 REEADGVyAASGGLR 9606 8663427 YES llicata Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713. 0.2 SIGNOR-42655 DAPK1 protein P53355 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates phosphorylation Thr119 LSRRLKVtGDLFDIM 9606 19395874 YES gcesareni We found that DAPk phosphorylates Beclin 1 on T119, a critical residue within its BH3 domain, and thus promotes Beclin 1 dissociation from Bcl-X(L) and autophagy induction. Here we report that T119 phosphorylation also reduces the interaction between Beclin 1 and Bcl-2, in line with the high degree of structural homology between the BH3 binding pockets of Bcl-2 and Bcl-X(L) proteins. 0.726 SIGNOR-185589 RPS6KB1 protein P23443 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 7838153 YES gcesareni Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii. 0.594 SIGNOR-34117 PRKCA protein P17252 UNIPROT PTGIR protein P43119 UNIPROT unknown phosphorylation Ser328 TPLSQLAsGRRDPRA 9606 BTO:0000007 9722557 YES lperfetto These results indicate that PKC-dependent phosphorylation is of critical importance to homologous regulation of hIP. Ser-328 is a primary site for PKC phosphorylation of hIP. 0.324 SIGNOR-249011 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 YES miannu In vitro phosphorylation and activation of p70β by mTOR and PDK1. replacement of Ser383 to Gly (S383G) reduced but still retained nearly half of the kinase activity of the wild-type. 0.834 SIGNOR-250293 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr250 PFLLDEDyEKVLGYV BTO:0000007 12540842 YES lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2. 0.343 SIGNOR-249371 CHFR protein Q96EP1 UNIPROT PBK protein Q96KB5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 24012691 YES miannu CHFR ubiquitinates and degrades TOPK. Our in vivo ubiquitination assays revealed that the polyubiquitination of TOPK occurs only in the presence of full length CHFR but not with the ΔRING or Δcysteine-rich domain deletion mutants (Fig. 2a). 0.347 SIGNOR-271471 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K12 protein Q12852 UNIPROT up-regulates binding 9606 BTO:0000938 11416147 YES gcesareni One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks 0.377 SIGNOR-108577 KLF3 protein P57682 UNIPROT CEBPA protein P49715 UNIPROT down-regulates transcriptional regulation 9606 18391014 NO fspada We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice. 0.3 SIGNOR-210117 LMO3 protein Q8TAP4 UNIPROT NHLH2 protein Q02577 UNIPROT up-regulates activity binding 9606 21573214 YES miannu Here we found that LMO3 forms a complex with HEN2 and acts as an upstream mediator for transcription of Mash1 in neuroblastoma. 0.412 SIGNOR-254827 AKT1 protein P31749 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 NO lperfetto Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1. 0.6 SIGNOR-79338 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273071 GATA3 protein P23771 UNIPROT CEBPB protein P17676 UNIPROT down-regulates binding 10090 15632071 YES fspada In the present study, we demonstrate that both gata-2 and gata-3 form protein complexes with ccaat/enhancer binding protein alpha (c/ebpalpha) and c/ebpbeta, members of a family of transcription factors that are integral to adipogenesis. []the interaction between gata and c/ebp factors is critical for the ability of gata to suppress adipocyte differentiation. 0.352 SIGNOR-132952 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr219 SIQGHNDyMCPATNQ 9606 BTO:0000150 20101225 YES gcesareni Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes. 0.447 SIGNOR-163562 PIP3 smallmolecule CHEBI:16618 ChEBI AKT3 protein Q9Y243 UNIPROT up-regulates chemical activation 9606 21779497 YES gcesareni When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival. 0.8 SIGNOR-175250 adapalene chemical CHEBI:31174 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9606 BTO:0000404 30836068 YES miannu Adapalene, the third-generation synthetic retinoid,selectively bound to specific RAR, thus activating genes responsible forcellular differentiation. It showed greatest affinity for subtypes RARβindermalfibroblasts (Kd value 34 nM) and RARγin the epidermis (Kdvalue 130 nM) 0.8 SIGNOR-258487 LPCAT1 protein Q8NF37 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI up-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272760 SAGA complex complex SIGNOR-C465 SIGNOR H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269635 MAP3K7 protein O43318 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity phosphorylation 10094049 YES lperfetto The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway|Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway. 0.562 SIGNOR-262833 MET-enkephalin smallmolecule CHEBI:6618 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257554 SEMA3B protein Q13214 UNIPROT NRP1 protein O14786 UNIPROT up-regulates activity binding 9606 25335892 YES miannu Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction. 0.753 SIGNOR-261814 GDF6 protein Q6KF10 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 16049014 YES lperfetto We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins. 0.6 SIGNOR-217526 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000567 15718470 YES gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. 0.748 SIGNOR-252612 KLHL2 protein O95198 UNIPROT WNK1 protein Q9H4A3 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23838290 YES miannu We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body. 0.47 SIGNOR-272119 GPR65 protein Q8IYL9 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 27287411 YES GPR65 is playing a critical role in phagocytic cells that require high levels of V-ATPase activity to maintain phagosomal and lysosomal pH, and this activity aids in the direct clearance of enteric pathogens. 0.271 SIGNOR-272502 AIMP1 protein Q12904 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9606 18448069 YES lperfetto Here, we report that AIMP1 negatively regulates TGF-_ signaling via stabilization of Smurf2. 0.391 SIGNOR-227470 PCDHA4 protein Q9UN74 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265665 Substance P smallmolecule CHEBI:80308 ChEBI TACR1 protein P25103 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257586 ethanol chemical CHEBI:16236 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 8355 BTO:0000964 8700149 YES inferred from family member miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. 0.8 SIGNOR-267794 PRKAA1 protein Q13131 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 SIGNOR-C15 12065600 YES llicata Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro. 0.398 SIGNOR-89760 afimoxifene chemical CHEBI:44616 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258595 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Thr23 ESPPVSDtPDEGDEP 9606 BTO:0001271 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo 0.29 SIGNOR-174836 KDM6A protein O15550 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys28 LATKAARkSAPATGG 9606 24561908 YES This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. 0.2 SIGNOR-260017 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 23431053 YES gcesareni Here, we report that phlpp1 is a binding protein for mst1 and it modulates the hippo pathway by dephosphorylating mst1 at the inhibitory thr(387) of mst1. 0.295 SIGNOR-201262 ESR1 protein P03372 UNIPROT CRH protein P06850 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000614 8408641 YES lperfetto Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. 0.341 SIGNOR-268721 PTEN protein P60484 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity 9606 18794881 NO lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). 0.731 SIGNOR-209856 ZWINT protein O95229 UNIPROT KNL1 complex complex SIGNOR-C363 SIGNOR form complex binding 27881301 YES lperfetto KNL1C (known as Spc105 complex in S. cerevisiae) contains the KNL1 and ZWINT subunits. 0.2 SIGNOR-265194 TP53 protein P04637 UNIPROT ZDHHC5 protein Q9C0B5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28775165 YES Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y 0.2 SIGNOR-261150 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR ERP44 protein Q9BS26 UNIPROT up-regulates 9606 11847130 NO miannu Like many ER folding factors, ERp44 transcripts are induced by agents that cause the accumulation of unfolded proteins in the ER. 0.7 SIGNOR-261047 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16882717 YES lpetrilli In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes. 0.497 SIGNOR-148396 C1S protein P09871 UNIPROT Complement C1 complex complex SIGNOR-C309 SIGNOR form complex binding -1 29449492 YES lperfetto The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases 0.707 SIGNOR-263394 PRKCH protein P24723 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by stabilization 9606 28939105 NO miannu The results of our present study show that PKCη positively regulates the anti-apoptotic Bcl-2 family protein Mcl-1 by preventing its degradation via the proteasomal pathway involving Mcl-1 ubiquitin ligase Mule. 0.2 SIGNOR-261908 MCF2 protein P10911 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.753 SIGNOR-260556 SMURF1 protein Q9HCE7 UNIPROT C7orf50 protein Q9BRJ6 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272693 NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 NO IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production 0.51 SIGNOR-254502 PDPK2P protein Q6A1A2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 15505410 YES gcesareni Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2. 0.2 SIGNOR-129965 CDK1 protein P06493 UNIPROT MAPK3 protein P27361-3 UNIPROT up-regulates activity phosphorylation Ser343 PTDEVGQsPAAVGLG 9606 26459638 YES miannu  We found that CDK1 phosphorylates Ser343 of ERK1c, thereby allowing the binding of phosphorylated ERK1c to a complex that consists of PI4KIIIβ (also known as PI4KB) and the 14-3-3γ dimer (encoded by YWHAB).  0.315 SIGNOR-277185 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser381 GYSFVAPsILFKRNA 9606 15568999 YES lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. 0.2 SIGNOR-131395 TUBGCP3 protein Q96CW5 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 YES lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” 0.781 SIGNOR-262327 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1044 YPFVRTGsPRRIQLS 9606 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. site-directed mutagenesis of s1044 to an alanine resulted in the specific loss of d5 when this mutant was ectopically expressed in t98g cells and labelled by [32p]orthophosphate (figure 4b), proving that phosphorylation of s1044 gave rise to the tryptic phosphopeptide d5: tgspr. 0.849 SIGNOR-104660 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.32 SIGNOR-161569 PLK1 protein P53350 UNIPROT OPTN protein Q96CV9 UNIPROT up-regulates phosphorylation Ser177 SSGSSEDsFVEIRMA 9606 22365832 YES lperfetto Here we show that at mitotic entry, plk1 phosphorylates optineurin (optn) at serine 177 and that this dissociates optn from the golgi-localized gtpase rab8, inducing its translocation into the nucleus. 0.538 SIGNOR-196367 EGLN3 protein Q9H6Z9 UNIPROT ADRB2 protein P07550 UNIPROT up-regulates quantity by stabilization hydroxylation Pro395 VGHQGTVpSDNIDSQ 9606 BTO:0000007 19584355 YES lperfetto We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation. 0.318 SIGNOR-262007 CSNK1A1 protein P48729 UNIPROT LGALS3 protein P17931 UNIPROT up-regulates phosphorylation Ser6 sLHDALSG 9606 BTO:0000150 15121858 YES llicata These results indicate that phosphorylation of gal-3 promotes its nuclear export after apoptotic stimuli through enhanced nuclear export. 0.309 SIGNOR-124583 SP3 protein Q02447 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 15708372 YES We characterized four Sp1/Sp3 binding sites in the proximal promoter of the PSA gene. In a luciferase assay, these sites contributed to the basal promoter activity in prostate cancer cells. In an electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we confirmed that Sp1 and Sp3 bind to these sites. Overexpression of wild-type Sp1 and Sp3 further upregulated the promoter activity, whereas overexpression of the Sp1 dominant-negative form or addition of mithramycin A significantly reduced the promoter activity and the endogenous mRNA level of PSA. 0.2 SIGNOR-253665 PRKCA protein P17252 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity phosphorylation Ser262 SGFVQSDsKRESVCN 23195996 YES lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] 0.2 SIGNOR-275672 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL2 protein P13500 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 NO Both NF-κBs bind to a conserved DNA motif (80) that is found in numerous IL-1–responsive genes, in particular the ones encoding IκBα (81), IL-6 (82), IL-8 (18, 83,84), monocyte chemoattractant protein 1 (MCP1) (28), and cyclooxygenase 2 (COX2) 0.579 SIGNOR-254509 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation 9606 16751101 YES lperfetto Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. 0.667 SIGNOR-217628 EGFR protein P00533 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 10026169 YES esanto Growth factor binding to receptor protein tyrosine kinases (r-ptks)1 induces their dimerization and trans-phosphorylation, creating docking sites for proteins containing sh2 and ptb protein interaction domains. Nck binds to the pdgf and egfr receptors (figure 3c). 0.399 SIGNOR-64731 FAM8A1 protein Q9UBU6 UNIPROT SYVN1 protein Q86TM6 UNIPROT up-regulates activity binding 9606 BTO:0000007 28827405 YES miannu FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp 0.579 SIGNOR-261348 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -1 2413024 YES lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 0.49 SIGNOR-248875 SB 505124 chemical CHEBI:100922 ChEBI ACVR1B protein P36896 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206736 CDC14B protein O60729 UNIPROT USP9X protein Q93008 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser2547 YEGSEEVsPPQTKDQ 32152317 YES Phosphosites were derived from Figure S1 lperfetto Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. 0.2 SIGNOR-275613 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser174 LESSPTAsGSSVSPG 9606 BTO:0000567 35469017 YES miannu CDK1–cyclin B1 mediates KIND1 and KIND2 phosphorylation at mitotic entry . MS of KIND1 and KIND2 immunoprecipitates from STLC-arrested HeLa cells confirmed the phosphorylation of KIND1-S179 and KIND2-S181 and revealed phosphorylation of closely adjacent serine residues (KIND1: SSphS174GphS176PVphS179PGLYSK; KIND2: GphS175GphS177IYphS180phS181PGLYSK), although to a weaker extent (Supplementary Table 2). 0.2 SIGNOR-276719 UNC5 proteinfamily SIGNOR-PF98 SIGNOR DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 YES miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. 0.2 SIGNOR-268168 BLOC-1 complex SIGNOR-C381 SIGNOR serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity relocalization 9606 23805129 YES lperfetto The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules 0.8 SIGNOR-265999 CDK5 protein Q00535 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity phosphorylation Thr212 VIEPLPVtPTRDVAT 9534 BTO:0004055 11604394 YES lperfetto Our previous work revealed that the neuronal p35/Cdk5 kinase associates with Pak1 in a RacGTP-dependent manner, causing hyperphosphorylation and down-regulation of Pak1 kinase activity. We have now demonstrated direct phosphorylation of Pak1 on threonine 212 by the p35/Cdk5 kinase. 0.538 SIGNOR-249328 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr680 IEDSREAtHSSGFSG 9606 23079597 YES lperfetto Phosphorylation of kard by plk1 promotes direct interaction of bubr1 with the pp2a-b56_ phosphatase that counters excessive aurora b activity at kinetochores. We propose that plk1 and bubr1 cooperate to stabilize kinetochore-microtubule interactions. Phosphorylation of t680 by plk1 is essential for kard function 0.84 SIGNOR-199222 CSNK1D protein P48730 UNIPROT TOP2B protein Q02880 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1132 QNQHDDSsSDSGTPS 9606 32015321 YES miannu Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.CK1 binds with and phosphorylates TOP2β at Ser1130 to promote its degradation by VM-26. 0.2 SIGNOR-277509 GSK3B protein P49841 UNIPROT BCL2L12 protein Q9HB09 UNIPROT up-regulates phosphorylation Ser156 SESPRPCsLPIRPCY 9606 BTO:0000527 22262180 YES lperfetto Gsk3b phosphorylates bcl2l12 at s156. Ectopic expression of gfp-fused bcl2l12 or bcl2l12a in u87mg cells leads to repression of apoptotic markers and protects against staurosporine (sts) insults, indicating an antiapoptotic role for both bcl2l12 and bcl2l12a. In contrast, no anti-apoptotic ability was seen in bcl2l12(s156a) 0.338 SIGNOR-195512 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity relocalization 9606 16890161 YES amattioni The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism. 0.834 SIGNOR-148668 NR1I3 protein Q14994 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 NO miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. 0.446 SIGNOR-254438 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates activity dephosphorylation Ser2 sFRKVVRQ 9606 17350576 YES Coronin 1B inhibits filament nucleation by Arp2/3 complex and this inhibition is attenuated by phosphorylation of Coronin 1B at Serine 2, a site targeted by SSH1L. Coronin 1B also directs SSH1L to lamellipodia where SSH1L likely regulates Cofilin activity via dephosphorylation 0.447 SIGNOR-248763 MRAP2 protein Q96G30 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. 0.506 SIGNOR-252367 TLN1 protein Q9Y490 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.587 SIGNOR-257616 THBS2 protein P35442 UNIPROT CD47 protein Q08722 UNIPROT up-regulates binding 9606 8550562 YES gcesareni We report here that iap is a receptor for the ts1 cbd and its vvm-containing peptides and that a function-blocking anti-iap mab inhibits the chemotactic response to ts1 and its cbd peptides in endothelial cells. 0.591 SIGNOR-39749 MMP13 protein P45452 UNIPROT FGB protein P02675 UNIPROT down-regulates quantity by destabilization cleavage Arg124 LQQERPIrNSVDELN -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain 0.2 SIGNOR-263615 KAT2B protein Q92831 UNIPROT H3Y1 protein P0DPK2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269614 KASH5 protein Q8N6L0 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.2 SIGNOR-263290 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7737130 YES gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. 0.779 SIGNOR-32421 HRK protein O00198 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates binding 9606 9130713 YES gcesareni Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1. 0.604 SIGNOR-47797 CAMK2A protein Q9UQM7 UNIPROT HOMER proteinfamily SIGNOR-PF59 SIGNOR down-regulates activity phosphorylation -1 18480293 YES miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation 0.396 SIGNOR-264699 SP1 protein P08047 UNIPROT GGH protein Q92820 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31739835 YES miannu Overexpression of Sp1 led to enhanced GGH promoter activity and GGH mRNA expression in allele-specific manners. These findings suggested that Sp1 acted as a positive regulator of human GGH transcription through the rs3758149 polymorphism in CEM/C1 cells. 0.2 SIGNOR-261350 a7/b1 integrin complex SIGNOR-C126 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269007 MYF5 protein P13349 UNIPROT DES protein P17661 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 8382796 YES lperfetto Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression 0.241 SIGNOR-241494 LATS2 protein Q9NRM7 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity phosphorylation Thr178 VYHYRINtASDGKLY -1 23852372 YES miannu  Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl.  Lats2 phosphorylates c-Abl at Thr197 in vitro. 0.362 SIGNOR-276497 MAP3K6 protein O95382 UNIPROT MAP3K6 protein O95382 UNIPROT up-regulates activity phosphorylation Thr806 GITPCTEtFTGTLQY 9606 17210579 YES Manara These results suggested that the induction of ASK2 phosphorylation in the presence of ASK1 is the consequence of autophosphorylation of ASK2. ASK1 thus appears to not only support the effective protein expression but also confer the kinase activity to ASK2. 0.2 SIGNOR-260774 SRC protein P12931 UNIPROT ARHGAP5 protein Q13017 UNIPROT up-regulates activity phosphorylation Tyr1109 KGYSDEIyVVPDDSQ -1 9819392 YES miannu Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. Phosphorylation of Y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-Src than by the EGF receptor and was efficiently catalyzed by c-Src in vitro, indicating that Y1105 is a selective and preferential target of c-Src both in vitro and in vivo. 0.606 SIGNOR-276170 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARRB2 protein P32121 UNIPROT up-regulates activity phosphorylation Ser14 TRVFKKSsPNCKLTV 10090 BTO:0002572 26324936 YES done miannu ERK1/2-dependent βarr2 phosphorylation on S14 and T276 induces CXCR4 intracellular sequestration. 0.2 SIGNOR-274018 TLN1 protein Q9Y490 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.653 SIGNOR-257622 Ndc80 complex complex SIGNOR-C361 SIGNOR KMN network complex SIGNOR-C366 SIGNOR form complex binding 18007590 YES lperfetto The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, 0.2 SIGNOR-265218 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser122 NIIHGSDsVESAEKE -1 8810265 YES miannu For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. 0.2 SIGNOR-250301 FILIP1L protein Q4L180 UNIPROT FLNC protein Q14315 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000165 32444788 YES miannu We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. 0.252 SIGNOR-262618 tRNA(Pro) smallmolecule CHEBI:29177 ChEBI Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270433 DOCK3 protein Q8IZD9 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.655 SIGNOR-260548 tadalafil chemical CHEBI:71940 ChEBI PDE11A protein Q9HCR9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000815 21189023 YES Luana All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11 0.8 SIGNOR-257888 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2K protein P61086 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.757 SIGNOR-271367 VCP protein P55072 UNIPROT AURKA protein O14965 UNIPROT down-regulates activity binding 6239 23649807 YES lperfetto The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts 0.314 SIGNOR-265044 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192814 EGR1 protein P18146 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 BTO:0001412 1864967 NO irozzo Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes. 0.7 SIGNOR-256088 CDK1 protein P06493 UNIPROT KIF11 protein P52732 UNIPROT up-regulates phosphorylation Thr926 LDIPTGTtPQRKSYL 9606 9235942 YES lperfetto The kinesin-related motor hseg5 is essential for centrosome separation, and its association with centrosomes appears to be regulated by phosphorylation of tail residue threonine 927 by the p34(cdc2) protein kinase.Phosphorylation also enhanced the specific binding of p150(glued) to the tail domain of hseg5 in vitro 0.639 SIGNOR-50169 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr397 RVIEDNEyTAREGAK 10090 BTO:0000776 10415030 YES CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508) 0.665 SIGNOR-248353 GNGT1 protein P63211 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 12507995 YES gcesareni Therefore, we conclude that in vivo, g beta gamma activates pi3k gamma by a mechanism assigning specific roles for both pi3k gamma subunits, i.e., membrane recruitment is mediated via the noncatalytic p101 subunit, and direct stimulation of g beta gamma with p110 gamma contributes to activation of pi3k gamma. 0.485 SIGNOR-96831 TFIIH complex SIGNOR-C457 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 YES lperfetto Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7. 0.306 SIGNOR-269356 RAB21 protein Q9UL25 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 0.418 SIGNOR-260620 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr293 HRIDGKTyVIKRVKY -1 16373505 YES Manara PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR. 0.2 SIGNOR-260784 tubastatin A chemical CHEBI:94186 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207450 PLEKHG6 protein Q3KR16 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.298 SIGNOR-260568 TWIST1 protein Q15672 UNIPROT PFDN4 protein Q9NQP4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255532 FBXL2 protein Q9UKC9 UNIPROT NLRP3 protein Q96P20 UNIPROT down-regulates quantity by destabilization binding Trp73 KAWAMAVwIFAAINR 9606 BTO:0000018 26037928 YES miannu LPS exposure reduces the ubiquitin-mediated proteasomal processing of NALP3 by inducing levels of an E3 ligase component, FBXO3, which targets FBXL2. The latter is an endogenous mediator of NALP3 degradation. FBXL2 recognizes Trp-73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation.  0.352 SIGNOR-272432 BTF3 protein P20290 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 17312387 NO In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. 0.251 SIGNOR-253948 TGFb proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 protein P37173 UNIPROT up-regulates activity binding 9606 22326956 YES miannu TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. 0.2 SIGNOR-256178 GRN protein P28799 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates binding 9606 21393509 YES gcesareni Collectively, these findings demonstrate that pgrn is a ligand of tnfr, an antagonist of tnf signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. 0.493 SIGNOR-172684 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI HNF4G protein Q14541 UNIPROT down-regulates quantity by repression 9606 9792724 NO miannu Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment. 0.8 SIGNOR-254444 RARB protein P10826 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 YES gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs 0.414 SIGNOR-133234 MAPK14 protein Q16539 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 25056917 YES P38α promotes multi‐site GATA‐2 phosphorylation, increasing its localization in nuclear foci enriched in an active form of RNA polymerase II and its capacity to regulate endogenous target genes. 0.27 SIGNOR-259946 PTGER3 protein P43115 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.271 SIGNOR-257111 CHEK2 protein O96017 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr182 SHFVRVStAQKSKKG 9606 BTO:0002181 26028025 YES miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. 0.527 SIGNOR-276908 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr125 VDPDNEAyEMPSEEG 9606 BTO:0000975;BTO:0000142 11744621 YES llicata Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers. 0.53 SIGNOR-113061 SCF-SKP2 complex SIGNOR-C136 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 20852628 YES gcesareni The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain 0.568 SIGNOR-243551 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 15367694 YES Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes 0.893 SIGNOR-252614 APOE protein P02649 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 YES gcesareni Several ligands for the vldl receptor have been identified in addition to tfpi. These include apolipoprotein e (apoe) 0.635 SIGNOR-106221 SCF-SKP2 complex SIGNOR-C136 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 10559858 YES miannu P45 SKP2 binds to a specific domain of E2F-1. We propose a model in which an SCFSKP2-dependent ubiquitination pathway contributes to the timely ubiquitination and degradation of E2F-1 in the S/G2 phases of the cell cycle. 0.382 SIGNOR-272557 NLGN2 protein Q8NFZ4 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.828 SIGNOR-264156 MAPK1 protein P28482 UNIPROT PFAS protein O15067 UNIPROT up-regulates phosphorylation Thr619 GQGDAPPtPLPTPVD 9606 32485148 YES miannu T619 in PFAS is required to mediate ERK2-dependent purine synthesis stimulation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation. 0.2 SIGNOR-267306 LHX4 protein Q969G2 UNIPROT POU1F1 protein P28069 UNIPROT up-regulates quantity by expression transcriptional regulation 10029 BTO:0000246 15998782 YES Luana We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression. 0.514 SIGNOR-266056 PRKCQ protein Q04759 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity phosphorylation Ser716 HILERFGsLTMDGGL 9606 31792381 YES TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation 0.2 SIGNOR-272472 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270384 PRKCA protein P17252 UNIPROT FMNL2 protein Q96PY5 UNIPROT up-regulates activity phosphorylation Ser1072 ARTAKRGsRFFCEPV -1 26256210 YES done miannu PKCα associates with and phosphorylates FMNL2 at S1072 within its Diaphanous autoregulatory region, leading to the release of formin autoinhibition. 0.2 SIGNOR-273796 SMAD5 protein Q99717 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 20957627 YES gcesareni Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. 0.674 SIGNOR-168737 GPR132 protein Q9UNW8 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257187 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263780 TLR2 protein O60603 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 YES scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.609 SIGNOR-266746 TFEB protein P19484 UNIPROT NDUFA13 protein Q9P0J0 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). 0.2 SIGNOR-276701 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates activity phosphorylation Tyr411 RVIEDNEyTAREGAK 9606 BTO:0000007 10934191 YES Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. autophosphorylation of Tyr-29 contributes significantly to the activation of Hck. 0.2 SIGNOR-251266 DYRK1A protein Q13627 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 YES lperfetto Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. 0.36 SIGNOR-106833 PPM1B protein O75688 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation -1 11104763 YES miannu In vitro, PP2Cbeta-1 dephosphorylated and inactivated TAK1. 0.55 SIGNOR-277154 FGG protein P02679 UNIPROT FN1 protein P02751 UNIPROT down-regulates activity binding 9606 2243140 YES Regulation miannu Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a). 0.552 SIGNOR-251970 PDPK1 protein O15530 UNIPROT AHCYL1 protein O43865 UNIPROT down-regulates activity phosphorylation Ser68 RSLSRSIsQSSTDSY 9534 17635105 YES lperfetto Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T| We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R 0.2 SIGNOR-249174 ITGB1BP1 protein O14713 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.309 SIGNOR-257656 FLT1 protein P17948 UNIPROT PHACTR1 protein Q9C0D0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21939755 NO miannu Recently, we identified a new Vascular Endothelial Growth Factor (VEGF)-A(165)-induced gene Phactr-1, (Phosphatase Actin Regulator-1). We found that neuropilin-1 (NRP-1) and VEGF-R1 depletion inhibited Phactr-1 mRNA expression while NRP-2 and VEGF-R2 depletion had no effect. 0.261 SIGNOR-260060 furtrethonium chemical CHEBI:134764 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258643 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2D4 protein Q9Y2X8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.736 SIGNOR-271341 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1062 AVKTVNEsASLRERI -1 7926007 YES lperfetto Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites. 0.348 SIGNOR-248905 DNMT3A protein Q9Y6K1 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 27639498 NO irozzo The DNA methyltransferase 3 genes (DNMT3A and DNMT3B) encode methyltransferases that catalyze the addition of a methyl group to the cytosine residue of CpG dinucleotide; therefore they play an essential role in DNA methylation and gene silencing regulatory processes. DNMT3A function is involved in hematopoietic stem cells (HSCs) renewal and myeloid differentiation. 0.7 SIGNOR-255714 PSME3 protein P61289 UNIPROT SIRT7 protein Q9NRC8 UNIPROT down-regulates quantity by destabilization binding 27511885 YES lperfetto Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ. 0.2 SIGNOR-275866 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser90 QHVRSHSsPASLQLG 9606 BTO:0000567 26183396 YES miannu In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. 0.258 SIGNOR-276926 MRPL22 protein Q9NWU5 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.692 SIGNOR-262371 sulpiride chemical CHEBI:32168 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition -1 7576010 YES miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I). 0.8 SIGNOR-258430 PKA proteinfamily SIGNOR-PF17 SIGNOR ARHGEF6 protein Q15052 UNIPROT down-regulates activity phosphorylation Ser640 RKTERKPsEEEYVIR 9606 BTO:0000132 26507661 YES lperfetto ARHGEF6 is a Rho guanine nucleotide exchange factor for Rac1 and constitutively bound to GIT1. NO and PGI2 activate PKG and PKA, respectively and both kinases phosphorylate ARHGEF6 on Ser-684 and possibly on Ser-640. Phosphorylation of ARHGEF6 results in the assembly of a GIT1-ARHGEF6–14-3-3 complex. These changes might contribute to PGI2- and NO-mediated Rac1 inhibition. 0.2 SIGNOR-272163 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR unknown phosphorylation 9606 16046471 YES lperfetto Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) .we now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. .Ikkbeta Plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. . 0.869 SIGNOR-217427 PRKCA protein P17252 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates phosphorylation Ser104 TKLTRIPsAKKYKDI 9606 BTO:0000149 15917297 YES miannu Pea-15 is phosphorylated on two ser residues, ser104 and ser116. Protein kinase c (pkc) phosphorylates ser104 / we report that phosphorylation of pea-15 blocks its interaction with erk1/2 in vitro and in vivo and that phosphorylation of both ser104 and ser116 is required for this effect. 0.385 SIGNOR-137841 DAMPS stimulus SIGNOR-ST18 SIGNOR MEFV protein O15553 UNIPROT up-regulates activity 16037825 NO lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-256422 RASSF1 protein Q9NS23 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 22683405 YES Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage gcesareni Rassf1a and mst1 co-exist as a complex localizing at microtubules throughout the cell cycle, of which the rassf1a mst1 interaction is stimulatory to the mst1 kinase activity. 0.806 SIGNOR-197744 PI3K complex SIGNOR-C156 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000830 15526160 YES miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. 0.279 SIGNOR-254951 NR1D2 protein Q14995 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24577401 YES miannu A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription. 0.467 SIGNOR-268006 SKIL protein P12757 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR down-regulates activity binding 9606 BTO:0000848 12793438 YES lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway 0.843 SIGNOR-253302 GLI3 protein P10071 UNIPROT MYCN protein P04198 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 NO gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1. 0.357 SIGNOR-188881 BTF3 protein P20290 UNIPROT IRAG1 protein Q9Y6F6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 17312387 NO In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. 0.2 SIGNOR-253946 PHF12 protein Q96QT6 UNIPROT TLE6 protein Q9H808 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 YES miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. 0.2 SIGNOR-266991 Upf-EJC complex SIGNOR-C367 SIGNOR Nonsense-mediated mRNA decay phenotype SIGNOR-PH175 SIGNOR up-regulates 9606 BTO:0000567 17803942 YES miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1. the hUpf complex communicates with the EJC and triggers NMD in the cytoplasm. 0.7 SIGNOR-265239 CDKN1A protein P38936 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 YES gcesareni P21 and p27 are key inhibitors of both cdk1 and cdk2. 0.88 SIGNOR-128442 UCHL3 protein P15374 UNIPROT UBA52 protein P62987 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.801 SIGNOR-270827 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates 9606 15953811 NO miannu A branch-point metabolite α-ketoglutarate is generated in the TCA cycle during the oxidation of carbohydrates and fatty acids and by glutamate dehydrogenase during the oxidative deamination of glutamate. The enzymes that form the mitochondrial α-ketoglutarate– dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes. 0.7 SIGNOR-267821 SFPQ protein P23246 UNIPROT TH protein P07101 UNIPROT down-regulates quantity by repression transcriptional regulation 20938049 YES lperfetto It has been reported that DJ-1 is a neuroprotective transcriptional co-activator that sequesters a transcriptional co-repressor polypyrimidine tract-binding protein-associated splicing factor (PSF) from the TH gene promoter. 0.2 SIGNOR-271697 PPP3CC protein P48454 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 10195903 YES Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 0.397 SIGNOR-248529 MAPK8 protein P45983 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 BTO:0000007;BTO:0000567 10551811 YES lperfetto The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. 0.557 SIGNOR-236018 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 9889196 YES lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. 0.942 SIGNOR-217328 HOXA10 protein P31260 UNIPROT EMX2 protein Q04743 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15494461 NO miannu EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation. 0.32 SIGNOR-254465 EIF2S1 protein P05198 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24714526 NO miannu Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy. 0.2 SIGNOR-251818 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 9099669 YES lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. 0.44 SIGNOR-248967 RUNX3 protein Q13761 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004850 14594802 NO miannu We find that LEF-1 and CBFalpha co-activate ELA2 expression. 0.2 SIGNOR-254554 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser396 TFDSLPSsPSSATPH -1 11500363 YES miannu eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A] 0.577 SIGNOR-250089 GTF2I protein P78347 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding 9606 BTO:0000007 12493763 YES lperfetto We identify a new family of HDAC1,2-associated complexes containing BHC110. Moreover, we define the polypeptide composition of a novel member of this family containing the candidate gene for X-linked mental retardation XFIM and the initiator-binding protein TFII-I. 0.405 SIGNOR-268539 MYC protein P01106 UNIPROT PPAT protein Q06203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 YES miannu PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria. 0.2 SIGNOR-267381 NFX1 protein Q12986 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 9606 BTO:0004117 18505829 YES miannu we investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression. 0.374 SIGNOR-226360 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-153483 ADCY7 protein P51828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-265007 CSNK2A1 protein P68400 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1572 ESGISLFsDDPESDP -1 10403822 YES llicata  Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity. 0.372 SIGNOR-250832 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser194 TPRKEDRsASSGAEG -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.285 SIGNOR-273970 GABRA6 protein Q16445 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.535 SIGNOR-263768 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Thr107 PKKERRRtESINSAF 9606 BTO:0000007 14636580 YES lperfetto In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues.  0.289 SIGNOR-249244 PTPN11 protein Q06124 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR down-regulates activity dephosphorylation 9606 16767162 YES miannu Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals. 0.433 SIGNOR-265824 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser356 DIKSNNWsLEDVTAS 9606 16216881 YES lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. 0.2 SIGNOR-140998 LYN protein P07948 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation Tyr8 MASGDTLyIATDGSE 9606 BTO:0002181 26198631 YES miannu In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B). 0.2 SIGNOR-276930 BCR-Dk complex SIGNOR-C435 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 YES scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). 0.714 SIGNOR-268441 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 YES Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif gcesareni Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. 0.58 SIGNOR-83732 L3MBTL2 protein Q969R5 UNIPROT RNF168 protein Q8IYW5 UNIPROT down-regulates quantity binding 9606 31225475 YES miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. 0.246 SIGNOR-266788 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 10339564 YES lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. 0.942 SIGNOR-217276 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates activity phosphorylation 9606 19620713 YES lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.687 SIGNOR-255261 PRKCA protein P17252 UNIPROT TACSTD2 protein P09758 UNIPROT down-regulates activity phosphorylation Ser322 GELRKEPsL 9606 BTO:0001109 31177095 YES done miannu  Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation. 0.2 SIGNOR-273821 DYRK1B protein Q9Y463 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 10090 15546868 YES lperfetto Mirk phosphorylates p27 at ser-10, thus stabilizing p27 and blocking its nuclear export and degradation 0.355 SIGNOR-235805 RBM7 protein Q9Y580 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 30824372 YES miannu Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb) via its release from the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP). these findings establish that RBM7 binds 7SK snRNP and that genotoxic stress activates P-TEFb by relocating it from 7SK snRNP to the CTD of Pol II. 0.2 SIGNOR-261182 DGC complex SIGNOR-C217 SIGNOR GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265436 TNIK protein Q9UKE5 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Thr322 SNVNRNStIENTRRH 9606 BTO:0002181 21690388 YES miannu Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.  0.2 SIGNOR-276334 FLT1 protein P17948 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276190 FUS protein P35637 UNIPROT DLG4 protein P78352 UNIPROT up-regulates quantity post transcriptional regulation 10090 BTO:0000142 32118033 YES lperfetto These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition. 0.27 SIGNOR-262103 ESR1 protein P03372 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 15808510 YES gcesareni Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1. 0.753 SIGNOR-135053 AKAP9 protein Q99996 UNIPROT TRIP10 protein Q15642 UNIPROT up-regulates activity binding 9606 BTO:0000182;BTO:0000666 27039663 YES Giulio Mechanistically, AKAP-9 interacted with cdc42 interacting protein 4 (CIP4) and regulated its expression. CIP4 levels were interrelated to the AKAP-9 level in CRC cells. Functionally, AKAP-9 was essential for TGF-β1-induced epithelial-mesenchymal transition of CRC cells, and CIP4 played a critical role in mediating the function of AKAP-9. Importantly, CIP4 expression was significantly up-regulated in human CRC tissues.|Co-immunoprecipitation assay revealed that AKAP-9 and CIP4 physically interacted with each other in Lovo and HT29 cells (Fig. 4B and C). 0.513 SIGNOR-260303 TFEB protein P19484 UNIPROT NDUFS4 protein O43181 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). 0.246 SIGNOR-276705 PRKCA protein P17252 UNIPROT EDF1 protein O60869 UNIPROT down-regulates activity phosphorylation Thr91 GRQSKGLtQKDLATK 9606 BTO:0001949 10816571 YES lperfetto EDF-1 was phosphorylated in vitro by PKC in the presence of Ca2+ and phospholipids | This results shows that introduction of a single negative charge by phosphorylation at Thr-91 inhibited CaM-EDF-1 interactions. 0.301 SIGNOR-249041 AKT1 protein P31749 UNIPROT COPS6 protein Q7L5N1 UNIPROT up-regulates phosphorylation Ser60 DHWIRMRsQEGRPVQ 9606 23095642 YES llicata Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6. 0.283 SIGNOR-252532 ITGAL protein P20701 UNIPROT AKAP9 protein Q99996 UNIPROT up-regulates activity binding 9606 BTO:0001945 16339516 YES Giulio However, association of CG-NAP/AKAP450 was signifi-cantly enhanced at 37°C in LFA-1-activated cells triggered toundergo motility. Taken together, our findings provide the first definitiveevidence that the protein CG-NAP/AKAP450 is a key scaffoldingcomponent of the multimolecular complex assembled in T cellsupon LFA cross-linking and is functionally indispensable for cellpolarity and migration induced by this integrin. 0.2 SIGNOR-260304 BMPR2 protein Q13873 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 YES lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). 0.627 SIGNOR-33443 CDC42BPB protein Q9Y5S2 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 10947843 YES Manara In this study, we have shown that MRCKb phosphorylated moesin at Thr-558 | We have shown that the phosphorylation is important to the formation of ®lopodia, and that MRCK may regulate this formation through the phosphorylation of ERM proteins at the tip of ®lopodia. 0.2 SIGNOR-260802 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC5R protein P33032 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257539 EIF1 protein P41567 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity relocalization 9606 20921384 YES lperfetto Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning 0.528 SIGNOR-269143 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 9606 SIGNOR-C3 18722121 YES llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity 0.2 SIGNOR-252772 FGF2 protein P09038 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates 9606 20974802 NO inferred from 70% of family members gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. 0.2 SIGNOR-269908 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr842 CTETFTGtLQYMAPE 9606 17937911 YES lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. 0.2 SIGNOR-158431 NMDA receptor_2A complex SIGNOR-C347 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 YES miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. 0.281 SIGNOR-266599 PRKCD protein Q05655 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 YES inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.396 SIGNOR-270275 MLXIPL protein Q9NP71 UNIPROT FAS protein P25445 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 15496471 YES Luana The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) 0.2 SIGNOR-267947 OPA3 protein Q9H6K4 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 20372962 NO lperfetto Optic atrophy 3 as a protein of the mitochondrial outer membrane induces mitochondrial fragmentation|Together, these results indicate that OPA3, as an integral MOM protein, has a crucial role in mitochondrial fission, and provides a direct link between mitochondrial morphology and optic atrophy. 0.7 SIGNOR-272988 TCF20 protein Q9UGU0 UNIPROT MMP3 protein P08254 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7760812 YES Luana This result indicates that expression of SPBP is sufficient to transactivate a minimal promoter containing a single copy of the SPRE, as well as the full-length stromelysin promoter. 0.417 SIGNOR-266223 panobinostat chemical CHEBI:85990 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257752 RARG protein P13631 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 YES inferred from family member lperfetto We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs 0.417 SIGNOR-270296 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0000527 21679342 YES gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. 0.8 SIGNOR-174593 KLHL18 protein O94889 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 9606 BTO:0001938 23213400 YES miannu We identify Aurora-A as a KLHL18-interacting partner. Overexpression of KLHL18 and CUL3 promotes Aurora-A ubiquitylation in vivo, and the CUL3-KLHL18-ROC1 ligase ubiquitylates Aurora-A in vitro. Our study reveals that the CUL3-KLHL18 ligase is required for timely entry into mitosis, as well as for the activation of Aurora-A at centrosomes.We also noticed that overexpression of both CUL3 and KLHL18 stimulated mono-ubiquitylation of Aurora-A as well (Fig. 8A,B). 0.368 SIGNOR-272021 NMBR protein P28336 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257422 clozapine chemical CHEBI:3766 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258513 HOXA13 protein P31271 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000942 21829694 YES Luana Analysis of normalized luciferase expression confirmed that wt HOXA13 regulates gene expression through the EphA7 cis-regulatory DNA element 0.291 SIGNOR-261631 Class I MHC:Antigen complex SIGNOR-C426 SIGNOR T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 31810556 NO scontino High-affinity peptide/MHC class I complexes that successfully pass the aforementioned “quality controls” will be transported through the Golgi apparatus to the cell membrane to elicit antigen-specific CD8+ T cell responses. 0.7 SIGNOR-267775 HNF4A protein P41235 UNIPROT CYP27A1 protein Q02318 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 11867220 NO miannu Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells. 0.302 SIGNOR-255198 P2RY12 protein Q9H244 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256991 MAPK1 protein P28482 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1457 HSKSPAYtPQNLDSE 9606 16314496 YES fstefani We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription. 0.354 SIGNOR-142462 PRKCD protein Q05655 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Thr46 PHRYRPGtVALREIR 9606 19363025 YES gcesareni We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation. 0.2 SIGNOR-185144 SHC1 protein P29353 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10090 BTO:0005065 17673906 YES lperfetto TGF-beta-induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well-characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. 0.769 SIGNOR-236363 CDC14B protein O60729 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity dephosphorylation 9606 18662541 YES lperfetto Cdc14B activates APC/C Cdh1 after DNA damage in G2.|Importantly, after DNA damage, thein vivo phosphorylation of wild type Cdh1 - but not that of Cdh1 (4xA) - increased after Cdc14B silencing (XREF_FIG), indicating that in response to genotoxic stress, Cdc14B dephosphorylates Cdh1 on the four sites phosphorylated by Cdk2. 0.314 SIGNOR-277017 BCL11A protein Q9H165 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004408 29606353 YES Gianni Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching. 0.446 SIGNOR-269067 MKRN1 protein Q9UHC7 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 23104211 YES miannu Biochemical analyses confirmed that MKRN1 targets p14ARF for ubiquitination and subsequent proteasome-dependent degradation.The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. 0.366 SIGNOR-272036 AKT proteinfamily SIGNOR-PF24 SIGNOR COPS6 protein Q7L5N1 UNIPROT up-regulates phosphorylation Ser60 DHWIRMRsQEGRPVQ 9606 23095642 YES llicata Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6. 0.2 SIGNOR-199254 CUL3 protein Q13618 UNIPROT KCTD10 protein Q9H3F6 UNIPROT up-regulates activity binding 9606 19782033 YES miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. 0.495 SIGNOR-264234 TEK protein Q02763 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 NO lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. 0.246 SIGNOR-241535 RPS6K proteinfamily SIGNOR-PF26 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 11500364 YES lperfetto We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity 0.2 SIGNOR-252775 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI up-regulates quantity precursor of 3702 30034403 YES lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. 0.8 SIGNOR-268563 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 9865696 YES lperfetto We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. 0.86 SIGNOR-62874 MMP13 protein P45452 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272358 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 1400883 YES scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. 0.8 SIGNOR-266943 TP53 protein P04637 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16990795 YES gcesareni P52 cooperates with p53 to regulate other known p53 target genes. 0.425 SIGNOR-149811 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation 9606 15780598 YES lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. 0.766 SIGNOR-134620 WNT5B protein Q9H1J7 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 19577541 NO fspada Wnt5b additionally appears to be a potent enhancer of adipogenic capacity by stimulation of ppargamma 0.253 SIGNOR-186625 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 12686604 YES lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. 0.312 SIGNOR-100188 phosphatidic acid smallmolecule CHEBI:16337 ChEBI long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity precursor of 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269658 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity 9606 17715225 NO miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. 0.2 SIGNOR-262504 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys102 GVFICRGkEDALVTK 30540930 YES lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) 0.271 SIGNOR-275894 PPP1R9A protein Q9ULJ8 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity binding 10090 BTO:0001976 15996550 YES miannu The Rho Family GEF Lfc Interacts with Neurabin and Spinophilin. Neurabin and spinophilin are homologous protein phosphatase 1 and actin binding proteins that regulate dendritic spine function. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc 0.341 SIGNOR-269177 TBC1D4 protein O60343 UNIPROT SLC2A4 protein P14672 UNIPROT down-regulates 9606 12637568 NO gcesareni These findings strongly indicate that insulin-stimulated phosphorylation of as160 is required for glut4 translocation and that this phosphorylation signals translocation through inactivation of the rab gap function. 0.665 SIGNOR-99303 ETS2 protein P15036 UNIPROT IBSP protein P21815 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 YES miannu Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin 0.2 SIGNOR-259873 CDK1 protein P06493 UNIPROT CC2D1A protein Q6P1N0 UNIPROT up-regulates activity phosphorylation Ser208 PASTPTYsPAPTQPA SIGNOR-C17 20171170 YES nucleus lperfetto We identified the Ser208 residue of Aki1 as a cyclin B1–Cdk1 phosphorylation site. Furthermore, cyclin B1–Cdk1 inhibitor treatment was shown to attenuate the level of Aki1 in complex with Scc1, suggesting that Aki1 phosphorylation by cyclin B1–Cdk1 contributes to Aki1–Scc1 complex formation. 0.2 SIGNOR-268297 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Thr278 LARRRKAtQVGEKTP -1 8182057 YES miannu The vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cAMP-dependent- (cAK) and cGMP-dependent protein kinase (cGK) in human platelets and other cardiovascular cells.‚  three VASP phosphorylation sites are phosphorylated by cAK and cGK. Thr, Ser I, and Ser 2 correspond to Thr278, Ser157, Ser239 of the VASP protein, respectively 0.504 SIGNOR-250065 YES1 protein P07947 UNIPROT WBP2 protein Q969T9 UNIPROT up-regulates activity phosphorylation Tyr231 AEAAASAyYNPGNPH 9606 BTO:0000093 21642474 YES miannu Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα. 0.305 SIGNOR-273582 IRF8 protein Q02556 UNIPROT NCF2 protein P19878 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 11483597 NO miannu we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. 0.293 SIGNOR-222789 RPL10L protein Q96L21 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.784 SIGNOR-262500 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser59 SETNQNSsSDSEAER -1 11711551 YES llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 0.379 SIGNOR-251045 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270374 MARCHF9 protein Q86YJ5 UNIPROT FCRL2 protein Q96LA5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271543 TCL1A protein P56279 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.825 SIGNOR-81680 BAZ2B protein Q9UIF8 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 YES miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. 0.2 SIGNOR-266620 tetrabenazine chemical CHEBI:9467 ChEBI SLC18A2 protein Q05940 UNIPROT down-regulates activity chemical inhibition 9606 8643547 YES miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. 0.8 SIGNOR-258491 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D4 protein O60343 UNIPROT unknown phosphorylation Ser588 RMRGRLGsVDSFERS 10090 BTO:0000011 11994271 YES gcesareni To determine directly whether AS160 was a substrate for Akt, we examined the phosphorylation of recombinant AS160, as well as mutant forms with Ser-588, Thr-642, or both converted to Ala, by recombinant Akt 1. 0.2 SIGNOR-245268 SCF-betaTRCP complex SIGNOR-C5 SIGNOR BHLHE40 protein O14503 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 25202122 YES miannu During unperturbed cell cycles, DEC1 is a highly unstable protein that is targeted for proteasome-dependent degradation by the SCF(βTrCP) ubiquitin ligase in cooperation with CK1. 0.346 SIGNOR-276853 Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 24311584 NO miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. 0.7 SIGNOR-263714 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763 12193595 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.2 SIGNOR-244735 estramustine chemical CHEBI:4868 ChEBI MAP2 protein P11137 UNIPROT down-regulates activity chemical inhibition -1 1647395 YES miannu Estramustine is a novel anti-microtubule drug shown to bind MAP-1 and MAP-2 (microtubule-associated proteins) in vitro. In this paper we have shown that estramustine specifically binds MAP-1A in Du 145a cells, resulting in disruption of MAP-1A microtubules and inhibition of type IV collagenase secretion. 0.8 SIGNOR-259298 palbociclib chemical CHEBI:85993 ChEBI CCND2 protein P30279 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205701 CSNK1A1 protein P48729 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 10617630 YES lperfetto In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes. 0.372 SIGNOR-73799 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.2 SIGNOR-183620 CSNK2A1 protein P68400 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser49 HKAELQGsDEDEHVR -1 9461343 YES llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  0.307 SIGNOR-250923 CHD2 protein O14647 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 10090 26895424 NO miannu We show in mouse cells that the cNHEJ-dependent fusion of chromosomes containing uncapped telomeres requires the activity of CHD2. Together, these findings argue that the chromatin response mediated by CHD2 is triggered by the presence of DSBs and promotes repair of these lesions by the canonical KU-dependent NHEJ pathway. 0.7 SIGNOR-264529 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser214 TVLTAQEsFSGSLGH -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.2 SIGNOR-276217 ROCK2 protein O75116 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 14701738 NO miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. 0.7 SIGNOR-261712 CDK1 protein P06493 UNIPROT TEX14 protein Q8IWB6 UNIPROT down-regulates quantity by destabilization phosphorylation Thr728 NLNNMSTtEEYLISK 9606 BTO:0000007 22405274 YES miannu Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction 0.334 SIGNOR-273522 ERCC6 protein Q03468 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 YES miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 0.3 SIGNOR-268822 RFX complex complex SIGNOR-C104 SIGNOR HLA-DMB protein P28068 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 NO Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. 0.364 SIGNOR-254016 Glycine cleavage system complex SIGNOR-C437 SIGNOR carbon dioxide smallmolecule CHEBI:16526 ChEBI up-regulates quantity chemical modification 9606 16051266 YES lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. 0.8 SIGNOR-268244 PPP2CA protein P67775 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT down-regulates dephosphorylation Ser387 ETGLYRIsGCDRTVK 9606 18201571 YES gcesareni We report here that (i) mgcracgap is phosphorylated by aurora b and cdk1, (ii) pp2a dephosphorylates aurora b and cdk1 phosphorylated sites and (iii) inhibition of pp2a abrogates mgcracgap/ect2 interaction. Therefore, pp2a may regulate cytokinesis by dephosphorylating mgcracgap and its interacting partners. 0.304 SIGNOR-160398 COL3A1 protein P02461 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Collagen is the major structural protein in skeletal muscle ECM;... type III collagen appears to be more evenly distributed between endomysium and epimysium 0.7 SIGNOR-254664 PTX3 protein P26022 UNIPROT CFH protein P08603 UNIPROT up-regulates activity binding 9606 19050261 YES miannu Our findings identify PTX3 as a unique FH ligand in that it can bind both of the two hot-spots of FH, namely SCR7 and SCR19-20 and indicate that PTX3 participates in the localization of functionally active FH. PTX3 binds FH without interfering with its complement inhibitory function. Therefore PTX3 may contribute to focusing FH regulatory action, prevent excessive complement activation, and thus exert an important function in the control of inflammation in response to tissue injury. 0.399 SIGNOR-252140 MAPK12 protein P53778 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser396 TFDSLPSsPSSATPH -1 12171600 YES miannu We have also shown that JNK11, JNK22 and SAPK3 p38 phosphorylate eEF2 kinase very poorly at Ser-396 0.329 SIGNOR-250137 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr444 NSLTPKStPVKTLPF 9606 SIGNOR-C83 9840932 YES lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk3 0.718 SIGNOR-62357 Ub:E2 complex SIGNOR-C497 SIGNOR RNF26 protein Q9BY78 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271018 OTX2 protein P32243 UNIPROT RBP3 protein P10745 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10354480 NO miannu OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments. 0.306 SIGNOR-254889 KLF3 protein P57682 UNIPROT KLF8 protein O95600 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000759 18687676 YES Luana Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.  0.255 SIGNOR-266049 FGR protein P09769 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 YES miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  0.328 SIGNOR-276368 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 YES lperfetto Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo 0.2 SIGNOR-259424 RAD21 protein O60216 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 20711430 NO Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice 0.7 SIGNOR-259975 GTF2I protein P78347 UNIPROT USF2 protein Q15853 UNIPROT up-regulates activity binding 9606 21282467 YES lperfetto TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription 0.347 SIGNOR-268537 BACH2 protein Q9BYV9 UNIPROT XBP1 protein P17861 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005014 24821775 NO miannu Expression and activity of the UPR downstream effector XBP1 is regulated positively by STAT5 and negatively by the B-cell-specific transcriptional repressors BACH2 and BCL6. 0.385 SIGNOR-253756 BCL2L1 protein Q07817 UNIPROT HIP1 protein O00291 UNIPROT down-regulates 9606 11007801 NO miannu Hip-1 activity was found to be independent of the ded-containing caspase 8 but was significantly inhibited by the antiapoptotic protein bcl-x(l), implicating the intrinsic pathway of apoptosis in hip-1-induced cell death. 0.2 SIGNOR-82460 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT up-regulates activity phosphorylation Tyr233 EEDGEPDyVNGEVAA 10090 BTO:0001930 14722116 YES miannu Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases. 0.591 SIGNOR-273577 EGFR protein P00533 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Tyr370 SLEISQSyTTTQRES -1 25601159 YES miannu Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. 0.399 SIGNOR-276872 BABAM2 protein Q9NXR7 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 YES lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer 0.2 SIGNOR-263209 DLG3 protein Q92796 UNIPROT NMDA proteinfamily SIGNOR-PF56 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 YES lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. 0.2 SIGNOR-266005 Ub:E2 complex SIGNOR-C497 SIGNOR MUL1 protein Q969V5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270999 PLCG1 protein P19174 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 9606 10913276 YES gcesareni We provide evidence that sos1, a p21ras-specific guanine nucleotide exchange factor, directly binds to the sh3 domain of plc-gamma1, and that the sh3 domain of plc-gamma1 is involved in sos1-mediated p21ras activation. 0.646 SIGNOR-80024 PIAS1 protein O75925 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity sumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 YES gcesareni Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. 0.379 SIGNOR-252735 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser484 IAVEYSDsEDDSSEF 9606 19012317 YES gcesareni Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo. 0.2 SIGNOR-182354 AKT1 protein P31749 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 YES lperfetto Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome. 0.703 SIGNOR-252497 NFIL3 protein Q16649 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates activity binding -1 12805554 YES miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins 0.2 SIGNOR-224248 EIF3F protein O00303 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.925 SIGNOR-266395 SLC27A2 protein O14975 UNIPROT fatty acyl-CoA smallmolecule CHEBI:37554 ChEBI up-regulates quantity chemical modification 9606 10198260 YES lperfetto Very-long-chain acyl-CoA synthetases (VLCS) activate very-long-chain fatty acids (VLCFA) containing 22 or more carbons to their CoA derivatives. 0.8 SIGNOR-260415 PTTG1 protein O95997 UNIPROT TIMP2 protein P16035 UNIPROT down-regulates quantity 9606 19351864 NO miannu Suppressing PTTG expression by siRNA decreased cell motility in both PTTG-HA/EC9706 and KYSE150 cells. By using mass spectrometric analysis, we identified that PTTG up-regulated S100A4 and galectin-1 secretion and down-regulated tissue inhibitor of metalloproteinase-2 secretion to the culture media. 0.2 SIGNOR-255069 CBL protein P22681 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by destabilization binding 9606 12496371 YES miannu In our present study, we demonstrate that ligand-mediated stimulation causes EphA2 to be internalized and degraded. The mechanism of this response involves ligand-mediated autophosphorylation of EphA2, which promotes an association between EphA2 and the c-Cbl adaptor protein. We also show that c-Cbl promotes stimulation-dependent EphA2 degradation.  0.637 SIGNOR-272590 ZFYVE9 protein O95405 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity relocalization 9606 20515759 YES lperfetto Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor. 0.908 SIGNOR-165786 UBE3A protein Q05086 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR down-regulates activity ubiquitination 9606 BTO:0000007 28559284 YES Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A 0.308 SIGNOR-270946 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248364 Camostat mesylate chemical CID:5284360 PUBCHEM TMPRSS2 protein O15393 UNIPROT down-regulates activity chemical inhibition 9606 32142651 YES Monia Ndeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells, efficiently blocked 2019-nCoV-S-driven entry into Caco-2 (TMPRSS2+) but not 293T (TMPRSS2- 110 ) cells while the CatB/L inhibitor E64d had the opposite effect 0.8 SIGNOR-261098 CDK1 protein P06493 UNIPROT NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Thr5 tPDEKLRL 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275589 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Thr290 NKLKPPGtPPPSSRK 10090 19560418 YES These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 0.26 SIGNOR-248381 PTK2B protein Q14289 UNIPROT STAP1 protein Q9ULZ2 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10518561 YES miannu In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. 0.352 SIGNOR-261818 haloperidol chemical CHEBI:5613 ChEBI SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 17419803 YES Simone Vumbaca These results suggest that haloperidol may irreversibly inactivate sigma-1 receptors in guinea pig and human cells, probably after metabolism to reduced haloperidol. 0.8 SIGNOR-261090 RNF31 protein Q96EP0 UNIPROT NR0B1 protein P51843 UNIPROT up-regulates quantity by stabilization monoubiquitination 9606 BTO:0002588 19237537 YES miannu RNF31 promotes monoubiquitination of DAX-1 in an RBR domain-dependent manner. In conclusion, our results suggest that the major DAX-1 modification observed in different experimental settings is likely to be monoubiquitination at one or more lysine residues (multiubiquitination) possibly located within the LBD of DAX-1. RNF31 stabilizes endogenous DAX-1. 0.438 SIGNOR-271786 AKT1 protein P31749 UNIPROT VIM protein P08670 UNIPROT up-regulates quantity by stabilization phosphorylation Ser39 TTSTRTYsLGSALRP 9606 20856200 YES llicata The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis. 0.646 SIGNOR-252511 TRAF7 protein Q6Q0C0 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 15001576 NO miannu Overexpression of traf7 induced caspase-dependent apoptosis. 0.7 SIGNOR-256666 olanzapine chemical CHEBI:7735 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258506 PRKCA protein P17252 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates phosphorylation Ser1494 TLTRDYNsLTRSEHS 9606 15121854 YES lperfetto Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures 0.53 SIGNOR-124498 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251592 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity precursor of 9606 32041144 YES miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. 0.8 SIGNOR-267553 CSNK2A1 protein P68400 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser202 PPTETGEsSQAEENI -1 1828073 YES llicata Two serines located in the C-terminal end of neuromodulin, Ser-192 and Ser-193, were identified as the major casein kinase II phosphorylation sites. 0.307 SIGNOR-250866 AURKB protein Q96GD4 UNIPROT SKA3 protein Q8IX90 UNIPROT up-regulates activity phosphorylation Ser159 SPRSPQLsDFGLERY -1 22371557 YES miannu Aurora B directly phosphorylated Ska1 and Ska3 in vitro, and expression of phosphomimetic mutants of Ska1 and Ska3 impaired Ska KT recruitment and formation of stable KT-MT fibers (K-fibers), disrupting mitotic progression. We propose that Aurora B phosphorylation antagonizes the interaction between the Ska complex and the KMN network, thereby controlling Ska recruitment to KTs and stabilization of KT-MT attachments. 0.456 SIGNOR-262661 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu53 RYNSGKLeEFVQGNL 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263686 EDNRB protein P24530 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-257428 FAAP100 protein Q0VG06 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.2 SIGNOR-263244 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr686 IITEYCRyGDLVDYL -1 19275932 YES miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  0.526 SIGNOR-276142 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR CEBPB protein P17676 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000527 25303533 YES miannu KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ. 0.268 SIGNOR-272456 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR PIK3R2 protein O00459 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23604317 YES miannu FBXL2 binds p85α and p85β. p85β is targeted for ubiquitylation and degradation by SCF FBXL2. 0.2 SIGNOR-272113 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT up-regulates activity phosphorylation Ser1453 DDDGDKWsLLLNGRD 9606 BTO:0000599 21189263 YES lperfetto ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking. 0.296 SIGNOR-272294 VHL protein P40337 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 16678111 YES Here we found that pVHL directly associates with and stabilizes p53 by suppressing Mdm2-mediated ubiquitination and nuclear export of p53. 0.452 SIGNOR-256594 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1679 NVKSKIGsTDNIKYQ -1 8631898 YES miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 0.419 SIGNOR-250164 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT up-regulates activity phosphorylation Ser326 QHPEMDFsKAKFN 9606 BTO:0000567 12852857 YES lperfetto Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites. 0.729 SIGNOR-103407 TSHB protein P01222 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 YES gcesareni Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners. 0.721 SIGNOR-88653 VPS11 protein Q9H270 UNIPROT HOPS tethering complex complex SIGNOR-C549 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.905 SIGNOR-273686 PI-103 chemical CHEBI:90524 ChEBI PIK3C2B protein O00750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206160 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR up-regulates relocalization 9606 25627476 YES lperfetto One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP.  0.2 SIGNOR-267007 SALL4 protein Q9UJQ4 UNIPROT CECR2 protein Q9BXF3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 33144328 YES miannu SALL4 activates Cecr2 by directly binging to its promotor region and CECR2 in turn promotes reprogramming through forming a SMARCA1-contained chromatin remodeling complex with its DTT domain.  0.2 SIGNOR-263893 CNOT4 protein O95628 UNIPROT RBM15 protein Q96T37 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 26575292 YES miannu We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4).  0.36 SIGNOR-271466 IRF1 protein P10914 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 NO miannu Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1 0.381 SIGNOR-226481 PPP1R8 protein Q12972 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity binding 9606 phosphorylation:Thr416 EANSRCQtPIKMKPN 23241245 YES Recruited NIPP1 enables the net phosphorylation of EZH2 by inhibiting its dephosphorylation by PP1. 0.361 SIGNOR-255665 ANP32A protein P39687 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 12522243 YES PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. 0.277 SIGNOR-259082 YARS1 protein P54577 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates quantity chemical modification 9606 16429158 YES miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr 0.8 SIGNOR-270522 VARS1 protein P26640 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 30755602 YES miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 0.8 SIGNOR-270529 WNT3A protein P56704 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates binding 9606 19910923 YES gcesareni It was also shown that wnt5a inhibits the beta-catenin pathway by competing with wnt3a for binding to fz2, and that the impairment of clathrin-mediated internalization does not affect this wnt5a inhibitory action. 0.752 SIGNOR-189117 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.345 SIGNOR-250805 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 YES llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. We propose that under physiological conditions, phosphorylation of Smad3 by CDK inhibits its transcriptional activity, contributing to a decreased level of p15 and an increased level of c-Myc, thus facilitating cell cycle progression from G1 to S phase. 0.742 SIGNOR-250750 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity binding 9606 33358571 YES miannu The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter 0.587 SIGNOR-277684 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Thr355 NKRRRSVtPPEEQQE 9606 23708659 YES lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. 0.2 SIGNOR-252779 LRIG1 protein Q96JA1 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates ubiquitination 9606 16123311 YES inferred from 70% of family members gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. 0.736 SIGNOR-269872 N-(6-fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide chemical CHEBI:91332 ChEBI ROCK2 protein O75116 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 19740074 YES miannu We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2. 0.8 SIGNOR-262230 dopamine smallmolecule CHEBI:18243 ChEBI noradrenaline smallmolecule CHEBI:33569 ChEBI up-regulates quantity precursor of 10090 7961964 YES brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. 0.8 SIGNOR-264182 RAPGEF5 protein Q92565 UNIPROT NRAS protein P01111 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.434 SIGNOR-183738 NFKBIE protein O00221 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 BTO:0001271 12835716 YES lperfetto Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe 0.588 SIGNOR-217361 (-)-anisomycin chemical CHEBI:338412 ChEBI JUND protein P17535 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-189672 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH11 protein P55287 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265829 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10550055 YES gcesareni Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner. 0.819 SIGNOR-72075 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RXRG protein P48443 UNIPROT up-regulates activity chemical activation 9606 17132853 YES miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 0.8 SIGNOR-256193 PLEKHA7 protein Q6IQ23 UNIPROT PDZD11 protein Q5EBL8 UNIPROT up-regulates activity binding 10116 BTO:0003618 30463011 YES Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33 0.381 SIGNOR-261253 C6 protein P13671 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 YES lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer 0.501 SIGNOR-263442 MMP13 protein P45452 UNIPROT COL2A1 protein P02458 UNIPROT down-regulates quantity by destabilization cleavage Gly906 EGPPGPQgLAGQRGI 9606 8609233 YES miannu Although it appears that MMP-1 and MMP-13 both cleave type II collagen initially at the same site, MMP-13 affects a secondary cleavage to produce a 1/4-size collagen fragment with an NH2 terminus three amino acids removed from the primary cleavage site.The present work has demonstrated expression of MMP-13 in human osteoarthritic cartilage and shown that MMP-13 has significant type II collagen degrading activity. 0.545 SIGNOR-256340 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation 9606 19433246 YES miannu Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic. 0.8 SIGNOR-268746 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 10482988 YES miannu Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. 0.445 SIGNOR-251148 PPM1D protein O15297 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity dephosphorylation 9606 23907458 YES miannu Activating dephosphorylation of RUNX2 by Wip1 increases its transcriptional activity on the Bax promoter. 0.445 SIGNOR-277110 HSPA9 protein P38646 UNIPROT MVD protein P53602 UNIPROT down-regulates activity binding 9534 12646231 YES miannu Mortalin binds to mevalonate pyrophosphate decarboxyl ase in mammalian cell. Mot-2 inactivates MPD resulting in decreased amounts of the steady state Ras protein. 0.343 SIGNOR-265890 CDON protein Q4KMG0 UNIPROT MAP3K7 protein O43318 UNIPROT unknown binding 10090 SIGNOR-C21 22337877 YES lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts 0.2 SIGNOR-235554 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser493 LSPRHRMsSPGVAGS 9606 BTO:0000801 29170386 YES Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. 0.246 SIGNOR-256098 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2114 RDIYKNDyYRKRGEG 9606 17416557 YES gcesareni In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products. 0.374 SIGNOR-154203 PRKAA1 protein Q13131 UNIPROT SIRT7 protein Q9NRC8 UNIPROT down-regulates quantity by destabilization phosphorylation Thr153 TLTHMSItRLHEQKL 27511885 YES lperfetto Here, the authors show that energy stress induces an AMPK-dependent phosphorylation of Sirt7, which promotes its ubiquitin-independent degradation by REGγ, resulting in the down-regulation of rRNA transcription and cell survival.|These results strongly suggest that the phosphorylation status of SirT7 at T153 plays a crucial role in determining its subcellular distribution, degradation and binding to REGγ. 0.2 SIGNOR-275864 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120152 MAPK1 protein P28482 UNIPROT PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation Thr361 EPFVSIPtPREKVAM 11493009 YES lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. 0.823 SIGNOR-249438 AMER1 protein Q5JTC6 UNIPROT APC protein P25054 UNIPROT up-regulates relocalization 9606 23151663 YES gcesareni Apc membrane recruitment protein 1 (amer1;alsoknownas wtx) 0.738 SIGNOR-199375 PP1 proteinfamily SIGNOR-PF54 SIGNOR CDC25C protein P30307 UNIPROT up-regulates binding 9606 14592972 YES lperfetto Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus. 0.2 SIGNOR-264654 IKK-complex complex SIGNOR-C14 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity by expression 9606 22056382 NO Tnf-α enhanced the transcriptional activity of a classical Notch target gene via Ikk2 by inducing histone H3 phosphorylation 0.2 SIGNOR-253586 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation 9606 19230643 YES gcesareni Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1. 0.347 SIGNOR-184130 PINK1 protein Q9BXM7 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Ser424 DHDNDKEsDVEI 9606 25305081 YES miannu PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death.|PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c. 0.2 SIGNOR-279093 MYC protein P01106 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9188852 NO gcesareni Our results suggest that this activation may involve at least two myc-dependent steps: the induction of cyclin e gene transcription followed by accumulation of cyclin e mrna in a protein synthesis-independent manner and the p27(kip1) association with cyce/cdk2 complexes containing newly synthesised cyce. 0.632 SIGNOR-49130 ALOX15 protein P16050 UNIPROT 15(S)-HETE smallmolecule CHEBI:15558 ChEBI up-regulates quantity chemical modification 9606 12517954 YES lperfetto In A549 cells activation of 15-LOX by IL-4 required the coactivation of histone acetyltransferases CREB-binding protein/p300 and led to a sizable production of 15(S)-HETE 0.8 SIGNOR-254094 CHMP4C protein Q96CF2 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.642 SIGNOR-265528 NEDD4 protein P46934 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 19864419 YES miannu Endogenous and overexpressed Nedd4 polyubiquitinate Spry2 via Lys(48) on ubiquitin and decrease its stability.  0.391 SIGNOR-271425 PTPRD protein P23468 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 NO miannu LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance 0.7 SIGNOR-264089 linifanib chemical CHEBI:91435 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193660 NR3C1 protein P04150 UNIPROT NR4A3 protein Q92570 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 NO gcesareni We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors. 0.291 SIGNOR-132309 TCF4 protein P15884 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22777675 NO miannu we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays. 0.329 SIGNOR-255390 AURKB protein Q96GD4 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 YES miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. 0.25 SIGNOR-276062 FFAR1 protein O14842 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.307 SIGNOR-257071 NR0B2 protein Q15466 UNIPROT ESRRG protein P62508 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11705994 NO gcesareni The current study also demonstrates that shp inhibits err_ transactivation. 0.465 SIGNOR-111620 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARA protein P10276 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 YES Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  0.8 SIGNOR-258138 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates activity phosphorylation Ser2054 GGNKRKLsTAMALIG 10090 BTO:0000801 12196520 YES miannu Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins. 0.506 SIGNOR-250327 AMPK complex SIGNOR-C15 SIGNOR RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 10090 SIGNOR-C15 SIGNOR-C3 18439900 YES lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK 0.52 SIGNOR-263046 Gbeta proteinfamily SIGNOR-PF4 SIGNOR UBTF protein P17480 UNIPROT down-regulates phosphorylation 9606 11741541 YES inferred from 70% family members lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna 0.2 SIGNOR-270080 IDE protein P14735 UNIPROT INS protein P01308 UNIPROT down-regulates quantity by destabilization cleavage -1 29596046 YES SARA IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds 0.72 SIGNOR-260986 WWC1 protein Q8IX03 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity 9606 BTO:0000007 20159598 NO Hippo pathway Gianni These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. 0.443 SIGNOR-261954 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT down-regulates activity phosphorylation Ser159 EKLFRSQsADAPGPT -1 18480293 YES miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation 0.2 SIGNOR-262685 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273072 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Ser1678 ITSEEERsPAKRGRK -1 30685087 YES lperfetto Nuclear import of 53BP1 is required for proper localization of 53BP1 and maintenance of genome integrity. 53BP1 has a classical bipartite nuclear localization signal (NLS) of sequence 1666-GKRKLITSEEERSPAKRGRKS-1686. Ser1678 within the 53BP1 NLS can be phosphorylated by CDK1/cyclin B, and a phosphomimetic substitution of Ser1678 with aspartate has been shown to negatively regulate nuclear import of 53BP1. 0.547 SIGNOR-264444 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation Ser1217 MSLENPLsPFSSDIN 9606 BTO:0000007 32294430 YES done miannu We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452.  0.469 SIGNOR-274099 ZNF462 protein Q96JM2 UNIPROT PBX1 protein P40424 UNIPROT down-regulates activity binding 9534 BTO:0000298 17353115 YES miannu We demonstrated that ZFPIP is expressed in embryonic female genital tract but also in other PBX1 expression domains such as the developing head and the limb buds. We further showed that ZFPIP is able to bind physically and in vivo to PBX1 and moreover, that it prevents the binding of HOXA9/PBX complexes to their consensus DNA site. We suggest that ZFPIP is a new type of PBX1 partner that could participate in PBX1 function during several developmental pathways. 0.309 SIGNOR-264477 oligopeptide smallmolecule CHEBI:25676 ChEBI peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity precursor of 9606 31810556 YES scontino While peptides loaded onto MHC class I molecules are 8‚Äì11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1. 0.8 SIGNOR-267770 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser390 KEAEEESsGGEEEDE 9606 BTO:0001938 11861906 YES llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. 0.38 SIGNOR-251070 AMPK complex SIGNOR-C15 SIGNOR TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 19584320 YES lperfetto Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity. 0.433 SIGNOR-216487 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000007 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.794 SIGNOR-252988 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR POLM protein Q9NP87 UNIPROT down-regulates activity phosphorylation Thr21 SGDAASStPPSTRFP -1 23933132 YES miannu  In vitro kinase assays showed that the S phase-associated Cdk2/cyclin A complex was able to phosphorylate Polμ. We identified Ser12, Thr21 (located in the BRCT domain) and Ser372 (located in loop1) as the target residues. Mutation of these residues to alanine indicated that Ser372 is the main phosphorylation site.Our evidences suggest that Polμ could be regulated in vivo by phosphorylation of the BRCT domain (Ser12/Thr21) and of Ser372, affecting the function of loop1. 0.27 SIGNOR-273598 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270796 SDHD protein O14521 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. 0.927 SIGNOR-266274 beta-Funaltrexamine chemical CHEBI:81527 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258773 RNF7 protein Q9UBF6 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity ubiquitination 9606 23136067 YES miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 0.347 SIGNOR-271447 NLGN4Y protein Q8NFZ3 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.2 SIGNOR-264158 ATM protein Q13315 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates activity phosphorylation Ser43 RNPEAALsPTFRSDS 32615088 YES miannu Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43. 0.2 SIGNOR-265969 EGFR protein P00533 UNIPROT SCAMP3 protein O14828 UNIPROT up-regulates activity phosphorylation Tyr41 QYATLDVyNPFETRE -1 9658162 YES miannu In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation 0.4 SIGNOR-262858 SOHLH1 protein Q5JUK2 UNIPROT ZP1 protein P60852 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16690745 YES Luana Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters. 0.2 SIGNOR-266077 SIRT2 protein Q8IXJ6 UNIPROT KAT2B protein Q92831 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 12887892 YES gcesareni Sir2 forms a complex with the acetyltransferase pcaf and myod and, when overexpressed, retards muscle differentiation. 0.531 SIGNOR-104248 NCOA4 protein Q13772 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10347167 YES miannu Identification of ara70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. / ppargamma and ara70 interact in the absence of the ppargamma ligand 15-deoxy-delta12,14-prostaglandin j2, although the addition of exogenous ligand enhances this interaction. 0.45 SIGNOR-67687 RELA protein Q04206 UNIPROT PCK2 protein Q16822 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000759 20137375 NO miannu NF-kappaB p65 was shown to inhibit transcription of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme in gluconeogenesis in the liver 0.266 SIGNOR-255072 CDC5L protein Q99459 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR form complex binding 9606 BTO:0000567 20176811 YES miannu In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27. 0.91 SIGNOR-271974 fosinoprilat chemical CHEBI:116962 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 9187274 YES miannu We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range. 0.8 SIGNOR-258613 PKA proteinfamily SIGNOR-PF17 SIGNOR CAD protein P27708 UNIPROT down-regulates activity phosphorylation Ser1406 GAGGRRLsSFVTKGY -1 17485345 YES miannu The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation.  0.2 SIGNOR-267442 TP53 protein P04637 UNIPROT MLH1 protein P40692 UNIPROT up-regulates quantity transcriptional regulation 9606 15781865 YES .... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron. 0.609 SIGNOR-257605 citrate(3-) smallmolecule CHEBI:16947 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR down-regulates activity binding 9606 31751601 YES miannu Once in the cytoplasm, citrate is able to inhibit phosphofructokinase 1 (PFK1) [4], the enzyme that is in charge of the “committed” step in glycolysis and converts fructose-6-phosphate to fructose-1, 6-bisphosphate (Fig. 1). In addition, citrate can inhibit PFK2, a bifunctional enzyme that regulates the rates of glycolysis and gluconeogenesis. Thus, a high level of citrate can lead to the reduction of glycolysis by directly inhibiting PFK1 and PFK2 and indirectly inhibiting PK. 0.8 SIGNOR-267579 NCOA2 protein Q15596 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 24239470 YES miannu The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis 0.901 SIGNOR-251531 STOML2 protein Q9UJZ1 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 18641330 YES Giorgia In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. 0.2 SIGNOR-260377 HDAC1 protein Q13547 UNIPROT MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR form complex binding 9606 BTO:0000567 9620804 YES Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. 0.753 SIGNOR-267738 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 BTO:0000562 12853467 YES lperfetto These findings suggest that pkb-dependent binding of 14-3-3s to phospho-ser483 of cardiac pfk-2 mediates the stimulation of glycolysis by growth factor. 0.653 SIGNOR-252464 ID1 protein P41134 UNIPROT CASK protein O14936 UNIPROT unknown binding 9606 15694377 YES miannu We identified a novel CASK-interacting protein, inhibitor of differentiation 1 (Id1) 0.406 SIGNOR-225149 CDK4 protein P11802 UNIPROT RUNX3 protein Q13761 UNIPROT down-regulates phosphorylation Ser356 SSSGGDRsPTRMLAS 9606 SIGNOR-C18 19351720 YES llicata Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation. 0.399 SIGNOR-185120 BECN1 protein Q14457 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 YES lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.936 SIGNOR-260315 WNT7A protein O00755 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0003006 15705594 NO Transfected Wnt-7a and Fzd-9 inhibit proliferation of NSCLC cells. 0.7 SIGNOR-278114 SPDEF protein O95238 UNIPROT MMP9 protein P14780 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003160 22761428 NO miannu Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. 0.36 SIGNOR-255218 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 YES lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.2 SIGNOR-124843 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT down-regulates activity phosphorylation Ser481 KEDGHRTsTSAVPNL -1 8810272 YES miannu Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin. 0.311 SIGNOR-250331 RAI1 protein Q7Z5J4 UNIPROT PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000614 22578325 NO miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 0.387 SIGNOR-266841 TLR9 protein Q9NR96 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 10090 22664090 YES scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.44 SIGNOR-266748 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258210 GPER1 protein Q99527 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates 9606 19549922 NO gcesareni Gpr30 also stimulates the pi3k pathway, elevating cellular pip3 levels, which is also predicted to activate nr5a receptors by direct binding of pip3 to the ligand binding domain . 0.8 SIGNOR-186206 Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 NO lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. 0.7 SIGNOR-273457 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 16778204 YES gcesareni Ptprj expression induces dephosphorylation of the ret(c634r) and, probably via an indirect mechanism, ret/ptc1 oncoproteins on two key ret autophosphorylation sites (tyr1062 and tyr905). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret 0.277 SIGNOR-147165 PAQR3 protein Q6TCH7 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR up-regulates activity binding 9606 BTO:0000007 26834238 YES miannu Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation.  0.249 SIGNOR-273738 SP4 protein Q02446 UNIPROT CRX protein O43186 UNIPROT up-regulates activity binding 9606 15781457 YES miannu Sp4 directly binds Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains. 0.388 SIGNOR-225333 NSMCE3 protein Q96MG7 UNIPROT NSMCE1 protein Q8WV22 UNIPROT up-regulates activity binding -1 20864041 YES miannu MAGE-G1 enhances NSE1 ubiquitin ligase activity in vitro. 0.2 SIGNOR-265489 RLIM protein Q9NVW2 UNIPROT LDB2 protein O43679 UNIPROT down-regulates quantity by destabilization polyubiquitination 10029 BTO:0000246 11882901 YES miannu Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway.  0.453 SIGNOR-272616 EZH2 protein Q15910 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 YES miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. 0.396 SIGNOR-260068 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ -1 10090741 YES miannu We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. 0.43 SIGNOR-250172 MMP2 protein P08253 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Ser240 ISRVDAAsLKGLNNL -1 9148753 YES miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. 0.694 SIGNOR-256350 PPP3CB protein P16298 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 YES CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). 0.252 SIGNOR-248363 MTA1 protein Q13330 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001211 22184117 NO miannu The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. 0.288 SIGNOR-254242 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192895 RBP2 protein P50120 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity relocalization 9606 31963453 YES lperfetto Either acting on the producing cell (autocrine signaling) or the receiving cell (paracrine signaling), RA is transferred into the nucleus by Cellular retinoic acid-binding protein 2 (CRABP2) [18]. Once inside the nucleus, RA binds to specific nuclear transcription factors named Retinoic acid receptors (RARs) 0.8 SIGNOR-265130 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR GSTP1 protein P09211 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000675 31024008 YES miannu Here, we show that loss of FBX8 accelerates chemical-induced colon tumorigenesis. FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC. 0.2 SIGNOR-272306 TGFB1 protein P01137 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000764 20846954 NO Regulation miannu We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. 0.367 SIGNOR-251922 H4C1 protein P62805 UNIPROT Nucleosome complex SIGNOR-C371 SIGNOR form complex binding -1 21812398 YES lperfetto The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.2 SIGNOR-265311 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNA12 protein Q03113 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 YES inferred from 70% family members milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. 0.2 SIGNOR-269968 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser278 VDTGITNsQTLIPDC 9606 10839544 YES lperfetto We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. 0.855 SIGNOR-78025 GNG12 protein Q9UBI6 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000586 16293724 YES gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. 0.398 SIGNOR-141795 SRC protein P12931 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 9792645 YES llicata C-src phosphorylates IkappaB On tyrosine 42|NF-kappaB is sequestered in the cytosol by IkappaBalpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation. 0.687 SIGNOR-60879 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572;BTO:0000801 SIGNOR-C14 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation 0.922 SIGNOR-235400 LYN protein P07948 UNIPROT CD79B protein P40259 UNIPROT up-regulates activity phosphorylation Tyr196 GMEEDHTyEGLDIDQ -1 9531288 YES Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b 0.677 SIGNOR-251398 SRC protein P12931 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Tyr4473 VEIGNPTyKMYEGGE 9606 18381291 YES lperfetto The observation that the wild type protein was phosphorylated to a higher level than the y4473f mutant again indicates that phosphorylation of the tyr4473 residue by v-src is occurring in these cellsmutation of tyr4473 to alanine, which abolishes snx17 binding, resulted in impaired receptor recycling and reduced amounts of the mature form of lrp1 on the cell surface 0.394 SIGNOR-178159 PRKG1 protein Q13976 UNIPROT PPP1R17 protein O96001 UNIPROT up-regulates phosphorylation Thr119 KKPRRKDtPALHMSP 9606 BTO:0001011 10051666 YES miannu Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1. 0.655 SIGNOR-263147 SMAD7 protein O15105 UNIPROT BMPR1B protein O00238 UNIPROT down-regulates 10090 10564272 NO gcesareni We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 0.697 SIGNOR-236864 DGC complex SIGNOR-C217 SIGNOR GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265439 RPS6KB1 protein P23443 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 YES lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain 0.96 SIGNOR-102051 PIAS1 protein O75925 UNIPROT SATB2 protein Q9UPW6 UNIPROT down-regulates activity sumoylation Lys233 YKKYKKIkVERVERE 9606 14701874 YES gianni We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1. 0.581 SIGNOR-268932 Cyclopamine chemical CHEBI:4021 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001757 12202832 YES gcesareni We investigate the therapeutic efficacy of the Hh pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell-like character. 0.8 SIGNOR-174432 MAPK1 protein P28482 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 YES lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. 0.335 SIGNOR-184172 OGG1 protein O15527 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 10090 26221032 NO miannu Cut repeats from the CUX1 protein were recently shown to stimulate 8-oxoguanine DNA glycosylase 1 (OGG1), an enzyme that removes oxidized purines from DNA and introduces a single strand break through its apurinic/apyrimidinic lyase activity to initiate base excision repair. 0.7 SIGNOR-263959 AP1 complex SIGNOR-C154 SIGNOR CCL2 protein P13500 UNIPROT up-regulates activity transcriptional regulation 9606 21561061 YES Luana 3b Potentiates AP-1-Dependent MCP-1 Promoter Activity 0.614 SIGNOR-260764 SNAP91 protein O60641 UNIPROT SYT1 protein P21579 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 YES miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. 0.631 SIGNOR-264114 EGFR protein P00533 UNIPROT NIBAN2 protein Q96TA1 UNIPROT up-regulates activity phosphorylation Tyr593 PIDWGEEySNSGGGG 9606 BTO:0002035 26721396 YES miannu  We demonstrate here that activated EGFR phosphorylates the Y593 residue of the protein known as family with sequence similarity 129, member B (FAM129B), which is overexpressed in many types of human cancer. FAM129B phosphorylation increased the interaction between FAM129B and Ras, resulting in reduced binding of p120-RasGAP to Ras. 0.2 SIGNOR-273637 NEDD4 protein P46934 UNIPROT LAPTM5 protein Q13571 UNIPROT up-regulates activity ubiquitination 9606 17116753 YES miannu These results suggest that LAPTM5 ubiquitination is mediated by Nedd4.|Thus, Nedd4 promotes the recruitment of GGA3 to LAPTM5, allowing LAPTM5 translocation from the Golgi to the lysosome with the aid of GGA3. 0.476 SIGNOR-278768 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone chemical CHEBI:91414 ChEBI WEE1 protein P30291 UNIPROT down-regulates chemical inhibition 9606 20068082 YES gcesareni Mk-1775 (merck). This wee1 inhibitor (ic50, 5.2nm) potentiates the activity of dna-damaging agents (e.g., gemcitabine, cisplatin, carboplatin) in vitro and in vivo, particularly in p53-negative cancers 0.8 SIGNOR-163173 HNF1B protein P35680 UNIPROT UMOD protein P07911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18846391 NO miannu UMOD transcription is activated by the transcription factor HNF1B. 0.366 SIGNOR-254441 RFX1 protein P22670 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 NO miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. 0.2 SIGNOR-253829 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BIRC3 protein Q13489 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9916987 NO gcesareni The iaps have been shown to be induced by nf-kappab or v-rel in multiple cell lines and conversely, hiap1 and hiap2 have been shown to activate nf-kappab possibly forming a positive feed-back loop. 0.668 SIGNOR-64103 GSK3B protein P49841 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates quantity by stabilization phosphorylation Ser256 LRRAIQLsMQGSSRN 9606 BTO:0000007 17434145 YES lperfetto Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3| 0.466 SIGNOR-264821 CSNK2A2 protein P19784 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser112 KRAGGEEsQFEMDI 9606 BTO:0000007 9806882 YES lperfetto The kinase is quite distinct from casein kinase 2, which also phosphorylates Ser-111 of 4E-BP1. The possible importance of these kinases in the phosphorylation of 4E-BP1 in fat cells is discussed. It is suggested that the phosphorylation of Ser-111 might be a priming event that facilitates the subsequent phosphorylation of Thr-36, Thr-45, Ser-64 and Thr69 by a rapamycin-sensitive process that initiates the dissociation of 4E-BP1 from eIF4E and hence the formation of the eIF4F complex. 0.333 SIGNOR-249334 Vps34 Complex I complex SIGNOR-C242 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 NO lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.7 SIGNOR-260325 EEF1A1P5 protein Q5VTE0 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269551 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT up-regulates activity phosphorylation Tyr866 EVHPAGRyVLCPSTT -1 9178760 YES llicata Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins 0.2 SIGNOR-250593 MIOS protein Q9NXC5 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 YES miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 0.945 SIGNOR-255301 NEDD4L protein Q96PU5 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 YES miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 0.283 SIGNOR-253464 MIF protein P14174 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 16636133 NO Regulation of expression miannu MIF inhibits cytodifferentiation and hemoglobin synthesis of MEL cells. 0.2 SIGNOR-251832 adenosine smallmolecule CHEBI:16335 ChEBI ADORA1 protein P30542 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257446 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120120 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr356 GTRSRSHtSEGTRSR 9606 18787837 YES llicata Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1. 0.57 SIGNOR-180825 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser554 PDSEASQsPQYSFES 9606 11110801 YES llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). 0.442 SIGNOR-84992 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified. 0.8 SIGNOR-266464 metformin chemical CHEBI:6801 ChEBI CRTC2 protein Q53ET0 UNIPROT down-regulates 9606 20577053 NO gcesareni It has been proposed that metformin stimulates crtc2 phosphorylation in response to metabolic signals such as energy stress through the lkb1-ampk/sik1 pathways, which promotes binding to 14-3-3 proteins, thereby sequestering crtc2 from the nucleus to the cytoplasm 0.8 SIGNOR-166361 KMT2C protein Q8NEZ4 UNIPROT MLL3 complex complex SIGNOR-C446 SIGNOR form complex binding 9606 34156443 YES miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 0.2 SIGNOR-268809 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser198 IRTHLSQsPRVPSKC 10090 19560418 YES These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 0.26 SIGNOR-248525 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by stabilization phosphorylation Thr1065 AKRPRVGtPLATEDS 9606 BTO:0001109 28945223 YES miannu In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.  0.2 SIGNOR-276744 FYN protein P06241 UNIPROT DCC protein P43146 UNIPROT up-regulates activity phosphorylation Tyr1420 TEDSANVyEQDDLSE 10090 BTO:0001909 15557120 YES miannu Fyn tyrosine kinase, but not Src, regulates the phosphorylation of DCC in N1E-115 neuroblastoma cells.Both DCC phosphorylation and Netrin-1-induced axon outgrowth are impaired in Fyn(-/-) CN and spinal cord explants. We propose that DCC is regulated by tyrosine phosphorylation and that Fyn is essential for the response of axons to Netrin-1. these results show that DCC is phosphorylated by Fyn, but not Src, in N1E-115 cells, and that tyrosines 1261 and 1418 are the major phosphorylation sites of Fyn in vivo. 0.57 SIGNOR-268176 TP53INP1 protein Q96A56 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 22421968 YES gcesareni Tp53inp1 is also able to interact with atg8-family proteins 0.346 SIGNOR-196664 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr726 KEHNFSFyPTFQSHP 10090 BTO:0001516 16627759 YES lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. 0.2 SIGNOR-271922 TLN1 protein Q9Y490 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.583 SIGNOR-257620 beta-Funaltrexamine chemical CHEBI:81527 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258771 EGFR protein P00533 UNIPROT EPB41 protein P11171 UNIPROT down-regulates phosphorylation Tyr660 RLDGENIyIRHSNLM 9606 1647028 YES lperfetto The phosphorylation site has been localized to the 8-kda domain, which has one tyrosine, tyrosine-418. The 8-kda region is required for the assembly of the spectrin/actin complex, and phosphorylation by egfr reduced the ability of protein 4.1 to promote the assembly of the spectrin/actin/protein 4.1 ternary complex 0.401 SIGNOR-20452 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 14670079 YES gcesareni We further demonstrate that phospho-mkk1/mkk2 antibodies recognize npm on the c-terminal region, which is phosphorylated by cdc2 (cell division control kinase-2) during g2/m-phase. biochemical and immunocytochemistry analyses verified that the phospho-mkk1/mkk2 antibodies cross-reacted with npm that was phosphorylated at thr234 and thr237 during g2/m-phase, which are the same sites that are targeted by cdc2 (cell division cycle protein-2) during mitosis. 0.519 SIGNOR-120334 RELA protein Q04206 UNIPROT IEX-1L protein O75353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9703517 NO gcesareni Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here. 0.2 SIGNOR-59542 ATP7A protein Q04656 UNIPROT SOD3 protein P08294 UNIPROT up-regulates activity 10090 29301787 YES lperfetto Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide. 0.695 SIGNOR-272267 mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 15829723 NO apalma Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K (47). This latter event has great potential importance for the promotion of muscle growth by the IGF-I/Akt/mTOR pathway, because p70S6k is a potent stimulator of protein synthesis that can be activated by increases in muscle contraction 0.7 SIGNOR-256064 CAMK2A protein Q9UQM7 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr574 VDNIRSAtPEALAFV 9606 BTO:0000938 BTO:0000142 12486117 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.373 SIGNOR-96628 PRKCB protein P05771 UNIPROT CFLAR protein O15519 UNIPROT up-regulates quantity by stabilization phosphorylation Ser193 LQAAIQKsLKDPSNN 9606 BTO:0000664 19343040 YES miannu  Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins 0.2 SIGNOR-276146 HHIP protein Q96QV1 UNIPROT SHH protein Q15465 UNIPROT down-regulates activity binding 10090 10050855 YES lperfetto Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal. 0.896 SIGNOR-65078 NMDA receptor_2B complex SIGNOR-C348 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 YES miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  0.8 SIGNOR-264219 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr304 SSHKGFHyKH 9606 BTO:0000567 19059208 YES miannu We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. 0.2 SIGNOR-262855 naproxen chemical CHEBI:7476 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 9057869 YES miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 0.8 SIGNOR-258603 CNR1 protein P21554 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity 9606 BTO:0002036 25012566 NO lperfetto We subsequently analyzed whether Gαo modulates the cellular activities of Necdin. Notably, expression of Gαo significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oα-coupled receptor, augmented cell growth suppression, which was mediated by Gαo and Necdin in U87MG cells containing CB1R, Gαo, and Necdin as normal components. 0.462 SIGNOR-253389 PIM1 protein P11309 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 16146838 NO lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. 0.7 SIGNOR-256657 NEDD4L protein Q96PU5 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15586017 YES Regulation of localization miannu The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane. 0.774 SIGNOR-251948 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser103 EGISQESsEEEQ -1 2806554 YES llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. 0.331 SIGNOR-250893 TP53 protein P04637 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 20181957 YES miannu P53 directly induces the expression of Siah-1 and in turn formation of a unique SCF-like complex (SCF(TBL1)) comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin β-like 1 (TBL1), and APC 0.373 SIGNOR-271953 SLC44A2 protein Q8IWA5 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 12761501 NO Giorgia Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways 0.2 SIGNOR-260390 MSI1 protein O43347 UNIPROT NUMB protein P49757 UNIPROT down-regulates binding 9606 20477901 YES Inhibits translation gcesareni The study confirmed p21(cip1) and numb proteins as targets of musashi1, suggesting additionally p27(kip1) in cell-cycle regulation and jagged-1 in notch . 0.445 SIGNOR-165617 RFC1 protein P35251 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 YES lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 0.864 SIGNOR-265505 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23332504 NO fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. 0.284 SIGNOR-192477 IL6 protein P05231 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 10116 BTO:0001103 23869758 NO andrea cerquone perpetuini IL-6 induced dose-dependent increase in satellite cell proliferation by activating the JAK2/STAT3/cyclin D1 pathway.Treatment with 1 ng/ml IL-6 for 3 h significantly increased p-STAT3+/MyoD+ cell numbers by 44% compared to control media only . 0.755 SIGNOR-255415 INTS10 protein Q9NVR2 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.78 SIGNOR-261473 POU5F1 protein Q01860 UNIPROT DKK1 protein O94907 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.35 SIGNOR-254934 TTI1 protein O43156 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 YES miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. 0.649 SIGNOR-272004 DLG3 protein Q92796 UNIPROT Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.51 SIGNOR-270885 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 11583623 YES amattioni Xiap is an endogenous inhibitor of caspase-3 0.939 SIGNOR-110837 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK1 protein P39086 UNIPROT up-regulates activity chemical activation 9606 27586965 YES miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors 0.8 SIGNOR-264470 L-serine chemical CHEBI:17115 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates activity chemical activation 9606 23064226 YES inferred from family member We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. 0.8 SIGNOR-270286 IKBKE protein Q14164 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0000551 23691078 YES lperfetto Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation. 0.407 SIGNOR-252949 FYN protein P06241 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr323 DEPVADPyDQSFESR 9606 15735648 YES fstefani T cell src family kinases and zap70 activate p38 by phosphorylating tyr323. 0.487 SIGNOR-134293 IKZF1 protein Q13422 UNIPROT Lymphopoiesis phenotype SIGNOR-PH111 SIGNOR up-regulates activity 9606 BTO:0000725 25085254 NO The Ikaros family of DNA binding proteins are critical regulators of lymphocyte differentiation. In multipotent hematopoietic progenitors, Ikaros supports transcriptional priming of genes promoting lymphocyte differentiation. 0.7 SIGNOR-259958 PRKCZ protein Q05513 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr560 TSEPVQLtPDDEDAI 9606 11141077 YES gcesareni Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylation 0.2 SIGNOR-85505 FIP1L1 protein Q6UN15 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 14749727 YES miannu Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. 0.901 SIGNOR-121649 pentazocine chemical CHEBI:7982 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258934 WNT3A protein P56704 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 YES gcesareni We demonstrate here that prototype canonical Wnt3a and noncanonical Wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-LRP5/6 and Ror1/2, respectively-through a common mechanism that involves their Wnt-dependent coupling to the Frizzled (Fzd) coreceptor and recruitment of shared components, including dishevelled (Dvl), axin, and glycogen synthase kinase 3 (GSK3) 0.639 SIGNOR-169654 SMO protein Q99835 UNIPROT GATA3 protein P23771 UNIPROT up-regulates activity 17139329 YES fferrentino That GATA is a downstream effector of the hedgehog pathway. 0.2 SIGNOR-253527 Ub:E2 complex SIGNOR-C497 SIGNOR RAD18 protein Q9NS91 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271095 ITGA4 protein P13612 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.858 SIGNOR-253293 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263788 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 10398585 YES lperfetto Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation 0.58 SIGNOR-249332 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 10737616 YES lperfetto Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease. 0.564 SIGNOR-249417 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120080 Ub:E2 complex SIGNOR-C497 SIGNOR MAEA protein Q7L5Y9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271048 TTK protein P33981 UNIPROT USP16 protein Q9Y5T5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr554 EVLTSSPtRNLNGAY 9606 BTO:0002181 28380042 YES miannu  Usp16 is a TTK phosphorylation substrate.  0.371 SIGNOR-277351 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT down-regulates activity dephosphorylation Tyr730 DMKPGVSyVVPTKAD -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254710 SMARCE1 protein Q969G3 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.791 SIGNOR-270744 CDK2 protein P24941 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr821 KISEGLPtPTKMTPR 9606 SIGNOR-C83 9139732 YES miannu We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. 0.884 SIGNOR-47895 CSNK2B protein P67870 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser575 AGESLDQsMEEEEEE 9606 BTO:0000567 12591939 YES llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 0.327 SIGNOR-251063 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Ser224 EKSYRHRsAFIVHKR 9606 BTO:0002552 31399647 YES miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. 0.2 SIGNOR-276755 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates quantity binding 9606 14960576 YES amattioni Smac/diablo selectively causes the rapid degradation of c-iap1 and c-iap2 in hela cells. Smac binding to c-iap via its n-terminal iap-binding motif is the prerequisite for this effect 0.791 SIGNOR-121886 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 22021368 NO apalma In normal hematopoiesis, AML1 suppresses NF-κB signaling and thus may contribute to inhibition of excessive proliferation of hematopoietic cells. 0.7 SIGNOR-255692 terazosin chemical CHEBI:9445 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001260 9379432 YES miannu Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication 0.8 SIGNOR-258669 RNF31 protein Q96EP0 UNIPROT CASP1 protein P29466 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0005111 32122970 YES miannu HOIP forms a constitutive interaction with caspase-1 and mediates the linear ubiquitination of the CARD pro-domain. Upon engagement of apoptosis, caspase-1 and caspase-8 cleave HOIP at Asp-348 and Asp-387, limiting the ability of LUBAC to ubiquitinate substrates. 0.2 SIGNOR-272191 wortmannin chemical CHEBI:52289 ChEBI MYLK protein Q15746 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207791 SRC protein P12931 UNIPROT FHIT protein P49789 UNIPROT up-regulates activity phosphorylation Tyr114 FHRNDSIyEELQKHD -1 15835917 YES lperfetto The human tumor suppressor Fhit is a homodimeric histidine triad (HIT) protein of 147 amino acids which has Ap3A hydrolase activity. We have recently discovered that Fhit is phosphorylated in vivo and is phosphorylated in vitro by Src kinaseMALDI-TOF and HPLC-ESI tandem mass spectrometry of intact Fhit and proteolytic peptides of Fhit demonstrated that Fhit is phosphorylated on Y114 on either one or both subunitsThe decreases in the values of Km and kcat for the phosphorylated forms in comparison to those of unphosphorylated Fhit favor the formation and lifetime of the Fhit_Ap3A complex, which may enhance the tumor suppressor activity of Fhit. 0.467 SIGNOR-247134 tamsulosin chemical CHEBI:9398 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258470 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR DUSP1 protein P28562 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001103 17158101 NO Andrea Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis 0.275 SIGNOR-255744 BRCA1 protein P38398 UNIPROT ACACA protein Q13085 UNIPROT down-regulates activity binding -1 phosphorylation: ser1263 FSDSPPQsPTFPEAG 16698035 YES ACCA binds BRCA1 when phosphorylated onSer1263, thus supporting a model in which controlof lipid synthesis would be mediated at least in part,viaphosphorylation of the Ser1263. 0.549 SIGNOR-267474 CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18697834 NO Simone Vumbaca we showed that β-catenin, a key component of the canonical Wnt-signalling cascade, is present in quiescent satellite cells in the inactive form, but subsequently becomes activated following satellite-cell activation. This observation suggests that the proliferation initiated by the Wnt-signalling cascade does not have to rely on transcription of β-catenin, but rather on activation of this protein, which is already present within the quiescent satellite cells. 0.7 SIGNOR-255654 ABL2 protein P42684 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr686 IITEYCRyGDLVDYL -1 19275932 YES miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  0.303 SIGNOR-276140 KIF5C protein O60282 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 NO miannu The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue. 0.7 SIGNOR-264066 SPI1 protein P17947 UNIPROT ITGAM protein P11215 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12393465 NO apalma CD11b is regulated by PU.1 and its promoter contains putative binding sites of AML1. In this case AML1-ETO interaction and down-regulation of important myeloid transcription factors like PU.1 and AML1 could explain the lower CD11b expression 0.577 SIGNOR-255661 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258111 PTPRJ protein Q12913 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 12062403 YES Primary sequence determinants responsible for site-selective dephosphorylation of the PDGF beta-receptor by the receptor-like protein tyrosine phosphatase DEP-1|DEP-1 dephosphorylation of original and chimeric phospho-peptides spanning the preferred pY1021 0.581 SIGNOR-248704 RUNX2 protein Q13950 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 NO gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast 0.427 SIGNOR-107166 AMOTL2 protein Q9Y2J4 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 9606 BTO:0000007 phosphorylation:Tyr107 KGEELPTyEEAKAHS 21937427 YES lperfetto These data support an idea that Amotl2 Tyr-103 can be phosphorylated by FGF receptor tyrosine kinase activity. We then determined whether Amotl2 Tyr-103 is required for its interaction with c-Src. |Amotl2 promotes MAPK/ERK activation via c-Src, which is dependent on phosphorylation of tyrosine residue at position 103 but independent of the C-terminal PDZ-binding domain. 0.259 SIGNOR-271870 PAMPs stimulus SIGNOR-ST11 SIGNOR FCN2 protein Q15485 UNIPROT up-regulates activity binding -1 11907111 YES lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. 0.7 SIGNOR-263407 MRAP protein Q8TCY5 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor. 0.759 SIGNOR-252360 NAE complex SIGNOR-C131 SIGNOR CUL5 protein Q93034 UNIPROT up-regulates activity neddylation 9606 25504797 YES lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. 0.636 SIGNOR-243166 Caspase 1 complex complex SIGNOR-C220 SIGNOR IL1B protein P01584 UNIPROT up-regulates activity cleavage Asp27 DDLFFEAdGPKQMKC -1 1919001 YES lperfetto IL-1 converting enzyme (ICE) specifically cleaves the human IL-1 beta precursor at two sequence-related sites: Asp27-Gly28 (site 1) and Asp116-Ala117 (site 2). Cleavage at Asp116-Ala117 results in the generation of mature, biologically active IL-1 beta.  0.802 SIGNOR-256375 SRC protein P12931 UNIPROT CNKSR1 protein Q969H4 UNIPROT up-regulates activity phosphorylation Tyr665 KEQNRELySEGLGAW 26319181 YES lperfetto We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. 0.505 SIGNOR-275920 MTNR1B protein P49286 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.45 SIGNOR-256850 MAPK14 protein Q16539 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR -1 9543386 YES miannu P38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins. 0.439 SIGNOR-250091 ECM stimulus SIGNOR-ST20 SIGNOR A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259050 POMC protein P01189 UNIPROT MC4R protein P32245 UNIPROT up-regulates activity binding 9606 20694162 YES miannu α-MSH can activate both melanocortin 4 receptors (MC4R) and melanocortin 1 receptors (MC1R) 0.777 SIGNOR-252373 PRKG1 protein Q13976 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization 0.274 SIGNOR-186788 CSNK2A1 protein P68400 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates phosphorylation Ser2 sGDEMIFD 9606 BTO:0000567 16225457 YES lperfetto The n-terminal domain of the human eif2beta subunit and the ck2 phosphorylation sites are required for its function. These results suggest that ser2 and ser67 contribute to the important role of the n-terminal region of eif2beta for its function in mammals. 0.35 SIGNOR-140994 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269374 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-209992 GIGYF2 protein Q6Y7W6 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 20670374 YES miannu We demonstrated that, in cultured cells and mammalian brains, GIGYF2 interacts and colocalises with Grb10, promoting ligand‐induced ubiquitination of IGF‐1R, and thereby regulates receptor degradation 0.597 SIGNOR-260057 SIAH1 protein Q8IUQ4 UNIPROT KHDRBS3 protein O75525 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 15163637 YES miannu We found that SIAH1 bound to an octapeptide sequence in T-STAR targeting it for proteasome-dependent degradation.  0.473 SIGNOR-272671 RPL11 protein P62913 UNIPROT TP73 protein O15350 UNIPROT up-regulates binding 9606 25301064 YES miannu We report that rpl5 and rpl11 can also enhance the transcriptional activity of a p53 homolog tap73 0.359 SIGNOR-205514 bosutinib chemical CHEBI:39112 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001056 23409026 YES miannu Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. 0.8 SIGNOR-259271 AP-2 complex complex SIGNOR-C245 SIGNOR Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 10116 BTO:0000142 15496985 NO lperfetto Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples 0.7 SIGNOR-260416 PRKCZ protein Q05513 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates activity phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000007 9512493 YES lperfetto The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells. 0.545 SIGNOR-248996 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Tyr934 PAHASDEiYEIMQKC 9606 19275932 YES Manara C-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970) | These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis. 0.526 SIGNOR-260931 CUL3 protein Q13618 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 YES miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. 0.315 SIGNOR-268846 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules 0.704 SIGNOR-251601 GATA1 protein P15976 UNIPROT ZNF268 protein Q14587 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001271 22235304 NO miannu Here we found that gata-1, a master regulator of erythropoiesis, repressed the promoter activity and transcription of znf268 0.371 SIGNOR-195410 RAGAC complex SIGNOR-C113 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity relocalization 9606 20381137 YES gcesareni The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb 0.688 SIGNOR-228158 SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 11073979 NO ggiuliani As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B) 0.582 SIGNOR-255783 CNR1 protein P21554 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257346 N-(4-methoxyphenyl)sulfonyl-N-[2-[2-(1-oxido-4-pyridin-1-iumyl)ethenyl]phenyl]acetamide chemical CHEBI:91440 ChEBI PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193309 PAK1 protein Q13153 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 12876277 YES lperfetto We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation. 0.58 SIGNOR-244924 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser985 SNVSPAIsIHEIGAV -1 10487978 YES miannu Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation) 0.2 SIGNOR-250282 NFASC protein O94856 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 YES miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. 0.744 SIGNOR-266717 Non-structural protein 10 protein P0C6X7-PRO_0000037317 UNIPROT MT-CO2 protein P00403 UNIPROT down-regulates activity binding 9606 16157265 YES lperfetto This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication. 0.2 SIGNOR-260254 LPAR2 protein Q9HBW0 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257257 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.893 SIGNOR-248626 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser428 GPQRERKsSSSSEDR 9606 10869359 YES lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf 0.2 SIGNOR-244160 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 8069916 YES gcesareni Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. 0.719 SIGNOR-33133 SPRY1 protein O43609 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates binding 9606 11585837 YES gcesareni Taken together, these results establish mammalian sprouty proteins as important negative regulators of growth factor signaling and suggest that sprouty proteins act downstream of the grb2.Sos Complex to selectively uncouple growth factor signals from ras activation and the map kinase pathway. 0.386 SIGNOR-110948 PTPRS protein Q13332 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 NO miannu LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance 0.7 SIGNOR-264091 SMARCB1 protein Q12824 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.839 SIGNOR-270755 CDK4 protein P11802 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by destabilization phosphorylation Ser105 AYTPPPVsPRFSFPG 9606 BTO:0000567 21447557 YES miannu Finally, CDK4 phosphorylated GATA4 directly, which promoted the degradation of GATA4 in cultured cells. 0.356 SIGNOR-276317 E2F1 protein Q01094 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 23213415 YES gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes 0.652 SIGNOR-199952 ITGB4 protein P16144 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.583 SIGNOR-257720 CDK1 protein P06493 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 YES gcesareni We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5 0.3 SIGNOR-173677 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Thr216 RSSSSEStGTPSNPD 9606 11983168 YES fstefani Cyclin g also binds in vivo and in vitro to mdm2 and markedly stimulates the ability of pp2a to dephosphorylate mdm2 at t216. Our data imply that the function of cyclin g is to serve as a negative regulator of p53 by activating mdm2 through dephosphorylation. 0.398 SIGNOR-86736 CSNK2B protein P67870 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 BTO:0000938 BTO:0000142 23374587 YES The effect has been demonstrated using Q01105-2 miannu Ckii-mediated phosphorylation at ser9 hinders nuclear import of set 0.246 SIGNOR-200806 PRKG2 protein Q13237 UNIPROT PTS protein Q03393 UNIPROT up-regulates phosphorylation Ser19 AQVSRRIsFSASHRL 9606 10531334 YES gcesareni Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps 0.528 SIGNOR-71751 PCSK1 protein P29120 UNIPROT IAPP protein P10997 UNIPROT up-regulates activity cleavage Lys72 VGSNTYGkRNAVEVL -1 10931181 YES lperfetto The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule 0.446 SIGNOR-261782 SWI/SNF complex complex SIGNOR-C92 SIGNOR CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12138206 NO irozzo INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex [.]. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G(0)-G(1) arrest. These results together indicate that cyclin D1 is a direct target for repression by INI1/hSNF5. 0.5 SIGNOR-256293 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 10913154 YES lperfetto Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition 0.844 SIGNOR-251510 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NOS2 protein P35228 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 NO apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. 0.453 SIGNOR-255353 VEPH1 protein Q14D04 UNIPROT LATS2 protein Q9NRM7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 NO In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 0.2 SIGNOR-177077 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 YES lperfetto Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. 0.2 SIGNOR-244699 carbachol chemical CHEBI:3385 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258620 CDK11A protein Q9UQ88 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser174 TPAVPPVsEDEDDDD 19520772 YES lperfetto CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression|We show that PAK1 is a substrate of CDK11p58 and can be strongly activated upon phosphorylation. 0.385 SIGNOR-273026 ATP smallmolecule CHEBI:15422 ChEBI PRKAG1 protein P54619 UNIPROT down-regulates chemical inhibition 9606 SIGNOR-C15 21399626 YES gcesareni Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive 0.8 SIGNOR-172822 ATM protein Q13315 UNIPROT WRAP53 protein Q9BUR4 UNIPROT up-regulates activity phosphorylation Ser64 PVAGSAVsQELREGD 9606 BTO:0001938 27715493 YES done miannu Here, we show that in response to various types of DNA damage, including IR and UV, WRAP53β is phosphorylated on serine residue 64 by ATM with a time-course that parallels its accumulation at DNA lesions. Interestingly, recruitment of phosphorylated WRAP53β (pWRAP53βS64) to sites of such DNA damage promotes its interaction with γH2AX at these locations.  0.338 SIGNOR-273511 MAPK14 protein Q16539 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser7 sPAPLSPL 9606 22128155 YES gcesareni Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin 0.52 SIGNOR-177927 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 NO apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. 0.7 SIGNOR-255580 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR PDGFA protein P04085 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 YES miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. 0.2 SIGNOR-251567 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser141 TVKQKYLsFTPPEKD -1 10075701 YES miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. 0.2 SIGNOR-250228 KDM4B protein O94953 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 NO miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. 0.2 SIGNOR-263730 P2RY11 protein Q96G91 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257386 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 12586835 YES gcesareni The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424). 0.385 SIGNOR-98215 SLBP protein Q14493 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265417 MMP26 protein Q9NRE1 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272370 MECP2 protein P51608 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 NO miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 0.37 SIGNOR-254579 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G2 protein P78344 UNIPROT up-regulates activity stabilization 9606 17581632 YES lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 0.386 SIGNOR-269156 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM31 protein Q9BZY9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270979 TLN1 protein Q9Y490 UNIPROT ITGB4 protein P16144 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.494 SIGNOR-257627 pazopanib hydrochloride chemical CHEBI:71217 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 17620431 YES miannu The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. 0.8 SIGNOR-259168 BAIAP2 protein Q9UQB8 UNIPROT ENAH protein Q8N8S7 UNIPROT up-regulates activity binding 9606 BTO:0000452 11696321 YES miannu We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia. 0.568 SIGNOR-268423 PRKCB protein P05771 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 YES gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619. 0.443 SIGNOR-37474 CIB2 protein O75838 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR up-regulates activity binding 9606 35408910 YES miannu So far, two integrins have been found to interact with CIB2: αIIbβ3 is expressed by platelets and megakaryocytes and, apparently, a common target for all CIB family members, at odds with α7Bβ1D, which seems to be CIB2-specific and is expressed in skeletal muscles. 0.2 SIGNOR-269668 PRKD3 protein O94806 UNIPROT GIT1 protein Q9Y2X7 UNIPROT unknown phosphorylation Ser46 RSLGRHIsIVKHLRH 9606 22893698 YES lperfetto We propose that phosphorylation of git1 on serine 46 by pkd3 represents a molecular switch by which git1 localization, paxillin trafficking, and cellular protrusive activity are regulated. 0.361 SIGNOR-191839 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 9606 BTO:0000007 22863277 NO inferred from 70% of family members milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. 0.8 SIGNOR-269864 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity precursor of 9606 24786789 YES miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. 0.8 SIGNOR-266509 CKM complex complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.383 SIGNOR-273159 Laminin-5 complex SIGNOR-C184 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.546 SIGNOR-253219 PTPN13 protein Q12923 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation 9606 19307596 YES miannu Mechanistically, RIL suppresses Src activation through interacting with Src and PTPL1, allowing PTPL1 dependent dephosphorylation of Src at the activation loop.|Our results reveal a novel Src inactivation cycle in which reversion-induced LIM preferentially recognizes active Src and facilitates PTPL1-mediated inactivation of Src. 0.539 SIGNOR-277125 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 14701756 YES gcesareni These results suggest that chip can interact with the smad1/smad4 proteins and block bmp signal transduction through the ubiquitin-mediated degradation of smad proteins. 0.329 SIGNOR-120731 LRSAM1 protein Q6UWE0 UNIPROT TSG101 protein Q99816 UNIPROT down-regulates quantity monoubiquitination 9606 BTO:0000007 15256501 YES miannu Tal increases ubiquitylation of Tsg101 and affects its solubility in a RING- and PTAP-dependent manner.  Tal-mediated ubiquitylation of Tsg101 inactivates this sorting function and concomitantly translocates Tsg101 from relatively insoluble membrane subdomains. Presumably, the coordinated action of Tal and a deubiquitylation enzyme (DUB) enables recycling of Tsg101 and reloading of cargo. 0.528 SIGNOR-271509 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser4 sPLSKKRR 9606 9099746 YES lperfetto Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1 0.406 SIGNOR-47162 Ub:E2 complex SIGNOR-C497 SIGNOR RNF111 protein Q6ZNA4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271010 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. 0.8 SIGNOR-266499 GTF2H1 protein P32780 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 YES lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.905 SIGNOR-269316 CHAMP1 protein Q96JM3 UNIPROT MAD2L2 protein Q9UI95 UNIPROT up-regulates activity binding 9606 21063390 YES miannu Here, we report a novel regulator for accurate chromosome segregation, chromosome alignment-maintaining phosphoprotein (CAMP). We identified CAMP as a MAD2L2-interacting protein. Spindle localization of MAD2L2 was abrogated by CAMP depletion (Supplementary Figure S2A) 0.498 SIGNOR-264904 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2L5 protein A0A1B0GUS4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271365 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 NO lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin 0.393 SIGNOR-250561 EIF2B2 protein P49770 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.801 SIGNOR-269125 ZNRF3 protein Q9ULT6 UNIPROT FZD4 protein Q9ULV1 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 YES Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. 0.564 SIGNOR-260115 PRKAA1 protein Q13131 UNIPROT DNMT1 protein P26358 UNIPROT down-regulates activity phosphorylation Ser714 DNIPEMPsPKKMHQG -1 28143904 YES lperfetto Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity 0.2 SIGNOR-264783 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120052 seliciclib chemical CHEBI:45307 ChEBI TP53 protein P04637 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206577 HAUS6 protein Q7Z4H7 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 19029337 NO miannu FAM29A interacts with the NEDD1-gamma-tubulin complex and recruits this complex to the spindle, which, in turn, promotes MT polymerization. 0.7 SIGNOR-261420 Caspase 8 complex complex SIGNOR-C231 SIGNOR CYCS protein P99999 UNIPROT up-regulates activity 9606 BTO:0000661 10364179 NO Translocation from Mitochondria to Cytosol lperfetto Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect. 0.48 SIGNOR-256473 L-serine chemical CHEBI:17115 ChEBI PKM protein P14618 UNIPROT up-regulates activity chemical activation 9606 23064226 YES We show that serine can bind to and activate human PKM2, and that PKM2 activity in cells is reduced in response to serine deprivation. 0.8 SIGNOR-251557 GFI1 protein Q99684 UNIPROT CYP27B1 protein O15528 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15947108 NO miannu Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells. 0.2 SIGNOR-254205 RFX complex complex SIGNOR-C104 SIGNOR HLA-DMA protein P28067 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.327 SIGNOR-253993 DDHD2 protein O94830 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269652 Erythrocytic spectrin complex SIGNOR-C384 SIGNOR Cell_shape phenotype SIGNOR-PH182 SIGNOR up-regulates 9606 24302288 NO lperfetto Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes. 0.7 SIGNOR-266032 NCBP2 protein P52298 UNIPROT Cap-binding complex complex SIGNOR-C440 SIGNOR form complex binding 9606 26382858 YES lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 0.969 SIGNOR-268358 COX5B protein P10606 UNIPROT Oxidative_phosphorylation phenotype SIGNOR-PH78 SIGNOR up-regulates 10090 23021218 NO lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 0.7 SIGNOR-253102 ABCA7 protein Q8IZY2 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 9606 27472885 NO miannu Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD. 0.7 SIGNOR-265175 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation 9606 20208177 YES Pyruvate dehydrogenase phosphatase (PDP) is a mitochondrial serine phosphatase that activates phosphorylated pyruvate dehydrogenase complex by dephosphorylation 0.732 SIGNOR-251664 PRKDC protein P78527 UNIPROT JUN protein P05412 UNIPROT unknown phosphorylation Ser249 LSPIDMEsQERIKAE -1 8464713 YES lperfetto Here, we show that the DNA-PK modifies c-Jun in vitro and that serine residue 249 (Ser-249) is required for phosphorylation to occur. This residue corresponds to one of three sites of c-Jun that are phosphorylated in vivo and which negatively regulate c-Jun DNA binding in vitro. However, we find that phosphorylation of c-Jun by the DNA-PK does not interfere with DNA binding, indicating that phosphorylation at other sites is required for this effect. 0.407 SIGNOR-248934 NMDA receptor_2A complex SIGNOR-C347 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264132 PEX6 protein Q13608 UNIPROT PEX1 protein O43933 UNIPROT up-regulates activity binding 10029 12717447 YES Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions. 0.669 SIGNOR-253615 WNT6 protein Q9Y6F9 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 NO fspada We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b 0.462 SIGNOR-176193 FHIT protein P49789 UNIPROT AKT2 protein P31751 UNIPROT down-regulates 9606 BTO:0000551 16407838 NO miannu Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis 0.249 SIGNOR-143703 risperidone chemical CHEBI:8871 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258525 LTB4R protein Q15722 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257086 RASSF1 protein Q9NS23 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates binding 9606 21808241 YES Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage milica Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization. 0.806 SIGNOR-269950 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1716180 YES lperfetto Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response. 0.484 SIGNOR-21324 GAPDH protein P04406 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity chemical modification 9606 11724794 YES miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion 0.8 SIGNOR-266494 CSNK2A1 protein P68400 UNIPROT NKX2-5 protein P52952 UNIPROT up-regulates activity phosphorylation Ser164 FKQQRYLsAPERDQL 9534 BTO:0004055 9858576 YES llicata Mutational analysis and in vitro kinase assays suggested that this 40-kDa Csx/Nkx2.5 kinase is a catalytic subunit of casein kinase II (CKII) that phosphorylates the serine residue between the first and second helix of the homeodomain. This CKII site is phosphorylated in vivo. CKII-dependent phosphorylation of the homeodomain increased Csx/Nkx2. 5 DNA binding. Serine-to-alanine mutation at the CKII phosphorylation site reduced transcriptional activity when the carboxyl-terminal repressor domain was deleted. 0.333 SIGNOR-250924 SLBP protein Q14493 UNIPROT H2AJ protein Q9BTM1 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265412 YAP1 protein P46937 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 YES Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4 gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. 0.85 SIGNOR-201471 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.43 SIGNOR-145128 DPM3 protein Q9P2X0 UNIPROT DPM complex complex SIGNOR-C289 SIGNOR form complex binding 9606 10835346 YES lperfetto Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. 0.786 SIGNOR-262565 diazepam chemical CHEBI:49575 ChEBI GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. 0.8 SIGNOR-263799 XRCC6 protein P12956 UNIPROT PRKDC protein P78527 UNIPROT up-regulates relocalization 9606 19133841 YES gcesareni Ku and dna-pkcs only interact in the presence of dna and recruitment of dna-pkcs to sites of dna damage in vivo is ku-dependent. Inward translocation of ku allows dna-pkcs to interact with the extreme termini of the dna, allowing two dna-pkcs molecules to interact across the dsb in a so-called synaptic complex . This interaction stimulates the kinase activity of dna-pkcs, promoting phosphorylation in trans across the dsb (discussed in more detail below). Once assembled at the dna ends, the dna-pkcs-ku-dsb complex serves to tether the ends of the dsb together and protects the dna ends from nuclease attack. 0.94 SIGNOR-183276 CAMK2A protein Q9UQM7 UNIPROT CD44 protein P16070 UNIPROT up-regulates activity phosphorylation Ser706 LNGEASKsQEMVHLV 9606 BTO:0000452 11463356 YES lperfetto In previous studies we have demonstrated that a key control point for this receptor is the phosphorylation of CD44 on a conserved cytoplasmic serine residue, Ser(325). This modification is not required for efficient ligand binding, but is an essential component of CD44-dependent cell migration on a hyaluronan substratum. We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase. 0.2 SIGNOR-109502 KAT6A protein Q92794 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0001271 SIGNOR-C54 23431171 YES miannu We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression 0.668 SIGNOR-201486 PKNOX1 protein P55347 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20864515 NO miannu Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content. 0.2 SIGNOR-254924 FANCD2 protein Q9BXW9 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates activity binding 9606 BTO:0005035 phosphorylation:Ser331 KSKGRASsSGNQESS 19861535 YES lperfetto Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction 0.812 SIGNOR-263238 ANGPTL1 protein O95841 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 15284220 YES gcesareni In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2. 0.507 SIGNOR-127354 3-[8-amino-1-(2-phenyl-7-quinolinyl)-3-imidazo[1,5-a]pyrazinyl]-1-methyl-1-cyclobutanol chemical CHEBI:91402 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193675 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE 9606 10377430 YES lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. 0.764 SIGNOR-252872 AMPK complex SIGNOR-C15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 17900900 YES lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation 0.351 SIGNOR-216484 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser37 EDLTDELsLNKISAD -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.2 SIGNOR-276207 MSN protein P26038 UNIPROT MSN/PDZD8 complex SIGNOR-C61 SIGNOR form complex binding 9606 21549406 YES miannu These results demonstrated that both human moesin and its newly identified binding partner, pdzd8 had similar effects on host mt networks, suggesting that they are likely to function as part of a stable mt regulatory complex. 0.318 SIGNOR-173647 MAPK10 protein P53779 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 NO gcesareni Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria; these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins. 0.26 SIGNOR-124001 TRIM23 protein P36406 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 BTO:0003682 19176615 YES miannu We show here that the upregulation of NF-kappaB by UL144 is dependent upon cellular tripartite motif 23 (TRIM23) protein. We propose a mechanism by which UL144 activates NF-kappaB through a direct interaction with the cellular protein TRIM23 in a complex containing TRAF6. we propose that TRIM23 mediates TRAF6 autoubiquitination in the presence of UL144, resulting in the virally controlled activation of NF-κB stimulation at early times of HCMV infection. 0.313 SIGNOR-266655 CDK1 protein P06493 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser76 EEEDEALsPAKGQKP 9606 BTO:0000567 12851383 YES lperfetto We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner. 0.364 SIGNOR-103242 PLCB1 protein Q9NQ66 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification -1 23880553 YES miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. 0.8 SIGNOR-256497 EMX1 protein Q04741 UNIPROT NRP1 protein O14786 UNIPROT up-regulates quantity by expression transcriptional regulation -1 26534986 YES Luana EMX1 activates the transcription of Nrp1 in vitro. 0.2 SIGNOR-261593 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser3205 TPLPEDNsMNVDQDG 9606 BTO:0000773 12186630 YES lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. 0.2 SIGNOR-249157 WWP1 protein Q9H0M0 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25071155 YES miannu WWP1 in complex with WWP2 specifically regulates ΔNp73.  In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.  0.283 SIGNOR-272232 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 22798428 YES gcesareni Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr. 0.699 SIGNOR-252531 SIRT7 protein Q9NRC8 UNIPROT RAN protein P62826 UNIPROT down-regulates activity deacetylation Lys37 HLTGEFEkKYVATLG 31075303 YES Ran ID inferred from sequence: KRHLTGEFEKKYVATLGVEV lperfetto N this study, we demonstrated that SIRT7 interacts with a small GTPase, Ras-related nuclear antigen (Ran), and deacetylates Ran at K37. |The nuclear export by CRM1 requires an interaction with the small GTPase Ras-related nuclear antigen (Ran), which cycles between GTP- and GDP-bound states. The binding of Ran GTP to CRM1 in the nucleus increases the affinity of CRM1 for cargo proteins [[18], [19], [20]]. Interestingly, Ran is a lysine-acetylated protein 0.2 SIGNOR-275849 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258921 IL22 protein Q9GZX6 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 12941475 YES fspada In addition, il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4. 0.893 SIGNOR-86340 CSNK2A1 protein P68400 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser261 TSGEDTLsDSDDEDD -1 1425701 YES llicata Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263. 0.447 SIGNOR-250920 EGFR protein P00533 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr354 LMLRLQDyEEKTKKA 9606 BTO:0000017 15647376 YES lperfetto Ezrin was initially identified as a substrate for tyrosine phosphorylation by egfr (bretscher, 1989) and phosphorylation of residues y145 and y353 were detected to high stoichiometry after egf treatment . Phosphorylation of ezrin at y353 has been delineated to signal survival during epithelial cell differentiation via the phosphatidylinositol 3-kinase (pi3k)/akt pathway. 0.53 SIGNOR-133215 MEF2A protein Q02078 UNIPROT MYH10 protein P35580 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.317 SIGNOR-238763 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-267529 SOX6 protein P35712 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26893351 YES We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST 0.292 SIGNOR-255824 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0004300 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor 0.7 SIGNOR-256229 MYC protein P01106 UNIPROT CDK4 protein P11802 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12835716 YES gcesareni C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation 0.57 SIGNOR-102734 SRC protein P12931 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Tyr45 GLEPVGHyEEVELTE 9606 16640565 YES llicata Src kinase phosphorylates s6k in the n-terminus. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vitro. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vivo. 0.342 SIGNOR-146292 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser321 NSNASTVsGRLSPIM 9606 20110348 YES lperfetto Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export 0.2 SIGNOR-163676 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser142 AVSDSLPsNSLKKSS 9606 BTO:0000671 12628002 YES lperfetto Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149) 0.702 SIGNOR-99135 ADAMTS4 protein O75173 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Glu392 PRNITEGeARGSVIL 9606 9202061 YES lperfetto Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE373 0.766 SIGNOR-266984 nitrendipine chemical CHEBI:7582 ChEBI KCNN4 protein O15554 UNIPROT down-regulates activity chemical inhibition 9606 9730970 YES miannu IK was blocked by the classical inhibitors of the Gardos channel charybdotoxin (IC50 28 nM) and clotrimazole (IC50 153 nM) as well as by nitrendipine (IC50 27 nM), Stichodactyla toxin (IC50 291 nM), margatoxin (IC50 459 nM), miconazole (IC50 785 nM), econazole (IC50 2.4 microM), and cetiedil (IC50 79 microM). Finally, 1-ethyl-2-benzimidazolinone, an opener of the T84 cell IK channel, activated hIK with an EC50 of 74 microM. 0.8 SIGNOR-258831 SSTR4 protein P31391 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.503 SIGNOR-256680 CDK1 protein P06493 UNIPROT RAB1A protein P62820 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 1902553 YES Giulio We now present biochemical evidence for a mitosis-specific p34cdc2 phosphorylation of RablAp and Rab4p.We also show that the distribution of RablAp and Rab4p between cytosolic and membrane-bound forms is different in interphase and mitotic cells. 0.524 SIGNOR-261284 FOXO proteinfamily SIGNOR-PF27 SIGNOR Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 15109499 NO gcesareni Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. 0.7 SIGNOR-252932 Caspase 8 complex complex SIGNOR-C231 SIGNOR BID protein P55957 UNIPROT up-regulates activity cleavage Asp60 GYDELQTdGNRSSHS 9606 BTO:0000093 9727492 YES amattioni Caspase-8 cleaves bid at aspartic acid residue 60 (asp60) cleavage of bid by casp8 releases its potent proapoptotic activity 0.879 SIGNOR-256443 TBR1 protein Q16650 UNIPROT AUTS2 protein Q8WXX7 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 20615956 YES miannu Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. 0.359 SIGNOR-266836 CFH protein P08603 UNIPROT CRP protein P02741 UNIPROT down-regulates activity binding 9606 BTO:0004910 26961257 YES miannu In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. 0.552 SIGNOR-252145 CDK1 protein P06493 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr219 ASLSLPAtPVGKGTE -1 12556484 YES done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites 0.659 SIGNOR-274074 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1542 EEQQLEEsGPHDLTE 9606 BTO:0000150 10550055 YES lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm 0.819 SIGNOR-72072 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser396 NTVDLHIsNSHPLSL -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.822 SIGNOR-178399 TAP1 protein Q03518 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity relocalization 9606 31810556 YES scontino Following cytosolic proteolysis, antigenic peptides are recruited to the ER and translocated to its lumen by the Transporter associated with Antigen Processing (TAP). 0.8 SIGNOR-267778 PHA-680632 chemical CID:11249084 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206097 IL1RL1 protein Q01638 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 YES miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  0.654 SIGNOR-277704 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-203476 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT up-regulates activity deacetylation Lys67 ANVKAAPkIIDTGGG 9606 BTO:0002806 30327428 YES miannu SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR 0.512 SIGNOR-262294 A4/b1 integrin complex SIGNOR-C162 SIGNOR JAG1 protein P78504 UNIPROT up-regulates quantity by expression 10090 25786978 NO lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. 0.302 SIGNOR-253287 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 18372406 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.703 SIGNOR-178141 PLK1 protein P53350 UNIPROT WDCP protein Q9H6R7 UNIPROT up-regulates activity phosphorylation Ser686 RSDVFRDsFSHSPGA 9606 BTO:0000007 30297404 YES miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. we performed in vitro kinase assays followed by mass spectrometry and found that two sites (S686 and S695) in this cluster were phosphorylated. Thus, all of these results are in agreement that this cluster is phosphorylated by PLK1. 0.2 SIGNOR-273730 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001321 11909978 YES NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. 0.264 SIGNOR-253667 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr457 YVSPRIStPQTNTVP 9606 BTO:0000567 30021153 YES lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. 0.2 SIGNOR-265035 ARHGAP4 protein P98171 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.478 SIGNOR-260460 TERF1 protein P54274 UNIPROT Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 15383534 YES lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. 0.753 SIGNOR-263316 MAML1 protein Q92585 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 17300219 YES gcesareni The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. 0.2 SIGNOR-265362 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18719589 NO induction of mitochondrial biogenesis fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways 0.289 SIGNOR-180314 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 10090 BTO:0000944 11579209 YES lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. 0.788 SIGNOR-235499 AKT1 protein P31749 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 31057087 YES miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 0.2 SIGNOR-259405 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser346 DRSDIESsSDEEDSE 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273992 CRX protein O43186 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation -1 18849347 NO miannu Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. 0.368 SIGNOR-253815 RRAGC protein Q9HB90 UNIPROT RAGBC complex SIGNOR-C115 SIGNOR form complex binding 9606 20381137 YES gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant 0.792 SIGNOR-228173 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser174 LRKGTLGsKGQKTTQ -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273492 SL-327 chemical CHEBI:92211 ChEBI MAP2K5 protein Q13163 UNIPROT down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 YES gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. 0.8 SIGNOR-104933 LCK protein P06239 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 17998336 YES gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. 0.565 SIGNOR-159168 OTUB1 protein Q96FW1 UNIPROT UBE2N protein P61088 UNIPROT down-regulates binding 9606 21763684 YES gcesareni The deubiquitinating enzyme otub1 suppresses rnf168 dependent ubiquitination by direct the e2 ligase ubc13 0.706 SIGNOR-175050 ULK1 protein O75385 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 YES gcesareni Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit. 0.503 SIGNOR-173050 IL12A protein P29459 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 YES gcesareni Like il-12, il-23 binds to the il-12r subunit il-12rbeta1. 0.571 SIGNOR-87677 RABGEF1 protein Q9UJ41 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 27411398 YES lperfetto AP-1/sigma1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation. 0.923 SIGNOR-260707 zolmitriptan chemical CHEBI:10124 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 10193663 YES Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  0.8 SIGNOR-258341 NFATC2 protein Q13469 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11796223 YES lperfetto Upon dephosphorylation by calcineurin, nfatc2, also referred to as nfatp/nfat1, translocates to the nucleus where it directly associates with mef2a and -d. Nfatc2 stimulates mef2-dependent transcription by facilitating recruitment of the p300 coactivator to mef2-response elements. 0.582 SIGNOR-117589 STK33 protein Q9BYT3 UNIPROT AKAP3 protein O75969 UNIPROT up-regulates quantity by stabilization phosphorylation -1 37146716 YES lperfetto Differential phosphoproteomic analysis and in vitro kinase assay identified novel phosphorylation substrates of STK33, fibrous sheath components AKAP3 and AKAP4, whose expression levels decreased in testis after deletion of Stk33. 0.2 SIGNOR-272955 CAMK2A protein Q9UQM7 UNIPROT ID1 protein P41134 UNIPROT up-regulates activity phosphorylation Ser36 GEVVRCLsEQSVAIS 9606 BTO:0001620 29079782 YES miannu Here we show that CaMKII can directly phosphorylate Beclin 1 at Ser90 to promote K63-linked ubiquitination of Beclin 1 and activation of autophagy. 0.2 SIGNOR-277367 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257530 STK39 protein Q9UEW8 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 BTO:0000142 10980603 YES gcesareni Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress, 0.362 SIGNOR-81541 TSC22D3 protein Q99576 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 BTO:0000007 11468175 YES GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. 0.358 SIGNOR-253299 PHF2 protein O75151 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. 0.2 SIGNOR-264520 Ku-0063794 chemical CHEBI:85572 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 BTO:0000887;BTO:0001260 20884880 YES gcesareni Sgk-1 activation in response to stretch is blocked by insulin-like growth factor (igf)-1 receptor inhibitor and mammalian target of rapamycin complex (mtorc)2 inhibitor (ku-0063794) but not mtorc1 inhibitor (rapamycin). 0.8 SIGNOR-168188 SETBP1 protein Q9Y6X0 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 22566606 NO miannu Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors 0.42 SIGNOR-197321 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity precursor of 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271811 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr992 LSRGQEVyVKKTMGR -1 11513602 YES lperfetto Isoelectric focusing electrophoresis and mass spectrometric analysis of a tie2 autophosphorylation time course showed that tyr992 on the putative activation loop was phosphorylated first followed by tyr1108 in the c-terminal tail autophosphorylation of tie2 to produce ptie2 resulted in a 100-fold increase in kcat and a 460-fold increase in kcat/km. 0.2 SIGNOR-109790 SF3B3 protein Q15393 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 YES lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). 0.932 SIGNOR-268405 CIITA protein P33076 UNIPROT MYOG protein P15173 UNIPROT down-regulates binding 9606 BTO:0001103 28163303 YES apalma During early stages of myogenesis, CIITA binds directly to myogenin (MYOG) and inactivates it, preventing MYOG-mediated induction of myogenic genes that are required for muscle differentiation and function 0.2 SIGNOR-255111 HACD3 protein Q9P035 UNIPROT FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 YES Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, 0.2 SIGNOR-267762 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CACNB1 protein Q02641 UNIPROT up-regulates activity phosphorylation Ser348 IVYIKITsPKVLQRL 9534 BTO:0000298 16406008 YES miannu Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs. 0.2 SIGNOR-262965 EXOC3 protein O60645 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.932 SIGNOR-270778 EIF2B3 protein Q9NR50 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.734 SIGNOR-269136 SALL4 protein Q9UJQ4 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21526180 NO miannu we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples 0.265 SIGNOR-255122 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10230396 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.432 SIGNOR-67392 RUNX1 protein Q01196 UNIPROT GP1BA protein P07359 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17725493 NO miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. 0.401 SIGNOR-254195 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120040 PKA proteinfamily SIGNOR-PF17 SIGNOR NR5A2 protein O00482 UNIPROT up-regulates activity phosphorylation Ser510 LPEIRAIsMQAEEYL 9606 BTO:0000093 16109788 YES miannu  PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469.  0.2 SIGNOR-276041 ATM protein Q13315 UNIPROT NOP53 protein Q9NZM5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser233 ARLHTKPsQAPAVEV 9606 BTO:0000007 27829214 YES miannu PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1.  0.2 SIGNOR-273506 VARS1 protein P26640 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 30755602 YES miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 0.8 SIGNOR-270528 KIFC1 protein Q9BW19 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 33361741 NO miannu Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer 0.7 SIGNOR-266114 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR ATF2 protein P15336 UNIPROT up-regulates activity binding 9606 10085140 YES lperfetto Here we report that the transcription factor atf-2 (also called cre-bp1) is bound by a hetero-oligomer of smad3 and smad4 upon tgf-beta stimulation. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity. 0.597 SIGNOR-65583 Ub:E2 complex SIGNOR-C497 SIGNOR SCAF11 protein Q99590 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271007 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser64 PRGRPKGsKNKGAAK 9606 10617144 YES fspada In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64 0.263 SIGNOR-73610 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004408 15353555 NO miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. 0.7 SIGNOR-255682 KANK1 protein Q14678 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates activity binding 10090 BTO:0000944 19171758 YES miannu In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells. Kank interacts with IRSp53 through their coiled-coil domains. Kank affected the interaction between IRSp53 and Rac1 and partially affected that between IRSp53 and cdc42 (Fig. 3). 0.342 SIGNOR-265553 COL1A2 protein P08123 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.478 SIGNOR-253248 MEIS1 protein O00470 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 NO irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. 0.7 SIGNOR-255865 S100A4 protein P26447 UNIPROT MYH9 protein P35579 UNIPROT down-regulates activity binding 10090 BTO:0005138 16707441 YES miannu Our results show that S100A4 regulates cell polarization during directed motility by affecting the localization of protrusions through interactions with myosin-IIA, with S100A4 expressing cells displaying few side protrusions and extensive forward protrusions during chemotaxis compared with control cells. The mechanisms by which these antibodies and S100A4 increase protrusive activity and promote cellular motility are not well understood, but the observation that S100A4 can inhibit the actin-activated ATPase of myosin-IIA (34) suggests that S100A4 could function as a myosin-IIA inhibitor in vivo. 0.418 SIGNOR-269282 LNX1 protein Q8TBB1 UNIPROT KCNA4 protein P22459 UNIPROT down-regulates quantity by destabilization ubiquitination -1 22889411 YES miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.The C-terminal LNX1 PDZ1-binding motifs of the ATP-binding cassette, subfamily A member 1 (ABC-1), PBK, glutamate receptor, ionotropic, N-methyl d-aspartate 1 (GRIN1), and Claudin-17 significantly promoted the ubiquitination of the corresponding artificial degrons by LNX1ΔPDZ234. 0.283 SIGNOR-272899 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 10090 BTO:0002572 SIGNOR-C3 20670887 YES lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation 0.926 SIGNOR-167184 GGCX protein P38435 UNIPROT vitamin K epoxide smallmolecule CHEBI:28371 ChEBI up-regulates activity chemical modification 9606 31226734 YES lperfetto GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. 0.8 SIGNOR-265917 TRHR protein P34981 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0001379 23248581 YES scontino TRH receptors are textbook calcium-mobilizing receptors: they are coupled to Gq and G11, which activate phospholipase Cβ (PLCβ). 0.489 SIGNOR-267202 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr650 PMELEPMySNVNPGD -1 12051764 YES miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. 0.2 SIGNOR-274008 ALDH1A2 protein O94788 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity chemical modification 9606 21621639 YES lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. 0.8 SIGNOR-265126 ULK3 protein Q6PHR2 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 19878745 YES Manara We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro. | Our data suggest that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins. 0.672 SIGNOR-260797 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Met) smallmolecule CHEBI:29173 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270395 MAPK8 protein P45983 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 YES gcesareni Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation. 0.463 SIGNOR-145297 RPL36 protein Q9Y3U8 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.856 SIGNOR-262464 SLC38A9 protein Q8NBW4 UNIPROT leucine smallmolecule CHEBI:25017 ChEBI up-regulates quantity relocalization 9606 29053970 YES SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins 0.8 SIGNOR-255313 GSK3A protein P49840 UNIPROT MAF protein O75444 UNIPROT up-regulates phosphorylation 9606 18042454 YES miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. 0.2 SIGNOR-159358 KDM6A protein O15550 UNIPROT HOXC6 protein P09630 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.26 SIGNOR-260028 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation 9606 BTO:0000149 15886098 YES amattioni Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations. 0.694 SIGNOR-136958 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser683 TKEFFRRsKIAVFDK -1 8848293 YES lperfetto Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG). 0.708 SIGNOR-248954 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 10864927 YES lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.844 SIGNOR-216765 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe635 HHQKLVFfAEDVGSN -1 10605825 YES lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. 0.489 SIGNOR-261774 MYOG protein P15173 UNIPROT FBXO32 protein Q969P5 UNIPROT down-regulates activity binding 9534 19631210 YES llicata Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin. 0.512 SIGNOR-237854 PLCG1 protein P19174 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 17562871 NO gcesareni We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1. 0.538 SIGNOR-155747 CDC73 protein Q6P1J9 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 16630820 YES gcesareni Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo 0.694 SIGNOR-146282 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR ERCC3 protein P19447 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 30762924 YES miannu These results led us to propose a model that spironolactone may trigger the phosphorylation of XPB at Ser90 by CDK7, which promotes the recognition and polyubiquitination of XPB by SCFFBXL18 for proteasomal degradation. 0.421 SIGNOR-277435 PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 YES lperfetto Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellshere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo 0.481 SIGNOR-164642 MAPKAPK3 protein Q16644 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser244 PPLRRSPsRTEKQEE -1 15850461 YES miannu Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.482 SIGNOR-263082 Urotensin II smallmolecule CHEBI:80244 ChEBI UTS2R protein Q9UKP6 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257590 Vincristine sulfate chemical CHEBI:79401 ChEBI FN1 protein P02751 UNIPROT down-regulates activity chemical inhibition 9606 30599272 YES miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 0.8 SIGNOR-259252 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120108 imatinib methanesulfonate chemical CHEBI:31690 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;VIRAL ABL gcesareni 0.8 SIGNOR-193387 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation 0.886 SIGNOR-249484 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 17601773 YES lperfetto Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. 0.337 SIGNOR-217312 PTP4A3 protein O75365 UNIPROT EZR protein P15311 UNIPROT down-regulates activity dephosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0001109 18078820 YES Here we report the identification of Ezrin as a specific and direct cellular substrate of PRL-3. In HCT116 colon cancer cell line, Ezrin was identified among the cellular proteins whose phosphorylation level decreased upon ectopic over-expression of wtPRL-3 but not of catalytically inactive PRL-3 mutants. Although PRL-3 over-expression in HCT116 cells appeared to affect Ezrin phosphorylation status at both tyrosine residues and Thr567, suppression of the endogenous protein by RNA interference pointed to Ezrin-Thr567 as the residue primarily affected by PRL-3 action. 0.277 SIGNOR-248342 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE11A protein Q9HCR9 UNIPROT up-regulates activity phosphorylation Ser162 RALLRKAsSLPPTTA -1 18312413 YES miannu The N-terminus has two phosphorylation sites for cyclic nucleotide monophosphate-dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP-dependent protein kinase decreased the EC50 value for cGMP from 72 to 23 μm. Effect of phosphorylations at Ser117 and Ser162. Here, serine phosphorylation by the catalytic subunit of cAK, albeit not known whether at position 117, 162 or both, increased cGMP affinity about threefold. 0.2 SIGNOR-276179 PRKG2 protein Q13237 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Ser553 KNAHAKAsRTSSKHK 9606 BTO:0002181 21177494 YES miannu  PKGII directly phosphorylated and stimulated SHP-1 activity 0.2 SIGNOR-276288 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8422248 YES lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. 0.485 SIGNOR-248927 UBE2G2 protein P60604 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by destabilization ubiquitination 9606 BTO:0001379 29892818 YES inferred from family member scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. 0.2 SIGNOR-270244 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 24890514 NO apalma The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation 0.7 SIGNOR-255573 ULK1 protein O75385 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser88 LVMNMLKsSFATCVL 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274031 ATP8B1 protein O43520 UNIPROT ATP2B2 protein Q01814 UNIPROT up-regulates 9606 BTO:0000630 19478059 NO lperfetto Consequently ATP8B1 deficiency, with a secondary disturbance of membrane lipid asymmetry, likely inhibits PMCA2 activity and affects the efficiency of mechanotransduction. 0.2 SIGNOR-262584 IRX1 protein P78414 UNIPROT RALGPS1 protein Q5JS13 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. 0.2 SIGNOR-261668 RPS7 protein P62081 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.82 SIGNOR-262417 UBE2D2 protein P62837 UNIPROT VPS18 protein Q9P253 UNIPROT up-regulates activity binding 9606 BTO:0000007 16203730 YES miannu VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.  0.321 SIGNOR-271549 KLHL25 protein Q9H0H3 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 22578813 YES miannu We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination. 0.408 SIGNOR-272049 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000938 17591690 YES gcesareni Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro, 0.731 SIGNOR-156414 LRRK2 protein Q5S007 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 8537411 YES lperfetto This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process. 0.552 SIGNOR-39433 AKT proteinfamily SIGNOR-PF24 SIGNOR FAS protein P25445 UNIPROT down-regulates 9606 15004527 NO gcesareni Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27 0.2 SIGNOR-123239 ADCK5 protein Q3MIX3 UNIPROT SOX9 protein P48436 UNIPROT up-regulates activity phosphorylation Ser181 YQPRRRKsVKNGQAE 32277958 YES lperfetto Here we investigated the mechanism of ADCK5 involved in regulating invasion and migration of lung cancer cells, and showed that ADCK5 might regulate the expression of tumor oncogene human pituitary tumor transforming gene-1 (PTTG1) by phosphorylating transcription factor SOX9|Mutagenesis of potential serine phosphorylation sites on SOX9 indicated that serine 181 might be required to maintain transcription activation of SOX9 as well as increase PTTG1 levels. 0.2 SIGNOR-264567 FUS protein P35637 UNIPROT AGRN protein O00468 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 28515487 NO This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease 0.272 SIGNOR-262807 F12 protein P00748 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 YES lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. 0.47 SIGNOR-261856 ATM protein Q13315 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates activity phosphorylation Ser26 LRGNPSSsQVDEEQM 9606 BTO:0002137 26774286 YES In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7 0.426 SIGNOR-259942 MAPK3 protein P27361 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Thr30 PSSSEIFtPAHEENV 9606 25728771 YES lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation 0.2 SIGNOR-264772 CDS2 protein O95674 UNIPROT CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates chemical modification 9606 25375833 YES lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). 0.8 SIGNOR-267020 HK2 protein P52789 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266446 Ub:E2 complex SIGNOR-C497 SIGNOR DTX3 protein Q8N9I9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271107 RBX1 protein P62877 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 11295495 YES gcesareni The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. 0.449 SIGNOR-106781 PPP1CC protein P36873 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates dephosphorylation 9606 14718519 YES lpetrilli We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI. 0.467 SIGNOR-121277 NKX2-5 protein P52952 UNIPROT LYL1 protein P12980 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19608273 NO Sequence analysis of the LYL1 promoter region revealed potential binding sites for transcription factors HOXA10, LMO2 and NKX2-5. Overexpression analysis, reporter gene assays and chromatin immuno-precipitation confirmed their activating impact on LYL1 expression. In conclusion, we identified multiple mechanisms which activate LYL1 in leukemic cells, including structural genomic alterations, namely microdeletion or amplification, together with the involvement of prominent oncogenic transcription factors. 0.314 SIGNOR-253655 PTPN6 protein P29350 UNIPROT ACTG1 protein P63261 UNIPROT down-regulates dephosphorylation Tyr218 DIKEKLCyVALDFEQ 9606 BTO:0000776 12646642 YES gcesareni Our data suggest that shp-1 plays a pivotal role in reorganization of cytoskeletal architecture inducing actin dephosphorylation. These results clearly demonstrate the direct interaction of shp-1 with actin 0.2 SIGNOR-99565 lurasidone chemical CHEBI:70735 ChEBI ADRA2A protein P08913 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 20404009 YES Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. 0.8 SIGNOR-257842 SMURF2 protein Q9HAU4 UNIPROT SKIL protein P12757 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002181;BTO:0005493 11389444 YES lperfetto Tgf-beta also induces the association of smurf2 with the transcriptional co-repressor snon and we show that smad2 can function to mediate this interaction. This allows smurf2 hect domain to target snon for ubiquitin-mediated degradation by the proteasome. 0.738 SIGNOR-236090 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation 9606 BTO:0000776 9012831 YES gcesareni We now describe a protein, bap-135, that is associated with btk in b cells and is a substrate for phosphorylation by btk.Taken together, these observations suggest that bap-135 may reside downstream of btk in a signaling pathway originating at the bcr. 0.517 SIGNOR-46060 AMPK complex SIGNOR-C15 SIGNOR ACACA protein Q13085 UNIPROT down-regulates activity phosphorylation Ser80 LHIRSSMsGLHLVKQ 9606 29899443 YES Human ACC1 is inactivated by phosphorylation at Ser80, Ser1201 and Ser1216 by AMP-activated protein kinase (AMPK) 0.558 SIGNOR-267475 ROR2 protein Q01974 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Wnt5a induces homodimerization and activation of ror2 receptor tyrosine kinase 0.2 SIGNOR-199588 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 18204439 YES lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. 0.716 SIGNOR-160411 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT up-regulates quantity phosphorylation Ser133 PVLKAHQsHSAEIES 9606 BTO:0000007 23649622 YES done miannu TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.Serines are listed from left to right: 133, 185, 187, 188, 190, and 198. 0.717 SIGNOR-273815 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 20457564 NO gcesareni The nuclear factor NF-kappaB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-kappaB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules. 0.7 SIGNOR-245039 SIRT5 protein Q9NXA8 UNIPROT ACOX1 protein Q15067 UNIPROT down-regulates activity catalytic activity 9606 BTO:0000007 29491006 YES Monia SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation. 0.26 SIGNOR-261210 BMI1 protein P35226 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 19884659 NO gcesareni Chromatin immunoprecipitation assays revealed the bmi-1 transcriptionally downregulated expression of the tumor suppressor pten in tumor cells through direct association with the pten locus. 0.551 SIGNOR-189040 CTSH protein P09668 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 YES miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 0.283 SIGNOR-256325 RGS6 protein P49758 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates binding 9606 17609107 YES flangone Numb binds to integrin-betas and localizes to clathrin-coated structures 0.2 SIGNOR-156762 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT up-regulates quantity phosphorylation Ser188 RELLSISsESLQARK 9606 BTO:0000007 23649622 YES done miannu TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.Serines are listed from left to right: 133, 185, 187, 188, 190, and 198. 0.717 SIGNOR-273816 CARM1 protein Q86X55 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity methylation Arg223 PAPTPNPrASLNHST 9606 BTO:0000725 24332853 YES miannu We have found that PRMT4 is highly expressed in HSPCs, where it functions as an inhibitor of myeloid differentiation (Figure 7G). In these cells, PRMT4 methylates RUNX1 at R223, promoting the assembly of a DPF2-containing transcriptional co-repressive complex, and repressing transcription at the miR-223 locus. 0.282 SIGNOR-261967 androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity precursor of 9606 BTO:0001363 16166196 YES lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. 0.8 SIGNOR-268665 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT up-regulates activity phosphorylation Tyr455 PARSSDSyAVIDLKK 9606 11432792 YES miannu The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type 0.601 SIGNOR-250203 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 9753670 NO gcesareni Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5 0.348 SIGNOR-60471 UBE2N protein P61088 UNIPROT UBE2V1 protein Q13404 UNIPROT up-regulates activity binding 9606 20551964 YES lperfetto Ubc13, the partner of rnf8 and rnf168, usually cooperates with an e2-like protein, uev1 (also known as ube2v1) or mms2 (also known as ube2v2), for the synthesis of lys63-linked polyubiquitin chains. 0.853 SIGNOR-166177 KLHL12 protein Q53G59 UNIPROT SEC31B protein Q9NQW1 UNIPROT up-regulates activity binding 9606 BTO:0000567 22358839 YES miannu By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division. 0.551 SIGNOR-272014 BRCA1 protein P38398 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity 9606 BTO:0000356;BTO:0001033 11244506 NO The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell lines. 0.753 SIGNOR-253974 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1336 RFMDGSPyAHMFEMS 9606 BTO:0000007 11024032 YES Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed. 0.767 SIGNOR-251173 CHUK protein O15111 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation 9606 BTO:0000093 18490760 YES gcesareni Insulin activation of mtor requires akt in a manner that involves ikkalpha, preferentially to ikkbeta, and tsc2 phosphorylation 0.296 SIGNOR-178664 PTPN11 protein Q06124 UNIPROT PDCD1 protein Q15116 UNIPROT down-regulates activity dephosphorylation 9606 32437509 YES miannu Related to the latter notion, we recently showed that SHP2 dephosphorylates PD-1 to disassemble the PD-1:SHP2 complex ( xref ). 0.658 SIGNOR-277052 afimoxifene chemical CHEBI:44616 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258594 MFF protein Q9GZY8 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity relocalization 9606 21149567 YES gcesareni Mff functions as an essential factor in mitochondrial recruitment of Drp1. 0.602 SIGNOR-245957 HLX protein Q14774 UNIPROT JUN protein P05412 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20008130 YES Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. 0.2 SIGNOR-261623 D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity precursor of 9606 11724794 YES miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion 0.8 SIGNOR-266496 amisulpride chemical CHEBI:64045 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258365 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT down-regulates activity phosphorylation Tyr897 GACEHRGyLYLAIEY -1 11080633 YES lperfetto The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an activated-like conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated. 0.2 SIGNOR-246662 PKC proteinfamily SIGNOR-PF53 SIGNOR AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser180 TIFASCDsKRTDVTG -1 19761816 YES miannu Taken together this data shows that AQP4 in gliomas is the target of PKC phosphorylation, and albeit significantly phosphorylated at rest, phosphorylation can be further enhanced by PKC activation.This data suggests that in gliomas water permeability through AQP4 is under the regulation of PKC via phosphorylation of S180. 0.2 SIGNOR-276260 SMOC1 protein Q9H4F8 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 NO lperfetto The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells 0.2 SIGNOR-260404 SIGMAR1 protein Q99720 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization stabilization 9606 BTO:0000815 29117944 YES Barakat We propose that Sigma1 is a ligand-operated scaffolding protein that promotes the stability, processing, assembly, and trafficking of specific proteins in the secretory pathway of cancer cells. In support of this hypothesis, we found that siRNA-mediated knockdown of Sigma1 resulted in a significant decrease in PD-L1 protein levels in triple-negative MDA-MB-231 breast cancer and androgen-independent PC3 prostate cancer cells 0.2 SIGNOR-274974 LYL1 protein P12980 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21536859 NO miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. 0.2 SIGNOR-253923 SCF-FBW7 complex SIGNOR-C135 SIGNOR BIRC2 protein Q13490 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16510124 YES miannu Since Fbxo7 is one component of the SCF complex, we tried to determine whether overexpression of Fbxo7 could promote cIAP1 ubiquitination in the hope to reveal functional aspects of the cIAP1–Fbxo7 interaction. cIAP1-Flag was co-expressed with or without Fbxo7 in 293T cells. In conclusion, our results show that overexpression of Fbxo7 promotes the ubiquitination of cIAP1. 0.308 SIGNOR-271553 F12 protein P00748 UNIPROT KLKB1 protein P03952 UNIPROT up-regulates activity cleavage Arg390 CTTKTSTrIVGGTNS 9606 BTO:0000131 28966616 YES lperfetto FXIIa activates two serine proteinases, factor XI (FXI) and plasma prekallikrein (PK) that drive the coagulation and kallikrein–kinin systems, respectively 0.605 SIGNOR-263518 KLF4 protein O43474 UNIPROT SRF protein P11831 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 YES gcesareni Klf4 antagonizes contractile gene expression through diverse mechanisms including (i) inhibiting the binding of srf-myocd or srf-mrtfs to the carg box by direct association with srf. 0.369 SIGNOR-174258 PAX3 protein P23760 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 20006729 YES gcesareni Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1. 0.428 SIGNOR-162100 PPP2CA protein P67775 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity dephosphorylation Thr216 RSSSSEStGTPSNPD 10090 11983168 YES cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells 0.453 SIGNOR-248636 UBE2N protein P61088 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates activity ubiquitination -1 19240029 YES miannu We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s. 0.538 SIGNOR-272737 MAP1B protein P46821 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000938 10649507 YES lperfetto MAP1B is a microtubule-associated phosphoprotein that is particularly highly expressed in developing neurons.  0.7 SIGNOR-264844 JAG2 protein Q9Y219 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 10958687 YES gcesareni Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2 0.635 SIGNOR-81367 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser262 LRIAKTPsPPEEPSP 9606 BTO:0000142 15262992 YES lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd 0.396 SIGNOR-126839 C10orf90 protein Q96M02 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0001938 24240685 YES miannu The E3 activity of FATS is required for promoting p53 stability and activation in response to DNA damage.FATS is an E2-independent ubiquitin ligase that stabilizes p53 and promotes its activation in response to DNA damage. Here, we show that FATS acts as a p53 activator by inhibiting Mdm2 binding to p53 and stimulating non-proteolytic polyubiquitination of p53. 0.46 SIGNOR-272142 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR MCM3 protein P25205 UNIPROT up-regulates phosphorylation Thr722 EEMPQVHtPKTADSQ 9606 21965652 YES lperfetto In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722. 0.618 SIGNOR-216694 BBC3 protein Q9BXH1 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates binding 9606 15694340 YES gcesareni Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. 0.752 SIGNOR-133817 PPP2R2A protein P63151 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 9774674 YES lperfetto In this report, we show that another WD-40 repeat protein, the B_ subunit of protein phosphatase 2A, associates with the cytoplasmic domain of type I TGF-_ receptors. [...] We therefore conclude that B_ specifically and directly associates with the type I receptor cytoplasmic domain in vitro. 0.535 SIGNOR-227517 PRKACA protein P17612 UNIPROT CA9 protein Q16790 UNIPROT up-regulates phosphorylation Thr443 RRQHRRGtKGGVSYR 9606 22037869 YES llicata Here, we report that thr443 phosphorylation at the intracellular domain of ca ix by protein kinase a (pka) is critical for its activation in hypoxic cells, with the fullest activity of ca ix also requiring dephosphorylation of ser448. 0.2 SIGNOR-176973 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.366 SIGNOR-259017 DOK1 protein Q99704 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.325 SIGNOR-257697 PLK1 protein P53350 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2439 SFLSGEPsQADVQPL 9606 BTO:0000552 31597699 YES miannu As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F). 0.402 SIGNOR-277490 BMS-754807 chemical CHEBI:88339 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190497 DHODH protein Q02127 UNIPROT coenzyme Q10 smallmolecule CHEBI:46245 ChEBI down-regulates quantity chemical modification 9606 30449682 YES miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway 0.8 SIGNOR-267431 Serdemetan chemical CID:11609586 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193504 CASP8 protein Q14790 UNIPROT CASP8AP2 protein Q9UKL3 UNIPROT up-regulates binding 9606 17245429 YES gcesareni The caspase-8-binding protein flice-associated huge protein (flash) would form a molecular complex with caspase-8, thereby presumably activating the mitochondrial apoptosis pathway by regulating caspase-8 activity. 0.448 SIGNOR-152473 SLC2A4 protein P14672 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 17403369 YES Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis 0.8 SIGNOR-267288 TDGF1 protein P13385 UNIPROT TGFB1 protein P01137 UNIPROT down-regulates activity binding 9606 17030617 YES lperfetto Ere, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-beta. Cripto bound TGF-beta and reduced the association of TGF-beta with its type I receptor, TbetaRI. 0.2 SIGNOR-150006 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16371461 YES lperfetto Phosphorylated gli3 can bind beta-trcp directly both in vitro and in vivo, resulting in polyubiquitination of gli3 and processing through proteasome activity 0.67 SIGNOR-143171 TRAF2 protein Q12933 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates polyubiquitination 9606 20047764 YES miannu Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1 0.434 SIGNOR-271427 WNT4 protein P56705 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 NO gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. 0.312 SIGNOR-60373 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.288 SIGNOR-276089 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR LATS1 protein O95835 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 15688006 YES Two of these, S909 and T1079, were required for Lats1 activation. milica Since the N-terminal half of Lats1 (residues 1¬ñ588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1. 0.2 SIGNOR-270217 (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester chemical CHEBI:103931 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258464 CSNK2A1 protein P68400 UNIPROT CTNNA1 protein P35221 UNIPROT down-regulates phosphorylation Ser641 TPEELDDsDFETEDF 9606 BTO:0000527 19941816 YES gcesareni We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641. 0.391 SIGNOR-161847 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser748 RFARRSVsDNDIRKY 9606 BTO:0000150 16551632 YES llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I 0.509 SIGNOR-252493 RNF8 protein O76064 UNIPROT BLM protein P54132 UNIPROT up-regulates activity ubiquitination 9606 BTO:0001938 23708797 YES miannu Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of .  0.338 SIGNOR-272115 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.759 SIGNOR-219328 MAP1LC3B protein Q9GZQ8 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates binding 9606 BTO:0000007 19250911 YES gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1. 0.558 SIGNOR-184252 CDK5 protein Q00535 UNIPROT STXBP2 protein Q15833 UNIPROT down-regulates phosphorylation Thr572 IGSSHILtPTRFLDD 9606 BTO:0000938 17716669 YES lperfetto It was shown that munc18 inhibition of neuronal syntaxin 1 can be overcome by cdk5 phosphorylation, indicating that structural change disrupts the syntaxin-munc18 interaction. 0.2 SIGNOR-157528 NCBP3 protein Q53F19 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 26382858 NO lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 0.7 SIGNOR-268362 SEC31B protein Q9NQW1 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.664 SIGNOR-265287 PPP2CA protein P67775 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR form complex binding 9606 23454242 YES gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. 0.834 SIGNOR-243442 PROK1 protein P58294 UNIPROT PROKR1 protein Q8TCW9 UNIPROT up-regulates binding 9606 12054613 YES gcesareni The present study demonstrates that eg-vegf/prokineticin 1 and a peptide closely related to eg-vegf, prokineticin 2, are cognate ligands of two orphan g-protein-coupled receptors designated zaq (=eg-vegf/pk-r1) and i5e (=eg-vegf/pk-r2) 0.412 SIGNOR-89084 DCTPP1 protein Q9H773 UNIPROT dCMP 3'-end residue smallmolecule CHEBI:53119 ChEBI up-regulates quantity by expression chemical modification 10116 31377845 YES lperfetto Our data indicate that DCTPP1 is crucially involved in the provision of dCMP for thymidylate biosynthesis, introducing a new player in the regulation of pyrimidine dNTP levels and the maintenance of genomic integrity 0.8 SIGNOR-261333 HAT1 protein O14929 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys6 kGGKGLGK -1 11585814 YES lperfetto During nucleosome assembly in vivo, newly synthesized histone H4 is specifically diacetylated on lysines 5 and 12 within the H4 NH(2)-terminal tail domain. The highly conserved "K5/K12" deposition pattern of acetylation is thought to be generated by the Hat1 histone acetyltransferase, which in vivo is found in the HAT-B complex. 0.2 SIGNOR-264791 EGR1 protein P18146 UNIPROT COL10A1 protein Q03692 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 NO Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) 0.2 SIGNOR-251921 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2A complex SIGNOR-C347 SIGNOR up-regulates activity chemical activation 9606 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate 0.8 SIGNOR-264128 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT unknown phosphorylation Ser292 QLLRRESsVGYRVPA 9606 21209314 YES llicata Here, we report the identification of serine 292 in rin1 as an in vivo pkd phosphorylation site. we demonstrate that phosphorylation at serine 292 controls rin1-mediated inhibition of cell migration by modulating the activation of abl kinases. 0.402 SIGNOR-170877 IL5RA protein Q01344 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 7602114 YES Jak 2 is physically associated with the IL-5b receptor. The binding of IL-5 to its receptor results in tyrosine phosphorylation and activation of Jak 2 tyrosine kinase within 1 to 3 min. 0.6 SIGNOR-254352 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IFNG protein P01579 UNIPROT up-regulates quantity 9606 BTO:0002417 32454942 NO miannu interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology 0.7 SIGNOR-263818 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-200809 DUSP12 protein Q9UNI6 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity dephosphorylation 9606 33811209 YES miannu Our study showed that DUSP12 inhibited ASK1-JNK activation and DUSP12 can directly bind to and dephosphorylate ASK1. 0.25 SIGNOR-277032 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 19620713 YES gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.731 SIGNOR-187181 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 10956646 YES gcesareni Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys. 0.78 SIGNOR-81360 ADORA2B protein P29275 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.523 SIGNOR-256910 Dinaciclib chemical CID:46926350 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191325 STK26 protein Q9P289 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 19386264 YES lperfetto Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. Mst4 phosphorylates the regulatory t567 residue of ezrin. 0.2 SIGNOR-185563 USP24 protein Q9UPU5 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000018 27991932 YES lperfetto In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. |Knockdown of USP24 decreases Bax and p300 levels 0.2 SIGNOR-275606 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SP1 protein P08047 UNIPROT up-regulates binding 9606 10671503 YES lperfetto Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1. 0.559 SIGNOR-216334 NCSTN protein Q92542 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 YES lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) 0.964 SIGNOR-209711 NR1D1 protein P20393 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 12821652 NO miannu Mutations of the 5' or 3' half-sites of the response element totally abrogated PPARgamma binding and transcriptional activation, identifying this site as a novel type of functional PPARgamma response element. Finally, ectopic expression of Rev-Erbalpha in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARgamma ligand rosiglitazone. These results identify Rev-Erbalpha as a target gene of PPARgamma in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation. 0.7 SIGNOR-268023 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE -1 12297295 YES llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  0.679 SIGNOR-250940 CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 25451943 NO gcesareni Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) ² plays an essential role. 0.7 SIGNOR-250562 ROCK2 protein O75116 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 14701738 NO miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. 0.7 SIGNOR-261722 CTBP1 protein Q13363 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23303449 NO irozzo Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Additionally, the inhibitor of cyclin-dependent protein kinases (CDKs), p16INK4a, whose loss has been related to the pathogenesis of melanoma, was repressed by CtBP1 as well. 0.412 SIGNOR-259195 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 12185584 YES lperfetto Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies. 0.622 SIGNOR-91542 DAMPS stimulus SIGNOR-ST18 SIGNOR AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR up-regulates 9606 25720354 NO scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 0.7 SIGNOR-267854 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-119221 PTPRC protein P08575 UNIPROT SKAP1 protein Q86WV1 UNIPROT up-regulates activity dephosphorylation Tyr232 EEEKEETyDDIDGFD 9606 BTO:0000661 11909961 YES Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity. Furthermore, overexpression of SKAP55-Y232F also caused the tyrosine hyperphosphorylation of Fyn with a decreased kinase activity. Thus, SKAP55 is an essential adapter to couple CD45 with the Src family kinases for dephosphorylation and, thus, positively regulates TCR signaling. 0.361 SIGNOR-248360 MTMR1 protein Q13613 UNIPROT 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-) smallmolecule CHEBI:57923 ChEBI down-regulates quantity chemical modification 9606 18429927 YES miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 0.8 SIGNOR-269804 RSPO2 protein Q6UXX9 UNIPROT LGR4 protein Q9BXB1 UNIPROT up-regulates binding 9606 21693646 YES gcesareni Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation. 0.765 SIGNOR-174486 NFKBIZ protein Q9BYH8 UNIPROT IL17A protein Q16552 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000782 20383124 YES Luana In cooperation with RORγt and RORα, IκBζ enhances Il17a expression by binding directly to the regulatory region of the Il17a gene.  0.381 SIGNOR-266210 NDUFA13 protein Q9P0J0 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added 0.793 SIGNOR-262153 RUNX2 protein Q13950 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15564063 NO miannu Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression. 0.472 SIGNOR-255078 FOXA1 protein P55317 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 16331276 NO miannu We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1. 0.321 SIGNOR-142940 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1373652 YES gcesareni The question of whether protein tyrosine phosphatases (ptpases) dephosphorylate a multiply phosphorylated peptide in a random or ordered manner was investigated using the synthetic triphosphotyrosyl peptide trdiy(p)etdy(p)y(p)rk, corresponding to the major sites of autophosphorylation of the insulin receptor, as a substrate for four purified ptpases. 0.622 SIGNOR-18018 KDM6B protein O15054 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 24561908 YES This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. 0.2 SIGNOR-265361 RPL39L protein Q96EH5 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.728 SIGNOR-262491 ALK protein Q9UM73 UNIPROT ALK protein Q9UM73 UNIPROT up-regulates activity phosphorylation Tyr1278 FGMARDIyRASYYRK -1 15938644 YES llicata ALK SelectiVely Phosphorylates the First Tyrosine in Its A-Loop Peptide. 0.2 SIGNOR-250575 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 BTO:0000007 10764727 YES gcesareni The low affinity neurotrophin receptor p75ntr can mediate cell survival as well as cell death of neural cells by ngf and other neurotrophins. 0.835 SIGNOR-76832 LRP5 protein O75197 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization relocalization 9606 11336703 YES lperfetto Lrp-5, a close homolog of lrp-6 (hey et al., 1998), functions as a coreceptor for wnt proteins in mammalian cells and that it can transduce the canonical wnt signals, at least in part by binding and recruiting axin to membranes 0.683 SIGNOR-227930 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4D protein Q6B0I6 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273469 PPP1CA protein P62136 UNIPROT PFN1 protein P07737 UNIPROT up-regulates dephosphorylation Ser138 MASHLRRsQY 9606 22479341 YES lperfetto Knockdown of the catalytic subunit of pp1 (pp1c_), but not pp2a (pp2ac_), increased ps137-pfn1 levels. Pp1c_ binds pfn1 in cultured cells, and this interaction was increased by a phosphomimetic mutation of pfn1 at ser-137 (s137d). Together, these data define pp1 as the principal phosphatase for ser-137 of pfn1 0.247 SIGNOR-196816 RPL21 protein P46778 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.857 SIGNOR-262478 GATA2 protein P23769 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21853041 NO miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. 0.441 SIGNOR-256062 Ub:E2 complex SIGNOR-C497 SIGNOR PCGF1 protein Q9BSM1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271059 CREBBP protein Q92793 UNIPROT RELA protein Q04206 UNIPROT up-regulates acetylation 9606 SIGNOR-C6 16382138 YES gcesareni Rela is also acetylated at several sites by p300 and cbp 0.879 SIGNOR-143396 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Ser11 KRIAKRRsPPADAIP -1 15014043 YES miannu Human RCC1 is phosphorylated on Ser 2 and Ser 11 in mitosis by Cdc2 kinase. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. 0.505 SIGNOR-262702 RPEL1 protein Q2QD12 UNIPROT D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI up-regulates quantity chemical modification 9606 34775382 YES miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. 0.8 SIGNOR-267069 EFNA5 protein P52803 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 YES gcesareni Members of the epha subfamily of receptor tyrosine kinases and their ephrin-a ligands have been implicated in the guidance of retinal axons along the anterior-posterior axis of the chick optic tectum. 0.922 SIGNOR-52467 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 16046550 YES The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.342 SIGNOR-138908 SELENOS protein Q9BQE4 UNIPROT DERL1 protein Q9BUN8 UNIPROT up-regulates activity binding 9606 BTO:0000567 15215856 YES miannu VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97. 0.2 SIGNOR-261370 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000459 SIGNOR-C13 10469655 YES lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. 0.853 SIGNOR-70465 RTKs proteinfamily SIGNOR-PF38 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity phosphorylation 9606 30889378 YES miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. 0.2 SIGNOR-259032 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr811 RPSFSTIyQELQSIR 9606 8663427 YES llicata Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713. 0.2 SIGNOR-42659 CHIR-98014 chemical CID:53396311 PUBCHEM GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190988 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1109 FDEIELAyRRRPPRS -1 11024032 YES Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. 0.767 SIGNOR-251171 AKT proteinfamily SIGNOR-PF24 SIGNOR PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser295 VIRPRRRsSCVSLGE 10090 BTO:0000944 10454575 YES PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B 0.2 SIGNOR-251483 GSK3B protein P49841 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0001103 15829723 NO apalma GSK-3beta is a serine/threonine kinase that can block translation that is initiated by eukaryotic initiation factor-2B (24) and may thereby reduce protein synthesis. 0.7 SIGNOR-255110 MAP2K1 protein Q02750 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12270934 NO lperfetto We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process. 0.263 SIGNOR-235325 PIP3 smallmolecule CHEBI:16618 ChEBI WIPI1 protein Q5MNZ9 UNIPROT up-regulates chemical activation 9606 22082875 YES gcesareni We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes. 0.8 SIGNOR-177169 RPS6KA5 protein O75582 UNIPROT NR4A1 protein P22736 UNIPROT unknown phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000007 16223362 YES lperfetto In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo. 0.384 SIGNOR-249296 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000552 15254178 YES lperfetto Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. We next aimed to identify novel factors that control damage-induced p53 phosphorylation in a keratinocyte model system, and discovered that the epithelial stem cell marker _Np63_ is a novel ATM regulator that controls p53 Serine-15 phosphorylation through transcription of the ATM kinase. 0.843 SIGNOR-126753 PIK-90 chemical CID:6857685 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206232 CYP24A1 protein Q07973 UNIPROT calcitetrol smallmolecule CHEBI:47799 ChEBI up-regulates quantity chemical modification 30080183 YES lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). 0.8 SIGNOR-270571 TGFB1 protein P01137 UNIPROT ENG protein P17813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002741 21146604 NO miannu In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor. 0.71 SIGNOR-255202 ZNF140 protein P52738 UNIPROT FCGR3B protein O75015 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0002269 11470777 YES Luana Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription. 0.2 SIGNOR-266214 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Asn) smallmolecule CHEBI:29172 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269482 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser191 YSFYSTCsGQKAIKK -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273487 CCAR2 protein Q8N163 UNIPROT SUV39H1 protein O43463 UNIPROT down-regulates activity binding 26158765 YES lperfetto Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation. 0.347 SIGNOR-267664 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0000725 23645839 NO apalma Prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion 0.8 SIGNOR-255685 SRC protein P12931 UNIPROT HCN4 protein Q9Y3Q4 UNIPROT up-regulates phosphorylation Tyr531 RRQYQEKyKQVEQYM 9606 17977941 YES fspada These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531. 0.371 SIGNOR-158707 SKP2 protein Q13309 UNIPROT IDH2 protein P48735 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Thr197 GTFKMVFtPKDGSGV 34929314 YES lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome 0.2 SIGNOR-267626 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 YES lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  0.342 SIGNOR-249072 AKT3 protein Q9Y243 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 BTO:0000150 20231902 YES inferred from 70% of family members gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. 0.271 SIGNOR-269941 ARNT protein P27540 UNIPROT FOS protein P01100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21544813 NO lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC 0.287 SIGNOR-253696 ADCY6 protein O43306 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-265001 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 12591950 YES The effect has been demonstrated using O43521-2 gcesareni Here, we demonstrate that jnk phosphorylates two members of the bh3-only subgroup of bcl2-related proteins (bim and bmf) that are normally sequestered by binding to dynein and myosin v motor complexes. Phosphorylation by jnk causes release from the motor complexes 0.758 SIGNOR-98396 ILK protein Q13418 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 9736715 YES acerquone Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation. 0.778 SIGNOR-60115 CYP24A1 protein Q07973 UNIPROT propan-2-ol smallmolecule CHEBI:17824 ChEBI up-regulates quantity chemical modification 30080183 YES lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). 0.8 SIGNOR-270574 Ub:RING_E3 complex SIGNOR-C519 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 NO miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 0.7 SIGNOR-271383 CSNK2A1 protein P68400 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser11 DFGFFSSsESGAPEA -1 3128543 YES llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. 0.309 SIGNOR-250842 KANSL2 protein Q9H9L4 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. 0.667 SIGNOR-267163 perfluorohexanesulfonic acid chemical CHEBI:132448 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268764 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.91 SIGNOR-252825 TLN1 protein Q9Y490 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.62 SIGNOR-257613 WWP2 protein O00308 UNIPROT SLC11A2 protein P49281 UNIPROT down-regulates quantity ubiquitination 10029 BTO:0000246 18776082 YES lperfetto Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2|This promotes DMT1 ubiquitination and degradation by WWP2. 0.3 SIGNOR-268852 lovastatin chemical CHEBI:40303 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 1597859 YES miannu A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). 0.8 SIGNOR-258351 PTGER3 protein P43115 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.455 SIGNOR-256859 MAPK14 protein Q16539 UNIPROT RBSN protein Q9H1K0 UNIPROT up-regulates phosphorylation 9606 16138080 YES gcesareni We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes. 0.2 SIGNOR-140146 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C17 14749395 YES lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. 0.365 SIGNOR-121601 SH3RF1 protein Q7Z6J0 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 9482736 YES gcesareni Posh interacts with the gtp form of rac but not the gdp form 0.263 SIGNOR-55811 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser54 RVKALPLsPRKRLGD 9606 SIGNOR-C83 9889196 YES lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. 0.942 SIGNOR-63891 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CHUK protein O15111 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 10321728 YES miannu We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.  0.538 SIGNOR-272548 PRMT3 protein O60678 UNIPROT ALDH1A1 protein P00352 UNIPROT down-regulates activity binding 9606 BTO:0000007 33495566 YES miannu We identified the specific residues in the catalytic domain of PRMT3 that facilitate interaction with the C-terminal region of ALDH1A1. PRMT3 inhibits the enzymatic activity of ALDH1A1 and negatively regulates the expression of retinoic acid responsive genes in a methyltransferase activity independent manner.  0.2 SIGNOR-276751 TLN1 protein Q9Y490 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.486 SIGNOR-257621 UBE4B protein O95155 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 15611659 YES miannu We further demonstrate that Ufd2 directly and efficiently ubiquitylates securin in vitro and is required for securin polyubiquitylation in vivo. This is the first description of a physiologic substrate for Ufd2, establishing this E4 enzyme as an important regulator of chromosome condensation and separation during mitosis in human cells.  0.2 SIGNOR-271523 SETDB2 protein Q96T68 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity methylation Lys 10 RTKQTARkSTGGKAP 9606 BTO:0000007 20404330 YES miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. 0.2 SIGNOR-263894 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates quantity phosphorylation 9606 BTO:0000007 16714285 YES miannu NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome. 0.759 SIGNOR-271596 RAD23B protein P54727 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR up-regulates activity binding 24086043 YES lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.571 SIGNOR-275696 sorafenib chemical CHEBI:50924 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 21654832 YES gcesareni Inhibition of map kinases mek, jnk, p38, and multikinases (braf, craf, vegfp by sorafenib) in wm-115 and m14 human melanoma cell lines led to either significant reduction or complete inhibition of the plk-1 protein expression. 0.8 SIGNOR-174039 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Ser172 SLDRPFIsEGTTLKD 9606 8576253 YES lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta 0.722 SIGNOR-246728 RACK1 protein P63244 UNIPROT Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR up-regulates activity binding 9606 BTO:0000007 19785988 YES miannu In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex 0.2 SIGNOR-272782 FOXE1 protein O00358 UNIPROT TGFB3 protein P10600 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21177256 NO miannu The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets. 0.349 SIGNOR-254174 ATM protein Q13315 UNIPROT RNF20 protein Q5VTR2 UNIPROT up-regulates activity phosphorylation Ser172 SSSEEMEsQLQERVE 9606 BTO:0000007 21362549 YES miannu ATM-Mediated Phosphorylation of RNF20 and RNF40 in Response to DNA Damage and Its Requirement for Damage-Induced H2B Monoubiquitylation  0.522 SIGNOR-276314 PLK1 protein P53350 UNIPROT AHR protein P35869 UNIPROT down-regulates activity phosphorylation Ser489 ENNFFNEsMNECRNW -1 37988371 YES miannu In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events.  0.251 SIGNOR-277885 CAMK2B protein Q13554 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 9686569 YES gcesareni Stimulation via cd2 activated multiple signal transduction pathways, resulting in phosphorylation of distinct sites of stathmin. Ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. 0.513 SIGNOR-59358 MAPK8IP2 protein Q13387 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 9733513 YES gcesareni Thus, both jip1 and jip2 selectively bind the mapkk isoform mkk7. 0.677 SIGNOR-59944 DAG1 protein Q14118 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.579 SIGNOR-255983 IKBKE protein Q14164 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 YES gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). 0.401 SIGNOR-154775 PKC proteinfamily SIGNOR-PF53 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity phosphorylation Ser262 SGFVQSDsKRESVCN 23195996 YES lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] 0.2 SIGNOR-275674 RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity binding 9606 BTO:0000007 15854902 YES lperfetto Rheb binds and regulates the mTOR kinase. 0.95 SIGNOR-135770 TGFB1 protein P01137 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity 9606 19114990 NO lperfetto First, TGF-beta can rapidly activate PI3K, as indicated by the phosphorylation of its downstream effector Akt 0.274 SIGNOR-217812 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 15851026 YES gcesareni Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin. 0.489 SIGNOR-135692 IFNG protein P01579 UNIPROT S100A10 protein P60903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0002923 12645529 NO miannu The effect of interferon (IFN)-gamma on p11 expression was studied in two human epithelial cell lines (BEAS-2B and HeLa). Treatment with IFN-gamma resulted in increased steady-state levels of p11 mRNA and protein expression, with a time-dependent and dose-dependent effect. 0.266 SIGNOR-255236 GTF2H1 protein P32780 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates quantity by destabilization phosphorylation Thr433 DCDFGDLtPLDF -1 10428966 YES TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase. 0.435 SIGNOR-251260 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity precursor of 9606 31024440 YES brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT 0.8 SIGNOR-264186 CAMK2D protein Q13557 UNIPROT KCNQ1 protein P51787 UNIPROT down-regulates activity phosphorylation Ser484 PHFMRTNsFAEDLDL 29410121 YES lperfetto CaMKII regulates KCNQ1 at S484 during sustained β-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF. 0.2 SIGNOR-275479 TAF9 protein Q16594 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.534 SIGNOR-269582 CBLB protein Q13191 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11375397 YES lperfetto Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity. 0.759 SIGNOR-236519 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.552 SIGNOR-89162 HDLBP protein Q00341 UNIPROT CSF1R protein P07333 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 33941620 YES miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. 0.342 SIGNOR-266696 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 14967450 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.595 SIGNOR-121988 EXOSC2 protein Q13868 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.95 SIGNOR-261387 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser381 CIPTAGMsPSRSNTI 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.632 SIGNOR-249459 Brivanib alaninate chemical CID:11154925 PUBCHEM FGFR3 protein P22607 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190723 EEF1A1 protein P68104 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269513 dothiepin chemical CHEBI:36798 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258699 AIP protein O00170 UNIPROT TFF1 protein P04155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 21984905 YES In this study, we show that XAP2 is recruited to the promoter of ERα regulated genes like the breast cancer marker gene pS2 or GREB1 and negatively regulate the expression of these genes in MCF-7 cells. 0.2 SIGNOR-253643 PAK1 protein Q13153 UNIPROT PGAM proteinfamily SIGNOR-PF78 SIGNOR down-regulates phosphorylation 9606 BTO:0000130 12189148 YES Activated pak1|inferred from family member gcesareni Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. 0.2 SIGNOR-270283 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 YES gcesareni FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4 0.605 SIGNOR-248055 AURKB protein Q96GD4 UNIPROT SHCBP1 protein Q8NEM2 UNIPROT up-regulates activity phosphorylation Ser634 QIKKKRLsELGITQA 9606 BTO:0000567 23704356 YES miannu AurB phosphorylates Ser634 of SHCBP1 during mitosis. We generated a phosphorylation site mutant, S634A-SHCBP1, which was prematurely recruited to the central spindle during anaphase and inhibited furrowing.  0.372 SIGNOR-273552 NFIL3 protein Q16649 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11316793 YES miannu E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. All PAR proteins activate, whereas E4BP4 suppresses the mPer1 promoter through the same sequence 0.346 SIGNOR-268056 RBPJ protein Q06330 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15866158 YES Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J_ protein to the p21 promoter. 0.307 SIGNOR-252032 MAP3K12 protein Q12852 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Ser257 ISGQLVDsIAKTRDA 9606 25594179 YES miannu As expected, DLK significantly increased MKK4 phosphorylation on Ser257 / Thr261, and myrAKT1 enhanced MKK4 phosphorylation on Ser78 (XREF_FIG).|While MKK4 activated by DLK had strong activity in phosphorylating JNK3, MKK4 expressed with DLK and AKT1 together exhibited little activity, even though the two samples had similar levels of Ser257 / Thr261 phosphorylation (XREF_FIG). 0.571 SIGNOR-279629 TP53INP2 protein Q8IXH6 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 19056683 YES gcesareni Tp53inp2 is a scaffold protein that recruits lc3 and/or lc3-related proteins to the autophagosome membrane by interacting with the transmembrane protein vmp1 0.408 SIGNOR-182614 MOB1A protein Q9H8S9 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates binding 9606 21084559 YES Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1 0.941 SIGNOR-269866 VHL protein P40337 UNIPROT DAB2 protein P98082 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000037 15824735 NO miannu three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. 0.2 SIGNOR-255602 quetiapine chemical CHEBI:8707 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 BTO:0000529 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258535 LAT protein O43561 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 YES lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. 0.2 SIGNOR-246055 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 8845374 YES lperfetto The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site. 0.624 SIGNOR-44243 KCNC2 protein Q96PR1 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 YES miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height 0.8 SIGNOR-265585 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE 9606 14625308 YES lperfetto Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signalingthis identifies irak-1 as a novel type of adapter protein, which employs its own kinase activity to introduce negative charges adjacent to the protein interaction domain, which anchors irak-1 at the active receptor complex. Thus, irak-1 regulates its own availability as an adapter molecule by sequential autophosphorylation. 0.2 SIGNOR-119216 FOXJ1 protein Q92949 UNIPROT EFHC1 protein Q5JVL4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.356 SIGNOR-266934 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120088 SIRT7 protein Q9NRC8 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 YES lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 0.2 SIGNOR-275871 AREL1 protein O15033 UNIPROT MTX2 protein O75431 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 34584540 YES lperfetto Therefore, these results implied that AREL1 ubiquitinates and promotes the degradation of MTX2. 0.2 SIGNOR-267674 AKT2 protein P31751 UNIPROT MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 NO gcesareni It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. 0.637 SIGNOR-101324 CDK2 protein P24941 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser263 CKLFDSPsLCSSSTR 9606 17110335 YES gcesareni We show here that dna-responsive checkpoints activate pp2a/b56delta phosphatase complexes to dephosphorylate cdc25 at a site distinct from ser287 (t138), the phosphorylation of which is required for 14-3-3 release. 0.829 SIGNOR-150839 PTPRK protein Q15262 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT up-regulates activity dephosphorylation 9606 BTO:0003009 31934854 YES We show that PTPRK acts via the transmembrane E3 ubiquitin ligase ZNRF3, a negative regulator of Wnt signaling promoting Wnt receptor degradation, which is also expressed in the organizer. 0.354 SIGNOR-260110 STMN1 protein P16949 UNIPROT TTL protein Q8NG68 UNIPROT down-regulates binding 9606 23624152 YES miannu Stathmin depresses ttl tubulin tyrosination activityin vitro. 0.389 SIGNOR-193465 PRKAA1 protein Q13131 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 SIGNOR-C15 19217427 YES gcesareni Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site. 0.2 SIGNOR-184052 UHMK1 protein Q8TAS1 UNIPROT PAM protein P19021 UNIPROT unknown phosphorylation Ser946 DRLSTEGsDQEKEDD 9606 BTO:0004055 10574929 YES lperfetto Although P-CIP2 interacts with stathmin, it does not phosphorylate stathmin. Site-directed mutagenesis, phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM-Ser(949) is the major site phosphorylated by P-CIP2. B 0.445 SIGNOR-247009 MAPK8 protein P45983 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 9030579 YES llicata The a/b domain of human ppargamma1 was phosphorylated in vivo, and this was abolished either by mutation of serine 84 to alanine (s84a) or coexpression of a phosphoprotein phosphatase. In vitro, this domain was phosphorylated by erk2 and jnk, and this was markedly reduced in the s84a mutant. Thus, phosphorylation of a mitogen-activated protein kinase site in the a/b region of ppargamma inhibits both ligand-independent and ligand-dependent transactivation functions. 0.528 SIGNOR-46518 BAG5 protein Q9UL15 UNIPROT PRKN protein O60260 UNIPROT down-regulates activity binding 9606 BTO:0000007 15603737 YES Monia Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity Immunoprecipitation (IP) of GFP-parkin resulted in the coimmunoprecipitation of both Hsp70 and BAG5 or BAG5(DARA) (Figure 4A). Furthermore, IP of GFP-parkin resulted in the coimmunoprecipitation of BAG5 or BAG5 (DARA) in the absence of overexpressed Hsp70. Taken together, these data demonstrate that BAG5 can directly inhibit parkin-mediated autoubiquitinylation independently of Hsp70. 0.2 SIGNOR-261198 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr423 NSLNEEWyVSYITRP -1 8702662 YES Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro 0.753 SIGNOR-251381 SREBF1 protein P36956 UNIPROT ELOVL6 protein Q9H5J4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 18226595 YES Luana These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c. 0.45 SIGNOR-267943 KAT2B protein Q92831 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity acetylation 32917954 YES SimoneGraziosi NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase 0.47 SIGNOR-269270 INSR protein P06213 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Tyr198 EERKEDQyMKMTVCL 15870194 YES lperfetto Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK 0.479 SIGNOR-275514 GLS2 protein Q9UI32 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI down-regulates quantity chemical modification 9606 22049910 YES Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. 0.8 SIGNOR-266909 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 19478061 YES Transfection of wild-type PTPRD resulted in the specific dephosphorylation of STAT3 at tyrosine 705, a residue that must be phosphorylated for STAT3 to be active 0.518 SIGNOR-248442 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 9534 BTO:0004055 15367659 YES lperfetto Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. 0.517 SIGNOR-249270 GAS2L3 protein Q86XJ1 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 24706950 NO miannu Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs.  0.7 SIGNOR-273702 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr167 NKDYHLQtCCGSLAY 9606 16216881 YES gcesareni We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk. 0.2 SIGNOR-141022 TESK1 protein Q15569 UNIPROT TESK1 protein Q15569 UNIPROT up-regulates activity phosphorylation Ser220 EPLAVVGsPYWMAPE -1 10207045 YES Manara These results suggest that autophosphorylation of Ser-215 is an important step to positively regulate the kinase activity of TESK1. 0.2 SIGNOR-260825 AKT1 protein P31749 UNIPROT BTK protein Q06187 UNIPROT down-regulates quantity by destabilization phosphorylation Ser51 FERGRRGsKKGSIDV 9606 BTO:0003289 23754751 YES miannu The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain.  0.296 SIGNOR-276466 GSK1059615 chemical CHEBI:71955 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252667 SOSTDC1 protein Q6X4U4 UNIPROT WNT10B protein O00744 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.381 SIGNOR-242698 FZD2 protein Q14332 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 18077588 YES areggio Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. 0.666 SIGNOR-258965 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates 26721223 NO Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity. 0.7 SIGNOR-255493 PSPC1 protein Q8WXF1 UNIPROT LMX1B/SFPQ/PSPC1 complex complex SIGNOR-C106 SIGNOR form complex binding 10090 BTO:0000669 23308148 YES miannu LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo. 0.407 SIGNOR-223973 ACAT1 protein P24752 UNIPROT PDP1 protein Q9P0J1 UNIPROT down-regulates activity acetylation 34289383 YES lperfetto We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) 0.341 SIGNOR-267635 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB2 protein Q00653 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 14676825 YES lperfetto Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase. 0.552 SIGNOR-217175 phenylalanine smallmolecule CHEBI:28044 ChEBI Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates quantity precursor of 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.8 SIGNOR-270444 CCR4-NOT complex complex SIGNOR-C439 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI down-regulates quantity by destabilization chemical modification 9606 31320642 YES lperfetto CCR4-NOT is a conserved multiprotein complex which regulates eukaryotic gene expression principally via shortening of poly(A) tails of messenger RNA or deadenylation. |The poly(A) tails at 3′ ends of eukaryotic mRNAs are crucial for their cytoplasmic stability and to enhance the initiation of translation. Newly synthesized metazoan mRNAs possess long poly(A) tails1, and following export to the cytoplasm the tails are reported to be ~60–80 nucleotides on average at steady state2. Poly(A) tails are also important for translational efficiency at the embryonic stage2 and the length of the poly(A) tail was reported to be correlated with translational efficiency3. The multisubunit CCR4-NOT complex is principally responsible for efficient processive shortening of poly(A) tails, or deadenylation, in addition to other function 0.8 SIGNOR-268312 LEF1 protein Q9UJU2 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 16936075 NO The other members of the Lef1 HMGB1 protein super-family, Tcf1 and Tcf3, were also expressed in the PSM and the newly formed somites, although at a lower level than was Lef1. gcesareni Furthermore, we show that direct activation is mediated by binding of the tcf-lef/ - catenin complex to the myf5 epaxial enhancer and to a newly identified element upstream of this enhancer. 0.252 SIGNOR-149170 PKC proteinfamily SIGNOR-PF53 SIGNOR GNE protein Q9Y223 UNIPROT up-regulates activity phosphorylation 10116 BTO:0000759 10745088 YES lperfetto Protein kinase C phosphorylates and regulates UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase|Furthermore, PKC phosphorylates UDP-GlcNAc 2-epimerase and this phosphorylation results in an upregulation of the UDP-GlcNAc 2-epimerase enzyme activity. 0.2 SIGNOR-266072 AURKB protein Q96GD4 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser278 QKVAERRsSPLLRRK 9606 22865920 YES lperfetto We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions 0.258 SIGNOR-198650 SHMT2 protein P34897 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity chemical modification 9606 32439610 YES lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 0.8 SIGNOR-268227 RPS6KA5 protein O75582 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 12628924 YES lperfetto Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276. 0.62 SIGNOR-217424 CSNK2A1 protein P68400 UNIPROT PRPF3 protein O43395 UNIPROT up-regulates phosphorylation Thr494 TEAVQDPtKVEAHVR 9606 17932117 YES lperfetto Our findings provide new insights into the biology of hprp3p and suggest that the loss of hprp3p phosphorylation at thr494 is a key step for initiating thr494met aberrant interactions within u4/u6 snrnp complex and that these are likely linked to the rp18 phenotype. 0.2 SIGNOR-158319 Ub:E2 complex SIGNOR-C497 SIGNOR RNF149 protein Q8NC42 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271201 PRDM14 protein Q9GZV8 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 20953172 NO miannu We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer. 0.623 SIGNOR-255067 HIF1A protein Q16665 UNIPROT KDM5C protein P41229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.259 SIGNOR-271564 STK4 protein Q13043 UNIPROT Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates phosphorylation 9606 21808241 YES MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. 0.9 SIGNOR-269856 CC2D1A protein Q6P1N0 UNIPROT RAD21 protein O60216 UNIPROT up-regulates activity binding 20171170 YES centrosome lperfetto Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. | In the centrosome, it regulates spindle pole localization of the cohesin subunit Scc1, thereby mediating centriole cohesion during mitosis. 0.2 SIGNOR-268294 AURKA protein O14965 UNIPROT KCTD12 protein Q96CX2 UNIPROT up-regulates activity phosphorylation Ser243 ITVCGKTsLAKEVFG 9606 BTO:0000567 28869606 YES miannu  In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer-promoting effects. 0.273 SIGNOR-273544 SF3B1 protein O75533 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 YES lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). 0.939 SIGNOR-268403 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 10980595 YES inferred from 70% family members llicata We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway 0.2 SIGNOR-270014 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE 9534 BTO:0000298 8557118 YES lperfetto PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. 0.365 SIGNOR-248939 STOML2 protein Q9UJZ1 UNIPROT SDHD protein O14521 UNIPROT up-regulates activity 9606 20359165 NO Giorgia We found that SLP-2hi cells had significantly higher activities of NADH dehydrogenase and succinate dehydrogenase (P < 0.05), complexes I and II of the electron transport chain. 0.21 SIGNOR-260383 AICA-Ribotide chemical CID:16760280 PUBCHEM PRKAA2 protein P54646 UNIPROT up-regulates chemical activation 9606 BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 19491292 YES gcesareni Aicar-induced ampk phosphorylation inhibits cell cycle transition, reducing differentiation of myoblasts into myotubes, through pgc-1alpha-foxo3a-p21. 0.8 SIGNOR-186055 P2RY10 protein O00398 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257287 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 YES lperfetto Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability 0.368 SIGNOR-77705 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 YES lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation 0.6 SIGNOR-29923 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 BTO:0000671 15694384 YES llicata Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925. 0.2 SIGNOR-133845 F11 protein P03951 UNIPROT F9 protein P00740 UNIPROT up-regulates activity cleavage 9606 BTO:0000131 20110423 YES lperfetto Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX.|The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets. 0.483 SIGNOR-263537 FOXO3 protein O43524 UNIPROT GALT protein P07902 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000975 17975019 NO miannu Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death. 0.2 SIGNOR-254186 SRC protein P12931 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates activity phosphorylation Tyr594 TYVDPHTyEDPNQAV 9606 24457997 YES gcesareni SRC phosphorylates EPHA2 on Tyr594|. It is therefore likely that this phosphorylation site is included in the binding motif of an additional signalling molecule required for cell transformation. 0.452 SIGNOR-246104 KLF7 protein O75840 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0004055 14729953 NO miannu KLF7 stimulates p21WAF1/Cip1 transcription 0.271 SIGNOR-224624 SOX4 protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0000038 17875931 YES irozzo We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein. 0.591 SIGNOR-256138 OGDC complex SIGNOR-C397 SIGNOR NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 15953811 YES miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. 0.8 SIGNOR-266259 ADRB2 protein P07550 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.424 SIGNOR-256952 MET protein P08581 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr56 DRPQEVSyTDTKVIG 9606 BTO:0000972 30711629 YES miannu  MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells.  0.308 SIGNOR-277428 ITK protein Q08881 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Tyr223 LKKVVALyDYMPMNA -1 12573241 YES Btk-SH3 mutant Y223A was not phosphorylated by Itk. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role 0.496 SIGNOR-251333 PRKAA1 protein Q13131 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 SIGNOR-C15 11971957 YES gcesareni Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka. 0.343 SIGNOR-86133 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys121 GESVYGEkRVSISEG 30540930 YES lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) 0.271 SIGNOR-275895 AKT proteinfamily SIGNOR-PF24 SIGNOR NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 YES lperfetto Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype. 0.2 SIGNOR-244318 doramapimod chemical CHEBI:40953 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190332 FGR protein P09769 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr925 DRSNDKVyENVTGLV 9606 12387730 YES gcesareni Phosphorylated on tyrosine residues upon activation. Phosphorylation at tyr-925 is important for interaction with grb2 and depends on the complex formation between fak and the src-kinase fgr. 0.551 SIGNOR-94405 Neurokinin B smallmolecule CHEBI:80312 ChEBI TACR3 protein P29371 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257588 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys205 RDLINLAkKRTNIIP 30540930 YES lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) 0.27 SIGNOR-275896 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT up-regulates activity phosphorylation Ser398 DSLPSSPsSATPHSQ -1 14709557 YES miannu Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity. 0.491 SIGNOR-250157 UPF2 protein Q9HAU5 UNIPROT Upf-EJC complex SIGNOR-C367 SIGNOR form complex binding 9606 BTO:0000567 17803942 YES miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1 0.973 SIGNOR-265238 MAPK8 protein P45983 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 12917434 YES lperfetto Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1 0.709 SIGNOR-117852 MUSK protein O15146 UNIPROT WNT11 protein O96014 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Like ror, musk has an extracellular region with homolgogy to the frizzled crd, binding of which by wnt11 stimulates a pcp-like pathway during neuromuscular development 0.457 SIGNOR-199518 MAML3 protein Q96JK9 UNIPROT NOTCH4 protein Q99466 UNIPROT up-regulates binding 9606 12370315 YES esanto Whereas maml1 and maml2 functioned efficiently as coactivators with each of the notch receptors to transactivate a notch target hes1 promoter construct, maml3 functioned more efficiently with icn4 than with other forms of icn. 0.867 SIGNOR-94103 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 23382875 YES gcesareni Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4. 0.746 SIGNOR-200813 PRKD3 protein O94806 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser498 RPLSRTQsSPLPQSP 18692497 YES lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. 0.265 SIGNOR-275928 MRPS17 protein Q9Y2R5 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 BTO:0000934 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.2 SIGNOR-261453 PRKD2 protein Q9BZL6 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 34010649 YES lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-275947 JAK2 protein O60674 UNIPROT BRD4 protein O60885 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr97 VKLNLPDyYKIIKTP 9606 BTO:0002181 34290255 YES miannu JAK2 induces tyrosine phosphorylation of BRD4 at Y97/Y98, resulting in BRD4 stabilization.  0.325 SIGNOR-277313 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17419683 NO lperfetto Binding of n-shh to ptch1 inhibits repression of smo, leading to activationof some genes and de-repression of others through the effects of smo on the gli family of transcription factors. 0.708 SIGNOR-154240 erlotinib hydrochloride chemical CHEBI:53509 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191502 PRKCA protein P17252 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.392 SIGNOR-275955 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248377 48S_initiation_complex complex SIGNOR-C454 SIGNOR 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR up-regulates activity binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.2 SIGNOR-269169 DVL1 protein O14640 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 23151663 NO gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. 0.583 SIGNOR-199384 MMP9 protein P14780 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates cleavage 9606 10652271 YES gcesareni We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation. 0.593 SIGNOR-74461 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22337874 YES lperfetto The E3 ubiquitin ligase, MDM2, uses a dual-site mechanism to ubiquitinate and degrade the tumor suppressor protein p53, involving interactions with the N-terminal hydrophobic pocket and the acidic domain of MDM2. 0.968 SIGNOR-196116 INTS4 protein Q96HW7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity binding 9606 16239144 YES miannu The Integrator Complex Can Directly Associate with the C-Terminal Domain of RNA Polymerase II Largest Subunit 0.54 SIGNOR-261185 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. 0.559 SIGNOR-195654 Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 BTO:0000143 25195934 NO miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.7 SIGNOR-270750 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 20331961 YES milica The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits). 0.459 SIGNOR-164679 HSP90AB1 protein P08238 UNIPROT CBLL1 protein Q75N03 UNIPROT up-regulates quantity binding 9606 BTO:0000007 31952268 YES miannu By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity. 0.2 SIGNOR-271475 FOXO3 protein O43524 UNIPROT NOTCH3 protein Q9UM47 UNIPROT down-regulates quantity transcriptional regulation 10090 24749067 NO gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. 0.306 SIGNOR-244079 COP1 protein Q8NHY2 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 YES lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes 0.2 SIGNOR-154514 KANSL3 protein Q9P2N6 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 26243146 NO miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. 0.7 SIGNOR-267169 CDH4 protein P55283 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.525 SIGNOR-265866 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr797 ERPGGTPtPVIAYSK -1 19448668 YES miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. 0.38 SIGNOR-262881 GDF5 protein P43026 UNIPROT ID3 protein Q02535 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004291 16716349 NO Regulation miannu GDF5 induces ID1 and ID3 in HUVSMC by a smad-dependent, MAPK-independent pathway. GDF5 binds to specific receptors, thereby inducing phosphorylation and translocation of smad1 to the nucleus where it is involved in the regulation of transcription. 0.2 SIGNOR-251872 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 YES lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity 0.59 SIGNOR-171247 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLPRPE 10090 BTO:0000944 11313479 YES Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity. 0.764 SIGNOR-252873 AMFR protein Q9UKV5 UNIPROT UBL4A protein P11441 UNIPROT down-regulates activity polyubiquitination Lys48 QRLLFKGkALADGKR 9606 BTO:0000007 24424410 YES miannu USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding. 0.521 SIGNOR-272856 PBX1 protein P40424 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21746878 YES miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. 0.267 SIGNOR-267241 CDK5 protein Q00535 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 YES gcesareni Pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. Increasing doses of cdk2 resulted in increased phosphorylation of the thr-320 site. Phosphorylation of this site in pp1 corresponded to decreased pp1 activity. 0.395 SIGNOR-92269 PLK3 protein Q9H4B4 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser73 VSTQELYsIPEDQEP -1 16481012 YES miannu Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.  0.659 SIGNOR-276051 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 20022946 YES lperfetto These data suggest that mTORC1- and likely mTORC2-associated mTOR Ser-2481 autophosphorylation directly monitors intrinsic mTORC-specific catalytic activity 0.682 SIGNOR-235484 PRKCA protein P17252 UNIPROT TP73 protein O15350 UNIPROT up-regulates activity phosphorylation Ser388 VPQPLVDsYRQQQQL 9606 19158275 YES miannu Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.  0.2 SIGNOR-276235 NDUFA2 protein O43678 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.862 SIGNOR-262154 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 YES gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation 0.642 SIGNOR-252454 INHA protein P05111 UNIPROT TGFBR3 protein Q03167 UNIPROT down-regulates binding 9606 10746731 YES gcesareni Type iii tgf-beta receptor, betaglycan, can function as an inhibin co-receptor with actrii. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing actrii and betaglycan. ability of betaglycan to facilitate inhibin antagonism of activin 0.588 SIGNOR-76470 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity relocalization 9606 18632848 YES amattioni The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism. 0.834 SIGNOR-179469 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation -1 17525164 YES miannu AMPK enhances mPer2 degradation and CKIɛ activity by phosphorylating Ser-389 of CKIɛ. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2.  0.901 SIGNOR-276065 AKT1 protein P31749 UNIPROT YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 YES llicata Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined. 0.672 SIGNOR-116587 Ub:E2 complex SIGNOR-C497 SIGNOR RC3H1 protein Q5TC82 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271005 PPP2CA protein P67775 UNIPROT MAP2K2 protein P36507 UNIPROT down-regulates dephosphorylation 9606 20626350 YES gcesareni In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a. 0.491 SIGNOR-166652 CEBPA protein P49715 UNIPROT SFTPD protein P35247 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001910 11912209 YES Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D. 0.259 SIGNOR-254042 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 YES gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. 0.378 SIGNOR-75898 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR FGA protein P02671 UNIPROT up-regulates activity binding 9606 BTO:0000132 16418530 YES lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. 0.579 SIGNOR-253359 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.345 SIGNOR-250806 MAPK11 protein Q15759 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 NO Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). 0.2 SIGNOR-251833 rauwolscine chemical CHEBI:48562 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 9459568 YES miannu These studies display the usefulness of [3H]rauwolscine as an antagonist radioligand for the cloned human 5-HT2B receptor. The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor 0.8 SIGNOR-258690 CSNK2A1 protein P68400 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates activity phosphorylation Thr23 ALGPFPDtQDDFLKW 10090 BTO:0004475 9722526 YES 2 miannu Regulation of erythroid Krƒppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. the transactivation capability of EKLF is augmented by co-transfection of CKIIalpha. in vitro assays demonstrate that CKIIalpha interacts with EKLF, and that the EKLF interaction domain is phosphorylated by CKII only at Thr-41 0.344 SIGNOR-241361 NMUR2 protein Q9GZQ4 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257402 CSNK1A1 protein P48729 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10617630 YES lperfetto In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes. 0.372 SIGNOR-73795 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191436 F2R protein P25116 UNIPROT RAB3A protein P20336 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254845 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.839 SIGNOR-269254 CAMK2G protein Q13555 UNIPROT RYR1 protein P21817 UNIPROT unknown phosphorylation Ser2843 KKKTRKIsQSAQTYD 8380342 YES llicata Phosphorylation of serine 2843 in ryanodine receptor-calcium release channel of skeletal muscle by cAMP-, cGMP- and CaM-dependent protein kinase. 0.395 SIGNOR-250704 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser741 TKADKRRsVRIGSYI 9606 7539802 YES miannu Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity 0.53 SIGNOR-28601 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 23708659 YES lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. 0.366 SIGNOR-202113 H2AX protein P16104 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates binding 9606 16377563 YES fstefani Here, we demonstrate that mammalian mdc1/nfbd1 directly binds to phospho-h2ax (gammah2ax) by specifically interacting with the phosphoepitope at the gammah2ax carboxyl terminus. 0.2 SIGNOR-143377 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity phosphorylation 9606 23616010 YES lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. 0.2 SIGNOR-233523 PTPRG protein P23470 UNIPROT BMX protein P51813 UNIPROT down-regulates activity dephosphorylation Tyr40 LTKTNLSyYEYDKMK -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.261 SIGNOR-254693 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2054 LLKNGANkDMQNNRE 9606 17636029 YES gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. 0.415 SIGNOR-156919 Ub:E2 complex SIGNOR-C497 SIGNOR AMFR protein Q9UKV5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271104 NPY protein P01303 UNIPROT Food intake phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0000614 10195157 NO miannu Neuropeptide Y (NPY) stimulates food intake and promotes weight gain, whereas melanocortins have the opposite effect. 0.7 SIGNOR-263505 SEPTIN12 protein Q8IYM1 UNIPROT SEPTIN6 protein Q14141 UNIPROT down-regulates binding 9606 BTO:0000567 18047794 YES miannu Sept12 interacts with sept6 and this interaction alters the filament structure of sept6 in hela cells. 0.2 SIGNOR-159537 AKT proteinfamily SIGNOR-PF24 SIGNOR GABRB2 protein P47870 UNIPROT up-regulates activity phosphorylation Ser472 SRLRRRAsQLKITIP 9606 BTO:0000007 12818177 YES miannu Here we report that Akt phosphorylates, both in vitro and in vivo, the type A gamma-aminobutyric acid receptor (GABA(A)R), the principal receptor mediating fast inhibitory synaptic transmission in the mammalian brain. Akt-mediated phosphorylation increases the number of GABA(A)Rs on the plasma membrane surface, thereby increasing the receptor-mediated synaptic transmission in neurons. These results identify the GABA(A)R as a novel substrate of Akt, thereby linking Akt to the regulation of synaptic strength. 0.2 SIGNOR-262619 CDK1 protein P06493 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr1161 FFNPVCAtPNSKILK 9606 29771379 YES miannu Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization. 0.489 SIGNOR-265994 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7230 KPSSRAAsPTRSSSS 9606 BTO:0004905 21295697 YES lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. 0.436 SIGNOR-264428 UMPS protein P11172 UNIPROT orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI down-regulates quantity chemical modification 9606 18020427 YES miannu Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate). 0.8 SIGNOR-253581 MMP2 protein P08253 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Arg719 VMGRGHArLVHVEEP -1 9344465 YES lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.635 SIGNOR-261739 EIF2AK1 protein Q9BQI3 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19946423 NO Regulation of expression miannu Translation of α- and β-globin is tightly controlled by eIF2 and downregulated by HRI. 0.2 SIGNOR-251781 MAPK8 protein P45983 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 15538382 YES lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. 0.713 SIGNOR-252965 MAPK1 protein P28482 UNIPROT PLA2G4A protein P47712 UNIPROT unknown phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 BTO:0000567 9468497 YES llicata The inhibitor of the 38-kda stress-activated protein kinase (p38(mapk)), sb 203580, reduced phosphorylation of both ser-505 and ser-727 by 50 and 60%, respectively, in thrombin-stimulated platelets. 0.655 SIGNOR-55706 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 20110348 YES gcesareni Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. 0.403 SIGNOR-252973 DNMT3A protein Q9Y6K1 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 NO miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family 0.378 SIGNOR-255809 NOTCH proteinfamily SIGNOR-PF30 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates BTO:0001103 12361602 NO apalma Taken together, these results show that Notch-1 activity promotes myogenic cell proliferation and that attenuation of Notch-1 activity by its antagonist Numb causes cells to exit from the cell cycle, express MRFs, and undergo myogenic differentiation. 0.7 SIGNOR-255376 CDC7 protein O00311 UNIPROT MCM4 protein P33991 UNIPROT up-regulates phosphorylation 9606 21070963 YES gcesareni Activation of the eukaryotic replicative dna helicase, the mcm2-7 complex, requires phosphorylation by cdc7/dbf4 (dbf4-dependent kinase or ddk), which, in turn, depends on prior phosphorylation of mcm2-7 by an unknown kinase (or kinases).we propose that the resulting mec1 modification of mcm4 and mcm6 further activates ddk phosphorylation of mcm2-7 ( fig. 7aii ). 0.958 SIGNOR-169453 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr33 KFKNEDLtDELSLNK -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.2 SIGNOR-276205 PCK1 protein P35558 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 30193097 YES miannu √Ǭ†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).√Ǭ† 0.8 SIGNOR-266588 ZNF224 protein Q9NZL3 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 17900823 NO inferred from family member miannu We previously reported that ZNF224, a novel Kr√ºppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. 0.489 SIGNOR-270227 ELF4 protein Q99607 UNIPROT ELF4/RUNX1 complex SIGNOR-C47 SIGNOR form complex binding 9606 BTO:0001271 10207087 YES miannu We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function 0.352 SIGNOR-66960 BBC3 protein Q9BXH1 UNIPROT BAX protein Q07812 UNIPROT up-regulates relocalization 9606 BTO:0000551 19439449 YES gcesareni Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis. 0.49 SIGNOR-185671 NFYC protein Q13952 UNIPROT PHGDH protein O43175 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18378410 NO miannu Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. 0.2 SIGNOR-255211 ABL1 protein P00519 UNIPROT MUC1 protein P15941 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr1243 NGGSSLSyTNPAVAA 9606 16888623 YES Manara The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site.  0.456 SIGNOR-260830 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 YES The effect has been demonstrated using Q01196-8 miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 0.2 SIGNOR-138985 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 BTO:0000007 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.2 SIGNOR-262983 TDRD3 protein Q9H7E2 UNIPROT SNRPN protein P63162 UNIPROT unknown binding -1 15955813 YES miannu the TDRD3 GST-Tudor protein interacted strongly with methylated SmB/B′ and SmD but not with SmE. These results suggest that the Tudor domains of SMN and SPF30 likely interact with assembled snRNPs, whereas the Tudor domain of TDRD3 might bind unassembled methylated Sm proteins. 0.2 SIGNOR-253518 IFNA1 protein P01562 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 YES miannu Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.632 SIGNOR-260334 MARK2 protein Q7KZI7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser355 EADLPEPsEKQPAAA -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.706 SIGNOR-275436 dovitinib; bis(lactic acid) chemical CID:56973714 PUBCHEM KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191421 FAM20C protein Q8IXL6 UNIPROT FGF23 protein Q9GZV9 UNIPROT down-regulates activity phosphorylation Ser180 IPRRHTRsAEDDSER 9606 24706917 YES Manara Here we show that Fam20C directly phosphorylates FGF23 on Ser(180) | Our above results support, phosphorylation of FGF23 at Ser180 inhibits O-glycosylation and would therefore promote hormone proteolysis and thus inactivation.  0.638 SIGNOR-260925 COL1A2 protein P08123 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 11007770 NO gcesareni The present study was designed to further characterize tgfbeta up-regulation of col1a2 and more generally, to increase our understanding of the tgfbeta signaling pathway that controls ecm accumulation. 0.7 SIGNOR-82405 SIRT7 protein Q9NRC8 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity deacetylation Lys38 PSTGGVKkPHRYRPG 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275884 TGFB2 protein P61812 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252283 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HEY2 protein Q9UBP5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12548545 NO gcesareni SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. 0.2 SIGNOR-254338 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser980 VHAPRRCsDGGAHGY 9606 10693759 YES lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. 0.467 SIGNOR-75359 U2AF2 protein P26368 UNIPROT ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR form complex binding 9606 9237760 YES miannu Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35. 0.766 SIGNOR-50173 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 14965271 YES lperfetto Fas (CD95) is activated by its natural ligand FasL 0.903 SIGNOR-216292 PRKAA2 protein P54646 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C15 20647423 YES gcesareni Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions. 0.2 SIGNOR-166905 EPS15 protein P42566 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity binding 10029 BTO:0002988 15383614 YES gcesareni We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role 0.754 SIGNOR-243278 AURKB protein Q96GD4 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser184 GKKSGKKsYLSGGAG 9606 23226345 YES lperfetto Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1 0.368 SIGNOR-200079 SIX1 protein Q15475 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 9826681 NO gcesareni We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4. 0.441 SIGNOR-62104 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr265 KDPKRRMtIAQSLEH 9606 15611134 YES gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. 0.2 SIGNOR-132467 NDUFA9 protein Q16795 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5) 0.83 SIGNOR-262160 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation -1 15133517 YES inferred from 70% family members miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291‚Äì356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. 0.2 SIGNOR-270193 CDK7 protein P50613 UNIPROT RARA protein P10276 UNIPROT unknown phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 11955452 YES llicata Thus, we demonstrate that the cdk7 kinase of tfiih phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes. 0.545 SIGNOR-116582 AKT1 protein P31749 UNIPROT HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser199 SQRGRSGsGNFGGGR 9606 18562319 YES gcesareni Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199. 0.412 SIGNOR-252519 GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 8479541 YES GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Furthermore, our results indicate that the interaction domains of sos1 and grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. 0.912 SIGNOR-39163 8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one chemical CHEBI:91361 ChEBI PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194865 MAOA protein P21397 UNIPROT 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). 0.8 SIGNOR-264003 IRX1 protein P78414 UNIPROT PHYHIPL protein Q96FC7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.2 SIGNOR-261659 WIF1 protein Q9Y5W5 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 10201374 YES gcesareni Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities. 0.559 SIGNOR-66892 ITGB3 protein P05106 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.915 SIGNOR-253206 Ub:E2 complex SIGNOR-C497 SIGNOR RFPL3 protein O75679 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271148 Terfenadine chemical CHEBI:9453 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9395068 YES miannu We have previously shown that terfenadine can inhibit both Kv1.5 and HERG with its effects on HERG being approximately 10‐fold more potent 0.8 SIGNOR-258673 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12771128 YES gcesareni A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. 0.46 SIGNOR-101282 MAP3K8 protein P41279 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 BTO:0000776; BTO:0000801 16484370 NO Mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands 0.356 SIGNOR-256078 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 YES inferred from 70% family members gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3. 0.2 SIGNOR-270015 PDE2A protein O00408 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 36476859 YES lperfetto We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice.  0.369 SIGNOR-275730 HRAS protein P01112 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k 0.662 SIGNOR-175192 ADK protein P55263 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI down-regulates quantity chemical modification 9606 33961946 YES miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 0.8 SIGNOR-267838 TRIP11 protein Q15643 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 9256431 YES inferred from 70% of family members miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. 0.422 SIGNOR-269879 AURKA protein O14965 UNIPROT NDEL1 protein Q9GZM8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser251 LTPSARIsALNIVGD 10090 17060449 YES miannu Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry. Interestingly, NDEL1 phosphorylated by Aurora-A was rapidly downregulated thereafter by ubiquitination-mediated protein degradation. 0.601 SIGNOR-263159 CSNK2A1 protein P68400 UNIPROT TFAP2A protein P05549 UNIPROT up-regulates phosphorylation Ser429 TDNNAKSsDKEEKHR 9606 21777522 YES lperfetto Ck2 phosphorylates ap-2_ and increases its transcriptional activity 0.307 SIGNOR-175130 cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity precursor of 9606 9634533 YES miannu In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol. 0.8 SIGNOR-267250 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser384 RLLAALEvASAAMAK 9606 20643644 YES Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. 0.2 SIGNOR-260795 ACVR1B protein P36896 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity phosphorylation Thr88 PKTYVDLtNEETTDS 9606 BTO:0000007 18039968 YES miannu ALK4 phosphorylated TTRAP in vitro (Fig. 6A). The band migrating at the position of TTRAP was excised and analyzed by LC-MS/MS. One TTRAP peptide was phosphorylated either on T88 and T92, or on T92 only (Fig. 6B). 0.28 SIGNOR-262611 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Ser39 ELERVNLsAAQTLRA 9606 19370760 YES llicata Stk25 phosphorylates ccm3 at serine 39 and threonine 43 0.767 SIGNOR-185388 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-268074 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Ser518 KYATPAPsAKSSPSK 9606 BTO:0000938 16611631 YES lperfetto Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5 0.469 SIGNOR-145991 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259808 nitric oxide smallmolecule CHEBI:16480 ChEBI M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 24669294 NO apalma While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines 0.7 SIGNOR-255556 FGFR3 protein P22607 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0000527 22891331 YES llicata Fgfrs phosphorylate pten at tyrosine 240 0.426 SIGNOR-191797 KCNB2 protein Q92953 UNIPROT VAPA protein Q9P0L0 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 YES lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. 0.2 SIGNOR-262124 ANKLE2 protein Q86XL3 UNIPROT VRK1 protein Q99986 UNIPROT down-regulates 9606 22770216 NO miannu Lem4 inhibits the activity of baf's kinase vrk-1 during mitotic exit 0.797 SIGNOR-198103 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation Ser832 GISPYFSsRRSSEAS 9606 BTO:0000007 16611981 YES lperfetto The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. 0.561 SIGNOR-249589 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX10 protein P56693 UNIPROT down-regulates activity phosphorylation Thr240 GQSHGPPtPPTTPKT 9606 BTO:0002806 29295999 YES miannu Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity.ERK2 directly phosphorylates SOX10 at T240 and T244. 0.2 SIGNOR-277821 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity precursor of 26083061 YES lperfetto Mitochondrial aconitase and succinate dehydrogenase were among the earliest mammalian Fe-S proteins identified.|The enzymatic activity of both proteins depends on the presence of intact Fe-S clusters 0.8 SIGNOR-262132 PPARG protein P37231 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates quantity by repression 9606 BTO:0000801 17681149 NO lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways 0.615 SIGNOR-249555 ACTL6A protein O96019 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.851 SIGNOR-132916 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 SIGNOR-C3 20516213 YES fstefani The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. 0.711 SIGNOR-165799 SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C85 21454478 YES inferred from 70% family members lperfetto Upon ligand binding, the specific heteromeric transmembrane serine/threonine kinase receptor complexes undergo phosphorylation/activation and subsequently phosphorylate the two ser residues in the c-terminal sxs motif of specific r-smads, smad1/5/8 for bmp pathway and smad2/3 for tgf-_/activin signaling. The activated r-smads then associate with co-smad, smad4. The heteromeric complexes translocate into the nucleus, where they bind to dna directly or indirectly to regulate the transcription of specific genes. 0.2 SIGNOR-269952 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 23431053 YES milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation 0.635 SIGNOR-201302 RXRB protein P28702 UNIPROT RARB protein P10826 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 1310351 NO gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.665 SIGNOR-16680 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K10 protein Q02779 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 YES gcesareni Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks. 0.356 SIGNOR-97003 LYN protein P07948 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.618 SIGNOR-249383 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity precursor of 9606 22718265 YES miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. 0.8 SIGNOR-267544 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Gly71 FSASVLTgKLTTVFL -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.298 SIGNOR-263581 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr258 DMKETKYtVDKRFGM 9606 11152499 YES tpavlidou We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity. 0.2 SIGNOR-85777 PTPN11 protein Q06124 UNIPROT IRF8 protein Q02556 UNIPROT down-regulates activity dephosphorylation 9606 27769062 YES miannu We found that Bcr-abl-induced, Shp2 dependent dephosphorylation of Icsbp impaired repression of GAS2 by this transcription factor. 0.353 SIGNOR-277173 IL10 protein P22301 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000938 BTO:0001264 23357618 NO miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. 0.263 SIGNOR-253503 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Val) smallmolecule CHEBI:29183 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269500 serotonin smallmolecule CHEBI:28790 ChEBI HTR4 protein Q13639 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264294 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser784 GVPFRRPsTFGIPRL 9606 BTO:0000671 12082086 YES lperfetto G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells 0.568 SIGNOR-89853 FYN protein P06241 UNIPROT DLG2 protein Q15700 UNIPROT up-regulates activity phosphorylation Tyr348 TRPPEPVySTVNKLC -1 13129934 YES miannu Recombinant PSD-93 was phosphorylated by Fyn in vitro, and Tyr-384 was identified as a major phosphorylation site. In COS7 cells, exogenously expressed PSD-93 was phosphorylated, dependent on its membrane localization. In addition, tyrosine-phosphorylated PSD-93 was able to bind to Csk, a negative regulator of Src family kinases, in vitro as well as in a brain lysate. 0.367 SIGNOR-262874 MAPK14 protein Q16539 UNIPROT CFLAR protein O15519 UNIPROT up-regulates phosphorylation 9606 19597496 YES There are three isoforms of cellular FLIP (c-FLIP): FLIPL, FLIPS and FLIPR gcesareni Here we demonstrate that m. tuberculosis?induced Tnf triggered reactive oxygen species?dependent Activation of ask1 and the tyrosine kinase c-abl (a000161) in mouse macrophages and that flips was phosphorylated on tyr211 and ser4 by c-abl and p38, respectively. 0.373 SIGNOR-187001 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr472 EPIQEANyVPMTPGT 9606 BTO:0000527;BTO:0000017 9890893 YES lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). 0.76 SIGNOR-236412 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Thr232 YSSNSGPtRREDKFM 9606 15793569 YES llicata In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues. 0.655 SIGNOR-134855 UPF3B protein Q9BZI7 UNIPROT Upf-EJC complex SIGNOR-C367 SIGNOR form complex binding 9606 BTO:0000567 17803942 YES miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1 0.962 SIGNOR-265236 FYN protein P06241 UNIPROT ACP1 protein P24666 UNIPROT up-regulates activity phosphorylation Tyr133 LIIEDPYyGNDSDFE 9534 BTO:0004055 9038134 YES We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP. 0.383 SIGNOR-251150 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 15611135 YES gcesareni We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. 0.261 SIGNOR-132563 TNFRSF17 protein Q02223 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates 9606 10903733 NO miannu Overexpression of bcma activates the p38 mapk 0.2 SIGNOR-79495 PSMD2 protein Q13200 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.893 SIGNOR-263344 FLNA protein P21333 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity 9606 18667433 NO areggio Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration.  0.507 SIGNOR-258973 AKT proteinfamily SIGNOR-PF24 SIGNOR METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 3627513 YES lperfetto The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells 0.2 SIGNOR-244307 MED23 protein Q9ULK4 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.738 SIGNOR-266665 ZM 336372 chemical CID:5730 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207911 RELA protein Q04206 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates binding 9606 15988006 YES gcesareni P65 and histone deacetylases 4 cooperate to inhibit the ability of mef2 factors to induce the klf2 promoter 0.316 SIGNOR-138368 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser649 VPPSPSLsRHSSPHQ 11427888 YES Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. 0.685 SIGNOR-251240 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TSPYL2 protein Q9H2G4 UNIPROT up-regulates activity phosphorylation Ser20 RRLSSSEsPQRDPPP 9606 BTO:0000567 11395479 YES llicata We observed that a CDA1 mutant with the two consensus CDK phosphorylation sites abolished (S20A and T340A) disabled its capacity to inhibit cell growth, indicating that these sites are important for the function of this protein. Furthermore, we showed that these sites are phosphorylated by cyclin/CDKs in vitro, suggesting that these kinases may regulate CDA1 function in vivo.  0.339 SIGNOR-250752 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser27 TASRPSSsRSYVTTS -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248879 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18423396 NO fspada Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation. 0.85 SIGNOR-178269 CCN4 protein O95388 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 10116 11782444 YES Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway. 0.2 SIGNOR-256269 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS1 protein O95835 UNIPROT up-regulates 9606 23075495 NO gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. 0.8 SIGNOR-199196 ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) 0.8 SIGNOR-256036 BMPR1A protein P36894 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR up-regulates activity phosphorylation 9606 8893010 YES ggiuliani Conversely, Smad1 and DPC4 formed a complex when the cells were stimulated with BMP4 but not with activin of TGF-beta. 0.712 SIGNOR-255778 leucine smallmolecule CHEBI:25017 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 NO Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 0.7 SIGNOR-268011 TAL1 protein P17542 UNIPROT TSG101 protein Q99816 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 17229889 YES miannu These data suggest that Tal mediates polyubiquitylation of the lysine residues in the VPS28-binding region of TSG101, leading to subsequent degradation of TSG101. 0.2 SIGNOR-271636 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser511 DSPFYRDsLPGSQRK 9606 BTO:0000150 17693255 YES gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. 0.641 SIGNOR-157300 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-267503 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates quantity precursor of 9606 21173190 YES lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† 0.8 SIGNOR-267016 FLT3 protein P36888 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates activity 9606 BTO:0002144 28194038 NO inferred from family member FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity 0.264 SIGNOR-270268 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 14536078 YES gcesareni Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380 0.446 SIGNOR-118559 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 22094256 YES lperfetto We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627) 0.623 SIGNOR-177255 RARB protein P10826 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 NO lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. 0.2 SIGNOR-268549 HK3 protein P52790 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266447 SERPINA1 protein P01009 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 YES gcesareni In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp 0.323 SIGNOR-41180 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 10608806 YES lperfetto In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage. 0.855 SIGNOR-73432 NR1I3 protein Q14994 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19702527 NO miannu Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding. 0.471 SIGNOR-254863 IQSEC2 protein Q5JU85 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 27009485 YES miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. 0.2 SIGNOR-264915 ABL1 protein P00519 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Tyr433 KIPQDGDyEFLKSWT 10116 21715626 YES Manara In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. 0.343 SIGNOR-260927 CBFA2T3 protein O75081 UNIPROT ZNF652 protein Q9Y2D9 UNIPROT down-regulates activity binding 9606 BTO:0000007 20116376 YES Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. 0.51 SIGNOR-253954 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FGF1 protein P05230 UNIPROT down-regulates activity chemical inhibition -1 17620431 YES miannu Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases.  0.8 SIGNOR-259166 PRKACA protein P17612 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser338 IEKRYRSsINDKIIE 9606 16381800 YES llicata Sterol regulatory element-binding protein 1 is negatively modulated by pka phosphorylation. ser338 of srebp-1a and ser314 of srebp-1c are pka phosphorylation sites. 0.2 SIGNOR-143392 TRIP12 protein Q14669 UNIPROT RNF168 protein Q8IYW5 UNIPROT down-regulates activity ubiquitination 9606 BTO:0001938 22884692 YES miannu Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. 0.466 SIGNOR-266783 KDM4C protein Q9H3R0 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23698634 NO miannu The expression of KDM4C gene was increased in spheres from colorectal cancer (CRC) cells and the knockdown (KD) of KDM4C eliminated colonosphere formation. KDM4C KD decreased the expression of JAG1 gene, and the downregulation of JAG1 gene recapitulated the impaired colonosphere formation. 0.2 SIGNOR-254542 PRKCD protein Q05655 UNIPROT BAG3 protein O95817 UNIPROT up-regulates phosphorylation Ser187 SSSSSSAsLPSSGRS 9606 23108398 YES lperfetto Pkc_-mediated phosphorylation of bag3 at ser187 site induces epithelial-mesenchymal transition and enhances invasiveness in thyroid cancer fro cells. we showed that bag3 was implicated in epithelial-mesenchymal transition (emt) procedure, and phosphorylation state at ser187 site had a critical role in emt regulation by bag3. 0.251 SIGNOR-199316 MAPK1 protein P28482 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Ser160 GVTKAISsPTVSRLT -1 17693641 YES miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. 0.355 SIGNOR-262928 MAPK3 protein P27361 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 YES lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2. 0.265 SIGNOR-182782 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 17204478 YES lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). 0.798 SIGNOR-263431 MTX2 protein O75431 UNIPROT SAM complex complex SIGNOR-C422 SIGNOR form complex binding 31387448 YES lperfetto The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. 0.738 SIGNOR-267682 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 19561641 YES gcesareni Phosphorylation of threonine 395 has been linked to the proteasome-mediated degradation of full length cyclin e 0.955 SIGNOR-186418 CSNK2A1 protein P68400 UNIPROT OTUD5 protein Q96G74 UNIPROT up-regulates activity phosphorylation Ser177 EVGAGYNsEDEYEAA -1 22245969 YES miannu Here we show that phosphorylation of the human deubiquitinase DUBA (OTUD5) at a single residue, Ser177, is both necessary and sufficient to activate the enzyme. Treatment with CK2 could activate DUBA purified from E. coli, and this activity was associated with a species monophosphorylated at Ser177 (Fig. 1d). 0.2 SIGNOR-265872 CHEK1 protein O14757 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity phosphorylation Ser331 KSKGRASsSGNQESS 9606 BTO:0005035 19861535 YES lperfetto In this study, we report a novel phosphorylation site serine 331 (S331) of FANCD2, the pivotal downstream player of the Fanconi anemia pathway. Phosphorylation of S331 is important for its DNA damage-inducible monoubiquitylation, resistance to DNA cross-linkers, and in vivo interaction with FANCD1/BRCA2.|In vitro and in vivo experiments show that phosphorylation of S331 is mediated by CHK1, 0.586 SIGNOR-263252 DNMT1 protein P26358 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000775 32905139 YES Gianni Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35) 0.489 SIGNOR-269053 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr69 ERQLNGTyAIAGGKA 9606 BTO:0000661 7961936 YES We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. 0.618 SIGNOR-251396 GCG protein P01275 UNIPROT LATS1 protein O95835 UNIPROT up-regulates 9606 23075495 NO gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. 0.272 SIGNOR-199202 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr637 KFGSLDTyLKKNKNC 9606 BTO:0000007 19364823 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. 0.2 SIGNOR-235885 KDM6B protein O15054 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 22025054 YES lperfetto JMJD3 seems to function by controlling expression of the transcription factor IRF4, which in turn is required for M2 polarization of macrophages in vitro and in vivo. Although this pathway is strongly supported by genetic. 0.423 SIGNOR-249540 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.564 SIGNOR-89193 MAP3K7 protein O43318 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 17110930 YES Barakat Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK 0.644 SIGNOR-274146 FASN protein P49327 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI down-regulates quantity chemical modification 9606 15507492 YES Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-267212 MN1 protein Q10571 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 17494859 NO irozzo MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment. 0.7 SIGNOR-256016 PRKD1 protein Q15139 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000661 1370476 YES lperfetto Thus, phosphorylation of PLC-gamma 1 by PKC or PKA at serine 1248 may modulate the interaction of PLC-gamma 1 with the protein tyrosine kinase or the protein tyrosine phosphatase; this altered interaction may, at least in part, be responsible for the decreased tyrosine phosphorylation of PLC-gamma 1 seen in PMA- and forskolin-treated Jurkat cells. 0.404 SIGNOR-248846 PRKAA1 protein Q13131 UNIPROT UCP3 protein P55916 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001103 17609368 NO gcesareni Severalin vivostudies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochromec, uncoupling protein 3 (ucp-3)] (1518) and proteins involved in glucose uptake (glut4) (1820) are increased at the transcriptional level in skeletal muscle. 0.329 SIGNOR-156831 STAT3 protein P40763 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22669242 NO miannu Thus we infected C2C12 myofibers with a recombinant adenovirus expressing a mutant, constitutively activated STAT3 (cSTAT3) known to possess increased DNA binding/transcriptional activity. Consistent with wasting, atrogin-1 expression was also markedly increased (Fig. 3A). Thus STAT3 activation is by itself sufficient to induce muscle fiber wasting in cell culture. 0.281 SIGNOR-255331 PCCA protein P05165 UNIPROT PCC complex SIGNOR-C414 SIGNOR form complex binding 9606 15890657 YES miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. 0.891 SIGNOR-267182 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 10567572 YES gcesareni G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2.. 0.581 SIGNOR-72361 zotepine chemical CHEBI:32316 ChEBI DRD4 protein P21917 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258555 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 8157000 YES gcesareni To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1. 0.732 SIGNOR-262292 A6/b4 integrin complex SIGNOR-C174 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 9428518 YES miannu Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. 0.428 SIGNOR-259033 CSF2 protein P04141 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates binding 9606 BTO:0000876 BTO:0001103 9680354 YES apalma GM-CSF elicits these diverse responses through the GM-CSF receptor (GMR). 0.861 SIGNOR-255581 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser259 SQRQRSTsTPNVHMV 9534 BTO:0004055 12801936 YES miannu Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259). 0.499 SIGNOR-250041 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 9606 BTO:0001544 19261608 YES The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. 0.62 SIGNOR-248328 ASXL1 protein Q8IXJ9 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates activity binding 9606 16606617 YES irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. 0.283 SIGNOR-255931 MYF5 protein P13349 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. 0.7 SIGNOR-37409 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 22933625 NO apalma Recent findings have shown that IL-10 stimulation of macrophages isolated from skeletal muscles increases the phagocytic activity of macrophages 0.7 SIGNOR-255443 TGFBR2 protein P37173 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 9435577 YES lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. 0.434 SIGNOR-227528 NAIP protein Q13075 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.515 SIGNOR-256403 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 8702662 YES lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function 0.804 SIGNOR-42960 fludrocortisone chemical CHEBI:50885 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258706 MLL2 complex complex SIGNOR-C88 SIGNOR PAX7/MLL2 complex complex SIGNOR-C91 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 YES miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.2 SIGNOR-198623 Starvation stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 23000343 NO lperfetto Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activationSTARV 0.7 SIGNOR-209796 MAPK3 protein P27361 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 9606 12163482 YES lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein 0.268 SIGNOR-91143 FGD3 protein Q5JSP0 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.648 SIGNOR-260553 F7 protein P08709 UNIPROT F10 protein P00742 UNIPROT up-regulates activity binding 9606 BTO:0000131 SIGNOR-C319 29880919 YES lperfetto TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively. 0.54 SIGNOR-263545 IL27 protein Q8NEV9 UNIPROT IL27RA protein Q6UWB1 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 14764690 YES gcesareni Wsx-1 and glycoprotein 130 constitute a signal-transducing receptor for il-27. 0.71 SIGNOR-121799 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK9 protein P45984 UNIPROT down-regulates chemical inhibition 9606 11717429 YES gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). 0.8 SIGNOR-111986 TET1 protein Q8NFU7 UNIPROT PTEN protein P60484 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27121319 YES irozzo We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands 0.373 SIGNOR-259096 FOXO4 protein P98177 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 YES miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. 0.264 SIGNOR-260091 PRKACA protein P17612 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity phosphorylation Ser1598 RNAARRDsVLAASRD -1 12529267 YES miannu IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site. 0.555 SIGNOR-249996 pralatrexate chemical CHEBI:71223 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 23409799 YES miannu Pralatrexate is a small molecule with a chemical formula C23H23N7O5 and a molecular weight of 477.48 g/mol (Box 1). It competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. 0.8 SIGNOR-259352 SIRT1 protein Q96EB6 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 19299583 YES lperfetto Using Per2:luciferase transcriptional reporter assays in HEK293 cells (Fig. 2C-E; S2), we show that inhibition of NAMPT by FK866 led to a significant increase in the CLOCK:BMAL1-driven transcription of the Per2:luciferase reporter (Fig. 2C), indicating that reduced NAMPT-mediated NAD+ biosynthesis released CLOCK:BMAL1 from the SIRT1-dependent suppression. 0.779 SIGNOR-253722 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 9029153 YES lperfetto Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_ 0.434 SIGNOR-216698 KAT6B protein Q8WYB5 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 SIGNOR-C54 11965546 YES miannu Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation. 0.402 SIGNOR-117335 DDX5 protein P17844 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 15660129 YES miannu The dead box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor 0.701 SIGNOR-133341 CDK1 protein P06493 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates activity phosphorylation Ser185 NRHSPSWsPDGRRRQ 9606 20890132 YES miannu In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. Interestingly, the Cdc2/cyclin B1 phosphorylation site Ser185 of Nlp is required for its recognition by PLK1, which enable Nlp depart from centrosomes to allow the establishment of a mitotic scaffold at the onset of mitosis . 0.421 SIGNOR-259830 CDK1 protein P06493 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Ser426 TQPNINDsLEITKLD 9606 14657031 YES lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation 0.703 SIGNOR-119873 ZMYM2 protein Q9UBW7 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates activity binding 10090 BTO:0004593 31363497 YES miannu In this work, we identified ZMYM2/ZFP198, which physically associates with NANOG as a key negative regulator of NANOG-mediated reprogramming of both epiblast stem cells and somatic cells. 0.3 SIGNOR-269802 PTGER4 protein P35408 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.313 SIGNOR-257032 TNF protein P01375 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR up-regulates 10090 BTO:0000133 15972951 NO lperfetto Second, LPS-mediated aggravation of anti-MPO IgG-induced glomerulonephritis was attenuated, but not prevented, by pretreatment with neutralizing anti-TNF-α antibodies. 0.2 SIGNOR-270588 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193537 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity phosphorylation Ser416 SVDDLANsGQVGTAR 9606 9155023 YES lperfetto Tbetarii kinase is regulated intricately by autophosphorylation on at least three serine residues. Phosphorylation of ser416 inhibits receptor function. 0.2 SIGNOR-48412 PLK1 protein P53350 UNIPROT CTNNB1 protein P35222 UNIPROT unknown phosphorylation Ser718 QDDPSYRsFHSGGYG 9606 19001871 YES lperfetto Ser-718 of beta-catenin was directly phosphorylated by recombinant plk1thus it may be possible that function of the additional phosphorylation site(s) in cooperation with the ser-718 is required for the regulation of _-catenin at m phase 0.399 SIGNOR-182150 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 BTO:0000567 12670868 YES miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. 0.2 SIGNOR-264484 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates dephosphorylation 9606 SIGNOR-C110 10644691 YES acerquone Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin. 0.435 SIGNOR-74231 MAP4K1 protein Q92918 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates 9606 10224067 NO gcesareni These studies establish that hpk1 acts as an upstream activator for the tak1-sek-jnk1 module in relaying the tgf-_ signal into the nuclei in 293t cells. 0.555 SIGNOR-67321 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser157 GSILSDIsFDKTDES 9606 19468302 YES llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. 0.639 SIGNOR-185746 ERN1 protein O75460 UNIPROT OS9 protein Q13438 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18417469 NO miannu Here we characterize the function in ER quality control of two proteins derived from alternative splicing of the OS-9 gene. OS-9.1 and OS-9.2 are ubiquitously expressed in human tissues and are amplified in tumors. They are transcriptionally induced upon activation of the Ire1/Xbp1 ER-stress pathway. 0.426 SIGNOR-261063 DYDC1 protein Q8WWB3 UNIPROT Acrosome_assembly phenotype SIGNOR-PH156 SIGNOR up-regulates 9606 19545932 NO miannu Knockdown of Dydc1 blocks spermatogenesis and acrosome biogenesis 0.7 SIGNOR-263881 MAPK3 protein P27361 UNIPROT SCNN1B protein P51168 UNIPROT down-regulates quantity by destabilization phosphorylation Thr615 QALPIPGtPPPNYDS -1 11805112 YES lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. 0.279 SIGNOR-249447 PTGER3 protein P43115 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257203 REST protein Q13127 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR form complex binding 9606 20080105 YES 1 miannu Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex. 0.768 SIGNOR-239217 acetate smallmolecule CHEBI:30089 ChEBI acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity precursor of 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271824 DGC complex SIGNOR-C217 SIGNOR GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265435 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 YES gcesareni Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation. 0.794 SIGNOR-32977 CLTA protein P09496 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 YES lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  0.765 SIGNOR-260667 LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 YES gcesareni Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation. 0.757 SIGNOR-149182 CYP11B1 protein P15538 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 33117906 YES lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone 0.8 SIGNOR-268683 WASHC1 protein A8K0Z3 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 YES lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. 0.2 SIGNOR-261020 ERG protein P11308 UNIPROT EPB41L3 protein Q9Y2J2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20860828 NO miannu EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. 0.2 SIGNOR-253918 MSH2 protein P43246 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR form complex binding 9606 15064730 YES miannu The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors. 0.813 SIGNOR-123702 H2AC4 protein P04908 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 YES miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.2 SIGNOR-263719 PRKCI protein P41743 UNIPROT LLGL2 protein Q6P1M3 UNIPROT up-regulates activity phosphorylation Ser653 LKKSLRQsFRRMRRS 9615 BTO:0000837 12725730 YES miannu This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner. 0.688 SIGNOR-263180 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.2 SIGNOR-275960 BMS-265246 chemical CID:5329775 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190434 CSNK2A1 protein P68400 UNIPROT SLK protein Q9H2G2 UNIPROT down-regulates phosphorylation Ser348 SDLSIASsEEDKLSQ 9606 16837460 YES gcesareni Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity. 0.2 SIGNOR-147883 ANK2 protein Q01484 UNIPROT DCTN4 protein Q9UJW0 UNIPROT up-regulates quantity relocalization 10090 BTO:0001103 19109891 YES miannu We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4. 0.624 SIGNOR-266713 TYMS protein P04818 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI down-regulates quantity chemical modification 9606 21876188 YES lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. 0.8 SIGNOR-268231 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 16782899 YES gcesareni Here we report that fak directly interacts with the hepatocyte growth factor receptor c-met. Phosphorylation of c-met at tyr-1349 and, to a lesser extent, tyr-1356 is required for its interaction with the band 4.1 and ezrin/radixin/moesin homology domain (ferm domain) of fak. met-fak interaction leads to fak activation and subsequent contribution to hepatocyte growth factor-induced cell motility and cell invasion. 0.496 SIGNOR-147179 JAK2 protein O60674 UNIPROT SLC6A8 protein P48029 UNIPROT down-regulates activity relocalization 443947 BTO:0000964 22407360 YES miannu Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane. 0.2 SIGNOR-265807 SLA protein Q13239 UNIPROT KIT protein P10721 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0001538 24284075 YES miannu In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves the SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitylation which, in turn, is followed by receptor degradation 0.2 SIGNOR-263143 KRAS protein P01116 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. 0.91 SIGNOR-175204 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr681 DIYSTDYyRVGGRTM 9606 9099755 YES gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 0.2 SIGNOR-47179 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 23175611 YES The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. 0.407 SIGNOR-199797 CSNK2A1 protein P68400 UNIPROT SLITRK1 protein Q96PX8 UNIPROT up-regulates activity phosphorylation Ser695 DCGSHSLsD -1 19640509 YES miannu In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides. 0.2 SIGNOR-273633 MBD5 protein Q9P267 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 20700456 NO miannu The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA.Our data suggest that MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. One isoform of MBD5 is highly expressed in oocytes, which suggests a possible role in epigenetic reprogramming after fertilization. 0.7 SIGNOR-266773 CRTC2 protein Q53ET0 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 YES CRTC2 knockdown attenuates glucocorticoid-responsive GILZ mRNA expression in HeLa cells 0.2 SIGNOR-256109 EFNB1 protein P98172 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 YES gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. 0.761 SIGNOR-52517 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDK7 protein P50613 UNIPROT up-regulates activity phosphorylation Thr170 GSPNRAYtHQVVTRW -1 11113184 YES lperfetto Activating phosphorylation of CDK7 by CDC2 and CDK2. The ability of pure CDK2-cyclin A to activate CDK7 in T170-dependent fashion (Fig. ​(Fig.3C,3C, lane 2) strongly suggested a direct phosphorylation mechanism. Tryptic phosphopeptide mapping confirmed that both CDK2-cyclin A (Fig. ​(Fig.4A)4A) and CDC2-cyclin B (Fig. ​(Fig.4D)4D) phosphorylated CDK7 on both S164 and T170. 0.644 SIGNOR-270806 PRKCA protein P17252 UNIPROT CFLAR protein O15519 UNIPROT up-regulates quantity by stabilization phosphorylation Ser193 LQAAIQKsLKDPSNN 9606 BTO:0000664 19343040 YES miannu  Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins 0.2 SIGNOR-276147 Saracatinib chemical CID:10302451 PUBCHEM SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206691 PKA proteinfamily SIGNOR-PF17 SIGNOR CDK18 protein Q07002 UNIPROT up-regulates activity phosphorylation Ser14 KNFKRRFsLSVPRTE 28361970 YES lperfetto We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro.  0.2 SIGNOR-264559 PI3K complex SIGNOR-C156 SIGNOR superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity 23994464 NO apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release 0.8 SIGNOR-255011 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT down-regulates activity binding 10090 BTO:0005787 24627466 YES lperfetto Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. 0.846 SIGNOR-251715 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 BTO:0000150 20530684 YES lperfetto The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry. 0.595 SIGNOR-216721 NAB2 protein Q15742 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 22128144 NO miannu In the present study, we investigated the molecular basis for the differential regulation of TRAIL in helped versus helpless CD8(+) T cells by comparing their transcriptional profiles, and have identified a transcriptional corepressor, NGFI-A binding protein 2 (Nab2), that is selectively induced in helped CD8(+) T cells. Enforced expression of Nab2 prevents TRAIL induction after restimulation of primary helpless CD8(+) T cells, and expression of a dominant-negative form of Nab2 in helped CD8(+) T cells impairs their secondary proliferative response that is reversible by TRAIL blockade. 0.2 SIGNOR-253893 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr378 ESQAGSDtDVEEGKA 9606 18678890 YES gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. 0.347 SIGNOR-179887 NKD1 protein Q969G9 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 20858476 YES gcesareni Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation 0.703 SIGNOR-167984 Ub:E2 complex SIGNOR-C497 SIGNOR UBOX5 protein O94941 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271150 DPYSL2 protein Q16555 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000938 25040932 NO lperfetto In the non-phosphorylated state, CRMP2 binding to tubulin induces the promotion of tubulin polymerisation leading to dendrite outgrowth while 0.7 SIGNOR-264841 N-[(2S)-1-[[(2S)-1-[[3-[4-(Aminomethyl)piperidine-1-carbonyl]phenyl]methylamino]-3-methyl-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]-1,2-oxazole-5-carboxamide chemical CID:49843508 PUBCHEM F2RL1 protein P55085 UNIPROT down-regulates activity chemical inhibition 9606 20873792 YES Simone Vumbaca Agonist GB110 (19, EC50 0.28 μM) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca2+ release in HT29 human colorectal carcinoma cells. 0.8 SIGNOR-261125 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDC25A protein P30304 UNIPROT up-regulates ubiquitination 9606 15340381 YES lperfetto Scfb-trcp has recently been shown to degrade phosphorylated cdc25a in the s and g2 phases. 0.48 SIGNOR-217178 UQCR10 protein Q9UDW1 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.928 SIGNOR-262199 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 YES lperfetto Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes. 0.877 SIGNOR-235478 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates activity phosphorylation Ser166 LGARAKEsLDLRAHL -1 11121119 YES lperfetto In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation. 0.344 SIGNOR-249069 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2V2 protein Q15819 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.475 SIGNOR-271369 diethylstilbestrol chemical CHEBI:41922 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258598 MEN1 protein O00255 UNIPROT MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 YES irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. 0.2 SIGNOR-255868 LCK protein P06239 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 17998336 NO gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. 0.582 SIGNOR-159164 TNF protein P01375 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 NO inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b. 0.258 SIGNOR-267811 CLASP1 protein Q7Z460 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates activity binding 9606 BTO:0000567 15631994 YES lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 0.609 SIGNOR-265094 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.621 SIGNOR-161678 SRC protein P12931 UNIPROT SPTAN1 protein Q13813 UNIPROT up-regulates phosphorylation Tyr1176 AVQQQEVyGMMPRDE 9606 11971983 YES llicata Using mutagenesis on recombinant peptides, we identified the residue y1176 located in the calpain cleavage site of alpha ii-spectrin, near the sh3 domain, as an in vitro substrate for src kinase and lmw-ptp a. phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro. 0.562 SIGNOR-86718 very long-chain (R)-3-hydroxyacyl-CoA(4-) smallmolecule CHEBI:85440 ChEBI very long-chain 2,3-trans-enoyl CoA(4-) smallmolecule CHEBI:83728 ChEBI up-regulates quantity precursor of 9606 18554507 YES miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. 0.8 SIGNOR-267916 CIITA protein P33076 UNIPROT HLA-DRB5 protein Q30154 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002417 10886240 NO These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma. 0.468 SIGNOR-254013 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 9606 10791892 YES gcesareni Ser787 in the proline-rich region of human map4 is a critical phosphorylation site that reduces its activity to promote tubulin polymerization. Phosphorylation on ser-787 negatively regulates map4 activity to promote microtubule assembly. 0.498 SIGNOR-77087 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM27 protein P14373 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271073 FEV protein Q99581 UNIPROT ICAM1 protein P05362 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12761502 NO miannu Fev acts as a transcriptional repressor through its dna-binding ets domain and alanine-rich domain. / we show here that fev dramatically represses both basal and ectopically ets-activated transcription driven by the icam-1 promoter, and that the effect is dose dependent. 0.2 SIGNOR-101246 regorafenib chemical CHEBI:68647 ChEBI TAP1 protein Q03518 UNIPROT down-regulates activity chemical inhibition 9606 26254357 YES miannu It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG3 0.8 SIGNOR-259204 miR-29c mirna URS000075B799_9606 RNAcentral TET2 protein Q6N021 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 22983574 YES Gianni Transcriptional regulation of miR-10a/b by TWIST-1 in myelodysplastic syndromes 0.4 SIGNOR-268854 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR DLX5 protein P56178 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 12815054 NO ggiuliani Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining 0.315 SIGNOR-255837 SH2B2 protein O14492 UNIPROT INSR protein P06213 UNIPROT down-regulates binding 9606 BTO:0000975 11498022 YES lperfetto APS couples c-Cbl to the insulin receptor, resulting in ubiquitination of the insulin receptor. 0.62 SIGNOR-109694 TFEB protein P19484 UNIPROT NDUFA1 protein O15239 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). 0.2 SIGNOR-276700 ATP5F1B protein P06576 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261397 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation -1 9094314 YES gcesareni We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1) 0.8 SIGNOR-243274 PTPN11 protein Q06124 UNIPROT ITK protein Q08881 UNIPROT down-regulates activity dephosphorylation 9606 33624224 YES miannu Using genetic and pharmacological approaches, we discovered that SHP2 dephosphorylates ITK specifically downstream of PD-1 and that this event was associated with PD-1 inhibitory cellular functions. 0.324 SIGNOR-277174 PICALM protein Q13492 UNIPROT CLTC protein Q00610 UNIPROT up-regulates binding 9606 16491119 YES miannu Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro 0.748 SIGNOR-144683 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Ser548 MRKSQRSsKGSEILL -1 21642394 YES miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. 0.2 SIGNOR-276333 AM/b2 integrin complex SIGNOR-C170 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269019 dacomitinib chemical CHEBI:132268 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 23405260 YES gcesareni The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor. 0.8 SIGNOR-200902 BMS-740808 chemical CID:6914623 PUBCHEM F10 protein P00742 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190488 Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity binding 9606 30205058 YES miannu The exocyst is a multisubunit protein complex that was first identified and characterized in budding yeast. This complex mediates the tethering of secretory vesicles to the plasma membrane prior to fusion mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Sec3 interacts with PI(4,5)P2 (red dots) in the plasma membrane. Its interaction with the t-SNARE protein Sso promotes the assembly of the Sso–Sec9 binary t-SNARE complex. 0.442 SIGNOR-270793 adapalene chemical CHEBI:31174 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9606 30836068 YES miannu Adapalene, the third-generation synthetic retinoid,selectively bound to specific RAR, thus activating genes responsible forcellular differentiation. It showed greatest affinity for subtypes RARβ in dermal fibroblasts (Kd value 34 nM) and RARγ in the epidermis (Kdvalue 130 nM) 0.8 SIGNOR-258488 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT up-regulates activity phosphorylation Ser481 ILAKSPQsTRAVAPQ 9606 BTO:0000599 21189263 YES lperfetto ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking. 0.296 SIGNOR-272293 DNAJC14 protein Q6Y2X3 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 15525720 NO lperfetto Mutations in the gene encoding DJ-1 have also been linked to familial Parkinson€™s disease. Other studies have suggested that DJ-1 protects cells from oxidative damage, and mutations in DJ-1 may therefore contribute to in- creased levels of oxidative stress. 0.7 SIGNOR-249698 PRKCI protein P41743 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.2 SIGNOR-251635 HNRNPA1 protein P09651 UNIPROT Alternative_Splicing_Regulation phenotype SIGNOR-PH204 SIGNOR up-regulates 9606 17371836 NO We demonstrate that Sam68 binds the mRNA for Bcl-x and affects its alternative splicing 0.7 SIGNOR-268687 TOM40 complex complex SIGNOR-C421 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 18423394 NO lperfetto The sorting and assembly pathway of outer membrane proteins involves three machineries: the translocase of the outer membrane (TOM complex) the sorting and assembly machinery (SAM complex) and the MDM complex (mitochondrial distribution and morphology). 0.7 SIGNOR-267688 LCK protein P06239 UNIPROT LAX1 protein Q8IWV1 UNIPROT up-regulates activity phosphorylation Tyr294 AFQCCRDyENVPAAD 9606 BTO:0000007 12359715 YES miannu Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85.  0.4 SIGNOR-273527 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 10116 BTO:0000452 1749429 YES lperfetto Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation. 0.501 SIGNOR-236682 NKX3-1 protein Q99801 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16697957 YES miannu Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. 0.502 SIGNOR-251547 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 2861485 YES gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. 0.303 SIGNOR-23958 DCAF1 protein Q9Y4B6 UNIPROT EDVP complex SIGNOR-C530 SIGNOR form complex binding 9606 BTO:0000007 19287380 YES miannu We named this E3 ligase complex containing EDD, DDB1 and VPRBP proteins as EDVP complex to distinguish it from the previously identified Cul4-Roc1-DDB1-VPRBP E3 ligase complex.  0.2 SIGNOR-271789 perfluorooctanoic acid chemical CHEBI:35549 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 BTO:0000150 35370244 YES miannu Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor α (PPARα) is a key process by which PFOA affects the malignancy of estrogen receptor α (ERα)-positive breast cancer cells. 0.8 SIGNOR-268753 NCOR1 protein O75376 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22395773 YES FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. 0.707 SIGNOR-253507 TFAP2D protein Q7Z6R9 UNIPROT ST8SIA2 protein Q92186 UNIPROT up-regulates quantity by expression transcriptional regulation 9031 24462686 YES lperfetto We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2 and the ST8SIA2 promoter.|We show that ST8SIA2 is induced by AP-2δ overexpression in chick retina. We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2δ and the ST8SIA2 promoter. 0.337 SIGNOR-268992 EGLN2 protein Q96KS0 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity hydroxylation 9606 24990963 YES lperfetto Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase.|Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. 0.287 SIGNOR-261998 WRC complex complex SIGNOR-C191 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 20332100 NO miannu The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex. 0.7 SIGNOR-253578 CHEK1 protein O14757 UNIPROT MDM4 protein O15151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 YES lperfetto The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes. 0.521 SIGNOR-178067 SP1 protein P08047 UNIPROT NDUFV1 protein P49821 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000931 17786189 NO miannu Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin. 0.2 SIGNOR-255206 HDAC1 protein Q13547 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 23242655 NO Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells. 0.657 SIGNOR-254029 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 16166196 YES lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. 0.8 SIGNOR-268662 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9606 21798082 YES lperfetto Pip3 acts in turn as a docking site for two kinases, phosphoinositide-dependent kinase 1 (PDK1) and AKT, and the subsequent phosphorylation of AKT at serine 308 by PDK1, leading to AKT activation. 0.8 SIGNOR-175253 AKT1 protein P31749 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. 0.661 SIGNOR-252526 SLC9A6 protein Q92581 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265605 TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 18758450 YES lperfetto Here we report that the ubiquitin ligase (e3) traf6 interacts with a consensus motif present in tbetari. The tbetari-traf6 interaction is required for tgf-beta-induced autoubiquitylation of traf6 and subsequent activation of the tak1-p38/jnk pathway, which leads to apoptosis. 0.2 SIGNOR-180562 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 11333986 YES lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.2 SIGNOR-107416 FZR1 protein Q9UM11 UNIPROT ANLN protein Q9NQW6 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 16040610 YES miannu  Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin. 0.266 SIGNOR-272654 DCTN6 protein O00399 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9534 BTO:0004055 phosphorylation:Thr186 KTMKGSStPVKN 23455152 YES lperfetto Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores. 0.375 SIGNOR-264798 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser342 ASSVYTRsTGEQEIS 9534 BTO:0000298 10085131 YES gcesareni Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. 0.2 SIGNOR-249675 DNAJC11 protein Q9NVH1 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 10090 BTO:0000312 25111180 NO Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. T 0.7 SIGNOR-261147 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191024 celecoxib chemical CHEBI:41423 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190928 SMARCE1 protein Q969G3 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.884 SIGNOR-132942 ponatinib chemical CHEBI:78543 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206280 KDM6B protein O15054 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 NO lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. 0.7 SIGNOR-249564 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB1 protein P19838 UNIPROT up-regulates activity ubiquitination 9534 BTO:0004055 11295495 YES lperfetto The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. 0.521 SIGNOR-217190 SNRPE protein P62304 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.835 SIGNOR-270630 OPTN protein Q96CV9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0005118 22194658 NO same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. 0.7 SIGNOR-259876 SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 YES lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. 0.892 SIGNOR-39237 SIRT4 protein Q9Y6E7 UNIPROT GLUD2 protein P49448 UNIPROT down-regulates activity glycosylation 9606 16959573 YES miannu We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. 0.507 SIGNOR-268559 miR-29b mirna URS0000150A7D_9606 RNAcentral TET2 protein Q6N021 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 18568019 YES miannu In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation. 0.4 SIGNOR-256310 CASP8 protein Q14790 UNIPROT CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 9727491 YES gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. 0.741 SIGNOR-58118 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258458 SMARCAD1 protein Q9H4L7 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 21549307 YES 1 miannu SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin 0.319 SIGNOR-239835 CREB1 protein P16220 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.282 SIGNOR-253791 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAG3 protein O95817 UNIPROT up-regulates activity phosphorylation Thr285 GSPARSStPLHSPSP 9606 BTO:0000016 27659916 YES miannu ERK-dependent phosphorylation of BIS following H2O2 treatment. 0.2 SIGNOR-274071 ASNS protein P08243 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-267531 CHAF1B protein Q13112 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 15657354 NO miannu Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT. 0.294 SIGNOR-254570 FBH1 protein Q8NFZ0 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding -1 25585578 YES miannu The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64. 0.2 SIGNOR-272451 PPP2R3C protein Q969Q6 UNIPROT PPP5C protein P53041 UNIPROT up-regulates activity binding 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function 0.346 SIGNOR-272480 Erythrocytic spectrin complex SIGNOR-C384 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates binding 9606 24302288 YES lperfetto Spectrin is a member of the F-actin-crosslinking protein superfamily. 0.7 SIGNOR-266030 2-(Decan-2-ylamino)ethyl 4-aminobenzoate chemical CID:50729 PUBCHEM TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 18258442 YES Luana As shown in Table 1 all of the bisanthrapyrazoles inhibited the decatenation activity of human topoisomerase IIα in the low micromolar concentration range 0.8 SIGNOR-257768 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 20966354 YES lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. 0.767 SIGNOR-252695 GAB1 protein Q13480 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 11043767 YES lperfetto We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1. 0.45 SIGNOR-83343 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Ser87 GDDEDACsDTEATEA -1 8288648 YES llicata Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action. 0.307 SIGNOR-251022 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization ubiquitination Lys371 DFIKTTVkELIS 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). 0.3 SIGNOR-272835 ATP5PB protein P24539 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261401 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL 9606 19661060 YES Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.379 SIGNOR-260886 LRRC4 protein Q9HBW1 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 YES miannu A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles 0.425 SIGNOR-264051 HPS6 protein Q86YV9 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR form complex binding 9606 15030569 YES lperfetto Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS8 0.772 SIGNOR-260690 GADD45A protein P24522 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 SIGNOR-C17 10362260 YES gcesareni Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex 0.709 SIGNOR-68221 AP3M2 protein P53677 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 YES miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) 0.744 SIGNOR-268520 olaparib chemical CHEBI:83766 ChEBI PARP3 protein Q9Y6F1 UNIPROT down-regulates activity chemical inhibition 9606 25981132 YES miannu The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT. 0.8 SIGNOR-259320 SMC3 protein Q9UQE7 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates activity binding 9534 BTO:0000318 9528857 YES 2 miannu We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions. 0.297 SIGNOR-241278 P2RY14 protein Q15391 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257210 DEPTOR protein Q8TB45 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.726 SIGNOR-205600 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Ser370 TRQTPVDsPDDTALS -1 11733037 YES miannu  Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities. 0.608 SIGNOR-250371 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 YES lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. 0.79 SIGNOR-252353 PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 11875759 YES lperfetto PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT. 0.8 SIGNOR-228145 WNT1 protein P04628 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity 9606 BTO:0001103 21902831 NO gcesareni Wnt1 and wnt7a stimulation of precursor cells activates protein kinase a (pka), which, through the phosphorylation of creb, induces the expression of the myogenic transcription factors myf5, myod and pax3, resulting in the myogenic commitment of embryonic precursors. 0.268 SIGNOR-176572 RPTOR protein Q8N122 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.862 SIGNOR-205627 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 BTO:0000759 24692351 NO scontino TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis. 0.7 SIGNOR-267488 LAMA2 protein P24043 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.42 SIGNOR-255984 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 YES lperfetto In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression 0.2 SIGNOR-216713 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr472 ICALRHLtSRHQEAE 9606 BTO:0000938 24117889 YES lperfetto Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552. 0.289 SIGNOR-202833 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2D1 protein P51668 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.833 SIGNOR-271311 FOXL2 protein P58012 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19010791 NO miannu Foxl2 can directly activate the transcription of sirt1 0.502 SIGNOR-182300 MAPK8 protein P45983 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 12058028 YES gcesareni The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro. 0.671 SIGNOR-89440 AX/b2 integrin complex SIGNOR-C171 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269020 NEDD4 protein P46934 UNIPROT AP1G2 protein O75843 UNIPROT up-regulates activity monoubiquitination 9606 BTO:0001950 18772139 YES miannu Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination. 0.402 SIGNOR-272634 A11/b1 integrin complex SIGNOR-C168 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269017 ADRB1 protein P08588 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.391 SIGNOR-256901 RAB2A protein P61019 UNIPROT TRIP11 protein Q15643 UNIPROT up-regulates activity binding 9606 BTO:0000567 25473115 YES Sara Vesicle-associated Rab2 then mediates attachment to the Rab2 binding site within the central coiled-coil region of GMAP-210, bringing the vesicle into closer proximity to the target membrane. GMAP-210 function in vivo is dependent upon its ability to tether membranes, which is mediated exclusively by the amino-terminal ALPS motif. Binding to Rab2 is also important for GMAP-210 function, although it is dispensable for tethering per se. 0.395 SIGNOR-261300 ATG14 protein Q6ZNE5 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 10090 BTO:0000944 19270693 YES lperfetto Characterization of the new proteins revealed that atg14l enhances vps34 lipid kinase activity and upregulates autophagy, 0.881 SIGNOR-235448 SMURF1 protein Q9HCE7 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity ubiquitination 9606 12738770 YES lperfetto Smurf1 interacts directly with Cbfa1 and mediates Cbfa1 degradation in a ubiquitin- and proteasome-dependent manner. 0.504 SIGNOR-236083 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates deubiquitination 9606 16027725 YES gcesareni Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases 0.378 SIGNOR-138876 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CG protein P48736 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258300 CDK2 protein P24941 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 17409098 YES gcesareni Ubiquitination and subsequent degradation play a critical role in regulating the levels of p27 during cell cycle progression. Here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3). 0.95 SIGNOR-154188 KRAS protein P01116 UNIPROT CARM1 protein Q86X55 UNIPROT down-regulates activity 9606 BTO:0000304 27840030 NO lperfetto Interestingly, overexpression of KRASG12V (an activating mutant) in BxPC-3 cells, a PDAC cell line carrying wild-type KRAS, led to a 40% decrease of CARM1 protein and consequent hypomethylation or activation of MDH1|These observations indicate that KRAS suppresses CARM1-mediated MDH1 methylation, contributing to Gln metabolism in pancreatic cancer. 0.272 SIGNOR-267640 TRIM27 protein P14373 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates 9606 BTO:0000671 12807881 NO miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. 0.2 SIGNOR-102022 DNA_damage stimulus SIGNOR-ST1 SIGNOR MLH1/PMS2 complex SIGNOR-C59 SIGNOR up-regulates -1 10542278 NO miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. 0.7 SIGNOR-259062 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys77 KYWWKNCkMWAIGIT 9606 BTO:0000007 23353890 YES miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. 0.329 SIGNOR-272095 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser87 PLKQKQPsFSAKKMT 9606 BTO:0000567 24781523 YES miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase 0.31 SIGNOR-276381 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000007 SIGNOR-C13 11158290 YES lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. 0.853 SIGNOR-104807 EIF3_complex complex SIGNOR-C401 SIGNOR 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity binding 9606 16920360 YES miannu EIF3 binds 40S and inhibits the association of 60S. Structural analysis suggests that eIF3 performs this scaffolding function by binding to the 40S subunit on its solvent-exposed surface rather than on its interface with the 60S subunit, where the decoding sites exist. This location of eIF3 seems ideally suited for its other proposed regulatory functions, including reinitiating translation on polycistronic mRNAs and acting as a receptor for protein kinases that control protein synthesis. 0.614 SIGNOR-266401 JMJD1C protein Q15652 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 32034158 YES miannu We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state. 0.2 SIGNOR-265169 PKA proteinfamily SIGNOR-PF17 SIGNOR PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Thr73 YGGEKFAtLAELVQY 9606 BTO:0002181 25802336 YES miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  0.2 SIGNOR-276893 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11781820 YES lperfetto Phosphorylation of tyr412 can occur autocatalytically by a trans-mechanism and cause activation of otherwise inactive c-abl, suggesting a positive feedback loop on c-abl activity. 0.2 SIGNOR-113659 HAUS1 protein Q96CS2 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 YES lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) 0.807 SIGNOR-262319 GSK3B protein P49841 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT down-regulates binding 9606 17726008 YES gcesareni Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways 0.368 SIGNOR-157541 RUBCN protein Q92622 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates binding 9606 19270693 YES gcesareni The run or cysteine-rich domain of rubicon appears to be inhibitory to the binding of rubicon to beclin 1 and vps34 0.2 SIGNOR-184547 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser93 SSLLSRSsSGYFSFD 9606 BTO:0002181 23912711 YES miannu  We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.  0.377 SIGNOR-276247 PSME2 protein Q9UL46 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 35932807 YES lperfetto While PA28alpha beta is responsible for promoting peptidase activity of proteasome to facilitate MHC-I antigen processing, but unable to promote protein degradation, PA28gamma is well-known to not only promote peptidase activity but also proteolytic activity of proteasome. 0.63 SIGNOR-275868 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248746 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Microtubule-based_movement phenotype SIGNOR-PH170 SIGNOR up-regulates 16440056 NO lperfetto Dyneins are large multi-subunit protein complexes that undertake a wide range of roles within the cell. They are adenosine triphosphate (ATP)–driven, microtubule minus-end-directed molecular motors that can be divided, based on function, into two classes: axonemal and cytoplasmic dyneins 0.7 SIGNOR-265019 PRKCA protein P17252 UNIPROT CASR protein P41180 UNIPROT down-regulates phosphorylation Thr888 FKVAARAtLRRSNVS 9606 21135065 YES llicata Casr(t888) is a protein kinase c (pkc) phosphorylation site in the receptor's intracellular domain that has previously been identified as a critical negative regulator of casr downstream signaling in vitro, thus, casr(t888) represents a functionally important, inhibitory phosphorylation site that contributes to the control of pth secretion. 0.352 SIGNOR-170334 MLST8 protein Q9BVC4 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.885 SIGNOR-205609 pevonedistat chemical CHEBI:145535 ChEBI UBE2F protein Q969M7 UNIPROT down-regulates quantity chemical inhibition 9606 BTO:0001109 19360080 YES Monia MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme; A single dose of MLN4924 resulted in a dose- and time-dependent decrease of NEDD8–cullin levels as early as 30 min after administration of compound 0.8 SIGNOR-261067 denosumab antibody DB06643 DRUGBANK TNFSF11 protein O14788 UNIPROT down-regulates activity binding 9606 BTO:0000372 18685421 YES miannu Denosumab, a novel, fully human monoclonal antibody specific to RANKL, suppresses bone resorption markers in patients with a variety of metastatic tumors and is being investigated in multiple clinical trials for the prevention and treatment of bone metastases. 0.4 SIGNOR-259891 PP1 proteinfamily SIGNOR-PF54 SIGNOR GSK3B protein P49841 UNIPROT up-regulates activity dephosphorylation Ser9 SGRPRTTsFAESCKP 26088133 YES lperfetto Anchored PP1 may relieve PKA-mediated inhibition of GSK3beta by dephosphorylating Ser-9, providing bi-directional control of AKAP220 complex formation in response to cAMP. 0.2 SIGNOR-264820 CASP2 protein P42575 UNIPROT Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR form complex binding 9606 20158568 YES miannu The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. 0.862 SIGNOR-262641 CDK2 protein P24941 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser373 SSRSAPAsPNHAGVL 9606 20810654 YES gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. 0.369 SIGNOR-167830 DUSP6 protein Q16828 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation 9606 22521266 YES gcesareni Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase). 0.428 SIGNOR-252903 PYGM protein P11217 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267389 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr143 AVSPGTLtPTGVVSG 26933062 YES lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. 0.389 SIGNOR-276591 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 17466630 YES lperfetto Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. 0.419 SIGNOR-216884 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 17204478 YES lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). 0.798 SIGNOR-263437 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KMT5A protein Q9NQR1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 YES lperfetto First, we found that pr-set7 is phosphorylated at ser 29 (s29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinb complex, s29 phosphorylation also functions to stabilize pr-set7 by directly inhibiting its interaction with the anaphase-promoting complex (apc), an e3 ubiquitin ligase. 0.2 SIGNOR-216856 CDK2 protein P24941 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 SIGNOR-C16 16582606 YES gcesareni In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue. 0.344 SIGNOR-145577 WWTR1 protein Q9GZV5 UNIPROT PPARG protein P37231 UNIPROT down-regulates binding 9606 22153608 YES gcesareni Kmp also enhanced the association of taz with ppar_, thereby suppressing the gene transcription of ppar_ targets and resulting in diminished adipocyte differentiation. 0.311 SIGNOR-195215 SPI1 protein P17947 UNIPROT IRF8 protein Q02556 UNIPROT up-regulates activity binding 9606 BTO:0001413 11483597 YES miannu We found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. 0.595 SIGNOR-222880 PIN1 protein Q13526 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity isomerization 9606 phosphorylation:Ser416;Ser497;Thr345 GFPSKTDsPSCEYSR;GSLCSVFsPSFVQWE;GADSDVEtPSNFGKY 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.2 SIGNOR-263015 KAT6A protein Q92794 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys120 FLHSGTAkSVTCTYS 9606 BTO:0001271 SIGNOR-C54 23431171 YES miannu We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression 0.668 SIGNOR-201482 PRKCA protein P17252 UNIPROT SPAG1 protein Q07617 UNIPROT unknown phosphorylation Ser326 VERDLKNsEAASETQ -1 11517287 YES lperfetto In-vitro incubation with [_-32P]ATP showed that HSD-3.8 protein can be phosphorylated by PKC. The phosphate is probably linked to the serine residue presenting the sequence X LysXX SerX. 0.307 SIGNOR-249109 PDGFRA protein P16234 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 15489898 YES gcesareni The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells. 0.488 SIGNOR-247984 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 10029 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.601 SIGNOR-249396 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys21 EGPRDGLkKERLLDD 9606 7479976 YES gcesareni Here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. 0.541 SIGNOR-26573 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 YES lperfetto Although the receptor-associated tyrosine kinases Jak2 and Tyk2 are activated after the recruitment of IL-13 to its receptor (containing IL-4R and IL-13R1), IL-4 stimulates Jak1 activation. 0.715 SIGNOR-249529 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273098 DET1 protein Q7L5Y6 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 YES lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes 0.793 SIGNOR-154508 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser68 FLEQPICsVQPIDLN 9606 23166821 YES llicata We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5 0.2 SIGNOR-199785 PHF10 protein Q8WUB8 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.622 SIGNOR-270716 TP53 protein P04637 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates binding 9606 10207072 YES gcesareni Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo. 0.912 SIGNOR-66956 CXCL1 protein P09341 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16885213 NO gcesareni The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i). 0.2 SIGNOR-148457 MARK2 protein Q7KZI7 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 22072711 YES The effect has been demonstrated using Q92974-2 gcesareni We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation 0.504 SIGNOR-177100 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT down-regulates quantity by destabilization sumoylation Lys391 QTGLLKIkTEPLDFN 9534 16061479 YES Luisa Pc2 can act directly as an E3 ligase for SIP1 sumoylation.SIP1 sumoylation having a negative effect on its repression of E-cadherin transcription. 0.331 SIGNOR-268955 brimonidine chemical CHEBI:3175 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258902 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189168 ARHGAP30 protein Q7Z6I6 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.457 SIGNOR-260487 RNF128 protein Q8TEB7 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000661 17114425 YES miannu We found that RhoGDIα and RhoGDIβ are ubiquitin E3 substrates of GRAIL. GRAIL uses nonlysine 48-ubiquitin linkage in polyubiquitinating RhoGDI. GRAIL was subsequently demonstrated to bind and ubiquitinate RhoGDI, although GRAIL-mediated ubiquitination of RhoGDI did not result in proteosomal degradation. Our data suggest that ubiquitination of RhoGDI by GRAIL does not result in proteolytic degradation. In fact, GRAIL activity appeared to increase RhoGDI stability. 0.266 SIGNOR-271622 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR MACROH2A1 protein O75367 UNIPROT up-regulates activity monoubiquitination 9606 BTO:0000007 15897469 YES miannu BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex. t present, we cannot discriminate the main role in vivo of the polyubiquitinated or monoubiquitinated MACROH2A1, because both modifications can be detected (Fig. 2 d and e and ref. 34).Importantly, RNAi-mediated knock-down of CULLIN3 or SPOP results in loss of MACROH2A1 from the inactivated X chromosome (Xi), leading to reactivation of the Xi in the presence of inhibitors of DNA methylation and histone deacetylation. No significant changes in protein stability were observed, suggesting that ubiquitination serves regulatory functions other than protein degradation of BMI1 and MACROH2A1 0.2 SIGNOR-272660 SMAD5 protein Q99717 UNIPROT GATA3 protein P23771 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.31 SIGNOR-268943 THR proteinfamily SIGNOR-PF84 SIGNOR RARA protein P10276 UNIPROT up-regulates activity binding 9606 15650024 YES inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.2 SIGNOR-267779 COPII vesicle complex SIGNOR-C370 SIGNOR Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 9606 30605680 NO lperfetto Coat protein complex (COP) II vesicles export newly synthesized secretory proteins from the endoplasmic reticulum (ER) 0.7 SIGNOR-265297 YWHAG protein P61981 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 14701738 YES miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase 0.267 SIGNOR-261713 RAP1GDS1 protein P52306 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 21242305 YES miannu Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc 0.632 SIGNOR-171347 SMURF1 protein Q9HCE7 UNIPROT CALCOCO1 protein Q9P1Z2 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272688 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT unknown phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0001412 8692915 YES gcesareni Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. 0.414 SIGNOR-246231 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser90 QHVRSHSsPASLQLG 26375055 YES lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity 0.258 SIGNOR-276518 Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 NO lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. 0.7 SIGNOR-273455 EEF1A1P5 protein Q5VTE0 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269553 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr259 ASVDSSLyNLPRSYS 9606 BTO:0000007 19881549 YES lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis 0.703 SIGNOR-236310 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR ROR2 protein Q01974 UNIPROT down-regulates activity phosphorylation Ser864 PKPSSHHsGSGSTST 9606 21078818 YES gcesareni We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a. 0.332 SIGNOR-228026 crizotinib chemical CHEBI:64310 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191136 GATA6 protein Q92908 UNIPROT CYP11A1 protein P05108 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002850 15284005 NO miannu The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells. 0.325 SIGNOR-254197 SCF-FBW7 complex SIGNOR-C135 SIGNOR TOP2A protein P11388 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003492 21254166 YES miannu Evidence that Fbw7 acts as the E3-ligase mediating the degradation of topoIIα in HDAC inhibitor-treated PLC5 cells.  0.344 SIGNOR-276302 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr234 AQPEQDEyDIPRHLL 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246397 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 YES Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. 0.2 SIGNOR-248424 PAMPs stimulus SIGNOR-ST11 SIGNOR TLR4 protein O00206 UNIPROT up-regulates activity 9606 BTO:0000801 19946286 NO lperfetto The lipopolysaccharide (LPS) of Gram negative bacteria is a wellknown inducer of the innate immune response1. Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common pattern in structurally diverse LPS molecules. 0.7 SIGNOR-249516 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1213 GSSDDVRyVNAFKFM 9606 11583921 YES tpavlidou Vegfr-1 mutated at y1213, y1242, and y1333 were constructed and expressed in pae cells, to the same level as that of pae/vegfr-1 cells. The mutated vegfr-1 y1213f expressed in pae cells was kinase inactive. 0.2 SIGNOR-110850 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr531 NTTGSDNtDTEGS 9606 17936701 YES PVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. 0.346 SIGNOR-266900 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 10713164 YES gcesareni SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. 0.6 SIGNOR-75782 GSK3B protein P49841 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 YES lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 0.62 SIGNOR-245432 LDHA protein P00338 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI down-regulates quantity chemical modification 9606 24929216 YES Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. 0.8 SIGNOR-266918 PLK1 protein P53350 UNIPROT CEP55 protein Q53EZ4 UNIPROT up-regulates phosphorylation Ser436 PTAALNEsLVECPKC 9606 16198290 YES lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. s425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436...enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. 0.554 SIGNOR-140898 RING E3 ligase proteinfamily SIGNOR-PF106 SIGNOR Ub:RING_E3 complex SIGNOR-C519 SIGNOR form complex binding 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 0.2 SIGNOR-271377 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.2 SIGNOR-251446 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273103 PLEKHA7 protein Q6IQ23 UNIPROT TSPAN33 protein Q86UF1 UNIPROT up-regulates activity binding 10116 BTO:0003618 30463011 YES Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. 0.401 SIGNOR-261250 PAK2 protein Q13177 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates activity phosphorylation Ser39 RRGRATDsLPGKFED 9606 BTO:0000007 15234964 YES miannu Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. When 293T cells are subjected to apoptotic induction by hydrogen peroxide, Mnk1 is phosphorylated at both Thr(22) and Ser(27). These results indicate a role for Pak2 in the down-regulation of translation initiation in apoptosis by phosphorylation of Mnk1. 0.421 SIGNOR-250221 ARAF protein P10398 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation 9606 21779497 YES gcesareni Active raf phosphorylates mek. 0.753 SIGNOR-175142 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176837 ABCC4 protein O15439 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR up-regulates activity binding 9606 BTO:0000132 23805129 YES lperfetto The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2).  0.2 SIGNOR-265996 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation -1 8954982 YES llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. 0.324 SIGNOR-251036 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000671 18701453 YES lperfetto We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation. 0.364 SIGNOR-236026 HPN protein P05981 UNIPROT F7 protein P08709 UNIPROT up-regulates activity cleavage Arg212 NASKPQGrIVGGKVC -1 7814421 YES lperfetto Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation|In contrast, an activation cleavage site factor VII mutant, R152E factor VII, was not cleaved by hepsin-transfected cells, suggesting that factor VII and S344A factor VII were activated on these cells by cleavage of the Arg152-Ile153 peptide bond. I 0.348 SIGNOR-263638 dehydroepiandrosterone chemical CHEBI:28689 ChEBI androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI up-regulates quantity precursor of 9606 BTO:0001363 30943210 YES lperfetto Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone 0.8 SIGNOR-268659 XL765 chemical CHEBI:71958 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207878 GLI1 protein P08151 UNIPROT GLI1/GLI2 complex SIGNOR-C450 SIGNOR form complex binding 9606 BTO:0000304 32766732 YES GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. 0.456 SIGNOR-269209 CBP/p300 complex SIGNOR-C6 SIGNOR EPCAM protein P16422 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11505407 NO miannu The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects. 0.254 SIGNOR-254791 CDK1 protein P06493 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation Thr376 QVAPRAGtPGFRAPE 9606 10846177 YES gcesareni Hucdc7 and ask proteins can also be phosphorylated by cdks in vitro. Among four possible cdk phosphorylation sites of hucdc7, replacement of thr-376, corresponding to the activating threonine of cdk, with alanine (t376a mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. 0.536 SIGNOR-78311 TBR1 protein Q16650 UNIPROT FOXP2 protein O15409 UNIPROT up-regulates activity binding 9606 25232744 YES miannu We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. 0.556 SIGNOR-266831 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 15849194 YES Ser112 corresponds to EIRSRHSsYPAGTED lperfetto Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD|Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112. 0.659 SIGNOR-81165 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A11 protein P48066 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206990 NTN4 protein Q9HB63 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 BTO:0001484 25881791 YES miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. 0.609 SIGNOR-268184 palbociclib chemical CHEBI:85993 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205704 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 YES lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. 0.2 SIGNOR-244595 CHEK1 protein O14757 UNIPROT E2F6 protein O75461 UNIPROT down-regulates activity phosphorylation Ser12 RPARKLPsLLLDPTE -1 23954429 YES miannu the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters. 0.572 SIGNOR-266370 KMT2C protein Q8NEZ4 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30385408 YES miannu MLL3 enhances the transcription of PD-L1 and regulates anti-tumor immunity. We found that MLL3 bound to the enhancer of PD-L1. 0.2 SIGNOR-260040 Frizzled proteinfamily SIGNOR-PF11 SIGNOR GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 YES gcesareni Wnt7a binding to fzd7 activates pi3k through a g protein alpha s- dependent mechanism. 0.2 SIGNOR-253125 BAK1 protein Q16611 UNIPROT ENDOG protein Q14249 UNIPROT up-regulates 9606 12941691 NO gcesareni We show that the mitochondrial outer-membrane permeabilization induced by bax-, tbid- or bax/bak-dependent pro-apoptotic drugs results in the release of cytochrome c, smac/diablo and htra2/omi, but that subsequent caspase activation is required to induce the translocation of endog in addition to aif into the cytosol. 0.292 SIGNOR-86406 CHEK2 protein O96017 UNIPROT RASGRF1 protein Q13972 UNIPROT down-regulates phosphorylation Ser287 PITHDDVsSIFLNSE 9606 17110335 YES miannu During interphase, cdc25 is inhibited by ser287 phosphorylation (xenopus cdc25;ser 216 in human cdc25c) and this inhibitory phosphorylation is maintained by dna-responsive checkpoints / s287 is targeted by many kinases, including chk1, chk2, ctak-1, pka, p38 and mapkap kinase-2 suggesting that phosphorylation of this site may integrate multiple signaling inputs. 0.403 SIGNOR-150843 PRKCB protein P05771 UNIPROT MEP1B protein Q16820 UNIPROT down-regulates quantity phosphorylation Ser687 KKYRERMsSNRPNLT 9534 12941954 YES miannu These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate. 0.2 SIGNOR-263173 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258183 SRC protein P12931 UNIPROT TXK protein P42681 UNIPROT up-regulates activity phosphorylation Tyr420 RYVLDDEyVSSFGAK 9606 11353545 YES lperfetto We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association. 0.348 SIGNOR-247346 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser44 LENDFFNsPPRKTVR 9606 15004009 YES lperfetto Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia 0.506 SIGNOR-216682 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys215 TSTHLLLkEDEGVDD 31476572 YES lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. 0.2 SIGNOR-275680 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr171 RGTLRKGtLGSKGQK -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273488 PKI-402 chemical CID:44187953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206259 RET protein P07949 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates binding 9606 12087092 YES amattioni Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret. 0.613 SIGNOR-90158 MBD4 protein O95243 UNIPROT CYP27B1 protein O15528 UNIPROT up-regulates quantity by expression transcriptional regulation 23195996 YES lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] 0.377 SIGNOR-275682 MBD4 protein O95243 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 23195996 NO lperfetto The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively.  0.7 SIGNOR-275683 MBD4 protein O95243 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23195996 NO lperfetto The base excision repair DNA N-glycosylase MBD4 (also known as MED1), an interactor of the DNA mismatch repair protein MLH1, plays a central role in the maintenance of genomic stability of CpG sites by removing thymine and uracil from G:T and G:U mismatches, respectively.  0.7 SIGNOR-275684 UVB radiation stimulus SIGNOR-ST17 SIGNOR DDB1 protein Q16531 UNIPROT up-regulates 24086042 NO lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). 0.7 SIGNOR-275685 GNAO1 protein P09471 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates -1 10224115 NO G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. 0.7 SIGNOR-256525 RNF8 protein O76064 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates ubiquitination 9606 20551964 YES gcesareni Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist. 0.2 SIGNOR-166174 PYY protein P10082 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 YES esanto Maml3 forms complexes in vivo with icn and csl and functiosn as transcriptional coactivators for notch signaling. 0.642 SIGNOR-114749 NOX1 protein Q9Y5S8 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.7 SIGNOR-264714 TGFBR1 protein P36897 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 9606 19726546 YES lperfetto Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity. 0.281 SIGNOR-227496 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.2 SIGNOR-252083 hsa-miR-338-3p mirna URS00000254A6_9606 RNAcentral GLI1 protein P08151 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004169 29069716 NO Parnian Transfection of MHCC-97H cells with the miR-338-3p mimic resulted in a significant decrease in Gli1 protein and mRNA expression, transfection with the miR-338-3p inhibitor had the opposite effect. 0.4 SIGNOR-277974 phosphatidic acid smallmolecule CHEBI:16337 ChEBI MAPK1 protein P28482 UNIPROT up-regulates chemical activation 9606 BTO:0000887;BTO:0001103 20231899 YES gcesareni In addition, extracellular signal-regulated kinase (erk) is stimulated by ampk-induced pld1 activation through the formation of phosphatidic acid (pa), which is a product of pld 0.8 SIGNOR-164289 CHRM2 protein P08172 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.401 SIGNOR-256828 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267391 TFAP4 protein Q01664 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 BTO:0001109 19505873 YES miannu We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads. 0.283 SIGNOR-226590 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates phosphorylation 9606 16862148 YES acerquone Rock phosphorylates filgap, and this phosphorylation stimulates its racgap activity and is a requirement for filgap-mediated bleb formation 0.434 SIGNOR-148262 NOTCH1 protein P46531 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19151708 NO gcesareni Notch1 directly induces transcription of pin1 0.385 SIGNOR-183458 PRKCZ protein Q05513 UNIPROT STK11 protein Q15831 UNIPROT up-regulates phosphorylation Ser307 IRQIRQHsWFRKKHP 9606 BTO:0000887;BTO:0001103;BTO:0001260 19414597 YES llicata Here, we have identified s307 as a novel phosphorylation site in lkb1 and provide evidence that, in multiple cell types, phosphorylation of this site by protein kinase c ? (pkc-?) Induces nucleocytoplasmic transport of lkb1. 0.321 SIGNOR-185640 ITGAX protein P20702 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.83 SIGNOR-253193 ERCC6 protein Q03468 UNIPROT RAD23B protein P54727 UNIPROT up-regulates activity 24086043 NO lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.456 SIGNOR-275694 Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR PROC protein P04070 UNIPROT up-regulates activity cleavage 9606 BTO:0000131 29880919 YES lperfetto Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). 0.72 SIGNOR-263526 ACTB protein P60709 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.493 SIGNOR-270717 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 25309941 NO Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). 0.7 SIGNOR-255489 TGFB3 protein P10600 UNIPROT TGFB3 protein P10600 UNIPROT up-regulates binding 9606 16885528 YES gcesareni The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge 0.2 SIGNOR-148611 NLGN3 protein Q9NZ94 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.83 SIGNOR-264157 RNF31 protein Q96EP0 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 24469399 YES miannu Involvement of Gln271 and Asp275 of NEMO in LUBAC-mediated linear polyubiquitination.vHOIP NZF1 also recognizes NEMO, and this recognition is involved in linear polyubiquitination of NEMO. Linear chains conjugated to NEMO are recognized by NEMO in trans on another IKK complex, thereby inducing multimerization of the IKK complex and trans autophosphorylation of IKK2. 0.849 SIGNOR-272052 Gbeta proteinfamily SIGNOR-PF4 SIGNOR STAT5A protein P42229 UNIPROT up-regulates phosphorylation 9606 BTO:0000975 10194762 YES inferred from 70% family members gcesareni Serine 780 is the only substrate in full-length stat5a for active erk 0.2 SIGNOR-270004 GATA1 protein P15976 UNIPROT NBEAL2 protein Q6ZNJ1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000132 28082341 NO lperfetto In conclusion, we herein show a long-distance regulatory region with GATA1 binding sites as being a strong enhancer for NBEAL2 expression. 0.375 SIGNOR-261881 CNTNAP2 protein Q9UHC6 UNIPROT CNTN1 protein Q12860 UNIPROT up-regulates activity relocalization 10090 BTO:0001221 11069942 YES Gianni These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr. 0.477 SIGNOR-269074 DDX5 protein P17844 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 10090 BTO:0000165 17960593 YES miannu P68 (ddx5) interacts with runx2 and regulates osteoblast differentiation. / p68 is a novel co-activator for runx2 0.454 SIGNOR-236974 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 15849194 YES llicata P21-activated kinase 1 (pak1)-dependent phosphorylation of raf-1 regulates its mitochondrial localization, phosphorylation of bad, and bcl-2 association. moreover, the mitochondrial translocation of raf-1 and the interaction between raf-1 and bcl-2 are regulated by raf-1 phosphorylation at ser-338/ser-339. 0.2 SIGNOR-135679 SOX17 protein Q9H6I2 UNIPROT GLI2 protein P10070 UNIPROT up-regulates 10090 33083751 NO SimoneGraziosi Sox17 ablation lowered endogenous Gli2 and Olig2+ cells 0.298 SIGNOR-269218 MAML3 protein Q96JK9 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 12370315 YES gcesareni We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors. 0.884 SIGNOR-254323 STK39 protein Q9UEW8 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates activity phosphorylation 16990453 YES lperfetto This phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1 0.602 SIGNOR-264642 JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 YES lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities 0.2 SIGNOR-137627 regorafenib chemical CHEBI:68647 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259211 ACAT1 protein P24752 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity acetylation 34289383 YES lperfetto We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) 0.394 SIGNOR-267633 NOC3L protein Q8WTT2 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 15564382 NO Fad24, a mammalian homolog of Noc3p, is a positive regulator in adipocyte differentiation 0.7 SIGNOR-253060 alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 YES miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. 0.8 SIGNOR-270808 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 19584320 YES lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.49 SIGNOR-216495 PPP1R1B protein Q9UD71 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates activity binding 9606 BTO:0000938 10604473 YES miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  0.59 SIGNOR-264958 PTPN21 protein Q16825 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 15143158 YES gcesareni Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling. 0.642 SIGNOR-124774 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TH protein P07101 UNIPROT up-regulates phosphorylation 9606 7901013 YES inferred from 70% family members gcesareni In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11 0.2 SIGNOR-270055 PRKCD protein Q05655 UNIPROT ADRA2A protein P08913 UNIPROT up-regulates activity phosphorylation Ser247 RRTRVPPsRRGPDAV 10029 BTO:0000246 11732925 YES lperfetto Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling. 0.532 SIGNOR-249126 EFL1 protein Q7Z2Z2 UNIPROT EIF6 protein P56537 UNIPROT up-regulates 9606 BTO:0001271 21536732 NO miannu Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits 0.2 SIGNOR-173492 NAALAD2 protein Q9Y3Q0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity chemical modification 9606 10085079 YES miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. 0.8 SIGNOR-267543 TFDP1 protein Q14186 UNIPROT RRM1 protein P23921 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.283 SIGNOR-253866 CCL19 protein Q99731 UNIPROT ACKR4 protein Q9NPB9 UNIPROT up-regulates activity binding 9606 BTO:0001938 23341447 YES Luana  In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines. 0.663 SIGNOR-268416 SIRT1 protein Q96EB6 UNIPROT CRTC1 protein Q6UUV9 UNIPROT up-regulates deacetylation 9606 BTO:0000938 BTO:0000142 22179316 YES miannu Sirt1 deacetylates and activates torc1 0.281 SIGNOR-191568 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT down-regulates transcriptional regulation 9606 20584981 NO fspada Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program.  0.291 SIGNOR-210074 GNGT1 protein P63211 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.424 SIGNOR-252686 ER stress stimulus SIGNOR-ST9 SIGNOR PRNP protein F7VJQ1 UNIPROT up-regulates 9606 BTO:0000007 21478263 NO ER stress specifically increases the synthesis of AltPrP from PrP cDNA. 0.7 SIGNOR-253609 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0002552 17967874 YES gcesareni The increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. 0.843 SIGNOR-158636 PI-103 chemical CHEBI:90524 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252651 JAK1 protein P23458 UNIPROT SNX8 protein Q9Y5X2 UNIPROT up-regulates activity phosphorylation Tyr126 MLLHKFPyRMVPALP 9606 BTO:0000007 29180417 YES miannu IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKβ to the JAK1 complex.  0.342 SIGNOR-273645 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates phosphorylation Ser49 IEGMILLsELSRRRI 9606 10563826 YES lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b. 0.89 SIGNOR-72152 EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 YES lperfetto The egf-r coimmunoprecipitated with p85 alpha 0.781 SIGNOR-252672 AMPK complex SIGNOR-C15 SIGNOR HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887 21565617 YES lperfetto We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases. 0.272 SIGNOR-216658 RHOBTB1 protein O94844 UNIPROT PDE5A protein O76074 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 30896450 YES miannu RhoBTB1 augmented the cGMP response to nitric oxide by restraining the activity of phosphodiesterase 5 (PDE5) by acting as a substrate adaptor delivering PDE5 to the Cullin-3 E3 Ring ubiquitin ligase complex for ubiquitination inhibiting PDE5. 0.2 SIGNOR-272312 EXOC7 protein Q9UPT5 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 12687004 NO gcesareni So, the exocyst might have a crucial role in the targeting of the glut4 vesicle to the plasma membrane, perhaps directing the vesicle to the precise site of fusion 0.547 SIGNOR-100242 RNF138 protein Q8WVD3 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16714285 YES miannu Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome. 0.307 SIGNOR-271595 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Thr87 GVPAEGRtPPPFPGE 9606 BTO:0000887 11342557 YES lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation 0.341 SIGNOR-107680 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity precursor of 9606 3013232 YES miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. 0.8 SIGNOR-266237 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2214 GGRSVPTtPLQVAAP 9606 18794356 YES miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. 0.375 SIGNOR-181026 TGFB2 protein P61812 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 11157754 YES gcesareni We show that tbetarii-b, an alternatively spliced variant of the tgf-beta type ii receptor, is a tgf-beta2 binding receptor, which mediates signalling via the smad pathway in the absence of any tgf-beta type iii receptor 0.753 SIGNOR-104795 BCAR1 protein P56945 UNIPROT PKN3 protein Q6P5Z2 UNIPROT up-regulates activity binding 10090 BTO:0002572 30422386 YES lperfetto Taken together, the data suggest that p130Cas expression induces PKN3 activation and this activation is independent of p130Cas–PKN3 interaction. 0.2 SIGNOR-264573 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser499 VKSRWSGsQQVEQPT 9606 12551925 YES gcesareni For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1. 0.557 SIGNOR-97644 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206385 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 19303846 YES lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation 0.894 SIGNOR-227878 NOSIP protein Q9Y314 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 25546391 YES miannu  NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice.  0.339 SIGNOR-271498 SRC protein P12931 UNIPROT FLOT1 protein O75955 UNIPROT up-regulates activity phosphorylation Tyr56 NVKSEKVyTRHGVPI 9606 BTO:0001583 24983503 YES done miannu Taken together, we conclude that mitochondrial c-Src phosphorylates flotillin-1 at Tyr56 and Tyr149, and that these phosphorylations are required for its interaction with CxII and the prevention of ROS production. 0.335 SIGNOR-273805 SRP19 protein P09132 UNIPROT SRP72 protein O76094 UNIPROT up-regulates activity binding -1 30649418 YES miannu Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. 0.942 SIGNOR-261166 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT RPS2 protein P15880 UNIPROT down-regulates activity binding -1 33188728 YES miannu Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5. 0.2 SIGNOR-262508 CHMP2A protein O43633 UNIPROT Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates -1 30989108 NO miannu ESCRT-III has been proposed to assemble inside the membrane neck formed at a late stage of a budding vesicle or an enveloped virus. The membrane neck needs to be constricted to proceed to membrane fission, thereby splitting the vesicle or virus from the cellular membrane. CHMP2A and CHMP3 are engaged late in ESCRT-III assembly, recruit VPS4 (31, 42), and block Snf7 (CHMP4) polymerization 0.7 SIGNOR-260844 KLF4 protein O43474 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0003292 18379898 NO miannu The results showed the upregulation of the HSP73 constitutive expression by KLF4 overexpression in both C2C12 cells and murine RAW264.7 macrophages; in response to heat stress, however, few changes were observed in the levels of HSP73 by KLF4 overexpression. 0.2 SIGNOR-254544 RABEP1 protein Q15276 UNIPROT RAB5A protein P20339 UNIPROT up-regulates binding 9606 11452015 YES miannu We have previously shown that rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of rabex-5, a rab5 nucleotide exchange factor, and the effector rabaptin-5. 0.928 SIGNOR-109352 PRKCD protein Q05655 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 16418226 YES gcesareni Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation. 0.595 SIGNOR-143828 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Ser387 LSEQNRAsPLPSGLL 9606 19561641 YES gcesareni Phosphorylation of threonine 395 has been linked to the proteasome-mediated degradation of full length cyclin e 0.955 SIGNOR-186414 OTUB1 protein Q96FW1 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity deubiquitination 19383985 YES lperfetto OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells. 0.545 SIGNOR-276529 PPP2CA protein P67775 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates dephosphorylation Tyr159 SKPPYTDyVSTRWYR 9606 15988018 YES lperfetto In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif. 0.2 SIGNOR-138432 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH2 protein P19022 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265842 CDK1 protein P06493 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser696 EKNYALPsPATTEGG 9606 20169205 YES llicata Cdc2 is the raptor ser696, thr706 kinase 0.386 SIGNOR-163849 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 22492984 YES lperfetto Bim, and puma bind with high affinity to all pro-survival proteins 0.832 SIGNOR-196935 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192771 methionine smallmolecule CHEBI:16811 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264750 flumazenil chemical CHEBI:5103 ChEBI GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto Receptors containing the alpha4 or alpha6 subunits, together with beta and gamma2, do not bind the traditional BZ agonists, including zolpidem, but demonstrate high affinity for some ligands, notably the imidazobenzodiazepines such as flumazenil and Ro15-4513, or bretazenil 0.8 SIGNOR-263807 TRAF3 protein Q13114 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16306937 NO miannu TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10), but is dispensable for expression of pro-inflammatory cytokines. 0.33 SIGNOR-256077 perfluorononanoic acid chemical CHEBI:38397 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268769 ESCRT-III complex SIGNOR-C379 SIGNOR Cytoskeleton_organization phenotype SIGNOR-PH89 SIGNOR up-regulates 9606 26775243 NO miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. 0.7 SIGNOR-265535 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 12857726 YES gcesareni The tyrosine kinase pp60c-src has also been identified as a good substrate of ptp1b leading to an activation of this kinase (27). 0.78 SIGNOR-103607 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 YES lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. 0.386 SIGNOR-249184 orotate smallmolecule CHEBI:30839 ChEBI orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity precursor of 9606 2912371 YES miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). 0.8 SIGNOR-267434 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 10090 BTO:0000165 17151142 NO lperfetto These results indicate that TNF-alpha regulates myogenesis and muscle regeneration as a key activator of p38. 0.372 SIGNOR-235370 PDLIM2 protein Q96JY6 UNIPROT RELA protein Q04206 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17468759 YES miannu Here we report that PDLIM2 negatively regulated NF-kappaB activity, acting as a nuclear ubiquitin E3 ligase targeting the p65 subunit of NF-kappaB. PDLIM2 bound to p65 and promoted p65 polyubiquitination. 0.348 SIGNOR-271651 dexamethasone chemical CHEBI:41879 ChEBI CEBPD protein P49716 UNIPROT up-regulates quantity by expression 9606 8754811 NO fspada The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively 0.8 SIGNOR-43254 HDAC1 protein Q13547 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 BTO:0000887 11684023 YES gcesareni Interaction of myod with hdac1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression. 0.547 SIGNOR-111243 GOPC protein Q9HD26 UNIPROT ADRB1 protein P08588 UNIPROT down-regulates relocalization 9606 15358775 YES miannu Overexpression of cal reduces surface expression of beta1ar. Interaction with cal promotes retention of beta1ar within the cell 0.343 SIGNOR-128791 SLC25A13 protein Q9UJS0 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity relocalization 9606 12084073 YES miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 0.8 SIGNOR-265155 KEAP1 protein Q14145 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9534 BTO:0001538 17046835 YES miannu Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Keap1 is a Bric-a-Brac (BTB) 2 -Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. 0.723 SIGNOR-272646 AMPK complex SIGNOR-C15 SIGNOR AMOTL1 protein Q8IY63 UNIPROT up-regulates quantity by stabilization phosphorylation Ser793 SSLRPARsVPSIAAA 9606 BTO:0000007 25373897 YES miannu we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. 0.2 SIGNOR-263105 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Thr577 AENGLLMtPCYTANF 9606 10980595 YES llicata We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway 0.729 SIGNOR-81464 SCF-betaTRCP complex SIGNOR-C5 SIGNOR ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 11238952 YES miannu Here we show that the F-box protein betaTrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for IkappaBalpha and beta-catenin degradation, is colocalized in the nucleus with ATF4, a member of the ATF-CREB bZIP family of transcription factors, and controls its stability. ATF4 ubiquitination in HeLa cells is enhanced in the presence of betaTrCP. 0.328 SIGNOR-272580 CDK11A protein Q9UQ88 UNIPROT CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR form complex binding -1 12082095 YES lperfetto Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3| 0.393 SIGNOR-273117 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 16439210 YES gcesareni We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity. 0.782 SIGNOR-142949 USF1 protein P22415 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19389701 NO gcesareni Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes 0.248 SIGNOR-185575 SIK2 protein Q9H0K1 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 BTO:0006293 35277657 YES miannu Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation. 0.2 SIGNOR-275399 PPAT protein Q06203 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity chemical modification 9606 8106516 YES Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed‚Äù 0.8 SIGNOR-267190 HSPA1A protein P0DMV8 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 21730050 YES gcesareni Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex 0.632 SIGNOR-251668 SRC protein P12931 UNIPROT PANX1 protein Q96RD7 UNIPROT up-regulates activity phosphorylation Tyr199 KYPIVEQyLKTKKNS 9606 BTO:0005101 30814251 YES done miannu We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198. Using a PANX1 Tyr198-specific antibody, SFK inhibitors, SRC knockdown, temperature-dependent SRC cells, and kinase assays, we found that PANX1-mediated ATP release and vasoconstriction involves constitutive phosphorylation of PANX1 Tyr198 by SRC. 0.379 SIGNOR-273806 BKM120 chemical CHEBI:71954 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190386 RUNX2 protein Q13950 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004850 14594802 NO miannu We find that LEF-1 and CBFalpha co-activate ELA2 expression. 0.256 SIGNOR-254552 PIEZO1 protein Q92508 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 YES lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). 0.388 SIGNOR-262571 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser231 FGDDEDDsGTEES 9606 BTO:0000567 11546811 YES llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  0.352 SIGNOR-251059 ARNT protein P27540 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17012224 YES miannu Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. 0.644 SIGNOR-259910 MAPK14 protein Q16539 UNIPROT RBSN protein Q9H1K0 UNIPROT up-regulates phosphorylation Ser215 ESLSTHTsPSQSPNS 9606 16138080 YES lperfetto We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes 0.2 SIGNOR-140143 GNAI2 protein P04899 UNIPROT TNFAIP8 protein O95379 UNIPROT up-regulates activity binding 9606 20607800 YES TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation 0.2 SIGNOR-256492 CCNA1 protein P78396 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001884 15829981 NO miannu SiRNA mediated silencing of cyclin A1 in highly cyclin A1 expressing ML1 leukemic cells significantly slowed S phase entry, decreased proliferation and inhibited colony formation.  0.7 SIGNOR-255734 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser300 SMSDPGVsYRTREEI -1 11486000 YES lperfetto Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes. 0.871 SIGNOR-109651 1038915-60-4 chemical CID:24958200 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194402 LRRK2 protein Q5S007 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 9606 22303461 YES gcesareni Lrrk2 directly phosphorylates tubulin-associated tau, but not free tau;(iii) lrrk2 phosphorylates tau at thr181 as one of the target sites;. furthermore, we revealed that lrrk2-mediated phosphorylation of tau reduces its tubulin-binding ability. 0.529 SIGNOR-195756 HRAS protein P01112 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9534 BTO:0004055 8052307 YES lperfetto In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k 0.845 SIGNOR-252689 GSK3B protein P49841 UNIPROT EIF2B3 protein Q9NR50 UNIPROT down-regulates binding 9606 21798082 YES gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). 0.261 SIGNOR-175520 RBPJ protein Q06330 UNIPROT MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 21873209 YES gcesareni When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects. 0.877 SIGNOR-176200 GDF11 protein O95390 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 12414726 YES gcesareni Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2 0.626 SIGNOR-95309 CH5132799 chemical CID:49784945 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252648 CSRP3 protein P50461 UNIPROT MYF6 protein P23409 UNIPROT up-regulates activity binding 10090 BTO:0004058 9234731 YES 2 miannu we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. 0.447 SIGNOR-241096 SRC protein P12931 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Tyr21 IENEEQEyVQTVKSS 9606 24103589 YES lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf 0.39 SIGNOR-202796 SMN complex complex SIGNOR-C158 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 9323129 NO lperfetto These findings suggest a role for SMN and SIP1 in spliceosomal snRNP biogenesis and function and provide a likely molecular mechanism for the cause of SMA 0.7 SIGNOR-253123 CUL5 protein Q93034 UNIPROT DAB1 protein O75553 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 24210661 YES miannu SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. 0.327 SIGNOR-272140 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr178 EEAERKLySGAQTDG 9606 BTO:0000661 7961936 YES We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. 0.618 SIGNOR-251392 Caspase 3 complex complex SIGNOR-C221 SIGNOR CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 YES amattioni Caspase-3 is required for the activation of caspases 6 0.618 SIGNOR-256467 pimozide chemical CHEBI:8212 ChEBI STAT5A protein P42229 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001545 23264850 YES miannu We have identified the psychotropic drug pimozide as an effective inhibitor of STAT5 function. Pimozide inhibits the tyrosine phosphorylation of STAT5, leading to the death of AML cells through the induction of apoptosis. 0.8 SIGNOR-260125 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000195 17289681 YES The effect has been demonstrated using P34152-3 gcesareni We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress. 0.648 SIGNOR-152971 FANCL protein Q9NW38 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 SIGNOR-C300 17396147 YES lperfetto Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.9 SIGNOR-263250 SYVN1 protein Q86TM6 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29731393 YES miannu NRF2 is negatively regulated by three E3 ubiquitin ligase complexes: the KEAP1-CUL3-RBX1 complex, the β-TrCP-SKP1-CUL1-RBX1 complex, and HRD1. 0.2 SIGNOR-267360 CSNK2A1 protein P68400 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Thr236 VEKFKDNtIPDKVKK 9606 15064744 YES lperfetto Inhibition of protein kinase ck2 enzyme activity in vivo resulted in an enhanced nuclear localization of cdc25c. Thus, phosphorylation of cdc25c at threonine 236 is an important signal for the retention of cdc25c in the cytoplasm 0.302 SIGNOR-123713 AKT1 protein P31749 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR up-regulates phosphorylation 9606 BTO:0000887 17964260 YES lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. 0.602 SIGNOR-217670 apraclonidine chemical CHEBI:2788 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation -1 8784451 YES miannu we describe full details of our studies with 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline (AGN 193080, 3), a potent, selective α2 adrenoceptor agonist that does not cross the blood−brain barrier. 0.8 SIGNOR-258498 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207779 CH5132799 chemical CID:49784945 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190943 MAOB protein P27338 UNIPROT (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 YES Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. 0.8 SIGNOR-269747 TFE3 protein P19532 UNIPROT GABARAPL1 protein Q9H0R8 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells 0.324 SIGNOR-276821 PAK1 protein Q13153 UNIPROT ITGB3BP protein Q13352 UNIPROT up-regulates phosphorylation Ser28 SKITRKKsVITYSPT 9606 BTO:0000150 18521086 YES lperfetto Serine 28 phosphorylation of nrif3 confers its co-activator function for estrogen receptor-alpha transactivation. p21-activated protein kinase 1 (pak1) phosphorylates eralpha at ser305 and this modification is important in eralpha transactivation function. 0.2 SIGNOR-178795 INTS3 protein Q68E01 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.894 SIGNOR-261485 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 3930339 YES ulcerative colitis gcesareni 0.8 SIGNOR-251702 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 11333986 YES lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.2 SIGNOR-107420 PIP3 smallmolecule CHEBI:16618 ChEBI WDR45B protein Q5MNZ6 UNIPROT up-regulates activity chemical activation 9606 BTO:0001938 28561066 YES miannu All WIPI members fold into seven-bladed β-propeller proteins that bind PtdIns3P and co-localize at nascent autophagosomes. 0.8 SIGNOR-268476 FGF18 protein O76093 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 YES tpavlidou Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes 0.729 SIGNOR-42368 MAPK1 protein P28482 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 YES miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. 0.318 SIGNOR-260086 GSK3A protein P49840 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 35487243 YES miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 0.631 SIGNOR-275398 N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide chemical CHEBI:91389 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189525 ESR1 protein P03372 UNIPROT CYP19A1 protein P11511 UNIPROT down-regulates quantity by repression transcriptional regulation 11973645 YES lperfetto By binding to S1, ERalpha down-regulates the aromatase promoter activity. 0.517 SIGNOR-271683 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT up-regulates activity chemical activation 9606 31226734 YES lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) 0.8 SIGNOR-265916 CDK5 protein Q00535 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 YES lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. 0.2 SIGNOR-198111 4-(4-fluoronaphthalen-1-yl)-6-isopropylpyrimidin-2-amine chemical CID:196968 PUBCHEM HTR2B protein P41595 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206658 CDK5RAP2 protein Q96SN8 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19282672 YES Giulio These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter 0.309 SIGNOR-260313 PIK3R3 protein Q92569 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9415396 YES gcesareni The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha 0.742 SIGNOR-252723 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Thr221 KDEILPTtPISEQKG 9606 19059439 YES Manara Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA 0.2 SIGNOR-260895 SIRT1 protein Q96EB6 UNIPROT 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 ChEBI up-regulates quantity chemical modification 9606 18662546 YES miannu The SIRT1 catalytic reaction involves the breakdown of one NAD+ molecule for each deacetylated acetyl lysine and the generation of nicotinamide and O-acetyl-ADP-ribose. 0.8 SIGNOR-267963 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14993291 NO gcesareni Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes 0.684 SIGNOR-123087 PKN1 protein Q16512 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser23 WNLENRFsGWYDADL 9606 BTO:0000130 12189148 YES llicata Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. 0.254 SIGNOR-91606 PER2 protein O15055 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 22260161 NO apalma We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML) 0.7 SIGNOR-256371 KDM5B protein Q9UGL1 UNIPROT SOX2 protein P48431 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 31776402 YES lperfetto Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. 0.309 SIGNOR-273450 EPHB3 protein P54753 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates activity phosphorylation Tyr614 VYIDPFTyEDPNEAV -1 9674711 YES Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. a single amino acid substitution (Y614F) clearly reduces the phosphotyrosine content of HEK2 and abrogates its ability to bind rasGAP, Crk and Fyn indicating that this residue functions as major phosphorylation and multi-docking site. 0.2 SIGNOR-251126 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates binding 9606 15722337 YES miannu The interaction of phosphorylated grb10 with 14-3-3 may lead to the translocation of grb10 back to the cytosol 0.2 SIGNOR-134198 CEP43 protein O95684 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates relocalization 9606 16314388 YES miannu Fop also binds to eb1 and is required for localizing eb1 to the centrosome 0.2 SIGNOR-142400 NGFR protein P08138 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14699954 NO amattioni Neurotrophin binding to p75ntr has also been shown to induce apoptosis 0.7 SIGNOR-256655 TLR9 protein Q9NR96 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 YES scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.439 SIGNOR-266749 PGLS protein O95336 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI down-regulates quantity chemical modification 9606 31586547 YES miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). 0.8 SIGNOR-267057 MAML1 protein Q92585 UNIPROT CCNT1 protein O60563 UNIPROT up-regulates relocalization 9606 15546612 YES gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. 0.2 SIGNOR-130712 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 YES lperfetto Raptor phosphorylation by ULK1 was sufficient to completely block Rheb-induced mTORC1 activity in cells as well as mTORC1 kinase activity invitro 0.572 SIGNOR-209910 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18468895 YES Luana Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors 0.8 SIGNOR-257946 HOXC13 protein P31276 UNIPROT FOXN1 protein O15353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21191399 NO miannu Hoxc13-dependent activation of foxn1 is part of a regulatory cascade controlling the expression of terminal differentiation markers. 0.527 SIGNOR-170850 CEBPA protein P49715 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003697 18583320 YES Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells. 0.335 SIGNOR-254043 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT up-regulates activity phosphorylation Tyr1055 VPEGHEYyRVREDGD 9606 BTO:0000452 8702790 YES lperfetto These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation. 0.2 SIGNOR-43092 ANKRD26 protein Q9UPS8 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 21669876 NO lperfetto Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts. 0.7 SIGNOR-266071 MAPK8 protein P45983 UNIPROT APLP2 protein Q06481 UNIPROT up-regulates phosphorylation Thr736 VEVDPMLtPEERHLN 9606 14970211 YES lperfetto Phosphorylation at the thr(668) residue of app (with respect to the numbering conversion for the app 695 isoform) and the thr(736) residue of aplp2 (with respect to the numbering conversion for the aplp2 763 isoform) in their cytoplasmic domains acts as a molecular switch for their protein-protein interaction and is implicated in neural function(s) and/or alzheimer's disease pathogenesis. Here we demonstrate that both app and aplp2 can be phosphorylated by jnk at the thr(668) and thr(736) residues, respectively, in response to cellular stress. 0.363 SIGNOR-122196 NR2C2 protein P49116 UNIPROT LHCGR protein P22888 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000318 10644740 YES Luana Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription. 0.2 SIGNOR-266217 AMER1 protein Q5JTC6 UNIPROT WT1 protein P19544 UNIPROT up-regulates binding 9606 19416806 YES miannu Wtx binds wt1, a zinc-finger transcription factor that is inactivated in wilms tumor. / the ability of wtx to enhance wt1-mediated transactivation suggests a physiologically significant interaction between these 2 tumor suppressors. 0.438 SIGNOR-185644 F2RL3 protein Q96RI0 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257245 KIF7 protein Q2M1P5 UNIPROT GLI1 protein P08151 UNIPROT up-regulates quantity by stabilization binding 10090 19549984 YES lperfetto Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. 0.621 SIGNOR-209608 SMC3 protein Q9UQE7 UNIPROT MXD3 protein Q9BW11 UNIPROT down-regulates activity binding 9534 BTO:0000318 9528857 YES 2 miannu We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions. 0.297 SIGNOR-241281 GNG2 protein P59768 UNIPROT GNB1 protein P62873 UNIPROT up-regulates activity binding 10696571 YES GNG2 dissociates from the activated receptor, bound with GNB1 as stable dimer. 0.94 SIGNOR-251106 tri-mu-sulfido-mu3-sulfido-triiron chemical CHEBI:21137 ChEBI Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. 0.8 SIGNOR-267734 SP2 protein Q02086 UNIPROT IRF1 protein P10914 UNIPROT up-regulates activity binding 9606 BTO:0000552 19482358 YES miannu Sp2 could be also able to interact with IRF-1 and this interaction is also observed on DNA indicating that by this way Sp2 is able to modulate IRF-1 transcriptional activity. 0.339 SIGNOR-226478 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259453 canagliflozin chemical CHEBI:73274 ChEBI SLC5A2 protein P31639 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190850 NSD1 protein Q96L73 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates methylation 9606 20080798 YES lperfetto Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. 0.463 SIGNOR-217388 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM15 protein Q9C019 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271215 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr8 MEELQDDyEDMMEEN 9606 10942405 YES llicata Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites. 0.452 SIGNOR-80792 AKT1 protein P31749 UNIPROT ATXN1 protein P54253 UNIPROT up-regulates quantity by stabilization phosphorylation Ser775 ATRKRRWsAPESRKL 9606 BTO:0000567 12757707 YES Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation. 0.411 SIGNOR-252561 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 15905173 YES lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain 0.2 SIGNOR-137251 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 YES miannu In vitro kinase assay revealed that PDHA could be readily phosphorylated by active AMPK complex in a dose-dependent manner (Figure 6C).  0.254 SIGNOR-276836 GMPS protein P49915 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 24462112 YES miannu In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex. 0.379 SIGNOR-204409 EEF2 protein P13639 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 30082469 NO gianni … several key regulators of nervous system translation, including eukaryotic initiation factor 2α (eIF2α), the mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1), and the eukaryotic elongation factor 2 (eEF2). These pathways regulate the overall rate of protein synthesis in neurons and have selective effects on the translation of specific messenger RNAs (mRNAs 0.7 SIGNOR-268628 CYC-116 chemical CID:6420138 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191221 NFYC protein Q13952 UNIPROT NFY complex SIGNOR-C1 SIGNOR form complex binding 9606 BTO:0000801;BTO:0000876 9885213 YES lperfetto Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding. 0.966 SIGNOR-63019 ITLN1 protein Q8WWA0 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 35186726 NO ITLN1 increases Akt phosphorylation in adipocytes, osteoblasts, and mesenchymal cells. |n mesenchymal stem cells, ITLN1 also leads to Akt-mediated proliferation, resistance to oxidative stress, and secretion of proangiogenic factors 0.313 SIGNOR-272499 DIABLO protein Q9NR28 UNIPROT CASP9 protein P55211 UNIPROT up-regulates 9606 10929711 NO gcesareni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. 0.735 SIGNOR-80215 PKI-402 chemical CID:44187953 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206253 PDHA2 protein P29803 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 YES miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. 0.669 SIGNOR-267832 JUN protein P05412 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20338993 NO miannu The activated c-Jun protein has been proven to activate binding to the MMP-13 promoter and also upregulate the amount of MMP-13. 0.394 SIGNOR-254539 SNAI2 protein O43623 UNIPROT HPGD protein P15428 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004078 17575121 NO miannu the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. 0.264 SIGNOR-255172 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr159 HDLGEDIyDCVPCED 9606 12454019 YES miannu To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor. 0.593 SIGNOR-95976 MSTN protein O14793 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 19357233 NO miannu In the current study, it was demonstrated that myostatin inhibits activation of Akt, in both myoblasts and myotubes. 0.491 SIGNOR-255339 MMP11 protein P24347 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272356 TGFBR1 protein P36897 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates activity binding 9606 9865696 YES lperfetto Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex 0.63 SIGNOR-62868 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 11390389 YES Manara Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence 0.385 SIGNOR-260808 CDS1 protein Q92903 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 25375833 YES lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). 0.8 SIGNOR-267018 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 15069075 YES gcesareni Thus, pkc-zeta might promote feedback ir/irs-1 complex formation and irs-1 tyrosine phosphorylation through phosphorylation of ser318. 0.722 SIGNOR-123738 SP1 protein P08047 UNIPROT CYP27A1 protein Q02318 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11867220 NO miannu Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells. 0.319 SIGNOR-255199 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI AXL protein P30530 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190401 2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid chemical CHEBI:95066 ChEBI SGK2 protein Q9HBY8 UNIPROT down-regulates activity chemical inhibition -1 18794135 YES lperfetto GSK650394 quantitatively inhibits the activity of SGK1 and SGK2 in a scintillation proximity assay. 0.8 SIGNOR-262018 2-[(3-bromo-5-tert-butyl-4-hydroxyphenyl)methylidene]propanedinitrile chemical CHEBI:93757 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189368 U0126 chemical CHEBI:90693 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 9873633 YES lperfetto The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. 0.8 SIGNOR-244958 CAPN2 protein P17655 UNIPROT GSK3A protein P49840 UNIPROT up-regulates activity cleavage 9606 25969760 YES lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase 0.2 SIGNOR-251612 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr438 LYKRNFDtGLQEYKS 9606 21545357 YES lperfetto Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions. 0.2 SIGNOR-173643 L-thyroxine smallmolecule CHEBI:18332 ChEBI THRA protein P10827 UNIPROT up-regulates activity chemical activation 10116 BTO:0000759 2158622 YES miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 0.8 SIGNOR-258382 CCL1 protein P22362 UNIPROT CCR8 protein P51685 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000785 12645948 YES gcesareni Ccl1 activates the mapk pathway in ccr8-transfected cho cells. 0.725 SIGNOR-99401 SENP1 protein Q9P0U3 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates desumoylation 9606 17981124 YES miannu Sumo-specific protease 1 is essential for stabilization of hif1alpha during hypoxia / our results support a model in which sumoylated hif1_ is unstable but can be stabilized when sumo is removed by senp1 0.325 SIGNOR-158891 RHAG protein Q02094 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.403 SIGNOR-266020 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR IL17A protein Q16552 UNIPROT up-regulates transcriptional regulation 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. 0.478 SIGNOR-255027 SIRT4 protein Q9Y6E7 UNIPROT GLUD1 protein P00367 UNIPROT down-regulates activity glycosylation 9606 16959573 YES miannu We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. 0.619 SIGNOR-267828 PEX14 protein O75381 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity binding -1 15798189 YES miannu The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7. 0.929 SIGNOR-253027 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.735 SIGNOR-193378 NR3C1 protein P04150 UNIPROT KAT2B protein Q92831 UNIPROT up-regulates activity relocalization 32917954 YES SimoneGraziosi NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase 0.547 SIGNOR-269233 TBX2 protein Q13207 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24470334 NO TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells 0.7 SIGNOR-251562 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT up-regulates guanine nucleotide exchange factor 9606 10982832 YES miannu Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases. 0.76 SIGNOR-81645 RET protein P07949 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 16153436 YES lperfetto We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1). 0.434 SIGNOR-244643 MLF1 protein P58340 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 15861129 NO miannu Mlf1 induces p53-dependent cell cycle arrest 0.289 SIGNOR-135943 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser343 TVSKTETsQVAPA -1 11910029 YES lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. 0.44 SIGNOR-249148 MAPK1 protein P28482 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation -1 8929531 YES lperfetto The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL. 0.459 SIGNOR-44858 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 YES lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. 0.678 SIGNOR-109563 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 10733900 YES amattioni Crk could bind to both pdgf alpha- and beta-receptors in vivo 0.608 SIGNOR-75884 CDK6 protein Q00534 UNIPROT CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR form complex binding 9606 8114739 YES lperfetto Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. 0.951 SIGNOR-250681 VARS1 protein P26640 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 30755602 YES miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 0.8 SIGNOR-270527 IGF2 protein P01344 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 22810696 YES lperfetto These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients. 0.821 SIGNOR-251495 miR-29b mirna URS0000150A7D_9606 RNAcentral DNMT3A protein Q9Y6K1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9913 28255176 YES Target prediction analysis revealed that ZNF423 was a potential target of bta-miR-23a. Dual-luciferase reporter assay revealed that bta-miR-23a directly targeted the 3′-UTR of ZNF423. 0.4 SIGNOR-255927 RABEP1 protein Q15276 UNIPROT RABGEF1 protein Q9UJ41 UNIPROT up-regulates binding 9606 11452015 YES miannu We show that rabaptin-5 increases the exchange activity of rabex-5 on rab5. 0.942 SIGNOR-109395 FOXO3 protein O43524 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 NO lperfetto Sirt1 inhibited foxo3's ability to induce cell death. 0.7 SIGNOR-217887 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 7737130 YES gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. 0.697 SIGNOR-32429 IFNG protein P01579 UNIPROT RFX5 protein P48382 UNIPROT up-regulates activity 9606 BTO:0000567 9177217 NO 2 miannu Transcriptional Activation by the RFX5 Activation Domain Is IFN-_-Inducible in HeLa Cells. 0.283 SIGNOR-241368 BCL2L1 protein Q07817 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 YES gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax 0.747 SIGNOR-152983 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser23 YLQARKPsDCDSKEL -1 15946941 YES done miannu PKA Phosphorylates GRK7 on Ser23 and Ser36. Phosphorylation by PKA inhibits GRK7 activity 0.2 SIGNOR-274081 GATA1 protein P15976 UNIPROT KIT protein P10721 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27858941 NO miannu DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene 0.396 SIGNOR-254771 LRIG3 protein Q6UXM1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates 9606 23723069 NO miannu Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors. 0.28 SIGNOR-202183 Caspase 3 complex complex SIGNOR-C221 SIGNOR BAD protein Q92934 UNIPROT up-regulates activity cleavage 9606 BTO:0000938 15231831 YES lperfetto Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant. 0.534 SIGNOR-256455 MRPS6 protein P82932 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.707 SIGNOR-261440 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258105 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0003316 10781582 YES lperfetto Serine 15 phosphorylation of p53 leads to a stabilization of p53 by reducing its interaction with murine double minute 2, a negative regulatory partner[...]These results strongly suggest that both ERKs and p38 kinase have a direct role in UVB-induced phosphorylation of p53 at serine 15 in vivo. 0.772 SIGNOR-226614 BRSK1 protein Q8TDC3 UNIPROT WEE1 protein P30291 UNIPROT unknown phosphorylation Ser642 KKMNRSVsLTIY -1 15150265 YES llicata HsSAD1 protein produced in Sf9 cells phosphorylated the GST-fused human wild-type Wee1A fragment but not its S642A mutant produced inEscherichia coli (Fig. 2). The kinase-dead hsSAD1 mutant (K59A) failed to phosphorylate the wild-type Wee1A fragment. 0.44 SIGNOR-250601 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 6749443 YES bronchial ashma gcesareni 0.8 SIGNOR-251696 PRKCA protein P17252 UNIPROT NOXO1 protein Q8NFA2 UNIPROT up-regulates phosphorylation Thr346 AIQSRCCtVTRRALE 9606 23957209 YES llicata Phosphorylation of thr341 allows noxo1 to sufficiently interact with noxa1, an interaction that participates in nox1 activation. 0.2 SIGNOR-202482 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR KLF16 protein Q9BXK1 UNIPROT up-regulates activity phosphorylation Tyr10 AAVACVDyFAADVLM 22203677 YES lperfetto Phosphorylation of KLF16 was confirmed by in vivo (32)P incorporation and controlled by a Y10F site-directed mutant. Inhibition of Src-type tyrosine kinase signaling as well as the nonphosphorylatable Y10F mutation disrupted KLF16-mediated gene silencing, demonstrating that its function is regulatable rather than constitutive. 0.2 SIGNOR-275586 Av/b6 integrin complex SIGNOR-C179 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269028 PAK1 protein Q13153 UNIPROT AURKA protein O14965 UNIPROT up-regulates phosphorylation Thr288 APSSRRTtLCGTLDY 9606 24867643 YES lperfetto The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability 0.416 SIGNOR-205110 SNIP1 protein Q8TAD8 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates binding 9606 SIGNOR-C6 10887155 YES gcesareni In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4 0.589 SIGNOR-78984 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT unknown phosphorylation Tyr707 DVYSTDYyRVGGHTM 10090 BTO:0000944 10533983 YES miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. 0.2 SIGNOR-250207 PDE2A protein O00408 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR down-regulates activity binding 36476859 YES lperfetto We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice.  0.385 SIGNOR-275731 MDC1 protein Q14676 UNIPROT RNF8 protein O76064 UNIPROT up-regulates relocalization 9606 18678647 YES gcesareni Rnf8 relocalizes to dna damage sites via a phospho-dependent interaction with mdc1 0.757 SIGNOR-179820 TRIM8 protein Q9BZR9 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity polyubiquitination Lys158 ALIHRDLkPPNLLLV 22084099 YES K63 miannu These results suggest that TRIM8 could mediate K63-linked polyubiquitination of TAK1 at residue K158.These results suggest that TRIM8 is involved in TNFα- and IL-1β–induced NF-κB activation by mediating K63-linked TAK1 polyubiquitination and subsequent activation. 0.344 SIGNOR-271890 ARHGEF5 protein Q12774 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.615 SIGNOR-260533 MTF1 protein Q14872 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15378601 NO miannu MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase. 0.287 SIGNOR-254601 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207302 RBX1 protein P62877 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 YES lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes 0.868 SIGNOR-154511 PIAS4 protein Q8N2W9 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates binding 9606 SIGNOR-C9 12904571 YES gcesareni Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity. 0.557 SIGNOR-104541 MMP14 protein P50281 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272382 PELI1 protein Q96FA3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates quantity by expression ubiquitination 9606 17997719 YES lperfetto These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells. 0.767 SIGNOR-159055 NODAL protein Q96S42 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0004094 15531507 NO Regulation miannu Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. 0.7 SIGNOR-256656 ASIP protein P42127 UNIPROT ATRN protein O75882 UNIPROT up-regulates binding 9606 BTO:0001253 11137996 YES gcesareni Attractin is a low-affinity receptor for agouti protein, but not agrp, in vitro and in vivo. 0.391 SIGNOR-85496 CHM protein P24386 UNIPROT RABGGTA protein Q92696 UNIPROT down-regulates activity binding 9606 BTO:0000007 18532927 YES miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. 0.77 SIGNOR-265570 SLC24A1 protein O60721 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264400 MAPK3 protein P27361 UNIPROT SP3 protein Q02447 UNIPROT up-regulates phosphorylation Ser73 CSKIGPPsPGDDEEE 9606 17685427 YES gcesareni Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. 0.299 SIGNOR-157276 EFNA2 protein O43921 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 10072375 YES tpavlidou Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8) 0.817 SIGNOR-65416 AMPK complex SIGNOR-C15 SIGNOR EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 22669845 YES lperfetto In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation 0.423 SIGNOR-216503 CSNK2A1 protein P68400 UNIPROT SIRT1 protein Q96EB6 UNIPROT unknown phosphorylation Ser659 FHGAEVYsDSEDDVL 9606 19236849 YES llicata We demonstrate that sirt1 is a substrate for protein kinase ck2 both in vitro and in vivo. Both, deletion construct analyses and serine-to-alanine mutations identified sirt1 ser-659 and ser-661 as major ck2 phosphorylation sites that are phosphorylated in vivo as well. 0.635 SIGNOR-184151 IFNB1 protein P01574 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 YES gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.674 SIGNOR-105934 FARP2 protein O94887 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19276662 NO Regulation of expression miannu FIR induced the expression of IAP1, IAP2, XIAP Survivin, MnSOD, TNFalpha, pAKT and IL-1alpha 0.2 SIGNOR-251761 miR-23a mirna URS00001CC864_9606 RNAcentral ZNF423 protein Q2M1K9 UNIPROT down-regulates quantity post transcriptional regulation 9606 19800867 YES These results suggest that the anti-adipogenic effect of miR-27b in hMADS cells is due, at least in part, to suppression of PPARgamma. 0.4 SIGNOR-255934 FYN protein P06241 UNIPROT LCP2 protein Q13094 UNIPROT down-regulates phosphorylation 9606 9047237 YES lperfetto P59fyn_phosphorylated slp-76 at intermediate levels but, significantly, this phosphorylation failed to induce vav?SLP-76 complex formation 0.754 SIGNOR-46851 EIF4E2 protein O60573 UNIPROT EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR form complex binding 9606 30917308 YES lperfetto 4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression 0.611 SIGNOR-261010 LTBP1 protein Q14766 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates activity binding 9606 BTO:0003247 8432736 YES lperfetto Together these data form strong support for the hypothesis that the LTBP plays an essential role in the activation of latent TGF-b in heterotypic cultures. 0.637 SIGNOR-235754 PAMPs stimulus SIGNOR-ST11 SIGNOR FCN3 protein O75636 UNIPROT up-regulates activity binding -1 11907111 YES lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. 0.7 SIGNOR-263406 CSNK2A1 protein P68400 UNIPROT ABCF1 protein Q8NE71 UNIPROT unknown phosphorylation Ser140 AALIQDQsEEEEEEE 9606 17894550 YES gcesareni We demonstrate that abc50 is a phosphoprotein and is phosphorylated at two sites by ck2. These sites, ser-109 and ser-140, lie in the nterminal part of abc50 but are not required for the binding of abc50 to eif2. 0.2 SIGNOR-157937 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 23086937 YES miannu The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. 0.368 SIGNOR-272039 MAPK8 protein P45983 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation 9606 14517246 YES gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin 0.837 SIGNOR-118220 PRKCD protein Q05655 UNIPROT FSCN1 protein Q16658 UNIPROT down-regulates activity phosphorylation Ser39 KVNASASsLKKKQIW 9606 BTO:0000931 8647875 YES lperfetto Phosphorylation of human fascin inhibits its actin binding and bundling activities. 0.325 SIGNOR-248944 Lig4-Xrcc4 complex complex SIGNOR-C354 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates -1 19837014 YES miannu The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. 0.7 SIGNOR-264534 AKT1 protein P31749 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser457 RGRKRFVsEGDGGRL 9606 16357133 YES gcesareni Our results show that akt specifically phosphorylates ser(67) and ser(457) residues of pdcd4 in vitro and in vivo. We further show that phosphorylation of pdcd4 by akt causes nuclear translocation of pdcd4. 0.435 SIGNOR-252488 TP53 protein P04637 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 15077116 YES gcesareni P53 interacts with the pro-apoptotic mitochondrial membrane protein bak 0.69 SIGNOR-124122 NCOA1 protein Q15788 UNIPROT STAT5B protein P51692 UNIPROT up-regulates binding 9606 BTO:0000149 12954634 YES miannu Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain. 0.323 SIGNOR-100261 TBK1 protein Q9UHD2 UNIPROT STX17 protein P56962 UNIPROT up-regulates activity phosphorylation Ser202 SQQEKIDsIADHVNS 9606 BTO:0000007 30827897 YES done miannu Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13+FIP200+ mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202. 0.292 SIGNOR-273812 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 9668047 YES gcesareni Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer. 0.593 SIGNOR-59137 PRKACA protein P17612 UNIPROT KCNJ12 protein Q14500 UNIPROT down-regulates activity phosphorylation Ser431 QRPYRREsEI 9534 11181181 YES miannu Phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97.‚  0.283 SIGNOR-249998 enalaprilat (anhydrous) chemical CHEBI:4786 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition 10116 7527095 YES miannu The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. 0.8 SIGNOR-258429 GDNF protein P39905 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.2 SIGNOR-252186 CDON/SPAG9 complex SIGNOR-C21 SIGNOR ABL1 protein P00519 UNIPROT unknown binding 9606 19470755 YES lperfetto We report that abl associates with both cdo and jlp during myoblast differentiation 0.522 SIGNOR-217019 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 YES miannu Human, mouse, and rat PPARα were activated by PFOA isomers and PFOS. 0.8 SIGNOR-268789 DHRS9 protein Q9BPW9 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 YES lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 0.8 SIGNOR-265117 BCL2L1 protein Q07817 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 YES amattioni Bcl-xl bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim) 0.747 SIGNOR-55549 AKT1 protein P31749 UNIPROT TP53RK protein Q96S44 UNIPROT up-regulates phosphorylation Ser250 RLRGRKRsMVG 9606 17712528 YES gcesareni Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250. 0.297 SIGNOR-252503 ICAM4 protein Q14773 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.334 SIGNOR-266019 CSNK1D protein P48730 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1479 SSSSTKGtYFPAILN 9606 35487243 YES miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 0.2 SIGNOR-275402 PTPN6 protein P29350 UNIPROT KIT protein P10721 UNIPROT down-regulates binding 9606 9528781 YES miannu Shp-1 binds and negatively modulates the c-kit receptor by interaction with tyrosine 569 in the c-kit juxtamembrane domain. 0.575 SIGNOR-56104 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD -1 21457715 YES Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. 0.645 SIGNOR-260307 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 17535812 YES lperfetto The activation of several major anti-apoptotic signaling pathways correlates with an increase in the phosphorylation of bad on ser-112, ser-136, and ser-155. These phosphorylation events result in bad inactivation through sequestration by 14-3-3 proteins 0.659 SIGNOR-155293 WNT3A protein P56704 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by stabilization 10090 17943183 NO Regulation miannu Wnt3a markedly stimulated matrix assembly of microfibrillar proteins, including Fbn-1, by cultured fibroblasts, suggesting that Wnts contribute to increased microfibrillar matrices in Tsk skin.Wnt3a stimulates Fbn-1 matrix formation. 0.273 SIGNOR-251894 DUSP6 protein Q16828 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). 0.904 SIGNOR-269926 STAG proteinfamily SIGNOR-PF52 SIGNOR Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 YES lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin 0.919 SIGNOR-263314 CSNK1A1 protein P48729 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser20 PLSQETFsDLWKLLP 9606 20041275 YES llicata Our data support the concept that non-primed phosphorylation of p53 by ck1 is an isoform-specific reaction preferentially affecting s20 0.596 SIGNOR-162648 SIRT1 protein Q96EB6 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 YES gcesareni We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation. 0.601 SIGNOR-252456 TTM complex complex SIGNOR-C305 SIGNOR Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates activity relocalization 27025256 YES lperfetto Terb1 and Sun1 are two key proteins linking the meiotic telomeres to the NE. Terb1 participates in telomere fortification by recruiting cohesins to the site 0.2 SIGNOR-263307 CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 11884404 NO fferrentino Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma. 0.7 SIGNOR-250564 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 9430701 YES gcesareni Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids. 0.8 SIGNOR-54943 MAPK14 protein Q16539 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8702807 NO gcesareni This result suggests that the p38mapk cascade could be involved in the negative regulation of cyclin d1 transcription and thus antagonize the mitogen-dependent stimulation of cyclin d1 transcription mediated, at least in part, by the p42/p44mapk cascade. 0.426 SIGNOR-43096 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 9372954 YES llicata We have mapped a major site of phosphorylation by cak to ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo. 0.459 SIGNOR-53311 PIM3 protein Q86V86 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 YES done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  0.2 SIGNOR-273897 AMPK complex SIGNOR-C15 SIGNOR RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser621 PKINRSAsEPSLHRA 9606 9091312 YES lperfetto Ampk also phosphorylated full-length, kinase-defective raf-1 (k375m) to generate two [32p]phosphopeptides, one co-migrating with synthetic tryptic peptide containing phospho-ser621 and the other with phospho-ser259 0.298 SIGNOR-216616 glyburide chemical CHEBI:5441 ChEBI CFTR protein P13569 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000944 1281220 YES miannu The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively. 0.8 SIGNOR-258344 AKT2 protein P31751 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 BTO:0000150 20231902 YES inferred from 70% of family members gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. 0.262 SIGNOR-269937 ITCH protein Q96J02 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates ubiquitination 9606 BTO:0001253 10940313 YES gcesareni Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain. 0.643 SIGNOR-254331 PTPN1 protein P18031 UNIPROT TYK2 protein P29597 UNIPROT down-regulates activity dephosphorylation 9606 15780598 YES lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. 0.645 SIGNOR-134564 RPN1 protein P04843 UNIPROT OST-B complex complex SIGNOR-C536 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.787 SIGNOR-272072 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser56 NDDPLLRsAGKVRDI 9606 BTO:0000565 28630147 YES miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 0.371 SIGNOR-266416 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF9 protein Q86YJ5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271249 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000830 20535135 NO miannu Specifically, SCF-induced activation of JAK2 in human mast cells has been shown to activate STAT5 and STAT6. STAT5 contributes to mast cell homeostasis, by mediating proliferation, survival, and mediator release. 0.7 SIGNOR-256233 RASGEF1C protein Q8N431 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.2 SIGNOR-161511 NEXMIF protein Q5QGS0 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000938 27822498 NO miannu Xpn regulates N-cadherin and β1-integrin expression at the transcriptional level in PC12 cells 0.2 SIGNOR-269660 FGF12 protein P61328 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.255 SIGNOR-253432 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR H3C1 protein P68431 UNIPROT up-regulates activity methylation Lys28 LATKAARkSAPATGG 9606 24987060 YES miannu The presence of trimethylation of H3K27 (H3K27me3) at promoter regions is associated with gene repression. This modification is generated by the Polycomb repressive complex 2 (PRC2), composed of the SET domain-containing histone methyltransferase (HMT) EZH2 (enhancer of zeste homolog 2) or its functional homologue EZH1, and core accessory proteins (EED, SUZ12, and RbAp48) (Fig. 1A). 0.2 SIGNOR-260449 MRAP protein Q8TCY5 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. 0.475 SIGNOR-252366 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 9606 BTO:0000142 16401070 YES lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1. 0.2 SIGNOR-143485 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000142 22232668 YES gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 0.722 SIGNOR-195347 U0126.EtOH chemical CHEBI:90692 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck lperfetto 0.8 SIGNOR-244961 ABL1 protein P00519 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 11593427 YES gcesareni Jak2 peptide substrate studies indicated that the Bcr-Abl and Abl tyrosine kinases specifically phosphorylated Y1007 of Jak2 but only poorly phosphorylated Y1008. Phosphorylation of Y1007 of Jak2 is known to be critical for its tyrosine kinase activation. 0.411 SIGNOR-245365 VAPB protein O95292 UNIPROT VAPB-PTPIP51 complex complex SIGNOR-C275 SIGNOR form complex binding 10116 BTO:0000142 30841933 YES lperfetto Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. 0.607 SIGNOR-262118 IL17B protein Q9UHF5 UNIPROT IL17RB protein Q9NRM6 UNIPROT up-regulates binding 9606 BTO:0000130 BTO:0000975;BTO:0000142;BTO:0000671 10749887 YES gcesareni Here we report on the discovery of a novel il-17 homolog (il-17b), together with the identification of a novel cell surface receptor that specifically binds to it. We detail the molecular cloning, tissue distribution, and expression of both il-17b and il-17br, describe thein vivo activity of il-17b, and demonstrate binding to il-17br. 0.747 SIGNOR-76544 HP protein P00738 UNIPROT hb:hp complex SIGNOR-C149 SIGNOR form complex binding 9606 11854029 YES miannu CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis. 0.2 SIGNOR-255283 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 20419129 YES lperfetto Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta. 0.2 SIGNOR-165026 Neuronal AP-3 complex SIGNOR-C445 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 YES miannu Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.377 SIGNOR-268525 DAXX protein Q9UER7 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates binding 9606 23405218 YES gcesareni The optimal function of mdm2 requires daxx, which stabilizes mdm2 through the deubiquitinase hausp/usp7 and also directly promotes mdm2's ubiquitin ligase activity towards p53. 0.672 SIGNOR-200892 PPP2CA protein P67775 UNIPROT DDHD1 protein Q8NEL9 UNIPROT unknown dephosphorylation Ser727 TIPSPVTsPVLSRRH -1 11328814 YES miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity 0.2 SIGNOR-262976 AARS1 protein P49588 UNIPROT Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI up-regulates quantity chemical modification 9606 32314272 YES miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). 0.8 SIGNOR-270447 DCK protein P27707 UNIPROT 2'-deoxyadenosine 5'-monophosphate(2-) smallmolecule CHEBI:58245 ChEBI up-regulates quantity chemical modification 20637175 YES lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis 0.8 SIGNOR-275808 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser7 sSSSYRRM -1 2500966 YES miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. 0.309 SIGNOR-250071 TMED5 protein Q9Y3A6 UNIPROT TMED10 protein P49755 UNIPROT up-regulates activity binding 9606 BTO:0000567 19948005 YES Sara P28 forms hetero-oligomeric complexes with p23. p23 is a major determinant for efficient targeting of p28 to the ERGIC 0.569 SIGNOR-261298 PKA proteinfamily SIGNOR-PF17 SIGNOR AQP2 protein P41181 UNIPROT up-regulates activity phosphorylation Ser256 REVRRRQsVELHSPQ 9615 BTO:0000837 12194985 YES lperfetto For Ser-256 in AQP2, this hypothesis is in line with data from Zeleninaet al. (35), who showed that in isolated rat inner medulla prostaglandin E2 induces internalization of AQP2 without decreasing the amount of PKA-phosphorylated AQP2.|Phosphorylation of Ser-256 Is Necessary and Sufficient for Localization of AQP2 in the Apical Plasma Membrane 0.2 SIGNOR-264563 MAP4K3 protein Q8IVH8 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation Thr538 LGDAKTNtFCGTPDY 9606 BTO:0000782 21983831 YES llicata We report that the kinase glk (map4k3) directly activated pkc-? During tcr signaling. 0.381 SIGNOR-176744 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr406 DASSQDCyDIPRAFP 9606 BTO:0000527;BTO:0000017 9890893 YES lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). 0.76 SIGNOR-236396 SEMA3A protein Q14563 UNIPROT NRP1 protein O14786 UNIPROT down-regulates binding 9606 10196546 YES gcesareni Semaphorins a and e act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors. 0.913 SIGNOR-66661 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 YES gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. 0.357 SIGNOR-252509 CDK5 protein Q00535 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser75 NSSDTVTsPQRAGPL 9606 BTO:0000938 10544291 YES llicata These results present compelling evidence that cdk5/p35 kinase is responsible for the novel phosphorylation of c-src at ser75 in neuronal cells, raising the intriguing possibility that c-src acts as an effector of cdk5/p35 kinase during neuronal development. 0.39 SIGNOR-71950 MEF2C protein Q06413 UNIPROT MECP2 protein P51608 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20513142 NO Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. 0.347 SIGNOR-254025 RNF10 protein Q8N5U6 UNIPROT MEOX2 protein P50222 UNIPROT up-regulates activity binding 10090 BTO:0000944 16335786 YES miannu RFN10 co-immunoprecipitates with MEOX2. RNF10 potentiates MEOX2 transcriptional activation 0.375 SIGNOR-236968 PLAGL2 protein Q9UPG8 UNIPROT SFTPC protein P11686 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000353 17618602 NO miannu nuclear PLAGL2 occupied and transactivated the endogenous SP-C promoter in lung cells. 0.298 SIGNOR-254927 CEBPA protein P49715 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22260161 NO apalma We have previously shown that PER2 is a downstream CCAAT-enhancer-binding protein (C/EBP)-target gene, and its disruption might be involved in the initiation and progression of acute myelogenous leukemia (AML) 0.425 SIGNOR-256369 RXRB protein P28702 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 10976919 YES gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr 0.635 SIGNOR-81455 GOT1 protein P17174 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-268062 SMAD7 protein O15105 UNIPROT SMURF proteinfamily SIGNOR-PF29 SIGNOR up-regulates activity relocalization 9606 19352540 YES lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. 0.898 SIGNOR-253258 selumetinib chemical CHEBI:90227 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258281 ROCK2 protein O75116 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Thr14 KKQFHKAtQKVSEKV 9606 16164598 YES llicata We identified the phosphorylation site of endophilin a1 at thr-14 endophilin t14d inhibited egf receptor internalization. Furthermore, phosphorylation of endophilin by rho-kinase inhibited the binding to cin85. 0.437 SIGNOR-140466 MAPK3 protein P27361 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Ser745 KSRQNLQsPTSSRAT 9606 BTO:0000007 17804409 YES esanto Erk phosphorylated inos on ser745. Mutation of ser745 to ala did not affect basal inos activity but eliminated inos phosphorylation and activation in response to b1r agonist. 0.354 SIGNOR-157711 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203608 VHL protein P40337 UNIPROT IREB2 protein P48200 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0003781 15777842 YES miannu We show here that IRP2 can interact with pVHL in co-transfection/co-immunoprecipitation assays. Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2. 0.359 SIGNOR-271421 CDX2 protein Q99626 UNIPROT LCT protein P09848 UNIPROT up-regulates quantity by expression transcriptional regulation 9148757 YES By electrophoretic mobility-shift assay it was shown that the factor Cdx-2 (a homoeodomain-protein related to caudal) binds to a TTTAC sequence in the CE-LPH1. Furthermore it was demonstrated that Cdx-2 is able to activate reporter gene transcription by binding to CE-LPH1. 0.363 SIGNOR-253964 RBPJ protein Q06330 UNIPROT GTF2A2 protein P52657 UNIPROT up-regulates binding 9606 9620850 YES Inhibits transcription gcesareni Rbp interacts with two transcriptional coactivators: dtafii110, a subunit of tfiid, and tfiia to repress transcription. The domain of dtafii110 targeted by rbp is the same domain that interacts with tfiia 0.2 SIGNOR-57832 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser338 DEASATVsKTETSQV -1 11910029 YES lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. 0.44 SIGNOR-249147 AKT1 protein P31749 UNIPROT ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 YES llicata Akt phosphorylates s554 in acap1 0.484 SIGNOR-252483 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity precursor of 9606 BTO:0000050 9814482 YES lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. 0.8 SIGNOR-268675 RXRB protein P28702 UNIPROT NR2F2 protein P24468 UNIPROT up-regulates binding 9606 10900149 YES gcesareni Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site. 0.275 SIGNOR-79452 antigen smallmolecule CHEBI:59132 ChEBI BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 YES scontino The recognition of antigen by the BCR initiates BCR signaling cascade. 0.8 SIGNOR-268202 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206364 15(S)-HETE smallmolecule CHEBI:15558 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9606 12517954 YES lperfetto 15(S)-HETE is a ligand for PPARγ in IL-4-stimulated A549 cells 0.8 SIGNOR-254095 MMP7 protein P09237 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272397 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 8381049 YES inferred from 70% family members gcesareni Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane. 0.2 SIGNOR-270096 PKA proteinfamily SIGNOR-PF17 SIGNOR SMN1 protein Q16637 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 BTO:0000007 19103745 YES lperfetto PKA increases SMN complex formation and SMN stability.|As expected, SMN was phosphorylated by PKA (Fig. ​(Fig.6D).6D). 0.2 SIGNOR-253114 atomoxetine chemical CHEBI:127342 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition -1 9871604 YES miannu The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. 0.8 SIGNOR-259071 ELP1 protein O95163 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 12058026 NO gcesareni Ikap efficiently and specifically enhanced jnk activation induced by ectopic expression of mekk1 and ask1, upstream activators of jnk 0.2 SIGNOR-89334 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 BTO:0000944 7518560 YES lperfetto Erbb1 recruites grb2 through sh2 domain;from these studies, we concluded that grb2 binds directly to the egfr at y-1068, to a lesser extent at y-1086, and indirectly at y-1173. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). 0.923 SIGNOR-235721 BCL2L1 protein Q07817 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17446862 YES gcesareni The anti-apoptotic proteins bcl-2 and bcl-x(l) bind and inhibit beclin-1, an essential mediator of autophagy. 0.915 SIGNOR-154480 TNFSF15 protein O95150 UNIPROT TNFRSF25 protein Q93038 UNIPROT up-regulates binding 9606 14585074 YES amattioni The ligand of dr3 is tl1a 0.775 SIGNOR-103078 INSR protein P06213 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates binding 9606 10803466 YES gcesareni Insulin induces the ir-grb7 interaction in cells expressing physiological levels of the proteins, suggesting that grb7 is implicated in insulin signaling. 0.418 SIGNOR-77153 cetuximab antibody DB00002 DRUGBANK EGFR protein P00533 UNIPROT down-regulates activity binding 9606 BTO:0001615 16336752 YES miannu Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment. 0.4 SIGNOR-259890 POLDIP3 protein Q9BY77 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR up-regulates activity binding 9606 BTO:0000567 22928037 YES miannu PDIP3 and ZC11A Function in mRNA Export. PDIP3 and ZC11A associate with UAP56 and the TREX complex in an ATP-dependent manner. 0.616 SIGNOR-268515 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 18936167 YES These results therefore suggest that the autoactivation residues Y1054 and Y1059 are targeted by DEP-1 and that this results in the inhibition of kinase activity and the consequent general dephosphorylation of VEGFR2. 0.698 SIGNOR-248709 TWIST1 protein Q15672 UNIPROT MMP2 protein P08253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20646316 NO miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. 0.376 SIGNOR-255525 PPP1R1C protein Q8WVI7 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity binding 18310074 YES lperfetto IPP5, a novel inhibitor of protein phosphatase 1, suppresses tumor growth and progression of cervical carcinoma cells by inducing G2/M arrest 0.39 SIGNOR-275726 AGPAT4 protein Q9NRZ5 UNIPROT 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI down-regulates quantity chemical modification 9606 21173190 YES lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† 0.8 SIGNOR-267015 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser197 DRVSRSSsPLKTGEQ 9534 BTO:0000298 12756254 YES miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. 0.879 SIGNOR-250124 RB1 protein P06400 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8242749 YES gcesareni A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition. 0.569 SIGNOR-37139 CD38 protein P28907 UNIPROT NMN(+) smallmolecule CHEBI:14648 ChEBI down-regulates quantity chemical modification 9606 18626062 YES miannu CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide 0.8 SIGNOR-264252 SMAD6 protein O43541 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 11737269 YES lperfetto Smad6 interacts with tak1 and tab1, and smad7 with tab1 0.2 SIGNOR-112636 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206835 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr710 DLQEAEKtIGRSRST -1 12030846 YES miannu MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition 0.583 SIGNOR-262885 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser434 SFEPKIRsPRRFIGS 10090 BTO:0002572 12782654 YES lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. 0.96 SIGNOR-101332 VARLITINIB chemical CID:42642648 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189903 PKMYT1 protein Q99640 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 BTO:0000567 9001210 YES Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2 lperfetto Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory. 0.751 SIGNOR-45729 FOXI1 protein Q12951 UNIPROT CFTR protein P13569 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20972246 NO miannu Results of transiently transfected vas deferens cells with either the -33G wild-type or the -33A variant CFTR directed luciferase reporter gene confirmed that the -33A variant, which alters the FOXI1 (Forkhead box I1) binding, significantly decreases the CFTR promoter activity. 0.253 SIGNOR-254176 dabrafenib chemical CHEBI:75045 ChEBI NEK9 protein Q8TD19 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0005011 29112787 YES Monia We have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. We confirmed NEK9 to be a potent target of dabrafenib by in vitro kinase assays, with inhibition of NEK9 observed in the single-digit nanomolar range. 0.8 SIGNOR-261072 SNCAIP protein Q9Y6H5 UNIPROT Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR up-regulates 9606 19224863 NO miannu Synphilin-1 interacts in vivo with α-synuclein, and their coexpression promotes the formation of Lewy body-like inclusions 0.7 SIGNOR-272596 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15109499 NO lperfetto Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. 0.439 SIGNOR-232174 PRKCA protein P17252 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 YES lperfetto Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. 0.346 SIGNOR-115714 KAT5 protein Q92993 UNIPROT SRSF2 protein Q01130 UNIPROT down-regulates acetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 YES miannu In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation. 0.467 SIGNOR-170594 MDH1 protein P40925 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-268099 EGFR protein P00533 UNIPROT SCAMP3 protein O14828 UNIPROT unknown phosphorylation Tyr41 QYATLDVyNPFETRE -1 9658162 YES llicata SCAMP3 Is Tyrosine Phosphorylated by EGFR in Vitro 0.4 SIGNOR-251096 (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide chemical CHEBI:91449 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252658 PPP4C protein P60510 UNIPROT CDK1 protein P06493 UNIPROT down-regulates activity dephosphorylation 9606 18347064 YES miannu PP4c efficiently dephosphorylates Cdk1 sites of NDEL1 but does not dephosphorylate the Aurora A site.|We also found that PP4c negatively regulates Cdk1 activity in interphase. 0.398 SIGNOR-277162 FYN protein P06241 UNIPROT PGD protein P52209 UNIPROT up-regulates activity phosphorylation Tyr481 GTVSSSSyNA 9606 30824700 YES lperfetto 6PGD is phosphorylated at tyrosine (Y) 481 by Src family kinase Fyn. This phosphorylation enhances 6PGD activity by increasing its binding affinity to NADP+ and therefore activates the PPP for NADPH and ribose-5-phosphate, which consequently detoxifies intracellular reactive oxygen species (ROS) and accelerates DNA synthesis. 0.2 SIGNOR-265758 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Ser241 RRIPYRYsDELNEII 9606 17197699 YES gcesareni Enzymatic activity, inhibited; 0.2 SIGNOR-151767 TRAF1 protein Q13077 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates binding 9606 8069916 YES gcesareni Traf1 and traf2 can form homo- and heterotypic dimers. 0.635 SIGNOR-34768 TLR4 protein O00206 UNIPROT Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20596954 NO fstefani Regulation of toll-like receptor signaling in the innate immunity. 0.7 SIGNOR-166488 Vicriviroc Malate chemical CID:10218922 PUBCHEM CCR5 protein P51681 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207657 POLR3B protein Q9NW08 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.863 SIGNOR-266132 bufexamac chemical CHEBI:31317 ChEBI HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 21258344 YES Luana  We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. 0.8 SIGNOR-257891 AKT2 protein P31751 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 YES lperfetto Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212 0.2 SIGNOR-153327 PRKACA protein P17612 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity phosphorylation Thr288 APSSRRTtLCGTLDY -1 11039908 YES miannu Aurora2 is regulated by phosphorylation. phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro. 0.511 SIGNOR-250337 CDS2 protein O95674 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 25375833 YES lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). 0.8 SIGNOR-267021 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK10 protein P53779 UNIPROT down-regulates chemical inhibition 9606 11717429 YES gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor. 0.8 SIGNOR-111980 RAE1 protein P78406 UNIPROT NUP98 protein P52948 UNIPROT up-regulates activity binding 9606 16036565 YES miannu Nup98 is a major interacting partner of Rae1 and known to beinvolved in mRNA export. 0.882 SIGNOR-260868 CREB1 protein P16220 UNIPROT NR2F6 protein P10588 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.265 SIGNOR-253793 RAD51 protein Q06609 UNIPROT BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 YES lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer 0.737 SIGNOR-263206 N-(3-methoxy-5-methyl-2-pyrazinyl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]-3-pyridinesulfonamide chemical CHEBI:94573 ChEBI EDNRA protein P25101 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207902 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser365 GQRDRSSsAPNVHIN 9606 10869359 YES Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo 0.459 SIGNOR-251471 TRAF6 protein Q9Y4K3 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR down-regulates quantity ubiquitination 9606 BTO:0000007 28980855 YES inferred from family member The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. 0.2 SIGNOR-270271 CDK1 protein P06493 UNIPROT DUT protein P33316-2 UNIPROT up-regulates quantity phosphorylation Ser11 SEETPAIsPSKRARP -1 8631817 YES miannu DUTPase Is Phosphorylated at a Consensus Cyclin-dependent Protein Kinase Site: in Vitro Phosphorylation of Ser-11 by p34cdc2. It is conceivable that the exclusive phosphorylation of DUT-N may play a role in nuclear targeting of this protein. Taken a step further, Ser-11 may confer the ability of DUT-N to localize in specific regions of the nucleus where the dUTPase function is required. The Ser-11 Ala mutant should aid in the testing of these hypotheses. 0.386 SIGNOR-262693 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys694 SPLACTNkRPRPEGM 9606 21791603 YES miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). 0.58 SIGNOR-272732 CDH23 protein Q9H251 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.288 SIGNOR-265861 CCP110 protein O43303 UNIPROT CETN2 protein P41208 UNIPROT up-regulates activity binding 9606 16760425 YES miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. 0.697 SIGNOR-265967 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189359 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser772 LFKKIFPsLELNITD 9606 24614225 YES lperfetto Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity. 0.2 SIGNOR-91403 SMURF2 protein Q9HAU4 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR down-regulates ubiquitination 9606 22298955 YES inferred from 70% of family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.786 SIGNOR-269845 UBE3A protein Q05086 UNIPROT PSMD2 protein Q13200 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28559284 YES lperfetto Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits. 0.277 SIGNOR-265133 SAGA complex complex SIGNOR-C465 SIGNOR H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269634 NFKB1 protein P19838 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR form complex binding 9606 9450761 YES gcesareni Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna 0.713 SIGNOR-55375 SOCS1 protein O15524 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 24890514 NO apalma Socs1 associates with CSF-1R pTyr-697 and pTyr721 binding sites to inhibit proliferation by an unknown mechanism 0.7 SIGNOR-255575 GAB2 protein Q9UQC2 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 24737791 YES milica The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival 0.52 SIGNOR-252677 SOCS1 protein O15524 UNIPROT IFNG protein P01579 UNIPROT down-regulates 9606 21628332 NO lperfetto SOCS1 inhibits macrophage responses to IFN-g, and SOCS1-deficient mice develop symptoms of severe systemic autoimmune and inflammatory disease. 0.554 SIGNOR-249571 USP1 protein O94782 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 34188037 YES miannu  Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.  0.2 SIGNOR-277308 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 19282669 YES lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.594 SIGNOR-252963 MCM7 protein P33993 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 YES The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. 0.771 SIGNOR-261677 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 20577053 NO gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. 0.2 SIGNOR-252916 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9727491 YES gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. 0.735 SIGNOR-256466 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PPARG protein P37231 UNIPROT down-regulates activity relocalization 9606 18596912 YES inferred from 70% family members lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform 0.2 SIGNOR-270008 WNK4 protein Q96J92 UNIPROT SLC12A3 protein P55017 UNIPROT down-regulates activity 22342722 NO lperfetto Evidences from early studies using Xenopus oocytes and mammalian cells indicate that WNK4 inhibits NCC and PHAII-causing mutations relieve the inhibition 0.58 SIGNOR-264632 CDH17 protein Q12864 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.703 SIGNOR-265856 PIK3C3 protein Q8NEB9 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 10090 19270693 YES lperfetto The beclin 1-vps34 interaction regulates autophagy. 0.935 SIGNOR-184521 CASP8AP2 protein Q9UKL3 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates binding 9606 SIGNOR-C13 22075988 YES gcesareni In addition, both cleavage products of c-flip turned out to be inducers of nf-kb activity by binding to the ikk complex. 0.246 SIGNOR-177104 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207084 LYN protein P07948 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 YES lperfetto Phosphorylation of FcgammaRIIa/c by Lyn is clearly dependent on the presence of Y-298, since all mutants lacking this residue are not phosphorylated by this PTK. This result suggests that Y-298 might be the only tyrosine residue of FcgammaRIIa/c phos- phorylated by Lyn. 0.607 SIGNOR-249379 UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 BTO:0000567 17106237 YES lperfetto UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis. 0.86 SIGNOR-150825 THRA protein P10827 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 15650024 YES gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.417 SIGNOR-133246 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1717 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248811 FLT3 protein P36888 UNIPROT IDH1 protein O75874 UNIPROT up-regulates activity phosphorylation Tyr391 PNVQRSDyLNTFEFM -1 34289383 YES lperfetto Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity 0.424 SIGNOR-267630 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser669 DFKDRVQsKIGSLDN -1 8999860 YES miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules 0.314 SIGNOR-250287 NUAK1 protein O60285 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 21317932 YES gcesareni Here we showed that in the presence of wild-type lkb1, nuak1 directly interacts with and phosphorylates p53 in vitro and in vivo. 0.545 SIGNOR-172008 DVL3 protein Q92997 UNIPROT FRAT1 protein Q92837 UNIPROT up-regulates binding 9606 BTO:0000567 BTO:0000671 12556519 YES gcesareni These results indicate that cki epsilon-dependent phosphorylation of dvl enhances the formation of a complex of dvl-1 with frat-1 and that this complex leads to the activation of the wnt signaling pathway. 0.453 SIGNOR-97877 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 11113114 YES gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. 0.417 SIGNOR-85005 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 20940030 NO gcesareni Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53. 0.516 SIGNOR-168457 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr423 NSLNEEWyVSYITRP 9606 BTO:0000782 8702662 YES lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function 0.804 SIGNOR-42972 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr579 RYIEDEDyYKASVTR 9606 11337490 YES lperfetto Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-pest-mediated dephosphorylation. / dephosphorylation of tyr402 and tyr579/580 by ptp-pest 0.545 SIGNOR-107502 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser170 SFKLSGFsFKKNKKE -1 1560845 YES gcesareni Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin 0.729 SIGNOR-249670 DLG4 protein P78352 UNIPROT Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.476 SIGNOR-270905 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 19956600 YES gcesareni We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks. 0.654 SIGNOR-161924 FCHO2 protein Q0JRZ9 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 YES lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth 0.574 SIGNOR-260717 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 16928683 YES gcesareni Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation 0.2 SIGNOR-148992 CSNK2A1 protein P68400 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT down-regulates activity phosphorylation Ser390 LFPVCHDsDESDTAK -1 25066127 YES miannu This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. 0.2 SIGNOR-276650 N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91439 ChEBI IKBKE protein Q14164 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190792 SMAD2 protein Q15796 UNIPROT SMAD2/SMURF2 complex SIGNOR-C11 SIGNOR form complex binding 9606 11389444 YES gcesareni We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases. 0.778 SIGNOR-108487 EXT1 protein Q16394 UNIPROT EXT1/EXT2 complex SIGNOR-C51 SIGNOR form complex binding 9606 11518722 YES miannu Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs 0.58 SIGNOR-109938 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000150 10550055 YES lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks 0.819 SIGNOR-72056 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207090 CAMK2A protein Q9UQM7 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Ser843 DVRLSRGsIDREDGS 9606 15845548 YES gcesareni Furthermore, activated camkii directly phosphorylated the recombinant cooh-terminal region of fak at a residue equivalent to ser-843. 0.272 SIGNOR-135631 TRADD protein Q15628 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 14585074 YES amattioni Tradd recruits caspase-8 0.908 SIGNOR-118591 NCSTN protein Q92542 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 10993067 YES Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. 0.941 SIGNOR-81936 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr703 DHAEAALyKNLLHSK 9606 10377264 YES miannu Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr 0.2 SIGNOR-68643 TNFSF13 protein O75888 UNIPROT TNFRSF17 protein Q02223 UNIPROT up-regulates binding 9606 BTO:0000782 10973284 YES gcesareni April is involved in stimulation of b and t cell function. April functions via binding to bcma and taci and competes with tall-i for receptor binding. 0.685 SIGNOR-81386 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.2 SIGNOR-159377 VX-745 chemical CHEBI:90528 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207684 RUNX1 protein Q01196 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 26910834 NO miannu RUNX1high was positively associated with miR-155, miR-125a, miR-99b, miR-133a, miR-130a, miR-25 and miR-92a-1. MiR-155 was previously found to function as an oncogene in CN-AML 0.4 SIGNOR-255800 NANOG protein Q9H9S0 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.459 SIGNOR-253160 AKT1 protein P31749 UNIPROT TBC1D4 protein O60343 UNIPROT unknown phosphorylation Thr642 QFRRRAHtFSHPPSS 9606 16880201 YES llicata 14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642. 0.763 SIGNOR-252494 F2R protein P25116 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 9606 BTO:0000007 22972936 NO inferred from 70% of family members milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. 0.2 SIGNOR-269860 CEBPA protein P49715 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates activity 10090 BTO:0000725 19706798 NO Conditional cebpa deficiency in adult mice blocks the transition from common myeloid progenitors (CMP) to granulocyte monocyte progenitors (GMP) resulting in the accumulation of myeloid blasts 0.7 SIGNOR-259966 INTS12 protein Q96CB8 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.749 SIGNOR-261470 NFE2L2 protein Q16236 UNIPROT CAT protein P04040 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493435 YES miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 0.427 SIGNOR-254651 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPB protein P17676 UNIPROT up-regulates quantity by expression 9606 8754811 NO fspada The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively 0.8 SIGNOR-43310 SOCS1 protein O15524 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR up-regulates activity binding 9534 10747851 YES miannu Recent evidence indicates that SOCS1 interacts with elongins B and C, which are components of a ubiquitin ligase complex, VCB (VHL/elonginC/B), based on the VHL (von Hippel Lindau) tumor suppressor protein. 0.548 SIGNOR-272564 CHRM3 protein P20309 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.395 SIGNOR-257224 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCAR protein P24071 UNIPROT up-regulates activity relocalization 12768205 NO lperfetto Both monomeric and dimeric IgA can bind to FcalphaRI, and monomeric or dimeric IgA immune complexes can activate phagocytosis and other immune responses through the clustering of FcalphaRI 0.7 SIGNOR-264859 PTPN1 protein P18031 UNIPROT CAV1 protein Q03135 UNIPROT unknown dephosphorylation Tyr14 VDSEGHLyTVPIREQ -1 16388599 YES The scaffolding protein caveolin-1 is also a participant in these pathways and is specifically phosphorylated on tyrosine 14, when these pathways are activated. Here, we provide evidence that PTP1B can efficiently catalyze the removal of the phosphoryl group from phosphocaveolin-1. 0.572 SIGNOR-248430 PRKCB protein P05771 UNIPROT ICOSLG protein O75144 UNIPROT up-regulates activity phosphorylation Ser285 RDRCLQHsYAGAWAV 9606 BTO:0000567 24837102 YES done miannu PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction  0.2 SIGNOR-273797 ruxolitinib chemical CHEBI:66919 ChEBI JAK1 protein P23458 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206667 CSNK2A1 protein P68400 UNIPROT SHOX protein O15266 UNIPROT up-regulates phosphorylation Ser106 EKREDVKsEDEDGQT 9606 16325853 YES lperfetto We show also that casein kinase ii phosphorylates shox on serine 106 efficiently in vitro. S106a shox mutant, defective in phosphorylation, does not activate transcription and fails to induce cell-cycle arrest and apoptosis 0.338 SIGNOR-142875 NEB protein P20929 UNIPROT WASL protein O00401 UNIPROT up-regulates binding 9606 21798082 YES gcesareni Igf1-akt signaling, by inhibiting gsk3b, allows the interaction of n-wasp with the unphosphorylated nebulin;the consequent recruitment of n-wasp to the z-disk promotes actin nucleation and elongation of actin filaments. 0.352 SIGNOR-175671 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR PRKN protein O60260 UNIPROT up-regulates activity binding 10090 BTO:0002572 phosphorylation: ser65 24784582 YES The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. 0.2 SIGNOR-270343 BTG2 protein P78543 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 21172304 NO Androgen-induced promoter activation and expression of prostate-specific antigen (PSA) are significantly attenuated by BTG2. 0.2 SIGNOR-253658 POU2AF1 protein Q16633 UNIPROT POU2F1 protein P14859 UNIPROT up-regulates binding 9606 BTO:0000776 12727885 YES miannu Obf1 enhances transcriptional potential of oct1. 0.623 SIGNOR-100968 2-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine chemical CID:49830260 PUBCHEM VCP protein P55072 UNIPROT down-regulates activity chemical inhibition -1 23316025 YES Luana Inhibition of p97 by ML240 and ML241 is ATP competitive. To determine the mechanism by which ML240 and ML241 inhibited p97 ATPase, we evaluated rates of ATP hydrolysis at different concentrations of ATP. ML240 and ML241 inhibited p97competitively with respect to ATP with a Kivalues of 0.22 mm and 0.35 mm respectively. 0.8 SIGNOR-261093 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser383 IHFWSTLsPIAPRSP 10090 BTO:0000944 7889942 YES lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency. 0.562 SIGNOR-235455 vatalanib chemical CHEBI:90620 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207642 AKT2 protein P31751 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 YES gcesareni Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155. 0.523 SIGNOR-81110 SIRT2 protein Q8IXJ6 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates deacetylation 9606 BTO:0000887;BTO:0001103 12887892 YES gcesareni Sir2-mediated deacetylation of myod can be expected to inhibit its transcriptional capabilities. 0.377 SIGNOR-104251 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr284 CPGRDRRtEEENLRK 9606 20959462 YES llicata Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity. 0.718 SIGNOR-168749 TTK protein P33981 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 YES lperfetto Ttk phosphorylation of thr735 was associated with partial inhibition of nuclear targeting of c-abl. 0.28 SIGNOR-181064 CASP1 protein P29466 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.321 SIGNOR-261747 4-(3-chloro-2-fluorophenoxy)-1-[[6-(2-thiazolylamino)-2-pyridinyl]methyl]-1-cyclohexanecarboxylic acid chemical CHEBI:125340 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194411 ATM protein Q13315 UNIPROT SMC1A protein Q14683 UNIPROT up-regulates activity phosphorylation Ser966 GEDSVSGsQRISSIY 9606 BTO:0005521 11877376 YES Atm phosphorylates Smc1 on serines 957 and 966 in vitro and in vivo, and expression of an Smc1 protein mutated at these phosphorylation sites abrogates the ionizing irradiation-induced S phase cell cycle checkpoint 0.704 SIGNOR-255589 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207299 SETBP1 protein Q9Y6X0 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 22566606 NO miannu Setbp1 activates hoxa9 and hoxa10 expression in myeloid progenitors 0.344 SIGNOR-197318 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193543 UBE2I protein P63279 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates sumoylation Lys25 PETGRTVkEPEGPPP 9606 19744555 YES miannu Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2 0.697 SIGNOR-187901 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr96 QDHSHLLySTIPRMQ -1 11382764 YES lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 0.922 SIGNOR-246508 hsa-miR-182-5p mirna URS00001CC379_9606 RNAcentral GNA13 protein Q14344 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001061 23329838 YES Parnian Taken together these data indicate that GNA13 is an important target of miR-182 and -200a, which bind to the 3'-UTR of GNA13 and down-regulate its protein expression in PC3 cells 0.4 SIGNOR-278021 AKT2 protein P31751 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 YES gcesareni Creb is a nuclear target for activation via the growth factor-dependent ser/thr kinase akt/pkb. When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. 0.512 SIGNOR-62253 CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 YES lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. 0.638 SIGNOR-53582 EXOC5 protein O00471 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.917 SIGNOR-270780 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates activity phosphorylation Tyr516 PVIENPQyFGITNSQ 10090 BTO:0000944 10533983 YES miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc 0.2 SIGNOR-250204 RELN protein P78509 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 17584923 NO Luana Reln, encoding an extracellular signaling molecule essential for neuronal lamination and synaptic plasticity 0.7 SIGNOR-265772 COL2A1 protein P02458 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates activity binding 9606 BTO:0000249 25169886 YES lperfetto Isolation, cloning, and sequence analysis of the integrin subunit alpha10, a beta1-associated collagen binding integrin expressed on chondrocytes. 0.488 SIGNOR-253347 ATR protein Q13535 UNIPROT XPC protein Q01831 UNIPROT up-regulates binding 9606 23422745 YES gcesareni Atrand atm physically interacted with xpc and promptly localized to the uv damage sites. 0.478 SIGNOR-201112 KCNIP4 protein Q6PIL6 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity relocalization 8355 BTO:0000964 24811166 YES Luisa KChIP4 increased the current amplitude of Kv4.2, decelerated the inactivation, and accelerated the recovery from inactivation of Kv4.2. KChIP.is known to promote the translocation of Kv4.2 from the endoplasmic reticulum or Golgi to the cell surface 0.773 SIGNOR-269004 PAK1 protein Q13153 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 10092231 YES miannu P21-activated kinase 1 (PAK1) phosphorylates MLCK, resulting in decreased MLCK activity.  0.555 SIGNOR-250317 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 19584320 YES lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.49 SIGNOR-216491 reserpine chemical CHEBI:28487 ChEBI SLC18A1 protein P54219 UNIPROT down-regulates activity chemical inhibition 9606 8643547 YES miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. 0.8 SIGNOR-258492 BACH1 protein O14867 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000150 22875853 NO Transcriptional network analysis identifies BACH1 as a master regulator of breast cancer bone metastasis 0.7 SIGNOR-259337 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.423 SIGNOR-248294 copper(1+) smallmolecule CHEBI:49552 ChEBI SOD2 protein P04179 UNIPROT up-regulates activity chemical activation 1542024 YES lperfetto Copper as a cofactor and regulator of copper,zinc superoxide dismutase 0.8 SIGNOR-272300 BZW2 protein Q9Y6E2 UNIPROT ATF4 protein P18848 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31643092 NO miannu Subsequent research reveals that BZW2 induces ATF4 translation which is a pro‐oncogenic transcription factor 0.413 SIGNOR-261222 MYC protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 YES gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a 0.765 SIGNOR-102743 HSD17B2 protein P37059 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification -1 8099587 YES Luana 17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone.  0.8 SIGNOR-269764 PAM protein P19021 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates activity cleavage 9606 23084901 YES lperfetto Nevertheless, overall the results of this study show that peptide sequence recognition is an important aspect of the interactions of the prohormone substrates prooxytocin (3d) and procalcitonin (7e) with PAM, which is mirrored in the potency of analogous peptidomimetic glycolate inhibitors of the enzyme. 0.2 SIGNOR-268551 PPP2R5B protein Q15173 UNIPROT CASP3 protein P42574 UNIPROT up-regulates dephosphorylation Ser150 FRGDRCRsLTGKPKL 9606 BTO:0000130 15569672 YES gcesareni Dephosphorylation of caspase-3 at ser150 site by pp2a increased caspase-3 activity,which was essential to trigger apoptosis in neutrophils. 0.2 SIGNOR-131435 NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 NO lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). 0.7 SIGNOR-262141 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 19303846 YES lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation 0.894 SIGNOR-227874 PPP2CA protein P67775 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser664 QSAFAGFsFVNPKFE 9606 11959144 YES PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex 0.378 SIGNOR-248639 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR BMI1 protein P35226 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 15897469 YES miannu BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex. Polyubiquitination of endogenous BMI1 could not be detected, suggesting that only a small amount of the protein undergoes this modification. No significant changes in protein stability were observed, suggesting that ubiquitination serves regulatory functions other than protein degradation of BMI1 and MACROH2A1 0.354 SIGNOR-272661 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120112 BCOR protein Q6W2J9 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 YES miannu BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E. 0.378 SIGNOR-252236 TAOK3 protein Q9H2K8 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 YES gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2 0.291 SIGNOR-201333 ATG2B protein Q96BY7 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001938 28561066 NO miannu WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. 0.7 SIGNOR-268486 PGK1 protein P00558 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. 0.8 SIGNOR-266505 YY1 protein P25490 UNIPROT COX7C protein P15954 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9092564 NO miannu Mutation of both YY1 sites eliminates most of the promoter activity. Mutation at the upstream YY1 site significantly reduces the efficiency of transcript initiation at the major start site and thus plays the dominant role in COX7C regulation. 0.257 SIGNOR-255617 CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776;BTO:0003076 8816467 NO lperfetto Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis 0.459 SIGNOR-43927 PELI2 protein Q9HAT8 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates ubiquitination 9606 17997719 YES gcesareni These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4. 0.78 SIGNOR-159058 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBA1A protein Q71U36 UNIPROT down-regulates activity chemical inhibition 9606 15579115 YES miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 0.8 SIGNOR-259255 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr88 KHLVALYtRDEHFAI -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.34 SIGNOR-250911 mifepristone chemical CHEBI:50692 ChEBI NR3C1 protein P04150 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258709 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR GAP43 protein P17677 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 26865625 YES miannu  In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation. 0.2 SIGNOR-266770 KIFC1 protein Q9BW19 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 33361741 NO miannu Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer 0.7 SIGNOR-266117 EP300 protein Q09472 UNIPROT RELA protein Q04206 UNIPROT up-regulates acetylation 9606 SIGNOR-C6 16382138 YES gcesareni Rela is also acetylated at several sites by p300 and cbp 0.821 SIGNOR-143399 DUSP10 protein Q9Y6W6 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 10391943 YES gcesareni Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk 0.705 SIGNOR-68986 CEBPG protein P53567 UNIPROT LTF protein P02788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15588942 NO miannu C/EBP_ interacts with C/EBP_ through the leucine-zipper–containing domain. C/EBP_ and C/EBP_ synergistically activate transcription of lactoferrin promoter 0.2 SIGNOR-225015 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9534 BTO:0004055 10196136 YES lperfetto We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly. 0.711 SIGNOR-227917 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 18840653 YES gcesareni Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well. 0.565 SIGNOR-181546 EIF1B protein O60739 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates activity relocalization 9606 20921384 YES lperfetto Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning 0.464 SIGNOR-269145 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000527;BTO:0000017 9890893 YES lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). 0.76 SIGNOR-236404 E2F1 protein Q01094 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23542036 NO miannu We show here that EAPP stimulates the MDR1 promoter resulting in higher PGP levels. Independently of EAPP, E2F1 also increases the activity of the MDR1 promoter. 0.2 SIGNOR-253841 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 YES gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. 0.738 SIGNOR-90533 SRC protein P12931 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Tyr1311 DSKVDLIyQNTTAMT 9606 BTO:0000007 22898603 YES miannu  We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. 0.635 SIGNOR-276373 NLRP3 protein Q96P20 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.745 SIGNOR-256410 SLC2A3 protein P11169 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 23506862 YES miannu GLUThe SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose T1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells. 0.8 SIGNOR-267461 MMP1 protein P03956 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272377 CNKSR1 protein Q969H4 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates binding 9606 22830020 YES gcesareni Cnk1 binds to rassf1a and promotes apoptosis through a pathway that requires rassf1a and mst kinases. 0.403 SIGNOR-198432 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase 0.744 SIGNOR-40427 SMURF proteinfamily SIGNOR-PF29 SIGNOR TGFBR2 protein P37173 UNIPROT down-regulates activity ubiquitination 9606 22298955 YES lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. 0.2 SIGNOR-253265 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 11782488 YES gcesareni Bmk1 activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2. 0.8 SIGNOR-113773 UPF2 protein Q9HAU5 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 31636381 NO miannu Our data indicate that proper synaptic plasticity and cognitive function requires UPF2.  0.7 SIGNOR-265235 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Thr4460 GFQHQRMtNGAMNVE 9606 15272003 YES lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. 0.2 SIGNOR-127215 WDR24 protein Q96S15 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 YES miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 0.91 SIGNOR-255302 MAPK14 protein Q16539 UNIPROT ELK3 protein P41970 UNIPROT up-regulates phosphorylation Ser363 LSPVAPLsPARLQGP 9606 9130707 YES gcesareni Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase. 0.379 SIGNOR-47685 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser794 QHLRLSTsSGRLLYA 9606 12624099 YES lperfetto Sik2 could phosphorylate ser(794) of human irs-1 0.568 SIGNOR-99059 AURKB protein Q96GD4 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14583461 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-118890 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser1985 DSVTRATsDNLQVRG 28882890 YES Phosphosite is derived from Figure 2 lperfetto C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation| Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. 0.491 SIGNOR-275783 NEDD4L protein Q96PU5 UNIPROT SCN1A protein P35498 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 YES miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 0.292 SIGNOR-253457 PRKACA protein P17612 UNIPROT RYR2 protein Q92736 UNIPROT up-regulates activity phosphorylation Ser2808 YNRTRRIsQTSQVSV -1 14532276 YES miannu PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure 0.477 SIGNOR-250079 MAPK1 protein P28482 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 YES gcesareni Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. 0.727 SIGNOR-161518 YARS1 protein P54577 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 16429158 YES miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr 0.8 SIGNOR-270520 YY1 protein P25490 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15291746 NO miannu These results designate YY1 as the factor responsible for the intron 1-mediated boost of the HSD3B2 gene basal promoter activity. 0.2 SIGNOR-255619 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17012224 YES miannu Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1. 0.682 SIGNOR-259909 GSK3A protein P49840 UNIPROT ANKRD28 protein O15084 UNIPROT down-regulates activity phosphorylation Ser1007 INRYTNTsKTVSFEA -1 phosphorylation:Ser1011 TNTSKTVsFEALPIM 17023142 YES lperfetto We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K 0.2 SIGNOR-264792 LGALS3 protein P17931 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000664 21821001 NO miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. 0.255 SIGNOR-261905 MMP12 protein P39900 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272357 TLR4 protein O00206 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 28137827 YES miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. 0.416 SIGNOR-263652 NEK6 protein Q9HC98 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 YES done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  0.2 SIGNOR-273894 NOTCH1 protein P46531 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11591772 NO lperfetto Nf-kappab activity is regulated by notch-1 via transcriptional control of nf-kappab. 0.378 SIGNOR-110963 PTPRO protein Q16827 UNIPROT VCP protein P55072 UNIPROT down-regulates activity dephosphorylation 9606 23533167 YES miannu An important aspect of this study is that tyrosine dephosphorylation of VCP by PTPRO sensitizes HepG2 cells to Doxorubicin, a chemotherapeutic drug commonly used for a variety of cancers. 0.423 SIGNOR-277063 ETS1 protein P14921 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11175361 NO miannu Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis 0.7 SIGNOR-259869 PRKAA2 protein P54646 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 14651849 YES gcesareni Under energy starvation conditions, the amp-activated protein kinase (ampk) phosphorylates tsc2 and enhances its activity. 0.549 SIGNOR-119541 DMTF1 protein Q9Y222 UNIPROT BCL3 protein P20749 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 NO Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  0.2 SIGNOR-261583 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser30 TPRSRERsPSPLRGN 9606 BTO:0000671 15910284 YES lperfetto Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells. 0.26 SIGNOR-137474 Caspase 3 complex complex SIGNOR-C221 SIGNOR ACIN1 protein Q9UKV3 UNIPROT up-regulates cleavage 9606 10490026 YES amattioni Induces apoptotic chromatin condensation after activation by casp3 0.627 SIGNOR-256449 tositumomab and iodine i 131 tositumomab antibody DB00081 DRUGBANK MS4A1 protein P11836 UNIPROT down-regulates activity binding 9606 14748653 YES miannu Tositumomab is an immunoglobulin G murine monoclonal antibody that binds to the CD20 antigen on the surface of normal and malignant human B-cells. Tositumomab is linked covalently with iodine-131 to produce the radioimmunoconjugate iodine-131 tositumomab (Bexxar). The iodine-131 tositumomab regimen was approved by the US Food and Drug Administration in June 2003 for the treatment of patients with CD20-positive, follicular non-Hodgkin's lymphoma, both with and without transformation, whose disease is refractory to rituximab (Rituxan) and has relapsed following chemotherapy. 0.4 SIGNOR-259903 FLT3 protein P36888 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000222;BTO:0001946 BTO:0000887;BTO:0001103 23704355 NO gcesareni Here we report the identification of flt3l (fms-like tyrokine kinase 3 ligand) signaling as a novel regulator of skeletal myogenesis 0.7 SIGNOR-202105 SMO protein Q99835 UNIPROT GNB1 protein P62873 UNIPROT up-regulates binding 9606 16885213 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.383 SIGNOR-148537 AURKA protein O14965 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates activity phosphorylation Ser291 DVHMVSDsDGDDFED 9606 18790738 YES llicata This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1 0.2 SIGNOR-180891 ARF6 protein P62330 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 14565977 NO miannu ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha 0.7 SIGNOR-264908 MMP25 protein Q9NPA2 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272392 KIF11 protein P52732 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 21969468 NO lperfetto The C-terminal fragment interferes with the TPX2–Eg5 interaction, relieving the inhibition of TPX2 on Eg5 and generating the observed spindle lengthening. According to this model, TPX2 and Eg5 should localize to microtubules in the spindle midzone. 0.7 SIGNOR-265098 MAPK1 protein P28482 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 YES gcesareni Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130. 0.364 SIGNOR-185215 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser281 DGTGDTSsEEDEDEE -1 11278496 YES llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. 0.375 SIGNOR-250996 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 YES PVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. 0.346 SIGNOR-269111 seliciclib chemical CHEBI:45307 ChEBI CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206562 CSNK2A2 protein P19784 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 YES lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. 0.307 SIGNOR-275740 873837-23-1 chemical CID:46930994 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190470 CDK4 protein P11802 UNIPROT MYOG protein P15173 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 YES gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.329 SIGNOR-176530 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887 11114197 YES gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. 0.509 SIGNOR-85110 BACE1 protein P56817 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Asp616 EISEVKMdAEFRHDS 9606 10931940 YES lperfetto Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform. 0.793 SIGNOR-261763 VASP protein P50552 UNIPROT ATIC protein P31939 UNIPROT up-regulates activity phosphorylation Tyr104 RVVACNLyPFVKTVA 9606 BTO:0002181 18845790 YES miannu ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity.  0.342 SIGNOR-276172 AKT1 protein P31749 UNIPROT MVD protein P53602 UNIPROT up-regulates activity phosphorylation Ser96 LARKRRNsRDGDPLP 10090 25378391 YES miannu Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation. 0.2 SIGNOR-265891 CHEK2 protein O96017 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser376 PLLPRVSsYLVPIQF 9606 BTO:0001938 17101782 YES lperfetto Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein 0.72 SIGNOR-150746 RBPJ protein Q06330 UNIPROT CIR1 protein Q86X95 UNIPROT up-regulates binding 9606 9874765 YES amattioni In the mechanism of cbf1-mediated repression, cbf1 binds to a unique corepressor cir. Targeting of cir to cbf1 is an important component of repression. Cir binds to histone deacetylase and to sap30 and serves as a linker between cbf1 and the histone deacetylase complex. 0.668 SIGNOR-62932 AKT1 protein P31749 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 YES gcesareni Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40 0.781 SIGNOR-252544 HSP90AA1 protein P07900 UNIPROT PPP5C protein P53041 UNIPROT up-regulates binding 9606 15577939 YES miannu Hsp90 causes substantial activation of ppp5 by competing for tpr_phosphatase domain contacts and allowing access to the catalytic site. 0.77 SIGNOR-131564 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser561 PRKFSKFsLYKQLHR 9606 10441128 YES gcesareni Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells. 0.713 SIGNOR-69934 EIF5B protein O60841 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity binding 9606 30211544 YES lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. 0.624 SIGNOR-269121 Ub:E2 complex SIGNOR-C497 SIGNOR LTN1 protein O94822 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271149 HSP90AA1 protein P07900 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 27353360 YES Here we show that the stability of the tumour suppressor folliculin (FLCN) depends on the chaperone function of Hsp90. 0.305 SIGNOR-256505 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates activity chemical activation 9606 18321241 YES miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). 0.8 SIGNOR-259241 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 9606 17360704 YES gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. 0.2 SIGNOR-252813 PRKACA protein P17612 UNIPROT TPH1 protein P17752 UNIPROT up-regulates activity phosphorylation Ser58 RKSKRRNsEFEIFVD -1 9109552 YES miannu The activation of tryptophan hydroxylase by protein kinase A is mediated by the phosphorylation of serine-58 within the regulatory domain of the enzyme. 0.351 SIGNOR-250062 N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide chemical CHEBI:91467 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189945 glutamic acid smallmolecule CHEBI:18237 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264752 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding 9606 1904542 YES irozzo The proteins encoded by the proto-oncogenes c-fos and c-jun (Fos and Jun, respectively) form a heterodimeric complex that regulates transcription by interacting with the DNA-regulatory element known as the activator protein 1 (AP-1) binding site. 0.952 SIGNOR-256363 G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 23279204 NO SARA G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs 0.7 SIGNOR-260983 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.41 SIGNOR-249668 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-252980 POU5F1 protein Q01860 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.498 SIGNOR-253161 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.7 SIGNOR-265814 AKT1 protein P31749 UNIPROT TKT protein P29401 UNIPROT up-regulates activity phosphorylation Thr382 GCATRNRtVPFCSTF 9606 BTO:0000567 24981175 YES lperfetto Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis. 0.282 SIGNOR-265101 Avacopan chemical CID:49841217 PUBCHEM C5AR2 protein Q9P296 UNIPROT down-regulates activity binding 9606 31734405 YES lperfetto CCX168 (avocapan), a C5aR antagonist, has proven its safety and efficiency in phase I and phase II trials conducted in AAV patients. 0.8 SIGNOR-263474 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 12576312 YES miannu Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro 0.504 SIGNOR-250064 CACNA2D3 protein Q8IZS8 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 31746409 NO miannu Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells. 0.7 SIGNOR-266854 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI PRIM2 protein P49643 UNIPROT up-regulates activity chemical activation 26083061 YES lperfetto Human DNA primase, are Fe-S proteins. The loss of an iron-sulfur cluster in RAD3 helicase results in a failure to unwind DNA1 0.8 SIGNOR-262134 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 YES gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2). 0.676 SIGNOR-59659 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT up-regulates binding 9606 11544529 YES fstefani Mal (myd88-adapter-like) is required for toll-like receptor-4 signal transduction. 0.779 SIGNOR-110337 AMPK complex SIGNOR-C15 SIGNOR NAMPT protein P43490 UNIPROT up-regulates quantity 10090 18477450 NO gcesareni Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt 0.272 SIGNOR-238824 CREB1 protein P16220 UNIPROT NR2F1 protein P10589 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000152 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.271 SIGNOR-253792 CTSS protein P25774 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 11920402 NO lperfetto Cathepsins K and S have been implicated in various aspects of extracellular matrix degradation and inflammatory responses. 0.7 SIGNOR-253319 WASHC2C protein Q9Y4E1 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 YES lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. 0.2 SIGNOR-261016 SLC24A4 protein Q8NFF2 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264397 RAN protein P62826 UNIPROT XPOT protein O43592 UNIPROT up-regulates activity binding 9606 9660920 YES miannu The first step in export appears to be the formation of a trimeric tRNA/exportin-t/RanGTP complex. tRNA and RanGTP bind to exportin-t in a highly cooperative manner: tRNA increases the affinity of exportin-t for RanGTP apparently 300-fold (Figure 5A); conversely, RanGTP has to increase the affinity of exportin-t for tRNA by the same factor. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus 0.814 SIGNOR-261392 BMP2 protein P12643 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 10090 BTO:0001957 11714695 YES lperfetto For this, bmp-2 binds first to the high affinity receptor bri and then recruits brii into the signaling complex. 0.861 SIGNOR-237000 MAPK3 protein P27361 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 YES llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. 0.392 SIGNOR-188143 NFKB1 protein P19838 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 17350185 YES Luana  The effect of TNF-alpha on the Bmp4 promoter is mediated through NF-kB. 0.2 SIGNOR-266086 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr785 NSLISSDyELLSDPT 9606 18250158 YES lperfetto The phosphorylation of wt jak3 and y980f/y981f/y785f mutant jak3 is presumably mediated through autophosphorylation at distinct jak3 sites within this model systemhosphorylation of jak3 on y785 has been reported to create a binding site for the adaptor protein sh2b-beta 0.2 SIGNOR-160660 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCA protein P17252 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191490 SNS-314 Mesylate chemical CID:24995523 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207105 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser177 LITPGSGsIYSSPGL 9606 BTO:0000567 35469017 YES miannu CDK1–cyclin B1 mediates KIND1 and KIND2 phosphorylation at mitotic entry . MS of KIND1 and KIND2 immunoprecipitates from STLC-arrested HeLa cells confirmed the phosphorylation of KIND1-S179 and KIND2-S181 and revealed phosphorylation of closely adjacent serine residues (KIND1: SSphS174GphS176PVphS179PGLYSK; KIND2: GphS175GphS177IYphS180phS181PGLYSK), although to a weaker extent (Supplementary Table 2). 0.2 SIGNOR-276713 IL17RA protein Q96F46 UNIPROT IL17R complex complex SIGNOR-C260 SIGNOR form complex binding 9606 BTO:0001946 32024054 YES lperfetto Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response. 0.548 SIGNOR-261335 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity binding 9606 10497253 YES lperfetto Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7. 0.648 SIGNOR-70950 ARPC1A protein Q92747 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 YES The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc 0.877 SIGNOR-251515 POU5F1 protein Q01860 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.426 SIGNOR-253165 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser280 VDGTGDTsSEEDEDE 9606 11278496 YES lperfetto TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels 0.677 SIGNOR-246630 PFDN1 protein O60925 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 YES miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) 0.949 SIGNOR-270932 CSNK2A1 protein P68400 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 BTO:0000938 BTO:0000142 23374587 YES The effect has been demonstrated using Q01105-2 miannu Ckii-mediated phosphorylation at ser9 hinders nuclear import of set 0.366 SIGNOR-200798 RELA protein Q04206 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates binding 9606 10207072 YES lperfetto Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo. 0.85 SIGNOR-217655 BAX protein Q07812 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 10629050 YES Following Bid-induced conformational change lperfetto Following bid-induced conformational change, bax oligomerizes and inserts tightly within the outer mitochondrial membrane. The integration of bax in the outer mitochondrial membrane is followed by cytochrome crelease 0.2 SIGNOR-73895 SRC protein P12931 UNIPROT PBK protein Q96KB5 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr272 DFDDEAYyAALGTRP 9606 BTO:0000038 27016416 YES miannu Phosphorylation of TOPK at Y74, Y272 by Src increases the stability of TOPK and promotes tumorigenesis of colon 0.396 SIGNOR-277217 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Thr1225 SRRPRLEtILSLLVS -1 27292631 YES miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. 0.304 SIGNOR-274063 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1197 HIQTPMLsQEQAQPP 9606 15173573 YES lperfetto Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp 0.271 SIGNOR-125073 TULP3 protein O75386 UNIPROT GPR161 protein Q8N6U8 UNIPROT up-regulates activity relocalization 10090 23332756 YES Upon knockdown of Tulp3 using siRNA in IMCD3 cells, ciliary localization of Gpr161 was severely reduced 0.606 SIGNOR-259938 sunitinib chemical CHEBI:38940 ChEBI PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 BTO:0000776 20185585 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-163953 MTOR protein P42345 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000661 34535949 YES Barakat Furthermore, we confirmed also in Jurkat cells that the specific silencing of both ERK1/2 and mTOR by siRNA downregulates Drp1 phosphorylation on Ser616 0.346 SIGNOR-275430 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT down-regulates activity phosphorylation Ser493 CPPECPEsLHDLMCQ 9606 BTO:0002181 33388549 YES miannu Concurrently, ROCK1 was able to phosphorylate GSK-3β at Ser9, which phosphorylated Src at Ser51 and Ser492 residues, leading to Src inactivation 0.383 SIGNOR-277544 BTG2 protein P78543 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 NO miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 0.2 SIGNOR-254650 ARNTL2 protein Q8WYA1 UNIPROT CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR form complex binding 19605937 YES lperfetto Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription 0.683 SIGNOR-253710 ABL1 protein P00519 UNIPROT RB1 protein P06400 UNIPROT unknown phosphorylation Tyr805 RIPGGNIyISPLKSP 9606 BTO:0001271 16158058 YES llicata Rb-induced apoptosis is compromised by abl-catalysed phosphorylation of rb at y805. 0.569 SIGNOR-140396 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser188 RKRHKSDsISLSFDE 9606 15169778 YES lperfetto Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylationhere we show that pkb inhibits mdm2 self-ubiquitination via phosphorylation of mdm2 on ser(166) and ser(188) 0.2 SIGNOR-244300 IL6R protein P08887 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 23869758 YES miannu On binding of IL-6 to its receptor IL-6R, JAK2 is phosphorylated, then STAT3 is phosphorylated by JAK2 0.568 SIGNOR-254405 ponatinib chemical CHEBI:78543 ChEBI RIPK3 protein Q9Y572 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000661 25801024 YES Federica Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3 0.8 SIGNOR-261083 ICI D1694 chemical CHEBI:5847 ChEBI TYMS protein P04818 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206403 SRC protein P12931 UNIPROT ENO1 protein P06733 UNIPROT up-regulates phosphorylation Tyr44 SGASTGIyEALELRD 9606 24841372 YES lperfetto The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways 0.411 SIGNOR-205092 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates activity phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000782 11700305 YES lperfetto We identify catalytic domain fragments of protein kinase c (pkc) delta and pkcbetai/ii as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin cd18 chain. The sites phosphorylated in vitro were identified as ser-745 and thr-758. Pkc-mediated phosphorylation of cd18 after cell stimulation could lead to the recruitment of 14-3-3 proteins to the activated integrin, which may play a role in regulating its adhesive state or ability to signal. 0.33 SIGNOR-111495 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 YES Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. 0.91 SIGNOR-252861 PRKACA protein P17612 UNIPROT PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser56 NLQLPPLsQRQSERA 9534 BTO:0000298 12441002 YES miannu PKA-mediated phosphorylation of Ser-56 in UCR1 of PDE4B4 leads to activation of this long isoform 0.604 SIGNOR-250024 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Thr275 LVDSKAKtRSAGCAA 9606 9312068 YES lperfetto Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1 0.723 SIGNOR-51211 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 28531279 NO miannu The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3 0.364 SIGNOR-260328 RAB10 protein P61026 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 0.417 SIGNOR-260618 NR3C1 protein P04150 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity transcriptional regulation 10090 22848740 YES miannu We show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress. 0.415 SIGNOR-255759 CRYAA protein P02489 UNIPROT CRYBB2 protein P43320 UNIPROT up-regulates activity binding 9606 22982024 YES miannu Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin. 0.2 SIGNOR-252155 SLIT1 protein O75093 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 YES gcesareni Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis. 0.382 SIGNOR-68327 MAPK14 protein Q16539 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation Thr250 NSCTPITtPELTTPC 9606 9155017 YES lperfetto Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38. Erk and p38 phosphorylate MNK1 and Mnk2. 0.671 SIGNOR-48342 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1248 PTAENPEyLGLDVPV -1 1706616 YES  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. 0.2 SIGNOR-251128 RHOA protein P61586 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates activity binding 9606 25010901 YES gcesareni Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase 0.809 SIGNOR-196740 MAML1 protein Q92585 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation 9606 17300219 YES gcesareni We speculated that maml1, in addition to recruiting p300, might directly interact with histones to facilitate histone acetylation. We had observed acetylation of the histones h3 and h4. 0.2 SIGNOR-153041 CENPX protein A8MT69 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.2 SIGNOR-265201 LY294002 chemical CHEBI:65329 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 YES gcesareni Here we show that inhibition of pi3-k activity by the pharmacological agent ly294002 affects early processes of myoblast differentiation including the transcriptional activation of myogenin. 0.8 SIGNOR-252647 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9259419 YES rheumatoid arthritis gcesareni 0.8 SIGNOR-251695 Ub:E2 complex SIGNOR-C497 SIGNOR LRSAM1 protein Q6UWE0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271053 SLC9A5 protein Q14940 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265595 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-252922 ERCC6 protein Q03468 UNIPROT NEIL1 protein Q96FI4 UNIPROT up-regulates activity binding 9606 19179336 YES Regulation miannu CSB stimulates NEIL1 incision activity in vitro, and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells. 0.344 SIGNOR-251931 APC-c complex SIGNOR-C150 SIGNOR CLSPN protein Q9HAW4 UNIPROT down-regulates quantity by destabilization ubiquitination 18662541 YES lperfetto Claspin Is Degraded in G0 and G1 via the APC/CCdh1 Ubiquitin Ligase 0.26 SIGNOR-274056 GOPC protein Q9HD26 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates binding 9606 21311563 YES gcesareni Npist binds beclin 1 by a ccd 0.524 SIGNOR-171896 IGF2 protein P01344 UNIPROT IGF2R protein P11717 UNIPROT up-regulates binding 9606 11867533 YES fspada Insulin-like growth factor ii receptor (igf2r) is a multifunctional cell surface receptor implicated in tumour suppression. Its growth inhibitory activity has been associated with an ability to bind igf-ii. 0.728 SIGNOR-115250 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.655 SIGNOR-131634 UHRF1 protein Q96T88 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005192 20037778 NO miannu we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter. 0.2 SIGNOR-254224 NRTN protein Q99748 UNIPROT RET protein P07949 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 YES gcesareni A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling 0.714 SIGNOR-49122 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii 0.777 SIGNOR-203568 sirolimus chemical CHEBI:9168 ChEBI CD80 protein P33681 UNIPROT down-regulates quantity by repression 9606 18652845 NO miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. 0.8 SIGNOR-255475 UGP2 protein Q16851 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity chemical modification 9606 8631325 YES miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. 0.8 SIGNOR-267928 LAMB3 protein Q13751 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR form complex binding 9211848 YES lperfetto Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2. 0.647 SIGNOR-253236 tamoxifen chemical CHEBI:41774 ChEBI GPER1 protein Q99527 UNIPROT up-regulates chemical activation 9606 15539556 YES gcesareni The finding that the antiestrogens tamoxifen and ici 182,780, and an environmental estrogen, ortho,para-dichlorodiphenyldichloroethylene (o,p'-dde), have high binding affinities to the receptor and mimic the actions of e2 has important implications for both the development and treatment of estrogen-dependent breast cancer. 0.8 SIGNOR-130395 MAP2K6 protein P52564 UNIPROT CRK protein P46108 UNIPROT up-regulates phosphorylation 9606 8663074 YES gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily. 0.2 SIGNOR-42384 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser248 DLDILHNsSQMKSMS 9606 BTO:0000567 25670858 YES lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 0.587 SIGNOR-265227 CSF3 protein P09919 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 YES gcesareni The gcsf:gcsf-r complex formed a 2:2 stoichiometry by means of a cross-over interaction between the ig-like domains of gcsf-r and gcsf. the ig-like domain cross-over structure necessary for gcsf-r activation is consistent with previously reported thermodynamic and mutational analyses. 0.765 SIGNOR-144743 ESRRA protein P11474 UNIPROT NR2F6 protein P10588 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000156 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.248 SIGNOR-253796 PIK3C2A protein O00443 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates chemical modification 9606 23119004 YES gcesareni Pi3ks phosphorylate the d3 position of membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (pip3). 0.8 SIGNOR-199367 RPS6K proteinfamily SIGNOR-PF26 SIGNOR WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 9606 BTO:0000149 24269383 YES llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity. 0.2 SIGNOR-252809 NHLH2 protein Q02577 UNIPROT ASCL1 protein P50553 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21573214 NO miannu Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1. 0.241 SIGNOR-254823 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248378 tRNA(His) smallmolecule CHEBI:29178 ChEBI His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates quantity precursor of 9606 10430027 YES miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 0.8 SIGNOR-270491 Caspase 8 complex complex SIGNOR-C231 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 NO amattioni Downstream of caspase-8 activation, apoptosis induction takes place 0.7 SIGNOR-256549 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191304 NOTCH proteinfamily SIGNOR-PF30 SIGNOR MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 12370315 YES flangone Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages 0.2 SIGNOR-254346 CSNK2A1 protein P68400 UNIPROT FKBP4 protein Q02790 UNIPROT down-regulates activity phosphorylation Thr143 EFKGEDLtEEEDGGI -1 9405642 YES llicata Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. | Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90 0.343 SIGNOR-250865 SYNE2 protein Q8WXH0 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.534 SIGNOR-263283 Matrine chemical CHEBI:6700 ChEBI OPRK1 protein P41145 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194316 FLT3 protein P36888 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15626738 NO FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells 0.336 SIGNOR-261549 RLF protein Q13129 UNIPROT RIT1 protein Q92963 UNIPROT up-regulates activity binding 9606 10545207 YES miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. 0.309 SIGNOR-220799 RAD21 protein O60216 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 YES lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin 0.967 SIGNOR-263311 CSNK2A2 protein P19784 UNIPROT CASQ2 protein O14958 UNIPROT unknown phosphorylation Ser385 DDDDDDNsDEEDNDD -1 1985907 YES llicata Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH). 0.375 SIGNOR-250980 CDKN1B protein P46527 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 YES gcesareni P21 and p27 are key inhibitors of both cdk1 and cdk2. 0.657 SIGNOR-128445 IRF4 protein Q15306 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 11956291 NO IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production 0.525 SIGNOR-254501 TCF7L2 protein Q9NQB0 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates activity transcriptional regulation 20492721 NO FFerrentino These findings suggested that miR-210 could promote adipogenesis by repressing WNT signaling through targeting Tcf7l2. 0.7 SIGNOR-253519 SRSF7 protein Q16629 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates binding 9606 18364396 YES miannu 9g8 and srp20 also enhance the tap rna-binding activity 0.668 SIGNOR-161338 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 9606 11153911 YES gcesareni The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway. 0.78 SIGNOR-85942 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 12717439 YES Manara Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. | These results suggest that the Ser 364 site is phosphorylated by Chk2 and that anti-P-Ser 364 recognises the phosphorylated site in E2F-1. 0.487 SIGNOR-260822 CTSG protein P08311 UNIPROT SERPIND1 protein P05546 UNIPROT down-regulates activity cleavage Val458 QATTVTTvGFMPLST -1 2318847 YES miannu Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC. 0.444 SIGNOR-256509 SERPINC1 protein P01008 UNIPROT F10 protein P00742 UNIPROT down-regulates activity cleavage 31030036 YES lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 0.876 SIGNOR-264138 PAK1 protein Q13153 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 12151336 YES gcesareni Histone h3 is a substrate of pak1 both in vitro and in vivo, and it specifically interacted with pak1 but not pak2 or pak3. Site-directed mutagenesis indicated that pak1 phosphorylates histone h3 on ser10. 0.2 SIGNOR-265363 migalastat chemical CHEBI:135923 ChEBI GLA protein P06280 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003676 10866822 YES Federica 1-Deoxygalactonojirimycin was the most potent inhibitor of a-Gal A with an IC50 value of 0.04mm. 0.8 SIGNOR-261076 MAPK3 protein P27361 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL -1 32482868 YES lperfetto ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation 0.706 SIGNOR-236250 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates activity phosphorylation Tyr702 FGMSRDVySTDYYRV 10090 BTO:0000944 10533983 YES miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc 0.2 SIGNOR-250205 UVB radiation stimulus SIGNOR-ST17 SIGNOR calciol smallmolecule CHEBI:28940 ChEBI up-regulates quantity chemical modification 9606 BTO:0001253 30080183 YES lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin 0.7 SIGNOR-270562 CD19 protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000899 10201980 YES lperfetto Phosphorylation of CD19 Y484 and Y515, and linked activation of phosphatidylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. 0.521 SIGNOR-252669 NR4A3 protein Q92570 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 30455429 NO miannu Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. 0.7 SIGNOR-259398 SREBF2 protein Q12772 UNIPROT NPC1L1 protein Q9UHC9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21123766 NO miannu Our results showed a positive correlation between changes in NPC1L1 and changes in both SREBP-2 and HNF-4α mRNA expression, a finding that supports the notion that these transcription factors stimulate intestinal NPC1L1 expression. 0.566 SIGNOR-254452 Integrator complex complex SIGNOR-C265 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 9606 26220997 NO lperfetto  In vivo knockdown and rescue experiments confirmed that the 3′ end processing of HVS pre-miRNAs also depends on Integrator activity. Interaction between Integrator and HVS primary miRNA (pri-miRNA) substrates that contain only the miRNA 3′ box was confirmed by coimmunoprecipitation and an in situ proximity ligation assay (PLA) 0.7 SIGNOR-261475 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP153 protein P49790 UNIPROT unknown phosphorylation 9606 19767751 YES inferred from 70% family members llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. 0.2 SIGNOR-270159 SMAD3 protein P84022 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 23032366 NO lperfetto PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. 0.561 SIGNOR-245441 SST protein P61278 UNIPROT SSTR4 protein P31391 UNIPROT up-regulates binding 9606 10433861 YES gcesareni The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity. 0.776 SIGNOR-82496 SOD1 protein P00441 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates activity binding 10090 BTO:0001279 20797535 YES P00441:p.Gly38Arg (mutation causing interaction) Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS|With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane. 0.425 SIGNOR-262798 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004408 29606353 YES Gianni Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching. 0.446 SIGNOR-269066 PPP2CA protein P67775 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity dephosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0001023 16596250 YES Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. 0.433 SIGNOR-248617 topotecan chemical CHEBI:63632 ChEBI TOP1MT protein Q969P6 UNIPROT down-regulates activity chemical inhibition 9606 11166732 YES miannu Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma. 0.8 SIGNOR-259318 RLIM protein Q9NVW2 UNIPROT ZFP42 protein Q96MM3 UNIPROT down-regulates quantity by destabilization ubiquitination 22596162 YES lperfetto RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout embryonic stem cells show an increased level of REX1. 0.337 SIGNOR-269002 ATG3 protein Q9NT62 UNIPROT GABARAP protein O95166 UNIPROT up-regulates activity binding -1 16303767 YES lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) 0.847 SIGNOR-141868 MYC protein P01106 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by stabilization 9606 26049753 NO Overexpression of c-MYC resulted in SIRT1 deubiquitination, whereas c-MYC knockdown led to decrease in SIRT1 protein stability and expression. 0.573 SIGNOR-261558 DAXX protein Q9UER7 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates binding 9606 9743501 YES gcesareni Daxx was found to activate the jnk kinase kinase ask1, and overexpression of a kinase-deficient ask1 mutant inhibited fas- and daxx-induced apoptosis and jnk activation. 0.841 SIGNOR-60164 SLC9A1 protein P19634 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265600 TRIB3 protein Q96RU7 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity binding 9606 BTO:0000007 BTO:0000759 12791994 YES llicata TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. 0.618 SIGNOR-252644 CHMP2B protein Q9UQN3 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.682 SIGNOR-265530 RPS6KB1 protein P23443 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 2846551 YES gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. 0.247 SIGNOR-23757 FLT3 protein P36888 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14592841 NO This data confirms that PU.1 is a downstream target of activated C/EBPα and is suppressed in FLT3/ITD-expressing cells as a result of C/EBPα suppression. 0.621 SIGNOR-261530 SDCBP protein O00560 UNIPROT SOX4 protein Q06945 UNIPROT up-regulates activity binding 10090 BTO:0003104 11498591 YES miannu Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation. 0.539 SIGNOR-223089 TP53 protein P04637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 NO miannu P53 is a nuclear transcription factor with a pro-apoptotic function 0.7 SIGNOR-255678 EXOC5 protein O00471 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.941 SIGNOR-270788 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 BTO:0000671 18986304 YES llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). 0.2 SIGNOR-182053 dutasteride chemical CHEBI:521033 ChEBI ESR2 protein Q92731 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191445 VCP protein P55072 UNIPROT DERL1 protein Q9BUN8 UNIPROT up-regulates activity binding 9606 BTO:0000567 15215856 YES miannu VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97. 0.884 SIGNOR-261372 LCK protein P06239 UNIPROT LAX1 protein Q8IWV1 UNIPROT up-regulates activity phosphorylation Tyr373 SNEDSSDyENVLTAK 9606 BTO:0000007 12359715 YES miannu Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85.  0.4 SIGNOR-273528 alvocidib chemical CHEBI:47344 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191532 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 YES Manara We show that Abl directly phosphorylates PKD at Tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of PKD 0.34 SIGNOR-260791 SIRT5 protein Q9NXA8 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity catalytic activity 9606 27113762 YES Monia Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes. 0.278 SIGNOR-261211 VIPAS39 protein Q9H9C1 UNIPROT CHEVI complex complex SIGNOR-C269 SIGNOR form complex binding 9606 BTO:0000007 29778605 YES lperfetto It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named "CHEVI") 0.758 SIGNOR-261831 KSR1 protein Q8IVT5 UNIPROT ARAF protein P10398 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 YES miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 0.566 SIGNOR-273876 NFE2L2 protein Q16236 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18629308 NO miannu When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression. 0.2 SIGNOR-254645 resiquimod chemical CHEBI:36706 ChEBI TLR8 protein Q9NR97 UNIPROT up-regulates activity chemical activation 9606 15661881 YES miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. 0.8 SIGNOR-259247 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 22049910 YES Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. 0.8 SIGNOR-266907 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000551 22505454 YES gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. 0.396 SIGNOR-196953 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206130 PTPN6 protein P29350 UNIPROT JAK1 protein P23458 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 YES gcesareni We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation. 0.645 SIGNOR-119197 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Thr250 KEEVVGLtETSSQPK 9606 BTO:0000776 7678037 YES llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase erine threonine phosphorylation and may stimulate CKII activity in B cells. 0.307 SIGNOR-250917 INVS protein Q9Y283 UNIPROT DVL1 protein O14640 UNIPROT down-regulates ubiquitination 9606 15852005 YES gcesareni Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation 0.64 SIGNOR-135766 TLE5 protein Q08117 UNIPROT SIX3 protein O95343 UNIPROT down-regulates activity binding -1 12441302 YES lperfetto Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes 0.2 SIGNOR-234586 ETS1 protein P14921 UNIPROT SLC26A3 protein P40879 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 7935445 NO miannu Ets-1 activates the DRA promoter in B cells. 0.2 SIGNOR-254085 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser652 LERPFRPsVTSVGHV -1 24548923 YES miannu Akt phosphorylates S637 and S645 in the linker region of Carma1  0.523 SIGNOR-276620 CDKN1A protein P38936 UNIPROT PCNA protein P12004 UNIPROT down-regulates binding 9606 22911014 YES gcesareni P21 exerts its effect on the cell cycle not only by inhibiting cyclin/cdk complexes, but also by inhibiting proliferating cell nuclear antigen (pcna) 0.765 SIGNOR-191939 PTPRO protein Q16827 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 24708807 YES miannu In addition, this group found that PTPRO dephosphorylated STAT3 at Y705 and S727 then attenuated STAT3 signalling. 0.376 SIGNOR-277062 NGFR protein P08138 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 14699954 NO amattioni Jnk3 is expressed exclusively in the nervous system and recent evidence indicates that this jnk isoform may be required for p75ntr-mediated cell death 0.448 SIGNOR-120561 CDK1 protein P06493 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates phosphorylation Ser1126 IAPSTNSsPVLKTKP 9606 11747808 YES lperfetto Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro 0.573 SIGNOR-113126 CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 16161044 YES gcesareni In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm. 0.87 SIGNOR-140412 vatalanib chemical CHEBI:90620 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207645 CAMK2A protein Q9UQM7 UNIPROT LRRC7 protein Q96NW7 UNIPROT unknown phosphorylation Ser1439 IQTKGQRsMDGYPEQ 11160423 YES llicata In contrast, phosphorylation of densin-180 by CaMKII at serine-1397 only slightly decreases its affinity for CaMKII. The specific interaction of densin-180 with holoenzymes of CaMKII containing only alpha-subunit and the increased affinity of CaMKII for densin-180 after autophosphorylation suggest that densin-180 may be involved in localization of activated CaMKII synthesized in dendrites. 0.427 SIGNOR-250634 PRL protein P01236 UNIPROT KRT14 protein P02533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 20103718 NO Regulation miannu PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. 0.281 SIGNOR-251902 CUDC-907 chemical CID:54575456 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191206 SMURF1 protein Q9HCE7 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27858941 YES miannu DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1 0.262 SIGNOR-254776 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates activity phosphorylation 9606 15066263 YES miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts 0.734 SIGNOR-268289 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 27023846 NO miannu Mitochondrial ribosomes (mitoribosomes) perform protein synthesis inside mitochondria, the organelles responsible for energy conversion and adenosine triphosphate production in eukaryotic cells. 0.7 SIGNOR-261487 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 9312068 YES gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. 0.698 SIGNOR-51203 MTOR protein P42345 UNIPROT DAP protein P51397 UNIPROT down-regulates activity phosphorylation Ser51 DQEWESPsPPKPTVF 9606 20537536 YES miannu A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51. 0.395 SIGNOR-259812 AR protein P10275 UNIPROT ARG1 protein P05089 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001321 20711410 NO miannu The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. 0.2 SIGNOR-253738 AKT1 protein P31749 UNIPROT SH2B2 protein O14492 UNIPROT unknown phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 YES Serine 588 of APS is a newly identified target for protein kinase B in intact cells and in vitro. The precise function of this PKB-mediated phosphorylation event is not entirely clear but may be responsible for regulating cellular localization and will be the subject of future investigation. 0.401 SIGNOR-252577 GSK3B protein P49841 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity phosphorylation Ser78 PMGPHSMsVPTTPTL 9606 BTO:0000007 29137318 YES miannu GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.  0.275 SIGNOR-277371 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 9753485 YES Crohn's Disease gcesareni 0.8 SIGNOR-251703 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2110 FGLARDIyKNDYYRK 9606 17416557 YES gcesareni In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products. 0.374 SIGNOR-154199 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH10 protein Q9Y6N8 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265828 Calcineurin complex SIGNOR-C155 SIGNOR NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 YES gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. 0.574 SIGNOR-252312 EP300 protein Q09472 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 SIGNOR-C6 10944526 YES gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo. 0.68 SIGNOR-81053 LDHA protein P00338 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000164 9192621 NO The lactate dehydrogenase-A gene (LDH-A), whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, was identified as a c-Myc-responsive gene. 0.7 SIGNOR-259370 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCA protein P17252 UNIPROT down-regulates chemical inhibition 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-190344 BTF3 protein P20290 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17312387 NO In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. 0.2 SIGNOR-253950 EREG protein O14944 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 16829981 YES gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 0.59 SIGNOR-147856 KLF2 protein Q9Y5W3 UNIPROT THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19661484 NO miannu Thrombomodulin upregulation was independent of NF-kappaB signaling, a principal target of proteasome inhibitors, but was instead a direct consequence of increased expression of the Krüppel-like transcription factors, KLF2 and KLF4. 0.429 SIGNOR-254543 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 8940173 YES lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor 0.581 SIGNOR-45122 TRIM63 protein Q969Q1 UNIPROT TNNI1 protein P19237 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 YES miannu We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s. 0.361 SIGNOR-272736 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK -1 8756661 YES lperfetto these data suggest that phosphorylation of ZAP-70 is initiated by a heterologous trans-phosphorylation of ZAP-70 by Lck on Tyr- 493. 0.618 SIGNOR-226628 PIAS1 protein O75925 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates sumoylation 9606 20016603 YES gcesareni Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation. 0.495 SIGNOR-162156 Org 27569 chemical CID:44828492 PUBCHEM CNR1 protein P21554 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-195097 GSK690693 chemical CHEBI:90677 ChEBI AKT3 protein Q9Y243 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193006 RND1 protein Q92730 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 17251915 YES gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor 0.322 SIGNOR-152811 PCDHA3 protein Q9Y5H8 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265668 hydrosulfide smallmolecule CHEBI:29919 ChEBI Vasodilation phenotype SIGNOR-PH223 SIGNOR up-regulates 26539823 NO lperfetto We have recently shown, that in arterial (HAEC) end venular (HUVEC) endothelial cells, GPBAR1 agonism increases the expression/ activity of cystathione-γ-liase (CSE, CTH, EC 4.4.1), a key enzyme in the “trans-sulfuration pathway” that generates hydrogen sulfide (H2S), a vasodilatory agent 0.7 SIGNOR-275831 heme smallmolecule CHEBI:30413 ChEBI FBXO22 protein Q8NEZ5 UNIPROT up-regulates activity chemical activation 9606 31257023 YES Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. 0.8 SIGNOR-259332 PI4KB protein Q9UBF8 UNIPROT phosphatidylinositol 4-phosphate smallmolecule CHEBI:37530 ChEBI up-regulates quantity chemical modification 9534 22253445 YES lperfetto Interestingly, we found that PI4P, the product of PI4KB catalysis, creates a lipid microenvironment that is required for SARS-CoV S-mediated entry. 0.8 SIGNOR-260732 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 YES gcesareni Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. 0.344 SIGNOR-75997 HLX protein Q14774 UNIPROT CDKN1C protein P49918 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003980 20008130 YES Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. 0.2 SIGNOR-261620 PRKACA protein P17612 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 YES miannu Ser-42 can be phosphorylated by either protein kinase A or protein kinase C 0.329 SIGNOR-249999 SKP1 protein P63208 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR form complex binding 9606 BTO:0001109 phosphorylation:Thr286 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1  0.957 SIGNOR-271630 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1363 HVQSVLLtPQDEFFI 9606 BTO:0002181 19797085 YES miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  0.354 SIGNOR-276264 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120252 FYN protein P06241 UNIPROT CD79B protein P40259 UNIPROT up-regulates activity phosphorylation Tyr207 DIDQTATyEDIVTLR -1 9531288 YES CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b 0.671 SIGNOR-251155 ARHGEF6 protein Q15052 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0000599 23776207 NO lperfetto Expression of the phospho-mimicking ACAP4 mutant promotes ARF6-dependent cell migration. 0.7 SIGNOR-272237 LEPR protein P48357 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates activity binding 27154742 YES lperfetto The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex 0.333 SIGNOR-253077 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Ser387 ETGLYRIsGCDRTVK 9606 BTO:0000567 12689593 YES lperfetto We also report that aurora b phosphorylates mgcracgap on serine residues and that this modification induces latent gap activity toward rhoa in vitro. 0.779 SIGNOR-100569 PRKCH protein P24723 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.2 SIGNOR-251634 CYSLTR1 protein Q9Y271 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.403 SIGNOR-257225 DCAF12 protein Q5T6F0 UNIPROT MAGEA3 protein P43357 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002806 31267705 YES miannu  The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6 0.2 SIGNOR-272254 nocodazole chemical CHEBI:34892 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194838 OGDHL protein Q9ULD0 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 YES miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. 0.655 SIGNOR-267833 MRPL36 protein Q9P0J6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.723 SIGNOR-262361 TAOK2 protein Q9UL54 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 YES gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. 0.275 SIGNOR-201327 PRKCZ protein Q05513 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 14657655 YES gcesareni Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent. 0.596 SIGNOR-119889 AP-2 complex complex SIGNOR-C245 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 YES lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  0.6 SIGNOR-260663 CBLB protein Q13191 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 10542134 YES miannu Here we describe that overexpression of cbl-b, a homologue of the c-cbl protooncogene, inhibits EGFR-induced apoptosis in MDA-MB-468 breast cancer cells. Overexpression of cbl-b results in a shortened duration of EGFR activation upon EGF stimulation. This is demonstrated by decreased amounts of phosphorylated EGFR as well as by inhibition of multiple downstream signaling pathways. The inhibition of signaling by cbl-b results from increased ubiquitination and degradation of the activated EGFR.  0.759 SIGNOR-272934 MAPK8 protein P45983 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 14967141 YES gcesareni Jnk phosphorylates bad at threonine 201, thereby inhibiting bad association with the antiapoptotic molecule bcl-x(l) 0.685 SIGNOR-121940 PRKCA protein P17252 UNIPROT GPM6A protein P51674 UNIPROT up-regulates activity phosphorylation Thr10 ENMEEGQtQKGCFEC 10116 BTO:0001009 12359212 YES miannu In summary, a CNS neuron-specific membrane glycoprotein, M6a, could act as a novel NGF-gated Ca2+ channel through the phosphorylation with PKC and augments [Ca2+]i in M6a-S cells. 0.324 SIGNOR-263163 FABP3 protein P05413 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264457 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 BTO:0000459 20921139 YES lperfetto we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2. 0.786 SIGNOR-168252 TBX2 protein Q13207 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 9606 24470334 YES We have found that TBX2 is highly up regulated in both ERMS and ARMS subtypes of RMS and demonstrate that TBX2 is a repressor of myogenesis by binding to MyoD and myogenin and inhibiting their activity. 0.31 SIGNOR-251560 GATA1 protein P15976 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates activity 10090 12032775 NO Studies involving point mutants of GATA-1 have shown that a direct physical interaction between GATA-1 and FOG-1 is essential for normal human erythroid and megakaryocyte maturation in vivo. 0.7 SIGNOR-259961 lurasidone chemical CHEBI:70735 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10030 20404009 YES Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. 0.8 SIGNOR-259465 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg424 KNMEDLHrHIFWEPD -1 12372819 YES miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. 0.313 SIGNOR-256515 ABL1 protein P00519 UNIPROT APBB1 protein O00213 UNIPROT up-regulates phosphorylation Tyr547 VQKFQVYyLGNVPVA 9606 15031292 YES lperfetto The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain. 0.415 SIGNOR-123476 CSNK1E protein P49674 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 BTO:0000782 3133391 YES gcesareni Moreover, in response to wnt3a, p120-catenin is phosphorylated at ser268, a modification dependent on ck1epsilon activity, which disrupts its interaction with e-cadherin and, subsequently, with lrp5/6, promoting the release of ck1epsilon/p120-catenin from the wnt receptor complex. 0.289 SIGNOR-24443 SLC9A1 protein P19634 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265591 MOG protein Q16653 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 33290135 NO SimoneGraziosi Myelin oligodendrocyte glycoprotein (MOG) is a nervous system protein expressed by oligodendrocytes to constitute the myelin sheath. 0.7 SIGNOR-269232 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser649 VPPSPSLsRHSSPHQ -1 2117608 YES llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. 0.33 SIGNOR-250880 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline chemical CHEBI:94782 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190919 RBX1 protein P62877 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 14676825 YES gcesareni Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase. 0.281 SIGNOR-120342 CSNK2A1 protein P68400 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser574 EEVSDKGsDSEEEET 9606 23287549 YES lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. 0.291 SIGNOR-265269 IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 10090 BTO:0000887 14623899 YES lperfetto As shown previously, IRS-1 was required for insulin-stimulated phosphorylation of Akt in 32D cells, which is consistent with the binding and activation of PI3K by IRS-1 during insulin stimulation 0.722 SIGNOR-236618 HIF1A protein Q16665 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 8955077 NO inferred from family member miannu we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1. 0.337 SIGNOR-270229 MMP1 protein P03956 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272354 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT down-regulates activity phosphorylation Ser510 SSSNEGDsDRDEKKR 9606 BTO:0000007 15659405 YES llicata CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity. 0.703 SIGNOR-250959 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A3-B3 complex SIGNOR-C140 SIGNOR up-regulates activity chemical activation 9606 15036565 YES gcesareni One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP) 0.8 SIGNOR-243967 SNCA protein P37840 UNIPROT ER stress stimulus SIGNOR-ST9 SIGNOR up-regulates 9606 12666095 NO lperfetto Furthermore, mutant isoforms of alpha-synuclein more readily oligomerize, and it has been suggested that its tendency to aggregate into misfolded structures may confer toxic properties to the protein. 0.7 SIGNOR-249702 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr286 VEGDAAEtPPRPRTP 10090 BTO:0000944 11684694 YES llicata Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. | suggesting that Thr286 in MEK1 is a site of cdk5/p35 phosphorylation that inhibits MEK1 activity. 0.499 SIGNOR-250653 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr402 PEQSKRStMVGTPYW -1 10075701 YES miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites 0.2 SIGNOR-250230 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser24 APIRRRSsNYRAYAT 9606 18550549 YES gcesareni Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144. 0.272 SIGNOR-178884 PELI3 protein Q8N2H9 UNIPROT JUN protein P05412 UNIPROT up-regulates 9606 12874243 NO gcesareni Pellino3 leads to activation of c-jun and elk-1, but not nf-kappab 0.278 SIGNOR-103989 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0001271;BTO:0000876 11742995 YES lperfetto The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription 0.409 SIGNOR-217201 AKT1 protein P31749 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser286 LRSCSLGsLGALGPA -1 27407113 YES miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  0.2 SIGNOR-274067 tRNA(Cys) smallmolecule CHEBI:29167 ChEBI Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates quantity precursor of 9606 11347887 YES miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. 0.8 SIGNOR-270475 MAP1LC3B protein Q9GZQ8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 YES gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. 0.837 SIGNOR-156356 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8887554 YES lperfetto We show that mapkap kinase-2 phosphorylates creb at ser133 in vitro. 0.69 SIGNOR-44384 IL6 protein P05231 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates 10090 23531613 NO AMPK phosphorylation was increased nearly fourfold (Fig. 2C) with the high dose of IL-6 0.246 SIGNOR-255338 PGM1 protein P36871 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-267930 CAMK2A protein Q9UQM7 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000938 BTO:0000142 20643921 YES gcesareni Nmda-dependent internalization of gabab receptors requires activation of ca2+/calmodulin-dependent protein kinase ii (camkii), which associates with gabab receptors in vivo and phosphorylates serine 867 (s867) in the intracellular c terminus of the gabab1 subunit. 0.237 SIGNOR-166846 AXIN1 protein O15169 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates binding 9606 BTO:0000007 12878610 YES gcesareni Mekk4, also binds to axin in vivo and mediates axin-induced jnk activation. 0.421 SIGNOR-104003 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser630 VLSSTFLsPQCSPQH 9606 BTO:0000007 16141410 YES In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity 0.398 SIGNOR-251248 RAD50 protein Q92878 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 17713585 YES fstefani To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. 0.2 SIGNOR-157478 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9534 BTO:0004055 16705159 YES 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner 0.2 SIGNOR-244553 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser36 PSEGRQPsPSPSPTE 9606 BTO:0001271 15093545 YES The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). 0.36 SIGNOR-124240 RET protein P07949 UNIPROT AFAP1L2 protein Q8N4X5 UNIPROT up-regulates activity phosphorylation Tyr54 SSSSDEEyIYMNKVT 9606 BTO:0000007 19060924 YES miannu RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha. 0.331 SIGNOR-263192 AKT2 protein P31751 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 YES gcesareni Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155. 0.523 SIGNOR-81114 USP9X protein Q93008 UNIPROT SMN1 protein Q16637 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 23112048 YES lperfetto Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron 0.28 SIGNOR-253113 glutamine smallmolecule CHEBI:28300 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 NO Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 0.7 SIGNOR-268009 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates activity phosphorylation Thr320 AISDTTTtFCGTPEY 10548550 YES miannu SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. 0.462 SIGNOR-250279 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15536164 NO miannu Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG. 0.418 SIGNOR-254798 FOXM1 protein Q08050 UNIPROT SLC27A2 protein O14975 UNIPROT up-regulates quantity by expression 9606 31949772 NO lperfetto FOXM1 as a prognostic biomarker promotes endometrial cancer progression via transactivation of SLC27A2 expression. 0.2 SIGNOR-260414 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 YES lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  0.764 SIGNOR-263216 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 17130464 YES Translocation from Cytoplasm to Nucleus lperfetto Phosphorylation of pras40-thr246 by pkb/akt, and pras40-ser183 and pras40-ser221 by mtorc1 results in dissociation from mtorc1, and its binding to 14-3-3 proteins. 0.729 SIGNOR-252540 mTORC2 complex SIGNOR-C2 SIGNOR ELP1 protein O95163 UNIPROT up-regulates activity phosphorylation Ser1174 SETSSVVsGSEMSGK 29925953 YES lperfetto Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174 0.2 SIGNOR-275542 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-252976 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9606 14701738 YES miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. 0.29 SIGNOR-261711 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273053 NR4A3 protein Q92570 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 30455429 YES miannu NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis. 0.2 SIGNOR-259399 ITGB8 protein P26012 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates 9606 BTO:0000142 11970960 NO lperfetto Integrin _v_8-mediated tgf_ activation is also required to regulate neurovascular homeostasis in the adult brain 0.558 SIGNOR-117386 SRCAP protein Q6ZRS2 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003160 20432434 NO miannu ShRNA mediated knockdown of SRCAP resulted in decreased H2A.Z binding at the enhancer region of the PSA promoter and decreased expression of PSA in prostate cancer cells. 0.2 SIGNOR-255220 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Ser33 SETQHRGsAPHSESD 9606 22727668 YES llicata We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1 0.2 SIGNOR-197989 GRIA3 protein P42263 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 NO miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses 0.7 SIGNOR-264613 HOXB1 protein P14653 UNIPROT OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000946 9556594 YES Luana Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively 0.274 SIGNOR-261633 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser337 DPRGRLRsADSENAL 9606 12761205 YES lperfetto Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 2 0.2 SIGNOR-101216 ACVR1 protein Q04771 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR form complex binding 9606 7791754 YES lperfetto Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. 0.714 SIGNOR-33287 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176801 CDX2 protein Q99626 UNIPROT TFF3 protein Q07654 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0004055 17182120 YES The transcription of human TFF3 reporter genes was significantly up-regulated by the transient overexpression of CDX2 in COS-7 cells and AGS gastric cells. 0.392 SIGNOR-253967 CDK5 protein Q00535 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Ser8 MGTVLSLsPSYRKAT 9606 18326489 YES lperfetto When overexpressed with cdk5, a large fraction of the double mutant p35(s8a/t138a) co-sedimented with microtubules (fig. 5b), further supporting the idea that the phosphorylation at these two residues by cdk5 is inhibitory to the microtubule association. 0.943 SIGNOR-177963 JUN protein P05412 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 NO lperfetto Functional data suggest that c-Jun is not merely a target for activation by many of the extracellular stimuli, but that it plays a role in mediating the cellular response. In the case of growth control, three lines of evidence suggest that the transcription factor AP-1, which is composed of Fos–Jun and Jun–Jun dimers, mediates cell proliferation in response to external growth signals in the form of peptide growth factors. 0.7 SIGNOR-233467 NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates quantity binding 10090 BTO:0002572 18625840 YES gcesareni We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7 0.483 SIGNOR-245084 CH5132799 chemical CID:49784945 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190949 EYA3 protein Q99504 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Tyr143 ATQASQEy 9606 20965415 YES gcesareni Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3. 0.2 SIGNOR-168927 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1222 PAFDNLYyWDQDPPE -1 1706616 YES  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. 0.2 SIGNOR-251130 ANAPC1 protein Q9H1A4 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.881 SIGNOR-252001 LRRC4 protein Q9HBW1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25526788 NO miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. 0.354 SIGNOR-264054 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT up-regulates activity phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 BTO:0001615 32238881 YES lperfetto Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. 0.2 SIGNOR-275583 silodosin chemical CHEBI:135929 ChEBI ADRA1A protein P35348 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206914 CDK2 protein P24941 UNIPROT UBE2A protein P49459 UNIPROT up-regulates phosphorylation Ser120 LDEPNPNsPANSQAA 9606 11953320 YES llicata Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity. 0.374 SIGNOR-116508 EGR1 protein P18146 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 NO Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) 0.2 SIGNOR-251917 RIPK2 protein O43353 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity phosphorylation Ser176 KWRMMSLsQSRSSKS 9606 16824733 YES amattioni In summary, our results indicate that s176 is a regulatory autophosphorylation site for rip2 and that s176 phosphorylation can be used to monitor the activation state of rip2. 0.2 SIGNOR-229701 CEBPA protein P49715 UNIPROT FTO protein Q9C0B1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 24877091 NO lperfetto CCAAT/Enhancer-Binding Protein 𝛼 Is a Crucial 0.346 SIGNOR-261805 CSNK2B protein P67870 UNIPROT USO1 protein O60763 UNIPROT up-regulates activity phosphorylation Ser942 EEEDELEsGDQEDED -1 10931861 YES llicata Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. | Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae 0.336 SIGNOR-251082 BAK1 protein Q16611 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 11175253 YES amattioni Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux 0.2 SIGNOR-105203 APOA1 protein P02647 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates 9606 20642861 YES miannu ApoA-I increases cholesterol release in mature human adipocytes. 0.8 SIGNOR-252104 CDK1 protein P06493 UNIPROT GOLGA2 protein Q08379 UNIPROT down-regulates phosphorylation Ser37 REYQQRNsPGVPTGA 9606 9753325 YES lperfetto Cdc2 kinase directly phosphorylates the cis-golgi matrix protein gm130 and is required for golgi fragmentation in mitosis. Mitotic fragmentation of the golgi apparatus can be largely explained by disruption of the interaction between gm130 and the vesicle-docking protein p115. Here we identify a single serine (ser-25) in gm130 as the key phosphorylated target and cdc2 as the responsible kinase 0.673 SIGNOR-60281 GNG2 protein P59768 UNIPROT SRC protein P12931 UNIPROT up-regulates activity 15345719 NO In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation 0.465 SIGNOR-251108 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity binding -1 10497253 YES lperfetto Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7. 0.669 SIGNOR-70947 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CITED1 protein Q99966 UNIPROT up-regulates binding 9606 9660950 YES lperfetto The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276. 0.2 SIGNOR-216331 EIF2S1 protein P05198 UNIPROT ATF4 protein P18848 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24714526 NO miannu Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy. 0.638 SIGNOR-251820 DNM2 protein P50570 UNIPROT MYO1C protein O00159 UNIPROT up-regulates binding 9606 17257598 YES miannu Dynamin bind directly to the sh3 domain of myo1e / an intriguing possibility is that binding of dynamin and synaptojanin to myo1e tail may activate motor activity since it has been demonstrated that myo1e atpase activity is autoinhibited by its sh3 domain 0.356 SIGNOR-152910 CREB1 protein P16220 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 17668895 NO gcesareni Phosphorylation of creb by msk has been linked to the of nur77, nor1 and c-fos downstream of mapkin various cell types 0.661 SIGNOR-157151 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22286761 NO gcesareni Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. 0.272 SIGNOR-195534 PRDM14 protein Q9GZV8 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 NO SimoneGraziosi SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. 0.7 SIGNOR-269261 UBE2A protein P49459 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination Lys164 AVVISCAkDGVKFSA 9606 19706603 YES gcesareni Pcna is mono-ubiquitinated through rad6 and rad18, modified by lysine-63-linked multi-ubiquitination--which additionally requires mms2, ubc13 and rad5--and is conjugated to sumo by ubc9. The first of these is monoubiquitination of lysine 164 on one or more of the pcna subunits by the e2-e3 complex of rad6-rad18. 0.477 SIGNOR-187761 FGF14 protein Q92915 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.282 SIGNOR-253417 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 BTO:0000007 14983059 YES gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. 0.408 SIGNOR-122978 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 11108261 YES lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. 0.765 SIGNOR-84963 EXTL1 protein Q92935 UNIPROT SHH protein Q15465 UNIPROT down-regulates binding 9606 BTO:0000142 15614771 YES gcesareni A study in mice suggests that ext1 proteins might negatively regulate shh signaling by synthesizing hspgs, which sequester the ligand 0.295 SIGNOR-132606 GLS2 protein Q9UI32 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 22049910 YES miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. 0.8 SIGNOR-266911 PRKACA protein P17612 UNIPROT AANAT protein Q16613 UNIPROT up-regulates activity phosphorylation Ser205 HPFLRRNsGC -1 11336675 YES miannu AANAT1–207 was phosphorylated in vitro at both PKA sites, Thr-31 and Ser-205. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations.  0.321 SIGNOR-250324 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr742 HMVQTNHyQVSGYPG 9606 BTO:0000195 17289681 YES The effect has been demonstrated using P34152-3 gcesareni We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress. 0.648 SIGNOR-152967 SKP2 protein Q13309 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates ubiquitination 9606 15998794 YES gcesareni Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. 0.771 SIGNOR-138490 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189930 STAT1/STAT3 complex SIGNOR-C118 SIGNOR JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR form complex binding 10090 15284024 YES lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. 0.794 SIGNOR-235658 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 YES gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. 0.681 SIGNOR-253000 BRCA1-B complex complex SIGNOR-C298 SIGNOR G1/S_transition_checkpoint phenotype SIGNOR-PH147 SIGNOR up-regulates 25400280 NO lperfetto Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation 0.7 SIGNOR-263225 SMAD4 protein Q13485 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR form complex binding 9606 9436979 YES lperfetto Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. 0.67 SIGNOR-103618 PP1 proteinfamily SIGNOR-PF54 SIGNOR NEK2 protein P51955 UNIPROT down-regulates dephosphorylation 9606 17283141 YES lperfetto Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1 0.2 SIGNOR-264667 MICU2 protein Q8IYU8 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.657 SIGNOR-270860 POT1/ACD complex SIGNOR-C64 SIGNOR Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 15383534 YES lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. 0.858 SIGNOR-263318 RPRD1B protein Q9NQG5 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004953 30518842 YES lperfetto These results indicated that CREPT regulates the Cyclin B1 expression via directly targeting its promoter region during transcription. 0.2 SIGNOR-265500 CDC14B protein O60729 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT unknown dephosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 YES Here, we demonstrate that SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1, and dephosphorylated by the phosphatases CDC14A and CDC14B. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation|Additionally, we found that SIRT2, like other Cdk1 targets, can be dephosphorylated by the phosphatases CDC14A and CDC14B. In contrast to a published report (8), we did not observe any degradation of SIRT2 by the 26 S proteasome in response to CDC14B overexpression|However, we cannot exclude the possibility that phosphorylation of serine 368 might affect the activity of SIRT2 on other unidentified acetylated substrates. 0.407 SIGNOR-248338 KMT2A protein Q03164 UNIPROT KAT8 protein Q9H7Z6 UNIPROT up-regulates binding 9606 15960975 YES miannu Mll1 and mof can form a stable complex in vivo / given that an interaction of dmof with msl1 through its zinc finger is essential for correct targeting of mof to the male x chromosome 0.486 SIGNOR-138245 ADAMTS13 protein Q76LX8 UNIPROT VWF protein P04275 UNIPROT down-regulates activity cleavage 9606 23020315 YES miannu Proteolytic degradation of VWF by ADAMTS-13 downregulates the proinflammatory potential of VWF.  0.6 SIGNOR-251966 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide chemical CHEBI:95008 ChEBI BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 Other YES The effect has been demonstrated using Q07817-1 gcesareni 0.8 SIGNOR-207462 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.34 SIGNOR-250907 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 10197981 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 0.745 SIGNOR-66749 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.741 SIGNOR-178367 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT down-regulates activity phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 YES lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. 0.386 SIGNOR-249187 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr387 VYFTYDPySEEDPDE -1 10214954 YES Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. 0.643 SIGNOR-251377 PRKAA1 protein Q13131 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr101 IVLNKGKtIFRFSAT 9606 BTO:0002181 30759345 YES miannu AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5. 0.2 SIGNOR-277432 CDK5R1 protein Q15078 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates binding 9606 15013773 YES miannu In brain, p35 or p25 exists with and activates cdk5 0.943 SIGNOR-123387 MAPK1 protein P28482 UNIPROT STIM1 protein Q13586 UNIPROT up-regulates phosphorylation Ser575 LVEKLPDsPALAKKA 9606 BTO:0000222 22298426 YES gcesareni The netrin-2-mediated nfatc3 activation was coincident with robust interactions between cdo and stim1 in myoblasts and the erk-mediated stim1 phosphorylation at serine 575 0.351 SIGNOR-192788 MAX protein P61244 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 8425218 YES esanto In vivo transactivation assays suggest that myc-max and mad-max complexes have opposing functions in transcription and that max plays a central role in this network of transcription factors 0.743 SIGNOR-39137 SRC protein P12931 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 15320955 YES llicata C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases. 0.67 SIGNOR-128273 SMUG1 protein Q53HV7 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275712 TUBB protein P07437 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 17429065 YES lperfetto Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. 0.2 SIGNOR-232113 BCORL1 protein Q5H9F3 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity binding 9606 BTO:0000567 17379597 YES irozzo BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor. 0.481 SIGNOR-259114 MAP3K6 protein O95382 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 RHTDDEMtGYVATRW 9534 8622669 YES Manara These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase 0.2 SIGNOR-260916 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 NO miannu The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m. 0.359 SIGNOR-254658 MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 NO Simone Vumbaca Finally, MRF4 may be responsible for the final myogenic events of the fully differentiated myofiber 0.7 SIGNOR-255645 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194922 VASP protein P50552 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 NO miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. 0.7 SIGNOR-268390 CSNK2A1 protein P68400 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates phosphorylation Thr2159 NGATEQRtSSKESSP 9606 BTO:0000938 17088250 YES miannu We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment. 0.334 SIGNOR-150471 SESN1 protein Q9Y6P5 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR down-regulates activity binding 10090 BTO:0002572 25457612 YES We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2 0.429 SIGNOR-253559 RAG2 protein P55895 UNIPROT MTOR protein P42345 UNIPROT up-regulates relocalization 9606 22790199 YES gcesareni Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated. 0.267 SIGNOR-198245 MTOR protein P42345 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates activity phosphorylation Ser550 KITSLSSsLDTSLDF 9606 BTO:0001938 26139536 YES miannu MTOR phosphorylates UVRAG at serine 550 and serine 571 0.408 SIGNOR-276920 MAP3K20 protein Q9NYL2 UNIPROT ARHGDIB protein P52566 UNIPROT down-regulates activity phosphorylation 9606 19272173 YES miannu In the present study, we provide evidence that ZAK serves as a RhoGDIbeta kinase, and demonstrate the phosphorylation of RhoGDIbeta by ZAK in vitro, as well as the physical association between ZAK and RhoGDIbeta.|These two proteins could negatively regulate one another such that ZAK suppresses RhoGDIbeta functions through phosphorylation and RhoGDIbeta counteracts the effects of ZAK by physical interaction. 0.2 SIGNOR-279633 Vincristine sulfate chemical CHEBI:79401 ChEBI TUBB4A protein P04350 UNIPROT down-regulates activity chemical inhibition 9606 30599272 YES miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 0.8 SIGNOR-259250 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 YES The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. 0.2 SIGNOR-164671 BCLAF1 protein Q9NYF8 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17938203 NO Luana These results demonstrate that Btf positively regulates TP53 expression through CPE-TP53. 0.413 SIGNOR-261568 ACD protein Q96AP0 UNIPROT RPA1 protein P27694 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 YES lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA 0.2 SIGNOR-263328 AKT2 protein P31751 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 YES gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf 0.272 SIGNOR-78681 Caspase 3 complex complex SIGNOR-C221 SIGNOR IL18 protein Q14116 UNIPROT up-regulates activity cleavage Asp76 MTDSDCRdNAPRTIF 9606 BTO:0001370 9334240 YES lperfetto Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells.|Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. 0.484 SIGNOR-256379 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 10090 23729744 YES apalma Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster) 0.739 SIGNOR-255371 CSNK2A2 protein P19784 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser263 GEDTLSDsDDEDDEE -1 1425701 YES llicata Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263. 0.368 SIGNOR-251015 SRC protein P12931 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates activity phosphorylation Tyr99 REMLEGFyEEISKGR 10090 24331927 YES miannu Our results show that only Src can efficiently phosphorylate FHOD1 at Y99 to enable the downstream activation by ROCK. 0.307 SIGNOR-276612 HOXA9 protein P31269 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 YES 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. 0.621 SIGNOR-241162 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 15592458 YES gcesareni Here, we report that the 45-kda variant of the protein tyrosine phosphatase tcptp (tc45) can recognize delta egfr as a cellular substrate 0.634 SIGNOR-132316 GSK3A protein P49840 UNIPROT GYS1 protein P13807 UNIPROT down-regulates phosphorylation Ser641 YRYPRPAsVPPSPSL 9606 BTO:0000887;BTO:0001103 14593110 YES gcesareni Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase 0.412 SIGNOR-118927 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 20626350 YES gcesareni Msk (mitogen- and stress-activated kinase) 1 and 2 can directly phosphorylate and activate transcription factors such as creb, atf1, the nf- b isoform p65 and stat (signal transducer and activator of transcription) 1 and 3 0.386 SIGNOR-166664 TGFBR1 protein P36897 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 10090 BTO:0005065 17673906 YES lperfetto We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases. 0.547 SIGNOR-227503 GSK3B protein P49841 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser129 QKRREILsRRPSYRK 10116 12162494 YES GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant 0.69 SIGNOR-251233 ERBB2 protein P04626 UNIPROT MSI1 protein O43347 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20443831 NO gcesareni We investigated the possibilities that erbb2 may regulate downstream mediators of notch1 signaling to induce musashi1 (which enhances notch1 signaling). 0.266 SIGNOR-165195 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT up-regulates quantity by stabilization 9606 32644488 NO lperfetto VWF plays a crucial role in hemostasis through platelet adhesion facilitation and coagulation factor VIII stabilization 0.788 SIGNOR-261865 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0003807 11971971 YES lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. 0.2 SIGNOR-244792 PRKCD protein Q05655 UNIPROT NCF4 protein Q15080 UNIPROT up-regulates activity phosphorylation Thr154 LRRLRPRtRKVKSVS 9606 BTO:0000738 9804763 YES lperfetto P40(phox) is phosphorylated on threonine 154 and serine 315 during activation of the phagocyte NADPH oxidase. Implication of a protein kinase c-type kinase in the phosphorylation process. 0.355 SIGNOR-249012 PIM proteinfamily SIGNOR-PF34 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000785 18467333 YES gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. 0.2 SIGNOR-259434 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT up-regulates phosphorylation Tyr342 RLIKEDVyLSHDHNI 9606 BTO:0000150 12121988 YES miannu Autophosphorylation increases enzyme activity of wild-type brk but not of a y342a mutant form of brk. 0.2 SIGNOR-90604 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 23422745 YES gcesareni The phosphorylation of atr and atm substrates, chk1, chk2, h2ax, and brca1 was significantly reduced or abrogated in mutant cells. 0.8 SIGNOR-201050 IRX1 protein P78414 UNIPROT ANPEP protein P15144 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. 0.2 SIGNOR-261663 ID1 protein P41134 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0004136 26084673 YES apalma We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation; 0.334 SIGNOR-255942 DUSP9 protein Q99956 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 21908610 YES gcesareni In addition, although mutation of ser-58 to either alanine or glutamic acid does not affect the intrinsic catalytic activity of dusp9/mkp-4, phospho-mimetic (ser-58 to glu) substitution inhibits both the interaction of dusp9/mkp-4 with erk2 and p38? In vivo and its ability to dephosphorylate and inactivate these map kinases. 0.698 SIGNOR-176586 PHLPP2 protein Q6ZVD8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 YES gcesareni Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt. 0.772 SIGNOR-135046 MMP19 protein Q99542 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage -1 10922468 YES lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function 0.4 SIGNOR-266980 MAP3K1 protein Q13233 UNIPROT CRTC1 protein Q6UUV9 UNIPROT up-regulates phosphorylation 9606 18784253 YES miannu We report on the activation oftorc1through mekk1-mediated phosphorylation. 0.322 SIGNOR-180816 mTORC1 complex SIGNOR-C3 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR down-regulates 9606 23863160 NO lperfetto Historically, it was known that autophagy was switched off when mTORC1 was active and that inhibition of mTORC1 was a potent autophagy inducer. 0.7 SIGNOR-209922 RPA2 protein P15927 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates binding 9606 20068082 YES gcesareni Ssdna lesions are then coated by replication protein a (rpa), recruiting atr/atrip (atr-interacting protein) complexes via recognition and association of rpa-ssdna by atrip. 0.685 SIGNOR-163176 OSM protein P13725 UNIPROT OSMR protein Q99650 UNIPROT up-regulates binding 9606 16286453 YES gcesareni The oncostatin m receptor (osmr) is part of receptor complexes for oncostatin m and interleukin-31. 0.792 SIGNOR-141588 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Tyr435 ARPVKGAyREHPYGR 9606 16179349 YES lperfetto We show that BRK phosphorylates Sam68 on all three tyrosines in the nuclear localization signal. 0.747 SIGNOR-249293 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11101851 YES gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. 0.923 SIGNOR-84827 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(His) smallmolecule CHEBI:29178 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269488 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1407 KSQNSQEsTADESED 9606 12086603 YES lperfetto These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint 0.788 SIGNOR-90117 GNB1 protein P62873 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000938 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.563 SIGNOR-145119 SFPQ protein P23246 UNIPROT TOP1 protein P11387 UNIPROT up-regulates binding 9606 9756848 YES miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i 0.372 SIGNOR-60563 HUWE1 protein Q7Z6Z7 UNIPROT POLL protein Q9UGP5 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys273 AYSVQGDkWRALGYA 9606 BTO:0000567 22203964 YES miannu We found that Pol λ can be ubiquitinated by the E3 ligase Mule in vitro and in vivo and that this interaction is functionally connected to the phosphorylation-dependent stabilization of Pol λ by Cdk2/cyclinA.  0.309 SIGNOR-272905 monoisononyl phthalate chemical CHEBI:132593 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268780 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation 9606 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). 0.91 SIGNOR-175288 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser294 RAANLWPsPLMIKRS 9606 BTO:0000150 23390529 YES lperfetto The pi3k/akt pathway is necessary to activate cdk2, which phosphorylates eralphaser294, and mediates the binding between pin1 and eralpha 0.478 SIGNOR-200867 PRKCA protein P17252 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 BTO:0000007 20110267 YES llicata Phosphorylation of nadph oxidase activator 1 (noxa1) on serine 282 by map kinases and on serine 172 by protein kinase c and protein kinase a prevents nox1 hyperactivation. 0.291 SIGNOR-163667 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr941 EETGTEEyMKMDLGP 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). 0.868 SIGNOR-157754 bisphenol A chemical CHEBI:33216 ChEBI TPO protein P07202 UNIPROT down-regulates activity chemical inhibition -1 17379648 YES miannu Half-maximal inhibition of TPO by BPA and F21388 occurred at 174 and 37.5 mol/liter in the guaiacol assay. 0.8 SIGNOR-268786 PIM proteinfamily SIGNOR-PF34 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17643117 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. 0.2 SIGNOR-259409 CDK1 protein P06493 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser104 FSFDTDRsPAPMSCD 9606 22071694 YES lperfetto Furthermore, active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro and Serine 44 on BimL has been identified as a Cdk1 phosphorylation site. Collectively, these results suggest that Cdk1/cyclin B1-dependent hyper-phosphorylation of Bim during prolonged mitotic arrest is an important cell death signal. 0.405 SIGNOR-267985 PROK2 protein Q9HC23 UNIPROT PROKR2 protein Q8NFJ6 UNIPROT up-regulates binding 9606 12024206 YES gcesareni We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2) 0.664 SIGNOR-87919 CHEK2 protein O96017 UNIPROT PSME3 protein P61289 UNIPROT up-regulates activity phosphorylation Ser247 EKIKRPRsSNAETLY 9606 BTO:0001938 25361978 YES miannu REGγ interacts with DBC1 and is phosphorylated by Chk2. 0.349 SIGNOR-273611 ABL1 protein P00519 UNIPROT PRDX2 protein P32119 UNIPROT down-regulates activity phosphorylation Tyr193 NVDDSKEyFSKHN -1 20178744 YES miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. 0.284 SIGNOR-276280 nepicastat chemical CHEBI:139334 ChEBI DBH protein P09172 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194625 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity 9606 17715225 NO miannu SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7. 0.2 SIGNOR-262503 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-200030 RRAGC protein Q9HB90 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates binding 9606 20006481 YES lperfetto Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor. 0.698 SIGNOR-217547 HASPIN protein Q8TF76 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Thr4 tKQTARKS 9606 20705812 YES miannu Here we show that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is necessary for CPC accumulation at centromeres and that the CPC subunit Survivin binds directly to H3T3ph. 0.2 SIGNOR-275428 SKI protein P12755 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 10575014 YES lperfetto Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling. 0.727 SIGNOR-232123 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 NO lperfetto The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. 0.7 SIGNOR-272278 NCOA1 protein Q15788 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 BTO:0000149 12954634 YES miannu Ncoa-1/src-1 is an essential coactivator of stat5 that binds to the fdl motif in the alpha-helical region of the stat5 transactivation domain. 0.406 SIGNOR-100258 CIITA protein P33076 UNIPROT HLA-A protein P04439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 10329350 NO Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression. 0.517 SIGNOR-254020 FOXO3 protein O43524 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14976264 NO lperfetto Sirt1 inhibited foxo3's ability to induce cell death. 0.7 SIGNOR-256645 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser750 QTEEEEHsCLEQAS 9606 SIGNOR-C14 SIGNOR-C14 10195894 YES lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response 0.2 SIGNOR-66352 POGLUT1 protein Q8NBL1 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates glycosylation 9606 22872643 YES O-glycosilation gcesareni O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus. 0.605 SIGNOR-254319 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH24 protein Q86UP0 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265840 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10085134 YES Amphiregulin is an autocrine growth factor gcesareni The epidermal growth factor receptor (EGFR) mediates the actions of a family of bioactive peptides that include epidermal growth factor (EGF) and amphiregulin (AR) 0.771 SIGNOR-65576 (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide chemical CHEBI:131158 ChEBI APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206850 TERF2 protein Q15554 UNIPROT Shelterin complex complex SIGNOR-C306 SIGNOR form complex binding 9606 BTO:0000567 15383534 YES lperfetto Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins. 0.808 SIGNOR-263317 SREBF1 protein P36956 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 YES gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) 0.29 SIGNOR-142297 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT down-regulates phosphorylation 9606 18042454 YES miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. 0.26 SIGNOR-159438 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 10090 22848740 YES When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form. 0.41 SIGNOR-255756 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation Ser1452 LPSSSPRsPSGLRPR 9606 BTO:0000007 32294430 YES done miannu We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452.  0.406 SIGNOR-274102 CDK5 protein Q00535 UNIPROT APP protein P05067 UNIPROT unknown phosphorylation Thr743 VEVDAAVtPEERHLS 10116 BTO:0000938 10936190 YES llicata In vitro, active cyclin-dependent kinase 5 (Cdk5) phosphorylated the cytoplasmic domain of APP at Thr(668). Treatment of mature neurons with an antisense oligonucleotide to Cdk5 suppressed Cdk5 expression and significantly diminished the level of phosphorylated APP. The expression of APP was unaffected in antisense-treated neurons. These results indicate that in neurons APP is phosphorylated by Cdk5, and that this may play a role in its localization. 0.566 SIGNOR-250651 DUSP5 protein Q16690 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 10224087 YES gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway 0.759 SIGNOR-67358 Ub:E2 complex SIGNOR-C497 SIGNOR NFXL1 protein Q6ZNB6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271175 CSNK2A3 protein Q8NEV1 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 YES lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. 0.269 SIGNOR-275743 SRSF11 protein Q05519 UNIPROT APOE protein P02649 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 10090 31269452 YES miannu We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling. 0.2 SIGNOR-269671 CNTF protein P26441 UNIPROT CRLF1 protein O75462 UNIPROT up-regulates binding 9606 11294841 YES lperfetto We recently demonstrated that cardiotrophin-like cytokine (clc) associates with the soluble orphan receptor cytokine-like factor-1 (clf) to form a heterodimeric cytokine that displayed activities only on cells expressing the tripartite cntf receptor on their surface 0.391 SIGNOR-106635 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193549 SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0003298 26893351 YES In adipocytes, in addition to the direct regulation of PPARγ andC/EBP expression, we showed that SOX6 inhibitsWNT signaling by binding to β-catenin, potentially leading to its degradation 0.653 SIGNOR-255825 TNPO1 protein Q92973 UNIPROT PER1 protein O15534 UNIPROT up-regulates activity relocalization 9606 29377895 YES lperfetto The non-classical nuclear import carrier Transportin 1 modulates circadian rhythms through its effect on PER1 nuclear localization 0.269 SIGNOR-262102 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH15 protein P55291 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265832 PD173074 chemical CHEBI:63448 ChEBI FGFR3 protein P22607 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205728 RELA protein Q04206 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20975042 YES svumbaca In addition, we show that the transcription of IL1B depends on a positively acting p65/c-Rel/ikbb complex 0.553 SIGNOR-256237 DPF2 protein Q92785 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity binding 9606 24332853 YES miannu The interaction between RUNX1 and DPF2 is dependent on the RUNX1 methylation status 0.2 SIGNOR-261966 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 YES lperfetto Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity 0.2 SIGNOR-236506 HSD17B11 protein Q8NBQ5 UNIPROT androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363 30943210 YES lperfetto Testicular 17betaHSD3 converts DHEA to androstenediol and androstenedione to testosterone 0.8 SIGNOR-268660 NTRK1 protein P04629 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12446789 YES gcesareni Grit translocation was regulated by receptor stimulation 0.601 SIGNOR-95809 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). 0.868 SIGNOR-157750 JMJD1C protein Q15652 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 32034158 YES miannu We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state. 0.2 SIGNOR-265171 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser759 REFAKFQsERSRARY 9606 20507994 YES llicata Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration. 0.452 SIGNOR-165702 TIMM22 protein Q9Y584 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 YES lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). 0.677 SIGNOR-267706 PRKACA protein P17612 UNIPROT CDK16 protein Q00536 UNIPROT down-regulates phosphorylation Ser153 SRRLRRVsLSEIGFG 9606 BTO:0000142 22184064 YES llicata Here, we report that cdk16 is activated by membrane-associated cyclin y (ccny). Treatment of transfected human cells with the protein kinase a (pka) activator forskolin blocked, while kinase inhibition promoted, ccny-dependent targeting of cdk16-green fluorescent protein (gfp) to the cell membrane. Ccny binding to cdk16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential pka phosphorylation site. 0.315 SIGNOR-191623 ECM stimulus SIGNOR-ST20 SIGNOR A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259046 SP7 protein Q8TDD2 UNIPROT IFITM5 protein A6NNB3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23530031 NO miannu Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation. 0.365 SIGNOR-254219 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser531 RTHSAGTsPTITHQK -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251297 PLK4 protein O00444 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser325 PTTVNKRsVNVNAAS 33351100 YES lperfetto We found that PLK4-mediated phosphorylation of NEDD1 at its S325 amino acid residue directly promotes both NEDD1 binding to SAS-6 and recruiting SAS-6 to the centrosome. |Collectively, our results demonstrate that PLK4-regulated NEDD1 facilitates initiation of the cartwheel assembly and of daughter centriole biogenesis in mammals. 0.592 SIGNOR-272996 TP53 protein P04637 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15377670 NO miannu We isolated a p53-regulated gene named ndrg1 (n-myc down-regulated gene 1). Its expression is induced by dna damage in a p53-dependent fashion. 0.527 SIGNOR-129183 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HES1 protein Q14469 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001938 24300895 NO These data indicate that basal NFκB activity at the conserved +26/+34 site of the HES1 gene promotes its expression, and that glucocorticoids can silence HES1 by inhibiting this activity. 0.2 SIGNOR-253063 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser18 SPADDSLsNSEEEPD 9606 21559372 YES llicata Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist. 0.2 SIGNOR-173668 SRC protein P12931 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates activity phosphorylation Tyr2217 ELQDSRVyVSSL 9606 BTO:0000007 17942635 YES miannu Cotransfection of human embryonic kidney (HEK)-293 cells with hCa(v)1.2b and c-Src resulted in tyrosine phosphorylation of the calcium channel, which was prevented by nitration of tyrosine residues by peroxynitrite. Whole cell calcium currents were reduced by 58 + 5% by the Src kinase inhibitor PP2 and 64 + 6% by peroxynitrite.  0.444 SIGNOR-276081 SRC protein P12931 UNIPROT CDCP1 protein Q9H5V8 UNIPROT unknown phosphorylation Tyr734 KDNDSHVyAVIEDTM 9606 14739293 YES lperfetto Phosphorylation of gp140 and p80 are mediated by Src family kinases at multiple Tyr residues including Tyr(734). 0.53 SIGNOR-246457 PTGIR protein P43119 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256949 MYC protein P01106 UNIPROT SFRP1 protein Q8N474 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004896; BTO:0004300 17485441 NO gcesareni c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity 0.356 SIGNOR-245360 NDUFB2 protein O95178 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 0.785 SIGNOR-262165 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates activity phosphorylation Ser196 RSLEVWGsQEALEEA 9606 30327428 YES ATR mediated phosphorylation of XPA on S196 enhances cAMP-mediated optimization of NER, and is promoted by SIRT1-mediated deacetylation of XPA on K63, K67 and K215. 0.493 SIGNOR-258985 SMAD7 protein O15105 UNIPROT TAB3 protein Q8N5C8 UNIPROT up-regulates binding 9606 17384642 YES gcesareni The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling. 0.383 SIGNOR-153920 IGFBP5 protein P24593 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity 10090 BTO:0000165 18762576 NO These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop. 0.7 SIGNOR-255940 CDK19 protein Q9BWU1 UNIPROT PAK1 protein Q13153 UNIPROT unknown phosphorylation Ser174 TPAVPPVsEDEDDDD 9606 19520772 YES llicata Here, we identified p21 activated kinase 1 (pak1) as a new cdk11(p58) substrate and we mapped a new phosphorylation site of ser174 on pak1 0.332 SIGNOR-185000 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ASB2 protein Q96Q27 UNIPROT up-regulates activity phosphorylation Ser371 RIRRSGVsPLHLAAE 24044920 YES lperfetto Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. |Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation. 0.2 SIGNOR-272239 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Thr540 KRLSRSVtMRKSQRS -1 21642394 YES miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. 0.2 SIGNOR-276330 DNMT3B protein Q9UBC3 UNIPROT DPP6 protein P42658 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000596 23409053 YES lperfetto In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells. 0.327 SIGNOR-268964 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8557118 YES gcesareni PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. 0.365 SIGNOR-243199 HAP1 protein P54257 UNIPROT KIF5C protein O60282 UNIPROT up-regulates activity binding 9606 31757889 YES miannu HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro 0.402 SIGNOR-264062 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRB3 protein P79483 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 YES miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. 0.2 SIGNOR-271410 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Thr643 EELNKRQtQKDLEHA 9606 17396146 YES gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. 0.418 SIGNOR-154171 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 20956975 YES fspada Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (gr) in adipogenesis have not been well characterized yet. Here, we show that inhibition of gr activity using the gr antagonist ru486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (mef) differentiation into adipocytes 0.8 SIGNOR-168562 spiperone chemical CHEBI:9233 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258894 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Ser544 RSVTMRKsQRSSKGS -1 21642394 YES miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. 0.2 SIGNOR-276331 Class I MHC:Antigen complex SIGNOR-C426 SIGNOR TCR complex SIGNOR-C153 SIGNOR up-regulates activity binding 9606 31001252 YES scontino The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes. 0.2 SIGNOR-267993 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 17158707 YES lperfetto The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity 0.2 SIGNOR-53784 PRKCA protein P17252 UNIPROT GRIN2A protein Q12879 UNIPROT unknown phosphorylation Ser1416 ASYCSRDsRGHNDVY 10116 11104776 YES lperfetto PKC-dependent phosphorylation of NR2A(Ser(1416)) as a key mechanism in inhibiting alphaCaMKII-binding and promoting dissociation of alphaCaMKII.NR2A complex. 0.505 SIGNOR-249065 YAP1 protein P46937 UNIPROT TUBB protein P07437 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276571 HPS5 protein Q9UPZ3 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR form complex binding 9606 15030569 YES lperfetto Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS7 0.705 SIGNOR-260689 C1QA protein P02745 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR form complex binding -1 29449492 YES lperfetto C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1). 0.645 SIGNOR-263390 MAPK1 protein P28482 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser257 ESHPKPSsPRQESTR 10090 BTO:0000944 15060146 YES miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. 0.318 SIGNOR-260087 RXRA protein P19793 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.681 SIGNOR-16668 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Thr355 NFSSSPStPVGSPQG 9606 19801649 YES llicata Mlk2 inhibits e47 transactivation activity on the trkb promote 0.2 SIGNOR-161544 FYN protein P06241 UNIPROT NOX4 protein Q9NPH5 UNIPROT down-regulates activity phosphorylation Tyr566 LSNQNNSyGTRFEYN -1 27525436 YES miannu We found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. 0.271 SIGNOR-277273 KDM4B protein O94953 UNIPROT TP53I3 protein Q53FA7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 NO miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. 0.2 SIGNOR-263731 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206133 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr1009 LDTSSVLyTAVQPNE 9606 1396585 YES llicata These data show that tyrosine phosphorylation of plc-gamma is dependent on autophosphorylation of the pdgf beta-receptor at tyr1009 and tyr1021. 0.2 SIGNOR-18575 SPI1 protein P17947 UNIPROT EGR2 protein P11161 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16923394 NO miannu PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation 0.371 SIGNOR-256040 DYNLL2 protein Q96FJ2 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates binding 9606 20921139 YES gcesareni The beclin 1 vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1 interacting protein ambra1 and dynein light chains 1/2 0.461 SIGNOR-168289 ATM protein Q13315 UNIPROT KHSRP protein Q92945 UNIPROT up-regulates phosphorylation Ser274 MILIQDGsQNTNVDK 9606 21329876 YES lperfetto The atm kinase directly binds to and phosphorylates ksrp, leading to enhanced interaction between ksrp and pri-mirnas and increased ksrp activity in mirna processing 0.423 SIGNOR-172123 UMPS protein P11172 UNIPROT UMP smallmolecule CHEBI:16695 ChEBI up-regulates quantity chemical modification 9606 2912371 YES miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). 0.8 SIGNOR-267440 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR LATS2 protein Q9NRM7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0005907 25026211 YES miannu CRL4 DCAF1 ubiquitylates and inhibits Lats. 0.2 SIGNOR-272230 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser8 MPLNRTLsMSSLPGL -1 2117608 YES miannu Phosphorylation of rabbit muscle glycogen synthase by cyclic AMP-dependent protein kinase has been shown to enhance subsequent phosphorylation by casein kinase I . phosphorylation at Ser7 is required for modification of Ser10 by casein kinase I. 0.507 SIGNOR-249988 TCF3 protein P15923 UNIPROT CR2 protein P20023 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11739509 NO miannu We have previously described the presence of an intronic element that is required for both cell- and stage-specific expression of CR2. In this study, we report the identification of a cell type-specific repressor element within the proximal promoter. By supershift analysis this element binds members of the basic helix-loop-helix family of proteins, in particular E2A gene products. Mutational analysis demonstrates that binding of E2A proteins is critical for functioning of this repressor. Thus, E2A activity is key not only for early B cell development, but also for controlling CR2 expression, a gene expressed only during later stages of ontogeny. 0.281 SIGNOR-255387 CCKBR protein P32239 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.507 SIGNOR-257412 PAX3 protein P23760 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 NO gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. 0.479 SIGNOR-181621 PCSK1 protein P29120 UNIPROT Corticotropin protein P01189-PRO_0000024969 UNIPROT up-regulates quantity cleavage 24631756 YES lperfetto POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide 0.2 SIGNOR-268724 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr320 RKDTKEIyTHFTCAT -1 33139573 YES miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. 0.462 SIGNOR-277228 SMOC1 protein Q9H4F8 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 NO lperfetto The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells 0.2 SIGNOR-260402 AMPK complex SIGNOR-C15 SIGNOR RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser635 DTHFRSPsSSVGSPP 9606 19815529 YES lperfetto We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635). 0.283 SIGNOR-216592 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 19574738 YES gcesareni Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c 0.858 SIGNOR-186621 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18468895 YES Luana Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors 0.8 SIGNOR-257943 UBR5 protein O95071 UNIPROT SOX2 protein P48431 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys115 YKYRPRRkTKTLMKK 9606 BTO:0002428 30894683 YES miannu We identified UBR5 as a major ubiquitin E3 ligase that induces SOX2 degradation through ubiquitinating SOX2 at lysine 115. 0.256 SIGNOR-277446 GSK3B protein P49841 UNIPROT TCAP protein O15273 UNIPROT down-regulates quantity by destabilization phosphorylation Ser157 GALRRSLsRSMSQEA 9606 32937135 YES lperfetto GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites. 0.2 SIGNOR-264852 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 19881549 YES lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis 0.703 SIGNOR-236318 CHMP6 protein Q96FZ7 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.672 SIGNOR-265526 SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR RORC protein P51449 UNIPROT up-regulates 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. 0.438 SIGNOR-255026 TGFB1 protein P01137 UNIPROT CDK4 protein P11802 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000763 8402878 NO gcesareni Here we show that tgf beta 1 induces suppression of cdk4 synthesis in g1 in mink lung epithelial cells. 0.282 SIGNOR-39045 Ub:E2 complex SIGNOR-C497 SIGNOR ZNF521 protein Q96K83 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271103 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser5 sESFTMAS 9606 19647517 YES lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry 0.962 SIGNOR-187396 CEBPA protein P49715 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 NO miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. 0.49 SIGNOR-253830 PDGFRA protein P16234 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 7535778 YES miannu Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production. 0.649 SIGNOR-28176 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR PDE5A protein O76074 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 30896450 YES miannu RhoBTB1 augmented the cGMP response to nitric oxide by restraining the activity of phosphodiesterase 5 (PDE5) by acting as a substrate adaptor delivering PDE5 to the Cullin-3 E3 Ring ubiquitin ligase complex for ubiquitination inhibiting PDE5. 0.2 SIGNOR-272314 RIMBP3C protein A6NJZ7 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.265 SIGNOR-264362 HCRTR1 protein O43613 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256876 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR LATS1 protein O95835 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0005907 25026211 YES miannu CRL4 DCAF1 ubiquitylates and inhibits Lats. 0.361 SIGNOR-272229 tolcapone chemical CHEBI:63630 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition 9606 9681662 YES Simone Vumbaca Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P=0.008), respectively, in the liver; consistent results were obtained with the other tissues. 0.8 SIGNOR-261091 GATA1 protein P15976 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8195185 NO irozzo Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3. 0.502 SIGNOR-256051 TNFRSF17 protein Q02223 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 10903733 NO miannu Overexpression of bcma activates the p38 mapk 0.2 SIGNOR-79498 BS-181 hydrochloride chemical CID:49867928 PUBCHEM CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190783 HIF1A protein Q16665 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity transcriptional regulation 9606 8387214 YES Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription. 0.773 SIGNOR-256592 NANOG protein Q9H9S0 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16840789 YES Luana We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog.  0.2 SIGNOR-266080 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 21902831 YES lperfetto Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation. 0.523 SIGNOR-216706 RABGEF1 protein Q9UJ41 UNIPROT RAB5A protein P20339 UNIPROT up-regulates binding 9606 11452015 YES miannu We have previously shown that rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of rabex-5, a rab5 nucleotide exchange factor, and the effector rabaptin-5. 0.923 SIGNOR-109398 JUN protein P05412 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 23151663 NO amattioni Planar cell polarity (PCP) signalling is prominently involved in the regulation of cell polarity, cell motility and morphogenetic movements, throught the activation of JUN transcription factor. 0.7 SIGNOR-229760 FZR1 protein Q9UM11 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates activity binding 9606 19822757 YES lperfetto Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity 0.76 SIGNOR-265081 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000150 22418700 YES gcesareni Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members. 0.8 SIGNOR-259442 INTS8 protein Q75QN2 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.742 SIGNOR-261472 MAPK3 protein P27361 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 12792650 YES lperfetto Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk 0.536 SIGNOR-101548 TFAP4 protein Q01664 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 19505873 NO miannu AP-4 Mediates E-box-dependent Complex Formation for Transcriptional Repression of HDM2 0.2 SIGNOR-226596 MAF protein O75444 UNIPROT ETS1 protein P14921 UNIPROT down-regulates binding 9606 9566892 YES miannu Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity. 0.426 SIGNOR-56808 CHEK1 protein O14757 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity phosphorylation Ser296 GFSKHIQsNLDFSPV 8355 15707391 YES lperfetto This suggests that Ser296 is probably one of the sites autophosphorylated when Chk1 is fully activated [21], despite the sequence surrounding Ser296 (FSKHIQS296NL) being only weakly related to the optimal Chk1-recognition motif (M/I/L/V)-X-(R/K)-X-X-(S/T), where (S/T) is the phosphorylated residue 0.2 SIGNOR-219240 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser285 QRVPSYDsFDSEDYP 9606 BTO:0000782 12475968 YES lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition 0.31 SIGNOR-96342 PTPN6 protein P29350 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity dephosphorylation Tyr446 SLYSQPFyTGYFGYK 9606 BTO:0002181 32779804 YES miannu We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446. 0.2 SIGNOR-277526 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Thr1362 YEEHIPYtHMNGGKK -1 8463287 YES lperfetto Therefore, the present study directly identifies threonine 1336 in the HIR as a phosphorylation site for insulin and PMA. 0.348 SIGNOR-248933 MLH1 protein P40692 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 9500552 NO Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer 0.7 SIGNOR-257595 TAF5 protein Q15542 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.897 SIGNOR-263929 pazopanib chemical CHEBI:71219 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 YES Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. 0.8 SIGNOR-257738 ERBB4 protein Q15303 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.394 SIGNOR-146885 MORF4L1 protein Q9UBU8 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.757 SIGNOR-269299 C1QB protein P02746 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR form complex binding -1 29449492 YES lperfetto C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1). 0.647 SIGNOR-263388 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser194 NGKKKRKsLAKRIRE 9606 17540176 YES miannu Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function 0.289 SIGNOR-155353 PRKAA2 protein P54646 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 SIGNOR-C15 21459323 YES gcesareni Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372 0.328 SIGNOR-173031 HES1 protein Q14469 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 16682003 YES gcesareni Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression. 0.598 SIGNOR-146684 SETD5 protein Q9C0A6 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity methylation Lys37 APSTGGVkKPHRYRP -1 31515109 YES miannu SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. 0.2 SIGNOR-264622 cyclosporin A chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates chemical inhibition 9606 15276472 YES gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-252307 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9606191 NO lperfetto Here we report the identification of smad3/smad4 binding sequences, termed caga boxes, within the promoter of the human pai-1 gene. 0.589 SIGNOR-57776 AXIN1 protein O15169 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 10829020 YES gcesareni We found that in contrast to axin, dvl2 activation of jnk does not require mekk1. 0.516 SIGNOR-77591 MAP3K3 protein Q99759 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation 9606 12912994 YES gcesareni Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5. 0.719 SIGNOR-104637 CDH12 protein P55289 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.508 SIGNOR-265852 DCAF1 protein Q9Y4B6 UNIPROT LATS1 protein O95835 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0005907 25026211 YES miannu CRL4 DCAF1 ubiquitylates and inhibits Lats. 0.2 SIGNOR-272226 KLF2 protein Q9Y5W3 UNIPROT mir-143 mirna URS0000008A99_9606 RNAcentral up-regulates quantity transcriptional regulation 9606 25477897 YES miannu Overexpression of miR-155 leads to the activation of the PI3K-Akt pathway through negative regulation of Src Homology 2 domain-containing Inositol-5-Phosphatase (SHIP1). 0.4 SIGNOR-255769 FBXW7 protein Q969H0 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002552 phosphorylation:Ser391;Ser396 SEKGLELsPPHASEA;ELSPPHAsEASQMS 28581525 YES lperfetto CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. 0.2 SIGNOR-264898 ACSS1 protein Q9NUB1 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI down-regulates quantity chemical modification 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271830 CTCF protein P49711 UNIPROT TERT protein O14746 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16326864 YES miannu CTCF binds the proximal exonic region of hTERT and inhibits its transcription 0.328 SIGNOR-253832 BRSK1 protein Q8TDC3 UNIPROT CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 YES lperfetto Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.507 SIGNOR-124839 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser695 MSQPSTAsNSLPEPA 9606 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251281 dapagliflozin chemical CHEBI:85078 ChEBI SLC5A2 protein P31639 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191289 TP53 protein P04637 UNIPROT PMAIP1 protein Q13794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10807576 NO Nuclear p53 amattioni Expression of noxa was dependent on p53. Noxa represent a mediator of p53-dependent apoptosis. 0.7 SIGNOR-76152 agomelatine chemical CHEBI:134990 ChEBI HTR2C protein P28335 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189474 MAPK3 protein P27361 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Thr388 VYFKPSLtPSGEFRK 9606 19767751 YES llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. 0.392 SIGNOR-188147 NR5A1 protein Q13285 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 NO miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.472 SIGNOR-254869 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 9606 12058027 YES miannu In cells transfected with pkc? Or pkc? The phosphorylation of ser876 was markedly more pronounced than the phosphorylation of ser706/ser710 / the phosphorylation of ser706/ser710 in pkd2 reflects the activation of the kinase. 0.2 SIGNOR-89415 TFCP2 protein Q12800 UNIPROT TF protein P02787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20796026 NO miannu Ectopic expression of CP2 led to increased transferrin expression at both the mRNA and protein levels, whereas knockdown of CP2 down-regulated transferrin mRNA and protein expression. 0.2 SIGNOR-255429 MAP3K1 protein Q13233 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 8131746 YES lperfetto Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity. 0.66 SIGNOR-244881 ASXL1 protein Q8IXJ9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 26470845 NO lperfetto Consistently, our results show that ASXL1 mutations are associated with lower expression levels of p15INK4B and a proliferative advantage of hematopoietic progenitors in primary bone marrow cells, and that depletion of ASXL1 in multiple cell lines results in resistance to growth inhibitory signals. 0.7 SIGNOR-241614 miR-199a mirna URS0000759977_9606 RNAcentral RPS6 protein P62753 UNIPROT up-regulates activity 10090 21986534 YES This overexpression of miR-155 may suppress the expression of C/EBPβ and CREB by directly targeting their 3' untranslated regions (3' UTRs) 0.4 SIGNOR-255936 BMS-265246 chemical CID:5329775 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190431 N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide chemical CHEBI:91360 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates activity chemical inhibition -1 16162000 YES miannu A novel structural class of 4-phenyl-5-pyridyl-1,3-thiazoles was optimized as inhibitors of p38 MAP kinase and the proinflammatory cytokine TNF-α. it only significantly inhibited p38α (IC50 = 7.1 nM) and p38β (IC50 = 200 nM) in a concentration-dependent manner and was approximately 28 times more selective for p38α over p38β. 0.8 SIGNOR-262222 p38 proteinfamily SIGNOR-PF16 SIGNOR CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser491 GSCCTIMsPGEMEKH 9606 BTO:0000567 21930785 YES miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  0.2 SIGNOR-276363 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Thr336 GDDEASAtVSKTETS -1 9099669 YES lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. 0.44 SIGNOR-248969 CRBN protein Q96SW2 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR form complex binding 9606 22649780 YES gcesareni The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors 0.788 SIGNOR-234805 FOXJ3 protein Q9UPW0 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 19914232 YES Luana Foxj3 transcriptionally activates Mef2c and regulates adult skeletal muscle fiber type identity. 0.317 SIGNOR-261606 RORB protein Q92753 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24737872 YES miannu As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression. 0.478 SIGNOR-268003 MELK protein Q14680 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser169 VLRNITNsQAPDGRR 9606 15908796 YES lperfetto We demonstrate that cdc25b is phosphorylated in vitro by peg3 on serine 169this phosphorylated form of cdc25b accumulates during mitosis, and is localized to the centrosomes 0.534 SIGNOR-137378 PPP1CA protein P62136 UNIPROT NEK2 protein P51955 UNIPROT down-regulates dephosphorylation 9606 17283141 YES gcesareni Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1 0.375 SIGNOR-152949 MIR1-1 mirna URS000075CF56_9606 RNAcentral PAX7 protein P23759 UNIPROT down-regulates quantity post transcriptional regulation 9606 24708856 YES irozzo In this study, bioinformatic prediction combined with pathway analysis and validation by qRT-PCR revealed that miR-155 expression positively correlates with the expression of the AP-1 genes c-JUN and FOS, which are known to induce myeloid differentiation 0.4 SIGNOR-256124 MAP2K1 protein Q02750 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates activity phosphorylation Thr382 EFDTNYAtDDDIVFE 9606 BTO:0000007 28169830 YES Here, we show that activation of serotonin 5-HT2C receptors, which engage Erk1/2 pathway via a _-arrestin-dependent mechanism, promotes MEK-dependent _-arrestin2 phosphorylation at Thr383 0.586 SIGNOR-252027 WNT7B protein P56706 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763;BTO:0001260 15923619 YES gcesareni Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling. 0.669 SIGNOR-137931 SIRT6 protein Q8N6T7 UNIPROT TNF protein P01375 UNIPROT up-regulates deacetylation Lys20 AEEALPKkTGGPQGS 9606 23552949 YES gcesareni Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine 0.314 SIGNOR-201662 luminespib chemical CHEBI:83656 ChEBI HSP90AA1 protein P07900 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190038 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr313 SSEPVGIyQGFEKKT 9534 BTO:0000298 11381116 YES The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2). 0.525 SIGNOR-251384 Sitagliptin phosphate monohydrate chemical CID:11591741 PUBCHEM DPP4 protein P27487 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206923 SRC protein P12931 UNIPROT MMP3 protein P08254 UNIPROT up-regulates activity 23967200 NO C-Src-induced STAT3 activation regulates MMP3 levels 0.34 SIGNOR-251109 DAGLB protein Q8NCG7 UNIPROT episterol ester smallmolecule CHEBI:52393 ChEBI up-regulates quantity chemical modification 9606 26787883 YES miannu Diacylglycerol lipases (DAGLŒ± and DAGLŒ≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. 0.8 SIGNOR-264265 SOX9 protein P48436 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000849 19273910 NO miannu Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. 0.373 SIGNOR-255190 MEN1 protein O00255 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 11526476 YES miannu Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner. 0.463 SIGNOR-110067 HMGA2 protein P52926 UNIPROT E4F1 protein Q66K89 UNIPROT down-regulates binding 9606 14645522 YES miannu Here we show that hmga2 associates with the e1a-regulated transcriptional repressor p120(e4f), interfering with p120(e4f) binding to the cyclin a promoter 0.371 SIGNOR-119537 MK-8245 chemical CID:24988881 PUBCHEM SCD protein O00767 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194420 SRC protein P12931 UNIPROT GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 YES inferred from family member gcesareni These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit. 0.27 SIGNOR-270262 IFNG protein P01579 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 NO lperfetto IFN-_ induces socs1 gene expression through an inducible factor 0.554 SIGNOR-236809 CAMK1 protein Q14012 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity phosphorylation Thr157 GIRKRPAtDDSSTQN 10090 23707388 YES Monia We also demonstrate that i) CaMKI phosphorylates p27 at Thr157and Thr198 in human cells and at Thr170and Thr197in mouse cells to modulate its subcellular localization; 0.305 SIGNOR-261195 A10/b1 integrin complex SIGNOR-C167 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269016 RPS11 protein P62280 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.889 SIGNOR-262441 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249344 58131-57-0 chemical CID:42640 PUBCHEM MDM4 protein O15151 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194856 SMAD7 protein O15105 UNIPROT STRAP protein Q9Y3F4 UNIPROT up-regulates binding 9606 10757800 YES gcesareni Strap recruits smad7 to the activated type i receptor and forms a complex 0.609 SIGNOR-76771 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Ser215 PLTSPGGsPGGCPGE 9606 BTO:0001131 9630228 YES lperfetto Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4. 0.589 SIGNOR-109781 RASSF6 protein Q6ZTQ3 UNIPROT STK3 protein Q13188 UNIPROT down-regulates binding 9606 22830020 YES gcesareni When rassf 6 is bound to mst2, rassf 6 inhibits mst2 activity, thus, inhibiting its role in the hippo pathway. 0.658 SIGNOR-198463 ATR protein Q13535 UNIPROT MCC protein P23508 UNIPROT up-regulates activity phosphorylation Ser118 SELRSELsQSQHEVN 9606 BTO:0001109 21779472 YES miannu MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. 0.2 SIGNOR-273514 MAVS protein Q7Z434 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates relocalization 9606 16406812 YES gcesareni Another protein suggested to play a role in caspase-8 translocation to mitochondria is the mitochondrial membrane protein cardif 0.585 SIGNOR-143572 GSK3B protein P49841 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity phosphorylation Thr153 EALLGQAtPPGTGQF 9606 21873430 YES miannu  Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. 0.287 SIGNOR-276355 D2HGDH protein Q8N465 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity 26178471 NO lperfetto Here we show that wild-type D2HGDH elevates α-KG levels 0.8 SIGNOR-253131 SRC protein P12931 UNIPROT GLRB protein P48167 UNIPROT up-regulates phosphorylation Tyr435 RDFELSNyDCYGKPI 9606 BTO:0000938 BTO:0000142;BTO:0000671 11882681 YES gcesareni These findings indicate that glyr function is upregulated by ptks and this modulation is dependent on the tyrosine-413 residue of the beta subunit. 0.27 SIGNOR-115705 SMAD4 protein Q13485 UNIPROT SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 9436979 YES lperfetto Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. 0.2 SIGNOR-255833 MMP24 protein Q9Y5R2 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272391 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Thr27 WAKGRREtYLCYVVK 9606 18417471 YES llicata We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43 0.325 SIGNOR-178248 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL -1 SIGNOR-C3 10567431 YES lperfetto We report here that a mammalian recombinant p70alpha polypeptide, extracted in an inactive form from rapamycin-treated cells, can be directly phosphorylated by the mTOR kinase in vitro predominantly at the rapamycin-sensitive site Thr-412. mTOR-catalyzed p70alpha phosphorylation in vitro is accompanied by a substantial restoration in p70alpha kinase activity toward its physiologic substrate 0.96 SIGNOR-72357 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 YES Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo. 0.495 SIGNOR-248616 JDP2 protein Q8WYK2 UNIPROT JUN protein P05412 UNIPROT down-regulates activity binding 9606 18671972 YES miannu JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE). 0.608 SIGNOR-226398 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 23708659 YES lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. 0.2 SIGNOR-252793 IGF1R protein P08069 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity phosphorylation Tyr250 DMGHLKYyLAPKIED -1 28924044 YES miannu In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination. 0.2 SIGNOR-277252 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 1716180 YES lperfetto Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response. 0.484 SIGNOR-21320 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.7 SIGNOR-131568 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr499 EGEEQSQyMHVGSCQ 9606 11812778 YES gcesareni The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties. 0.311 SIGNOR-114645 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI AFP protein P02771 UNIPROT down-regulates quantity by repression 9606 9792724 NO miannu In this report, we show a distinctive effect of all-trans-retinoic acid (RA) in Hep3B cells. RA caused a marked decrease in AFP transcripts. 0.8 SIGNOR-254443 MAPK1 protein P28482 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser93 ALQRQPPsPKQLEEE -1 16226275 YES lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| 0.812 SIGNOR-249436 SIRT1 protein Q96EB6 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity deacetylation 9606 BTO:0001103 22395773 YES lperfetto SIRT1 controls the acetylation of FOXO transcription factors, which are important regulators of lipid and glucose metabolism as well as stress response. On the other hand, SIRT1 can also stimulate the gluconeogenic transcriptional program by deacetylating and activating FOXO1. 0.81 SIGNOR-253509 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 NO miannu Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes 0.7 SIGNOR-260441 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D4 protein O60343 UNIPROT unknown phosphorylation Thr642 QFRRRAHtFSHPPSS 9606 16880201 YES llicata 14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642. 0.2 SIGNOR-148342 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001109;BTO:0000018 19567821 YES miannu The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. 0.8 SIGNOR-262226 CDK13 protein Q14004 UNIPROT CyclinK/CDK13 complex SIGNOR-C38 SIGNOR form complex binding 9606 22012619 YES miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells 0.917 SIGNOR-176844 GNG3 protein P63215 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.383 SIGNOR-252684 AKT3 protein Q9Y243 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 YES gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. 0.261 SIGNOR-201129 Dinaciclib chemical CID:46926350 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191322 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 YES We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα 0.456 SIGNOR-256116 WT1 protein P19544 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10490105 YES lperfetto The Wilms Tumor Suppressor WT1 Encodes a Transcriptional Activator of amphiregulin 0.396 SIGNOR-251745 ACACA protein Q13085 UNIPROT Food intake phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0003336 25343030 NO miannu Leptin exerts an inhibitory effect on AMPK in the hypothalamus, thereby stimulating ACC and subsequently suppressing food intake. 0.7 SIGNOR-263509 OGA protein O60502 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR up-regulates activity deglycosylation 9606 26399441 YES lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 0.2 SIGNOR-267609 RET protein P07949 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 8183561 YES gcesareni We have shown that the sh2 domain of the adaptor protein shc coimmunoprecipitates with all the ret. 0.655 SIGNOR-36902 CDH8 protein P55286 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.677 SIGNOR-265870 ZNF148 protein Q9UQR1 UNIPROT SOX18 protein P35713 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 18496767 NO miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells 0.258 SIGNOR-254821 DNMT1 protein P26358 UNIPROT BAG1 protein Q99933 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18413740 NO lperfetto DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation 0.2 SIGNOR-254108 PPP2CA protein P67775 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT down-regulates activity dephosphorylation Thr17 MRNRRNDtLDSTRTL 9606 BTO:0000007 20110357 YES done miannu Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity. 0.2 SIGNOR-273793 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates activity chemical inhibition 9606 26347206 YES miannu Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation. 0.8 SIGNOR-259448 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1009 DESSDDDsDSEEPSK 9606 BTO:0000661 10066810 YES llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  0.435 SIGNOR-251031 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.91 SIGNOR-252822 AKT1 protein P31749 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr299 QSRKRLAtSSASSQS 9606 BTO:0002181 32123010 YES miannu Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation. 0.2 SIGNOR-277515 LRIG3 protein Q6UXM1 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates 9606 23723069 NO miannu Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors. 0.306 SIGNOR-202180 RAC1 protein P63000 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 21712438 NO gcesareni Hypertonicity activates p38 via a rac1-osm-mekk3-mkk3-p38 pathway. 0.535 SIGNOR-174602 MYCT1 protein Q8N699 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000670;BTO:0000738 30283340 NO miannu Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo 0.7 SIGNOR-261728 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates activity phosphorylation Ser299 EGEDDRDsANGEDDS 9606 15687492 YES gcesareni In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C. 0.355 SIGNOR-133536 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR JUP protein P14923 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 YES miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 0.2 SIGNOR-265819 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 11971190 YES lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation 0.2 SIGNOR-117575 EIF6 protein P56537 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR up-regulates quantity binding 9606 10085284 YES lperfetto The beta4 integrin interactor p27(BBP/eIF6) is an essential nuclear matrix protein involved in 60S ribosomal subunit assembly. 0.493 SIGNOR-269151 SOX6 protein P35712 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 NO Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. 0.311 SIGNOR-251808 MID1 protein O15344 UNIPROT HMG20B protein Q9P0W2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 28760657 YES miannu The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35. MID1 is implicated in BRAF35 ubiquitination promoting atypical poly-ubiquitination via K6-, K27- and K29-linkages. We found that MID1 depletion alters BRAF35 localization in these structures and increases BRAF35 stability affecting its cytoplasmic abundance 0.244 SIGNOR-272317 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates activity phosphorylation Ser102 KDGNGYIsAAELRHV -1 26675311 YES miannu Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. 0.423 SIGNOR-266354 alogliptin chemical CHEBI:72323 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition -1 22475866 YES Luana Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization. 0.8 SIGNOR-258333 BAX protein Q07812 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates relocalization 9606 14585074 YES Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi 0.543 SIGNOR-87109 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser3 sKRAKAKT 9606 22136066 YES lperfetto Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity 0.278 SIGNOR-192792 CRTC2 protein Q53ET0 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity binding 9606 26652733 YES We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR). 0.294 SIGNOR-256101 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.463 SIGNOR-270899 GRIK3 protein Q13003 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 YES lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine 0.8 SIGNOR-268274 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19114991 YES lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity 0.742 SIGNOR-182971 VAV1 protein P15498 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 7227 23525006 YES We identify the GTP exchange factor (GEF) Vav as a key regulator of Rac activity downstream of RTKs in a developmentally regulated cell migration event 0.764 SIGNOR-259081 PMF1 protein Q6P1K2 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR form complex binding -1 27881301 YES lperfetto Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits 0.835 SIGNOR-265192 Serum stimulus SIGNOR-ST3 SIGNOR PRKAA2 protein P54646 UNIPROT down-regulates 9606 19584320 NO miannu Ampk is activated under conditions of low energy charge and typically inhibits anabolic reactions and promotes catabolism 0.7 SIGNOR-186644 CREB1 protein P16220 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 NO Luana Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state 0.7 SIGNOR-261288 Brivanib alaninate chemical CID:11154925 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190726 DNA_damage stimulus SIGNOR-ST1 SIGNOR XAB2 protein Q9HCS7 UNIPROT up-regulates 24086043 NO lperfetto TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. 0.7 SIGNOR-275692 EGFR protein P00533 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr136 GDCCYEEyKDRKREN 22198508 YES lperfetto Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue|We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. 0.2 SIGNOR-275549 YES1 protein P07947 UNIPROT SOCS1 protein O15524 UNIPROT down-regulates activity phosphorylation Tyr80 LLDACGFyWGPLSVH -1 31101761 YES miannu SOCS1 is phosphorylated on Y80 by SRC family kinase members SRC and YES1. 0.2 SIGNOR-276858 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000562 23457334 YES lperfetto Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (pfkfb2) isoenzyme by amino acids. 0.2 SIGNOR-192260 SRC protein P12931 UNIPROT VCL protein P18206 UNIPROT down-regulates activity phosphorylation Tyr1133 WVRKTPWyQ 9534 15229287 YES lperfetto The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail. 0.759 SIGNOR-247428 VAMP3 protein Q15836 UNIPROT LE-TGN SNARE complex SIGNOR-C157 SIGNOR form complex binding 9606 BTO:0000567 18195106 YES lperfetto We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport 0.726 SIGNOR-253082 Immunoglobulin mu heavy chain protein P0DOX6 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323265 YES scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. 0.2 SIGNOR-268187 NXPH1 protein P58417 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 YES gcesareni Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1 0.549 SIGNOR-62699 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr444 NSLTPKStPVKTLPF 9606 9840932 YES lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk3 0.715 SIGNOR-217256 CHEK2 protein O96017 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity phosphorylation Ser60 DNTAGCTsAGPHFNP 4932 24647101 YES ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes. 0.377 SIGNOR-262794 THAP12 protein O43422 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 10542257 YES lperfetto The mammalian kinases PKR and HRI and the yeast kinase GCN2 specifically phosphorylate Ser-51 on the alpha subunit of the translation initiation factor eIF2.  0.2 SIGNOR-249029 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI up-regulates quantity precursor of 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269097 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.41 SIGNOR-249685 Clinofibrate chemical CHEBI:31412 ChEBI HMGCR protein P04035 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191085 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 8626452 YES fstefani Here we characterize a new map kinase phosphatase, mkp-2, that is induced in human peripheral blood t cells with phorbol 12-myristate 13-acetate and is expressed in a variety of nonhematopoietic tissues as well. We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively. 0.761 SIGNOR-40926 YES1 protein P07947 UNIPROT YES1 protein P07947 UNIPROT up-regulates activity phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 9794236 YES lperfetto Autophosphorylation of Src and Yes blocks their inactivation by Csk phosphorylation 0.2 SIGNOR-247014 AKT proteinfamily SIGNOR-PF24 SIGNOR SKI protein P12755 UNIPROT down-regulates phosphorylation Thr458 QPRKRKLtVDTPGAP 9606 19875456 YES llicata The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7 0.2 SIGNOR-188969 SRC protein P12931 UNIPROT KRT19 protein P08727 UNIPROT unknown phosphorylation Tyr391 LEGQEDHyNNLSASK 9606 21049038 YES llicata Human k19 tyrosine 391 is phosphorylated, potentially by src kinase, and is the first well-defined tyrosine phosphorylation site of any keratin protein. 0.289 SIGNOR-169273 AKT proteinfamily SIGNOR-PF24 SIGNOR BEX1 protein Q9HBH7 UNIPROT up-regulates quantity by stabilization phosphorylation Ser102 KLREKQLsHSLRAVS 10116 BTO:0001009 16498402 YES miannu Phosphorylation of Bex1 in Ser105 by the serine–threonine kinase AKT stabilizes Bex1 and protects it from proteasomal degradation 0.2 SIGNOR-262614 BZW2 protein Q9Y6E2 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity binding 9606 31643092 YES miannu BZW2, as an evolutionary highly conserved protein, interacts with eIF2 and eIF3 and promotes ternary complex formation in vitro 0.253 SIGNOR-261220 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation 0.91 SIGNOR-252836 AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 YES Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. 0.2 SIGNOR-251473 MAPK14 protein Q16539 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates quantity by destabilization phosphorylation Ser310 LYNFMCNsSCVGGMN -1 30301786 YES miannu P38α phosphorylates and destabilizes p63. 0.308 SIGNOR-277414  UBE2I protein P63279 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates sumoylation Lys263 CNVSVPIkDELLPVM 9606 15208321 YES miannu Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263) 0.277 SIGNOR-126048 SSH1 protein Q8WYL5 UNIPROT CORO1B protein Q9BR76 UNIPROT up-regulates dephosphorylation Ser2 sFRKVVRQ 9606 17350576 YES gcesareni Coronin 1b inhibits filament nucleation by arp2/3 complex and this inhibition is attenuated by phosphorylation of coronin 1b at serine 2, a site targeted by ssh1l. 0.447 SIGNOR-153604 PRKCZ protein Q05513 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser975 VRMKRPSsVKSLRSE -1 15081397 YES lperfetto PKCzeta phosphorylates KIBRA at serine 975 and 978 0.705 SIGNOR-249262 TBK1 protein Q9UHD2 UNIPROT PBXIP1 protein Q96AQ6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser147 REEGRCSsSDDDTDV 9606 BTO:0000007 24488098 YES done miannu MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Phosphorylation of HPIP on serine 147 by TBK1 promotes E2-mediated GREB1 expression. 0.29 SIGNOR-273811 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 YES gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation 0.642 SIGNOR-252451 TYK2 protein P29597 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates activity phosphorylation Tyr693 TERGDKGyVPSVFIP 9606 16324152 YES miannu IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693. 0.654 SIGNOR-279303 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1191 GELSRSPsPFTHTHL 9606 BTO:0000551 19683496 YES gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. 0.497 SIGNOR-187599 GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0000664 10411939 YES irozzo Here we demonstrate that a region of the PU.1 Ets domain (the winged helix–turn–helix wing) interacts with the conserved carboxyl-terminal zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 transactivation of critical myeloid target genes. 0.578 SIGNOR-256071 IRF5 protein Q13568 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 22378047 NO lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. 0.7 SIGNOR-249562 REL protein Q04864 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR form complex binding 9606 BTO:0000671 9056676 YES miannu Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel. 0.675 SIGNOR-46945 LFNG protein Q8NES3 UNIPROT DLL3 protein Q9NYJ7 UNIPROT up-regulates binding 9606 10934472 YES gcesareni We find that mammalian lunatic fringe (lfng) inhibits jagged1-mediated signalling and potentiates delta1-mediated signalling through notch1. 0.449 SIGNOR-80524 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24024136 YES irozzo In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs). 0.487 SIGNOR-256275 ITGB1BP1 protein O14713 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257646 N-[(4-chlorophenyl)methyl]-2-[(2R,6S)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide chemical CHEBI:94175 ChEBI SHH protein Q15465 UNIPROT down-regulates chemical inhibition 9606 BTO:0000527 21679342 YES gcesareni More recently, robotnikinin was identified as a compound that binds to shh and blocks its ability to induce pathway activity at the level of ptch. 0.8 SIGNOR-174429 IL3 protein P08700 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 10082541 NO lperfetto We previously reported that NFIL3 is an IL-3-responsive gene in Baf-3 cells 0.528 SIGNOR-242763 CHEK1 protein O14757 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity phosphorylation Ser612 MYLSPVRsPKKKGST 9606 17380128 YES llicata These results suggest that ser612 is phosphorylated by chk1/2 after dna damage, leading to the formation of prb-e2f-1. phosphorylation of prb at ser612 enhanced the formation of a complex between prb and e2f-1 0.422 SIGNOR-153904 WDCP protein Q9H6R7 UNIPROT KIF2A protein O00139 UNIPROT up-regulates activity binding 9606 BTO:0000007 30297404 YES miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11.  0.2 SIGNOR-273732 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr442 KILEEVRyIANRFRC 9606 BTO:0000938 16251431 YES lperfetto Alpha7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinasesmutant alpha7 nachrs lacking cytoplasmic loop tyrosine residues because of alanine replacement of tyr-386 and tyr-442 were more active than wild-type receptorsexpression of active src reduced _7 nachr activity 0.2 SIGNOR-141311 MCM complex SIGNOR-C268 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 19946136 NO The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. 0.7 SIGNOR-261678 MT-ND5 protein P03915 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 0.771 SIGNOR-262148 Ub:E2 complex SIGNOR-C497 SIGNOR RBBP6 protein Q7Z6E9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271183 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser712 EEEESDSsETEKEDD -1 21296876 YES miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis 0.2 SIGNOR-276249 IRF4 protein Q15306 UNIPROT CD68 protein P34810 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000801 12676954 NO However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element. 0.298 SIGNOR-254284 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 11175253 YES amattioni Activated tbid results in an allosteric activation of bak 0.822 SIGNOR-105210 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 23663276 YES milica Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna. 0.731 SIGNOR-202042 EIF3_complex complex SIGNOR-C401 SIGNOR Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity stabilization 9606 17581632 YES lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 0.637 SIGNOR-269154 AKT1 protein P31749 UNIPROT MAP2K4 protein P45985 UNIPROT down-regulates phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0000007 11707464 YES lperfetto Akt phosphorylated sek1 on serine 78. 0.593 SIGNOR-236494 LHB protein P01229 UNIPROT LHCGR protein P22888 UNIPROT up-regulates binding 9606 10446903 YES gcesareni Hcg is a heterodimeric glycoprotein hormone, consisting of a common? -subunit and a hormone-specific ?-Subunit (2). It binds to the lh receptor (lhr). 0.683 SIGNOR-70028 YY2 protein O15391 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 15087442 YES Luana YY2 activated the p53 promoter. However, in contrast to YY1, which represses the activity of c-Fos, YY2 increased the activity of the c-Fos promoter. 0.573 SIGNOR-266213 NEK1 protein Q96PY6 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates activity binding 28426283 YES lperfetto It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents 0.282 SIGNOR-275842 SLC9A4 protein Q6AI14 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265603 ARHGEF6 protein Q15052 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000132 26507661 YES lperfetto ARHGEF6 is a Rho guanine nucleotide exchange factor for Rac1 and constitutively bound to GIT1. NO and PGI2 activate PKG and PKA, respectively and both kinases phosphorylate ARHGEF6 on Ser-684 and possibly on Ser-640. Phosphorylation of ARHGEF6 results in the assembly of a GIT1-ARHGEF6–14-3-3 complex. These changes might contribute to PGI2- and NO-mediated Rac1 inhibition. 0.622 SIGNOR-272167 DRD4 protein P21917 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 YES miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC 0.46 SIGNOR-264995 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 14976264 YES lperfetto Sirt1 inhibited foxo3's ability to induce cell death. 0.911 SIGNOR-122408 LSM-1988 chemical CHEBI:92015 ChEBI PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189394 afatinib chemical CHEBI:61390 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189356 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 YES lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 0.642 SIGNOR-217008 SCF-FBW7 complex SIGNOR-C135 SIGNOR FOXM1 protein Q08050 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26912724 YES miannu GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7. 0.305 SIGNOR-277209 CSNK2A1 protein P68400 UNIPROT AIP protein O00170 UNIPROT unknown phosphorylation Ser43 FHYRTLHsDDEGTVL 9534 12361709 YES llicata Protein kinase CK2 (CK2) was identified as the 45-kDa kinase from COS 1 cell or liver extracts that was responsible for phosphorylation of serine 43 in the XAP2 peptide 39-57. Loss of phosphorylation at any or all of the serine residues did not significantly affect the ability of XAP2-FLAG to bind to the murine AhR in rabbit reticulocyte lysate or Hsp90 in COS-1 cells. 0.307 SIGNOR-250824 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser20 KSSDFLEsAELDSGG -1 18408713 YES miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) 0.2 SIGNOR-276160 ITGB4 protein P16144 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 9428518 YES gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. 0.2 SIGNOR-54615 IDH1 protein O75874 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 26178471 YES lperfetto Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (Œ±-KG) 0.8 SIGNOR-261828 FHIT protein P49789 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 BTO:0000551 15313915 NO miannu We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein. 0.473 SIGNOR-127915 ABL1 protein P00519 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT down-regulates phosphorylation Tyr1073 PSGQPTPyATTQLIQ 9606 10892742 YES gcesareni Abl functions to antagonize robo signaling both abl and ena can directly bind to robo's cytoplasmic domain. 0.605 SIGNOR-78993 RAD51C protein O43502 UNIPROT XRCC3 protein O43542 UNIPROT up-regulates activity relocalization 9606 23438602 NO lperfetto It is likely that the recruitment of RAD51C to the sites of DNA lesions can promote XRCC3 phosphorylation and activate the DNA damage response pathway(s) in the S and G2 phases.  0.666 SIGNOR-263260 TP73 protein O15350 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 17700533 NO miannu Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. 0.7 SIGNOR-255473 NUP93 protein Q8N1F7 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.716 SIGNOR-262081 RBM15 protein Q96T37 UNIPROT RBM15/NXF1 complex SIGNOR-C67 SIGNOR form complex binding 9606 17001072 YES miannu Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression. 0.49 SIGNOR-149883 PRKACA protein P17612 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 9660950 YES llicata The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka). 0.515 SIGNOR-58972 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser90 QHVRSHSsPASLQLG 26375055 YES lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity 0.262 SIGNOR-276522 NR3C1 protein P04150 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001372 9430225 NO In thymocytes and peripheral T cells, GILZ gene expression is induced by DEX 0.413 SIGNOR-253295 BAK1 protein Q16611 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates relocalization 9606 14585074 YES Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi 0.296 SIGNOR-118908 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Thr2511 VPEHPFLtPSPESPD -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.551 SIGNOR-273178 USP20 protein Q9Y2K6 UNIPROT CLSPN protein Q9HAW4 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 25355518 YES miannu USP20 deubiquitinates and stabilizes Claspin. 0.509 SIGNOR-272821 CASP3 protein P42574 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000142 10200555 NO amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation 0.7 SIGNOR-66860 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 20626350 YES gcesareni Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1. 0.614 SIGNOR-166661 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 YES gcesareni Transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells. 0.817 SIGNOR-52005 APOA5 protein Q6Q788 UNIPROT LPL protein P06858 UNIPROT up-regulates activity binding 9606 21773006 YES Regulation miannu Apo A5 binds to and enhances the activity of lipoprotein lipase (LPL) enzyme 0.717 SIGNOR-251845 TRAF7 protein Q6Q0C0 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates binding 9606 15001576 YES miannu Traf7 specifically interacts with and activates mekk3. 0.485 SIGNOR-123221 SP1 protein P08047 UNIPROT DHCR24 protein Q15392 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22431021 NO miannu activation of Sp1 by oxidative stress is involved in the promotion of expression of DHCR24 by HCV. 0.2 SIGNOR-255200 GNAI3 protein P08754 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity binding 9606 19703466 YES miannu Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma) 0.594 SIGNOR-267851 KAT2B protein Q92831 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269611 BCL2L11 protein O43521 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 YES gcesareni Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. 0.784 SIGNOR-133832 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM3B protein Q7LBC6 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273471 NDC80 protein O14777 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR form complex binding 27881301 YES lperfetto Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits 0.967 SIGNOR-265188 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser25 PPSPEVGsPLLCRPA 9606 11110801 YES llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). 0.442 SIGNOR-84988 CSTF2 protein P33240 UNIPROT CSTF complex complex SIGNOR-C441 SIGNOR form complex binding 9606 10669729 YES lperfetto We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other.  0.929 SIGNOR-268366 ATF4 protein P18848 UNIPROT WARS1 protein P23381 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269429 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 10090 BTO:0002572;BTO:0000801 21232017 YES lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. 0.895 SIGNOR-235407 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser465 HNPISSVs 9534 9748228 YES ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif 0.702 SIGNOR-251439 ERBB3 protein P21860 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.519 SIGNOR-146864 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 YES lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. 0.711 SIGNOR-227911 TRIM65 protein Q6PJ69 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003172 31332286 YES miannu Ubiquitin ligase TRIM65 promotes colorectal cancer metastasis by targeting ARHGAP35 for protein degradation 0.2 SIGNOR-272256 MAPKAPK5 protein Q8IW41 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 17254968 YES gcesareni Furthermore, we show that prak activates p53 by direct phosphorylation. We propose that phosphorylation of p53 by prak following activation of p38 mapk by ras plays an important role in ras-induced senescence and tumor suppression. 0.759 SIGNOR-152850 CRIPAK protein Q8N1N5 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 BTO:0000150 BTO:0000149 16278681 YES gcesareni We further found that cripak interacted with pak1 through the n-terminal regulatory domain and inhibited pak1 kinase in both in vitro and in vivo assays. 0.416 SIGNOR-141467 VAV1 protein P15498 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000782 9200440 YES gcesareni Hese data imply that c-cbl is a molecular adapter that regulates the function of vav 0.691 SIGNOR-49188 GSK3B protein P49841 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser33 LPENNVLsPLPSQAM 9606 11483158 YES Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity. 0.727 SIGNOR-251258 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 23400686 YES gcesareni Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1. 0.85 SIGNOR-252534 KLF14 protein Q8TD94 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates quantity by repression transcriptional regulation 19088080 NO lperfetto Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2. 0.2 SIGNOR-271696 2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide chemical CID:121427831 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates quantity chemical inhibition 9606 29764999 YES Monia DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells 0.8 SIGNOR-261094 SRGAP3 protein O43295 UNIPROT RAC2 protein P15153 UNIPROT down-regulates 9606 12447388 NO miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. 0.551 SIGNOR-95921 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-249681 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 9606 17190791 YES gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1). 0.447 SIGNOR-151671 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR form complex binding 9606 BTO:0000007 14636569 YES lperfetto These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer 0.841 SIGNOR-263208 PTPN11 protein Q06124 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates dephosphorylation Tyr718 IPERDSRySQPLHEE 9606 19287004 YES lperfetto Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively. 0.368 SIGNOR-184604 UVB radiation stimulus SIGNOR-ST17 SIGNOR EDN1 protein P05305 UNIPROT up-regulates 9606 9767234 NO miannu UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes. 0.7 SIGNOR-252383 SPI1 protein P17947 UNIPROT CD68 protein P34810 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000801 12676954 NO However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element. 0.328 SIGNOR-254286 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 BTO:0003323 12485996 YES lperfetto The major genetic evidence supporting ubiquitin ligase function for BRCA1 in vivo comes from studies on the FANCD2 protein. Whereas in wild‐type cells the FANCD2 protein co‐localizes with BRCA1 in nuclear foci and becomes monoubiquitylated in response to DNA damage, HCC1937 cells, which encode a mutated form of BRCA1, are largely defective for both monoubiquitylation of FANCD2 and foci formation 0.71 SIGNOR-263237 MAPK3 protein P27361 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 12955074 YES gcesareni Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase. 0.704 SIGNOR-100270 PRKACA protein P17612 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2347 TTCCRRSsNVSYKYS 9606 8318012 YES lperfetto Pka phosphorylates the cytoplasmic mpr 300 domain at ser20 and at a non-identified site, 0.2 SIGNOR-37839 SEC24B protein O95487 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.717 SIGNOR-265290 Av/b3 integrin complex SIGNOR-C177 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269026 PPP3CA protein Q08209 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates dephosphorylation 9606 21880741 YES gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. 0.566 SIGNOR-176379 STAT3 protein P40763 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30029643 NO Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway. 0.7 SIGNOR-256257 E2F1 protein Q01094 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.682 SIGNOR-253854 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation 9606 7478566 YES gcesareni For example, inactivation of sos through phosphorylation by the downstream mapk 0.634 SIGNOR-26338 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT down-regulates activity phosphorylation Thr391 TTHIRTHtGEKPFAC 10090 BTO:0000944 8662759 YES llicata Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10. 0.465 SIGNOR-250857 ANXA3 protein P12429 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity 9606 BTO:0000018 27995049 NO miannu We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. 0.2 SIGNOR-262210 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT unknown phosphorylation Tyr345 PERNEGVyTAIAVQE 9606 11163214 YES Manara PSTPIP1 was phosphorylated by ABL1, and growth factor–induced PSTPIP1 phosphorylation was diminished in Abl null fibroblasts. 0.598 SIGNOR-260809 GATA1 protein P15976 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 NO Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. 0.379 SIGNOR-251804 GNG2 protein P59768 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. 0.476 SIGNOR-154255 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser622 ILSTAMLsLGSGISQ 9534 BTO:0000298 11865049 YES llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  0.74 SIGNOR-250815 PP1 proteinfamily SIGNOR-PF54 SIGNOR CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Ser175 FGLARAFsLAKNSQP 9606 21533037 YES lperfetto Protein phosphatase-1 activates cdk9 by dephosphorylating ser175 0.2 SIGNOR-264671 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206838 CH5132799 chemical CID:49784945 PUBCHEM PIK3C2B protein O00750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190940 ATM protein Q13315 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000887 18534819 NO lperfetto The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity. 0.448 SIGNOR-244392 MEF2A protein Q02078 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7739551 YES lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. 0.588 SIGNOR-238709 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRA protein P10827 UNIPROT up-regulates activity binding 9606 BTO:0001073 29407449 YES scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. 0.8 SIGNOR-267255 NFATC1 protein O95644 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21871017 YES miannu NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration 0.316 SIGNOR-264026 DUSP6 protein Q16828 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 YES gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). 0.904 SIGNOR-103146 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277667 Cy3-bifunctional dye zwitterion chemical CHEBI:37990 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257859 EIF3J protein O75822 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.783 SIGNOR-266391 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 18498746 YES gcesareni Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf). 0.758 SIGNOR-178686 HSPA8 protein P11142 UNIPROT RNF5 protein Q99942 UNIPROT up-regulates activity binding 9606 BTO:0000007 21148293 YES miannu JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex 0.387 SIGNOR-271493 APBA1 protein Q02410 UNIPROT CASK protein O14936 UNIPROT up-regulates activity binding 9534 11036064 YES miannu Interaction with Munc18 increases Mint1 binding to CASK. 0.851 SIGNOR-264041 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 NO We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα. 0.46 SIGNOR-256117 BMP2 protein P12643 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 9606 22298955 NO gcesareni Neogenin, a transmembranous protein, was re-ported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation 0.697 SIGNOR-195564 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation -1 9155018 YES These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways 0.575 SIGNOR-253012 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates quantity binding 9606 BTO:0000007;BTO:0000567 14523016 YES amattioni Smac3, a novel Smac/DIABLO splicing variant, accelerates XIAP auto-ubiquitination and destruction 0.914 SIGNOR-118411 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000443 12270934 YES lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. 0.2 SIGNOR-244795 CREB1 protein P16220 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity binding 9606 15126506 YES lperfetto We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity 0.308 SIGNOR-124711 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 8622703 YES lperfetto We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrosine 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr. 0.2 SIGNOR-40611 PTPN6 protein P29350 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation Tyr680 RDIYSTDyYRVGGRT 10116 phosphorylation: tyr496 HIIENPQyFSDACVH 14662744 YES Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. 0.477 SIGNOR-248468 PDPK1 protein O15530 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Thr423 PEQSKRStMVGTPYW 9534 BTO:0000298 10995762 YES miannu P21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). We identify threonine 423, a conserved threonine in the activation loop of kinase subdomain VIII, as the PDK1 phosphorylation site on PAK1. 0.358 SIGNOR-250267 RBL2 protein Q08999 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity transcriptional regulation 10090 10801445 NO gcesareni Furthermore, muscle cells overexpressing p130 had reduced levels of the muscle-promoting factor MyoD. In addition, p130 repressed the transactivation capacity of MyoD, an effect abolished by co-transfection of pRb 0.372 SIGNOR-241943 Wnt proteinfamily SIGNOR-PF40 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization 17081971 NO The central player in the canonical Wnt cascade is β-catenin, a cytoplasmic protein whose stability is regulated by the destruction complex. 0.2 SIGNOR-256240 IL22RA1 protein Q8N6P7 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 12087100 NO gcesareni Il-22 also induced serine phosphorylation of stat3 on ser(727). 0.65 SIGNOR-90162 CALM3 protein P0DP25 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates binding 9606 11796223 YES inferred from 70% of family members miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.642 SIGNOR-269891 STAT3 protein P40763 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 10347215 NO lperfetto The data presented this far show that the JAK-STAT signaling pathway and specifically Stat3 and Jak1 are required for induction of IL-10-dependent anti-inflammatory and developmental responses in macrophages. 0.7 SIGNOR-249547 2-(hydroxymethyl)-4-(1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl)phenol chemical CHEBI:64064 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 YES Luana The affinity measurements (log KD values of −5.73, −9.26 and −6.33 for β1, β2 and β3, respectively), show that salmeterol has high affinity for the β2-adrenoceptor.  0.8 SIGNOR-257852 SMO protein Q99835 UNIPROT GNAT2 protein P19087 UNIPROT up-regulates binding 9606 16885213 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.262 SIGNOR-148534 PRDM16 protein Q9HAZ2 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 YES _activating its transcriptional function fspada Prdm16 stimulates brown adipogenesis by binding to ppar-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function 0.47 SIGNOR-180298 NOTCH2 protein Q04721 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 9528794 YES gcesareni In an effort to identify processes that regulate e47, and potentially b-cell development, we found that activated notch1 and notch2 effectively inhibit e47 activity. 0.273 SIGNOR-56222 calciol smallmolecule CHEBI:28940 ChEBI vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity precursor of 9606 BTO:0001253 30080183 YES lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin 0.8 SIGNOR-270564 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH16 protein O75309 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265833 EIF4E protein P06730 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 15094766 NO lperfetto A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex 0.7 SIGNOR-236806 STK3 protein Q13188 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Thr180 DTMAKRNtVIGTPFW 9606 BTO:0000150 20231902 YES gcesareni Consistent with previous studies, sts alone induces mst2 cleavage and autophosphorylation of thr180, an indicator of mst2 activation, as well as apoptosis. 0.2 SIGNOR-164310 PFKL protein P17858 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266468 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM3 protein O75382 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271146 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 BTO:0000567 17615152 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. 0.703 SIGNOR-156868 Hypoxia stimulus SIGNOR-ST25 SIGNOR KDM4B protein O94953 UNIPROT up-regulates 9606 30759871 NO miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia. 0.7 SIGNOR-263735 ABL1 protein P00519 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 YES gcesareni Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro. 0.402 SIGNOR-114091 GNB1 protein P62873 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR form complex binding 9606 23994464 YES apalma Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit 0.94 SIGNOR-255004 VRK1 protein Q99986 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr73 ADQTPTPtRFLKNCE 9606 15105425 YES gcesareni Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level. 0.372 SIGNOR-124334 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG 9606 SIGNOR-C14 11460167 YES lperfetto Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta. 0.755 SIGNOR-109490 PPM1B protein O75688 UNIPROT DYRK1A protein Q13627 UNIPROT down-regulates activity dephosphorylation Ser258 NTNFRGVsLNLTRKF 9606 33380426 YES miannu In conclusion, our study demonstrates that DYRK1A autophosphorylates Ser258, the dephosphorylation target of PPM1B, and PPM1B negatively regulates DYRK1A activity.|We found that PPM1B dephosphorylates DYRK1A at Ser258, contributing to the inhibition of DYRK1A activity. 0.236 SIGNOR-277108 AVPR2 protein P30518 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.588 SIGNOR-256754 PRKAR2A protein P13861 UNIPROT PRKAR2A protein P13861 UNIPROT up-regulates activity phosphorylation Ser99 SRFNRRVsVCAETYN -1 6293815 YES miannu RII subunit containing the 'autophosphorylation' site (Ser-95) 0.2 SIGNOR-250073 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205746 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT up-regulates dephosphorylation Tyr531 FTATEPQyQPGENL 9606 12496362 YES gcesareni Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule. 0.397 SIGNOR-96764 DVL2 protein O14641 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000331 10196136 YES amattioni Dvl is required for lrp6 phosphorylation, which is essential for subsequent steps of signal transduction. 0.689 SIGNOR-66362 MTMR1 protein Q13613 UNIPROT 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI up-regulates quantity chemical modification 9606 18429927 YES miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 0.8 SIGNOR-269805 INTS5 protein Q6P9B9 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.905 SIGNOR-261465 VX-745 chemical CHEBI:90528 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 11892915 YES gcesareni Vx-745 was reported to be active against several isotypes of p38 mapk, including p38alpha, p38beta and p38gamma 0.8 SIGNOR-115782 RAB8A protein P61006 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 18694559 NO miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110 0.7 SIGNOR-252148 PTPN1 protein P18031 UNIPROT EPOR protein P19235 UNIPROT down-regulates activity dephosphorylation 9606 14527337 YES lperfetto In vivo interaction between EPO-R and PTP1B suggested that PTP1B dephosphorylates the EPO-R intracellularly.|Protein tyrosine phosphatase 1B participates in the down-regulation of erythropoietin receptor signalling. 0.46 SIGNOR-276994 GIT1 protein Q9Y2X7 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity binding 9606 BTO:0000599 23325602 YES miannu We found both MAT2B variants interact with GIT1. MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. 0.391 SIGNOR-261245 SIRT7 protein Q9NRC8 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity deacetylation Lys37 TPSTCGVkPHRYRPG 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275879 alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity precursor of 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-267935 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr166 LYCDPRGtLRKGTLG -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273491 IL23A protein Q9NPF7 UNIPROT IL12RB1 protein P42701 UNIPROT up-regulates binding 9606 12023369 YES gcesareni Like il-12, il-23 binds to the il-12r subunit il-12rbeta1. 0.644 SIGNOR-87739 MBP protein P02686 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 31066630 NO SimoneGraziosi Myelin basic protein (MBP) is essential for the compaction of the two adjacent cytoplasmic membrane surfaces into the major dense line of myelin. 0.7 SIGNOR-269230 IL17A protein Q16552 UNIPROT IL17RA protein Q96F46 UNIPROT up-regulates binding 9606 BTO:0000782 9367539 YES gcesareni Binding studies suggest that recombinant hil-17 binds to the hil-17r with low affinity. Monoclonal antibodies (mabs) generated against the hil-17r were able to block the il-17-induced production of cytokine from human foreskin fibroblast (hff) cells. 0.924 SIGNOR-53249 KIFC1 protein Q9BW19 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 33361741 NO miannu Kinesin Family Member C1 (KIFC1) Regulated by Centrosome Protein E (CENPE) Promotes Proliferation, Migration, and Epithelial-Mesenchymal Transition of Ovarian Cancer 0.7 SIGNOR-266115 PTK6 protein Q13882 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10913193 YES gcesareni Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle 0.747 SIGNOR-80020 DNA_damage stimulus SIGNOR-ST1 SIGNOR ATM protein Q13315 UNIPROT up-regulates activity 9606 BTO:0000007 12556884 NO miannu Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. 0.7 SIGNOR-253376 BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT down-regulates activity binding 9606 BTO:0000776;BTO:0000785 8183370 YES lperfetto Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax. 0.635 SIGNOR-36898 TNFSF11 protein O14788 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 17572386 NO miannu Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation 0.7 SIGNOR-253044 ACD protein Q96AP0 UNIPROT POT1/ACD complex SIGNOR-C64 SIGNOR form complex binding 9606 17237768 YES miannu We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme. 0.884 SIGNOR-152318 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 YES In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. 0.686 SIGNOR-251329 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA1 protein P42261 UNIPROT up-regulates activity chemical activation 10090 15115814 YES lperfetto AMPA glutamate receptor subunit (GluR1) 0.8 SIGNOR-261432 CREB1 protein P16220 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 20577053 NO gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 0.25 SIGNOR-268145 IFNW1 protein P05000 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 YES gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.758 SIGNOR-105982 KLF15 protein Q9UIH9 UNIPROT RHO protein P08100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 NO miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 0.273 SIGNOR-253817 SIRT1 protein Q96EB6 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity deacetylation 24870244 YES lperfetto The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha. 0.2 SIGNOR-275499 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT up-regulates activity phosphorylation Ser25 PELLVVGsRPELGRW 9606 BTO:0000007 21728993 YES miannu In the present study, we demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser(25) as the residue involved in this modification. We also show that Ser(25) is phosphorylated both in vitro and in vivo by AMPK.  0.351 SIGNOR-276338 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM35 protein Q9UPQ4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270974 nintedanib chemical CHEBI:85164 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 18559524 YES Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. 0.8 SIGNOR-257805 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0000567 11070080 YES gcesareni P300 acetylates and activates the tumor suppressor p53 after dna damage. 0.912 SIGNOR-84074 SATB1 protein Q01826 UNIPROT CD52 protein P31358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 17343824 NO miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 0.2 SIGNOR-255131 PFDN4 protein Q9NQP4 UNIPROT Prefoldin co-chaperone complex SIGNOR-C513 SIGNOR form complex binding 9606 32699605 YES miannu The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6) 0.942 SIGNOR-270933 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser544 RSVTMRKsQRSSKGS 9606 24505490 YES llicata A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498. 0.2 SIGNOR-204550 FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000165 19319192 YES miannu We previously showed that the level of MAFbx protein increased in skeletal muscle during aging and/or food deprivation. Immunoprecipitation of the SCFMAFbx complexes from mouse atrophic muscles exhibited ubiquitination activity by using MyoD as substrate. Food deprivation and oxidative stress–induced atrophy increase polyubiquitination by the SCFMAFbx pathway and degradation of MyoD by the proteasome 0.561 SIGNOR-271802 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Ser407 STEQTLAsDTDSSLD 9606 11062067 YES lperfetto The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro. 0.221 SIGNOR-83711 PRKCA protein P17252 UNIPROT CORO1B protein Q9BR76 UNIPROT down-regulates phosphorylation Ser2 sFRKVVRQ 9606 16027158 YES lperfetto We have identified serine 2 (ser-2) on coronin 1b as the major residue phosphorylated by pkc in vivo.In this work, we show that coronin 1b interacts in vivo with the arp2/3 complex and that this interaction is inhibited by pkc phosphorylation. 0.325 SIGNOR-138733 CREB5 protein Q02930 UNIPROT LY96 protein Q9Y6Y9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002813 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253806 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT down-regulates activity phosphorylation Ser43 QTPSKPAsADGHRGP 9606 BTO:0002181 33388549 YES miannu Concurrently, ROCK1 was able to phosphorylate GSK-3β at Ser9, which phosphorylated Src at Ser51 and Ser492 residues, leading to Src inactivation 0.383 SIGNOR-277543 PMS2 protein P54278 UNIPROT MLH1/PMS2 complex SIGNOR-C59 SIGNOR form complex binding 9606 10542278 YES miannu Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_ 0.758 SIGNOR-71777 PAK2 protein Q13177 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 YES lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, 0.51 SIGNOR-159768 AGTR1 protein P30556 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32201502 NO MIANNU Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis. 0.7 SIGNOR-260233 EPHB2 protein P29323 UNIPROT SYNJ1 protein O43426 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 15821731 YES lperfetto Ephb2 causes tyrosine phosphorylation in the proline-rich domain of synaptojanin 1, and inhibits both the interaction with endophilin and the 5'-phosphatase activity of synaptojanin 1 0.568 SIGNOR-135274 PKI-402 chemical CID:44187953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252654 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser507 TDLCFLNsPIFKQKK 9606 17621308 YES lperfetto Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507) 0.2 SIGNOR-156882 MTOR protein P42345 UNIPROT EIF4EBP2 protein Q13542 UNIPROT down-regulates phosphorylation 9606 23100465 YES gcesareni Here, we show that cancer cells acquire resistance to astori by downregulating eukaryotic translation initiation factor (eif4e)-binding proteins (4e-bps-eif4ebp1, eif4ebp2). 0.66 SIGNOR-199258 MTA1 protein Q13330 UNIPROT MTA1/DJ1 complex complex SIGNOR-C123 SIGNOR form complex binding 9606 21368136 YES 1 miannu We found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. 0.328 SIGNOR-239739 ITK protein Q08881 UNIPROT BMX protein P51813 UNIPROT up-regulates activity phosphorylation Tyr224 DSNSKKIyGSQPNFN -1 12573241 YES Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. 0.334 SIGNOR-251332 CDK7 protein P50613 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 YES lperfetto Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7. 0.414 SIGNOR-81170 HASPIN protein Q8TF76 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9606 BTO:0000567 24413556 YES miannu Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis. 0.2 SIGNOR-275420 HES1 protein Q14469 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 16282371 NO Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1 0.7 SIGNOR-253058 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser125 HGSDSVEsAEKEIGL -1 8810265 YES miannu For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. 0.2 SIGNOR-250198 BRSK2 protein Q8IWQ3 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 YES gcesareni Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli. 0.291 SIGNOR-176594 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Thr519 EDPYAGStDENTDSE 9606 BTO:0000567 15367657 YES llicata XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1. 0.461 SIGNOR-251051 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 22298955 YES gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation 0.459 SIGNOR-195606 YWHAQ protein P27348 UNIPROT PRKD1 protein Q15139 UNIPROT down-regulates -1 10092600 NO lperfetto 14-3-3tau strongly down-regulates pkcmu kinase activity in vitro 0.328 SIGNOR-65951 LTK protein P29376 UNIPROT CBL protein P22681 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 YES gcesareni Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85. 0.369 SIGNOR-49528 PAX7 protein P23759 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103;BTO:0002314 22493066 NO lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells 0.7 SIGNOR-219371 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM5 protein Q9C035 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270980 Ub:E2 complex SIGNOR-C497 SIGNOR RMND5B protein Q96G75 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271256 valsartan chemical CHEBI:9927 ChEBI AGTR1 protein P30556 UNIPROT down-regulates activity chemical inhibition 9606 8577935 YES miannu The binding characteristics of the angiotensin AT1 receptor antagonist valsartan were investigated in different animal species and tissues. 0.8 SIGNOR-258489 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Thr202 HDHTGFLtEYVATRW 1712480 YES lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| 0.2 SIGNOR-249471 TRIM24 protein O15164 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19909775 YES miannu We found that trim24/transcriptional intermediary factor 1alpha (tif1alpha), which is known as a ligand-dependent nuclear receptor co-regulator, interacts with ar and enhances transcriptional activity of ar 0.397 SIGNOR-189113 MAPT protein P10636 UNIPROT Neurofibrillary tangle formation phenotype SIGNOR-PH58 SIGNOR down-regulates 9606 11578751 NO lperfetto Tau is a multifunctional microtubule-associated protein that plays major roles in the assembly of microtubules, the stabilization of microtubules against dynamic instability, and in bridging these polymers with other cytoskeletal filaments 43, 44, 45, 46 and 47. In normal brain, the equilibrium between phosphorylations and dephosphorylations of tau modulates the stability of the cytoskeleton and consequently axonal morphology. The earliest modification found in Alzheimer brains consists of hyperphosphorylations on tau by the action of different protein kinase and phosphatase systems that appear to lead to structural and conformational changes in this protein, thus affecting its binding with tubulin and the capacity to promote microtubule assembly 0.7 SIGNOR-251639 SP1 protein P08047 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 11867623 YES Luana Sp1 and Sp3 Activate Transcription Driven by the AS Promoter 0.2 SIGNOR-268019 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7234 RAASPTRsSSSASQS 9606 BTO:0004905 21295697 YES lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. 0.436 SIGNOR-264429 AXIN1 protein O15169 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity binding 9606 17529994 YES amattioni The axin dix domain has a novel structural fold largely composed of beta-strands that engage in head-to-tail self-interaction to form filaments in the crystal 0.2 SIGNOR-155218 PML protein P29590 UNIPROT ZFYVE9 protein O95405 UNIPROT up-regulates binding 9606 15356634 YES gcesareni Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. 0.573 SIGNOR-128744 MAPK3 protein P27361 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 YES gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity. 0.515 SIGNOR-48355 WZ4002 chemical CHEBI:61400 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207827 COPS5 protein Q92905 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 11818334 YES gcesareni We report a novel mechanism of smad4 degradation. Jab1 interacts directly with smad4 and induces its ubiquitylation for degradation 0.434 SIGNOR-114697 LPCAT4 protein Q643R3 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI up-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272770 BIRC2 protein Q13490 UNIPROT CASP2 protein P42575 UNIPROT down-regulates binding 9606 16701639 YES gcesareni However, among hiap1, hiap2 and xiap, only hiap2 binds and inhibits caspase-2. 0.499 SIGNOR-146738 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 16085715 YES gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. 0.641 SIGNOR-139477 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser83 PRRSPRIsFFLEKEN -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.628 SIGNOR-276119 PIK3R6 protein Q5UE93 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity binding 25753393 YES lperfetto P84 forms a negative regulatory complex with p110gamma to control PI3Kgamma signalling during cell migration|Our findings suggest that p84 binding to p110γ may represent a novel negative feedback signal that terminates PI3Kγ activity. 0.516 SIGNOR-275724 CASP1 protein P29466 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.789 SIGNOR-256400 NR0B2 protein Q15466 UNIPROT HNF4A protein P41235 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10594021 NO gcesareni Here we show that shp inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (hnf-4) and the retinoid x receptor (rxr) by at least two mechanisms shp also competes with coactivators for binding to ligand-activated rxr, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of shp-mediated repression. 0.43 SIGNOR-73032 AKT1 protein P31749 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21777568 YES gcesareni We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner. 0.423 SIGNOR-195549 BLM protein P54132 UNIPROT UIMC1 protein Q96RL1 UNIPROT up-regulates activity binding 9606 BTO:0001938 23708797 YES miannu Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of .  0.329 SIGNOR-272116 ENOBOSARM chemical CID:11326715 PUBCHEM AR protein P10275 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-195892 PHKG2 protein P15735 UNIPROT PYGM protein P11217 UNIPROT up-regulates activity phosphorylation Ser15 QEKRKQIsVRGLAGV 9606 BTO:0002049 22225877 YES It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 0.55 SIGNOR-267400 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 16613856 YES gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation. 0.525 SIGNOR-146122 GUCY1A1 protein Q02108 UNIPROT GUCY1A3-B3 complex SIGNOR-C140 SIGNOR form complex binding 9606 10977868 YES gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity 0.2 SIGNOR-243983 LCK protein P06239 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr759 LYDVSRMyVDPSEIN 9606 12181444 YES gcesareni In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme. 0.557 SIGNOR-91477 RNF139 protein Q8WU17 UNIPROT SREBF2 protein Q12772 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 YES miannu Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner  0.478 SIGNOR-271958 mTORC2 complex SIGNOR-C2 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser436 INQSTLPsQQNRFPD 9606 BTO:0002036 34343821 YES miannu Here we report the ability of mTORC2 to directly phosphorylate YAP at serine 436 (Ser436) positively regulating YAP activity. 0.281 SIGNOR-277569 TRAF2 protein Q12933 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 9774977 YES lperfetto Traf2 is a strong activator of ask1 0.736 SIGNOR-60747 UBE2V1 protein Q13404 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 11057907 YES lperfetto We find that traf6, a ring domain protein, functions together with ubc13/uev1a to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (k63) of ubiquitin 0.698 SIGNOR-83603 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser692 GQLMSQPsTASNSLP 9606 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251280 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS3 protein P23396 UNIPROT unknown phosphorylation 9606 15950189 YES inferred from 70% family members llicata Erk phosphorylates threonine 42 residue of ribosomal protein s3. 0.2 SIGNOR-270145 MAPK11 protein Q15759 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser771 SASSTLGsPENEEHI 9606 SIGNOR-C3 21757713 YES llicata Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation. 0.353 SIGNOR-174870 N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide chemical CHEBI:91407 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191247 CDC42BPA protein Q5VT25 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW BTO:0000567 11340065 YES llicata Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment. 0.405 SIGNOR-250721 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser298 EKLAKHEsQQDYSKG 9606 20363754 YES lperfetto Pkd phosphorylates cortactin in vitro and in vivo at serine 298 thereby generating a 14-3-3 binding motif. In vitro, a phosphorylation-deficient cortactin-s298a protein accelerated vca-arp-cortactin-mediated synergistic actin polymerization and showed reduced f-actin binding 0.421 SIGNOR-164756 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 10090 26260587 YES lperfetto IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. 0.799 SIGNOR-249546 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0005248 8758906 YES irozzo We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine. 0.2 SIGNOR-255999 IRAK4 protein Q9NWZ3 UNIPROT PELI2 protein Q9HAT8 UNIPROT up-regulates phosphorylation 9606 12860405 YES gcesareni Pellino2 is one of the firstsubstrates identified for irak1 andirak4. 0.638 SIGNOR-103717 CCL2 protein P13500 UNIPROT CCR4 protein P51679 UNIPROT up-regulates activity binding 9606 17160712 YES gcesareni CCR2 and CCR4 are two cell surface receptors that bind CCL2 0.488 SIGNOR-237555 nilutamide chemical CHEBI:7573 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194649 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0000142 1411546 YES gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product 0.742 SIGNOR-19244 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser139 YFLGSSFsPVRCGGP 9606 BTO:0000007 23051732 YES lperfetto In particular, we found that Cdc14A inhibits Wee1 degradation through the dephosphorylation of Ser-123 and Ser-139 residues.  0.545 SIGNOR-267470 PTPN13 protein Q12923 UNIPROT STK25 protein O00506 UNIPROT down-regulates activity dephosphorylation 9606 17657516 YES To investigate dephosphorylation of CCM3 by FAP-1, phosphorylated GST-CCM3 was incubated with cdFAP-1, and reactions were analyzed by autoradiography. Again, GST-STK25 phosphorylated GST-CCM3 and possessed autophosphorylation activity. cdFAP-1 of 0.005 U were sufficient to dephosphorylate GST-CCM3 as well as the kinase GST-STK25.|More recently, the Golgi matrix protein GM130 was shown to function as a scaffold protein for STK25 and to activate STK25 through stimulation of autophosphorylation. 0.421 SIGNOR-248711 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-249677 FZD5 protein Q13467 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23151663 YES areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  0.658 SIGNOR-258957 NOG protein Q13253 UNIPROT BMP7 protein P18075 UNIPROT down-regulates activity binding -1 12478285 YES We report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. 0.852 SIGNOR-256484 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 YES lperfetto The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation 0.2 SIGNOR-252081 KAT5 protein Q92993 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000007 21936881 YES llicata Tip60 regulates myoblast differentiation by enhancing the transcriptional activity of MyoD via their physical interactions. 0.365 SIGNOR-237675 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity phosphorylation Ser467 KASSRRSsFSMEEGD 10090 BTO:0000968 23599343 YES This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor. 0.33 SIGNOR-255316 DUSP7 protein Q16829 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150 BTO:0001253 9788880 YES gcesareni Pyst2 preferentially dephosphorylates and inactivates p42 map kinase in vitro and in vivo 0.797 SIGNOR-60871 MAPK12 protein P53778 UNIPROT NUP62 protein P37198 UNIPROT down-regulates quantity by destabilization phosphorylation Ser272 SGTSTTTsTAATATA 9606 BTO:0000007 30401435 YES miannu We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1).  0.2 SIGNOR-277416 SNX5 protein Q9Y5X3 UNIPROT DOCK1 protein Q14185 UNIPROT up-regulates activity binding 9606 BTO:0000567 18596235 YES miannu SNX5 Is a Novel Binding Partner of the DHR1 Domain of DOCK180. In summary, we found that DOCK180 regulates transport of CI-MPR via SNX5 binding. 0.346 SIGNOR-269441 MAPK1 protein P28482 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 YES lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2. 0.249 SIGNOR-182770 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 9687510 YES lperfetto Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38,. 0.61 SIGNOR-59454 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 YES gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.407 SIGNOR-84056 ITPR1 protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity chemical modification 9606 24646566 YES miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. 0.8 SIGNOR-256238 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 10116 7535768 YES Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185 0.761 SIGNOR-248718 Histone H2A proteinfamily SIGNOR-PF70 SIGNOR Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 YES miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.2 SIGNOR-267756 KIF2C protein Q99661 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272535 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser1137 EGPTRRLsLPGQLGA 9606 10488078 YES lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) 0.307 SIGNOR-70718 ATM protein Q13315 UNIPROT PPM1G protein O15355 UNIPROT up-regulates activity phosphorylation Ser183 GTGEEPGsQGLNGEA -1 26324325 YES ATM indeed mediated PPM1G phosphorylation at S183, and mutation of this residue (S183A) abrogated detection with the phospho-specific antibody 0.303 SIGNOR-255591 1-[4-Amino-7-(3-hydroxypropyl)-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-fluoroethanone chemical CID:644243 PUBCHEM RPS6KA2 protein Q15349 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0002135 31505737 YES miannu Since p90RSK was activated in the diabetic hearts in mice, we investigated whether FMK (an inhibitor of p90RSK) could protect INS-1 cells (a pancreatic β-cell line) from HG-induced β-cell dysfunction and glucotoxicity. 0.8 SIGNOR-262231 SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. 0.684 SIGNOR-255838 WWC1 protein Q8IX03 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity 9606 BTO:0000007 20159598 NO Hippo pathway Gianni These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. 0.368 SIGNOR-261953 PGD protein P52209 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI up-regulates quantity chemical modification 9606 34775382 YES miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. 0.8 SIGNOR-267061 ELF1 protein P32519 UNIPROT FCER1A protein P12319 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000732 11971001 NO Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1|These up-regulating effects of PU.1 and YY1 with GATA-1 were inhibited by overexpression of Elf-1, indicating that Elf-1 serves as a repressor for the alpha-chain gene expression 0.2 SIGNOR-254287 SRC protein P12931 UNIPROT FXN protein Q16595 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr118 EDLADKPyTFEDYDV 9606 BTO:0000007 25948553 YES lperfetto We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation. 0.2 SIGNOR-275585 BUB1 protein O43683 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity relocalization 11402067 YES lperfetto Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity 0.727 SIGNOR-252017 SNRNP200 protein O75643 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.782 SIGNOR-270624 CRHR1 protein P34998 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 22869609 YES lperfetto Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3 0.452 SIGNOR-268618 TP53 protein P04637 UNIPROT NR4A3 protein Q92570 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30455429 YES miannu We showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. p53 transactivates the NR4A3 promoter in H1299 cells. 0.264 SIGNOR-256200 RNF170 protein Q96K19 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0000567 21610068 YES miannu In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound. 0.432 SIGNOR-271913 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 YES gcesareni We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence. 0.857 SIGNOR-72458 OTUD5 protein Q96G74 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000007 17991829 YES miannu TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains. DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1. 0.774 SIGNOR-265873 FCAR protein P24071 UNIPROT Cytokine_production phenotype SIGNOR-PH166 SIGNOR up-regulates 9606 BTO:0000130;BTO:0000801;BTO:0000876;BTO:0000399 30766540 NO lperfetto IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages 0.7 SIGNOR-264860 FBXO3 protein Q9UK99 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0004573 18809579 YES miannu O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.  0.464 SIGNOR-271743 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Thr179 FAKTFVGtPYYMSPE 9606 17197699 YES gcesareni Enzymatic activity, inhibited; 0.2 SIGNOR-151771 phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI CRLS1 protein Q9UJA2 UNIPROT up-regulates activity chemical activation 10090 16678169 YES lperfetto The mitochondrial phospholipid cardiolipin is synthesized from cytidinediphosphate-diacylglycerol and phosphatidylglycerol, a process catalyzed by the enzyme cardiolipin synthase. 0.8 SIGNOR-267029 ARIH1 protein Q9Y4X5 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 33879767 YES miannu We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. 0.2 SIGNOR-277553 PIN4 protein Q9Y237 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates 9606 BTO:0000567 12860119 NO lperfetto Par14 is a pre-rRNA processing factor involved in mammalian ribosome biogenesis, Par14 deficiency slowed cell growth (Fig. 3A) and reduced the production of 18 and 28 S rRNAs  0.7 SIGNOR-265755 TP53 protein P04637 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates 9606 15073170 NO gcesareni Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb. 0.357 SIGNOR-252816 PKA proteinfamily SIGNOR-PF17 SIGNOR HDAC4 protein P56524 UNIPROT up-regulates activity phosphorylation -1 30661366 YES miannu  In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. 0.2 SIGNOR-277424 NAT10 protein Q9H0A0 UNIPROT PARP1 protein P09874 UNIPROT up-regulates quantity by stabilization acetylation Lys949 PKGKHSVkGLGKTTP 9606 BTO:0000007 31616951 YES done miannu MORC2 directly interacts with PARP1. MORC2 mediates the interaction between PARP1 and NAT10 and thereby promotes NAT10-mediated PARP1 acetylation at K949, which blocks CHFR-mediated ubiquitination and degradation of PARP1. 0.2 SIGNOR-273715 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 Other YES The effect has been demonstrated using Q07817-1 gcesareni 0.8 SIGNOR-189153 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 17157250 YES lperfetto Ndpk-b directly binds and activates kca3.1 by phosphorylating histidine 358 in the carboxyl terminus of kca3.1 0.42 SIGNOR-151130 PRKCQ protein Q04759 UNIPROT PKCtheta/Nfix complex SIGNOR-C121 SIGNOR form complex binding 10090 BTO:0000165 20178747 YES llicata In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. 0.2 SIGNOR-238019 PTEN protein P60484 UNIPROT SP1 protein P08047 UNIPROT down-regulates activity dephosphorylation 9606 21603612 YES miannu Moreover, PTEN downregulates p75NTR expression by decreasing DNA-binding activity of Sp1 .|PTEN dephosphorylates the Sp1 transcription factor , the phosphorylation status of which directly impacts its ability to bind to some DNA promoter regions , . 0.421 SIGNOR-277119 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 YES We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell 0.481 SIGNOR-254301 TWIST2 protein Q8WVJ9 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 NO miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells 0.278 SIGNOR-255513 BCKDK protein O14874 UNIPROT BCKDHA protein P12694 UNIPROT down-regulates phosphorylation Ser337 TYRIGHHsTSDDSSA 9606 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000671 3947057 YES gcesareni Phosphorylation sites and inactivation of branched-chain alpha-ketoacid dehydrogenase isolated from rat heart, bovine kidney, and rabbit liver, kidney, heart, brain, and skeletal muscle. 0.608 SIGNOR-25084 AURKAIP1 protein Q9NWT8 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.661 SIGNOR-261461 GH1 protein P01241 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15665309 NO Luana Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells 0.2 SIGNOR-261627 SRGAP3 protein O43295 UNIPROT RAC3 protein P60763 UNIPROT down-regulates 9606 12447388 NO miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. 0.556 SIGNOR-95964 DAPK3 protein O43293 UNIPROT RPL13A protein P40429 UNIPROT up-regulates phosphorylation Ser77 PYHFRAPsRIFWRTV 9606 BTO:0000801 18995835 YES lperfetto Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro 0.402 SIGNOR-182117 COLGALT1 protein Q8NBJ5 UNIPROT ADIPOQ protein Q15848 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 28428430 YES We conclude that GLT25D1 regulates HMW adiponectin secretion and lipid accumulation, consistent with changes in mice after high-fat feeding. These results suggest a novel function of GLT25D1 leading to decreased HMW adiponectin secretion in early obesity. 0.2 SIGNOR-261149 TEK protein Q02763 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 18401423 YES miannu Tie2-R849W induced STAT1 phosphorylation at Y701 independent of ligand stimulation.|Together, Tie2-R849W induced functional activation of STAT1, leading to increased expression of STAT1-responsive gene like IRF1. 0.301 SIGNOR-279131 MAPK12 protein P53778 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 YES miannu Activated SAPK3 phosphorylates the mitochondrial protein Sab. we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391 0.443 SIGNOR-250140 PPP2CA protein P67775 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 17188031 YES We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity. 0.2 SIGNOR-248640 KLHL18 protein O94889 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0001938 23213400 YES miannu We identify Aurora-A as a KLHL18-interacting partner. Overexpression of KLHL18 and CUL3 promotes Aurora-A ubiquitylation in vivo, and the CUL3-KLHL18-ROC1 ligase ubiquitylates Aurora-A in vitro. Our study reveals that the CUL3-KLHL18 ligase is required for timely entry into mitosis, as well as for the activation of Aurora-A at centrosomes. 0.415 SIGNOR-272022 MARK2 protein Q7KZI7 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser873 VDDQKAGsPSRDVGP 9606 22883624 YES gcesareni Gab1 brings par1 and par3 into a transient complex, stimulating par3 phosphorylation by par1 0.494 SIGNOR-198742 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 BTO:0000938 18332217 YES lperfetto We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2. 0.396 SIGNOR-216725 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the FoxO family, and stimulates protein synthesis via the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3b (GSK3B). 0.87 SIGNOR-175285 TNFRSF17 protein Q02223 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 10903733 NO miannu Overexpression of bcma activates jnk 0.2 SIGNOR-79492 iodide smallmolecule CHEBI:16382 ChEBI diiodine smallmolecule CHEBI:17606 ChEBI up-regulates quantity precursor of 9606 23349248 YES miannu After transport through the apical membrane, I‚àí is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). 0.8 SIGNOR-268119 SLC25A12 protein O75746 UNIPROT aspartic acid smallmolecule CHEBI:22660 ChEBI up-regulates quantity relocalization 9606 12084073 YES miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 0.8 SIGNOR-265156 PLK1 protein P53350 UNIPROT CHEK2 protein O96017 UNIPROT unknown phosphorylation Thr26 SQPHGSVtQSQGSSS -1 12493754 YES lperfetto Plk1 overexpression enhances phosphorylation of Chk2 at Thr-68. Plk1 phosphorylates recombinant Chk2 in vitro. 0.492 SIGNOR-249180 UV stress stimulus SIGNOR-ST7 SIGNOR MAP3K4 protein Q9Y6R4 UNIPROT up-regulates 9606 9305639 NO lperfetto Overexpression of a dominant-negative MTK1 mutant [MTK1(K/R)] strongly inhibited the activation of the p38 pathway by environmental stresses (osmotic shock, UV and anisomycin)[]These results indicate that MTK1 is a major mediator of environmental stresses that activate the p38 MAPK pathway 0.7 SIGNOR-226605 CASP1 protein P29466 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.703 SIGNOR-256402 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 16293724 YES lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. 0.894 SIGNOR-227885 ALDH9A1 protein P49189 UNIPROT 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI up-regulates quantity chemical modification 9606 11802770 YES miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). 0.8 SIGNOR-269693 SRC protein P12931 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 BTO:0000182 27447856 YES lperfetto Here, we demonstrate that Src kinase directly phosphorylates Y88 paxillin|In this study, we also show how pY88 paxillin transduces a signal to activate Akt 0.807 SIGNOR-263977 BMPR1B protein O00238 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates phosphorylation 9606 9335504 YES inferred from 70% of family members llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. 0.708 SIGNOR-269846 GRPEL1 protein Q9HAV7 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.604 SIGNOR-267691 SETD5 protein Q9C0A6 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 32299058 NO The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression 0.7 SIGNOR-268627 GSK3B protein P49841 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr266 ARHLQENtQSHMRML 9606 BTO:0002181 30806153 YES miannu TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. 0.48 SIGNOR-277438 ID4 protein P47928 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21531766 NO miannu We found that ID4 enhanced SOX2 protein expression by suppressing microRNA-9* (miR-9*), which can repress SOX2 by targeting its 3'-untranslated region.  0.409 SIGNOR-255180 Telatinib chemical CID:9808844 PUBCHEM KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207227 SHC1 protein P29353 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0000782 8995379 YES gcesareni T cell activation effects an increase in grap association with p36/38, shc, sos, and dynamin. 0.507 SIGNOR-45528 ZM447439 chemical CHEBI:91376 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207920 PPAT protein Q06203 UNIPROT Purine biosynthesis phenotype SIGNOR-PH186 SIGNOR up-regulates activity 9606 28029518 NO The first reaction in the de novo purine biosynthetic pathway is the conversion of PRPP to 5-phosphoribosylamine (PRA) by PRPP amidotransferase (PPAT) and is presumed to be rate-limiting. 0.7 SIGNOR-267188 Ub:E2 complex SIGNOR-C497 SIGNOR RNF214 protein Q8ND24 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271088 oxybutynin chemical CHEBI:7856 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 22243489 YES Luana  Compared to the reference compound oxybutynin, an antagonist used for the treatment of OAB,(5) the newly synthesized 1,4-dioxane derivatives exhibit a higher potency. 0.8 SIGNOR-258328 L-homocysteine zwitterion smallmolecule CHEBI:58199 ChEBI L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI up-regulates quantity precursor of 9606 23981774 YES lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 0.8 SIGNOR-275826 MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9552384 NO gcesareni C-myc has emerged as one of the central regulators of mammalian cell proliferation. 0.7 SIGNOR-56572 MCM6 protein Q14566 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 YES The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. 0.781 SIGNOR-261676 SNAI1 protein O95863 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000567 29305973 NO miannu Our findings show that Snai1 mediates repression of PXDN and consolidate a role for this ECM-modifier during EMT. 0.7 SIGNOR-265252 VHL protein P40337 UNIPROT SPARC protein P09486 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000037 15824735 NO miannu three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. 0.2 SIGNOR-255603 NUP62 protein P37198 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR form complex binding 10116 BTO:0000154 2050741 YES Simone Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. 0.94 SIGNOR-261258 CD74 protein P04233 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 BTO:0000007;BTO:0000876 19665027 YES miannu Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling. 0.532 SIGNOR-187461 IL23A protein Q9NPF7 UNIPROT IL23R protein Q5VWK5 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 YES gcesareni We identify a novel member of the hemopoietin receptor family as a subunit of the receptor for il-23, il-23r. 0.861 SIGNOR-87805 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 YES lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376, and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 0.341 SIGNOR-166714 RORA protein P35398 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 YES miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. 0.242 SIGNOR-266847 S1PR1 protein P21453 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.503 SIGNOR-256713 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser604 FQSTSVKsPKTVSPP 9606 BTO:0001033 23188829 YES miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. 0.2 SIGNOR-263063 Caspase 3 complex complex SIGNOR-C221 SIGNOR BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization cleavage Asp1155 ETPDDLLdDGEIKED 9606 12149654 YES miannu We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable. 0.474 SIGNOR-256432 PIM1 protein P11309 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 YES gcesareni Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival. 0.481 SIGNOR-262961 USP6 protein P35125 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 20418905 NO miannu These data confirm that tre17 activates nfkappab in a usp-dependent manner 0.2 SIGNOR-164949 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 12270934 YES lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. 0.75 SIGNOR-235940 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGC3 protein Q9UN70 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265696 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 YES irozzo To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity. 0.661 SIGNOR-256290 GATOR1 complex SIGNOR-C192 SIGNOR RRAGA protein Q7L523 UNIPROT down-regulates activity gtpase-activating protein -1 23723238 YES GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. 0.875 SIGNOR-253562 ATM protein Q13315 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Ser112 KRAGGEEsQFEMDI 9606 11146653 YES lperfetto Here we report that atm... phosphorylates 4e-bp1 at ser 111cells lacking atm kinase activity exhibit a significant decrease in the insulin-induced dissociation of 4e-bp1 from eif-4e. 0.513 SIGNOR-85619 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 16046550 YES The effect has been demonstrated using Q01196-8 gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.2 SIGNOR-138932 CDK2 protein P24941 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates phosphorylation Thr847 FRYIPPNtPENFWEV 9606 19202191 YES llicata Collectively, these findings thereby provided strong support for ctip thr-847 indeed being a cdk target. it is established that both cdk-dependent and checkpoint-dependent phosphorylations are required for activation of sae2/ctip in vivo 0.616 SIGNOR-183840 SIK1 protein P57059 UNIPROT CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation Ser167 MTPTQPEsFSSGSQD 9606 16817901 YES miannu These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities. 0.494 SIGNOR-147669 RHOA protein P61586 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000132 35267019 YES miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. 0.76 SIGNOR-268429 MAPK3 protein P27361 UNIPROT SULT4A1 protein Q9BR01 UNIPROT down-regulates phosphorylation Thr11 SEAETPStPGEFESK 9606 BTO:0000938 BTO:0000142 20920535 YES gcesareni The phosphorylation of sult4a1 allows interaction with pin1, which then promotes degradation of the sulfotransferase. 0.2 SIGNOR-168248 Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 10090 BTO:0001086 19279220 NO miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.7 SIGNOR-270727 PEX6 protein Q13608 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 NO The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis. 0.7 SIGNOR-253617 SLC20A2 protein Q08357 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 11009570 YES lperfetto 0.8 SIGNOR-270580 KIT protein P10721 UNIPROT SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates phosphorylation 9606 15526160 YES apalma Binding of SCF to c-Kit leads to a rapid increase in SFK kinase activity 0.593 SIGNOR-254995 IL2 protein P60568 UNIPROT IL2RA protein P01589 UNIPROT up-regulates binding 9606 16477002 YES miannu Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c). 0.927 SIGNOR-144537 PPP3CC protein P48454 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 YES In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. 0.402 SIGNOR-248524 entinostat chemical CHEBI:132082 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257904 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodo-L-thyronine smallmolecule CHEBI:11684 ChEBI up-regulates quantity small molecule catalysis 20978344 YES inferred from family member The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4) 0.8 SIGNOR-270305 CRY1 protein Q16526 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. 0.939 SIGNOR-267975 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C3 19690328 YES lperfetto The complementary inhibitory mechanism in which mtorc1 phosphorylates the autophagy regulatory complex containing unc-51-like kinase 1 (ulk1), the mammalian atg13 protein, and focal adhesion kinase interacting protein of 200 kd (fip200) has also been elucidated. 0.849 SIGNOR-187611 CyclinY/CDK14 complex SIGNOR-C541 SIGNOR CCNY protein Q8ND76 UNIPROT down-regulates quantity by destabilization phosphorylation Ser73 STIFLSKsQTDVREK 9606 BTO:0000599 24794231 YES lperfetto Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation|Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex 0.829 SIGNOR-273009 MTCH1 protein Q9NZJ7 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 12377771 NO SARA PSAP is an important regulator of apoptosis 0.7 SIGNOR-260994 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR TJP2 protein Q9UDY2 UNIPROT up-regulates 9606 21529719 NO milica Another junction protein, the tight junction protein ZO-2, binds to YAP/TAZ, facilitating their nuclear translocation. 0.7 SIGNOR-230703 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192868 KIF5A protein Q12840 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 31753031 YES miannu Postsynaptic density protein 95 (PSD-95) is transported by KIF5 to dendritic regions 0.314 SIGNOR-264065 AL/b2 integrin complex SIGNOR-C169 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269018 CCP110 protein O43303 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 12361598 NO miannu Reduction in CP110 Protein Levels or Loss of CP110 Phosphorylation Promotes Centrosome Separation. 0.7 SIGNOR-265964 MAP1LC3B protein Q9GZQ8 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates binding 9606 22170151 YES gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe. 0.834 SIGNOR-191549 KDM6A protein O15550 UNIPROT ZBTB16 protein Q05516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29736013 YES miannu UTX catalytic activity has been reported to upregulate expression of the master transcription factor PLZF and to modulate superenhancer accessibility in invariant natural killer T cells. 0.311 SIGNOR-260038 ETS2 protein P15036 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 YES miannu We demonstrated that Ets2 is capable of binding to and transactivating the OPN promoter using gel shift and transient transfection assays 0.252 SIGNOR-259872 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 21679342 YES gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. 0.8 SIGNOR-174417 conivaptan chemical CHEBI:681850 ChEBI AVPR2 protein P30518 UNIPROT down-regulates activity chemical inhibition -1 20471258 YES Luana One of the targets, 13d, demonstrated improved V2-receptor binding and was further profiled for comparison with conivaptan, the program’s mixed V1a/V2 standard (Table 4). Compound 13d displayed similar V1a-receptor affinity, albeit with a 30-fold weaker V2-receptor affinity when compared to conivaptan. 0.8 SIGNOR-257844 GPS1 protein Q13098 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.924 SIGNOR-270765 AT9283 chemical CID:11696609 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190014 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr301 PPGEDSDtDVDDDSR 9606 18678890 YES gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. 0.347 SIGNOR-179883 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCI protein P41743 UNIPROT up-regulates activity binding 9606 14967450 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. 0.8 SIGNOR-242581 FGF9 protein P31371 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 NO FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1 gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts 0.307 SIGNOR-134797 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 14744793 YES lperfetto Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. 0.652 SIGNOR-249480 MAML1 protein Q92585 UNIPROT CCNC protein P24863 UNIPROT up-regulates relocalization 9606 15546612 YES gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. 0.445 SIGNOR-130709 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Ser27 SFGFTRTsARRRLAD 21880142 YES miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2. PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. 0.307 SIGNOR-266299 STUB1 protein Q9UNE7 UNIPROT IRS4 protein O14654 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 30026872 YES miannu IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP). 0.2 SIGNOR-277616 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257786 STAT3 protein P40763 UNIPROT KRT17 protein Q04695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 21796151 NO miannu IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. 0.259 SIGNOR-255234 Ub:E2 complex SIGNOR-C497 SIGNOR RNF216 protein Q9NWF9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270971 CDK7 protein P50613 UNIPROT PCGF6 protein Q9BYE7 UNIPROT unknown phosphorylation Ser30 LPPPPPVsPPALTPA -1 12167161 YES llicata In addition, we find that serine 32 of MBLR is specifically phosphorylated during mitosis, most likely by CDK7, a component of the basal transcriptional machinery. | These results indicate that, at least in vitro, MBLR is a substrate for CDK7 phosphorylation. 0.305 SIGNOR-250769 KLF6 protein Q99612 UNIPROT ATF3 protein P18847 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001321 18755691 YES Luana KLF6 binds directly to and activates the ATF3 promoter. 0.394 SIGNOR-266051 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.6 SIGNOR-34665 PRKCQ protein Q04759 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15364919 YES Manara Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). 0.566 SIGNOR-260906 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24024136 YES irozzo In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs). 0.47 SIGNOR-256277 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 9606 15379552 YES lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) 0.2 SIGNOR-129188 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser185 KTTQNRYsFYSTCSG -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273494 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 YES llicata By using a phospho-specific antibody, we show that abl directly phosphorylates pkd at tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of pkd 0.34 SIGNOR-99255 PAX2/TLE4 complex SIGNOR-C152 SIGNOR WT1 protein P19544 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002295 16631587 YES Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. 0.448 SIGNOR-252291 NEDD4L protein Q96PU5 UNIPROT CLCN5 protein P51795 UNIPROT down-regulates quantity by destabilization ubiquitination 9267 BTO:0003069 15489223 YES miannu The presence of albumin triggers the formation of an endocytic complex that includes ClC-5. (iii) Nedd4-2 is recruited to this complex and ubiquitinates ClC-5. This ubiquitination by Nedd4-2 shunts ClC-5 into the albumin uptake/degradative pathway. 0.292 SIGNOR-272665 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Ser2155 GFAEAIHsPQVAGVP 9606 18794356 YES miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. 0.375 SIGNOR-181014 NLK protein Q9UBE8 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 20118921 YES gcesareni Nlk-phosphorylated notch1icd is impaired in its ability to form a transcriptionally_ active_ ternary_ complex. 0.382 SIGNOR-163697 α-D-glucose smallmolecule CHEBI:17925 ChEBI Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 23680095 YES miannu Glycolysis is a cytoplasmic non-oxidative reaction for glucose degradation that is composed of 9 pro cesses. A non-specific HK enzyme by using ATP phosphorylates glucose following entrance to the cell and converts it to G6P. 0.7 SIGNOR-267959 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206670 TBL1Y protein Q9BQ87 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates quantity by destabilization binding 9606 18374649 YES Luana TBL1 interacts in vivo with CtBP and promote its proteasomal degradation 0.2 SIGNOR-260902 GGCX protein P38435 UNIPROT PROC protein P04070 UNIPROT up-regulates activity carboxylation 9606 28125048 YES lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z 0.571 SIGNOR-265925 AKT1 protein P31749 UNIPROT LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr324 GGRSREGtMELRTTP 9606 22044535 YES llicata Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis. 0.383 SIGNOR-252516 BRD3 protein Q15059 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 BTO:0003292 28045112 YES lperfetto Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3 0.317 SIGNOR-262044 NHLH2 protein Q02577 UNIPROT MAOA protein P21397 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 22169038 NO miannu SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter 0.399 SIGNOR-254829 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 10523516 YES gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. 0.783 SIGNOR-71423 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 YES gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. 0.2 SIGNOR-118542 SLC27A6 protein Q9Y2P4 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264467 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 7993631 YES gcesareni We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type. 0.2 SIGNOR-35626 CBL protein P22681 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity binding 10090 BTO:0001516 19276253 YES Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. 0.437 SIGNOR-255739 mTORC1 complex SIGNOR-C3 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 NO The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. 0.7 SIGNOR-256063 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI PTGER3 protein P43115 UNIPROT up-regulates chemical activation 9606 15299086 YES gcesareni Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4. 0.8 SIGNOR-127738 CDK2 protein P24941 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates phosphorylation Ser158 FVSHSHIsPIKPTEA 9606 19066288 YES llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1 0.282 SIGNOR-182761 MDH2 protein P40926 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-268100 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 18204439 YES lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. 0.716 SIGNOR-252957 NTN1 protein O95631 UNIPROT NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 28245592 YES miannu Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins. 0.824 SIGNOR-268169 PRKCA protein P17252 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 YES Translocation from Endosome to Lysosome fspada In this study, we demonstrated that ser396 and ser398 are phosphorylated by pkc and, that phosphorylation of ser398 is particularly involved in pmainduced desensitization of the h1r. 0.2 SIGNOR-66015 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT unknown phosphorylation Ser418 QQRKALLsPFSTPVR -1 15952796 YES lperfetto We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites. 0.298 SIGNOR-249406 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser164 CKGFFRRsITKNAVY 9606 18755856 YES llicata Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154. 0.325 SIGNOR-180541 DOCK8 protein Q8NF50 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 28028151 YES lperfetto Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation.  0.766 SIGNOR-268412 GRIA2 protein P42262 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 NO miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses 0.7 SIGNOR-264612 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR4 protein O95977 UNIPROT up-regulates activity chemical activation 9606 10753843 YES These results indicate that EDG-6 is a high affinity receptor for SPP, which couples to a G(i/o) protein, resulting in the activation of growth-related signaling pathways 0.8 SIGNOR-261143 NFIB protein O00712 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268901 TNFRSF17 protein Q02223 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 10903733 NO miannu Overexpression of bcma activates jnk 0.291 SIGNOR-79489 HMGB2 protein P26583 UNIPROT POU2F2 protein P09086 UNIPROT up-regulates activity binding 10090 7720710 YES 2 miannu HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins 0.32 SIGNOR-240108 ATP(4-) smallmolecule CHEBI:30616 ChEBI 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI up-regulates quantity precursor of 23258413 YES lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. 0.8 SIGNOR-276594 POMC protein P01189 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity 9606 BTO:0000848 16274845 NO miannu Alpha-MSH is an anti-inflammatory peptide which signals by binding to the melanocortin-1 receptor (MC1R) and elevating cyclic AMP in several different cells and tissues. The carboxyl terminal peptides of alpha-MSH (KPV/GKPV) are the smallest minimal sequences that prevent inflammation, but it is not known if they operate via MC1R or cyclic AMP. Immobilized alpha-melanocyte stimulating hormone 10-13 (GKPV) inhibits tumor necrosis factor-alpha stimulated NF-kappaB activity. 0.256 SIGNOR-252371 MLH1/PMS2 complex SIGNOR-C59 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 29175432 NO MLH1 and PMS2 proteins form the MutLα heterodimer, which plays a major role in DNA mismatch repair (MMR) in humans 0.7 SIGNOR-257600 lurasidone chemical CHEBI:70735 ChEBI ADRA2C protein P18825 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 20404009 YES Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. 0.8 SIGNOR-257837 sunitinib chemical CHEBI:38940 ChEBI PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 21423276 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-172923 POLR2L protein P62875 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 9606 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.908 SIGNOR-266151 folic acid smallmolecule CHEBI:27470 ChEBI dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity precursor of 9606 BTO:0000575 19706381 YES lperfetto However, since the synthesis of folic acid (FA, pteroylglutamic acid) as a provitamin in 1945, DHFR has taken on another role: reduction of FA to 7,8-DHF (Fig. 1) 0.8 SIGNOR-268263 ENO1 protein P06733 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 BTO:0000318 2005901 YES Luana This result suggests that MBP-1 in vivo acts as a sequence-specific repressor. 0.412 SIGNOR-261594 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr77 DPCSLIPtPDKEDDD 9606 14536078 YES gcesareni Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380 0.446 SIGNOR-118563 PAX3 protein P23760 UNIPROT TBX2 protein Q13207 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002267 25211658 YES lperfetto We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3 0.346 SIGNOR-249596 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 11390389 YES Manara Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence 0.385 SIGNOR-260807 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline smallmolecule CHEBI:94276 ChEBI GLI1 protein P08151 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0001130 17494766 YES gcesareni Gant61 was able to efficiently block gli1 as well as gli2-induced transcription 0.8 SIGNOR-154753 SKA1 protein Q96BD8 UNIPROT SKA complex complex SIGNOR-C364 SIGNOR form complex binding -1 22483620 YES lperfetto We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. 0.911 SIGNOR-265197 PJA1 protein Q8NG27 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates ubiquitination 9606 16247473 YES gcesareni The present study indicates that praja, a ring finger e3 ubiquitin ligase, interacts with elf and ubiquitinates it. 0.404 SIGNOR-141216 ESR1 protein P03372 UNIPROT UGT1A4 protein P22310 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 19546240 NO miannu our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy. 0.3 SIGNOR-254075 CHEK2 protein O96017 UNIPROT TTK protein P33981 UNIPROT unknown phosphorylation Thr288 SPDCDVKtDDSVVPC 9606 19151762 YES llicata Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir 0.292 SIGNOR-183470 PTTG1 protein O95997 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates activity binding 9606 15737063 YES lperfetto Prior to anaphase, separase is kept inactive by its inhibitor securin 0.945 SIGNOR-275538 NatA complex SIGNOR-C415 SIGNOR H2AX protein P16104 UNIPROT down-regulates activity acetylation 9606 BTO:0001109 21351257 YES miannu The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer.  lack of acetylation by hNatA activated H2A.X and Chk2 in both HCT116 cell lines independent of TP53 status (Fig. 6). 0.2 SIGNOR-267227 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18487050 YES Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  0.8 SIGNOR-257795 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg494 CAKTKQLrVVNGIPT -1 12372819 YES miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. 0.313 SIGNOR-256514 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Ser96 KTQLNPTsLQKLFRE 9606 15319445 YES gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. 0.2 SIGNOR-259432 ADAM10 protein O14672 UNIPROT EGF protein P01133 UNIPROT up-regulates activity cleavage 9606 26284334 YES miannu Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin 0.564 SIGNOR-259840 halothane chemical CHEBI:5615 ChEBI KCNK3 protein O14649 UNIPROT up-regulates activity chemical activation 10090 20519544 YES Luana We further demonstrate that TASK channels are required for normal sensitivity to immobilizing effects of halothane and isoflurane and to sedative/hypnotic effects of halothane. 0.8 SIGNOR-257846 CDK3 protein Q00526 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser118 LHPPPQLsPFLQPHG 26202215 YES lperfetto CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3 0.259 SIGNOR-273187 U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11739736 NO miannu The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing. 0.7 SIGNOR-263945 TLX1 protein P31314 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates activity binding 9606 BTO:0000661 15897879 YES 2 miannu HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade. 0.301 SIGNOR-240722 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK -1 10734133 YES miannu Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant. 0.378 SIGNOR-75894 MAPK1 protein P28482 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser333 KGLVSPQsPQKSDCQ 9606 BTO:0000782;BTO:0000785 9649500 YES gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. 0.49 SIGNOR-58481 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 YES gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.722 SIGNOR-134549 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194551 Ub:E2 complex SIGNOR-C497 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271287 mTORC2 complex SIGNOR-C2 SIGNOR SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 18925875 YES lperfetto Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422) 0.659 SIGNOR-217016 TNKS protein O95271 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization 9606 BTO:0000007 19759537 YES Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. 0.519 SIGNOR-261249 SIRT7 protein Q9NRC8 UNIPROT SAR1A protein Q9NR31 UNIPROT up-regulates activity deacetylation 9606 BTO:0002181 28790157 YES SARA SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding 0.2 SIGNOR-260978 RNF111 protein Q6ZNA4 UNIPROT SUMO2 protein P61956 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23530056 YES miannu Arkadia ubiquitinates poly-SUMO2 chains in a SIM- and RING-dependent manner. 0.625 SIGNOR-272882 PEX5 protein P50542 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000007 ubiquitination:Lys209 VAKVDDPkLANSEFL 26344566 YES Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.  0.372 SIGNOR-262793 IHH protein Q14623 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 YES lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. 0.837 SIGNOR-61311 TDP2 protein O95551 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0002181 21980489 YES miannu TTRAP associates with TRAF6.The TAK1-TTRAP-TRAF6 complex is stabilized by ubiquitylation and recruited to TβRI. 0.378 SIGNOR-277189 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI MAPK9 protein P45984 UNIPROT down-regulates chemical inhibition 9606 18922779 YES BI-78D3 is substrate competitive. gcesareni Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell. 0.8 SIGNOR-181650 DNMT3B protein Q9UBC3 UNIPROT BAG1 protein Q99933 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 NO lperfetto DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation 0.326 SIGNOR-254109 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser242 MDKRKDPsSVDIKKV -1 10480872 YES llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. 0.347 SIGNOR-250773 CDK18 protein Q07002 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity 9606 BTO:0000567 28361970 NO lperfetto PCTK3/CDK18 regulates cell migration and adhesion by negatively modulating FAK activity 0.2 SIGNOR-264561 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser145 VVCGDRAsGYHYNAL 9606 18755856 YES llicata Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154. 0.325 SIGNOR-180537 HDAC5 protein Q9UQL6 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 11062529 YES gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. 0.705 SIGNOR-84023 aliskiren fumarate chemical CHEBI:53777 ChEBI REN protein P00797 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189483 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR DKK1 protein O94907 UNIPROT up-regulates activity 15229249 NO Exposure of the cultures to beta-amyloid peptide (βAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1).  0.7 SIGNOR-255482 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Thr387 HKKLMFKtEGPDSD 9606 BTO:0001321 15659650 YES lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. 0.779 SIGNOR-217861 PRKACA protein P17612 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser1018 QVEFRRLsISAESQS 10487978 YES miannu Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. Ser1018 within this multiphosphorylation domain is phosphorylated by PKA and is a major site of regulatory phosphorylation in vivo 0.431 SIGNOR-250026 MAPK3 protein P27361 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser93 ALQRQPPsPKQLEEE -1 16226275 YES lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| 0.692 SIGNOR-249475 MRPL23 protein Q16540 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.2 SIGNOR-262370 CDK1 protein P06493 UNIPROT PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 SIGNOR-C17 15541388 YES llicata Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles. 0.553 SIGNOR-130439 GRIA1 protein P42261 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 10090 BTO:0000938 15115814 NO lperfetto The targeting and clustering of AMPA and NMDA receptors to synapses in the CNS is essential for efficient excitatory synaptic transmission 0.7 SIGNOR-261433 BCORL1 protein Q5H9F3 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity binding 9606 BTO:0000567 17379597 YES irozzo BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor. 0.44 SIGNOR-259113 COX14 protein Q96I36 UNIPROT MITRAC complex complex SIGNOR-C538 SIGNOR form complex binding 9606 BTO:0000007 23260140 YES By analyzing MITRAC12 interaction partners, we show that recently identified assembly factors, such as c12orf62, CMC1, and the novel assembly factor MITRAC15, are constituents of MITRAC complexes 0.378 SIGNOR-272482 TYK2 protein P29597 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity phosphorylation 9606 27782195 YES miannu JAK1 and TYK2 will phosphorylate and activate STAT1 and STAT2 respectively, leading to the formation of the ternary interferon-stimulated gene factor 3 (ISGF3) complex, composed of STAT1, STAT2 and interferon regulatory factor 9 (IRF9). 0.788 SIGNOR-279133 GATA1 protein P15976 UNIPROT GP1BA protein P07359 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17725493 NO miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. 0.545 SIGNOR-254191 CASP3 protein P42574 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.405 SIGNOR-261743 PIM1 protein P11309 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 17643117 YES gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. 0.2 SIGNOR-265366 ATF4 protein P18848 UNIPROT SIGMAR1 protein Q99720 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22079628 NO miannu we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress. 0.382 SIGNOR-253750 ASPSCR1 protein Q9BZE9 UNIPROT VCPKMT protein Q9H867 UNIPROT up-regulates binding 9606 23349634 YES gcesareni In the case of vcp, methylation by mettl21d was stimulated by the addition of the ubx cofactor aspscr1, which we show directly interacts with the methyltransferase. 0.342 SIGNOR-200572 TM9SF4 protein Q92544 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 29125601 NO miannu In the present study, we report a novel autophagy-related protein TM9SF4, which plays a functional role in the induction phase of autophagic process. Overexpression of TM9SF4 promoted autophagic flux in HEK293 cells. 0.7 SIGNOR-266704 TET1 protein Q8NFU7 UNIPROT ZNF382 protein Q96SR6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27708339 YES irozzo Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. 0.2 SIGNOR-259095 ULK1 protein O75385 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 BTO:0000567;BTO:0000938 BTO:0000142 11146101 YES gcesareni N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions 0.639 SIGNOR-85614 AMPK complex SIGNOR-C15 SIGNOR MCU protein Q8NE86 UNIPROT up-regulates activity phosphorylation Ser57 TVHQRIAsWQNLGAV -1 30858581 YES lperfetto Cellular ATP levels drop during early mitosis, and the mitochondrial Ca2+ transients boost mitochondrial respiration to restore energy homeostasis. This is achieved through mitosis-specific MCU phosphorylation and activation by the mitochondrial translocation of energy sensor AMP-activated protein kinase (AMPK). |In vitro kinase assays showed that AMPK immunoprecipitated from cells as well as recombinant AMPK phosphorylated MCU at Ser57 0.2 SIGNOR-275548 AKT1 protein P31749 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Ser695 EERMRMEsRRQATVS -1 23264741 YES miannu  Here we show that soluble growth factors enhance integrin signaling through Akt phosphorylation of FAK at Ser695 and Thr700.  0.431 SIGNOR-276437 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. 0.728 SIGNOR-183640 ANKS1B protein Q7Z6G8 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 26356309 NO miannu AIDA-1 is highly enriched in postsynaptic density (PSD) fractions and is considered a major component of the PSD complex. 0.7 SIGNOR-264226 ATP smallmolecule CHEBI:15422 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 33961946 YES miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 0.8 SIGNOR-267837 4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid chemical CHEBI:64210 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 YES Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  0.8 SIGNOR-258140 BAP1 protein Q92560 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 26416890 NO lperfetto The BAP1/ASXL2 Histone H2A Deubiquitinase Complex Regulates Cell Proliferation and is Disrupted in Cancer. 0.7 SIGNOR-241660 DNMT3B protein Q9UBC3 UNIPROT BAG3 protein O95817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 NO lperfetto In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+) 0.2 SIGNOR-254111 SNX8 protein Q9Y5X2 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity binding 9606 BTO:0000007 29180417 YES miannu IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKβ to the JAK1 complex.  0.2 SIGNOR-273646 RUNX3 protein Q13761 UNIPROT ING1 protein Q9UK53 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.248 SIGNOR-255099 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 YES miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. 0.392 SIGNOR-250394 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 10090 BTO:0000944 7889942 YES lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency. 0.562 SIGNOR-235471 acetyl-CoA smallmolecule CHEBI:15351 ChEBI malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity precursor of 9606 20952656 YES miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA 0.8 SIGNOR-267107 ABL1 protein P00519 UNIPROT CRK protein P46108 UNIPROT down-regulates activity phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 21779437 YES lperfetto Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl 0.76 SIGNOR-175135 PFKFB4 protein Q16877 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity chemical modification 9606 15170386 YES Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure‚Äì function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2 0.8 SIGNOR-267264 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 10636859 YES gcesareni Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation. 0.2 SIGNOR-73967 PRKCA protein P17252 UNIPROT ITPKA protein P23677 UNIPROT down-regulates activity -1 9374536 YES lperfetto In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity). 0.371 SIGNOR-248991 AHCYL1 protein O43865 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT up-regulates activity binding 9606 BTO:0000007 21317537 YES miannu IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities. 0.672 SIGNOR-263135 RB1 protein P06400 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 21524151 NO lperfetto Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. 0.7 SIGNOR-245486 FBXW7 protein Q969H0 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0002524 17298674 YES miannu Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme 0.891 SIGNOR-271641 RPS6KA1 protein Q15418 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0001103 21798082 YES lperfetto Negative feedback involves s6k, which inactivates irs by phosphorylation at multiple sites, thus inducing its degradation and altered cell localization. 0.358 SIGNOR-175687 RBBP6 protein Q7Z6E9 UNIPROT YBX1 protein P67809 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 18851979 YES miannu RBBP6 interacts with multifunctional protein YB-1 through its RING finger domain, leading to ubiquitination and proteosomal degradation of YB-1 0.317 SIGNOR-271773 Ub:E2 complex SIGNOR-C497 SIGNOR RNF167 protein Q9H6Y7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271224 ROCK1 protein Q13464 UNIPROT Satellite_cells_self-renewal phenotype SIGNOR-PH100 SIGNOR up-regulates transcriptional regulation BTO:0001103 23290138 NO apalma FN in the satellite cell niche is required for the maintenance of the overall satellite cell pool during muscle regeneration. Moreover, FN is necessary to potentiate Wnt7a signaling through the Fzd7/Scd4 receptor complex, which controls the regulation of satellite stem cell numbers 0.7 SIGNOR-255850 zileuton chemical CHEBI:10112 ChEBI ALOX5 protein P09917 UNIPROT down-regulates activity chemical inhibition 10116 1848634 YES miannu 5-lipoxygenase inhibitory activity of zileuton. 0.8 SIGNOR-258363 BMS-754807 chemical CHEBI:88339 ChEBI IGF1R protein P08069 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001802 19996272 YES lperfetto BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR 0.8 SIGNOR-262027 MYD88 protein Q99836 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 10090 BTO:0000906 16306937 YES Using MyD88 as a prototypical adaptor, we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6. 0.695 SIGNOR-256079 PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification 9606 23140367 YES miannu Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). 0.8 SIGNOR-251558 SLC16A3 protein O15427 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 NO lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. 0.7 SIGNOR-242468 CNTRL protein Q7Z7A1 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR down-regulates 9606 18694559 NO miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state 0.7 SIGNOR-252150 FUS protein P35637 UNIPROT MATR3 protein P43243 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 27731383 YES P35637:p.Pro525Leu (mutation disrupting interaction) Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates. 0.486 SIGNOR-262822 AV412 chemical CID:11700696 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190050 DLG3 protein Q92796 UNIPROT NMDA receptor_2D complex SIGNOR-C350 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 YES lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. 0.646 SIGNOR-266009 ERG protein P11308 UNIPROT CXCL8 protein P10145 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001949 19359602 NO miannu ERG can inhibit the activity of the IL-8 promoter in a dose dependent manner. 0.2 SIGNOR-253912 UVB radiation stimulus SIGNOR-ST17 SIGNOR IL1A protein P01583 UNIPROT up-regulates 9606 9767234 NO miannu UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes. 0.7 SIGNOR-252384 PLK1 protein P53350 UNIPROT MRE11 protein P49959 UNIPROT down-regulates activity phosphorylation Ser649 EVIEVDEsDVEEDIF 9606 BTO:0001938 28512243 YES miannu Plk1 phosphorylates Mre11 at S649.Mre11 phosphorylation at S649/S688 inhibits its binding to dsDNA and antagonizes the ATM signaling. 0.2 SIGNOR-265943 RNF19A protein Q9NV58 UNIPROT CASR protein P41180 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16513638 YES miannu Coexpression with dorfin decreased the amount of total CaR protein and increased CaR ubiquitination, whereas a dominant negative fragment of dorfin had opposite effects. dorfin-mediated proteasomal degradation of immature CaR occurs from the endoplasmic reticulum. Because endogenous CaR in Madin-Darby canine kidney cells is also subject to degradation from the endoplasmic reticulum, dorfin-mediated ubiquitination may contribute to a general mechanism for CaR quality control during biosynthesis. 0.382 SIGNOR-271456 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. 0.2 SIGNOR-183661 MCHR2 protein Q969V1 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257390 RELA protein Q04206 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 SIGNOR-C13 18174238 YES gcesareni Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment 0.718 SIGNOR-160330 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 14556242 YES lperfetto In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. 0.942 SIGNOR-118615 SCN11A protein Q9UI33 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 NO miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. 0.7 SIGNOR-253453 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates phosphorylation Tyr1325 RLLEGNFyGSLFSVP 9606 19834457 YES gcesareni The nr2a subunit of the nmda receptor is tyrosine-phosphorylated, with tyr 1325 as its one of the major phosphorylation site. Tyr 1325 phosphorylation site is required for src-induced potentiation of the nmda receptor channel in the striatum. Tyr 1325 was most prominently phosphorylated by fyn in vitro. 0.733 SIGNOR-188527 CSNK2A1 protein P68400 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1067 GDVEGSQsQDEGEGS 9606 18442975 YES gcesareni Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm. 0.2 SIGNOR-178483 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates binding 9606 14967450 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. gcesareni The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. 0.8 SIGNOR-121956 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192623 AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 24130457 NO lperfetto AP-2 is the core-organizing element in clathrin-mediated endocytosis. During the formation of clathrin-coated vesicles, clathrin and endocytic accessory proteins interact with AP-2 in a temporally and spatially controlled manner 0.7 SIGNOR-260705 JAZF1 protein Q86VZ6 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 15302918 YES miannu Tip27 interacts specifically with tak1 / tip27 functions as a tak1-selective repressor 0.454 SIGNOR-127900 ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-265003 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr730 PNLFVALyDFVASGD 9606 16912036 YES Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 0.2 SIGNOR-260810 IRF8 protein Q02556 UNIPROT CYBB protein P04839 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 11483597 NO miannu we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. 0.349 SIGNOR-222710 IRF2BPL protein Q9H1B7 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000498 29374064 YES miannu FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. 0.2 SIGNOR-267153 GAN protein Q9H2C0 UNIPROT CUL3 protein Q13618 UNIPROT up-regulates activity binding 10090 BTO:0000142 18680552 YES miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. 0.671 SIGNOR-268944 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12050114 YES gcesareni Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation. 0.355 SIGNOR-88716 axitinib chemical CHEBI:66910 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 YES gcesareni Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine. 0.8 SIGNOR-171860 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser246 FPKSRLSsVSVTYCS 9606 19182667 YES lperfetto Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters 0.2 SIGNOR-183596 TRAF6 protein Q9Y4K3 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 17572386 NO miannu TRAF6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation. 0.7 SIGNOR-253046 HSPG2 protein P98160 UNIPROT PTPRS protein Q13332 UNIPROT up-regulates binding 9606 11865065 YES gcesareni We demonstrate here that cptpsigma is a heparin-binding protein and that its basal lamina ligands include the heparan sulfate proteoglycans (hspgs) agrin and collagen xviii. 0.253 SIGNOR-115246 RPS6KA1 protein Q15418 UNIPROT CDC34 protein P49427 UNIPROT down-regulates quantity by destabilization phosphorylation Thr162 KGKDREYtDIIRKQV -1 27786305 YES miannu RSK1 phosphorylated Thr162 on UBE2R1.RSK1 induced self-ubiquitination and destabilisation of UBE2R1 by phosphorylation. 0.336 SIGNOR-277330 CSNK2A1 protein P68400 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Thr1318 YQNTTAMtIYENLAP 9606 BTO:0002181 24583284 YES miannu CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation. 0.2 SIGNOR-277876 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 9606 BTO:0000149 24269383 YES llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. 0.2 SIGNOR-203302 ANK1 protein P16157 UNIPROT ATP2A1 protein O14983 UNIPROT down-regulates activity binding 9986 28487373 YES lperfetto We recently reported that small ankyrin 1 (sAnk1) interacts with the sarco(endo)plasmic reticulum Ca2+-ATPase in skeletal muscle (SERCA1) to inhibit its activity. 0.294 SIGNOR-265927 DGC complex SIGNOR-C217 SIGNOR GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265440 CYP1B1 protein Q16678 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000093 8790407 YES Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. 0.8 SIGNOR-269756 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser139 RRGLLYDsDEEDEER 9606 16446360 YES gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. 0.962 SIGNOR-143988 acadesine chemical CHEBI:28498 ChEBI PRKAG1 protein P54619 UNIPROT up-regulates chemical activation 9606 SIGNOR-C15 16879084 YES gcesareni The activation of the ampk pathway by exendin-4 was induced by aicar, which was inhibited by compound c. 0.8 SIGNOR-148337 hsa-mir-223 mirna URS000037EC34_9606 RNAcentral Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 24708856 YES miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. 0.4 SIGNOR-255763 NFIX protein Q14938 UNIPROT PKCtheta/Nfix complex SIGNOR-C121 SIGNOR form complex binding 10090 BTO:0000165 20178747 YES llicata In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. 0.2 SIGNOR-238016 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194628 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr84 EHSDSEMyVMPAEEN 9606 BTO:0000776 12456653 YES llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. 0.805 SIGNOR-96048 IQSEC2 protein Q5JU85 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 27009485 NO miannu These data demonstrate that the reduction of BRAG1 results in a reduction of synaptic transmission. Together with the data showing that overexpression of BRAG1 enhances synaptic transmission, these data highlight the role of BRAG1 in the bidirectional regulation of synaptic transmission. 0.7 SIGNOR-264905 RPS6KA3 protein P51812 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity 9606 20383198 NO lperfetto We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions. 0.2 SIGNOR-252038 MMP1 protein P03956 UNIPROT COL2A1 protein P02458 UNIPROT down-regulates quantity by destabilization cleavage Gly774 RGDVGEKgPEGAPGK -1 17318226 YES lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  0.445 SIGNOR-272338 SREBF1 protein P36956 UNIPROT Lipogenesis phenotype SIGNOR-PH30 SIGNOR up-regulates 10090 15589694 NO lperfetto In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin induced glucose metabolism (particularly in lipogenesis), 0.7 SIGNOR-228614 RIMS3 protein Q9UJD0 UNIPROT UNC13B protein O14795 UNIPROT up-regulates activity relocalization 9606 31679900 YES miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle 0.266 SIGNOR-264384 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 21757713 YES lperfetto The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation. 0.384 SIGNOR-217544 CSMD1 protein Q96PZ7 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 9606 22538441 NO miannu CSMD1 inhibits tumor growth, angiogenesis, and survival rate in vivo 0.7 SIGNOR-265150 FGF2 protein P09038 UNIPROT ALPL protein P05186 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004473 19049325 NO miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. 0.375 SIGNOR-252194 CRBN protein Q96SW2 UNIPROT IKZF3 protein Q9UKT9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000725 29496670 YES miannu IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34+ cells by the CRBN E3 ubiquitin ligase. 0.582 SIGNOR-272319 tyrphostin AG 1478 chemical CHEBI:75404 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189377 EGFR protein P00533 UNIPROT KCNN1 protein Q92952 UNIPROT up-regulates activity phosphorylation Tyr109 KRKRLSDyALIFGMF 9606 BTO:0000007 23496660 YES miannu These results demonstrate the novel information that hSKCa1 channels are inhibited by genistein, T25 and AG556 via EGFR tyrosine kinase inhibition, which is related to the phosphorylation of Tyr(109) in the N-terminus.  0.2 SIGNOR-276490 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR JARID2 protein Q92833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23435416 YES lperfetto JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells| we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein.| Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS 0.2 SIGNOR-249597 SLC25A1 protein P53007 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity relocalization 9606 29651165 YES SLC25A1, a mitochondrial carrier that promotes the flux of citrate/isocitrate across the mitochondria, in exchange for the entry of cytosolic malate 0.8 SIGNOR-267289 CTR9 protein Q6PD62 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 YES miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  0.942 SIGNOR-269834 NFE2 protein Q16621 UNIPROT HBD protein P02042 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 NO Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. 0.391 SIGNOR-251843 MAPK14 protein Q16539 UNIPROT CASP3 protein P42574 UNIPROT down-regulates phosphorylation Ser150 FRGDRCRsLTGKPKL 9606 BTO:0000130 14970175 YES gcesareni Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response. 0.775 SIGNOR-122099 KDM2A protein Q9Y2K7 UNIPROT RELA protein Q04206 UNIPROT down-regulates demethylation Lys218 EIFLLCDkVQKEDIE 9606 SIGNOR-C13 20080798 YES miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. 0.46 SIGNOR-163384 PCSK2 protein P16519 UNIPROT Corticotropin protein P01189-PRO_0000024969 UNIPROT up-regulates quantity cleavage 24631756 YES lperfetto POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide 0.2 SIGNOR-268725 MOB1A protein Q9H8S9 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 YES Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1 0.941 SIGNOR-169752 CXCR4 protein P61073 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0005387 19584257 NO lperfetto However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype 0.7 SIGNOR-252266 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Thr447 NASGSTStPAPSRTA 10653665 YES Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3). Phosphorylation resulted in a 6-fold increase in V(max) and the conversion of citrate dependence from sigmoidal, displaying negative cooperativity, to hyperbolic. 0.365 SIGNOR-251219 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser750 QTEEEEHsCLEQAS 9606 18957422 YES lperfetto Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma 0.343 SIGNOR-181806 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193534 HDAC2 protein Q92769 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 YES miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells 0.702 SIGNOR-264499 NXF1 protein Q9UBU9 UNIPROT RBM15/NXF1 complex SIGNOR-C67 SIGNOR form complex binding 9606 17001072 YES miannu Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression. 0.49 SIGNOR-149880 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Ser372 VAATPPPsTASAPAA 9606 BTO:0000938 BTO:0000142 16627622 YES esanto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. 0.519 SIGNOR-146220 EEF1A1P5 protein Q5VTE0 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269546 APH1A protein Q96BI3 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12522139 YES gcesareni Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity. 0.947 SIGNOR-97068 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 16782899 YES llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain 0.496 SIGNOR-147199 SB 505124 chemical CHEBI:100922 ChEBI ACVR1C protein Q8NER5 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206739 MIF protein P14174 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16636133 NO Regulation of expression miannu MIF inhibits cytodifferentiation and hemoglobin synthesis of MEL cells. 0.2 SIGNOR-251831 SWI/SNF complex complex SIGNOR-C92 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity binding 9606 20506188 YES miannu Our findings indicate that RUNX1 interacts with the human SWI/SNF complex to control hematopoietic-specific gene expression. 0.454 SIGNOR-261965 HBB protein P68871 UNIPROT ADAMTS13 protein Q76LX8 UNIPROT down-regulates activity 9606 15367436 NO Regulation of binding miannu Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher. 0.2 SIGNOR-251748 SMAD7 protein O15105 UNIPROT MAP3K1 protein Q13233 UNIPROT down-regulates 9606 10085121 NO lperfetto Overexpression of smad7 can inhibit the mekk-1-mediated stimulation of smad2 transcriptional activity 0.265 SIGNOR-65572 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 YES gcesareni Mutation of Rad51 Tyr315, but not Tyr205, Tyr191, or Tyr54 to phenylalanine abolished Rad51 tyrosine phosphorylation by c-Abl (Fig. 3 b). These results strongly suggest that c-Abl phosphorylates Rad51 Tyr315 in vivo 0.772 SIGNOR-247594 RHOA protein P61586 UNIPROT PKN2 protein Q16513 UNIPROT up-regulates activity binding 10090 BTO:0004732 27270401 YES no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. 0.832 SIGNOR-275466 IKK-complex complex SIGNOR-C14 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser25 AERGLGPsPAGDGPS 10090 BTO:0002572 23332762 YES lperfetto Ikk phosphorylates bad at serine-26 (ser26) and primes it for inactivation. 0.263 SIGNOR-209776 NR4A3 protein Q92570 UNIPROT BBC3 protein Q9BXH1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30455429 YES miannu Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. 0.2 SIGNOR-259396 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser180 GSSASFIsDTFSPYT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252327 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001412 8394219 NO We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death. 0.7 SIGNOR-255723 UBE2D2 protein P62837 UNIPROT TRIM5 protein Q9C035 UNIPROT up-regulates activity binding 9606 BTO:0000567 18312418 YES miannu Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B.  0.458 SIGNOR-271670 TOP2B protein Q02880 UNIPROT SST protein P61278 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 NO lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development 0.2 SIGNOR-242305 ZC3H12A protein Q5D1E8 UNIPROT GATA2 protein P23769 UNIPROT up-regulates quantity post transcriptional regulation 9606 BTO:0000007 30842549 YES Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA 0.2 SIGNOR-259943 Jervine chemical CHEBI:6088 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0000527 21679342 YES gcesareni Cyclopamine (c27h41no2) and jervine (c27h39no3) were discovered and in particular, a series of studies with the hh pathway inhibitor, cyclopamine, has brought about this expectation. cyclopamine suppresses the hh signaling pathway through direct interaction with smo. 0.8 SIGNOR-174420 IL21 protein Q9HBE4 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 YES gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex 0.609 SIGNOR-108858 U2AF2 protein P26368 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR form complex binding 9606 8647433 YES miannu The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35). 0.2 SIGNOR-41948 tandutinib chemical CHEBI:90237 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207212 WNT2 protein P09544 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.672 SIGNOR-131730 HOMER1 protein Q86YM7 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity binding 9606 BTO:0000938 17243894 YES miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD 0.744 SIGNOR-264243 THEM4 protein Q5T1C6 UNIPROT AKT1 protein P31749 UNIPROT down-regulates binding 9606 11598301 YES gcesareni Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308. 0.698 SIGNOR-111003 GNB1 protein P62873 UNIPROT GNG2 protein P59768 UNIPROT up-regulates activity binding 10696571 YES GNB1 dissociates from the receptor, bound with GNG2 as stable dimer 0.94 SIGNOR-251105 RXRA protein P19793 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 YES inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr). 0.723 SIGNOR-270292 EHF protein Q9NZC4 UNIPROT DCDC2 protein Q9UHG0 UNIPROT down-regulates quantity by repression transcriptional regulation 22733135 NO Mechanistically, we found that the ETS transcription factor ESE3/EHF, which is expressed in normal prostate and frequently lost in prostate tumors, maintained DCDC2 repressed by binding to a novel identified ETS binding site in the gene promoter. 0.264 SIGNOR-254279 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-) smallmolecule CHEBI:57923 ChEBI 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI up-regulates quantity precursor of 9606 18429927 YES miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 0.8 SIGNOR-269806 PRKCA protein P17252 UNIPROT L1CAM protein P32004 UNIPROT down-regulates activity phosphorylation Thr1172 ARPMKDEtFGEYRSL 9606 BTO:0000304 20335502 YES miannu CKII phosphorylates T1172 of the L1 CD and phosphorylation of T1172 is responsible for loss of 2C2 signal. 0.2 SIGNOR-276283 BCL3 protein P20749 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 15469820 YES gcesareni We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, -3, and -6 0.428 SIGNOR-129801 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 9606 12040173 YES lperfetto The binding of tnf to tnf-r1 triggers a series of intracellular events that ultimately result in the activation of two major transcription factors, nuclear factor kb (nf-kb) and c-jun. 0.93 SIGNOR-88216 MAP1LC3C protein Q9BXW4 UNIPROT WDFY3 protein Q8IZQ1 UNIPROT up-regulates activity binding 9606 BTO:0000567 24668264 YES miannu Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy. 0.595 SIGNOR-266795 IL26 protein Q9NPH9 UNIPROT IL20RA protein Q9UHF4 UNIPROT up-regulates binding 9606 BTO:0001253 17208301 YES gcesareni The mrna expression level of il10, il19, il20, il22, il24, il26, il28b, il29 and their receptors il10ra, il10rb, il20ra, il20rb, il22ra1, il22ra2, il28ra was compared in skin biopsies of children and adults and in childrens' skin cells by quantitative real-time pcr (qrt-pcr). 0.6 SIGNOR-151920 CDH5 protein P33151 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.759 SIGNOR-265867 CBLB protein Q13191 UNIPROT FLT3 protein P36888 UNIPROT down-regulates activity ubiquitination 10090 BTO:0001516 19276253 YES miannu Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo. 0.327 SIGNOR-260106 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser57 KKDRFYRsILPGDKT 9534 BTO:0000298 9032240 YES miannu Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation. 0.2 SIGNOR-250219 RAB6C protein Q9H0N0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 NO miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons 0.7 SIGNOR-266875 RASSF1 protein Q9NS23 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity binding 9606 22195963 YES lperfetto Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating K-Ras-RASSF1A€“MST2 complex, as reported here. 0.697 SIGNOR-249588 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT unknown dephosphorylation 9606 BTO:0000527 15808505 YES gcesareni These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3 0.62 SIGNOR-135008 PAMPs stimulus SIGNOR-ST11 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates 9606 25720354 NO scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 0.7 SIGNOR-267857 CILK1 protein Q9UPZ9 UNIPROT CILK1 protein Q9UPZ9 UNIPROT up-regulates phosphorylation Tyr159 SKPPYTDyVSTRWYR 9606 15988018 YES lperfetto Ick is activated by dual phosphorylation of the tdy motif. Phosphorylation of tyr-159 in the tdy motif requires ick autokinase activity 0.2 SIGNOR-138424 MAPK3 protein P27361 UNIPROT LIFR protein P42702 UNIPROT down-regulates phosphorylation Ser1044 WNLVSPDsPRSIDSN 9606 7777512 YES gcesareni Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044. 0.299 SIGNOR-32757 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2276 SFKSALSerPSKSPA -1 26051540 YES irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. 0.472 SIGNOR-259120 RASSF1 protein Q9NS23 UNIPROT STK3 protein Q13188 UNIPROT up-regulates binding 9606 21808241 YES Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage milica Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization. 0.697 SIGNOR-175790 SOX4 protein Q06945 UNIPROT DICER1 protein Q9UPY3 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000848 22689055 YES .... showed that Sox4 positively regulates Dicer expression by binding to its promoter sequences and enhancing its activity. We found that knockdown of Dicer enhances the matrigel invasion of melanoma cells by at least twofold. In addition, we revealed that overexpression of exogenous Dicer reverts the enhanced melanoma cell invasion upon Sox4 knockdown 0.395 SIGNOR-258987 PKA proteinfamily SIGNOR-PF17 SIGNOR BRSK2 protein Q8IWQ3 UNIPROT up-regulates activity phosphorylation Thr260 VDAARRLtLEHIQKH -1 16870137 YES miannu BRSK2 is activated by cyclic AMP-dependent protein kinase A through phosphorylation at Thr260 0.2 SIGNOR-276056 NKX2-2 protein O95096 UNIPROT ERMN protein Q8TAM6 UNIPROT up-regulates quantity by expression transcriptional regulation 21221725 YES lperfetto Further study revealed that Nkx2.2 could bind JN promoter and its overexpression increase the promoter activity of JN. 0.249 SIGNOR-268965 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 YES lperfetto Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro. 0.58 SIGNOR-121869 MAP2K2 protein P36507 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 BTO:0000142 1411546 YES inferred from 70% of family members gcesareni The primary structure of mek, a protein kinase that phosphorylates the erk gene product 0.2 SIGNOR-269895 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Thr2068 LLDEYNVtPSPPGTV 9606 BTO:0000007 12794074 YES lperfetto We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093. 0.482 SIGNOR-101570 imiquimod chemical CHEBI:36704 ChEBI TLR8 protein Q9NR97 UNIPROT up-regulates activity chemical activation 9606 15661881 YES miannu Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively. 0.8 SIGNOR-259245 Fostamatinib disodium chemical CID:25008120 PUBCHEM SYK protein P43405 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206373 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21633182 YES miannu Interestingly, SIRT1 suppresses PPARγ but activates PGC-1α , and thus affects the clock network through multiple mechanisms. 0.798 SIGNOR-268033 PP121 chemical CHEBI:50915 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206289 CBL protein P22681 UNIPROT INSR protein P06213 UNIPROT down-regulates ubiquitination 9606 11498022 YES gcesareni Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor 0.526 SIGNOR-109688 FOXL2 protein P58012 UNIPROT CYP11A1 protein P05108 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 NO miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. 0.39 SIGNOR-254177 POU2F1 protein P14859 UNIPROT HOXD11 protein P31277 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25301728 NO miannu Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11 0.262 SIGNOR-205564 MAPK3 protein P27361 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser255 HATSGALsPAKDCGS 9606 9535909 YES lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. 0.636 SIGNOR-249465 SETD1B protein Q9UPS6 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 32546568 YES miannu SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. 0.2 SIGNOR-265578 PTPRC protein P08575 UNIPROT JAK3 protein P52333 UNIPROT down-regulates activity dephosphorylation 10090 11201744 YES CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling 0.457 SIGNOR-248359 HSPB1 protein P04792 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by stabilization binding 9606 18241680 YES miannu GTP cyclohydrolase I (GCH), an oligomeric protein composed of 10 identical subunits, is required for the synthesis of neurotransmitters; mutations in GCH are associated with dopa-responsive dystonia (DRD) and hyperphenylalaninemia. Mutated GCH proteins are unstable and prone to dominant-negative effect. We show herein that expression of the GCH mutant GCH-201E or the splicing variant GCH-II caused intracellular inclusion bodies. When Hsp27 was expressed together with the GCH mutants, Hsp27 expression decreased the formation of inclusion bodies by GCH (as assessed by immunofluorescence) and decreased the amount of insoluble GCH mutant proteins (as assessed by Western blot). we demonstrated that Hsp27 increases the expression of the wild-type GCH protein, causes the appearance of the soluble GCH-II protein, and decreases the quantities of insoluble mutated GCH protein. Therefore, it is likely that Hsp27 improves the folding of mutated GCH proteins, so they can stay in free cytosolic compartment. 0.2 SIGNOR-252222 G8RGG88B68 smallmolecule SID:135317436 PUBCHEM IFNAR2 protein P48551 UNIPROT up-regulates activity chemical activation -1 15898717 YES miannu To significantly improve the pharmacological properties of the drug, a pegylated form of IFNalpha(2a) was developed (PEGASYS). This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side-chain of IFNalpha(2a). Here, we report the detailed structural, kinetic, and thermodynamic analysis of the binding to the extracellular domain of the receptor IFNAR2 of (40)PEG-IFNalpha(2a) and its isolated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively, in comparison with unmodified IFNalpha(2a). 0.8 SIGNOR-259391 EGLN3 protein Q9H6Z9 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity binding 9606 BTO:0000007 23732909 YES lperfetto Here we report that EGLN3, but not EGLN1 or -2, interacts with and inhibits K63-linked ubiquitination of IKKγ. The effect appears to be related to inhibition of IKKγ ubiquitination mediated by cIAP1 rather than to stimulation of IKKγ deubiquitination by the deubiquitinases A20 and CYLD (cylindromatosis). EGLN3 does not affect the protein levels of cIAP1 or its E2 ubiquitin-conjugating enzymes UbcH5 and Ubc13. EGLN3 hydroxylase activity is not responsible for its effect on IKKγ ubiquitination and NF-κB signaling. Instead, interaction with IKKγ is required for the ability of EGLN3 to inhibit IKKγ ubiquitination and IKK-NF-κB signaling. 0.327 SIGNOR-262005 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT down-regulates activity phosphorylation Thr337 VKSFSRRtPNSSSYC 9606 BTO:0000567 26080397 YES miannu ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. 0.2 SIGNOR-266203 7-Hydroxystaurosporine chemical CID:72271 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 20068082 YES gcesareni The clinical use of ucn-01, the first chk1 inhibitor evaluated in humans, is limited by its prolonged plasma half-life due to extensive plasma binding to alfa1 acidic glycoprotein 0.8 SIGNOR-163222 CLK4 protein Q9HAZ1 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates activity phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 BTO:0000007 35592512 YES done miannu Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor. 0.2 SIGNOR-274117 CREBBP protein Q92793 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity acetylation 9606 25545885 YES miannu C-terminal acetylation of p53 by p300/CBP and PCAF promotes an open conformation of p53 by preventing the occlusion of the DNA binding domain by the C-terminal tail. This enhances p53 transcriptional activity, leading to growth arrest and/or apoptosis 0.912 SIGNOR-261495 RHOA protein P61586 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 23450633 NO gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. 0.7 SIGNOR-192114 propan-2-ol smallmolecule CHEBI:17824 ChEBI TLCD3B protein Q71RH2 UNIPROT up-regulates activity binding 9606 BTO:0000140 30010626 YES lperfetto Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2 0.8 SIGNOR-270575 Ub:E2 complex SIGNOR-C497 SIGNOR RNF141 protein Q8WVD5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271204 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1145 RDKRESDsERLKRTS 9606 15590641 YES gcesareni Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites. 0.2 SIGNOR-132243 RIN1 protein Q13671 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 12783862 YES gcesareni The interaction between egfr and rin1 delineates a novel signal transduction pathway between egfr and its effectors, rin1, rab5a, and ras, which together coordinate and regulate both signaling and membrane trafficking. 0.404 SIGNOR-101530 GNG12 protein Q9UBI6 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 YES gcesareni In the non-canonical wntpathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor 0.2 SIGNOR-152612 PTPN2 protein P17706 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 12138178 YES gcesareni The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation. 0.735 SIGNOR-90818 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR KRAS protein P01116 UNIPROT up-regulates 9606 19483050 NO lperfetto A recurrent gene fusion between echinoderm microtubule-associated protein-like 4 (EML4;and, occasionally, of other fusion partners) and the anaplastic lymphoma kinase (ALK) geneoccurs in of NSCLCs , resulting in activation of a potent ALK fusion protein.ALK fusion protein is usually found in never-smoker subjects. Although relatively rare, therelative paucity of fusion proteins known to contribute to lung cancer pathogenesis makes this a finding of biological interest. Although present understanding of the ALK fusion protein is limited, it may play a role in activating RAS. Thus it is negatively associated with thepresence of KRAS or EGFR mutations, and may favour ADC histology and never-smokerstatus. 0.2 SIGNOR-253216 Cyclopamine chemical CHEBI:4021 ChEBI CXCL1 protein P09341 UNIPROT down-regulates chemical inhibition 9606 16885213 YES gcesareni Cyclopamine and other inhibitors of hh signaling were found to inhibit smo coupling to gi in a manner consistent with inverse agonism. 0.8 SIGNOR-148469 ROCK1 protein Q13464 UNIPROT LPP protein Q93052 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 22886954 NO miannu Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression 0.2 SIGNOR-198118 RPS6KA1 protein Q15418 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 YES lperfetto We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue. 0.544 SIGNOR-182497 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Thr326 ENPPNKMtQEKLEES 9606 22727668 YES llicata We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1 0.2 SIGNOR-197993 LRRK2 protein Q5S007 UNIPROT LARS1 protein Q9P2J5 UNIPROT down-regulates activity phosphorylation Thr293 NIFLVAAtLRPETMF -1 30411383 YES miannu In this study, we elucidated that leucyl-tRNA synthetase (LRS) was an LRRK2 kinase substrate and identified T293 as an LRRK2 phosphorylation site. LRRK2-meidated LRS phosphorylation or G2019S can lead to impairment of LRS editing, increased ER stress, and accumulation of autophagy markers. 0.2 SIGNOR-277417 APBA1 protein Q02410 UNIPROT Exocytosis phenotype SIGNOR-PH157 SIGNOR up-regulates 9606 BTO:0000938 11036064 NO miannu As neurexins have been proposed to function in neuronal cell adhesion, it is possible that they define specific sites at the plasma membrane and that Mint complexes and Mint1-CASK complexes on neurexin are involved in the localized recruitment of Munc18 to the sites of exocytosis. In support of this hypothesis, both CASK and Mint1 have been reported to be localized at synapses 0.7 SIGNOR-264043 TM4SF1 protein P30408 UNIPROT SDCBP2 protein Q9H190 UNIPROT up-regulates activity relocalization 33015133 YES lperfetto TM4SF1 functions as a membrane adaptor connecting DDR1 to syntenin2. 0.402 SIGNOR-272401 E2F1 protein Q01094 UNIPROT ELF4 protein Q99607 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20805247 NO miannu we determined that E2F1 specifically binds to MEF promoter and transactivates MEF. 0.246 SIGNOR-253849 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 YES lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3beta (GSK3B). The AKT-mediated phosphorylation of glycogen synthase kinase 3b on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 0.792 SIGNOR-245416 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR3 protein Q9UBY5 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193564 ADGRG1 protein Q9Y653 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0000142 31515243 YES lperfetto Binding of collagen III to ADGRG1 provides a canonical example of adhesion GPCR interactions with ECM proteins (Luo et al., 2011). Identified by an in vitro biotinylation/proteomics approach, extracellular interactions with collagen III were subsequently proven capable of activating ADGRG1-mediated signaling via Gα12/13 followed by RhoA activation to regulate corticogenesis 0.2 SIGNOR-272344 PKCtheta/Nfix complex SIGNOR-C121 SIGNOR MEF2A protein Q02078 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000165 20178747 YES llicata In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. 0.338 SIGNOR-238022 TAF2 protein Q6P1X5 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.885 SIGNOR-263931 ESR1 protein P03372 UNIPROT NR0B2 protein Q15466 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10648597 NO gcesareni We demonstrate that shp variants, carrying either interaction-defective nr box mutations or a deletion of the repressor domain, have lost the capacity to inhibit agonist-dependent transcriptional estrogen receptor activation. 0.648 SIGNOR-74288 WEE1 protein P30291 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 16096060 YES gcesareni The wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (cdk1), thereby delaying entry into mitosis until appropriate conditions have been met 0.858 SIGNOR-139491 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity precursor of 9606 11381136 YES miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. 0.8 SIGNOR-268104 HMOX1 protein P09601 UNIPROT HBA1 protein P69905 UNIPROT down-regulates activity 9606 10490932 YES Regulation miannu Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme 0.253 SIGNOR-251813 CREB5 protein Q02930 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding -1 8440710 YES 2 miannu CRE-BPa binds to CRE with higher affinity than to the 12-O-tetradecanoylphorbol-13-acetate response element as a homodimer or a CRE-BPa/c-Jun or CRE-BPa/CRE-BP1 heterodimer. 0.511 SIGNOR-240397 FUS protein P35637 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates activity sumoylation Lys298 MGVVECAkHELLQPF 9606 BTO:0000007 19946338 YES gcesareni Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity. 0.337 SIGNOR-249657 KAT2A protein Q92830 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269599 CDK1 protein P06493 UNIPROT CREM protein Q03060 UNIPROT down-regulates quantity by destabilization phosphorylation Ser277 ASPGSLHsPQQLAEE 10090 BTO:0001077 11466319 YES miannu  The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.  0.297 SIGNOR-275979 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser287 WEPPGRAsPSQGSSP 9606 14697653 YES lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.259 SIGNOR-120455 Ub:E2 complex SIGNOR-C497 SIGNOR RNF225 protein M0QZC1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271261 EIF5 protein P55010 UNIPROT 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.754 SIGNOR-269163 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity precursor of 9606 32041144 YES miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. 0.8 SIGNOR-267550 SMURF2 protein Q9HAU4 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps. 0.501 SIGNOR-193119 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation -1 11287604 YES inferred from 70% family members lperfetto Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 0.2 SIGNOR-270200 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AE/b7 integrin complex SIGNOR-C186 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.383 SIGNOR-259010 AP2S1 protein P53680 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR form complex binding 31671891 YES lperfetto The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit 0.916 SIGNOR-260421 GXYLT2 protein A0PJZ3 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22117070 YES Xylosylation in ER membrane. gcesareni Recently, we have shown (28) that two members of the human glycosyltransferase 8 family (gt8) (29), gxylt1 and gxylt2 (glucoside-xylosyltransferase 1/2), are able to transfer the first alfa1,3-linked xylose to o-glucosylated mammalian notch egf repeats. 0.383 SIGNOR-177714 KRN-633 chemical CID:9549295 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193585 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 YES gcesareni In mammals, pdhc is tightly regulated by phosphorylation-dephosphorylation of three serine residues in the thiamin-dependent pyruvate dehydrogenase (e1) component. In vivo, inactivation of human pdhc correlates mostly with phosphorylation of serine 264, which is located at the entrance of the substrate channel leading to the active site of e1. 0.685 SIGNOR-154656 leukotriene B4(1-) smallmolecule CHEBI:57461 ChEBI LTB4R protein Q15722 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257534 NLGN3 protein Q9NZ94 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.825 SIGNOR-264167 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates activity phosphorylation Ser870 KEDSAYGsQSVEQEA 10090 BTO:0000785 15084608 YES lperfetto Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52. 0.791 SIGNOR-124230 Pravadoline chemical CID:56463 PUBCHEM PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206322 FH protein P07954 UNIPROT ATF2 protein P15336 UNIPROT up-regulates activity binding -1 28628081 YES miannu Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes. 0.2 SIGNOR-266314 SMAD7 protein O15105 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates 9606 17438144 NO gcesareni Smad7 repressed smad3/4-, smad2/4-, and smad1/4-enhanced reporter gene expression. 0.58 SIGNOR-154390 CDH1 protein P12830 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates activity binding 9606 24336504 YES miannu Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm. 0.685 SIGNOR-265821 471905-41-6 chemical CID:9803433 PUBCHEM APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194358 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 1715686 YES gcesareni Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta. 0.305 SIGNOR-21307 RAC3 protein P60763 UNIPROT CIB1 protein Q99828 UNIPROT up-regulates activity binding 10029 BTO:0000246 11756406 YES Gianni We here report that CIB, a protein that binds to the alpha(IIb)beta(3) fibrinogen receptor, interacts exclusively with activated (V12) Rac3 but not Rac1 or Rac2. Binding of V12Rac3 to CIB was mediated by the C-terminal end of Rac3 and by Rac3 membrane localization 0.349 SIGNOR-269060 RAC1 protein P63000 UNIPROT ALS2 protein Q96Q42 UNIPROT up-regulates activity binding 9606 BTO:0000567 30485418 YES miannu Thus, in our system, activeRac1 may recruit ALS2 only at the very early stage ofmacropinocytosis including membrane ruffles, suggest-ing that ALS2 is retained by some other mechanismsuntil Rab conversion. 0.531 SIGNOR-277777 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Ser408 GPLPRAPsISTVEPK 9606 26190112 YES Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. 0.334 SIGNOR-259860 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser696 EKNYALPsPATTEGG 9606 SIGNOR-C3 21071439 YES llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.518 SIGNOR-169514 PTGS2 protein P35354 UNIPROT IL4 protein P05112 UNIPROT up-regulates 9606 22225874 YES FFerrentino Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression 0.445 SIGNOR-255967 HMGCS2 protein P54868 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 29597274 YES lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis 0.8 SIGNOR-267658 CEP250 protein Q9BV73 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 BTO:0000567 24769208 NO lperfetto C-NAP1 which is located in the proximal ends of the centriole is an important factor for maintaining cohesion of centrioles in interphase 0.7 SIGNOR-265498 ezogabine chemical CHEBI:68584 ChEBI KCNQ3 protein O43525 UNIPROT up-regulates chemical activation 9606 Other YES Selleck;anticonvulsant for KCNQ2/3 currents gcesareni 0.8 SIGNOR-206541 HIPK3 protein Q9H422 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD -1 11034606 YES FIST/HIPK3 causes FADD phosphorylation, thereby promoting FIST/HIPK3-FADD-Fas interaction.¬† Phosphorylation occurs on Ser194 close to the COOH terminus of human FADD| Fas ligand-induced activation of Jun NH(2)-terminal kinase is impaired by overexpressed active FIST/HIPK3 0.437 SIGNOR-251272 PTGER3 protein P43115 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12038972 YES gcesareni Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i) 0.45 SIGNOR-88143 ATP smallmolecule CHEBI:15422 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 33961946 YES miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 0.8 SIGNOR-268079 ARHGAP17 protein Q68EM7 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000132 26507661 YES lperfetto ARHGAP17 is a Rho GTPase-activating protein of Rac1 0.565 SIGNOR-272166 LPAR6 protein P43657 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257120 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity relocalization 9606 9865696 YES lperfetto We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex. 0.86 SIGNOR-232126 CHEK2 protein O96017 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr284 APTRTPAtAPVPARA 9606 18971944 YES llicata Chk2 formed a complex with xrcc1, the ber scaffold protein, and phosphorylated xrcc1 in vivo and in vitro at thr(284). our results are consistent with the phosphorylation of xrcc1 by atm-chk2 facilitating recruitment of downstream ber proteins to the initial damage recognition/excision step to promote ber. 0.516 SIGNOR-181816 TNF protein P01375 UNIPROT LZTR1 protein Q8N653 UNIPROT down-regulates quantity by destabilization 9606 16356934 NO Induction of Apoptosis by Staurosporine, TNFŒ±, and TRAIL Induces Degradation of LZTR-1 by Caspase- and Proteasome-dependent Pathways 0.2 SIGNOR-253612 DOK1 protein Q99704 UNIPROT ITGB5 protein P18084 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.295 SIGNOR-257691 EZR protein P15311 UNIPROT FES protein P07332 UNIPROT up-regulates relocalization 9606 18046454 YES miannu The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin. 0.396 SIGNOR-159496 SMAD3 protein P84022 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 14638857 YES gcesareni Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd 0.544 SIGNOR-119374 EPGN protein Q6UW88 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0001801 16469638 YES gcesareni They both bind to betacellulin and the heparin-binding ligand, hb-egf, as well as to two low-affinity ligands, epiregulin and epigen. 0.394 SIGNOR-144399 ATG13 protein O75143 UNIPROT ULK2 protein Q8IYT8 UNIPROT up-regulates binding 9606 19225151 YES gcesareni He mammalian atg13 binds both ulk1 and ulk2 and mediates the interaction of the ulk proteins with fip200. The binding of atg13 stabilizes and activates ulk and facilitates the phosphorylation of fip200 by ulk 0.749 SIGNOR-184123 LIPH protein Q8WWY8 UNIPROT LPAR2 protein Q9HBW0 UNIPROT up-regulates binding 9606 BTO:0000661 9525886 YES gcesareni When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity. 0.294 SIGNOR-56093 prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 3308494 NO apalma The results suggest a role for prostanoids in the regulation of both human myoblast proliferation and differentiation 0.7 SIGNOR-255362 NF1 protein P21359 UNIPROT ADCY8 protein P40145 UNIPROT up-regulates 9606 BTO:0000938 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.399 SIGNOR-204289 glycine smallmolecule CHEBI:15428 ChEBI GLRA3 protein O75311 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 YES miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 0.8 SIGNOR-264982 p38 proteinfamily SIGNOR-PF16 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation -1 12171600 YES inferred from 70% family members miannu Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%. 0.2 SIGNOR-270127 PIM proteinfamily SIGNOR-PF34 SIGNOR RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 19911008 YES llicata In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276. 0.2 SIGNOR-259411 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000567 SIGNOR-C13 10469655 YES lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). 0.746 SIGNOR-70457 AKT proteinfamily SIGNOR-PF24 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 YES llicata Akt regulates ranbp3 phosphorylation in vitro and in vivo 0.2 SIGNOR-160900 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.417 SIGNOR-249285 PPP2CB protein P62714 UNIPROT KRT8 protein P05787 UNIPROT unknown dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000182 16554440 YES K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts. 0.2 SIGNOR-248588 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;VIRAL ABL gcesareni 0.8 SIGNOR-193372 ETV3 protein P41162 UNIPROT ETV3 protein P41162 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22028471 YES miannu ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation. 0.2 SIGNOR-262778 N-[(4-chlorophenyl)methyl]-2-[(2R,6S)-5,12-dioxo-2-phenyl-1-oxa-4-azacyclododec-8-en-6-yl]acetamide chemical CHEBI:94175 ChEBI SHH protein Q15465 UNIPROT down-regulates chemical inhibition 9606 BTO:0001253 19151731 YES gcesareni More recently, robotnikinin was identified as a compound that binds to shh and blocks its ability to induce pathway activity at the level of ptch. 0.8 SIGNOR-183465 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248692 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 YES lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 0.2 SIGNOR-252798 IL15RA protein Q13261 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity 9606 30029643 NO areggio In addition, level of mRNAs encoding C/EBPa, PPARg and FABP4, the classic adipogenic markers, was significantly lower in samples administrated with IL-15 0.2 SIGNOR-256228 U0126 chemical CHEBI:90693 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 9873633 YES gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. U0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. 0.8 SIGNOR-62895 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Thr161 LGLPEEEtELDNLTE -1 9407077 YES llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. 0.475 SIGNOR-251024 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation Tyr1035 IETDKEYyTVKDDRD -1 12559972 YES Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD) 0.535 SIGNOR-251364 SLC18A2 protein Q05940 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR up-regulates activity binding 9606 BTO:0000132 23805129 YES lperfetto The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules 0.2 SIGNOR-265997 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser293 EESYDTEsEFTEFTE 9606 BTO:0000782 8622692 YES llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. 0.58 SIGNOR-40510 FKBP4 protein Q02790 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 10090 BTO:0000947 19545546 YES We noted that FK506 altered nuclear localization of the GR and inhibited expression of GR-responsive genes. Furthermore, si-RNA knockdown of FKBP4 gene, coding for the immunophilin FKBP52, inhibited cortisol-activated GR nuclear translocation 0.719 SIGNOR-252034 VHL protein P40337 UNIPROT CDKN1C protein P49918 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000037 15824735 NO miannu three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL. 0.2 SIGNOR-255601 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser676 LSQRFTFsPGQDIQL 9606 11110801 YES llicata In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676). 0.442 SIGNOR-84996 AKT1 protein P31749 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser134 ANLNRSTsVPENPKS 9606 BTO:0000731 24291004 YES lperfetto Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus 0.486 SIGNOR-252543 PRKACA protein P17612 UNIPROT GP1BB protein P13224 UNIPROT down-regulates activity phosphorylation Ser191 ARAAARLsLTDPLVA -1 2504723 YES miannu Platelet glycoprotein Ib beta is phosphorylated on serine 166 by cyclic AMP-dependent protein kinase. phosphorylation of this residue may contribute to the inhibitory actions of cyclic AMP by inhibiting collagen-induced polymerization of actin. 0.312 SIGNOR-249986 TSC22D3 protein Q99576 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates activity binding 9606 BTO:0000007 11468175 YES GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. 0.327 SIGNOR-253298 ZBTB32 protein Q9Y2Y4 UNIPROT ZBTB16/ZBTB32 complex SIGNOR-C80 SIGNOR form complex binding 9606 10572087 YES miannu We show that fazf is a transcriptional repressor and it readily forms heterodimers with plzf. 0.361 SIGNOR-72380 (-)-anisomycin chemical CHEBI:338412 ChEBI JUN protein P05412 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-189632 SPOP protein O43791 UNIPROT MACROH2A1 protein O75367 UNIPROT up-regulates activity binding 9606 BTO:0000007 15897469 YES miannu Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex. 0.2 SIGNOR-272657 SP1 protein P08047 UNIPROT MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 YES lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. 0.32 SIGNOR-241490 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR UBTF protein P17480 UNIPROT down-regulates phosphorylation 9606 11741541 YES inferred from 70% family members lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna 0.2 SIGNOR-270181 PRKACA protein P17612 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates phosphorylation 10090 BTO:0000944 23644383 YES inferred from 70% of family members milica Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381. 0.2 SIGNOR-269863 MECP2 protein P51608 UNIPROT GRIA2 protein P42262 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 22262897 YES Luana Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A. 0.323 SIGNOR-264684 TNF protein P01375 UNIPROT DNAH10 protein Q8IVF4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 31836722 NO miannu The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation. 0.2 SIGNOR-265551 TP53 protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 10329733 NO lperfetto P53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. 0.748 SIGNOR-271677 SLC20A1 protein Q8WUM9 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 11009570 YES lperfetto Three families of NPCs have been reported to date. The type I family consists of a single species (NaPi-1), which has thus far been found only in rabbit kidney.28 The type II family consists of six species homologues, NaPi 2 to 7, that are expressed predominantly in renal epithelial tissues.The type III family is the most recently identified and consists of two members, Pit-1 (also called Glvr-1) and Pit-2 (also called Ram-1).34 0.8 SIGNOR-270579 ANGPT2 protein O15123 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 9723709 YES lperfetto Angiopoietin-1 and -2, bound to tek with similar affinities, and angiopoietin-1 effectively induced tek phosphorylation in hematopoietic cells. Angiopoietin-2 also induced a low level of tek phosphorylation and weakened the phosphorylation induced by angiopoietin-1 0.924 SIGNOR-59808 trastuzumab antibody DB00072 DRUGBANK ERBB2 protein P04626 UNIPROT down-regulates activity binding 9606 29017563 YES miannu HER2+ breast cancer is associated with poor prognosis and high mortality rates, but the development of HER2-targeted therapies, such as originator trastuzumab (Herceptin®), has substantially improved patient survival. 0.4 SIGNOR-259904 KCNC1 protein P48547 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 YES miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height 0.8 SIGNOR-265586 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207857 APEX1 protein P27695 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 14630715 YES Luana These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8.  0.2 SIGNOR-261564 ATP6V1H protein Q9UI12 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.796 SIGNOR-277749 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 12676795 NO Luana Activation of the Ras-MAPK/Erk signaling cascade is essential for neurotrophin-promoted differentiation of neurons and PC12 cells. 0.7 SIGNOR-264978 Ub:E2 complex SIGNOR-C497 SIGNOR MDM4 protein O15151 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271129 ARRY-520 chemical CID:44224257 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189891 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23939472 NO miannu We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. 0.265 SIGNOR-261368 PRKACA protein P17612 UNIPROT CD44 protein P16070 UNIPROT up-regulates phosphorylation Ser697 AVEDRKPsGLNGEAS 9606 16785995 YES lperfetto Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains. 0.2 SIGNOR-147208 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17967874 YES lperfetto In this study, we show that the increased interaction between B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. 0.843 SIGNOR-158632 GLI2 protein P10070 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 NO lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. 0.708 SIGNOR-209632 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT down-regulates activity phosphorylation Ser38 ASEHRKSsKPIMEKR -1 9389649 YES lperfetto Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro. 0.33 SIGNOR-248993 PITX2 protein Q99697 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 20978076 NO gcesareni We show that pitx2 is crucial for the onset of myod gene expression in limb muscle progenitors and that it acts on the myod core enhancer. 0.436 SIGNOR-169107 SP1 protein P08047 UNIPROT RHO protein P08100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15781457 NO miannu Sp4 and Sp1 are activators of the rod opsin promoter 0.2 SIGNOR-225385 RPS6K proteinfamily SIGNOR-PF26 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 BTO:0000551 21423205 YES lperfetto Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin. 0.2 SIGNOR-252802 G6PD protein P11413 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 YES miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle 0.8 SIGNOR-267052 Opsonization phenotype SIGNOR-PH150 SIGNOR Membrane attack complex complex SIGNOR-C313 SIGNOR up-regulates -1 30552328 NO lperfetto CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers 0.7 SIGNOR-263455 RFX complex complex SIGNOR-C104 SIGNOR HLA-DMB protein P28068 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.364 SIGNOR-253999 GSK3A protein P49840 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Ser1387 QPLSKSSsSPELQTL 16959574 YES gcesareni Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation. 0.362 SIGNOR-149377 KHSRP protein Q92945 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 10090 BTO:0000165 16364914 YES lperfetto Importantly, KSRP knockdown in C2C12 GM cells (Figure 2D) stabilized endogenous my- ogenin and p21 transcripts (Figure 2E). Furthermore, stable knockdown of KSRP, using shRNA, induced the accumulation of p21 mRNA in C2C12 GM while it did not affect the expression of late myogenic markers (MHC and muscle-creatine kinase [MCK]) 0.252 SIGNOR-235859 CBLB protein Q13191 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000661 8626404 YES lperfetto Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2. 0.569 SIGNOR-236051 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr444 RFIGSPRtPVSPVKF 10116 15774499 YES lperfetto Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats 0.606 SIGNOR-134662 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194548 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT down-regulates quantity by destabilization sumoylation Lys866 PLNLTFIkKEFSNSN 9534 BTO:0001538 16061479 YES Luisa Pc2 can act directly as an E3 ligase for SIP1 sumoylation.SIP1 sumoylation having a negative effect on its repression of E-cadherin transcription. 0.331 SIGNOR-269113 DUSP10 protein Q9Y6W6 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 10391943 YES gcesareni Mkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk, but not mapk/erk. p38 is a preferred substrate 0.694 SIGNOR-68983 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK14 protein Q16539 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni 0.8 SIGNOR-189699 UIMC1 protein Q96RL1 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 17525342 YES gcesareni Rap80 specifically recruits brca1 to dna damage sites and functions with brca1 in g2/m checkpoint control 0.91 SIGNOR-155201 Fatty acid stimulus SIGNOR-ST19 SIGNOR SIRT6 protein Q8N6T7 UNIPROT up-regulates 9606 25815987 YES miannu Intriguingly, SIRT6 is chromatin bound, controls lipid metabolism, and is enzymatically activated by fatty acids 0.7 SIGNOR-268156 WNT10B protein O00744 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 12055200 NO fspada We have identified wnt10b as a potent inhibitor of adipogenesis that must be suppressed for preadipocytes to differentiate in vitro 0.7 SIGNOR-89131 tyrphostin B42 chemical CHEBI:131968 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189386 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 21205641 YES lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.49 SIGNOR-216457 AKT proteinfamily SIGNOR-PF24 SIGNOR ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation 9606 22085529 YES miannu Both mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) 1/2 and phosphatidylinositide-3-OH kinase (PI3K)/Akt pathways regulate activation of E-twenty-six (ETS)-like transcription factor 1 (Elk-1) in U138 glioblastoma cells. The phosphatidylinositide-3-OH kinase (PI3K)/Akt pathway was also involved in the Elk-1 activation. Activation of the Elk-1 led to an increased survival and a proliferative response with the EGF stimulation in the U138 glioblastoma cells. 0.2 SIGNOR-259029 PRKG1 protein Q13976 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates phosphorylation Thr276 SIWKGVKtSGKVVWV 9606 BTO:0000567 17913921 YES gcesareni These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5. 0.382 SIGNOR-158186 USP8 protein P40818 UNIPROT RNF41 protein Q9H4P4 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 23750007 YES irozzo Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins. 0.879 SIGNOR-259105 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.257 SIGNOR-159458 IRS2 protein Q9Y4H2 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0004087 24811175 YES lperfetto Insulin receptor substrate 1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate PI3K, only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells. 0.704 SIGNOR-252696 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser392 VSGASPEsISSLLSE -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262909 PDGFRB protein P09619 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 10026169 YES gcesareni The sh2 domains of grb2, nck, and grb4 all precipitated activated pdgf receptor with similar efficiency. 0.614 SIGNOR-64740 RIN1 protein Q13671 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 11784866 YES gcesareni We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1. 0.635 SIGNOR-113967 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 YES gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. 0.341 SIGNOR-88744 tofacitinib citrate chemical CHEBI:71197 ChEBI JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207311 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15829969 YES lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9. 0.791 SIGNOR-135384 GFI1 protein Q99684 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates 9606 20861919 NO irozzo In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation. 0.7 SIGNOR-256084 NUMA1 protein Q14980 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.617 SIGNOR-117203 LAMB1 protein P07942 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR form complex binding 7496033 YES lperfetto Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1. 0.629 SIGNOR-253233 ROCK1 protein Q13464 UNIPROT DPYSL2 protein Q16555 UNIPROT unknown phosphorylation Thr555 DNIPRRTtQRIVAPP 9534 10818093 YES lperfetto We produced an antibody that specifically recognizes CRMP-2 phosphorylated at Thr-555. Using this antibody, we found that Rho-kinase phosphorylated CRMP-2 downstream of Rho in COS7 cells.  0.422 SIGNOR-249042 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser103 ESSLSSEsSESSDAG 9606 BTO:0000567 21807946 YES miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). 0.2 SIGNOR-276349 Ub:E2 complex SIGNOR-C497 SIGNOR RNF19A protein Q9NV58 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270970 DVL1 protein O14640 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 17569865 YES amattioni The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization. 0.706 SIGNOR-156072 TTK protein P33981 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Ser928 SRLATNTsAPDLKNV 9606 BTO:0000567 31253867 YES miannu We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation.  0.2 SIGNOR-277458 MMP7 protein P09237 UNIPROT SPP1 protein P10451 UNIPROT up-regulates activity cleavage 25545242 YES lperfetto In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA. 0.705 SIGNOR-253321 SIRT7 protein Q9NRC8 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 YES lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 0.2 SIGNOR-275875 TGFb proteinfamily SIGNOR-PF5 SIGNOR TGFBR2 protein P37173 UNIPROT up-regulates activity binding 9606 BTO:0000801 22703233 YES miannu TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex. 0.2 SIGNOR-256179 KDM5D protein Q9BY66 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264309 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM5 protein P41594 UNIPROT up-regulates activity chemical activation 9606 25042998 YES miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate 0.8 SIGNOR-264070 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267882 ABL1 protein P00519 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr222 IGAGKGKyYAVNFPM 10116 25219501 YES Manara C-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer's disease. 0.285 SIGNOR-260928 GRIK5 protein Q16478 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 YES lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine 0.8 SIGNOR-268276 LRP1B protein Q9NZR2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000038; BTO:0000675 28408316 NO irozzo Forced expression of LRP1B in SW480 and SW620 cells inhibited the growth, migration and anchorage-independent growth of cancer cells. 0.7 SIGNOR-259091 VPS72 protein Q15906 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.67 SIGNOR-269290 THR proteinfamily SIGNOR-PF84 SIGNOR GATA2 protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 YES scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. 0.2 SIGNOR-267275 RRM2 protein P31350 UNIPROT Ribonucleotide reductase complex SIGNOR-C233 SIGNOR form complex binding 9606 14583450 YES miannu Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2. 0.933 SIGNOR-259364 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 YES lperfetto Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity. 0.66 SIGNOR-235587 GSK3B protein P49841 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser58 SFFKEPDsGSHSRQS 9606 BTO:0002181 22692215 YES miannu GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3  phosphorylation, whereas the Ser-66 is not (Fig. 4D). 0.2 SIGNOR-277646 MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9534 BTO:0004055 8974401 YES lperfetto ASK1 activated SEK1 and MKK3 up to 7.0- and 11.8-fold, respectively 0.598 SIGNOR-226672 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage 9606 BTO:0000131 29880919 YES lperfetto Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes 0.6 SIGNOR-263528 GRPR protein P30550 UNIPROT PLA2G1B protein P04054 UNIPROT up-regulates binding 9606 17251915 YES gcesareni Grpr stimulation activates phospholipase a2 (pla2) and cyclooxygenase 2 (cox2), which leads to prostaglandin e2 (pge2) production and ep receptor stimulation. 0.255 SIGNOR-152756 HMGB1 protein P09429 UNIPROT HOXD9 protein P28356 UNIPROT up-regulates activity binding 10090 BTO:0000944 8890171 YES miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain.ƒ‚‚ The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. 0.334 SIGNOR-236956 alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity precursor of 9606 8631325 YES miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. 0.8 SIGNOR-267924 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Ser165 HNHTTHMsLVGTFPW 9606 15342622 YES gcesareni Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation. 0.2 SIGNOR-128573 AKT1 protein P31749 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 YES gcesareni Pim-1, PKC, and Akt1 kinases phosphorylate Thr-145 and Ser-146 sites on p21 protein. Phosphorylation at Thr-145 promotes cytoplasmic translocation and stability of p21. Ser-146 phosphorylation mediated by Akt1 enhances p21 stabilization and promotes cell survival. 0.84 SIGNOR-157790 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 9889196 YES lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. 0.942 SIGNOR-63895 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR AR protein P10275 UNIPROT down-regulates activity dephosphorylation Ser83 QQQQQETsPRQQQQQ 9606 27858941 YES miannu DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway 0.297 SIGNOR-254759 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation 9606 9792677 YES gcesareni Rsk-b is a p38alphamapk substrate, and activated by p38alphamapk and, more weakly, by erk1 0.603 SIGNOR-60995 TUBB1 protein Q9H4B7 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10116 17118269 NO lperfetto However, evidence suggests that the detyrosination/tyrosination cycle of alpha-tubulin may be linked in some cell types to cell division and proliferationNF-Y 0.7 SIGNOR-242138 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT down-regulates activity phosphorylation Ser249 LSPIDMEsQERIKAE -1 1846781 YES lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. 0.711 SIGNOR-18684 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2A protein P29274 UNIPROT up-regulates activity binding -1 14662005 YES Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. 0.8 SIGNOR-268420 PRKAG2 protein Q9UGJ0 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates activity phosphorylation Ser257 GLHRAEQsLHDLQER 10090 BTO:0000452 31381180 YES miannu STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE 0.2 SIGNOR-277297 CXCR4 protein P61073 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0000007 33073183 YES Marta Tosoni Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner 0.56 SIGNOR-278102 EDN1 protein P05305 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12847114 NO Regulation of expression miannu βMHC expression was markedly augmented by PE and ET, suggesting the transformation of myosin. endothelin-1 (ET) 0.28 SIGNOR-251955 AFF2 protein P51816 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR up-regulates activity binding 9606 17135274 YES miannu Af4 associates with P-TEFb and stimulates its kinase activity. P-TEFb also phosphorylates AF4 which down-regulates its transactivation activity, providing a negative feedback mechanism for the control of P-TEFb elongation activity 0.39 SIGNOR-266801 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT up-regulates activity 9606 21966368 NO Regulation miannu Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms 0.464 SIGNOR-251858 NFATC1 protein O95644 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000776 11163226 NO scontino In this study, the roles of NFATc1 and NFATc2 in T and B cells were examined. These results further characterize NFAT as a transcription factor family that plays a critical role in the regulation of lymphocyte effector differentiation. 0.7 SIGNOR-270537 Yellow AB chemical CHEBI:82554 ChEBI PTCH1 protein Q13635 UNIPROT down-regulates chemical inhibition 9606 17970037 YES gcesareni Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation. 0.8 SIGNOR-158650 OSU-03012 chemical CHEBI:131196 ChEBI PDPK1 protein O15530 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-197715 RPLP1 protein P05386 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.828 SIGNOR-262450 DPM2 protein O94777 UNIPROT DPM complex complex SIGNOR-C289 SIGNOR form complex binding 9606 10835346 YES lperfetto Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. 0.786 SIGNOR-262564 PEX26 protein Q7Z412 UNIPROT PEX6 protein Q13608 UNIPROT up-regulates activity binding 10029 12717447 YES Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions. 0.779 SIGNOR-253614 nintedanib chemical CHEBI:85164 ChEBI FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition -1 18559524 YES Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. 0.8 SIGNOR-257806 FBXO5 protein Q9UKT4 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates ubiquitination 9606 11751633 YES gcesareni Emi1 binds cdh1 and inhibits apc-cdh1 activity. 0.756 SIGNOR-113385 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 YES lperfetto The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. 0.8 SIGNOR-244930 WNT5B protein Q9H1J7 UNIPROT FZD6 protein O60353 UNIPROT up-regulates binding 9606 BTO:0000551;BTO:0000848 16273260 YES gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. 0.667 SIGNOR-141443 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 24702154 YES Eotaxin (CCL11) is a specific ligand for CCR3 and serves as a potent chemoattractant for eosinophils 0.936 SIGNOR-254356 FBXO22 protein Q8NEZ5 UNIPROT BSG protein P35613 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 28117675 YES miannu FBXO22 mediates poly-ubiquitination and degradation of CD147. Classically, F-box protein together with Skp1 and Cullin 1 constitute Skp-Cullin-F box ubiquitin E3 ligase (SCFs) 0.428 SIGNOR-272787 AKT2 protein P31751 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser167 GGRERLAsTNDKGSM 9534 BTO:0001538 11139588 YES AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. 0.51 SIGNOR-251490 CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 37104883 NO lperfetto Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. 0.7 SIGNOR-273191 2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide chemical CHEBI:91426 ChEBI SYK protein P43405 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 30744170 YES lperfetto The Selective SYK Inhibitor BAY 61-3606 Enhances the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells 0.8 SIGNOR-262020 TNKS2 protein Q9H2K2 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates ubiquitination 9606 19759537 YES gcesareni Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. 0.696 SIGNOR-188036 SP7 protein Q8TDD2 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 11792318 NO Giulio Giuliani Our results established that the novel transcription factor Osx is required for osteoblast differentiation and hence for bone formation. 0.7 SIGNOR-255449 ICE1 protein Q9Y2F5 UNIPROT ELL/ICE1 complex SIGNOR-C48 SIGNOR form complex binding 9606 BTO:0001271 22195968 YES miannu The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes. 0.57 SIGNOR-193486 CTSK protein P43235 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 11920402 NO lperfetto Cathepsins K and S have been implicated in various aspects of extracellular matrix degradation and inflammatory responses. 0.7 SIGNOR-253318 CTNNB1 protein P35222 UNIPROT AFF3 protein P51826 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26214578 NO irozzo We demonstrate that AFF3 is a new target of Wnt/β-catenin pathway involved in ACC, acting on transcription and RNA splicing. 0.283 SIGNOR-259192 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 YES gcesareni Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation. 0.678 SIGNOR-33040 BCL6 protein P41182 UNIPROT LITAF protein Q99732 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001518 23795761 NO miannu BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6. 0.352 SIGNOR-253758 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 YES gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity 0.775 SIGNOR-252472 WNT7A protein O00755 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates activity binding 9606 BTO:0000972 31886205 YES Marta Tosoni These findings suggested that Wnt7a upregulated P21 and P27 by inactivating SKP2. 0.2 SIGNOR-278876 N-(3-aminopropyl)-N-[(1R)-1-[7-chloro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]-2-methylpropyl]-4-methylbenzamide chemical CHEBI:94692 ChEBI KIF11 protein P52732 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193483 SMAD3 protein P84022 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR form complex binding 9606 26194464 YES mrosina In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation 0.596 SIGNOR-255034 3-phenanthryl hydrogen sulfate chemical CHEBI:37459 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition -1 7576010 YES miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. 0.8 SIGNOR-258438 VRK1 protein Q99986 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser62 FGPARNDsVIVADQT 9606 15105425 YES gcesareni Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level. 0.372 SIGNOR-124330 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR NRAS protein P01111 UNIPROT up-regulates activity 9534 8402896 NO miannu BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation. 0.2 SIGNOR-261506 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 22021368 NO apalma Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB. 0.7 SIGNOR-256654 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr344 PPEQETFyEQPPLVQ 9606 BTO:0000782 14557276 YES lperfetto We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling. 0.639 SIGNOR-118695 AKT1 protein P31749 UNIPROT ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 YES gcesareni Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B. 0.427 SIGNOR-245255 CSNK2A1 protein P68400 UNIPROT CERS5 protein Q8N5B7 UNIPROT up-regulates activity phosphorylation Ser355 DRSDVESsSEEEDVT 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273987 PTPMT1 protein Q8WUK0 UNIPROT phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI up-regulates chemical modification 10090 21641550 YES lperfetto PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. 0.8 SIGNOR-267025 FYN protein P06241 UNIPROT ARHGAP33 protein O14559 UNIPROT down-regulates phosphorylation Tyr406 PLLTYQLyGKFSEAM 9606 16777849 YES acerquone Tcgap interacted with fyn and was phosphorylated by fyn, with tyr-406 in the gap domain as a major fyn-mediated phosphorylation site. Fyn suppressed the gap activity of wild-type tcgap 0.462 SIGNOR-147156 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Ser59 GGQESQPsPLALLAA 10090 BTO:0000944 11598016 YES gcesareni Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation 0.414 SIGNOR-248240 WNT10A protein Q9GZT5 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 NO fspada We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b 0.466 SIGNOR-176187 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7535768 YES Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185 0.761 SIGNOR-248717 SHC1 protein P29353 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity 10090 BTO:0000944 17673906 NO lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. 0.712 SIGNOR-242622 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 NO lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth 0.791 SIGNOR-252703 MAP3K3 protein Q99759 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 12809556 YES gcesareni Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation 0.449 SIGNOR-102294 ATM protein Q13315 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity phosphorylation Ser219 SKLLMIIsQKDTFHS 9606 BTO:0000567 11375976 YES lperfetto Telomeric protein pin2/trf1 as an important atm target in response to double strand dna breaks. activated atm directly phosphorylated pin2/trf1 preferentially on the conserved ser(219)-gln site in vitro and in vivo. 0.572 SIGNOR-108419 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation 9606 10567572 YES amattioni Jnk was capable of phosphorylating bcl-2. Phosphorylation of bcl-2 inactivates the molecule 0.581 SIGNOR-72364 ATM protein Q13315 UNIPROT XPA protein P23025 UNIPROT unknown phosphorylation Ser173 VKKNPHHsQWGDMKL -1 16540648 YES llicata Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown). 0.611 SIGNOR-250579 PAK5 protein Q9P286 UNIPROT DNPEP protein Q9ULA0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser119 VKRRSRRsQVGFQQV 9606 BTO:0000150 31219614 YES lperfetto We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. | PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway. 0.2 SIGNOR-275651 SLC24A1 protein O60721 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264395 SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130;BTO:0000150;BTO:0000551 BTO:0000975 9129046 YES gcesareni The major ligand for p-selectin on leukocytes is p-selectin glycoprotein ligand-1 (PSGL-1) 0.926 SIGNOR-47625 MTA1 protein Q13330 UNIPROT MTA3 protein Q9BTC8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18719363 NO miannu MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. 0.655 SIGNOR-254595 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 YES llicata Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo 0.2 SIGNOR-252770 JUN protein P05412 UNIPROT SMAD3/JUN complex SIGNOR-C86 SIGNOR form complex binding 9606 9732876 YES gcesareni These results show a ligand-dependent association of smad3 with c-jun 0.75 SIGNOR-59867 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-75017 CALM2 protein P0DP24 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 YES miannu The calmodulin-binding region is located between amino acids 51 and 96 0.462 SIGNOR-266321 MAPK14 protein Q16539 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10116 15486195 YES miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. 0.32 SIGNOR-260442 CSF2 protein P04141 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001571 2479426 NO Regulation of expression miannu Granulocyte-macrophage colony-stimulating factor reactivates fetal hemoglobin synthesis in erythroblast clones from normal adults. 0.2 SIGNOR-251776 KPNA2 protein P52292 UNIPROT RNMT protein O43148 UNIPROT down-regulates activity binding 9606 26942677 YES lperfetto KPNA2 Inhibits RNMT Activity|We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor. 0.413 SIGNOR-265502 Calcineurin complex SIGNOR-C155 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates dephosphorylation 9606 21880741 YES gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. 0.557 SIGNOR-252322 MLH1 protein P40692 UNIPROT MLH1/PMS1 complex SIGNOR-C58 SIGNOR form complex binding 9606 10542278 YES miannu We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_. 0.694 SIGNOR-71768 KATNAL2 protein Q8IYT4 UNIPROT TUBE1 protein Q9UJT0 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001363 29136647 YES miannu KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin 0.2 SIGNOR-267176 HSP90AA1 protein P07900 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 21511880 YES gcesareni We report the crucial underlying role of the intranuclear heat shock protein 90 molecular chaperone complex in pulsatile GR regulation. Pharmacological interference of heat shock protein 90 (HSP90) with geldanamycin during the intranuclear chaperone cycle completely ablated GR's cyclical activity, cyclical cAMP response element-binding protein (CREB) binding protein (CBP)/p300 recruitment, and the associated cyclical acetylation at the promoter region. 0.734 SIGNOR-251667 ENAH protein Q8N8S7 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 NO miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. 0.7 SIGNOR-268389 Erlin complex SIGNOR-C532 SIGNOR ITPR2 protein Q14571 UNIPROT down-regulates quantity by destabilization binding 10119 BTO:0003293 19240031 YES miannu Here we report that the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex that binds to IP(3)R tetramers immediately after their activation and is required for their processing. The complex is ring-shaped (diameter approximately 250A(),) and RNA interference-mediated depletion of SPFH1 and SPFH2 blocks IP(3)R polyubiquitination and degradation.  0.35 SIGNOR-271916 ANK3 protein Q12955 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity binding 9606 BTO:0000007 17620337 YES miannu Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton. 0.324 SIGNOR-266710 RPS6KA5 protein O75582 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 10464286 YES gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-265348 Ub:E2 complex SIGNOR-C497 SIGNOR BIRC8 protein Q96P09 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270957 TNFRSF13C protein Q96RJ3 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 BTO:0000776 24432023 NO lperfetto Non-canonical nf-kb signaling initiated by baff influences b cell biology at multiple junctures. 0.7 SIGNOR-204361 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser400 SRDESTDsGLSMSSY 9606 21364637 YES miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells 0.2 SIGNOR-277645 CAMK2B protein Q13554 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 15980064 YES lperfetto These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. 0.2 SIGNOR-217493 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 BTO:0000567 12670868 YES miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. 0.2 SIGNOR-264482 okadaic acid chemical CHEBI:44658 ChEBI STK4 protein Q13043 UNIPROT up-regulates 9606 23493077 NO gcesareni Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway. 0.8 SIGNOR-201554 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser576 CAEMREDsARVYENV 9606 11781100 YES lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta 0.309 SIGNOR-249137 WARS1 protein P23381 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 0.8 SIGNOR-270514 PLCG1 protein P19174 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 YES gcesareni Phosphorylation at Ser-146 by PKCδ increases p21 stability 0.262 SIGNOR-262962 GEM protein P55040 UNIPROT CACNB2 protein Q08289 UNIPROT down-regulates activity binding 9606 14701738 YES miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. 0.2 SIGNOR-261720 HMOX1 protein P09601 UNIPROT STC2/HMOX1 complex SIGNOR-C244 SIGNOR form complex binding BTO:0000298 22503972 YES Giorgia Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme. 0.344 SIGNOR-260388 LRRC4B protein Q9NT99 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 YES miannu A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles 0.37 SIGNOR-264052 MCM3 protein P25205 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 YES The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. 0.782 SIGNOR-261673 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 17311002 YES gcesareni However, the same cells were highly sensitive to the irreversible dual-specificity egfr/erbb2 kinase inhibitor hki-272, as were those overexpressing wild-type erbb2. 0.8 SIGNOR-153318 CYFIP1 protein Q7L576 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 YES miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems 0.904 SIGNOR-253568 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIFR protein P42702 UNIPROT down-regulates phosphorylation 9606 7777512 YES inferred from 70% family members gcesareni Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044. 0.2 SIGNOR-270134 NSMCE4A protein Q9NXX6 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 YES miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks 0.832 SIGNOR-265486 PTPN2 protein P17706 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15780598 YES lperfetto Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5. 0.735 SIGNOR-93998 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr566 SLNQEDIyITTESLT 10029 BTO:0000246 12907755 YES PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 0.295 SIGNOR-248394 CSNK1A1 protein P48729 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 SIGNOR-C110 19293931 YES gcesareni In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] 0.577 SIGNOR-184696 NBR1 protein Q14596 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 YES gcesareni Nbr1 and p62 interact and form oligomers. 0.473 SIGNOR-184273 UBE2D1 protein P51668 UNIPROT KPC complex SIGNOR-C523 SIGNOR up-regulates activity binding 10090 BTO:0000944 15531880 YES miannu  We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation.  Polyubiquitination activity of KPC was apparent with only Ubc4 or UbcH5A. 0.472 SIGNOR-271514 FGF11 protein Q92914 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253418 UBR5 protein O95071 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21726808 YES lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase |UBR5 ubiquitinates the acetylated PEPCK1 0.308 SIGNOR-267600 IFNA2 protein P01563 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates quantity by stabilization 9606 22171011 YES 2 miannu IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9. 0.478 SIGNOR-240684 RDH10 protein Q8IZV5 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 YES lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 0.8 SIGNOR-265120 SMURF2 protein Q9HAU4 UNIPROT SMAD9 protein O15198 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.643 SIGNOR-193390 PIP3 smallmolecule CHEBI:16618 ChEBI AKT2 protein P31751 UNIPROT up-regulates activity chemical activation 9606 21779497 YES lperfetto When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival. 0.8 SIGNOR-175247 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 YES lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase 0.535 SIGNOR-263417 BPTF protein Q12830 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 YES miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. 0.69 SIGNOR-268817 GDNF protein P39905 UNIPROT LAMA3 protein Q16787 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.2 SIGNOR-252175 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 6239 SIGNOR-C15 17900900 YES lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. 0.517 SIGNOR-219247 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 SIGNOR-C9 15241418 YES llicata We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase 0.745 SIGNOR-126744 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 9606 18098337 YES lperfetto BRAF kinase is a downstream target of KRAS and activates the MAPK pathway. 0.877 SIGNOR-160043 DPF3 protein Q92784 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.743 SIGNOR-270690 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 20331961 YES milica The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits). 0.454 SIGNOR-230761 acetylsalicylic acid chemical CHEBI:15365 ChEBI PTGS2 protein P35354 UNIPROT down-regulates chemical inhibition 9606 11809688 YES gcesareni Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects. 0.8 SIGNOR-114380 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser394 TRQTPVDsPDDSTLS 10090 BTO:0002572 12782654 YES lperfetto S6K1 is a positive regulator of protein synthesis, and its activity is induced by mTOR-mediated phosphorylation. 0.96 SIGNOR-101328 warfarin chemical CHEBI:10033 ChEBI VKORC1 protein Q9BQB6 UNIPROT down-regulates activity chemical inhibition 9606 27941861 YES lperfetto Warfarin and vitamin K compete for binding to Phe55 in human VKOR|Our results challenge the prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor. 0.8 SIGNOR-265911 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT down-regulates activity dephosphorylation Tyr703 DHAEAALyKNLLHSK -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254709 CDK1 protein P06493 UNIPROT ESCO1 protein Q5FWF5 UNIPROT down-regulates phosphorylation 9606 23314252 YES gcesareni We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases , cdc7-dbf4 and the gsk-3 homolog mck1. 0.475 SIGNOR-200400 POLG2 protein Q9UHN1 UNIPROT DNA polymerase gamma complex SIGNOR-C378 SIGNOR form complex binding -1 19837034 YES lperfetto Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit. 0.716 SIGNOR-265718 SOX11 protein P35716 UNIPROT SPAST protein Q9UBP0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22574173 NO miannu we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. 0.363 SIGNOR-254886 JAG2 protein Q9Y219 UNIPROT JAG1 protein P78504 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 9315665 NO gcesareni Immunohistochemistry revealed coexpression of jagged2 and notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human jagged2 with murine c2c12 myoblasts inhibited myogenic differentiation, accompanied by increased notch1 and the appearance of a novel 115-kda notch1 fragment. Exposure of c2c12 cells to jagged2 led to increased amounts of notch mrna as well as mrnas for a second notch receptor, notch3, and a second notch ligand, jagged1. Constitutively active forms of notchl in c2c12 cells also induced increased levels of the same set of mrnas, suggesting positive feedback control of these genes initiated by binding of jagged2 to notch1. 0.411 SIGNOR-236888 IKZF3 protein Q9UKT9 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates activity 10090 BTO:0004731 14718515 NO Here we show that the Ikaros family member, Aiolos, is specifically required for the generation of these plasma cells. Failure to generate high affinity plasma cells in the BM and to sustain serum antibody titers is apparent after both primary and secondary immunization of Aiolos−/− mice with a range of hapten concentrations. 0.7 SIGNOR-259952 TESK2 protein Q96S53 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11418599 YES lperfetto Like tesk1, tesk2 phosphorylated cofilin specifically at ser-3 and induced formation of actin stress fibers and focal adhesions. 0.504 SIGNOR-108753 WDHD1 protein O75717 UNIPROT CLSPN protein Q9HAW4 UNIPROT up-regulates activity binding 9606 BTO:0001109 26082189 YES miannu And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR. Significantly, And-1 binds directly to ssDNA and facilitates the association of Claspin with ssDNA. 0.392 SIGNOR-262665 TP53 protein P04637 UNIPROT FAS protein P25445 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 9841917 YES Nuclear p53 amattioni In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene, 0.603 SIGNOR-62376 CD38 protein P28907 UNIPROT nicotinamide smallmolecule CHEBI:17154 ChEBI up-regulates quantity chemical modification 9606 18626062 YES miannu CD38 is also able to catalyze the degradation of the NAD precursor nicotinamide mono-nucleotide (NMN) into nicotinamide 0.8 SIGNOR-264253 P2RY2 protein P41231 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257233 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 10090 BTO:0001103 17609368 YES gcesareni AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter 0.502 SIGNOR-228646 HDAC1 protein Q13547 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 11171972 YES miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. 0.711 SIGNOR-222124 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 BTO:0000452 19318349 YES gcesareni PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells. 0.643 SIGNOR-248075 MAPK14 protein Q16539 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 YES lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 0.281 SIGNOR-264446 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR EIF3F protein O00303 UNIPROT up-regulates activity phosphorylation Thr119 GAARVIGtLLGTVDK 19245811 YES lperfetto Here, we identified a second eIF3f phosphorylation site (Thr119) by CDK11(p46) during apoptosis. We demonstrated that eIF3f is directly phosphorylated by CDK11(p46) in vivo. Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis.  0.516 SIGNOR-273132 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 21423276 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-172908 CSF1R protein P07333 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates 9606 24890514 YES apalma Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway 0.369 SIGNOR-255570 PAH protein P00439 UNIPROT phenylalanine smallmolecule CHEBI:28044 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors 0.8 SIGNOR-263988 PPARGC1A protein Q9UBK2 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.244 SIGNOR-255055 TNF protein P01375 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 21514273 NO via a ?-catenin-dependent pathway fspada Tumor necrosis factor-? (TNF-alpha) Is known to suppress adipocyte differentiation via a Beta-catenin-dependent pathway. 0.7 SIGNOR-173421 MAML1 protein Q92585 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11101851 YES gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. 0.79 SIGNOR-84838 CD40 protein P25942 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000776 18635759 YES lperfetto Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3. 0.844 SIGNOR-179473 CDK5 protein Q00535 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR form complex binding 9606 11331872 YES lperfetto Induced p35 forms a complex with Cdk5 and activates its kinase activity 0.943 SIGNOR-250683 NR3C1 protein P04150 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 8878484 YES fspada We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter. 0.531 SIGNOR-44376 PKI-587 chemical CID:44516953 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205986 KMN network complex SIGNOR-C366 SIGNOR Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 18007590 NO lperfetto Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis. 0.7 SIGNOR-265215 SMO protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT up-regulates activity binding 9606 23074268 YES lperfetto it was proposed that Smo might signal through activation of Gi proteins to reduce PKA activity. 0.427 SIGNOR-199162 IL21 protein Q9HBE4 UNIPROT BCL6 protein P41182 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0000785 22486304 NO miannu Interleukin-21 inhibits humoral response to an hiv dna vaccine by enhancing bcl-6 andpax-5expression. 0.398 SIGNOR-196918 PKA proteinfamily SIGNOR-PF17 SIGNOR SMN complex complex SIGNOR-C158 SIGNOR up-regulates quantity by stabilization phosphorylation 9606 BTO:0000007 19103745 YES lperfetto PKA increases SMN complex formation and SMN stability. 0.2 SIGNOR-253122 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 21316371 YES gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) 0.341 SIGNOR-171907 LINC complex complex SIGNOR-C303 SIGNOR Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 24481844 NO lperfetto The extensive covalent and non-covalent attachments as well as the binding avidity between three KASH domains with three SUN domains are thought to enable the LINC complex to transmit force between the cytoskeleton and the nucleoskeleton 0.7 SIGNOR-263293 E2F1 protein Q01094 UNIPROT TFDP1 protein Q14186 UNIPROT up-regulates activity binding 10029 8832394 YES 2 miannu The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3. 0.814 SIGNOR-240547 PIP3 smallmolecule CHEBI:16618 ChEBI ZFYVE1 protein Q9HBF4 UNIPROT up-regulates chemical activation 9606 18725538 YES gcesareni Dfcp1 contains two fyve domains (thus explaining its pi(3)p binding) 0.8 SIGNOR-180527 NR1D1 protein P20393 UNIPROT NR2E3 protein Q9Y5X4 UNIPROT up-regulates 9606 15190009 NO gcesareni Our results show that nr1d1 (rev-erb?) Also functions as a transcriptional activator of rod genes in the presence of nr2e3 0.4 SIGNOR-125658 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[(3-methyl-4-oxo-6-quinazolinyl)amino]phenyl]benzamide chemical CHEBI:91354 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190146 KLHL3 protein Q9UH77 UNIPROT WNK1 protein Q9H4A3 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 23387299 YES miannu CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms. 0.564 SIGNOR-272099 IL31RA protein Q8NI17 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782 18926762 YES gcesareni Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex. 0.495 SIGNOR-161342 leucine smallmolecule CHEBI:25017 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264748 spermidine smallmolecule CHEBI:16610 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 NO apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism 0.7 SIGNOR-255553 PRKCB protein P05771 UNIPROT EEF1A2 protein Q05639 UNIPROT up-regulates activity phosphorylation Ser53 AAEMGKGsFKYAWVL 10090 20923971 YES miannu PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein. 0.2 SIGNOR-263166 SRF protein P11831 UNIPROT IL6 protein P05231 UNIPROT up-regulates 9606 22225874 YES FFerrentino Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy. 0.281 SIGNOR-255966 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates activity sumoylation Lys490 QCPRKVIkMESEEGK 9534 BTO:0000298 9756909 YES lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. 0.779 SIGNOR-270541 CDK7 protein P50613 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Thr433 DCDFGDLtPLDF 9606 10428966 YES lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. 0.494 SIGNOR-69780 RNF135 protein Q8IUD6 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity ubiquitination Lys909 QTLYSKWkDFHFEKI 9606 BTO:0000007 19017631 YES miannu Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region. 0.763 SIGNOR-265569 BAK1 protein Q16611 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 NO miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. 0.7 SIGNOR-261493 AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 11069105 YES lperfetto Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. 0.405 SIGNOR-216623 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10656682 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-74839 KCNB2 protein Q92953 UNIPROT VAPB protein O95292 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 YES lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. 0.2 SIGNOR-262123 FAS protein P25445 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 14585074 YES lperfetto The fas receptor, upon binding to the fasl, trimerizes 0.2 SIGNOR-85991 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189978 DAB2IP protein Q5VWQ8 UNIPROT ZEB1 protein P37275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27858941 NO miannu Through inhibition of PI3K–AKT signaling, DAB2IP also represses ZEB1, another CSC determinant. 0.268 SIGNOR-254772 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR2 protein P37173 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193778 AURKA protein O14965 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser380 ATLARRDsLQKPGLE 9606 21822051 YES lperfetto In the present study, aurora a was demonstrated to phosphorylate lats2 on serine 380 (s380) during mitosistogether, the results suggest that the aurora a-lats1/2-aurora b axis might be a novel pathway that regulates accurate mitotic progression by ensuring the proper mitotic localization of lats2. 0.381 SIGNOR-175939 MEN1 protein O00255 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 11526476 YES lperfetto Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner. 0.423 SIGNOR-217406 AKT proteinfamily SIGNOR-PF24 SIGNOR RANBP3 protein Q9H6Z4 UNIPROT up-regulates quantity phosphorylation Ser57 HGTGHPEsAGEHALE 9606 BTO:0000007 18280241 YES miannu Akt phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo. RanBP3 phosphorylation increases its affinity towards Ran 0.2 SIGNOR-276150 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 16049944 YES lperfetto Zap-70 is modified by auto-phosphorylation of various tyrosine residues and is activated by specific phosphorylation of the tyrosine residue y-493 0.2 SIGNOR-139098 ESR1 protein P03372 UNIPROT F12 protein P00748 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 9794469 NO miannu Transcription of the FXII gene is stimulated by estrogens through specific interaction of the estrogen receptor alpha (ER alpha) with an estrogen response element present on FXII promoter. 0.2 SIGNOR-254072 TGFB2 protein P61812 UNIPROT KRT1 protein P04264 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16258965 NO Regulation miannu Immunolocalization of the epithelial marker cytokeratin demonstrates decreased staining by 48 hr after the addition of TGFβ1 or TGFβ2 0.2 SIGNOR-251885 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-181271 ITCH protein Q96J02 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21093410 YES miannu Collectively, our present findings suggest that MDM2 promotes Itch-mediated degradation of p73 through the interaction with Itch in HeLa cells 0.565 SIGNOR-278699 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190182 CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR G2/M_transition phenotype SIGNOR-PH52 SIGNOR up-regulates 9606 29870721 NO lperfetto Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. 0.7 SIGNOR-267572 TIMM10 protein P62072 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 YES lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). 0.713 SIGNOR-267701 NOTCH proteinfamily SIGNOR-PF30 SIGNOR SNW1 protein Q13573 UNIPROT up-regulates binding 9606 10713164 YES gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. 0.2 SIGNOR-254337 BCL2L1 protein Q07817 UNIPROT VDAC1 protein P21796 UNIPROT down-regulates activity binding 10365962 YES lperfetto The anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly 0.567 SIGNOR-249614 CCT129202 chemical CID:16202152 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190877 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 25948473 YES lperfetto Stimulation of Toll-like receptor (TLR) 4 leads to the activation of both MyD88-dependent and MyD88-independent pathways through the recruitment of adaptors TIRAP/MyD88 and TRIF/TRAM, respectively. 0.634 SIGNOR-110215 TNFRSF17 protein Q02223 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 10903733 NO inferred from 70% of family members miannu Overexpression of bcma activates the p38 mapk 0.265 SIGNOR-269917 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 15808510 YES gcesareni Ikkalpha phosphorylates eralpha, aib1/src-3, and histone h3. 0.396 SIGNOR-135050 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCB protein P05771 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191493 NRF1 protein Q16656 UNIPROT SLC46A1 protein Q96NT5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20724482 NO miannu Overexpression of NRF-1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression. 0.337 SIGNOR-254884 SEC62 protein Q99442 UNIPROT Protein_translocation phenotype SIGNOR-PH176 SIGNOR up-regulates 22375059 NO lperfetto We demonstrated, with a similar knockdown approach, a precursor-specific involvement of mammalian Sec63 in the initial phase of co-translational protein transport into the ER. 0.7 SIGNOR-265281 DOK1 protein Q99704 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257675 SRGAP3 protein O43295 UNIPROT RAC1 protein P63000 UNIPROT down-regulates 9606 12447388 NO miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. 0.564 SIGNOR-95918 FASN protein P49327 UNIPROT Lipogenesis phenotype SIGNOR-PH30 SIGNOR up-regulates 9606 20373869 NO lperfetto Fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis 0.7 SIGNOR-242874 INPP4B protein O15327 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity dephosphorylation 9606 26411369 YES lperfetto In support, the increase in PTEN caused by INPP4B knockdown was associated with increased phosphorylation of the Ser380, Thr382, Thr383 and Ser385 cluster of the protein (XREF_FIG), which is known to increase PTEN half-life, in colon cancer cells.|Exogenous INPP4B could pull down and dephosphorylate endogenous PTEN, suggesting that effect of INPP4B on PTEN in colon cancer cells is not due to cell-type-specific characteristics of INPP4B per se.|INPP4B downregulates PTEN in colon cancer cells. 0.631 SIGNOR-277018 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 9606 21620960 YES lperfetto Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. 0.764 SIGNOR-252866 CD38 protein P28907 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity relocalization 10090 17287729 NO lperfetto CD38 is critical for social behaviour by regulating oxytocin secretion|Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. 0.366 SIGNOR-268544 CDK1 protein P06493 UNIPROT TEX14 protein Q8IWB6 UNIPROT down-regulates quantity by destabilization phosphorylation Thr727 SNLNNMStTEEYLIS 9606 BTO:0000007 22405274 YES miannu Cdk1 phosphorylation of Tex14 is required for the Tex14-Plk1 interaction 0.334 SIGNOR-273524 MAPK3 protein P27361 UNIPROT SOX9 protein P48436 UNIPROT up-regulates transcriptional regulation 9606 20457810 NO fspada Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression. 0.382 SIGNOR-209965 HAUS6 protein Q7Z4H7 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity binding 9606 BTO:0000567 19029337 YES miannu FAM29A recruits NEDD1 to spindle MTs. Ectopically expressed NEDD1 and FAM29A interact with each other. 0.812 SIGNOR-261421 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 22298955 YES lperfetto Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7 0.684 SIGNOR-217709 EEF1A1 protein P68104 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 NO lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.7 SIGNOR-269393 ABI1 protein Q8IZP0 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 YES lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  0.861 SIGNOR-261872 WNT5B protein Q9H1J7 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.635 SIGNOR-131882 BFAR protein Q9NZS9 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates binding 9606 BTO:0000093 11733517 YES gcesareni We also demonstrate that the mitochondrial protein bar, which has been shown to simultaneously bind caspase-8 and bcl-2 0.37 SIGNOR-112585 Early macropinosomes phenotype SIGNOR-PH228 SIGNOR Late macropinosomes phenotype SIGNOR-PH229 SIGNOR up-regulates 9606 39000072 NO miannu The early macropinosomes continue to mature into late macropinosomes, which fuse with lysosomes and degrade their cargos. 0.7 SIGNOR-277789 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194334 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity chemical activation 9606 18321241 YES miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). 0.8 SIGNOR-259240 HDAC3 protein O15379 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 25726523 YES lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 0.257 SIGNOR-275662 GRIK2 protein Q13002 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 YES lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine 0.8 SIGNOR-268273 MMP3 protein P08254 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272396 KDM4B protein O94953 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 30759871 YES miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways. 0.2 SIGNOR-263734 RBM8A protein Q9Y5S9 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 YES miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. 0.918 SIGNOR-265242 AKT proteinfamily SIGNOR-PF24 SIGNOR MEF2D protein Q14814 UNIPROT up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 NO lperfetto Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1. 0.2 SIGNOR-244303 MAPKAPK2 protein P49137 UNIPROT SRF protein P11831 UNIPROT unknown phosphorylation Ser103 RGLKRSLsEMEIGMV 9606 BTO:0000567 10318869 YES llicata Mk2 phosphorylates srf in vitro at ser-103 0.582 SIGNOR-67448 SMAD3 protein P84022 UNIPROT CEBPA protein P49715 UNIPROT down-regulates activity binding 10090 12524424 YES gcesareni Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters 0.376 SIGNOR-241924 DUSP7 protein Q16829 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 YES gcesareni Identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor. 0.314 SIGNOR-104545 LSM-1131 chemical CHEBI:91398 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189873 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT down-regulates activity binding 9606 10548111 YES amattioni The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7). 0.939 SIGNOR-71954 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 21454675 YES gcesareni Receptor-type protein tyrosine phosphatase beta (rptp-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (hgfr/met) function. 0.365 SIGNOR-173004 EPAS1 protein Q99814 UNIPROT PTPRZ1 protein P23471 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15833863 NO miannu A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Ten genes were preferentially activated by HIF-2alpha, including two (CACNA1A and PTPRZ1) implicated in neurologic diseases. 0.262 SIGNOR-264333 CCND1 protein P24385 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 18177723 NO andrea cerquone perpetuini Cyclin D1 is necessary for proliferation of different cell types, including myogenic cells. 0.7 SIGNOR-255412 RPS6KA3 protein P51812 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 YES lperfetto The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. 0.386 SIGNOR-184595 SRMS protein Q9H3Y6 UNIPROT DOK1 protein Q99704 UNIPROT unknown phosphorylation 9606 BTO:0000007 23822091 YES lperfetto These data indicate that ectopically‐expressed GFP‐SRMS interacts with and mediates the phosphorylation of overexpressed GFP‐Dok1. 0.415 SIGNOR-264569 PKI-587 chemical CID:44516953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205989 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0000776 8657103 YES lperfetto Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771. 0.774 SIGNOR-246572 SCN10A protein Q9Y5Y9 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 YES miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. 0.8 SIGNOR-253408 GSN protein P06396 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR down-regulates quantity binding 9606 BTO:0000132 27871158 YES lperfetto Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. 0.7 SIGNOR-261835 SMC3 protein Q9UQE7 UNIPROT MXI1 protein P50539 UNIPROT down-regulates activity binding 9534 BTO:0000318 9528857 YES 2 miannu We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions. 0.404 SIGNOR-241223 WWTR1 protein Q9GZV5 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates binding 9606 23431053 YES YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. 0.869 SIGNOR-201459 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Ser474 RTHFPQFsYSASIRE 10090 BTO:0000944 15367694 YES Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes 0.748 SIGNOR-248631 AVEN protein Q9NQS1 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity binding -1 18571408 YES miannu These data suggest that Aven overexpression can activate ATM and that Aven phosphorylation in a positive feedback loop enforces Aven activity, making it a more potent ATM activator. 0.382 SIGNOR-262638 CD27 protein P26842 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12324477 NO gcesareni Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively. 0.2 SIGNOR-93317 PARD6A protein Q9NPB6 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity binding 9606 BTO:0000007 22544755 YES lperfetto The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization, and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains. 0.2 SIGNOR-227489 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Thr82 HSMSVPTtPTLGFST 9606 17604322 YES lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 0.2 SIGNOR-262960 SUCLA2 protein Q9P2R7 UNIPROT Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR form complex binding 9606 32627745 YES miannu Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). 0.986 SIGNOR-266262 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of -1 8099587 YES Luana 17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone.  0.8 SIGNOR-269763 CDT1 protein Q9H211 UNIPROT MCM complex SIGNOR-C268 SIGNOR up-regulates activity binding 9606 BTO:0000007 14672932 YES Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1. 0.789 SIGNOR-261679 C5 protein P01031 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 cleavage:Arg751 HKDMQLGrLHMKTLL 30552328 YES complement C5b fragment: PRO_0000005989 lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer 0.62 SIGNOR-263440 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 19143636 YES lperfetto Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor. 0.384 SIGNOR-209859 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates activity binding 9606 BTO:0000801 18852293 YES lperfetto IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. 0.942 SIGNOR-249527 PPP1R3A protein Q16821 UNIPROT GYS1 protein P13807 UNIPROT up-regulates dephosphorylation 9606 BTO:0000887;BTO:0001103 8250835 YES gcesareni In skeletal muscle, the activation of glycogen synthase by insulin involves the dephosphorylation of serine residues that are phosphorylated by gsk3 and dephosphorylated by the glycogen-associated form of protein phosphatase-l (pp1g). 0.501 SIGNOR-37301 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 NO miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. 0.7 SIGNOR-268387 AKT proteinfamily SIGNOR-PF24 SIGNOR HK2 protein P52789 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000192 31435020 YES K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization 0.2 SIGNOR-259985 NPFF protein O15130 UNIPROT NPFFR2 protein Q9Y5X5 UNIPROT up-regulates binding 9606 11024015 YES gcesareni Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems 0.771 SIGNOR-82961 CFH protein P08603 UNIPROT CFI protein P05156 UNIPROT up-regulates activity binding 9606 26806831 YES lperfetto FH also serves as cofactor for the serine protease factor I (FI) that cleaves C3b into iC3b, unable to form C3 convertase (Fig 1B). 0.92 SIGNOR-263490 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ -1 12435421 YES miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly 0.434 SIGNOR-250008 CAMK2A protein Q9UQM7 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.279 SIGNOR-275785 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000142 20308788 YES The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. 0.2 SIGNOR-164663 Tosedostat chemical CID:15547703 PUBCHEM ANPEP protein P15144 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207372 ipilimumab antibody DB06186 DRUGBANK CTLA4 protein P16410 UNIPROT down-regulates activity binding 9606 BTO:0005594 18049334 YES miannu The inhibitory receptor CTLA4 has a key role in peripheral tolerance of T cells for both normal and tumor-associated antigens. CTLA4 blockade with ipilimumab induces cancer regression in some patients with metastatic clear cell renal cancer, even if they have not responded to other immunotherapies. 0.4 SIGNOR-259894 PRKCD protein Q05655 UNIPROT ANKRD54 protein Q6NXT1 UNIPROT up-regulates activity phosphorylation 9606 28924458 YES miannu The mechanism by which phosphorylation of Ankrd54 by PKC\u03b4 enhances cytoplasmic accumulation of Ankrd54 and its interaction with Lyn remains to be determined.|This revealed, in agreement with the biochemical analysis, that PKCdelta significantly promotes cytoplasmic accumulation of Ankrd54. 0.2 SIGNOR-279259 PRKCD protein Q05655 UNIPROT CNTNAP1 protein P78357 UNIPROT down-regulates activity phosphorylation 9606 19632305 YES miannu Inhibition of PKCdelta increased p190 activity, while PKCdelta overexpression diminished p190 activity.|We further show that PKC\u03b4 was able to phosphorylate and bind distinct domains of p190. 0.2 SIGNOR-279260 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 29901072 YES miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. 0.8 SIGNOR-262221 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 BTO:0000782 12151396 YES gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk 0.352 SIGNOR-91059 WDR83 protein Q9BRX9 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates binding 9606 15118098 YES lperfetto Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. 0.532 SIGNOR-244964 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0003298 BTO:0001103 30029643 NO In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway. 0.7 SIGNOR-256256 KPNA4 protein O00629 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 YES gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. 0.287 SIGNOR-165314 CDK2 protein P24941 UNIPROT ATRIP protein Q8WXE1 UNIPROT unknown phosphorylation Ser239 VIKPEACsPQFGKTS 9606 17638878 YES lperfetto Two novel phosphorylation sites on atrip were identified, s224 and s239 0.578 SIGNOR-156932 PLK1 protein P53350 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates activity phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 BTO:0000567 21642957 YES done miannu We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1. 0.61 SIGNOR-273888 EGFR protein P00533 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR up-regulates activity phosphorylation 9606 15284024 YES Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. 0.631 SIGNOR-252088 LPAR6 protein P43657 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.358 SIGNOR-257286 RNF7 protein Q9UBF6 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity polyubiquitination 9606 10851089 YES miannu SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34.  0.747 SIGNOR-271443 clomipramine chemical CHEBI:47780 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter. 0.8 SIGNOR-258875 JNK proteinfamily SIGNOR-PF15 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 YES lperfetto Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities. 0.2 SIGNOR-105758 3-methyladenine chemical CHEBI:38635 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205636 USO1 protein O60763 UNIPROT GOLGB1 protein Q14789 UNIPROT up-regulates activity binding 9606 23555793 YES miannu The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane. 0.84 SIGNOR-261237 ABCA7 protein Q8IZY2 UNIPROT APP protein P05067 UNIPROT down-regulates quantity relocalization 9606 BTO:0000142 27472885 NO miannu Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD. 0.406 SIGNOR-265176 RET protein P07949 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 27994058 YES miannu In detail, RET and PTC3 induced STAT1 overexpression and phosphorylation at Ser 727 and Tyr 701. 0.275 SIGNOR-279277 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 YES Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  0.8 SIGNOR-258137 L3MBTL1 protein Q9Y468 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity binding 9606 29018219 YES lperfetto L3MBTL1, a tumor suppressor with high affinity for H4K20me2, can block 53BP1 binding at DSBs 0.404 SIGNOR-262059 URB597 chemical CID:1383884 PUBCHEM FAAH protein O00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207615 GUCA2A protein Q02747 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 10845107 YES gcesareni Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney 0.771 SIGNOR-78096 NVP-ADW742 chemical CID:9825149 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194883 ERC1 protein Q8IUD2 UNIPROT CHUK protein O15111 UNIPROT up-regulates binding 9606 SIGNOR-C14 15218148 YES miannu Elks likely functions by recruiting ikappabalpha to the ikk complex and thus serves a regulatory function for ikk activation. 0.589 SIGNOR-126430 MAOB protein P27338 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-264002 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone chemical CHEBI:91454 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190443 TTC19 protein Q6DKK2 UNIPROT CHMP4B protein Q9H444 UNIPROT up-regulates activity binding 9606 BTO:0000567 SIGNOR-C379 20208530 YES miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. 0.418 SIGNOR-265541 CDK5 protein Q00535 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation Thr235 YEKDDKLtPKIGFPW 9606 BTO:0000971 12769842 YES llicata Increased ezrin expression and activation by CDK5 coincident with acquisition of the senescent phenotype. 0.465 SIGNOR-250665 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270840 NOTCH1 protein P46531 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001454 10933396 NO gcesareni Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression 0.417 SIGNOR-80333 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 BTO:0000130 14499342 YES lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. 0.769 SIGNOR-118044 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF1 protein Q8TCQ1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271243 MRPS2 protein Q9Y399 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding P82664 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.745 SIGNOR-261449 CASP3 protein P42574 UNIPROT DFFA protein O00273 UNIPROT up-regulates activity cleavage 9606 9108473 YES lperfetto DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3. 0.754 SIGNOR-47416 LRFN2 protein Q9ULH4 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 NO miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. 0.7 SIGNOR-264099 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270420 MAPK3 protein P27361 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser312 SYLSQMTsPSIHSTT 9606 19801668 YES llicata In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation. 0.563 SIGNOR-188347 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr17 RVSSYRRtFGGAPGF 9606 BTO:0000971 10574968 YES lperfetto We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin 0.317 SIGNOR-249032 GSK3B protein P49841 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation 9606 20932480 YES miannu Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687 0.345 SIGNOR-168392 MAPRE1 protein Q15691 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates binding 17889670 YES lperfetto Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170) 0.7 SIGNOR-264831 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 YES miannu A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. 0.727 SIGNOR-188911 maraviroc chemical CHEBI:63608 ChEBI CCR5 protein P51681 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194248 PAX3 protein P23760 UNIPROT MEOX1 protein P50221 UNIPROT up-regulates activity binding -1 11423130 YES miannu We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family. 0.423 SIGNOR-222235 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB2 protein P05107 UNIPROT up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.2 SIGNOR-259023 NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 23612709 NO miannu Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin 0.2 SIGNOR-255465 GOLGA7 protein Q7Z5G4 UNIPROT ZDHHC9 protein Q9Y397 UNIPROT up-regulates activity binding 9606 BTO:0000007 16000296 YES miannu DHHC9 and GCP16 form a protein complex, and DHHC9 requires GCP16 for protein fatty acyltransferase activity and protein stability. 0.685 SIGNOR-261353 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr286 SVPSAAVtPLNESLQ 9606 15767678 YES gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.744 SIGNOR-134537 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB2 protein Q00722 UNIPROT up-regulates 23994464 YES apalma However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits 0.545 SIGNOR-255015 EZH2 protein Q15910 UNIPROT HOXB13 protein Q92826 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 22808286 NO miannu EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. 0.405 SIGNOR-254144 RANBP9 protein Q96S59 UNIPROT DYRK1B protein Q9Y463 UNIPROT down-regulates activity binding 9606 BTO:0000007 14500717 YES llicata Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met adaptor Ran-binding protein M. 0.418 SIGNOR-238008 PHA-665752 chemical CHEBI:90197 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206088 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 21423276 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-172917 TWIST2 protein Q8WVJ9 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255496 N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide chemical CHEBI:91370 ChEBI PTK2 protein Q05397 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206067 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates relocalization 9606 23151663 YES gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6. 0.292 SIGNOR-199650 PTPN1 protein P18031 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 YES Overexpression of PTP1B increased Src specific activity in colon cancer cells by reducing phosphorylation at Y530 of Src. 0.78 SIGNOR-248422 lysine smallmolecule CHEBI:25094 ChEBI Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270410 PRKG1 protein Q13976 UNIPROT TRPC6 protein Q9Y210 UNIPROT down-regulates activity phosphorylation Thr70 RLAHRRQtVLREKGR -1 19961855 YES miannu PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q).  0.489 SIGNOR-276272 ITGB1BP1 protein O14713 UNIPROT ITGB7 protein P26010 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.288 SIGNOR-257664 BAZ2B protein Q9UIF8 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 YES miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. 0.2 SIGNOR-266623 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR MYC protein P01106 UNIPROT up-regulates activity 9606 19855079 YES apalma We demonstrate that in addition to blocking myeloid differentiation, PLZF-RARα also promotes proliferation/self-renewal via the aberrant regulation of cell cycle–associated genes such as c-Myc, providing a basis for studying the aberrant response of this leukemia subtype to retinoic acid. 0.2 SIGNOR-256374 AKT1 protein P31749 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 19526459 YES llicata Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1. 0.363 SIGNOR-252525 IKBKE protein Q14164 UNIPROT TRAF3IP2 protein O43734 UNIPROT up-regulates activity phosphorylation Ser328 KVILNYPsPWDHEER 9606 21822257 YES miannu IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function. 0.416 SIGNOR-262883 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 33064660 YES miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. 0.8 SIGNOR-267721 NUAK1 protein O60285 UNIPROT MAPT protein P10636 UNIPROT up-regulates quantity phosphorylation Ser673 RVQSKIGsLDNITHV 9606 27720485 YES miannu These results confirm that the effect of Nuak1 over tau levels is mainly due to tau phosphorylation at Ser356 by Nuak1.|Western blot analysis revealed that a 50% reduction in Nuak1 was sufficient to decrease tau levels in the brain (XREF_FIG). 0.249 SIGNOR-279306 WNT1 protein P04628 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 10090 BTO:0000887 16936075 YES lperfetto Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6) 0.7 SIGNOR-217827 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation -1 16226275 YES inferred from 70% family members lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| 0.2 SIGNOR-270111 ESR1 protein P03372 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16169518 YES gcesareni Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k. 0.661 SIGNOR-252675 RUNX1 protein Q01196 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29958106 YES miannu RUNX1 represses MYC expression through direct binding at three downstream enhancer elements 0.337 SIGNOR-260093 NDUFA11 protein Q86Y39 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5) 0.808 SIGNOR-262142 CERS1 protein P27544 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 YES done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  0.8 SIGNOR-273993 PDCD1 protein Q15116 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 28286692 NO Barakat Programmed cell death-1 (PD-1) is a major regulator of T-cell exhaustion, and blocking the PD-1 pathway restores T-cell function and improves pathogen control and tumor eradication. Immunotherapy targeting the PD-1 inhibitory receptor pathway has demonstrated significant antitumor activity. 0.7 SIGNOR-275413 NEK2 protein P51955 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 30968157 YES miannu NEK2 silencing reduced the phosphorylation of beta-catenin at Ser33 and Ser37, but did not decrease the level of total beta-catenin.|NEK2 slightly decreased the level of total beta-catenin (XREF_FIG). 0.47 SIGNOR-278172 denopamine chemical CHEBI:135359 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257860 DNAJC6 protein O75061 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates activity relocalization 24789820 YES lperfetto Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane. 0.883 SIGNOR-260719 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 11971971 YES gcesareni Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. 0.744 SIGNOR-86713 SLC44A2 protein Q8IWA5 UNIPROT choline smallmolecule CHEBI:15354 ChEBI up-regulates activity relocalization 9606 21367571 YES lperfetto Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it 0.8 SIGNOR-260409 HOMER proteinfamily SIGNOR-PF59 SIGNOR SHANK1 protein Q9Y566 UNIPROT up-regulates activity binding 9606 17243894 YES miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD 0.2 SIGNOR-264698 SOCS1 protein O15524 UNIPROT VAV1 protein P15498 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0000298 10747851 YES miannu SOCS1 stimulates the polyubiquitination of VAV proteins in vivo, which was stabilized by proteasomal inhibitors. These results suggest that SOCS1 programs VAV degradation by acting as a substrate-specific recognition component of a VCB-like ubiquitin ligase complex. 0.597 SIGNOR-272559 PRKACA protein P17612 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS -1 12853467 YES miannu PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚  0.445 SIGNOR-250025 NR3C1 protein P04150 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8639160 YES gcesareni We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins 0.742 SIGNOR-251679 CARS1 protein P49589 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270805 hsa-miR-338-3p mirna URS00000254A6_9606 RNAcentral CDH2 protein P19022 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004169 29069716 YES Parnian MiR-338-3p represents a new class of miRNA that suppresses EMT and metastasis via regulation of the SHH/Gli1 pathway and direct targeting of N-cadherin. 0.4 SIGNOR-277976 MYOD1 protein P15172 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR form complex binding 10090 BTO:0001103 18094043 YES lperfetto MyoD omodimers or heterodimers of MyoD plus E12 or E47 serve as transcription factor complexes that bind to CANNTG consensus sites in the promoter regions of genes, performing major functions in specification and differentiation of skeletl muscle precursor cells. 0.805 SIGNOR-241548 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation Tyr393 RLMTGDTyTAHAGAK 9534 BTO:0004055 11163214 YES lperfetto Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated. 0.439 SIGNOR-235568 SIX4 protein Q9UIU6 UNIPROT UBA52 protein P62987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 9826681 NO gcesareni We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4. 0.2 SIGNOR-62178 BMP10 protein O95393 UNIPROT ACVRL1 protein P37023 UNIPROT up-regulates binding 9606 17068149 YES acerquone Taken together, our results sug- gest that bmp9 and bmp10 are two spe- cific alk1 ligands that may physiologi- cally trigger the effects of alk1 on angiogenesis 0.708 SIGNOR-150201 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887 11160134 YES lperfetto Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation. 0.2 SIGNOR-244784 PLXNB3 protein Q9ULL4 UNIPROT FSCN1 protein Q16658 UNIPROT up-regulates activity 10090 BTO:0000526 21706053 NO miannu Sema5A regulates the phosphorylation states of fascin-1 through plexin-B3. 0.337 SIGNOR-268374 apigenin chemical CHEBI:18388 ChEBI CYP2C9 protein P11712 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189802 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 22378047 NO IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype 0.789 SIGNOR-254515 CWC27 protein Q6UX04 UNIPROT Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11991638 NO Purification and characterization of native pliceosomes suitable for three-dimensional structural analysis 0.7 SIGNOR-261148 MDGA2 protein Q7Z553 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26206665 NO miannu Enhanced protein expression of p53 and p21 by MDGA2 was confirmed in MDGA2 overexpressed cells and xenograft tumours. 0.2 SIGNOR-264242 MEF2C protein Q06413 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 7739551 YES lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. 0.564 SIGNOR-238652 KLF11 protein O14901 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 10207080 NO Regulation miannu Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. 0.2 SIGNOR-251828 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 YES gcesareni Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a. 0.636 SIGNOR-143696 CASP8 protein Q14790 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 NO amattioni Downstream of caspase-8 activation, apoptosis induction takes place 0.7 SIGNOR-90612 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 21993628 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-176757 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser495 KTMIRKRsFGNPFEG 9606 22778263 YES lperfetto Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity 0.2 SIGNOR-198150 Ub:E2 complex SIGNOR-C497 SIGNOR RNF145 protein Q96MT1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270995 LYN protein P07948 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 YES miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation 0.2 SIGNOR-262676 AFF1 protein P51825 UNIPROT AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 BTO:0000664 20153263 YES 1 miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. 0.459 SIGNOR-239231 STK4 protein Q13043 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 YES gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. 0.594 SIGNOR-191847 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 22083140 YES lperfetto The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. 0.894 SIGNOR-227881 MYB protein P10242 UNIPROT GSTM1 protein P09488 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14576818 YES Functional analysis of the GSTM1 promoter using reporter assays indicated that both the DNA binding and transactivation domains of Myb were required for transcriptional activation 0.2 SIGNOR-253975 STK11 protein Q15831 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity phosphorylation Thr77 KCVTIQRtLDGRLQV 9606 20974850 YES miannu LKB1 inhibits the DNA binding and the transcriptional activity of Smad4.|We further demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr 77 of its DNA-binding domain. 0.629 SIGNOR-278193 SP3 protein Q02447 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15479157 NO miannu we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity. 0.2 SIGNOR-255203 HIP1 protein O00291 UNIPROT REST protein Q13127 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21832040 NO miannu HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). 0.2 SIGNOR-255076 SIRT7 protein Q9NRC8 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 YES lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 0.2 SIGNOR-275873 chloroquine chemical CHEBI:3638 ChEBI TNF protein P01375 UNIPROT down-regulates quantity 9606 32283152 NO miannu Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19. 0.8 SIGNOR-260853 AMHR2 protein Q16671 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 14746809 YES gcesareni See table2 0.431 SIGNOR-121596 CREB1 protein P16220 UNIPROT BDNF protein P23560 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000142 32603820 YES miannu Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF. 0.489 SIGNOR-265062 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL 9534 BTO:0000298 8557118 YES lperfetto PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. 0.365 SIGNOR-248937 CDK1 protein P06493 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation 9606 29971233 YES miannu Cdk1 phosphorylates Cdc20 to negatively regulate its ability to bind and activate the APC/C. 0.934 SIGNOR-279321 4-Iodo-3-nitrobenzamide chemical CID:9796068 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193474 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000567 12356755 YES gcesareni Here we show that glucocorticoids synergistically enhance nthi-induced tlr2 expression via specific up-regulation of the mapk phosphatase-1 (mkp-1) that, in turn, leads to dephosphorylation and inactivation of p38 mapk, the negative regulator for tlr2 expression. 0.804 SIGNOR-93873 RAF1 protein P04049 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 11427728 YES gcesareni Raf-1 interacts with the proapoptotic, stress-activated protein kinase ask1 (apoptosis signal-regulating kinase 1) in vitro and in vivo. 0.396 SIGNOR-109023 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1337 QVFYNSEyGELSEPS 9606 BTO:0000394 12881528 YES lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. 0.2 SIGNOR-104088 citrate(3-) smallmolecule CHEBI:16947 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 19286649 YES miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. 0.8 SIGNOR-267100 BLK protein P51451 UNIPROT CGAS protein Q8N884 UNIPROT down-regulates activity phosphorylation Tyr215 LLNTGSYyEHVKISA 30356214 YES lperfetto DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. 0.2 SIGNOR-275844 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates phosphorylation Ser1112 LLEDGSEsPAKRICP 9606 BTO:0001938 11157749 YES gcesareni When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity 0.849 SIGNOR-104656 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity phosphorylation 9606 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. 0.729 SIGNOR-209759 RUNX2 protein Q13950 UNIPROT TNFSF11 protein O14788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 NO gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast 0.475 SIGNOR-107242 RIT1 protein Q92963 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 10090 BTO:0000944 23791108 YES It is possible that RIT1 interacts with RAF1 and that gain-of-function mutations in RIT1 and RAF1 exert similar effects in heart development. 0.549 SIGNOR-251650 FHIT protein P49789 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 NO miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. 0.27 SIGNOR-159870 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Ser87 AAAGPALsPVPPVVH 9606 18570871 YES gcesareni Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy. 0.581 SIGNOR-179092 PPM1G protein O15355 UNIPROT SRSF3 protein P84103 UNIPROT down-regulates activity dephosphorylation 9606 34290239 YES miannu Here, we found that the PPM1G regulated SRSF3, and high levels of PPM1G decreased SRSF3 activity in HCC cells.|PPM1G interacted with SRSF3 and dephosphorylated SRSF3. 0.2 SIGNOR-277048 PRKD1 protein Q15139 UNIPROT TLR5 protein O60602 UNIPROT up-regulates phosphorylation Ser805 YQLMKHQsIRGFVQK 9606 BTO:0002181 17442957 YES lperfetto Pkd phosphorylated the tlr5-derived target peptide in vitro, and phosphorylation of the putative target serine 805 in hek 293t cell-derived tlr5 was identified by mass spectrometry. These results demonstrate that both pkd1 and pkd2 are required for inflammatory responses following tlr2, tlr4, or tlr5 activation, although pkd1 is more strongly involved 0.353 SIGNOR-154473 CAMK2A protein Q9UQM7 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2426 ASGDRPPsVSSVHSE 9606 22888005 YES lperfetto We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. 0.2 SIGNOR-191773 MAPKAPK3 protein Q16644 UNIPROT HSPB1 protein P04792 UNIPROT unknown phosphorylation Ser15 FSLLRGPsWDPFRDW -1 8774846 YES miannu MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15) 0.684 SIGNOR-250159 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR MECOM protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 YES irozzo We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. 0.2 SIGNOR-255858 MEF2A protein Q02078 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 9418854 YES lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. 0.741 SIGNOR-54086 PIK3C3 protein Q8NEB9 UNIPROT 1-phosphatidyl-1D-myo-inositol 3-phosphate smallmolecule CHEBI:17283 ChEBI up-regulates chemical modification 9606 8999962 YES gcesareni Vps34p phosphorylates phosphatidylinositol (ptdins) at the 3?-Position of the inositol ring, but not ptdins. 0.8 SIGNOR-45606 IKBKB protein O14920 UNIPROT RBFOX2 protein O43251 UNIPROT up-regulates activity phosphorylation 9606 20686657 YES miannu Phosphorylation of RTA by IKKbeta increases RTA transcriptional activity and consequently viral mRNA production. 0.2 SIGNOR-279336 WNT10B protein O00744 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 12055200 YES fspada Inhibition of adipogenesis by wnt10b is likely mediated by‚ wnt‚ receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 8 0.618 SIGNOR-210164 2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide chemical CHEBI:91367 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190245 PRDM1 protein O75626 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates quantity transcriptional regulation 10090 12052884 YES Gianni Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner. 0.502 SIGNOR-269089 CKM complex complex SIGNOR-C406 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates activity phosphorylation Ser375 PVDEDRLsPLVAADS 9606 22945643 YES lperfetto Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation. 0.362 SIGNOR-273138 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR1 protein P21453 UNIPROT up-regulates chemical activation 9606 16794003 YES gcesareni The evidence suggests that s1p acting on s1p receptors coupled to gq 0.8 SIGNOR-147227 ARNT protein P27540 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22387692 NO lperfetto The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. 0.644 SIGNOR-253705 IL1RN protein P18510 UNIPROT IL1R1 protein P14778 UNIPROT down-regulates activity binding 9606 2876877 YES Gianni Homozygous truncating mutations result in lack of secreted interleukin-1–receptor antagonist protein, which inhibits the proinflammatory cytokines interleukin-1α and interleukin-1β 0.897 SIGNOR-262302 TP53RK protein Q96S44 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17712528 YES gcesareni The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of prpk to cos-7 cells. Prpk was shown to bind to p53 and to phosphorylate p53 at ser-15. 0.759 SIGNOR-157471 TAK-960 chemical CID:53357478 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207200 dabigatran chemical CHEBI:70752 ChEBI F2 protein P00734 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190314 MEF2C protein Q06413 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates -1 23001426 NO Luana  In brain, MEF2C is essential for early neurogenesis, neuronal migration, and differentiation.  0.7 SIGNOR-265800 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001583 21873430 YES miannu  Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. 0.436 SIGNOR-276356 ADAM17 protein P78536 UNIPROT TGFA protein P01135 UNIPROT up-regulates activity cleavage 9606 26284334 YES miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF 0.49 SIGNOR-259841 IL20RB protein Q6UXL0 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000782;BTO:0000876 12941475 NO gcesareni Il-20 induces cheratin proliferation and stat-3 signal transduction pathway 0.509 SIGNOR-86305 KAT2A protein Q92830 UNIPROT SLC44A2 protein Q8IWA5 UNIPROT up-regulates quantity 9606 BTO:0003065 21367571 NO lperfetto Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it 0.2 SIGNOR-260408 PRKACA protein P17612 UNIPROT POLD3 protein Q15054 UNIPROT down-regulates phosphorylation Ser458 GKANRQVsITGFFQR 9606 22148433 YES llicata In this study, we identified s458, located in the pcna-interacting protein (pip-box) motif of p68, as a phosphorylation site for pka. Phosphomimetic mutation of s458 resulted in a decrease in p68 affinity for pcna as well as the processivity of pol _. 0.2 SIGNOR-195203 CASP8 protein Q14790 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.333 SIGNOR-261752 MAML1 protein Q92585 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 16530044 YES gcesareni Maml-1 is preassociated with other components of the transcriptional machinery, such as p300 0.65 SIGNOR-145057 SERPINE1 protein P05121 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 10368279 NO gcesareni Pai-1 is the physiological inhibitor of the fibrinolytic pathway 0.7 SIGNOR-68481 ERBB3 protein P21860 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.415 SIGNOR-146867 NOTCH proteinfamily SIGNOR-PF30 SIGNOR IL7R protein P16871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 NO lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells 0.2 SIGNOR-254345 ACTB protein P60709 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.506 SIGNOR-269293 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT up-regulates phosphorylation Tyr685 LDARPSLyAQVQKPP 9606 BTO:0000975 16909109 YES llicata In vitro src assay, the ve-cadherin cytoplasmic domain is directly phosphorylated by purified src as well as the tyrosine residue 685 (tyr)685-containing peptide finally, we found that in a vegf-induced wound-healing assay, cadherin adhesive activity was impaired by src kinase inhibitors.RPSLY(685)aqvq. 0.568 SIGNOR-148818 CUDC-907 chemical CID:54575456 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191212 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates dephosphorylation 9606 20016286 YES gcesareni Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity. 0.391 SIGNOR-162146 KDM5A protein P29375 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates binding 7227 BTO:0000782 20231316 YES lperfetto In this study, we show that the histone demethylase kdm5a associated with rbp-j protein and is essential for notch/rbp-j target gene silencing in vitro. 0.385 SIGNOR-219250 MYC protein P01106 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity transcriptional regulation 9606 17785433 YES inferred from family member Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. 0.452 SIGNOR-270270 YBX1 protein P67809 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17822788 NO miannu YB-1 binds to the MMP-13 promoter sequence and represses MMP-13 transactivation via the AP-1 site. 0.2 SIGNOR-255615 ARHGEF9 protein O43307 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.834 SIGNOR-260534 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 BTO:0000399 10706854 YES Activation of ERK2 and p38 by eotaxin is mediated through CCR3. 0.248 SIGNOR-256092 AT-406 chemical CID:25022340 PUBCHEM BIRC2 protein Q13490 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189954 LPAR2 protein Q9HBW0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 15856019 YES gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. lpa2 also can couple to the gi/o, g12/13, and gqfamilies. 0.49 SIGNOR-135834 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser370 PAVPPRPsADLILNR 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.552 SIGNOR-89174 GSK3B protein P49841 UNIPROT FBXO4 protein Q9UKT5 UNIPROT up-regulates phosphorylation Ser12 EPRSGTNsPPPPFSD 9606 21242966 YES lperfetto Gsk3beta-mediated phosphorylation of fbx4 ser12 during the g1/s transition regulates fbx4 dimerization, which in turn governs fbx4-driven e3 ligase activity. 0.2 SIGNOR-171648 icariin chemical CHEBI:78420 ChEBI PDE5A protein O76074 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193363 ITGA7 protein Q13683 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR form complex binding 9606 BTO:0000222;BTO:0002319 10199978 YES lperfetto The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle. 0.772 SIGNOR-241508 JUN protein P05412 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 10369069 NO miannu Co-transfection of WT cells with a c-jun expression vector and either of the AP-1 luciferase constructs demonstrated that c-jun could activate gene expression from both the consensus and the MDR1 AP-1 sites in a dose dependent manner. 0.344 SIGNOR-254534 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 16679294 YES gcesareni Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action 0.261 SIGNOR-146672 AIP protein O00170 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity transcriptional regulation 9606 BTO:0000093 21984905 YES The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor α. 0.291 SIGNOR-253644 HDAC5 protein Q9UQL6 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 9606 11062529 YES gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. 0.695 SIGNOR-84026 FLT3 protein P36888 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 10090 25477897 YES miannu The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC 0.4 SIGNOR-255796 RELA protein Q04206 UNIPROT MET protein P08581 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0002895 19530226 YES gcesareni Together, these results indicate that the Met gene is a direct target of NFkappaB and that Met participates in NFkappaB-mediated cell survival. 0.25 SIGNOR-241929 POLR1D protein P0DPB6 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.895 SIGNOR-266146 PLK1 protein P53350 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Thr37 SDAKLEPtNVQTVTC 9606 21041660 YES lperfetto Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression. 0.567 SIGNOR-169184 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 8642285 YES irozzo Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant.These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation. 0.2 SIGNOR-255813 UBIAD1 protein Q9Y5Z9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000362 30518913 NO miannu This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. 0.7 SIGNOR-256205 DYRK1A protein Q13627 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 12809556 YES gcesareni In the present study, dyrk1a is shown to directly interact with and phosphorylate rcan1 at ser112 and thr192 residues. Dyrk1a-mediated phosphorylation of rcan1 at ser112 primes the protein for the gsk3_-mediated phosphorylation of ser108. 0.563 SIGNOR-102290 F2RL1 protein P55085 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254859 RNF220 protein Q5VTB9 UNIPROT SIN3B protein O75182 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 20170641 YES miannu Here we identify RNF220 (RING finger protein 220) as a novel ubiquitin ligase for Sin3B. RNF220 specifically interacts with Sin3B both in vitro and in vivo. Sin3B can be regulated by the ubiquitin-proteasome system. Co-expression of RNF220 promotes the ubiquitination and proteasomal degradation of Sin3B. 0.429 SIGNOR-271943 PIM2 protein Q9P1W9 UNIPROT EIF4EBP1 protein Q13541 UNIPROT up-regulates activity phosphorylation 9606 19290049 YES miannu Further, PIM2 triggered phosphorylation of AKT and 4EBP1 (XREF_FIG) clearly demonstrating the activation of PI3K pathway. 0.414 SIGNOR-279091 aloxistatin chemical CHEBI:101381 ChEBI CTSL protein P07711 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 32142651 YES miannu Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. 0.8 SIGNOR-260282 SRC protein P12931 UNIPROT NCKIPSD protein Q9NZQ3 UNIPROT up-regulates activity phosphorylation 9606 23342115 YES miannu These results indicate that phosphorylation of SPIN90 by Src is essential for its synaptic targeting. 0.415 SIGNOR-279387 PPARG protein P37231 UNIPROT JUN protein P05412 UNIPROT up-regulates activity 9606 BTO:0000801 17681149 NO lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways 0.586 SIGNOR-249558 ICAM1 protein P05362 UNIPROT ITGAX protein P20702 UNIPROT up-regulates binding 9606 7679388 YES gcesareni Using assays to quantify cd11c-mediated cell adhesion, we demonstrate that cd11c recognizes icam-2 and vcam-1. The cd11c-binding site on vcam-1 appears to be different from that used by the integrin alpha4. 0.678 SIGNOR-31388 DDR1 protein Q08345 UNIPROT TM4SF1 protein P30408 UNIPROT up-regulates activity binding 30187813 YES lperfetto Gao et al have demonstrated that in metastatic breast cancer cell, DDR1 interacts with cell surface Transmembrane 4 L Six Family Member 1 (TM4SF1) and regulates tumor dormancy and reactivation [3]. The interaction between DDR1 and TM4SF1 is collagen dependent and control Protein Kinase C Alpha (PKCa) mediated downstream JAK-STAT signaling pathway [3] (Figure 3). Interestingly the data also showed that TM4SF1 failed to interact with DDR2.  0.424 SIGNOR-272400 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.411 SIGNOR-252885 NLRX1 protein Q86UT6 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity relocalization 9606 BTO:0002181 18219313 NO Giorgia NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time. 0.259 SIGNOR-260358 ZM447439 chemical CHEBI:91376 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207923 MIB1 protein Q86YT6 UNIPROT PCM1 protein Q15154 UNIPROT down-regulates ubiquitination 9606 BTO:0001938 24121310 YES miannu  We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation.  0.372 SIGNOR-272878 QRICH1 protein Q2TAL8 UNIPROT WARS2 protein Q9UGM6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269411 PAK1 protein Q13153 UNIPROT VIM protein P08670 UNIPROT unknown phosphorylation Ser56 SRSLYASsPGGVYAT 9606 BTO:0000887;BTO:0001260 15766329 YES llicata In the present study, pak1 was able to phosphorylate vimentin on ser-56 in vitro. 0.2 SIGNOR-134520 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 BTO:0000782 12151396 YES gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. 0.341 SIGNOR-91075 PARD6A protein Q9NPB6 UNIPROT PARD6/SMURF1 complex SIGNOR-C112 SIGNOR form complex binding 9606 BTO:0004183 15761148 YES lperfetto The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT. 0.637 SIGNOR-227559 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM2 protein Q14416 UNIPROT up-regulates activity chemical activation 9606 25042998 YES miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate 0.8 SIGNOR-264071 STAT3 protein P40763 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11278729 YES lperfetto Coexpression of activated c-Src and Stat3 synergistically induced strong HGF promoter activity in SP1 cells 0.62 SIGNOR-251742 AGPAT5 protein Q9NUQ2 UNIPROT 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI down-regulates quantity chemical modification 9606 21173190 YES lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† 0.8 SIGNOR-267012 PTPRH protein Q9HD43 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 28065597 YES miannu We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling. 0.288 SIGNOR-277090 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 YES lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity 0.757 SIGNOR-232142 HOXA11 protein P31270 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001549 17688409 NO miannu Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. 0.294 SIGNOR-254469 PF-04691502 chemical CID:25033539 PUBCHEM AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck;inhibitor of phosphorylation of AktT308 and AktS473 gcesareni 0.8 SIGNOR-205977 CEP43 protein O95684 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR form complex binding 9606 16314388 YES miannu Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring. 0.2 SIGNOR-142358 MAP2K6 protein P52564 UNIPROT PAK6 protein Q9NQU5 UNIPROT up-regulates phosphorylation Tyr566 KSLVGTPyWMAPEVI 9606 15550393 YES llicata Moreover, pak6 was directly activated by mkk6, and mutation of tyrosine 566 in a consensus mkk6 site (threonine-proline-tyrosine, tpy) in the activation loop of the pak6 kinase domain prevented activation by mkk6. 0.2 SIGNOR-130975 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates activity phosphorylation Ser529 SNSGRARsDPTHQHR 9606 BTO:0001938 17229891 YES llicata In the present study, we show that DYRK1A autophosphorylates, via an intramolecular mechanism, on Ser-520, in the PEST domain of the protein. | Instead, we demonstrate that this phosphorylation allows the binding of 14-3-3beta, which in turn stimulates the catalytic activity of DYRK1A. 0.2 SIGNOR-251090 ARHGEF12 protein Q9NZN5 UNIPROT RHOA protein P61586 UNIPROT up-regulates guanine nucleotide exchange factor 9606 BTO:0001271 11094164 YES gcesareni Here, we show that larg can activate rho in vivo 0.905 SIGNOR-84657 CALM3 protein P0DP25 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 YES miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.627 SIGNOR-266343 CDS1 protein Q92903 UNIPROT CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates chemical modification 9606 25375833 YES lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). 0.8 SIGNOR-267017 TRIM27 protein P14373 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 33385414 YES miannu Mechanically, TRIM27 ubiquitinates and degrades PPARgamma, following induces cleaved Caspase-3 and IL-1beta expression. 0.289 SIGNOR-278734 SGK1 protein O00141 UNIPROT SMO protein Q99835 UNIPROT down-regulates binding 9606 25790864 YES gcesareni SGK1 is known to inhibit another intrinsic pathway, the Hedgehog pathway, through downregulation of SMO and the GLI transcription factor family 0.2 SIGNOR-251673 TCAP protein O15273 UNIPROT Sarcomere_organization phenotype SIGNOR-PH165 SIGNOR up-regulates activity binding 9606 BTO:0001103 9804419 YES lperfetto The giant muscle protein titin (connectin) is essential in the temporal and spatial control of the assembly of the highly ordered sarcomeres (contractile units) of striated muscle.  0.7 SIGNOR-264855 CDK1 protein P06493 UNIPROT STMN1 protein P16949 UNIPROT up-regulates activity phosphorylation Ser25 QAFELILsPRSKESV 9606 8125092 YES lperfetto 0.64 SIGNOR-279803 RASGEF1A protein Q8N9B8 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.383 SIGNOR-183829 ACOT4 protein Q8N9L9 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271806 FOXO3 protein O43524 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001482 15705665 YES We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs). 0.396 SIGNOR-255950 ADIPOQ protein Q15848 UNIPROT ADIPOR1 protein Q96A54 UNIPROT up-regulates binding 9606 16622416 YES milica Two adiponectin receptors, adipor1 and adipor2, have recently been identified. 0.675 SIGNOR-146170 COP1 protein Q8NHY2 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 19805145 YES miannu MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism 0.2 SIGNOR-271893 CTDSPL protein O15194 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity dephosphorylation Ser807 PGGNIYIsPLKSPYK 9606 15051889 YES ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms. 0.298 SIGNOR-248304 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194640 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 BTO:0000007 11259409 YES miannu JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein. 0.339 SIGNOR-250083 CRADD protein P78560 UNIPROT Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR form complex binding 9606 20158568 YES miannu The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. 0.923 SIGNOR-262642 EAF1 protein Q96JC9 UNIPROT ELL protein P55199 UNIPROT up-regulates binding 9606 16006523 YES miannu Positive regulation of ell elongation activity depends on stable binding of eaf1 to the ell n terminus 0.846 SIGNOR-138516 PIM1 protein P11309 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 20663873 YES miannu Pim-1 phosphorylates Cdh1 and impairs binding of this protein to another APC/C complex member, CDC27. These modifications inhibit Skp2 from degradation.Pim-1 Impairs Cdh1 and CDC27 Interaction and Phosphorylates Cdh1. 0.317 SIGNOR-259820 INTS4 protein Q96HW7 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.763 SIGNOR-261467 pralidoxime chemical CHEBI:8354 ChEBI ACHE protein P22303 UNIPROT up-regulates activity chemical activation -1 21215642 YES Luana These compounds were synthesized, evaluated in vitro on human AChE (hAChE) inhibited by tabun, paraoxon, methylparaoxon and DFP and then compared to commercial hAChE reactivators (pralidoxime, HI-6, trimedoxime, obidoxime, methoxime) or previously prepared compounds (K027, K203). Three of these novel compounds showed a promising ability to reactivate hAChE comparable or better than the used standards.  0.8 SIGNOR-257889 SLC2A2 protein P11168 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 25421524 YES The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. 0.8 SIGNOR-267386 CASP8 protein Q14790 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 NO amattioni Downstream of caspase-8 activation, apoptosis induction takes place 0.7 SIGNOR-256639 Melanotan II chemical CID:92432 PUBCHEM MC4R protein P32245 UNIPROT up-regulates activity binding BTO:0000614 17702843 YES lperfetto Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases. 0.8 SIGNOR-253066 metformin chemical CHEBI:6801 ChEBI PCK1 protein P35558 UNIPROT down-regulates quantity 9606 17909097 NO gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. 0.8 SIGNOR-158062 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 10913145 YES gcesareni We find that, in vitro, pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. 0.375 SIGNOR-79955 (S)-selisistat chemical CHEBI:90371 ChEBI SIRT1 protein Q96EB6 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191511 GATA2 protein P23769 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8195185 NO irozzo Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3. 0.431 SIGNOR-256052 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15109499 YES Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers 0.2 SIGNOR-252929 AKT1 protein P31749 UNIPROT NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 YES llicata Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype. 0.424 SIGNOR-198913 F2RL1 protein P55085 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254843 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr129 ITEIADLtQKIFDLR 9606 BTO:0000671 18986304 YES llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). 0.2 SIGNOR-182049 WNT5A protein P41221 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 9606 BTO:0000887;BTO:0001103 9753670 NO gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. 0.32 SIGNOR-60379 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7889942 YES inferred from 70% family members gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.2 SIGNOR-270075 ENAH protein Q8N8S7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 NO miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. 0.7 SIGNOR-268392 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 15070733 YES gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. 0.641 SIGNOR-123832 PRKCD protein Q05655 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 23814099 YES miannu We next demonstrated by immunoprecipitation that IL-32\u03b2 interacted with PKC\u03b4 and C/EBP\u03b1, thereby mediating C/EBP\u03b1 Ser-21 phosphorylation by PKC\u03b4. 0.2 SIGNOR-279427 BHLHE40 protein O14503 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 14672706 NO lperfetto Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression 0.532 SIGNOR-253716 SPDYA protein Q5MJ70 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 33015044 YES lperfetto Speedy/RINGO A, a noncanonical activator of CDK2, was recently identified as a key regulator for CDK2 recruitment to meiotic telomeres 0.791 SIGNOR-263310 LPAR3 protein Q9UBY5 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 15856019 YES gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. 0.399 SIGNOR-135846 Ub:E2 complex SIGNOR-C497 SIGNOR RNFT2 protein Q96EX2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271263 NSF protein P46459 UNIPROT SNAP25 protein P60880 UNIPROT down-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 16679567 YES miannu NSF is an important regulator of SNARE assembly/disassembly. NSF binds to SNAP-25, while in complex with other SNAREs, and hydrolyzes adenosine triphosphate to disassemble the SNARE complex down to monomers 0.724 SIGNOR-263974 COL1A2 protein P08123 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I 0.7 SIGNOR-254663 Gbeta proteinfamily SIGNOR-PF4 SIGNOR POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation 9606 23024368 YES inferred from 70% family members gcesareni Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5. 0.2 SIGNOR-270085 Ub:E2 complex SIGNOR-C497 SIGNOR RNF148 protein Q8N7C7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271197 PRKAA1 protein Q13131 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 YES miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex 0.2 SIGNOR-276839 CNKSR1 protein Q969H4 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15845549 YES gcesareni Here we demonstrate that the connector enhancer of ksr1, cnk1, mediates src-dependent tyrosine phosphorylation and activation of raf-1. Cnk1 binds preactivated raf-1 and activated src and forms a trimeric complex. 0.71 SIGNOR-135674 SIRT1 protein Q96EB6 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 BTO:0000007 14976264 NO lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress 0.7 SIGNOR-267285 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser43 FGYQRRAsDDGKLTD 9606 7935389 YES gcesareni Pka can inhibit raf-1 function directly via phosphorylation of the raf-1 kinase domain 0.557 SIGNOR-34761 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.257 SIGNOR-159462 CAMK2D protein Q13557 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates phosphorylation Thr554 RGLSRQEtFDSETQE 9606 20194790 YES The effect has been demonstrated using Q08289-2 gcesareni We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells. 0.411 SIGNOR-164067 CSNK1D protein P48730 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 11165242 YES miannu Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). 0.807 SIGNOR-268001 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT down-regulates activity phosphorylation Ser313 LDLEESSsSDHAERP 10029 BTO:0000246 7876239 YES The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization. 0.2 SIGNOR-251442 AMPK complex SIGNOR-C15 SIGNOR MAPK14 protein Q16539 UNIPROT up-regulates activity 10090 20660302 NO P38 MAPK mediates the effect of AMPK on Gr induced transcriptional activity 0.28 SIGNOR-255951 TDGF1 protein P13385 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates activity binding 9606 19874624 YES Regulation miannu Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors. 0.727 SIGNOR-251938 FOXO3 protein O43524 UNIPROT STK11 protein Q15831 UNIPROT down-regulates quantity transcriptional regulation 22848740 YES SGK-1 Negatively Regulates LKB1 Expression via FOXO3 Transcription Factor 0.633 SIGNOR-255758 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAQ protein P50148 UNIPROT up-regulates binding 9606 20331961 YES inferred from 70% family members gcesareni The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits) 0.2 SIGNOR-269966 AKT1 protein P31749 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates activity phosphorylation Ser72 PPRKRLKsKGSDKDF 9606 19270695 YES miannu We further show that Akt1 phosphorylates Skp2 at Ser72, which is required to disrupt the interaction between Cdh1 and Skp2. 0.516 SIGNOR-278274 WNT4 protein P56705 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 NO gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. 0.294 SIGNOR-60370 LYN protein P07948 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 YES miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  0.357 SIGNOR-276369 SRC protein P12931 UNIPROT NEDD4 protein P46934-4 UNIPROT up-regulates activity phosphorylation Tyr585 DGEKGLDyGGVAREW 9606 25292214 YES miannu Activation of c-Src by epidermal growth factor (EGF) also promoted tyrosine phosphorylation and enhanced the activity of NEDD4.  0.417 SIGNOR-276860 FLT3 protein P36888 UNIPROT PARP1 protein P09874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21228325 NO Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls  0.25 SIGNOR-261554 pemetrexed disodium chemical CHEBI:63722 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 YES miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). 0.8 SIGNOR-259289 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.762 SIGNOR-253682 PTH protein P01270 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17656568 NO miannu Parathyroid hormone (PTH) functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We have already shown that PTH stimulates the expression of matrix metalloproteinase-13 (MMP-13), which is responsible for degrading components of extracellular matrix. 0.446 SIGNOR-254234 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2J1 protein Q9Y385 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.587 SIGNOR-271342 SUCLG2 protein Q96I99 UNIPROT Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR form complex binding 9606 32627745 YES miannu Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS). 0.93 SIGNOR-266264 CDKN2A protein Q8N726 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity relocalization 9606 23416275 YES fstefani We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53. 0.764 SIGNOR-192697 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser44 GKSSVLEsLVGRDLL 9606 25192600 YES miannu The schematic for GSK3beta phosphorylating Drp1 at Ser 40 and Ser 44 was shown. 0.389 SIGNOR-278479 FANCI protein Q9NVI1 UNIPROT Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR form complex binding 9606 BTO:0000007 17412408 YES lperfetto Immunoprecipitation of HA-FLAG-tagged FANCI expressed in 293T cells with antibodies against either HA or FLAG, but not MYC, resulted in coimmunoprecipitation of endogenous FANCD2|The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage. 0.956 SIGNOR-263269 Ub:E2 complex SIGNOR-C497 SIGNOR RNF151 protein Q2KHN1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271158 TNF protein P01375 UNIPROT CTSK protein P43235 UNIPROT up-regulates quantity by expression transcriptional regulation 11920402 NO lperfetto This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme. 0.359 SIGNOR-253317 HTR1E protein P28566 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257100 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 YES gcesareni In the absence of hedgehog signaling, gli1 is transcriptionally repressed, gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation, and gli3 is processed to a cleaved repressor. 0.567 SIGNOR-154222 NMUR2 protein Q9GZQ4 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257352 OPTN protein Q96CV9 UNIPROT NEFL protein P07196 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 NO same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. 0.267 SIGNOR-259881 CDKN1A protein P38936 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 7626805 YES gcesareni P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases. 0.941 SIGNOR-29957 MLXIPL protein Q9NP71 UNIPROT ACACA protein Q13085 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 15496471 YES Luana The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) 0.435 SIGNOR-267946 TRAF6 protein Q9Y4K3 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT up-regulates activity binding 9606 10075662 YES miannu TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation. 0.728 SIGNOR-253045 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser304 YEDDDYVsKKSKHEE 9606 10993082 YES lperfetto Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity 0.646 SIGNOR-82033 CSNK1A1 protein P48729 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity 0.416 SIGNOR-183658 ER stress stimulus SIGNOR-ST9 SIGNOR BBC3 protein Q9BXH1 UNIPROT up-regulates 9606 22492984 NO miannu Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins 0.7 SIGNOR-196938 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr939 QICKGMEyLGSRRCV 9606 18250158 YES lperfetto Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro 0.2 SIGNOR-160668 dacomitinib chemical CHEBI:132268 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205936 DEAF1 protein O75398 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000142 29636529 YES Gianni The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription 0.437 SIGNOR-269064 STAT3 protein P40763 UNIPROT PDAC-associated neural remodeling (PANR) phenotype SIGNOR-PH233 SIGNOR up-regulates 9606 BTO:0000584 29269518 NO miannu Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell–promoting factor LIF supports PDAC-associated neural remodeling (PANR).Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. 0.7 SIGNOR-278038 PPP1R1C protein Q8WVI7 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity binding 18310074 YES lperfetto IPP5, a novel inhibitor of protein phosphatase 1, suppresses tumor growth and progression of cervical carcinoma cells by inducing G2/M arrest 0.39 SIGNOR-275725 FBXO31 protein Q5XUX0 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 YES miannu FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. 0.324 SIGNOR-277380 STARD13 protein Q9Y3M8 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.643 SIGNOR-260521 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 21983014 NO In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression. 0.398 SIGNOR-254258 PRKACA protein P17612 UNIPROT LCP1 protein P13796 UNIPROT up-regulates phosphorylation Ser5 sVSDEEMM 9606 BTO:0000007 16636079 YES gcesareni Phosphorylation on ser5 increases the f-actin-binding activity of l-plastin and promotes its targeting to sites of actin assembly in cells. L-plastin phosphorylation require protein kinase a. 0.327 SIGNOR-146287 PKA proteinfamily SIGNOR-PF17 SIGNOR PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 YES done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  0.2 SIGNOR-273898 PKA proteinfamily SIGNOR-PF17 SIGNOR SEC14L2 protein O76054 UNIPROT up-regulates activity phosphorylation Ser289 VQISRGSsHQVEYEI -1 15680919 YES done miannu  Thus, phosphorylation of SPF at Ser-289 appears necessary for maximal stimulation of squalene monooxygenase activity in vitro and absolutely required for the stimulation of cholesterol synthesis in cell culture. the 2.3-fold activation of SPF by PKA was reduced by 60% in the S289A mutant, indicating that phosphorylation of this site contributes to the activation of SPF. 0.2 SIGNOR-273788 SP1 protein P08047 UNIPROT SLC19A3 protein Q9BZV2 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 15217784 NO miannu In transiently transfected Drosophila SL2 cells, both SP1 and SP3 transactivated the SLC19A3 minimal promoter in a dose-dependent manner and in combination demonstrated an additive stimulatory effect. 0.271 SIGNOR-255215 LTC4S protein Q16873 UNIPROT leukotriene C4(2-) smallmolecule CHEBI:57973 ChEBI up-regulates quantity chemical modification 9606 27365393 YES miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). 0.8 SIGNOR-277257 AURKA protein O14965 UNIPROT SPIN1 protein Q9Y657 UNIPROT up-regulates activity phosphorylation Ser109 LNKDERVsALEVLPD 9606 BTO:0000567 22258766 YES miannu The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function. 0.243 SIGNOR-273549 PPP1CA protein P62136 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity dephosphorylation Ser127 PQHVRAHsSPASLQL 9606 21909427 YES lperfetto In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.|PP1A dephosphorylates endogenous YAP2 at serine 127. 0.667 SIGNOR-276999 NR1I2 protein O75469 UNIPROT CYP3A4 protein P08684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000003 18540626 NO miannu Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals. 0.52 SIGNOR-254835 Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 YES lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. 0.74 SIGNOR-256472 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2A protein P49459 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.673 SIGNOR-271361 ACP3 protein P15309 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity chemical modification -1 18940592 YES Luana Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. 0.8 SIGNOR-269739 CHEK2 protein O96017 UNIPROT CDK11B protein P21127 UNIPROT up-regulates activity phosphorylation 9606 23178491 YES miannu CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11p110|Unexpectedly, CHK2 kinase constitutively phosphorylated CDK11(p110) in a DNA damage-independent manner. 0.2 SIGNOR-279458 CYSLTR1 protein Q9Y271 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257135 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser238 QGTPLTCsPNVENRG 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.287 SIGNOR-276101 RPS17 protein P08708 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.904 SIGNOR-262434 CBP/p300 complex SIGNOR-C6 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 21131905 YES lperfetto These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. 0.2 SIGNOR-265322 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser20 LQYYYSSsEDEDSDH 9606 16717095 YES lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. 0.385 SIGNOR-146833 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 12419246 YES lperfetto Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7 0.684 SIGNOR-217703 GTP smallmolecule CHEBI:15996 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 YES miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. 0.8 SIGNOR-270812 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Thr310 GTARRTGtPSDPRRR -1 12885254 YES GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro 0.388 SIGNOR-251235 PINK1 protein Q9BXM7 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates phosphorylation Ser65 DYNIQKEsTLHLVLR 24784582 YES Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. 0.603 SIGNOR-270341 WNK3 protein Q9BYP7 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates activity phosphorylation 21613606 YES lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs 0.526 SIGNOR-264625 ITGB1BP1 protein O14713 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257641 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 10090 12242151 YES lperfetto We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c. 0.832 SIGNOR-92939 GRM8 protein O00222 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. 0.8 SIGNOR-264939 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259706 NFE2L2 protein Q16236 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000599 26194347 NO irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. 0.7 SIGNOR-256263 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr329 RALTEDStQTSDTAT -1 7836371 YES gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. 0.2 SIGNOR-249664 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176817 HBB protein P68871 UNIPROT CD163 protein Q86VB7 UNIPROT up-regulates activity binding 9606 16522161 YES Regulation miannu These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells. 0.44 SIGNOR-251746 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18509061 YES gcesareni We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf. 0.479 SIGNOR-178713 DNMT1 protein P26358 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 NO miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 0.348 SIGNOR-254574 APC-c complex SIGNOR-C150 SIGNOR FBXW5 protein Q969U6 UNIPROT down-regulates quantity by destabilization ubiquitination 21725316 YES lperfetto We show that FBXW5 levels are controlled by the anaphase-promoting (APC/C) complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset the centrosome duplication machinery. 0.398 SIGNOR-275477 CHKA protein P35790 UNIPROT PLIN2 protein Q99541 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr232 TKLHSRAyQQALSRV 9606 BTO:0000527 34929314 YES lperfetto In addition, as a protein kinase, CHKalpha2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth  0.2 SIGNOR-267649 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 7227 22162134 YES lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch 0.78 SIGNOR-219269 CSNK2A1 protein P68400 UNIPROT RIOK1 protein Q9BRS2 UNIPROT up-regulates quantity by stabilization phosphorylation Thr410 MEIASQRtKEERSSQ 9606 BTO:0000007 29384474 YES miannu Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1.  0.332 SIGNOR-273630 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide chemical CHEBI:91433 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-195543 HIPK2 protein Q9H2X6 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation 9606 16212962 YES miannu HIPK2 inhibits both MDM2 gene and protein by, respectively, p53-dependent and independent regulations.|This p53-independent effect is likely mediated by HIPK2 catalytic activity and we found that HIPK2 phosphorylates MDM2 in vitro. 0.538 SIGNOR-279465 FGD2 protein Q7Z6J4 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.482 SIGNOR-260552 DYRK3 protein O43781 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates activity phosphorylation Ser1330 PAFGRVSsPPNAMMS 9606 BTO:0000578 31066068 YES miannu Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. 0.2 SIGNOR-275451 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2A protein P28223 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257521 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1875 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273064 LCK protein P06239 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr42 DSMKDEEyEQMVKEL 14534291 YES lperfetto Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors 0.585 SIGNOR-249374 Osmotic_stress stimulus SIGNOR-ST28 SIGNOR FUS protein P35637 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 NO We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne 0.7 SIGNOR-262815 FBXW11 protein Q9UKB1 UNIPROT ZNF281 protein Q9Y2X9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001615 phosphorylation:Ser638 PRVDLHTsGEHSELV 29179460 YES lperfetto E3 ligase the beta-transducin repeat-containing protein 2 (beta-TrCP2) governs the ubiquitination and degradation of ZNF281. In human CRC specimens, endogenous beta-TrCP2 were inversely correlated with ZNF281. 0.2 SIGNOR-264897 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 8816480 YES gcesareni In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1 0.634 SIGNOR-43947 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Thr991 SAYTYERtLMMEQRS 9606 24043619 YES Manara WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048.  0.445 SIGNOR-260912 Volasertib chemical CID:10461508 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190290 CREBBP protein Q92793 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity acetylation Lys399 SGPCERRkSPLQDPF 9606 BTO:0000007 17923090 YES lperfetto By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2. 0.347 SIGNOR-217783 CREB1 protein P16220 UNIPROT UXT protein Q9UBK9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 17761951 NO lperfetto The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells. 0.2 SIGNOR-254092 CSNK2A1 protein P68400 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by stabilization phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 19923321 YES lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. 0.348 SIGNOR-161771 MTNR1B protein P49286 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257102 PRKACA protein P17612 UNIPROT RGS14 protein O43566 UNIPROT up-regulates activity phosphorylation Ser260 NAALRREsQGSLNSS -1 12534294 YES miannu RGS14 is phosphorylated in vitro at Ser258 and Thr494 by PKA. cAMP-induced phosphorylation as an important modulator of RGS14 function since phosphorylation could enhance RGS14 binding to Galpha(i)-GDP 0.338 SIGNOR-250045 FOXN1 protein O15353 UNIPROT DSG4 protein Q86SJ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19683850 NO miannu we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle. 0.381 SIGNOR-254182 TP53 protein P04637 UNIPROT PMS2 protein P54278 UNIPROT up-regulates quantity transcriptional regulation 9606 15781865 YES .... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron. 0.581 SIGNOR-257604 MDH1 protein P40925 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-266287 SNIP1 protein Q8TAD8 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.435 SIGNOR-270671 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 19282669 YES inferred from 70% family members lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.2 SIGNOR-270020 GSK3B protein P49841 UNIPROT MAML1 protein Q92585 UNIPROT down-regulates phosphorylation 9606 19740771 YES gcesareni We found that gsk3beta inhibits maml1 transcriptional activity by directly targeting the n-terminal domain of maml1 0.2 SIGNOR-187896 RASGEF1B protein Q0VAM2 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.297 SIGNOR-183835 SPX protein Q9BT56 UNIPROT GALR3 protein O60755 UNIPROT up-regulates activity binding 9606 BTO:0000007 24517231 YES lperfetto Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III. 0.346 SIGNOR-268575 BGJ-398 chemical CHEBI:63451 ChEBI FGFR2 protein P21802 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190266 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Ser96 KTQLNPTsLQKLFRE 9606 15319445 YES gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. 0.419 SIGNOR-128260 AKT proteinfamily SIGNOR-PF24 SIGNOR RAC1 protein P63000 UNIPROT down-regulates activity phosphorylation Ser71 YDRLRPLsYPQTDVF 9606 BTO:0003476 10617634 YES gcesareni The results suggest that Akt kinase of the phosphoinositide 3-kinase signal transduction pathway phosphorylates serine 71 of Rac1 as one of its authentic substrates and modulates the Rac1 signal transduction pathway through phosphorylation. 0.2 SIGNOR-248036 AMFR protein Q9UKV5 UNIPROT SERPINI1 protein Q99574 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21507957 YES miannu In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. 0.296 SIGNOR-272756 Loratadine chemical CHEBI:6538 ChEBI SLC6A15 protein Q9H2J7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 25318072 YES Simone Vumbaca Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B0AT2. Our studies provide thefirst chemical tool for B0AT2. 0.8 SIGNOR-261092 AMFR protein Q9UKV5 UNIPROT INSIG1 protein O15503 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25003069 YES miannu The ubiquitination of Insig-1 is mediated by gp78 and regulated by sterols.|gp78 mediates the degradation of Insig-1 and Insig-2. 0.526 SIGNOR-278567 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001103 15829723 YES apalma IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt. 0.791 SIGNOR-255106 UBE3A protein Q05086 UNIPROT DLG4 protein P78352 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 17121805 YES miannu E6-induced degradation of DLG4 depends on E6AP in vivo.  Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro. 0.35 SIGNOR-271397 MYC protein P01106 UNIPROT HLA-C protein P10321 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 NO miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. 0.256 SIGNOR-254602 STT3B protein Q8TCJ2 UNIPROT OST-B complex complex SIGNOR-C536 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.75 SIGNOR-272070 CALM2 protein P0DP24 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 YES miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.522 SIGNOR-266324 corticosterone smallmolecule CHEBI:16827 ChEBI 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 YES lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone 0.8 SIGNOR-268674 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 YES gcesareni Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. 0.474 SIGNOR-252618 LRRFIP2 protein Q9Y608 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 15677333 YES gcesareni In particular, a previously unrecognized activator, lrrfip2 (leucine-rich repeat in flightless interaction protein 2), was found that interacts with dvl to increase the cellular levels of _-catenin and activate _-catenin/lef/tcf-dependent transcriptional activity 0.387 SIGNOR-133429 CXCL3 protein P19876 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 38309677 YES miannu CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively 0.722 SIGNOR-277719 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile chemical CHEBI:95341 ChEBI JAK1 protein P23458 UNIPROT down-regulates activity chemical inhibition 9606 20363976 YES Luana INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). 0.8 SIGNOR-257833 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM6A protein O15550 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273462 A8/b1 integrin complex SIGNOR-C165 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates 15721307 NO lperfetto We previously showed that α8β1-mediated adhesion of cells to fibronectin resulted in phosphorylation of FAK | FAK can activate PI3 kinase, either directly or indirectly through Src kinase [23]. 0.551 SIGNOR-253309 CSF2RA protein P15509 UNIPROT JAK2 protein O60674 UNIPROT up-regulates 9606 9028317 NO gcesareni We show that the amount of jak2 physically associated with gm-csfr beta chain is increased after gm-csf stimulation and that gm-csf triggers both beta chain and jak2 tyrosine phosphorylation 0.531 SIGNOR-46334 NANOG protein Q9H9S0 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.453 SIGNOR-253166 PPM1D protein O15297 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates dephosphorylation Thr183 RQADSEMtGYVVTRW 9606 15870257 YES gcesareni Ppm1d selectively inhibits p38 activation by dephosphorylating thr 180. 0.297 SIGNOR-135976 doramapimod chemical CHEBI:40953 ChEBI TNF protein P01375 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190335 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 12789342 YES gcesareni Ikk-alpha interacts with creb-binding protein and in conjunction with rel a is recruited to nf-kappab-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone h3. 0.519 SIGNOR-101539 EN1 protein Q05925 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.452 SIGNOR-265776 PKC proteinfamily SIGNOR-PF53 SIGNOR NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation 9606 BTO:0001853 24379783 YES inferred from 70% family members lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.2 SIGNOR-269971 MAPK3 protein P27361 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 YES gcesareni Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms 0.718 SIGNOR-44949 ORC6 protein Q9Y5N6 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 YES lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA 0.944 SIGNOR-267562 ACOT8 protein O14734 UNIPROT glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity chemical modification 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271813 TBP protein P20226 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 YES lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. 0.748 SIGNOR-269562 CTNNB1 protein P35222 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 19175684 NO gcesareni In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs. 0.442 SIGNOR-183532 YY1 protein P25490 UNIPROT FCER1A protein P12319 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000732 11971001 NO Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells 0.2 SIGNOR-254290 N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide chemical CHEBI:91401 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192880 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 7503989 YES gcesareni Wortmannin inhibited the activity of partially purified pi3-kinase from calf thymus, as well as the pi3-kinase activity in anti-pi3-kinase p85 immunoprecipitates from rbl-2h3 cells, at a concentration as low as 1.0 nm and with ic50 values of 3.0 nm. 0.8 SIGNOR-26677 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Thr384 LCEDLPGtEDFVGHQ -1 8662852 YES we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 0.693 SIGNOR-251199 SDC4 protein P31431 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1. 0.357 SIGNOR-199632 IFNG protein P01579 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 NO miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection 0.7 SIGNOR-261033 FOXP2 protein O15409 UNIPROT AUTS2 protein Q8WXX7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25232744 YES miannu By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets. 0.326 SIGNOR-266832 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 YES lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 0.929 SIGNOR-252599 CHEK1 protein O14757 UNIPROT WEE1 protein P30291 UNIPROT up-regulates activity phosphorylation Ser642 KKMNRSVsLTIY 9606 28396830 YES miannu CHK1 phosphorylates Wee1 on Ser642, preventing it from being targeted for extranuclear translocation and activating its CDK1\u2010directed kinase activity xref , xref . 0.61 SIGNOR-279027 JAK1 protein P23458 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity phosphorylation Tyr496 PPALAKGyLKQDPLE 10433356 YES Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). 0.809 SIGNOR-251339 DCAF4 protein Q8WV16 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000567 32014991 YES miannu DCAF4-mediated ubiquitination of OPTN facilitates the degradation of DBR-exposed SOD1. OPTN is involved in degradation of DBR-exposed SOD1. These data demonstrate that DCAF4-including CRL4 complex mediates OPTN ubiquitination at lysine 501, and this ubiquitination is absent in the ALS-related OPTNmut. 0.564 SIGNOR-272211 TSLP protein Q969D9 UNIPROT CRLF2 protein Q9HC73 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11418668 YES gcesareni Human tslp is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human tslp receptor and the il-7r alpha-chain. 0.924 SIGNOR-108920 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 YES miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 0.2 SIGNOR-256321 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 YES lperfetto Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression. 0.2 SIGNOR-244634 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI EPHB4 protein P54760 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194916 PHLPP2 protein Q6ZVD8 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity dephosphorylation Thr387 TMKRRDEtMQPAKPS 9606 20513427 YES PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. 0.2 SIGNOR-248730 FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation 10090 BTO:0001516 12796379 YES FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation. 0.604 SIGNOR-261516 trichostatin A chemical CHEBI:46024 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258011 AXL protein P30530 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr376 DRVKSTAyLSPQELE 9606 BTO:0000007 31230815 YES done miannu TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6). 0.2 SIGNOR-274119 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT up-regulates activity phosphorylation Tyr345 PERNEGVyTAIAVQE 9534 BTO:0004055 11163214 YES PSTPIP1 was phosphorylated by c-Abl. Tyr-344 is a major c-Abl phosphorylation site.PSTPIP1 was able to bridge c-Abl to the PEST-type PTPs. 0.598 SIGNOR-251431 PRKACA protein P17612 UNIPROT SNAPIN protein O95295 UNIPROT up-regulates activity phosphorylation Ser50 HVHAVREsQVELREQ 11283605 YES miannu PKA-phosphorylation of Snapin significantly increases its binding to synaptosomal-associated protein-25 (SNAP-25). Mutation of Snapin serine 50 to aspartic acid (S50D) mimics this effect of PKA phosphorylation 0.307 SIGNOR-250053 AXIN1 protein O15169 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni Other proteins, such as the serine/threonine kinase fused (fu), can function in concert with the e3 ligase smurf to regulate ubiquitination and proteolysis of the bmp receptor 0.331 SIGNOR-195552 F2 protein P00734 UNIPROT F2RL3 protein Q96RI0 UNIPROT up-regulates binding 9606 22318735 YES gcesareni Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4). 0.697 SIGNOR-196003 ACVR2A protein P27037 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 9748228 YES fspada The major bmp7 type i receptor observed was alk2, 0.664 SIGNOR-60234 GATA2 protein P23769 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 NO fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. 0.7 SIGNOR-78659 RPA2 protein P15927 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 NO lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.7 SIGNOR-275706 CBLC protein Q9ULV8 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 12226085 YES miannu In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.  0.761 SIGNOR-272605 Viral_replication stimulus SIGNOR-ST23 SIGNOR Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 31226023 NO miannu Double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. 0.7 SIGNOR-260587 ziprasidone chemical CHEBI:10119 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258505 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity precursor of 9606 10720211 YES lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. 0.8 SIGNOR-268230 CDK5 protein Q00535 UNIPROT DLC1 protein Q96QB1 UNIPROT up-regulates activity phosphorylation Ser946 SVSPCPSsPKQIHLD 9606 BTO:0002181 25452387 YES miannu The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin.  0.2 SIGNOR-276446 RBL2 protein Q08999 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 10090 BTO:0000165 10801445 NO gcesareni Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program. 0.7 SIGNOR-267287 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 17429065 YES lperfetto Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. 0.2 SIGNOR-217631 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258453 GSK3B protein P49841 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser274 TKASSVAsSDKGSCC 9606 BTO:0002181 27432879 YES miannu Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser275 0.285 SIGNOR-277245 CBP/p300 complex SIGNOR-C6 SIGNOR ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 NO lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. 0.2 SIGNOR-254100 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000599 10187842 YES inferred from 70% family members lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. 0.2 SIGNOR-270180 IGF1 protein P05019 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 NO inferred from 70% of family members lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. 0.275 SIGNOR-269890 NUP54 protein Q7Z3B4 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.658 SIGNOR-262078 AKT2 protein P31751 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 17386266 YES lperfetto Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity. 0.584 SIGNOR-236705 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 19303846 YES lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation 0.894 SIGNOR-227870 NVP-AEW541 chemical CID:11476171 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194892 AMPK complex SIGNOR-C15 SIGNOR ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Ser761 QSIPRSAsYPCAAPR 9606 25266655 YES miannu Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. 0.249 SIGNOR-266365 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser163 KRFSFKKsFKLSGFS -1 1560845 YES gcesareni Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin 0.729 SIGNOR-249650 DUX4 protein Q9UBX2 UNIPROT HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24278031 NO miannu HEY1, a repressor of myogenesis, is activated by DUX4 through a MaLR promoter. 0.274 SIGNOR-253840 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates relocalization 9606 19289081 YES gcesareni Ranbp3 directly recognizes dephosphorylated smad2/3, which results from the activity of nuclear smad phosphatases, and mediates nuclear export of smad2/3 in a ran-dependent manner 0.39 SIGNOR-184608 YBX1 protein P67809 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17072343 NO miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 0.247 SIGNOR-255612 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Thr514 SVTPKTVtPASSAKT 10116 BTO:0000938 15652488 YES lperfetto Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it 0.723 SIGNOR-133255 NECAP1 protein Q8NC96 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR up-regulates activity binding 9606 24130457 YES lperfetto Knockdown and functional rescue studies demonstrate that through these interactions, NECAP 1 and AP-2 cooperate to increase the probability of clathrin-coated vesicle formation and to control the number, size, and cargo content of the vesicles. 0.485 SIGNOR-260710 IRF4 protein Q15306 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity 9606 BTO:0000801 22378047 YES lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. 0.454 SIGNOR-249560 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192604 DAPK3 protein O43293 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 YES lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. 0.487 SIGNOR-188789 SYN2 protein Q92777 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 YES miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 0.2 SIGNOR-269182 SOS1 protein Q07889 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23132018 YES lperfetto The enhancement of H-Ras GTP levels induced by oncogenic K-Ras was abrogated when the expression of endogenous Sos was suppressed, implicating Sos as an essential intermediate in the cross talk between oncogenic K-Ras and WT H-Ras. 0.892 SIGNOR-59472 WNT5A protein P41221 UNIPROT FZD6 protein O60353 UNIPROT up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 YES gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. 0.697 SIGNOR-141437 KAT6A protein Q92794 UNIPROT KAT6A/KAT6B complex SIGNOR-C54 SIGNOR form complex binding 9606 BTO:0001271 17694082 YES miannu Like gcn5/pcaf and p300/cbp, moz and morf are transcriptional co-activators with intrinsic hat activity. 0.414 SIGNOR-157304 GATA1 protein P15976 UNIPROT CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004475 19825991 NO miannu Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. 0.51 SIGNOR-254190 FZD2 protein Q14332 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 NO fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) 0.2 SIGNOR-80604 PSENEN protein Q9NZ42 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates cleavage 9606 12522139 YES gcesareni Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex. 0.959 SIGNOR-97113 ME1 protein P48163 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI down-regulates quantity chemical modification 9606 33064660 YES miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. 0.8 SIGNOR-267722 ODC1 protein P11926 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI down-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) 0.8 SIGNOR-256037 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity phosphorylation Ser66 QGSPPDIsPYEVPPL 10090 BTO:0000783;BTO:0002284 16407209 YES Here we show that a minor portion of IPF1/PDX1 is phosphorylated on serine 61 and/or serine 66 in pancreatic beta-cells. This phosphorylated form of IPF1/PDX1 preferentially accumulates following proteasome inhibition, an effect that is prevented by inhibition of glycogen synthase kinase 3 (GSK3) activity. 0.2 SIGNOR-255544 CDKN1B protein P46527 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 SIGNOR-C16 17409098 YES gcesareni P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e). 0.95 SIGNOR-154191 SOX5 protein P35711 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 NO miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1 0.428 SIGNOR-251759 GATA1 protein P15976 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12432220 NO irozzo Furthermore, GATA-1 has been shown to auto-regulate its own gene expression. 0.2 SIGNOR-256057 TPO protein P07202 UNIPROT TG protein P01266 UNIPROT up-regulates activity catalytic activity 9606 23349248 YES miannu After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). 0.505 SIGNOR-259914 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser422 LSTPVVLsPGPQKP 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.2 SIGNOR-252084 PKN1 protein Q16512 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation 9606 17251915 YES gcesareni At the same time, rho signals to c-jun n-terminal kinase (jnk) and p38 through rock and protein kinase n (pkn), leading to the transcriptional regulation of jun 0.379 SIGNOR-152765 KMT2A protein Q03164 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 22303254 NO Polycomb group (PcG) and Trithorax group (TrxG) proteins are epigenetic regulators that control gene expression through modulating chromatin structure and addition of posttranslational modifications (PTMs) on histones 0.7 SIGNOR-268626 TBCK protein Q8TEA7 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 23977024 NO miannu Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule. 0.7 SIGNOR-266701 MAP3K7 protein O43318 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization 9606 BTO:0000567 9480845 NO lperfetto Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene. 0.67 SIGNOR-55716 ALK protein Q9UM73 UNIPROT ATIC protein P31939 UNIPROT up-regulates activity phosphorylation Tyr104 RVVACNLyPFVKTVA 9606 BTO:0002181 18845790 YES miannu ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity. ATIC activity is enhanced in the presence of NPM-ALK in vitro.The ATIC activity is enhanced by NPM-ALK in HEK-293T-Rex cells. 0.377 SIGNOR-276171 MAPK10 protein P53779 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 20395206 YES gcesareni With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation. 0.886 SIGNOR-164800 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 16331690 YES gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. 0.348 SIGNOR-142945 MAP3K7 protein O43318 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity phosphorylation 9606 24535827 YES miannu Collectively, TAK1 activates RIPK3, RIPK3 activates TAK1, and RIPK1 activates RIPK3 and facilitates interaction between TAK1 and RIPK3.|We found that prolonged and hyperactivation of TAK1 induced phosphorylation and activation of RIPK3, leading to necrosis without caspase activation. 0.2 SIGNOR-279634 MED13L protein Q71F56 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 YES miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. 0.77 SIGNOR-266702 NCOA2 protein Q15596 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18584035 YES gcesareni Collectively, our data provide the first evidence that erbeta-deficiency protects against diet-induced ir and glucose intolerance which involves an augmented ppargamma signaling in adipose tissue. Moreover, our data suggest that the coactivators src1 and tif2 are involved in this interaction. 0.77 SIGNOR-179175 DIO1 protein P49895 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 1400883 YES scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. 0.8 SIGNOR-266945 PRKAA1 protein Q13131 UNIPROT BTRC protein Q9Y297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser82 SLRQTYNsCARLCLN 9606 BTO:0002419 31406304 YES miannu Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1.  0.2 SIGNOR-277475 ULK2 protein Q8IYT8 UNIPROT PRKAG3 protein Q9UGI9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 YES gcesareni Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. 0.2 SIGNOR-173095 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser257 SWLGARSsRPASPCN -1 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276767 CCNK protein O75909 UNIPROT CyclinK/CDK12 complex SIGNOR-C37 SIGNOR form complex binding 9606 22012619 YES miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells 0.942 SIGNOR-176783 RUVBL2 protein Q9Y230 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 YES miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. 0.509 SIGNOR-270940 CREB1 protein P16220 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 11081181 YES lperfetto Transcriptional activation of the proopiomelanocortin gene by cyclic AMP-responsive element binding protein|Further, expression of a dominant inhibitory mutant of CREB reduced cAMP stimulated transcription of the full length POMC promoter and the PTRE. 0.37 SIGNOR-268620 APH1A protein Q96BI3 UNIPROT NCSTN protein Q92542 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 YES gcesareni By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. 0.967 SIGNOR-93259 ACVR1 protein Q04771 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 NO gcesareni We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 0.758 SIGNOR-236848 Gbeta proteinfamily SIGNOR-PF4 SIGNOR STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 9731215 YES inferred from 70% family members lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. 0.2 SIGNOR-270082 MAPK1 protein P28482 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity phosphorylation 9606 9872331 YES miannu ERK2 phosphorylates Stat3 on three serine-containing peptides and decreases its tyrosine phosphorylation induced by EGF treatment.|Here, we report that ERK2 activated by its upstream kinase, MEK1, represses Stat3 transcriptional activity induced by Src or Jak-2. 0.749 SIGNOR-279635 PTPN6 protein P29350 UNIPROT NFAT5 protein O94916 UNIPROT down-regulates activity dephosphorylation Tyr143 PKRHTVLyISPPPED 9606 BTO:0000007 20351292 YES We confirmed that SHP-1 is inhibitory by overexpressing it, which reduces TonEBP/OREBP transcriptional activity at 500 mosmol/kg. SHP-1 dephosphorylates TonEBP/OREBP at a known regulatory site, Y143, both in vivo and in vitro. It inhibits TonEBP/OREBP by both reducing TonEBP/OREBP nuclear localization, which is Y143 dependent, and by lowering high NaCl-induced TonEBP/OREBP transactivating activity 0.344 SIGNOR-248467 ITGB4 protein P16144 UNIPROT PMP22 protein Q01453 UNIPROT up-regulates activity binding 10090 16436605 YES Regulation miannu PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types. 0.406 SIGNOR-251896 PPM1D protein O15297 UNIPROT MDM4 protein O15151 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser403 DLAHSSEsQETISSM 9606 19808970 YES lperfetto Here, we present evidence that Wip1 specifically dephosphorylates MdmX at Ser403 and indirectly suppresses phosphorylation of MdmX at Ser342 and Ser376.|Thus, Wip1 may need to be inhibited in the early stage of DNA damage response to facilitate rapid MdmX degradation. 0.431 SIGNOR-276951 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.564 SIGNOR-161557 CASP8 protein Q14790 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity 9606 BTO:0000661 10364179 NO Translocation from Mitochondria to Cytosol lperfetto Caspase-8 triggered rapid cytochrome c release from mitochondria. The effect was indirect. 0.48 SIGNOR-68225 PAK1 protein Q13153 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 BTO:0001033 29572236 NO miannu  RAC1 activation induces the actin remodeling and membrane ruffling necessary to form macropinosomes by activating PAK kinases 0.7 SIGNOR-277768 FOXO3 protein O43524 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 14976264 NO lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress 0.7 SIGNOR-217881 PRKCD protein Q05655 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Ser167 LFPSFIHsQKRNPQT 9935 24211614 YES Manara Endothelin-1 stimulates catalase activity through the PKCδ-mediated phosphorylation of serine 167. 0.266 SIGNOR-260904 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Ser20 LYPGLADsAPSCPQN 9606 BTO:0000392 11907111 YES lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase 0.535 SIGNOR-263420 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.383 SIGNOR-199183 PSMB4 protein P28070 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.891 SIGNOR-263355 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser245 PSTSPRAsVTEESWL 9606 BTO:0001061 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276770 SPOP protein O43791 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 15897469 YES miannu Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30). 0.661 SIGNOR-272659 LRRC4 protein Q9HBW1 UNIPROT CDK2 protein P24941 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 NO miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. 0.348 SIGNOR-264058 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 YES gcesareni Regulation of mammalian pdc activity is accomplished in large part by phosphorylation (resulting in inactivation) of the e1 component by a family of pyruvate dehydrogenase kinases (pdk 14 isozymes) and dephosphorylation (leading to activation) of phosphorylated e1 by a set of specific phosphatases (phosphopyruvate dehydrogenase phosphatase 12 isozymes) (1, 3-6). The subunit of the e1 component has three phosphorylation sites, named site 1 (ser-264), site 2 (ser-271), and site 3 (ser-203), and phosphorylation of any one of these three sites results in inactivation 0.678 SIGNOR-154640 MC5R protein P33032 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257337 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2078 EGSYETAkVLLDHFA 9606 17636029 YES gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. 0.415 SIGNOR-156923 PASK protein Q96RG2 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation 9606 23853095 YES miannu In vitro, PASK directly phosphorylates GSK3\u03b2 on its inactivating phosphorylation site Ser(9).|We conclude that PASK phosphorylates and inactivates GSK3\u03b2, thereby preventing PDX-1 serine phosphorylation and alleviating GSK3\u03b2-mediated PDX-1 protein degradation in pancreatic \u03b2-cells. 0.288 SIGNOR-279639 SRC protein P12931 UNIPROT PRMT5 protein O14744 UNIPROT down-regulates activity phosphorylation Tyr324 DNLESQTyEVFEKDP 9606 BTO:0002181 32759981 YES miannu Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity. 0.262 SIGNOR-277523 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 BTO:0000567 17301055 NO Barakat Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission 0.7 SIGNOR-274132 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 YES gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. 0.378 SIGNOR-75902 DLX3 protein O60479 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17060321 NO gcesareni Here we show that bmp2 induces dlx3, a homeodomain protein that activates runx2 gene transcription. Small interfering rna knockdown studies in osteoblasts validate that dlx3 is a potent regulator of runx2. 0.398 SIGNOR-150177 SDC4 protein P31431 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1. 0.247 SIGNOR-199638 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). 0.868 SIGNOR-157730 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation 9606 34144039 YES miannu PDGFR\u03b2 binds and phosphorylates Abl2 in cells.|We report here the molecular mechanisms by which PDGFR\u03b2 binds, phosphorylates, and activates the Abl2 kinase. 0.303 SIGNOR-279640 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr102 RAAMFPEtLDEGMQI -1 12432063 YES miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  0.47 SIGNOR-275993 DLST protein P36957 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 YES miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. 0.905 SIGNOR-266254 TLX1 protein P31314 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 BTO:0002504 22516263 YES irozzo We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. 0.468 SIGNOR-259097 ULK1 protein O75385 UNIPROT ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Ser14 EYQRLEAsYSDSPPG 9606 27934868 YES miannu Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. 0.583 SIGNOR-266369 TRAF6 protein Q9Y4K3 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. 0.933 SIGNOR-205458 DEPTOR protein Q8TB45 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.724 SIGNOR-205603 PIK3R4 protein Q99570 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 10090 27411398 YES lperfetto Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity 0.939 SIGNOR-260709 DNMT1 protein P26358 UNIPROT DNMT1/DNMT3A complex SIGNOR-C42 SIGNOR form complex binding 9606 12145218 YES miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation 0.782 SIGNOR-90836 CDK1 protein P06493 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser439 AGSPFQSsPLSLGSR 9606 SIGNOR-C17 16880739 YES llicata Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis. 0.288 SIGNOR-148354 6-[2-tert-butyl-5-(6-methyl-2-pyridinyl)-1H-imidazol-4-yl]quinoxaline chemical CHEBI:91391 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206715 Crenolanib chemical CID:10366136 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191124 ID1 protein P41134 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0004136 26084673 YES apalma We have determined that Id1 physically interacts with AKT1, through its C-terminal region, and promotes AKT1 phosphorylation; 0.334 SIGNOR-255658 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 18545270 YES lperfetto Tradd recruits fadd 0.78 SIGNOR-177958 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPB protein P17676 UNIPROT down-regulates activity binding 9606 12524424 YES lperfetto C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs. 0.578 SIGNOR-97117 NFE2L2 protein Q16236 UNIPROT G6PD protein P11413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 NO miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 0.327 SIGNOR-267354 CD40LG protein P29965 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates 9606 BTO:0000776 19047375 NO gcesareni Coimmunoprecipitation and western blot analysis showed that heptp was phosphorylated in a pka-dependent manner, which inactivated heptp and allowed for increased free p38 mapk to be phosphorylated by the mapk cascade that was activated by cd40l 0.2 SIGNOR-182519 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization ubiquitination Lys569 DLHVVRPkLPKPPTD 10090 35670107 YES lperfetto TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels 0.2 SIGNOR-272540 NUMA1 protein Q14980 UNIPROT TUBAC Family proteinfamily SIGNOR-PF110 SIGNOR up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.248 SIGNOR-116717 PCSK7 protein Q16549 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 NO lperfetto The levels of ikb_? Where reduced in cells overexpressing mkk6 [] these results indicated that mkk6 was able to promote the degradation of the NF-kappaB inhibitor, in a p38-dependent manner. 0.2 SIGNOR-235837 GTF2I protein P78347 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity relocalization 9606 21282467 YES lperfetto Moreover, the inhibitory effect of TFII-I on transcription is mediated by its ability to recruit corepressor complexes, including histone deacetylase 3 (HDAC3) (25, 133), histone H3K4-specific demethylase LSD1 (48), and components of the polycomb repressor complex 0.405 SIGNOR-268540 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.2 SIGNOR-134628 PRKCD protein Q05655 UNIPROT PTPN22 protein Q9Y2R2 UNIPROT down-regulates phosphorylation Ser35 FLKLKRQsTKYKADK 9606 BTO:0000782 18056643 YES llicata We show that lyp is phosphorylated exclusively at ser-35 by pkc both in vitro and in vivo. our data establish a mechanism by which pkc could attenuate the cellular function of lyp, thereby augmenting t cell activation. 0.314 SIGNOR-159591 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 12808134 YES lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). 0.748 SIGNOR-252611 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation 0.889 SIGNOR-216389 AFF4 protein Q9UHB7 UNIPROT AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 BTO:0000664 20153263 YES 1 miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. 0.548 SIGNOR-239224 EPHB2 protein P29323 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 9632142 YES lperfetto We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation 0.565 SIGNOR-58142 AL/b2 integrin complex SIGNOR-C169 SIGNOR ICAM1 protein P05362 UNIPROT up-regulates activity binding 10090 BTO:0003104 12808052 YES lperfetto The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity. 0.834 SIGNOR-253364 BKM120 chemical CHEBI:71954 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252656 cabozantinib chemical CHEBI:72317 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207842 ABTB1 protein Q969K4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 11494141 NO miannu Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. 0.7 SIGNOR-260046 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191012 PTPN2 protein P17706 UNIPROT STAT6 protein P42226 UNIPROT down-regulates activity dephosphorylation 9606 17210636 YES gcesareni These results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors 0.678 SIGNOR-235192 PP121 chemical CHEBI:50915 ChEBI PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206304 S1PR3 protein Q99500 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.516 SIGNOR-257388 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763;BTO:0000149 10197981 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-66759 NEDD4L protein Q96PU5 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity ubiquitination 9606 33608556 YES miannu Nedd4l promotes TRAF3 to interact with cIAP1/2 and HECTD3.|Ubiquitination of TRAF3 by Nedd4l promotes interaction of TRAF3 with proteins such as cIAP1/2, HECTD3, and TBK1. 0.27 SIGNOR-278587 NFE2L2 protein Q16236 UNIPROT PPAT protein Q06203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 NO miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 0.2 SIGNOR-267358 SP3 protein Q02447 UNIPROT SCNN1A protein P37088 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 12684058 NO Regulation of expression miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. 0.2 SIGNOR-251951 MMP20 protein O60882 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272388 POMC protein P01189 UNIPROT MC1R protein Q01726 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.765 SIGNOR-268700 BRCC ubiquitin ligase complex complex SIGNOR-C295 SIGNOR TP53 protein P04637 UNIPROT unknown ubiquitination 9606 BTO:0000007 14636569 YES lperfetto However, since the same domain of p53 is also the target of ubiquitination by MDM2 protein, further in vivo experiments are required to demonstrate the biological relevance of p53 ubiquitination by BRCC.|The Extreme C Terminus of p53 Is Ubiquitinated by BRCC 0.598 SIGNOR-263210 ZMYND8 protein Q9ULU4 UNIPROT ZMYND8 protein Q9ULU4 UNIPROT up-regulates activity binding 9606 BTO:0000007 27477906 YES lperfetto We identified ZMYND8 as a transcriptional corepressor of the H3K4 demethylase JARID1D|Co-immunoprecipitation between ectopically expressed FLAG-tagged JARID1D and endogenous ZMYND8 protein. 0.2 SIGNOR-262037 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25838379 NO lperfetto The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes. 0.7 SIGNOR-262333 α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR glycogen smallmolecule CHEBI:28087 ChEBI up-regulates quantity precursor of 9606 26199317 YES miannu Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains 0.8 SIGNOR-268138 IFTAP protein Q86VG3 UNIPROT BTF3 protein P20290 UNIPROT down-regulates activity binding 9606 BTO:0000567 18433331 YES lperfetto Furthermore, we co-immunoprecipitated HEPIS with BTF3, a component of the RNA pol II initiation complex, and observed reduced proliferation of HeLa cells transfected with the HEPIS gene. 0.2 SIGNOR-260252 CTDNEP1 protein O95476 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 17141153 YES lperfetto We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors (bmprs). Dullard preferentially complexes with the bmp type ii receptor (bmprii) and partially colocalizes with the caveolin-1-positive compartment, suggesting that dullard promotes bmpr degradation via the lipid raft-caveolar pathway 0.291 SIGNOR-150998 MYCBP2 protein O75592 UNIPROT RAN protein P62826 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 26304119 YES Monia MYCBP2 Is a Nuclear GEF for Ran in DRG Neurons—Next, we studied whether or not MYCBP2 modulates the interaction between Ran/RanGAP1. MYCBP2 contains an N-terminal RCC1-like domain (Fig. 8C) (13), and RCC1 is a known GEF for Ran, indicating a potential functional interaction between MYCBP2 and Ran. 0.296 SIGNOR-261204 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000007 23979597 YES miannu  We showed that PHF8 interacts with the CDC20-containing APC (APC(cdc20)) primarily during mitosis. we demonstrate that mutations of the LXPKXLF motif abrogate polyubiquitylation of PHF8 by the APC. APC substrates are typically cell cycle regulators, and consistent with this, the loss of PHF8 leads to prolonged G2 phase and defective mitosis. 0.877 SIGNOR-272880 TG protein P01266 UNIPROT Colloid phenotype SIGNOR-PH185 SIGNOR up-regulates 9606 24251883 NO scontino The thyroid gland is unique among endocrine glands in storing its principle hormonal product—the two very small thyroid hormones (TH)—as components of a 1000-fold larger precursor—thyroglobulin (Tg)—that is secreted and stored in the colloid, outside of the thyroid cell. Moreover, the thyroid cell is part of a layer of similar cells—the thyroid follicular epithelium—that completely encloses the secreted Tg and segregates it from the circulation. 0.7 SIGNOR-267135 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 9606 BTO:0002181 34010649 YES miannu PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-277558 MAPK14 protein Q16539 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates transcriptional regulation 10116 11904165 NO ggiuliani These data indicate that TGF-beta1-induced p38 activation is involved in TGF-beta1-stimulated collagen synthesis. 0.7 SIGNOR-255958 SMURF1 protein Q9HCE7 UNIPROT FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28408404 YES miannu Smurf1 mediates Kindlin-2 proteasomal degradation.|Smurf1 promotes polyubiquitination of Kindlin-2. 0.2 SIGNOR-278614 PTGES3 protein Q15185 UNIPROT HSP90AA1 protein P07900 UNIPROT up-regulates activity binding -1 9817749 YES lperfetto The mutant Hsp90 proteins tested are defective in the binding and ATP hydrolysis-dependent cycling of the co-chaperone p23, which is thought to regulate the binding and release of substrate polypeptide from Hsp90.  0.916 SIGNOR-262831 POU2F1 protein P14859 UNIPROT HOXD10 protein P28358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25301728 NO miannu Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11 0.2 SIGNOR-205540 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252657 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation 9606 23024368 YES inferred from 70% family members gcesareni Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5. 0.2 SIGNOR-270185 CREB1 protein P16220 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 NO gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 0.25 SIGNOR-268144 CAMK4 protein Q16566 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0001271 12835716 YES lperfetto Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. All these kinases target CREB on S133 to activate CREB. 0.707 SIGNOR-102722 GSK3B protein P49841 UNIPROT ETS1 protein P14921 UNIPROT up-regulates quantity by stabilization phosphorylation Ser269 DRLTQSWsSQSSFNS 9606 BTO:0000007 34023818 YES miannu Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration. 0.2 SIGNOR-277561 PAMPs stimulus SIGNOR-ST11 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR up-regulates 9606 20404851 NO lperfetto the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) 0.7 SIGNOR-216295 LCMT1 protein Q9UIC8 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity methylation Leu309 RRTPDYFl -1 18394995 YES lperfetto Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1) 0.66 SIGNOR-265751 BRCC3 protein P46736 UNIPROT H2AC11 protein P0C0S8 UNIPROT down-regulates deubiquitination 9606 20656690 YES gcesareni Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a 0.2 SIGNOR-167142 CAMK2G protein Q13555 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation Ser1760 RAIGRLSsMAMISGL 2160950 YES llicata Phosphorylation of MLC kinase by CaM protein kinase II increased the dissociation constant of MLC kinase for calmodulin about 10 times without changing the Vmax. The location of the phosphorylation sites was identified by isolating and sequencing the tryptic phosphopeptides of MLC kinase. The preferred site was identified as serine 512 and the second site as serine 525. These sites are the same as the sites phosphorylated by cAMP-dependent protein kinase. 0.331 SIGNOR-250700 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL10 protein P22301 UNIPROT up-regulates quantity by expression 22933625 NO apalma P38 activation contributes to the macrophage phenotype switch in injured muscle, which could elevate production of IL-10 (63), creating positive feedback for the phenotype switch 0.7 SIGNOR-255448 DNA polymerase epsilon complex SIGNOR-C377 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9534 BTO:0004055 12930972 NO lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). 0.7 SIGNOR-265514 PLK1 protein P53350 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 11897663 YES lperfetto The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase. 0.803 SIGNOR-115993 PIM1 protein P11309 UNIPROT RP9 protein Q8TA86 UNIPROT unknown phosphorylation Ser212 KKRKHKSsKSNEGSD -1 10931201 YES miannu PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase. 0.2 SIGNOR-263029 ATR protein Q13535 UNIPROT MCM4 protein P33991 UNIPROT up-regulates phosphorylation 9606 21070963 YES gcesareni Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6. 0.724 SIGNOR-169412 nutlin-3A chemical CID:11433190 PUBCHEM MDM2 protein Q00987 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194874 CBP/p300 complex SIGNOR-C6 SIGNOR RELA protein Q04206 UNIPROT up-regulates acetylation 9606 16382138 YES lperfetto Rela is also acetylated at several sites by p300 and cbp 0.85 SIGNOR-217210 VASP protein P50552 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 NO miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. 0.7 SIGNOR-268393 DEPTOR protein Q8TB45 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity binding 9606 BTO:0000007 19446321 YES DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival 0.726 SIGNOR-251658 LRRK2 protein Q5S007 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity phosphorylation Thr474 KFLQEALtMRQFDHP 9606 26365310 YES miannu LRRK2 inhibits FAK activation in a kinase dependent manner, meaning that the G2019S gain-of-function mutation results in the excessive inhibition of FAK activation and microglial motility.|Taken together, these results suggest that LRRK2 directly phosphorylate FAK at T474. 0.2 SIGNOR-278281 CHEK1 protein O14757 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Thr12 KQTARKStGGKAPRK 9606 18243098 YES gcesareni We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c. 0.2 SIGNOR-160557 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Ser27 PFRDSPLsSRLLDDG 9606 BTO:0000887 11342557 YES lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation 0.341 SIGNOR-107676 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI OXER1 protein Q8TDS5 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268776 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser5 sSKKRKPK 9606 BTO:0000801;BTO:0000876 15221008 YES llicata We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling. 0.327 SIGNOR-126568 KCNB1 protein Q14721 UNIPROT VAPB protein O95292 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 YES lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. 0.2 SIGNOR-262121 SEM1 protein P60896 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.2 SIGNOR-263343 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr57 RAGETRFtDTRKDEQ 9606 phosphorylation:Thr57 RAGETRFtDTRKDEQ 8386634 YES gcesareni Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2 0.405 SIGNOR-38561 GMPS protein P49915 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 6698284 YES miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). 0.8 SIGNOR-267341 AKT1 protein P31749 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates quantity phosphorylation Ser257 PSRPPRPsRPPPPTP 9606 BTO:0000815 30517763 YES miannu AKT1-mediated phosphorylation of ITCH at Ser257 drives its nuclear translocation 0.319 SIGNOR-272922 F2R protein P25116 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254847 Y-27632 chemical CHEBI:75393 ChEBI ROCK1 protein Q13464 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207890 BTK protein Q06187 UNIPROT WAS protein P42768 UNIPROT unknown phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 10068673 YES llicata These results indicate that btk phosphorylates wasp on its tyrosine 291 0.742 SIGNOR-86004 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr969 VSECPHTyQNRRPFS 9606 31395582 YES lperfetto A mutation at tyrosine 969, which inhibits activation of downstream signaling by FLT3-ITD. 0.2 SIGNOR-271919 ROS stimulus SIGNOR-ST2 SIGNOR ARNT protein P27540 UNIPROT up-regulates quantity by expression 22387692 NO lperfetto Although the regulation mechanism of the ARNT expression is largely unknown, earlier studies reported that the human ARNT protein level was decreased by hydrogen peroxide or reactive oxygen species. 0.7 SIGNOR-253689 DLG3 protein Q92796 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.533 SIGNOR-270897 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCND1 protein P24385 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189972 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 7493944 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.581 SIGNOR-246276 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 YES lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus 0.91 SIGNOR-252835 NEK6 protein Q9HC98 UNIPROT BSG protein P35613 UNIPROT down-regulates activity phosphorylation Ser368 GSAPLKSsGQHQNDK 9606 31016558 YES done miannu These results indicate that NEK6 directly interacts with CD147 and phosphorylates the protein at serine-252 in Huh-7 cells. 0.2 SIGNOR-273882 D-thyroxine smallmolecule CHEBI:30659 ChEBI THRA protein P10827 UNIPROT up-regulates activity chemical activation 9606 6777394 YES miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. 0.8 SIGNOR-258402 DUSP6 protein Q16828 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation 9606 20638106 YES lperfetto Dual-specificity phosphatase six (DUSP6, MKP3, or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on ERK-2 (MAPK1) to inactivate the ERK-2 kinase. 0.904 SIGNOR-277006 superoxide smallmolecule CHEBI:18421 ChEBI SOD3 protein P08294 UNIPROT up-regulates activity precursor of 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272274 BKM120 chemical CHEBI:71954 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190389 MAP3K7 protein O43318 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 9480845 NO lperfetto These results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway. 0.596 SIGNOR-55713 KDM6A protein O15550 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 YES miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase 0.252 SIGNOR-260036 SPRY4 protein Q9C004 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 9606 BTO:0002058 20501643 NO miannu Spry4 expression induces a reversal of the epithelial to mesenchymal transition characteristic of tumor cells. Treatment of a non-transformed lung epithelial cell line with shRNA to Spry4 led to decreased expression of epithelial markers and increased cell growth, supporting the concept of Spry4 acting as a tumor suppressor. 0.7 SIGNOR-253036 MDGA2 protein Q7Z553 UNIPROT DMAP1 protein Q9NPF5 UNIPROT up-regulates quantity by stabilization binding 9606 26206665 YES miannu The anti-tumorigenic effect of MDGA2 was mediated through direct stabilising of DNA methyltransferase 1 associated protein 1 (DMAP1), which played a tumour suppressive role in gastric cancer. MDGA2 expression and MG132 treatment increased the level of DMAP1, suggesting that the MDGA2–DMAP1 interaction stabilises DMAP1 by inhibiting its ubiquitin-mediated degradation. 0.348 SIGNOR-264240 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Tyr340 RGQRDSSyYWEIEAS 10090 BTO:0001482 8876196 YES  JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process. 0.616 SIGNOR-251361 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 9606 BTO:0000567 20682768 YES lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva 0.391 SIGNOR-167336 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser276 PLPSPTAsPNHTLAP -1 11113134 YES llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  0.522 SIGNOR-250649 AGRP protein O00253 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.551 SIGNOR-268714 AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity relocalization 9606 25720354 YES scontino APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place. 0.8 SIGNOR-267861 CCR6 protein P51684 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0000584 37398643 NO miannu Senescent tumor cells acquire SASP with enhanced secretion of CCL20, acting on CCR6 receptors of precursor macrophages to favor the immunocompromised M2 phenotype.  0.7 SIGNOR-278043 NAB2 protein Q15742 UNIPROT EGR2 protein P11161 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000414 20506119 NO miannu Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. 0.577 SIGNOR-253888 AKT proteinfamily SIGNOR-PF24 SIGNOR CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 YES lperfetto Furthermore, ha-tagged akt can phosphorylate gst-cct_ protein in vitro 0.2 SIGNOR-244172 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr1320 Y>1319 9606 BTO:0002181 24583284 YES miannu CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation. 0.635 SIGNOR-277877 CDK11B protein P21127 UNIPROT CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR form complex binding -1 12082095 YES lperfetto We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1). 0.651 SIGNOR-273119 VEZF1 protein Q14119 UNIPROT EDN1 protein P05305 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004294 11504723 YES miannu Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone 0.277 SIGNOR-266884 CSNK2A1 protein P68400 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser726 PLKMEPQsPGEVKKL 23858473 YES phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. 0.2 SIGNOR-273428 NRF1 protein Q16656 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 NO lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC 0.557 SIGNOR-268999 DPM1 protein O60762 UNIPROT DPM complex complex SIGNOR-C289 SIGNOR form complex binding 9606 10835346 YES lperfetto Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3. 0.786 SIGNOR-262563 TNF protein P01375 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity 10090 10485710 NO lperfetto Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). 0.273 SIGNOR-70616 TREX complex complex SIGNOR-C444 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 22928037 NO miannu The conserved TREX complex, which contains UAP56, Aly, CIP29, and the multi-subunit THO complex, functions in mRNA export. 0.7 SIGNOR-268514 FGG protein P02679 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR form complex binding -1 25427968 YES lperfetto Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively). 0.763 SIGNOR-263393 N-(2-chlorophenyl)-4-[[2-[4-[2-(4-ethyl-1-piperazinyl)-2-oxoethyl]anilino]-5-fluoro-4-pyrimidinyl]amino]benzamide chemical CHEBI:91365 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190029 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser246 DSVSDQFsVEFEVES 9606 20708156 YES gcesareni Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination 0.346 SIGNOR-167509 Sin3B_complex complex SIGNOR-C409 SIGNOR H3Y2 protein P0DPK5 UNIPROT down-regulates activity binding 9606 21041488 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.2 SIGNOR-266976 PRKACA protein P17612 UNIPROT PRKAR2B protein P31323 UNIPROT up-regulates activity phosphorylation Ser114 NRFTRRAsVCAEAYN 9606 15187164 YES gcesareni Serine 114 phosphorylation is required for both nuclear localization and down-regulation of il-2 production by riibeta. 0.881 SIGNOR-125545 RCOR1 protein Q9UKL0 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 10449787 NO miannu We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity. 0.27 SIGNOR-220695 AKT1 protein P31749 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates activity phosphorylation Ser87 FIFMRRSsLLSRSSS 9606 16282323 YES lperfetto Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL). 0.568 SIGNOR-252487 IKK-complex complex SIGNOR-C14 SIGNOR NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 15494311 YES Translocation from Nucleus to Cytoplasm lperfetto Nf-kappab transcription requires ikkalpha to phosphorylate smrt on chromatin, stimulating the exchange of corepressor for coactivator complexes. Ikk directly phosphorylates smrt to stimulate nuclear export. Ikkalpha orchestrates smrt derepression, a prerequisite for nf-kappab transcription and survival. 0.41 SIGNOR-216393 PIP5K1C protein O60331 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 9367159 YES miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities 0.8 SIGNOR-277287 STK3 protein Q13188 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates phosphorylation -1 BTO:0000007 16930133 YES milica In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav 0.834 SIGNOR-230716 CDK1 protein P06493 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser160 PVRLLGHsPVLRNIT 9606 SIGNOR-C17 12107172 YES lperfetto We demonstrate that serine 146 is required for two crucial features of cdc25b1. It is essential for cdc25b1 to function as a mitotic inducer and to prevent cdc25b1 export from the nucleus. We also show that serine 146 is phosphorylated in vitro by cdk1-cyclin b. Serine 146 phosphorylation is proposed to be a key event in the regulation of the cdc25b function 0.828 SIGNOR-90451 ULK3 protein Q6PHR2 UNIPROT GLI3 protein P10071 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 19878745 YES Manara We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro 0.56 SIGNOR-260799 CAMK2A protein Q9UQM7 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.279 SIGNOR-275784 CHUK protein O15111 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 SIGNOR-C14 15084260 YES gcesareni Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. 0.571 SIGNOR-124203 GNB5 protein O14775 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 BTO:0004032 21303898 YES miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC 0.454 SIGNOR-264996 YAP1 protein P46937 UNIPROT CDCA5 protein Q96FF9 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276565 NOTCH1 protein P46531 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0001271;BTO:0000785 16847353 NO gcesareni We identified c-myc as a direct target of notch1 0.668 SIGNOR-147944 TDGF1 protein P13385 UNIPROT MSTN protein O14793 UNIPROT down-regulates 9606 23129614 NO fstefani We provide evidence that cripto modulates myogenic cell determination and promotes proliferation by antagonizing the tgf-beta ligand myostatin. 0.313 SIGNOR-192436 NR3C1 protein P04150 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 YES We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα 0.292 SIGNOR-256118 MMP12 protein P39900 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272380 SRC protein P12931 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates phosphorylation Tyr341 SEEQLQLyWAMDSTF 9606 20525694 YES gcesareni Phosphorylation of a critical tyrosine (tyr-341) in the linker region of cbl-c by src or a phosphomimetic mutation of this tyrosine (y341e) is sufficient to increase the e3 activity of cbl-c. 0.538 SIGNOR-165862 HNF1B protein P35680 UNIPROT AKR1C4 protein P17516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003846 2044952 NO 2 miannu Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene.HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C. 0.2 SIGNOR-239960 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 23708659 YES lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. 0.2 SIGNOR-252781 NDUFA5 protein Q16718 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. 0.829 SIGNOR-262156 CUDC-101 chemical CID:24756910 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191148 HAUS2 protein Q9NVX0 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 YES lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) 0.821 SIGNOR-262323 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176825 DAPK1 protein P53355 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 15616583 YES gcesareni Conversely, dapk promotes the cytoplasmic retention of erk, thereby inhibiting erk signaling in the nucleus. 0.565 SIGNOR-132610 TAOK2 protein Q9UL54 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 YES gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2 0.279 SIGNOR-201330 ANKRD11 protein Q6UB99 UNIPROT RAB13 protein P51153 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 YES miannu Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.  0.2 SIGNOR-266738 ITGB5 protein P18084 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.771 SIGNOR-253208 DZIP3 protein Q86Y13 UNIPROT H2AC1 protein Q96QV6 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHH 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271761 GNE protein Q9Y223 UNIPROT N-acyl-D-mannosamine 6-phosphate(2-) smallmolecule CHEBI:57666 ChEBI up-regulates quantity chemical modification 10745088 YES lperfetto UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate. 0.8 SIGNOR-266074 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI COMT protein P21964 UNIPROT up-regulates 9606 17612537 NO Regulation of expression miannu Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA. 0.8 SIGNOR-251962 HECTD2 protein Q5U5R9 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 26157031 YES miannu We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. 0.39 SIGNOR-272421 GSK3B protein P49841 UNIPROT AURKA protein O14965 UNIPROT down-regulates activity phosphorylation 9606 26835416 YES miannu However, phosphorylation of AurA by GSK3B on S283/4 is known to promote autophosphorylation on S342 that is inhibitory to AurA activity, making it likely that GSK3B can govern AurA stability indirectly through conformational effects.|In this study, GSK3B was proposed to promote FBXW7 targeting of AurA through priming a phospho-degron located in the kinase domain. 0.558 SIGNOR-279718 SMARCD2 protein Q92925 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.762 SIGNOR-270706 AKT1 protein P31749 UNIPROT TMIGD2 protein Q96BF3 UNIPROT up-regulates activity phosphorylation Ser220 GKDQRGQsIYSTSFP 9606 BTO:0001973 31341021 YES miannu We observed that IGPR-1 is activated by shear stress and tensile force and that flow shear stress-mediated IGPR-1 activation modulates remodeling of endothelial cells. Mechanistically, shear stress stimulated activation of AKT Ser/Thr kinase 1 (AKT1), leading to phosphorylation of IGPR-1 at Ser-220.  0.2 SIGNOR-273481 GPR119 protein Q8TDV5 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257415 AKT proteinfamily SIGNOR-PF24 SIGNOR MAPK14 protein Q16539 UNIPROT down-regulates activity 9606 BTO:0000150 12697749 NO lperfetto Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1 0.2 SIGNOR-244288 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RXRG protein P48443 UNIPROT up-regulates activity chemical activation 9606 18321241 YES miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). 0.8 SIGNOR-259239 AGPAT4 protein Q9NRZ5 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 21173190 YES lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† 0.8 SIGNOR-267014 CDC7 protein O00311 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates activity phosphorylation Ser410 SSMDSKSsGWGM 9606 23424178 YES miannu We show CDC7 robustly phosphorylates TDP-43 at pathological residues S409/410 in C. elegans, in vitro, and in human cell culture. 0.2 SIGNOR-278257 SV2A protein Q7L0J3 UNIPROT SYT1 protein P21579 UNIPROT up-regulates quantity binding 9606 BTO:0000938 26903854 YES miannu Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs. 0.536 SIGNOR-264116 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1196 GAVENPEyLTPQGGA 9606 BTO:0000150 15156151 YES gcesareni Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227 0.2 SIGNOR-124856 COL6A6 protein A6NMZ7 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. 0.7 SIGNOR-254677 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT down-regulates phosphorylation Thr373 VSMLSLNtPNSNRKR 9606 SIGNOR-C17 16170345 YES lperfetto We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341 0.578 SIGNOR-140549 RPN2 protein P04844 UNIPROT OST-B complex complex SIGNOR-C536 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.757 SIGNOR-272074 GPHN protein Q9NQX3 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 NO miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. 0.7 SIGNOR-264975 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT up-regulates activity phosphorylation Ser654 YVEVFKNsDKEDDQE 9606 17006539 YES gcesareni A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK. 0.2 SIGNOR-149952 GSK3B protein P49841 UNIPROT CTNND2 protein Q9UQB3 UNIPROT down-regulates quantity phosphorylation 9606 20623542 YES miannu Therefore, our data which supports that partial inhibition of GSK-3beta increases delta-catenin expression, raises an interesting possibility that delta-catenin may be an important downstream target of GSK-3beta signaling that participates in modulating neuronal morphology.|We demonstrate that GSK-3beta forms a stable complex with delta-catenin and phosphorylates delta-catenin in neurons, an event that mediates ubiquitination and subsequent proteasome degradation of delta-catenin. 0.347 SIGNOR-279719 TRIM63 protein Q969Q1 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 NO areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX), are markedly induced in almost all types of atrophy. 0.7 SIGNOR-254993 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 8143061 YES asthma gcesareni 0.8 SIGNOR-251706 ERG protein P11308 UNIPROT CDH5 protein P33151 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18195090 YES Luana Erg overexpression resulted in an approximate 1.8-fold transactivation of VE-cadherin promoter activity. Thus, our data indicate that Erg drives constitutive VE-cadherin expression in human ECs  0.278 SIGNOR-261595 Activated PSC phenotype SIGNOR-PH224 SIGNOR ACTA2 protein P62736 UNIPROT up-regulates quantity 9606 BTO:0000988 28232471 YES miannu Upon activa- tion, PSCs express the myofibroblast protein α-smooth mus- cle actin (αSMA, gene name Acta2) and secrete factors that stimulate tumor growth, cell survival, and metastasis. As a result of the selective high expression of αSMA, we refer to these periglandular FAP+ αSMAhigh fibroblasts as myofibroblastic CAFs (myCAFs). 0.7 SIGNOR-277677 FOXO3 protein O43524 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity transcriptional regulation 10090 BTO:0002314 24749067 NO gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. 0.375 SIGNOR-244076 STAT3 protein P40763 UNIPROT CD46 protein P15529 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17699108 NO miannu The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays. 0.268 SIGNOR-255238 CYP11B2 protein P19099 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity chemical modification 9606 BTO:0000050 9814482 YES lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. 0.8 SIGNOR-268676 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7318 RPGSRAGsRAGSRAS 9606 BTO:0004905 21295697 YES lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. 0.436 SIGNOR-264432 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Thr316 GTASSRKtLWNQELY 21880142 YES miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. 0.307 SIGNOR-266298 MEF2C protein Q06413 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.431 SIGNOR-238718 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269380 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser330 LDGTSGFsPAPKLVE 9534 BTO:0000298 14623875 YES llicata DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase. 0.573 SIGNOR-251087 CTTN protein Q14247 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 11231575 YES Cortactin binds directly to the Arp2/3 complex and activates it to promote nucleation of actin filaments. 0.645 SIGNOR-251519 NFE2L2 protein Q16236 UNIPROT TXN protein P10599 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000552 18629308 NO miannu When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression. 0.404 SIGNOR-254646 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH4 protein P55283 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265844 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Ser60 VYQVSRTsGGAGGLG -1 12686604 YES lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro. 0.545 SIGNOR-100111 mTORC1 complex SIGNOR-C3 SIGNOR JMJD1C protein Q15652 UNIPROT up-regulates activity phosphorylation Thr505 KFVSRPPtPKCVIDI 9606 BTO:0000007 32034158 YES miannu We show that, by direct interaction with USF-1, JMJD1C is recruited to lipogenic promoters. We also show that JMJD1C is phosphorylated at T505 by mammalian target of rapamyci (mTOR) to be recruited to lipogenic genes in response to insulin/feeding. we detected phosphorylation of WT JMJD1C but not T505A mutant when we co-transfected JMJD1C constructs along with the mTORC1 in 293FT cells 0.242 SIGNOR-265168 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 16331690 YES The effect has been demonstrated using Q13507-3 llicata The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263. 0.408 SIGNOR-142961 SPOP protein O43791 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 0.48 SIGNOR-272827 GSK3B protein P49841 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity phosphorylation 9606 25118933 YES miannu GSK3\u03b2 is an important serine/threonine kinase to regulate PPAR\u03b3 coactivator-1\u03b1 degradation. , GSK3\u03b2 reduces PPAR\u03b3 coactivator-1\u03b1 levels by phosphorylating PPAR\u03b3 coactivator-1\u03b1 and subsequently stimulating PPAR\u03b3 coactivator-1\u03b1 degradation by the ubiquitin-proteasomal system.|Within them, GSK3beta, which can phosphorylate PGC-1alpha and promote its ubiquitin mediated degradation , , was upregulated significantly in mnd2 mouse brain and spinal cord compared with that in wide-type mice (XREF_FIG). 0.477 SIGNOR-279723 TRPS1 protein Q9UHF7 UNIPROT GDF5 protein P43026 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0005092 18363966 NO Regulation of expression miannu Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1. 0.306 SIGNOR-251866 GPR25 protein O00155 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 29727602 YES GPR25 is expressed in human memory T-cells and NK-cells and identified as a primary causal gene associated with autoimmune |Within the class A GPCR family, GPR25 shares a relatively high degree of amino acid sequence identity (29e34%) with vertebrate Apelin receptor (APLNR) diseases revealed by cis-eQTL mapping based on a genome-wide association study (GWAS). 0.25 SIGNOR-272501 haloperidol chemical CHEBI:5613 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258372 SMAD1/4 complex SIGNOR-C85 SIGNOR PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004058 12589053 NO lperfetto Overexpression of Smad6, a natural antagonist for Smad1, blocked PPARgamma expression and adipocytic differentiation induced by BMP2 0.285 SIGNOR-236233 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser181 NPLLRKEsAPPSLRR 9606 18339811 YES Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. 0.2 SIGNOR-248604 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser82 VDILRKVsGHPNIIQ -1 7935360 YES miannu Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81. 0.2 SIGNOR-250389 RPL17 protein P18621 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.763 SIGNOR-262482 DDB1 protein Q16531 UNIPROT DDB2/DDB1 complex SIGNOR-C39 SIGNOR form complex binding 9606 BTO:0000567 9418871 YES miannu Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna 0.937 SIGNOR-54093 PLK1 protein P53350 UNIPROT PLEKHG6 protein Q3KR16 UNIPROT up-regulates phosphorylation Thr574 HLVVTEDtDEDAPLV 9606 BTO:0000567 18694934 YES lperfetto We reported previously that a guanine nucleotide exchange factor, myogef, localizes to the central spindle, activates rhoa, and is required for cytokinesis. In this study, we have found that plk1 (polo-like kinase 1) can phosphorylate myogef, thereby recruiting myogef to the central spindle as well as enhancing myogef activity toward rhoa. The in vitro kinase assay shows that plk1 can phosphorylate myogef on threonine 574. 0.415 SIGNOR-179954 P-TEFb complex SIGNOR-C238 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 19516275 NO miannu Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits the positive transcription elongation factor b (P-TEFb), which is a key RNA polymerase II (Pol II) transcriptional regulator. In transfected cells, mutated NPM1 associated with, and sequestered, HEXIM1 in cytoplasm, resulting in higher transcription of RNA pol II target genes, among which were some positive regulators of cell-cycle progression such as cyclin D1 and anti-apoptotic proteins such as Mcl-1 0.7 SIGNOR-260136 TFIIIC complex SIGNOR-C392 SIGNOR RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 9308965 YES lperfetto Transcription by RNA polymerase III (Pol III) requires multiple general initiation factors that, in isolated form, assemble onto the promoter in an ordered fashion. Here, it is shown that all components required for transcription of the VA1 and tRNA genes, including TFIIIB, TFIIIC, and RNA Pol III, can be coimmunopurified from a HeLa cell line that constantly expresses a FLAG epitope-tagged subunit of human RNA Pol III. 0.468 SIGNOR-266182 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 8119945 YES gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. 0.858 SIGNOR-36271 UCK1 protein Q9HA47 UNIPROT uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity chemical modification 11306702 YES lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 0.8 SIGNOR-275858 GOLGA2 protein Q08379 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT up-regulates activity binding 9606 23555793 YES miannu The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane. 0.878 SIGNOR-261239 RPS6KA1 protein Q15418 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 BTO:0000551 21423205 YES lperfetto Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin. 0.451 SIGNOR-172899 GUCY1A2-B2 complex SIGNOR-C137 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 YES gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types 0.8 SIGNOR-244090 TAL1 protein P17542 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0004911 29713515 NO The truncated form TAL1-s is required for erythroid progenitors differentiation, while the full-length protein TAL1-l is required for megakaryocytic differentiation of progenitor cells. 0.7 SIGNOR-259970 DOK1 protein Q99704 UNIPROT ITGB7 protein P26010 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.325 SIGNOR-257695 MYLK2 protein Q9H1R3 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr80 NEPHESRtNSDIVET 9606 BTO:0000007 21556048 YES llicata Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis. 0.403 SIGNOR-238118 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 YES gcesareni Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax 0.2 SIGNOR-259418 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 YES gcesareni CK2 hyperactivates AKT by phosphorylation at Ser129 0.372 SIGNOR-252595 JUN protein P05412 UNIPROT LORICRIN protein P23490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 12200429 NO miannu Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. 0.2 SIGNOR-254536 BNIP2 protein Q12982 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity binding 9606 BTO:0000222 18678706 YES lperfetto Cdo-bnip-2-cdc42 complex stimulates cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation. 0.708 SIGNOR-179861 MYCT1 protein Q8N699 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 NO miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 0.2 SIGNOR-261732 FGF1 protein P05230 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates binding 9606 11030354 YES lperfetto Crystal structure of a ternary fgf-fgfr-heparin complex reveals a dual role for heparin in fgfr binding and dimerization. 0.914 SIGNOR-83143 mir-206 mirna URS0000389B41_9606 RNAcentral PAX7 protein P23759 UNIPROT down-regulates quantity post transcriptional regulation 10090 20819939 YES We show that miR-1 and miR-206 facilitate satellite cell differentiation by restricting their proliferative potential. We identify Pax7 as one of the direct regulatory targets of miR-1 and miR-206. Inhibition of miR-1 and miR-206 substantially enhances satellite cell proliferation and increases Pax7 protein level in vivo 0.4 SIGNOR-255921 SPAG9 protein O60271 UNIPROT MAP3K7 protein O43318 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 YES lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts 0.2 SIGNOR-235548 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation Ser189; Ser283 SGILGITsPSADTNK;DMKANLAsPTPADIG 9606 BTO:0003079 22593617 YES Gianni In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5. 0.2 SIGNOR-269088 SNRNP70 protein P08621 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.91 SIGNOR-270677 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser619 RELTNRHsLPFSLPS 9606 BTO:0000782 11024037 YES lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  0.322 SIGNOR-249054 CHGA protein P10645 UNIPROT Peptide_hormone_processing phenotype SIGNOR-PH88 SIGNOR up-regulates 10090 12456801 NO CgA was initially identified as the major soluble matrix protein of secretory vesicles formed in neuroendocrine cells. Its functions include modulation of secretory granule stability, prohormone processing, and regulation of peptide sorting into secretory pathways 0.7 SIGNOR-254275 FPR2 protein P25090 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256888 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR -1 11062067 YES Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1). 0.751 SIGNOR-251419 BECN1 protein Q14457 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity binding 9606 BTO:0000567 23478334 YES lperfetto We show that Beclin-1 interacts directly with Zwint-1-a component of the KMN (KNL-1/Mis12/Ndc80) complex-which is essential for kinetochore-microtubule interactions. This suggests that Beclin-1 acts downstream of the KMN complex to influence the recruitment of outer kinetochore proteins and promotes accurate kinetochore anchoring to the spindle during mitosis. 0.436 SIGNOR-265027 AKT proteinfamily SIGNOR-PF24 SIGNOR TAL1 protein P17542 UNIPROT down-regulates phosphorylation Thr90 EARHRVPtTELCRPP 9606 BTO:0000782;BTO:0001271 15930267 YES miannu Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo. 0.2 SIGNOR-137942 S100A8 protein P05109 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000876 16690079 YES miannu Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner 0.2 SIGNOR-261937 ATM protein Q13315 UNIPROT UCK1 protein Q9HA47 UNIPROT down-regulates quantity by destabilization phosphorylation 31938050 YES lperfetto ATM also phosphorylates UCK1 at S145, significantly enhancing the KLHL2-UCK1 complex formation|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. 0.2 SIGNOR-275963 IL5 protein P05113 UNIPROT IL5RA protein Q01344 UNIPROT up-regulates binding -1 8567620 YES fspada Single chain and wt il5 also had similar binding affinity for soluble il5 receptor alpha chain, the specificity subunit of the il5 receptor, as measured kinetically with an optical biosensor. 0.883 SIGNOR-40039 MDM2 protein Q00987 UNIPROT EP300 protein Q09472 UNIPROT down-regulates binding 9606 BTO:0000567 11070080 YES gcesareni Mdm2, a negative-feedback regulator of p53, inhibited p300-mediated p53 acetylation by complexing with these two proteins. 0.686 SIGNOR-84077 NFYB protein P25208 UNIPROT NFY complex SIGNOR-C1 SIGNOR form complex binding 9606 9885213 YES lperfetto Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding. 0.964 SIGNOR-63016 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206361 PFAS protein O15067 UNIPROT N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI down-regulates quantity chemical modification 9606 33179964 YES miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. 0.8 SIGNOR-267309 STK4 protein Q13043 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity phosphorylation Ser140 GKKATQAsQEY 9606 20921231 YES miannu Western blot and kinase assay results with a mutant S139A H2AX confirmed that MST1 phosphorylates H2AX at Ser-139. 0.2 SIGNOR-278457 CDC42 protein P60953 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 9606 21902831 NO lperfetto Precisely how this complex results in p38 activation is not known, but complex recruitment of the gtpase cdc42 is required for p38 phosphorylation. 0.601 SIGNOR-176501 PRKACA protein P17612 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 YES lperfetto Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka). 0.556 SIGNOR-188577 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT up-regulates activity phosphorylation Ser380 PEQIKEDsLSEESAD -1 21880710 YES miannu Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. 0.429 SIGNOR-262938 POLR3E protein Q9NVU0 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.851 SIGNOR-266129 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.394 SIGNOR-89260 tetra-mu3-sulfido-tetrairon chemical CHEBI:49883 ChEBI BRCA1-B complex complex SIGNOR-C298 SIGNOR form complex binding 25400280 YES lperfetto Another BRCA1 complex, the BRCA1‚ÄìB complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‚Äêphase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‚Äêphase checkpoint activation 0.8 SIGNOR-269475 RAB6A protein P20340 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 NO miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons 0.7 SIGNOR-266873 PRKCD protein Q05655 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser715 GYRQDDPsYRSFHSG 9606 25639486 YES Manara Moreover, protein kinase Cδ, which directly phosphorylates β-catenin at Ser715, is required for the TRIM33–β-catenin interaction. | Phosphorylation of β-catenin Ser715 is critical for TRIM33-induced β-catenin degradation 0.269 SIGNOR-260897 ATM protein Q13315 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity phosphorylation 9606 23890999 YES lperfetto ATM, bound to the NKX3.1 homeodomain, phosphorylates NKX3.1, leading to ubiquitination and degradation.|The suggestion that NKX3.1 was a substrate for ATM and that NKX3.1 (serine 1981 and three other)Q phosphorylation led to NKX3.1 degradation implied that ATM and NKX3.1 are involved in a regulatory loop wherein NKX3.1 activates ATM, which in turn phosphorylates NKX3.1, leading to its degradation. 0.362 SIGNOR-279726 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206358 SMAD7 protein O15105 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates binding 9606 14718519 YES lpetrilli We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI. 0.678 SIGNOR-121280 CDKN1B protein P46527 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 18423396 NO fspada Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation. 0.7 SIGNOR-178278 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 23603988 YES gcesareni We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation 0.535 SIGNOR-201935 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates relocalization 9606 11238441 YES lperfetto Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels 0.358 SIGNOR-105497 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ -1 15946941 YES done miannu PKA Phosphorylates GRK7 on Ser23 and Ser36. Phosphorylation by PKA inhibits GRK7 activity 0.2 SIGNOR-274080 CREB5 protein Q02930 UNIPROT ATP6V0E1 protein O15342 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253801 ATM protein Q13315 UNIPROT POLL protein Q9UGP5 UNIPROT up-regulates activity phosphorylation Thr204 EASDGEEtQVSAADL 9606 BTO:0000007 28109743 YES done miannu We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ.  0.354 SIGNOR-273510 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 9606 12510059 YES gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.771 SIGNOR-96948 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT up-regulates phosphorylation 9606 10828059 YES The effect has been demonstrated using Q08499-4 llicata The short pde4d1 isoenzyme is activated by erk2 phosphorylation this signifies that erk2 phosphorylated pde4d1 at a single site, ser491, that is cognate to the single erk2 phosphorylation site (ser579) found in pde4d3. 0.353 SIGNOR-77559 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.716 SIGNOR-262997 SYCP1 protein Q15431 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 YES miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. 0.684 SIGNOR-264197 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT up-regulates activity phosphorylation Tyr456 NVYYGQDyRNKYKAP -1 20417104 YES miannu Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C). 0.285 SIGNOR-262607 hsa-miR-491-5p mirna URS00001919B0_9606 RNAcentral BID protein P55957 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 BTO:0002575 25299770 YES MiR-491-5p induces BIM expression, promotes its dephosphorylation, and increases its binding to MCL1, facilitating apoptosis in IGROV1-R10 cells. 0.4 SIGNOR-277948 MAPK1 protein P28482 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 YES gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. 0.56 SIGNOR-118546 SMAD3 protein P84022 UNIPROT SMAD3/JUN complex SIGNOR-C86 SIGNOR form complex binding 9606 9732876 YES gcesareni These results show a ligand-dependent association of smad3 with c-jun 0.75 SIGNOR-59873 KAT2A protein Q92830 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 SIGNOR-C465 34811519 YES lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269593 TRAF6 protein Q9Y4K3 UNIPROT TAB3 protein Q8N5C8 UNIPROT up-regulates activity binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. 0.713 SIGNOR-205461 ANK1 protein P16157 UNIPROT SLN protein O00631 UNIPROT down-regulates activity binding 9606 28487373 YES lperfetto These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity. 0.257 SIGNOR-265930 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206382 PPP3CA protein Q08209 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 NO gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.506 SIGNOR-84035 DLD protein P09622 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 YES miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. 0.856 SIGNOR-266545 NPTX1 protein Q15818 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity relocalization 10090 23069675 YES lperfetto Immunofluorescence staining and subcellular fractionation analyses revealed increased mitochondrial translocation of Bad and Bax proteins from cytoplasm following OGD (4 h) and simultaneously increased release of Cyt C from mitochondria followed by activation of caspase-3. NP1 protein was immunoprecipitated with Bad and Bax proteins; OGD caused increased interactions of NP1 with Bad and Bax, thereby, facilitating their mitochondrial translocation and dissipation of mitochondrial membrane potential 0.2 SIGNOR-261439 CTH protein P32929 UNIPROT L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275822 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14522900 NO miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction 0.876 SIGNOR-254484 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity ubiquitination 9606 19917253 YES lperfetto Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation 0.804 SIGNOR-232104 NR3C1 protein P04150 UNIPROT CAV1 protein Q03135 UNIPROT up-regulates binding 9606 23339905 YES gcesareni He mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay. 0.381 SIGNOR-251683 ETNK1 protein Q9HBU6 UNIPROT ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI down-regulates quantity chemical modification 36583229 YES lperfetto ETNK1 encodes ethanolamine kinase 1, which is involved in the de novo biosynthesis of phosphatidylethanolamine and is responsible for the phosphorylation of ethanolamine to phosphoethanolamine 0.8 SIGNOR-275642 ELP4 protein Q96EB1 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 YES miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. 0.868 SIGNOR-269711 TGFBR1 protein P36897 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 YES lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. 0.381 SIGNOR-227525 PPM1B protein O75688 UNIPROT CDK9 protein P50750 UNIPROT unknown dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 YES gcesareni Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function 0.372 SIGNOR-181396 IC-87114 chemical CHEBI:90686 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21048785 YES gcesareni Ic87114 is a selective pi3kinhibitor. 0.8 SIGNOR-169213 SERPINE1 protein P05121 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 10368279 NO gcesareni Pai-1 is now being identified as a key player in the link between coagulation and the cell adhesion pathways involved in tissue remodeling and metastasis. Active pai-1 (but not its latent or cleaved forms) binds tightly to the adhesive glycoprotein vitronectin in the extracellular matrix. 0.7 SIGNOR-68478 SH3GLB1 protein Q9Y371 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 NO miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 0.7 SIGNOR-263886 APH1A protein Q96BI3 UNIPROT PSENEN protein Q9NZ42 UNIPROT up-regulates binding 9606 12522139 YES gcesareni Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex. 0.962 SIGNOR-97104 PTPN5 protein P54829 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates activity dephosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 19625523 YES lperfetto In addition, STEP 61 dephosphorylates the tyr 1472 on the NR2B subunit of the NMDAR, which promotes internalization of the NMDAR complex. 0.548 SIGNOR-276991 PPP3CB protein P16298 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 26000950 YES Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation. 0.377 SIGNOR-255307 POLR1B protein Q9H9Y6 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.872 SIGNOR-266154 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20921405 NO gcesareni Nf-kb activation following t-cell receptor engagement induces the expression of mdm2 through interaction with nf-kb sites in its p1 promoter 0.372 SIGNOR-168296 NF2 protein P35240 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 10090 BTO:0003324 27402866 YES Hippo pathway Gianni NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart. 0.412 SIGNOR-269948 CEBPA protein P49715 UNIPROT F9 protein P00740 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8075306 NO Transactivation by the CCAAT/enhancer binding protein alpha of the wild-type and mutated factor IX promoter (-192 to +38) resulted in an approximately four-fold and approximately two-fold, respectively, increase of CAT activity 0.286 SIGNOR-254040 CRK protein P46108 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 YES HPK1 phosphorylated Crk mainly on threonine and weakly on serine gcesareni We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk. 0.685 SIGNOR-63988 GSK3B protein P49841 UNIPROT JUNB protein P17275 UNIPROT down-regulates quantity by destabilization phosphorylation Ser251 QTVPEARsRDATPPV 9606 BTO:0000567 22710716 YES miannu  Thus, JunB phosphorylation at S251 and T255 by GSK3β is primed by phosphorylation at S259 by a yet to-be-identified kinase.Phosphorylation at S251, T255 and S259 is required for JunB degradation. 0.2 SIGNOR-276418 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 YES Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase. 0.68 SIGNOR-248324 BAMBI protein Q13145 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 2662247 YES gcesareni Bmp-2 mediates phosphorylated smad1 (psmad1) or, with loss of bmprii, psmad3-dependent recruitment of disheveled (dvl) to promote rhoa-rac1 signaling necessary for motility. 0.515 SIGNOR-23037 EPHB6 protein O15197 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates activity binding 9606 34360976 YES miannu We suggest that although mammalian EphB6 is kinase-negative, it has retained the allosteric regulatory mechanisms involving the juxtamembrane and the SAM domain linker that are used to regulate the kinase activity of kinase-active Eph receptors. he inability to recruit c-Cbl by EphB6 meant that heightened levels of EphA2 remained active in the cell because they had evaded c-Cbl-mediated degradation. The authors suggest that mutation of residues 901–926 within EphB6 reduces the flexibility of the SAM domain such that c-Cbl cannot be recruited. 0.274 SIGNOR-273852 FLT1 protein P17948 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr154 QLNDSAAyYLNDLDR -1 33139573 YES miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. 0.257 SIGNOR-277230 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Thr24 TDESLEStRRILGLA 9606 12930825 YES lperfetto Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion. 0.33 SIGNOR-249229 GATA3 protein P23771 UNIPROT CEBPA protein P49715 UNIPROT down-regulates binding 9606 17139329 YES fferrentino Whereas others, such as GATA2/3 and SMAD3, physically interact with C/EBPα to inhibit its transcriptional activity on the Pparg2 promoter. 0.361 SIGNOR-250569 NFIA protein Q12857 UNIPROT ANOS1 protein P23352 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268872 CDH4 protein P55283 UNIPROT CDH15 protein P55291 UNIPROT down-regulates quantity by repression 10090 BTO:0000165 18701479 NO lperfetto Taken together, these data show that (a) R-cadherin decreases the expression of M-cadherin and (b) N-cadherin and M-cadherin only slightly accumulate at the cell contacts in R-cadherin–expressing myoblasts. 0.413 SIGNOR-253106 KHSRP protein Q92945 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 BTO:0000130;BTO:0000876 2848118 YES gcesareni Ksrp was shown to interact with the c-terminus of dvl3. We show that ksrp negatively regulates wnt/beta-catenin signaling at the level of post-transcriptional ctnnb1 (beta-catenin) mrna stability. 0.2 SIGNOR-23800 FOXJ1 protein Q92949 UNIPROT TEKT1 protein Q969V4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.364 SIGNOR-266936 PAK1 protein Q13153 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 12198493 YES gcesareni In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152. 0.789 SIGNOR-92065 GTF3C3 protein Q9Y5Q9 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 YES lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains 0.881 SIGNOR-266186 RABGGTA protein Q92696 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity lipidation 9606 BTO:0000007 18532927 YES miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional 0.568 SIGNOR-265574 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR SAV1 protein Q9H4B6 UNIPROT up-regulates activity phosphorylation 9606 21084559 YES miannu Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. 0.2 SIGNOR-256184 orantinib chemical CHEBI:91088 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207438 RBSN protein Q9H1K0 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto Rabenosyn-5 is another FYVE-domain-containing Rab5 effector that localizes to EE 0.2 SIGNOR-260624 ATR protein Q13535 UNIPROT CDS1 protein Q92903 UNIPROT up-regulates 9606 15530773 NO gcesareni The pikk kinases serve as transducers of the damege signel, ultimately phosphorylating and activating the downstream effector kinases: checkpoint kinases 1 and 2. 0.348 SIGNOR-130187 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 11960013 YES lperfetto In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1. 0.686 SIGNOR-117315 TNFRSF21 protein O75509 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 YES amattioni Dr6 interacts with tradd 0.582 SIGNOR-100184 TKT protein P29401 UNIPROT D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI down-regulates quantity chemical modification 9606 24929114 YES miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. 0.8 SIGNOR-267085 RAB14 protein P61106 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 0.431 SIGNOR-260619 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Thr107 LGIDDLEtMPDDLLT 9606 BTO:0002181 25795775 YES miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA.  0.2 SIGNOR-276448 PRKACA protein P17612 UNIPROT PDE3A protein Q14432 UNIPROT unknown phosphorylation Ser312 SKSHRRTsLPCIPRE 9606 16153182 YES llicata Ser312 of pde3a was phosphorylated in an h-89-sensitive response to forskolin, indicative of phosphorylation by pka (camp-dependent protein kinase), but phosphorylation at this site did not stimulate 14-3-3 binding. 0.505 SIGNOR-140289 RAB21 protein Q9UL25 UNIPROT Early macropinosomes phenotype SIGNOR-PH228 SIGNOR up-regulates binding 9606 19693279 NO miannu It was demonstrated that wild-type Rab21 was transiently associated with macropinosomes. Rab21 was recruited to the macropinosomes after a decrease in PI(4,5)P(2) and PI(3,4,5)P(3) levels. Although Rab21 was largely colocalized with Rab5, the recruitment of Rab21 to the macropinosomes lagged a minute behind that of Rab5, and preceded that of Rab7. 0.7 SIGNOR-277782 NPM1 protein P06748 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates activity binding 10090 16199867 YES gcesareni The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division 0.553 SIGNOR-245073 AP3D1 protein O14617 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 YES lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) 0.93 SIGNOR-260683 RFC5 protein P40937 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 YES lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 0.77 SIGNOR-265509 KDM6B protein O15054 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys28 LATKAARkSAPATGG 9606 24561908 YES This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. 0.2 SIGNOR-260018 PML protein P29590 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0001271 15093545 NO gcesareni The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor 0.7 SIGNOR-256659 PHA-848125 chemical CID:16718576 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206151 PAK1 protein Q13153 UNIPROT BCL6 protein P41182 UNIPROT down-regulates activity phosphorylation 9606 22723377 YES miannu The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase-activated protein kinase PAK1. 0.2 SIGNOR-253930 AKT1 protein P31749 UNIPROT MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation Ser516 KTSSRRSsMSMEETE 9606 BTO:0002181 27702651 YES miannu We found that AKT phosphorylates MITF at S510. Phosphorylated MITF S510 enhances its affinity to TP53 and promotes CDKN1A expression. Phosphorylation of MITF by AKT induces its degradation 0.44 SIGNOR-277281 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 11733498 YES lperfetto Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1. 0.2 SIGNOR-112549 NCBP1 protein Q09161 UNIPROT IRF8 protein Q02556 UNIPROT up-regulates activity binding 9606 BTO:0001413 11483597 YES miannu we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. 0.2 SIGNOR-222939 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr1018 RLSADSGyIIPLPDI 9823 BTO:0004007 7535778 YES miannu We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ. 0.2 SIGNOR-250250 BTG2 protein P78543 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity binding 9606 BTO:0000093 22493435 YES miannu BTG2 stimulation of antioxidant gene expression is also NFE2L2-dependent. We further demonstrate that BTG2 is a binding partner for NFE2L2 and increases its transcriptional activity. 0.2 SIGNOR-254647 SMO protein Q99835 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 9606 23074268 YES gcesareni Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion. 0.424 SIGNOR-199156 SREBF2 protein Q12772 UNIPROT PON2 protein Q15165 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19497963 NO miannu UPA upregulated PON2 expression in a sterol regulatory binding protein-2 (SREBP-2)-dependent manner, since blocking SREBP-2 maturation by 4-(2-aminoethyl)-benzenesulfonyl fluoride abolished uPA-stimulation of PON2, whereas inhibition of SREBP-2 catabolism by N-acetyl-leucyl-norleucinal had an opposite effect. 0.276 SIGNOR-255225 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser171 RILNHDTsFAKTFVG 9606 17197699 YES gcesareni Enzymatic activity, induced; 0.2 SIGNOR-151755 CDK8 protein P49336 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 25818643 YES miannu As a consequence, CDK8 overexpression promoted p27 degradation, whereas CDK8 knockdown reduced it.|We also show that CDK8 promotes phosphorylation of p27 at T187 and then induces p27 ubiquitination and degradation in a Skp2-dependent manner. 0.289 SIGNOR-278513 STAT1 protein P42224 UNIPROT NOS2 protein P35228 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19029990 YES lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. 0.428 SIGNOR-249497 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates activity 10090 BTO:0000452 16892090 NO inferred from family member HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host 0.7 SIGNOR-270309 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 11093753 YES gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. lpa2 also can couple to the gi/o, g12/13, and gqfamilies. 0.624 SIGNOR-84559 RNF168 protein Q8IYW5 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR up-regulates quantity ubiquitination 9606 31225475 YES miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. 0.2 SIGNOR-266784 PAK1 protein Q13153 UNIPROT ATG5 protein Q9H1Y0 UNIPROT up-regulates quantity by stabilization phosphorylation Thr101 SALPWNItVHFKSFP 36528756 YES lperfetto Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. |As PAK1-mediated phosphorylation at residue T101 protects ATG5 from ubiquitination-dependent degradation 0.2 SIGNOR-275835 PPP2R2B protein Q00005 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates activity binding 9606 21075311 YES gcesareni Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation. 0.332 SIGNOR-243511 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0003316 11777913 YES miannu 4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. 0.434 SIGNOR-250098 STUB1 protein Q9UNE7 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17239458 YES miannu The ErbB2 kinase domain is required for GA-induced and CHIP-dependent ErbB2 ubiquitination and degradation . 0.626 SIGNOR-278645 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267950 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr467 KKLNPKKyEGGRELS -1 8631326 YES miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). 0.2 SIGNOR-262896 GTF3A protein Q92664 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity binding 9308965 YES lperfetto At present, it is known that transcription factors TFIIIB, TFIIIC2, TFIIIC1, and TFIIIA (5S gene only) are involved in transcription of tRNA, VA RNA, and 5S RNA genes by human RNA Pol III. 0.468 SIGNOR-266180 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity ubiquitination 10090 35670107 YES STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination 0.2 SIGNOR-270349 TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 YES lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. 0.937 SIGNOR-40043 KLF8 protein O95600 UNIPROT CTBP2 protein P56545 UNIPROT up-regulates activity binding 10090 BTO:0000944 10756197 YES miannu Here we report the characterisation of KLF8/ZNF741/BKLF3 (KLF8). We demonstrate that this protein is able to bind CACCC-boxes in DNA and can repress gene expression by associating with CtBP co-repressors. 0.531 SIGNOR-236962 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.333 SIGNOR-248553 CDC42 protein P60953 UNIPROT WAS protein P42768 UNIPROT up-regulates activity binding 9606 BTO:0000132 27871158 YES lperfetto Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex 0.957 SIGNOR-261869 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 16751101 YES lpetrilli Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. 0.621 SIGNOR-146922 5,15-Diphenyl-21H,23H-porphine chemical CID:10895852 PUBCHEM STAT3 protein P40763 UNIPROT down-regulates activity chemical inhibition 9606 26260587 YES gcesareni 15-DPP is an effective STAT3 inhibitor and blocks IL10-mediated signalling in macrophages leading to altered regulation of CNV 0.8 SIGNOR-238549 AR protein P10275 UNIPROT CYP7B1 protein O75881 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 16630558 NO miannu DHT and overexpression of androgen receptor (AR) suppressed CYP7B1 promoter activity and CYP7B1-mediated catalysis in kidney-derived HEK293 cells. 0.289 SIGNOR-253739 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr784 MYGSGSRtPMYGSQT 9606 16427012 YES lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif 0.776 SIGNOR-143927 KRAS protein P01116 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates activity binding 9606 22195963 YES lperfetto Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex K-Ras-RASSF1A€“MST2 complex, as reported here 0.647 SIGNOR-249585 SPTAN1 protein Q13813 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 9624143 NO Cleaved by CASP3 amattioni A-fodrin cleavage contributes to blebbing 0.7 SIGNOR-57897 PRKCA protein P17252 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Ser76 VQDTSGTsPVHDAAR 9606 22558186 YES lperfetto Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation. 0.2 SIGNOR-197285 DHX30 protein Q7L2E3 UNIPROT FASTKD2 protein Q9NYY8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25683715 NO miannu DHX30 siRNA treatment resulted in an increase of FASTKD2 levels, and FASTKD5 was increased in cells treated with siRNA for GRSF1. 0.383 SIGNOR-261225 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation Ser480 PVPHSGSsGYGSLGS -1 30425162 YES miannu Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2 0.901 SIGNOR-277419 AMPK complex SIGNOR-C15 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity phosphorylation 9606 23863160 YES lperfetto Under energy deprivation, AMPK positively regulates ULK1 to induce autophagy, with various studies revealing that AMPK binds to and phosphorylates ULK1 0.432 SIGNOR-209913 NRL protein P54845 UNIPROT RHO protein P08100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 NO miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 0.443 SIGNOR-253819 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22521266 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-252920 SLC5A5 protein Q92911 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 10116 28192058 YES scontino Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis.  0.8 SIGNOR-266961 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 YES lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. 0.431 SIGNOR-249092 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNK18 protein Q7Z418 UNIPROT down-regulates activity phosphorylation Ser252 QAMERSNsCPELVLG -1 18397886 YES miannu Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. PKA was used to phosphorylate serine 264 in our further in vitro experiments. 0.2 SIGNOR-263154 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 BTO:0000007 9724739 YES gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 0.751 SIGNOR-244982 GTF2A1 protein P52655 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR form complex binding 9606 BTO:0000567 7724559 YES lperfetto TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit. 0.94 SIGNOR-266197 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 YES Does not bind to the ERBB1, ERBB2 and ERBB3 receptors gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.695 SIGNOR-122062 SIRT1 protein Q96EB6 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 20713551 NO miannu Overexpression of SIRT1 enhanced both FoxO reporter activity and nuclear levels of FoxO1. Protein expression of MDR1 and gene transcriptional activity were also up-regulated by SIRT1 overexpression. 0.257 SIGNOR-255139 FGF14 protein Q92915 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.258 SIGNOR-253437 YWHAQ protein P27348 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11433030 YES gcesareni 14-3-3tau associates with and activates the mef2d transcription factor during muscle cell differentiation. 0.582 SIGNOR-109139 CHEK1 protein O14757 UNIPROT RHOB protein P62745 UNIPROT up-regulates activity phosphorylation Thr175 REVFETAtRAALQKR 9606 30297842 YES miannuccelli Phosphorylation of RhoB enhances its interaction with the TSC2, and promotes its sumoylation by PIAS1, which is required for RhoB/TSC complex to translocate to lysosomes.Phosphorylation of RhoB enhances its interaction with the TSC|We identified that Thr173 and Thr175 of RhoB was phosphorylated by Chk1 using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) (Supplementary Fig.\u00a06f). 0.328 SIGNOR-279728 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr575 RQSPEDVyFSKSEQL -1 21538645 YES gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates 0.659 SIGNOR-246031 IRX1 protein P78414 UNIPROT KDR protein P35968 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. 0.2 SIGNOR-261664 ceramide smallmolecule CHEBI:17761 ChEBI sphingomyelin smallmolecule CHEBI:64583 ChEBI up-regulates quantity precursor of 9606 18184806 YES miannu Ceramide is a common precursor for both sphingomyelin and glycosphingolipids, which are ubiquitous components of membranes in mammalian cells and play important roles in cell growth, differentiation, and apoptosis 0.8 SIGNOR-268497 CSNK1E protein P49674 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 YES lperfetto We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms. 0.637 SIGNOR-227976 LYN protein P07948 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.707 SIGNOR-268206 olanzapine chemical CHEBI:7735 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 BTO:0001311 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258507 RPS6KA5 protein O75582 UNIPROT ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 BTO:0002181 12213813 YES lperfetto Activated, overexpressed MSK1 was able to phosphorylate ER81 at Ser191 and Ser216. Mutation of these residues strongly impairs ER81-responsive promoter activity. 0.464 SIGNOR-262987 CBLB protein Q13191 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates quantity ubiquitination 9606 35288194 YES miannu Cbl-b modulated TrkA ubiquitination and function in the dorsal root ganglion of mice.|Viral expression of constitutively active Cbl-b in DRGs of osteoarthritic mice effectively repressed TrkA protein level and more importantly, alleviated mechanical allodynia and heat hyperalgesia. 0.277 SIGNOR-278690 S100A9 protein P06702 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001545 28137827 NO miannu S100A9 induces differentiation of acute myeloid leukemia cells through TLR4. 0.7 SIGNOR-261922 SKIL protein P12757 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 12793438 YES lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway 0.8 SIGNOR-236099 FBXL7 protein Q9UJT9 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002268 25778398 YES miannu Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation. 0.307 SIGNOR-272436 MYD88 protein Q99836 UNIPROT DHX9 protein Q08211 UNIPROT up-regulates activity binding 9606 BTO:0002042 20696886 YES miannu We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing. 0.489 SIGNOR-260955 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 18162466 YES These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms, 0.341 SIGNOR-248326 MLL1 complex complex SIGNOR-C89 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.2 SIGNOR-268801 PIM proteinfamily SIGNOR-PF34 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000574 16146838 NO miannu The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. 0.7 SIGNOR-255732 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL10 protein P22301 UNIPROT up-regulates 9606 BTO:0000801 32454942 NO miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation 0.7 SIGNOR-263823 Ub:E2 complex SIGNOR-C497 SIGNOR NEURL3 protein Q96EH8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271211 ROR2 protein Q01974 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 18667433 YES gcesareni Wnt5a stimulation induces activation of the c-jun n-terminal kinase jnk at the wound edge in a ror2-dependent manner, and inhibiting jnk activity abrogates wnt5a-induced lamellipodia formation and mtoc reorientation 0.459 SIGNOR-179671 ENO2 protein P09104 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266525 CHEK2 protein O96017 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser93 ARMMSTEsANSFTLI 9606 BTO:0002552 32187724 YES lperfetto We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration 0.299 SIGNOR-264556 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Ser) smallmolecule CHEBI:29179 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269496 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates quantity by stabilization phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17210579 YES Manara ASK2 Activates ASK1 by Phosphorylation 0.55 SIGNOR-260832 GPC6 protein Q9Y625 UNIPROT WNT5A protein P41221 UNIPROT down-regulates activity binding 9606 BTO:0000007 31756413 YES miannu GPC6 binds to Wnt5a and inhibits its release from producing cells. Based on theseresults, and in our finding that GPC6 inhibits non-canonical Wnt signaling in the developing intestine,we tested the hypothesis that GPC6 binds to Wnt5aat the surface of the Wnt5a-producing mesenchymalcells and restrains its release from them. 0.374 SIGNOR-264030 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 21808241 YES gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. 0.635 SIGNOR-175825 GUCY1A2 protein P33402 UNIPROT GUCY1A2-B3 complex SIGNOR-C138 SIGNOR form complex binding 9606 10977868 YES gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity 0.2 SIGNOR-243977 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 22334659 YES gcesareni Phosphorylation at thr-116 and thr-226 of orc2 occurs by cyclin-dependent kinase during the s phase and is maintained until the m phase. Phosphorylation of orc2 at thr-116 and thr-226 dissociated the orc2-5 from chromatin. 0.755 SIGNOR-196048 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr806 PLLLIVEyAKYGSLR 9606 14711813 YES llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation. 0.2 SIGNOR-121153 SLC19A1 protein P41440 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity relocalization 9606 10787414 YES lperfetto The differential polarized distribution of the reduced-folate transporter (RFT-1) and folate receptor alpha (FRalpha), the two proteins involved in the transport of folate, has been characterized in normal mouse retinal pigment epithelium (RPE) and in cultured human RPE cells. 0.8 SIGNOR-268266 S1PR2 protein O95136 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.529 SIGNOR-257215 MYO3A protein Q8NEV4 UNIPROT MYO3A protein Q8NEV4 UNIPROT down-regulates activity phosphorylation Thr919 TRHARETtNMKTQTV 9534 24214986 YES Manara We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work 0.2 SIGNOR-260924 DNMT1 protein P26358 UNIPROT IL32 protein P24001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 20889550 NO lperfetto A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-κB and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells.|Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection. 0.341 SIGNOR-254126 MARCHF9 protein Q86YJ5 UNIPROT SLAMF1 protein Q13291 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271537 PRKCA protein P17252 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 YES lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. 0.2 SIGNOR-202780 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 10653583 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. 0.2 SIGNOR-236483 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.636 SIGNOR-143688 CGRRF1 protein Q99675 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002548 31801577 YES miannu CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation. 0.2 SIGNOR-272220 ITGB2 protein P05107 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.753 SIGNOR-253192 IL20RA protein Q9UHF4 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000782;BTO:0000876 12941475 NO gcesareni Il-20 induces cheratin proliferation and stat-3 signal transduction pathway 0.581 SIGNOR-86269 PPARGC1A protein Q9UBK2 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23217713 YES miannu PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy 0.34 SIGNOR-256152 KMT5B protein Q4FZB7 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity methylation Lys21 GGAKRHRkVLRDNIQ -1 24396869 YES miannu SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. 0.2 SIGNOR-266651 CYP11A1 protein P05108 UNIPROT pregnenolone smallmolecule CHEBI:16581 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 YES lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. 0.8 SIGNOR-268632 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 10966616 YES gcesareni Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr) 0.791 SIGNOR-81379 AATK protein Q6ZMQ8 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates binding 9606 BTO:0000007 BTO:0000142 14521924 YES gcesareni Apoptosis-associated tyrosine kinase is a cdk5 activator p35 binding protein. 0.444 SIGNOR-118403 HDAC4 protein P56524 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 BTO:0000887 10737771 YES gcesareni We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2. 0.565 SIGNOR-76231 p38 proteinfamily SIGNOR-PF16 SIGNOR DDIT3 protein P35638 UNIPROT up-regulates activity phosphorylation -1 8650547 YES Luana Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase 0.2 SIGNOR-260724 APH1B protein Q8WW43 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 YES gcesareni By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. 0.908 SIGNOR-93310 PRKCB protein P05771 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates activity phosphorylation Ser184 LARRASVsARATGTA -1 19805577 YES miannu  This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload. 0.2 SIGNOR-276265 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636-5 UNIPROT down-regulates activity phosphorylation Thr231 KKVAVVRtPPKSPSS -1 21204788 YES miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.255 SIGNOR-273927 N-hydroxy-1-[(4-methoxyphenyl)methyl]-6-indolecarboxamide chemical CHEBI:94192 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189684 NCOA1 protein Q15788 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.2 SIGNOR-255061 MBL2 protein P11226 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding 9606 BTO:0000392 9087411 YES lperfetto The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). 0.75 SIGNOR-263414 GLUD2 protein P49448 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9913 11254391 YES miannu Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. 0.8 SIGNOR-268557 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 16461343 YES In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22. 0.75 SIGNOR-248836 CSNK2A1 protein P68400 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates phosphorylation Ser226 KEREKEIsDDEAEEE 9606 18591256 YES gcesareni Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation. 0.334 SIGNOR-179260 CSNK2A1 protein P68400 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates phosphorylation Ser255 PKIEDVGsDEEDDSG 9606 18591256 YES gcesareni Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation. 0.334 SIGNOR-179264 RIMS3 protein Q9UJD0 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 YES miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle 0.283 SIGNOR-264379 FCER1A protein P12319 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR form complex binding 9606 BTO:0000830 16470226 YES Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. 0.68 SIGNOR-254959 CTNNB1 protein P35222 UNIPROT TCF4 protein P15884 UNIPROT up-regulates activity binding 9606 BTO:0000007 11713476 YES amattioni beta-catenin interacts with the TCF/Lef family transcription factors. 0.689 SIGNOR-178042 KDM2B protein Q8NHM5 UNIPROT RNF2 protein Q99496 UNIPROT up-regulates activity binding 9606 17296600 YES miannu BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. The assembly of Fbxl10-BcoR complex(es), the associations among its various subunits, and its functional significance remain to be characterized but are presently under investigation. 0.61 SIGNOR-252242 BTG2 protein P78543 UNIPROT CAT protein P04040 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 NO miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 0.2 SIGNOR-254648 FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 11459935 YES gcesareni Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. T 0.728 SIGNOR-235150 FBXO27 protein Q8NI29 UNIPROT LAMP2 protein P13473 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 28743755 YES miannu Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment.We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy. 0.2 SIGNOR-272323 HLF protein Q16534 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23415677 NO miannu Ectopic hlf expression inhibits apoptosis in murine and human cells, suggesting that hlf is regulating a conserved transcriptional program that inhibits cell death. 0.7 SIGNOR-201034 PRKCB protein P05771 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 YES lperfetto We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function. 0.298 SIGNOR-249026 DGC complex SIGNOR-C217 SIGNOR GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626543 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265442 BAX protein Q07812 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 NO miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. 0.7 SIGNOR-261494 WT1 protein P19544 UNIPROT Urogenital_tract phenotype SIGNOR-PH71 SIGNOR up-regulates activity 10090 10101119 NO The Wilms' Tumour gene WT1 has important functions during development. Knock-out mice were shown to have defects in the urogenital system and to die at embryonic day E13.5, probably due to heart failure. 0.7 SIGNOR-252302 SCN3A protein Q9NY46 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 YES miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. 0.8 SIGNOR-253409 HCRTR2 protein O43614 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257008 NOXA1 protein Q86UR1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity 9606 19879762 YES lperfetto BH3-only proteins containing only a single BH domain and including Puma, Noxa, Bid and Bad as well as other factors are particularly important for such neutralisation, binding and regulating the anti-apoptotic Bcl-2 proteins to promote apoptosis 0.2 SIGNOR-209684 EXOC4 protein Q96A65 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.959 SIGNOR-270787 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 YES The effect has been demonstrated using Q08499-2 llicata Long pde4d forms are inhibited by erk2 phosphorylation 0.353 SIGNOR-77574 1-[5-bromo-4-methyl-2-[[(2S)-2-morpholinyl]methoxy]phenyl]-3-(5-methyl-2-pyrazinyl)urea chemical CHEBI:124917 ChEBI CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193787 GATA1 protein P15976 UNIPROT ZFPM1 protein Q8IX07 UNIPROT up-regulates activity binding 9606 21853041 YES miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. 0.797 SIGNOR-256059 TNKS2 protein Q9H2K2 UNIPROT TERF1 protein P54274 UNIPROT down-regulates activity ADP-ribosylation -1 11739745 YES lperfetto Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres. 0.55 SIGNOR-263376 IL5 protein P05113 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 21106848 NO It has been reported that IL-5 family members and selected chemotactic factors can activate the PI3K-Akt pathway in human blood eosinophils 0.395 SIGNOR-254351 COP1 protein Q8NHY2 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000078 32795415 YES Gianni We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. 0.2 SIGNOR-261924 MAPK11 protein Q15759 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser116 VTPHSPSsPVGSVLL 9606 BTO:0000007 16713578 YES miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles 0.264 SIGNOR-262947 PEX14 protein O75381 UNIPROT PEX13 protein Q92968 UNIPROT up-regulates activity binding -1 15798189 YES miannu Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import 0.919 SIGNOR-253029 HIF-1 complex complex SIGNOR-C418 SIGNOR PDK1 protein Q15118 UNIPROT up-regulates quantity transcriptional regulation 10090 16517405 YES We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. 0.41 SIGNOR-267480 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263783 DTD1 protein Q8TEA8 UNIPROT CDC45 protein O75419 UNIPROT up-regulates activity binding -1 25258324 YES done miannu The DNA unwinding element (DUE)-binding protein (DUE-B) binds to replication origins coordinately with the minichromosome maintenance (MCM) helicase and the helicase activator Cdc45 in vivo, and loads Cdc45 onto chromatin in Xenopus egg extracts. In egg extracts alanine mutation of the DUE-B C-terminal phosphorylation sites blocks Cdc45 loading and inhibits DNA replication. The effects of DUE-B C-terminal phosphorylation reveal a novel S phase kinase regulatory mechanism for Cdc45 loading and MCM helicase activation. 0.504 SIGNOR-273973 NCOA1 protein Q15788 UNIPROT APOA5 protein Q6Q788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.405 SIGNOR-255064 TSC complex SIGNOR-C101 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 NO lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor 0.776 SIGNOR-217907 DERA protein Q9Y315 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 25229427 YES miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. 0.8 SIGNOR-267098 DLX5 protein P56178 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates -1 19195802 NO Luana DLX5 and adjacent DLX6 are homeobox genes working in neurogenesis. 0.7 SIGNOR-265797 MBD4 protein O95243 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275714 RAB2A protein P61019 UNIPROT PRKCI protein P41743 UNIPROT down-regulates activity binding 9606 BTO:0000567 14570876 YES Sara Rab2 Binds to the PKCι/λ Regulatory Domain and Inhibits PKCι/λ-dependent GAPDH Phosphorylation 0.457 SIGNOR-261301 AURKA protein O14965 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 18615013 YES gcesareni We find that aurora a (aurka) can directly phosphorylate plk1 on thr 210;activation of plk1 requires phosphorylation of a conserved threonine residue (thr 210). 0.664 SIGNOR-179422 SNRNP27 protein Q8WVK2 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.446 SIGNOR-270642 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. 0.91 SIGNOR-252832 PKC proteinfamily SIGNOR-PF53 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser667 SSLIRKRsTRRSVRG 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.2 SIGNOR-272513 NOTCH1 protein P46531 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 NO gcesareni Other notch target genes identi__ed in the thymoma cell line were dtx1 (gene for deltex1), i__-202, i__-204, i__-d3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a). 0.263 SIGNOR-149730 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 NO lperfetto It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor. 0.2 SIGNOR-244314 CHEK2 protein O96017 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates activity phosphorylation Ser473 SGVKRSRsGEGEVSG 9606 26158765 YES miannuccelli In particular, Chk2 phosphorylates KAP1 on Ser473 decreasing the interaction between KAP1 and HP1 proteins: this post translational modification promotes HP1\u03b2 mobilization and the reorganization of chromatin structure favoring the repair of DNA breaks inside heterochromatin [ , ].|Of note, phosphorylation of S473 by Chk2 decreases the interaction between KAP1 and HP1 proteins and is necessary for HP1\u03b2 mobilization, a key event for DNA repair in the heterochromatin [ - ]. 0.412 SIGNOR-279730 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 0.607 SIGNOR-161597 EFNA1 protein P20827 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 17420126 YES gcesareni Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells. 0.817 SIGNOR-154298 ADAM17 protein P78536 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 10090 18344021 YES apalma Two ADAMs have been implicated in the S2 cleavage of Notch. In Drosophila, ADAM10 ortholog Kuzbanian is the main protease mediating Notch processing [35–38]. In mouse cells in vitro, ADAM17, and not ADAM10, appears to be a protease responsible for Notch cleavage 0.739 SIGNOR-255370 CHEK2 protein O96017 UNIPROT PML protein P29590 UNIPROT unknown phosphorylation Ser117 ESLQRRLsVYRQIVD 9606 12402044 YES llicata Hcds1/chk2 phosphorylates pml at ser 117 in vitro. hcds1/chk2 phosphorylates pml in vivo. 0.399 SIGNOR-94872 PLK1 protein P53350 UNIPROT STK3 protein Q13188 UNIPROT down-regulates activity phosphorylation Ser15 KSKLKKLsEDSLTKQ 9606 BTO:0002181 37739411 YES miannu  We conclude that TRIM69A promotes multi-site phosphorylation of MST2.We demonstrate that TRIM69 stimulates formation of an MST2-PLK1 complex and promotes phosphorylation of MST2 at S15, a known PLK1 site. PLK1-mediated MST2 phosphorylation at S15 is necessary for subsequent phosphorylation of NEK2A to dissociate c-NAP1 from daughter centrioles (7). Thus, we provide a new molecular mechanism by which TRIM69 promotes MST2- and PLK1-mediated centrosome disjunction. 0.332 SIGNOR-277904 FBXW12 protein Q6X9E4 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding -1 26171402 YES miannu FBXW12 causes depletion of endogenous and plasmid-derived IL-22R in lung epithelia, binds the E3 ligase constituent Skp-1, and facilitates ubiquitination of IL-22R in vitro. 0.544 SIGNOR-272427 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 27660409 YES diabetic macular edema gcesareni They differ according to their glucocorticoid-receptor binding affinities (dexamethasone > triamcinolone > fluocinolone) and their lipophilicity (triamcinolone > fluocinolone > dexamethasone), characteristics that may partially explain their relative potencies 0.8 SIGNOR-251694 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT up-regulates activity phosphorylation Tyr418 LSGEDDAyCTFPSRD 9534 BTO:0000298 8700888 YES In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. 0.63 SIGNOR-251340 PIK3C3 protein Q8NEB9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 10698680 NO acerquone Pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1) 0.435 SIGNOR-252633 Guanfacine chemical CHEBI:5558 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258920 TACR3 protein P29371 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256937 CSNK1A1 protein P48729 UNIPROT PRMT1 protein Q99873 UNIPROT up-regulates activity phosphorylation 9606 28943242 YES miannuccelli CSNK1a1 directly bound and phosphorylated PRMT1 to control its genomic targeting to PRMT1-sustained proliferation genes as well as PRMT1-suppressed differentiation genes.|Taken together, these data support a provisional model in which CSNK1a1 directs PRMT1 to genomic targets that promote self-renewal and suppress terminal differentiation.In the context of transcription regulation, PRMT1 has been generally considered as a transcriptional co-activator. 0.2 SIGNOR-279733 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 11158290 YES lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. 0.869 SIGNOR-217403 DOLK protein Q9UPQ8 UNIPROT dolichyl beta-D-mannosyl phosphate smallmolecule CHEBI:17624 ChEBI up-regulates quantity chemical modification -1 16923818 YES lperfetto Dolichol kinase (DK) catalyzes the CTP-dependent phosphorylation of dolichol in the biosynthesis de novo and possibly the recycling of dolichyl monophosphate in yeast and mammals. 0.8 SIGNOR-262567 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 18394876 YES gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. 0.681 SIGNOR-253001 ADX-47273 chemical CID:11383075 PUBCHEM GRM5 protein P41594 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189338 EID1 protein Q9Y6B2 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates activity binding 11073989 YES lperfetto Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. 0.406 SIGNOR-253380 EGFR protein P00533 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000150 22693070 YES lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation. 0.879 SIGNOR-235692 TSHR protein P16473 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0001379 32698392 YES scontino Activation of TSHR and the linked signaling cascades through binding of circulating TSH plays a pivotal role in controlling thyrocyte growth and in regulating thyroid hormone production/secretion. This is executed through switching on different subtypes of G proteins and signaling pathways. Among them, the Gαs- and Gαq-induced cascades are of the greatest importance, as they have been tightly linked to specific intracellular signal transductions downstream of TSHR in response to stimulations 0.56 SIGNOR-267138 PAK1 protein Q13153 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Ser299 KNLGYRDsGYYWEVP 9606 BTO:0000848 15710605 YES lperfetto Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism. 0.267 SIGNOR-236342 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Thr187 KRNTVIGtPFWMAPE 9534 BTO:0004055 12223493 YES lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity. 0.2 SIGNOR-247581 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 YES milica Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling 0.914 SIGNOR-67964 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser161 SPTEDPRsPPACSSS 9606 10330152 YES lperfetto The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a). 0.595 SIGNOR-67520 PCM1 protein Q15154 UNIPROT CEP250 protein Q9BV73 UNIPROT up-regulates relocalization 9606 15659651 YES miannu Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1 0.549 SIGNOR-133334 PRKACA protein P17612 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15328345 YES gcesareni Nedd4-2 was a substrate for phosphorylation by pka in vitro and in cells;three nedd4-2 residues were phosphorylated by pka and were required for camp to inhibit nedd4-2 (relative functional importance ser-327 > ser-221 > thr-246). 0.2 SIGNOR-128429 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates activity binding 10090 BTO:0000165 11282024 YES lperfetto Bmp-4 and gdf-5 are known to bind to activin 0.851 SIGNOR-235376 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 YES gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases. 0.669 SIGNOR-62585 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression 9606 BTO:0001103 20219869 YES apalma Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation. 0.486 SIGNOR-255358 PRKAA2 protein P54646 UNIPROT ACACB protein O00763 UNIPROT down-regulates activity phosphorylation Ser222 PTMRPSMsGLHLVKR 9606 14613924 YES miannu ACCβ(Ser221) is a known target for AMPK in human skeletal muscle 0.648 SIGNOR-250316 MTMR4 protein Q9NYA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 20061380 YES gcesareni Here we demonstrate that myotubularin-related protein 4 0.516 SIGNOR-163034 EREG protein O14944 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates binding 9606 16829981 YES inferred from 70% of family members gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4. 0.894 SIGNOR-269873 veliparib chemical CHEBI:62880 ChEBI PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189183 PRKG1 protein Q13976 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Thr143 RCFTRKYtLPPGVDP 9606 19593530 YES 11383510: to test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization 0.274 SIGNOR-186792 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. 0.75 SIGNOR-236675 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates activity phosphorylation Ser1042 GGMQRKLsVALAFVG 10090 BTO:0000801 12196520 YES miannu Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins. 0.506 SIGNOR-250326 SAAL1 protein Q96ER3 UNIPROT CDK6 protein Q00534 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 30513680 NO Giorgia This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1/SAAL1 siRNA at the post-transcriptional level. The CDK6, expression of which is up-regulated by the SPACIA1/SAAL1 expression, might be a critical factor in the exacerbation of CIA. 0.2 SIGNOR-260386 RPS6KA1 protein Q15418 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 18722121 YES lperfetto Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity 0.459 SIGNOR-217553 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT up-regulates activity phosphorylation Tyr395 CLPGTVEyQVPTSLR 10090 BTO:0000165 20603078 YES miannu Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. 0.723 SIGNOR-273845  AD/b2 integrin complex SIGNOR-C172 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.453 SIGNOR-257716 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr 132 DYHNPGyLVVLPD 9606 29915297 YES Isoform O43561-2 Barakat In the presence of the catalytically inactive LckK273R, the phosphorylation of LAT Y132 and Y191 residues by Zap70K362E were considerably increased 0.769 SIGNOR-274561 ATG12/5/16L1 complex SIGNOR-C109 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates -1 23321721 NO lperfetto Dissecting the role of the Atg12-Atg5-Atg16 complex during autophagosome formation 0.7 SIGNOR-226702 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 YES lperfetto Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. 0.551 SIGNOR-74931 SRC protein P12931 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Tyr325 AISEELPySEYFEYF -1 30317579 YES miannu C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).  0.386 SIGNOR-277484 MAPK1 protein P28482 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr507 GLGENLLtHLPEEIG 9606 BTO:0000007 30865892 YES miannu Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. 0.323 SIGNOR-277442 acetyl-CoA smallmolecule CHEBI:15351 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates activity 9606 10893421 NO Acetyl-CoA carboxylase (ACC) catalyzes the first committed step of the fatty acid synthetic pathway. Although ACC has often been proposed to be a major rate-controlling enzyme of this pathway, no direct tests of this proposal in vivo 0.7 SIGNOR-267383 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 19282669 YES lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.594 SIGNOR-252962 GH1 protein P01241 UNIPROT PRLR protein P16471 UNIPROT up-regulates binding 9606 7984244 YES gcesareni Hprl does not bind to the hgh receptor, but hgh binds to both the hghr and hprlr, and mutagenesis studies have shown that the receptor-binding sites on hgh overlap. 0.776 SIGNOR-35575 MAK protein P20794 UNIPROT MAK protein P20794 UNIPROT up-regulates activity phosphorylation Thr157 LRSQPPYtDYVSTRW 9606 21986944 YES Manara We conclude that dual phosphorylation on the TDY motif is crucial for MAK activity, and that the autokinase activity is required for this phosphorylation 0.2 SIGNOR-260779 FCN2 protein Q15485 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding 9606 BTO:0000392 11907111 YES lperfetto H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP. 0.787 SIGNOR-263411 STXBP1 protein P61764 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity binding 10116 9395480 YES miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. 0.921 SIGNOR-264042 ATF4 protein P18848 UNIPROT NUPR1 protein O60356 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19946894 NO lperfetto Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4. 0.386 SIGNOR-253730 HAUS5 protein O94927 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 YES lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) 0.756 SIGNOR-262317 EGFR protein P00533 UNIPROT AXL protein P30530 UNIPROT up-regulates activity phosphorylation Tyr779 ADCLDGLyALMSRCW 9606 27775700 YES miannuccelli In this study, we have identified for the first time a direct interaction between EGFR and Axl RTKs, with EGF and EGFR induced activation of Axl as a novel signalling pathway to invasion in cancer cells.|The activation of Axl was shown to occur through direct phosphorylation by EGFR of Axl tyrosine 779, one of the key residues within Axl that serves as a multi-substrate docking site for further downstream signalling. 0.431 SIGNOR-279734 EIF2AK2 protein P19525 UNIPROT MAPT protein P10636 UNIPROT up-regulates quantity phosphorylation 9606 32716602 YES miannuccelli Interestingly, PKR phosphorylated tau directly and no detectable labeling occurred when tau was incubated with 32 P\u2010ATP alone (Figure\u00a0 xref right).|PKR kinase directly regulates tau expression and Alzheimer's disease-related tau phosphorylation. 0.2 SIGNOR-279735 FYN protein P06241 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr313 SSEPVGIyQGFEKKT 9606 33995031 YES miannuccelli In conclusion, our in vitro data and previous report ( xref ) demonstrate that Fyn phosphorylation of Y311 on PKC\u03b4 activates the apoptotic signaling cascade in DAergic neurons in response to neurotoxic insults. 0.596 SIGNOR-279737 CSNK2A1 protein P68400 UNIPROT DEK protein P35659 UNIPROT up-regulates phosphorylation Ser32 MPGPREEsEEEEDED 9606 16809543 YES amattioni Dek phosphorylated at serines 19 and 32. Dek and its phosphorylation are required for intron removal 0.35 SIGNOR-147365 MYC protein P01106 UNIPROT HLA-F protein P30511 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8206526 NO miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. 0.2 SIGNOR-254605 DYRK3 protein O43781 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 23415227 YES lperfetto When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40 0.34 SIGNOR-201002 FYN protein P06241 UNIPROT ZDHHC5 protein Q9C0B5 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr533 REPSPVRyDNLSRHI 9606 26334723 YES miannuccelli Our study demonstrates that under basal conditions, PSD-95 and Fyn cooperatively stabilize DHHC5 at the synaptic membrane through Fyn-mediated phosphorylation of DHHC5 at tyrosine residue 533 and the subsequent inhibition of DHHC5 association with endocytic proteins (Fig. 10). 0.388 SIGNOR-279738 GRK2 protein P25098 UNIPROT TP53INP2 protein Q8IXH6 UNIPROT down-regulates activity phosphorylation 9606 27568556 YES miannuccelli In conclusion, experimental results demonstrate that GRK2 chronically downregulates DOR functional competence at the PM in peripheral sensory neurons, as well as peripheral DOR anti-nociception in vivo.|These data demonstrate that BK does not affect GRK2 mediated phosphorylation of DOR at its primary desensitization site. 0.2 SIGNOR-279739 GLI1/GLI2 complex SIGNOR-C450 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 32766732 YES GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells 0.562 SIGNOR-269213 GSK3B protein P49841 UNIPROT CLOCK protein O15516 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 19946213 YES miannuccelli The results showed that recombinant GSK-3\u03b2 can specifically phosphorylate CLOCK and that this phosphorylation is abrogated in the presence of GSK-3 inhibitor BIO ( xref ).|the over-expression of constitutive active GSK-3β increases an unstable phospho-CLOCK while an inactive GSK-3β inhibits phosphorylation 0.341 SIGNOR-279741 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252331 ESR1 protein P03372 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 20682797 NO miannu Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. these data indicate that JMJD2B is a bona fide target of ERα and its expression in ER-positive breast cancer cells is mainly dependent on ERα. 0.605 SIGNOR-263737 SPI1 protein P17947 UNIPROT miR-338 mirna URS000075E706_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 23132946 NO irozzo We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells. 0.4 SIGNOR-255886 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) smallmolecule CHEBI:60110 ChEBI phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI up-regulates quantity precursor of 10090 21641550 YES lperfetto PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. 0.8 SIGNOR-267027 PRKCA protein P17252 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser24 DMKVRKSsTPEEVKK 9606 BTO:0001271 22855535 YES lperfetto Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization 0.2 SIGNOR-198482 edoxaban chemical CHEBI:85973 ChEBI F10 protein P00742 UNIPROT down-regulates activity chemical inhibition -1 20503967 YES Luana Replacing the chloroindole P1 moiety of 100 with a 5-chloropyridin-2-yloxalamide group provided 101 (edoxaban, DU-176b). Compound 101 is a potent inhibitor of human FXa in vitro (FXa Ki = 0.56 nM), with >10 000-fold selectivity against relevant serine proteases, and demonstrated good anticoagulant activity (PT2× = 0.26 μM) and activity in various animal models of thrombosis, with minimal bleeding 0.8 SIGNOR-257845 PPP2CB protein P62714 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity dephosphorylation Thr216 RSSSSEStGTPSNPD 10090 11983168 YES cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells 0.398 SIGNOR-248593 TRIM39 protein Q9HCM9 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002552 23213260 YES miannu Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. 0.352 SIGNOR-272020 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT up-regulates transcriptional regulation 10116 8943212 NO fspada We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells 0.683 SIGNOR-210149 ANXA1 protein P04083 UNIPROT FPR3 protein P25089 UNIPROT up-regulates activity binding 9606 BTO:0000007 15187149 YES We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2. 0.617 SIGNOR-259438 MUTYH protein Q9UIF7 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275716 CHEK2 protein O96017 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 12835754 YES lperfetto Activated chk2 in turn phosphorylates cdc25c at serine-216 contributing to the g2/m checkpoints. Cds1 phosphorylates and inactivates cdc25 in vitro|CDC25C is phosphorylated on Ser 216 throughout interphase, but not in mitosis. This creates a binding site for 14‐3‐3 proteins | It has been suggested that 14‐3‐3 protein binding is responsible for retaining Cdc25C in the cytoplasm during interphase, thereby contributing to the prevention of premature initiation of mitotic events 0.856 SIGNOR-102779 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 YES Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs 0.75 SIGNOR-258993 NFE2 protein Q16621 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 NO Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. 0.527 SIGNOR-251841 MAPK1 protein P28482 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser643 KILIASPsPTHIHKE 9606 BTO:0000567 18519666 YES lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ 0.585 SIGNOR-178727 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 7493944 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.2 SIGNOR-246256 vorinostat chemical CHEBI:45716 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257917 WWP2 protein O00308 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 19274063 YES lperfetto WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells|Here, we report that human WWP2, an E3 ubiquitin (Ub)-protein ligase, interacts with OCT4 specifically through its WW domain and enhances Ub modification of OCT4 both in vitro and in vivo. 0.454 SIGNOR-268850 ARAP3 protein Q8WWN8 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.519 SIGNOR-260457 ZW10 protein O43264 UNIPROT DCTN2 protein Q13561 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 SIGNOR-C357 20462495 YES lperfetto ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores 0.687 SIGNOR-265016 DUSP10 protein Q9Y6W6 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 26305722 YES miannu The inactivation of IRF3 by MKP5 is dependent on MKP5 phosphatase activity or its binding to IRF3.|This is confirmed since MKP5 phosphatasedeficient mutant is unable to dephosphorylate IRF3 and MKP5 mutant lacking IRF3 binding motifs fails to suppress IRF3 nuclear translocation upon virus infection. 0.2 SIGNOR-277146 PIM1 protein P11309 UNIPROT RPS19 protein P39019 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 16266891 YES gcesareni The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay. 0.439 SIGNOR-141411 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257914 GCG protein P01275-PRO_0000011258 UNIPROT GLP1R protein P43220 UNIPROT up-regulates activity binding 9606 BTO:0000783 35065096 YES miannu GLP-1 and GIP exert their physiological actions via stimulation of the two G protein-coupled receptors (GPCRs): the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR), respectively. 0.782 SIGNOR-278133 POU2F1 protein P14859 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 NO miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 0.2 SIGNOR-254432 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 BTO:0000007 22863277 NO milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. 0.8 SIGNOR-198553 ISYNA1 protein Q9NPH2 UNIPROT 1D-myo-inositol 1-phosphate smallmolecule CHEBI:18297 ChEBI up-regulates quantity chemical modification 9606 15464731 YES lperfetto Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate. 0.8 SIGNOR-254131 COPS8 protein Q99627 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.928 SIGNOR-270770 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258844 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 BTO:0000007 28630438 YES miannu NUP98-HOXA9 has an activator-repressor role in transcriptional regulation driven by p300 and HDAC1 interactions. The chromosomal translocation t(7;11)(p15, p15), encoding the fusion protein NUP98-HOXA9 (NHA9), is a rare poor risk cytogenetic event in AML associated with a particularly poor prognosis.In summary, NHA9 deregulates the expression of key leukemic genes, including MEIS1-HOXA9-PBX3 complex, through the enhancer binding and the direct interaction of the fusion protein with HDAC and p300 transcriptional regulators. 0.2 SIGNOR-261498 SEPTIN9 protein Q9UHD8 UNIPROT ARHGEF18 protein Q6ZSZ5 UNIPROT down-regulates binding 9606 15558029 YES miannu In transient expression analyses, sept9b inhibited sa-rhogef-dependent rho activation in cos7 and hela cells. 0.2 SIGNOR-131184 RNF8 protein O76064 UNIPROT H1-2 protein P16403 UNIPROT down-regulates polyubiquitination 9606 BTO:0000815 30517763 YES miannu ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. 0.2 SIGNOR-272928 PRKCQ protein Q04759 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Ser323 LCLQKDPsKRPTAAE -1 14988727 YES miannu Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. 0.486 SIGNOR-276007 PP2 chemical CHEBI:78331 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 11782488 YES gcesareni Herbimycin a and pp2, specific inhibitors of src family kinases, both inhibited h2o2-mediated c-src and bmk1 activation. 0.8 SIGNOR-113776 DUSP7 protein Q16829 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 20626350 YES gcesareni The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues 0.657 SIGNOR-166577 MAPK8IP1 protein Q9UQF2 UNIPROT MAP3K12 protein Q12852 UNIPROT down-regulates binding 9606 11432832 YES gcesareni Jip inhibits dlk dimerization. 0.517 SIGNOR-109046 JNK proteinfamily SIGNOR-PF15 SIGNOR ANXA3 protein P12429 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000608 26095609 NO miannu ANXA3 Induces a Feed-Forward Loop that Is Mediated by the MKK4/JNK Signaling Cascade. To substantiate the importance of the JNK/AP-1 pathway in ANXA3-driven HCC, we performed rescue experiments using the JNK-specific inhibitor (JNKi) SP600125. JNKi suppressed the oncogenic properties conferred by ANXA3 overexpression, as evidenced by the diminished abilities of HCC cells to form colonies, migrate, invade, induce angiogenesis, form hepatospheres, and resist apoptosis and chemotherapy (Figures 6F–6J). Interestingly, treatment of parental HCC cells or HCC cells overexpressing ANXA3 with JNKi resulted in not only a reduction in JNK activity and modulation of downstream target genes (c-MYC and p21) but also a marked decrease in ANXA3 expression, suggesting that ANXA3 induces a feed-forward loop that is mediated by MKK4/JNK signaling (Figures 6K–6L). 0.2 SIGNOR-262216 HTR3D protein Q70Z44 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 NO miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  0.7 SIGNOR-264319 FYN protein P06241 UNIPROT CD79B protein P40259 UNIPROT up-regulates activity phosphorylation Tyr196 GMEEDHTyEGLDIDQ -1 9531288 YES CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b 0.671 SIGNOR-251154 KCTD11 protein Q693B1 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity 15249678 NO In absence of Hh lperfetto REN(KCTD11) seems to inhibit medulloblastoma growth by negatively regulating the Hedgehog pathway because it antagonizes the Gli-mediated transactivation of Hedgehog target genes, by affecting Gli1 nuclear transfer, and its growth inhibitory activity is impaired by Gli1 inactivation. 0.352 SIGNOR-249592 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. 0.64 SIGNOR-164416 ACAN protein P16112 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 9606 BTO:0003858 16051604 YES lperfetto Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation. 0.319 SIGNOR-266988 DUSP26 protein Q9BV47 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity dephosphorylation Ser194 QNRSGAMsPMSWNSD 9606 24548998 YES lperfetto This multi-functionality of fadd may depend primarily on its subcellular location. Fadd shuttles between the cytosol and the nucleus and this signal is unclear;however, fadd trafficking requires phosphorylation of the protein on ser194dusp26 suppresses cell proliferation by fadd dephosphorylation 0.367 SIGNOR-204559 PPM1A protein P35813 UNIPROT IKBKE protein Q14164 UNIPROT down-regulates activity dephosphorylation Ser172 DDDEKFVsVYGTEEY 9606 27419230 YES miannu PPM1A directly dephosphorylates both MAVS and TBK1 and IKKepsilon.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon. 0.28 SIGNOR-277072 MECP2 protein P51608 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0004102 18952054 YES Luana The interaction of MeCP2 with the 2BI3 and 2BI5 sites was strikingly reduced in neurons maintained in the presence of TTX (Fig. 2C). This result is consistent with the classical view of MeCP2 as a general transcriptional repressor, in that the reduced association leads to increased expression of NR2B. 0.35 SIGNOR-264685 RIPK1 protein Q13546 UNIPROT Necrosis phenotype SIGNOR-PH3 SIGNOR up-regulates 9606 14965271 NO amattioni Fas-induced necrosis requires rip 0.7 SIGNOR-121901 ITCH protein Q96J02 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 18334649 YES miannu  Itch catalyzed ubiquitination of ErbB4 CYT-1, promoted its localization into intracellular vesicles, and stimulated degradation of ErbB4 CYT-1 0.605 SIGNOR-271416 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 8663074 YES gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily. 0.66 SIGNOR-42390 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser537 DNSMSVPsPTSATKT 10090 BTO:0000964 34048556 YES lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. 0.258 SIGNOR-268338 creatine smallmolecule CHEBI:16919 ChEBI CKM protein P06732 UNIPROT up-regulates activity chemical activation 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265810 CHKA protein P35790 UNIPROT choline smallmolecule CHEBI:15354 ChEBI down-regulates quantity chemical modification 27149373 YES lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes 0.8 SIGNOR-275637 PRKN protein O60260 UNIPROT SYT11 protein Q9BT88 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 12925569 YES miannu Parkin binds to the C2A and C2B domains of synaptotagmin XI resulting in the polyubiquitination of synaptotagmin XI. Parkin-mediated ubiquitination also enhances the turnover of sytXI. 0.2 SIGNOR-272672 IFNA1 protein P01562 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity binding 9534 BTO:0004055 11278538 YES lperfetto Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.614 SIGNOR-219298 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI UTY protein O14607 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273460 GRPR protein P30550 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257159 Ub:E2 complex SIGNOR-C497 SIGNOR RNF6 protein Q9Y252 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271032 EMSY protein Q7Z589 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity binding 9606 BTO:0000567 14651845 YES miannu The EMSY protein interacts precisely with a highly conserved transactivating region at the N terminus of the breast cancer protein BRCA2, and has endogenous transcriptional repressor activity when recruited to a high basal promoter. We have suggested that the independent activation domain of BRCA2 within exon 3 might have some role in transcription (Milner et al., 1997). The identification of the repressor protein EMSY, which binds and silences this domain, is consistent with such a function. 0.2 SIGNOR-263915 DPYSL5 protein Q9BPU6 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity binding 9606 BTO:0000938 25040932 YES lperfetto The studies on CRMP5 function show that, by interacting with tubulin and MAP2, this protein inhibits neurite growth especially at the dendritic level and restricts the promotional effect of CRMP2 on axon and dendrite growth 0.2 SIGNOR-264836 SRC protein P12931 UNIPROT SDHA protein P31040 UNIPROT up-regulates activity phosphorylation Tyr215 SLRYDTSyFVEYFAL 9606 BTO:0001583 22823520 YES miannu Phosphorylation-site analysis selects c-Src targets, including NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) at Tyr(193) of respiratory complex I and SDHA (succinate dehydrogenase A) at Tyr(215) of complex II. The phosphorylation of these sites by c-Src is supported by an in vivo assay using cells expressing their phosphorylation-defective mutants.  0.267 SIGNOR-276420 CCNO protein P22674 UNIPROT CDK13 protein Q14004 UNIPROT up-regulates activity binding 37197505 YES lperfetto Cyclin O promotes lung cancer progression and cetuximab resistance via cell cycle regulation and CDK13 interaction|CCNO promoted tumor cell proliferation and survival in vivo via CDK13| 0.271 SIGNOR-275618 ABL1 protein P00519 UNIPROT AHSA1 protein O95433 UNIPROT up-regulates activity phosphorylation Tyr223 LTSPEELyRVFTTQE 9606 26235616 YES Manara Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity 0.251 SIGNOR-260938 SOCS3 protein O14543 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates 9606 16543409 NO lperfetto Suppressor of cytokine signaling (SOCS)-3 was shown to inhibit IL-1-induced transcription and activation of NFkappaB and the MAPKs JNK and p38, but the mechanism is unknown 0.391 SIGNOR-253052 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR -1 9614189 YES miannu S214 can be rapidly and selectively phosphorylated in vitro by PKA, and this single site strongly affects tau's ability to bind and stabilize microtubules. 0.434 SIGNOR-250006 PTPRF protein P10586 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 11121408 YES gcesareni Here we show that lar reduces the constitutive tyrosine autophosphorylation and kinase activity of ret-men2a but not ret-men2b, accompanying a significant decrease of phosphorylation of phospholipase cgamma, akt, and erk1/2. 0.2 SIGNOR-85166 CIT protein O14578 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity binding 9606 BTO:0000565 16431929 YES miannu We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase. 0.722 SIGNOR-266424 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser360 PRIFQGYsFVAPSIL 9606 BTO:0000567 10806207 YES llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. 0.603 SIGNOR-77216 Bombesin smallmolecule CHEBI:80229 ChEBI GRPR protein P30550 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257509 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK2 protein Q13002 UNIPROT up-regulates activity chemical activation 9606 27586965 YES miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors 0.8 SIGNOR-264471 PTP4A2 protein Q12974 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation 9606 14643450 YES amattioni Cells overexpressing prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity 0.2 SIGNOR-119478 RHOH protein Q15669 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 BTO:0000661 17028588 YES irozzo These findings suggest that RhoH is a critical regulator of thymocyte development and TCR signaling by mediating recruitment and activation of Zap70. 0.459 SIGNOR-259084 SMARCA2 protein P51531 UNIPROT SMARCC2 protein Q8TAQ2 UNIPROT up-regulates binding 9606 10078207 YES miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. 0.9 SIGNOR-65435 SFPQ protein P23246 UNIPROT NONO/SFPQ complex SIGNOR-C62 SIGNOR form complex binding 9606 9756848 YES miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i 0.711 SIGNOR-60560 PIK3CG protein P48736 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser39 FPASQTPsKPASADG 9606 27169346 YES miannuccelli 3.3 Phosphorylation of Src on serine residue 70 (S70) by PI3Kgamma modulates Src kinase activity.|These data suggest that S70 phosphorylation is the likely amino acid residue critical for PI3Kgamma mediated Src activation (XREF_FIG).|Importantly, reduced phosphorylation was observed for the S39A and S70A Src mutants suggesting that PI3Kgamma may phosphorylate Src at residues S39 and S70 in vitro (XREF_FIG). 0.365 SIGNOR-279748 PIM1 protein P11309 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity phosphorylation Thr210 YDGERKKtLCGTPNY 9606 24771642 YES miannuccelli This data strongly indicates that Pim1 phosphorylates PLK1 at threonine 210, a site previously reported to be phosphorylated by aurora A kinase during mitosis. 0.294 SIGNOR-279749 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258711 ofatumumab antibody DB06650 DRUGBANK MS4A1 protein P11836 UNIPROT down-regulates activity binding 9606 BTO:0001546 28580841 YES miannu Ofatumumab is a human IgG1κ monoclonal antibody that binds to a membrane-proximal epitope of CD20 molecule expressed on the surface of B lymphocytes. Ofatumumab, the second-generation anti-CD20 antibody, induces cell lysis through complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity. Ofatumumab is approved as monotherapy and in combination with chlorambucil for the treatment of fludarabine- and alemtuzumab-refractory CLL patients and previously untreated CLL patients, respectively. 0.4 SIGNOR-259897 potassium(1+) smallmolecule CHEBI:29103 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 11506885 NO miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height 0.7 SIGNOR-265590 SATB1 protein Q01826 UNIPROT HSPA6 protein P17066 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 17343824 NO miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 0.2 SIGNOR-255134 NFIX protein Q14938 UNIPROT RBFOX3 protein A6NFN3 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268913 PRKACA protein P17612 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 30017192 YES miannu In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia. 0.267 SIGNOR-259413 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC3 protein P33778 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271983 EGFR protein P00533 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr5 yLDPNLNH 9606 20802513 YES llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. 0.594 SIGNOR-167650 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser405 VTVSRASsSRSVRTT 9606 BTO:0001271 8034666 YES lperfetto Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo. 0.498 SIGNOR-248912 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation -1 22306293 YES inferred from family member PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In¬†vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor 0.2 SIGNOR-270312 CREBRF protein Q8IUR6 UNIPROT HERPUD1 protein Q15011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16940180 YES Luana Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element. 0.2 SIGNOR-261575 mTORC2 complex SIGNOR-C2 SIGNOR FBXW8 protein Q8N3Y1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser85 DVASRSRsPLAREGA 10090 BTO:0002572 23142081 YES miannu MTORC2 stabilizes Fbw8 by phosphorylation at Ser86 0.264 SIGNOR-271940 EP300 protein Q09472 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity acetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 YES gcesareni Using acetylation assays, p300 was found to effectively acetylate RelA/p65 across the amino-acid region containing 1€“317 0.821 SIGNOR-238778 PKN1 protein Q16512 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation 9606 17251915 YES gcesareni Phosphorylation of mltkalpha by pknalpha enhances its kinase activity 0.2 SIGNOR-152768 SB-202190 chemical CHEBI:79090 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206697 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM3A protein Q9Y4C1 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273479 CDK1 protein P06493 UNIPROT TOB2 protein Q14106 UNIPROT up-regulates activity phosphorylation Ser254 PAPQSQLsPNAKEFV -1 32404348 YES done miannu Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. 0.2 SIGNOR-273591 ASXL1 protein Q8IXJ9 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22897849 NO miannu ASXL1 siRNA in human primary CD34+ cells form cord blood results in upregulation of HOXA5 and HOXA9 with ASXL1 knockdown (KD) as revealed by quantitative real-time PCR 0.435 SIGNOR-256127 FBXW7 protein Q969H0 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15546612 YES lperfetto Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. 0.614 SIGNOR-130706 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT up-regulates activity binding 9606 9732876 YES lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos 0.712 SIGNOR-229545 TIMM9 protein Q9Y5J7 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 YES lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). 0.573 SIGNOR-267702 BMI1 protein P35226 UNIPROT NDN protein Q99608 UNIPROT down-regulates 9606 BTO:0000007 24392140 NO lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, whereas Bmi1 counteracts necdin-mediated repression of E2F1-dependent Cdk1 promoter activity. 0.252 SIGNOR-253386 ACTL6A protein O96019 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.65 SIGNOR-269295 CDK2 protein P24941 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 22369944 YES fspada Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. 0.395 SIGNOR-196372 SLITRK1 protein Q96PX8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 19640509 NO miannu Phosphorylation of SLITRK1 on the CK2 phosphorylation site modulated SLITRK1-enhanced neurite outgrowth. 0.7 SIGNOR-273658 ATF4 protein P18848 UNIPROT IARS1 protein P41252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269427 SUN2 protein Q9UH99 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity binding 9606 BTO:0000567 10818110 YES Sara Rab5ip represents a novel rab5 interacting protein that may function on endocytic vesicles as a receptor for rab5-GDP and participate in the activation of rab5 0.421 SIGNOR-261309 NYYJKMXNVNFOFQ-MHZLTWQESA-N chemical CID:9829836 PUBCHEM ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana There were several β3-selective compounds (e.g. AZ 40140d, L 755507, L 748337 and TAK 677) 0.8 SIGNOR-257856 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 YES gcesareni Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling. 0.441 SIGNOR-48677 CSNK1A1 protein P48729 UNIPROT FOXG1 protein P55316 UNIPROT up-regulates phosphorylation Ser19 MIPKSSFsINSLVPE 9606 BTO:0000938 BTO:0000142 17435750 YES llicata Cki phosphorylation of ser 19 of foxg1 promotes nuclear import 0.2 SIGNOR-154386 isoleucine smallmolecule CHEBI:24898 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264749 AURKA protein O14965 UNIPROT TPX2 protein Q9ULW0 UNIPROT up-regulates activity phosphorylation Ser125 QRRSLRLsAQKDLEQ 9606 BTO:0000567 26240182 YES lperfetto Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells 0.965 SIGNOR-265088 RNF5 protein Q99942 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates quantity by destabilization ubiquitination Lys150 EISAVCEkGNFNVAH 9606 BTO:0000007 19285439 YES miannu The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection. 0.2 SIGNOR-271484 episterol ester smallmolecule CHEBI:52393 ChEBI CNR1 protein P21554 UNIPROT up-regulates activity chemical activation 9606 BTO:0000142 29751000 YES miannu 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. 0.8 SIGNOR-264266 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9534 BTO:0004055 8052307 YES lperfetto In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k 0.924 SIGNOR-236443 KDR protein P35968 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 BTO:0001949 11278468 YES Gianni 0.503 SIGNOR-261917 AREG protein P15514 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation 9606 7679104 YES gcesareni Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor 0.626 SIGNOR-31199 CDK2 protein P24941 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 17601773 YES fspada Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. 0.395 SIGNOR-156509 KLKB1 protein P03952 UNIPROT KNG1 protein P01042 UNIPROT up-regulates activity cleavage Arg389 PPGFSPFrSSRIGEI 9606 BTO:0000131 cleavage:Arg390 CTTKTSTrIVGGTNS 28966616 YES lperfetto Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1). 0.778 SIGNOR-263548 WNT11 protein O96014 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Musk has an extracellular region with homology to the frizzled crd,binding of which by wnt11 stimulates a pcp-like pathway during neuromuscolar development. Here, we show that in vivo, wnt11r and wnt4a initiate musk translocation from muscle membranes to recycling endosomes we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase 0.457 SIGNOR-199641 BTRC protein Q9Y297 UNIPROT ATF2 protein P15336 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 33861966 YES miannu Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). 0.2 SIGNOR-267830 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr334 QAEEEAVyEEPPEQE 9606 BTO:0000782 14557276 YES lperfetto We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling. 0.639 SIGNOR-118691 MECP2 protein P51608 UNIPROT RELN protein P78509 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 NO miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 0.38 SIGNOR-254578 RUNX1 protein Q01196 UNIPROT ANKRD26 protein Q9UPS8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000843 24430186 YES lperfetto In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs. 0.2 SIGNOR-266069 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189993 Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 15776021 NO miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. 0.7 SIGNOR-263878 PLK1 protein P53350 UNIPROT MAP9 protein Q49MG5 UNIPROT up-regulates phosphorylation Ser289 SDENKENsFSADHVT 9606 20615875 YES lperfetto We also demonstrate that asap is a novel substrate of plk1 phosphorylation and have identified serine 289 as the major phosphorylation site by plk1 in vivo. Asap phosphorylated on serine 289 is localized to centrosomes during mitosis, but this phosphorylation is not required for its plk1-dependent localization at the spindle poles. We show that phosphorylated asap on serine 289 contributes to spindle pole stability in a microtubule-dependent manner 0.276 SIGNOR-166564 NHS protein Q6T4R5 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR up-regulates activity relocalization 9606 20332100 YES miannu Excessive cell spreading and lamellipod extension as a result of NHS knockdown is likely to be a result of loss of WAVE complex regulation, leading to overactive WAVE activity or a dysregulation of nascent focal adhesions in lamellipodia.WAVE and NHS protein partners Abi1 and HSPC300, and the p34 subunit of the Arp2/3 complex, consistently localized at the edges of cells treated with NHS siRNA, independent of EGF stimulation and WAVE complex activation. These data show that localization of Abi1 and HSPC300 was altered in the absence of NHS. 0.2 SIGNOR-253577 CAMK2G protein Q13555 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser19 KGFRRAVsELDAKQA 1680128 YES llicata  In both isoforms, Ser-40 was found to be phosphorylated by PKA, and Ser-19 and Ser-40 were found to be phosphorylated by CaM-PK II. The putative phosphorylation site generated by alternative splicing (Ser-31) was phosphorylated specifically by CaM-PK II in TH-2 only. | Unlike TH-1, phosphorylation of TH-2 by CaM-PK II resulted in an increase of the Ki value for dopamine. 0.333 SIGNOR-250709 PTEN protein P60484 UNIPROT GLI1 protein P08151 UNIPROT down-regulates 9606 17157787 NO PTEN is a suppressor of RAS-AKT function gcesareni Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code 0.354 SIGNOR-151134 ramipril chemical CHEBI:8774 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 6097265 YES miannu 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl] - (1S,3S,5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (Hoe 498) is a new, very effective and long lasting, nonsulfhydryl angiotensin I converting enzyme inhibitor. 0.8 SIGNOR-258400 DDC protein P20711 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal 0.8 SIGNOR-263992 INS protein P01308 UNIPROT COMT protein P21964 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000542 17612537 NO Regulation of expression miannu Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA. 0.321 SIGNOR-251961 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194631 miR-370-3p mirna URS00004900F1_9606 RNAcentral WNT7A protein O00755 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003137 29549123 YES Marta Tosoni Of note, the microRNA miR-370-3p directly repressed Wnt7a expression and thereby suppressed UBC cell invasion, which was partially restored by Wnt7a overexpression. 0.4 SIGNOR-278866 WNT7A protein O00755 UNIPROT MMP10 protein P09238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003137 29549123 YES Marta Tosoni We first proved that Wnt7a activated the canonical Wnt pathway through direct regulation of the MMP10 gene. 0.2 SIGNOR-278867 WNT7A protein O00755 UNIPROT MMP1 protein P03956 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003137 29549123 YES Marta Tosoni Because MMP1 is also another direct target of the canonical Wnt pathway (22), Wnt7a overexpression upregulated MMP1/10 to degrade the extracellular matrix and to facilitate UBC cell invasion. 0.262 SIGNOR-278868 GRK6 protein P43250 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 30936203 NO Marta Tosoni Taken together, our data suggest that GRK6 contributes to CXCR4 degradation by facilitating ubiquitination of CXCR4. 0.562 SIGNOR-278869 NPFFR2 protein Q9Y5X5 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0000608 36497331 NO Marta Tosoni NPFFR2 activation by the NPFF peptide also increased cell migration in SNU739 cells. 0.7 SIGNOR-278870 NPFFR2 protein Q9Y5X5 UNIPROT Cell_invasion phenotype SIGNOR-PH226 SIGNOR up-regulates 9606 BTO:0000608 36497331 NO Marta Tosoni NPFFR2 Increases Invasiveness and Migration in HCC Cancer Cells 0.7 SIGNOR-278871 LPAR6 protein P43657 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity binding 9606 BTO:0000578 23182454 YES Marta Tosoni LPAR1 is reported to associate with Gia,G12/13a,orGqa; LPAR3 with Gia or Gqa; and LPAR6 withGia,G12/13a,orGsa. 0.322 SIGNOR-278872 LPAR6 protein P43657 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000578 23182454 YES Marta Tosoni LPAR1 is reported to associate with Gia,G12/13a,orGqa; LPAR3 with Gia or Gqa; and LPAR6 withGia,G12/13a,orGsa. 0.322 SIGNOR-278873 WNT7A protein O00755 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000972 31886205 NO Marta Tosoni These results suggest that Wnt7a represses growth of liver cancer Hep3B cells. 0.7 SIGNOR-278874 WNT7A protein O00755 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 9606 BTO:0000972 31886205 NO Marta Tosoni Wnt7a Protein Inhibits Migration of HCC Cells by Downregulating EMT 0.7 SIGNOR-278875 GNAI1 protein P63096 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR down-regulates 9606 BTO:0003191 23691483 YES Marta Tosoni GNAI1 can signifi cantly inhibit the migration and metastasis of HCC cells. 0.7 SIGNOR-278877 PPARGC1A protein Q9UBK2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates 9606 19491292 NO gcesareni Nuclear pgc-1alpha and foxo3a respond in a reciprocal manner following aicar treatment. 0.579 SIGNOR-252970 PRKCZ protein Q05513 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser144 GDVGALEsLRGNADL 9606 16287866 YES gcesareni Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets ser144 is the atypical protein kinase c isoform zeta (pkczeta). 0.349 SIGNOR-141629 BBOX1 protein O75936 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 11802770 YES miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. 0.8 SIGNOR-269698 vatalanib chemical CHEBI:90620 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207648 CEBPB protein P17676 UNIPROT PCK2 protein Q16822 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000608 8093246 NO miannu C/EBP beta can regulate PEPCK gene transcription by acting through the CRE and that C/EBP beta, together with CREB, may contribute to the cAMP responsiveness of the PEPCK promoter. 0.327 SIGNOR-253773 GNAO1 protein P09471 UNIPROT CREB1 protein P16220 UNIPROT down-regulates 9606 BTO:0006001 39580518 NO Marta Tosoni These data demonstrate that GNAO1 overexpression decreases CREB protein expression 0.247 SIGNOR-278886 HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates activity binding -1 37450419 YES Marta Tosoni Activation of MET by HGF. MET and HGF form the asymmetric 2 : 2 complex. The dimeric METundergoes autophosphorylation and activates downstream signaling pathways, leading to cellular responses 0.928 SIGNOR-278887 GNAO1 protein P09471 UNIPROT TRIM21 protein P19474 UNIPROT down-regulates 9606 BTO:0006001 39580518 YES Marta Tosoni Mechanistically, GNAO1 recruited TRIM21 and facilitated TRIM21-mediated ubiquitination.  0.2 SIGNOR-278888 PTK2 protein Q05397 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Tyr666 GWMEDYDyVHLQGKE 11604500 YES lperfetto FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD. 0.81 SIGNOR-249112 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 17151142 NO [...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation 0.372 SIGNOR-253600 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid chemical CHEBI:94640 ChEBI GRM3 protein Q14832 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193772 FOXO proteinfamily SIGNOR-PF27 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity transcriptional regulation 10090 24749067 NO gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. 0.2 SIGNOR-254306 LCK protein P06239 UNIPROT PRKCQ protein Q04759 UNIPROT unknown phosphorylation Tyr90 SETTVELySLAERCR 9606 10652356 YES llicata Tyrosine 90 (tyr-90) in the regulatory domain of pkctheta was identified as the major phosphorylation site by lck. 0.566 SIGNOR-74574 Melanin-concentrating hormone smallmolecule CHEBI:80254 ChEBI MCHR2 protein Q969V1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257541 Immune_response phenotype SIGNOR-PH17 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 NO miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. 0.7 SIGNOR-261035 F2RL2 protein O00254 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256904 PRKCA protein P17252 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity phosphorylation Ser18 KRRRTGGsLRGNPSS 9606 BTO:0000567 28850619 YES miannu Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation. 0.345 SIGNOR-277249 hsa-miR-127-5p mirna URS00000A33DB_9606 RNAcentral WNT7A protein O00755 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 BTO:0004828 30867752 YES Marta Tosoni The results indicated that miR-127 inhibited GC progression by upregulating Wnt7a expression. 0.4 SIGNOR-278889 TSHB protein P01222 UNIPROT TSH complex SIGNOR-C412 SIGNOR form complex binding 9606 BTO:0001379 8196184 YES scontino TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors. 0.68 SIGNOR-267047 OTX1 protein P32242 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation -1 18849347 NO miannu Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. 0.307 SIGNOR-254887 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000222 BTO:0000887;BTO:0001103 16611834 YES gcesareni Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta. 0.645 SIGNOR-146105 GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 YES gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required 0.596 SIGNOR-37973 PRKG1 protein Q13976 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser24 APIRRRSsNYRAYAT 9606 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.358 SIGNOR-134644 OPRM1 protein P35372 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.639 SIGNOR-256990 BMP7 protein P18075 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 9748228 YES acerquone We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes. 0.545 SIGNOR-60240 ERBB2 protein P04626 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 8816440 YES gcesareni Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3. 0.613 SIGNOR-147838 USP9X protein Q93008 UNIPROT WT1 protein P19544 UNIPROT up-regulates quantity by stabilization deubiquitination 32152317 YES lperfetto Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. 0.2 SIGNOR-275614 HDAC7 protein Q8WUI4 UNIPROT PLAGL2 protein Q9UPG8 UNIPROT down-regulates deacetylation 9606 16207715 YES miannu Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7. 0.258 SIGNOR-140953 UNII-XH2662798I chemical CID:16156006 PUBCHEM H3-3A protein P84243 UNIPROT down-regulates 9606 20068082 NO gcesareni Pf-00477736 also significantly enhances docetaxel efficacy in vitro and in vivo, in association with decreased cdc25c cytoplasmic phosphorylation (ser216) and histone h3 phosphorylation (ser10)(42). 0.8 SIGNOR-163130 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 8816480 YES lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 0.713 SIGNOR-235742 CDK5 protein Q00535 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 17202132 YES gcesareni We observed that phosphorylation of protein phosphatase 1 (PP1) on Thr320 is reduced in brain extracts from Egr-1-/- mice, indicating that a kinase downstream of Egr-1 phosphorylates PP1. In HEK 293 cells co-transfected with PP1 and Cdk5, Cdk5 phosphorylates PP1. In vitro, Cdk5 purified from bovine brain phosphorylates bacterially expressed recombinant PP1 0.395 SIGNOR-151803 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Thr523 AGSTDENtDSEEHQE 9606 BTO:0000567 15367657 YES llicata XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1. 0.461 SIGNOR-251052 FOXA1 protein P55317 UNIPROT HSPA1B protein P0DMV9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 19486887 NO miannu The results showed overexpression of Foxa1 promoted the expression of HSP72, while Foxa1 depletion, induced by antisense oligonucleotides, decreased the expression of HSP72 in MCF-7 cells under normal and heat stress condition. 0.2 SIGNOR-254165 MED21 protein Q13503 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.813 SIGNOR-266678 hsa-miR-9-5p mirna URS00004208C5_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003960 24170200 YES The miR-9-mediated silencing of CXCR4 led to the inactivation of the p38 MAPK pathway. 0.4 SIGNOR-277951 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9122197 NO gcesareni P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis 0.752 SIGNOR-47541 CREM protein Q03060 UNIPROT IL2 protein P60568 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 12626549 YES Luana In this study we show that CREM is transcriptionally induced in T cells following stimulation through CD3 and CD28, binds to the IL-2 promoter in vivo, and suppresses IL-2 production. 0.482 SIGNOR-261576 RAC1 protein P63000 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 YES gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. 0.75 SIGNOR-248250 MKRN4P protein Q13434 UNIPROT MAP4K3 protein Q8IVH8 UNIPROT down-regulates quantity ubiquitination Lys650 PVAIPAHkLPDRILP 9606 34610951 YES miannu MKRN4 ubiquitinated GLK at Lys650 residue.|Remarkably, MKRN4 overexpression induced GLK protein degradation in HEK293T cells and Jurkat T cells (figure 5A and B). 0.2 SIGNOR-278658 JAK3 protein P52333 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Tyr415 ALGINSGySKRALML 9606 20176813 YES miannu We identified three kinases capable of phosphorylating pld2 in vitro-epidermal growth factor receptor (egfr), jak3, and src (with jak3 reported for the first time in this study)-that phosphorylate an inhibitory, an activator, and an ambivalent (one that can yield either effect) site, respectively. Mass spectrometry analyses indicated the target of each of these kinases as y(296) for egfr, y(415) for jak3, and y(511) for src. 0.407 SIGNOR-163858 SATB1 protein Q01826 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000725 23563689 NO miannu Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc 0.336 SIGNOR-224835 MTOR protein P42345 UNIPROT EIF4EBP3 protein O60516 UNIPROT up-regulates phosphorylation 9606 14967450 YES gcesareni While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase. 0.358 SIGNOR-122035 UNG protein P13051 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275711 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT up-regulates quantity deubiquitination 9606 BTO:0003704 27302062 YES Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes. 0.451 SIGNOR-266905 EFR3A protein Q14156 UNIPROT KRAS protein P01116 UNIPROT up-regulates quantity binding 9606 BTO:0000007 34504076 YES miannu EFR3A directly binds to active KRAS through its C-terminus. EFR3A promotes the localization and nanoclustering of KRAS at the plasma membrane. 0.2 SIGNOR-269094 Monobutylphthalate chemical CHEBI:88522 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 BTO:0000816 16326050 YES miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast 0.8 SIGNOR-268750 WNT8A protein Q9H1J5 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.62 SIGNOR-131984 HTR1D protein P28221 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.374 SIGNOR-257000 VAMP8 protein Q9BV40 UNIPROT STX17-VAMP8 SNARE complex complex SIGNOR-C551 SIGNOR form complex binding 9606 BTO:0000007 23217709 YES miannu Here, we identify syntaxin 17 (Stx17) as the autophagosomal SNARE required for fusion with the endosome/lysosome. Stx17 localizes to the outer membrane of completed autophagosomes but not to the isolation membrane (unclosed intermediate structures); for this reason, the lysosome does not fuse with the isolation membrane. Stx17 interacts with SNAP-29 and the endosomal/lysosomal SNARE VAMP8. 0.92 SIGNOR-273711 SYVN1 protein Q86TM6 UNIPROT SERPINI1 protein Q99574 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21507957 YES miannu In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. 0.2 SIGNOR-272757 SOD1 protein P00441 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity binding 9606 BTO:0001279 15233914 YES P00441:p.Gly94Ala (mutation disrupting interaction) Familial amyotrophic lateral sclerosis (ALS)-linked mutations in the copper-zinc superoxide dismutase (SOD1) gene cause motor neuron death in about 3% of ALS cases. While the wild-type (wt) protein is anti-apoptotic, mutant SOD1 promotes apoptosis.|We now demonstrate that both wt and mutant SOD1 bind the anti-apoptotic protein Bcl-2, providing evidence of a direct link between SOD1 and an apoptotic pathway. This interaction is evident in vitro and in vivo in mouse and human spinal cord.|These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein. 0.506 SIGNOR-262799 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 8846788 YES gcesareni However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. 0.511 SIGNOR-44356 PRKD1 protein Q15139 UNIPROT STK17B protein O94768 UNIPROT up-regulates activity phosphorylation 9606 21148796 YES miannuccelli Coexpression of DRAK2 and a constitutively active PKD mutant (CA-PKD1; PKD1-S738/742E) were sufficient to greatly enhance DRAK2 autophosphorylation, supporting the hypothesis that PKD catalytic activity promotes DRAK2 function.|We note that PKD was able to phosphorylate DRAK2 outside of its C terminus, suggesting that PKD mediated phosphorylation occurs on a site in the 1-290 fragment of DRAK2. 0.252 SIGNOR-279753 FBXW7 protein Q969H0 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 22388891 YES miannu Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α 0.396 SIGNOR-272907 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser228 EEDTSFEsLSKFNVK 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.742 SIGNOR-262718 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 BTO:0000887;BTO:0001103 17609368 YES lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. 0.502 SIGNOR-216647 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10074433 YES gcesareni We conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin. we found that the binding of beta-trcp to beta-catenin was direct. 0.746 SIGNOR-65429 GABPB2 protein Q8TAK5 UNIPROT HCFC1 protein P51610 UNIPROT down-regulates activity binding 9606 BTO:0000567 10675337 YES miannu The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation 0.2 SIGNOR-221318 CSNK2B protein P67870 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.286 SIGNOR-251054 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 YES lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. 0.628 SIGNOR-233435 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000785 16847353 YES lperfetto C-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma 0.626 SIGNOR-209593 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates phosphorylation Ser295 VIRPRRRsSCVSLGE 9606 10454575 YES esanto Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b. 0.687 SIGNOR-252583 IL1R1 protein P14778 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 9625767 YES inferred from 70% of family members lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab 0.379 SIGNOR-269883 GTF3C5 protein Q9Y5Q8 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 YES lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains 0.913 SIGNOR-266184 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.394 SIGNOR-89272 aspartic acid smallmolecule CHEBI:22660 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264754 FOXO proteinfamily SIGNOR-PF27 SIGNOR IGFBP1 protein P08833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10358076 NO miannu Reporter gene studies in hepg2 hepatoma cells show that fkhr stimulates insulin-like growth factor-binding protein-1 promoter activity through an irs 0.2 SIGNOR-252925 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser828 EHDSAEGsHTSGQSN 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.328 SIGNOR-276517 TP53 protein P04637 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 27692180 YES inferred from family member miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. 0.412 SIGNOR-270272 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys21 EGPRDGLkKERLLDD 9606 9990853 YES gcesareni We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. 0.541 SIGNOR-64317 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr8 MEELQDDyEDMMEEN -1 10942405 YES The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton 0.452 SIGNOR-251413 PABPN1 protein Q86U42 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 YES lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. 0.8 SIGNOR-268320 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation 9606 20626350 YES gcesareni Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2 0.611 SIGNOR-166625 hsa-miR-326 mirna URS00000A939F_9606 RNAcentral SMO protein Q99835 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002035 25173582 NO Parnian The upregulation of miR-326 not only inhibited the activity of the Hh pathway but also reduced the expression of additional Hh signaling components, including GLI1, N-myc, and CyclinD1. 0.4 SIGNOR-277979 AAK1 protein Q2M2I8 UNIPROT NUMB protein P49757 UNIPROT unknown phosphorylation Thr102 LRVVDEKtKDLIVDQ 9606 18657069 YES llicata Numb is phosphorylated by aak1, while little aak1-dependent phosphorylation is observed in t102a numb immunoprecipitants 0.46 SIGNOR-179610 miR-199a mirna URS0000759977_9606 RNAcentral MTOR protein P42345 UNIPROT up-regulates activity 9606 26055960 YES miannu Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation. 0.4 SIGNOR-255803 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser330 MEEDSYDsFGEPSYP -1 9558331 YES llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. 0.365 SIGNOR-250801 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 YES lperfetto Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. 0.2 SIGNOR-249573 ETV4 protein P43268 UNIPROT VIM protein P08670 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093;BTO:0000815 8895512 NO miannu Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3. 0.2 SIGNOR-254070 DSCAM protein O60469 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 YES miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. 0.2 SIGNOR-264277 MRPS7 protein Q9Y2R9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.764 SIGNOR-267730 MYC protein P01106 UNIPROT HECTD4 protein Q9Y4D8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 YES miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 0.2 SIGNOR-267144 BCL11A protein Q9H165 UNIPROT HBG2 protein P69892 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 NO Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. 0.446 SIGNOR-251800 PTK6 protein Q13882 UNIPROT SFPQ protein P23246 UNIPROT down-regulates activity phosphorylation 9606 19439179 YES miannuccelli BRK phosphorylates PSF promoting its cytoplasmic localization and cell cycle arrest.|These data suggest that BRK activity impedes the ability of PSF to bind RNA.To map the PSF tyrosine residues phosphorylated by BRK and assess if the PSF N-terminal is required for phosphorylation, we co-transfected HEK293 cells with various GFP-PSF deletion mutants in the presence or absence myc-BRK-YF. 0.53 SIGNOR-279754 AURKB protein Q96GD4 UNIPROT RPRD1B protein Q9NQG5 UNIPROT up-regulates activity phosphorylation Ser145 KATEEKKsLKRTFQQ 30518842 YES lperfetto Mechanistically, we revealed that CREPT/RPRD1B interacted with Aurora B to regulate the expression of Cyclin B1 in gastric cancer cells. Interestingly, Aurora B phosphorylates S145 in a well-conserved motif of CREPT/RPRD1B. We proposed that phosphorylation of CREPT/RPRD1B by Aurora B is required for promoting the transcription of Cyclin B1 0.2 SIGNOR-265499 RIPK4 protein P57078 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity phosphorylation Ser480 REARKYAsGLLKAGL 9606 23371553 YES miannuccelli Co-transfection of a RIPK4-GFP fusion increased the percentage of cells containing DVL2 puncta to more than 75% ( and ), suggesting that RIPK4 facilitates DVL2 signalosome formation.|Phosphorylation of DVL2 at Ser 298 and Ser 480 by RIPK4 favored canonical Wnt signaling. 0.441 SIGNOR-279757 LCK protein P06239 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 10090 BTO:0000782 15735648 YES miannu Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323. 0.473 SIGNOR-276029 PRKCA protein P17252 UNIPROT F11R protein Q9Y624 UNIPROT unknown phosphorylation Ser284 KVIYSQPsARSEGEF 9606 BTO:0000130;BTO:0000876 11027562 YES gcesareni We also demonstrated phosphorylation of ser 284, a putative pkc phosphorylation site, by immunoblotting with anti-phosphoserine-jam antibody in thrombin-stimulated platelets. 0.322 SIGNOR-83037 MMP1 protein P03956 UNIPROT COL3A1 protein P02461 UNIPROT down-regulates quantity by destabilization cleavage Gly774 IGPPGPAgQPGDKGE -1 17318226 YES lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  0.35 SIGNOR-272339 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 YES inferred from 70% family members gcesareni Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms 0.2 SIGNOR-270144 PTH1R protein Q03431 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt. 0.337 SIGNOR-199533 Gbeta proteinfamily SIGNOR-PF4 SIGNOR XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 27846390 YES inferred from 70% family members lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.¬† 0.2 SIGNOR-269999 LRRK1 protein Q38SD2 UNIPROT RAB7A protein P51149 UNIPROT up-regulates activity phosphorylation Ser72 AGQERFQsLGVAFYR 9606 33459343 YES miannu Overall, these data suggest that LRRK1 is able to phosphorylate endogenous Rab7A at Ser72. 0.387 SIGNOR-278212 TRIP10 protein Q15642 UNIPROT ARHGAP17 protein Q68EM7 UNIPROT down-regulates activity binding 9606 BTO:0000132 26507661 YES lperfetto Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex. 0.502 SIGNOR-272158 PRKCG protein P05129 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 YES gcesareni Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. 0.401 SIGNOR-37541 SP4 protein Q02446 UNIPROT RHO protein P08100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15781457 NO miannu Sp4 and Sp1 are activators of the rod opsin promoter 0.2 SIGNOR-225382 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR TELO2 protein Q9Y4R8 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23263282 YES miannu Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins. 0.256 SIGNOR-272000 EEF1E1 protein O43324 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.91 SIGNOR-270360 PML protein P29590 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 15356634 YES gcesareni Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. 0.546 SIGNOR-128741 CAMK2G protein Q13555 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.271 SIGNOR-275793 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CASP3 protein P42574 UNIPROT down-regulates activity 9606 BTO:0002882 11684015 NO lperfetto BCR/ABL Tyrosine Kinase Enhances Expression of RAD51 by Stimulation of STAT5-Mediated Transactivation and Inhibition of Caspase-3-Dependent Degradation| 0.2 SIGNOR-271704 CBP/p300 complex SIGNOR-C6 SIGNOR DDX5 protein P17844 UNIPROT up-regulates binding 9606 12527917 YES miannu Cbp/p300 interact with p68 rna helicase / the atpase activity of p68 is required for the specific transcriptional activation of cbp 0.474 SIGNOR-97274 ATM protein Q13315 UNIPROT FBXO31 protein Q5XUX0 UNIPROT up-regulates phosphorylation Ser278 LMKFIYTsQYDNCLT 9606 BTO:0000150;BTO:0001130 19412162 YES lperfetto We find that dna damage induced by gamma-irradiation results in increased fbxo31 levels, which requires phosphorylation of fbxo31 by the ddr-initiating kinase atm 0.406 SIGNOR-185635 AKT1 protein P31749 UNIPROT NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Ser600 PARQRIRsCVSAENF 9606 12409306 YES esanto Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity. 0.262 SIGNOR-252591 SUV39H1 protein O43463 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 23435416 NO lperfetto The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation 0.404 SIGNOR-249601 TRIM25 protein Q14258 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 17392790 YES lys63 miannu The carboxy-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIG-I; this interaction effectively delivers the Lys 63-linked ubiquitin moiety to the N-terminal CARDs of RIG-I, resulting in a marked increase in RIG-I downstream signalling activity.  Thus, we demonstrate that TRIM25 E3 ubiquitin ligase induces the Lys 63-linked ubiquitination of RIG-I, which is crucial for the cytosolic RIG-I signalling pathway to elicit host antiviral innate immunity. 0.802 SIGNOR-271645 PIM1 protein P11309 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17643117 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. 0.2 SIGNOR-156946 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT down-regulates activity phosphorylation Ser503 AAEFQKKsGSAHRPK 9534 BTO:0004055 8626492 YES miannu GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity. 0.31 SIGNOR-250050 FBXO45 protein P0C2W1 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.26 SIGNOR-272183 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr156 ADEDEDDyHNPGYLV 9606 BTO:0000782 11368773 YES lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. 0.769 SIGNOR-247018 RAB32 protein Q13637 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR up-regulates activity relocalization 9606 23247405 YES lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. 0.2 SIGNOR-260700 rituximab antibody DB00073 DRUGBANK MS4A1 protein P11836 UNIPROT down-regulates activity binding 9606 20350663 YES miannu Rituximab is a class I chimeric anti-CD20 antibody that has shown efficacy in chronic lymphocytic leukemia (CLL), both as a single agent and in combination with traditional chemotherapies. 0.4 SIGNOR-259902 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1365 TKTSPKLsNKELKPQ 9606 BTO:0003492 21254166 YES miannu  This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361. 0.597 SIGNOR-276300 PRKAA1 protein Q13131 UNIPROT PRPS1 protein P60891 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 YES lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. 0.2 SIGNOR-265729 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates activity binding 9606 BTO:0000399 10706854 YES Eotaxin and other CC chemokines acting via CC chemokine receptor-3 (CCR3) are believed to play an integral role in the development of eosinophilic inflammation in asthma and allergic inflammatory diseases. 0.936 SIGNOR-256091 HIPK2 protein Q9H2X6 UNIPROT AATF protein Q9NY61 UNIPROT down-regulates quantity phosphorylation 9606 25210797 YES miannu HIPK2 phosphorylates Che-1.|Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation. 0.346 SIGNOR-278942 BCL2L1 protein Q07817 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity binding 9606 9539746 YES lperfetto Bcl2l1 associates with casp9 and apaf-1 in mammalian cells.Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation 0.682 SIGNOR-56402 RNF111 protein Q6ZNA4 UNIPROT AP2M1 protein Q96CW1 UNIPROT up-regulates ubiquitination 9606 20965945 YES gcesareni Arkadia ubiquitylated the _?2 Subunit at lys130. In addition, arkadia interacted with the ap2 complex, and modified endocytosis of epidermal growth factor receptor (egfr) induced by egf. Arkadia thus appears to regulate egf signalling by modulating endocytosis of egfr through interaction with ap2 complex. 0.2 SIGNOR-168931 Ub:E2 complex SIGNOR-C497 SIGNOR UHRF2 protein Q96PU4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270958 MAPKAPK5 protein Q8IW41 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser19 KGFRRAVsELDAKQA 9606 12421349 YES The effect has been demonstrated using P07101-3 gcesareni Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation of both ser40 and ser19 induced a high-affinity binding of 14-3-3 proteins, but only the interaction of 14-3-3 with ser19 increased the hth1 activity. 0.2 SIGNOR-95479 AKT1 protein P31749 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Thr90 EARHRVPtTELCRPP 9606 BTO:0000782;BTO:0001271 15930267 YES miannu Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo. 0.374 SIGNOR-252479 SOX9 protein P48436 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20530484 NO miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. 0.333 SIGNOR-255187 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 1303753 YES gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. 0.577 SIGNOR-16247 RPGRIP1L protein Q68CZ1 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates demethylation 9606 20080798 YES lperfetto Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. 0.2 SIGNOR-217412 HEXIM1 protein O94992 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates activity relocalization 9606 BTO:0000815 31776402 YES lperfetto We previously reported that the tumor suppressor HEXIM1 is a mediator of KDM5B recruitment to its target genes, and HEXIM1 is required for the inhibition of nuclear hormone receptor activity by KDM5B.  0.2 SIGNOR-273439 ATM protein Q13315 UNIPROT TDP1 protein Q9NUW8 UNIPROT up-regulates phosphorylation Ser81 PKRQKSGsQEDLGWC 9606 19851285 YES lperfetto Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk) 0.543 SIGNOR-188772 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.422 SIGNOR-248307 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.4 SIGNOR-259019 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI MST1R protein Q04912 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190407 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 YES gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.703 SIGNOR-84053 PIK-294 chemical CID:24905149 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206202 TRIM13 protein O60858 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21333377 YES miannu Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. 0.353 SIGNOR-271852 959122-11-3 chemical CID:24768261 PUBCHEM DGAT1 protein O75907 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205695 PDGFRB protein P09619 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 YES llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. 0.552 SIGNOR-167658 FABP2 protein P12104 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264456 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser118 GEAAEPGsPTAAEGE -1 8034575 YES lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | We conclude that the primary phosphorylation site is Ser116 | 0.729 SIGNOR-248907 IC-87114 chemical CHEBI:90686 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206190 PIN4 protein Q9Y237 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 9606 BTO:0000567 12860119 NO lperfetto Par14 is a pre-rRNA processing factor involved in mammalian ribosome biogenesis, Par14 deficiency slowed cell growth (Fig. 3A) and reduced the production of 18 and 28 S rRNAs  0.7 SIGNOR-265754 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT down-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 452646 11551945 YES miannu MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription 0.611 SIGNOR-250145 GIGYF1 protein O75420 UNIPROT EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR form complex binding 9606 30917308 YES lperfetto 4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression 0.611 SIGNOR-261011 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser492 MTLTKSRsFTSSYAI 9606 19261611 YES llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. 0.2 SIGNOR-184464 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000007 12138205 YES Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator. 0.557 SIGNOR-252572 citrate(3-) smallmolecule CHEBI:16947 ChEBI ACACA protein Q13085 UNIPROT up-regulates activity binding 9606 6138356 YES miannu Citrate, an allosteric activator of acetyl-CoA carboxylase, induces polymerization of an inactive protomeric form of the enzyme into an active filamentous form composed of 10-20 protomers.  0.8 SIGNOR-267104 MAPKAPK2 protein P49137 UNIPROT UBE2J1 protein Q9Y385 UNIPROT down-regulates quantity by destabilization phosphorylation Ser184 KELARQIsFKAEVNS 9606 BTO:0000567 24020373 YES miannu Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production. These findings strongly suggest that MK2 directly phosphorylates Ube2j1 at Ser(184) upon p38-activating stress in vivo. 0.335 SIGNOR-263091 MAPK1 protein P28482 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates phosphorylation Ser734 NSSRFPPsPLASKPT 9606 15616583 YES gcesareni Dapk interacts with erk through a docking sequence within its death domain and is a substrate of erk. Phosphorylation of dapk at ser 735 by erk increases the catalytic activity of dapk both in vitro and in vivo 0.565 SIGNOR-132614 TP53 protein P04637 UNIPROT GLS2 protein Q9UI32 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22307140 YES Luana Glutaminase 2 (GLS2) can be directly transactivated by p53 and can therefore mediate p53-dependent regulation of cellular energy metabolism. G 0.63 SIGNOR-268041 neostigmine chemical CHEBI:7514 ChEBI ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001239 17888667 YES Luana AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. 0.8 SIGNOR-257758 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates deacetylation 9606 15126506 YES gcesareni Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes. 0.911 SIGNOR-252993 CAMK4 protein Q16566 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 YES gcesareni Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. 0.707 SIGNOR-153940 ITSN1 protein Q15811 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 YES lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth 0.579 SIGNOR-260714 TRIM59 protein Q8IWR1 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity 9606 BTO:0000567; BTO:0002181 22588174 NO Giorgia TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal 0.259 SIGNOR-260374 ATG12 protein O94817 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR form complex binding 9606 BTO:0000007 18321988 YES lperfetto Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex). 0.867 SIGNOR-226689 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Ser77 TFDPPLHsTAIYADE 9606 17081991 YES lperfetto S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions 0.74 SIGNOR-150453 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser193 AEVDPDMsWSSSLAT 9606 BTO:0001938 12815053 YES lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. 0.54 SIGNOR-249217 ZNF224 protein Q9NZL3 UNIPROT ALDOA protein P04075 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17900823 NO miannu We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. 0.489 SIGNOR-255627 IMPDH2 protein P12268 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity chemical modification 9606 19480389 YES miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). 0.8 SIGNOR-267335 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GTF2I protein P78347 UNIPROT up-regulates phosphorylation 9606 10648599 YES inferred from 70% family members lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. 0.2 SIGNOR-270057 (-)-anisomycin chemical CHEBI:338412 ChEBI p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates chemical activation 9606 Other YES CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb gcesareni 0.8 SIGNOR-269916 DTL protein Q9NZJ0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000007 24962565 YES miannu TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner 0.694 SIGNOR-272848 CCNC protein P24863 UNIPROT CyclinC/CDK19 complex SIGNOR-C544 SIGNOR form complex binding 9606 BTO:0004173 25344755 YES lperfetto We found that in MOLT-16 cells cyclin C physically interacts with CDK19 (Fig. 5a) and activates its kinase activity (Fig. 5e and Supplementary Fig. 4f,g). 0.913 SIGNOR-273154 MAP3K8 protein P41279 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity phosphorylation Thr559 TGDYIPGtETHMAPE 9606 9742107 YES lperfetto In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha 0.557 SIGNOR-249387 FGFR3 protein P22607 UNIPROT TET2 protein Q6N021 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr1902 TRISLVFyQHKSMNE 9606 BTO:0000976 33097695 YES miannu FGFR3∆7-9, but not wild-type FGFR3, directly interacts with TET2 and phosphorylates TET2 at Y1902 site, leading to the ubiquitination and proteasome-mediated degradation of TET2. 0.25 SIGNOR-277535 STK19 protein P49842 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity phosphorylation Ser89 FAINNSKsFADINLY 9606 BTO:0003476 30712867 YES lperfetto STK19 Phosphorylates NRAS Protein at Serine 89|STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation.| 0.306 SIGNOR-264566 SRC protein P12931 UNIPROT ING1 protein Q9UK53 UNIPROT down-regulates activity phosphorylation Ser126 S-->P 9606 23585863 YES miannuccelli Src Decreases the Stability and Level of ING1.|This study, as well as a previous report identifying Ser-126 of ING1 as a kinase target, confirm that ING1 stability is also regulated by phosphorylation. However, the mechanism may be complex since phosphorylation of Ser-126 stabilizes the protein while phosphorylation by Src reduces ING1 stability and causes a relocalization of ING1 from the nucleus to the cytoplasm. 0.367 SIGNOR-279760 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr105 LQTFGHNtMDAVPKI 9606 BTO:0000007 21321328 YES miannu We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. 0.578 SIGNOR-263131 GADD45A protein P24522 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 20626350 YES gcesareni Gadd45alfa appears to act as an endogenous inhibitor of the alternative p38alfa-activation pathway in t-cell, by binding to p38alfa and preventing tyr323 phosphorilation 0.462 SIGNOR-166584 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 10428798 YES lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. 0.419 SIGNOR-217288 SGK1 protein O00141 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates phosphorylation Ser227 QQRRRITsVQPPTGL 9606 BTO:0001271 21147854 YES lperfetto Here, we report that the serum- and glucocorticoid-inducible protein kinase sgk1 remarkably reduced the protein stability of the active form of notch1 through fbw7activated sgk1 phosphorylated fbw7 at serine 227 0.291 SIGNOR-170404 AKT1 protein P31749 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Thr60 EYRRRRHtMDKDSRG 9606 16081417 YES llicata Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt. 0.394 SIGNOR-252481 CBX5 protein P45973 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-264488 SMARCC2 protein Q8TAQ2 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.829 SIGNOR-270616 MAPK1 protein P28482 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 10090 BTO:0000782 16888006 YES lperfetto ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition 0.534 SIGNOR-148616 CDK4 protein P11802 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 SIGNOR-C18 18071316 YES llicata This skp2-dependent destruction of rassf1a requires phosphorylation of the latter on serine-203 by cyclin d-cyclin-dependent kinase 4. 0.41 SIGNOR-159849 RNF111 protein Q6ZNA4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 YES gcesareni Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. 0.653 SIGNOR-236876 PRDM1 protein O75626 UNIPROT CIITA protein P33076 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000776 12626569 NO miannu The positive regulatory domain i binding factor 1 (prdi-bf1 or blimp-1) protein represses the transcription of specific target genes, including c-myc, the mhc class ii trans-activator, pax-5, and cd23b 0.421 SIGNOR-99116 EFNA3 protein P52797 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 YES gcesareni Eph receptors are activated by their ligands, which are membrane-anchored molecules 0.826 SIGNOR-52315 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser313 TALHRSKsHEFQLGH 10090 19560418 YES These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 0.26 SIGNOR-248382 RAB5A protein P20339 UNIPROT PIK3R4 protein Q99570 UNIPROT up-regulates activity binding 10090 27411398 YES lperfetto Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity 0.423 SIGNOR-260708 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269350 EPAS1 protein Q99814 UNIPROT KDM1A protein O60341 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.28 SIGNOR-271588 FBXW11 protein Q9UKB1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 10321728 YES miannu We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.  0.783 SIGNOR-272546 TRIM28 protein Q13263 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 17900823 NO inferred from family member miannu We previously reported that ZNF224, a novel Kr√ºppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. 0.2 SIGNOR-270228 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8557118 YES gcesareni PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. 0.365 SIGNOR-249671 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.411 SIGNOR-252882 SCF-betaTRCP complex SIGNOR-C5 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 11359933 YES miannu Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCF(Fbw1a) consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed betaTrCP1) induces ubiquitination of Smad3.  0.443 SIGNOR-272944 INTS11 protein Q5TA45 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.2 SIGNOR-261462 PRKG1 protein Q13976 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.358 SIGNOR-134640 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL4 protein P05112 UNIPROT up-regulates 9606 BTO:0000801 32454942 NO miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation 0.7 SIGNOR-263822 MTMR2 protein Q13614 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity chemical modification 9606 18429927 YES miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 0.8 SIGNOR-269808 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP73 protein O15350 UNIPROT up-regulates 9606 17700533 YES miannu These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated. 0.8 SIGNOR-255472 Phenelzine chemical CHEBI:8060 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  0.8 SIGNOR-258743 SRC protein P12931 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates quantity phosphorylation Tyr188 MTPQFTPyYVAPQVL 9606 26042227 YES miannuccelli These data strongly suggest that PRAK phosphorylation by Src on Y188 and Y216 drives the relocalization of PRAK to focal adhesion structures during cell adhesion. 0.373 SIGNOR-279761 AMPK complex SIGNOR-C15 SIGNOR CHKA protein P35790 UNIPROT up-regulates activity phosphorylation Ser279 KKLHKLLsYNLPLEL 9606 BTO:0000527 34929314 YES lperfetto Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation. 0.2 SIGNOR-267647 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB1 protein P01911 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 YES The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.283 SIGNOR-253977 CACNA2D3 protein Q8IZS8 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 27583705 YES miannu Our findings showed that increased intracellular calcium (Ca2+ ) mediated by overexpression of CACNA2D3 induced mitochondrial-mediated apoptosis, upregulation of NLK (through the Wnt/Ca2+ pathway) and inhibition of the epithelial-to-mesenchymal transition. 0.8 SIGNOR-266853 AKT1 protein P31749 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 15538381 YES llicata Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity. 0.656 SIGNOR-130376 CDK1 protein P06493 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser321 KCQRLFRsPSMPCSV 9606 20801879 YES gcesareni Ser(321) is phosphorylated in mitosis by cdk1. The mitotic phosphorylation of ser(321) acts to maintain full activation of cdc25b by disrupting 14-3-3 binding to ser(323) and enhancing the dephosphorylation of ser(323) to block 14-3-3 binding to this site. 0.828 SIGNOR-167641 PRKCA protein P17252 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Ser12 KSKPKDAsQRRRSLE -1 2996780 YES lperfetto We propose that protein kinase C is responsible for this modification based on the following evidence. First, the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and teleocidin, and synthetic diacylglycerol, known activators of protein kinase C in vivo, cause nearly complete phosphorylation of pp60src at serine 12. Second, among five purified serine/threonine-specific protein kinases tested, only protein kinase C phosphorylates pp60c-src and pp60v-src in vitro at serine 12. Third, purified protein kinase C phosphorylates a synthetic peptide corresponding to the N-terminal 20 amino acids of pp60c-src at serine 12. The physiological significance of this novel phosphorylation is discussed. 0.599 SIGNOR-248893 CDK4 protein P11802 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 YES gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.512 SIGNOR-176527 JUN protein P05412 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004603 13679379 YES Luana Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.  0.826 SIGNOR-261604 JNK proteinfamily SIGNOR-PF15 SIGNOR STMN1 protein P16949 UNIPROT down-regulates phosphorylation 9606 20630875 YES inferred from 70% family members gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress. 0.2 SIGNOR-269982 TBX2 protein Q13207 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 YES lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS 0.52 SIGNOR-249594 STAT1 protein P42224 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 15778351 YES miannu We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2. 0.548 SIGNOR-254532 MAPK9 protein P45984 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 NO JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax. gcesareni Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria;these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins. 0.298 SIGNOR-124023 UPF2 protein Q9HAU5 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity binding -1 18066079 YES miannu UPF2 and UPF3b increase UPF1 ATPase activity 0.979 SIGNOR-265246 EP300 protein Q09472 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR form complex binding 9606 21131905 YES lperfetto Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators. 0.667 SIGNOR-170273 PRKG2 protein Q13237 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Ser712 SDKRRPPsAELYSNA 9606 BTO:0000498 29935031 YES miannu PKG II inhibited PDGFRβ activation in gastric cancer via phosphorylating Ser712 of this RTK. 0.272 SIGNOR-277401 ELOVL6 protein Q9H5J4 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267887 N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. 0.8 SIGNOR-267307 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.759 SIGNOR-219312 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity relocalization 9606 20704570 YES lperfetto Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses 0.39 SIGNOR-232107 Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR BID protein P55957 UNIPROT up-regulates activity cleavage 9606 20158568 YES miannu Inactive caspase-2 monomers are recruited to the PIDDosome in response to certain cellular stresses. This results in dimerization and activation of caspase-2. Caspase-2 cleaves and activates Bid to induce MOMP eventually resulting in activation of executioner caspases by caspase-9-mediated cleavage. 0.568 SIGNOR-262644 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser789 QSVDKVTsPTKV 9606 BTO:0001260 10514499 YES lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. 0.476 SIGNOR-71045 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 YES lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 0.616 SIGNOR-249445 TRIM38 protein O00635 UNIPROT TRIM38 protein O00635 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21306652 YES miannu Our study shows that, similar to other TRIM family members, TRIM38 is localized in the cytoplasm. TRIM38 increases ubiquitination of other cellular proteins and catalyzes self-ubiquitination. TRIM38 also promotes K63- and K48-linked ubiquitination of cellular proteins. An intact RING domain is important for the functions of TRIM38. In addition, enterovirus 71 infection induces TRIM38 degradation. 0.2 SIGNOR-271906 ATF4 protein P18848 UNIPROT NARS1 protein O43776 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269422 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001544 19261608 YES The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. 0.759 SIGNOR-248327 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 YES The effect has been demonstrated using P10636-8 gcesareni Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase. 0.43 SIGNOR-60651 DUSP1 protein P28562 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 9020184 YES gcesareni Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2. 0.788 SIGNOR-46079 STK4 protein Q13043 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity phosphorylation Thr1061 KMDWIFHtIKQHALN -1 38060450 YES miannu MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061  0.2 SIGNOR-277920 LUBAC complex SIGNOR-C527 SIGNOR TRIM25 protein Q14258 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21292167 YES miannu HOIL-1L/HOIP LUBAC induces TRIM25 ubiquitination and degradation.Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner. 0.468 SIGNOR-271859 FERMT3 protein Q86UX7 UNIPROT ITGB3 protein P05106 UNIPROT up-regulates activity binding 10090 BTO:0000132;BTO:0003292 18278053 YES lperfetto Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner 0.649 SIGNOR-266066 FASN protein P49327 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI down-regulates quantity chemical modification 9606 15507492 YES Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-267759 TTL protein Q8NG68 UNIPROT TUBA8 protein Q9NY65 UNIPROT down-regulates tyrosination 9606 22020298 YES miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization 0.31 SIGNOR-176930 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Arg334 KNCPKKTrNLKKITR -1 7989361 YES lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. 0.6 SIGNOR-263628 CDK1 protein P06493 UNIPROT NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr142 QEWIPPStPYK 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275587 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM51 protein Q9BSJ1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270962 TNF protein P01375 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 10485710 YES gcesareni Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k) 0.296 SIGNOR-70625 SRC protein P12931 UNIPROT TIAM1 protein Q13009 UNIPROT down-regulates activity phosphorylation Tyr384 DAARQGVyENFRREL 9606 19285946 YES miannuccelli Here, we show that Tiam1 is phosphorylated on Y384 by Src. 0.656 SIGNOR-279763 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT unknown phosphorylation Thr119 GAARVIGtLLGTVDK 9606 19245811 YES lperfetto Here, we identified a second eif3f phosphorylation site (thr119) by cdk11p46 during apoptosis.Thr119 is located in the mov34 domain of eif3f which is important for both the translational inhibitory function of eif3ffurther studies of how eif3f phosphorylation regulates its function will refine insights into the mechanism and regulation of translation initiation, apoptotic signaling, and tumorigenesis. 0.516 SIGNOR-184185 CASP1 protein P29466 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 YES lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. 0.385 SIGNOR-261755 WICH complex SIGNOR-C449 SIGNOR RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity binding 9606 16603771 YES miannu We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling. 0.411 SIGNOR-268829 DIO proteinfamily SIGNOR-PF83 SIGNOR iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 YES scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† 0.8 SIGNOR-267045 MINK1 protein Q8N4C8 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Thr322 SNVNRNStIENTRRH 9606 BTO:0002181 21690388 YES miannu Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.  0.2 SIGNOR-276336 RPS6K proteinfamily SIGNOR-PF26 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 18722121 YES lperfetto Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity 0.461 SIGNOR-252794 MTOR protein P42345 UNIPROT ATG13 protein O75143 UNIPROT down-regulates phosphorylation 9606 19211837 YES gcesareni Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2. 0.649 SIGNOR-183965 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 YES The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. 0.342 SIGNOR-138920 GRIK1 protein P39086 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 YES lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine 0.8 SIGNOR-268272 ELK4 protein P28324 UNIPROT INSIG2 protein Q9Y5U4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20145255 YES Luana Under these conditions, a significant reduction in INSIG2 expression was only observed when SAP1a siRNA was used. These observations provide supporting evidence that SAP1a may be one of the transactivators of the human INSIG2 promoter. 0.2 SIGNOR-261592 RABGGTA protein Q92696 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity lipidation 9606 BTO:0000007 18532927 YES miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional 0.624 SIGNOR-265572 ITGAM protein P11215 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 23994464 YES apalma Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. 0.772 SIGNOR-255041 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.394 SIGNOR-89288 Pr3-ANCA complex SIGNOR-C475 SIGNOR Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000133 2161532 NO lperfetto ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. 0.7 SIGNOR-270584 CTNNB1 protein P35222 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 10090 BTO:0004086 17420453 NO Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells. 0.7 SIGNOR-256534 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 23632474 YES Neratinib (HKI-272) is a tyrosine kinase inhibitor, under investigation for the treatment breast cancer and other solid tumours. gcesareni Ineratinib is a potent irreversible pan-erbb tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (her)-2-positive breast cancer and other solid tumours. 0.8 SIGNOR-202015 succinate(2-) smallmolecule CHEBI:30031 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. 0.8 SIGNOR-266275 ATG101 protein Q9BSB4 UNIPROT ATG13 protein O75143 UNIPROT up-regulates binding 9606 19597335 YES gcesareni Furthermore, atg101 is important for the stability and basal phosphorylation of atg13 and ulk1 0.959 SIGNOR-186989 PRKCZ protein Q05513 UNIPROT VIM protein P08670 UNIPROT up-regulates activity phosphorylation Ser34 SRSYVTTsTRTYSLG 9606 BTO:0001033 33525953 YES miannu Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells. 0.2 SIGNOR-277622 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT down-regulates phosphorylation Ser1565 LSPFRRHsWGPGKNA 9606 15229649 YES llicata Elevation of the cellular concentration of camp activates the pka holoenzyme anchored to akap-lbc, which phosphorylates the anchoring protein on the serine 1565. This phosphorylation event induces the recruitment of 14-3-3, which inhibits the rho-gef activity of akap-lbc. 0.332 SIGNOR-126723 TGFBR2 protein P37173 UNIPROT USP2 protein O75604 UNIPROT up-regulates activity phosphorylation Ser225 SRVPEIIsPTYRPIG -1 29490279 YES miannu Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. 0.2 SIGNOR-273603 MAPK1 protein P28482 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Thr30 PSSSEIFtPAHEENV 9606 25728771 YES lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation 0.2 SIGNOR-264774 CDK16 protein Q00536 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 NVRVSNGsPSLERMD 9606 BTO:0000567 25205104 YES lperfetto In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells.|Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target. 0.333 SIGNOR-273016 PH 797804 chemical CHEBI:82715 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206079 Membrane attack complex complex SIGNOR-C313 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR up-regulates -1 30552328 NO lperfetto CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers 0.7 SIGNOR-263456 Nalorphine chemical CHEBI:7458 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.8 SIGNOR-258664 FYN protein P06241 UNIPROT BSG protein P35613-2 UNIPROT up-regulates activity phosphorylation Tyr140 PVTDWAWyKITDSED 9606 BTO:0000849 32291412 YES miannu Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment. 0.269 SIGNOR-273999 MRAP2 protein Q96G30 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000246 19329486 YES miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor. 0.537 SIGNOR-252361 EEF1A1 protein P68104 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269520 TAOK3 protein Q9H2K8 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 23431053 YES inferred from 70% of family members gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2 0.291 SIGNOR-269949 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Ser32 RSEDARSsPSQRRRG 9606 BTO:0000567 SIGNOR-C83 12714602 YES lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. 0.766 SIGNOR-100881 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 9606 21873209 YES lperfetto When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects. 0.95 SIGNOR-209702 MEIS1 protein O00470 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 NO irozzo To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells. 0.7 SIGNOR-255860 CYP24A1 protein Q07973 UNIPROT calcitriol smallmolecule CHEBI:17823 ChEBI down-regulates quantity chemical modification 30080183 YES lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). 0.8 SIGNOR-270572 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr31 GGGSMGDyMAQEDDW 9606 23454549 YES lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin 0.557 SIGNOR-192195 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103;BTO:0002314 22493066 YES lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells NICD regulates Pax7 through interaction with RBP-J_, which binds to two consensus sites upstream of the Pax7 gene. 0.377 SIGNOR-219365 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000763;BTO:0000149 10197981 YES llicata Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain. 0.745 SIGNOR-66742 SRPK1 protein Q96SB4 UNIPROT ARSF protein P54793 UNIPROT up-regulates activity phosphorylation 9606 21157379 YES miannuccelli Phosphorylation by SRPK1 drives ASF from the cytosol to the nucleus.|Phosphorylation of ASF by SR protein kinase 1 (SRPK1) in the cytosol results in ASF relocation to the nucleus, whereas phosphorylation of ASF by Clk and Sty releases ASF from speckles and recruits it into nascent transcripts where ASF regulates alternative splicing. 0.2 SIGNOR-279765 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI up-regulates quantity precursor of 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-268071 NSMCE1 protein Q8WV22 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 YES miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks 0.878 SIGNOR-265483 SHANK2 protein Q9UPX8 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.297 SIGNOR-264584 CDC7 protein O00311 UNIPROT ESCO1 protein Q5FWF5 UNIPROT down-regulates phosphorylation 9606 23314252 YES gcesareni We show here that eco1 degradation requires the sequential actions of cdk1 and two additional kinases, cdc7-dbf4 and the gsk-3 homolog mck1. 0.432 SIGNOR-200397 RBX1 protein P62877 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR form complex binding 9606 BTO:0001109 phosphorylation:Thr286 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1  0.954 SIGNOR-271629 miR-27b mirna URS000075B0A5_9606 RNAcentral PPARG protein P37231 UNIPROT down-regulates quantity post transcriptional regulation 10116 26239616 YES Luana Overexpression of miR-132 significantly reduced the expression levels of MeCP2, at both the mRNA and protein level, whereas downregulation of miR-132 increased the mRNA and protein expression levels of MeCP2 0.4 SIGNOR-264608 MAP3K5 protein Q99683 UNIPROT COX7A2L protein O14548 UNIPROT up-regulates activity phosphorylation 9606 28039481 YES miannu Phosphorylation of EB1 by ASK1 promotes the binding of EB1 to CLIP-170 and p150 glued. 0.2 SIGNOR-278341 VDAC1 protein P21796 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10365962 NO lperfetto Our results indicate that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis. 0.7 SIGNOR-249615 Secukinumab (Cosentyx) antibody DB09029 DRUGBANK IL17A protein Q16552 UNIPROT down-regulates activity binding 9606 30793255 YES Secukinumab (Cosentyx®), a first-in-class fully human monoclonal antibody against interleukin-17A 0.4 SIGNOR-272494 BAG1 protein Q99933 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity binding 9606 BTO:0000661 7834747 YES lperfetto Cloning and functional analysis of BAG-1: A novel Bcl-2-binding protein with anti-cell death activity| 0.415 SIGNOR-254118 CDKL5 protein O76039 UNIPROT LRRC4C protein Q9HCJ2 UNIPROT unknown phosphorylation Ser631 PLLIRMNsKDNVQET 9606 22922712 YES llicata Cdkl5 binds and phosphorylates the cell adhesion molecule ngl-1. This phosphorylation event ensures a stable association between ngl-1 and psd95. 0.428 SIGNOR-192035 TLN1 protein Q9Y490 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.718 SIGNOR-257618 SNTB1 protein Q13884 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.503 SIGNOR-255992 DUSP1 protein P28562 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 10617468 YES inferred from 70% of family members gcesareni The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1. 0.833 SIGNOR-269930 PAN2-PAN3 deadenylation complex complex SIGNOR-C553 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI down-regulates quantity by destabilization chemical modification 9606 34280615 YES miannu There are two major deadenylase complexes, Ccr4-Not and Pan2-Pan3, which shorten the 3′ poly(A) tail of mRNA and are conserved from yeast to human.The Ccr4-Not complex has two catalytic subunits including the Ccr4 (Carbon catabolite repressor 4) and Pop2 (PGK promoter directed overproduction). The Pan2-Pan3 complex comprises the catalytic subunit Pan2, a member of the RNase D family, and the regulatory subunit Pan3. Degradation of mRNA begins with either shortening of the poly(A) tail by deadenylases or removal of 5′ cap structure by the decapping enzyme Dcp1-Dcp2. 0.8 SIGNOR-273872 adenosine smallmolecule CHEBI:16335 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 33961946 YES miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). 0.8 SIGNOR-267836 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Thr92 EVPDVTAtPARLLFF 9606 18676833 YES gcesareni Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons. 0.42 SIGNOR-216900 RXRB protein P28702 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. 0.665 SIGNOR-16677 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR OPTN protein Q96CV9 UNIPROT up-regulates activity polyubiquitination Lys501 LQLAVLLkENDAFED 9606 BTO:0000567 32014991 YES miannu DCAF4-mediated ubiquitination of OPTN facilitates the degradation of DBR-exposed SOD1. OPTN is involved in degradation of DBR-exposed SOD1. These data demonstrate that DCAF4-including CRL4 complex mediates OPTN ubiquitination at lysine 501, and this ubiquitination is absent in the ALS-related OPTNmut. 0.2 SIGNOR-272209 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000938 17591690 YES llicata We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active 0.731 SIGNOR-156426 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 YES lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. 0.79 SIGNOR-252357 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 YES gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. 0.793 SIGNOR-90525 PJA2 protein O43164 UNIPROT PRKAR2B protein P31323 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 YES miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits 0.2 SIGNOR-271858 Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 NO miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.7 SIGNOR-270906 TBK1 protein Q9UHD2 UNIPROT VPS37C protein A5D8V6 UNIPROT down-regulates activity phosphorylation 9606 21270402 YES miannuccelli We have identified that TBK1 may target and phosphorylate VPS37C, a structural component of ESCRT-I complex, and serve as a ratelimiting factor in the control of PTAP-dependent (HIV-1, MLV/p6, and EIAV/PTAP), but not PPPY-dependent (MLV, EIAV/PPPY) retrovirus budding, independent of its role in IFN-I signaling. 0.367 SIGNOR-279768 LYN protein P07948 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.618 SIGNOR-249384 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 BTO:0000776 10473617 YES llicata Activation of the serine kinase protein kinase d (pkd)/pkcmicro is controlled by the phosphorylation of two serine residues within its activation loop via a pkc-dependent signaling cascade. In this study we have identified the c-terminal serine 916 residue as an in vivo phosphorylation site within active pkd/pkcmu. moreover, using different mutants of pkd/pkcmu, we show that serine 916 is not trans-phosphorylated by an upstream kinase but is rather an autophosphorylation event that occurs following activation of pkd/pkcmu. 0.2 SIGNOR-70525 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9606 17132853 YES miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 0.8 SIGNOR-256196 CCNA2 protein P20248 UNIPROT CyclinA2/CDK18 complex SIGNOR-C547 SIGNOR form complex binding 33781185 YES lperfetto PCTAIRE kinases (PCTKs) are a CDK subfamily, characterized by serine to cysteine mutation in the consensus PSTAIRE motif, involved in binding to the cyclin. One member of this class is PCTK3, which has two isoforms (a and b) and is also known as CDK18. After being activated by cyclin A2 or phosphorylation at Ser12 by PKA, PCTK3 can perform several functions. 0.393 SIGNOR-273437 TBX5 protein Q99593 UNIPROT FGF10 protein O15520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18451335 NO miannu TBX5 is expressed, among others, in the embryonic heart and forelimbs.8 In the heart, it regulates transcription of downstream genes such as the atrial natriuretic factor (NPPA) and fibroblast growth factor 10 (FGF10) by the binding to T-box binding elements (TBEs),11 often in combination with the NKX2-5 transcription factor. 0.447 SIGNOR-255383 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr243 ARRLCDLyYINSPEL 9606 22195962 YES llicata Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1 0.347 SIGNOR-191723 TEK protein Q02763 UNIPROT TIE1 protein P35590 UNIPROT up-regulates activity phosphorylation 9606 15851516 YES miannuccelli Thus, Tie2 was able to induce Tie1 phosphorylation.|When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner. 0.348 SIGNOR-279769 MAP2K1 protein Q02750 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 12270934 YES inferred from 70% of family members lbriganti Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. 0.2 SIGNOR-269909 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001412 11283671 YES irozzo AML1–ETO inhibits CEBPA autoregulation in myeloid cells.[…]It was also demonstrated that AML1–ETO and C/EBPα physically interact in vivo. 0.2 SIGNOR-255700 tyrphostin B42 chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity 9606 11368440 YES gcesareni The Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel 0.8 SIGNOR-238293 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1265 FPMTPTTyKGSVDNQ 9606 BTO:0000394 12881528 YES lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. 0.2 SIGNOR-104080 WNK3 protein Q9BYP7 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation 21613606 YES lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs 0.499 SIGNOR-264626 NARS2 protein Q96I59 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270465 EXOSC7 protein Q15024 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.921 SIGNOR-261386 PIM1 protein P11309 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser683 QAQDRKLsTKEALDE 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.439 SIGNOR-272511 FLI1 protein Q01543 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001549 17688409 NO miannu Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells. Mutation of the GATA-1 and the Ets-1 motifs amplified the expression of HOXA10 in HEL and K562 cells, confirming the importance of these cis-acting elements in regulating HOXA10 expression in megakaryocytic cells. Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. 0.2 SIGNOR-254471 PD-153035 hydrochloride chemical CHEBI:91075 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205716 KLHL20 protein Q9Y2M5 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 20389280 YES miannu Here, we identify the BTB-Kelch protein KLHL20 as a negative regulator of DAPK. KLHL20 binds DAPK and Cullin 3 (Cul3) via its Kelch-repeat domain and BTB domain, respectively. The KLHL20-Cul3-ROC1 E3 ligase complex promotes DAPK polyubiquitination, thereby inducing the proteasomal degradation of DAPK. 0.486 SIGNOR-271961 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser561 MANDSDDsISAATNK -1 28436950 YES miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. 0.2 SIGNOR-265894 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Ser385 RYSDTTDsDPENEPF 9606 BTO:0001938 15987703 YES lperfetto We provide evidence suggesting that LKB1 phosphorylates PTEN at residue S385 in combination either with S380, T382 or T383 0.605 SIGNOR-247446 IDH3A protein P50213 UNIPROT IDH complex SIGNOR-C396 SIGNOR form complex binding 9606 28139779 YES miannu Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 0.729 SIGNOR-266248 BTK protein Q06187 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 YES lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated 0.494 SIGNOR-98086 NDUFV2 protein P19404 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.86 SIGNOR-262184 HOXC10 protein Q9NYD6 UNIPROT LAMB2 protein P55268 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000298 10835276 YES Luana The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells. 0.2 SIGNOR-261645 SNRPG protein P62308 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.729 SIGNOR-270659 SHPK protein Q9UHJ6 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity phosphorylation 9606 22682222 YES miannu The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose 0.8 SIGNOR-267084 MAPK14 protein Q16539 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 12589053 NO fspada Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma.  0.395 SIGNOR-210090 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr642 RGVHHIDyYKKTSNG 9606 BTO:0001130 18670643 YES lperfetto Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4. 0.2 SIGNOR-179776 TRAF6 protein Q9Y4K3 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity 9606 BTO:0000007 16371247 NO The activation of Cot-MKK1-ERK1/ERK2 signalling pathway by IL-1 is dependent on the activity of the transducer protein TRAF6. 0.418 SIGNOR-252254 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser518 PSTSKAVsPPHLDGP 9606 BTO:0000551 16873060 YES gcesareni Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517. 0.342 SIGNOR-148306 LMNA protein P02545 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 23401537 NO lperfetto Mammalian lamin meshworks consist of two types of lamin proteins, A type and B type, and it has been reported that nuclear blebs are enriched in A-type lamins. 0.7 SIGNOR-83706 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191481 CIITA protein P33076 UNIPROT S100A4 protein P26447 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17143014 NO miannu IFN-gamma represses S100A4 promoter activity through induction of the class II transactivator (CIITA). 0.324 SIGNOR-253776 PEX1 protein O43933 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 NO The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis. 0.7 SIGNOR-253616 ziprasidone chemical CHEBI:10119 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258500 DUOX2 protein Q9NRD8 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.7 SIGNOR-264720 RAPH1 protein Q70E73 UNIPROT ENAH protein Q8N8S7 UNIPROT up-regulates activity binding 9606 20417104 YES miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. 0.545 SIGNOR-268425 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-138471 PPARGC1A protein Q9UBK2 UNIPROT CAV3 protein P56539 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 NO Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. 0.2 SIGNOR-254261 ACTL6B protein O94805 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.682 SIGNOR-270758 GRIK1 protein P39086 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264942 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser1006 GHGVRRAsDPVRTGS 9606 10693759 YES lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. 0.467 SIGNOR-75339 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCG protein P05129 UNIPROT down-regulates chemical inhibition 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-190356 PRC1 protein O43663 UNIPROT KIF23 protein Q02241 UNIPROT up-regulates activity binding 9606 15297875 YES miannu These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins. 0.573 SIGNOR-265989 HBA1 protein P69905 UNIPROT CYP2E1 protein P05181 UNIPROT up-regulates activity 9606 BTO:0000575 19325051 NO Regulation miannu Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. 0.2 SIGNOR-251765 EGFR protein P00533 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates phosphorylation Tyr66 LHQEDNDyINASLIK 9606 9355745 YES llicata After binding to egfr, ptp1b becomes tyrosine-phosphorylated at tyr-66 phosphorylation of ptp1b by egfr enhances its catalytic activity 0.759 SIGNOR-52950 MID2 protein Q9UJV3 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 35266954 YES miannu The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity. 0.2 SIGNOR-278763 TFEB protein P19484 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; 0.391 SIGNOR-276559 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 11108261 YES lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. 0.2 SIGNOR-244243 SCF-FBW7 complex SIGNOR-C135 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 21282377 YES miannu  These data suggest that the E3 ligase SCFFbxw7-α degrades p-DEK in a GSK-3β–dependent manner.Therefore, the phosphorylation of DEK by GSK-3β is a crucial step to mediate Tpm RNA splicing. 0.289 SIGNOR-276304 NKD1 protein Q969G9 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 BTO:0000671 15064403 YES gcesareni Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation 0.703 SIGNOR-123695 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.621 SIGNOR-161581 RRAGD protein Q9NQL2 UNIPROT RAGBD complex SIGNOR-C116 SIGNOR form complex binding 9606 20381137 YES gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant 0.78 SIGNOR-228182 CAMK2G protein Q13555 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser568 PQATRQTsVSGPAPP 3118371 YES llicata Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II. 0.447 SIGNOR-250707 PPP1CA protein P62136 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 16630891 YES We have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins 0.271 SIGNOR-251649 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization phosphorylation Ser104 KDHSGSEsPISDEEE 9606 24662826 YES miannu At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. 0.287 SIGNOR-276629 beta-Funaltrexamine chemical CHEBI:81527 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258772 SLBP protein Q14493 UNIPROT H2BC20P protein Q6DN03 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265382 RBX1 protein P62877 UNIPROT Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR form complex binding 9606 BTO:0001109 phosphorylation:Thr286 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1  0.844 SIGNOR-271626 A4/b7 integrin complex SIGNOR-C187 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269031 GSK3B protein P49841 UNIPROT CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 YES lperfetto We have previously shown that both basal and camp-induced degradation of cyclin d3 in reh cells is dependent on thr-283 phosphorylation by glycogen synthase kinase-3beta (gsk-3beta). 0.434 SIGNOR-142880 HARS1 protein P12081 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270803 ZSTK-474 chemical CHEBI:90545 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252646 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12270934 NO lperfetto We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process. 0.2 SIGNOR-244773 MAVS protein Q7Z434 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity binding 9606 25636800 YES miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. 0.832 SIGNOR-260144 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser31 QDVLGEEsPLGKPAM 9606 SIGNOR-C14 SIGNOR-C14 12657630 YES IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKK≈í‚⧠mediates IKK≈í‚â• phosphorylation under physiologic signaling conditions. IKK≈í‚â• is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the I≈í‚à´B kinase complex.both Tax and TNF induce phosphorylation of human IKK≈í‚â• at Ser-31, Ser-43, and Ser-376. 0.962 SIGNOR-251285 AMOT protein Q4VCS5 UNIPROT YAP1 protein P46937 UNIPROT down-regulates relocalization 9606 BTO:0000567 21205866 YES gcesareni Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition. 0.733 SIGNOR-201135 RPS18 protein P62269 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.887 SIGNOR-262433 DLGAP5 protein Q15398 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264600 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000007 11154281 YES lperfetto We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253. 0.794 SIGNOR-252989 vatalanib chemical CHEBI:90620 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258309 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194952 COL4A6 protein Q14031 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 YES lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. 0.42 SIGNOR-272352 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Thr205 PLKTGEQtPPHEHIC 9534 BTO:0000298 12756254 YES miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. 0.879 SIGNOR-250127 CSNK2A1 protein P68400 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser149 RRGASDLsSEEGWRL -1 8954982 YES llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. 0.326 SIGNOR-250950 Apelin smallmolecule CID:56841713 PUBCHEM APLNR protein P35414 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257460 DAP3 protein P51398 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.761 SIGNOR-261459 LRFN1 protein Q9P244 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 NO miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. 0.7 SIGNOR-264100 FAM83A protein Q86UY5 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273761 AKT1S1 protein Q96B36 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.801 SIGNOR-205597 FSCN1 protein Q16658 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10090 BTO:0000526 21706053 NO miannu Plexin-B3 interacts with the actin-binding protein fascin-1. The present finding suggests fascin-1 as a potential effector of plexin-B3 to mediate the signal of Sema5A in glioma cells.Sema5A and plexin-B3 remodel F-actin cytoskeleton and induce fascin-1 translocation in glioma cells. 0.7 SIGNOR-268375 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT unknown phosphorylation Thr440 LDSCNSLtPKSTPVK BTO:0000007 10095772 YES llicata In summary, our work has identified several phosphorylation sites for cyclin A/Cdk2 in B-Myb and shown that mutation of at least one of these sites has a strong effect on the inducibility of the B-Myb transactivation potential by cyclin A/Cdk2. 0.718 SIGNOR-250738 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser26 GTASRPSsSRSYVTT -1 11895474 YES miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.  0.307 SIGNOR-250237 Ub:E2 complex SIGNOR-C497 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271042 CAMK2A protein Q9UQM7 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Ser325 EQLSRELsTLRNLFK -1 1314426 YES llicata These studies implicate Ser276 of CIEBPP as the major in vim phosphorylation site for CaMKII. | Phosphorylation of serine at position 276 within the leucine zipper of C/EBP beta appeared to confer calcium-regulated transcriptional stimulation of a promoter that contained binding sites for C/EBP beta. 0.327 SIGNOR-250617 DNAJC3 protein Q13217 UNIPROT EIF2AK2 protein P19525 UNIPROT down-regulates activity binding 9606 BTO:0000567 25329545 YES gcesareni The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK 0.634 SIGNOR-246207 EDN1 protein P05305 UNIPROT EDNRA protein P25101 UNIPROT up-regulates binding 9606 16597412 YES gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. 0.88 SIGNOR-145759 Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT AGTR2 protein P50052 UNIPROT up-regulates activity binding 9606 32201502 YES MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways 0.2 SIGNOR-260237 HOXB3 protein P14651 UNIPROT OTX2 protein P32243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000946 9556594 YES Luana Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively 0.2 SIGNOR-261635 BDNF protein P23560 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32603820 NO miannu BDNF is a central driver of synaptic plasticity and memory formation and its decreased levels may contribute to the degeneration of specific neuronal populations and progressive atrophy of neurons in the AD-affected brain 0.7 SIGNOR-265063 UQCRFS1 protein P47985 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.936 SIGNOR-262190 CSNK2A1 protein P68400 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser203 PTETGESsQAEENIE -1 1828073 YES llicata Phosphorylation of neuromodulin (GAP-43) by casein kinase II. Identification of phosphorylation sites and regulation by calmodulin.| 0.307 SIGNOR-250867 PTPN1 protein P18031 UNIPROT PITX1 protein P78337 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr179 EDVYAAGySYNNWAA 9606 27752061 YES lperfetto PTP1B dephosphorylates PITX-1 at Y160, 175 and Y179.|Through directly dephosphorylating PITX-1 at Y160, Y175 and Y179, PTP1B promoted proteasomal degradation of PITX-1, thus leaded in downregulating p120RasGAP and CRC cell survival. 0.354 SIGNOR-276973 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Thr568 SPGVPMQtPCFTLQY 9606 BTO:0000567 10806207 YES llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. 0.603 SIGNOR-77220 CHD2 protein O14647 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 29962935 YES miannu CHD2 also showed an interaction with MyoD, a master regulator of skeletal muscle differentiation, and together MyoD and CHD2 bind to myogenic gene promoters. 0.2 SIGNOR-264525 SCN9A protein Q15858 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 YES miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. 0.8 SIGNOR-253403 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269342 PRKCA protein P17252 UNIPROT ITPKB protein P27987 UNIPROT down-regulates activity -1 9374536 YES lperfetto However, when assayed in the presence of calcium/calmodulin, the activity of the B isoform was decreased following phosphorylation by either protein kinase. 0.36 SIGNOR-248990 INS protein P01308 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity 10116 15069075 NO lperfetto The mechanism by which the phosphorylation of ser307 or ser318 inhibits irs-1 tyrosine phosphorylation is not known. Prolonged insulin-stimulation inhibits irs-1 binding to the phosphorylated npey motif in the juxta-membrane region of the irbeta -subunit. 0.679 SIGNOR-236625 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC10 protein Q969S8 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-202108 PPP2CA protein P67775 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 24726876 YES miannu RACK1 Negatively Regulates the Type I IFN pathway. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. 0.314 SIGNOR-260944 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Ser469 AHEENPEsILDEHVQ -1 17318175 YES lperfetto Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling. 0.784 SIGNOR-249192 5-carboxamidotryptamine chemical CHEBI:48292 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258888 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 9271428 YES gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. 0.2 SIGNOR-50598 2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide chemical CHEBI:125569 ChEBI PPARD protein Q03181 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001950 27489280 YES lperfetto We performed reporter assays to examine the effect of NeoB on the transcriptional activity of specific nuclear hormone receptors, including PPARs, retinoic acid receptor (RAR), ER, and LXR, in uninfected Huh7-25 cells (Fig. 3A). NeoB did not have a significant effect [...] in contrast to the transcriptional repression by known antagonists as positive controls (GW6471, GSK0660, FH535, Ro41-5253, and 4-hydroxytamoxifen) (Fig. 3A) 0.8 SIGNOR-262014 PKN1 protein Q16512 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 14970201 YES lperfetto Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules. 0.291 SIGNOR-122191 CASK protein O14936 UNIPROT CASK-Mint1-Veli complex complex SIGNOR-C561 SIGNOR form complex binding 9606 BTO:0000938 16842202 YES miannu The CASK-Mint1-Veli complex acts as an adaptor protein complex interacting with -neurexin, the current model proposes that the CASK- Mint1-Veli complex functions as a nucleation site for the assembly of proteins involved in synaptic junctions and synaptic vesicle exocytosis (Fig. 3a). 0.845 SIGNOR-278899 LIN7C protein Q9NUP9 UNIPROT CASK-Mint1-Veli complex complex SIGNOR-C561 SIGNOR form complex binding 9606 BTO:0000938 16842202 YES miannu The CASK-Mint1-Veli complex acts as an adaptor protein complex interacting with -neurexin, the current model proposes that the CASK- Mint1-Veli complex functions as a nucleation site for the assembly of proteins involved in synaptic junctions and synaptic vesicle exocytosis (Fig. 3a). 0.779 SIGNOR-278900 ACTN1 protein P12814 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity by stabilization binding 9606 27871158 YES lperfetto Actin exists in polymer where filamin and α-actinin act as cross-linkers with approximately 1:10 ratios 0.7 SIGNOR-261852 EFNA2 protein O43921 UNIPROT EPHA6 protein Q9UF33 UNIPROT up-regulates binding 9606 10072375 YES tpavlidou Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8) 0.749 SIGNOR-65419 SNAP25 protein P60880 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR form complex binding 9606 BTO:0000938 30267828 YES miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. 0.958 SIGNOR-263967 POT1 protein Q9NUX5 UNIPROT RPA1 protein P27694 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 YES lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA 0.294 SIGNOR-263325 GSK3B protein P49841 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr273 TTWTGSRtAPYTPNL 10090 BTO:0000944 25373906 YES miannu In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.  0.398 SIGNOR-276440 CH5132799 chemical CID:49784945 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190946 MAPKAPK2 protein P49137 UNIPROT TSC2 protein P49815 UNIPROT unknown phosphorylation Ser1254 TALYKSLsVPAASTA 9606 12582162 YES llicata Both in vitro and in vivo experiments demonstrate that the p38-activated kinase mk2 (also known as mapkapk2) is directly responsible for the phosphorylation of ser(1210). 0.658 SIGNOR-98201 tandutinib chemical CHEBI:90237 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258296 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser108 DVEELTAsQREAAER 9606 19647517 YES lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry 0.962 SIGNOR-187388 NMDA receptor_2B complex SIGNOR-C348 SIGNOR CAMK2A protein Q9UQM7 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD 0.679 SIGNOR-264215 ITSN1 protein Q15811 UNIPROT CDC42 protein P60953 UNIPROT up-regulates binding 9606 15824104 YES gcesareni Full-length intersectin-l exhibited little ability to stimulate nucleotide exchange on cdc42 0.848 SIGNOR-135377 GADD45GIP1 protein Q8TAE8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.64 SIGNOR-262385 TPR protein P12270 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates binding 9606 18981471 YES miannu Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20). 0.309 SIGNOR-181975 FYN protein P06241 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation 9606 23150273 YES miannu Subsequently, Lck and Fyn phosphorylate and activate the Syk family kinase ZAP-70 when it is recruited to the phosphorylated ITAM motifs xref . 0.573 SIGNOR-279043 NEK2 protein P51955 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates phosphorylation Ser14 LKKSFQDsLEDIKKR 9606 17621308 YES lperfetto Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507) 0.2 SIGNOR-156878 GRK6 protein P43250 UNIPROT DRD2 protein P14416 UNIPROT down-regulates activity phosphorylation 9606 26694375 YES miannu GRK6 is located predominantly in dopaminergic neurons [ xref ] and functionally phosphorylates DRD2. 0.448 SIGNOR-279046 PRDM1 protein O75626 UNIPROT FCER2 protein P06734 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000776 11342629 NO In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability 0.256 SIGNOR-253926 CCKAR protein P32238 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.265 SIGNOR-256906 EPX protein P11678 UNIPROT PRG2 protein P13727 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 YES miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. 0.434 SIGNOR-261703 RPS6KA1 protein Q15418 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser1798 GQRKRLIsSVEDFTE 9606 BTO:0000007 15342917 YES lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 0.767 SIGNOR-128634 PTTG1 protein O95997 UNIPROT LGALS1 protein P09382 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002428 19351864 NO miannu PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR. 0.2 SIGNOR-255068 SLIT1 protein O75093 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding 9606 16226035 YES gcesareni Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit. 0.896 SIGNOR-141111 BRAP protein Q7Z569 UNIPROT USP15 protein Q9Y4E8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23105109 YES miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. 0.267 SIGNOR-272029 OGDC complex SIGNOR-C397 SIGNOR 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 15953811 YES miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. 0.8 SIGNOR-266257 HIF1A protein Q16665 UNIPROT ALDOA protein P04075 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8955077 NO miannu we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1. 0.337 SIGNOR-254422 CSNK2A1 protein P68400 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser92 VAELTSLsDEDSGKG 9606 19923321 YES lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. 0.348 SIGNOR-161775 Orexin A smallmolecule CHEBI:80319 ChEBI HCRTR2 protein O43614 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257511 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 20516213 YES lperfetto The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. 0.479 SIGNOR-217153 PRKCB protein P05771 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser2 sTVHEILC -1 8898866 YES lperfetto A comparison of the phosphorylation patterns obtained identified Ser-II as the protein kinase C site responsible for regulating the annexin II-p11 interaction. Ser-II lies within the sequence mediating p11 binding, i.e. amino-acid residues 1 to 14 of annexin II, and phosphorylation at this site most likely leads to a direct spatial interference with p11 binding. 0.333 SIGNOR-248956 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 YES lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone 0.8 SIGNOR-268673 TRIM62 protein Q9BVG3 UNIPROT TRIM62 protein Q9BVG3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23402750 YES miannu A ubiquitination assay performed in HEK293T cells further confirmed the E3 ubiquitin ligase activity and self-ubiquitination activity of TRIM62 and the requirement of the RING finger domain. Importantly, the treatment of HEK293T cells with a proteasome inhibitor stabilized poly-ubiquitinated TRIM62, indicating that self-ubiquitination promoted the proteasomal degradation of TRIM62.  0.2 SIGNOR-272102 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser367 DTRSLEIsQSYTTTQ 9606 21149446 YES gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. 0.2 SIGNOR-170477 USP13 protein Q92995 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0006155 27923907 YES done miannu  In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. 0.353 SIGNOR-274124 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 10217147 YES Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. 0.91 SIGNOR-252839 AKT proteinfamily SIGNOR-PF24 SIGNOR RARA protein P10276 UNIPROT down-regulates phosphorylation Ser96 FVCQDKSsGYHYGVS 9606 BTO:0000551 16417524 YES miannu We report that akt, which is constitutively activated in nsclc cells, phosphorylates raralpha and inhibits its transactivation. / mutation of ser96 to alanine abrogated the suppressive effect of akt. 0.2 SIGNOR-143721 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.251 SIGNOR-268589 STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 BTO:0000782 22767500 NO lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. 0.7 SIGNOR-261900 IFNGR1 protein P15260 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR form complex binding 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. 0.741 SIGNOR-249485 GRK2 protein P25098 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser205 LCDFNPKsSKQCKDV 9606 22704991 YES llicata Moreover, we demonstrate that phosphorylation of ser204 in clcb is required for efficient endocytosis of a subset of gpcrs and identify g protein-coupled receptor kinase 2 (grk2) as a kinase that can phosphorylate clcb on ser204. Overexpression of clcb(s204a) specifically inhibits the endocytosis of those gpcrs whose endocytosis is grk2-dependent. 0.2 SIGNOR-197873 ZNRF3 protein Q9ULT6 UNIPROT FZD6 protein O60353 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 YES Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. 0.612 SIGNOR-260114 PIK3CD protein O00329 UNIPROT PIK3CD protein O00329 UNIPROT down-regulates phosphorylation Ser1039 NWLAHNVsKDNRQ 9606 10064595 YES gcesareni Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo in vitro autophosphorylation of p110delta completely down-regulates its lipid kinase activity. 0.2 SIGNOR-65186 Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 28347630 NO miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation 0.7 SIGNOR-266829 PRKCB protein P05771 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 YES lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. 0.364 SIGNOR-249084 FOXO3 protein O43524 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 BTO:0000007 14976264 NO lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress 0.7 SIGNOR-267283 EEF1A1P5 protein Q5VTE0 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269548 PPP2CA protein P67775 UNIPROT PREX2 protein Q70Z35 UNIPROT up-regulates activity dephosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 YES miannu PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. 0.2 SIGNOR-277184 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR POLL protein Q9UGP5 UNIPROT up-regulates quantity by stabilization phosphorylation Thr553 GPGRVLPtPTEKDVF 9606 BTO:0000007 18688254 YES miannu Pol λ phosphorylation prevents degradation. Recently, we identified Pol λ as an interaction partner of cyclin-dependent kinase 2 (CDK2) that is central to the cell cycle G1/S transition and S-phase progression. This interaction leads to in vitro phosphorylation of Pol λ, and its in vivo phosphorylation pattern during cell cycle progression mimics the modulation of CDK2/cyclin A. Experiments with phosphorylation-defective mutants suggest that phosphorylation of Thr 553 is important for maintaining Pol λ stability, 0.336 SIGNOR-273595 DYRK4 protein Q9NR20 UNIPROT DYRK4 protein Q9NR20 UNIPROT up-regulates activity phosphorylation Tyr264 SSCYEHQkVYTYIQS 9606 21127067 YES Manara Autophosphorylation of DYRK4 in the Activation Loop Is Required for Kinase Activity 0.2 SIGNOR-260827 CDC42BPA protein Q5VT25 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity phosphorylation Ser234 MEDGTVQsSVAVGTP 9534 BTO:0000298 11283256 YES miannu N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D). 0.2 SIGNOR-275974 IMPDH2 protein P12268 UNIPROT MKI67 protein P46013 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30518405 NO miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. 0.2 SIGNOR-260958 CSNK1E protein P49674 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity phosphorylation Ser349 QNWEEADsMKSSVES 9606 26928339 YES miannu  CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3.  0.307 SIGNOR-277212 LYL1 protein P12980 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 NO miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. 0.2 SIGNOR-198276 Linsitinib chemical CID:11640390 PUBCHEM INSR protein P06213 UNIPROT down-regulates activity chemical inhibition 10090 24712877 YES lperfetto Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice 0.8 SIGNOR-262029 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT up-regulates activity phosphorylation Thr143 ALKHVKEtQPPETVQ -1 BTO:0000567 24485452 YES In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents 0.318 SIGNOR-253557 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP2K4 protein P45985 UNIPROT down-regulates activity phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0002181 11707464 YES miannu Akt (Protein Kinase B) Negatively Regulates SEK1 by Means of Protein Phosphorylation. In vitro and in vivo (32)P labeling indicated that Akt phosphorylated SEK1 on serine 78. The SEK1 mutant SEK1(S78A) was resistant to Akt-induced inhibition.  0.2 SIGNOR-275980 NPFF protein O15130 UNIPROT NPFFR1 protein Q9GZQ6 UNIPROT up-regulates binding 9606 11024015 YES gcesareni Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems 0.746 SIGNOR-82916 GATA6 protein Q92908 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates quantity by expression transcriptional regulation 19666519 NO lperfetto Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. 0.245 SIGNOR-253149 PAK1 protein Q13153 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser118 QVKIWRRsYDVPPPP 9606 BTO:0000130 12189148 YES Activated pak1 gcesareni Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. 0.2 SIGNOR-91594 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr107 AYPATGPyGAPAGPL 9606 20600357 YES llicata In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility. 0.355 SIGNOR-166493 HSPA8 protein P11142 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR form complex binding 9606 BTO:0000567 20176811 YES miannu In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27. 0.62 SIGNOR-271972 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser324 LTSVSRGsSLKILSK 9606 10521508 YES Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. 0.2 SIGNOR-260898 ARID1A protein O14497 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.758 SIGNOR-270743 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 12707358 YES lperfetto These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. 0.363 SIGNOR-100784 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr80 QDNVDQTySEELCYT -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.245 SIGNOR-273558 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264928 AP1G1 protein O43747 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 YES lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) 0.823 SIGNOR-260687 KPC complex SIGNOR-C523 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000944 15531880 YES miannu  We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation.  Polyubiquitination activity of KPC was apparent with only Ubc4 or UbcH5A. 0.44 SIGNOR-271513 tryptophan smallmolecule CHEBI:27897 ChEBI Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates quantity precursor of 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) 0.8 SIGNOR-270516 PDIA6 protein Q15084 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity 10090 BTO:0000944 24508390 YES A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine148 in the luminal domain of the sensor, 0.317 SIGNOR-256536 GF proteinfamily SIGNOR-PF39 SIGNOR RTKs proteinfamily SIGNOR-PF38 SIGNOR up-regulates activity binding 9606 17306385 YES miannu Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. 0.2 SIGNOR-256163 TIMM50 protein Q3ZCQ8 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.647 SIGNOR-267696 CDK5 protein Q00535 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates activity phosphorylation Ser1123 RSRSRSRsPRPRGDS 10116 BTO:0004102 12824184 YES llicata We demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival.  0.341 SIGNOR-250663 CABLES1 protein Q8TDN4 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity binding -1 25361894 YES miannu Our study also showed that Cables1 increases the level of p21 and decreases the level of pRb, but does not affect the other cell cycle-related proteins we studied. Induction of apoptosis by Cables1, which occurs partially through inhibiting Cdk2 activity and upregulating p21, is prevented by Akt phosphorylation and 14-3-3 binding. 0.492 SIGNOR-276759 CABIN1 protein Q9Y6J0 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates 9606 17172641 NO gcesareni Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity. 0.669 SIGNOR-151205 MAPK3 protein P27361 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 19327116 YES gcesareni Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes. 0.667 SIGNOR-184917 OSI-420 chemical CID:18924996 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-195248 DNMT1 protein P26358 UNIPROT RELN protein P78509 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 NO miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 0.432 SIGNOR-254575 TXK protein P42681 UNIPROT TXK protein P42681 UNIPROT up-regulates phosphorylation Tyr91 KIQVKALyDFLPREP 9606 12081135 YES lperfetto Evidence of autophosphorylation in txk: y91 is an autophosphorylation site. the results suggest that phosphorylated txk is an active form to promote ifn-gamma synthesis 0.2 SIGNOR-89844 NFIB protein O00712 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.282 SIGNOR-268897 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CACNA1B protein Q00975 UNIPROT up-regulates activity phosphorylation Ser446 ADLCAVGsPFARASL 9534 16406008 YES miannu Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs. 0.2 SIGNOR-262967 ICE2 protein Q659A1 UNIPROT ELL/ICE2 complex SIGNOR-C49 SIGNOR form complex binding 9606 BTO:0001271 22195968 YES miannu The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes. 0.643 SIGNOR-193603 PAX2 protein Q02962 UNIPROT WT1 protein P19544 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16631587 YES Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter. 0.599 SIGNOR-252290 AKT1 protein P31749 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Thr700 MESRRQAtVSWDSGG 9606 31138602 YES miannuccelli In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis . 0.431 SIGNOR-279777 AKT1 protein P31749 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity phosphorylation Thr145 QTRDRIGtGGSVVDC 9606 27036023 YES miannuccelli Furthermore, phosphorylation of Smurf1 by Akt1 was carried out specifically on the T145 residue, as mutation of this site abolished recognition of Smurf1 by the Akt1 phosphorylation motif antibody (Figure 5D).|We also identified that Smurf1 itself is targeted for phosphorylation by Akt1 and Akt2, regulating its stability. 0.352 SIGNOR-279778 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-269967 DAB2IP protein Q5VWQ8 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 BTO:0001033 26512963 YES miannu DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. 0.346 SIGNOR-254761 LSM-1231 chemical CHEBI:91471 ChEBI NTRK2 protein Q16620 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259759 CASP3 protein P42574 UNIPROT DFFB protein O76075 UNIPROT up-regulates cleavage 9606 9108473 YES gcesareni Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation 0.683 SIGNOR-47419 Laminin-5 complex SIGNOR-C184 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 8832392 YES lperfetto The initial adhesion of PA-JEB and normal keratinocytes to laminin-1 and laminin-5, both ligands for alpha 6 beta 1 and alpha 6 beta 4, was similar. 0.597 SIGNOR-253253 HTRA2 protein O43464 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 11583623 YES gcesareni Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo. 0.709 SIGNOR-110834 TRRAP protein Q9Y4A5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.743 SIGNOR-269288 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1139 TCSPQPEyVNQPDVR -1 1706616 YES  Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. 0.2 SIGNOR-251127 CREBBP protein Q92793 UNIPROT CSK protein P41240 UNIPROT up-regulates binding 9606 10801129 YES gcesareni Here we present cbp--a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the sh2 domain of csk. Cbp is involved in the membrane localization of csk and in the csk-mediated inhibition of c-src. 0.534 SIGNOR-77139 SPTB protein P11277 UNIPROT Erythrocytic spectrin complex SIGNOR-C384 SIGNOR form complex binding 9606 BTO:0000424 24302288 YES lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell 0.741 SIGNOR-266024 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser12 TKRTADSsSSEDEEE 9606 21245376 YES gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. 0.367 SIGNOR-171699 FOXO3 protein O43524 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 YES miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. 0.248 SIGNOR-260100 AKT2 protein P31751 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser326 SSVDTLLsPTALIDS 9606 35080342 YES miannuccelli AKT2 also phosphorylated S326 of HSF1 but showed weak ability to activate HSF1.|AKT2 promoted a significant increase in HSF1 activity , but the effect was modest while AKT3 had no significant effect on HSF1 activity ( Fig. 1A-C ) . 0.31 SIGNOR-279779 XXYLT1 protein Q8NBI6 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 22117070 YES Xylosylation in ER membrane gcesareni Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains. 0.313 SIGNOR-254333 MYOG protein P15173 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 7739551 YES Simone Vumbaca [...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site. 0.432 SIGNOR-255642 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR AURKB protein Q96GD4 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0002268 23370391 YES miannu The SCF complex contains a catalytic core consisting of Skp1, Cullin1, and the E2 ubiquitin-conjugating (Ubc) enzyme and a F box component that acts as a receptor targeting numerous substrates via phosphodegron elicited interactions. our screening studies suggested that FBXL2 also targets Aurora B protein for ubiquitination and degradation. 0.29 SIGNOR-272098 NUMA1 protein Q14980 UNIPROT TUBA4A protein P68366 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.513 SIGNOR-116788 RPL37A protein P61513 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.825 SIGNOR-262462 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT unknown phosphorylation Ser7 sSAEGAAK 10090 12773393 YES lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin. 0.365 SIGNOR-249215 KAT2B protein Q92831 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 11058129 YES gcesareni P/caf was found to interact directly with smad3 in vitro. Moreover, smad2 and smad3 interacted with p/caf upon tgf-beta type i receptor activation in cultured mammalian cells. these results demonstrate the co-activator function of p/caf for smad2 and smad3. 0.676 SIGNOR-83607 TTBK2 protein Q6IQ55 UNIPROT KIF2A protein O00139 UNIPROT down-regulates activity phosphorylation Ser135 SSAQQNGsVSDISPV 9534 26323690 YES Manara TTBK2 phosphorylates KIF2A primarily at growing MT ends and counteracts the depolymerization activity of KIF2A 0.406 SIGNOR-260926 THRA protein P10827 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 15650024 YES inferred from 70% of family members gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.43 SIGNOR-269851 HRH1 protein P35367 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256921 verteporfin chemical CHEBI:32293 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0005079 27073720 NO Verteporfin inhibits cell proliferation 0.7 SIGNOR-278127 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 SIGNOR-C15 22669845 YES gcesareni In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation 0.491 SIGNOR-197734 AKT2 protein P31751 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000150 12697749 YES lperfetto Akt2 interacts with and phosphorylates ask1 at ser-83 resulting in inhibition of its kinase activity 0.645 SIGNOR-100588 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity precursor of 9606 24929114 YES miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. 0.8 SIGNOR-268140 TJP2 protein Q9UDY2 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23829894 YES milica The Crumbs complex component AMOT co-localizes with MST1_ 2, LATS1_ 2 and YAP in a complex at the tight junction to control cell growth. Zona occludens-2 (ZO-2) in the tight junction, and a-catenin, b-catenin, or PTPN14 in the adherence junction, also bind to YAP_TAZ. 0.518 SIGNOR-230754 MCOLN1 protein Q9GZU1 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 26000950 YES Induction of autophagy and lysosomal biogenesis via TFEB required MCOLN1-mediated calcineurin activation, linking lysosomal calcium signaling to both calcineurin regulation and autophagy induction. 0.8 SIGNOR-255308 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 YES lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. 0.727 SIGNOR-40353 NEK9 protein Q8TD19 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser377 EKAGLPRsINTDTLS -1 22818914 YES miannu Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of γ-tubulin to the centrosome in mitotic cells. 0.426 SIGNOR-263016 PTGER1 protein P34995 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257194 FYN protein P06241 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.633 SIGNOR-268216 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR up-regulates activity chemical activation 26083061 YES lperfetto Respiratory chain complexes I–III depend on Fe-S clusters for function 0.8 SIGNOR-262137 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. 0.746 SIGNOR-272713 (-)-anisomycin chemical CHEBI:338412 ChEBI FOSB protein P53539 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-189629 PCSK7 protein Q16549 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation 9606 12435397 YES gcesareni In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site 0.2 SIGNOR-95622 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192892 KLHL7 protein Q8IXQ5 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000675 29032201 YES miannu Kelch-like protein 7 (KLHL7) is a component of Cul3-based Cullin-RING ubiquitin ligase. In this study, we report that KLHL7 increases terminal uridylyl transferase 1 (TUT1) ubiquitination involved in nucleolar integrity. 0.4 SIGNOR-272320 GRK3 protein P35626 UNIPROT C3AR1 protein Q16581 UNIPROT down-regulates activity phosphorylation 9606 21799898 YES lperfetto These findings suggest that in agonist-stimulated mast cells GRK2 and GRK3 may phosphorylate C3aR at the same or distinct sites to promote receptor desensitization. 0.2 SIGNOR-279781 GRK6 protein P43250 UNIPROT CXCR2 protein P25025 UNIPROT down-regulates quantity phosphorylation 9606 28529637 YES lperfetto GRK2 mainly phosphorylates CXCR1, while GRK6 mediates CXCR2 phosphorylation .|Overexpression of GRK6 or treatment with CXCR2 siRNA suppresses CXCR2 expression in dorsal root ganglion and significantly reduces pain in animal model of neuropathic pain , . 0.562 SIGNOR-279782 PTPN2 protein P17706 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation 9606 33603165 YES lperfetto Since PTPN2 dephosphorylates and inactivates Src [ xref ], the increase of pY439 might have resulted from reduced dephosphorylation or elevated Src activity or both. 0.72 SIGNOR-276996 caesium(1+) chemical CHEBI:49547 ChEBI KCNJ13 protein O60928 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9620703 YES miannu Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations 0.8 SIGNOR-258926 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.288 SIGNOR-276088 NBEA protein Q8NFP9 UNIPROT DLG3 protein Q92796 UNIPROT up-regulates activity binding BTO:0000227 23277425 YES lperfetto Interestingly, a recent proteomic analysis (Lauks et al., 2012) revealed that Nbea binds SAP102, which interacts with glutamate receptors early in the biosynthetic route and regulates their targeting. This finding, along with the interaction of Nbea with the glycine receptor beta subunit (del Pino et al., 2011), further strengthens the notion that Nbea targets neurotransmitter receptors to synapses. 0.42 SIGNOR-266004 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 10581258 YES gcesareni In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.461 SIGNOR-72691 CSNK2A2 protein P19784 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 23374587 YES The effect has been demonstrated using Q01105-2 miannu Ckii-mediated phosphorylation at ser9 hinders nuclear import of set 0.259 SIGNOR-200802 PPM1B protein O75688 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity dephosphorylation 9606 23320500 YES miannu Furthermore we show that PPM1B can directly dephosphorylate PPARgamma, both in intact cells and in vitro.|In addition PPM1B increases PPARγ-mediated transcription via dephosphorylation of Ser(112).|The serine/threonine phosphatase PPM1B (PP2Cbeta) selectively modulates PPARgamma activity. 0.372 SIGNOR-277073 GRM4 protein Q14833 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. 0.8 SIGNOR-264935 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 28713870 NO svumbaca These data argue that, in TH2 cells, STAT3 is required for T cell IL-10 production, which in turn reinforces its own expression 0.789 SIGNOR-256234 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CEP68 protein Q76N32 UNIPROT down-regulates quantity by destabilization ubiquitination 25503564 YES lperfetto We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCF(βTrCP) (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser 332, allowing recognition by βTrCP. 0.337 SIGNOR-275622 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251292 hsa-miR-491-5p mirna URS00001919B0_9606 RNAcentral BCL2L1 protein Q07817 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002575 25299770 YES We found that miR-491-5p efficiently induces apoptosis in IGROV1-R10 cells by directly inhibiting BCL-XL expression and by inducing BIM accumulation in its dephosphorylated form. 0.4 SIGNOR-277947 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2Q2 protein Q8WVN8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.511 SIGNOR-271329 RPS26 protein P62854 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.888 SIGNOR-262425 BDKRB1 protein P46663 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.447 SIGNOR-257411 ATM protein Q13315 UNIPROT AVEN protein Q9NQS1 UNIPROT up-regulates activity phosphorylation Ser308 NILPDQTsQDLKSKE -1 18571408 YES miannu Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site). 0.382 SIGNOR-262637 TFDP1 protein Q14186 UNIPROT CDK1 protein P06493 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.582 SIGNOR-253859 PPP3CC protein P48454 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 YES CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). 0.251 SIGNOR-248508 ATM protein Q13315 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 EGDDAEDsQGESEED 9606 BTO:0001109 17157788 YES lperfetto The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. |DNA damage stabilizes Che-1 protein|In addition, substitution of Che-1 Ser187 with an alanine (Che-1S187A) prevented Che-1 phosphorylation by ATM (Figure 2F), supporting this residue as an ATM-target site. 0.356 SIGNOR-264415 GRM3 protein Q14832 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 YES miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. 0.349 SIGNOR-264083 JAK2 protein O60674 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation 9606 9575217 YES gcesareni Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein 0.865 SIGNOR-56894 SPAG9 protein O60271 UNIPROT ABL1 protein P00519 UNIPROT unknown binding 9606 BTO:0000222 SIGNOR-C21 19470755 YES lperfetto We report that abl associates with both cdo and jlp during myoblast differentiation 0.527 SIGNOR-185765 HTR3E protein A5X5Y0 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 NO miannu The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release.  0.7 SIGNOR-264318 TERT protein O14746 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR up-regulates 11327115 NO lperfetto Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers 0.7 SIGNOR-252292 NMDA proteinfamily SIGNOR-PF56 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor 0.2 SIGNOR-264801 CAPN2 protein P17655 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 YES lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase 0.285 SIGNOR-251613 FAM83F protein Q8NEG4 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273751 ERBB3 protein P21860 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.707 SIGNOR-146861 GATA3 protein P23771 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21536859 NO miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. 0.2 SIGNOR-253920 FGFR3 protein P22607 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates activity phosphorylation Tyr15 RQLGDGTyGSVLLGR -1 30782830 YES miannu FGF signaling partially abolished ICK's kinase activity, through FGFR-mediated ICK phosphorylation at conserved residue Tyr15, which interfered with optimal ATP binding. 0.2 SIGNOR-277436 PKC proteinfamily SIGNOR-PF53 SIGNOR ARHGEF6 protein Q15052 UNIPROT down-regulates activity phosphorylation Ser684 GSSTRKDsIPQVLLP 9606 BTO:0000132 26507661 YES lperfetto Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex. 0.2 SIGNOR-272161 CCAR2 protein Q8N163 UNIPROT HDAC3 protein O15379 UNIPROT down-regulates activity binding 26158765 YES lperfetto Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation. 0.254 SIGNOR-267665 PDXP protein Q96GD0 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity dephosphorylation Ser3 sGVAVSDG -1 15580268 YES Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily. 0.447 SIGNOR-248764 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates activity chemical inhibition -1 23515850 YES lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro 0.8 SIGNOR-262022 GSK3A protein P49840 UNIPROT NEFH protein P12036 UNIPROT down-regulates activity phosphorylation 9606 8627328 YES lperfetto Our results demonstrate that whereas GSK-3 alpha, GSK-3 beta, and cdk-5 will all phosphorylate NF-H, they generate different antibody reactivity profiles. 0.254 SIGNOR-279783 GSK3B protein P49841 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by destabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9606 29107113 YES lperfetto A previous study has demonstrated that GSK3B triggers the degradation of BCL2 by inducing phosphorylation of BCL2 at Ser70, which induced autophagy by interrupting the interaction between BECN1 and BCL2 [32]. 0.2 SIGNOR-279784 CID 132010322 chemical CID:132010322 PUBCHEM BRD3 protein Q15059 UNIPROT down-regulates activity chemical inhibition 9606 31969702 YES Luana ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 0.8 SIGNOR-261104 SGK1 protein O00141 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE 10090 19965929 YES We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1-/- cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone. 0.606 SIGNOR-255925 MCM4 protein P33991 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 YES The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. 0.777 SIGNOR-261674 FGF6 protein P10767 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 YES gcesareni The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors. 0.752 SIGNOR-42380 DAXX protein Q9UER7 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 BTO:0000584 26428317 NO Telomere length must be maintained for the immortalization of malignant cells […] alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors 0.7 SIGNOR-256596 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates phosphorylation Tyr153 RGNADLAyILSMEPC 9606 15657060 YES gcesareni C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9. 0.514 SIGNOR-133260 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT down-regulates activity sumoylation 9606 BTO:0000007 16061479 YES miannu Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP 0.331 SIGNOR-225481 TSPAN12 protein O95859 UNIPROT NDP protein Q00604 UNIPROT up-regulates 9606 19837033 NO Genetic Interaction gcesareni Tspan12 genetically interacts with norrin or lrp5 0.561 SIGNOR-188661 AKT1 protein P31749 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates activity phosphorylation Ser897 RVSIRLPsTSGSEGV 9606 35869144 YES lperfetto As non-canonical EphA2 activation requires phosphorylation of EphA2 at serine 897 by pAkt (Fig.\u00a02b), we sought to determine the effect of PTEN-mediated Akt regulation on invasion. 0.356 SIGNOR-279787 hsa-miR-582-3p mirna URS00002573C3_9606 RNAcentral SFRP1 protein Q8N474 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003009 26468775 YES Parnian MiR-582-3p directly targets multiple negative regulators of the Wnt pathway. | Overall, our results demonstrate that miR-582-3p activates Wnt signalling by targeting AXIN2, DKK3 and SFRP1 enhances stem cell-like traits; and leads to tumour recurrence and poor prognosis in NSCLC patients. 0.4 SIGNOR-278019 DDOST protein A0A024RAD5 UNIPROT OST-A complex complex SIGNOR-C535 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.755 SIGNOR-272062 PI-103 chemical CHEBI:90524 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206169 PD318088 chemical CID:10231331 PUBCHEM MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205740 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 12058027 YES gcesareni Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs. 0.2 SIGNOR-89431 CEBPD protein P49716 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 10649448 NO gcesareni We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPdelta; C/EBPdelta then binds to PPARgamma2 promoter and transactivates PPARgamma2 gene expression. 0.593 SIGNOR-253062 HES1 protein Q14469 UNIPROT PTGDS protein P41222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002605 15743775 NO miannu knock-down of Hes-1 mRNA by RNA interference significantly enhanced the L-PGDS mRNA level, indicating that the L-PGDS gene expression is repressed by the Notch-Hes signaling. 0.2 SIGNOR-255424 IRF4 protein Q15306 UNIPROT FCER2 protein P06734 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11342629 NO IFN-regulatory factor 4 (IRF-4) plays a critical role in mature B cell function. Using the transcriptional regulation of the human B cell activation marker CD23 as a model system, we have previously demonstrated that IRF-4 is induced in response to B cell-activating stimuli and that it acts as a transactivator of CD23 gene expression. 0.267 SIGNOR-253933 AT-406 chemical CID:25022340 PUBCHEM BIRC3 protein Q13489 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189957 RNF111 protein Q6ZNA4 UNIPROT ESRP2 protein Q9H6T0 UNIPROT up-regulates activity ubiquitination 9606 26522722 YES miannu These findings suggest that Arkadia ubiquitinates ESRP2 and potentiates the splicing function of ESRP2 ( ). 0.389 SIGNOR-278613 HIPK2 protein Q9H2X6 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Thr880 QTIVIPDtPSPTVSV 9606 BTO:0002181 24145406 YES miannu  Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. 0.2 SIGNOR-276601 NFYA protein P23511 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15496512 NO miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. 0.2 SIGNOR-252232 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-119996 RAB22A protein Q9UL26 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 0.48 SIGNOR-260621 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr120 HKFNVTGtPEQYVPY 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275596 N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide chemical CHEBI:91467 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189942 lisinopril chemical CHEBI:43755 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 12540854 YES Monia The structure of tACE bound to the potent inhibitor lisinopril shows that the inhibitor binds in a highly ordered (overall B-factor of 15.26 A˚ 2) 0.8 SIGNOR-261070 ATR protein Q13535 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser717 KDGGPVTsQESGQKL 9606 16943440 YES lperfetto In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents 0.672 SIGNOR-149305 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr514 TFCGTPDyIAPEILQ 9534 BTO:0000298 11381116 YES The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2). 0.525 SIGNOR-251386 GSK3B protein P49841 UNIPROT RBM38 protein Q9H0Z9 UNIPROT down-regulates phosphorylation Ser195 DQYPYAAsPATAASF 9606 24142875 YES lperfetto Here, we showed that rnpc1 is phosphorylated at ser195 by glycogen synthase kinase 3 (gsk3). We also provided evidence that ser195 phosphorylation converts rnpc1 from a repressor to an activator of p53. 0.2 SIGNOR-203011 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248745 BAZ1B protein Q9UIG0 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 YES miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 0.561 SIGNOR-268826 PRKDC protein P78527 UNIPROT MCC protein P23508 UNIPROT up-regulates activity phosphorylation Ser120 LRSELSQsQHEVNED 9606 BTO:0001109 21779472 YES miannu MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. 0.2 SIGNOR-273531 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates phosphorylation Ser1150 LERGRKVsIVSKPVL 9606 BTO:0000887;BTO:0001260 19103606 YES gcesareni Rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser(1150) and attenuated p190a rhogap activity in cos7 cells. 0.414 SIGNOR-182849 CYLD protein Q9NQC7 UNIPROT CCND1 protein P24385 UNIPROT up-regulates 9606 BTO:0001286 16713561 NO gcesareni Cyld was also recently shown to deubiquitylate the p50 and p52 co-activator bcl-3, leading to both cyclin d1 expression and proliferation in keratinocytes 0.391 SIGNOR-146777 SOD1 protein P00441 UNIPROT hydrogen peroxide smallmolecule CHEBI:16240 ChEBI up-regulates quantity chemical modification 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272287 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 28139779 YES miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 0.8 SIGNOR-266250 DAB2 protein P98082 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT up-regulates activity binding 9606 27858941 YES miannu In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation. 0.521 SIGNOR-254744 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity dephosphorylation 9606 BTO:0000093 11154267 YES lperfetto Expression of Cdc25A mRNA and protein was induced by E(2) in control and p16(INK4a)-expressing MCF-7 cells; however, functional activity of Cdc25A was inhibited in cells expressing p16(INK4a). Inhibition of Cdc25A activity in p16(INK4a)-expressing cells was associated with depressed Cdk2 activity 0.829 SIGNOR-245449 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9606 9687510 YES lperfetto Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3) 0.762 SIGNOR-252753 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser670 CGKRFTRsDELQRHK 9606 BTO:0000887;BTO:0001260 18258854 YES llicata Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter. 0.485 SIGNOR-160766 TFAP2A protein P05549 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 NO miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 0.279 SIGNOR-255402 FBXL12 protein Q9NXK8 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 10090 BTO:0001078 26124079 YES miannu We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members. 0.683 SIGNOR-272816 JAK2 protein O60674 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Tyr333 QRYRLVPyGNHSYLE 9606 BTO:0001535 34131122 YES miannu Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. 0.298 SIGNOR-277567 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258289 (-)-selegiline chemical CHEBI:9086 ChEBI MAOB protein P27338 UNIPROT down-regulates activity chemical inhibition -1 21377879 YES Luana All the compounds were found as extremely potent and selective towards MAO-B, (Table 2) with at least 100 times more potent than the positive control selegiline.  0.8 SIGNOR-258136 MEF2D protein Q14814 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 7739551 YES lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. 0.571 SIGNOR-238715 PIK3R1 protein P27986 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 YES lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.936 SIGNOR-242637 ATM protein Q13315 UNIPROT RAD50 protein Q92878 UNIPROT unknown phosphorylation Ser635 KLFDVCGsQDFESDL 9606 17570479 YES llicata The ms/ms fragmentation spectra (figure s7) confirmed the phosphorylation of rad50 at the predicted atm substrate site, s635, in agreement with published data 0.813 SIGNOR-156077 MAP3K14 protein Q99558 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity phosphorylation 9606 20651737 YES lperfetto As nik levels increase, nik presumably becomes activated by autophosphorylation (p). 0.2 SIGNOR-167063 EXOC1 protein Q9NV70 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.889 SIGNOR-270784 serotonin smallmolecule CHEBI:28790 ChEBI HTR3D protein Q70Z44 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264292 MYOD1 protein P15172 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 17111365 NO Regulation miannu Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. 0.387 SIGNOR-251958 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation 9606 19237534 YES inferred from 70% family members lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. 0.2 SIGNOR-270201 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NME1 protein P15531 UNIPROT up-regulates phosphorylation Ser120 GRNIIHGsDSVESAE 9606 18234856 YES lperfetto Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates. 0.272 SIGNOR-216825 PHF2 protein O75151 UNIPROT ARID5B protein Q14865 UNIPROT up-regulates activity binding 9606 BTO:0000007 21532585 YES miannu We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity. 0.559 SIGNOR-264514 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10428798 YES lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. 0.419 SIGNOR-217292 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 31422819 YES miannu Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. 0.8 SIGNOR-266921 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 20577053 YES gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 0.742 SIGNOR-166372 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr326 EVLEDNDyGRAVDWW 9534 BTO:0004055 11445557 YES lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. 0.676 SIGNOR-252623 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr163 FDAILYYyQSGGRIR 9606 BTO:0000938 BTO:0000671 19166614 YES gcesareni Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein. 0.378 SIGNOR-183523 SMURF1 protein Q9HCE7 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. 0.659 SIGNOR-195651 RASGEF1B protein Q0VAM2 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.299 SIGNOR-161481 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser197 KEDRSASsGAEGDVS -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.321 SIGNOR-273963 CSNK2A2 protein P19784 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser261 TSGEDTLsDSDDEDD -1 1425701 YES llicata Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263. 0.368 SIGNOR-251014 GRM8 protein O00222 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 YES miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. 0.439 SIGNOR-264081 YAP1 protein P46937 UNIPROT TEAD2 protein Q15562 UNIPROT up-regulates binding 9606 23431053 YES Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. 0.883 SIGNOR-201468 Av/b3 integrin complex SIGNOR-C177 SIGNOR KRAS protein P01116 UNIPROT up-regulates activity binding 9606 BTO:0000584 32745890 YES Oncogenic RAS miannu Oncogenic RAS requires a protein scaffold to induce downstream signaling and macropinocytosis, three separate studies have identified upstream and downstream regulators that help drive this process in cancer cells. Anchorage-independent growth of cancer cells is supported by avb3 integrins which can be clustered by the extracellular lectin, galectin-3 to drive mutant RAS-mediated macropinocytosis for nutrient supplementation and growth of anchorage-independent cells. Secreted galectin-3 was found to bind to the N-glycans on surface avb3 integrins, clustering the integrins on the surface of the nonadherent cells for the recruitment of mutant KRAS as a signaling platform for inducing macropinocytosis. 0.356 SIGNOR-277742 FBXL12 protein Q9NXK8 UNIPROT ALDH3B1 protein P43353 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001078 26124079 YES miannu We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members. 0.321 SIGNOR-272815 PRKAR2A protein P13861 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.895 SIGNOR-258757 CDK2 protein P24941 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 YES gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. 0.676 SIGNOR-187607 RUVBL2 protein Q9Y230 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.735 SIGNOR-269291 RPS6KA1 protein Q15418 UNIPROT OSTF1 protein Q92882 UNIPROT down-regulates activity phosphorylation Ser202 TDAVRTLsNAEDYLD 9606 BTO:0000567 21501342 YES done miannu SH3P2 was phosphorylated on Ser(202) by ribosomal S6 kinase (RSK) in an ERK pathway-dependent manner, and such phosphorylation inhibited the ability of SH3P2 to suppress cell motility.  0.352 SIGNOR-273838 CASP3 protein P42574 UNIPROT GSN protein P06396 UNIPROT down-regulates cleavage 9606 BTO:0000130 9323209 YES amattioni Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation. 0.638 SIGNOR-51652 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DIAPH1 protein O60610 UNIPROT up-regulates quantity by stabilization phosphorylation Thr768 PVLPFGLtPKKLYKP 9606 BTO:0002588 23325789 YES miannu  DIAPH1 is phosphorylated in response to dibutyryl cAMP (Bt2cAMP) at Thr-759 via a pathway that requires extracellular signal-related kinase (ERK).We also show that Bt2cAMP promotes the PKA- and ERK-dependent phosphorylation of DIAPH1 at T759 and that mutation of this site alters the stability of the protein and the rate of cAMP-stimulated mitochondrial movement. 0.2 SIGNOR-276483 TERT protein O14746 UNIPROT Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR up-regulates 18680434 YES lperfetto Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity 0.7 SIGNOR-263334 CHEK1 protein O14757 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Ser47 EVVGGTDsSMDVFHL 9606 14585975 YES llicata We found that endogenous p73alpha is serine phosphorylated by endogenous chk1 upon dna damage, which is a mechanism required for the apoptotic-inducing function of p73alpha. 0.535 SIGNOR-118913 NFY complex SIGNOR-C1 SIGNOR TOP2A protein P11388 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25328138 YES lperfetto The expression of human TOP2A is controlled by its promoter region that contains two GC boxes and five CCAAT boxes. NF-Y recognizes and binds to the ICBs. This binding of NF-Y to the TOP2A promoter can be promoted by HMGB1/2 and inhibited by pRb. 0.271 SIGNOR-242526 PLK2 protein Q9NYY3 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation 9606 29448085 YES miannu Other investigators have demonstrated that Plk2 phosphorylates mutant p53 in a positive feedback loop. 0.591 SIGNOR-278980 JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 9852261 YES gcesareni Stat6 activation is mediated through jak1 and jak2 tyrosine kinases 0.764 SIGNOR-62582 Elongator complex complex SIGNOR-C466 SIGNOR TUBA1C protein Q9BQE3 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 YES miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 0.255 SIGNOR-269720 MC3R protein P41968 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257142 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr472 KLAEGSAyEEVPTSM 9606 BTO:0000142 1689310 YES llicata We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation. 0.84 SIGNOR-20980 ANGPT1 protein Q15389 UNIPROT TIE1 protein P35590 UNIPROT up-regulates binding 9606 11172728 YES gcesareni We reasoned that there may be cooperative interactions among the angiopoietins (i.e., ligands for tie2) and tie1, the orphan receptor. 0.451 SIGNOR-105199 MTOR protein P42345 UNIPROT LARP6 protein Q9BRS8 UNIPROT up-regulates activity phosphorylation Ser348 DPESNPTsPMAGRRH 10116 BTO:0002741 28112218 YES done miannu Binding of La ribonucleoprotein domain family, member 6 (LARP6) to collagen mRNAs regulates their translation and is necessary for high type I collagen expression. Here we show that mTORC1 phosphorylates LARP6 on S348 and S409. The S348A/S409A mutant of LARP6 acts as a dominant negative protein in collagen biosynthesis, which retards secretion of type I collagen and causes excessive posttranslational modifications. 0.2 SIGNOR-273679 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 BTO:0000938 12040039 YES gcesareni Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun. 0.884 SIGNOR-88212 DHODH protein Q02127 UNIPROT (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI down-regulates quantity chemical modification 9606 30449682 YES miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway 0.8 SIGNOR-267430 CSNK2A1 protein P68400 UNIPROT HSPH1 protein Q92598 UNIPROT down-regulates activity phosphorylation Ser509 PTEENEMsSEADMEC -1 12558502 YES llicata Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro. 0.329 SIGNOR-250901 Ub:E2 complex SIGNOR-C497 SIGNOR MEX3A protein A1L020 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271137 KRN-633 chemical CID:9549295 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193588 JMJD1C protein Q15652 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 32034158 YES miannu We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state. 0.2 SIGNOR-265170 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 12591950 YES gcesareni Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf). 0.758 SIGNOR-98399 hsa-miR-1-5p mirna URS000075C105_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000196 21752897 YES MiR-1 affects CXCR4 protein synthesis by facilitating the specific degradation of CXCR4 mRNA. 0.4 SIGNOR-277928 PINK1 protein Q9BXM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation 9606 35059394 YES miannu Simultaneously overexpressing PINK1 significantly reduced the levels of exogenous total and phosphorylated tau proteins (Figures 4A,B,E).|Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy-lysosome pathway, indicating that PINK1 may be a potential target for AD treatment. 0.384 SIGNOR-279250 CCR4-NOT complex complex SIGNOR-C439 SIGNOR NANOS3 protein P60323 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 YES lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins 0.335 SIGNOR-268350 PHLPP1 protein O60346 UNIPROT PRKCA protein P17252 UNIPROT down-regulates quantity dephosphorylation Ser657 QSDFEGFsYVNPQFV 9606 BTO:0000067 18162466 YES gcesareni In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha 0.25 SIGNOR-237043 NFE2L3 protein Q9Y4A8 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by repression transcriptional regulation 15385560 YES lperfetto Deletion mutation analysis revealed that Nrf3 repression of NQO1 gene expression required heterodimerization and DNA binding domains but not transcriptional activation domain of Nrf3. 0.338 SIGNOR-268976 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser42 TRTYSLGsALRPSTS -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248881 HMOX1 protein P09601 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0004296 21037234 NO irozzo In conclusion, AMPK stimulates HO-1 gene expression in human ECs via the Nrf2/antioxidant responsive element signaling pathway. The induction of HO-1 mediates the antiapoptotic effect of AMPK, and this may provide an important adaptive response to preserve EC viability during periods of metabolic stress. 0.7 SIGNOR-256302 S1PR3 protein Q99500 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257437 RPS6KA6 protein Q9UK32 UNIPROT RPS6KA6 protein Q9UK32 UNIPROT up-regulates activity phosphorylation Ser232 DQEKKAYsFCGTVEY 15632195 YES lperfetto These mutants had minimal kinase activity and showed profoundly decreased phosphorylation at Ser232 compared with wild-type RSK4 (Fig 10B), suggesting that RSK4 can autophosphorylate at Ser232. 0.2 SIGNOR-275797 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Thr394 SGLPPPRtAMLDGNY -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.286 SIGNOR-262749 JAK2 protein O60674 UNIPROT APOA1 protein P02647 UNIPROT up-regulates activity 9606 14668333 YES miannu ApoA-I interactions with ABCA1 and lipid efflux to apoA-I were substantially impaired by inhibiting or abolishing JAK2, whereas ABCA1 protein levels were unaffected, and ABCA1 cholesterol translocase activity was only slightly reduced. The most likely explanation for these findings is that JAK2 promotes apolipoprotein interactions with ABCA1 or a closely proximal site, and this facilitates the removal of cellular lipids. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells 0.298 SIGNOR-252107 FOXP1 protein Q9H334 UNIPROT HIP1R protein O75146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 23884370 NO miannu Hip1r was confirmed as a direct foxp1 target / hip1r repression by foxp1 0.294 SIGNOR-202370 PHB2 protein Q99623 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 YES lperfetto Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation. 0.366 SIGNOR-235843 TNFRSF1A protein P19438 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates 9606 10795740 YES We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation 0.832 SIGNOR-256251 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity binding 9606 9020361 YES lperfetto NIK binds to Traf2 and stimulates NF-kappaB activity. 0.585 SIGNOR-46215 LETM1 protein O95202 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10090 29123128 YES lperfetto LETM1 is a mitochondrial inner membrane protein and several reports suggest that it mediates mitochondrial Ca2+ uptake and extrusion in a gradient-dependent manner 0.8 SIGNOR-262541 3-[[3-[(dimethylamino)methyl]anilino]-phenylmethylidene]-N,N-dimethyl-2-oxo-1H-indole-6-carboxamide chemical CHEBI:91423 ChEBI MAP2K5 protein Q13163 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190374 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser301 DAVLPEQsPGDFDFN 9606 22966201 YES llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. 0.322 SIGNOR-198984 TFAP2C protein Q92754 UNIPROT CRABP2 protein P29373 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 NO miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 0.25 SIGNOR-255398 NRXN3 protein Q9Y4C0 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626547 YES miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites 0.824 SIGNOR-265457 alvimopan chemical CHEBI:135686 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition -1 18313920 YES Luana A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors. 0.8 SIGNOR-257774 CRY2 protein Q49AN0 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. 0.929 SIGNOR-267976 DAB2IP protein Q5VWQ8 UNIPROT 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR down-regulates activity binding 9606 27858941 YES miannu DAB2IP then displaces the inhibitory binding between ASK1 and 14-3-3 protein, favoring ASK1 activation 0.299 SIGNOR-254773 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-252923 serotonin smallmolecule CHEBI:28790 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 31024440 YES brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). 0.8 SIGNOR-264188 PYGL protein P06737 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 YES miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267393 STK40 protein Q8N2I9 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000078 32795415 YES Gianni The COP1-interacting protein STK40 (Durzynska et al., 2017), which was detected in c/EBPβ complexes from BMDMs (Figure 1B), also appeared to contribute to the suppression of c/EBPβ in microglia. Specifically, deletion of the STK40 pseudokinase increased the amount of c/EBPβ protein without increasing the amount of Cebpb mRNA 0.28 SIGNOR-261925 POLR1E protein Q9GZS1 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.797 SIGNOR-266153 PRL protein P01236 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 9606 12679477 NO Regulation miannu PRL inhibits lipoprotein lipase activity in human white adipose tissue 0.328 SIGNOR-251851 PPP2CB protein P62714 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 17188031 YES We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity. 0.2 SIGNOR-248597 HSPA5 protein P11021 UNIPROT ATF6 protein P18850 UNIPROT down-regulates activity binding 9606 31226023 YES miannu Similar to PERK and IRE1, ATF6 is activated by ER stress-induced dissociation from GRP78 0.82 SIGNOR-260179 MAPK10 protein P53779 UNIPROT KIF5C protein O60282 UNIPROT down-regulates activity phosphorylation Ser176 CTERFVSsPEEVMDV -1 19525941 YES miannu Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176 0.32 SIGNOR-262950 p38 proteinfamily SIGNOR-PF16 SIGNOR KRT20 protein P35900 UNIPROT up-regulates activity phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 YES miannu P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13. 0.2 SIGNOR-263070 Ub:E2 complex SIGNOR-C497 SIGNOR MYLIP protein Q8WY64 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271127 GATA4 protein P43694 UNIPROT HAMP protein P81172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 21609320 NO miannu Co-transfection of a GATA-4 expression vector with a hepcidin promoter reporter construct enhanced hepcidin promoter transcriptional activity. 0.2 SIGNOR-254196 LIFR protein P42702 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 24710148 YES milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). 0.604 SIGNOR-204850 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser709 SEEEEEEsDSSETEK 21296876 YES lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. 0.2 SIGNOR-275504 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by stabilization phosphorylation Ser405 QARAHGLsLIPSTGL 9606 25605940 YES miannu We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. 0.436 SIGNOR-276475 PI-103 chemical CHEBI:90524 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206166 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.631 SIGNOR-249442 TPX2 protein Q9ULW0 UNIPROT KIF11 protein P52732 UNIPROT down-regulates activity binding 26018074 YES lperfetto Dimeric, but not monomeric, Eg5 was differentially inhibited by full-length and truncated TPX2, demonstrating that dimerization or residues in the neck region are important for the interaction of TPX2 with Eg5.  0.499 SIGNOR-265097 FADS2 protein O95864 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267912 TNF protein P01375 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates 9606 10485710 NO gcesareni Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). 0.254 SIGNOR-70619 ASTN2 protein O75129 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000142 28506896 NO miannu The role of astrotactin and Brinp proteins has been partially characterized, with ASTN1 and ASTN2 demonstrated to facilitate glial-guided neuronal migration during brain development 0.7 SIGNOR-269814 PRKAA1 protein Q13131 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 17900900 YES gcesareni The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. 0.445 SIGNOR-157941 MAPK14 protein Q16539 UNIPROT EPS15 protein P42566 UNIPROT up-regulates phosphorylation Ser796 RSINKLDsPDPFKLN 9606 24269888 YES lperfetto Tnf-_ induces phosphorylation of eps15 at ser-796eps15 is a substrate for p38_these results suggest an attractive model in which p38 phosphorylates both eps15 and egfr to trigger efficient endocytosis 0.346 SIGNOR-203315 CDK2 protein P24941 UNIPROT ARID4A protein P29374 UNIPROT down-regulates phosphorylation Ser1007 QHNFSVAsPLTLSQD 9606 21148318 YES lperfetto We identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation 0.427 SIGNOR-170451 TWIST1 protein Q15672 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255535 USP36 protein Q9P275 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by stabilization deubiquitination 21268071 YES lperfetto Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36|Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life. 0.32 SIGNOR-272280 RPL29 protein P47914 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.862 SIGNOR-262471 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17548358 YES gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. 0.333 SIGNOR-155381 LTBP2 protein Q14767 UNIPROT FBN1 protein P35555 UNIPROT up-regulates activity binding 9606 BTO:0000452 19681046 YES Regulation miannu LTBP-2 interacts with fibrillin-1. The association of LTBP-2 with the ECM always coincided with that of fibrillin-1, and in fibroblast cultures the appearance of fibrillar fibrillin-1 structures preceded the assembly of LTBP-2 network. 0.301 SIGNOR-251891 EPAS1 protein Q99814 UNIPROT KDM2A protein Q9Y2K7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271581 PLK1 protein P53350 UNIPROT CCNT1 protein O60563 UNIPROT down-regulates activity phosphorylation Ser564 KTYSLSSsFSSSSST 9606 BTO:0002181 23977272 YES miannu  Further analysis indicated that Plk1 could phosphorylate cyclin T1 at Ser564 and inhibit the kinase activity of cyclin T1/Cdk9 complex on phosphorylation of the C-terminal domain (CTD) of RNA polymerase II.  0.38 SIGNOR-276501 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT up-regulates dephosphorylation 9606 BTO:0000776;BTO:0003076 11994288 YES gcesareni These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3, 0.455 SIGNOR-87154 MMP3 protein P08254 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272373 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR NRARP protein Q7Z6K4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0000782 11783997 YES gcesareni These observations demonstrate that the nrarp gene is an evolutionarily conserved transcriptional target of the notch signaling pathway. 0.408 SIGNOR-113786 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CEBPA protein P49715 UNIPROT down-regulates phosphorylation 9606 BTO:0000876 14701740 YES inferred from 70% family members lperfetto Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21. 0.2 SIGNOR-270066 IFNL2 protein Q8IZJ0 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 YES gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. 0.709 SIGNOR-96206 BCR-Mk complex SIGNOR-C433 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 YES scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). 0.714 SIGNOR-268439 SU11274 chemical CID:9549297 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207123 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity dephosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 YES Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism 0.732 SIGNOR-252054 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser288 DATEKDAsKKSDSNP 9534 BTO:0001538 23519612 YES miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. 0.318 SIGNOR-262709 GSK2126458 chemical CID:25167777 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252645 CCL19 protein Q99731 UNIPROT CCR7 protein P32248 UNIPROT up-regulates activity binding 9606 BTO:0000007 19497875 YES CCL19 and CCL21 are endogenous agonists for the seven-trans membrane receptor CCR7. 0.784 SIGNOR-278123 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1213 GSSDDVRyVNAFKFM 9606 9722576 YES tpavlidou By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor. 0.2 SIGNOR-59750 PRKAA1 protein Q13131 UNIPROT NAMPT protein P43490 UNIPROT up-regulates quantity transcriptional regulation 10090 18477450 NO gcesareni Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt 0.298 SIGNOR-238598 MT-CYB protein P00156 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.884 SIGNOR-262193 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. 0.2 SIGNOR-255856 PRKCD protein Q05655 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Ser302 GRGGRGGsRARNLPL 9606 10329716 YES lperfetto Ser302 is a major k protein site phosphorylated by pkcdelta in vitrothe ability of pkc_ to inducibly bind and phosphorylate k protein may serve not only to alter the activity of k protein itself, but k protein may also provide an avenue for pkc_ to engage in a cross-talk with other k protein molecular partners in response to specific changes in the extracellular environment 0.345 SIGNOR-67515 AVPR1A protein P37288 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.446 SIGNOR-256805 LCK protein P06239 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates activity phosphorylation Tyr688 FAEPYNLySSLKELV 9534 BTO:0004055 9461588 YES the regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85. 0.622 SIGNOR-251383 DCAF12 protein Q5T6F0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0002806 31267705 YES miannu  The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6 0.456 SIGNOR-272264 YAP1 protein P46937 UNIPROT SGK1 protein O00141 UNIPROT up-regulates quantity by expression transcriptional regulation 35216681 NO lperfetto Importantly, YAP-dependent regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) is required to activate mTORC1/SREBP and stimulate de novo lipogenesis. 0.281 SIGNOR-276585 PRKG2 protein Q13237 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Ser557 AKASRTSsKHKEDVY 9606 BTO:0002181 21177494 YES miannu  PKGII directly phosphorylated and stimulated SHP-1 activity 0.2 SIGNOR-276287 adenosine smallmolecule CHEBI:16335 ChEBI ADORA2B protein P29275 UNIPROT up-regulates activity binding -1 14662005 YES Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. 0.8 SIGNOR-268421 MEF2D protein Q14814 UNIPROT DES protein P17661 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 25653159 YES lperfetto Ectopic expression of myogenin and a specific Mef2 isoform induced myogenic differentiation without activating endogenous MyoD expression. Under these conditions, the regulatory sequences of late gene loci were not in close proximity, and these genes were prematurely activated. 0.2 SIGNOR-241504 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates 9606 11777913 NO gcesareni Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126. 0.434 SIGNOR-113566 TRAM-34 chemical CHEBI:34990 ChEBI KCNN4 protein O15554 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207426 SGK1 protein O00141 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser1132 RDRVRSMsGGHGLRV -1 27451907 YES miannu SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.  0.58 SIGNOR-277265 FGF17 protein O60258 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 YES tpavlidou Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes 0.687 SIGNOR-42365 ATM protein Q13315 UNIPROT LAMTOR5 protein O43504 UNIPROT up-regulates activity phosphorylation 9606 23667255 YES lperfetto Strikingly, we found that the kinase ataxia telangiectasia mutated (ATM) phosphorylated HBXIP at Ser (108).|The knockdown of ATM by siRNA remarkably decreased the levels of serine phosphorylation and blocked the nuclear import of HBXIP. 0.336 SIGNOR-279791 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Thr282 RGKEGPGtPTRSSVI 9606 BTO:0001271 18246121 YES llicata Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects. 0.282 SIGNOR-160630 SIK2 protein Q9H0K1 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Ser91 ENLKKSLsCANLSTF 9606 24561619 YES lperfetto Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion 0.331 SIGNOR-204648 LETM1 protein O95202 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 BTO:0000567 18628306 NO lperfetto We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains. 0.7 SIGNOR-262545 NAE complex SIGNOR-C131 SIGNOR CUL7 protein Q14999 UNIPROT up-regulates activity neddylation 9606 25504797 YES lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. 0.466 SIGNOR-243172 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole chemical CHEBI:92005 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258857 TGFB3 protein P10600 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 11157754 YES miannu T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation 0.866 SIGNOR-104798 PPP1CA protein P62136 UNIPROT CDC25C protein P30307 UNIPROT up-regulates binding 9606 14592972 YES gcesareni Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus. 0.5 SIGNOR-118917 NTF3 protein P20783 UNIPROT NTRK3 protein Q16288 UNIPROT up-regulates binding 9606 1653651 YES gcesareni Trkc, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. 0.848 SIGNOR-20699 seliciclib chemical CHEBI:45307 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206574 GABRB1 protein P18505 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.614 SIGNOR-263757 ATM protein Q13315 UNIPROT MACROD2 protein A1Z1Q3 UNIPROT down-regulates activity phosphorylation 9606 28069995 YES lperfetto We found that MacroD2 is exported from the nucleus upon DNA damage and that this depends on the ATM-induced phosphorylation of the MacroD2 C-terminal IDR.|ATM activation leads to phosphorylation of the MacroD2 C-terminal region. 0.2 SIGNOR-279792 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 9535909 YES inferred from 70% family members lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. 0.2 SIGNOR-270148 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 YES lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. 0.685 SIGNOR-109621 FOXF1 protein Q12946 UNIPROT GH2 protein P01242 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16772323 NO miannu Overexpression of FOXF1 in BeWo and HepG2 cells induced the GHV promoter, whereas overexpression of FOXF2 was without effect. These studies indicate that FOXF1 induces GHV expression by interaction with a FOXF1/FOXF2 cis-element in the proximal promoter. 0.2 SIGNOR-254175 AKT1 protein P31749 UNIPROT RNF11 protein Q9Y3C5 UNIPROT down-regulates quantity phosphorylation Thr135 DWLMRSFtCPSCMEP 9606 BTO:0003474 16123141 YES gcesareni Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity 0.457 SIGNOR-252558 F2 protein P00734 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates binding 9606 BTO:0001253 11356985 YES gcesareni Other major aspects of par-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of par-2. 0.61 SIGNOR-108183 GADL1 protein Q6ZQY3 UNIPROT beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity chemical modification 9606 22718265 YES miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. 0.8 SIGNOR-267546 NADP(3-) smallmolecule CHEBI:58349 ChEBI NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity precursor of 9606 34775382 YES miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. 0.8 SIGNOR-268111 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. 0.918 SIGNOR-202030 ATM protein Q13315 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity phosphorylation 9606 20042274 YES lperfetto Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5\u20137,18] , whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5\u201319] .|Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5-7,18], whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5-19]. 0.43 SIGNOR-279793 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI2 protein P10070 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150;BTO:0000551 19860666 YES gcesareni Both molecules gant58 and gant61 were capable of interfering with gli1 as well as gli2-mediated transcription in a dose-dependent manner 0.8 SIGNOR-188866 SMURF1 protein Q9HCE7 UNIPROT SMAD6 protein O43541 UNIPROT down-regulates activity relocalization 9606 22298955 YES lperfetto Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm. 0.83 SIGNOR-105931 AKT2 protein P31751 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 YES gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. 0.262 SIGNOR-201125 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2B complex SIGNOR-C348 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 YES lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically 0.8 SIGNOR-268278 BRK1 protein Q8WUW1 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 YES lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  0.847 SIGNOR-261875 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.342 SIGNOR-259004 EGR1 protein P18146 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003336 29212876 YES miannu Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC. 0.619 SIGNOR-263508 STK3 protein Q13188 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Thr228 PQWNESFtFKLKPSD 9606 BTO:0002181 26414765 YES miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  0.2 SIGNOR-277176 ANAPC11 protein Q9NYG5 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.864 SIGNOR-252010 KAT2A protein Q92830 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity acetylation 24870244 YES lperfetto The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha. 0.2 SIGNOR-275498 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr24 ELDSKLNyKPPPQKS 9606 19321744 YES llicata Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes. 0.395 SIGNOR-184912 PKLR protein P30613 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 YES miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). 0.8 SIGNOR-266535 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.411 SIGNOR-252880 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT unknown phosphorylation Ser418 QQRKALLsPFSTPVR -1 15952796 YES lperfetto We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites. 0.374 SIGNOR-249405 TEC protein P42680 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 YES lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated 0.2 SIGNOR-98098 CBP/p300 complex SIGNOR-C6 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 YES gcesareni Cbp/p300 and pcaf are coactivators for myod and mef-2c during myogenic commitment and differentiation 0.715 SIGNOR-83840 NMDA receptor_2A complex SIGNOR-C347 SIGNOR CAMK2A protein Q9UQM7 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD 0.663 SIGNOR-264214 CENPW protein Q5EE01 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.635 SIGNOR-265202 CENPU protein Q71F23 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.814 SIGNOR-265203 CDK1 protein P06493 UNIPROT RNMT protein O43148 UNIPROT up-regulates activity phosphorylation Thr77 SSSCGKDtPSKKRKL 9606 BTO:0000007 26942677 YES lperfetto We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor. 0.255 SIGNOR-265501 HDAC5 protein Q9UQL6 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 11062529 YES gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. 0.709 SIGNOR-84029 TNF protein P01375 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 NO inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. 0.258 SIGNOR-270239 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRB4 protein P13762 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys254 FIYFRNQkGHSGLQP 9606 19117940 YES miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. 0.2 SIGNOR-271407 MITF protein O75030 UNIPROT TRPM1 protein Q7Z4N2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14744763 NO miannu Mice homozygously mutated in MITF showed a dramatic decrease in TRPM1 expression. Finally, the slope of TRPM1 induction by MITF was particularly steep compared with other MITF target genes, suggesting it is a sensitive indicator of MITF expression and correspondingly of melanocytic differentiation. 0.424 SIGNOR-254588 ACVR1 protein Q04771 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 9748228 YES fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 0.758 SIGNOR-60171 tolcapone chemical CHEBI:63630 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition 10090 26919286 YES miannu The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice. 0.8 SIGNOR-258475 CSNK2A2 protein P19784 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.286 SIGNOR-250979 CSNK2A1 protein P68400 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 24962073 YES lperfetto CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1 0.2 SIGNOR-267666 DIO3 protein P55073 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 YES scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. 0.8 SIGNOR-266952 Hypoxia stimulus SIGNOR-ST25 SIGNOR HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates 9606 27692180 NO miannu Hypoxia-Inducible Factor-1 (HIF-1) is a key transcription factor that regulates gene expression under hypoxic conditions (Semenza, 2012, 2010a). HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life 0.7 SIGNOR-267449 PPP4C protein P60510 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity dephosphorylation Thr435 PTQAGEGtLSEALLQ 9606 15073167 YES Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation 0.361 SIGNOR-248549 ATM protein Q13315 UNIPROT USP10 protein Q14694 UNIPROT up-regulates activity phosphorylation Thr42 SGTVLCGtQAVDKLP 9606 35627217 YES lperfetto As shown, both AKT and ATM increase the activity of USP10.|Yuan et al. demonstrated that ATM could phosphorylate USP10 at Thr42 and Ser337 upon the DNA-damage response and USP10 was translocated into the nucleus, where the N-terminus of USP10 (amino acids 1\u2013100) binds to p53 and inhibits its ubiquitination [27]. 0.252 SIGNOR-279795 PRKCB protein P05771 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 YES lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. 0.328 SIGNOR-248977 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 20708153 YES lperfetto Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation 0.321 SIGNOR-167488 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser757 NARVKKEsGSSAAGI 9606 BTO:0000007 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h). 0.2 SIGNOR-264510 SRC protein P12931 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Tyr331 PYSEYFEyFAPDFTL -1 30317579 YES miannu C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).  0.386 SIGNOR-277486 GSK3B protein P49841 UNIPROT GPHN protein Q9NQX3 UNIPROT down-regulates phosphorylation Ser270 LSTTPSEsPRAQATS 9606 BTO:0000142 23408424 YES miannu Identification of gsk3_ as the kinase targeting ser-270 /phosphorylation at ser-270 promotes gephyrin processing by calpain 0.283 SIGNOR-200957 ERCC5 protein P28715 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 NO lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.7 SIGNOR-275709 CYP17A1 protein P05093 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268654 FYN protein P06241 UNIPROT TOM1L1 protein O75674 UNIPROT up-regulates activity phosphorylation Tyr460 AVTTEAIyEEIDAHQ -1 11711534 YES Tyr-457, located in the presumed Src SH2 binding site, is the predominant tyrosine residue that is phosphorylated by Fyn.Fyn can phosphorylate Srcasm, and association of these molecules relies on cooperative binding between the SH2 and SH3 domains of Fyn and corresponding canonical binding sites in Srcasm. Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner. The evidence suggests that Srcasm may help promote Src family kinase signaling in cells. 0.434 SIGNOR-251185 CSNK1D protein P48730 UNIPROT MTSS1 protein O43312 UNIPROT down-regulates quantity by destabilization phosphorylation Ser322 SSVSSHDsGFISQDA 9606 BTO:0000567 24318128 YES miannu Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.  0.328 SIGNOR-276611 DNMT1 protein P26358 UNIPROT BAG4 protein O95429 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 NO lperfetto In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+) 0.2 SIGNOR-254112 MAPK1 protein P28482 UNIPROT PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser659 YQSMIPQsPSPPLDE -1 11030732 YES miannu The short-form PDE4B2 isoenzyme was activated by Erk2 phosphorylation. These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid. 0.269 SIGNOR-275970 2-[[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine chemical CHEBI:93274 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258880 PTMA protein P06454 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 BTO:0000567 12522243 YES PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. 0.365 SIGNOR-259079 CAMK1 protein Q14012 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887 11114197 YES gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation. 0.42 SIGNOR-85022 PPARGC1A protein Q9UBK2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by repression transcriptional regulation 10090 BTO:0001103 20404331 NO lperfetto Capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression 0.579 SIGNOR-252969 PIP3 smallmolecule CHEBI:16618 ChEBI WIPI2 protein Q9Y4P8 UNIPROT up-regulates chemical activation 9606 22082875 YES gcesareni We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes. 0.8 SIGNOR-177226 LEPR protein P48357 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0001282 18718905 YES miannu Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules. 0.773 SIGNOR-263491 Caspase 3 complex complex SIGNOR-C221 SIGNOR PTCH1 protein Q13635 UNIPROT down-regulates activity cleavage Asp1405 CPGYPETdHGLFEDP 9606 12907805 YES lperfetto Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain. 0.321 SIGNOR-256438 LIG4 protein P49917 UNIPROT Lig4-Xrcc4 complex complex SIGNOR-C354 SIGNOR form complex binding -1 19837014 YES miannu The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals. 0.951 SIGNOR-264533 EEF1A2 protein Q05639 UNIPROT Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269525 PAK1 protein Q13153 UNIPROT MORC2 protein Q9Y6X9 UNIPROT up-regulates activity phosphorylation Ser739 ATPSRKRsVAVSDEE 9606 23260667 YES miannu In support of this notion, selective knockdown of endogenous PAK1 significantly reduced the association of MORC2 with chromatin (XREF_FIG, compare lane 4 with 3).|PAK1 phosphorylation of MORC2 on serine 739 regulates an ATPase-dependent chromatin remodeling following DSB damage and facilitates efficient DSB repair. 0.366 SIGNOR-278414 PAK6 protein Q9NQU5 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser187 LNSAAYSsPKLRGTL 9606 25726523 YES miannu In addition, PAK5 knockdown also markedly reduced the association of GATA1 with HDAC3/4.|PAK5 phosphorylates the transcription factor GATA1 mainly at Ser161 and Ser 187, phosphorylated GATA1 recruits more HDAC3/4 to the promoter of E-cadherin and consequently suppresses the transcription of E-cadherin gene and promotes the EMT of breast cancer cells. 0.2 SIGNOR-278415 PAK6 protein Q9NQU5 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser161 SSLPVPNsAYGGPDF 9606 25726523 YES miannu In addition, PAK5 knockdown also markedly reduced the association of GATA1 with HDAC3/4.|PAK5 phosphorylates the transcription factor GATA1 mainly at Ser161 and Ser 187, phosphorylated GATA1 recruits more HDAC3/4 to the promoter of E-cadherin and consequently suppresses the transcription of E-cadherin gene and promotes the EMT of breast cancer cells. 0.2 SIGNOR-278416 CSNK1A1 protein P48729 UNIPROT AHCYL1 protein O43865 UNIPROT unknown phosphorylation Ser77 SSTDSYSsAASYTDS 9534 17635105 YES lperfetto Residue 68 resides in a consensus phosphorylation site for PKD (Figure 1A) [22,23]. Interestingly, phosphorylation of Ser68 could allow for subsequent phosphorylation of Ser71, Ser74, Ser77 and Ser80 by CK1, for which the consensus phosphorylation site is pS/T-X-X-S/T 0.2 SIGNOR-249185 ERN1 protein O75460 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates activity 9606 31226023 NO miannu The kinase activity of IRE1 also activates a signaling cascade that ultimately activates c-Jun N-terminal kinase (JNK) 0.317 SIGNOR-260177 ICOS protein Q9Y6W8 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 18641334 YES ICOS ligation in concert with TCR stimulation results in strong PI3K activation in T lymphocytes. The ICOS cytoplasmic tail contains an YMFM motif that binds the p85alpha subunit of class IA PI3K, similar to the YMNM motif of CD28, suggesting a redundant function of the two receptors in PI3K signaling. 0.496 SIGNOR-272539 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000596 24942200 YES flangone During neural fate specification, nuclear translocation of ERK1/2 is critical for its activation of Sox2 transcription. More-over, melatonin-induced Sox2 expression, through ERK1/ 2 activation, could locate between base pairs2719 and 1708 in the mouse Sox2 gene. 0.2 SIGNOR-241977 FHL2 protein Q14192 UNIPROT SPHK1 protein Q9NYA1 UNIPROT down-regulates activity binding 10090 BTO:0000562 16888242 YES llicata FHL2/SLIM3 decreases cardiomyocyte survival by inhibitory interaction with sphingosine kinase-1. 0.424 SIGNOR-237775 ATM protein Q13315 UNIPROT USP10 protein Q14694 UNIPROT up-regulates activity phosphorylation Ser337 ASGTLPVsQPKSWAS 9606 35627217 YES lperfetto As shown, both AKT and ATM increase the activity of USP10.|Yuan et al. demonstrated that ATM could phosphorylate USP10 at Thr42 and Ser337 upon the DNA-damage response and USP10 was translocated into the nucleus, where the N-terminus of USP10 (amino acids 1\u2013100) binds to p53 and inhibits its ubiquitination [27]. 0.252 SIGNOR-279796 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity dephosphorylation 9606 23015147 YES Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT). 0.825 SIGNOR-253329 LCK protein P06239 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 17998336 YES inferred from 70% of family members gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. 0.2 SIGNOR-269899 POU1F1 protein P28069 UNIPROT TSHB protein P01222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001379 10931853 YES scontino CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-β promoter. The human TSH-β promoter contains three well defined Pit-1 DNA-binding sites. 0.439 SIGNOR-267205 CDK2 protein P24941 UNIPROT USP37 protein Q86T82 UNIPROT up-regulates activity phosphorylation Ser628 MVNSCITsPSTPSKK 9606 SIGNOR-C83 21596315 YES lperfetto There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity 0.447 SIGNOR-265045 SB-202190 chemical CHEBI:79090 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206694 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr227 PAPPEGAtPTSPVGH 9606 BTO:0000848 BTO:0001253 20959475 YES lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). 0.713 SIGNOR-252954 AKT2 protein P31751 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 10377430 YES lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. 0.657 SIGNOR-68652 ILK protein Q13418 UNIPROT PPP1R14B protein Q96C90 UNIPROT up-regulates activity phosphorylation Thr57 VRRQGKVtVKYDRKE -1 12144526 YES lperfetto We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin 0.396 SIGNOR-265741 ATXN7 protein O15265 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.671 SIGNOR-269576 DDC protein P20711 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity chemical modification 7955 23940784 YES brain lperfetto AADC is responsible for the decarboxylation step in the catecholamine and dopamine biosynthesis. Dopamine and serotonin can be synthesized by AADC from L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively [7]. A deficiency in AADC will lead to reduced biogenic monoamines, including dopamine, norepinephrine, epinephrine, and serotonin 0.8 SIGNOR-263987 KANSL1 protein Q7Z3B3 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 26243146 NO miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. 0.7 SIGNOR-267170 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT up-regulates quantity by stabilization phosphorylation Ser1463 IVNYSRAsINSLLSD 10090 29301787 YES lperfetto Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466 0.261 SIGNOR-272268 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257911 VAV1 protein P15498 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 BTO:0000725 9151714 YES Barakat In summary, we demonstrate here that Y315 in ZAP-70 is required to interact with the Vav SH2 domain, and is critical for ZAP-70–mediated gene activation. 0.837 SIGNOR-274150 MAP3K11 protein Q16584 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates 9606 9733513 NO gcesareni This scaffold protein selectively enhanced jnk activation by the mlk signaling pathway. 0.324 SIGNOR-59884 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 26194464 YES MARCO ROSINA Taken together, ERK-mediated Smad2 linker phosphorylation is responsible for TH17 differentiation 0.2 SIGNOR-255020 ATR protein Q13535 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity phosphorylation 9606 29192227 YES miannu Phosphorylation of UPF1 by the PIKKs SMG1, ATM and ATR is stimulated in response to DNA damage. 0.369 SIGNOR-278911 PTEN protein P60484 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity binding 9606 BTO:0000007 25829446 YES irozzo Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity. 0.619 SIGNOR-259190 DCAF1 protein Q9Y4B6 UNIPROT LATS2 protein Q9NRM7 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0005907 25026211 YES miannu CRL4 DCAF1 ubiquitylates and inhibits Lats. 0.2 SIGNOR-272227 GPR119 protein Q8TDV5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257308 MAOB protein P27338 UNIPROT 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-264004 PRKCD protein Q05655 UNIPROT CHAT protein P28329 UNIPROT up-regulates quantity phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000930 15381704 YES lperfetto Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity. 0.311 SIGNOR-249271 noradrenaline smallmolecule CHEBI:33569 ChEBI adrenaline smallmolecule CHEBI:33568 ChEBI up-regulates quantity precursor of 9606 7961964 YES brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). 0.8 SIGNOR-264183 CSNK2A1 protein P68400 UNIPROT NR1H3 protein Q13133 UNIPROT down-regulates phosphorylation Ser198 SLPPRASsPPQILPQ 9606 BTO:0000801 18250151 YES llicata Ck2? Also phosphorylated lxr? At s198 in vitro, suggesting that ck2 may be a bona fide s198 kinase. our results show that macrophage lxr? Phosphorylation at s198 affects the transcriptional activity of the receptor in a gene-specific manner (fig. ?(Fig.3a)3a) and restricts the repertoire of genes regulated by lxr? 0.2 SIGNOR-160640 DRAM2 protein Q6UX65 UNIPROT RHOA protein P61586 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 NO irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. 0.2 SIGNOR-259142 TFEC protein O14948 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 NO miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. 0.2 SIGNOR-222551 PRKCB protein P05771 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Thr705 WKLQRAItILDTEKS 9606 BTO:0000007 24920628 YES miannu PKCβII causes the downregulation of TRPV1 by phosphorylating the channel. The increased threonine phosphorylation was substantially reduced by mutating Thr705, showing that Thr705 is indeed a major PKCβII phosphorylation site. 0.2 SIGNOR-276638 LDB1 protein Q86U70 UNIPROT LHX2 protein P50458 UNIPROT up-regulates activity binding 9606 BTO:0000007 17005264 YES miannu Cofactor CLIM2 promotes the repressive action of LIM homeodomain transcription factor Lhx2 in the expression of porcine pituitary glycoprotein hormone alpha subunit gene. 0.539 SIGNOR-223962 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0004428 12510059 YES lperfetto Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylationOne of the specific Ser phosphorylation sites in IRS-1 that has been proposed to negatively modulate the insulin signal is Ser312 (numbered according to the human sequence). Prior studies have demonstrated that IRS-1 associates with and is phosphorylated by JNK in vitro on Ser312 0.771 SIGNOR-236591 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257908 CDX2 protein Q99626 UNIPROT FUT2 protein Q10981 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000182;BTO:0000391 22547830 NO miannu We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. 0.2 SIGNOR-254610 NKX2-3 protein Q8TAU0 UNIPROT MADCAM1 protein Q13477 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 10790368 YES Luana We provide evidence that NKX2.3 can activate MAdCAM-1 transcription directly 0.428 SIGNOR-266219 MAP1LC3A protein Q9H492 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates binding 9606 22170151 YES gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe. 0.855 SIGNOR-191543 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 YES esanto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. 0.519 SIGNOR-146224 CASP1 protein P29466 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates activity binding 9606 BTO:0000007 20197547 YES Our data so far indicated colocalization of SphK2 with caspase-1 at the plasma membrane after induction of apoptosis.These observations supported caspase-1–dependent cleavage of SphK2 at its N-terminus as a prerequisite for its release. 0.248 SIGNOR-268831 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 YES miannu AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively.  0.254 SIGNOR-277895 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR G0/G1_transition phenotype SIGNOR-PH219 SIGNOR up-regulates 12640120 NO lperfetto Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0. 0.7 SIGNOR-273192 CDK1 protein P06493 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 11553333 YES lperfetto Phosphorylation of 4e-bp1 is critical in causing its dissociation from eif-4e, leaving 4e available to form translationally active eif-4f complexes, switching on mrna translation. We show that the cyclin-dependent kinase, cdc2, phosphorylates 4e-bp1 at thr-70 and that phosphorylation of this site is permissive for ser-65 phosphorylation. Crucially, the increased phosphorylation of 4e-bp1 during mitosis results in its complete dissociation from eif-4e. 0.397 SIGNOR-110416 AMPK complex SIGNOR-C15 SIGNOR KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 YES miannu Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559.  0.291 SIGNOR-273736 PRKCA protein P17252 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Thr174 KVPVTHEtQEECLGM -1 27368100 YES miannu These results suggest that PKC activates JAK2 and thereby STAT3 by directly phosphorylating T174 and S518.  0.26 SIGNOR-277262 KLHL2 protein O95198 UNIPROT WNK2 protein Q9Y3S1 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23838290 YES miannu We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body. 0.441 SIGNOR-272120 CDK5 protein Q00535 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Ser85 HQQPQSSsPVYGSSA 9606 14970194 YES miannu Thus, phosphorylation of paxillin is involved in NGF-induced neurite extension of PC-12 cells, probably through regulating focal adhesion organization.|cdk5 and p38MAPK phosphorylates Ser 85 on paxillin in vitro. 0.377 SIGNOR-278921 LCK protein P06239 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 14766232 YES lperfetto The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and _-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and _-catenin 0.461 SIGNOR-247058 CBLC protein Q9ULV8 UNIPROT RET protein P07949 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24466333 YES miannu Here we show that Cbl-c binds wild-type and MEN2A isoforms of the receptor tyrosine kinase, RET, and that Cbl-c enhances ubiquitination and degradation of activated RET.|We show that Cbl-c negatively regulates RET by ubiquitinating and downregulating the activated RTK while Enigma positively regulates activated RET by preventing Cbl-c binding to RET and thus preventing RET ubiquitination and degradation while promoting RET mitogenic signaling. 0.368 SIGNOR-278674 TWIST2 protein Q8WVJ9 UNIPROT SRPX protein P78539 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.208 SIGNOR-255497 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 BTO:0000150 17254967 YES lperfetto Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27 0.497 SIGNOR-152835 SNUPN protein O95149 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR up-regulates quantity relocalization 9606 BTO:0000567 9670026 YES miannu Here, we describe the isolation and cDNA cloning of a 45 kDa protein, termed snurportin1, which interacts specifically with m3G-cap but not m7G-cap structures. Snurportin1 enhances the m3G-capdependent nuclear import of U snRNPs in both Xenopus laevis oocytes and digitonin-permeabilized HeLa cells, demonstrating that it functions as an snRNP-specific nuclear import receptor. 0.46 SIGNOR-272081 AXL protein P30530 UNIPROT YES1 protein P07947 UNIPROT up-regulates activity phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 BTO:0001007 33941853 YES miannu Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. 0.2 SIGNOR-277555 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates phosphorylation 9606 12912994 YES gcesareni Mek5 is the mapk kinase that phosphorylates and activates erk5 in response to growth factors, oxidative stress, and hyperosmotic conditions. 0.702 SIGNOR-104631 AURKA protein O14965 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation 9606 25090971 YES lperfetto Because Aur-A phosphorylates and activates LIMK1 , we examined the activation status of LIMK1 during mitosis in cells treated with MLN8237.|Because Aur-A phosphorylates and activates LIMK1 [ xref ], we examined the activation status of LIMK1 during mitosis in cells treated with MLN8237. 0.262 SIGNOR-279799 DUSP22 protein Q9NRW4 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity dephosphorylation Ser118 LHPPPQLsPFLQPHG 9606 17384676 YES These results strongly suggest that DUSP22 acts as a negative regulator of the ERalpha-mediated signaling pathway|whereas E2-induced phosphorylation and activation of ERalpha was suppressed by overexpression of DUSP22 but not catalytically inactive mutants. 0.261 SIGNOR-248827 PRKACA protein P17612 UNIPROT DNAJC5 protein Q9H3Z4 UNIPROT unknown phosphorylation Ser10 DQRQRSLsTSGESLY 9606 BTO:0000938 18951872 YES gcesareni Csp is phosphorylated in vivo on a single residue, ser10, and this phosphorylation regulates its cellular functions,[...]PKA Phosphorylation of full-length csp protein stimulated 14-3-3 binding, and this was abolished in a ser10-ala mutant csp, confirming the binding site as phospho-ser10 0.326 SIGNOR-181788 serotonin smallmolecule CHEBI:28790 ChEBI HTR3E protein A5X5Y0 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264291 AR protein P10275 UNIPROT UBE2C protein O00762 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19632176 YES miannu The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint. 0.398 SIGNOR-251543 NOTCH1 protein P46531 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR down-regulates 10090 9601631 NO Luana Signalling through activated Notch is known both to control multiple cell fate determinations (in both invertebrates and vertebrates) and to inhibit developmental processes, such as neurogenesis 0.7 SIGNOR-265769 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230396 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.432 SIGNOR-67396 RPL22 protein P35268 UNIPROT RPL22L1 protein Q6P5R6 UNIPROT down-regulates 9606 23990801 NO miannu We find that rpl22 directly represses expression of rpl22l1 mrna by binding to an internal hairpin structure. 0.411 SIGNOR-202600 TNF protein P01375 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 11287630 NO lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase 0.481 SIGNOR-244458 EP300 protein Q09472 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11796223 YES lperfetto Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription. 0.743 SIGNOR-232162 PRKCZ protein Q05513 UNIPROT NREP protein Q16612 UNIPROT down-regulates quantity by destabilization phosphorylation Ser59 LGSSELRsPRISYLH 9606 BTO:0004605 16229809 YES done miannu Site-directed mutagenesis of S59A retarded P311 degradation and induced glioma cell motility. In contrast, S59D mutation resulted in the rapid degradation of P311 and reduced glioma cell migration.Taken together, our results show that the serine phosphorylation of P311 is dependent on the function of both PKCε and PKCz. 0.2 SIGNOR-273831 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CELF6 protein Q96J87 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001109 31534127 YES miannu CELF6 is degraded by ubiquitin-dependent proteasome pathway. The cell cycle-dependent expression of CELF6 is mediated through the ubiquitin-proteasome pathway, SCF-β-TrCP recognizes a nonphospho motif in CELF6 and regulates its proteasomal degradation. 0.2 SIGNOR-269043 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity phosphorylation Ser11 SGFESYGsSSYGGAG -1 9295339 YES lperfetto We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13 0.58 SIGNOR-248980 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr8 MTAKMETtFYDDALN 9606 BTO:0000848 21177766 YES lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) 0.268 SIGNOR-170768 CSNK2A1 protein P68400 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser146 FYKRRGAsDLSSEEG -1 8954982 YES llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. 0.326 SIGNOR-250949 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr200 SMESIDDyVNVPESG 9606 11368773 YES lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. 0.769 SIGNOR-247026 UVB radiation stimulus SIGNOR-ST17 SIGNOR PAH protein P00439 UNIPROT up-regulates 9606 9204951 NO miannu UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine. 0.7 SIGNOR-252207 CDK1 protein P06493 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser96 SFSVKDPsPLYDMLR 9606 15735705 YES lperfetto Cdc2p34 phosphorylates mdmx on ser 96 in vitro. Mutation within this site (mdmx(s96a)) impairs, whereas phosphomimic substitution (mdmx(s96d)) increases the cytoplasmic localization of mdmx, suggesting that cdk2/cdc2p34 phosphorylation is required for export of mdmx from the nucleus 0.407 SIGNOR-134388 MLL3 complex complex SIGNOR-C446 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 34156443 YES miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 0.2 SIGNOR-268811 MED26 protein O95402 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.669 SIGNOR-266664 CDK1 protein P06493 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 10931950 YES gcesareni Phosphorylation of kip1 on thr-187, by cdk1 and cdk2 leads to protein ubiquitination and proteasomal degradation. 0.657 SIGNOR-80230 APOA1 protein P02647 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity 9606 14668333 NO miannu ApoA-I Stimulates JAK2 Autophosphorylation. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells 0.298 SIGNOR-252108 CDK5 protein Q00535 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL 9606 17440046 YES llicata Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue 0.48 SIGNOR-154405 MDM2 protein Q00987 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity ubiquitination 9606 18665269 YES miannu Mdm2 Induces Mono-Ubiquitination of FOXO4.|higher amounts of Mdm2 transfected resulted in reduced FOXO4 transcriptional activity. 0.629 SIGNOR-278656 GIGYF2 protein Q6Y7W6 UNIPROT EIF4E2/GIGYF2 complex complex SIGNOR-C257 SIGNOR form complex binding 9606 BTO:0000568 22751931 YES SARA A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated. 0.693 SIGNOR-261009 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0003316 11777913 YES miannu 4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. 0.434 SIGNOR-250099 MAP2K3 protein P46734 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 YES done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. 0.606 SIGNOR-273950 KAT2A protein Q92830 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269594 RPS6KA5 protein O75582 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates phosphorylation 9606 15010469 YES gcesareni We found that msk1 phosphorylated histone h2a on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by msk1. 0.2 SIGNOR-265314 HDAC1 protein Q13547 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18588516 NO miannu The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor). 0.611 SIGNOR-254228 DOK1 protein Q99704 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257673 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 ASAAGGLsPVTNLTV 9606 BTO:0000017 28192398 YES miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  0.65 SIGNOR-277340 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 15621017 YES Thus, the increased immunoreactivity of CaMKII-α of the remaining neurons may be the consequence of the altered calcium dynamics in neurons. There is evidence indicating that CaMKII might participate in tau phosphorylation in AD. 0.595 SIGNOR-255490 KLHL17 protein Q6TDP4 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9534 BTO:0000298 17062563 YES miannu Here, we report that actinfilin is able to bind to GluR6, a kainate-type glutamate receptor subunit, and target GluR6 for degradation. Like many members of its protein family, actinfilin acts as a substrate adaptor, binding Cullin 3 (Cul3) and linking GluR6 to the E3 ubiquitin-ligase complex. Together our data demonstrate that actinfilin acts as a scaffold, linking GluR6 to the Cul3 ubiquitin ligase to provide a novel mechanism for kainate receptor degradation. 0.326 SIGNOR-271613 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Met666 VIVITLVmLKKKQYT -1 8943232 YES lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261789 SCF-SKP2 complex SIGNOR-C136 SIGNOR CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization ubiquitination -1 phosphorylation:Ser399;Thr395 GLLTPPQsGKKQSSG;PLPSGLLtPPQSGKK 11533444 YES lperfetto The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro 0.646 SIGNOR-267558 HLX protein Q14774 UNIPROT EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003980 20008130 YES Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. 0.262 SIGNOR-261621 FLT3 protein P36888 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 10090 10080542 YES gcesareni FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc 0.603 SIGNOR-245060 LPAR4 protein Q99677 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.383 SIGNOR-256785 MST1 protein P26927 UNIPROT MST1R protein Q04912 UNIPROT up-regulates binding 9606 8062829 YES gcesareni P185ron is a tyrosine kinase activated by msp 0.896 SIGNOR-31107 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA8 protein Q9Y5G5 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265680 KLF15 protein Q9UIH9 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 15664998 NO lperfetto Moreover, KLF15 and C/EBPalpha acted synergistically to increase the activity of the PPARgamma2 gene promoter in 3T3-L1 adipocytes. 0.436 SIGNOR-235331 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 21945940 YES lperfetto Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion. 0.2 SIGNOR-216568 TBXA2R protein P21731 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.469 SIGNOR-257023 MARCHF9 protein Q86YJ5 UNIPROT IGHD protein P01880 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271542 ADRA1B protein P35368 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.504 SIGNOR-256807 AMT protein P48728 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 YES lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. 0.735 SIGNOR-268242 EP300 protein Q09472 UNIPROT CAV3 protein P56539 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 NO Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. 0.2 SIGNOR-254259 MAPK8 protein P45983 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser358 GQISAGYsPVIDCHT 9606 BTO:0002181 23608534 YES miannu Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome.  0.374 SIGNOR-276492 LPR5/6 complex SIGNOR-C219 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 19107203 YES PPPSPxS motif in LRP6/5 must be phosphorylated. miannu These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin. 0.707 SIGNOR-256177 NCL protein P19338 UNIPROT MYBL1 protein P10243 UNIPROT down-regulates activity binding 9606 BTO:0000007 10660576 YES miannu We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity. 0.418 SIGNOR-221233 HACD4 protein Q5VWC8 UNIPROT FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 YES Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, 0.2 SIGNOR-267763 MYLIP protein Q8WY64 UNIPROT LRP8 protein Q14114 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20427281 YES miannu Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. 0.445 SIGNOR-271486 PRKCB protein P05771 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 YES gcesareni Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. 0.328 SIGNOR-115718 CDK2 protein P24941 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 15964852 YES lperfetto Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation at ser-130. 0.954 SIGNOR-149416 MST1 protein P26927 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 YES lperfetto The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells 0.2 SIGNOR-171005 C5AR2 protein Q9P296 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity by expression 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.8 SIGNOR-263470 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 10790373 YES miannu  Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3. 0.564 SIGNOR-272569 CSNK1E protein P49674 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates activity phosphorylation Ser280 DGGIYIGsIMKGGAV -1 24993822 YES miannu Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3. 0.668 SIGNOR-276645 PTPN1 protein P18031 UNIPROT STAT6 protein P42226 UNIPROT down-regulates activity dephosphorylation 9606 22156494 YES miannu Phosphorylated STAT6 may also serve as a cytoplasmic substrate for PTP1B since overexpression of PTP1B leads to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity, whereas PTP1B deficiency increases IL-4-induced STAT6 signaling in B-cells. 0.327 SIGNOR-277122 AKT3 protein Q9Y243 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 YES gcesareni Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta 0.412 SIGNOR-187062 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263792 ENMD-2076 chemical CID:16041424 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191469 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 11863375 YES miannu Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2 0.8 SIGNOR-266924 PTPN1 protein P18031 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation 9606 28919207 YES miannu PTP1B inactivation prevents TrkA exit from soma and causes receptor degradation, suggesting a " gate-keeper " mechanism that ensures targeting of inactive receptors to axons to engage with ligand.|We identify a gate keeping mechanism in which TrkA receptors, destined for transcytosis, are dephosphorylated in neuronal soma by the ER-resident tyrosine phosphatase, PTP1B. 0.378 SIGNOR-277081 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192607 CDK2 protein P24941 UNIPROT ELK4 protein P28324 UNIPROT up-regulates activity phosphorylation Ser387 LSPVAPLsPARLQGA 9606 26028036 YES miannu Phosphorylation of ELK4 at Thr194 and Ser387 by CDK2 is required for EGF-induced cell transformation. 0.363 SIGNOR-278210 hsa-miR-374b-5p mirna URS000033F45D_9606 RNAcentral WNT16 protein Q9UBV4 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003582 26100275 YES Parnian These data suggest that miR-374b may negatively regulate the expression of Wnt16 and AKT1 by directly targeting the 3'-UTR of their mRNA. 0.4 SIGNOR-278855 A5/b1 integrin complex SIGNOR-C163 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269012 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Thr186 KREKRRStSRQFVDG 9606 BTO:0000567 14744859 YES llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 0.779 SIGNOR-250590 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT up-regulates activity dephosphorylation -1 25624455 YES miannu a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.26 SIGNOR-254722 SMARCA2 protein P51531 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.834 SIGNOR-269817 DAB2IP protein Q5VWQ8 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity binding 9606 27858941 YES miannu DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1 0.837 SIGNOR-254748 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017876 YES llicata Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation. 0.659 SIGNOR-176858 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 10644691 YES In addition, PP2C expression relieves Axin-mediated repression of LEF-1-dependent transcription. PP2C utilizes Axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that PP2C is a positive regulator of Wnt signal transduction and mediates its effects through the dephosphorylation of Axin. 0.435 SIGNOR-248488 AURKA protein O14965 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser539 TSLSPRSsLSSPSPP 9606 21878642 YES llicata We identified the highly conserved ser(539) as the primary phosphorylation site for aurora kinases. 0.25 SIGNOR-176359 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 19279133 YES flangone Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs. 0.438 SIGNOR-242055 STIP1 protein P31948 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 YES miannu Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine. 0.934 SIGNOR-261411 NAE complex SIGNOR-C131 SIGNOR CUL2 protein Q13617 UNIPROT up-regulates activity neddylation 9606 25504797 YES lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. 0.533 SIGNOR-243154 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Ser393 RGELIPIsPSTEVGG BTO:0000007 10593981 YES llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 0.718 SIGNOR-250734 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization ubiquitination Lys284 VKSANVKkADSSTTK 9606 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). 0.3 SIGNOR-272830 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268658 LPAR5 protein Q9H1C0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.354 SIGNOR-257205 NEUROG1 protein Q92886 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 18400164 NO lperfetto While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis 0.7 SIGNOR-265172 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NCOA3 protein Q9Y6Q9 UNIPROT down-regulates phosphorylation Ser728 VVKQEQLsPKKKENN 9606 22163316 YES lperfetto We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase. 0.314 SIGNOR-216892 NARS1 protein O43776 UNIPROT tRNA(Asn) smallmolecule CHEBI:29172 ChEBI down-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270453 dexamethasone chemical CHEBI:41879 ChEBI CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-250568 NMI protein Q13287 UNIPROT SOX10 protein P56693 UNIPROT down-regulates activity binding 9606 16214168 YES miannu We identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific. 0.429 SIGNOR-225602 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 15526160 YES miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. 0.791 SIGNOR-254950 MAPK8 protein P45983 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 15538382 YES lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. 0.61 SIGNOR-130381 MAPK1 protein P28482 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser428 KVAASPKsPTAALNE 9606 16198290 YES lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. 0.367 SIGNOR-140894 VRK1 protein Q99986 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 15378002 YES flangone Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription 0.513 SIGNOR-127073 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Thr233 DDEDDSGtEES 9606 BTO:0000567 11546811 YES llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  0.352 SIGNOR-251061 MECOM protein Q03112 UNIPROT PBX1 protein P40424 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 19767769 NO miannu In this study, we identified pbx1, a proto-oncogene in hematopoietic malignancy, as a target gene of evi-1. Overexpression of evi-1 increased pbx1 expression in hematopoietic stem/progenitor cells 0.424 SIGNOR-188155 PKA proteinfamily SIGNOR-PF17 SIGNOR ENAH protein Q8N8S7 UNIPROT up-regulates activity phosphorylation 9606 15066263 YES miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts 0.2 SIGNOR-268285 SMAD6 protein O43541 UNIPROT TBX6 protein O95947 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 19561075 YES miannu Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. 0.327 SIGNOR-272785 AMPK complex SIGNOR-C15 SIGNOR CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 21331044 YES lperfetto Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target. 0.285 SIGNOR-216529 RPS6KB1 protein P23443 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 YES llicata Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway, which in turn promotes the transcriptional activity of myc. 0.305 SIGNOR-178590 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191430 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MCL1 protein Q07820 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 18676833 YES inferred from 70% family members fstefani We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1. 0.2 SIGNOR-270042 Brivanib alaninate chemical CID:11154925 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190732 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT up-regulates activity binding 9606 BTO:0000782 15851487 YES lperfetto Baff specifically binds baff receptor 0.784 SIGNOR-135713 ASAP2 protein O43150 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity gtpase-activating protein -1 10022920 YES miannu Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. 0.667 SIGNOR-269706 IRS1 protein P35568 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 20966354 YES lperfetto Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin. 0.721 SIGNOR-168985 Activated PSC phenotype SIGNOR-PH224 SIGNOR LIF protein P15018 UNIPROT up-regulates 9606 BTO:0000584 30996350 YES miannu We reveal that leukemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells.  0.7 SIGNOR-277985 DHCR7 protein Q9UBM7 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity chemical modification 9606 9634533 YES miannu In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol. 0.8 SIGNOR-267252 SMURF1 protein Q9HCE7 UNIPROT ANKS4B protein Q8N8V4 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272678 metformin chemical CHEBI:6801 ChEBI NR0B2 protein Q15466 UNIPROT up-regulates quantity by expression 9606 17909097 NO gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. 0.8 SIGNOR-158059 GPR119 protein Q8TDV5 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.413 SIGNOR-256768 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser386 LRGAQAAsPAKGEPS 9606 BTO:0000567 23348582 YES phosphorylation site remapping based on mass spec table lperfetto Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. 0.503 SIGNOR-272971 CSNK2A1 protein P68400 UNIPROT PSMA3 protein P25788 UNIPROT unknown phosphorylation Ser250 SLKEEDEsDDDNM -1 8619999 YES llicata Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery. 0.382 SIGNOR-250939 EP300 protein Q09472 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates quantity by stabilization acetylation Lys378 TIRMSFVkGWGAEYR 9606 16862174 YES miannu Smad proteins are crucial for the intracellular signaling of transforming growth factor-beta (TGF-beta). Upon their receptor-induced activation, Smad proteins are phosphorylated and translocated to the nucleus to activate the transcription of a select set of target genes. Here, we show that the co-activator p300/CBP bound and acetylated Smad3 as well as Smad2 in vivo, and that the acetylation was stimulated by TGF-beta.A major acetylation site of Smad3 by p300/CBP is Lys-378 in the MH2 domain (Smad3C) known to be critical for the regulation of transcriptional activity. 0.736 SIGNOR-260431 KLF1 protein Q13351 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates activity binding 10090 BTO:0004475 12556498 YES irozzo The present study also shows that EKLF itself inhibits FLI-1 activity. As suggested above for the inhibition of EKLF activity, the inhibition of FLI-1 activity most probably involves the indirect recruitment of EKLF to FLI-1 target promoters by protein-protein interaction. 0.371 SIGNOR-256046 PRKCZ protein Q05513 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates quantity by stabilization phosphorylation Ser345 RGDGSGFsL 9606 BTO:0002181 23249950 YES miannu APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation. 0.841 SIGNOR-276433 AKT1 protein P31749 UNIPROT SIRT6 protein Q8N6T7 UNIPROT down-regulates activity phosphorylation Ser338 PKRERPTsPAPHRPP 9606 25074979 YES miannu AKT1 interacts with and phosphorylates SIRT6 on Ser 338.|Because AKT1 suppresses SIRT6 protein abundance by decreasing its stability, we investigated whether MDM2 is involved in this process. 0.533 SIGNOR-278465 AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 NO miannu c-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. 0.7 SIGNOR-254952 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity deacetylation 9606 BTO:0000007 14976264 YES lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress 0.911 SIGNOR-252994 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT JUN protein P05412 UNIPROT down-regulates activity 9606 BTO:0000007 17715225 NO miannu SARS-CoV nsp1 inhibits c-Jun expression and phosphorylation. 0.2 SIGNOR-262505 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT unknown phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 YES llicata In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. 0.49 SIGNOR-117339 ITGB1 protein P05556 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.706 SIGNOR-253188 RAB9A protein P51151 UNIPROT GCC2 protein Q8IWJ2 UNIPROT up-regulates activity 18195106 YES lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector 0.538 SIGNOR-253087 PRKCG protein P05129 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 YES lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. 0.399 SIGNOR-249088 RNF111 protein Q6ZNA4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 YES lperfetto Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. 0.684 SIGNOR-235394 valrubicin chemical CHEBI:135876 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 16019763 YES miannu Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis. 0.8 SIGNOR-259383 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr4 yTVVYFPV 9606 BTO:0000150 19254954 YES llicata Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly, 0.438 SIGNOR-184383 AKT2 protein P31751 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. 0.289 SIGNOR-186776 PAMPs stimulus SIGNOR-ST11 SIGNOR MBL2 protein P11226 UNIPROT up-regulates activity binding 17204478 YES lperfetto In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2) 0.7 SIGNOR-263405 Norzotepine chemical CID:10041551 PUBCHEM SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 20223878 YES Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. 0.8 SIGNOR-257831 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser25 VVLCSCPsPSMVRTQ 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity 0.2 SIGNOR-236777 LGALS3 protein P17931 UNIPROT BAD protein Q92934 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000664 21821001 NO miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. 0.2 SIGNOR-261907 LRP6 protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 19107203 YES PPPSPxS motif in LRP6/5 must be phosphorylated. lperfetto These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin.These Observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. 0.732 SIGNOR-227942 CYP11A1 protein P05108 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 33117906 YES lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. 0.8 SIGNOR-268633 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.91 SIGNOR-252853 MEF2C protein Q06413 UNIPROT CDKL5 protein O76039 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20513142 NO Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. 0.35 SIGNOR-254031 2-hydroxyglutarate smallmolecule CHEBI:132941 ChEBI FOXP3 protein Q9BZS1 UNIPROT down-regulates activity chemical inhibition 9606 33114536 NO Luana Moreover, glutamate oxaloacetate transaminase 1 (GOT1), an enzyme involved in glutamine metabolism, exerts pro-inflammatory effects by producing 2-hydroxyglutarate, which hinders the expression of FOXP3 and thus blocks the formation of Tregs. 0.8 SIGNOR-268042 PTK2 protein Q05397 UNIPROT TLN1 protein Q9Y490 UNIPROT up-regulates activity binding 9606 15688067 YES miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.687 SIGNOR-257731 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 BTO:0000848 BTO:0001253 20959475 YES lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). 0.713 SIGNOR-252955 PAK1 protein Q13153 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation Thr659 KIEINLStRMDHMVS 9606 BTO:0002181 33432150 YES miannu Pak1 phosphorylates NLRP3 to promote inflammasome activation. 0.2 SIGNOR-277547 SNS-314 Mesylate chemical CID:24995523 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207099 perfluorohexanesulfonic acid chemical CHEBI:132448 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268761 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates phosphorylation 9606 18756288 YES lperfetto Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. 0.583 SIGNOR-217029 FBXW11 protein Q9UKB1 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates ubiquitination 9606 14988407 YES gcesareni We have identified scf(beta-trcp1), a ubiquitin (e3) ligase, as a critical determinant for the protein degradation of smad4 protein. 0.2 SIGNOR-123060 RPS6KA1 protein Q15418 UNIPROT CCT2 protein P78371 UNIPROT up-regulates phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 21440620 YES lperfetto Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process. 0.249 SIGNOR-172986 Neurokinin A smallmolecule CHEBI:80311 ChEBI TACR2 protein P21452 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257587 MK-2206 chemical CHEBI:67271 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 BTO:0001286 21841310 YES gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. 0.8 SIGNOR-252461 DOK1 protein Q99704 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.297 SIGNOR-257680 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257866 HDLBP protein Q00341 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding 9606 BTO:0000150 33941620 YES miannu We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. 0.2 SIGNOR-266697 ATG16L1 protein Q676U5 UNIPROT CLTC protein Q00610 UNIPROT up-regulates binding 9606 20639872 YES gcesareni Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors. 0.461 SIGNOR-166702 AKT1 protein P31749 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 15896703 YES gcesareni We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism. 0.428 SIGNOR-252477 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.435 SIGNOR-259024 CASP8 protein Q14790 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity cleavage Asp324 RMQSLQLdCVAVPSS 9606 BTO:0000007;BTO:0000093;BTO:0000567 10521396 YES amattioni These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability. 0.909 SIGNOR-71265 TRADD protein Q15628 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 BTO:0000007;BTO:0001412;BTO:0000567 8943045 YES amattioni The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD. N-terminal domain of tradd may become accessible to traf2, thereby permitting recruitment of the traf2/ciap1 heterocomplex. 0.697 SIGNOR-45134 MICU1 protein Q9BPX6 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.699 SIGNOR-270871 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr153 SEDIKSYyTVRQLEL -1 11506178 YES lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B 0.788 SIGNOR-249369 CYP11B2 protein P19099 UNIPROT aldosterone smallmolecule CHEBI:27584 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 YES lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone 0.8 SIGNOR-268685 TMEM258 protein P61165 UNIPROT OST-B complex complex SIGNOR-C536 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.485 SIGNOR-272068 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Ser197 AAQRCTIsYRAPELF -1 18184589 YES Manara Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition. 0.2 SIGNOR-260804 SYCP3 protein Q8IZU3 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 YES miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. 0.636 SIGNOR-264200 GRM5 protein P41594 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264348 LRRC4 protein Q9HBW1 UNIPROT CDK4 protein P11802 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 NO miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. 0.2 SIGNOR-264059 ELF4 protein Q99607 UNIPROT CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000782 14625302 NO miannu Myeloid elf1-like factor is a potent activator of interleukin-8 expression in hematopoietic cells 0.241 SIGNOR-119204 STAT3 protein P40763 UNIPROT RORC protein P51449 UNIPROT up-regulates 9606 18454151 NO The inflammatory cytokines IL-6, IL-21 and IL-23 share signaling pathways by activating both STAT1 and STAT3, while IL-1beta is thought to activate the kinases IRAK1 and IRAK2 through recruitment of the adaptor MyD88. Thus, STAT3 is likely to be a common denominator in the induction of RORgammaT and IL-17 expression 0.638 SIGNOR-254303 CHMP5 protein Q9NZZ3 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.706 SIGNOR-265527 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT up-regulates activity phosphorylation 10090 2470098 YES Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. 0.691 SIGNOR-259930 E2F5 protein Q15329 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates activity binding 9606 BTO:0001938 10783242 YES miannu Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. These results indicate that phosphorylation of E2F-5 at the CDK site at position 251 by cyclin E–Cdk2 augments transcription by enhancing the interaction of E2F-5 with p300/CBP co-activator proteins. 0.575 SIGNOR-262733 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity phosphorylation 9606 23912711 YES miannu Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.|BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by \u03b2TrCP1. 0.377 SIGNOR-279009 AURKB protein Q96GD4 UNIPROT BUB1 protein O43683 UNIPROT up-regulates activity phosphorylation 9606 34861183 YES miannu Although our analysis identified only one of the 15 sites implicated in Bub1-Mad1 interaction, it suggests that following its rapamycin-induced dimerization, Ipl1 phosphorylates Bub1, and potentially Mad1, to drive eSAC signaling. 0.748 SIGNOR-279010 BTK protein Q06187 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity phosphorylation 9606 9751072 YES miannu Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action. 0.382 SIGNOR-279011 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding 9606 25875593 YES irozzo C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site. 0.952 SIGNOR-256367 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 19282669 YES inferred from 70% family members lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.717 SIGNOR-270146 IL17A protein Q16552 UNIPROT KRT17 protein Q04695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 21796151 NO miannu IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. 0.342 SIGNOR-255232 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 NO Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. 0.7 SIGNOR-254973 Naloxone benzoylhydrazone chemical CID:9601084 PUBCHEM OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258422 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates transcriptional regulation 9606 18719589 NO Induction of mitochondrial biogenesis fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways 0.289 SIGNOR-210056 PSMA1 protein P25786 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.861 SIGNOR-263363 CDK8 protein P49336 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. 0.2 SIGNOR-273173 INO80 complex complex SIGNOR-C498 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 25016522 NO miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.7 SIGNOR-270858 NPTX1 protein Q15818 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity binding 10090 BTO:0000938 15115814 YES inferred from family member lperfetto We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. 0.335 SIGNOR-270235 XL-647 chemical CID:10458325 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207860 PTPRJ protein Q12913 UNIPROT LAT protein O43561 UNIPROT down-regulates activity dephosphorylation 9606 11259588 YES Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation 0.353 SIGNOR-248696 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of -1 8099587 YES Luana 17 beta-HSD type 2 was capable of catalyzing the interconversion of testosterone and androstenedione as well as estradiol and estrone.  0.8 SIGNOR-269761 pipamperone chemical CHEBI:78549 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258571 MAPK3 protein P27361 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates activity phosphorylation Ser284 RRDYDDMsPRRGPPP 9606 11231586 YES lperfetto Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353. 0.345 SIGNOR-105238 PPP2CA protein P67775 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 20704570 YES gcesareni Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a. 0.2 SIGNOR-167480 VHL protein P40337 UNIPROT KLF10 protein Q13118 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003781 18359287 NO lperfetto In this study, we show that both TGFBI and KLF10 are down-regulated by VHL in 786-0 cells, and that KLF10 may serve as a transactivator of the TGFBI promoter. 0.2 SIGNOR-253213 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 15342917 YES lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 0.723 SIGNOR-256311 ECM stimulus SIGNOR-ST20 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259037 HDAC2 protein Q92769 UNIPROT ZNF318 protein Q5VUA4 UNIPROT up-regulates activity binding 9606 BTO:0001321 16469430 YES Monia A central domain of TZF is required for repression of AR-mediated transactivation. The results revealed that HDAC2 was coimmunoprecipitated with TZF (Fig. 6A), These results indicate that AR, TZF and HDAC2 form a ternary complex during the repression of AR-mediated transactivation. 0.33 SIGNOR-261188 CACNA1G protein O43497 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 NO miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). 0.7 SIGNOR-264329 ERCC1 protein P07992 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 NO lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.7 SIGNOR-275710 PKP2 protein Q99959 UNIPROT DSP protein P15924 UNIPROT up-regulates quantity by stabilization binding 10090 BTO:0003264 22781308 YES Simone In contrast to the proper membrane localization of PKP2 and DSP after cotransfection of both WT proteins, mutant PKP2 C796R protein was not able to interact with FLAG-DSP to enable assembly at the junctional plaque, indicating the requirement of functional PKP2 for DSP integration into the desmosome. 0.786 SIGNOR-261254 ALDH2 protein P05091 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity binding -1 phosphorylation:Thr429 MQILKFKtIEEVVGR 28056995 YES lperfetto Consistent with previous data, HDAC3 only bound to the ATP6V0E2 promoter in the presence of ALDH2.|Taken together, our data demonstrate that in the macrophages of LDLR-KO or ALDH2 rs671 mutant, AMPK phosphorylates ALDH2 at T356, which enables its nuclear translocation. Once in the nucleus, ALDH2 binds to HDAC3 and suppresses the transcription and protein expression of ATP6V0E2. 0.2 SIGNOR-271867 DVL2 protein O14641 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 17529994 YES lperfetto Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex. 0.652 SIGNOR-227920 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 10542228 YES gcesareni Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2. 0.296 SIGNOR-71764 GLUL protein P15104 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity chemical modification 9606 30158707 YES miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. 0.8 SIGNOR-267826 CDK5 protein Q00535 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by destabilization phosphorylation Thr314 LPSEAGPtPCAPASF 9534 BTO:0004055 30712943 YES lperfetto Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT 1A receptor via phosphorylation|5-HT1AR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop. 0.27 SIGNOR-264406 KSR1 protein Q8IVT5 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Thr269 NVHMVSTtLPVDSRM 9606 11134016 YES lperfetto Here we show that phosphorylation of c-raf-1 on thr(269) by ksr is necessary for optimal activation in response to egf stimulation. 0.653 SIGNOR-85386 ELOC protein Q15369 UNIPROT Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR form complex binding 10090 BTO:0000165 19300455 YES miannu Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation.  Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb. 0.2 SIGNOR-271797 MAP4K1 protein Q92918 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates phosphorylation Thr165 ISAQIGAtLARRLSF 9606 BTO:0000782 15743830 YES gcesareni Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase d1. 0.2 SIGNOR-134490 SPRY4 protein Q9C004 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR down-regulates 9606 BTO:0002283 20501643 NO The reduction of cell mobility and invasion demonstrated with Spry4 expression suggests that Spry4 may act on downstream targets to inhibit metastasis. 0.7 SIGNOR-278110 BCR protein P11274 UNIPROT YWHAZ protein P63104 UNIPROT unknown phosphorylation Thr232 LTLWTSDtQGDEAEA -1 16045749 YES llicata We show here that BCR interacts with at least five isoforms of 14-3-3 in vivo and phosphorylates 14-3-3tau on Ser233 and to a lesser extent 14-3-3zeta on Thr233 0.331 SIGNOR-250595 NFIB protein O00712 UNIPROT SLIT1 protein O75093 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.249 SIGNOR-268899 FBXW8 protein Q8N3Y1 UNIPROT Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR up-regulates activity binding 10090 BTO:0002572 23142081 YES miannu Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin ligase substrate-targeting subunit, Fbw8. mTORC2 stabilizes Fbw8 by phosphorylation at Ser86, allowing the insulin-induced translocation of Fbw8 to the cytosol where it mediates IRS-1 degradation.  We provide evidence that mTORC2 can stabilize Fbw8, the substrate-targeting subunit of the CUL7 E3 ligase complex that has been shown to mediate degradation of IRS-1 . 0.769 SIGNOR-271942 APC-c complex SIGNOR-C150 SIGNOR PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 0.443 SIGNOR-272750 KIF2B protein Q8N4N8 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272534 levomethadone chemical CHEBI:136003 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258809 MAPK8 protein P45983 UNIPROT CDT1 protein Q9H211 UNIPROT down-regulates activity phosphorylation Thr29 PPKLACRtPSPARPA 9606 21856198 YES miannu In this pathway, stress activates JNK1, which phosphorylates Cdt1 on T29, thereby inhibiting the interaction with HBO1, a co-activator of Cdt1 necessary for licensing. 0.369 SIGNOR-278445 TRIM25 protein Q14258 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity ubiquitination 9606 27626314 YES miannu We demonstrate that TRIM25 polyubiquitinates ERG in vitro and that inactivation of TRIM25 resulted in reduced polyubiquitination and stabilization of ERG.|Our previous discovery of USP9X as an ERG stabilizing deubiquitinase suggests that reduction of ERG protein levels by TRIM25 mediated proteasomal degradation is prevented by expression of USP9X in fusion positive prostate cancer cells.|Using several biochemical assays we show that TRIM25 mediates the polyubiquitination of full-length ERG as well as N-terminally truncated ERG. 0.301 SIGNOR-278732 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT up-regulates activity cleavage Asp390 LPQLTLPdSLTSAAS 17761173 YES lperfetto In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein 0.396 SIGNOR-260613 AKT3 protein Q9Y243 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 YES gcesareni Ser-136 is the major phosphoacceptor site for akt;akt can weakly phosphorilate ser-155. 0.54 SIGNOR-81122 CCNC protein P24863 UNIPROT CyclinC/CDK3 complex SIGNOR-C545 SIGNOR form complex binding 9606 BTO:0004173 25344755 YES lperfetto Cyclin C was cloned as a growth-promoting G1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumor suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase, as well as CDK8 and CDK3. 0.68 SIGNOR-273156 IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 12242293 YES lperfetto We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1 0.913 SIGNOR-92994 HMGB1 protein P09429 UNIPROT HOXD3 protein P31249 UNIPROT up-regulates activity binding -1 8890171 YES miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. 0.298 SIGNOR-219980 FGR protein P09769 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Tyr530 FTSTEPQyQPGENL -1 9208935 YES An eicosapeptide encompassing the C-terminal tail of c-Src (Tyr527) which is conserved in most Src-related protein kinases, is phosphorylated by C-terminal Src kinase (CSK) and by the two Src-related protein kinases c-Fgr and Lyn, with similar kinetic constants.  0.647 SIGNOR-251145 SGK1 protein O00141 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 18570873 YES gcesareni Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna.|Akt acts downstream of PI3K to phosphorylate p27 at T157 and T198, leading to impaired nuclear p27 import, p27 accumulation in the cytoplasm, and loss of cyclin E-Cdk2 inhibition 0.469 SIGNOR-179121 COL4A4 protein P53420 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 YES lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. 0.457 SIGNOR-272350 DVL2 protein O14641 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates binding 9606 23151663 YES gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl-associated activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. 0.642 SIGNOR-199500 CCNO protein P22674 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity binding 37197505 YES lperfetto CDK2 is the predominant activating complex form of CCNO, but CCNO can bind to CDK1 to form an activating complex in the absence of CDK2. 0.335 SIGNOR-275617 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000938 10558990 YES lperfetto The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival. 0.2 SIGNOR-252782 RBX1 protein P62877 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR form complex binding 9606 11574546 YES miannu The von Hippel-Lindau tumor-suppressor protein (pVHL) forms a protein complex (VCB-Cul2) with elongin C, elongin B, Cul-2, and Rbx1, which functions as a ubiquitin-protein ligase (E3). The alpha-subunits of the hypoxia-inducible factors have been identified as targets for the VCB-Cul2 ubiquitin ligase.  0.8 SIGNOR-271520 PTPRG protein P23470 UNIPROT ITGAL protein P20701 UNIPROT down-regulates activity 9606 25624455 NO miannu PTPRG activation inhibits chemoattractantinduced LFA-1 affinity triggering and mediated adhesion in human primary monocytes. we show that PTPRG is a novel negative regulator of LFA-1 high-affinity-state triggering and mediated arrest by chemoattractants in human primary monocytes. Notably, PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role (37). In our context, SRC appears inhibited by PTPRG activation (Table I), thus making it unlikely that the antiadhesive effect of PTPRG is mediated by SRC activation. 0.2 SIGNOR-254736 SLC24A1 protein O60721 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264390 ATM protein Q13315 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Ser272 LSDTDSHsQDLGSPE 9606 BTO:0000763 11278446 YES lperfetto Hyperphosphorylation of hrad9 induced by ir is dependent on atm. Ser(272) of hrad9 is phosphorylated directly by atm in vitro. / our results suggest that the atm-mediated phosphorylation of hrad9 is required for ir-induced checkpoint activation. 0.766 SIGNOR-105243 SAGA complex complex SIGNOR-C465 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269637 EDNRA protein P25101 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.448 SIGNOR-256923 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Thr133 KLPTDNQtKKPETYL 9606 BTO:0000130 17217339 YES lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation. 0.38 SIGNOR-152023 MAP3K8 protein P41279 UNIPROT PLCB3 protein Q01970 UNIPROT up-regulates activity phosphorylation Ser537 PSLEPQKsLGDEGLN 9606 21868363 YES miannu Additionally, we found that PAR1-induced Ca2+ signals are transduced through Tpl2, which activates phospholipase C\u03b23 by phosphorylation at Ser537.|These findings raised the question whether Tpl2, which phosphorylates PLCbeta 3 at Ser537 (this report) regulates Ca 2+ signaling in thrombin stimulated cells through phosphorylation of PLCbeta 3 at this site. 0.2 SIGNOR-278519 MAPK14 protein Q16539 UNIPROT JDP2 protein Q8WYK2 UNIPROT unknown phosphorylation Thr148 VRTDSVKtPESEGNP -1 12225289 YES miannu Wild-type JDP2 exhibited efficient phosphorylation by the p38 kinase, the mutant JDP2 T%)A did not incorporate labelled Figure 5 JDP2 C-terminal domain is necessary but not sufficient for p38 phosphorylation (A) p38 phosphorylated JDP2 at Thr-148. Bacterially purified His-JDP2 (Wt) or His-JDP2 T148A (Ala) were incubated with bacterially purified activated p38 F327S [21] in the presence of [γ- 32P]ATP for 30 min. Proteins were resolved by SDS/PAGE (12 % gel), dried and exposed to autoradiography. (B) The JDP2 C-terminal domain is necessary but not sufficient for phosphorylation by p38 kinase. Bacterially purified GST fusion proteins with full-length JDP2 (Wt) C-terminally truncated JDP2 (∆C) and JDP2 C-terminal fragment (Dock) were used in an in vitro kinase assay as described in (A). A representative experiment is presented. (C) In vitro kinase assay using GST-JDP2 (JDP2wt), JDP2 ∆C and JDP2-Dock as substrates with either activated p38 or HA-JNK2 kinases. Protein mixtures were resolved by SDS/PAGE, fixed, dried and analysed by PhosphorImaging. The results represent meansS.E.M. from three independent experiments. phosphate in the presence of activated p38 kinase. This indicates that both p38 and JNK kinases are able to integrate stress signals to JDP2 Thr-148 0.381 SIGNOR-250100 PRKAA1 protein Q13131 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.284 SIGNOR-251619 FOXO1 protein Q12778 UNIPROT GK protein P32189 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18805788 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription foxo1 localizes to the nucleus, where it represses hnf-4-dependent activity of the gk promoter as a corepressor. 0.251 SIGNOR-181268 MED19 protein A0JLT2 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.851 SIGNOR-266663 PRL protein P01236 UNIPROT KRT19 protein P08727 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 20103718 NO Regulation miannu PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. 0.26 SIGNOR-251905 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser682 SMNASRLsQPGQLMS 9606 BTO:0000007 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251278 ITGB1 protein P05556 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.757 SIGNOR-253170 TARDBP protein Q13148 UNIPROT DICER1 protein Q9UPY3 UNIPROT up-regulates quantity post transcriptional regulation 7227 32620127 YES lperfetto Molecularly, we observed that TBPH regulates the expression levels of Dicer-2 by direct protein-mRNA interactions in vivo.|In agreement with this idea, we found that the suppression of TDP-43 induces the downregulation of Dicer in human neuroblastoma cell lines signifying that the TDP-43 function is required to prevent defects in Dicer protein expression or stability 0.374 SIGNOR-262114 FNTA protein P49354 UNIPROT MRAS protein O14807 UNIPROT up-regulates activity 9606 24294527 YES lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. 0.2 SIGNOR-242553 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Ser104 FSFDTDRsPAPMSCD 9606 12591950 YES lperfetto Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58) 0.2 SIGNOR-98384 IQGAP1 protein P46940 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity binding 15695813 YES lperfetto Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.  0.714 SIGNOR-261889 EEF1A2 protein Q05639 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269528 PI3K complex SIGNOR-C156 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 18721898 NO lperfetto Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3. 0.579 SIGNOR-252705 CDON protein Q4KMG0 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 YES lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts 0.2 SIGNOR-235551 SRC protein P12931 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 YES miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. 0.338 SIGNOR-276393 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.91 SIGNOR-252846 MAPK3 protein P27361 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation Ser159 DGSCSSSsPPLPVLG 9606 15632084 YES amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 0.854 SIGNOR-132975 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr579 VSSDGHEyIYVDPMQ 9606 BTO:0000599 9642269 YES miannu We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins. 0.2 SIGNOR-250254 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 YES lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 0.607 SIGNOR-161686 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr142 TENDDDVyRSLEELA 9606 12454019 YES miannu To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor. 0.593 SIGNOR-95972 Oxotremorine chemical CHEBI:7851 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258652 CSNK2A2 protein P19784 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Thr93 EAETLAEtEPERHLG 9606 BTO:0001130 16581776 YES llicata In vitro kinase assays followed by mass spectrometric analyses demonstrated that ck2 phosphorylated recombinant nkx3.1 on thr89 and thr93. We have also determined that nkx3.1 is degraded primarily through a proteasomal pathway, suggesting that phosphorylation by ck2 protects nkx3.1 from degradation. 0.315 SIGNOR-145505 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 YES gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity 0.631 SIGNOR-64169 PAX2 protein Q02962 UNIPROT PAX2/TLE4 complex SIGNOR-C152 SIGNOR form complex binding 9606 16631587 YES miannu Several Pax proteins are able to interact with groucho (TLE) family members. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. 0.456 SIGNOR-256359 SMO protein Q99835 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.515 SIGNOR-199159 GSK3B protein P49841 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity phosphorylation Ser66 NGMGPPFsVISSPMG 9606 BTO:0000007 29137318 YES miannu GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.  0.275 SIGNOR-277370 RPL34 protein P49207 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.839 SIGNOR-262467 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 YES miannu Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376 0.584 SIGNOR-166718 PDGFB protein P01127 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates binding 9606 11331882 YES miannu Pdgf-b activates both pdgfr-alpha and pdgfr-beta 0.906 SIGNOR-107400 PLK1 protein P53350 UNIPROT ANAPC1 protein Q9H1A4 UNIPROT up-regulates phosphorylation Ser355 AALSRAHsPALGVHS 9606 14657031 YES gcesareni Our analysis revealed an unexpected and unprecedented complexity of mitotic phosphorylation sites and suggests that other kinases than cdk1 and plk1 also contribute to apc phosphorylation. 0.523 SIGNOR-119881 MAPK1 protein P28482 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates activity phosphorylation Ser239 FRRGLDDsTGGTPLT 9606 BTO:0000007 12556484 YES lperfetto Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro. In the case of Nudel, the phosphorylation sites were also located in the S/TP motifs. Detailed mutagenesis study indicated that T219, S242, and T245 were phosphorylated by Cdc2, while T219 and T245 were phosphorylated by Erk2.|Phosphorylation of Nudel in M phase appears to positively modulate dynein motor activity. Both phosphorylated and unphosphorylated forms of Nudel were transported by dynein (Fig. 7 and 9 and data not shown), indicating that neither of them inactivated the dynein motor. On the other hand, both phospho-Nudel and Nudelpmt5 bound Lis1 more strongly than Nudel or Nudelmt5 did 0.375 SIGNOR-249421 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser263 NVGSPLSsPLSSMKS 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.35 SIGNOR-276108 FYN protein P06241 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 10090 BTO:0000775 14707117 YES done miannu TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation. 0.562 SIGNOR-273960 CXCL8 protein P10145 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates binding 9606 11350788 YES gcesareni Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades. 0.86 SIGNOR-107983 NPNT protein Q6UXI9 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 10090 22613833 YES lperfetto The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome. 0.679 SIGNOR-253344 PRKCB protein P05771 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 YES lperfetto Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration 0.2 SIGNOR-97942 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252318 FGG protein P02679 UNIPROT VWF protein P04275 UNIPROT down-regulates activity binding 9606 2243140 YES Regulation miannu Fibrinogen y-chain carboxyterminal (GQQHHLGGAKQAGDV) peptides inhibit fibrinogen, fibronectin (Fn), vitronectin, and von Willebrand factor (vWF) binding to the platelet glycoprotein Ilb-Illa complex (GP lIbII1a). 0.497 SIGNOR-251968 HDAC3 protein O15379 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity deacetylation -1 11486036 YES miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. 0.599 SIGNOR-268837 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Thr697 EMDSMPYtQNFISCN 9606 BTO:0000567 34198826 YES miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. 0.25 SIGNOR-276661 CDK5 protein Q00535 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 YES gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily. 0.377 SIGNOR-166682 TFE3 protein P19532 UNIPROT PIP4P1 protein Q86T03 UNIPROT up-regulates quantity by expression transcriptional regulation 29146937 NO lperfetto MEM55B levels are transcriptionally upregulated following TFEB and TFE3 activation by starvation or cholesterol-induced lysosomal stress. 0.2 SIGNOR-276828 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 YES lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm 0.819 SIGNOR-72068 MAPK14 protein Q16539 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates phosphorylation 9606 17003045 YES gcesareni We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3. 0.2 SIGNOR-149890 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr57 RAGETRFtDTRKDEQ 9606 BTO:0000007 12194824 YES gcesareni The activation of eef2 kinase by ampk, resulting in the phosphorylation and inactivation of eef2, provides a novel mechanism for the inhibition of protein synthesis. 0.787 SIGNOR-91751 CHIR 99021 chemical CHEBI:91091 ChEBI GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191000 AURKB protein Q96GD4 UNIPROT MYBBP1A protein Q9BQG0 UNIPROT unknown phosphorylation Ser1303 ARKKARLsLVIRSPS 9606 20177074 YES lperfetto We identified mybbp1a as a novel aurora b substrate and serine 1303 as the major phosphorylation site 0.389 SIGNOR-163903 JUNB protein P17275 UNIPROT LORICRIN protein P23490 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 12200429 NO miannu Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. 0.2 SIGNOR-254535 PICK1 protein Q9NRD5 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity binding 9534 BTO:0000298 25784538 YES inferred from family member miannu RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a‚Äìc). The existence of such complex is supported by our co-immunoprecipitation experiments shown above. 0.807 SIGNOR-270236 G6P proteinfamily SIGNOR-PF81 SIGNOR alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266571 CHEK2 protein O96017 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation 9606 22558186 YES gcesareni In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk. 0.286 SIGNOR-197281 PARP10 protein Q53GL7 UNIPROT G3BP1 protein Q13283 UNIPROT up-regulates activity post translational modification 9606 BTO:0001938 37873303 YES miannu Further, we pinpoint the core SG component, G3BP1, as a PARP10 substrate and find that PARP10 regulates SG assembly driven by both G3BP1 and its modeled mechanism. Intriguingly, while PARP10 only adds a single ADP-ribose unit to proteins, G3BP1 is PARylated, suggesting its potential role as a scaffold for protein recruitment. PARP10 knockdown alters the SG core composition, notably decreasing translation factor presence. 0.2 SIGNOR-273727 EFNB3 protein Q15768 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.837 SIGNOR-52621 C1QBP protein Q07021 UNIPROT C1QC protein P02747 UNIPROT down-regulates activity binding SIGNOR-C308 28018340 YES lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. 0.4 SIGNOR-263404 ZMYND8 protein Q9ULU4 UNIPROT VEGFA protein P15692 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 YES lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported 0.2 SIGNOR-262041 MMP10 protein P09238 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272378 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 9381178 YES Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. 0.823 SIGNOR-252562 BAD protein Q92934 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 BTO:0000830 15526160 NO miannu C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo. 0.7 SIGNOR-254953 ITGB1BP1 protein O14713 UNIPROT ITGB8 protein P26012 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.314 SIGNOR-257667 MRGPRX2 protein Q96LB1 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257260 RFX complex complex SIGNOR-C104 SIGNOR HLA-DOB protein P13765 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.257 SIGNOR-254000 perfluorooctanoic acid chemical CHEBI:35549 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 YES miannu Taken together, these data show that of the NRs studied, PPARα is the most likely target of PFOA and PFOS, although PPARγ is also activated to some extent. 0.8 SIGNOR-268788 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 15623525 YES lperfetto Src phosphorylates ezrin at tyrosine 477 and induces a phosphospecific association between ezrin and a kelch-repeat protein family member 0.647 SIGNOR-132907 SIAH1 protein Q8IUQ4 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates quantity ubiquitination 9606 18536714 YES miannu Downregulation of Siah-1 inhibits HIPK2 degradation and recovery from damage, driving the cells into apoptosis|Siah-1 knockdown increases HIPK2 stability and steady-state levels, whereas Siah-1 expression facilitates HIPK2 polyubiquitination, degradation and thereby inactivation. 0.515 SIGNOR-278715 DMTF1 protein Q9Y222 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 YES Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  0.2 SIGNOR-261582 ZNF692 protein Q9BU19 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17097062 NO gcesareni In this study, we demonstrate that a newly identified transcription factor, arebp, is a novel target of ampk. Arebps function is to repress transcription of the pepck gene upon phosphorylation by ampk. 0.2 SIGNOR-150556 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates activity phosphorylation Ser6 sKKRKFVA 9606 19059439 YES Manara Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA 0.2 SIGNOR-260894 GABRA2 protein P47869 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.612 SIGNOR-263753 HECTD1 protein Q9ULT8 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22431752 YES Monia We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Identification of Hsp90 in both proteomic screens suggested that members of the Hsp90 superfamily may be substrates of Hectd1. Myc-Hectd1ANK and HA-Hsp90bd (the fragment identified in the yeast two-hybrid screen) bind in an in vitro binding assay (Fig. 3 D) and when coexpressed in HEK293T cells. Hectd1 is required for K63-linked Ubn of Hsp90. Together, these results demonstrate that Hectd1-dependent Ubn of Hsp90 targets it away from the membrane and the secretory pathway. 0.2 SIGNOR-261199 ADRA1B protein P35368 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.278 SIGNOR-256950 CLOCK protein O15516 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR form complex binding -1 22653727 YES lperfetto Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock. 0.779 SIGNOR-253709 GRK5 protein P34947 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE -1 10852916 YES GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes Œ≤-synuclein phosphorylation by both GRK2 and GRK5 0.322 SIGNOR-251203 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR TUT1 protein Q9H6E5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000675 29032201 YES miannu Kelch-like protein 7 (KLHL7) is a component of Cul3-based Cullin-RING ubiquitin ligase. In this study, we report that KLHL7 increases terminal uridylyl transferase 1 (TUT1) ubiquitination involved in nucleolar integrity. 0.2 SIGNOR-272321 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser76 EEEDEALsPAKGQKP 9606 BTO:0000567 12851383 YES lperfetto We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner. 0.457 SIGNOR-103250 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity dephosphorylation Tyr1172 ISLDNPDyQQDFFPK -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.482 SIGNOR-254700 risperidone chemical CHEBI:8871 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258529 CSNK1A1 protein P48729 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1363 HVQSVLLtPQDEFFI 9606 BTO:0002181 19797085 YES miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  0.31 SIGNOR-276262 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 17204478 YES lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). 0.798 SIGNOR-263425 EPAS1 protein Q99814 UNIPROT KDM4C protein Q9H3R0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271585 BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 26330344 YES fferrentino BMP interacts with specific receptors on the cell surface, BMP receptor types 1 and 2 (BMPr1 and BMPr2). 0.928 SIGNOR-253547 AKT1 protein P31749 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Ser48 QLSLRTVsLGAGAKD 9606 BTO:0001345 25071014 YES miannu We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. 0.535 SIGNOR-276667 VAV1 protein P15498 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 9013873 NO gcesareni Vav may link gp130 activation to downstream mapk activation in hematopoietic cells. 0.509 SIGNOR-46064 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10949026 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.432 SIGNOR-81157 ATM protein Q13315 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser126 PPGTPLVsQDEKRDA 9606 21824916 YES lperfetto We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro. 0.462 SIGNOR-176012 PIM2 protein Q9P1W9 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation -1 31730483 YES miannu In addition to PIM1, also PIM2 and PIM3 were able to phosphorylate WT, but not MM NFATC1 in vitro (Fig. ​(Fig.22c). 0.261 SIGNOR-276772 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser20 APPVRMSsTIFSTGG -1 10075701 YES miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. 0.2 SIGNOR-250227 TSC2 protein P49815 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 NO lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor 0.848 SIGNOR-93133 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.282 SIGNOR-275790 Ub:E2 complex SIGNOR-C497 SIGNOR RNF222 protein A6NCQ9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271258 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.282 SIGNOR-275791 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Ser54 ELQPMPTsPGVDLQS 9606 SIGNOR-C83 12714602 YES lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. 0.766 SIGNOR-100885 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNJ1 protein P48048 UNIPROT up-regulates activity phosphorylation Ser201 FSKNAVIsKRGGKLC -1 12221079 YES miannu We conclude that ROMK1 is a substrate of PKC and that serine residues 4 and 201 are the two main PKC phosphorylation sites that are essential for the expression of ROMK1 in the cell surface. 0.2 SIGNOR-275990 PRKAA2 protein P54646 UNIPROT PPP1R12C protein Q9BZL4 UNIPROT down-regulates phosphorylation Ser452 AGLQRSAsSSWLEGT 9606 SIGNOR-C15 22137581 YES lperfetto Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo. 0.26 SIGNOR-195148 MAPK3 protein P27361 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Thr66 EPICSVNtPREVTLH -1 16226275 YES lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| 0.692 SIGNOR-249476 RPS6KA3 protein P51812 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT up-regulates quantity phosphorylation Ser57 HGTGHPEsAGEHALE 9606 BTO:0000007 18280241 YES miannu RSK phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo.RanBP3 phosphorylation increases its affinity towards Ran 0.329 SIGNOR-276148 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0004479 29507660 NO irozzo FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. 0.411 SIGNOR-255733 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7824938 YES gcesareni Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain. 0.779 SIGNOR-33918 HRK protein O00198 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 9130713 YES gcesareni Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1. 0.473 SIGNOR-47794 MAP3K20 protein Q9NYL2 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 11416147 YES gcesareni We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling. 0.2 SIGNOR-243348 KNL1 protein Q8NG31 UNIPROT BUB1 protein O43683 UNIPROT up-regulates binding 9606 17981135 YES gcesareni Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions 0.2 SIGNOR-158378 PTAFR protein P25105 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257174 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 17082196 YES lperfetto Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology. 0.2 SIGNOR-216515 RHOA protein P61586 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 8824197 YES areggio We found that in the human kidney epithelial cell line, 293T, Cdc42 and all Rho proteins, RhoA, RhoB, and RhoC, but not Rac or Ras can induce activation of JNK. 0.827 SIGNOR-258974 PLCB1 protein Q9NQ66 UNIPROT GNA11 protein P29992 UNIPROT up-regulates binding 9606 1322796 YES miannu Plc-_1 stimulates hydrolysis of gq/11-bound gtp and acts as a gtpase-activating protein (gap) for its physiologic regulator, gq/11 0.622 SIGNOR-17239 BMS-599626 chemical CID:10437018 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 17062696 YES AC480 significantly enhanced the radiosensitivity of HN-5 cells, expressing both EGFR and Her2. gcesareni The studies described here are intended to characterize the ability of bms-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (her) kinase family, to modulate signaling and growth of tumor cells that depend on her1 and/or her2. 0.8 SIGNOR-150190 HOXD12 protein P35452 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.378 SIGNOR-221896 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.564 SIGNOR-89197 AKT proteinfamily SIGNOR-PF24 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Thr1462 GLRPRGYtISDSAPS 10090 BTO:0000944 12150915 YES lperfetto We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. 0.2 SIGNOR-244365 TRIM27 protein P14373 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000671 12807881 NO miannu Here we show that ectopic expression of rfp in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria. 0.7 SIGNOR-102019 MAD2L2 protein Q9UI95 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity binding -1 11459826 YES miannu The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1 0.459 SIGNOR-264903 GGCX protein P38435 UNIPROT PROZ protein P22891 UNIPROT up-regulates activity carboxylation 9606 28125048 YES lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z 0.506 SIGNOR-265926 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr21 ENLEQEEyEDPDIPE 9606 10942405 YES llicata Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites. 0.452 SIGNOR-80788 AKT1 protein P31749 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates activity phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 11274386 YES lperfetto We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350 0.728 SIGNOR-252466 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr228 LNEGKHLyTLDGGDI 9606 12400005 YES gcesareni We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246 0.2 SIGNOR-94796 DDX17 protein Q92841 UNIPROT RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103 17011493 YES lperfetto We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod. 0.426 SIGNOR-149961 TRIM68 protein Q6AZZ1 UNIPROT TFG protein Q92734 UNIPROT down-regulates quantity ubiquitination 9606 24999993 YES miannu Having shown that TFG positively influences IFN-\u03b2 production and TRIM68 promotes ubiquitination and degradation of TFG, we next set out to determine whether this ubiquitination was involved in the inhibition of IFN-\u03b2 signalling.|Our results suggest that TRIM68 degrades TFG at a point of pathway convergence in which downstream events lead to the activation of both NF-kappaB and IRF3. 0.452 SIGNOR-278738 AKT proteinfamily SIGNOR-PF24 SIGNOR SIK1 protein P57059 UNIPROT down-regulates activity phosphorylation Ser435 VFRPRPVsPSSLLDT 9606 BTO:0000007 36806887 YES miannu  Mass spectrometry-based analyses demonstrated that salt-inducible kinase 1 (SIK1) binds AKT and undergoes AKT-mediated phosphorylation, which compromises SIK1 tumor-suppressive functions.  0.2 SIGNOR-277835 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 17183360 YES gcesareni Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . 0.358 SIGNOR-151422 AMFR protein Q9UKV5 UNIPROT CD3D protein P04234 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11724934 YES miannu Gp78 specifically recruits MmUBC7, a ubiquitin-conjugating enzyme (E2) implicated in ER-associated degradation (ERAD), through a region distinct from the RING finger. gp78 can target itself for proteasomal degradation in a RING finger- and MmUBC7-dependent manner. Importantly, gp78 can also mediate degradation of CD3-delta, a well-characterized ERAD substrate.  0.475 SIGNOR-272670 PAK1 protein Q13153 UNIPROT HACE1 protein Q8IYU2 UNIPROT down-regulates activity phosphorylation Ser385 LMKNKRDsTEITSIL 9606 BTO:0004980 29362425 YES Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases […] We have established in vitro that HACE1 is a direct target of PAK1 kinase activity. 0.2 SIGNOR-255537 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates activity chemical inhibition 9606 26347206 YES miannu Trametinib (Mekinist™) is a reversible and highly selective allosteric inhibitor of MEK1 and MEK2 with anticancer activity against metastatic melanoma carrying the BRAF V600 mutation. 0.8 SIGNOR-259447 VPS16 protein Q9H269 UNIPROT CORVET tethering complex complex SIGNOR-C550 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.863 SIGNOR-273696 QYDAFJUKVGVEKO-PKOVDKIBSA-N smallmolecule CID:16132339 PUBCHEM MRGPRX1 protein Q96LB2 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257543 RNF4 protein P78317 UNIPROT PML protein P29590 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23530056 YES miannu Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4. 0.488 SIGNOR-272884 PKA proteinfamily SIGNOR-PF17 SIGNOR SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation Ser555 AEGERRGsLAFIRSP 9606 BTO:0000195 38047302 YES miannu AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) phosphorylated NHE3 at S555. S555 is the primary site of phosphorylation by protein kinase A (PKA), but AMPK phosphorylated S555 independently of PKA. We conclude that AMPK activation inhibits NHE3 activity and NHE3 inhibition is associated with phosphorylation of NHE3 at S555 and S563. 0.2 SIGNOR-277847 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 12270934 YES lperfetto MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis. 0.752 SIGNOR-235352 MAPK3 protein P27361 UNIPROT SOX2 protein P48431 UNIPROT down-regulates activity phosphorylation Ser251 VKSEASSsPPVVTSS 9606 29556337 YES miannu Mass spectrum analysis was employed after an in vitro kinase assay in which cells were incubated with or without ERK1-active kinase, and the results demonstrated that Sox2 was phosphorylated by ERK1 directly at S251, which was further verified by western blotting for the specific antibody targeting S251 phosphorylated Sox2 after the in vitro kinase assay.|Mechanistically, ERK1 kinase promoted autophagic degradation of Sox2 via phosphorylation of Sox2 at Ser251 and further SUMOylation of Sox2 at Lys245 in non CSCs. 0.453 SIGNOR-279071 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22459801 NO miannu Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed. 0.47 SIGNOR-254643 DIO1 protein P49895 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 YES scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. 0.8 SIGNOR-266954 ATRX protein P46100 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 BTO:0000584 26428317 NO Telomere length must be maintained for the immortalization of malignant cells […] alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors 0.7 SIGNOR-256595 TIMM10 protein P62072 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 YES lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). 0.713 SIGNOR-267703 FBXO38 protein Q6PIJ6 UNIPROT KLF7 protein O75840 UNIPROT up-regulates activity binding 9534 BTO:0004055 14729953 YES miannu Interaction between MoKA and KLF7 was confirmed by the in vitro glutathione S-transferase pull-down assay and by coimmunoprecipitation of the proteins overexpressed in mammalian cells. Functional assays documented that MoKA is a KLF7 coactivator 0.577 SIGNOR-224621 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr832 LRYEGRVyHYRINTA 9606 16912036 YES Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 0.2 SIGNOR-260814 RUNX2 protein Q13950 UNIPROT RUNX2/EP300 complex SIGNOR-C211 SIGNOR form complex binding 10116 BTO:0002648 12697832 YES Giulio Giuliani More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex. 0.453 SIGNOR-255419 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248748 GABRA5 protein P31644 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.647 SIGNOR-263765 CTDSP1 protein Q9GZU7 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity dephosphorylation 9606 32764831 YES miannu CTDSP1 activates DNA-PKcs and enhances DNA-PKcs dependent topoI degradation in response to irinotecan .|Our novel finding indicates that CTDSP1 dephosphorylates DNA-PKcs, changes its kinase activity, and regulates irinotecan-induced topoI degradation. 0.2 SIGNOR-277101 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1247 KNENTEGsPQEDGVE 9606 BTO:0000567 7635160 YES llicata We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. similarly, phosphopeptide 4 was absent from a mutant protein lacking ser1246 0.526 SIGNOR-30244 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 YES lperfetto Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. 0.862 SIGNOR-216988 GHSR protein Q92847 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257322 GSK3B protein P49841 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser114 EEDHVDLsLSCTLVP 9606 BTO:0000093 17283049 YES lperfetto Glycogen synthase kinase 3beta phosphorylates p21waf1/cip1 for proteasomal degradation after uv irradiationhere, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (gsk-3beta) is required for its degradation in response to uv irradiation 0.401 SIGNOR-152941 DDX41 protein Q9UJV9 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity binding 10090 BTO:0002572 25704810 YES miannu The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. 0.2 SIGNOR-266403 GOT2 protein P00505 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity chemical modification 9606 31422819 YES miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-267514 entinostat chemical CHEBI:132082 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257905 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation Ser176 AKDVDQGsLCTSFVG 9606 SIGNOR-C14 9520446 YES lperfetto Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176. Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. 0.698 SIGNOR-55942 NFIX protein Q14938 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268910 CTBP1 protein Q13363 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23303449 NO irozzo Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Breast Cancer Susceptibility Gene 1(Brca1), a core protein in DNA damage repair, was repressed by CtBP1 in melanoma cells. 0.602 SIGNOR-259194 ADORA2B protein P29275 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.279 SIGNOR-257152 SAM complex complex SIGNOR-C422 SIGNOR TOM40 complex complex SIGNOR-C421 SIGNOR up-regulates activity binding 18423394 YES lperfetto Homology searches led to the identification of human Sam50 that is required for the biogenesis of human Tom40 [69]. A similar involvement was reported for metaxin 1 and metaxin 2 [70], which are homologs of Sam37 and Sam35, respectively 0.466 SIGNOR-267686 terbutaline chemical CHEBI:9449 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 20590599 YES Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) 0.8 SIGNOR-257870 KIF5B protein P33176 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272520 MAPK8 protein P45983 UNIPROT PKM protein P14618 UNIPROT up-regulates activity phosphorylation Thr365 CIMLSGEtAKGDYPL 9606 BTO:0002181 26258887 YES miannu Active JNK1 specifically activates PKM2 but not PKM1. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. 0.371 SIGNOR-276933 GFs stimulus SIGNOR-ST12 SIGNOR AKT2 protein P31751 UNIPROT up-regulates activity 9606 23300340 NO lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation 0.7 SIGNOR-245405 HDAC2 protein Q92769 UNIPROT CIITA protein P33076 UNIPROT down-regulates quantity by repression deacetylation 9606 BTO:0000801;BTO:0004576 19041327 YES miannu We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays. 0.414 SIGNOR-254231 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser551 ELQAPVRsPITRSFA 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.632 SIGNOR-249461 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser43 PAMLHLPsEQGAPET 9606 SIGNOR-C14 17977820 YES lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I 0.93 SIGNOR-216403 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Thr309 SDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 YES lperfetto The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma) 0.731 SIGNOR-236785 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.765 SIGNOR-252741 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 20179209 YES lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated 0.34 SIGNOR-163912 CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser238 SEESWTDsEVDSSCS 9606 BTO:0000007 26885618 YES lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| 0.356 SIGNOR-273121 ALK protein Q9UM73 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000762 27322022 YES lperfetto Subsequent studies revealed that ALK promoted cell migration through the P3K-AKT pathway via the p55γ regulatory subunit of PI3K. 0.378 SIGNOR-253217 RELB protein Q01201 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 26385063 NO miannu We have shown here for the first time the role of RelB on lymphocyte development in humans. In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies. 0.7 SIGNOR-263655 MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 18451303 YES gcesareni Here, we show that p38 mitogen-activated protein kinase (mapk) also inactivates gsk3beta by direct phosphorylation at its c terminus, and this inactivation can lead to an accumulation of beta-catenin. 0.291 SIGNOR-178603 Phenelzine chemical CHEBI:8060 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258744 CSNK2A1 protein P68400 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 YES lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. 0.269 SIGNOR-275739 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1015 MMVKRRDyLDLAAST 9606 14981541 YES llicata Opn upregulation depended on the integrity of the ret/ptc kinase and tyrosines y1015 and y1062, two major ret/ptc autophosphorylation sites. ret signalling mainly depends on three key tyrosine residues: tyrosine 905, in the activation loop, whose phosphorylation stabilizes the active conformation of the catalytic domain , tyrosine 1015, a docking site for phospholipase citalic gamma and tyrosine 1062. 0.2 SIGNOR-122915 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0001573 9565970 YES lperfetto Il-1ri is responsible for il-1 signaling 0.766 SIGNOR-56718 AP-2 complex complex SIGNOR-C245 SIGNOR HIP1 protein O00291 UNIPROT up-regulates activity binding 10116 11517213 YES Giorgia HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2.|Here we demonstrate that HIP1 colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP1 binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276–335 0.452 SIGNOR-260392 PPP1CA protein P62136 UNIPROT MECOM protein Q03112 UNIPROT down-regulates activity dephosphorylation Ser726 PLKMEPQsPGEVKKL 23858473 YES phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. 0.2 SIGNOR-273430 SLC38A1 protein Q9H2H9 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity relocalization 9606 26724577 YES Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. 0.8 SIGNOR-266912 PRKCG protein P05129 UNIPROT APTX protein Q7Z2E3 UNIPROT up-regulates phosphorylation Thr125 AKNPGLEtHRKRKRS 9606 19561170 YES llicata We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx. 0.32 SIGNOR-186409 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 YES gcesareni Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax 0.392 SIGNOR-78015 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4D protein Q08499 UNIPROT up-regulates activity phosphorylation Ser125 CRAMDRTsYAVETGH 9534 12023945 YES miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. 0.2 SIGNOR-273939 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1724 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248812 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 21460634 YES miannu AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1. 0.467 SIGNOR-216418 PPP2R5C protein Q13362 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates binding 9606 16456541 YES inferred from 70% of family members gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk 0.2 SIGNOR-269900 Av/b6 integrin complex SIGNOR-C179 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.594 SIGNOR-257725 AMPK complex SIGNOR-C15 SIGNOR GAPDH protein P04406 UNIPROT up-regulates activity phosphorylation Ser122 GAKRVIIsAPSADAP 10090 26626483 YES miannu Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated.  0.317 SIGNOR-267578 belinostat chemical CHEBI:61076 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257743 JUN protein P05412 UNIPROT MTHFR protein P42898 UNIPROT up-regulates 9606 18065414 NO lperfetto The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression 0.272 SIGNOR-253147 ixazomib citrate chemical CHEBI:90939 ChEBI PSMB5 protein P28074 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194536 RB1 protein P06400 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates 9606 14560017 NO gcesareni We find that active rb mediates histone deacetylation on cyclin a, cdc2, topoisomerase iialfa, and thymidylate synthase promoters. We also demonstrate that this deacetylation is hdac dependent, since the hdac inhibitor trichostatin a (tsa) prevented histone deacetylation at each promoter. 0.624 SIGNOR-118839 TOB1 protein P50616 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR down-regulates activity binding 9606 BTO:0000567 18377426 YES miannu We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob.  0.663 SIGNOR-273616 PPARGC1A protein Q9UBK2 UNIPROT NRF1 protein Q16656 UNIPROT up-regulates activity 9606 26971449 NO lperfetto PGC-1 family transcriptional coactivators enhance the activities of the nuclear respiratory factors NRF1 and NRF2, which induce transactivation of many genes encoding mitochondria-specific proteins involved in respiratory chain, mitochondrial DNA transcription/replication and protein import/assembly 0.709 SIGNOR-253391 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 18267068 YES lperfetto Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. 0.2 SIGNOR-249572 PAK4 protein O96013 UNIPROT PAK4 protein O96013 UNIPROT up-regulates activity phosphorylation Ser474 KEVPRRKsLVGTPYW 10090 BTO:0000944 11668177 YES lperfetto Here we demonstrate that PAK4 is frequently overexpressed in human tumor cell lines of various tissue origins. We also have identified serine (Ser-474) as the likely autophosphorylation site in the kinase domain of PAK4 in vivo. Mutation of this serine to glutamic acid (S474E) results in constitutive activation of the kinase. 0.2 SIGNOR-235867 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 YES gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.649 SIGNOR-252338 STAT5A protein P42229 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0001096 14530308 NO apalma Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells 0.7 SIGNOR-256663 CAMK2A protein Q9UQM7 UNIPROT CACNA1B protein Q00975 UNIPROT down-regulates phosphorylation Ser2120 ERRQPSSsSSEKQRF 9606 BTO:0000938 16982421 YES gcesareni Here, we report a direct modulation of ca(v)2.2 channel inactivation properties by 14-3-3, a family of signaling proteins involved in a wide range of biological processes.Wild-type gst fusion proteins containing the putative 14-3-3-binding motif (aa 2076__?2140) werein vitro phosphorylated at s2126 by either camkii or pka, as detected by thesequence- and phosphorylation-specific antibody, anti-ps2126 (middle panel). Phosphorylation of s2126 significantly increases its binding to recombinant 14-3-3? 0.317 SIGNOR-149684 TERB1 protein Q8NA31 UNIPROT TTM complex complex SIGNOR-C305 SIGNOR form complex binding 9606 BTO:0000007 30718482 YES lperfetto Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE 0.2 SIGNOR-263302 RPS6KB2 protein Q9UBS0 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation 9606 BTO:0000007 BTO:0001253 18296647 YES gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. 0.438 SIGNOR-160992 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 10090 11201744 YES CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 0.473 SIGNOR-248349 LYN protein P07948 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.655 SIGNOR-249382 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 19620713 YES gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.679 SIGNOR-187193 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1361 SPPKTKTsPKLSNKE 9606 BTO:0000567 7635160 YES llicata We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated. 0.526 SIGNOR-30252 ketoprofen chemical CHEBI:6128 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001061 18667313 YES Luana Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2.  0.8 SIGNOR-257811 chloroquine chemical CHEBI:3638 ChEBI ACE2 protein Q9BYF1 UNIPROT down-regulates activity chemical inhibition 9534 32020029 YES miannu Chloroquine is known to block virus infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. Our time-of-addition assay demonstrated that chloroquine functioned at both entry, and at post-entry stages of the 2019-nCoV infection in Vero E6 cells 0.8 SIGNOR-260223 DSCAM protein O60469 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 10116 BTO:0000938 18585357 NO miannu DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. 0.7 SIGNOR-268396 RAB6B protein Q9NRW1 UNIPROT VPS13B protein Q7Z7G8 UNIPROT up-regulates activity binding 10116 BTO:0003102 25492866 YES miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. 0.2 SIGNOR-266870 ARAP2 protein Q8WZ64 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.461 SIGNOR-260454 CAMK2G protein Q13555 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 22888005 YES gcesareni The kinase activity of camkii was essential for the activation of notch signaling. We also determined that camkii could enhance the association between notch1-ic and rbp-jk. Furthermore, the physical association between rbp-jk and smrt was substantially suppressed by camkii. We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. 0.2 SIGNOR-191777 RANBP2 protein P49792 UNIPROT TNPO1 protein Q92973 UNIPROT up-regulates activity binding 9606 BTO:0001938 32161167 YES lperfetto Nup358(806–1306), but not other regions, efficiently recruits importin β and transportin 1 0.455 SIGNOR-262111 PHKG1 protein Q16816 UNIPROT PYGL protein P06737 UNIPROT up-regulates activity phosphorylation Ser15 QEKRRQIsIRGIVGV 9606 BTO:0002049 22225877 YES It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 0.539 SIGNOR-267399 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001321 15659650 YES lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 0.779 SIGNOR-217795 NOTCH proteinfamily SIGNOR-PF30 SIGNOR LFNG protein Q8NES3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO gcesareni Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta. 0.2 SIGNOR-254336 SMAD3 protein P84022 UNIPROT CEBPB protein P17676 UNIPROT down-regulates activity binding 10090 12524424 YES gcesareni Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters 0.596 SIGNOR-250567 MMP17 protein Q9ULZ9 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272385 MSH2 protein P43246 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 9500552 NO Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer 0.7 SIGNOR-257594 FBXW8 protein Q8N3Y1 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 23142081 YES miannu Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin ligase substrate-targeting subunit, Fbw8. mTORC2 stabilizes Fbw8 by phosphorylation at Ser86, allowing the insulin-induced translocation of Fbw8 to the cytosol where it mediates IRS-1 degradation.  0.461 SIGNOR-271939 SOX9 protein P48436 UNIPROT CEBPD protein P49716 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19254573 YES fspada Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation 0.272 SIGNOR-184283 NAT8L protein Q8N9F0 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 19524112 YES miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. 0.8 SIGNOR-267524 dabrafenib chemical CHEBI:75045 ChEBI RAF1 protein P04049 UNIPROT down-regulates activity chemical inhibition -1 24720932 YES miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations 0.8 SIGNOR-259218 PBK protein Q96KB5 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 26745678 YES miannu TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.|These data confirm the phosphorylation of c-Jun by TOPK at serine 63 and 73 during the development of resistance to EGFR-targeted TKIs. 0.431 SIGNOR-278156 NUP214 protein P35658 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR up-regulates activity relocalization 9606 12917407 YES lperfetto We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import. 0.554 SIGNOR-217719 CSNK2A1 protein P68400 UNIPROT MYB protein P10242 UNIPROT down-regulates activity phosphorylation Ser11 RPRHSIYsSDEDDED -1 7735324 YES llicata For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants.  0.34 SIGNOR-250918 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Thr709 PKRLGAHtP 9606 14697653 YES lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.259 SIGNOR-120463 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 9606 12150915 YES gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. 0.728 SIGNOR-91045 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 7566348 YES fstefani The ability of p42 map and p44 map kinases, glycogen synthase kinases 3 alpha and 3 beta (gsk-3 alpha and gsk-3 beta) to phosphorylate tau in transfected cos cells was investigated. Both gsk-3 alpha and gsk-3 beta phosphorylated tau to produce a phf-like state of phosphorylation but the map kinases failed to induce such a transformation in tau. 0.43 SIGNOR-29364 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation 9606 31226734 YES lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. 0.613 SIGNOR-265921 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT unknown phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 20708153 YES lperfetto Remarkably, lc-ms confirmed that the predominant serine phosphorylation site of the recombinant carboxy-terminal domain of c-nap1 is s2392 at the predicted consensus phosphorylation sequence and to a lesser extent s2394. 0.321 SIGNOR-167492 GNAI1 protein P63096 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates -1 10224115 NO G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. 0.7 SIGNOR-256523 FBXO7 protein Q9Y3I1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0005490 30026574 YES miannu We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase.  0.651 SIGNOR-272315 PRKCA protein P17252 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser23 NDMKVRKsSTPEEVK 9606 BTO:0001271 22855535 YES lperfetto Pkc_ phosphorylates cofilin at ser-23 and/or ser-24 during degranulationthese results indicate that a novel pkc_-mediated phosphorylation event regulates cofilin by inhibiting its ability to depolymerize f-actin and bind to 14-3-3_, thereby promoting f-actin polymerization 0.2 SIGNOR-198478 WIPI2 protein Q9Y4P8 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates quantity binding 9606 BTO:0001938 28561066 YES miannu WIPI1 assists WIPI2 in recruiting ATG16L for LC3 lipidation. WIPI1-WIPI2 heterodimer may function more efficiently in ATG16L complex recruitment. 0.732 SIGNOR-268478 miR-146a mirna URS000075D8A0_9606 RNAcentral CXCR4 protein P61073 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 20516212 NO Luisa MiR-221 strongly upregulated GAX.ZEB2 is upregulated by serum and downregulates GAX, while the expression of miR-221 upregulates GAX and downregulates ZEB2. 0.4 SIGNOR-268952 DLL4 protein Q9NR61 UNIPROT KDR protein P35968 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18339870 NO gcesareni Dll4 down-regulates vascular endothelial growth factor (vegf) receptor 2 and nrp1 expression and inhibits vegf function 0.475 SIGNOR-178026 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT up-regulates activity phosphorylation Tyr307 QDPCTTIyVAATEPV 9534 BTO:0000298 11806999 YES All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. 0.657 SIGNOR-251182 HNF1A protein P20823 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8383844 NO inferred from family member miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators 0.311 SIGNOR-270224 PRKACA protein P17612 UNIPROT GLI1 protein P08151 UNIPROT down-regulates phosphorylation 16293631 YES We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1. 0.55 SIGNOR-253539 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR2 protein Q9HBW0 UNIPROT up-regulates chemical activation 9606 8276865 YES gcesareni Lpa activates its own g protein-coupled receptor(s) leading to stimulation of phospholipase c and inhibition of adenylate cyclase. 0.8 SIGNOR-37368 F11 protein P03951 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 YES lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. 0.491 SIGNOR-261857 IFNG protein P01579 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001030 10909770 NO Regulation of expression miannu The suppression of lipoprotein lipase expression in J774.2 macrophages by IFN-gamma and TNF-alpha is mediated at the transcriptional level. 0.355 SIGNOR-251854 CIITA protein P33076 UNIPROT HLA-E protein P13747 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11137213 NO HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA 0.494 SIGNOR-254019 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI TP53 protein P04637 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189999 BTK protein Q06187 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 BTO:0000007 10068673 YES done miannu These results demonstrate that WASP, under this experimental condition, can be tyrosine-phosphorylated by the kinase activity of Btk and that the direct interaction between WASP and the SH3 domain of Btk is required for this phosphorylation to occur. 0.742 SIGNOR-273958 SRC protein P12931 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates activity phosphorylation Tyr625 RSGTMNSyEMRKALE -1 35697802 YES miannu CAPN2 itself was a bone fide substrate of SRC that was primarily phosphorylated at Y625 by SRC and exhibited increased proteolysis activity upon phosphorylation. 0.523 SIGNOR-277598 BRCA1 protein P38398 UNIPROT MACROH2A1 protein O75367 UNIPROT up-regulates activity ubiquitination Lys123 KKRGSKGkLEAIITP 9606 28564596 YES miannu BRCA1 Ubiquitinates K123 of mH2A1 in a Ligase-Activity-Dependent Manner. 0.2 SIGNOR-278752 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT up-regulates activity phosphorylation Ser99 KLAVRLEsAWADRVR 23841590 YES lperfetto Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase n the present study, we add another level of complexity to PAK4 regulation by showing that phosphorylation at Ser99 is required for its targeting to the leading edge. This phosphorylation is mediated by PKD1 (protein kinase D1). Phosphorylation of PAK4 at Ser99 also mediates binding to 14-3-3 protein, and is required for the formation of a PAK4-LIMK-PKD1 complex that regulates cofilin activity and directed cell migration| 0.479 SIGNOR-275939 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT unknown phosphorylation Ser440 SPLLMILsQLLPQQR -1 10608806 YES llicata Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself. 0.2 SIGNOR-250576 NR5A1 protein Q13285 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19237537 YES miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. 0.48 SIGNOR-271787 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX9 protein P48436 UNIPROT up-regulates transcriptional regulation 9606 20457810 NO lperfetto Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression. 0.2 SIGNOR-244750 EIF2B4 protein Q9UI10 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.773 SIGNOR-269142 GSK3B protein P49841 UNIPROT BAX protein Q07812 UNIPROT up-regulates phosphorylation Ser163 GGWDGLLsYFGTPTW 9606 BTO:0000938 15525785 YES lperfetto Glycogen synthase kinase-3beta phosphorylates bax and promotes its mitochondrial localization during neuronal apoptosis. Gsk-3beta directly phosphorylated bax(alpha) on ser163 0.376 SIGNOR-130141 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr356 DSFETQRtPRKSNLD -1 9139732 YES llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. 0.862 SIGNOR-250760 TET3 protein O43151 UNIPROT OGT protein O15294 UNIPROT up-regulates binding 9606 23353889 YES miannu Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation 0.444 SIGNOR-200729 MRPL2 protein Q5T653 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.721 SIGNOR-262374 acetyl-CoA smallmolecule CHEBI:15351 ChEBI malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity precursor of 9606 20952656 YES miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA 0.8 SIGNOR-267108 CTNND1 protein O60716 UNIPROT ZBTB33 protein Q86T24 UNIPROT down-regulates 9606 23481205 NO gcesareni Nuclear signaling is affected by the interaction ofp120with kaiso, a transcription factor regulatingwnt-responsive genes. in addition, p120 cytoplasmic localization results in sequestration of kaiso in the cytoplasm and its inactivation 0.823 SIGNOR-192369 NPPA protein P01160 UNIPROT NPR1 protein P16066 UNIPROT up-regulates binding 9606 15911069 YES gcesareni Natriuretic peptide receptor-a (npra) is the biological receptor of the peptide hormones atrial natriuretic peptide (anp) and brain natriuretic peptide (bnp) 0.887 SIGNOR-137600 USP14 protein P54578 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 26523394 YES lperfetto The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor|We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation 0.448 SIGNOR-265057 ATF6 protein P18850 UNIPROT HYOU1 protein Q9Y4L1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001088 20861013 NO miannu We recently found that in cultured gastric cells, expression of endoplasmic reticulum (ER) chaperones (such as 150-kDa oxygen-regulated protein (ORP150) and glucose-regulated protein 78 (GRP78)) is induced by NSAIDs and confers protection against NSAID-induced apoptosis, which is important in the development of NSAID-induced gastric lesions. In this study we have found that co-culture of gastric cells with H. pylori suppresses the expression of ER chaperones. This suppression was regulated at the level of transcription and accompanied by a reduction in the level of activating transcription factor 6 (ATF6), one of the transcription factors for ER chaperone genes. 0.404 SIGNOR-253752 FURIN protein P09958 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22479394 YES Cleavage in Golgi gcesareni The proteolytic activity of furin responsible for processing full length notch-1 (p300) plays a critical role in notch signaling. 0.666 SIGNOR-196914 NUMA1 protein Q14980 UNIPROT TUBA8 protein Q9NY65 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.2 SIGNOR-116826 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT down-regulates activity phosphorylation Tyr770 LSAPFEQySPGGQDT 9606 BTO:0000007 11294897 YES lperfetto Ligand stimulation leads to autophosphorylation of fgfr3these results suggest that y770 may negatively regulate the activation of pi 3-kinase by constitutively activated fgfr3 0.2 SIGNOR-106746 PGD protein P52209 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI down-regulates quantity chemical modification 9606 34775382 YES miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. 0.8 SIGNOR-268112 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 9335504 YES llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 0.607 SIGNOR-52687 U2AF1 protein Q01081 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR form complex binding 9606 8647433 YES miannu The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35). 0.2 SIGNOR-41945 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 NO The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines 0.7 SIGNOR-253587 TFPT protein P0C1Z6 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.46 SIGNOR-270857 MRPL43 protein Q8N983 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.699 SIGNOR-262353 DAPK3 protein O43293 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH -1 15001356 YES llicata ZIP kinase phosphorylates p21(WAF1) at Thr145 and alanine-substituted mutations in the p21(WAF1) phosphorylation site alter its ability to be phosphorylated by ZIP kinase. | Transfected ZIPK can promote the phosphorylation of p21(WAF1) at Thr145 in vivo and can increase the half-life of p21(WAF1) 0.316 SIGNOR-251085 ETS2 protein P15036 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 11175361 NO miannu the constitutive expression of ets2 in myeloblast leukemic cells induces their differentiation to macrophages 0.7 SIGNOR-259871 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 YES gcesareni Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin 0.597 SIGNOR-182840 NDUFA3 protein O95167 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added 0.795 SIGNOR-262155 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT down-regulates activity dephosphorylation Ser1224 PASIMDEsVLGVSMF 9606 BTO:0000567 15737063 YES lperfetto Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase 0.737 SIGNOR-275532 PRKAA2 protein P54646 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 YES miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex 0.2 SIGNOR-276838 TRIB3 protein Q96RU7 UNIPROT COP1 protein Q8NHY2 UNIPROT up-regulates activity binding 9606 BTO:0000007 16794074 YES miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). 0.2 SIGNOR-271602 EFNB3 protein Q15768 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9484836 YES gcesareni Ephrin-b3, a ligand for the receptor ephb3, expressed at the midline of the developing neural tube. 0.821 SIGNOR-54711 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr180 EFKNIFGtPEFVAPE 9606 15611134 YES gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. 0.2 SIGNOR-132459 CTNNB1 protein P35222 UNIPROT FOXA2 protein Q9Y261 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22945641 NO gcesareni Our study indicates that beta-catenin regulates foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation 0.444 SIGNOR-198929 CHD4 protein Q14839 UNIPROT CD79A protein P11912 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000776 23071088 NO lperfetto However, NuRD complexes greatly reduce activation of the B cell-specific mb-1 (Cd79a) gene by the transcription factors EBF1 and Pax5|We conclude that repressive functions of MBD2-containing NuRD complexes are dependent on cooperative interactions between the major domains of CHD4 with histones and DNA and on binding of methylated DNA by MBD2. 0.249 SIGNOR-254090 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates activity phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 11689711 YES gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. 0.2 SIGNOR-249665 RMDN3 protein Q96TC7 UNIPROT VAPB-PTPIP51 complex complex SIGNOR-C275 SIGNOR form complex binding 10116 BTO:0000142 30841933 YES lperfetto Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. 0.607 SIGNOR-262119 KAT2B protein Q92831 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates acetylation 9606 BTO:0000782;BTO:0001271 22120716 YES gcesareni In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia. 0.601 SIGNOR-177749 L-arginine chemical CHEBI:16467 ChEBI NOS2 protein P35228 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 NO apalma In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT) 0.8 SIGNOR-255554 SPTAN1 protein Q13813 UNIPROT ERCC4 protein Q92889 UNIPROT up-regulates activity 19102630 NO lperfetto We have shown that in the nucleus alphaRIISp is involved in repair of DNA interstrand cross-links (13,14). It binds to purified DNA containing an interstrand crosslink; it colocalizes with the cross-link repair protein, XPF, in damage-induced nuclear foci after treatment of cells with a DNA interstrand cross-linking agent, and it is needed for the production of incisions by XPF at the site of an interstrand cross-link 0.286 SIGNOR-263276 MRPS16 protein Q9Y3D3 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 BTO:0000934 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.776 SIGNOR-261454 STK11 protein Q15831 UNIPROT SNRK protein Q9NRH2 UNIPROT up-regulates activity phosphorylation Thr173 QPGKKLTtSCGSLAY 9606 15733851 YES Manara We demonstrate that LKB1 activates SNRK by phosphorylating the T‐loop residue (Thr173) 0.368 SIGNOR-260824 IC-87114 chemical CHEBI:90686 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206193 Corticotropin protein P01189-PRO_0000024969 UNIPROT HSD3B1 protein P14060 UNIPROT up-regulates quantity 9606 24631756 NO lperfetto CTH signaling promotes the single steroidogenic rate limiting step, which is the conversion of cholesterol to pregnenolone by Cholesterol Side-Chain Cleavage Enzyme (P450scc), encoded in the CYP11A1 gene. This is conferred by a direct stimulating effect of ACTH on the promoter of CYP11A1 (Chung et al., 1997, Liu and Simpson, 1997, Hu et al., 2001). Further, it stimulates conversion of pregnenolone to 17-hydroxypregnenolone by upregulating the expression of 3β hydroxysteroid dehydrogenase enzyme (3β-HSD) 0.2 SIGNOR-268720 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 9606 BTO:0002181 34010649 YES miannu PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-277557 GPR84 protein Q9NQS5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.277 SIGNOR-256847 IL10 protein P22301 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000938 BTO:0001264 23357618 NO miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. 0.2 SIGNOR-253501 RUNX1 protein Q01196 UNIPROT Core Binding Factor complex complex SIGNOR-C214 SIGNOR form complex binding 9606 12495904 YES irozzo The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis 0.847 SIGNOR-255710 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK6 protein Q00534 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189996 UBE2L3 protein P68036 UNIPROT RNF19B protein Q6ZMZ0 UNIPROT up-regulates activity binding 9606 BTO:0000914 16709802 YES miannu We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and 0.482 SIGNOR-271591 KDM5D protein Q9BY66 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-265336 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT up-regulates quantity phosphorylation Ser198 LQARKENsMDTASQA 9606 BTO:0000007 23649622 YES done miannu TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.Serines are listed from left to right: 133, 185, 187, 188, 190, and 198. 0.717 SIGNOR-273818 ABL1 protein P00519 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Tyr367 TYLQSRYyRAPEIIL 9606 25944899 YES Manara The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage 0.403 SIGNOR-260936 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 BTO:0001103 15829723 YES apalma Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K 0.729 SIGNOR-255844 PIK3CG protein P48736 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates chemical modification 9606 21779497 YES gcesareni The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) 0.8 SIGNOR-175244 AZ 960 chemical CID:25099184 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190128 TCF12 protein Q99081 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR form complex binding 9606 16847330 YES 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. 0.672 SIGNOR-241119 WNT1 protein P04628 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 YES lperfetto Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth 0.708 SIGNOR-129577 HAP1 protein P54257 UNIPROT AHI1 protein Q8N157 UNIPROT up-regulates activity binding 9606 BTO:0000452 23532844 YES miannu Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knock-out mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis. 0.55 SIGNOR-269081 SMAD2 protein Q15796 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity 9606 BTO:0000599 10890911 NO lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity 0.452 SIGNOR-78988 RPS4Y2 protein Q8TD47 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.2 SIGNOR-262448 CUDC-907 chemical CID:54575456 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191209 CREB1 protein P16220 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8999965 NO miannu both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments. 0.2 SIGNOR-253789 SIRT1 protein Q96EB6 UNIPROT nicotinamide smallmolecule CHEBI:17154 ChEBI up-regulates quantity chemical modification 9606 18662546 YES miannu The SIRT1 catalytic reaction involves the breakdown of one NAD+ molecule for each deacetylated acetyl lysine and the generation of nicotinamide and O-acetyl-ADP-ribose. 0.8 SIGNOR-267964 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 15767678 YES gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. 0.722 SIGNOR-134558 CHFR protein Q96EP1 UNIPROT SMARCD1 protein Q96GM5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 YES miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. 0.307 SIGNOR-271459 AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 YES lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. 0.2 SIGNOR-244357 SGX-523 chemical CHEBI:90624 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206905 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23074268 NO gcesareni Canonical hh signaling plays an essential role in cell proliferation throught introduction of the genes encoding cyclin d1 and n-myc 0.575 SIGNOR-199126 APC-c complex SIGNOR-C150 SIGNOR IRS2 protein Q9Y4H2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 32554797 YES miannu We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1 Consistent with the APC/C's role in degrading cell cycle regulators. Consistent with this observation, we found that APC/C inhibition decreased the polyubiquitylation of HA-tagged IRS2 in HeLa cells treated with MG132 (Fig. 2G). 0.2 SIGNOR-272196 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 29958106 NO miannu In adult hematopoiesis, allelic CBFβ-SMMHC expression alters hematopoietic stem cell (HSC) differentiation, with clonal expansion of the short-term HSCs and pre-leukemic myeloid progenitor cells 0.7 SIGNOR-255736 CDK5 protein Q00535 UNIPROT APEX1 protein P27695 UNIPROT up-regulates activity phosphorylation Thr233 NKKNAGFtPQERQGF 9606 21727086 YES miannu Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5. 0.377 SIGNOR-276337 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT unknown phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 YES llicata Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation. 0.402 SIGNOR-113964 DVL1P1 protein P54792 UNIPROT CCDC88C protein Q9P219 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Daple binds to dvl and functions as a negative regulator of the wnt signalling pathway. 0.2 SIGNOR-199448 MCU protein Q8NE86 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.706 SIGNOR-270862 RET protein P07949 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Tyr9 ARTTSQLyDAVPIQS 10029 12738763 YES lperfetto Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1. 0.2 SIGNOR-235863 EGLN3 protein Q9H6Z9 UNIPROT BCL2L11 protein O43521-1 UNIPROT up-regulates quantity by stabilization hydroxylation Pro70 PLAPPASpGPFATRS 9606 31375625 YES lperfetto EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues 0.254 SIGNOR-262004 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT up-regulates activity phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 32238881 YES miannu Src enhances the stability of BCKDK.|We observed that, active Src distinctly phosphorylated the Y246 site of BCKDK. 0.2 SIGNOR-278347 NAE complex SIGNOR-C131 SIGNOR CUL4B protein Q13620 UNIPROT up-regulates activity neddylation 9606 25504797 YES lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. 0.613 SIGNOR-243163 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TP53 protein P04637 UNIPROT unknown phosphorylation Ser392 FKTEGPDsD -1 10884347 YES llicata Our previous data has shown that cyclin A-cdk2 is the major enzyme responsible for modifying p53 at Ser315 in vivo after irradiation damage and in this report we dissect the mechanism of cyclinA-cdk2 binding to and phosphorylation of p53. 0.809 SIGNOR-250751 seliciclib chemical CHEBI:45307 ChEBI CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206559 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity relocalization 9606 18596912 YES lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform 0.398 SIGNOR-179407 AP3S2 protein P59780 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 YES miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) 0.708 SIGNOR-268518 JAK2 protein O60674 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation Tyr1939 CEKYGPDyVPQKSHG -1 30944118 YES miannu Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin.  0.419 SIGNOR-277290 HABP4 protein Q5JVS0 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates activity binding 10116 15862299 YES llicata MEF2C DNA-binding activity is inhibited through its interaction with the regulatory protein Ki-1/57. 0.338 SIGNOR-238283 PBK protein Q96KB5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser533 AEMRGGRsPRPGSSA 9606 BTO:0002181 31378785 YES miannu We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.  0.2 SIGNOR-277472 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 YES miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. 0.2 SIGNOR-159432 NODAL protein Q96S42 UNIPROT LIF protein P15018 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20383200 NO Regulation miannu Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway. 0.266 SIGNOR-251941 N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide chemical CHEBI:91408 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207239 SYN1 protein P17600 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates activity binding 9606 BTO:0000938 15265865 YES miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 0.7 SIGNOR-269187 SMAD3 protein P84022 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 YES lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. 0.711 SIGNOR-229557 IL10 protein P22301 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000938 BTO:0001264 23357618 NO miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. 0.2 SIGNOR-253496 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates activity binding 9606 8006002 YES fspada BMP-4 bound to ALK-3 and ALK-6 efficiently 0.851 SIGNOR-236932 EZH2 protein Q15910 UNIPROT ALDH1A1 protein P00352 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 NO miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. 0.391 SIGNOR-254141 OXSR1 protein O95747 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity phosphorylation Thr84 LPSDFEHtIHVGFDA 9606 BTO:0000567 14707132 YES miannu OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. phosphorylation of PAK1 by OSR1 desensitizes PAK1 to activation by small G proteins, providing a modulatory input to PAK1 activity. 0.382 SIGNOR-250210 MAPK14 protein Q16539 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser941 S-->A 9606 BTO:0002181 38307877 YES miannu Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1's proteasomal degradation and negates the transcription of SHH signaling.  0.271 SIGNOR-277917 Ub:E2 complex SIGNOR-C497 SIGNOR G2E3 protein Q7L622 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271282 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -1 2413024 YES miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-164 0.347 SIGNOR-250014 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 NO miannu YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. 0.7 SIGNOR-277640 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 17317136 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. 0.559 SIGNOR-153402 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCB protein P05771 UNIPROT down-regulates chemical inhibition 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-190347 CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 17139329 NO fferrentino C/EBPα induces many adipocyte genes directly, and in vivo studies indicate an important role for this factor in the development of adipose tissue. 0.7 SIGNOR-132946 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH5 protein P33151 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265845 MAPK1 protein P28482 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 21666810 YES fstefani Like mk2, mk5 could be phosphorylated and activated by p38mapk and erk2 in vitro, but not by sapk?/Jnk3 0.481 SIGNOR-174076 COLGALT2 protein Q8IYK4 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates activity glycosylation -1 19075007 YES Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. 0.45 SIGNOR-261159 CALM1 protein P0DP23 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 24379783 YES lperfetto Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer 0.76 SIGNOR-251615 AMP smallmolecule CHEBI:456215 ChEBI MLXIPL protein Q9NP71 UNIPROT down-regulates activity chemical inhibition 10116 26984404 YES We discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. 0.8 SIGNOR-255668 NF2 protein P35240 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity binding 10090 BTO:0003324 27402866 YES Hippo pathway Gianni NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart. 0.327 SIGNOR-261955 CXCL10 protein P02778 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 YES miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. 0.786 SIGNOR-260969 PDPK1 protein O15530 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 15802604 YES gcesareni We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts. 0.549 SIGNOR-134866 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCG protein P05129 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191499 RRM1 protein P23921 UNIPROT Ribonucleotide reductase complex SIGNOR-C233 SIGNOR form complex binding 9606 14583450 YES miannu Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2. 0.933 SIGNOR-259363 WWTR1 protein Q9GZV5 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 20466877 YES gcesareni Taz physically interacts with myod through the ww domain and activates myod-dependent gene transcription. 0.276 SIGNOR-165414 chelerythrine chemical CHEBI:78373 ChEBI BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 12702731 YES gcesareni Chelerythrine inhibited the bclxl-bak bh3 peptide binding with ic50 of 1.5 micro m and displaced bax, a bh3-containing protein, from bclxl. 0.8 SIGNOR-100670 morphine chemical CHEBI:17303 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258765 HNF4A protein P41235 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 9794469 NO miannu Orphan receptor hepatocyte nuclear factor-4 antagonizes estrogen receptor alpha-mediated induction of human coagulation factor XII gene. In conclusion, our findings address a direct role for HNF-4 in modulating estrogen-dependent transcription of the FXII gene promoter. 0.22 SIGNOR-254073 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.91 SIGNOR-252854 PRKCA protein P17252 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 YES lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. 0.536 SIGNOR-249048 NRXN2 protein Q9P2S2 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 YES miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 0.262 SIGNOR-265460 GNAS protein P63092 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR down-regulates -1 10224115 NO miannu G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. 0.7 SIGNOR-256524 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207666 CROCC protein Q5TZA2 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 BTO:0000567 24035387 YES miannu C-Nap1 and rootletin have been previously reported to be the important centrosome linker components involved in centrosome cohesion. 0.7 SIGNOR-273706 MYCT1 protein Q8N699 UNIPROT CCND2 protein P30279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 NO miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 0.2 SIGNOR-261731 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Ser854 HPKPKQFsSFEKRAK 9606 21068236 YES lperfetto Phosphorylation of rig-i by casein kinase ii inhibits its antiviral response. Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) 0.2 SIGNOR-169400 SLC1A2 protein P43004 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 YES miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). 0.8 SIGNOR-264803 MMP21 protein Q8N119 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272389 MOB1B protein Q7L9L4 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 YES Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. 0.876 SIGNOR-169798 STAT3 protein P40763 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000452 26738736 NO miannu Collectively, the activation of IL-6/STAT3 pathway contributed to the PSCs-induced EMT i 0.7 SIGNOR-277690 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 24622840 YES miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. 0.822 SIGNOR-260154 (-)-anisomycin chemical CHEBI:338412 ChEBI JUNB protein P17275 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling;phospho-JunB (Thr102/Thr104) (D3C6) Rabbit mAb #8053 gcesareni 0.8 SIGNOR-189644 MAPK8 protein P45983 UNIPROT GRB7 protein Q14451 UNIPROT down-regulates quantity by destabilization phosphorylation Ser194 KYELFKSsPHSLFPE 9606 BTO:0000017 27658202 YES miannu Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. I 0.262 SIGNOR-277280 Ub:E2 complex SIGNOR-C497 SIGNOR KMT2C protein Q8NEZ4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271130 TAF10 protein Q12962 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.896 SIGNOR-263926 NTRK3 protein Q16288 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000938 10235685 YES gcesareni Unglycosylated trka core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules shc and plc-gamma. 0.618 SIGNOR-67404 NR3C1 protein P04150 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9590696 YES gcesareni Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP. 0.768 SIGNOR-251682 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 0.2 SIGNOR-244576 POLE4 protein Q9NR33 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR form complex binding 9606 BTO:0000567 10801849 YES lperfetto Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon. 0.916 SIGNOR-265521 POLR2M protein P0CAP2 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.454 SIGNOR-266169 PTK2B protein Q14289 UNIPROT GSN protein P06396 UNIPROT down-regulates activity phosphorylation 9606 12578912 YES miannu Our results demonstrate that PYK2 inhibits this EGTA stable gelsolin-actin monomer association.|PYK2 phosphorylates gelsolin at tyrosine residues and regulates gelsolin bioactivity, including decreasing gelsolin binding to actin monomer and increasing gelsolin binding to phosphatidylinositol lipids. 0.528 SIGNOR-278325 EFNA1 protein P20827 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9576626 YES gcesareni The best known function is their role in the guidance of migration of axons and cells in the nervous system through repulsive interactions 0.812 SIGNOR-56965 MAPK1 protein P28482 UNIPROT ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation Ser685 PMFSAPSsPMPTSST -1 9525907 YES miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. 0.2 SIGNOR-262944 CDK1 protein P06493 UNIPROT FEN1 protein P39748 UNIPROT down-regulates activity phosphorylation Ser187 MDCLTFGsPVLMRHL 9606 BTO:0000007 12853968 YES lperfetto Phosphorylation of human fen1 by cyclin-dependent kinase modulates its role in replication fork regulation.As a functional consequence of phosphorylation by cdk1-cyclin a in vitro, endo- and exonuclease activities of fen1 are reduced whereas its dna binding is not affected. 0.447 SIGNOR-103535 MC1R protein Q01726 UNIPROT Pigmentation phenotype SIGNOR-PH70 SIGNOR up-regulates 9606 19656324 NO miannu Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses. 0.7 SIGNOR-252374 BMX protein P51813 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity phosphorylation Tyr400 RQGLDEMySDVWKQL 9534 11877430 YES miannu Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes. 0.633 SIGNOR-262679 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates chemical activation 9606 22863277 YES gcesareni Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors. 0.8 SIGNOR-198526 SERPINA1 protein P01009 UNIPROT F2 protein P00734 UNIPROT down-regulates activity binding 9606 BTO:0000131 17635716 YES lperfetto Alpha1PI, historically known as alpha1-antitrypsin, is a 51 kDa, 394 amino acid glycoprotein, synthesized in the liver, circulating at c. 1.3 mg mL-1 with a half-life of 4.5 days 0.424 SIGNOR-263524 IYD protein Q6PHW0 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 28153798 YES scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. 0.8 SIGNOR-267034 FOXJ1 protein Q92949 UNIPROT DNAH11 protein Q96DT5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.361 SIGNOR-266931 CRX protein O43186 UNIPROT RHO protein P08100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 NO miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 0.471 SIGNOR-253820 ID2 protein Q02363 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.563 SIGNOR-241149 g-TuRC complex complex SIGNOR-C282 SIGNOR TUBG1 protein P23258 UNIPROT up-regulates activity binding -1 31862189 YES lperfetto Despite its asymmetric architecture, the γ-TuRC arranges γ-tubulins into a helical geometry poised to nucleate microtubules. 0.869 SIGNOR-262325 FOXA1 protein P55317 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 19127412 NO miannu Overexpression of foxa1 promoted apoptosis 0.7 SIGNOR-183153 N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI acetic acid smallmolecule CHEBI:15366 ChEBI up-regulates quantity precursor of 9606 17194761 YES miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. 0.8 SIGNOR-268085 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 YES miannu The AMP-activated protein kinase (AMPK) down-regulates the inward rectifier K+ channel Kir2.1. Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK. 0.256 SIGNOR-276324 EEF1A2 protein Q05639 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269541 PSMD8 protein P48556 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.915 SIGNOR-263345 GYPA protein P02724 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.366 SIGNOR-266018 NOTCH proteinfamily SIGNOR-PF30 SIGNOR ADAM19 protein Q9H013 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10933396 NO gcesareni Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene. 0.2 SIGNOR-254340 GRK2 protein P25098 UNIPROT CXCR2 protein P25025 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000763 22634615 YES miannu Upon activation, GRK2 phosphorylates CXCR2 and causes receptor desensitization and internalization, leading to down-regulation of neutrophil chemotaxis 0.2 SIGNOR-260647 CD79B protein P40259 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323266 YES scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. 0.656 SIGNOR-268189 TXNL4A protein P83876 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.752 SIGNOR-270638 TFEB protein P19484 UNIPROT WDFY1 protein Q8IWB7 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 NO lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 0.2 SIGNOR-276803 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 29953871 NO miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. 0.7 SIGNOR-264955 AP1 complex SIGNOR-C154 SIGNOR SPI1 protein P17947 UNIPROT up-regulates activity binding 9606 BTO:0004136 12393465 YES miannu These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1. 0.511 SIGNOR-260098 Cap-binding complex complex SIGNOR-C440 SIGNOR PUM3 protein Q15397 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320643 YES lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins 0.2 SIGNOR-268352 BDKRB1 protein P46663 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256907 FYN protein P06241 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 10383400 YES miannu Further indications of direct interaction are that p59fyn potentiates ?PKC Catalytic activity and that ?PKC Is a substrate for tyrosine phosphorylation by p59fyn. 0.345 SIGNOR-68798 DDIT3 protein P35638 UNIPROT TRIB3 protein Q96RU7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002183 18940792 NO miannu Exogenous CHOP expression enhanced the TRB3 gene induction by amino acid deprivation. 0.574 SIGNOR-253839 ZDHHC2 protein Q9UIJ5 UNIPROT AKAP5 protein P24588 UNIPROT up-regulates activity palmitoylation Cys36 KEKASMLcFKRRKKA 10116 BTO:0004553 25589740 YES Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms 0.331 SIGNOR-262295 LONP2 protein Q86WA8 UNIPROT TYSND1 protein Q2T9J0 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000567 22002062 YES miannu Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer. 0.659 SIGNOR-261054 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 YES gcesareni The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells. 0.873 SIGNOR-197622 RPS6KA1 protein Q15418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 YES lperfetto S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity. 0.36 SIGNOR-110917 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Thr177 VAGQLTDtMAKRNTV 9534 12223493 YES lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues 0.2 SIGNOR-247573 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9841871 YES lperfetto When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro. 0.656 SIGNOR-62372 STAT5A protein P42229 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 10072077 NO Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression 0.7 SIGNOR-254302 hsa-miR-199a-5p mirna URS0000554A4F_9606 RNAcentral VEGFA protein P15692 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005168 25444917 YES Parnian Taken together, these data demonstrated that miR-199a directly represses the VEGF-A protein expression through binding to the 3′UTR of the human VEGF-A gene. 0.4 SIGNOR-278862 CSNK2A1 protein P68400 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates phosphorylation Ser239 KDSSHYDsDGDKSDD 9606 15367661 YES lperfetto These results suggest that ck2 phosphorylation of serine 239 of gro/tle1 is important for its function during neuronal differentiation. 0.32 SIGNOR-129026 MICU2 protein Q8IYU8 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.657 SIGNOR-270877 452342-67-5 chemical CID:10202642 PUBCHEM TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193018 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263809 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 YES gcesareni ...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. 0.2 SIGNOR-249658 Ub:E2 complex SIGNOR-C497 SIGNOR ZXDC protein Q2QGD7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271279 EIF4G2 protein P78344 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity binding 9606 BTO:0000007 29530922 YES miannu Unlike eIF4GI/II, DAP5 binds eIF2β, a subunit of the eIF2 complex that delivers methionyl-tRNA to ribosomes. 0.752 SIGNOR-266385 IL17A protein Q16552 UNIPROT KLF3 protein P57682 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23332504 NO fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. 0.2 SIGNOR-192610 linifanib chemical CHEBI:91435 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193666 FBXO32 protein Q969P5 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 10090 BTO:0000165 19319192 YES miannu We previously showed that the level of MAFbx protein increased in skeletal muscle during aging and/or food deprivation. Immunoprecipitation of the SCFMAFbx complexes from mouse atrophic muscles exhibited ubiquitination activity by using MyoD as substrate. Food deprivation and oxidative stress–induced atrophy increase polyubiquitination by the SCFMAFbx pathway and degradation of MyoD by the proteasome 0.596 SIGNOR-271803 SMAD2 protein Q15796 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 10090 BTO:0000165 BTO:0001760 SIGNOR-C8 11160896 YES lperfetto Our studies indicate that smad2 and 4 (smad2/4) complexes cooperate with mef2 regulatory proteins in a gal4-based one-hybrid reporter gene assay. 0.391 SIGNOR-235846 DDX21 protein Q9NR30 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 9606 BTO:0000007 ; BTO:0001282 11823437 YES SARA C-Jun and RHII/Gu proteins interact in human cells at their endogenous level of expression. The helicase activity of RHII/Gu specifically facilitates c-Jun-mediated transcription. 0.456 SIGNOR-260977 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser645 LNEKARLsYSDKNLI 10090 BTO:0000944 11959144 YES PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex 0.3 SIGNOR-248595 ABL1 protein P00519 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation Tyr425 SDKYGLGyQLCDNSV 9606 27899378 YES Manara C-ABL can directly phosphorylate PLK1 and activate PLK1. | The above results indicate that c-ABL–mediated PLK1 Y425 phosphorylation regulates PLK1 ubiquitination and stability. 0.29 SIGNOR-260935 MAP2K6 protein P52564 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10347227 YES lperfetto However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2. 0.2 SIGNOR-236122 RIPK3 protein Q9Y572 UNIPROT GLUD1 protein P00367 UNIPROT up-regulates binding 9606 19632174 YES gcesareni Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro. 0.445 SIGNOR-187314 moclobemide chemical CHEBI:83531 ChEBI MAOA protein P21397 UNIPROT down-regulates activity chemical inhibition -1 21680183 YES Luana Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5–16) were found to be potent inhibitors of hMAO-A isoform with SIMAO-A in the order 103 and 104.  0.8 SIGNOR-258314 UTS2R protein Q9UKP6 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256922 KLHL13 protein Q9P2N7 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000567 17543862 YES miannu Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis. 0.574 SIGNOR-271659 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates chemical activation 9606 8276865 YES gcesareni Lpa activates its own g protein-coupled receptor(s). 0.8 SIGNOR-36389 MECOM protein Q03112 UNIPROT GATA2 protein P23769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000565 15889140 YES Luana Evi1 directly binds to the promoter region of GATA-2 and thus enhances the GATA-2 transcription. 0.36 SIGNOR-266062 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR up-regulates activity chemical activation 26083061 YES lperfetto Respiratory chain complexes I–III depend on Fe-S clusters for function 0.8 SIGNOR-262135 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249352 SORT1 protein Q99523 UNIPROT APOA1 protein P02647 UNIPROT up-regulates quantity binding 10029 BTO:0000246 23283348 YES miannu Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms. 0.331 SIGNOR-273722 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 YES lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. 0.551 SIGNOR-219217 COX6A1 protein P12074 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.731 SIGNOR-267747 LPAR3 protein Q9UBY5 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 YES gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. 0.465 SIGNOR-198544 panobinostat chemical CHEBI:85990 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257754 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH8 protein P55286 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265848 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0000452 11287630 YES lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten 0.766 SIGNOR-106574 perfluorododecanoic acid chemical CHEBI:90633 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 YES miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. 0.8 SIGNOR-268759 PPARGC1A protein Q9UBK2 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates quantity by repression transcriptional regulation 10090 BTO:0001103 20404331 NO lperfetto In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB 0.365 SIGNOR-217978 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser813 DIYSRRLsQETGLEI -1 1377674 YES miannu CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795. 0.484 SIGNOR-250351 UBE2I protein P63279 UNIPROT MITF protein O75030 UNIPROT down-regulates ubiquitination Lys308 SEARALAkERQKKDN 9606 10673502 YES lperfetto Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo. 0.564 SIGNOR-75117 PRKCH protein P24723 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 YES lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. 0.2 SIGNOR-202792 GZMB protein P10144 UNIPROT IGF2R protein P11717 UNIPROT up-regulates binding 9606 11081635 YES gcesareni The serine proteinase granzyme b is crucial for the rapid induction of target cell apoptosis by cytotoxic t cells. We now present evidence that this receptor is the cation-independent mannose 6-phosphate/insulin-like growth factor receptor (ci-mpr). Inhibition of the granzyme b ci-mpr interaction prevented granzyme b cell surface binding, uptake, and the induction of apoptosis. 0.408 SIGNOR-84314 CDK1 protein P06493 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 26352374 YES miannu Drp1 is phosphorylated at the Ser616 position and activated predominantly by CDK1. 0.467 SIGNOR-279394 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 YES gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. 0.333 SIGNOR-40493 PLK1 protein P53350 UNIPROT SRI protein P30626 UNIPROT unknown phosphorylation Thr155 YSTNGKItFDDYIAC 9606 24427308 YES lperfetto Sorcin interacts physically with plk1, is phosphorylated by plk1 and induces plk1 autophosphorylation, thereby regulating kinase activity. 0.375 SIGNOR-203732 PKA proteinfamily SIGNOR-PF17 SIGNOR Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 NO miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex 0.7 SIGNOR-264960 FOXA1 protein P55317 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19127412 NO miannu Foxa1 overexpression decreased the expression of bcl2, while foxa1 depletion increased the expression of bcl2 0.2 SIGNOR-161448 GRIK5 protein Q16478 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264346 NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates transcriptional regulation 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin 0.51 SIGNOR-255460 ACTL6A protein O96019 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.678 SIGNOR-270718 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr28 SLNQSSGyRYGTDPT -1 9425276 YES Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. 0.2 SIGNOR-251168 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation 9606 21419341 YES inferred from 70% family members gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. 0.2 SIGNOR-270161 MSL1 protein Q68DK7 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271977 ACSL4 protein O60488 UNIPROT Ferroptosis phenotype SIGNOR-PH234 SIGNOR up-regulates 9606 BTO:0003081 27565726 NO miannu Overexpression of ACSL4 promotes ferroptosis 0.7 SIGNOR-279851 CCT137690 chemical CID:25154041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190892 BRCA1 protein P38398 UNIPROT ERCC6 protein Q03468 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21756275 YES miannu BRCA1 polyubiquitinates CSB and this polyubiquitination and subsequent degradation of CSB occur following UV irradiation, even in the absence of Cockayne syndrome A (CSA) protein.  0.442 SIGNOR-272754 NR3C1 protein P04150 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 NO miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. 0.282 SIGNOR-254439 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates activity chemical inhibition -1 23515850 YES lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro 0.8 SIGNOR-262023 NEDD4 protein P46934 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 25088038 YES miannu NEDD4 promotes MDM2 ubiquitination in a dose- and time-dependent manner, whereas depletion of NEDD4 reduced the half-life of endogenous MDM2 [ xref ]. 0.467 SIGNOR-278769 ASTN1 protein O14525 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000142 28506896 NO miannu The role of astrotactin and Brinp proteins has been partially characterized, with ASTN1 and ASTN2 demonstrated to facilitate glial-guided neuronal migration during brain development 0.7 SIGNOR-269815 LATS2 protein Q9NRM7 UNIPROT CDC26 protein Q8NHZ8 UNIPROT up-regulates activity phosphorylation Thr7 tRLELKLD 25723520 YES lperfetto LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C 0.461 SIGNOR-275474 ELOVL5 protein Q9NYP7 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267891 CDK5 protein Q00535 UNIPROT DRD2 protein P14416 UNIPROT down-regulates activity phosphorylation Ser321 GLHSTPDsPAKPEKN 9606 24391960 YES miannu These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling. 0.384 SIGNOR-259401 Ub:E2 complex SIGNOR-C497 SIGNOR RNF10 protein Q8N5U6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271064 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser402 GSLERSQsRKDSLDD 9534 BTO:0000298 9353340 YES lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  0.391 SIGNOR-248986 CPE protein P16870 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates activity cleavage 9606 25767437 YES miannu First, OT preprohormone is produced, that will be cleaved and matured by successive enzymes. The OT gene encodes for the Pre-Pro-OT-Neurophysin I (pre-pro-hormone), which is cleaved by different enzymes to give rise to different OT intermediate forms and to the Neurophysin I, and finally to the mature amidated form that is released (Figure ​2). 0.2 SIGNOR-270338 CPT1A protein P50416 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267126 ALS2 protein Q96Q42 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity binding 9606 BTO:0000567 30485418 YES miannu ALS2 activates Rab5 on macropinosomes. Rab5 is activated and concurrently recruited to macropinosomes during ruffle closure. ALS2 depletion abolishes transient Rab5 activation on macropinosomes, while ALS2 is recruited to macropinosomes simultaneously with Rab5 activation. Thus, we conclude ALS2 activates Rab5 on macropinosomes. 0.734 SIGNOR-277776 B-WICH complex complex SIGNOR-C447 SIGNOR MYC protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0000567 25883140 YES miannu The B-WICH complex allows c-Myc to bind to a site in the IGS. c-Myc requires the B-WICH complex to remodel chromatin for its function. 0.295 SIGNOR-268842 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1222 ESSSTRRsSEDLSAY 9606 BTO:0000975 17360977 YES lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 0.2 SIGNOR-236729 GPR132 protein Q9UNW8 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.4 SIGNOR-257444 FBXL2 protein Q9UKC9 UNIPROT PIK3R2 protein O00459 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23604317 YES miannu FBXL2 binds p85α and p85β. p85β is targeted for ubiquitylation and degradation by SCF FBXL2. 0.366 SIGNOR-272111 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270424 CDC14B protein O60729 UNIPROT APC protein P25054 UNIPROT up-regulates dephosphorylation 9606 SIGNOR-C110 18662541 YES gcesareni The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1 0.2 SIGNOR-179636 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr564 LEEADNQtLDSYRNE -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.2 SIGNOR-276215 NONO protein Q15233 UNIPROT TOP1 protein P11387 UNIPROT up-regulates binding 9606 BTO:0000017 9756848 YES miannu We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i 0.374 SIGNOR-60557 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1616 TPQSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248803 CALM2 protein P0DP24 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 BTO:0001009 14701738 YES miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. 0.2 SIGNOR-266325 ABL1 protein P00519 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr52 LTRDETNyGIPQRAL 9606 19423701 YES lperfetto Phosphorylation of rack1 on tyrosine 52 by c-abl is required for insulin-like growth factor i-mediated regulation of focal adhesion kinase.Tyrosine 52 is further shown to be phosphorylated by c-abl kinase, and the c-abl inhibitor sti571 disrupts fak interaction with rack1 0.2 SIGNOR-185649 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD9 protein O15198 UNIPROT down-regulates ubiquitination 9606 22298955 YES inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.2 SIGNOR-270211 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 YES apalma Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K 0.929 SIGNOR-255107 SMAD1 protein Q15797 UNIPROT GATA3 protein P23771 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.291 SIGNOR-268938 ALDOB protein P05062 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266488 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 YES milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation 0.608 SIGNOR-201274 GSK3A protein P49840 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 16023596 YES gcesareni Similar to c-myc, similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation. 0.407 SIGNOR-138596 MAPK11 protein Q15759 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser113 STSVTPHsPSSPVGS 9606 BTO:0000007 16713578 YES miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles 0.264 SIGNOR-262946 RPS6KB1 protein P23443 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 17181399 NO gcesareni Finally, downregulation of p70 s6 kinase by sirna significantly enhanced the fgf-2-stimulated vegf release and phosphorylation of sapk/jnk. 0.421 SIGNOR-149367 PTCH1 protein Q13635 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR form complex binding 10090 21664576 YES lperfetto Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands. 0.584 SIGNOR-209602 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT up-regulates activity phosphorylation Ser398 DSLPSSPsSATPHSQ -1 14709557 YES miannu Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity. 0.497 SIGNOR-250158 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM45 protein Q9H8W5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271225 TGFBI protein Q15582 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 26387839 YES lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers 0.35 SIGNOR-253269 USP7 protein Q93009 UNIPROT DEPTOR protein Q8TB45 UNIPROT up-regulates quantity by stabilization deubiquitination -1 35216969 YES miannu Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay. 0.2 SIGNOR-277588 GAB1 protein Q13480 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12819203 YES gcesareni Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2. 0.315 SIGNOR-102586 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT -1 9199504 YES miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. 0.524 SIGNOR-250087 HSP90AA1 protein P07900 UNIPROT FER protein P16591 UNIPROT down-regulates activity phosphorylation Tyr714 RQEDGGVySSSGLKQ 9606 BTO:0002181 19159681 YES miannu Hsp90 and tyrosine616 are required for Fer tyrosine kinase activity.Taken together, our findings underscore the importance of Hsp90 and the residue, tyrosine616, which resides in the Hsp90 recognition loop, in maintaining Fer tyrosine kinase activity. 0.3 SIGNOR-277818 GSK3A protein P49840 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 YES gcesareni GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function. 0.636 SIGNOR-252434 CDK1 protein P06493 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Ser394 SKDAKVPsPPPGHKW -1 18408216 YES miannu In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells. 0.35 SIGNOR-276157 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 11208622 YES ashma gcesareni 0.8 SIGNOR-251687 RNF139 protein Q8WU17 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 YES miannu Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner  0.298 SIGNOR-271957 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 21808241 YES MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. 0.9 SIGNOR-175829 POMC protein P01189 UNIPROT OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.648 SIGNOR-258409 NRG2 protein O14511 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 YES gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.788 SIGNOR-26211 AGO2 protein Q9UKV8 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR form complex binding 9606 23661684 YES miannu 0.813 SIGNOR-143102 PIM1 protein P11309 UNIPROT RP9 protein Q8TA86 UNIPROT unknown phosphorylation Ser214 RKHKSSKsNEGSDSE -1 10931201 YES miannu PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase. 0.2 SIGNOR-263030 CNOT6L protein Q96LI5 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.812 SIGNOR-268311 FOXO1 protein Q12778 UNIPROT FSHB protein P01225 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004467 24065703 NO miannu We demonstrate that FOXO1 represses basal and GnRH-induced Fshb transcription in LβT2 cells. 0.346 SIGNOR-254185 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 10037602 YES gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. 0.858 SIGNOR-64968 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser139 YFLGSSFsPVRCGGP 9606 23051732 YES lperfetto However, when both Ser 123 and Ser 139 were modified (2A), although Wee1 was still phosphorylated by Cdk1, treatment with active Cdc14A did not decrease the phosphorylation signal to any significant extent (XREF_FIG, lane 5), indicating that Cdc14A dephosphorylates Wee1 at Ser 123 and Ser 139 residues.|Our results indicate that Wee1 is a substrate of Cdc14 phosphatases in human cells and that by reversing specific Cdk1 phosphorylation, the Cdc14A isoform induces Wee1 stability, which in turn directly inhibits Cdk1 activity. 0.545 SIGNOR-276953 ITGB1BP1 protein O14713 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257645 MAPK11 protein Q15759 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 20551513 NO gcesareni Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphorylated runx2, promoting its association with the coactivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs. 0.285 SIGNOR-166167 EDVP complex SIGNOR-C530 SIGNOR KATNA1 protein O75449 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 19287380 YES miannu EDVP-DYRK2 complex regulates Katanin p60 ubiquitination. Katanin p60 was polyubiquitinated in the presence of the intact DYRK2-EDVP, but its ubiquitination was severely reduced by the depletion of DYRK2, EDD, DDB1 or VPRBP (Fig. 3d). 0.311 SIGNOR-271793 CASP7 protein P55210 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.319 SIGNOR-261746 BRCA1 protein P38398 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 15549093 NO lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination 0.7 SIGNOR-251500 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000142 10226025 YES acerquone We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies. 0.748 SIGNOR-67367 ME1 protein P48163 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI down-regulates quantity chemical modification 9606 33064660 YES miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. 0.8 SIGNOR-267717 TEK protein Q02763 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 NO lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. 0.2 SIGNOR-241538 TMLHE protein Q9NVH6 UNIPROT N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:17311 ChEBI down-regulates quantity chemical modification 9606 11431483 YES miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 0.8 SIGNOR-269681 IL15RA protein Q13261 UNIPROT TYK2 protein P29597 UNIPROT up-regulates 9606 30029643 YES Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 0.245 SIGNOR-256253 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000801 24166242 YES lperfetto Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor. 0.906 SIGNOR-249511 BLOC1S1 protein P78537 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 YES lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. 0.73 SIGNOR-265936 SMURF1 protein Q9HCE7 UNIPROT CUEDC1 protein Q9NWM3 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272682 SP1 protein P08047 UNIPROT GFER protein P55789 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 18513187 NO miannu We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1. 0.2 SIGNOR-254450 PKN1 protein Q16512 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567 15791647 YES lperfetto A role for PKN1 in mediating arsenite-induced G(2)/M delay was supported by the finding that expression of a constitutively active form of PKN1 (PKN1AF3) in HeLa cells delayed the mitotic entry of cell cycle. Further experiments indicate that PKN1 directly phosphorylated serine 216 (Ser216) in Cdc25C, which then facilitated association between Cdc25C and 14-3-3. 0.53 SIGNOR-249277 ADSS2 protein P30520 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-267345 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9606 17132853 YES miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 0.8 SIGNOR-256195 PRKCB protein P05771 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 YES lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. 0.398 SIGNOR-249183 CDK4 protein P11802 UNIPROT KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation 9606 32827753 YES miannu Cdk4 phosphorylation on GCN5 augments the acetyltransferase catalytic activity of GCN5, by increasing maximal velocity (V ), whereas the Michaelis-Menten constant for Acetyl-CoA binding was unaffected.|Cdk4 phosphorylation on GCN5 augments the acetyltransferase catalytic activity of GCN5, by increasing maximal velocity (V max ), whereas the Michaelis-Menten constant for Acetyl-CoA binding was unaffected. 0.361 SIGNOR-279018 EPC1 protein Q9H2F5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.66 SIGNOR-269305 caffeine chemical CHEBI:27732 ChEBI PDE2A protein O00408 UNIPROT down-regulates activity chemical inhibition 36476859 YES lperfetto We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice.  0.8 SIGNOR-275729 PRKCQ protein Q04759 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.303 SIGNOR-249256 ATP(4-) smallmolecule CHEBI:30616 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269098 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr846 DGGGSDRyGSLRPGW 9606 BTO:0000763 20861316 YES lperfetto Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity 0.3 SIGNOR-168001 crizotinib chemical CHEBI:64310 ChEBI ALK protein Q9UM73 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191133 FANCC protein Q00597 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.923 SIGNOR-263246 calcium(2+) smallmolecule CHEBI:29108 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR up-regulates activity chemical activation 9606 21880741 YES miannu Except for nfat5, nfatc1c4 are activated upon a rise in intracellular ca2+, which stimulates the serine/threonine phosphatase activity of calcineurin the ca2+-calcineurin signal is the most important signal for regulating nfat activation, but the signal that leads to ca2+ influx during neural tube differentiation is still unclear. 0.8 SIGNOR-255462 EEF1D protein P29692 UNIPROT ITGA7 protein Q13683 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165 16129691 YES lperfetto alpha7 Integrin Expression Is Negatively Regulated by deltaEF1 during Skeletal Myogenesis 0.2 SIGNOR-241773 CHD8 protein Q9HCK8 UNIPROT MLL/SET subcomplex complex SIGNOR-C87 SIGNOR up-regulates activity binding 9606 BTO:0000946 20085832 YES miannu Chromodomain, helicase, DNA-binding protein 8 (CHD8) is an ATP-dependent chromatin remodeling enzyme that has been demonstrated to exist within a large protein complex which includes WDR5, Ash2L, and RbBP5, members of the Mixed Lineage Leukemia (MLL) histone modifying complexes. CHD8 forms a complex with the core WDR5/Ash2L/RbBP5 complex. CHD8 is required for recruitment of the WAR complex 0.429 SIGNOR-268807 antigen smallmolecule CHEBI:59132 ChEBI BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 YES scontino The recognition of antigen by the BCR initiates BCR signaling cascade. 0.8 SIGNOR-268204 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.476 SIGNOR-121994 1-(4,4-diphenylbut-3-enyl)-3-piperidinecarboxylic acid chemical CHEBI:91734 ChEBI SLC6A1 protein P30531 UNIPROT down-regulates activity chemical inhibition -1 7851497 YES miannu Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. 0.8 SIGNOR-258478 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr612 TLHTDDGyMPMSPGV 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). 0.868 SIGNOR-157742 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser19 EVCDERTsLMSAESP -1 8972483 YES llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  0.307 SIGNOR-250932 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4C protein Q08493 UNIPROT up-regulates activity phosphorylation Ser14 GEGAEACsRLSRSRG 9534 12023945 YES miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. 0.2 SIGNOR-273938 XL147 chemical CHEBI:71957 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207854 CDK1 protein P06493 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Ser1678 ITSEEERsPAKRGRK -1 30685087 YES lperfetto Nuclear import of 53BP1 is required for proper localization of 53BP1 and maintenance of genome integrity. 53BP1 has a classical bipartite nuclear localization signal (NLS) of sequence 1666-GKRKLITSEEERSPAKRGRKS-1686. Ser1678 within the 53BP1 NLS can be phosphorylated by CDK1/cyclin B, and a phosphomimetic substitution of Ser1678 with aspartate has been shown to negatively regulate nuclear import of 53BP1. 0.6 SIGNOR-264412 RPS6KC1 protein Q96S38 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates activity binding 9534 BTO:0000298 12077123 YES In vitro protein kinase assay showing that RPK118 has no protein kinase activity. miannu The PSK2 domain of RPK118 is required for binding to SPHK1 as demonstrated by the results from immunoprecipitation analyses (Fig. 6) as well as yeast two-hybrid screening (Fig. 1A). The overexpression of RPK118 in COS7 cells did not cause any change in the intracellular content of SPP with repeated experiments, and RPK118 binding to SPHK1 did not alter the enzymatic activity of SPHK1 in vitro (data not shown), suggesting that RPK118 may function only as an adaptor molecule for SPHK1 0.384 SIGNOR-273744 PFN1 protein P07737 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 18667433 NO areggio  Additionally, the association of Ror2 with the actin-binding protein filamin A is required for Wnt5a-induced JNK activation and polarized cell migration. 0.7 SIGNOR-258977 SP1 protein P08047 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 10669635 NO lperfetto These results suggest that PMA stimulates transcription of the Mn-SOD gene through an increase in Sp1 expression and thus implicate Sp1 as an effector mediating the PKC-signaling pathway elicited by extracellular signals. 0.399 SIGNOR-271693 PTPN2 protein P17706 UNIPROT STAT5B protein P51692 UNIPROT down-regulates activity dephosphorylation 9606 12359225 YES miannu In the previous study, we demonstrated that the nuclear isoform of T-cell protein-tyrosine phosphatase (TC-PTP) dephosphorylated and deactivated signal transducer and activator of transcription 5a (STAT5a) and STAT5b, thereby negatively regulating prolactin (PRL)-mediated signaling pathway. 0.732 SIGNOR-277126 SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 9843571 YES gcesareni TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. 0.711 SIGNOR-235168 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 19056373 YES gcesareni These results indicate that phosphorylation of Gli2 by PKA induces Gli2 processing and destabilization 0.467 SIGNOR-182573 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 10712517 YES gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). 0.624 SIGNOR-75655 AMPK complex SIGNOR-C15 SIGNOR SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation Ser555 AEGERRGsLAFIRSP 9606 BTO:0000195 38047302 YES miannu AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) phosphorylated NHE3 at S555. S555 is the primary site of phosphorylation by protein kinase A (PKA), but AMPK phosphorylated S555 independently of PKA. We conclude that AMPK activation inhibits NHE3 activity and NHE3 inhibition is associated with phosphorylation of NHE3 at S555 and S563. 0.2 SIGNOR-277849 ASXL1 protein Q8IXJ9 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 26470845 YES lperfetto Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals 0.276 SIGNOR-241759 glycine smallmolecule CHEBI:15428 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 18721822 YES miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 0.8 SIGNOR-264985 NAE1 protein Q13564 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 25568892 NO lperfetto Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway 0.7 SIGNOR-251579 GSK3B protein P49841 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser270 KMALTKAsSVASSDK 9606 BTO:0002181 27432879 YES miannu Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser274 0.285 SIGNOR-277244 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 16116087 YES gcesareni We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta. 0.2 SIGNOR-139870 SGK1 protein O00141 UNIPROT WNK4 protein Q96J92 UNIPROT up-regulates activity phosphorylation Ser1201 FPTSRRNsLQRSEPP -1 23054253 YES miannu In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM. 0.416 SIGNOR-276421 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 18394876 YES gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. 0.681 SIGNOR-178190 CENPC protein Q03188 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.663 SIGNOR-265200 FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 BTO:0001271 12681969 YES gcesareni Flt3 is activated by binding of its natural flt3-ligand (flt3-l), 0.884 SIGNOR-99750 RUNX3 protein Q13761 UNIPROT DNASE1 protein P24855 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255092 Protocadherin_alpha proteinfamily SIGNOR-PF100 SIGNOR Protocadherin_beta proteinfamily SIGNOR-PF102 SIGNOR up-regulates activity binding 9606 BTO:0000007 15347688 YES miannu We analyzed the expression of CNR/Pcdhalpha and Pcdhgamma in HEK293T cells and found that they formed a protein complex and that Pcdhgamma enhanced the surface expression of CNR/Pcdhalpha. This enhanced surface expression was confirmed by flow cytometry analysis and by marking cell surface proteins with biotin. The enhancement was observed using different combinations of CNR/Pcdhalpha and Pcdhgamma proteins. The surface expression activity was enhanced by the extracellular domains of the proteins, which could bind each other. Their cytoplasmic domains also had binding activity and influenced their localization. Their protein-protein interaction was also detected in extracts of mouse brain and two neuroblastoma cell lines. Thus, interactions between CNR/Pcdhalpha and Pcdhgamma regulate their surface expression and contribute to the combinatorial diversity of cell recognition proteins in the brain. 0.2 SIGNOR-269036 PTPRJ protein Q12913 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Tyr205 IMLNSKGyTKSIDIW 9606 19494114 YES gcesareni In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo. 0.407 SIGNOR-161536 CDK1 protein P06493 UNIPROT RFC1 protein P35251 UNIPROT down-regulates activity phosphorylation Thr506 KESKLERtPQKNVQG 9534 BTO:0004055 12930972 YES lperfetto Phosphorylation of the PCNA binding domain of the large subunit of replication factor C on Thr506 by cyclin-dependent kinases regulates binding to PCNA|Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. |Phosphorylation of either RF-Cp145 as a part of the RF-C complex or RF-Cp145 domain B by cdk-cyclin kinases inhibits their ability to bind PCNA. 0.246 SIGNOR-265504 SP3 protein Q02447 UNIPROT SOX18 protein P35713 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 18496767 NO miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells 0.284 SIGNOR-254820 SP2 protein Q02086 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates quantity by repression transcriptional regulation 7227 BTO:0001677 10744779 YES Luana Sp3 is an activator, and Sp2 a repressor, of the Ctpct promoter in SL2 cells. 0.2 SIGNOR-266230 AKT proteinfamily SIGNOR-PF24 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 YES lperfetto Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis. 0.2 SIGNOR-244373 TRIM58 protein Q8NG06 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity ubiquitination Lys172 ENWPKTLkLALEKER 23499489 YES lperfetto Specifically, the ubiquitin E3 ligase TRIM25 ubiquitinates K172 in the CARD2 of RIG-I, which is essential for the efficient interaction of RIG-I with MAVS and thereby for antiviral signal transduction  0.2 SIGNOR-264582 RALGDS protein Q12967 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates activity binding 9606 10545207 YES miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. 0.497 SIGNOR-220923 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25901680 NO lperfetto Ribosomes are translational machineries that catalyse protein synthesis. 0.7 SIGNOR-262412 SIRT7 protein Q9NRC8 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275886 CAMKK2 protein Q96RR4 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 19958286 YES gcesareni These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. 0.619 SIGNOR-161929 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TH protein P07101 UNIPROT up-regulates phosphorylation 9606 7901013 YES inferred from 70% family members gcesareni In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11 0.2 SIGNOR-270167 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC7 protein O00311 UNIPROT up-regulates activity phosphorylation Thr376 QVAPRAGtPGFRAPE -1 10846177 YES llicata Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks. 0.468 SIGNOR-250643 ATF2 protein P15336 UNIPROT ST3GAL5 protein Q9UNP4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002335 21699754 NO miannu Our results identified the core promoter region in the hST3Gal V promoter and for the first time demonstrated that ATF2 binding to the CREB/ATF binding site at -143 is essential for transcriptional activation of hST3Gal V in VPA-induced ARPE-19 cells. 0.2 SIGNOR-253745 AMG-208 chemical CHEBI:90626 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189507 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser126 NPEAESSsKEGELDA -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.71 SIGNOR-276115 dexamethasone chemical CHEBI:41879 ChEBI GLUL protein P15104 UNIPROT up-regulates quantity by expression 10090 8099704 NO miannu GS transcripts were measured by laser densitometry and normalized to actin, and GS specific activity was also determined. Following a single injection of dexamethasone (0.5 mg/kg), lung GS activity increased by 40% at 4 hours and by 75% at 8 hours. The dexamethasone-mediated increase in GS activity was associated with a marked increase in GS mRNA levels, which preceded the increase in enzyme activity by approximately 2 hours. 0.8 SIGNOR-267827 GUCY1B1 protein Q02153 UNIPROT GUCY1A3-B3 complex SIGNOR-C140 SIGNOR form complex binding 9606 10977868 YES gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity 0.2 SIGNOR-243986 SKI protein P12755 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 12419246 YES gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad5. 0.698 SIGNOR-195630 hsa-miR-92a-3p mirna URS00001DA458_9606 RNAcentral DKK3 protein Q9UBP4 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000793 21572098 YES Parnian We also documented that the MYCN-regulated miRNAs, miR-92a, mir-92b, efficiently decreased expression of a luciferase reporter containing the 3'UTR sequence from DKK3. 0.4 SIGNOR-278833 TP53 protein P04637 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 NO miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. 0.363 SIGNOR-255434 PPARGC1A protein Q9UBK2 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 20640476 NO Gianni However, in contrast to the role of AMPK, most reports to date indicate that PGC-1a induces gluconeogenesis 0.7 SIGNOR-209932 hsa-miR-148a-3p mirna URS00003BBF48_9606 RNAcentral CDH2 protein P19022 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002745 33026174 NO Parnian MiR-148a-3p overexpression increased the expression of E-cadherin, accompanying decreased N-cadherin and vimentin expression. 0.4 SIGNOR-278853 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity 0.2 SIGNOR-236298 FBXW7 protein Q969H0 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 24820417 YES miannu Fbw7 promotes degradation of GATA3 in a Thr-156-dependent manner.  0.403 SIGNOR-276635 CAPN1 protein P07384 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 YES lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase 0.297 SIGNOR-251586 TFAP4 protein Q01664 UNIPROT NFIA protein Q12857 UNIPROT up-regulates activity binding 9606 BTO:0001109 19505873 YES miannu We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads. 0.267 SIGNOR-226586 ZHX1 protein Q9UKY1 UNIPROT ZMYND11 protein Q15326 UNIPROT down-regulates activity binding 9606 BTO:0000007 17127430 YES miannu Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1. 0.491 SIGNOR-263898 STUB1 protein Q9UNE7 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates quantity by destabilization ubiquitination Lys284 WFCNRRQkGKRSSSD 9606 29511337 YES miannu CHIP overexpression decreased OCT4 stability through proteasomal degradation.|CHIP E3 ligase ubiquitinates OCT4 at lysine 284.|These data suggest that CHIP induces OCT4 ubiquitination and degradation. 0.303 SIGNOR-278562 RAMAC protein Q9BTL3 UNIPROT RNMT protein O43148 UNIPROT up-regulates activity binding 9606 27422871 YES lperfetto Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. 0.2 SIGNOR-268344 STUB1 protein Q9UNE7 UNIPROT CFTR protein P13569 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25879443 YES miannu Our results indicate that the post-endocytic ubiquitination of CFTR by CHIP is a critical step in the peripheral quality control of cell surface DeltaF508 CFTR. 0.471 SIGNOR-278668 NEURL1 protein O76050 UNIPROT JAG1 protein P78504 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26276215 YES miannu We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation.|Jagged1 is also regulated by the E3 ligase Neuralized-like1 (Neurl1), which induces the monoubiquitination of membrane tethered Jagged1 in the C-terminal region. 0.706 SIGNOR-278772 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 YES PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. 0.404 SIGNOR-248344 TOP2B protein Q02880 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 24463367 NO lperfetto Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells 0.7 SIGNOR-242533 TLRs proteinfamily SIGNOR-PF20 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 20404851 NO lperfetto The negative regulation of TLR-induced responses is important for sup- pressing inflammation and deleterious immune responses. 0.7 SIGNOR-216304 PATZ1 protein Q9HBE1 UNIPROT RNF4 protein P78317 UNIPROT down-regulates binding 9606 10713105 YES miannu In vitro and in vivo interaction between rnf4 and patz was demonstrated / patz acted as a transcriptional repressor, whereas its partner rnf4 behaved as a transcriptional activator./ the association of patz with rnf4 switches activation to repression 0.512 SIGNOR-75775 ULK3 protein Q6PHR2 UNIPROT GLI2 protein P10070 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 19878745 YES Manara We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro 0.619 SIGNOR-260798 NAE1 protein Q13564 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000938 25568892 NO lperfetto Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway 0.7 SIGNOR-256651 NOTCH1 protein P46531 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 19165418 YES gcesareni The intracellular part of the notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor rbp-j. 0.95 SIGNOR-183510 SLC9A7 protein Q96T83 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265606 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC3 protein Q9UN70 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265674 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates 9606 15843801 NO gcesareni We have identified a new cell population that expresses the transcription factors pax3 and pax7 (paired box proteins 3 and 7) but no skeletal-muscle-specific markers. 0.7 SIGNOR-135626 DIP2A protein Q14689 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity binding 10090 BTO:0000142 33781892 YES miannu DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain. 0.2 SIGNOR-266591 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates 9606 8069916 NO gcesareni Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. 0.719 SIGNOR-33843 HSD17B11 protein Q8NBQ5 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 YES lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. 0.8 SIGNOR-268666 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr25 APPPQPPtPALPHPP 9606 8846784 YES lperfetto Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation 0.769 SIGNOR-44351 AKT2 protein P31751 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates 9606 17604717 NO gcesareni Several studies have demonstrated that akt signaling can activate the nf-kb transcription factor downstream of a variety of stimuli, such as tumor necrosis factor (tnfalfa) 0.329 SIGNOR-156530 HTR1B protein P28222 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257115 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 UNIPROT up-regulates phosphorylation 9606 18042454 YES miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. 0.2 SIGNOR-159429 RB1 protein P06400 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 NO lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F 0.7 SIGNOR-245483 motesanib chemical CHEBI:51098 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194560 iron(3+) smallmolecule CHEBI:29034 ChEBI SLC40A1 protein Q9NP59 UNIPROT down-regulates quantity relocalization 9606 39534872 YES miannu Fe3+ is taken up by TFRC and exported by SLC40A1. Inside the cell, Fe3+ is reduced to Fe2+, with excess iron stored in ferritin (composed of FTH1 and FTL) or sequestered by MT1G. 0.8 SIGNOR-279857 CCT239065 chemical CID:44131523 PUBCHEM LCK protein P06239 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190910 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017876 YES llicata Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation. 0.659 SIGNOR-176866 DUSP4 protein Q13115 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 YES fstefani We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. . Mkp-2 had detectable activity against jnk2, although full inactivation of jnk2 was not observed even at the higher phosphatase concentration. 0.606 SIGNOR-40929 EEF1A2 protein Q05639 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269536 F2 protein P00734 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 YES gcesareni In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp 0.283 SIGNOR-41090 NEFH protein P12036 UNIPROT Neurofilament bundle assembly phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 8376466 NO miannu Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons. 0.7 SIGNOR-252390 PPM1B protein O75688 UNIPROT PAX2 protein Q02962 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000007 25631048 YES PPM1B can dephosphorylate the Pax2 activation domain and displace the adaptor protein PTIP, thus inhibiting H3K4 methylation and gene activation 0.2 SIGNOR-251712 TAOK2 protein Q9UL54 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000007 12665513 YES lperfetto Transfection studies demonstrated that TAO2 stimulates phosphorylation of the TCF Elk1 on the major activating site, Ser383, and that TAO2 stimulates transactivation of Elk1 and the related TCF, Sap1. 0.31 SIGNOR-246638 DAB2IP protein Q5VWQ8 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR up-regulates activity binding 9606 20080667 YES miannu DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation 0.2 SIGNOR-254753 IL1B protein P01584 UNIPROT KRT1 protein P04264 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17982242 NO Regulation of expression miannu IL-1β alone decreased the expression of E-cadherin and cytokeratin 0.248 SIGNOR-251883 PARD6/SMURF1 complex SIGNOR-C112 SIGNOR RHOA protein P61586 UNIPROT down-regulates ubiquitination 9606 15761148 YES lperfetto The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT. 0.674 SIGNOR-227492 MAP2 protein P11137 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000938 10704996 YES lperfetto MAP2 interacts with MTs through its tubulin-binding domain which mainly associates with the acidic region of the C-terminal region of tubulin|no neurite growth is observed when MAP2 expression is suppressed in neuronal cell cultures after treatment with specific antisense oligonucleotides 0.7 SIGNOR-264837 PDE4DIP protein Q5VU43 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates binding 9606 21569246 YES miannu Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a. 0.316 SIGNOR-173769 SRT1720 chemical CID:25232708 PUBCHEM SIRT1 protein Q96EB6 UNIPROT up-regulates activity chemical activation 9606 18046409 YES Selleck gcesareni Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. 0.8 SIGNOR-207114 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 10480932 YES lperfetto We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta. 0.744 SIGNOR-70607 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257964 RNF216 protein Q9NWF9 UNIPROT TLR8 protein Q9NR97 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31385713 YES miannu E3 ligase RNF216 (ring finger protein 216) targets TLR8 for ubiquitination and degradation.  0.257 SIGNOR-272257 AKT proteinfamily SIGNOR-PF24 SIGNOR CCNF protein P41002 UNIPROT up-regulates activity phosphorylation Thr31 RRRPRNLtILSLPED 9606 BTO:0001938 28954236 YES miannu AKT phosphorylation of cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. 0.2 SIGNOR-266360 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 BTO:0000007 22863277 YES milica The cAMP signaling cascade can activate protein kinase a (PKA) 0.8 SIGNOR-198492 PRKN protein O60260 UNIPROT ZNF746 protein Q6NUN9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000793 21376232 YES miannu . Parkin ubiquitinates and regulates the ubiquitin proteasomal degradation of PARIS  0.2 SIGNOR-272758 PFKFB4 protein Q16877 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification -1 30553771 YES miannu PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species 0.8 SIGNOR-268118 MMP11 protein P24347 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272379 LCK protein P06239 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates phosphorylation Tyr342 NMRPPFTyATLIRWA 9606 24155921 YES llicata Lck phosphorylated tyr-342 of foxp3 by immunoprecipitation and in vitro kinase assay, and the replacement of tyr-342 with phenylalanine (y342f) abolished the ability to suppress mmp9 expression. 0.401 SIGNOR-203089 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR DVL1 protein O14640 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16547521 YES miannu  KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation. 0.428 SIGNOR-271562 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000671 15069075 YES gcesareni Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta. 0.645 SIGNOR-123734 MAP1LC3B protein Q9GZQ8 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 20921139 NO lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation 0.7 SIGNOR-219403 CDKN1A protein P38936 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 24470334 NO The cell cycle regulator p21 is induced early in myoblast differentiation and functions to block cell cycle progression 0.7 SIGNOR-267286 GNA12 protein Q03113 UNIPROT PPP5C protein P53041 UNIPROT up-regulates activity binding 101841 BTO:0000298 12176367 YES Marta Tosoni In this study, we show that active forms of Gna12 and Gna13 specifically interact with PP5 through its TPR domain and activate its phosphatase activity about 2.5-fold. 0.326 SIGNOR-278080 GNA13 protein Q14344 UNIPROT PPP5C protein P53041 UNIPROT up-regulates activity binding 101841 BTO:0000298 12176367 YES Marta Tosoni In this study, we show that active forms of G12 and G13 specifically interact with PP5 through its TPR domain and activate its phosphatase activity about 2.5-fold. Active forms of G12 and G13 also enhance the arachidonic acid-stimulated PP5 phosphatase activity about 2.5-fold. 0.326 SIGNOR-278081 GNA12 protein Q03113 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity binding 9606 BTO:0000007 9796816 YES Marta Tosoni Here we show that Ga12 binds directly to, and stimulates the activity of, Bruton’s tyrosine kinase (Btk) and a Ras GTPase-activating protein, Gap1m, in vitro and in vivo 0.317 SIGNOR-278082 hsa-miR-146a mirna URS00005E1F00_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000815 23647548 YES Results indicated that CXCR4 expression was markedly reduced when miR-146a was over-expressed in MDA-MB-231 cells. 0.4 SIGNOR-277935 AMPD1 protein P23109 UNIPROT adenosine 5'-monophosphate smallmolecule CHEBI:16027 ChEBI down-regulates quantity chemical modification 9606 BTO:0001103 1631143 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. 0.8 SIGNOR-269772 CAMK4 protein Q16566 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates phosphorylation Ser91 RARPRKIsSPTGSKD 9606 BTO:0000887 21689744 YES lperfetto Here we show that calcium/calmodulin-dependent kinase iv (camk iv) specifically binds to the c terminus of phb2 and phosphorylates phb2 at serine 91. Camk iv effectively decreased phb2-mediated repression of mef2 activity through phosphorylation 0.338 SIGNOR-174437 CSNK2A1 protein P68400 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser748 DSEGFEDsFEEEEEE 9606 BTO:0000599 23287549 YES lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. 0.291 SIGNOR-265271 PIM1 protein P11309 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 19911008 YES llicata In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276. 0.2 SIGNOR-189125 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 BTO:0001538 10748061 YES miannu That phosphorylation of serines 77 and 79 by cdk7 could be responsible for efficient transcription was further supported by the observation that overexpressed cdk7 significantly enhanced transcription by hRARγ1WT but not by hRARγ1S77A/S79A (Fig. 9 B).  0.417 SIGNOR-277896 ABL1 protein P00519 UNIPROT VCL protein P18206 UNIPROT up-regulates activity phosphorylation Tyr822 KSFLDSGyRILGAVA 9606 24751539 YES miannu Abl is the tyrosine kinase that phosphorylates vinculin Y822.|Finally we show that Abl inhibition prevents vinculin actions in cadherin containing complexes, resulting in defects in cell stiffening. 0.38 SIGNOR-278464 IGF1R protein P08069 UNIPROT CSK protein P41240 UNIPROT up-regulates 9606 10026153 NO lperfetto The results suggest that c-src and csk are involved in igf-ir and ir signaling and that the interaction of csk with the igf-ir may play a role in the decrease in c-src activity following igf-i stimulation 0.347 SIGNOR-64676 NFIB protein O00712 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268902 CDH9 protein Q9ULB4 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.585 SIGNOR-265871 PPARA protein Q07869 UNIPROT PLIN2 protein Q99541 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 NO miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. 0.546 SIGNOR-255046 ASMT protein P46597 UNIPROT melatonin smallmolecule CHEBI:16796 ChEBI up-regulates quantity chemical modification -1 22775292 YES miannu Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS 0.8 SIGNOR-265475 UBE3A protein Q05086 UNIPROT MCM7 protein P33993 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 9852095 YES miannu The characterization of this interaction in turn led to the discovery that Mcm7 is a substrate for both E6-AP-dependent and -independent ubiquitination and is specifically targeted for degradation by the 26 S proteasome. 0.402 SIGNOR-272543 SND1 protein Q7KZF4 UNIPROT IGFBP3 protein P17936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23878061 NO irozzo Therefore, we concluded that SND1 could affect SMMC-7721 cells proliferation by regulating IGFBP3 expression and IGF signaling pathway. 0.2 SIGNOR-259140 YAP1 protein P46937 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 30348863 NO lperfetto Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. 0.26 SIGNOR-276584 ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 22863277 YES milica To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production. 0.8 SIGNOR-198486 WWTR1 protein Q9GZV5 UNIPROT PAX3 protein P23760 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 16300735 YES gcesareni These results indicate that pax3 specifically interacts with taz both in vitro and in vivo. 0.455 SIGNOR-236879 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser502 YFLQRRPsMKTLFVD 9606 BTO:0000007 11884385 YES lperfetto Direct phosphorylation of capsaicin receptor VR1 by protein kinase Cepsilon and identification of two target serine residues. | Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser(502) and Ser(800) were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP. 0.2 SIGNOR-249141 tyrosine smallmolecule CHEBI:18186 ChEBI L-dopa smallmolecule CHEBI:15765 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). 0.8 SIGNOR-264173 alvocidib chemical CHEBI:47344 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191529 ITGB6 protein P18564 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.489 SIGNOR-257724 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22469984 YES irozzo The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a 0.338 SIGNOR-259360 torin 2 chemical CHEBI:90682 ChEBI RPS6KB1 protein P23443 UNIPROT down-regulates 9606 23436801 NO gcesareni Torin2 inhibited mtorc1-dependent t389 phosphorylation on s6k (rps6kb1) 0.8 SIGNOR-201502 Dihydromorphine chemical CHEBI:4575 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258787 ER stress stimulus SIGNOR-ST9 SIGNOR BID protein P55957 UNIPROT up-regulates 9606 22492984 NO gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins 0.7 SIGNOR-196944 GPER1 protein Q99527 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000130 22203955 YES gcesareni However, grpr preferentially couples to galfaq proteins. 0.2 SIGNOR-195320 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity precursor of 9606 16939420 YES miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. 0.8 SIGNOR-267080 SLC34A1 protein Q06495 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 BTO:0000671 20335586 YES lperfetto Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa, 0.8 SIGNOR-270576 CDK5 protein Q00535 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates quantity phosphorylation Ser75 RQAFQIGsPWRTMDA 9606 29948941 YES miannu Cdk5 Phosphorylates ALDH1A1 at S75 and S274.|These results demonstrate that Cdk5 increases ALDH1A1 levels in neurotoxin exposed neuronal cells both at transcriptional level and by direct phosphorylation at S75 and S274 sites. 0.2 SIGNOR-279400 EFNA5 protein P52803 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9330863 YES gcesareni Highly promiscuous for ephrin-a ligands it binds preferentially efna5 and became active. 0.943 SIGNOR-52470 PKA proteinfamily SIGNOR-PF17 SIGNOR VASP protein P50552 UNIPROT up-regulates activity phosphorylation 9606 15066263 YES miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts 0.2 SIGNOR-268286 BMPR1B protein O00238 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates activity phosphorylation 9606 19620713 YES lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.707 SIGNOR-255264 ATR protein Q13535 UNIPROT PALB2 protein Q86YC2 UNIPROT up-regulates activity phosphorylation 9606 28089683 YES miannu ATR promotes PALB2 accumulation at DNA damage sites.|In the context of PALB2 regulation, the phosphorylation of PALB2 by ATR plays a positive role in PALB2 recruitment. 0.307 SIGNOR-279588 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity phosphorylation Ser970 HSQCLNSsPLSHHSQ 9606 11369754 YES lperfetto These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994. 0.454 SIGNOR-108257 CDK8 protein P49336 UNIPROT MED13 protein Q9UHV7 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 29212878 YES miannu Here, cyclin C-Cdk8 phosphorylation of Med13 most likely primes the phosphodegron for destruction. 0.901 SIGNOR-279687 PAK1 protein Q13153 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 YES gcesareni Phosphorylation of either ser(16) by pak1 or ser(27) by pkc decreased the affinity of galpha(z) for gbetagamma;phosphorylation of both residues by pkc caused no further effect. Pak1 thus regulates galpha(z) function by attenuating the inhibitory effects of both gaps and gbetagamma. 0.2 SIGNOR-48673 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCE protein Q02156 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191496 PPP2CA protein P67775 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates dephosphorylation 9606 20626350 YES lperfetto In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a. 0.558 SIGNOR-244941 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 YES lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 0.8 SIGNOR-265112 HIPK2 protein Q9H2X6 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 YES gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. 0.494 SIGNOR-158616 TP53INP1 protein Q96A56 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22421968 YES gcesareni Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir). 0.348 SIGNOR-196670 Caspase 7 complex complex SIGNOR-C232 SIGNOR PARP1 protein P09874 UNIPROT down-regulates cleavage 9606 11058599 YES amattioni Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis. 0.718 SIGNOR-256470 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.6 SIGNOR-34657 F2R protein P25116 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 22318735 YES gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13). 0.4 SIGNOR-196009 CSNK2A1 protein P68400 UNIPROT EIF4G2 protein P78344 UNIPROT up-regulates activity phosphorylation Ser902 ETAEEEEsEEEAD 9606 BTO:0000007 29530922 YES miannu DAP5(S902) is phosphorylated by CK2α. Phosphorylation of DAP5(S902) by CK2α is required for eIF2β binding. 0.226 SIGNOR-266384 AKT1 protein P31749 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity 9606 BTO:0000222 BTO:0000887;BTO:0001103 10896679 NO lperfetto Two candidates that may function as mediators of pi3-k in the phosphorylation of mef2 proteins are pkb and big map kinase 1. 0.551 SIGNOR-79335 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR PECAM1 protein P16284 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17442773 NO miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The platelet endothelial cell adhesion molecule PECAM1 is also downregulated by NUP98‐HOXA9. 0.2 SIGNOR-261500 NEK2 protein P51955 UNIPROT CDC20 protein Q12834 UNIPROT up-regulates activity phosphorylation 9606 20034488 YES miannu In summary, we have demonstrated that Nek2 can associate with and phosphorylate Mad2 and Cdc20.|The results presented here support a model in which Nek2 modulates the functions of Mad2 and Cdc20 in the mitotic checkpoint and elevation of Nek2 levels may contribute to chromosome instability by interfering with the control of the checkpoint. 0.945 SIGNOR-278366 CCL25 protein O15444 UNIPROT ACKR4 protein Q9NPB9 UNIPROT up-regulates activity binding 9606 BTO:0001938 23341447 YES Luana  In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines. 0.663 SIGNOR-268418 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 1159081 YES inflammation gcesareni 0.8 SIGNOR-251697 BRCA1 protein P38398 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 15549093 NO lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination 0.7 SIGNOR-267282 STAT1 protein P42224 UNIPROT IL12A protein P29459 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 19029990 NO lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. 0.545 SIGNOR-249499 JAK1 protein P23458 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23124025 YES lperfetto IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes 0.764 SIGNOR-249531 PD318088 chemical CID:10231331 PUBCHEM MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205737 PTPN13 protein Q12923 UNIPROT EFNB1 protein P98172 UNIPROT up-regulates activity dephosphorylation 9606 23811940 YES lperfetto Loss of PTPN13 function increases EFNB1 phosphorylation, enhances EFNB1 's interaction with ERBB1 and correlates with potentiated ERK1/2 activation.|Moreover, acquisition of PTPN13 loss-of-function mutations or its decreased expression (due to HPV infection or epigenetic silencing) may further enhance ERBB1 and EFNB1 mediated signals. 0.708 SIGNOR-277002 regorafenib chemical CHEBI:68647 ChEBI RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206418 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 BTO:0000782 15735151 YES gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 0.917 SIGNOR-134219 olaparib chemical CHEBI:83766 ChEBI PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-195019 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser11 KTKRTADsSSSEDEE 9606 21245376 YES gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. 0.367 SIGNOR-171695 CDK1 protein P06493 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 YES gcesareni Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1. 0.512 SIGNOR-252890 EGFR protein P00533 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr136 GDCCYEEyKDRKREN 9606 BTO:0000007 22198508 YES miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. 0.2 SIGNOR-276397 HCRT protein O43612 UNIPROT HCRTR2 protein O43614 UNIPROT up-regulates binding 9606 9491897 YES gcesareni Identification and initial biological characterization of two orexins as well as their two receptors 0.775 SIGNOR-55848 RCAN1 protein P53805 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR down-regulates activity binding 9606 12554096 YES MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure 0.606 SIGNOR-252341 BTRC protein Q9Y297 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR form complex binding 9606 10023660 YES gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. 0.824 SIGNOR-64496 GLI2 protein P10070 UNIPROT OLIG2 protein Q13516 UNIPROT up-regulates quantity transcriptional regulation 9606 NBK6142 NO SimoneGraziosi Therefore, Gli2 activity regulates the late phase of Olig2 gene expression in the ventral neuroepithelium and its subsequent production of OPC cells. 0.355 SIGNOR-269219 CHKB protein Q9Y259 UNIPROT O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI up-regulates quantity chemical modification 29928787 YES lperfetto In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells. 0.8 SIGNOR-275639 CLOCK protein O15516 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.777 SIGNOR-253634 E2F1 protein Q01094 UNIPROT PPARG protein P37231 UNIPROT up-regulates transcriptional regulation 9606 12110166 NO During clonal expansion fspada We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation 0.46 SIGNOR-210047 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser729 ASPQSPEsVDLVNEE 9606 11604491 YES llicata Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728. 0.57 SIGNOR-111047 PPP1R1B protein Q9UD71 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity binding 9606 BTO:0000938 10604473 YES miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  0.598 SIGNOR-264957 coenzyme Q10 smallmolecule CHEBI:46245 ChEBI ubiquinol smallmolecule CHEBI:17976 ChEBI up-regulates quantity precursor of 9606 30449682 YES miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway 0.8 SIGNOR-267429 SH3RF1 protein Q7Z6J0 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 YES gcesareni We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2. 0.31 SIGNOR-96952 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 YES lperfetto Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro. 0.2 SIGNOR-114094 MEF2D protein Q14814 UNIPROT MYH10 protein P35580 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.323 SIGNOR-238766 SP1 protein P08047 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9148896 NO lperfetto These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport. 0.359 SIGNOR-241485 KDM6A protein O15550 UNIPROT HOXA5 protein P20719 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.271 SIGNOR-260023 Caspase 6 complex complex SIGNOR-C228 SIGNOR LMNA protein P02545 UNIPROT down-regulates cleavage 9606 11058599 YES amattioni Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis. 0.661 SIGNOR-256457 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr751 SKDESVDyVPMLDMK 9606 18567737 YES gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. 0.69 SIGNOR-179076 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser111 KESLRSRsTRMSTVS 9606 17567953 YES lperfetto Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres. 0.73 SIGNOR-155894 TWIST1 protein Q15672 UNIPROT CSNK2A1 protein P68400 UNIPROT down-regulates 9606 22975381 NO amattioni Ck2-mediated phosphorylation at ser392 of p53 was attenuated in the presence of recombinant twist1 0.2 SIGNOR-192064 LRRK2 protein Q5S007 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation 9606 28553204 YES miannu LRRK2 Directly Phosphorylates RCAN1. 0.371 SIGNOR-278340 SNARE_complex complex SIGNOR-C346 SIGNOR Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 30267828 NO miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. 0.7 SIGNOR-265065 DCC protein P43146 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 BTO:0001484 25881791 NO miannu DCC constitutively expresses on the axonal surface. Netrin-1-binding to DCC induces chemoattraction 0.7 SIGNOR-268163 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 11781100 YES lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. 0.309 SIGNOR-249140 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 SIGNOR-C3 17510057 YES lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. 0.926 SIGNOR-154810 E2F1 protein Q01094 UNIPROT MT1G protein P13640 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000394 15735762 NO lperfetto The E2F transcription factors induce the expression of many genes in response to specific extracellular stimuli. Here, we show that human metallothionein 1G (hMT1G) promoter is upregulated by E2F1 upon VEGF stimulation of human aortic endothelial cells. 0.333 SIGNOR-254132 IL1R1 protein P14778 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 NO lperfetto The Il-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. 0.7 SIGNOR-171876 CYC-116 chemical CID:6420138 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191224 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 11390389 YES lperfetto C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1 0.385 SIGNOR-86017 CDC20 protein Q12834 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates activity binding 9606 BTO:0000567 19822757 YES lperfetto Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity 0.872 SIGNOR-265082 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT up-regulates activity phosphorylation Tyr136 EDDDANSyENVLICK 10090 BTO:0001930 14722116 YES miannu Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases. 0.591 SIGNOR-273576 TBK1 protein Q9UHD2 UNIPROT NUMA1 protein Q14980 UNIPROT up-regulates activity phosphorylation 9606 26656453 YES miannu Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells. 0.2 SIGNOR-278432 BAK1 protein Q16611 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 11175253 YES Translocation from Mitochondria to Cytosol amattioni Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux 0.564 SIGNOR-105206 PTEN protein P60484 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0001332 19903340 NO lperfetto PTEN-mediated suppression of the PI3K/AKT pathway is well established, accumulating evidence suggests that nuclear PTEN also plays a critical role in tumor suppression 0.635 SIGNOR-244439 MAPK8 protein P45983 UNIPROT DCX protein O43602 UNIPROT up-regulates activity phosphorylation 9606 21477071 YES miannu DCX phosphorylation by JNK1 is required for glioma suppression. 0.286 SIGNOR-279217 NFATC1 protein O95644 UNIPROT IL2 protein P60568 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10022916 YES Barakat Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses. 0.566 SIGNOR-275405 SELENOF protein O60613 UNIPROT UGGT2 protein Q9NYU1 UNIPROT up-regulates activity binding 9606 24415556 YES miannu The enzymatic activity of UGGT2 is enhanced by complex formation with Sep15 0.2 SIGNOR-261373 AMG 900 chemical CID:24856041 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189498 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000876 SIGNOR-C14 SIGNOR-C13 15611276 YES lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. 0.847 SIGNOR-132568 E2F1 protein Q01094 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22832221 NO gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. 0.678 SIGNOR-198470 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates activity binding 9606 BTO:0000567 10929711 YES amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. 0.914 SIGNOR-80218 ketanserin chemical CHEBI:6123 ChEBI SLC18A1 protein P54219 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000318 8643547 YES miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. 0.8 SIGNOR-258493 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 YES We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell 0.481 SIGNOR-254365 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT down-regulates activity phosphorylation Ser176 ERLKKMLsEGSVGEV -1 18480293 YES miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation 0.2 SIGNOR-262686 MYOD1 protein P15172 UNIPROT SMARCD3 protein Q6STE5 UNIPROT up-regulates binding 9606 15870273 YES lperfetto This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion 0.539 SIGNOR-136130 IL7 protein P13232 UNIPROT IL7R protein P16871 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 20089933 YES milica This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain. 0.914 SIGNOR-163548 PJA2 protein O43164 UNIPROT PRKAR1B protein P31321 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 YES miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits 0.2 SIGNOR-271857 NTRK1 protein P04629 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates binding 9606 BTO:0000938 15082760 YES lperfetto The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons. 0.539 SIGNOR-124198 PP121 chemical CHEBI:50915 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206295 (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol chemical CHEBI:94701 ChEBI RRM2 protein P31350 UNIPROT down-regulates activity chemical inhibition -1 7048062 YES miannu In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase 0.8 SIGNOR-258405 AVP protein P01185 UNIPROT BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 BTO:0000142 18402937 NO gcesareni Vp induces phosphorylation of the pro-apoptotic protein bad and prevents cytochrome c release. 0.2 SIGNOR-178197 2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine chemical CHEBI:91330 ChEBI ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191094 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207669 ULK2 protein Q8IYT8 UNIPROT PRKAB1 protein Q9Y478 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 YES gcesareni Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity 0.33 SIGNOR-173092 MK-2461 chemical CID:44137946 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194367 QRICH1 protein Q2TAL8 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 33384352 NO miannu QRICH1 promotes cell death and its translation is upregulated by the PERK-eIF2α axis under ER stress. 0.7 SIGNOR-269399 sapitinib chemical CHEBI:132986 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190149 masitinib chemical CHEBI:63450 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194257 WAY-600 chemical CID:25229526 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;ATP-competitive inhibitor mTOR gcesareni 0.8 SIGNOR-207788 CRP protein P02741 UNIPROT LPL protein P06858 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18708524 NO Regulation of expression miannu C-reactive protein enhances macrophage lipoprotein lipase expression. 0.372 SIGNOR-251852 ERBB4 protein Q15303 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.319 SIGNOR-146888 alvocidib chemical CHEBI:47344 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192038 ezogabine chemical CHEBI:68584 ChEBI KCNQ2 protein O43526 UNIPROT up-regulates chemical activation 9606 Other YES Selleck;anticonvulsant for KCNQ2/3 currents gcesareni 0.8 SIGNOR-206483 PIDD1 protein Q9HB75 UNIPROT Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR form complex binding 9606 20158568 YES miannu The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2. 0.849 SIGNOR-262643 CASP3 protein P42574 UNIPROT DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 10200555 NO amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation 0.7 SIGNOR-66863 PIK-75 Hydrochloride chemical CID:45265864 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252652 UBAP2 protein Q5T6F2 UNIPROT ANXA2 protein P07355 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0002181 27121050 YES Sara UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination 0.341 SIGNOR-261314 Elongator complex complex SIGNOR-C466 SIGNOR TUBA8 protein Q9NY65 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 YES miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 0.252 SIGNOR-269721 PHA-848125 chemical CID:16718576 PUBCHEM CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206148 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192780 DUSP4 protein Q13115 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 16849326 YES gcesareni This result suggests that dusp4 represses gluconeogenesis through dephosphorylation of p38 0.664 SIGNOR-147958 GW 3965 chemical CHEBI:79995 ChEBI NR1H3 protein Q13133 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193015 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11404076 YES gcesareni We find that Notch 3 IC, like Notch 1 IC, can bind the SKIP and PCAF proteins 0.6 SIGNOR-108499 rosiglitazone chemical CHEBI:50122 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 7768881 YES An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma) 0.8 SIGNOR-251646 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 12167711 YES gcesareni Hypophosphorylation of mdm2 augments p53 stability. 0.346 SIGNOR-91195 ADIPOR1 protein Q96A54 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 16622416 YES milica Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. 0.75 SIGNOR-146212 NODAL protein Q96S42 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0004094 15531507 NO Regulation miannu Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7. 0.7 SIGNOR-251935 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 9606 27563484 NO ggiuliani Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression. 0.593 SIGNOR-255836 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A12 protein P48065 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207031 PHA-767491 chemical CID:11715767 PUBCHEM CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206112 PF-03814735 chemical CID:49830590 PUBCHEM PTK2 protein Q05397 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205959 NOD2 protein Q9HC29 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18079694 NO miannu Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase. 0.37 SIGNOR-252412 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 23583303 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.476 SIGNOR-201687 SP6 protein Q3SY56 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates quantity by repression transcriptional regulation 19088080 NO lperfetto Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2. 0.309 SIGNOR-271695 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194563 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation 9606 21808241 YES inferred from 70% family members gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. 0.2 SIGNOR-270218 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 YES milica Both il-4 and il-13 use the IL-4R Chain as a component of their receptors. 0.896 SIGNOR-100753 SOX2 protein P48431 UNIPROT NR2E1 protein Q9Y466 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22194602 NO miannu Sox2 positively regulates tlx expression 0.374 SIGNOR-191714 dacomitinib chemical CHEBI:132268 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205942 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 10812968 YES amattioni Signal transduction by cntf requires that it bind first to cntfr alpha. Cntf activates downstream signaling molecules 0.791 SIGNOR-77408 TRPC6 protein Q9Y210 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates activity 9606 27383564 NO gcesareni TRPC6 channel-dependent [Ca2+]i elevation and sequential activation of the calcineurin. 0.2 SIGNOR-253328 AMOTL2 protein Q9Y2J4 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0001176 21937427 NO lperfetto Taking together, our data indicate that Amotl2 plays a pivotal role in polarity, migration and proliferation of angiogenic endothelial cells. 0.7 SIGNOR-271872 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 12393875 YES gcesareni Lpa-induced rac activation requires tiam1 0.749 SIGNOR-94691 FOS protein P01100 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 10090 2516828 YES The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities. 0.952 SIGNOR-252087 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 YES apalma Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh. 0.2 SIGNOR-255891 GTF3C6 protein Q969F1 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 YES lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains 0.868 SIGNOR-266183 MIB1 protein Q86YT6 UNIPROT DLL3 protein Q9NYJ7 UNIPROT up-regulates activity ubiquitination 9606 16140393 YES lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. 0.35 SIGNOR-209672 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 NO Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 0.7 SIGNOR-268016 GNAI3 protein P08754 UNIPROT TNFAIP8 protein O95379 UNIPROT up-regulates activity binding 9606 20607800 YES TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation 0.2 SIGNOR-256490 seliciclib chemical CHEBI:45307 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206568 NFIL3 protein Q16649 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 10090 BTO:0003104 10082541 NO lperfetto the effect of NFIL3 on cytokine-mediated cell survival was independent of an effect on cell proliferation. 0.7 SIGNOR-242760 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 9804834 YES llicata Casein kinase II catalyzes a mitotic phosphorylation on threonine 1342 of human DNA topoisomerase IIalpha 0.597 SIGNOR-250966 Telatinib chemical CID:9808844 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207221 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline chemical CHEBI:91387 ChEBI BMPR1A protein P36894 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193642 MTX1 protein Q13505 UNIPROT SAM complex complex SIGNOR-C422 SIGNOR form complex binding 31387448 YES lperfetto The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. 0.697 SIGNOR-267684 GSK1059615 chemical CHEBI:71955 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192693 RHEB protein Q15382 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity binding -1 25660019 YES Luana Rheb GTPase directly binds and activates PERK in vitro 0.2 SIGNOR-260873 HIP1 protein O00291 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 11007801 NO miannu Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain. 0.7 SIGNOR-256646 TNFAIP3 protein P21580 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 18164316 YES lperfetto A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6 0.701 SIGNOR-160223 CENPE protein Q02224 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity 10090 BTO:0000452 12925705 NO lperfetto CENP-E is required for efficient recruitment of BubR1, Mad1, and Mad2 to attached and newly unattached kinetochores 0.635 SIGNOR-252044 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates chemical inhibition 9606 19759537 YES gcesareni Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2. 0.8 SIGNOR-188054 RASSF5 protein Q8WWW0 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates activity binding 9606 22195963 YES lperfetto NORE1A can heterodimerize with RASSF1A and, thus, mediate K-Ras regulation of RASSF1A 0.542 SIGNOR-249587 TGFB1 protein P01137 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 19114990 YES lperfetto While association of the TGF_RI receptor with p85 requires TGF-_ stimulation. 0.258 SIGNOR-217960 3-(3-oxo-1H-indol-2-ylidene)-1H-indol-2-one chemical CHEBI:92322 ChEBI GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193402 IGF1R protein P08069 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 10471495 YES flangone Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway. 0.801 SIGNOR-70477 TGFB1 protein P01137 UNIPROT RNF111 protein Q6ZNA4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14657019 NO lpetrilli Expression of arkadia is down-regulated by tgf-beta. 0.2 SIGNOR-119669 IL1A protein P01583 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 NO lperfetto Interleukin-1 in the pathogenesis and treatment of inflammatory diseases 0.7 SIGNOR-171873 GLS protein O94925 UNIPROT Glutaminolysis phenotype SIGNOR-PH119 SIGNOR up-regulates activity 9606 28053289 NO Glutaminase is the rate-limiting enzyme in glutaminolysis and it is encoded by two different genes, GLS and GLS2. 0.7 SIGNOR-259999 A5/b1 integrin complex SIGNOR-C163 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity 15721307 NO lperfetto Previous reports indicated that the prosurvival signal mediated through α5β1-fibronectin interactions was due to increased Bcl-2 levels 0.2 SIGNOR-253310 SNS-314 Mesylate chemical CID:24995523 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207102 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 20663147 YES gcesareni Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. 0.843 SIGNOR-167152 APOC3 protein P02656 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 9606 17315402 NO Regulation miannu Apolipoprotein CIII inhibits the lipoprotein lipase. 0.645 SIGNOR-251850 AGPAT3 protein Q9NRZ7 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 12401205 YES gcesareni Pa can be generated by the acylation of lyso-pa by lyso-pa acyl transferases 0.8 SIGNOR-94864 MPO-ANCA complex SIGNOR-C474 SIGNOR ROS stimulus SIGNOR-ST2 SIGNOR up-regulates -1 2161532 NO lperfetto ANCA-induced release of ROS measured by chemiluminescence. 0.7 SIGNOR-270590 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser359 SPSTPVGsPQGLAGT 9606 19801649 YES llicata Mlk2 inhibits e47 transactivation activity on the trkb promote 0.2 SIGNOR-161531 F2 protein P00734 UNIPROT F2RL2 protein O00254 UNIPROT up-regulates binding 9606 11356985 YES gcesareni as noted previously, the human form of par-3 activated phosphoinositide signaling in response to thrombin when overexpressed in cos-7 cells 0.652 SIGNOR-108225 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT up-regulates binding 9606 1698556 YES gcesareni We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor. 0.934 SIGNOR-21193 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IL10 protein P22301 UNIPROT up-regulates quantity 10090 BTO:0004732 26208884 NO The mitogen activated protein kinases ERK1/2 play an important role in response to toll like receptor (TLR) activation and cytokine production, including IL-10 and IL-12. 0.2 SIGNOR-256080 regorafenib chemical CHEBI:68647 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206415 GSK690693 chemical CHEBI:90677 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193000 STC2 protein O76061 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 10090 BTO:0000298 29207625 NO lperfetto STC2 activates STAT3 signaling pathway in the hypothalamus and GT1-7 cells 0.2 SIGNOR-260406 Brivanib alaninate chemical CID:11154925 PUBCHEM FGFR2 protein P21802 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190720 seliciclib chemical CHEBI:45307 ChEBI CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206565 SKP1 protein P63208 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR form complex binding 9606 10023660 YES gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. 0.895 SIGNOR-64514 ARSA protein P15289 UNIPROT HBA1 protein P69905 UNIPROT up-regulates activity acetylation 9606 237937 YES Regulation miannu ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction. 0.2 SIGNOR-251773 6-[difluoro-[6-(1-methyl-4-pyrazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline chemical CHEBI:91417 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193522 orantinib chemical CHEBI:91088 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207441 PI-103 chemical CHEBI:90524 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206163 GDF2 protein Q9UK05 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 19175684 NO gcesareni Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs 0.255 SIGNOR-183535 MK-2461 chemical CID:44137946 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194384 LRIG1 protein Q96JA1 UNIPROT LRIG3 protein Q6UXM1 UNIPROT down-regulates 9606 23723069 NO miannu Lrig1 destabilizes lrig3, limiting lrig3's positive effects on receptors and identifying lrig3 as a new target of lrig1. 0.434 SIGNOR-202177 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation 9606 20626350 YES gcesareni Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e. 0.778 SIGNOR-166646 MET protein P08581 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 8662889 YES gcesareni To efficiently promote transformation met requires direct binding with grb2. 0.27 SIGNOR-42358 Tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate chemical CID:46907787 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 20871596 YES Simone Vumbaca JQ1 displaces BRD4 from nuclear chromatin in cells 0.8 SIGNOR-261123 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 BTO:0000567 12637538 YES Abl Phosphorylates and Activates PKD through Tyr463 Phosphorylation 0.34 SIGNOR-251430 COL2A1 protein P02458 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates binding 9606 9685391 YES gcesareni We have isolated a novel collagen type ii binding integrin, a10b1, 0.488 SIGNOR-59349 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 12408982 YES gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. 0.417 SIGNOR-95242 SGI-1776 chemical CID:24795070 PUBCHEM PIM3 protein Q86V86 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206896 BUB1 protein O43683 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 20888775 NO gcesareni The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac) 0.7 SIGNOR-168192 6-propyl-2-thiouracil smallmolecule CHEBI:8502 ChEBI DIO1 protein P49895 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001379 27347897 YES scontino The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU). 0.8 SIGNOR-267280 CUL4A protein Q13619 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 YES lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes 0.9 SIGNOR-154502 CCT129202 chemical CID:16202152 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190880 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22972936 YES milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. 0.564 SIGNOR-199010 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207248 CADM2 protein Q8N3J6 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 BTO:0000962 17967169 NO Gianni The adhesion molecule Necl-3/SynCAM-2 localizes to myelinated axons, binds to oligodendrocytes and promotes cell adhesion. 0.7 SIGNOR-268856 progesterone smallmolecule CHEBI:17026 ChEBI COMT protein P21964 UNIPROT down-regulates 17138778 NO Regulation of expression miannu Catechol-O-methyltransferase expression was down-regulated by progesterone or estrogen. 0.8 SIGNOR-251960 CHIR-124 chemical CID:11502647 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190973 dacomitinib chemical CHEBI:132268 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205939 FOXO3 protein O43524 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 15109499 NO gcesareni Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. 0.7 SIGNOR-241949 CDK18 protein Q07002 UNIPROT RB1 protein P06400 UNIPROT unknown phosphorylation -1 28361970 YES lperfetto Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro.  0.287 SIGNOR-264558 R406 chemical CID:11984591 PUBCHEM SYK protein P43405 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206340 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194913 GSK256066 chemical CID:9827968 PUBCHEM PDE4B protein Q07343 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192982 LHX2 protein P50458 UNIPROT CGA protein P01215 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 7513049 YES Luana In Cos cells, LH-2 activated the a-subunit promoter approximately twofold 0.266 SIGNOR-266055 LTBR protein P36941 UNIPROT Lymphoma phenotype SIGNOR-PH14 SIGNOR up-regulates 9606 17633025 NO lperfetto The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense. 0.7 SIGNOR-156902 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser143 PPFPSRDsGRLSPDL 9606 21658950 YES miannu Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis 0.2 SIGNOR-262656 NUMA1 protein Q14980 UNIPROT TUBB protein P07437 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.402 SIGNOR-116900 SFPQ protein P23246 UNIPROT LMX1B/SFPQ/PSPC1 complex complex SIGNOR-C106 SIGNOR form complex binding 10090 23308148 YES miannu LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo. 0.447 SIGNOR-223970 CSNK2A2 protein P19784 UNIPROT HNRNPC protein P07910 UNIPROT unknown phosphorylation Ser260 SEGGADDsAEEGDLL -1 12564933 YES llicata Protein kinase CK2 phosphorylates hnRNP-C1/C2 at S247 0.327 SIGNOR-251007 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207606 A6/b1 integrin complex SIGNOR-C164 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269013 Caspase 3 complex complex SIGNOR-C221 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 NO amattioni Caspase-3 is responsible for apoptosis execution 0.7 SIGNOR-256474 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190224 OGT protein O15294 UNIPROT PYGL protein P06737 UNIPROT up-regulates activity glycosylation Ser430 VDRLRRMsLIEEEGS 9606 BTO:0002181 34939084 YES Luana O-GlcNAcylation at Ser-430 promotes PYGL activity 0.2 SIGNOR-267988 PPP1R2 protein P41236 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates binding 9606 18250156 YES gcesareni Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1. 0.785 SIGNOR-160651 NCOR2 protein Q9Y618 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 YES Ncor2 is a Skip corepressor gcesareni Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt. 0.59 SIGNOR-74227 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193531 HDAC1 protein Q13547 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 17183360 YES gcesareni Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1. 0.572 SIGNOR-151425 AKT1 protein P31749 UNIPROT PRKACA protein P17612 UNIPROT up-regulates 9606 BTO:0000938 16537363 NO gcesareni Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation. 0.252 SIGNOR-252490 MAPK8 protein P45983 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 YES gcesareni Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. 0.308 SIGNOR-173417 Arry-380 chemical CID:42598643 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189882 PTPRB protein P23467 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 21454675 YES fstefani Expression of rptp-beta inhibits both mek1/2 and erk1/2 phosphorylation. 0.383 SIGNOR-173000 imatinib methanesulfonate chemical CHEBI:31690 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193393 pelitinib chemical CHEBI:38927 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205755 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 20068082 YES gcesareni Azd7762 is equally potent against chk2 in vitro. 0.8 SIGNOR-163119 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT unknown phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 YES lperfetto Dapk phosphorylates camkks511 was identified as the phosphorylation site 0.283 SIGNOR-126245 IL7 protein P13232 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 20089933 YES milica This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain. 0.709 SIGNOR-163545 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr465 GEEELSNyICMGGKG 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). 0.868 SIGNOR-157738 EIF4A2 protein Q14240 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR form complex binding 9606 BTO:0000671 11408474 YES miannu Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f. 0.816 SIGNOR-108512 CEBPA protein P49715 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity binding 9606 BTO:0004116 7862113 YES irozzo Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study. 0.317 SIGNOR-255701 nintedanib chemical CHEBI:85164 ChEBI FLT4 protein P35916 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190302 NEK2 protein P51955 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation 9606 15161910 YES esanto Nek2 directly phosphorylated nek11 in the c-terminal non-catalytic region and elevated nek11 kinase activity. 0.394 SIGNOR-124944 AMPK complex SIGNOR-C15 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 12065600 YES lperfetto Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro. 0.392 SIGNOR-216639 WNT1 protein P04628 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 11448771 YES gcesareni Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd) 0.724 SIGNOR-109250 APRT protein P07741 UNIPROT adenine smallmolecule CHEBI:16708 ChEBI down-regulates quantity chemical modification 9606 15196008 YES miannu In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP) SIGNOR-280464 APRT protein P07741 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 15196008 YES miannu In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP) SIGNOR-280465 APRT protein P07741 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 15196008 YES miannu In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP) SIGNOR-280466 APRT protein P07741 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 15196008 YES miannu In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP) SIGNOR-280467 adenine smallmolecule CHEBI:16708 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 15196008 YES miannu In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP) SIGNOR-280468 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 15196008 YES miannu In mammals, adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) is present in all tissues and provides the only known mechanism for the metabolic salvage of adenine resulting from the polyamine biosynthesis pathway or from dietary sources. Phosphoribosyltransferases (PRTases) catalyze the displacement of a PRPP α-1‘-pyrophosphate through a nitrogen-containing nucleophile. The reaction products are a β-1-substituted ribose 5‘-phosphate and a free pyrophosphate (PP) SIGNOR-280469 HPRT1 protein P00492 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280470 HPRT1 protein P00492 UNIPROT guanine smallmolecule CHEBI:16235 ChEBI down-regulates quantity chemical modification 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280471 HPRT1 protein P00492 UNIPROT guanosine 5'-monophosphate(2-) smallmolecule CHEBI:58115 ChEBI up-regulates quantity chemical modification 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280472 guanine smallmolecule CHEBI:16235 ChEBI guanosine 5'-monophosphate(2-) smallmolecule CHEBI:58115 ChEBI up-regulates quantity precursor of 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280473 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI guanosine 5'-monophosphate(2-) smallmolecule CHEBI:58115 ChEBI up-regulates quantity precursor of 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280474 HPRT1 protein P00492 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280475 HPRT1 protein P00492 UNIPROT hypoxanthine smallmolecule CHEBI:17368 ChEBI down-regulates quantity chemical modification 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280476 AMPD1 protein P23109 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI down-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280480 AMPD1 protein P23109 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280481 AMPD1 protein P23109 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI up-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280483 AMPD2 protein Q01433 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI down-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280485 AMPD2 protein Q01433 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280486 AMPD2 protein Q01433 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI up-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280488 AMPD3 protein Q01432 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI down-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280490 AMPD3 protein Q01432 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280491 AMPD3 protein Q01432 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI up-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280493 HPRT1 protein P00492 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280477 hypoxanthine smallmolecule CHEBI:17368 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280478 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 10338013 YES miannu Hypoxanthine phosphoribosyltransferase @HGPRTase; EC 2.4.2.8; hypoxanthine pyrophosphate phosphoribosyltransferase# is a purine salvage enzyme that catalyzes the reversible transfer of the 5-phosphoribosyl group between a-d-5-phosphoribosyl-1- pyrophosphate ~PRPP! and a purine base ~hypoxanthine or guanine! to form a purine nucleotide @inosine monophosphate ~IMP! or guanosine monophosphate ~GMP!#. SIGNOR-280479 AMPD1 protein P23109 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280482 AMP smallmolecule CHEBI:456215 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280484 AMPD2 protein Q01433 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280487 AMP smallmolecule CHEBI:456215 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280489 AMPD3 protein Q01432 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280492 AMP smallmolecule CHEBI:456215 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 26321268 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. SIGNOR-280494 MAPDA protein Q6DHV7 UNIPROT N(6)-methyl-AMP(2-) smallmolecule CHEBI:144842 ChEBI down-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280495 MAPDA protein Q6DHV7 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280496 MAPDA protein Q6DHV7 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280497 MAPDA protein Q6DHV7 UNIPROT methylammonium smallmolecule CHEBI:59338 ChEBI up-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280499 N(6)-methyl-AMP(2-) smallmolecule CHEBI:144842 ChEBI methylammonium smallmolecule CHEBI:59338 ChEBI up-regulates quantity precursor of 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280500 MAPDA protein Q6DHV7 UNIPROT N(6)-methyl-dAMP(2-) smallmolecule CHEBI:169976 ChEBI down-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280501 MAPDA protein Q6DHV7 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280502 MAPDA protein Q6DHV7 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280503 MAPDA protein Q6DHV7 UNIPROT methylammonium smallmolecule CHEBI:59338 ChEBI up-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280504 MAPDA protein Q6DHV7 UNIPROT 2'-deoxyinosine 5'-phosphate(2-) smallmolecule CHEBI:61194 ChEBI up-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280505 N(6)-methyl-dAMP(2-) smallmolecule CHEBI:169976 ChEBI 2'-deoxyinosine 5'-phosphate(2-) smallmolecule CHEBI:61194 ChEBI up-regulates quantity precursor of 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group.  SIGNOR-280506 1-(2,4-difluorophenyl)-3-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-fluorophenyl]urea chemical CHEBI:92822 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193573 MAPDA protein Q6DHV7 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 29884623 YES miannu We show that Arabidopsis thaliana and human cells require an N6-mAMP deaminase (ADAL, renamed MAPDA) to catabolize N6-mAMP to inosine monophosphate in vivo by hydrolytically removing the aminomethyl group. SIGNOR-280498 IL4 protein P05112 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 YES milica IL-4R Is a 140-kd protein that binds il-4 with high affinity 0.942 SIGNOR-100762 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral down-regulates activity chemical activation 9606 BTO:0000599 25965999 NO Parnian We found that treatment of HepG2 cells with LPA (12 h) moderately reduced miR-122 levels SIGNOR-280507 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 10542297 YES lperfetto Stat3 activation requires kinase function of tyk2. 0.686 SIGNOR-71781 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI PTGER4 protein P35408 UNIPROT up-regulates chemical activation 9606 15299086 YES gcesareni Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4. 0.8 SIGNOR-127789 NUMA1 protein Q14980 UNIPROT TUBA1A protein Q71U36 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.431 SIGNOR-116640 hsa-miR-155-5p mirna URS0000338542_9606 RNAcentral AGTR1 protein P30556 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003041 22525818 YES Parnian Functional studies have shown that miR-155 could directly bind to the 3′UTR of AGTR1 mRNAs and repress translation of AGTR1. 0.4 SIGNOR-277995 PTPN1 protein P18031 UNIPROT STAT5A protein P42229 UNIPROT down-regulates activity dephosphorylation Tyr694 LAKAVDGyVKPQIKQ 9534 10993888 YES A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b 0.675 SIGNOR-248428 58131-57-0 chemical CID:42640 PUBCHEM MDM4 protein O15151 UNIPROT down-regulates activity chemical inhibition -1 21075910 YES miannu Here we report the identification of a benzofuroxan derivative [7-(4-methylpiperazin-1-yl)-4-nitro-1-oxido-2,1,3-benzoxadiazol-1-ium, NSC207895] that could inhibit MDMX expression in cancer cells through a reporter-based drug screening. 0.8 SIGNOR-262246 MLL2 complex complex SIGNOR-C88 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.2 SIGNOR-268800 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 YES lperfetto Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. 0.954 SIGNOR-53576 hsa-miR-493-5p mirna URS0000077AED_9606 RNAcentral RHOC protein P08134 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001345 22057916 YES MiR-493 is a new tumor suppressor microRNA in bladder cancer and inhibits cell motility through down-regulation of RhoC and FZD4. 0.4 SIGNOR-277956 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 NO lperfetto During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2) 0.7 SIGNOR-272975 Benzofuro(3,2-d)pyrimidin-4(3H)-one, 8-chloro-2-((2S)-2-pyrrolidinyl)- chemical CID:135564632 PUBCHEM CDC7 protein O00311 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000179 22560567 YES Federica In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413. 0.8 SIGNOR-261105 PGR protein P06401 UNIPROT ESR1 protein P03372 UNIPROT up-regulates binding 9606 BTO:0000150 12612073 YES gcesareni Here we identify two domains of prb, erid-i and -ii, mediating a direct interaction with the ligand-binding domain of eralpha. 0.623 SIGNOR-98807 ECHS1 protein P30084 UNIPROT trans-dec-2-enoyl-CoA smallmolecule CHEBI:10723 ChEBI down-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280366 ECHS1 protein P30084 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280367 ECHS1 protein P30084 UNIPROT (S)-3-hydroxydecanoyl-CoA smallmolecule CHEBI:28325 ChEBI up-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280368 trans-dec-2-enoyl-CoA smallmolecule CHEBI:10723 ChEBI (S)-3-hydroxydecanoyl-CoA smallmolecule CHEBI:28325 ChEBI up-regulates quantity precursor of 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280369 PRCC protein Q92733 UNIPROT MAD2L2 protein Q9UI95 UNIPROT up-regulates relocalization 9606 15218244 YES miannu We found that the human papillary renal cell carcinoma-associated proteinprccinteracts with the cell cycle control proteinmad2b, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function. 0.497 SIGNOR-126516 HES5 protein Q5TA89 UNIPROT NEUROG1 protein Q92886 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 NO lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 0.406 SIGNOR-265141 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.2 SIGNOR-275951 IKBKB protein O14920 UNIPROT TARDBP protein Q13148 UNIPROT down-regulates quantity by destabilization phosphorylation Thr8 MSEYIRVtEDENDEP 9606 BTO:0002181 38197897 YES miannu IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. 0.2 SIGNOR-277861 PRKCA protein P17252 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 YES lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. 0.469 SIGNOR-249083 PAX5 protein Q02548 UNIPROT BZLF1 protein P03206 UNIPROT down-regulates activity binding 9606 BTO:0000776 23678172 YES Gianni ... we demonstrate that Pax5 inhibits Z-mediated lytic viral gene expression and the release of infectious viral particles in latently infected epithelial cell lines. Conversely, we found that shRNA-mediated knockdown of endogenous Pax5 in a Burkitt lymphoma B-cell line leads to viral reactivation. Furthermore, we show that Pax5 reduces Z activation of early lytic viral promoters in reporter gene assays and inhibits Z binding to lytic viral promoters in vivo. We confirm that Pax5 and Z directly interact SIGNOR-269082 ACAA2 protein P42765 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI down-regulates quantity chemical modification 9606 38656551 YES miannu Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial β oxidation, which plays an important role in fatty acid metabolism. 0.8 SIGNOR-280388 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2G protein Q13555 UNIPROT up-regulates chemical activation 9606 22944199 YES lperfetto Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell). 0.8 SIGNOR-198816 TRAF6 protein Q9Y4K3 UNIPROT IL1R1 protein P14778 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19232518 YES miannu We found that of all TRAFs and E3 ligases examined, TRAF6 preferentially ubiquitinated IL-1R1. 0.9 SIGNOR-278576 acetoacetyl-CoA(4-) smallmolecule CHEBI:57286 ChEBI acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity precursor of 9606 31268215 YES miannu The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2  0.8 SIGNOR-280428 PI4K2B protein Q8TCG2 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269100 SRC protein P12931 UNIPROT PLEKHG2 protein Q9H7P9 UNIPROT unknown phosphorylation Tyr489 SEPVKDPyVMFPQNA 9606 BTO:0000007 24378532 YES miannu Through deletion and base substitution mutagenesis we have identified Tyr489 of PLEKHG2 as the site phosphorylated by cSrc.Furthermore, PLEKHG2 is tyrosine phosphorylated at Tyr489 by ephrinB2 receptor signaling via cSrc. Investigation of the physiological function of tyrosine phosphorylation at Tyr489 in PLEKHG2 remains a subject for future studies. 0.2 SIGNOR-273537 PTPRR protein Q15256 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 11711538 YES gcesareni As shown, gst-ptp-sl dephosphorylated efficiently both erk2 and p38 wild typetogether, these results indicate that the defective association of the tyrosine phosphatase ptp-sl with erk2 d319n and p38 d316n mutations impairs the retention and inactivation in the cytosol of these map kinases by ptp-sl. 0.557 SIGNOR-111762 PHF8 protein Q9UPP1 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 33511404 YES miannu TopBP1 Interacts with PHF8 through residue R1314 of TopBP1. Importantly, PHF8 regulates TopBP1 protein level by preventing its ubiquitination and degradation mediated by the E3 ligase UBR5. 0.2 SIGNOR-273657 hsa-miR-30d-5p mirna URS000005CF5F_9606 RNAcentral BECN1 protein Q14457 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001611 24345332 YES parnian MiR-30d down-regulates beclin 1 expression by directly targeting its 3′-UTR. 0.4 SIGNOR-280433 hsa-miR-29a-5p mirna URS0000076995_9606 RNAcentral ATP1B1 protein P05026 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001248 22330642 YES parnian The progestin downregulated miRNA miR-29a targets the ATP1B1 3’UTR 0.4 SIGNOR-280434 hsa-miR-542-3p mirna URS00004F859B_9606 RNAcentral FZD7 protein O75084 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 27815069 YES parnian These results strongly indicated that miR-542-3p inhibited HCC cell growth by targeting the Wnt signaling pathway and by directly inhibiting FZD7. 0.4 SIGNOR-280435 CTNNB1 protein P35222 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0001950 15480989 NO parnian These observations suggest that the Wnt/β-catenin signal transduction pathway is involved much more commonly in the molecular pathogenesis of HCC than previously recognized because FZD7 overexpression occurred early in the disease process, stabilized wild-type β-catenin levels, and contributed to enhanced tumor cell migration. 0.7 SIGNOR-280436 WNT3 protein P56703 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 9606 BTO:0001950 18313787 YES parnian These experiments suggest that activation of the Wnt/β-catenin pathway by Wnt3 is mediated in part through FZD7 in HCC cells. 0.743 SIGNOR-280437 GNA12 protein Q03113 UNIPROT hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 25965999 NO parnian Our data indicates that Gα12 overexpressed in liver cancer mostly greatly dysregulates the expression of miR-122. 0.4 SIGNOR-280438 GNA12 protein Q03113 UNIPROT MET protein P08581 UNIPROT up-regulates activity 9606 BTO:0000599 25965999 NO parnian All of these results indicate that increased levels of Gα12 causes the induction of c-Met by deregulating miR-122. 0.2 SIGNOR-280439 SLC15A1 protein P46059 UNIPROT muramyl dipeptide smallmolecule CHEBI:59414 ChEBI up-regulates activity binding 9606 BTO:0005156 15521010 YES Tiberia HPepT1 transports muralyl dipeptide (MDP), activating NF-kB. 0.8 SIGNOR-280445 PLK1 protein P53350 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity phosphorylation Ser467 DSPVFEDsKAKPEQR 9606 27579997 YES miannu As illustrated in , the turnover of nuclear SREBP1a was attenuated in the presence of Plk1, confirming that Plk1 stabilizes nuclear SREBP1 by reducing its degradation.|Figure 2.Plk1 phosphorylates threonine 424, serine 467 and serine 486 in nuclear SREBP1 during mitosis. (A) In vitro kinase assay with recombinant nuclear SREBP1a and Plk1. 0.442 SIGNOR-279382 muramyl dipeptide smallmolecule CHEBI:59414 ChEBI NOD2 protein Q9HC29 UNIPROT up-regulates activity binding 9606 BTO:0000182 23275943 YES Tiberia MDP can activate several immune signaling pathways, including the NOD2-dependent pathway, through a specific interaction between NOD2 and MDP, resulting in nuclear factor-κB (NF-κB) activation. 0.8 SIGNOR-280446 muramyl dipeptide smallmolecule CHEBI:59414 ChEBI TLR2 protein O60603 UNIPROT up-regulates activity binding 9606 BTO:0004297 38510686 YES Tiberia The bacterial cell wall MDP (PGN) is a well-established Toll-like receptor 2 (TLR2) ligand, as demonstrated by the fact that TLR2-deficient mice display defective proinflammatory cytokine responses against PGN. 0.8 SIGNOR-280447 SLC18A2 protein Q05940 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 YES miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. 0.8 SIGNOR-269197 WNT5B protein Q9H1J7 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 BTO:0000551;BTO:0000848 16273260 YES gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. 0.635 SIGNOR-141440 CTDSP1 protein Q9GZU7 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates activity dephosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000007 26975371 YES gcesareni These results indicate that SCP1 is the phosphatase that counter-regulates the MAPK-mediated phosphorylation of S68-Twist1. 0.2 SIGNOR-245962 SMARCC2 protein Q8TAQ2 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.835 SIGNOR-270708 GZMA protein P12544 UNIPROT SET protein Q01105 UNIPROT down-regulates cleavage 9606 11555662 YES miannu Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity. 0.71 SIGNOR-110462 HOOK2 protein Q96ED9 UNIPROT CNTRL protein Q7Z7A1 UNIPROT up-regulates binding 9606 17140400 YES miannu Hook2 localizes to the centrosome, binds directly to centriolin/cep110 and contributes to centrosomal function 0.353 SIGNOR-150956 JARID2 protein Q92833 UNIPROT GATA4 protein P43694 UNIPROT down-regulates activity binding 10116 BTO:0003324 15542826 YES miannu JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4. 0.457 SIGNOR-224697 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR JUN protein P05412 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14739464 YES miannu We report that human DET1 (hDET1) promotes ubiquitination and degradation of the proto-oncogenic transcription factor c-Jun by assembling a multisubunit ubiquitin ligase containing DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A), Regulator of Cullins-1 (ROC1), and constitutively photomorphogenic-1.  Ablation of any subunit by RNA interference stabilized c-Jun and increased c-Jun-activated transcription. 0.371 SIGNOR-271500 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.278 SIGNOR-276085 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 22124607 YES lperfetto Moreover, we reported that TCPTP knockdown in PTP1B deficient MEFS further enhanced IR activation, consistent with the two PTPs acting in a coordinated manner to attenuate insulin signalling .|Therefore, the inhibition of PTPs such as PTP1B that attenuate IR activation and signalling might be particularly effective in alleviating insulin resistance.|The prototypic family member PTP1B (encoded by PTPN1) dephosphorylates the IR beta subunit Y1162 and Y1163 activation loop autophosphorylation site to attenuate insulin signalling in vivo . 0.788 SIGNOR-276946 PRKD1 protein Q15139 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 20179209 YES lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated 0.307 SIGNOR-163920 ABL2 protein P42684 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates activity phosphorylation 9606 15886098 YES miannu These findings suggested that RIN1 is phosphorylated by both ABL1 and ABL2. 0.615 SIGNOR-279676 SLC15A4 protein Q8N697 UNIPROT muramyl dipeptide smallmolecule CHEBI:59414 ChEBI up-regulates activity relocalization 9606 BTO:0005025 28450278 NO Tiberia SLC15A4 regulate MDP transport via bacterial ligands internalized endosomes. 0.8 SIGNOR-280448 XIAP protein P98170 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity ubiquitination Lys61 PLLDSERkDVLREAE 9606 BTO:0000567 31350258 YES Tiberia XIAP is the essential E3 for RIPK2 ubiquitination and interacts with RIPK2 through its baculoviral IAP-repeat (BIR). 0.627 SIGNOR-280449 MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 9606 BTO:0005937 39619146 YES Tiberia MyD88 recruits and activates IL-1 receptor-associated kinase-1 (IRAK-1), which subsequently leads to the activation of TNF receptor-associated factor 6 (TRAF6). 0.847 SIGNOR-280450 LUBAC complex SIGNOR-C527 SIGNOR RIPK2 protein O43353 UNIPROT up-regulates activity polyubiquitination Lys61 PLLDSERkDVLREAE 9606 BTO:0005096 33935757 YES Tiberia RIPK2 is subjected to N-terminal methionine (Met1)-linked polyubiquitination by LUBAC after the interaction between RIPK2 and XIAP. Thus, K63-linked polyubiquitination and recruitment of LUBAC are indispensable steps for NF-κB activation by RIPK2. 0.533 SIGNOR-280451 CCN2 protein P29279 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 18528331 YES gcesareni Igfbp-4 physically interacted with a wnt receptor, frizzled 8 (frz8), and a wnt co-receptor, low-density lipoprotein receptor-related protein 6 (lrp6), and inhibited the binding of wnt3a to frz8 and lrp6. 0.2 SIGNOR-178875 NOD2 protein Q9HC29 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 24670424 NO Tiberia NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression 0.384 SIGNOR-280463 STAT3 protein P40763 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26512963 NO miannu DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. 0.625 SIGNOR-254762 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Tyr259 KGRFAEVyKAKLKQN -1 9169454 YES lperfetto Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor. 0.2 SIGNOR-48859 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.288 SIGNOR-276090 SNAI2 protein O43623 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 20509143 NO miannu SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. 0.417 SIGNOR-255151 DYRK1A protein Q13627 UNIPROT SRSF2 protein Q01130 UNIPROT down-regulates activity phosphorylation 9606 21470964 YES miannu Dyrk1A inhibits SC35\u2032s activity to promote tau exon 10 inclusion.|Dyrk1A interacts with and phosphorylates SC35 and inhibits its activity to promote tau exon 10 inclusion. 0.408 SIGNOR-278307 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM43 protein Q96BQ3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271208 FAM162A protein Q96A26 UNIPROT VDAC1 protein P21796 UNIPROT up-regulates activity binding 9606 BTO:0001061 15082785 YES Giulio HGTD-P was coprecipitated with VDAC but not with ANT or cyclophilin D (Fig. 7A, left upper panel).|However, it is not clear at present whether HGTD-P participates directly in channel formation in association with VDAC or modulates its channel-forming activity. 0.2 SIGNOR-260293 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr86 YTLSRAQtVVVEYTH 9606 12496252 YES lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation 0.767 SIGNOR-96759 BMP4 protein P12644 UNIPROT BMP4 protein P12644 UNIPROT up-regulates binding 9606 11178121 YES lperfetto Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is anabsolute requirement for the biological action and interaction with receptors 0.2 SIGNOR-236169 PTEN protein P60484 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 22482061 YES lperfetto Antisense- or shRNA mediated downregulation of PTEN induced SRC Tyr416 phosphorylation, SRC activation, and ultimately elevated TZMB resistance, whereas induction of PTEN phosphatase activity directly dephosphorylated SRC Tyr416 residue and so abolished SRC activity .|These observations indicate that the loss of PTEN phosphatase activity induces SRC activation and so implicates SRC in shaping de novo TZMB resistance in PTEN deficient cells . 0.537 SIGNOR-277009 DYRK1B protein Q9Y463 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0000165;BTO:0000222;BTO:0001946 BTO:0000887;BTO:0001760 15851482 NO lperfetto Mirk diminishes the extent of myoblast apoptosis during the differentiation process, at least in part by direct modulation of p21cip1 localization. 0.7 SIGNOR-235731 PPM1F protein P49593 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation 9606 28906490 YES miannu However, our current work shows that POPX2 can downregulate TAK1 and affect the anti-apoptotic activities of TAK1, implying that silencing POPX2 could facilitate TAK1 activation and will lead to increased cell survival.|We have also demonstrated that POPX2 can directly dephosphorylate TAK1 (XREF_FIG). 0.396 SIGNOR-277047 SMARCAD1 protein Q9H4L7 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity binding 9606 21549307 YES 1 miannu SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin 0.504 SIGNOR-239838 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF2 protein Q12933 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270988 SAGA complex complex SIGNOR-C465 SIGNOR H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269633 N-[4-[(4-Ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[(E)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)ethenyl]-4-methylbenzamide chemical CID:53302361 PUBCHEM BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 32069833 YES lperfetto HG6-64-1 is a specific BRAF inhibitor 0.8 SIGNOR-261986 S1PR1 protein P21453 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257108 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Ser2 sPKRIAKR -1 15014043 YES miannu Human RCC1 is phosphorylated on Ser 2 and Ser 11 in mitosis by Cdc2 kinase. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. 0.505 SIGNOR-262701 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263816 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 YES The effect has been demonstrated using Q01196-8 gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.2 SIGNOR-138936 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser309 DSLSPVAsLPKQIFQ 25855382 YES lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant 0.376 SIGNOR-275560 PLK3 protein Q9H4B4 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser62 SSSGTLSsLETVSTQ -1 16481012 YES miannu Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.  0.659 SIGNOR-276052 RLF protein Q13129 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates activity binding 9606 10545207 YES miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. 0.2 SIGNOR-220920 ARVCF protein O00192 UNIPROT CDH5 protein P33151 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.344 SIGNOR-252129 RPL6 protein Q02878 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.876 SIGNOR-262456 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.552 SIGNOR-89150 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258006 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 BTO:0000007 10191262 YES lperfetto This is followed by the ptdins(3,4,5)p3-independent phosphorylation at thr256 that activates sgk, and is catalysed by pdk1 0.649 SIGNOR-236796 GAS6 protein Q14393 UNIPROT TYRO3 protein Q06418 UNIPROT up-regulates binding 9606 7867073 YES gcesareni We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. 0.571 SIGNOR-34414 TACR1 protein P25103 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.302 SIGNOR-257048 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1766 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248814 NLGN4Y protein Q8NFZ3 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.2 SIGNOR-264148 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 8376365 YES gcesareni Phosphorylation at either ser(16) or ser(63) strongly reduced or abolished the ability of stathmin to bind to and sequester soluble tubulin and its ability to act as a catastrophe factor by directly binding to the microtubules. The known in vivo phosphorylation sites of stathmin are ser-16 and ser-63 for cyclic amp-dependent protein kinase (pka). 0.31 SIGNOR-38318 CRYAB protein P02511 UNIPROT CRYGD protein P07320 UNIPROT up-regulates activity binding -1 20621668 YES miannu Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age. 0.521 SIGNOR-253621 CSNK2A1 protein P68400 UNIPROT RGS19 protein P49795 UNIPROT unknown phosphorylation Ser24 ADRPPSMsSHDTASP -1 10760275 YES llicata Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles. 0.33 SIGNOR-250943 CUDC-101 chemical CID:24756910 PUBCHEM HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262265 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 14967450 YES gcesareni Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4. 0.746 SIGNOR-121953 KPNA3 protein O00505 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 YES gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. 0.325 SIGNOR-254321 TSPAN33 protein Q86UF1 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates activity binding 10116 30463011 YES Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. 0.484 SIGNOR-261251 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1069 EDSFLQRySSDPTGA -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.482 SIGNOR-254699 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG -1 11955436 YES β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC) 0.894 SIGNOR-260015 BMX protein P51813 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity phosphorylation Tyr389 TKVELETyKQTRQGL 9534 11877430 YES miannu Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes. 0.633 SIGNOR-262678 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0001271 23431171 YES lperfetto We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression 0.495 SIGNOR-217198 GATAD2A protein Q86YP4 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.833 SIGNOR-263846 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser242 NQRKAKRsLAPRFDL 9606 11152499 YES tpavlidou We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity. 0.2 SIGNOR-85765 ANXA3 protein P12429 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001109;BTO:0000038 30998268 NO miannu ANXA3 downregulation evidently increased the apoptosis of HCT116 (Figure 2C) and SW480 (Figure 2D) cells, and Ox‐induced cell apoptosis was further aggravated by ANXA3 suppression. 0.7 SIGNOR-262208 NTRK3 protein Q16288 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000938 10092678 YES gcesareni We demonstrate that the phosphotyrosine binding domain of frs-2 directly binds the trk receptors at the same phosphotyrosine residue that binds the signaling adapter shc, suggesting a model in which competitive binding between frs-2 and shc regulates differentiation versus proliferation. 0.732 SIGNOR-65958 PPP5C protein P53041 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity dephosphorylation Ser338 RPRGQRDsSYYWEIE -1 16892053 YES Protein phosphatase 5 (PP5) was identified as an inactivator that associates with Raf-1 on growth factor stimulation and selectively dephosphorylates an essential activating site, Ser 338. The PP5-mediated dephosphorylation of Ser 338 inhibited Raf-1 activity and downstream signalling to MEK 0.461 SIGNOR-248537 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1619 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248735 cholesterol smallmolecule CHEBI:16113 ChEBI pregnenolone smallmolecule CHEBI:16581 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 YES lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. 0.8 SIGNOR-268629 fenoterol chemical CHEBI:149226 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1).  0.8 SIGNOR-257869 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49 protein P0CI25 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271152 ABL1 protein P00519 UNIPROT STH protein Q8IWL8 UNIPROT up-regulates activity phosphorylation 9606 21769920 YES miannu STH interacts with tau and Abl, and Abl phosphorylates STH on its single tyrosine residue. 0.2 SIGNOR-279353 MTAP protein Q13126 UNIPROT adenine smallmolecule CHEBI:16708 ChEBI up-regulates quantity chemical modification 9606 3091600 YES miannu The reaction catalyzed by the enzyme is fully reversible with a Keq of 1.39 X 10(-2) (in the direction of phosphorolysis) at 37 degrees C and pH 7.4. The Km values for 5'-methylthioadenosine, phosphate, adenine, and 5-methylthioribose 1-phosphate are 5, 320, 23, and 8 microM, respectively. 0.8 SIGNOR-278890 TFEB protein P19484 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Notably, TFEB regulates genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (for example, Cd36 and Fabps), and the β-oxidation of FFA in mitochondria (for example, Cpt1, Crat, Acadl, Acads and Hdad) and in peroxisomes (Cyp4a genes). 0.277 SIGNOR-276706 IRAK1 protein P51617 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 15465816 YES gcesareni Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation. 0.551 SIGNOR-129685 lysophosphatidylserine 14:0(1-) chemical CHEBI:72402 ChEBI P2RY10 protein O00398 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257558 Complement C1q complex SIGNOR-C308 SIGNOR Complement C1 complex complex SIGNOR-C309 SIGNOR form complex binding -1 29449492 YES lperfetto The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases 0.629 SIGNOR-263396 F2R protein P25116 UNIPROT LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 BTO:0000007 22972936 NO milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. 0.2 SIGNOR-192048 RPL37 protein P61927 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.837 SIGNOR-262463 PRKACA protein P17612 UNIPROT ITPKA protein P23677 UNIPROT up-regulates activity phosphorylation Ser121 LQQPRRLsTSSVSST -1 9374536 YES miannu Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328 0.327 SIGNOR-249994 hsa-miR-92b-5p mirna URS00001A7F58_9606 RNAcentral DKK3 protein Q9UBP4 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000793 21572098 YES Parnian We also documented that the MYCN-regulated miRNAs, miR-92a, mir-92b, efficiently decreased expression of a luciferase reporter containing the 3'UTR sequence from DKK3. 0.4 SIGNOR-278834 KLF2 protein Q9Y5W3 UNIPROT RELN protein P78509 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21530336 YES Luana KLF2 transactivates the reelin promoter in K562 cells. 0.2 SIGNOR-266048 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR2 protein P30874 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257582 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr1006 PATPLLDyALEVEKI 9606 BTO:0000007 32420483 YES done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. 0.265 SIGNOR-274107 pregnenolone smallmolecule CHEBI:16581 ChEBI progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 2243100 YES lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. 0.8 SIGNOR-268630 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 YES gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. 0.738 SIGNOR-90529 SMURF1 protein Q9HCE7 UNIPROT ENTR1 protein Q96C92 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272705 HOXA10 protein P31260 UNIPROT MYLK protein Q15746 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002196 15886193 YES Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively 0.2 SIGNOR-261643 MLNR protein O43193 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256880 DOK1 protein Q99704 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.297 SIGNOR-257681 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Thr63 LSSAWPGtLRSGMVP 9606 22721717 YES lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation 0.307 SIGNOR-197949 TP53 protein P04637 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19879762 YES lperfetto As a transcription factor, p53 induces several pro-apoptotic Bcl-2 members including Bax, Puma, Noxa and Bid, and represses the transcription of certain anti-apoptotic genes, including those encoding Bcl-2, Bcl-xL and survivin 3_and_5. 0.26 SIGNOR-209687 CLTC protein Q00610 UNIPROT AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.745 SIGNOR-260670 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates activity transcriptional regulation 9606 12244043 NO areggio Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes 0.638 SIGNOR-254987 CAMK2D protein Q13557 UNIPROT TPD52 protein P55327 UNIPROT unknown phosphorylation Ser176 KNSPTFKsFEEKVEN 9606 20032513 YES gcesareni Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation 0.2 SIGNOR-162630 serotonin smallmolecule CHEBI:28790 ChEBI HTR7 protein P34969 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264289 HIF-1 complex complex SIGNOR-C418 SIGNOR SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 YES miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 0.411 SIGNOR-267450 F2RL2 protein O00254 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257146 ACOT8 protein O14734 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271810 LYN protein P07948 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation Tyr383 IHTGDRPyVCPFDGC 9606 BTO:0002181 26198631 YES miannu In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B). 0.2 SIGNOR-276928 CCNA1 protein P78396 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 15829981 NO lperfetto Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth. 0.7 SIGNOR-249637 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258819 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 9606 15262992 YES lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. 0.265 SIGNOR-126859 UBIAD1 protein Q9Y5Z9 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity binding 9606 BTO:0000362 30518913 YES miannu This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. 0.2 SIGNOR-256206 DDR1 protein Q08345 UNIPROT CXCL5 protein P42830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003303 34237033 NO miannu  We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. 0.2 SIGNOR-277731 MAPK8 protein P45983 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 BTO:0000782 14517246 YES gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter. 0.751 SIGNOR-118217 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser671 RKRSTRRsVRGSQAQ 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.2 SIGNOR-272509 MDGA2 protein Q7Z553 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26206665 NO miannu Enhanced protein expression of p53 and p21 by MDGA2 was confirmed in MDGA2 overexpressed cells and xenograft tumours. 0.2 SIGNOR-264241 H2BC11 protein P06899 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 YES miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. 0.2 SIGNOR-263710 SIK1 protein P57059 UNIPROT CRTC3 protein Q6UUV7 UNIPROT down-regulates phosphorylation Ser162 SALNRTNsDSALHTS 9606 BTO:0000007;BTO:0000567 16817901 YES miannu These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities. 0.418 SIGNOR-147703 EAPP protein Q56P03 UNIPROT MAOB protein P27338 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980443 NO miannu we identified two novel transcriptional repressors of MAO B, E2F-associated phosphoprotein (EAPP) and R1 (RAM2/CDCA7L/JPO2), that down-regulate MAO B via MAO B core promoter, which contains Sp1 sites. 0.2 SIGNOR-253867 PRPF4 protein O43172 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.71 SIGNOR-270622 TRIM25 protein Q14258 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys7 kTYKYICR 9606 BTO:0000007 22626058 YES K48 miannu We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling.  0.769 SIGNOR-272041 SFN protein P31947 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity relocalization 9606 BTO:0005079 27073720 YES Verteporfin increases the level of 14-3-3σ, which promotes the translocation of YAP from nucleus to cytoplasm. 0.461 SIGNOR-278130 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003725 11439327 YES miannu We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line. 0.539 SIGNOR-272577 SMURF1 protein Q9HCE7 UNIPROT ANXA6 protein P08133 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272681 PTPN22 protein Q9Y2R2 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity dephosphorylation 9606 28786745 YES miannu Further, this explains how loss of PTPN22 and subsequent enhanced NLRP3 phosphorylation mediate a decrease in NLRP3 inflammasome activation.|Upon NLRP3 activation, PTPN22 dephosphorylates NLRP3 and thereby protects it from degradation, allowing robust inflammasome activity (summarized in Fig.S6). 0.356 SIGNOR-277056 MACF1 protein Q9UPN3 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000938 16815997 NO gcesareni In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes. 0.436 SIGNOR-147451 KCNE3 protein Q9Y6H6 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 YES miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height 0.8 SIGNOR-265589 AKT proteinfamily SIGNOR-PF24 SIGNOR VIM protein P08670 UNIPROT up-regulates quantity by stabilization phosphorylation Ser39 TTSTRTYsLGSALRP 9606 20856200 YES llicata The binding of akt (tail region) to vim (head region) results in vim ser39 phosphorylation enhancing the ability of vim to induce motility and invasion while protecting vim from caspase-induced proteolysis. 0.2 SIGNOR-167971 ZBTB7A protein O95365 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15662416 NO miannu Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. 0.367 SIGNOR-225900 GSK3B protein P49841 UNIPROT CABYR protein O75952 UNIPROT unknown phosphorylation Thr151 PATPKTTtPPSSPPP -1 15752768 YES GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated. 0.401 SIGNOR-251224 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1166 QKGSHQIsLDNPDYQ 9606 BTO:0000007 10347170 YES llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  0.371 SIGNOR-250624 TMED10 protein P49755 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 16641999 YES gcesareni Here we report that tmp21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage 0.651 SIGNOR-146364 SIRT7 protein Q9NRC8 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity deacetylation Lys18 LESDTAMkKGETLRK 28790157 YES lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. 0.26 SIGNOR-275901 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC3R protein P41968 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.2 SIGNOR-268706 PYCARD protein Q9ULZ3 UNIPROT Pyrin inflammasome complex SIGNOR-C226 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.716 SIGNOR-256414 Ionizing radiation stimulus SIGNOR-ST16 SIGNOR ELE1-RET fusion protein SIGNOR-FP10 SIGNOR up-regulates 9606 23128507 NO miannu In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents 0.7 SIGNOR-251984 SRC protein P12931 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Tyr773 DTANNPLyKEATSTF 9606 BTO:0003904 11723131 YES lperfetto The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength. 0.66 SIGNOR-247202 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 19573809 NO lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth 0.791 SIGNOR-252704 ASB2 protein Q96Q27 UNIPROT FLNA protein P21333 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 18799729 YES miannu ASB2 is the specificity subunit of an E3 ubiquitin ligase complex and is proposed to exert its effects by regulating the turnover of specific proteins; however, no ASB2 substrates had been identified. Here, we report that ASB2 targets the actin-binding proteins filamin A and B for proteasomal degradation.  0.443 SIGNOR-271740 PAX7/MLL1 complex complex SIGNOR-C90 SIGNOR MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 NO miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.492 SIGNOR-198638 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 NO Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. 0.7 SIGNOR-254374 NAE complex SIGNOR-C131 SIGNOR CUL4A protein Q13619 UNIPROT up-regulates activity neddylation 9606 25504797 YES lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. 0.624 SIGNOR-243160 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser272 RPRSKSQsSSNCSNP -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251290 CDK5 protein Q00535 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 YES lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. 0.2 SIGNOR-198115 RIOK1 protein Q9BRS2 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 28499923 NO miannu Furthermore, we show that RIOK1 activates NF-κB signaling and promotes cell cycle progression. 0.2 SIGNOR-278897 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser660 FSAERRNsILTETLH -1 1377674 YES miannu CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795. 0.484 SIGNOR-250349 ASCL1 protein P50553 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 24243019 NO lperfetto Here we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1|Accordingly, Ascl1-mutant mice show severe defects in neurogenesis 0.7 SIGNOR-265174 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21881539 NO lperfetto Concomitant attenuation of NR1D1 downregulation (-2.4-fold compared with -4.1-fold in placebo; P=0.04), a transcriptional repressor of ARNTL, supported the view that ramipril might modulate glucose homeostasis pathways involving the NR1D1 ARNTL axis. 0.669 SIGNOR-253719 Enolase proteinfamily SIGNOR-PF74 SIGNOR 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI down-regulates quantity chemical modification 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266531 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser768 DEAYVMAsVDNPHVC 9606 BTO:0000007 10347170 YES llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  0.371 SIGNOR-250625 PRKACA protein P17612 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.286 SIGNOR-262750 NEK1 protein Q96PY6 UNIPROT ME1 protein P48163 UNIPROT down-regulates activity phosphorylation Ser336 KKIWLVDsKGLIVKG 31735643 YES lperfetto PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. 0.2 SIGNOR-275570 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 19153083 YES gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation 0.726 SIGNOR-183480 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 23863160 NO lperfetto In mammals, two protein complexes, namely the ULK1/Atg13/FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin/Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. 0.7 SIGNOR-209907 F2RL1 protein P55085 UNIPROT RARG protein P13631 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254858 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 17251915 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp 0.2 SIGNOR-152814 CID 132010322 chemical CID:132010322 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 31969702 YES Monia ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 0.8 SIGNOR-261102 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys636 EITFLDAkKSLNLNI 9606 BTO:0000007 28448495 YES miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 0.2 SIGNOR-272802 NR2E3 protein Q9Y5X4 UNIPROT ESR1 protein P03372 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22174013 YES Luana NR2E3 directly regulates expression of ESR1 | Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes. 0.251 SIGNOR-266207 FANCB protein Q8NB91 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.843 SIGNOR-263241 TARDBP protein Q13148 UNIPROT GSK3B protein P49841 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004170 PMC7642658 YES lperfetto Importantly, we found that TDP-43 protein could interact with GSK3β mRNA and regulate the level of GSK3β protein translation. Taken together, our findings suggest that TDP-43 may activate the Wnt/β-catenin pathway by targeting the inhibition of GSK3β protein translation|TDP-43 activates Wnt/β-catenin pathway probably by inhibiting the GSK3β protein translation. A. Interaction between TDP-43 protein and GSK3β mRNA was analyzed using RIP assay. 0.267 SIGNOR-262113 YWHAZ protein P63104 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 YES miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. 0.277 SIGNOR-252397 CYLD protein Q9NQC7 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity deubiquitination 9606 12917691 YES lperfetto Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract) 0.676 SIGNOR-117860 KCNJ11 protein Q14654 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 YES lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. 0.659 SIGNOR-262055 regorafenib chemical CHEBI:68647 ChEBI FRK protein P42685 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259207 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 YES miannu The AMP-activated protein kinase (AMPK) down-regulates the inward rectifier K+ channel Kir2.1. Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK. 0.256 SIGNOR-276326 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 17615152 YES inferred from 70% family members gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.2 SIGNOR-270023 PLK1 protein P53350 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Thr406 AVYTKMMtKKPGMFF 9606 BTO:0000007 29138396 YES lperfetto We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD 0.346 SIGNOR-267580 DNM1 protein Q05193 UNIPROT Synaptic_vesicle_recycling phenotype SIGNOR-PH161 SIGNOR up-regulates 9606 BTO:0000938 10823955 NO miannu The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. 0.7 SIGNOR-264118 WEE2 protein P0C1S8 UNIPROT CDK1 protein P06493 UNIPROT down-regulates activity phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 11029659 YES miannu Recombinant Wee1B effectively phosphorylated cyclin B-associated Cdk1 on tyrosine-15, resulting in an inactivation of the kinase activity of Cdk1. 0.586 SIGNOR-279134 SYN3 protein O14994 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 NO miannu Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. 0.7 SIGNOR-264107 AP-1 complex complex SIGNOR-C248 SIGNOR AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.519 SIGNOR-260674 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination Lys62 CAVPIAQkSEPHSLS 9606 BTO:0002552 31732561 YES lperfetto AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination. 0.378 SIGNOR-267673 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1081 TGALTEDsIDDTFLP 9606 BTO:0000007 10347170 YES llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  0.371 SIGNOR-250622 DIP2A protein Q14689 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity acetylation 10090 BTO:0000142 31600191 YES miannu DIP2A binds to cortactin and modulates cortactin acetylation. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin. 0.2 SIGNOR-266589 fluoxetine chemical CHEBI:5118 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258738 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258649 PPP6C protein O00743 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity dephosphorylation 9606 19198648 YES miannu In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation.|PP6 may dephosphorylate sites in DNA-PKcs to reduce binding with heterodimer Ku proteins, because DNA-PK activation completely depends on Ku-mediated complex formation with DNA. 0.539 SIGNOR-277164 PIP3 smallmolecule CHEBI:16618 ChEBI MAPKAP1 protein Q9BPZ7 UNIPROT up-regulates activity chemical activation 9606 26293922 YES gcesareni PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation 0.8 SIGNOR-252429 ruxolitinib chemical CHEBI:66919 ChEBI JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206673 MCF2 protein P10911 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.777 SIGNOR-260558 MAPK14 protein Q16539 UNIPROT FOXC1 protein Q12948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser241 PSPPQPLsPAAALGS 31650548 YES lperfetto P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. 0.2 SIGNOR-275913 ABL1 protein P00519 UNIPROT YTHDC1 protein Q96MU7 UNIPROT down-regulates phosphorylation 9606 15175272 YES lperfetto We show that yt521-b is tyrosine phosphorylated by c-abl in the nucleus.We propose that tyrosine phosphorylation causes sequestration of YT521-B in an insoluble nuclear form, which abolishes the ability of YT521-B to change alternative splice sites. 0.306 SIGNOR-125167 GRHL2 protein Q6ISB3 UNIPROT ZEB1 protein P37275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 23814079 NO miannu we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. 0.432 SIGNOR-255624 MAPK3 protein P27361 UNIPROT SYN3 protein O14994 UNIPROT up-regulates phosphorylation Ser470 PQGQQPLsPQSGSPQ 9606 14732590 YES lperfetto A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. 0.2 SIGNOR-121402 BIRC3 protein Q13489 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 23070005 YES amattioni Ligand-stimulated aggregation of receptor complexes causes recruitment of multiple traf2 trimers, which in turn leads to cIAP1 or cIAP2 dimerization. 0.495 SIGNOR-199088 carfilzomib chemical CHEBI:65347 ChEBI PSMB1 protein P20618 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 YES miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. 0.8 SIGNOR-259307 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 12551923 YES gcesareni We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain. 0.604 SIGNOR-97635 PRKCA protein P17252 UNIPROT UNC5A protein Q6ZN44 UNIPROT down-regulates quantity phosphorylation Ser352 TSGFQPVsIKPSKAD 10116 BTO:0003036 16554470 YES miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. 0.2 SIGNOR-268180 Gbeta proteinfamily SIGNOR-PF4 SIGNOR KRT8 protein P05787 UNIPROT unknown phosphorylation 16554440 YES inferred from 70% family members lperfetto Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002). 0.2 SIGNOR-270003 CRK protein P46108 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 8524328 YES gcesareni These results indicate that crk binds to c-cbl in a tyrosine phosphorylation-dependent manner. 0.824 SIGNOR-39241 CSNK1A1 protein P48729 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 BTO:0002181 19797085 YES miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  0.31 SIGNOR-276261 OGA protein O60502 UNIPROT G6PD protein P11413 UNIPROT down-regulates activity deglycosylation Ser84 VADIRKQsEPFFKAT 9606 26399441 YES lperfetto O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth|O-GlcNAcylation of G6PD activates enzyme activity|G6PD is dynamically modified by O-GlcNAc at serine 84|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 0.2 SIGNOR-267605 SF3A2 protein Q15428 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 YES miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. 0.96 SIGNOR-263947 EP300 protein Q09472 UNIPROT MAML1 protein Q92585 UNIPROT up-regulates acetylation 9606 17300219 YES gcesareni The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. Furthermore, p300 acetylates maml1 and evolutionarily conserved lysine residues in the maml1 n-terminus are direct substrates for p300-mediated acetylation. 0.65 SIGNOR-153035 INSR protein P06213 UNIPROT DOK5 protein Q9P104 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 NO lperfetto Irs5/dok4 and irs6/dok5 represent two new signaling proteins with potential roles in insulin and igf-1 action 0.375 SIGNOR-101038 ATM protein Q13315 UNIPROT ZNF148 protein Q9UQR1 UNIPROT up-regulates phosphorylation Ser202 GEKPFQCsQCDMRFI 9606 17560543 YES lperfetto Here we found that zbp-89 is phosphorylated by atm kinase in vitro and in vivo. Disruption of the atm phosphorylation motif (202)sq within the zinc finger domain of zbp-89 attenuated its ability to enhance p21(waf1) activation by butyrate. Moreover, disruption of the atm phosphorylation site abrogated the ability of zbp-89 to potentiate butyrate induction of endogenous p21(waf1) expression. 0.36 SIGNOR-155634 SETD1B protein Q9UPS6 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 32546566 YES miannu SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. 0.2 SIGNOR-265576 CHN1 protein P15882 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates binding 9606 15013773 YES miannu _-chimaerin was identified to interact with the p35 activator of cdk5. The complex of _-chimaerin, cdk5 and p35 is enzymatically functional 0.338 SIGNOR-123439 RPL23 protein P62829 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.812 SIGNOR-262477 GSK3B protein P49841 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates phosphorylation 9606 12123574 YES gcesareni Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling. 0.464 SIGNOR-90608 HRH4 protein Q9H3N8 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256815 GSK3A protein P49840 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Thr385 ILTSNQKtLTPEKGQ 9606 BTO:0002181 31843895 YES miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. 0.263 SIGNOR-276761 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser236 DDSGTEEs 9606 12037680 YES llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  0.352 SIGNOR-251060 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 8027085 YES gcesareni Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids. 0.8 SIGNOR-35874 CDK2 protein P24941 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 17389604 YES gcesareni Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1 0.2 SIGNOR-154051 SRC protein P12931 UNIPROT ANXA1 protein P04083 UNIPROT unknown phosphorylation Thr216 AGERRKGtDVNVFNT 9606 24103589 YES lperfetto Location of sites in human lipocortin i that are phosphorylated by protein tyrosine kinases and protein kinases a and cthe primary site of phosphorylation by protein kinase c was also near the amino terminus at ser-27. The major site of phosphorylation by adenosine cyclic 3',5'-phosphate dependent protein kinase was on the carboxy-terminal half of the molecule at thr-216 0.39 SIGNOR-202800 RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates activity binding 10090 BTO:0000452 10795740 YES gcesareni We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation 0.675 SIGNOR-245026 RPS6KB1 protein P23443 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 YES gcesareni S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function. 0.775 SIGNOR-123997 ATR protein Q13535 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT down-regulates activity phosphorylation Ser19 GTSKCPPsQRVPALT 9606 BTO:0002181 18536714 YES miannu We have also demonstrated that DNA damage triggers disruption of the HIPK2-Siah-1 complex, resulting in HIPK2 stabilization and activation. Disruption of the HIPK2-Siah-1 complex is mediated by the ATM/ATR pathway and involves ATM/ATR-dependent phosphorylation of Siah-1 at Ser 19. 0.2 SIGNOR-276167 FYN protein P06241 UNIPROT DLG4 protein P78352 UNIPROT up-regulates phosphorylation Tyr523 REDSVLSyETVTQME 9606 BTO:0000938 BTO:0000142 18721130 YES llicata Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors. 0.563 SIGNOR-180449 LEF1 protein Q9UJU2 UNIPROT CLDN2 protein P57739 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0003569 14751232 NO lperfetto Activity of the claudin-2 promoter was elevated in mouse mammary epithelial C57 cells expressing Wnt-1. LEF-1, a nuclear effector of the Wnt signaling pathway which is involved in the regulation of cell differentiation and polarization, was found to bind directly to the claudin-2 promoter as revealed by electrophoretic mobility shift assays. Expression of LEF-1 and beta-catenin both enhanced claudin-2 promoter activity. 0.2 SIGNOR-254120 MAPK6 protein Q16659 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser189 YSHKGHLsEGLVTKW 9606 8621539 YES lperfetto Ser189 of erk3, which corresponds to thr183, one of the activating phosphorylation sites of erk2, is autophosphorylated in vitro and phosphorylated in vivo. 0.2 SIGNOR-40097 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates activity chemical inhibition -1 19759537 YES In biochemical activity assays, XAV939 strongly inhibited TNKS1 and TNKS2, with half-maximal inhibitory concentration values of 0.011 and 0.004 μM, respectively, but displayed much weaker effects on PARP1 and PARP2 0.8 SIGNOR-259994 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation Lys71 GILRRLKkYDNCWLA 9606 BTO:0000007 21726808 YES lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 0.544 SIGNOR-267603 IKBKB protein O14920 UNIPROT TMIGD2 protein Q96BF3 UNIPROT up-regulates activity phosphorylation Ser220 GKDQRGQsIYSTSFP 9606 BTO:0000007 32978258 YES miannu Manipulating the IκB kinase β activity coupled with in vivo and in vitro kinase assays demonstrated that IκB kinase β is a key serine/threonine kinase activated by autophagy stimuli and that it catalyzes phosphorylation of IGPR-1 at Ser220 The subsequent activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase, which leads to phosphorylation of the major pro-autophagy proteins ULK1 and Beclin-1 (BECN1), increased LC3-II levels, and accumulation of LC3 punctum.  0.2 SIGNOR-273642 RPS6KA3 protein P51812 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Thr1109 DRKIIATtLSKLKLE 9606 BTO:0002181 23608533 YES miannu We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. 0.2 SIGNOR-276463 TNF protein P01375 UNIPROT NOTCH4 protein Q99466 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004914 14586405 NO We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. 0.312 SIGNOR-253607 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTTG1 protein O95997 UNIPROT up-regulates phosphorylation 9606 10906323 YES inferred from 70% family members gcesareni Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function. 0.2 SIGNOR-270155 O-phosphoethanolamine smallmolecule CHEBI:17553 ChEBI GABARAP protein O95166 UNIPROT up-regulates chemical activation 9606 16303767 YES gcesareni Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) 0.8 SIGNOR-142011 HRAS protein P01112 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 YES lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. 0.837 SIGNOR-175183 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser302 TQRASRRsDSASSEP 9606 19366211 YES llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. 0.2 SIGNOR-185291 FAM83D protein Q9H4H8 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.385 SIGNOR-273749 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates phosphorylation Ser196 RSLEVWGsQEALEEA 9606 16540648 YES miannu Atr was the major kinase responsible for the cellular phosphorylation of xpa following uv irradiation / we propose that the phosphorylation of xpa by atr checkpoint may positively regulate ner activity and thus may facilitate the cells to recover from ner-related dna damages. 0.493 SIGNOR-145190 GSK3B protein P49841 UNIPROT STMN3 protein Q9NZ72 UNIPROT up-regulates activity phosphorylation Ser60 SFEVILKsPSDLSPE -1 22577147 YES lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta 0.265 SIGNOR-264882 GSK3B protein P49841 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR form complex binding 9606 BTO:0000586 9734785 YES lperfetto Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level. 0.839 SIGNOR-227299 CDK1 protein P06493 UNIPROT CDC23 protein Q9UJX2 UNIPROT up-regulates phosphorylation Thr565 NQGETPTtEVPAPFF 9606 14657031 YES lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation 0.635 SIGNOR-119821 GOT1 protein P17174 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-267510 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 10710310 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-75629 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser726 DTSPRHLsNVSSTGS -1 12435421 YES miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly 0.434 SIGNOR-250009 NPM1 protein P06748 UNIPROT FBP1 protein P09467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003081;BTO:0000849 30616754 YES lperfetto For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma 0.2 SIGNOR-267594 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr86 ARPLVEFyEEIKKYE 9606 BTO:0000007 16725308 YES miannu Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.  0.2 SIGNOR-266306 POT1 protein Q9NUX5 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 YES lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA 0.407 SIGNOR-263324 CDK5 protein Q00535 UNIPROT NES protein P48681 UNIPROT unknown phosphorylation Thr315 AENSRLQtPGGGSKT 10090 BTO:0000165 12832492 YES llicata We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts. 0.548 SIGNOR-250670 ATF3 protein P18847 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12881527 NO miannu Transcription from the ASNS (asparagine synthetase) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide evidence for a potential role of multiple predicted ATF3 isoforms in the transcriptional regulation of the ASNS gene in response to nutrient deprivation. 0.409 SIGNOR-253746 LRFN4 protein Q6PJG9 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 NO miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. 0.7 SIGNOR-264097 S100A8 protein P05109 UNIPROT TLR4 protein O00206 UNIPROT down-regulates activity binding 9606 28137827 YES miannu Interestingly, in the present study, we report that extracellular S100A9 induces terminal differentiation of myeloid leukemia cells in human and murine AMLs after TLR4 activation, which is highly expressed by primary myelomonocytic and monocytic leukemia cells. In contrast, anti-S100A8 induced the differentiation of AML cells, suggesting that the differentiation-promoting effect of S100A9 is inhibited by S100A8. ) S100A8 could bind to TLR4 and activate different signaling pathways, leading to the inhibition of cellular differentiation induced by S100A9. 0.533 SIGNOR-261921 oxotremorine M chemical CHEBI:38322 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258655 PRKAA1 protein Q13131 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 YES lperfetto Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. 0.829 SIGNOR-139158 CCDC102B protein Q68D86 UNIPROT LRRC45 protein Q96CN5 UNIPROT up-regulates activity binding 30404835 YES lperfetto CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis. 0.2 SIGNOR-275627 MAPK4 protein P31152 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0001109 30688659 YES miannu  Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308.  0.272 SIGNOR-275450 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 15448698 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-129402 BMPR1A protein P36894 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR up-regulates activity 10090 19620713 NO ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). 0.712 SIGNOR-255787 CBP/p300 complex SIGNOR-C6 SIGNOR KLF1 protein Q13351 UNIPROT up-regulates activity acetylation 9606 BTO:0002731 9707565 YES Regulation miannu CBP and p300, but Not P/CAF, Enhance EKLF Trans-activation in Erythroid Cells. We find that EKLF is an acetylated transcription factor, and that it interacts in vivo with CBP, p300, and P/CAF. However, its interactions with these histone acetyltransferases are not equivalent, as CBP and p300, but not P/CAF, utilize EKLF as a substrate for in vitro acetylation within its trans-activation region. 0.461 SIGNOR-251789 TLR5 protein O60602 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24709011 NO miannu These studies demonstrate a novel function of Toll-like receptor-5 (TLR5) in a human multiple myeloma (MM) cell line, KMS28BM. These cells express high levels of both TLR5 mRNA and protein. When cells were treated with the specific TLR5 ligand flagellin, proliferation was increased, and the secretion of IgG λ antibody and the expression of the pro-inflammatory cytokine IL-6 were increased via NF-κB activation through PI3K/AKT and p38 signaling. 0.466 SIGNOR-259868 RPN2 protein P04844 UNIPROT OST-A complex complex SIGNOR-C535 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.752 SIGNOR-272065 CDH4 protein P55283 UNIPROT CDH2 protein P19022 UNIPROT down-regulates quantity by repression 10090 BTO:0000165 18701479 NO lperfetto Taken together, these data show that (a) R-cadherin decreases the expression of M-cadherin and (b) N-cadherin and M-cadherin only slightly accumulate at the cell contacts in R-cadherin–expressing myoblasts. 0.512 SIGNOR-253107 CDC42 protein P60953 UNIPROT WASL protein O00401 UNIPROT up-regulates activity binding 9606 10219243 YES lperfetto In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules. 0.919 SIGNOR-261868 SIRT1 protein Q96EB6 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates quantity by destabilization deacetylation 10090 BTO:0001103 24003218 YES lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 0.81 SIGNOR-217975 SMARCB1 protein Q12824 UNIPROT SMARCA2 protein P51531 UNIPROT up-regulates activity binding 9606 10078207 YES miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. 0.923 SIGNOR-65181 R2SP co-chaperone complex SIGNOR-C517 SIGNOR PPFIA2 protein O75334 UNIPROT up-regulates quantity by stabilization binding 9606 29844425 YES miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. Remarkably, R2SP is required for liprin-α2 expression and for the assembly of liprin-α2 complexes, indicating that R2SP functions in quaternary protein folding. 0.2 SIGNOR-270942 BI 2536 chemical CID:11364421 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259702 ITGB1BP1 protein O14713 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.287 SIGNOR-257665 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT up-regulates phosphorylation Ser1782 GAEIITQsPGRSSVA 9606 BTO:0000567;BTO:0000938 BTO:0000142 11029056 YES gcesareni Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains 0.359 SIGNOR-83100 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr252 HDGTVTHtFCGTIEY -1 9445476 YES gcesareni The results presented here are consistent with PDK1 as the in vivo kinase responsible for mediating Thr252 phosphorylation in the catalytic domain of p70s6k. 0.727 SIGNOR-243338 DZIP3 protein Q86Y13 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271749 TBX21 protein Q9UL17 UNIPROT GATA3 protein P23771 UNIPROT down-regulates 9606 16386358 NO Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both 0.756 SIGNOR-254295 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1665 SPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248783 PTK2B protein Q14289 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates activity phosphorylation Tyr349 GNQFRANyFLQPELM 9606 21357692 YES miannu Pyk2 Induces Tyrosine Phosphorylation of NPHP1 at Tyr-46, Tyr-349, and Tyr-721.|The expression of wild-type Pyk2 enhances the amount of co-precipitating PACS-1 with wild-type NPHP1 compared with the presence of the kinase-dead variant of Pyk2. 0.462 SIGNOR-278271 CDK2 protein P24941 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 SIGNOR-C16 19237534 YES lperfetto In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression 0.2 SIGNOR-184160 STK4 protein Q13043 UNIPROT PDX1 protein P52945 UNIPROT down-regulates activity phosphorylation Thr11 EEQYYAAtQLYKDPC 9606 24633305 YES miannu MST1 directly phosphorylated PDX1 at Thr11, resulting in its ubiquitination, degradation and impaired insulin secretion.|Thus, kinase activity is required for MST1 induced PDX1 degradation. 0.2 SIGNOR-278303 TEAD proteinfamily SIGNOR-PF22 SIGNOR CNTF protein P26441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 31296870 YES miannu In this model, treatment with LIF, but not IL-6, significantly elevated YAP/TAZ-TEAD transcriptional activity and sequentially increased expression of YAP1-targeted genes, CNTF and ANKRD at mRNA, in human PDAC cells 0.2 SIGNOR-278034 MAPK1 protein P28482 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr219 ASLSLPAtPVGKGTE -1 12556484 YES done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites 0.287 SIGNOR-274076 SKOR1 protein P84550 UNIPROT LBX1 protein P52954 UNIPROT down-regulates activity binding 9606 BTO:0000007 15528197 YES llicata Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord. 0.558 SIGNOR-238004 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 YES lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively 0.2 SIGNOR-180784 tiotropium chemical CHEBI:90960 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition -1 8441333 YES miannu A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors. 0.8 SIGNOR-258484 NDUFS2 protein O75306 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. 0.867 SIGNOR-262176 AHCYL2 protein Q96HN2 UNIPROT PAPOLA protein P51003 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 YES lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. 0.2 SIGNOR-268330 paclitaxel chemical CHEBI:45863 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 28298489 YES miannu Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. 0.8 SIGNOR-259347 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14583461 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-118894 BMP2 protein P12643 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates 9606 22298955 NO gcesareni Neogenin, a transmembranous protein, was re-ported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation. 0.647 SIGNOR-195567 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Thr239 VPEMPGEtPPLSPID 9606 1846781 YES lperfetto Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity. 0.331 SIGNOR-21784 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr716 RPPSAELySNALPVG -1 8940081 YES miannu The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues. 0.2 SIGNOR-250256 UCHL5 protein Q9Y5K5 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 16027725 YES gcesareni Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases. 0.661 SIGNOR-138879 APC-c complex SIGNOR-C150 SIGNOR CDR2 protein Q01850 UNIPROT down-regulates quantity by destabilization ubiquitination 20383333 YES lperfetto Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. 0.2 SIGNOR-252024 RAPGEF5 protein Q92565 UNIPROT HRAS protein P01112 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.507 SIGNOR-183732 RUNX3 protein Q13761 UNIPROT CASP2 protein P42575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255094 TELO2 protein Q9Y4R8 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 YES miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. 0.578 SIGNOR-272003 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194340 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2516 FLTPSPEsPDQWSSS -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.243 SIGNOR-273168 CCND1 protein P24385 UNIPROT MSI1 protein O43347 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20443831 NO gcesareni We hypothesized that cyclin d1 may induce notch1 activity either by repressing numb or by inducing musashi 1 expression 0.283 SIGNOR-165186 CDK7 protein P50613 UNIPROT CAK complex complex SIGNOR-C456 SIGNOR form complex binding 9606 30860024 YES lperfetto CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.958 SIGNOR-269319 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates quantity by destabilization ubiquitination Lys629 DSSPGFSkEIAAALA 9606 BTO:0000007 17805301 YES miannu  In the presence of relevant cofactors (DDB1, DET1), COP1 promoted the ubiquitination of wild-type but not COP1-interaction defective VP/AA TORC2 (Fig. 3e). COP1 also stimulated the ubiquitination of TORC2(K213R) but had no effect on TORC2(K628R), suggesting an important role for Lys 628 in this regard (Fig. 3e). We performed mass spectrometry studies to characterize residues in TORC2 that undergo COP1-mediated ubiquitination. This analysis revealed one major (Lys 628) and one minor (Lys 213) site on TORC2 0.2 SIGNOR-271665 ZNF267 protein Q14586 UNIPROT MMP10 protein P09238 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 16054593 YES Luana Furthermore, ZNF267 binds to the MMP-10 promoter region as demonstrated by chromatin immunoprecipitation assays. In conclusion, our results suggest that ZNF267 as a negative transcriptional regulator of MMP-10  0.391 SIGNOR-266211 eprosartan chemical CHEBI:4814 ChEBI AGTR1 protein P30556 UNIPROT down-regulates activity chemical inhibition 9606 1309870 YES miannu The angiotensin II (AII) antagonist activity of (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophenepropanoic acid (SK&F 108566), was examined in a number of in vitro and in vivo assays. 0.8 SIGNOR-258347 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val58 KGVTVETvFSVDEFS -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.298 SIGNOR-263583 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser558 MQPPRSRsSIMSITA -1 24548923 YES miannu Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro.  0.523 SIGNOR-276254 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL -1 14709557 YES miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase 0.497 SIGNOR-250319 nalbuphine chemical CHEBI:7454 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258144 Goserelin chemical CHEBI:5523 ChEBI GNRHR protein P30968 UNIPROT up-regulates activity chemical activation 9606 BTO:0001033 22416801 YES miannu The efficacy of degarelix compared with a GnRH agonist (goserelin, plus flare protection with bicalutamide) was evaluated in a 12‐week trial in men with lower urinary tract symptoms secondary to prostate cancer. 0.8 SIGNOR-259161 HNF1B protein P35680 UNIPROT FXYD2 protein P54710 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000482 24204001 NO miannu Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT. 0.293 SIGNOR-254909 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2D complex SIGNOR-C350 SIGNOR up-regulates activity chemical activation 9606 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate 0.8 SIGNOR-264131 RHEB protein Q15382 UNIPROT FKBP8 protein Q14318 UNIPROT down-regulates binding 9606 17991864 YES gcesareni Rheb interacts directly with fkbp38 and prevents its association with mtor in a guanosine 5'-triphosphate (gtp)-dependent manner. 0.536 SIGNOR-159016 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates activity binding 9606 12782713 YES gcesareni MIF binds to the extracellular domain of CD74, and CD74 is required for MIF-induced activation of the extracellular signal-regulated kinase-1/2 MAP kinase cascade, cell proliferation, and PGE2 production 0.734 SIGNOR-252060 RPS25 protein P62851 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.909 SIGNOR-262426 CDC42BPA protein Q5VT25 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity phosphorylation Thr403 HLPFVGFtYTSSCVL 9534 BTO:0000298 11283256 YES miannu N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D). 0.2 SIGNOR-275973 MZF1 protein P28698 UNIPROT CCN2 protein P29279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25899830 NO miannu we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV. 0.2 SIGNOR-226307 PPP2CA protein P67775 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity dephosphorylation Ser59 GGQESQPsPLALLAA 9606 24382322 YES gcesareni These results indicate that the signals from TCDD or OP caused PP2A-mediated dephosphorylation of Sp1 at Ser-59 and induced CYP1A1 transcription 0.264 SIGNOR-248223 MAPK11 protein Q15759 UNIPROT HBP1 protein O60381 UNIPROT up-regulates phosphorylation Ser402 GFSKNCGsPGSSQLS 9606 14612426 YES lperfetto A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression. 0.426 SIGNOR-119134 PCBP2 protein Q15366 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 19881509 YES Giorgia PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. 0.645 SIGNOR-260360 LCK protein P06239 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 12181444 YES gcesareni In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme. 0.557 SIGNOR-91473 PRKAA1 protein Q13131 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser267 RVQSKIGsLDNITHV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.2 SIGNOR-275438 PPARG protein P37231 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 17681149 NO lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways 0.377 SIGNOR-249556 SLC1A5 protein Q15758 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity relocalization 9606 26724577 YES Fourteen of them [[SLC transporters] , capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. 0.8 SIGNOR-266914 NLK protein Q9UBE8 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser329 STISGRLsPIMTEQD 9534 BTO:0001538 20061393 YES done miannu Here, we report that the transforming growth factor-beta-activated kinase (TAK1)-Nemo-like kinase (NLK) pathway negatively regulates FOXO1. We show that NLK binds and phosphorylates FOXO1 at Pro-directed Ser/Thr residues in the transactivation domain. The phosphorylation by TAK1-NLK pathway inhibits the transcriptional activity of FOXO1 and excludes FOXO1 from the nucleus, which is independent of phosphatidylinositol 3-kinase/Akt pathway.  0.612 SIGNOR-273907 SETD1B protein Q9UPS6 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 32546567 YES miannu SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. 0.2 SIGNOR-265577 GABA-A proteinfamily SIGNOR-PF61 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268610 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001321 15659650 YES lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 0.779 SIGNOR-217799 SMAD7 protein O15105 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates binding 9606 16571110 YES gcesareni Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs 0.428 SIGNOR-145389 STUB1 protein Q9UNE7 UNIPROT CTBP2 protein P56545 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23410750 YES miannu Our data showed that CHIP depletion resulted in up-regulation of the steady-state level of CtBP2 ( Fig. 1 B) and that CHIP ubiquitinated CtBP2 for proteasomal degradation ( Fig. 3 A). 0.331 SIGNOR-278722 TIMM21 protein Q9BVV7 UNIPROT MITRAC complex complex SIGNOR-C538 SIGNOR form complex binding 9606 23260140 YES TIM21 is a constituent of MITRAC and presequence translocase complexes ► TIM21 ushers imported subunits of complexes I and IV to assembly intermediates 0.303 SIGNOR-272488 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW -1 9218798 YES SKK3 mediates the activation of SAPK4. Phosphorylation and activation of SAPK4 and SAPK2a by purified SKK3. 0.66 SIGNOR-251424 STK4 protein Q13043 UNIPROT SAFB protein Q15424 UNIPROT down-regulates activity phosphorylation 9606 23893242 YES miannu In the present study, we demonstrate that the chromatin scaffold protein SAFB1 interacts with and is phosphorylated by MST1 and is a novel regulator of AR capable of integrating signaling between the AR and MST1 networks. 0.2 SIGNOR-279296 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Tyr276 SDEDDEVyQVTVYQA 9606 21081495 YES lperfetto Mdm2 has three known c-abl phosphorylation sites (tyr276, tyr394, and tyr405)these data show that c-abl is important for reducing mdm2 and mdmx protein levels after genotoxic stress and suggest another cellular mechanism for the stabilization and activation of p53. 0.715 SIGNOR-169699 CLU protein P10909 UNIPROT IKBKB protein O14920 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001321 20068069 YES miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. 0.2 SIGNOR-271433 FAM20C protein Q8IXL6 UNIPROT VWF protein P04275 UNIPROT up-regulates activity phosphorylation 9606 30864273 YES miannu In vitro phosphorylation of von Willebrand factor by FAM20c enhances its ability to support platelet adhesion. 0.2 SIGNOR-279331 IKBKB protein O14920 UNIPROT TRIM23 protein P36406 UNIPROT down-regulates activity phosphorylation 9606 19716809 YES miannu Phosphorylation of ARD1 by IKKbeta reduced its growth suppression effect. 0.287 SIGNOR-279337 MAP3K14 protein Q99558 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17543278 YES miannu Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays.|When we transfected NIK into LNCaP cells, NIK was able to phosphorylate Stat3 at both tyrosine 705 and serine 727 residues. 0.26 SIGNOR-279340 AKT proteinfamily SIGNOR-PF24 SIGNOR EDC3 protein Q96F86 UNIPROT down-regulates activity phosphorylation Ser161 SFRRRHNsWSSSSRH 10029 BTO:0000246 20051463 YES miannu Together these data show that recombinant EDC3 co-immunoprecipitates with endogenous 14-3-3 isoforms in response to insulin in vivo and is phosphorylated at the putative 14-3-3 binding and AKT phosphorylation site Ser-161. Collectively, these data suggest that Ser-161 in EDC3 is phosphorylated in response to insulin principally by AKT and that this subsequently triggers 14-3-3 binding. Constitutive 14-3-3 binding to EDC3 alters p-body morphology and function 0.2 SIGNOR-262631 FBXL12 protein Q9NXK8 UNIPROT ALDH3A1 protein P30838 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001078 26124079 YES miannu We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members. 0.321 SIGNOR-272813 LPAR3 protein Q9UBY5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257229 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding -1 2467839 YES irozzo The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation. 0.952 SIGNOR-256361 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNA4 protein P22459 UNIPROT down-regulates activity phosphorylation Thr601 LKKFRSStSSSLGDK 9606 BTO:0000007 15955806 YES done miannu  In GIP receptor-expressing HEK293 cells, GIP reduced A-type peak ionic current amplitude of K(V)1.4 via activation of protein kinase A (PKA). Using mutant forms of K(V)1.4 with Ala-Ser/Thr substitutions in a potential PKA phosphorylation site, C-terminal phosphorylation was shown to be linked to GIP-mediated current amplitude decreases. 0.2 SIGNOR-273778 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4C protein Q08493 UNIPROT up-regulates activity phosphorylation Ser14 GEGAEACsRLSRSRG 9534 12023945 YES miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. 0.2 SIGNOR-275987 ASAP2 protein O43150 UNIPROT ARF5 protein P84085 UNIPROT up-regulates activity gtpase-activating protein -1 10022920 YES miannu Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. 0.498 SIGNOR-269707 Ub:E2 complex SIGNOR-C497 SIGNOR RLIM protein Q9NVW2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271054 MED18 protein Q9BUE0 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.881 SIGNOR-266672 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr128 LGGTETEySLLHMPS -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.245 SIGNOR-273559 AKT1 protein P31749 UNIPROT CABLES1 protein Q8TDN4 UNIPROT down-regulates activity phosphorylation Thr415 AFGARRNtIDSTSSF -1 25361894 YES miannu Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. 0.34 SIGNOR-276757 PRKCG protein P05129 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 BTO:0000007 14576165 YES lperfetto A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis. 0.2 SIGNOR-249238 CRHR1 protein P34998 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 22869609 YES lperfetto Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3 0.492 SIGNOR-268617 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 15096496 YES CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules 0.8 SIGNOR-267191 NEUROG1 protein Q92886 UNIPROT NEUROD2 protein Q15784 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000596 10814830 YES Luana Based on these results, we concluded that the transactivation of the NDRF gene by ngn1 is mediated through the E4 box, suggesting that the E4 box and its binding bHLH protein(s) may play an important role in the transcriptional regulation of the NDRF gene. 0.278 SIGNOR-266235 KATNAL2 protein Q8IYT4 UNIPROT TUBD1 protein Q9UJT1 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001363 29136647 YES miannu Here we show that KATNAL2 is critical for numerous aspects of this developmental process, including the initiation of the axoneme from the basal body, suppression of the spermatid centriole duplication cycle, sperm nuclear sculpting via the manchette, the attachment of the acrosome to the nucleus and the tethering of elongated spermatids to Sertoli cells via the tubulobulbar complex and ultimately sperm release via spermiation. KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin 0.257 SIGNOR-267175 GRK2 protein P25098 UNIPROT ADIPOR1 protein Q96A54 UNIPROT down-regulates quantity by destabilization phosphorylation Ser205 EKVSRTFsKLDYSGI 10090 BTO:0003324 35611695 YES miannu . GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1S205A overexpression. Moreover, AdipoR1S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function. 0.2 SIGNOR-277594 PHLPP2 protein Q6ZVD8 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 BTO:0001544 19261608 YES The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. 0.682 SIGNOR-248731 GNAS protein P63092 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 YES gcesareni Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7. 0.294 SIGNOR-191561 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 11242034 YES gcesareni Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily. 0.66 SIGNOR-105698 TGFBR2 protein P37173 UNIPROT VPS39 protein Q96JC1 UNIPROT up-regulates activity binding 9534 12941698 YES miannu TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling. 0.325 SIGNOR-261374 VPS18 protein Q9P253 UNIPROT PLK2 protein Q9NYY3 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16203730 YES miannu VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.  0.2 SIGNOR-271550 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT down-regulates activity phosphorylation Ser37 TASEHRKsSKPIMEK -1 9389649 YES lperfetto Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro. 0.33 SIGNOR-248992 JAG2 protein Q9Y219 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11006133 YES gcesareni These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors. 0.624 SIGNOR-82401 ARNT protein P27540 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity binding 14764593 YES lperfetto The functional transcription factor exists as a heterodimeric complex consisting of HIF-1alpha and the aryl hydrocarbon receptor nuclear translocator (ARNT). Association of HIF-1 with ARNT is required for its activity; however, no other role has been ascribed to this interaction. 0.786 SIGNOR-253720 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser100 QPQDKVIsGIAREKL 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.742 SIGNOR-262713 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.383 SIGNOR-161634 TNK2 protein Q07912 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Tyr269 QLRGDCMyAPLLGVP 9606 20383201 YES miannu Ack1 interacted with and phosphorylated AR protein at Tyr 267 and Ack1 was shown to be required for optimal AR target gene expression and AR recruitment.|Two intracellular tyrosine kinases, Ack1 (activated cdc42 associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. 0.546 SIGNOR-278194 SH3GLB2 protein Q9NR46 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 NO miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 0.7 SIGNOR-263887 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 YES The effect has been demonstrated using Q01196-8 miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 0.2 SIGNOR-138981 BST1 protein Q10588 UNIPROT NADP(+) smallmolecule CHEBI:18009 ChEBI down-regulates quantity chemical modification 9606 18626062 YES miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. 0.8 SIGNOR-264251 SMC3 protein Q9UQE7 UNIPROT MXD4 protein Q14582 UNIPROT down-regulates activity binding 9534 BTO:0000318 9528857 YES 2 miannu We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions. 0.297 SIGNOR-241284 RUNX2 protein Q13950 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22641097 NO miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. 0.395 SIGNOR-255080 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral SNAI1 protein O95863 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003792 26675258 YES Parnian The overexpression of miR-30a restored E-cadherin levels, and inhibited the expression of both vimentin and Snail. 0.4 SIGNOR-278000 ATR protein Q13535 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 17124492 YES lperfetto Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment 0.746 SIGNOR-150870 ACE2 protein Q9BYF1 UNIPROT Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32231345 NO doi.org/10.1101/2020.03.09.983247 miannu Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell–cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity. 0.7 SIGNOR-260286 BMS-554417 chemical CID:54754526 PUBCHEM INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190458 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 25190348 YES miannu MEKK2 can phosphorylate and activate MAP2K proteins MKK7 and MEK5, thereby promoting activation of JNK and ERK5, respectively [ xref ]. 0.602 SIGNOR-279212 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000552 14744793 YES gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. 0.652 SIGNOR-248070 TSSK3 protein Q96PN8 UNIPROT TSSK3 protein Q96PN8 UNIPROT up-regulates activity phosphorylation Ser166 PKSHRELsQTFCGST -1 16336268 YES Manara We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation. 0.2 SIGNOR-260785 MTCP1 protein P56278 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.451 SIGNOR-81674 CDK1 protein P06493 UNIPROT DLG1 protein Q12959 UNIPROT unknown phosphorylation Ser443 FLGQTPAsPARYSPV 9606 19066288 YES llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. 0.393 SIGNOR-182757 CHUK protein O15111 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Ser183 DGSPNAGsVEQTPKK 9606 23602409 YES miannu Reduced nuclear p27 was also found in MCF7 human breast cancer cells that were transiently transfected with an IKKalpha expression vector; increased IKKalpha expression resulted in a dose dependent decrease in nuclear p27 and increased cytoplasmic p27 (XREF_FIG).|We found that IKKalpha phosphorylates p27 at S183 to cause its nuclear export. 0.372 SIGNOR-278438 CHRM2 protein P08172 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates 9606 BTO:0000007 12665513 NO lperfetto Here we show that m2 muscarinic receptors and go require taos and mek3/6 as the primary intermediates activating p38 mapk in 293 cells 0.348 SIGNOR-235536 CSNK2A1 protein P68400 UNIPROT GPI protein P06744 UNIPROT down-regulates activity phosphorylation Ser185 GPRVWYVsNIDGTHI 9606 BTO:0000459 15637053 YES llicata It is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2) | These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity.  0.333 SIGNOR-250869 GSC protein P56915 UNIPROT EPHA7 protein Q15375 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000596 9417125 YES Luana We demonstrate that Goosecoid can act as a repressor of its own promoter activity in transient co-transfection experiments in mouse P19 cells and in Xenopus embryos. Autorepression depends on the presence of the homeodomain and is mediated through the prd element more proximal to the transcriptional start site. 0.2 SIGNOR-261613 PDK2 protein Q15119 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 19951971 YES lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a €œgain control€ for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity 0.748 SIGNOR-249630 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR KDM4A protein O75164 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000356 21768309 YES lperfetto SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation 0.331 SIGNOR-273443 CDK6 protein Q00534 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity phosphorylation 9606 32662822 YES miannu CDK4 and CDK6 phosphorylate TFEB and TFE3. 0.2 SIGNOR-279454 SRC protein P12931 UNIPROT SPRY2 protein O43597 UNIPROT up-regulates phosphorylation Tyr55 AIRNTNEyTEGPTVV 9606 15564375 YES lperfetto Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human sprouty 2 (hspry2) on residue y55. we show that hspry2 is a direct substrate for src family kinases, including src itself.Phosphorylation of hspry2 is required for hspry2 to inhibit activation of the extracellular signal-regulated kinase pathway. 0.564 SIGNOR-131189 CAMKK2 protein Q96RR4 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 15980064 YES lperfetto These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. 0.602 SIGNOR-217496 RITA1 protein Q96K30 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 21102556 YES gcesareni Thus, we propose that rita acts as a negative modulator of the notch signalling pathway, controlling the level of nuclear rbp-j/cbf-1, where its amounts are limiting. 0.418 SIGNOR-170089 RHOH protein Q15669 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity relocalization 10090 BTO:0004850 18089848 YES irozzo Therefore, RhoH functions as a Rac1 antagonist by inhibiting Rac1 translocation to the cell plasma membrane in the regulation of cell migration and F-actin assembly of HPCs 0.409 SIGNOR-259085 AIMP1 protein Q12904 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates binding 9606 18448069 YES lpetrilli Here, we report that aimp1 negatively regulates tgf-? Signaling via stabilization of smurf2. 0.391 SIGNOR-178498 Linsitinib chemical CID:11640390 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates activity chemical inhibition 10090 24712877 YES lperfetto Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice 0.8 SIGNOR-262028 ATM protein Q13315 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation Ser162 TCSENGVsLCLPRLE 9606 23435430 YES miannu Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH. 0.264 SIGNOR-276488 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BCL2 protein P10415 UNIPROT up-regulates phosphorylation 9606 10669763 YES inferred from 70% family members gcesareni Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both in vitro and in vivo molecular association. 0.2 SIGNOR-270064 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 SIGNOR-C83 11931757 YES lperfetto We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. 0.755 SIGNOR-116476 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser397 TYHSRDEsTDSGLSM 9606 BTO:0000007 20048001 YES lperfetto We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition 0.82 SIGNOR-218038 FYN protein P06241 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 YES gcesareni Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk. 0.748 SIGNOR-149174 DDIT4 protein Q9NX09 UNIPROT TSC2 protein P49815 UNIPROT up-regulates activity binding 9606 21460850 YES miannu  Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex. 0.638 SIGNOR-277469 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 12419246 YES lperfetto Thus, Ski/SnoN represses TGFβ signaling by multiple mechanisms. In addition to recruitment of a transcriptional repressor complex and dissociation of the transcriptional coactivator p300/CBP from the Smads 0.398 SIGNOR-217217 HCK protein P08631 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr354 SSNQELIyEGRRLVL 9606 BTO:0002181 28618271 YES miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  0.2 SIGNOR-276726 SF3B2 protein Q13435 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 YES lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). 0.924 SIGNOR-268404 POLR1H protein Q9P1U0 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16373708 NO miannu ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. 0.2 SIGNOR-259908 ZNF91 protein Q05481 UNIPROT FCGR3B protein O75015 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002269 11470777 YES Luana Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription. 0.2 SIGNOR-266215 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 6698284 YES miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). 0.8 SIGNOR-268095 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT up-regulates activity binding 10090 22664090 YES gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.2 SIGNOR-252066 IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 9716487 YES lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. 0.638 SIGNOR-238634 PAK1 protein Q13153 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Thr261 QYGLKMKtSRAFFSE 9606 BTO:0000150 18283314 YES llicata We found that pak1 phosphorylated ebp1 in vitro and mapped the phosphorylation site to threonine 261. these studies demonstrate for the first time that ebp1 is a substrate of pak1 and the importance of the pak1 phosphorylation site for the functional activity of ebp1 in breast cancer cells. 0.2 SIGNOR-160963 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248681 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 15383283 YES gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. 0.363 SIGNOR-129349 PRKCQ protein Q04759 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates activity phosphorylation Ser591 DKEKSKGsLKRK 9606 BTO:0000914 35258455 YES miannu SHP-1 phosphorylation is mediated through PKC-θ. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-θ promotes the inhibited SHP-1 'folded' state. Silencing PKC-θ maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in vivo. 0.2 SIGNOR-277590 MAPK9 protein P45984 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation 9606 25377781 YES miannu Activation of c-Src by JNK2 was accompanied by the phosphorylation of c-Src on threonine residue (s).|JNK2 directly phosphorylates c-Src and activates its auto phosphorylation. 0.356 SIGNOR-279221 SCN4A protein P35499 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 YES miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. 0.8 SIGNOR-253405 EPO protein P01588 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 NO Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. 0.35 SIGNOR-251783 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248514 CCT137690 chemical CID:25154041 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190898 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268585 PTK6 protein Q13882 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation Tyr64 VDTSQVLyEWEQGFS 9606 20026641 YES miannu PTK6 directly phosphorylates beta-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64.|The ability of PTK6 to negatively regulate beta-catenin and TCF transcription by modulating levels of TCF4 and TLE and Groucho could contribute to its growth-inhibitory activities in vivo. 0.305 SIGNOR-278288 PTK6 protein Q13882 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation Tyr333 NIMRTYTyEKLLWTT 9606 20026641 YES miannu PTK6 directly phosphorylates beta-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64.|The ability of PTK6 to negatively regulate beta-catenin and TCF transcription by modulating levels of TCF4 and TLE and Groucho could contribute to its growth-inhibitory activities in vivo. 0.305 SIGNOR-278289 RPS6KA1 protein Q15418 UNIPROT SLC9A3R1 protein O14745 UNIPROT up-regulates activity phosphorylation Thr156 ELRPRLCtMKKGPSG 9606 26862730 YES miannu In summary, these results demonstrate that Ras-RSK1 signaling promotes nuclear localization of EBP50.|Specifically, RSK1 phosphorylates EBP50 at threonine 156 (T156) residue in a cell cycle dependent manner, which is important for nuclear translocation of EBP50 to facilitate cellular proliferation and transformation. 0.33 SIGNOR-278290 SIRT5 protein Q9NXA8 UNIPROT IDH2 protein P48735 UNIPROT up-regulates activity catalytic activity 9606 27113762 YES Monia Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes. 0.41 SIGNOR-261212 CEBPB protein P17676 UNIPROT Neurodegeneration phenotype SIGNOR-PH139 SIGNOR up-regulates activity 10090 BTO:0000078 32795415 NO Gianni In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. 0.7 SIGNOR-261926 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser76 SNLQRMGsSESTDSG 9606 20068082 YES gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); 0.856 SIGNOR-163150 FGFR3 protein P22607 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 10918587 YES Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. 0.63 SIGNOR-251139 DVL1 protein O14640 UNIPROT RND1 protein Q92730 UNIPROT up-regulates 9606 23151663 NO gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. 0.273 SIGNOR-199387 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8422248 YES lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III 0.675 SIGNOR-248926 ADRA1A protein P35348 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257195 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity relocalization 9606 11163210 YES lperfetto Smurf2 is nuclear, but binding to smad7 induces export and recruitment to the activated tgf beta receptor, where it causes degradation of receptors and smad7 via proteasomal and lysosomal pathways. 0.87 SIGNOR-104996 SRC protein P12931 UNIPROT NECTIN2 protein Q92692 UNIPROT unknown phosphorylation Tyr505 EGEEEEEyLDKINPI -1 10962558 YES miannu An inhibitor specific for Src family kinase or expression of Csk reduced tyrosine phosphorylation of nectin-2delta. In addition, Src kinase tyrosine phosphorylates the recombinant cytoplasmic region of nectin-2delta in vitro. The major tyrosine phosphorylation site of nectin-2delta was Tyr505 in the cytoplasmic region 0.2 SIGNOR-263200 DTNBP1 protein Q96EV8 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates activity binding 10116 BTO:0000601 20531346 YES miannu Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. 0.353 SIGNOR-265660 ARHGAP30 protein Q7Z6I6 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.401 SIGNOR-260486 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser7 sSAEGAAK 9606 10739259 YES gcesareni Peptide mass and sequence analysis showed major and minor phosphorylation sites, respectively, at ser24 and ser28 in hmg-17, and ser20 and ser24 in hmg-14 a third phosphorylation site in hmg-14 was located at either ser6 or ser7phosphorylation of ser6 and ser7 may compromise the binding of hmgn1 protein to the binding domain of importin proteins, which in turn affects the nuclear transport and sub-cellular localization of hmgn1 protein. Protein kinase ck2 could potentially be an enzyme that regulates this process. 0.2 SIGNOR-76266 CXCL9 protein Q07325 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 YES miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. 0.781 SIGNOR-260970 GMPS protein P49915 UNIPROT guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity chemical modification 9606 6698284 YES miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). 0.8 SIGNOR-267338 COLGALT1 protein Q8NBJ5 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates activity glycosylation -1 19075007 YES Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. 0.408 SIGNOR-261152 8-hydroxy-5-[1-hydroxy-2-(propan-2-ylamino)butyl]-1H-quinolin-2-one chemical CHEBI:91585 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257857 ERBB2 protein P04626 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates activity phosphorylation -1 1706616 YES inferred from 70% of family members ¬†Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. 0.626 SIGNOR-269875 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-106478 SNAI2 protein O43623 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 22074556 NO miannu We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. 0.403 SIGNOR-255171 CTSG protein P08311 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Leu38 RSSKGRSlIGKVDGT -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.526 SIGNOR-263584 TRIM59 protein Q8IWR1 UNIPROT MACROH2A1 protein O75367 UNIPROT down-regulates quantity by destabilization polyubiquitination 31488827 YES miannu Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity.  0.2 SIGNOR-272931 MAP3K3 protein Q99759 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity phosphorylation Thr269 GGKRSRLtPVSPESS 9606 26279575 YES miannu MEKK3 overexpression, but not that of a kinase dead mutant, was able to induce the phosphorylation of p62 at T269 and S272 (XREF_FIG), which correlated with mTORC1 activation (XREF_FIG), suggesting that MEKK3 could be a bona fide regulator of p62 phosphorylation and mTORC1 activity. 0.555 SIGNOR-279532 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 9407116 YES lperfetto The src family kinase hck interacts with bcr-abl by a kinase-independent mechanism and phosphorylates the grb2-binding site of bcr 0.2 SIGNOR-53964 PRKCG protein P05129 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.293 SIGNOR-249255 SH3RF1 protein Q7Z6J0 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 16571722 YES gcesareni We find that posh and jips directly associate with one another to form a multiprotein complex, pjac (posh-jip apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for jnk activation and cell death in response to apoptotic stimuli. 0.284 SIGNOR-145393 MAP2K7 protein O14733 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 YES done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. 0.434 SIGNOR-273954 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-268075 PRKG2 protein Q13237 UNIPROT CTH protein P32929 UNIPROT down-regulates activity phosphorylation Ser377 SDTLIRLsVGLEDEE 25900831 YES lperfetto CO stimulated protein kinase G (PKG)-dependent phosphorylation of Ser(377) of CSE, inhibiting the production of H2S. 0.244 SIGNOR-275800 APC-c complex SIGNOR-C150 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 25092294 NO miannu We then found that the joint action of TRIP13 and p31comet also promotes MCC disassembly, releases APC/C from checkpoint inhibition, and inactivates the mitotic checkpoint. 0.7 SIGNOR-265978 STAT5A protein P42229 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12468433 YES We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling 0.635 SIGNOR-261548 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR aspartic acid smallmolecule CHEBI:22660 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270373 PINK1 protein Q9BXM7 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 32484300 YES miannu We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. 0.601 SIGNOR-279548 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr336 SKQSPIStPTSPGSL 9606 14741103 YES llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. 0.405 SIGNOR-250660 bethanechol chemical CHEBI:3084 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258624 KLF4 protein O43474 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates 9606 BTO:0000887;BTO:0001260 21673106 NO gcesareni Finally, we demonstrate that the basal expression of both myocd and mrtf-a is negatively regulated by klf4. . The mechanism of inhibition of myocd or mrtf-a by klf4 is currently unclear and warrants future study. 0.465 SIGNOR-174255 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 YES esanto We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase. 0.385 SIGNOR-133283 PTK2 protein Q05397 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates activity phosphorylation Tyr174 QKASAPTyPSLYSSY 9606 BTO:0000007 22493428 YES miannu  In addition, FAK directly phosphorylates Nanog in a dose-dependent manner by in vitro kinase assay and in cancer cells in vivo. The site-directed mutagenesis of Nanog tyrosines, Y35F and Y174F, blocked phosphorylation and binding by FAK. 0.274 SIGNOR-276410 NLRP1 protein Q9C000 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.645 SIGNOR-256407 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Thr1048 YQEKVHMtWTKDKYM 9606 24043619 YES Manara WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048.  0.445 SIGNOR-260910 IL1B protein P01584 UNIPROT ENPP1 protein P22413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 7479785 NO miannu Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes. IL-1 beta may be an important regulator of mineralization in chondrocytes by inhibiting TGF beta-induced PPi production and PC-1 expression. 0.2 SIGNOR-252199 RORA protein P35398 UNIPROT NLGN1 protein Q8N2Q7 UNIPROT up-regulates quantity by expression transcriptional regulation 28608249 YES lperfetto Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005). 0.2 SIGNOR-265136 PDCD1 protein Q15116 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 9606 BTO:0000782 22740686 NO Barakat MEK1/2 was phosphorylated and activated upon activation of T cells through TCR-CD3 and CD28, which resulted in phosphorylation of its downstream target ERK1/2, as determined by Western blotting analysis with an antibody specific for ERK1/2 phosphorylated at Thr202 and Tyr204, markers of activation. PD-1 substantially inhibited the activation of MEK1/2 and ERK1/2 0.262 SIGNOR-275411 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 YES lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 0.2 SIGNOR-249574 AKT1 protein P31749 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro 0.2 SIGNOR-98285 SHANK3 protein Q9BYB0 UNIPROT GRIA2 protein P42262 UNIPROT up-regulates quantity binding 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264602 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 10090 8387505 YES lperfetto The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases 0.73 SIGNOR-252762 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Thr147 PIPTRRHtFRRQNVR 9606 BTO:0000142 10441128 YES gcesareni Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells. 0.713 SIGNOR-69938 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr445 ANDVPSPyEVRGFPT -1 8631326 YES miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). 0.2 SIGNOR-262894 GALR3 protein O60755 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.278 SIGNOR-256998 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity destabilization 9606 BTO:0000567 16520378 YES Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation. 0.71 SIGNOR-266902 NEUROG2 protein Q9H2A3 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 18400164 NO lperfetto While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis 0.7 SIGNOR-265173 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation 9606 17900900 YES lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation 0.411 SIGNOR-252886 VRK1 protein Q99986 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 15378002 YES flangone Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription 0.513 SIGNOR-127069 CDK1 protein P06493 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation Ser337 IVSPPPSsPPSSLTT 9606 8087847 YES lperfetto Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro. 0.699 SIGNOR-36026 NEK6 protein Q9HC98 UNIPROT ACD protein Q96AP0 UNIPROT up-regulates activity phosphorylation Ser169 SNAGLSLsQLLDEMR 9606 BTO:0000007 27396482 YES lperfetto NEK6-mediated phosphorylation of human TPP1 regulates telomere length through telomerase recruitment|Shelterin component TPP1 plays critical roles in chromosome end protection and telomere length regulation. Specifically, TPP1 contains an OB-fold domain that provides an interface to recruit telomerase.| 0.2 SIGNOR-264424 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258570 SSTR5 protein P35346 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.28 SIGNOR-256969 ABL1 protein P00519 UNIPROT TFEB protein P19484 UNIPROT down-regulates activity phosphorylation 9606 33163944 YES miannu Our data show that c-Abl promotes TFEB tyrosine phosphorylation and that its inhibition induces TFEB activity.|c-Abl Inhibition Activates TFEB and Promotes Cellular Clearance in a Lysosomal Disorder Summary The transcription factor EB ( TFEB ) has emerged as a master regulator of lysosomal biogenesis , exocytosis , and autophagy , promoting the clearance of substrates stored in cells . 0.2 SIGNOR-279583 TGFB2 protein P61812 UNIPROT TGFBR3 protein Q03167 UNIPROT up-regulates binding 9606 10746731 YES gcesareni Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors. 0.518 SIGNOR-76473 N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. 0.8 SIGNOR-268102 SMARCE1 protein Q969G3 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.835 SIGNOR-270612 NDUFA6 protein P56556 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.836 SIGNOR-262157 SMO protein Q99835 UNIPROT GNGT1 protein P63211 UNIPROT up-regulates binding 9606 16885213 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.2 SIGNOR-148601 APC protein P25054 UNIPROT ODC1 protein P11926 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12112318 YES APC-dependent regulation of ornithine decarboxylase in human colon tumor cells|Upon induction of APC expression, ODC promoter activity and RNA levels were suppressed 0.268 SIGNOR-253670 MAPK3 protein P27361 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 BTO:0000782;BTO:0000801 17095509 YES gcesareni We found that in these cells, lipopolysaccharide stimulates the expression of mhc ii genes via the activation of erk1/2, which is mediated by toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of ciita isoform 1 that leads to its monoubiquitylation. 0.342 SIGNOR-150545 SMAD1/4 complex SIGNOR-C85 SIGNOR CEBPB protein P17676 UNIPROT up-regulates activity binding 9606 18854943 YES fferrentino This Smad1/4 complex can directly interact with Shn-2 and C/EBP a on the PPAR g promoter thus, resulting in the transcriptional activation of PPAR g 0.559 SIGNOR-253552 AP-2 complex complex SIGNOR-C245 SIGNOR DAB2 protein P98082 UNIPROT up-regulates activity binding 9606 BTO:0004784; BTO:0000567 11247302 YES Giorgia Dab2 is alternatively spliced and its localization depends on a region of the protein that contains two DPF motifs that are present in the p96 Dab2 protein and absent in the p67 splice variant. This region is sufficient to confer Dab2 binding to the alpha‐adaptin subunit of the clathrin adaptor protein, AP‐2.|These findings suggest that in addition to previously reported signal-transduction functions, Dab2 could also act as an adaptor protein that may regulate protein trafficking. 0.51 SIGNOR-260391 FOXA2 protein Q9Y261 UNIPROT AHSG protein P02765 UNIPROT up-regulates quantity by expression transcriptional regulation 16595698 NO lperfetto CCAAT enhancer binding protein beta and hepatocyte nuclear factor 3beta are necessary and sufficient to mediate dexamethasone-induced up-regulation of alpha2HS-glycoprotein/fetuin-A gene expression. 0.234 SIGNOR-271676 MYOD1 protein P15172 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR form complex binding 9606 16847330 YES 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. 0.672 SIGNOR-241122 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 15210796 YES gcesareni We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. 0.432 SIGNOR-126250 LATS1 protein O95835 UNIPROT PRPS2 protein P11908 UNIPROT down-regulates quantity by destabilization phosphorylation Thr285 EDKMKHCtKIQVIDI -1 34465890 YES miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. 0.2 SIGNOR-276506 FZD5 protein Q13467 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 10937998 NO fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) 0.2 SIGNOR-80607 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000176 14967450 YES inferred from 70% family members lperfetto Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.2 SIGNOR-270198 alvocidib chemical CHEBI:47344 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192449 ANKRD1 protein Q15327 UNIPROT NPPA protein P01160 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 18273862 YES In vitro calpain-mediated degradation assays, coupled to reporter gene analysis in transfected HeLa cells, strongly suggested that this mutation enhances both the stability of the ANKRD1/CARP protein and its transcriptional repression activity upon the cardiac-specific atrial natriuretic factor (ANF) promoter. 0.326 SIGNOR-253647 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr687 AQAFPVSySSSGARR 9534 BTO:0004055 8621380 YES lperfetto Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map  0.2 SIGNOR-248941 STK11 protein Q15831 UNIPROT PRMT5 protein O14744 UNIPROT up-regulates activity phosphorylation Thr139 TNLARVLtNHIHTGH -1 30289978 YES miannu We found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1.  0.2 SIGNOR-277411 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.564 SIGNOR-89186 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 BTO:0000150 19567672 YES llicata Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions 0.479 SIGNOR-186467 PKA proteinfamily SIGNOR-PF17 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates activity phosphorylation Ser189 QEYTVKLsNIPTIKR 9534 12646569 YES lperfetto Mutational analysis show that the putative mitochondrial targeting signal resides within the C-terminal 20 amino acid residues of the protein and that the targeting signal requires activation by phosphorylation at the C-terminal-most protein kinase A (PKA) site at Ser-189 or protein kinase C (PKC) site at Thr-193. 0.2 SIGNOR-264796 CDK1 protein P06493 UNIPROT SKA3 protein Q8IX90 UNIPROT up-regulates activity phosphorylation Thr358 SYENLLRtPTPPEVT 9606 28479321 YES miannu Cdk1 treatment further enhanced the binding of Ska3 2D to Ndc80, suggesting that phosphorylation of other Cdk1 sites in Ska3 further contributes to the Ndc80C-Ska3 interaction, although this contribution is not apparent in our kinetochore localization assay.We next purified the GST-Ndc80C Bonsai construct that lacks the loop region of Ndc80 as well as the coiled coil regions of Ndc80C [17].|Thus, Ska3 can be phosphorylated by Cdk1 on T358 and T360 sites in vitro.We next tested whether Ska3 was required for Ska1 or Ska2 localization. 0.394 SIGNOR-278376 PAK2 protein Q13177 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation Ser1208 MKSRRPKsSLPPVLG -1 10748018 YES miannu PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991. 0.532 SIGNOR-250222 CARS1 protein P49589 UNIPROT tRNA(Cys) smallmolecule CHEBI:29167 ChEBI down-regulates quantity chemical modification 9606 11347887 YES miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. 0.8 SIGNOR-270469 UBE3A protein Q05086 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity ubiquitination 9606 18193166 YES miannu E6-AP also directly ubiquitylated p53 in an in vitro ubiquitylation assay.|Our result suggests that E6-AP not only enhances the degradation of p53 but also regulates the neuronal cell growth. 0.681 SIGNOR-278681 P2RY2 protein P41231 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264307 DAPK1 protein P53355 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity phosphorylation Thr667 ILTGRGKtNQNTGMT 9606 BTO:0002181 28132841 YES miannu DAPK1 phosphorylates RIG-I in vitro at previously reported as well as other sites that limit 5'ppp-dsRNA sensing and virtually abrogate RIG-I activation. 0.33 SIGNOR-277336 ULK1 protein O75385 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity phosphorylation Ser762 YEIDLDTsDHAHLEH 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274036 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation 9606 19767751 YES inferred from 70% family members gcesareni Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. 0.2 SIGNOR-270041 HUWE1 protein Q7Z6Z7 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 31713291 YES miannu Taken together, these results are consistent with our hypothesis that HUWE1 directly poly-ubiquitinates and targets Chk1 to the proteasome. 0.299 SIGNOR-278568 CHKA protein P35790 UNIPROT KDR protein P35968 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 22711876 YES miannu Here, we show for the first time a possible mechanism by which CKI dependent phosphorylation of VEGFR2 at specific sites in its C-terminal tail triggers SCF beta-TRCP -mediated VEGFR2 ubiquitination and destruction. 0.249 SIGNOR-279029 EGFL7 protein Q9UHF1 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates activity binding 10090 BTO:0002881 19503073 YES miannu Here we have identified transmembrane receptors of the Notch family as EGFL7-binding molecules. Secreted EGFL7 binds to a region in Notch involved in ligand-mediated receptor activation, thus acting as an antagonist of Notch signalling. Expression of EGFL7 in neural stem cells (NSCs) in vitro decreased Notch-specific signalling and consequently, reduced proliferation and self-renewal of NSCs. 0.475 SIGNOR-266860 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.8 SIGNOR-270441 AXIN1 protein O15169 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates binding 9606 16601693 YES gcesareni Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. 0.711 SIGNOR-145851 COL1A1 protein P02452 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 10090 BTO:0000165 12496264 YES lperfetto Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins. 0.582 SIGNOR-253345 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr401 SKALRIStPLTGVRY 9606 BTO:0001938 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus) 0.679 SIGNOR-104719 GEMIN7 protein Q9H840 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 YES lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. 0.819 SIGNOR-253121 PKM protein P14618 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 15996096 YES miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). 0.8 SIGNOR-266536 DOT1L protein Q8TEK3 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 NO irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. 0.2 SIGNOR-255881 NLGN2 protein Q8NFZ4 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.828 SIGNOR-264161 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 20551513 YES ggiuliani Expression of a constitutively active mutant of MKK6 (MKK6-glu) (39), but not a kinase-inactive mutant of MKK6 (MKK6-K82A) (39), strongly promoted human MSC differentiation to osteoblasts as shown by increased ALP activity and extracellular matrix mineralization (Figure 4E). Furthermore, MKK6-glu‚Äìexpressing osteoblasts were treated with inhibitors of p38, JNK, and MEK (Figure 4F). Only treatment with the p38 inhibitor SB203580 blocked the effects of MKK6-glu. 0.744 SIGNOR-255780 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Thr713 SKRNSVDtATSSSLS -1 2117608 YES llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. 0.33 SIGNOR-250884 EIF2B1 protein Q14232 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.829 SIGNOR-269124 THR proteinfamily SIGNOR-PF84 SIGNOR RARG protein P13631 UNIPROT up-regulates activity binding 9606 15650024 YES inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.2 SIGNOR-267781 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser723 VITIDPAsPQSPESV 9606 11604491 YES llicata Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728. 0.57 SIGNOR-111039 CSNK2B protein P67870 UNIPROT OCLN protein Q16625 UNIPROT unknown phosphorylation Thr404 HYETDYTtGGESCDE 9606 12804768 YES llicata Mutagenesis of serine 407 to alanine resulted in reduced ability of the kinase to phosphorylate occludin. The threonine 403 to alanine mutant had a smaller effect but the double mutant (T403/S407A) was even less phosphorylated than either of the single mutants. These data are consistent with the claim that CK2 is the kinase in brain extracts responsible for phosphorylation of occludin. 0.416 SIGNOR-251080 ROMO1 protein P60602 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.383 SIGNOR-267690 PRKG2 protein Q13237 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity phosphorylation Ser863 TSTLPRNsGAGASSG 9606 18728399 YES miannu In cultured hippocampal neurons, activation of cGKII induces an accumulation of GluR1 on the cellular plasma membrane at extrasynaptic sites, and blockage of cGKII activity prevents the surface increase of GluR1, and also the increase in mEPSC frequency and amplitude, that follows a chemical form of LTP (chemLTP).|In this complex, cGKII phosphorylates GluR1 at serine 845 (S845), a site known to be phosphorylated also by PKA. 0.44 SIGNOR-278427 PTK6 protein Q13882 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 23027128 YES miannu B. PTK6 phosphorylates FAK at tyrosine residue 861.|Knockdown of PTK6 in the PC3 human prostate cancer cell line disrupts FAK and AKT activation and promotes anoikis, which can be rescued by exogenous expression of FAK. 0.264 SIGNOR-278428 OGT protein O15294 UNIPROT TET1 protein Q8NFU7 UNIPROT up-regulates activity glycosylation 9606 BTO:0002181 23729667 YES irozzo The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt. 0.441 SIGNOR-259184 Calcineurin complex SIGNOR-C155 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 NO gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.389 SIGNOR-252309 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 BTO:0000007 21059642 YES The effect has been demonstrated using Q01196-8 lperfetto Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.342 SIGNOR-216916 CDC42 protein P60953 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 YES gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. 0.942 SIGNOR-248243 COL15A1 protein P39059 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium 0.7 SIGNOR-254678 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248523 CDK2 protein P24941 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation 9606 26960431 YES miannu Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity.|Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry. 0.686 SIGNOR-279322 PRKCE protein Q02156 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates activity phosphorylation Thr91 RDARFRRtETDFSNL -1 15147202 YES lperfetto We have identified one specific phosphorylation site, threonine 91 (T91), in hGAD67 that can be phosphorylated by PKA using MALDI-TOF. Site-directed mutation of T91 to alanine abolished PKA-mediated phosphorylation and inhibition of GAD activity. 0.322 SIGNOR-249264 SHMT1 protein P34896 UNIPROT 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI up-regulates quantity chemical modification 9606 11802770 YES miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. 0.8 SIGNOR-269688 RET protein P07949 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 YES lperfetto The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity 0.323 SIGNOR-166514 SIX1 protein Q15475 UNIPROT EZR protein P15311 UNIPROT up-regulates quantity transcriptional regulation 9606 16488997 YES We now show that the gene encoding Ezrin is a direct transcriptional target of Six1. 0.343 SIGNOR-259374 PTK2 protein Q05397 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Tyr419 RLIEDNEyTARQGAK 9606 17828307 YES miannu Cell reconstitution showed that FAK catalytic activity is required for alpha5beta1-stimulated Src activation in part through direct FAK phosphorylation of Src at Tyr-418. 0.648 SIGNOR-278452 VRK2 protein Q86Y07 UNIPROT GAPDH protein P04406 UNIPROT up-regulates activity phosphorylation Ser151 LKIISNAsCTTNCLA 9606 BTO:0000578 37450367 YES miannu Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation.  0.2 SIGNOR-277840 NUPR1 protein O60356 UNIPROT ATF4 protein P18848 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19946894 NO lperfetto Nuclear protein 1 induced by ATF4 in response to various stressors acts as a positive regulator on the transcriptional activation of ATF4. 0.386 SIGNOR-253731 SGK1 protein O00141 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Ser1217 PGIMRRNsLSGSSTG 9606 27517916 YES miannu Constitutively active SGK1 S422D phosphorylates WNK4 at Ser-1169 [ xref ] and Ser-1196 [ xref ], relieving the inhibitory effect of WNK4 on NCC\u2019s activity [ xref , xref ].|SGK1 is thought to modulate NCC activity by inhibiting WNK4 , , ]. 0.416 SIGNOR-278453 ATOH7 protein Q8N100 UNIPROT POU4F2 protein Q12837 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 11172005 YES Luana Thus, these data suggest that the expression of Brn3b can be activated directly by Math5 and that it is also subject to positive feedback regulation by Brn3 proteins. 0.475 SIGNOR-261567 MAPK3 protein P27361 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation 9606 14967450 YES gcesareni Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1 0.292 SIGNOR-121991 PKA proteinfamily SIGNOR-PF17 SIGNOR SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 10571231 YES miannu Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation 0.2 SIGNOR-264108 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CAD protein P27708 UNIPROT up-regulates activity phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 BTO:0000007 23429703 YES Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. 0.2 SIGNOR-267197 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR FXR1 protein P51114 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 29142209 YES miannu Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinomaThe Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4.  0.315 SIGNOR-272797 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 9651347 YES gcesareni Our results indicate that ca2+ ions not only anchor the protein to membrane surfaces but also induce conformational changes resulting in pkc activation. 0.8 SIGNOR-58506 PHF12 protein Q96QT6 UNIPROT TLE3 protein Q04726 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 YES miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. 0.2 SIGNOR-266993 miR-155 mirna URS000062749E_9606 RNAcentral TRIB2 protein Q92519 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 20516212 YES Luisa ZEB2 is upregulated by serum and downregulates GAX, while the expression of miR-221 upregulates GAX and downregulates ZEB2. 0.4 SIGNOR-268956 TRPM7 protein Q96QT4 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Thr1045 LQPESMRtEKYDPMP 9606 22759789 YES miannu We present data indicating that TRPM7 phosphorylates PLCgamma2 at position Ser1164 in the C2-domain, and at position Thr1045 in the linker between the catalytic region and the C2 domain. 0.263 SIGNOR-278459 ATG4B protein Q9Y4P1 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates cleavage 9606 BTO:0000007;BTO:0000567 15187094 YES gcesareni Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16. 0.802 SIGNOR-125449 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 12054501 YES lperfetto Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction 0.442 SIGNOR-249166 MAST1 protein Q9Y2H9 UNIPROT PTEN protein P60484 UNIPROT down-regulates phosphorylation 9606 15951562 YES gcesareni Mast1 was found to associate to pten. 0.516 SIGNOR-138003 ATM protein Q13315 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity phosphorylation Ser214 KIQELQAsQEARADH 9606 24728176 YES miannu ATM mediated Mad1 Serine 214 phosphorylation regulates Mad1 dimerization and the spindle assembly checkpoint.|Together, these findings reveal an important role of ATM-mediated Mad1 Serine 214 phosphorylation in mitosis. 0.2 SIGNOR-278467 Nalmefene chemical CHEBI:7457 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258811 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAP2K1 protein Q02750 UNIPROT down-regulates activity phosphorylation Thr386 IGLNQPStPTHAAGV 9606 BTO:0000007 10567369 YES lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 0.2 SIGNOR-244561 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000782 18840653 YES gcesareni Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well. 0.565 SIGNOR-181550 PERP protein Q96FX8 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity ubiquitination 9606 25860612 YES We identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling 0.2 SIGNOR-255843 AURKA protein O14965 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 25217103 YES miannu In addition, Aurora-A overexpression is significantly correlated with increased cytoplasmic \u03b2-catenin expression in esophageal squamous cell carcinoma tissues.|We also demonstrate for the first time that Aurora-A directly interacts with \u03b2-catenin and phosphorylates \u03b2-catenin at Ser552 and Ser675. 0.346 SIGNOR-278468 SIRT2 protein Q8IXJ6 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 14522900 NO miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. 0.257 SIGNOR-254487 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding -1 9774108 YES gcesareni Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells. It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade. 0.876 SIGNOR-60663 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation Tyr397 SVSETDDyAEIIDEE 10090 BTO:0000944 19595712 YES We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis. 0.539 SIGNOR-248661 FZD3 protein Q9NPG1 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 14977528 YES gcesareni Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. 0.244 SIGNOR-122889 CRBN protein Q96SW2 UNIPROT SALL4 protein Q9UJQ4 UNIPROT down-regulates quantity by destabilization binding 9606 32071327 YES miannu Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phenocopy thalidomide-induced limb defects in humans. 0.2 SIGNOR-272208 WNT7B protein P56706 UNIPROT FZD10 protein Q9ULW2 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763;BTO:0001260 15923619 YES gcesareni Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling 0.645 SIGNOR-137934 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10980595 YES lperfetto We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway 0.2 SIGNOR-244692 SMURF proteinfamily SIGNOR-PF29 SIGNOR BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 YES inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps. 0.2 SIGNOR-270215 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 10209155 YES Amphiregulin is an autocrine growth factor lperfetto ErbB ligands include: EGF, transforming growth factor (TGF)_, and amphiregulin which only bind ErbB1 0.771 SIGNOR-67000 KDM1A protein O60341 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000567 15620353 YES miannu Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. 0.2 SIGNOR-264509 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT down-regulates phosphorylation 9606 25855382 YES miannu Based on the mechanism of Plk1 mediated degradation of SUZ12 and ZNF198 described in this study (XREF_FIG), we quantified expression levels of Plk1 and HOTAIR RNAs in liver tumors from X/c-myc bitransgenic mice.|We interpret these results to mean that HOTAIR facilitates ubiquitination of Plk1 phosphorylated SUZ12 and ZNF198 proteins, thereby accelerating their proteasomal degradation. 0.376 SIGNOR-278491 RUNX2 protein Q13950 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11331591 NO lperfetto Together, these results suggest that the inhibition of cbfa1 transcription by TGF-_ requires both the presence of CBFA1 and CBFA1 binding to the cbfa1 promoter. 0.2 SIGNOR-235533 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr449 IIQHCSNySTQELLR 9606 BTO:0000793 29022905 YES miannu In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation. 0.26 SIGNOR-277327 STK3 protein Q13188 UNIPROT Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates phosphorylation 9606 21808241 YES The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. 0.86 SIGNOR-269855 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24024136 YES irozzo In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs). 0.678 SIGNOR-256276 SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity 9606 24600449 NO miannu A main role of SOCS3 results from its binding to both the JAK kinase and the cytokine receptor, which results in the inhibition of STAT3 activation. 0.708 SIGNOR-255330 CAMK2G protein Q13555 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity phosphorylation Ser1076 NVASRMEsTGVMGNI 9606 BTO:0000007 8798667 YES llicata Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. | Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo. 0.554 SIGNOR-267845 Ub:E2 complex SIGNOR-C497 SIGNOR RNF39 protein Q9H2S5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271223 PRKCB protein P05771 UNIPROT protein Q5T7P8 UNIPROT up-regulates activity phosphorylation Thr283 DRKCKLQtRVHRKTL 9606 BTO:0001277 16111671 YES miannu We found by site-directed mutagenesis that Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain--a key region for the function of synaptotagmins--are the PKC target that regulates its inhibitory effect on acrosomal exocytosis. Similarly, we showed that Thr284 in the polybasic region of C2A (KCKLQTR) is the target for PKC-mediated phosphorylation in this domain. 0.2 SIGNOR-273565 ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) 0.8 SIGNOR-256035 SP1 protein P08047 UNIPROT CRX protein O43186 UNIPROT up-regulates activity binding 9606 15781457 YES miannu Zinc finger DNA-binding domains of both Sp1 and Sp3 interact with Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains. 0.324 SIGNOR-225336 PTEN protein P60484 UNIPROT ABI1 protein Q8IZP0 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser216 VPNDYMTsPARLGSQ 9606 32673396 YES lperfetto After dephosphorylation by PTEN, Abi1 is degraded by calpains.|We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway. 0.241 SIGNOR-276949 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser723 ELDYPMGsFEPSPYP 9606 BTO:0000567 34198826 YES miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. 0.25 SIGNOR-276658 MCU protein Q8NE86 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.724 SIGNOR-270865 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001950 25487801 YES Luana Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections.  0.8 SIGNOR-262312 KLHL20 protein Q9Y2M5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 26687681 YES miannu Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1 0.249 SIGNOR-272413 NUP42 protein O15504 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.2 SIGNOR-262097 Ub:E2 complex SIGNOR-C497 SIGNOR RC3H2 protein Q9HBD1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271006 MLL2 complex complex SIGNOR-C88 SIGNOR KDM6A protein O15550 UNIPROT up-regulates quantity by stabilization binding 9606 28669924 YES miannu KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. UTX is the complex’s H3K27 demethylase. 0.813 SIGNOR-268813 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser206 SSSTYPHsPTSSDPG 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.497 SIGNOR-248315 PLK1 protein P53350 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 12493754 YES gcesareni Plk1 overexpression enhances phosphorylation of chk2 at thr-68. 0.492 SIGNOR-96637 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser23 YLQARKPsDCDSKEL -1 15946941 YES miannu  We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA.Phosphorylation of GRK1 and GRK7 by PKA reduces the ability of GRK1 and GRK7 to phosphorylate rhodopsin in vitro. 0.2 SIGNOR-276036 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Thr346 TGENAGQtPMNINPQ 26375055 YES lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity 0.262 SIGNOR-276525 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. 0.569 SIGNOR-164479 CEBPB protein P17676 UNIPROT SFTPD protein P35247 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001910 11912209 YES Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D. 0.251 SIGNOR-254045 ERBB2 protein P04626 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 15173068 YES gcesareni The results presented here show for the first time that er redistribution to the cytoplasm and its interaction with her2 are important downstream effects of her2 overexpression, that erk1/2 is important for er cytoplasmic localization, and that subcellular localization of er may play a mechanistic role in determining the responsiveness of breast cancer cells to tamoxifen. 0.573 SIGNOR-124962 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Thr43 KVTTVVAtPGQGPDR 9606 BTO:0000150;BTO:0000680 16039586 YES lperfetto Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. 0.383 SIGNOR-138894 MAST2 protein Q6P0Q8 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation 9606 15951562 YES gcesareni We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status. 0.667 SIGNOR-138051 PAS complex complex SIGNOR-C190 SIGNOR 1-phosphatidyl-1D-myo-inositol 3-phosphate smallmolecule CHEBI:17283 ChEBI down-regulates quantity chemical modification -1 18950639 YES miannu PtdIns(3,5)P2 is synthesized from PtdIns(3)P through the action of mammalian PIKfyve or the yeast counterpart Fab1, both sole enzymes for PtdIns(3,5)P2 synthesis. PIKfyve and Fab1, in turn, are activated by the orthologous proteins, mammalian ArPIKfyve and yeast Vac14, to upregulate intracellular PtdIns(3,5)P2 production. PtdIns(3,5)P2 turnover is catalyzed, at least in part, by mammalian Sac3 or its yeast counterpart Fig4 0.8 SIGNOR-253533 IRS1 protein P35568 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10116 BTO:0001103 21798082 YES lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2). 0.767 SIGNOR-252694 PHLPP1 protein O60346 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates activity dephosphorylation Thr390 DSKFTRQtPVDSPDD 9606 21986499 YES gcesareni Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP. 0.573 SIGNOR-237454 RARA protein P10276 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 NO lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. 0.253 SIGNOR-268548 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr577 RRPPGLDySFDTCKP 9606 BTO:0000007 11294897 YES lperfetto Ligand stimulation leads to autophosphorylation of fgfr3 the absence of y577 (3y-577f) or y760 (3y-760f) resulted in a modest decrease in activity. 0.2 SIGNOR-106726 HAX1 protein O00165 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 18971376 YES lperfetto The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels. 0.37 SIGNOR-262052 PSMA4 protein P25789 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.843 SIGNOR-263366 MK-2461 chemical CID:44137946 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194390 XIAP protein P98170 UNIPROT TLE3 protein Q04726 UNIPROT up-regulates activity ubiquitination 9606 22304967 YES miannu These findings suggest that TLE3 ubiquitylation by XIAP may be required during Wnt pathway activation to facilitate its dissociation from TCF/Lef, allowing subsequent beta-catenin binding and transcriptional activation. 0.505 SIGNOR-278528 POLA1 protein P09884 UNIPROT DNA polymerase alpha:primase complex complex SIGNOR-C262 SIGNOR form complex binding -1 24043831 YES lperfetto At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation  0.98 SIGNOR-261343 AMER1 protein Q5JTC6 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000038 21498506 YES lperfetto We show that Amer1 binds directly to beta-catenin via a novel interaction motif, the REA repeats. This amino acid motif, including the core sequence arginine, glutamic acid and alanine, and this REA repeats mediate binding of Amer1 to the armadillo repeats of beta-catenin. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the plasma membrane. 0.776 SIGNOR-217950 CAMK2A protein Q9UQM7 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser643 CFTPKGSsLKIEERA 9606 BTO:0001260 2170388 YES gcesareni Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii 0.2 SIGNOR-22631 TWIST2 protein Q8WVJ9 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 21931630 NO miannu Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2. 0.471 SIGNOR-255592 TUBA8 protein Q9NY65 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 NO miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. 0.7 SIGNOR-269729 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0003892 11731619 YES PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site 0.378 SIGNOR-248657 NR3C1 protein P04150 UNIPROT NR3C2 protein P08235 UNIPROT up-regulates 9606 11154266 NO lperfetto These results indicate that functional interactions between the glucocorticoid and mineralocorticoid receptors in activating specific gene transcription are probably more complex than has been previously appreciated. 0.541 SIGNOR-85987 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser346 RAPSRKDsLESDSST 9606 21317289 YES gcesareni We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation 0.466 SIGNOR-172003 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4B protein O94953 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273466 CDK1 protein P06493 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Ser242 IPNGFGTsPLTPSAR -1 12556484 YES done miannu In this case, only NudelS2 and NudelS5 were phosphorylated. Therefore, T219, S242, and T245 of Nudel were phosphorylation sites of Cdc2 in vitro. In contrast, Erk2 only phosphorylated T219 and T245. These two sites, with surrounding sequences such as PATP from residues 217 to 220 and PLTP from 243 to 246, respectively, are indeed typical MAPK sites 0.659 SIGNOR-274073 Ub:E2 complex SIGNOR-C497 SIGNOR XIAP protein P98170 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271045 KDM5D protein Q9BY66 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264310 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264924 SMURF1 protein Q9HCE7 UNIPROT RAD23A protein P54725 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.293 SIGNOR-272691 EFNA1 protein P20827 UNIPROT EPHA6 protein Q9UF33 UNIPROT up-regulates binding 9606 9576626 YES tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity 0.81 SIGNOR-56962 diazepam chemical CHEBI:49575 ChEBI GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. 0.8 SIGNOR-263797 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Ser239 LIRGVKSsGKVVYFT 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.332 SIGNOR-262918 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates activity phosphorylation Ser405 QARAHGLsLIPSTGL -1 10587587 YES miannu Here, we show that Ser298, which locates downstream of the bHLHZip and was previously found to be mutated in individuals with WS2, plays an important role in MITF function. Glycogen synthase kinase 3 (GSK3) was found to phosphorylate Ser298 in vitro, thereby enhancing the binding of MITF to the tyrosinase promoter.  0.436 SIGNOR-275967 TRIM32 protein Q13049 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26307407 YES miannu This further supports that TRIM32 and Oct4 do physically interact, so that TRIM32 can specifically ubiquitinate Oct4 and thereby target it for degradation. 0.268 SIGNOR-278620 RPL5 protein P46777 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.894 SIGNOR-262457 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.604 SIGNOR-263432 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation Ser46 PASYSFCsGKGVGIK 9606 SIGNOR-C110 12000790 YES gcesareni We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45 . This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45) 0.554 SIGNOR-87437 tolbutamide chemical CHEBI:27999 ChEBI CFTR protein P13569 UNIPROT down-regulates activity chemical inhibition 10090 1281220 YES miannu The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively. 0.8 SIGNOR-258345 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 14585074 YES amattioni Trail interacts with tril-r1 and trail-r2 and activetes them 0.934 SIGNOR-101313 INS protein P01308 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates 9606 22521266 NO gcesareni In conclusion,insulinlikely promotes mkp-3 protein degradation 0.382 SIGNOR-197203 SP3 protein Q02447 UNIPROT IFITM5 protein A6NNB3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23530031 NO miannu Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation. 0.2 SIGNOR-254220 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258268 CRH protein P06850 UNIPROT KRT14 protein P02533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15468147 YES Regulation miannu CRH stimulated the expression of cytokeratin 1 and involucrin, and inhibited cytokeratin 14 on both mRNA and protein levels. 0.2 SIGNOR-251899 NHLRC1 protein Q6VVB1 UNIPROT SLC1A2 protein P43004 UNIPROT up-regulates activity ubiquitination 9606 33368637 YES miannu On the contrary, overexpression of the laforin/malin complex promotes the retention of GLT-1 at the plasma membrane.|This is due to a direct ubiquitination of GLT-1 by laforin and malin and/or to changes in the dynamics of its Nedd4.2-mediated endocytosis, which is assisted by specific adaptors (\u03b1- and \u03b2-arrestins). 0.2 SIGNOR-278586 STUB1 protein Q9UNE7 UNIPROT CBX4 protein O00257 UNIPROT down-regulates quantity by destabilization ubiquitination Lys178 LQYQGGHkEAPSPTC 9606 BTO:0002181 32111827 YES miannu The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.  0.2 SIGNOR-277513 SLC34A3 protein Q8N130 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 BTO:0000671 11880379 YES lperfetto Growth is critically dependent on the retention of a variety of nutrients. The kidney contributes to this positive external balance. In the present study, we isolated a cDNA from the human and rat kidney that encodes a growth-related Na(+)-dependent inorganic phosphate (P(i)) cotransporter (type IIc). 0.8 SIGNOR-270577 RUNX1 protein Q01196 UNIPROT CDKN2A protein Q8N726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12091906 NO irozzo AML1 binds to a six base pair DNA sequence (TGT/cGGT) that is present in many hematopoietic-specific genes.The p53 promoter does not contain any perfect AML1 DNA-binding sites (TGT/cGGT), but the human p14ARF promoter contains eight such sites (Fig. 1a), as well as multiple sites that match the broader consensus sequence (PyGPy/AGGT) or that have a single change from the consensus site.AML1 regulates the p14ARF promoter through an AML1 consensus DNA-binding site. 0.264 SIGNOR-255713 PDGFRB protein P09619 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 7535778 YES miannu Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production. 0.859 SIGNOR-28179 Neurofibrillary tangle formation phenotype SIGNOR-PH58 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11578751 NO lperfetto Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death 0.7 SIGNOR-251641 FLI1 protein Q01543 UNIPROT COL1A2 protein P08123 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24058639 NO miannu Fli1 functions as a potent transcriptional repressor of the col1a2 gene 0.246 SIGNOR-202685 aminoglutethimide chemical CHEBI:2654 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates activity chemical inhibition -1 19470632 YES Luana  A new naturally occurring relatively common alteration of enzyme structure at T201M increases enzyme activity and reduces the inhibitory effect of aminoglutethimide. 0.8 SIGNOR-257824 SMOC1 protein Q9H4F8 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 NO Giorgia The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells 0.2 SIGNOR-260385 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273075 OPALIN protein Q96PE5 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 18490449 NO SimoneGraziosi Opalin protein is a type 1 transmembrane sialylglycoprotein and an oligodendrocyte-specific component of myelin membranes. 0.7 SIGNOR-269229 KDM5B protein Q9UGL1 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264302 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM75 protein A6NK02 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271139 EPHB1 protein P54762 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates activity phosphorylation Tyr928 SAIKMVQyRDSFLTA 10029 BTO:0000246 12223469 YES  Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity. 0.2 SIGNOR-251123 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 YES gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.727 SIGNOR-55310 GPR35 protein Q9HC97 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256996 TPP1 protein O14773 UNIPROT Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR up-regulates 9606 22101936 NO miannu The mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres.  0.7 SIGNOR-272723 NGF protein P01138 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001676 16190874 NO miannu We examined intracellular signals required for NGF-induced expression of the GCH gene in PC12D cells. The activity of GCH was increased up to 5-fold after the NGF treatment. The human GCH promoter activity was significantly enhanced by NGF treatment. 0.25 SIGNOR-252228 CSNK2A1 protein P68400 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation Ser565 VISSSEDsDAENSSS 9606 BTO:0000551 16873060 YES llicata Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517. 0.342 SIGNOR-148310 FLT3 protein P36888 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 26049753 NO SIRT1 protein but not mRNA expression is increased in CD34+ cells from FLT3-ITD positive AML patients compared to FLT3 wild-type AML patients 0.35 SIGNOR-261555 Ub:E2 complex SIGNOR-C497 SIGNOR IHO1 protein Q8IYA8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271239 FYN protein P06241 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Tyr1320 NTTAMTIyENLAPVT 9606 BTO:0000007 22898603 YES miannu  We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. 0.366 SIGNOR-276374 FLT3 protein P36888 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14981546 NO FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression 0.322 SIGNOR-261525 PALB2 protein Q86YC2 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity binding 9606 BTO:0001938 19369211 YES lperfetto The BRCA1-PALB2 interaction is required for homologous recombination repair.Here, we report that PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex. 0.85 SIGNOR-244487 NXPH1 protein P58417 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 YES gcesareni Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1 0.549 SIGNOR-62775 ITGA4 protein P13612 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.809 SIGNOR-253175 TAOK2 protein Q9UL54 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 BTO:0001130 10660600 YES lperfetto Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway. 0.259 SIGNOR-74864 SIRT6 protein Q8N6T7 UNIPROT ME1 protein P48163 UNIPROT down-regulates activity deacetylation Lys337 KIWLVDSkGLIVKGR 31735643 YES lperfetto PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. 0.25 SIGNOR-275572 zotepine chemical CHEBI:32316 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258553 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.667 SIGNOR-258416 MRPS18C protein Q9Y3D5 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.701 SIGNOR-261450 HNF4A protein P41235 UNIPROT GFER protein P55789 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 18513187 NO miannu We also confirmed that activation and repression of hHSS transcription induced by Sp1 and HNF4alpha resulted from binding of these factors to these two cis-elements respectively. Overexpression of HNF4alpha led to a dramatic repression of the promoter activity and, in contrast, the activity was markedly elevated by overexpression of Sp1. 0.2 SIGNOR-254449 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT up-regulates activity phosphorylation 9606 20651737 YES lperfetto Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes. 0.698 SIGNOR-167060 Quadazocine chemical CID:115077 PUBCHEM OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258419 BTRC protein Q9Y297 UNIPROT YAP1 protein P46937 UNIPROT down-regulates ubiquitination 9606 SIGNOR-C5 23431053 YES gcesareni This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap. 0.543 SIGNOR-201138 DMPK protein Q09013 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 YES llicata Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.  0.289 SIGNOR-236982 LTB protein Q06643 UNIPROT LTBR protein P36941 UNIPROT up-regulates activity binding 9606 BTO:0000782 BTO:0000975 7995952 YES lperfetto These experiments point toward the lt-alpha 1/beta 2 complex as the predominant membrane form of lt on the lymphocyte surface, and this complex is the primary ligand for the lt-beta receptor. 0.843 SIGNOR-35759 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21697284 YES gcesareni Cocrystallization of the met kinase domain in complex with nvp-bvu972 revealed a key role for y1230 in binding of nvp-bvu972, as previously reported for multiple other selective met inhibitors. 0.8 SIGNOR-174555 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2I protein P63279 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.439 SIGNOR-271346 SCF-FBW7 complex SIGNOR-C135 SIGNOR SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 30865892 YES miannu Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. 0.2 SIGNOR-277444 UTS2R protein Q9UKP6 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.265 SIGNOR-257252 AKT1 protein P31749 UNIPROT HK2 protein P52789 UNIPROT up-regulates activity phosphorylation Thr473 QHRARQKtLEHLQLS 9606 BTO:0000192 31435020 YES K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization 0.445 SIGNOR-259984 AKT1 protein P31749 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR 9606 BTO:0000132 10896934 YES gcesareni A survey of several protein kinases revealed that Thr-753 was avidly phosphorylated by PDK1 and Akt/PKB in vitro. These observations suggest that activation of PDK1 and/or Akt/PKB in platelets may modulate the binding activity and/or specificity of beta(3) for signaling molecules. 0.612 SIGNOR-252552 AMPK complex SIGNOR-C15 SIGNOR SREBF1 protein P36956 UNIPROT down-regulates phosphorylation 9606 21892142 YES lperfetto Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation 0.317 SIGNOR-216564 FOXC1 protein Q12948 UNIPROT SOX4 protein Q06945 UNIPROT up-regulates quantity by expression transcriptional regulation 31650548 NO lperfetto Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX15 0.32 SIGNOR-275917 MAP4K3 protein Q8IVH8 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity phosphorylation Ser480 NTVWKQLsSSVTGLT -1 31431460 YES miannu GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration.  0.2 SIGNOR-277479 PHF12 protein Q96QT6 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 YES miannu Pf1 interacts with mSin3A in vivo. Gal4-Pf1 repressed activity of the reporter gene fivefold relative to Gal4 alone (Fig. ​(Fig.5A),5A), suggesting that DNA-bound Pf1 was capable of recruiting functional mSin3A complexes. 0.796 SIGNOR-266995 ADD1 protein P35611 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 YES lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] 0.341 SIGNOR-266037 MAPK14 protein Q16539 UNIPROT F3 protein P13726 UNIPROT down-regulates phosphorylation Ser290 GQSWKENsPLNVS 9606 23195225 YES lperfetto We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. Our current study has identified p38_ as a major kinase, responsible for the phosphorylation of ser258 within the cytoplasmic domain of tf 0.291 SIGNOR-199868 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR IGF2 protein P01344 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 YES miannu Insulin-like growth factor is required for RMS cell growth and IGF2 is expressed in an autocrine manner by the tumour cells. The IGF2 locus shows a loss of imprinting in both ERMS and ARMS tumours and expression of PAX3-FOXO1 can induce the upregulation of IGF2, thus enhancing the activation of IGF signalling pathway in ARMS 0.2 SIGNOR-251573 EGFR protein P00533 UNIPROT EZR protein P15311 UNIPROT unknown phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 BTO:0000017 15647376 YES lperfetto Here we report the identification of the tyrosine phosphorylation sites in ezrin using bacterially expressed protein as a substrate for in vitro phosphorylation with the egf receptor. tyrosines 145 and 353 were identified as the sites of phosphorylation. but as of yet the role of ezrin phosphorylation at y145 is unknown. 0.53 SIGNOR-133219 EDN1 protein P05305 UNIPROT MC1R protein Q01726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9767234 NO miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. 0.351 SIGNOR-252386 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 9606 SIGNOR-C3 18722121 YES llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity 0.2 SIGNOR-252773 BLOC-1 complex SIGNOR-C381 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 NO lperfetto BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton. 0.7 SIGNOR-265940 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr74 SAHARKEtEFLRLKR 9606 12493777 YES lperfetto We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo 0.2 SIGNOR-96687 PRKCB protein P05771 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity phosphorylation Ser466 SKASSRRsSFSMEEG 10090 23599343 YES This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor. 0.33 SIGNOR-255315 GABRA6 protein Q16445 UNIPROT GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.536 SIGNOR-263771 4-fluoro-N-{2-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]ethyl}benzamide chemical CHEBI:64101 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258893 NARS2 protein Q96I59 UNIPROT tRNA(Asn) smallmolecule CHEBI:29172 ChEBI down-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270461 GLUD1 protein P00367 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9913 11254391 YES Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. 0.8 SIGNOR-266916 SH2B1 protein Q9NRF2 UNIPROT CD79A protein P11912 UNIPROT down-regulates activity dephosphorylation 9606 32323266 YES scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. 0.2 SIGNOR-268457 CUL1 protein Q13616 UNIPROT RNF7 protein Q9UBF6 UNIPROT up-regulates activity binding 9606 10851089 YES miannu SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34.  0.856 SIGNOR-271444 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation 9606 16082221 YES gcesareni Atm directly and indirectly induces mdm2 and mdmx phosphorylation, resulting in decreased activity and stability of these proteins. We recently provided a mechanism for the reduced stability of mdm2 and mdmx by showing that atm-dependent phosphorylation lowers their affinity for the deubiquitinating enzyme hausp. 0.734 SIGNOR-139403 JAK2 protein O60674 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates phosphorylation Tyr738 WDQEAQIyELVAQTV 9606 20098430 YES gcesareni We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1 0.326 SIGNOR-163557 C4B protein P0C0L5 UNIPROT C3 convertase complex complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 YES complement C4b fragment:PRO_0000042703 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex 0.669 SIGNOR-263398 ACADVL protein P49748 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 20490924 YES miannu VLCAD is a dimer of two identical subunits bound to the inner mitochondrial membrane (Fig. 1) and accepts long chain acyl-CoAs as substrate (Fig. 4a).The different ACADs catalyze the following reaction: acyl-CoA + FAD - trans-2-enoyl-CoA + FADH2 0.8 SIGNOR-280304 OFD1 protein O75665 UNIPROT ATG13 protein O75143 UNIPROT down-regulates quantity by destabilization binding 9606 34027042 YES miannu The OFD1 protein inhibits autophagosome biogenesis by selective autophagy-mediated degradation of Autophagy Related 13 (ATG13), a component of the unc-51-like kinase (ULK1) autophagy initiation complex. 0.2 SIGNOR-269107 APIP protein Q96GX9 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 15262985 YES acerquone Taken together, these results suggest that apip functions to inhibit muscle ischemic damage by binding to apaf-1 in the apaf-1/caspase-9 apoptosis pathway. 0.526 SIGNOR-126797 RSPO2 protein Q6UXX9 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 YES Thrombospondin domains gcesareni We show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling. 0.265 SIGNOR-172719 AURKA protein O14965 UNIPROT PHLDA1 protein Q8WV24 UNIPROT down-regulates quantity by destabilization phosphorylation Ser95 PLCLLRVsLLCALRA 9606 BTO:0006218 21807936 YES miannu Aurora A directly phosphorylates PHLDA1 leading to its degradation. Aurora A phosphorylates PHLDA1 at Ser 98. 0.445 SIGNOR-273545 SRC protein P12931 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates activity phosphorylation Tyr179 TSCGSPNyAAPEVIS 9606 BTO:0002181 34673141 YES miannu We show here that Src signaling leads to direct phosphorylation of the AMPK-α subunit on a novel site, tyrosine 179, resulting in suppression of AMPK-T172 phosphorylation and autophagy upon integrin-mediated cell adhesion. 0.258 SIGNOR-277573 PIK3C2A protein O00443 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 9430633 NO gcesareni Activation of pi 3-kinase causes plc gamma ph domain-mediated membrane targeting and plc gamma activation. 0.398 SIGNOR-54707 PRKDC protein P78527 UNIPROT NR3C1 protein P04150 UNIPROT unknown phosphorylation Ser508 QQATTGVsQETSENP -1 9038175 YES lperfetto Phosphorylation of the GR fusion protein by DNA-PK mapped to a single site, Ser-527. This site occurs adjacent the GR nuclear localization sequence between the DNA and ligand binding domains of GR, and thus its phosphorylation, if confirmed, has the potential to affect receptor function in vivo. 0.349 SIGNOR-248965 PLK1 protein P53350 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates activity phosphorylation Thr1363 AGPHVPFtVFEEVCP 9606 BTO:0002181 17974570 YES miannu Although mutation of serine 1126 and threonine 1346 to alanine had no effect (lanes 2 and 5), additional mutation of threonine 1363 and serine 1399 rendered separase almost completely resistant to phosphorylation (lane 3). Serine 1399 seems to be the one residue within this large separase fragment that is most efficiently phosphorylated by polo-like kinase, because a corresponding point mutation was sufficient to reduce the labeling by 80% compared with wild type (lane 6). 0.771 SIGNOR-276083 PTTG1 protein O95997 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002430 19351864 NO miannu PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR. 0.271 SIGNOR-255070 ACADVL protein P49748 UNIPROT FAD(3-) chemical CHEBI:57692 ChEBI down-regulates quantity chemical modification 9606 20490924 YES miannu VLCAD is a dimer of two identical subunits bound to the inner mitochondrial membrane (Fig. 1) and accepts long chain acyl-CoAs as substrate (Fig. 4a).The different ACADs catalyze the following reaction: acyl-CoA + FAD - trans-2-enoyl-CoA + FADH2 0.8 SIGNOR-280305 TRIM41 protein Q8WV44 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 17893151 YES miannu RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear. 0.318 SIGNOR-271667 AIFM2 protein Q9BRQ8 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0003000 12135761 NO miannu The PRG3 gene is a potential p53 target gene in a p53‐dependent apoptosis pathway. These results clearly indicate that the ectopic expression of PRG3 induces apoptosis. 0.7 SIGNOR-261809 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates phosphorylation Ser187 RIMEKADsNKTRIDE 9606 BTO:0000938 18171919 YES llicata Phosphorylation of snap-25 at ser187 mediates enhancement of exocytosis by a phorbol ester in ins-1 cells. 0.353 SIGNOR-160313 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.32 SIGNOR-161658 FASTKD2 protein Q9NYY8 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 NO miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. 0.7 SIGNOR-261227 AZD-8055 chemical CHEBI:91329 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;ATP-competitive inhibitor mTOR gcesareni 0.8 SIGNOR-190215 hsa-mir-494-3p mirna URS0000535FDD_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001061 24644030 YES The constitutive overexpression of miR-494 downregulated the protein level of CXCR4, leading to suppression of proliferation, invasion, and migration of prostate cancer. 0.4 SIGNOR-277942 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr102 RAAMFPEtLDEGMQI 9606 BTO:0000007 12432063 YES llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin 0.6 SIGNOR-251066 ATM protein Q13315 UNIPROT FANCI protein Q9NVI1 UNIPROT unknown phosphorylation Ser730 LDKSADFsQSTSIGI 9606 BTO:0000007 17412408 YES Three phosphorylation sites were detected in a human KIAA1794 protein: S730, T952, S1121, and two other sites in the mouse protein S555, T558. We renamed the KIAA1794 protein as FANCI, since, as shown below, the locus encoding this protein is mutated in an individual with Fanconi anemia complementation group I 0.527 SIGNOR-255590 protein P0DOX5 UNIPROT Pr3-ANCA complex SIGNOR-C475 SIGNOR form complex binding 9606 27464484 YES lperfetto Although the majority of PR3-ANCAs are of the IgG isotype, the results of one study showed that PR3-ANCAs of the IgA isotype were present in up to 30% of patients with GPA SIGNOR-270594 protein P0DOX5 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR form complex binding 9606 27464484 YES lperfetto Although MPO-ANCAs of the IgA isotype are sometimes found in patients with IgA nephropathy or IgA vasculitis45, isotypes other than IgG have not been reported in patients with typical AAV, with the exception of a single patient with pauci-immune crescentic glomerulonephritis SIGNOR-270595 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation 9606 18243099 YES amattioni Direct phosphorylation of the aurora b regulator borealin by mps1 enhances aurora b activity and is essential for chromosome alignment 0.462 SIGNOR-160604 PCNA protein P12004 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR up-regulates activity binding 9534 BTO:0004055 12930972 YES lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). 0.773 SIGNOR-265511 MTNR1A protein P48039 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257101 ETV6 protein P41212 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15958056 NO Regulation of expression miannu Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis 0.2 SIGNOR-251793 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1195 HGHVSDAsISLGESV -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262905 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000007 19126544 YES lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. 0.486 SIGNOR-236030 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPA protein P49715 UNIPROT down-regulates activity binding 9606 12524424 YES lperfetto C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs. 0.367 SIGNOR-250571 MET protein P08581 UNIPROT MET protein P08581 UNIPROT up-regulates phosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 8302603 YES lperfetto Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation 0.2 SIGNOR-37723 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR TIAM1 protein Q13009 UNIPROT down-regulates quantity by destabilization phosphorylation Ser329 DVNAGEGsEFADSGI 9606 BTO:0002181 25124033 YES miannu Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site. 0.2 SIGNOR-276674 CDK1 protein P06493 UNIPROT USP9X protein Q93008 UNIPROT up-regulates activity phosphorylation Ser2547 YEGSEEVsPPQTKDQ 32152317 YES Phosphosites were derived from Figure S1 lperfetto Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. 0.279 SIGNOR-275608 NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32133002 NO miannu Both the NLRP3 inflammasome activation and the subsequent inflammation play significant roles in defending against viral infections. However, aberrant NLRP3 inflammasome activation or chronic inflammation can also lead to severe pathological injury. Accordingly, activation of the NLRP3 inflammasome and its associated inflammation is a double-edged sword for host to defense viral infection. Modulating the NLRP3 inflammasome activity can prove to be a promising strategy for the intervention of viral diseases. 0.7 SIGNOR-260346 FGFR2 protein P21802 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17543283 NO lperfetto Furthermore, in cultures receiving FGF-2 before adipogenic induction, mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a key transcription factor in adipogenesis, was upregulated. 0.282 SIGNOR-236220 Chaperone-mediated autophagy phenotype SIGNOR-PH118 SIGNOR HK2 protein P52789 UNIPROT down-regulates quantity by destabilization 9606 BTO:0004424 26323688 YES Our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability. 0.7 SIGNOR-261247 TGFBR1 protein P36897 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 18922473 YES gcesareni We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors 0.429 SIGNOR-241918 TRIM7 protein Q9C029 UNIPROT STING1 protein Q86WV6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 32126128 YES miannu RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation.|Finally, in vitro ubiquitination assays suggested that RNF90 promoted the ubiquitination of MITA directly (Fig 5E and 5F). 0.2 SIGNOR-278678 AKT proteinfamily SIGNOR-PF24 SIGNOR CLK2 protein P49760 UNIPROT up-regulates phosphorylation Thr127 RRRRRSRtFSRSSSQ 9606 BTO:0000567 20682768 YES lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva 0.2 SIGNOR-244218 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB4 protein P16144 UNIPROT up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.2 SIGNOR-259003 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 BTO:0000142 16401070 YES lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. 0.503 SIGNOR-143481 SS18 protein Q15532 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.628 SIGNOR-269782 MAPK8 protein P45983 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser205 GDNMLEPsPNMPWFK 9606 BTO:0002181 23608534 YES miannu Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome.  0.374 SIGNOR-276491 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Thr256 EHNSTTStFCGTPEY -1 10191262 YES miannu PDK1 activates SGK in vitro by phosphorylating Thr256. 0.649 SIGNOR-250275 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser111 SPPSPAPsSFSSTSV 9606 15448698 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-129410 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000459 SIGNOR-C13 10469655 YES lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. 0.853 SIGNOR-70473 oxandrolone chemical CHEBI:7820 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 10077001 YES miannu The anabolic steroids, oxandrolone and fluoxymesterone, have high inhibition constants for binding, yet induce the N/C interaction and stabilize AR at relatively low ligand concentrations and are AR agonists in vivo. 0.8 SIGNOR-259265 MAPK11 protein Q15759 UNIPROT MAPK11 protein Q15759 UNIPROT down-regulates activity phosphorylation Ser261 HARTYIQsLPPMPQK -1 26976637 YES miannu P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261 0.2 SIGNOR-277214 HCRTR2 protein O43614 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256729 CREB5 protein Q02930 UNIPROT ATF2 protein P15336 UNIPROT up-regulates activity binding 9534 BTO:0000318 8378084 YES miannu CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription 0.631 SIGNOR-219655 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser792 LTQSAPAsPTNKGVH 10090 SIGNOR-C15 SIGNOR-C3 18439900 YES lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK 0.692 SIGNOR-163463 IL5RA protein Q01344 UNIPROT SOX4 protein Q06945 UNIPROT up-regulates activity binding 10090 BTO:0003104 11498591 YES miannu Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation. 0.417 SIGNOR-223010 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 3063839 NO Regulation of expression miannu Cytokines, notably TNF and IL-1, suppress synthesis of lipoprotein lipase which decreases the rate of TGFA clearance. 0.391 SIGNOR-251853 FGFR1 protein P11362 UNIPROT LDHA protein P00338 UNIPROT up-regulates phosphorylation Tyr83 KIVSGKDyNVTANSK 9606 21969607 YES gcesareni We found that the oncogenic receptor tyrosine kinase fgfr1 directly phosphorylates ldh-a. Phosphorylation at y10 and y83 enhances ldh-a activity by enhancing the formation of active, tetrameric ldh-a and the binding of ldh-a substrate nadh, respectively. 0.367 SIGNOR-176734 RELN protein P78509 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 YES gcesareni The hypothesis that the vldl receptor signals in response to reelin binding was recently supported by studies (37) showing direct binding of reelin to the vldl receptor and changes in tyrosine phosphorylation in response to reelin-vldl receptor association. 0.79 SIGNOR-106295 GSK3B protein P49841 UNIPROT XIAP protein P98170 UNIPROT up-regulates activity phosphorylation Thr180 WPDYAHLtPRELASA 9606 BTO:0002181 29678905 YES miannu  We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAPT180A) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos.  0.395 SIGNOR-277390 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 21035469 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.595 SIGNOR-169154 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser293 FNTLAFPsMKRKDVV -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.657 SIGNOR-276130 LIMK2 protein P53671 UNIPROT SPOP protein O43791 UNIPROT down-regulates activity phosphorylation Ser171 VQDSVNIsGQNTMNM 9606 33311589 YES miannu LIMK2 phosphorylates SPOP at S59, S171 and S226.|Together, these results depict that LIMK2-mediated SPOP degradation is a key mechanism that regulates AR stability. 0.2 SIGNOR-278339 DLGAP2 protein Q9P1A6 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264591 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates activity phosphorylation Ser821 ARDIKNDsNYVVKGN 9823 7539802 YES lperfetto We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling. 0.53 SIGNOR-248897 SLITRK5 protein O94991 UNIPROT SHH protein Q15465 UNIPROT down-regulates activity binding 10090 BTO:0001593 34326333 YES miannu SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation. 0.2 SIGNOR-268437 ROCK1 protein Q13464 UNIPROT MYLK protein Q15746 UNIPROT up-regulates binding 9606 11283607 YES gcesareni Rock proteins are known to regulate mlc-phosphorylation, and apoptotic cells exhibit a gradual increase in levels of phosphorylated mlc concomitant with rock i cleavage. 0.316 SIGNOR-106552 LPAR4 protein Q99677 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257383 AKT1 protein P31749 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity phosphorylation Thr151 FCNGRGNtSGSHIVN 9606 BTO:0002181 35675814 YES miannu AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity 0.258 SIGNOR-277597 MDM2 protein Q00987 UNIPROT ARRB2 protein P32121 UNIPROT down-regulates quantity ubiquitination 9606 21389118 YES miannu Indeed, the ubiquitination of \u03b2-arrestin2 by Mdm2 H457S was severely reduced in comparison to Mdm2 wt ( xref ).|Loss of Mdm2 E3 ligase activity causes dominant nuclear localization of beta-arrestin2. 0.434 SIGNOR-278760 KDM6A protein O15550 UNIPROT ETS2 protein P15036 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 YES miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase 0.2 SIGNOR-260035 FLT3 protein P36888 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14981546 NO FLT3-ITD signaling contributes to transcriptional inhibition of p27Kip1 and Bim gene expression 0.29 SIGNOR-261524 ATM protein Q13315 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser239 DPMTQDGsQPMDTNM 9606 22588298 YES llicata On genotoxic stress, atm phosphorylates bmps-activated smad1 in the nucleus on s239, which disrupts smad1 interaction with protein phosphatase ppm1a, leading to enhanced activation and upregulation of smad1. 0.2 SIGNOR-197533 MVD protein P53602 UNIPROT HRAS protein P01112 UNIPROT up-regulates quantity by stabilization 9534 12646231 NO miannu An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B) 0.2 SIGNOR-265888 PTH1R protein Q03431 UNIPROT CYP27B1 protein O15528 UNIPROT up-regulates quantity 28363951 NO lperfetto These PTH actions are mainly mediated by Gsalpha signaling, which induces the expression of the gene encoding 25-hydroxyvitamin D 1alpha-hydroxylase (Cyp27b1) and destabilizes the transcript encoding vitamin D 24-hydroxylase (Cyp24a1) 0.302 SIGNOR-270554 CHEK2 protein O96017 UNIPROT ELAVL1 protein Q15717 UNIPROT down-regulates activity phosphorylation Thr118 SGLPRTMtQKDVEDM 9606 21745814 YES miannu Given the fact that Chk2 phosphorylates HuR at residues S88, S100 and T118 and that each individual phosphorylation site by Chk2 plays a distinct role in regulating HuR- binding to different target mRNAs, we further tested HuR mutants with alanine substitutions at each of the Chk2 phosphorylation sites. 0.551 SIGNOR-278162 HLF protein Q16534 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23415677 NO miannu Ectopic hlf expression inhibits apoptosis in murine and human cells, suggesting that hlf is regulating a conserved transcriptional program that inhibits cell death. 0.7 SIGNOR-256647 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Thr183 AGTSFMMtPYVVTRY 9606 9312068 YES gcesareni Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues. 0.698 SIGNOR-51199 CSNK2A1 protein P68400 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates phosphorylation Ser463 CNQDERIsKLEQQMA 9606 22355754 YES lperfetto We demonstrate that crn2 is a binding partner and substrate of protein kinase ck2, which phosphorylates crn2 at s463 in its c-terminal coiled coil domain 0.2 SIGNOR-196193 4-[6-[4-(methoxycarbonylamino)phenyl]-4-(4-morpholinyl)-1-pyrazolo[3,4-d]pyrimidinyl]-1-piperidinecarboxylic acid methyl ester chemical CHEBI:94742 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;ATP-competitive inhibitor mTOR gcesareni 0.8 SIGNOR-207809 MAPK1 protein P28482 UNIPROT DDHD1 protein Q8NEL9 UNIPROT unknown phosphorylation Ser727 TIPSPVTsPVLSRRH -1 11328814 YES miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity 0.2 SIGNOR-262972 CNR1 protein P21554 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.254 SIGNOR-257119 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity dephosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 YES gcesareni Pp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. 0.403 SIGNOR-163688 DTNBP1 protein Q96EV8 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 YES lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. 0.808 SIGNOR-265933 SLC4A10 protein Q6U841 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 9606 23056253 YES miannu The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons.  0.8 SIGNOR-264686 CAK complex complex SIGNOR-C456 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 YES lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.851 SIGNOR-269318 RPA2 protein P15927 UNIPROT MRE11 protein P49959 UNIPROT up-regulates binding 9606 19586055 YES fstefani The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. 0.2 SIGNOR-186648 SRC protein P12931 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr859 KKVSSTHyYLLPERP -1 36178070 YES miannu We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity.  0.385 SIGNOR-276342 XIAP protein P98170 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity ubiquitination 9606 19473982 YES miannu Finally, we found that XIAP can directly ubiquitinate PTEN in vitro.|Overexpression of XIAP induces polyubiquitination of PTEN and proteasome dependent decrease of PTEN protein levels. 0.69 SIGNOR-278751 NMBR protein P28336 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.47 SIGNOR-257373 NUP133 protein Q8WUM0 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.744 SIGNOR-262089 PTPRB protein P23467 UNIPROT ALK protein Q9UM73 UNIPROT down-regulates dephosphorylation 9606 BTO:0000785 17681947 YES gcesareni Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation. 0.335 SIGNOR-157175 ENO3 protein P13929 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266526 nilotinib chemical CHEBI:52172 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258258 vorinostat chemical CHEBI:45716 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257920 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Thr357 FELRKTQtSMSLGTT 10090 24012422 YES gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays 0.753 SIGNOR-266429 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000567 20736164 YES irozzo USP8 is known to deubiquitinate EGFR in response to ligand stimulation. USP8 depletion accelerates receptor turnover, whereas loss of hepatocyte growth factor-regulated substrate (Hrs) rescues this phenotype, indicating that USP8 protects EGFR from degradation via an Hrs-dependent pathway. [..]As EGFR stabilization against lysosomal turnover requires deubiquitination by USP8. 0.71 SIGNOR-259102 CDK12 protein Q9NYV4 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr134 LKFYDSNtVKQKYLS 9606 BTO:0004828 32483448 YES lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway 0.2 SIGNOR-273109 RYK protein P34925 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 15454084 YES gcesareni Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled 0.404 SIGNOR-129574 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257453 NHLRC1 protein Q6VVB1 UNIPROT PPP1R3C protein Q9UQK1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18029386 YES miannu Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. We show here that laforin and malin play a crucial role in the regulation of glycogen biosynthesis in FTO2B hepatoma cells. In these cells, the laforin–malin complex counteracts the glycogenic effect of PTG because it promotes its ubiquitination and degradation. 0.74 SIGNOR-271727 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity precursor of 9606 15953811 YES miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. 0.8 SIGNOR-266253 FIZ1 protein Q96SL8 UNIPROT NRL protein P54845 UNIPROT up-regulates activity binding 9913 12566383 YES miannu Interaction of Fiz1 and NRL-leucine zipper was validated by GST pulldown assays and co-immunoprecipitation from bovine retinal nuclear extracts. Fiz1 suppressed NRL- but not CRX-mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells. 0.551 SIGNOR-223796 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 21423276 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-172926 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX58 protein O95786 UNIPROT up-regulates 9606 19052324 YES miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. 0.7 SIGNOR-260141 TXK protein P42681 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9813138 YES lperfetto We demonstrate that rlk (resting lymphocyte kinase) is capable of phosphorylating ctla-4 at the yvkm motif. Consistent with this finding, rlk is capable of providing conditions for the binding of the sh2 domains of pi 3-kinase to the receptor. Ctla-4 is therefore the first known substrate for rlk suggesting the possibility that this kinase may participate in ctla-4 function 0.499 SIGNOR-61624 ARHGAP8 protein P85298 UNIPROT LAMTOR3 protein Q9UHA4 UNIPROT up-regulates activity binding 28092672 YES lperfetto Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. 0.252 SIGNOR-275551 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259705 NFE2L2 protein Q16236 UNIPROT MTHFD2 protein P13995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 NO miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 0.2 SIGNOR-267359 TIGAR protein Q9NQ88 UNIPROT beta-D-fructofuranose 2,6-bisphosphate(4-) smallmolecule CHEBI:58579 ChEBI down-regulates quantity chemical modification 9606 27803158 YES miannu TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR decreases glycolysis by functioning as a bisphosphatase that reduces levels of intracellular fructose-2,6-bisphosphate (Fru-2,6-P2) and 2,3-bisphosphoglycerate (7, 9), which are regulators of glycolysis. 0.8 SIGNOR-267364 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 10090 BTO:0000944 12169099 YES lperfetto c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells 0.501 SIGNOR-235526 SFN protein P31947 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates relocalization 9606 20940406 YES lperfetto Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding 0.2 SIGNOR-168540 MAP3K8 protein P41279 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000007 15466476 YES lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. 0.434 SIGNOR-129694 tandutinib chemical CHEBI:90237 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258298 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser295 LSDTPYDsSASYEKE 9606 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo 0.2 SIGNOR-174848 UBQLN2 protein Q9UHD9 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 10090 BTO:0001976 26521126 NO lperfetto We report that UBQLN2 up-regulation cause a cellular stress which leads to MAPK activation. Interestingly, kinases have been recently shown to have a critical role in TDP-43 accumulation in stress granules following a chronic stress 0.7 SIGNOR-262266 Cortistatin14 smallmolecule CID:16133803 PUBCHEM MRGPRX2 protein Q96LB1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257544 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity phosphorylation Ser142 TGTESMVsHRRERAR 9606 16965538 YES lperfetto Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development. 0.636 SIGNOR-217849 E2F1 protein Q01094 UNIPROT ISYNA1 protein Q9NPH2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 15464731 NO lperfetto Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate.|Here, we have characterized the minimal promoter of ISYNA1 and show that it is upregulated by E2F1. 0.31 SIGNOR-254130 ETS1 protein P14921 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity transcriptional regulation 9606 1722028 YES Furthermore, the possible involvement of an Ets protein in the control of c-fos has interesting implications for proto-oncogene cooperation in cellular growth control. 0.717 SIGNOR-256495 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 15306821 YES lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. 0.787 SIGNOR-127203 ACADVL protein P49748 UNIPROT (E)-hexadec-2-enoyl-CoA(4-) smallmolecule CHEBI:61526 ChEBI up-regulates quantity chemical modification 9606 20490924 YES miannu VLCAD is a dimer of two identical subunits bound to the inner mitochondrial membrane (Fig. 1) and accepts long chain acyl-CoAs as substrate (Fig. 4a).The different ACADs catalyze the following reaction: acyl-CoA + FAD - trans-2-enoyl-CoA + FADH2 0.8 SIGNOR-280306 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 YES lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex 0.416 SIGNOR-216944 superoxide smallmolecule CHEBI:18421 ChEBI SOD1 protein P00441 UNIPROT up-regulates activity precursor of 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272288 PPP1CC protein P36873 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 YES The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation 0.2 SIGNOR-248501 KSR1 protein Q8IVT5 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 YES miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 0.629 SIGNOR-273878 PRKACA protein P17612 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT down-regulates phosphorylation Ser559 KFRRGSGsACSLLCC 9606 17988215 YES llicata The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1. 0.2 SIGNOR-158950 NHLH2 protein Q02577 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21573214 NO miannu Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter. 0.35 SIGNOR-254828 CDK5 protein Q00535 UNIPROT SYN1 protein P17600 UNIPROT up-regulates phosphorylation Ser553 ARPPASPsPQRQAGP 9606 10880969 YES lperfetto Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin. 0.564 SIGNOR-78887 SIRT1 protein Q96EB6 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity deacetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 YES gcesareni SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310. 0.721 SIGNOR-238817 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258648 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 23263282 YES lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) 0.2 SIGNOR-200206 HIF1AN protein Q9NWT6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates hydroxylation Asn1955 LEASADAnIQDNMGR 9606 18299578 YES gcesareni We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation. 0.552 SIGNOR-161057 OXGR1 protein Q96P68 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257368 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT down-regulates activity phosphorylation Ser199 PKRKRKNsRVTFSED -1 9407077 YES miannu NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A 0.486 SIGNOR-250033 PRKACA protein P17612 UNIPROT ADD2 protein P35612 UNIPROT down-regulates activity phosphorylation Ser726 KKKEKVEs -1 8810272 YES miannu Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of - and -adducin, respectively, were identified as the major phosphorylation sites common for PKA and PKC. Phosphorylation by PKA, but not PKC, reduced the affinity of adducin for spectrin-F-actin complexes as well as the activity of adducin in promoting binding of spectrin to F-actin. 0.283 SIGNOR-250333 PRPF31 protein Q8WWY3 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.784 SIGNOR-270643 CACNA1B protein Q00975 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 20655485 YES miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. 0.8 SIGNOR-265069 SNRNP40 protein Q96DI7 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.711 SIGNOR-270644 EP300 protein Q09472 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 SIGNOR-C6 22298955 YES gcesareni Ski and snon also prevent smads from binding to the transcriptional coactivator p300/cbp 0.406 SIGNOR-195582 AKT proteinfamily SIGNOR-PF24 SIGNOR LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr324 GGRSREGtMELRTTP 9606 22044535 YES llicata Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis. 0.2 SIGNOR-177019 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 YES miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. 0.907 SIGNOR-250122 LBX1 protein P52954 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 19651985 YES Luana Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively  0.327 SIGNOR-266054 LHX1 protein P48742 UNIPROT OTX2 protein P32243 UNIPROT up-regulates activity binding 9606 BTO:0000567 10623575 YES miannu Here we show that OTX2 directly associates with LIM1 and HNF-3beta. The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3beta represses, OTX2-directed gene expression. 0.436 SIGNOR-221161 WNT3A protein P56704 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.698 SIGNOR-131826 M2_polarization phenotype SIGNOR-PH55 SIGNOR TGFb proteinfamily SIGNOR-PF5 SIGNOR up-regulates 9606 BTO:0000801 32454942 NO miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation 0.7 SIGNOR-263824 PRC1 protein O43663 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 15297875 NO miannu These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins 0.7 SIGNOR-265987 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273034 ROCK2 protein O75116 UNIPROT LPP protein Q93052 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22886954 NO miannu Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression 0.264 SIGNOR-191765 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4A protein P27815 UNIPROT up-regulates activity phosphorylation Ser145 ATSQRREsFLYRSDS 9534 BTO:0001538 12023945 YES miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. 0.2 SIGNOR-275985 PB28 dihydrochloride chemical CID:46861545 PUBCHEM SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000093 16891467 YES Federica Cyclohexylpiperazine derivative PB28, a σ2 agonist and σ1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer 0.8 SIGNOR-261111 ACADVL protein P49748 UNIPROT FADH2(2-) smallmolecule CHEBI:58307 ChEBI up-regulates quantity chemical modification 9606 20490924 YES miannu VLCAD is a dimer of two identical subunits bound to the inner mitochondrial membrane (Fig. 1) and accepts long chain acyl-CoAs as substrate (Fig. 4a).The different ACADs catalyze the following reaction: acyl-CoA + FAD - trans-2-enoyl-CoA + FADH2 0.8 SIGNOR-280307 Laminin-1 complex SIGNOR-C183 SIGNOR A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9361014 YES lperfetto Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI. 0.556 SIGNOR-253254 TESK1 protein Q15569 UNIPROT CFL2 protein Q9Y281 UNIPROT down-regulates activity phosphorylation Ser3 sGVTVNDE 9606 BTO:0001363 11418599 YES lperfetto Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin 0.321 SIGNOR-246719 SHH protein Q15465 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0002314 18662193 NO gcesareni Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors myf-5 and myod, decreases the up-regulation of insulin-like growth factor (igf)-1 and reduces the number of myogenic satellite cells at injured site. 0.409 SIGNOR-179629 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates phosphorylation Ser1236 PKPKPRPsITKATWE 9606 BTO:0000887;BTO:0001260 19103606 YES acerquone Here we show that rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser1150 and attenuated p190a rhogap activity in cos7 cells 0.414 SIGNOR-182853 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization 0.2 SIGNOR-186943 TGFB1 protein P01137 UNIPROT Activated PSC phenotype SIGNOR-PH224 SIGNOR up-regulates 9606 BTO:0000988 38540204 YES miannu Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction 0.7 SIGNOR-277679 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000586 SIGNOR-C110 16293724 YES gcesareni This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. 0.86 SIGNOR-141807 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 25728771 YES inferred from 70% family members lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation 0.2 SIGNOR-270188 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 26214522 YES Luana In this study, we have demonstrated that the PTPN1 gene, which encodes PTP1B, was a direct target of MECP2 and that PTP1B protein levels were dramatically increased in Mecp2-mutant mice and in fibroblasts derived from patients with RTT. 0.2 SIGNOR-264546 vandetanib chemical CHEBI:49960 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258306 LRRK2 protein Q5S007 UNIPROT ARFGAP1 protein Q8N6T3 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000142 22363216 YES gcesareni Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid. 0.58 SIGNOR-196267 FGF2 protein P09038 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 20974802 NO gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription 0.378 SIGNOR-168998 IRAK2 protein O43187 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000007 35486320 YES miannu Two additional proximal mediators were identified that are required for IL-1R–induced NF-κB activation: IRAK-2, a Pelle family member, and MyD88, a death domain–containing adapter molecule. IRAK-2 preferentially bound IL-1RI. A truncated version of IRAK-2 that lacked the first 96 amino acids [IRAK-2(97-590)] did not associate with IL-1RI, which suggests that the NH2-terminal segment docks with the cytoplasmic domain of IL-1RI. 0.696 SIGNOR-273854 ENG protein P17813 UNIPROT BMP10 protein O95393 UNIPROT up-regulates activity binding 9606 BTO:0003767 21737454 YES miannu Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays. 0.363 SIGNOR-276657 ammonium smallmolecule CHEBI:28938 ChEBI L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity precursor of 9606 30158707 YES miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. 0.8 SIGNOR-267823 acalabrutinib chemical CHEBI:167707 ChEBI BTK protein Q06187 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0006414 35597428 YES Marta Tosoni As expected, ibrutinib and acalabrutinib also inhibited autophosphorylation of BTK (on Y223) 0.8 SIGNOR-278086 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI (E)-hexadec-2-enoyl-CoA(4-) smallmolecule CHEBI:61526 ChEBI up-regulates quantity precursor of 9606 20490924 YES miannu VLCAD is a dimer of two identical subunits bound to the inner mitochondrial membrane (Fig. 1) and accepts long chain acyl-CoAs as substrate (Fig. 4a).The different ACADs catalyze the following reaction: acyl-CoA + FAD - trans-2-enoyl-CoA + FADH2 0.8 SIGNOR-280308 GABA-B receptor complex SIGNOR-C336 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 30541966 YES miannu GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. 0.429 SIGNOR-264965 HSBP1 protein O75506 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR up-regulates quantity relocalization 9606 BTO:0000007 29844016 YES lperfetto The Trimeric Coiled-Coil HSBP1 Protein Promotes WASH Complex Assembly at Centrosomes 0.2 SIGNOR-261007 CBP/p300 complex SIGNOR-C6 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 10944526 YES lperfetto Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo. 0.647 SIGNOR-217220 GNG3 protein P63215 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 17419683 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.383 SIGNOR-252685 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 BTO:0000459 18621737 YES lperfetto The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively. 0.87 SIGNOR-179446 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation 9606 25026293 YES miannu All of these results lead to the conclusion that PPM1A inhibits the TGF-\u03b2-induced the activity of Smad2, Smad3 and transcriotional responses, whereas depletion of PPM1A enhances the activation of TGF-\u03b2/Smads signaling in bladder cancer cells.|Protein phosphatase PPM1A has been reported to dephosphorylate TGF-\u03b2-activated Smad2/3, thus inhibiting the TGF-\u03b2 signaling pathway. 0.667 SIGNOR-277034 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10230394 YES gcesareni Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A|Collectively, these results implicate PKA as the principal mitochondria-based S112 kinase. 0.541 SIGNOR-67383 Elongator complex complex SIGNOR-C466 SIGNOR TUBA4A protein P68366 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 YES miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 0.252 SIGNOR-269722 RBX1 protein P62877 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR form complex binding 9606 22649780 YES gcesareni The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors 0.837 SIGNOR-234799 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Thr635 SQCGYSStIVHVPPP 9534 BTO:0000298 11865049 YES llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  0.74 SIGNOR-250820 USP9X protein Q93008 UNIPROT RPS27A protein P62979 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.503 SIGNOR-270826 PPM1L protein Q5SGD2 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000142;BTO:0000671 17456047 YES gcesareni Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation 0.318 SIGNOR-154554 TLK1 protein Q9UKI8 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity phosphorylation -1 11314006 YES The effect has been demonstrated using Q9UKI8-2 lperfetto Purified tlk1b phosphorylated histone h3 at s(10) with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone h3 is a physiological substrate for tlk1b. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events. 0.2 SIGNOR-265370 GSK3B protein P49841 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Thr180 KDDFQRLtPSYNADI 9606 BTO:0001033 32871104 YES miannu Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively. 0.2 SIGNOR-277528 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 18676833 YES gcesareni We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage. 0.528 SIGNOR-179808 RPS24 protein P62847 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.919 SIGNOR-262427 INPPL1 protein O15357 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 BTO:0000776 10942391 NO gcesareni Taken together, the data presented here demonstrate that ship inhibits akt primarily through regulation of akt membrane localization. 0.649 SIGNOR-80706 FAD(3-) chemical CHEBI:57692 ChEBI FADH2(2-) smallmolecule CHEBI:58307 ChEBI up-regulates quantity precursor of 9606 20490924 YES miannu VLCAD is a dimer of two identical subunits bound to the inner mitochondrial membrane (Fig. 1) and accepts long chain acyl-CoAs as substrate (Fig. 4a).The different ACADs catalyze the following reaction: acyl-CoA + FAD - trans-2-enoyl-CoA + FADH2 0.8 SIGNOR-280309 SGK2 protein Q9HBY8 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.52 SIGNOR-249130 Skp1-Pam E3 complex SIGNOR-C537 SIGNOR ZEB2 protein O60315 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.244 SIGNOR-272187 HDAC1 protein Q13547 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 YES miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells 0.727 SIGNOR-264500 MAP2K4 protein P45985 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 YES done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. 0.457 SIGNOR-273956 NFX1 protein Q12986 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 BTO:0004117 17267499 YES miannu NFX1-123 augments the activation of hTERT expression through interactions with PABPCs 0.344 SIGNOR-226011 MAPK1 protein P28482 UNIPROT TXNIP protein Q9H3M7 UNIPROT down-regulates quantity by destabilization phosphorylation Thr349 HRLESPTtPLLDDMD 9606 BTO:0000018 31320475 YES miannu ERK-dependent Txnip ubiquitination and proteasome degradation depended upon phosphorylation of a PXTP motif threonine (Thr349) located within the C-terminal α-arrestin domain and proximal to a previously characterized E3 ubiquitin ligase-binding site.  0.294 SIGNOR-277468 4E2RCat chemical CID:2287236 PUBCHEM EIF4G1 protein Q04637 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000414 21507972 YES miannu Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers. 0.8 SIGNOR-260188 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Thr185 KPGNLLLtTGGTLKI 9606 BTO:0000007;BTO:0000567 12805220 YES lperfetto It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity. 0.2 SIGNOR-101840 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 12193595 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-91742 AKT1 protein P31749 UNIPROT SKI protein P12755 UNIPROT down-regulates phosphorylation Thr458 QPRKRKLtVDTPGAP 9606 19875456 YES llicata The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7 0.338 SIGNOR-252527 SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 0.721 SIGNOR-235183 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.272 SIGNOR-276096 CDK1 protein P06493 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 SIGNOR-C17 24173284 YES lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A 0.58 SIGNOR-167779 AKT proteinfamily SIGNOR-PF24 SIGNOR ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 YES gcesareni Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B. 0.2 SIGNOR-245259 C3AR1 protein Q16581 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0001669 9108406 NO lperfetto  In summary, these findings indicate that C3a and C5a serve as chemotaxins for human mast cells. Anaphylatoxin-mediated recruitment of mast cells might play an important role in hypersensitivity and inflammatory processes. 0.7 SIGNOR-263472 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2E2 protein Q96LR5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.713 SIGNOR-271317 ponatinib chemical CHEBI:78543 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition 9606 23468082 YES miannu Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. 0.8 SIGNOR-259279 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2Q1 protein Q7Z7E8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.438 SIGNOR-271372 MED1 protein Q15648 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.811 SIGNOR-266667 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.2 SIGNOR-252082 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation Ser1217 MSLENPLsPFSSDIN 9606 BTO:0000007 32294430 YES done miannu We show here that CyclinD-Cdk4/6 activates mTORC1 by binding and phosphorylating TSC2 on Ser1217 and Ser1452.  0.406 SIGNOR-274101 TPO protein P07202 UNIPROT 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity chemical modification 9606 16098474 YES scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 0.8 SIGNOR-267030 SGK1 protein O00141 UNIPROT HTT protein P42858 UNIPROT down-regulates phosphorylation Ser419 GGRSRSGsIVELIAG 9606 14725621 YES llicata The serum- and glucocorticoid-induced kinase sgk inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. 0.373 SIGNOR-121349 PRKACA protein P17612 UNIPROT CACNA1S protein Q13698 UNIPROT up-regulates activity phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 YES miannu To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. 0.345 SIGNOR-263112 PRKAA1 protein Q13131 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser355 EADLPEPsEKQPAAA -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.2 SIGNOR-275440 RAE1 protein P78406 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 20498086 NO miannu The export of mRNAs is a multistep process, involving the packaging of mRNAs into messenger ribonucleoprotein particles (mRNPs), their transport through nuclear pore complexes, and mRNP remodeling events prior to translation. Ribonucleic acid export 1 (Rae1) and Nup98 are evolutionarily conserved mRNA export factors that are targeted by the vesicular stomatitis virus matrix protein to inhibit host cell nuclear export. these data suggest that the Rae1*Nup98 complex directly binds to the mRNP at several stages of the mRNA export pathway. 0.7 SIGNOR-260871 RELA protein Q04206 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 NO lperfetto Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2 0.533 SIGNOR-59960 ARHGEF1 protein Q92888 UNIPROT RHOA protein P61586 UNIPROT up-regulates guanine nucleotide exchange factor 9606 BTO:0000887;BTO:0001260 10836144 YES gcesareni Rhogefs catalyze the exchange of gdp for gtp and thereby activate rho. 0.831 SIGNOR-77914 PRKACA protein P17612 UNIPROT UBE3A protein Q05086 UNIPROT down-regulates activity phosphorylation Thr508 MYSERRItVLYSLVQ 10090 BTO:0000142 26255772 YES gcesareni These data suggest that PKA phosphorylation at T485 inhibits UBE3A ubiquitin ligase activity in cells. 0.329 SIGNOR-236899 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu62 NLERECVeETCSYEE -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263679 NPY protein P01303 UNIPROT NPY2R protein P49146 UNIPROT up-regulates binding 9606 9549761 YES gcesareni Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors. 0.837 SIGNOR-56568 PRKCD protein Q05655 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 18332134 YES Manara In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation. 0.353 SIGNOR-260875 Trifunctional enzyme complex SIGNOR-C564 SIGNOR (E)-hexadec-2-enoyl-CoA(4-) smallmolecule CHEBI:61526 ChEBI down-regulates quantity chemical modification 9606 30850536 YES miannu Membrane-bound mitochondrial trifunctional protein (TFP) catalyzes β-oxidation of long chain fatty acyl-CoAs, employing 2-enoyl-CoA hydratase (ECH), 3- hydroxyl-CoA dehydrogenase (HAD), and 3-ketothiolase (KT) activities consecutively.  0.8 SIGNOR-280310 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 BTO:0000887 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.275 SIGNOR-163796 CCNA1 protein P78396 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 15829981 NO lperfetto Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth. 0.7 SIGNOR-252255 PCDHA8 protein Q9Y5H6 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265671 MRTFB protein Q9ULH7 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 YES gcesareni Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf. 0.2 SIGNOR-174316 AKT proteinfamily SIGNOR-PF24 SIGNOR MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 19526459 YES llicata Here, we present evidence that akt inhibits mad1-mediated transcription repression by physical interaction with and phosphorylation of mad1. 0.2 SIGNOR-186130 AKT proteinfamily SIGNOR-PF24 SIGNOR XIAP protein P98170 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 VGRHRKVsPNCRFIN 9606 BTO:0001023 14645242 YES lperfetto Akt, including akt1 and akt2, interacts with and phosphorylates x-linked inhibitor of apoptosis protein (xiap) at residue serine-87 in vitro and in vivo. Phosphorylation of xiap by akt protects xiap from ubiquitination and degradation in response to cisplatin. 0.2 SIGNOR-244377 EIF3B protein P55884 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.951 SIGNOR-266399 FYCO1 protein Q9BQS8 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates activity binding 9606 BTO:0000007 26468287 YES Giulio The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures. 0.518 SIGNOR-260597 APOBEC3G protein Q9HC16 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 NO lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). 0.7 SIGNOR-261329 ADSS1 protein Q8N142 UNIPROT GDP smallmolecule CHEBI:17552 ChEBI up-regulates quantity chemical modification 9606 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-267350 CNTNAP1 protein P78357 UNIPROT CNTN1 protein Q12860 UNIPROT up-regulates activity relocalization 10090 BTO:0001221 11069942 YES Gianni These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr. 0.624 SIGNOR-269073 NCS1 protein P62166 UNIPROT DRD2 protein P14416 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000938 12351722 YES miannu Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization. 0.679 SIGNOR-263964 CDK1 protein P06493 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Thr550 PPINGSStPNPKIAS 9606 BTO:0000567 19509060 YES lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. 0.583 SIGNOR-272973 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR FGG protein P02679 UNIPROT up-regulates activity binding 9606 BTO:0000132 16418530 YES lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. 0.564 SIGNOR-253360 AURKA protein O14965 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates activity phosphorylation -1 16824953 YES lperfetto Loss of INCENP/Aurora B in Mitosis Correlates with Delocalization of MEI-S332|MEI-S332 Is Phosphorylated by Aurora B In Vitro|Of these, MEI-S332S124,125,126A was a poor substrate for Aurora B kinase in vitro 0.2 SIGNOR-252046 MARCHF5 protein Q9NX47 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 32015503 YES miannu MARCH5 promotes ubiquitination of MCL1 and NOXA.|Together, this suggests that degradation of MCL1 by MARCH5 depends on binding to NOXA, but degradation of NOXA may be promoted by additional E3-ligases if MCL1 levels become limited, or can simply no longer be degraded. 0.2 SIGNOR-278700 MAPK8 protein P45983 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 YES gcesareni By site-directed mutagenesis studies, we have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in prostate cancer cells. Further studies with the inhibitor of jun kinase (jnk) and phosphorylation mutant of bcl-xl reveal the augmentative role of jnk-mediated bcl-xl phosphorylation in apoptosis of prostate cancer cells. In summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl to permit prostate cancer cells to die by apoptosis 0.775 SIGNOR-99219 Trifunctional enzyme complex SIGNOR-C564 SIGNOR (S)-3-hydroxypalmitoyl-CoA smallmolecule CHEBI:27402 ChEBI up-regulates quantity chemical modification 9606 30850536 YES miannu Membrane-bound mitochondrial trifunctional protein (TFP) catalyzes β-oxidation of long chain fatty acyl-CoAs, employing 2-enoyl-CoA hydratase (ECH), 3- hydroxyl-CoA dehydrogenase (HAD), and 3-ketothiolase (KT) activities consecutively.  0.8 SIGNOR-280311 (E)-hexadec-2-enoyl-CoA(4-) smallmolecule CHEBI:61526 ChEBI (S)-3-hydroxypalmitoyl-CoA smallmolecule CHEBI:27402 ChEBI up-regulates quantity precursor of 9606 30850536 YES miannu Membrane-bound mitochondrial trifunctional protein (TFP) catalyzes β-oxidation of long chain fatty acyl-CoAs, employing 2-enoyl-CoA hydratase (ECH), 3- hydroxyl-CoA dehydrogenase (HAD), and 3-ketothiolase (KT) activities consecutively.  0.8 SIGNOR-280312 Trifunctional enzyme complex SIGNOR-C564 SIGNOR water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 30850536 YES miannu Membrane-bound mitochondrial trifunctional protein (TFP) catalyzes β-oxidation of long chain fatty acyl-CoAs, employing 2-enoyl-CoA hydratase (ECH), 3- hydroxyl-CoA dehydrogenase (HAD), and 3-ketothiolase (KT) activities consecutively.  0.8 SIGNOR-280313 TRPM7 protein Q96QT4 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Ser1164 AVKSGFRsVPLKNGY 9606 22759789 YES miannu We present data indicating that TRPM7 phosphorylates phospholipase C\u03b32 at position Ser1164 in the C2-domain, and at position Thr1045 in the linker between the catalytic region and the C2 domain. 0.263 SIGNOR-278460 FYN protein P06241 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15537652 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Here we provide evidence that fyn kinase, a member of the src kinase family, is involved in the uvb-induced phosphorylation of histone h3 at serine 10 0.2 SIGNOR-130274 IMMT protein Q16891 UNIPROT PINK1 protein Q9BXM7 UNIPROT up-regulates activity binding -1 27153535 YES miannu MIC60 Is Crucial for Parkin Recruitment and Transiently Interacts with PINK1 0.401 SIGNOR-266301 haloperidol chemical CHEBI:5613 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258523 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr447 ASSPSRAtRDNPTTS 9606 22820163 YES lperfetto Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1 0.335 SIGNOR-198357 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9606 BTO:0002882 11684015 YES lperfetto RAD51 is one of six mitotic human homologs of the E. coli RecA protein (RAD51-Paralogs) that play a central role in homologous recombination and repair of DNA double-strand breaks (DSBs).|Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance. 0.2 SIGNOR-271707 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Tyr182 ADAEMTGyVVTRWYR 9606 BTO:0000007 10066767 YES done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. 0.66 SIGNOR-273951 GNAS protein P63092 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 YES lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. 0.382 SIGNOR-227988 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser195 EKLRRRFsSLHFMVE 9606 15703181 YES lperfetto We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195. 0.2 SIGNOR-133884 HADHB protein P55084 UNIPROT Trifunctional enzyme complex SIGNOR-C564 SIGNOR form complex binding 9606 30850536 YES miannu Fatty acid β-oxidation is the major energy-producing process in all tissues and is performed by four consecutive reactions that cleave fatty acids. Mitochondrial trifunctional protein (TFP) performs the last three of these four reactions. TFP is composed of two subunits: the α-subunit contains the first two of the remaining three activities (ECH and HAD), while the β-subunit bears the KT activity (Fig. 1). 0.98 SIGNOR-280314 HADHA protein P40939 UNIPROT Trifunctional enzyme complex SIGNOR-C564 SIGNOR form complex binding 9606 30850536 YES miannu Fatty acid β-oxidation is the major energy-producing process in all tissues and is performed by four consecutive reactions that cleave fatty acids. Mitochondrial trifunctional protein (TFP) performs the last three of these four reactions. TFP is composed of two subunits: the α-subunit contains the first two of the remaining three activities (ECH and HAD), while the β-subunit bears the KT activity (Fig. 1). 0.98 SIGNOR-280315 Trifunctional enzyme complex SIGNOR-C564 SIGNOR (S)-3-hydroxypalmitoyl-CoA smallmolecule CHEBI:27402 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280316 Trifunctional enzyme complex SIGNOR-C564 SIGNOR NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280317 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 9606 BTO:0002181 34010649 YES miannu PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-277559 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxopalmitoyl-CoA smallmolecule CHEBI:15491 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280318 Trifunctional enzyme complex SIGNOR-C564 SIGNOR NADH(2-) smallmolecule CHEBI:57945 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280319 (S)-3-hydroxypalmitoyl-CoA smallmolecule CHEBI:27402 ChEBI 3-oxopalmitoyl-CoA smallmolecule CHEBI:15491 ChEBI up-regulates quantity precursor of 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280320 CD247 protein P20963 UNIPROT CD3 complex SIGNOR-C432 SIGNOR form complex binding 9606 12507424 YES miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules. 0.705 SIGNOR-255290 CNOT3 protein O75175 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.819 SIGNOR-268301 EPAS1 protein Q99814 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20534544 NO Regulation miannu We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. 0.248 SIGNOR-251792 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxopalmitoyl-CoA smallmolecule CHEBI:15491 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280321 Trifunctional enzyme complex SIGNOR-C564 SIGNOR coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280322 MAPK1 protein P28482 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser343 KSDCQPNsPTESCSS 9606 BTO:0000782;BTO:0000785 9649500 YES gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. 0.49 SIGNOR-58485 Trifunctional enzyme complex SIGNOR-C564 SIGNOR myristoyl-CoA(4-) smallmolecule CHEBI:57385 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280323 Trifunctional enzyme complex SIGNOR-C564 SIGNOR acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280324 3-oxopalmitoyl-CoA smallmolecule CHEBI:15491 ChEBI myristoyl-CoA(4-) smallmolecule CHEBI:57385 ChEBI up-regulates quantity precursor of 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280325 ACADL protein P28330 UNIPROT myristoyl-CoA(4-) smallmolecule CHEBI:57385 ChEBI down-regulates quantity chemical modification 9606 18227065 YES miannu Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Very-long-chain acyl-CoA dehydrogenase (VLCAD)3 is one of five acyl-CoA dehydrogenases (ACADs) that catalyze the initial, rate-limiting step of mitochondrial fatty acid β-oxidation, with distinct but overlapping fatty acyl chain-length specificities.When myristoyl-CoA was added, the yellow enzyme solution turned colorless, indicating that the enzyme flavin was reduced by the substrate. 0.8 SIGNOR-280326 ACADL protein P28330 UNIPROT FAD(3-) chemical CHEBI:57692 ChEBI down-regulates quantity chemical modification 9606 18227065 YES miannu Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Very-long-chain acyl-CoA dehydrogenase (VLCAD)3 is one of five acyl-CoA dehydrogenases (ACADs) that catalyze the initial, rate-limiting step of mitochondrial fatty acid β-oxidation, with distinct but overlapping fatty acyl chain-length specificities.When myristoyl-CoA was added, the yellow enzyme solution turned colorless, indicating that the enzyme flavin was reduced by the substrate. 0.8 SIGNOR-280327 ACADL protein P28330 UNIPROT trans-tetradec-2-enoyl-CoA smallmolecule CHEBI:27721 ChEBI up-regulates quantity chemical modification 9606 18227065 YES miannu Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Very-long-chain acyl-CoA dehydrogenase (VLCAD)3 is one of five acyl-CoA dehydrogenases (ACADs) that catalyze the initial, rate-limiting step of mitochondrial fatty acid β-oxidation, with distinct but overlapping fatty acyl chain-length specificities.When myristoyl-CoA was added, the yellow enzyme solution turned colorless, indicating that the enzyme flavin was reduced by the substrate. 0.8 SIGNOR-280328 ACADL protein P28330 UNIPROT FADH2(2-) smallmolecule CHEBI:58307 ChEBI up-regulates quantity chemical modification 9606 18227065 YES miannu Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Very-long-chain acyl-CoA dehydrogenase (VLCAD)3 is one of five acyl-CoA dehydrogenases (ACADs) that catalyze the initial, rate-limiting step of mitochondrial fatty acid β-oxidation, with distinct but overlapping fatty acyl chain-length specificities.When myristoyl-CoA was added, the yellow enzyme solution turned colorless, indicating that the enzyme flavin was reduced by the substrate. 0.8 SIGNOR-280329 myristoyl-CoA(4-) smallmolecule CHEBI:57385 ChEBI trans-tetradec-2-enoyl-CoA smallmolecule CHEBI:27721 ChEBI up-regulates quantity precursor of 9606 18227065 YES miannu Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Very-long-chain acyl-CoA dehydrogenase (VLCAD)3 is one of five acyl-CoA dehydrogenases (ACADs) that catalyze the initial, rate-limiting step of mitochondrial fatty acid β-oxidation, with distinct but overlapping fatty acyl chain-length specificities.When myristoyl-CoA was added, the yellow enzyme solution turned colorless, indicating that the enzyme flavin was reduced by the substrate. 0.8 SIGNOR-280330 bisphenol A chemical CHEBI:33216 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 31995776 YES miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 0.8 SIGNOR-268729 Trifunctional enzyme complex SIGNOR-C564 SIGNOR trans-tetradec-2-enoyl-CoA smallmolecule CHEBI:27721 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex. The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. 0.8 SIGNOR-280331 Trifunctional enzyme complex SIGNOR-C564 SIGNOR water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex. The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. 0.8 SIGNOR-280332 Trifunctional enzyme complex SIGNOR-C564 SIGNOR (S)-3-hydroxytetradecanoyl-CoA smallmolecule CHEBI:27466 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex. The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. 0.8 SIGNOR-280333 trans-tetradec-2-enoyl-CoA smallmolecule CHEBI:27721 ChEBI (S)-3-hydroxytetradecanoyl-CoA smallmolecule CHEBI:27466 ChEBI up-regulates quantity precursor of 9606 29551309 YES miannu In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex. The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. 0.8 SIGNOR-280334 Trifunctional enzyme complex SIGNOR-C564 SIGNOR (S)-3-hydroxytetradecanoyl-CoA smallmolecule CHEBI:27466 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280335 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxotetradecanoyl-CoA smallmolecule CHEBI:28726 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280336 (S)-3-hydroxytetradecanoyl-CoA smallmolecule CHEBI:27466 ChEBI 3-oxotetradecanoyl-CoA smallmolecule CHEBI:28726 ChEBI up-regulates quantity precursor of 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280337 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxotetradecanoyl-CoA smallmolecule CHEBI:28726 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280338 FZD4 protein Q9ULV1 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 27096005 YES areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. 0.75 SIGNOR-258958 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.497 SIGNOR-248309 Trifunctional enzyme complex SIGNOR-C564 SIGNOR lauroyl-CoA(4-) smallmolecule CHEBI:57375 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280339 3-oxotetradecanoyl-CoA smallmolecule CHEBI:28726 ChEBI lauroyl-CoA(4-) smallmolecule CHEBI:57375 ChEBI up-regulates quantity precursor of 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280340 ACADL protein P28330 UNIPROT lauroyl-CoA(4-) smallmolecule CHEBI:57375 ChEBI down-regulates quantity chemical modification 9606 18227065 YES miannu Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Very-long-chain acyl-CoA dehydrogenase (VLCAD)3 is one of five acyl-CoA dehydrogenases (ACADs) that catalyze the initial, rate-limiting step of mitochondrial fatty acid β-oxidation, with distinct but overlapping fatty acyl chain-length specificities.When myristoyl-CoA was added, the yellow enzyme solution turned colorless, indicating that the enzyme flavin was reduced by the substrate. 0.8 SIGNOR-280341 ACADL protein P28330 UNIPROT trans-dodec-2-enoyl-CoA(4-) smallmolecule CHEBI:57330 ChEBI up-regulates quantity chemical modification 9606 18227065 YES miannu Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Very-long-chain acyl-CoA dehydrogenase (VLCAD)3 is one of five acyl-CoA dehydrogenases (ACADs) that catalyze the initial, rate-limiting step of mitochondrial fatty acid β-oxidation, with distinct but overlapping fatty acyl chain-length specificities.When myristoyl-CoA was added, the yellow enzyme solution turned colorless, indicating that the enzyme flavin was reduced by the substrate. 0.8 SIGNOR-280342 lauroyl-CoA(4-) smallmolecule CHEBI:57375 ChEBI trans-dodec-2-enoyl-CoA(4-) smallmolecule CHEBI:57330 ChEBI up-regulates quantity precursor of 9606 18227065 YES miannu Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Very-long-chain acyl-CoA dehydrogenase (VLCAD)3 is one of five acyl-CoA dehydrogenases (ACADs) that catalyze the initial, rate-limiting step of mitochondrial fatty acid β-oxidation, with distinct but overlapping fatty acyl chain-length specificities.When myristoyl-CoA was added, the yellow enzyme solution turned colorless, indicating that the enzyme flavin was reduced by the substrate. 0.8 SIGNOR-280343 ECHS1 protein P30084 UNIPROT trans-dodec-2-enoyl-CoA(4-) smallmolecule CHEBI:57330 ChEBI down-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280344 ECHS1 protein P30084 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280345 ECHS1 protein P30084 UNIPROT (S)-3-hydroxylauroyl-CoA protein CHEBI:27668 UNIPROT up-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.2 SIGNOR-280346 trans-dodec-2-enoyl-CoA(4-) smallmolecule CHEBI:57330 ChEBI (S)-3-hydroxylauroyl-CoA protein CHEBI:27668 UNIPROT up-regulates quantity precursor of 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280347 HADH protein Q16836 UNIPROT (S)-3-hydroxylauroyl-CoA protein CHEBI:27668 UNIPROT down-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.2 SIGNOR-280348 HADH protein Q16836 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI down-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280349 HADH protein Q16836 UNIPROT 3-oxolauroyl-CoA smallmolecule CHEBI:27868 ChEBI up-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280350 HADH protein Q16836 UNIPROT NADH(2-) smallmolecule CHEBI:57945 ChEBI up-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280351 (S)-3-hydroxylauroyl-CoA protein CHEBI:27668 UNIPROT 3-oxolauroyl-CoA smallmolecule CHEBI:27868 ChEBI up-regulates quantity precursor of 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280352 FERMT2 protein Q96AC1 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 9606 BTO:0000007 26037143 YES miannu Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. 0.37 SIGNOR-266101 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxolauroyl-CoA smallmolecule CHEBI:27868 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280353 Trifunctional enzyme complex SIGNOR-C564 SIGNOR decanoyl-CoA smallmolecule CHEBI:28493 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280354 3-oxolauroyl-CoA smallmolecule CHEBI:27868 ChEBI decanoyl-CoA smallmolecule CHEBI:28493 ChEBI up-regulates quantity precursor of 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280355 ACADM protein P11310 UNIPROT decanoyl-CoA smallmolecule CHEBI:28493 ChEBI down-regulates quantity chemical modification 9606 3035565 YES miannu Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation.  0.8 SIGNOR-280356 ACADM protein P11310 UNIPROT FAD(3-) chemical CHEBI:57692 ChEBI down-regulates quantity chemical modification 9606 3035565 YES miannu Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation.  0.8 SIGNOR-280357 ACADM protein P11310 UNIPROT FADH2(2-) smallmolecule CHEBI:58307 ChEBI up-regulates quantity chemical modification 9606 3035565 YES miannu Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation.  0.8 SIGNOR-280358 ACADM protein P11310 UNIPROT trans-dec-2-enoyl-CoA smallmolecule CHEBI:10723 ChEBI up-regulates quantity chemical modification 9606 3035565 YES miannu Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation.  0.8 SIGNOR-280359 decanoyl-CoA smallmolecule CHEBI:28493 ChEBI trans-dec-2-enoyl-CoA smallmolecule CHEBI:10723 ChEBI up-regulates quantity precursor of 9606 3035565 YES miannu Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation.  0.8 SIGNOR-280360 MECR protein Q9BV79 UNIPROT trans-dec-2-enoyl-CoA smallmolecule CHEBI:10723 ChEBI down-regulates quantity chemical modification 9606 18479707 YES miannu The mitochondrial FAS II pathway includes a 2-enoyl thioester reductase (ETR1), also known as MECR. This enzyme (MECR/ETR1, EC 1.3.1.38) catalyzes in the fatty acid elongation cycle in the last step, which is the NADPH-dependent reduction of the Cα–Cβ double bond of the enoyl–ACP substrate molecule (Fig. 1). 0.8 SIGNOR-280361 MECR protein Q9BV79 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI down-regulates quantity chemical modification 9606 18479707 YES miannu The mitochondrial FAS II pathway includes a 2-enoyl thioester reductase (ETR1), also known as MECR. This enzyme (MECR/ETR1, EC 1.3.1.38) catalyzes in the fatty acid elongation cycle in the last step, which is the NADPH-dependent reduction of the Cα–Cβ double bond of the enoyl–ACP substrate molecule (Fig. 1). 0.8 SIGNOR-280362 MECR protein Q9BV79 UNIPROT decanoyl-CoA smallmolecule CHEBI:28493 ChEBI up-regulates quantity chemical modification 9606 18479707 YES miannu The mitochondrial FAS II pathway includes a 2-enoyl thioester reductase (ETR1), also known as MECR. This enzyme (MECR/ETR1, EC 1.3.1.38) catalyzes in the fatty acid elongation cycle in the last step, which is the NADPH-dependent reduction of the Cα–Cβ double bond of the enoyl–ACP substrate molecule (Fig. 1). 0.8 SIGNOR-280363 MECR protein Q9BV79 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI up-regulates quantity chemical modification 9606 18479707 YES miannu The mitochondrial FAS II pathway includes a 2-enoyl thioester reductase (ETR1), also known as MECR. This enzyme (MECR/ETR1, EC 1.3.1.38) catalyzes in the fatty acid elongation cycle in the last step, which is the NADPH-dependent reduction of the Cα–Cβ double bond of the enoyl–ACP substrate molecule (Fig. 1). 0.8 SIGNOR-280364 trans-dec-2-enoyl-CoA smallmolecule CHEBI:10723 ChEBI decanoyl-CoA smallmolecule CHEBI:28493 ChEBI up-regulates quantity precursor of 9606 18479707 YES miannu The mitochondrial FAS II pathway includes a 2-enoyl thioester reductase (ETR1), also known as MECR. This enzyme (MECR/ETR1, EC 1.3.1.38) catalyzes in the fatty acid elongation cycle in the last step, which is the NADPH-dependent reduction of the Cα–Cβ double bond of the enoyl–ACP substrate molecule (Fig. 1). 0.8 SIGNOR-280365 CTTNBP2NL protein Q9P2B4 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity binding 10116 23015759 YES miannu CTTNBP2NL interacts with cortactin and targets cortactin to stress fibers. 0.357 SIGNOR-261695 HADH protein Q16836 UNIPROT (S)-3-hydroxydecanoyl-CoA smallmolecule CHEBI:28325 ChEBI down-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280370 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI -1 11777913 YES lperfetto Here, using mass spectrometry, we identify the serum-responsive, rapamycin-sensitive sites as Ser 65 and Thr 70. | Phosphorylation of Thr 37/Thr 46 is followed by Thr 70 phosphorylation, and Ser 65 is phosphorylated last. Finally, we show that phosphorylation of Ser 65 and Thr 70 alone is insufficient to block binding to eIF4E, indicating that a combination of phosphorylation events is necessary to dissociate 4E-BP1 from eIF4E. 0.67 SIGNOR-249131 HADH protein Q16836 UNIPROT 3-oxodecanoyl-CoA smallmolecule CHEBI:28528 ChEBI up-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280371 (S)-3-hydroxydecanoyl-CoA smallmolecule CHEBI:28325 ChEBI 3-oxodecanoyl-CoA smallmolecule CHEBI:28528 ChEBI up-regulates quantity precursor of 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280372 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxodecanoyl-CoA smallmolecule CHEBI:28528 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280373 Trifunctional enzyme complex SIGNOR-C564 SIGNOR octanoyl-CoA smallmolecule CHEBI:15533 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280374 3-oxodecanoyl-CoA smallmolecule CHEBI:28528 ChEBI octanoyl-CoA smallmolecule CHEBI:15533 ChEBI up-regulates quantity precursor of 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280375 ACADM protein P11310 UNIPROT octanoyl-CoA smallmolecule CHEBI:15533 ChEBI down-regulates quantity chemical modification 9606 3035565 YES miannu Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation.  0.8 SIGNOR-280376 ACADM protein P11310 UNIPROT trans-oct-2-enoyl-CoA(4-) smallmolecule CHEBI:62242 ChEBI up-regulates quantity chemical modification 9606 3035565 YES miannu Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation.  0.8 SIGNOR-280377 octanoyl-CoA smallmolecule CHEBI:15533 ChEBI trans-oct-2-enoyl-CoA(4-) smallmolecule CHEBI:62242 ChEBI up-regulates quantity precursor of 9606 3035565 YES miannu Medium-chain acyl-CoA dehydrogenase (MCAD; acyl-CoA: (acceptor) 2,3- oxidoreductase, EC 1.3.99.3) is one of three similar enzymes that catalyze the initial step of fatty acid beta-oxidation.  0.8 SIGNOR-280378 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates activity phosphorylation Tyr328 YSPRSFEdCGGGYTP 9606 9467953 YES Manara Thus, we propose that the phosphorylation of tyrosine 328 and 360 within Bcr by Bcr ± Abl will drastically interfere with Bcr's kinase role in either signal transduction or some other cellular mechanism. 0.2 SIGNOR-260829 ECHS1 protein P30084 UNIPROT trans-oct-2-enoyl-CoA(4-) smallmolecule CHEBI:62242 ChEBI down-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280379 ECHS1 protein P30084 UNIPROT (S)-3-hydroxyoctanoyl-CoA smallmolecule CHEBI:28632 ChEBI up-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280380 trans-oct-2-enoyl-CoA(4-) smallmolecule CHEBI:62242 ChEBI (S)-3-hydroxyoctanoyl-CoA smallmolecule CHEBI:28632 ChEBI up-regulates quantity precursor of 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280381 HADH protein Q16836 UNIPROT (S)-3-hydroxyoctanoyl-CoA smallmolecule CHEBI:28632 ChEBI down-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280382 HADH protein Q16836 UNIPROT 3-oxooctanoyl-CoA smallmolecule CHEBI:28264 ChEBI up-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280383 CDK1 protein P06493 UNIPROT PKMYT1 protein Q99640 UNIPROT down-regulates activity phosphorylation 9606 21325631 YES miannu Active Cdk1 phosphorylates and inhibits Wee1 and Myt1 kinases and phosphorylates and activates the Cdc25 phosphatases. 0.751 SIGNOR-279600 (S)-3-hydroxyoctanoyl-CoA smallmolecule CHEBI:28632 ChEBI 3-oxooctanoyl-CoA smallmolecule CHEBI:28264 ChEBI up-regulates quantity precursor of 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280384 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB7 protein Q9Y5F8 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265711 COP1 protein Q8NHY2 UNIPROT ACACB protein O00763 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16794074 YES miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). 0.2 SIGNOR-271599 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxooctanoyl-CoA smallmolecule CHEBI:28264 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280385 Trifunctional enzyme complex SIGNOR-C564 SIGNOR hexanoyl-CoA(4-) smallmolecule CHEBI:62620 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280386 3-oxooctanoyl-CoA smallmolecule CHEBI:28264 ChEBI hexanoyl-CoA(4-) smallmolecule CHEBI:62620 ChEBI up-regulates quantity precursor of 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280387 ACAA2 protein P42765 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI down-regulates quantity chemical modification 9606 38656551 YES miannu Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial β oxidation, which plays an important role in fatty acid metabolism. 0.8 SIGNOR-280389 ACAA2 protein P42765 UNIPROT 3-oxo-fatty acyl-CoA smallmolecule CHEBI:15489 ChEBI up-regulates quantity chemical modification 9606 38656551 YES miannu Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial β oxidation, which plays an important role in fatty acid metabolism. 0.8 SIGNOR-280390 ACAA2 protein P42765 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 38656551 YES miannu Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial β oxidation, which plays an important role in fatty acid metabolism. 0.8 SIGNOR-280391 acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI 3-oxo-fatty acyl-CoA smallmolecule CHEBI:15489 ChEBI up-regulates quantity precursor of 9606 38656551 YES miannu Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial β oxidation, which plays an important role in fatty acid metabolism. 0.8 SIGNOR-280392 acyl-CoA(4-) chemical CHEBI:58342 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 38656551 YES miannu Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial β oxidation, which plays an important role in fatty acid metabolism. 0.8 SIGNOR-280393 ACADS protein P16219 UNIPROT hexanoyl-CoA(4-) smallmolecule CHEBI:62620 ChEBI down-regulates quantity chemical modification 9606 21237683 YES miannu Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of β-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. 0.8 SIGNOR-280394 ACADS protein P16219 UNIPROT FAD(3-) chemical CHEBI:57692 ChEBI down-regulates quantity chemical modification 9606 21237683 YES miannu Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of β-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. 0.8 SIGNOR-280395 ACADS protein P16219 UNIPROT trans-hex-2-enoyl-CoA(4-) smallmolecule CHEBI:62077 ChEBI up-regulates quantity chemical modification 9606 21237683 YES miannu Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of β-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. 0.8 SIGNOR-280396 ACADS protein P16219 UNIPROT FADH2(2-) smallmolecule CHEBI:58307 ChEBI up-regulates quantity chemical modification 9606 21237683 YES miannu Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of β-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. 0.8 SIGNOR-280397 hexanoyl-CoA(4-) smallmolecule CHEBI:62620 ChEBI trans-hex-2-enoyl-CoA(4-) smallmolecule CHEBI:62077 ChEBI up-regulates quantity precursor of 9606 21237683 YES miannu Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of β-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. 0.8 SIGNOR-280398 FAD(3-) chemical CHEBI:57692 ChEBI FADH2(2-) smallmolecule CHEBI:58307 ChEBI up-regulates quantity precursor of 9606 21237683 YES miannu Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of β-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. 0.8 SIGNOR-280399 ECHS1 protein P30084 UNIPROT trans-hex-2-enoyl-CoA(4-) smallmolecule CHEBI:62077 ChEBI down-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280400 ECHS1 protein P30084 UNIPROT (S)-3-hydroxyhexanoyl-CoA smallmolecule CHEBI:28276 ChEBI up-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280401 trans-hex-2-enoyl-CoA(4-) smallmolecule CHEBI:62077 ChEBI (S)-3-hydroxyhexanoyl-CoA smallmolecule CHEBI:28276 ChEBI up-regulates quantity precursor of 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280402 HADH protein Q16836 UNIPROT (S)-3-hydroxyhexanoyl-CoA smallmolecule CHEBI:28276 ChEBI down-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280403 HADH protein Q16836 UNIPROT 3-oxohexanoyl-CoA smallmolecule CHEBI:27648 ChEBI up-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280404 (S)-3-hydroxyhexanoyl-CoA smallmolecule CHEBI:28276 ChEBI 3-oxohexanoyl-CoA smallmolecule CHEBI:27648 ChEBI up-regulates quantity precursor of 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280405 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.572 SIGNOR-253683 Trifunctional enzyme complex SIGNOR-C564 SIGNOR 3-oxohexanoyl-CoA smallmolecule CHEBI:27648 ChEBI down-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280406 Trifunctional enzyme complex SIGNOR-C564 SIGNOR butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI up-regulates quantity chemical modification 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280407 3-oxohexanoyl-CoA smallmolecule CHEBI:27648 ChEBI butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI up-regulates quantity precursor of 9606 29551309 YES miannu The second step in the β-oxidation of fatty acids is the hydration of the trans-double bond to generate a 3-l-hydroxyacyl-coA ester, catalyzed by enoyl-coA hydratase. In the third step, 3-l-hydroxyacyl-coA dehydrogenase catalyzes the oxidation of the 3-l-hydroxyacyl-coA ester to a 3-ketoacyl-coA intermediate while NADH is generated from NAD+. The fourth and final step is the thiolytic cleavage of the chain by a ketothiolase, generating acetyl-coA and a fatty-acyl-coA two carbon atoms shorter. This shortened acyl-coA ester may start again the oxidation cycle. (Fig. 3) In humans, a single enzyme catalyzes the three last steps in the β-oxidation of long-chain fatty acids, the mitochondrial trifunctional protein (MTP) complex 0.8 SIGNOR-280408 ACSM3 protein Q53FZ2 UNIPROT butyrate smallmolecule CHEBI:17968 ChEBI down-regulates quantity chemical modification 9606 40953271 YES miannu Acyl-CoA synthetase medium-chain family member 3 (ACSM3) mainly accounts for catalyzing the MCFAs to produce the corresponding acyl-CoA, which is crucial for FAO 0.8 SIGNOR-280409 ACSM3 protein Q53FZ2 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 40953271 YES miannu Acyl-CoA synthetase medium-chain family member 3 (ACSM3) mainly accounts for catalyzing the MCFAs to produce the corresponding acyl-CoA, which is crucial for FAO 0.8 SIGNOR-280410 ACSM3 protein Q53FZ2 UNIPROT butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI up-regulates quantity chemical modification 9606 40953271 YES miannu Acyl-CoA synthetase medium-chain family member 3 (ACSM3) mainly accounts for catalyzing the MCFAs to produce the corresponding acyl-CoA, which is crucial for FAO 0.8 SIGNOR-280411 PRKD1 protein Q15139 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates quantity phosphorylation Ser324 LTSVSRGsSLKILSK 9606 27127886 YES miannu Inhibition of PKD activity restores membrane expression of CXCR4 and migration towards CXCL12 in BCR responsive cells in vitro.|This cascade consisted on a novel BCR dependent pathway in which PI3K-delta phosphorylates PKD, which in turn phosphorylates CXCR4 at Ser 324/325. 0.2 SIGNOR-279264 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.384 SIGNOR-129260 ACSM3 protein Q53FZ2 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 40953271 YES miannu Acyl-CoA synthetase medium-chain family member 3 (ACSM3) mainly accounts for catalyzing the MCFAs to produce the corresponding acyl-CoA, which is crucial for FAO 0.8 SIGNOR-280412 butyrate smallmolecule CHEBI:17968 ChEBI butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI up-regulates quantity precursor of 9606 40953271 YES miannu Acyl-CoA synthetase medium-chain family member 3 (ACSM3) mainly accounts for catalyzing the MCFAs to produce the corresponding acyl-CoA, which is crucial for FAO 0.8 SIGNOR-280413 ACADS protein P16219 UNIPROT butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI down-regulates quantity chemical modification 9606 11134486 YES miannu Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids  0.8 SIGNOR-280414 ACADS protein P16219 UNIPROT FAD(3-) chemical CHEBI:57692 ChEBI down-regulates quantity chemical modification 9606 11134486 YES miannu Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids  0.8 SIGNOR-280415 ACADS protein P16219 UNIPROT crotonoyl-CoA(4-) smallmolecule CHEBI:57332 ChEBI up-regulates quantity chemical modification 9606 11134486 YES miannu Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids  0.8 SIGNOR-280416 ACADS protein P16219 UNIPROT FADH2(2-) smallmolecule CHEBI:58307 ChEBI up-regulates quantity chemical modification 9606 11134486 YES miannu Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids  0.8 SIGNOR-280417 butyryl-CoA(4-) smallmolecule CHEBI:57371 ChEBI crotonoyl-CoA(4-) smallmolecule CHEBI:57332 ChEBI up-regulates quantity precursor of 9606 11134486 YES miannu Short-chain acyl-CoA dehydrogenase (SCAD) (EC 1.3.99.2) is the first enzyme of the mitochondrial short-chain β-oxidation spiral catalyzing the dehydrogenation of C4 and C6 fatty acids  0.8 SIGNOR-280418 ECHS1 protein P30084 UNIPROT crotonoyl-CoA(4-) smallmolecule CHEBI:57332 ChEBI down-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280419 ECHS1 protein P30084 UNIPROT water smallmolecule CHEBI:15377 ChEBI down-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280420 ECHS1 protein P30084 UNIPROT (S)-3-hydroxybutanoyl-CoA smallmolecule CHEBI:15453 ChEBI up-regulates quantity chemical modification 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280421 crotonoyl-CoA(4-) smallmolecule CHEBI:57332 ChEBI (S)-3-hydroxybutanoyl-CoA smallmolecule CHEBI:15453 ChEBI up-regulates quantity precursor of 9606 40804397 YES miannu The ECHS1 (short-chain enoyl-CoA hydratase 1) gene is critical for mitochondrial fatty acid β-oxidation and branched-chain amino acid metabolism. In particular, enzymatic assays and molecular characterization from the late 20th to early 21st century confirmed that ECHS1 catalyzes the hydration of short-chain enoyl-CoA, a key step in mitochondrial β-oxidation, essential for metabolic stability. 0.8 SIGNOR-280422 HADH protein Q16836 UNIPROT (S)-3-hydroxybutanoyl-CoA smallmolecule CHEBI:15453 ChEBI down-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280423 HADH protein Q16836 UNIPROT acetoacetyl-CoA(4-) smallmolecule CHEBI:57286 ChEBI up-regulates quantity chemical modification 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280424 (S)-3-hydroxybutanoyl-CoA smallmolecule CHEBI:15453 ChEBI acetoacetyl-CoA(4-) smallmolecule CHEBI:57286 ChEBI up-regulates quantity precursor of 9606 16176262 YES miannu 3-Hydroxyacyl-CoA dehydrogenase (HAD) functions in mitochondrial fatty acid beta-oxidation by catalyzing the oxidation of straight chain 3-hydroxyacyl-CoAs. 0.8 SIGNOR-280425 ACAT1 protein P24752 UNIPROT acetoacetyl-CoA(4-) smallmolecule CHEBI:57286 ChEBI down-regulates quantity chemical modification 9606 31268215 YES miannu The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2  0.8 SIGNOR-280426 ACAT1 protein P24752 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity chemical modification 9606 31268215 YES miannu The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2  0.8 SIGNOR-280427 ACAT1 protein P24752 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 9606 31268215 YES miannu The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2  0.8 SIGNOR-280429 ACAT1 protein P24752 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI down-regulates quantity chemical modification 9606 31268215 YES miannu The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2  0.8 SIGNOR-280430 MRE11 protein P49959 UNIPROT PIH1D1 protein Q9NWS0 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser688;Ser689;Ser561;Ser558 SKGVDFEsSEDDDDD;KGVDFESsEDDDDDP;MANDSDDsISAATNK;AEQMANDsDDSISAA 28436950 YES miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. 0.2 SIGNOR-265898 ACAT1 protein P24752 UNIPROT acetoacetyl-CoA(4-) smallmolecule CHEBI:57286 ChEBI up-regulates quantity precursor of 9606 31268215 YES miannu The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2  0.8 SIGNOR-280431 ACAT1 protein P24752 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 31268215 YES miannu The mitochondrial acetoacetyl‐CoA thiolase (commonly known as β‐ketothiolase [T2]; EC 2.3.1.9; encoded by the ACAT1 gene) is a ubiquitous and important enzyme for ketone body synthesis and degradation as well as in isoleucine catabolismIn the biosynthetic direction, thiolases catalyze the formation of a carbon‐carbon bond through a Claisen condensation mechanism (from two acetyl‐CoA molecules) and in the reverse, degradative direction a C‐C bond is broken through thiolysis (in the presence of CoA), resulting in chain shortening of the acyl chain by two carbon atoms (in case the substrate is an unbranched acyl chain) or by three atoms (in case the substrate is a 2‐methyl‐branched acyl chain), such as for example catalyzed by the T2  0.8 SIGNOR-280432 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral down-regulates activity 9606 BTO:0000599 25965999 NO parnian S1P treatment also significantly decreased miR-122 level 0.4 SIGNOR-280441 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral Metastasis phenotype SIGNOR-PH107 SIGNOR down-regulates 9606 BTO:0000599 25240815 NO parnian Both gain- of function and loss- of function assays indicate that miR-126-3p suppresses metastasis and angiogenesis in HCC cells. 0.4 SIGNOR-280442 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 9606 BTO:0000599 25240815 NO parnian Both gain- of function and loss- of function assays indicate that miR-126-3p suppresses metastasis and angiogenesis in HCC cells. 0.4 SIGNOR-280443 LRP6 protein O75581 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0004050 22570728 YES parnian LRP6 enhanced both cell migration and invasion in vitro 0.7 SIGNOR-280444 PELI3 protein Q8N2H9 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity ubiquitination 9606 BTO:0005937 23892723 YES Tiberia Pellino3 directly bound to the kinase RIP2 and catalyzed its ubiquitination 0.375 SIGNOR-280452 PELI3 protein Q8N2H9 UNIPROT IRF4 protein Q15306 UNIPROT down-regulates activity ubiquitination Lys48 LVWENEEkSIFRIPW 9606 BTO:0005025 37341064 YES Tiberia Peli3 induces the degradation of IRF4 through K48‐mediated ubiquitination |To detect the direct interaction of Peli3 and IRF4, Peli3 and IRF4 DNA constructs were transfected into HEK293 cells. 0.2 SIGNOR-280453 IRF4 protein Q15306 UNIPROT RIPK2 protein O43353 UNIPROT down-regulates activity binding 9606 BTO:0002181 24670424 YES Tiberia These studies demonstrate that inhibition of RICK (RIPK2) polyubiquitination by IRF4 involves polyubiquitination of the kinase domain of RICK and this inhibition is facilitated by binding of IRF4 to the kinase and/or intermediate domains of RICK. 0.479 SIGNOR-280454 TRIP6 protein Q15654 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0001370 34983535 YES Tiberia Our results revealed that TRIP6 could enhance TRAF6 oligomerization and TRAF6 autoubiquitination through its interaction 0.281 SIGNOR-280455 RIPK2 protein O43353 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000633 33935757 YES Tiberia Binding of bacterial MDP or viral RNA to NOD2 results in the association of RIPK2 with TRAF6 and subsequent activation of TRAF6. 0.684 SIGNOR-280456 ATG16L1 protein Q676U5 UNIPROT RIPK2 protein O43353 UNIPROT down-regulates activity binding 9606 BTO:0005096 33935757 YES Tiberia In human monocyte-derived dendritic cells, NOD2 activation by MDP induced physical interaction between ATG16L1 and RIPK2 and negatively regulated NF-κB activation. It is important to note that ATG16L1 acts synergistically with IRF4 to inhibit RIPK2 polyubiquitination. 0.384 SIGNOR-280457 ITCH protein Q96J02 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity binding 9606 BTO:0001109 40185717 YES Tiberia ITCH preferentially binds to RIPK2, promoting its K63-linked ubiquitination while simultaneously protecting YAP protein levels and maintaining its nuclear localization in CRC cells. 0.527 SIGNOR-280458 TIRAP protein P58753 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 9606 BTO:0005548 21829704 YES Tiberia These results indicate that TIRAP functions as an essential adaptor protein for RAGE, binding to ligand-activated phosphorylated RAGE and transducing a signal from it. 0.411 SIGNOR-280459 CLIP1 protein P30622 UNIPROT TIRAP protein P58753 UNIPROT down-regulates activity binding 9606 BTO:0005029 29222167 YES Tiberia CLIP170 promotes ubiquitination and degradation of TIRAP 0.2 SIGNOR-280460 TIRAP protein P58753 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0006328 19592497 YES Tiberia Mal interaction with TRAF6 is required for NF-κB transactivation 0.738 SIGNOR-280461 IKBKG protein Q9Y6K9 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 BTO:0001008 18412279 YES Tiberia IκB components are phosphorylated on two amino-terminal serine residues by the IκB kinase (IKK) complex, composed of two catalytic proteins, IKKα and IKKβ, and the regulatory subunit IKKγ (NEMO, IKBKG). This modification targets IκB for degradation by the proteasome, allowing the release and nuclear translocation of NF-κB. 0.848 SIGNOR-280462 MIB2 protein Q96AX9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity polyubiquitination Lys634 KVYQMLQkWVMREGI 9606 BTO:0000815 29642005 YES miannu Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation.  We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. MIB2 Ubiquitylates RIPK1 at Lysines K377 and K634 0.295 SIGNOR-272663 7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-2-ol chemical CHEBI:111176 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258725 SMURF2 protein Q9HAU4 UNIPROT UBE2D1 protein P51668 UNIPROT up-regulates activity ubiquitination Lys144 HAREWTQkYAM 9606 24709419 YES miannu Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS family E3, beta transducing repeat containing protein 1 (beta-TrCP1). 0.701 SIGNOR-278718 SMAD6 protein O43541 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates binding 9606 11737269 YES lpetrilli Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads. 0.567 SIGNOR-112642 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.564 SIGNOR-89205 NF1 protein P21359 UNIPROT ADCY10 protein Q96PN6 UNIPROT up-regulates 9606 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.273 SIGNOR-203921 VCP protein P55072 UNIPROT NGLY1 protein Q96IV0 UNIPROT up-regulates activity binding 9606 15362974 YES simone PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome. 0.694 SIGNOR-261058 MYC protein P01106 UNIPROT PFKM protein P08237 UNIPROT up-regulates quantity transcriptional regulation 10116 10823814 YES C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. 0.327 SIGNOR-259988 GSK3B protein P49841 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 20331603 YES lperfetto Phosphorylation of the residue Tyrosine in 216 position results in the constitutive activity of GSK-3beta and believed to be important target for signal transduction. 0.2 SIGNOR-217865 BRAF protein P15056 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 YES miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  0.262 SIGNOR-276404 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 BTO:0000007 SIGNOR-C3 10579915 YES lperfetto S6 kinases are under the control of the PI3K relative, mammalian Target Of Rapamycin (mTOR), which may serve an additional function as a checkpoint for amino acid availability. 0.96 SIGNOR-72682 CAMK2A protein Q9UQM7 UNIPROT NOS1 protein P29475 UNIPROT down-regulates activity phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 YES llicata It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation. 0.47 SIGNOR-250635 MS4A2 protein Q01362 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR form complex binding 9606 BTO:0000830 16470226 YES Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. 0.68 SIGNOR-254960 KAT6B protein Q8WYB5 UNIPROT KAT6A/KAT6B complex SIGNOR-C54 SIGNOR form complex binding 9606 17694082 YES miannu Like gcn5/pcaf and p300/cbp, moz and morf are transcriptional co-activators with intrinsic hat activity. 0.414 SIGNOR-157307 PRKACA protein P17612 UNIPROT FRAT1 protein Q92837 UNIPROT down-regulates phosphorylation Ser188 RLQQRRGsQPETRTG 9606 16982607 YES lperfetto Phosphorylation of ser188 by pka inhibited the ability of frat1 to activate beta-catenin-dependent transcription. 0.2 SIGNOR-149689 CSNK2B protein P67870 UNIPROT CSNK2B protein P67870 UNIPROT unknown phosphorylation Ser2 sSSEEVSW 9606 1939094 YES llicata Phosphorylation of the beta subunit of casein kinase II in human A431 cells. Identification of the autophosphorylation site | Cleavage of the beta subunit, that had been autophosphorylated in vitro, at tryptophan 9 and tryptophan 12 using N-chlorosuccinimide demonstrated that the autophosphorylation site is located near the amino terminus of the protein, most likely at serine 2 and serine 3. 0.2 SIGNOR-251062 CDK5 protein Q00535 UNIPROT NGEF protein Q8N5V2 UNIPROT up-regulates activity phosphorylation 9606 28769056 YES miannu Importantly, ephexin1, a Rho GEF, is phosphorylated by Cdk5 in vivo . 0.421 SIGNOR-279021 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 SIGNOR-C83 10428798 YES gcesareni Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. 0.478 SIGNOR-69710 hsa-miR-205-5p mirna URS0000446722_9606 RNAcentral LRP1 protein Q07954 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003765 24525843 YES Parnian Taken together, LRP-1 overexpression by the decreased miR-205 may promote the proliferation of DFSP cells.| LRP-1 is the direct target of miR-205. 0.4 SIGNOR-278835 hsa-miR-181a-5p mirna URS00003DA300_9606 RNAcentral RGS16 protein O15492 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000250 26013170 YES Parnian MiR-181a directly targets RGS16 through binding to the 3’UTR resulting in decreased RGS16 mRNA and protein. 0.4 SIGNOR-278843 FLT3 protein P36888 UNIPROT ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18559972 NO apalma In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors. 0.263 SIGNOR-255698 POMC protein P01189 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000047 20371771 YES lperfetto Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). 0.782 SIGNOR-268615 KLHL9 protein Q9P2J3 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000567 17543862 YES miannu Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis. 0.599 SIGNOR-271660 SUV39H1 protein O43463 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 23435416 NO lperfetto The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation 0.511 SIGNOR-249600 WNT3 protein P56703 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.63 SIGNOR-131820 RFX3 protein P48380 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 10090 32725242 NO miannu RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process. 0.7 SIGNOR-266927 TEC protein P42680 UNIPROT STAP1 protein Q9ULZ2 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10518561 YES miannu In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. 0.392 SIGNOR-261817 PAFAH1B1 protein P43034 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity binding 10090 BTO:0000938 11163259 YES miannu We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 is required for the proper distribution of NUDEL and cellular components regulated by CDHC function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex 0.843 SIGNOR-252157 GLI1 protein P08151 UNIPROT HHIP protein Q96QV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 NO lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. 0.626 SIGNOR-209623 SMARCA1 protein P28370 UNIPROT ST7 protein Q9NRC1 UNIPROT down-regulates quantity by repression transcriptional regulation 15485929 YES lperfetto Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes. 0.2 SIGNOR-268991 RCOR1 protein Q9UKL0 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR form complex binding 9606 20080105 YES 1 miannu Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex. 0.768 SIGNOR-239220 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 16495336 YES gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell 0.876 SIGNOR-144783 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 19115199 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-217613 NCAPD2 protein Q15021 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.97 SIGNOR-263905 RUNX2 protein Q13950 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates transcriptional regulation 10090 16574347 NO Giulio Giuliani Osx promoter activity was up-regulated by 2 fold after Runx2 over-expression in ATDC5 cells. Osx Is Phosphorylated by p38 at Ser-73 and Ser-77 0.51 SIGNOR-255410 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser314 RAREKRDsRNMEVQV 9606 15767678 YES gcesareni Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis. 0.332 SIGNOR-134580 FBXL5 protein Q9UKA1 UNIPROT NABP2 protein Q9BQ15 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000018 25249620 YES miannu Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation. 0.344 SIGNOR-271655 TLN1 protein Q9Y490 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.694 SIGNOR-257608 FBXL14 protein Q8N1E6 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0006155 27923907 YES done miannu  In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. 0.35 SIGNOR-274125 UBE2E1 protein P51965 UNIPROT ZSWIM2 protein Q8NEG5 UNIPROT up-regulates activity binding 9606 BTO:0000007 16522193 YES miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  0.338 SIGNOR-271555 ABL1 protein P00519 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT up-regulates activity phosphorylation Tyr267 KRRTEEKyGGDSDHP 9606 BTO:0000007 26126715 YES miannu The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response to DNA damage. When coexpressed in HEK293T cells, ABL phosphorylated DGCR8 at Tyr(267). 0.2 SIGNOR-262604 Phenelzine chemical CHEBI:8060 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu At the human dopamine transporter, sertraline and nomifensine were the most potent with KD's of 25±2 and 56±3, respectively. Except for these two compounds, most antidepressants were not potent at the human dopamine transporter. 0.8 SIGNOR-258745 PRKCA protein P17252 UNIPROT GRIA1 protein P42261 UNIPROT unknown phosphorylation Ser832 LIEFCYKsRSESKRM 9606 8663994 YES lperfetto In addition, protein kinase C specifically phosphorylates Ser-831 of GluR1 in HEK-293 cells and in cultured neurons. 0.714 SIGNOR-248950 ELOVL1 protein Q9BW60 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267896 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 YES gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. 0.258 SIGNOR-128714 E2F1 protein Q01094 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 22537161 NO lperfetto Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades 0.2 SIGNOR-254133 PRKAA1 protein Q13131 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 SIGNOR-C15 9636039 YES gcesareni Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase. 0.408 SIGNOR-58255 CDK2 protein P24941 UNIPROT TPX2 protein Q9ULW0 UNIPROT down-regulates activity phosphorylation Thr72 NLQQAIVtPLKPVDN -1 25688093 YES lperfetto In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle 0.294 SIGNOR-265099 CCNY protein Q8ND76 UNIPROT CDK14 protein O94921 UNIPROT up-regulates binding 9606 20059949 YES gcesareni L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6. 0.829 SIGNOR-162920 PRKAA1 protein Q13131 UNIPROT CYCS protein P99999 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001103 17609368 NO gcesareni Severalin vivostudies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochromec, uncoupling protein 3 (ucp-3)] (1518) and proteins involved in glucose uptake (glut4) (1820) are increased at the transcriptional level in skeletal muscle. 0.35 SIGNOR-156772 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 18570871 YES gcesareni Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex. 0.581 SIGNOR-179088 Kallidin smallmolecule CHEBI:6102 ChEBI BDKRB2 protein P30411 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257465 TRIM27 protein P14373 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 BTO:0000671 12807881 NO miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. 0.2 SIGNOR-102025 TLN1 protein Q9Y490 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.588 SIGNOR-257629 PIH1D1 protein Q9NWS0 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000093 24036451 YES miannu PIH1D1 interacts with mTOR complex 1 and enhances ribosome RNA transcription.PIH1D1 is important for mTORC1 assembly 0.339 SIGNOR-265897 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1795 VASPRRLsNVSSSGS -1 8631898 YES miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 0.419 SIGNOR-250166 PER2 protein O15055 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. 0.75 SIGNOR-267973 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0001130 1010227 YES gcesareni Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner. 0.712 SIGNOR-252819 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 16679294 YES gcesareni Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action 0.261 SIGNOR-146680 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates activity dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0000298 16291744 YES down-regulates binding to src lperfetto Here we report that protein-tyrosine phosphatase 1B (PTP 1B) is an alpha-actinin phosphatase. PTP 1B-dependent dephosphorylation of alpha-actinin was seen in COS-7 cells|No dephosphorylation was observed in cells coexpressing the alpha-actinin phosphorylation mutant Y12F and PTP 1B. |A reversible interaction between alpha-actinin and Src enables the dephosphorylation of alpha-actinin by PTP 1B, releasing Src 0.335 SIGNOR-270539 ADCY8 protein P40145 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-265002 STK26 protein Q9P289 UNIPROT ATG4B protein Q9Y4P1 UNIPROT up-regulates activity phosphorylation Ser383 RLERFFDsEDEDFEI 9606 29232556 YES miannu MST4 Induced p-S383 of ATG4B Enhances GSC Autophagic Activity and Tumorigenicity.|MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. 0.2 SIGNOR-278254 KANSL3 protein Q9P2N6 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. 0.621 SIGNOR-267162 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser216 PSGSGAAsPTGSAVD 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.256 SIGNOR-262762 Ub:E2 complex SIGNOR-C497 SIGNOR PCGF6 protein Q9BYE7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271037 GSK3B protein P49841 UNIPROT WT1 protein P19544 UNIPROT down-regulates quantity by destabilization phosphorylation Ser208 GCHTPTDsCTGSQAL 9606 33184107 YES miannu Glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8. 0.285 SIGNOR-277540 NFIB protein O00712 UNIPROT NFIB protein O00712 UNIPROT down-regulates activity binding 9606 9099724 YES 2 miannu Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function. 0.2 SIGNOR-240883 CAMK1 protein Q14012 UNIPROT CAMK1 protein Q14012 UNIPROT up-regulates activity phosphorylation Thr177 DPGSVLStACGTPGY -1 8253780 YES llicata CaM kinase I was autophosphorylated in a Ca2+/CaM-dependent manner at a threonyl residue (Thr-177) which is located at a position equivalent to that of the threonyl residue (Thr-197) autophosphorylated in cAMP-dependent protein kinase. 0.2 SIGNOR-250612 FREM1 protein Q5H8C1 UNIPROT NPNT protein Q6UXI9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22613833 YES lperfetto The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome. 0.366 SIGNOR-253308 BLOC-1 complex SIGNOR-C381 SIGNOR histamine smallmolecule CHEBI:18295 ChEBI up-regulates quantity relocalization 9606 23805129 YES lperfetto The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules 0.8 SIGNOR-265998 TRIM65 protein Q6PJ69 UNIPROT TNRC6A protein Q8NDV7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 24778252 YES miannu Ubiquitination assays demonstrate that TRIM65 is an ubiquitin E3 ligase for TNRC6 proteins. The combination of overexpression and knockdown studies establishes that TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6. 0.445 SIGNOR-272174 MC1R protein Q01726 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19656324 NO miannu Constitutive expression of MC1R in HaCaT keratinocytes inhibits basal and UVB-induced TNF-alpha production. the constitutive activity of MC1R results in elevated intracellular cAMP level, reduced NF-kappaB activity and decreased TNF-alpha transcription 0.289 SIGNOR-252375 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1333 ARGGQVFyNSEYGEL 9606 20431062 YES lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. 0.511 SIGNOR-165039 PIK3C3 protein Q8NEB9 UNIPROT PTEN protein P60484 UNIPROT up-regulates binding 9606 BTO:0000567 20212113 YES lperfetto Direct positive regulation of pten by the p85 subunit of phosphatidylinositol 3-kinase.Thus p85 regulates both p110-pi3k and pten-phosphatase enzymes through direct interaction 0.664 SIGNOR-164075 PRDM2 protein Q13029 UNIPROT HMOX1 protein P09601 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8654390 NO 2 miannu We show that a portion of MTB-Zf, including an N-terminal zinc-finger domain, binds in vitro to MTE and that the transient coexpression of MTB-Zf cDNA leads to transativation of the heme-oxygenase-1 gene promoter. 0.2 SIGNOR-241047 PAF1C complex SIGNOR-C471 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 BTO:0000567 20178742 YES miannu HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription. 0.46 SIGNOR-269837 PRKCQ protein Q04759 UNIPROT ARHGEF6 protein Q15052 UNIPROT up-regulates activity phosphorylation Ser488 LSASPRMsGFIYQGK 25694429 YES lperfetto Recently, we have reported that the active form of Rac 1 GTPase binds to the glycogen phosphorylase muscle isoform (PYGM) and modulates its enzymatic activity leading to T cell proliferation.|More specifically, αPIX, a known guanine nucleotide exchange factor for the small GTPases of the Rho family, preferentially Rac 1, mediates PYGM activation in Kit 225 T cells stimulated with IL-2. Using directed mutagenesis, phosphorylation of αPIX Rho-GEF serines 225 and 488 is required for activation of the Rac 1/PYGM pathway. 0.2 SIGNOR-272168 TP53 protein P04637 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000711 17564708 NO miannu we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ. 0.475 SIGNOR-255437 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 10090 BTO:0000944 18042541 YES gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). 0.68 SIGNOR-243530 miR221 mirna URS0000245997_9606 RNAcentral MEOX2 protein P50222 UNIPROT down-regulates quantity 10090 20819939 YES We show that miR-1 and miR-206 facilitate satellite cell differentiation by restricting their proliferative potential. We identify Pax7 as one of the direct regulatory targets of miR-1 and miR-206. Inhibition of miR-1 and miR-206 substantially enhances satellite cell proliferation and increases Pax7 protein level in vivo 0.4 SIGNOR-255922 GDF6 protein Q6KF10 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 16049014 YES gcesareni We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. Thus, the present approach provides a genomic paradigm for matching paralogous polypeptide ligands with a limited number of evolutionarily related receptors capable of activating specific downstream smad proteins. 0.592 SIGNOR-139093 PRKG1 protein Q13976 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates activity phosphorylation Ser26 VETLRRGsKFIKWDE 10116 BTO:0004576 11278298 YES lperfetto PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG. 0.538 SIGNOR-249079 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Arg70 ESGLTEYrLVSINKS -1 10978167 YES lperfetto Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site. 0.624 SIGNOR-263572 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Thr309 SDGATMKtFCGTPEY 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.748 SIGNOR-248630 MGluR proteinfamily SIGNOR-PF55 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. 0.8 SIGNOR-264930 MAP2K1 protein Q02750 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887 11160134 YES lperfetto Thus, at least three kinases mediate phosphorylation of ser307, including jnk, serine kinases in the pi 3-kinase cascade that are activated byinsulinor igf-1, and mek1-sensitive kinase cascades during tnf-alfa stimulation. 0.352 SIGNOR-236611 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR6 protein P50406 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257525 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI AKT1 protein P31749 UNIPROT up-regulates chemical activation 9606 16293724 YES gcesareni Pge2 also stimulated akt activity in a pi3k-dependent manner. 0.8 SIGNOR-141817 ATR protein Q13535 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Thr691 YGLEEYDtQDGIAIN 9606 16943440 YES lperfetto In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents 0.672 SIGNOR-149309 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.289 SIGNOR-249008 FOXO1 protein Q12778 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 NO inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.32 SIGNOR-267787 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr62 RRPESFTtPEGPKPR 9606 BTO:0000567 18490441 YES lperfetto Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase 0.413 SIGNOR-265259 TRIM33 protein Q9UPN9 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization binding 9606 25639486 YES Luana Tumour suppressor TRIM33 targets nuclear β-catenin degradation 0.457 SIGNOR-260896 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser418 VEEDPLNsGDDVSEQ -1 12107178 YES llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. 0.425 SIGNOR-250872 ETNK1 protein Q9HBU6 UNIPROT O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI up-regulates quantity chemical modification 36583229 YES lperfetto ETNK1 encodes ethanolamine kinase 1, which is involved in the de novo biosynthesis of phosphatidylethanolamine and is responsible for the phosphorylation of ethanolamine to phosphoethanolamine 0.8 SIGNOR-275641 PTK2 protein Q05397 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9416004 YES gcesareni Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors. 0.569 SIGNOR-252726 PTGER1 protein P34995 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256954 IFNG protein P01579 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation 0.766 SIGNOR-249487 GATA1 protein P15976 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates activity relocalization 9606 BTO:0000150 25726523 YES lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 0.583 SIGNOR-275665 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 16226275 YES First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185 0.812 SIGNOR-248483 FZD7 protein O75084 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 22179044 YES apalma In non-canonical Wnt signalling, Wnt proteins bind Fzd and glypican-4, to activate Dsh at the cell membrane, leading to activation of Rho and JNK 0.66 SIGNOR-255893 ARHGAP22 protein Q7Z5H3 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.528 SIGNOR-260477 EGFR protein P00533 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr277 LRDMISMyLPGAEVP 9606 31823521 YES miannu These data indicate that EGFR\u2010induced SOX2 Tyr277 phosphorylation prevents the autophagic degradation of SOX2 and enhances its stability. 0.48 SIGNOR-279036 LCK protein P06239 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr394 LNTIGLIyEKISLPK 9606 BTO:0002181 28618271 YES miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  0.2 SIGNOR-276723 RORA protein P35398 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24737872 YES miannu As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression. 0.687 SIGNOR-268002 EIF2AK2 protein P19525 UNIPROT NCK1 protein P16333 UNIPROT down-regulates activity phosphorylation 9606 18835251 YES miannu In these assays, we observed that GST\u2013Nck-1 was clearly phosphorylated by GST\u2013PKR while GST was not ( Fig. 4 , upper panels). 0.2 SIGNOR-279039 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates activity phosphorylation Ser379 DLILNRCsESTKRKL -1 24632950 YES miannu Of note, PKCδ, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation.PKCδ phosphorylates p47phox for K-Ras-induced ROS generation. PKCδ binds to the SH3-N domain and phosphorylates Ser348 and Ser379 residues in p47phox for K-RasV12-induced ROS generation and consequent malignant transformation. 0.448 SIGNOR-276622 GSK3B protein P49841 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser43 QTPSKPAsADGHRGP 9606 33388549 YES miannu P -Ser9 GSK-3\u03b2 phosphorylates Ser43, Ser51, and Ser493 residues of src, regulating src activity. 0.383 SIGNOR-278442 KRAS protein P01116 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 YES miannu The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. 0.876 SIGNOR-156906 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 15821101 YES gcesareni Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2 0.796 SIGNOR-135207 RAPGEF6 protein Q8TEU7 UNIPROT HRAS protein P01112 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.337 SIGNOR-183796 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257517 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser610 GPGPRRPsVASSVSE 9606 24554596 YES lperfetto These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. 0.374 SIGNOR-264765 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser278 PISSPTFsPIEFQIG 9606 23442801 YES lperfetto It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation 0.258 SIGNOR-201519 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 17339337 YES Manara Evaluation of these calcium calmodulin kinase superfamily members as candidate Ser(20) kinases in vivo has shown that only CHK1 or DAPK-1 can stimulate p53 transactivation and induce Ser(20) phosphorylation of p53.| Thus, endogenous CHK1 is required for the majority of Ser20 site phosphorylation of ectopically expressed p53 in H1299 cells. 0.79 SIGNOR-260776 DDB2 protein Q92466 UNIPROT DDB2/DDB1 complex SIGNOR-C39 SIGNOR form complex binding 9606 9418871 YES miannu Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna 0.937 SIGNOR-54099 HOXD3 protein P31249 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 14610084 YES Luana The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis. 0.25 SIGNOR-261650 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr655 GYADLDPyNSPGQEV -1 23770091 YES done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. 0.351 SIGNOR-273942 YY1 protein P25490 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 8266081 YES miannu Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1. 0.545 SIGNOR-268794 NCOA4 protein Q13772 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004191 18649734 NO The PSA promoter activity was detected by transient expression assay in the PC-J and LNCaP cells but not in androgen insensitive PC-3 cells. When the PC-J cells were cotransfected with androgen receptor, androgen receptor coactivators and PSA reporter vector cells, the reporter assays indicated that nuclear receptor coactivator 4 (NCOA4) but not androgen receptor activator 24 (ARA24) increased the sensitivity and maximum stimulation of dihydrotestosterone (DHT)-inducing PSA promoter activity. 0.327 SIGNOR-253659 FZD3 protein Q9NPG1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 14977528 YES gcesareni Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. 0.407 SIGNOR-122895 AURKA protein O14965 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser308 KAEFCNKsKQPGLAR 9606 14990569 YES lperfetto Previous studies have shown that the brca1 breast cancer tumor suppressor also localizes to the centrosome and that brca1 inactivation results in loss of the g(2)-m checkpoint. We demonstrate here that aurora-a physically binds to and phosphorylates brca1. We propose that brca1 phosphorylation by aurora-a plays a role in g(2) to m transition of cell cycle 0.676 SIGNOR-123065 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1626 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248769 DYRK2 protein Q92630 UNIPROT EDVP complex SIGNOR-C530 SIGNOR up-regulates activity binding 9606 BTO:0000007 19287380 YES miannu DYRK2 functions as an adaptor in the EDVP E3 ligase complex. These experiments suggest that DYRK2 functions as a molecular assembler required for the specific recruitment of EDD to DDB1-VPRBP, thus forming a novel EDVP E3 ligase complex. 0.448 SIGNOR-271792 PRKAA2 protein P54646 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 YES gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. 0.83 SIGNOR-139161 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser163 KRFSFKKsFKLSGFS -1 8557118 YES gcesareni PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. 0.365 SIGNOR-249651 ABL1 protein P00519 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 YES miannu Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. 0.2 SIGNOR-277519 PP1 proteinfamily SIGNOR-PF54 SIGNOR CCND3 protein P30281 UNIPROT up-regulates dephosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 YES lperfetto These results support the hypothesis that pp1 constitutively keeps cyclin d3 in a stable, dephosphorylated state 0.2 SIGNOR-264662 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 YES gcesareni Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation. 0.355 SIGNOR-88720 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr161 QGWVPSNyITPVNSL -1 34144039 YES miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. 0.303 SIGNOR-277306 FGR protein P09769 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr394 LNTIGLIyEKISLPK 9606 BTO:0002181 28618271 YES miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  0.2 SIGNOR-276722 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 YES In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4. 0.686 SIGNOR-251328 PRKCA protein P17252 UNIPROT F11R protein Q9Y624 UNIPROT unknown phosphorylation Thr92 DRVTFLPtGITFKSV -1 7646439 YES lperfetto Internal amino acid sequence analysis of the F11 antigen provided information concerning 68 amino acids and suggested two consensus phosphorylation sites for protein kinase C (PKC). The phosphorylation by PKC of the isolated F11 antigen was observed following stimulation by phorbol 12-myristate 13-acetate. 0.322 SIGNOR-248901 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity binding 9606 23431053 YES miannu The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. 0.2 SIGNOR-265820 SREBF2 protein Q12772 UNIPROT PON1 protein P27169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20728021 YES miannu we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity. 0.297 SIGNOR-255224 ATF3 protein P18847 UNIPROT PCLAF protein Q15004 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23593430 NO gcesareni P15(paf) is a direct transcriptional target of atf3 0.2 SIGNOR-201850 ITCH protein Q96J02 UNIPROT GLIS3 protein Q8NEA6 UNIPROT down-regulates quantity ubiquitination 9606 26147758 YES miannu Itch promotes proteolytic degradation of Glis3.|Since Itch interacts with and ubiquitinates Glis3, it was of interest to determine which regions were necessary for Itch directed degradation of Glis3. 0.331 SIGNOR-278653 MARCHF5 protein Q9NX47 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity ubiquitination 9606 19741096 YES miannu Cycloheximide-chase assay in the Neuro2a cells indicated that MITOL overexpression promoted mSOD1 degradation and suppressed both the mitochondrial accumulation of mSOD1 and mSOD1-induced reactive oxygen species generation.|In vitro ubiquitination assay revealed that MITOL directly ubiquitinates mSOD1. 0.2 SIGNOR-278654 ASH2L protein Q9UBL3 UNIPROT HMT complex SIGNOR-C19 SIGNOR form complex binding 9606 17500065 YES lperfetto The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes. 0.873 SIGNOR-154760 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid chemical CHEBI:91366 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258250 retinal smallmolecule CHEBI:15035 ChEBI all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity precursor of 9606 21621639 YES lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. 0.8 SIGNOR-265127 SMOC1 protein Q9H4F8 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT up-regulates quantity 10090 30127878 NO lperfetto In conclusion, the results of the present study suggested that SMOC1 silencing suppressed the Ang II-induced myocardial fibrosis of mouse MFBs through affecting the BMP2/Smad signaling pathway. 0.2 SIGNOR-260403 TACR2 protein P21452 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.259 SIGNOR-256736 PTPN6 protein P29350 UNIPROT TYK2 protein P29597 UNIPROT down-regulates 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 NO lperfetto We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation 0.606 SIGNOR-119200 SNAI1 protein O95863 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000599 27239445 NO Marta Tosoni Compelling evidence has demonstrated that SNAI1 plays a key role in the induction of EMT 0.7 SIGNOR-278097 SMURF2 protein Q9HAU4 UNIPROT KLF5 protein Q13887 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 34035464 YES miannu Consistent with these observations, another study documented that Smurf2 specifically destabilizes KLF5, that the degradation of KLF5 by Smurf2 is disrupted by the proteasome inhibitor MG132, and that Smurf2 ubiquitinates KLF5 . 0.371 SIGNOR-278781 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9841871 YES lperfetto When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro. 0.567 SIGNOR-62369 BRD7 protein Q9NPI1 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.666 SIGNOR-270601 RFX5 protein P48382 UNIPROT HLA-DRA protein P01903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000460 10586057 YES Luana In this report, we correlate the loss of IFN-γ induction of MHC class II genes with the identification of a molecular defect in an essential regulator, namely RFX5. | We have further confirmed this finding by showing that new RFX5 leucine mutants created in vitro are incapable of transactivating a class II promoter, suggesting the identification of residues essential for RFX activity. 0.503 SIGNOR-266228 CAMK2A protein Q9UQM7 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 YES gcesareni Receptor internalization, altered;intracellular localization 0.591 SIGNOR-97546 PIM1 protein P11309 UNIPROT FLT3 protein P36888 UNIPROT up-regulates quantity phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 BTO:0005720 24040307 YES Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway. 0.42 SIGNOR-259927 TLR4 protein O00206 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 28137827 YES miannu Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation. 0.486 SIGNOR-261929 ITGB2 protein P05107 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.664 SIGNOR-253204 TYMS protein P04818 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity chemical modification 9606 21876188 YES lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. 0.8 SIGNOR-268232 YWHAE protein P62258 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 12042314 YES miannu 14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue. 0.539 SIGNOR-88297 GALT protein P07902 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI down-regulates quantity chemical modification 9606 2011574 YES miannu Cytosolic galactose-1-phosphate uridylyltransferase (GALT) catalyzes the reaction of alpha-D-galactose 1-phosphate and UDP glucose to form D-glucose 1-phosphate and UDP galactose 0.8 SIGNOR-280268 EP300 protein Q09472 UNIPROT TBXAS1 protein P24557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 14565864 NO miannu We also showed that forced expression of p300 upregulated TXAS gene in a dose-dependent manner. Mutation of NF-E2 site, but not TATA or initiator site, abolished the p300-mediated activation of TXAS gene. 0.2 SIGNOR-253906 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002524 17298674 YES miannu Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme 0.564 SIGNOR-271639 PTEN protein P60484 UNIPROT RAB7A protein P51149 UNIPROT up-regulates activity dephosphorylation Ser72 AGQERFQsLGVAFYR 9606 26869029 YES lperfetto PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation. 0.373 SIGNOR-276960 TOPORS protein Q9NS56 UNIPROT TP53 protein P04637 UNIPROT down-regulates ubiquitination 9606 phosphorylation:Ser718 KDRDGYEsSYRRRTL 19473992 YES lperfetto Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. 0.462 SIGNOR-185848 BLK protein P51451 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr294 YETADGGyMTLNPRA -1 8756631 YES miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation 0.2 SIGNOR-262672 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 YES miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.272 SIGNOR-265947 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HYAL1 protein Q12794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004796 18718911 NO miannu In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription. 0.2 SIGNOR-253880 SLC9A8 protein Q9Y2E8 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265598 TBPL2 protein Q6SJ96 UNIPROT TAF3/TRF3 complex SIGNOR-C23 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 18851836 YES lperfetto We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation 0.664 SIGNOR-181614 UBE2E1 protein P51965 UNIPROT MPG protein P29372 UNIPROT up-regulates activity binding -1 25207814 YES miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E) 0.2 SIGNOR-271929 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 16308421 NO gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. 0.2 SIGNOR-252915 PDPK1 protein O15530 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 15209375 YES gcesareni One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.415 SIGNOR-126066 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD6 protein O43541 UNIPROT down-regulates activity relocalization 9606 22298955 YES lperfetto Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm. 0.2 SIGNOR-253261 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates activity binding 9606 BTO:0000801 18551128 YES lperfetto The GM-CSF receptor (CSF2R) is a heterodimer composed of a specific ligand-binding subunit (CSF2Ralpha) and a common signal-transduction subunit (CSF2Rbeta) 0.857 SIGNOR-249501 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by stabilization deacetylation Lys71 GILRRLKkYDNCWLA 9606 BTO:0000007 21726808 YES lperfetto Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 0.426 SIGNOR-267601 LPAR1 protein Q92633 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.542 SIGNOR-257091 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191409 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates 9606 22298955 NO gcesareni Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro. 0.354 SIGNOR-254335 porfimer chemical CHEBI:60652 ChEBI LDLR protein P01130 UNIPROT up-regulates activity chemical activation 9606 1450993 YES miannu Porphyrins are transported in blood mainly by lipoproteins, and the low density lipoprotein (LDL) receptor-mediated pathway is probably one of the important factors involved in the selective accumulation of porphyrins by tumor tissues, as cancer cells generally express much more LDL receptors than normal cells. 0.8 SIGNOR-259302 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 11909979 YES gcesareni Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1. 0.614 SIGNOR-116252 PIK3CD protein O00329 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 NO lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.7 SIGNOR-242655 CFAP53 protein Q96M91 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR up-regulates activity binding 10090 BTO:0000379 33347437 YES miannu CFAP53 associates with axonemal microtubules of tracheal cilia and interacts with dynein proteins and the docking complex (DC) 0.2 SIGNOR-265547 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr288 QCPVGFNtLAFPSMK -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.657 SIGNOR-276129 TIMM23 protein O14925 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.642 SIGNOR-267697 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 YES We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. 0.565 SIGNOR-248398 domperidone chemical CHEBI:31515 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258381 MCU_MICU3_variant complex SIGNOR-C501 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.8 SIGNOR-270873 CIB1 protein Q99828 UNIPROT ITGA2B protein P08514 UNIPROT up-regulates activity binding 10029 BTO:0000246 11756406 YES Gianni The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading 0.473 SIGNOR-269061 STOM protein P27105 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 YES lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] 0.35 SIGNOR-266040 MAPK14 protein Q16539 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 YES lperfetto In hela cells, prak was activated in response to cellular stress and proinflammatory cytokines. Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site. 0.636 SIGNOR-58135 ZFAT protein Q4KMQ4 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates quantity 10090 24663380 NO francesca Ano6 deficiency significantly reduces ERK/AKT phosphorylation. In addition, Ano6-KD also affected levels of phosphorylated and total AKT levels. 0.2 SIGNOR-261215 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR GADD45B protein O75293 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11713530 NO gcesareni Here we report that nf-kappab complexes downregulate the c-jun amino-terminal kinase (jnk) cascade, thus establishing a link between the nf-kappab and the jnk pathways. This link involves the transcriptional upregulation of gadd45beta/myd118, which downregulates jnk induced by the tnf receptor (tnf-r). 0.291 SIGNOR-111963 NSD1 protein Q96L73 UNIPROT PRB4 protein P10163 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003233 29156722 YES miannu We here demonstrate that NSD1 could bind to the promoter regions of PRB4 and activate promoter activity by reducing the binding of H3K27me2 and increasing the binding of H3K36me2 on PRB4 promoter. 0.343 SIGNOR-268459 CDK5 protein Q00535 UNIPROT TRIM59 protein Q8IWR1 UNIPROT up-regulates activity phosphorylation Ser308 LIPKMKIsPKRMSCS 31488827 YES miannu  Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. 0.2 SIGNOR-272929 EPAS1 protein Q99814 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.283 SIGNOR-271578 GNAI2 protein P04899 UNIPROT ADCY6 protein O43306 UNIPROT down-regulates activity binding 7108 BTO:0001240 8119955 YES Marta Tosoni Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3 0.521 SIGNOR-278078 PBRM1 protein Q86U86 UNIPROT S100A13 protein Q99584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000562 15601824 NO miannu We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues. 0.444 SIGNOR-132431 CBX3 protein Q13185 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity binding 9606 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-265324 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.617 SIGNOR-273922 CDK6 protein Q00534 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser325 STVSGRLsPIMASTE 9606 28778953 YES miannu CDK6 and cyclin D3 complex phosphorylates FOXO3 on S325.|Using cycloheximide (CHX), we observed that CDK6 knockdown decreased FOXO3 stability, particularly in platinum treated cells (Fig XREF_FIG A) and that, following platinum treatment, FOXO3 WT was more stable than the non phosphorylatable mutant FOXO3 S325A (Fig XREF_FIG B). 0.464 SIGNOR-279023 TP53 protein P04637 UNIPROT SCO2 protein O43819 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 YES miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. 0.638 SIGNOR-267463 CAD protein P27708 UNIPROT CAD protein P27708 UNIPROT up-regulates activity phosphorylation Thr1037 QQCRVLGtSPEAIDS -1 11986331 YES llicata Autophosphorylation resulted in a 2-fold increase in CPSase activity, an increased sensitivity to the feedback inhibitor UTP, and decreased allosteric activation by 5-phosphoribosyl-1-pyrophosphate 0.2 SIGNOR-250610 DAB1 protein O75553 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000142 22394407 YES lperfetto The induction of disabled-1 (dab-1) tyrosine phosphorylation, and the subsequent activation of src family kinases, were found to be essential steps for the activation of notch-1 signaling by reelin 0.379 SIGNOR-196438 TGFB1 protein P01137 UNIPROT CDK2 protein P24941 UNIPROT down-regulates 9606 SIGNOR-C16 10611320 NO gcesareni Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2. 0.282 SIGNOR-73537 FNTB protein P49356 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity 9606 24294527 YES lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. 0.461 SIGNOR-242565 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.247 SIGNOR-268600 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser467 DTSYVIEsDEDLEME 9606 BTO:0000007 24429382 YES llicata Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair. 0.642 SIGNOR-203741 WNT7A protein O00755 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.645 SIGNOR-131897 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 10521487 YES gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. 0.653 SIGNOR-252584 MACF1 protein Q9UPN3 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 BTO:0000938 16815997 NO flangone Macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. 0.297 SIGNOR-147457 DOCK7 protein Q96N67 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0000132 29187380 YES lperfetto As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover. 0.738 SIGNOR-261886 ARNT protein P27540 UNIPROT CA9 protein Q16790 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22387692 NO lperfetto The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. 0.522 SIGNOR-253706 CYP2R1 protein Q6VVX0 UNIPROT vitamin D smallmolecule CHEBI:27300 ChEBI down-regulates quantity chemical modification 9606 BTO:0000759 30080183 YES lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. 0.8 SIGNOR-270569 ARID5B protein Q14865 UNIPROT PHF2 protein O75151 UNIPROT up-regulates activity binding 9606 BTO:0000007 21532585 YES miannu We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity. 0.559 SIGNOR-264515 LSM-1231 chemical CHEBI:91471 ChEBI NTRK1 protein P04629 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258238 PCSK7 protein Q16549 UNIPROT CDC25B protein P30305 UNIPROT down-regulates phosphorylation 9606 11333986 YES gcesareni We propose that regulation of cdc25b phosphorylation by p38 is a critical event for initiating the g2/m checkpoint after ultraviolet radiation 0.2 SIGNOR-107423 ATF4 protein P18848 UNIPROT SARS1 protein P49591 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269424 USP36 protein Q9P275 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR up-regulates quantity by stabilization deubiquitination 22902402 YES lperfetto USP36, the human ortholog of Ubp10, complements the ubp10Δ allele for RNAPI stability, pre-rRNA processing, and cell growth in yeast, suggesting that deubiquitination of RNAPI may be conserved in eukaryotes. Our work implicates Ubp10/USP36 as a key regulator of rRNA production through control of RNAPI stability.|Human USP36 complements ubp10delta for RNA polymerase I deubiquitination and stability 0.258 SIGNOR-272292 PTPRC protein P08575 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 BTO:0000776;BTO:0003076 11994288 YES gcesareni These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3, 0.457 SIGNOR-87157 AURKB protein Q96GD4 UNIPROT DIAPH2 protein O60879 UNIPROT up-regulates phosphorylation Ser196 SLTSNPVsWVNNFGH 9606 21397845 YES lperfetto The microtubule binding fh2 domain of mdia3 is phosphorylated by aurora b kinase in vitro, and cells expressing the nonphosphorylatable mdia3 mutant cannot position chromosomes at the metaphase plate 0.288 SIGNOR-172803 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Ser893 PRYHKRTsSAVWNSP 9606 12925766 YES gcesareni Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites. 0.974 SIGNOR-118011 TFEB protein P19484 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; 0.41 SIGNOR-276558 SACM1L protein Q9NTJ5 UNIPROT Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR down-regulates 9534 BTO:0001444 22253445 NO lperfetto Ectopic Expression of Sac1 Phosphatase Inhibits SARS-CoV S-mediated Entry 0.7 SIGNOR-260735 DDX46 protein Q7L014 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.57 SIGNOR-270669 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Thr189 LLLTTGGtLKISDLG 9606 BTO:0000781 11430832 YES lperfetto These data suggest that the phosphorylation of thr-189 negatively regulates lkb1 activity. 0.2 SIGNOR-109028 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.432 SIGNOR-273146 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CCT2 protein P78371 UNIPROT up-regulates phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 21440620 YES lperfetto Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process. 0.2 SIGNOR-252780 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273049 GNA13 protein Q14344 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity binding 10090 BTO:0000944 12024019 YES P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation. 0.771 SIGNOR-256519 PRKAA1 protein Q13131 UNIPROT GSR protein P00390 UNIPROT up-regulates activity phosphorylation Thr507 TKADFDNtVAIHPTS 9606 BTO:0001890 31530934 YES miannu Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity.  0.289 SIGNOR-273734 SMC4 protein Q9NTJ3 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.817 SIGNOR-263909 ATR protein Q13535 UNIPROT USP20 protein Q9Y2K6 UNIPROT down-regulates activity phosphorylation 9606 25355518 YES miannu On the other hand, USP20 is phosphorylated by ATR, which disrupts the interaction between USP20 and HERC2, resulting in USP20 stabilization.|USP20 phosphorylation by ATR is important for its stabilization and checkpoint activation. 0.306 SIGNOR-278393 ROCK1 protein Q13464 UNIPROT RND3 protein P61587 UNIPROT up-regulates phosphorylation Ser11 RRASQKLsSKSIMDP 9606 15775972 YES lperfetto We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability. 0.709 SIGNOR-134703 AMG 900 chemical CID:24856041 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189495 SETMAR protein Q53H47 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000007 25024738 NO miannu We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination.  Phosphorylated Chk1 phosphorylates S495 of Metnase. Phosphorylated Metnase decreases the interaction of DDB1 with Chk1, reducing Chk1 targeting to the Cul4a E3 ubiquitin ligase, increasing Chk1 stability. 0.491 SIGNOR-273609 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203516 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 21078818 YES gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt Beta-catenin signaling. 0.809 SIGNOR-253128 FBXO32 protein Q969P5 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 11717410 NO Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases 0.7 SIGNOR-255342 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates activity phosphorylation Ser514 SAPIRSAsQAEEEPS 10441130 YES miannu Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation 0.429 SIGNOR-249714 TG protein P01266 UNIPROT Thyroid_hormonogenesis phenotype SIGNOR-PH110 SIGNOR up-regulates 9606 BTO:0004710 30886364 NO miannu In humans, the thyroid hormones T3 and T4 are synthesized in the thyroid gland in a process that crucially involves the iodoglycoprotein thyroglobulin. The overall structure of thyroglobulin is conserved in all vertebrates. Upon thyroglobulin delivery from thyrocytes to the follicular lumen of the thyroid gland via the secretory pathway, multiple tyrosine residues can become iodinated to form mono-iodotyrosine (MIT) and/or di-iodotyrosine (DIT); however, selective tyrosine residues lead to preferential formation of T4 and T3 at distinct sites. 0.7 SIGNOR-259915 L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275813 CSNK2A2 protein P19784 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation Thr142 DSVTKLLtDVQLMKG 9606 12659875 YES lperfetto Transcriptional activity and dna binding of heat shock factor-1 involve phosphorylation on threonine 142 by ck2.As hsf1 is activated by heat shock simultaneously with the nuclear translocation of the protein kinase ck2, we have investigated the role of ck2 in hsf1 activatio 0.349 SIGNOR-99606 HNRNPH1 protein P31943 UNIPROT SRC protein P12931 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 BTO:0000938 9858532 YES lperfetto HnRNP H is a component of a splicing enhancer complex that activates a c-src alternative exon in neuronal cells. 0.291 SIGNOR-261273 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267955 procainamide chemical CHEBI:8428 ChEBI ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition -1 9301662 YES miannu With the aim of performing a rigorous test of the anti-AChE properties of our compounds, the kinetics of enzyme inhibition were studied in purified enzyme preparations. The inhibition data are shown in Table 1. Additionally, known competitive inhibitors of AChE (procainamide and edrophonium) were included in the study for comparative purposes. 0.8 SIGNOR-258668 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1RN protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000876 20032313 NO miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. 0.333 SIGNOR-254794 ADRA2B protein P18089 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-257109 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser18 RRLLFACsPPPASQP 9606 BTO:0002181 34363019 YES miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  0.2 SIGNOR-276736 FFAR3 protein O14843 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256678 ACACB protein O00763 UNIPROT malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity chemical modification 9606 20952656 YES miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA 0.8 SIGNOR-267110 Ub:E2 complex SIGNOR-C497 SIGNOR RFPL2 protein O75678 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271253 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 22049910 YES miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. 0.8 SIGNOR-266906 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser693 PYKSEMDsMPYTQNF 9606 BTO:0000567 34198826 YES miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. 0.25 SIGNOR-276663 MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 YES lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. 0.63 SIGNOR-45366 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser13 GQDMSQVsGKESPPV 9606 BTO:0001271 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo 0.29 SIGNOR-174824 PDH complex SIGNOR-C402 SIGNOR acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification 9606 29059435 YES miannu The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. 0.8 SIGNOR-266541 NUP98 protein P52948 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.687 SIGNOR-262098 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.2 SIGNOR-263010 GUCA2B protein Q16661 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 10845107 YES gcesareni Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney. 0.618 SIGNOR-78120 CALM3 protein P0DP25 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 YES miannu The calmodulin-binding region is located between amino acids 51 and 96 0.462 SIGNOR-266337 CNR1 protein P21554 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.263 SIGNOR-257211 SMURF1 protein Q9HCE7 UNIPROT C9orf78 protein Q9NZ63 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272674 SCF-betaTRCP complex SIGNOR-C5 SIGNOR TIAM1 protein Q13009 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 25124033 YES miannu Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site. 0.34 SIGNOR-276675 TGFB1 protein P01137 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000249 20930330 NO miannu TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line. 0.268 SIGNOR-252200 SPI1 protein P17947 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26622774 NO miannu In the present study, PU.1 siRNA was demonstrated to efficiently inhibit the transcription level of oncogene MEIS1 in the human acute myeloid non-MLL leukemia U937 cell line. In addition, PU.1, as a positive regulator of MEIS1, performed a crucial role in maintaining cell proliferation. 0.373 SIGNOR-256002 STAT4 protein Q14765 UNIPROT LAMTOR5 protein O43504 UNIPROT up-regulates activity binding 9606 22740693 YES miannu It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. here we first report that the transcription factor STAT4 plays a role in regulating S100A4 mediated by HBXIP in breast cancer. 0.327 SIGNOR-255247 LYPLA2 protein O95372 UNIPROT GAP43 protein P17677 UNIPROT down-regulates quantity by destabilization deacetylation Cys3 cCMRRTKQ 9606 BTO:0000567 21152083 YES miannu Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43. In this work, we investigated the deacylation of growth-associated protein-43 (GAP-43), a dually acylated protein at cysteine residues 3 and 4. Thus, the results demonstrate that APT-2 is the protein thioesterase involved in the acylation/deacylation cycle operating in GAP-43 subcellular distribution.we demonstrated that the reduction in the protein level was abrogated when cells were also treated with proteasome inhibitors (chloroquine, MG132 and lactacystin) which strongly suggest that GAP-43 deacylation is an early and necessary step for its later ubiquitination and degradation by the proteasome. In addition, it also suggests that acyl-protein thioesterase levels not only regulate palmitate turnover but also global protein turnover of GAP-43. 0.476 SIGNOR-266767 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr344 SSMPGGStPVSSANM 9606 7592773 YES lperfetto Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition 0.355 SIGNOR-29525 RPL9 protein P32969 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.865 SIGNOR-262452 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2D complex SIGNOR-C350 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 YES lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically 0.8 SIGNOR-268280 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15109499 NO miannu Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers 0.439 SIGNOR-252070 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9823 BTO:0001840 SIGNOR-C3 23486913 YES lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation 0.926 SIGNOR-219262 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 17035229 YES SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.432 SIGNOR-248792 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination Lys784 HVKLERLkQVNGMFP 9606 BTO:0000938 17283082 YES lperfetto Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage. 0.67 SIGNOR-249577 RXRB protein P28702 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 YES gcesareni We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active. 0.695 SIGNOR-123094 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 10090 BTO:0000759 34861291 YES miannu Perfluorooctane sulfonate (PFOS) is a stable environmental contaminant that can activate peroxisome proliferator-activated receptor alpha (PPARα). These results indicate that mouse PPARα can be activated in the liver by PFOS causing increased expression of Acox1, Cyp4a10 and histopathological changes in the liver. 0.8 SIGNOR-268754 SATB1 protein Q01826 UNIPROT IL23A protein Q9NPF7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 17343824 NO miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 0.2 SIGNOR-255132 PP2B proteinfamily SIGNOR-PF18 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 NO inferred from 70% family members gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.2 SIGNOR-269993 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser124 PALKRSHsDSLDHDI 9606 20068082 YES gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). 0.856 SIGNOR-163134 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition 9606 15284455 YES SimoneGraziosi Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain.  0.8 SIGNOR-269264 Lipid peroxidation phenotype SIGNOR-PH235 SIGNOR Ferroptosis phenotype SIGNOR-PH234 SIGNOR up-regulates 9606 BTO:0003081 37834426 YES miannu  ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell’s antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC. 0.7 SIGNOR-279880 STK39 protein Q9UEW8 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000988 21317537 YES lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, 0.348 SIGNOR-264644 RPS6KA3 protein P51812 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 YES lperfetto We therefore conclude that rsk1/rsk2 are novel activators of yb-1, able to phosphorylate the serine 102 residue. 0.539 SIGNOR-182165 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.725 SIGNOR-153417 PLK1 protein P53350 UNIPROT KIZ protein Q2M2Z5 UNIPROT up-regulates phosphorylation Thr379 WSTSSDLtISISEDD 9606 16980960 YES lperfetto Here, we identify a novel centrosomal substrate of plk1, kizuna (kiz), depletion of which causes fragmentation and dissociation of the pericentriolar material from centrioles at prometaphase, resulting in multipolar spindles. Plk1 maintains the integrity of the spindle poles by phosphorylating kiz. 0.517 SIGNOR-149630 CAV1 protein Q03135 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264454 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser244 GTHYSVQsDIWSMGL 9606 8131746 YES gcesareni Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf 0.573 SIGNOR-36453 SETD5 protein Q9C0A6 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity methylation -1 31515109 YES miannu SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. 0.2 SIGNOR-265350 NAIP protein Q13075 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 BTO:0000938 15280366 YES gcesareni These results demonstrate that naip is distinct from the other iaps, both in demonstrating a ligand-dependent caspase-9 interaction and in demonstrating a distinct mechanism of inhibition. 0.459 SIGNOR-127193 MCC complex SIGNOR-C382 SIGNOR APC-c complex SIGNOR-C150 SIGNOR down-regulates activity binding 9606 BTO:0000567 25092294 YES miannu The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. 0.793 SIGNOR-265977 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR IL22RA1 protein Q8N6P7 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 26171402 YES miannu FBXW12 causes depletion of endogenous and plasmid-derived IL-22R in lung epithelia, binds the E3 ligase constituent Skp-1, and facilitates ubiquitination of IL-22R in vitro. 0.2 SIGNOR-272428 MARK2 protein Q7KZI7 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates activity phosphorylation Ser366 KTLPRSSsMAAGLER 9606 21282462 YES miannu Par1b directly phosphorylates IRSp53 on S366 in cell lysates and stimulates phosphorylation on S453/3/5 via an indirect mechanism.|These data are consistent with a scenario in which Par1b phosphorylation inhibits IRSp53 function. 0.463 SIGNOR-278411 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr209 TRKHYQPyAPPRDFA 9606 BTO:0000661 22936936 YES lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals 0.689 SIGNOR-198751 STUB1 protein Q9UNE7 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27007160 YES miannu Via this mechanism, CHIP ubiquitinates and degrades glucocorticoid receptor (GR), androgen receptor (AR), estrogen receptor (ER), ErbB2, and alpha-synuclein, only when bound to Hsp . 0.479 SIGNOR-278782 CHEK1 protein O14757 UNIPROT E2F6 protein O75461 UNIPROT down-regulates activity phosphorylation Ser52 EDNVQYVsMRKALKV -1 23954429 YES miannu the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters. 0.572 SIGNOR-266371 SRC protein P12931 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT down-regulates activity phosphorylation 9606 26280531 YES miannu Prior phosphorylation of Y395 dramatically increases the rate of EGFR phosphorylation of Mig6 on Y394 in vitro, and suppression of Src activity pharmacologically or by shRNA decreased phosphorylation of Mig6 on this site in cells, impairing EGFR binding and inhibition.|We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395. 0.415 SIGNOR-279116 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation 10090 BTO:0003620 11201744 YES CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling 0.473 SIGNOR-248347 DZIP3 protein Q86Y13 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTSATVG 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271752 GSK3B protein P49841 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 16543145 YES gcesareni We investigated the role of glycogen synthase kinase-3 (gsk-3), which is inactivated by akt, for its role in the regulation of apoptosis. Upon il-3 withdrawal, protein levels of mcl-1 decreased but were sustained by pharmacological gsk-3, which prevented cytochrome c release and apoptosis. Mcl-1 was phosphorylated by gsk-3 at a conserved gsk-3 phosphorylation site (s159). S159 phosphorylation of mcl-1 was induced by il-3 withdrawal or pi3k inhibition and prevented by akt or gsk-3, and it led to increased ubiquitinylation and degradation of mcl-1. 0.501 SIGNOR-145200 BBS1 protein Q8NFJ9 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 YES lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 0.869 SIGNOR-262558 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Ser518 KGGTPAGsARGSPTR 9606 16611631 YES lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.364 SIGNOR-145975 PPP2CA protein P67775 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). 0.648 SIGNOR-269918 PHKG2 protein P15735 UNIPROT PYG proteinfamily SIGNOR-PF96 SIGNOR up-regulates activity phosphorylation 9606 BTO:0002049 22225877 YES miannu It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 0.663 SIGNOR-267962 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1101 GCRRRHSsETFSSTP 9606 BTO:0000975 17360977 YES lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 0.722 SIGNOR-236022 CSNK2A1 protein P68400 UNIPROT L1CAM protein P32004 UNIPROT unknown phosphorylation Ser1181 GEYRSLEsDNEEKAF 10116 BTO:0000142 8592152 YES llicata Serine to alanine substitutions in these peptides indicate that the CKII phosphorylation site is at Ser1,181. | Finally, in vivo radiolabeling indicates that Ser1,181 is phosphorylated in newborn rat brain. These data show that CKII is associated with and able to phosphorylate L1. 0.49 SIGNOR-250913 Varespladib chemical CID:155815 PUBCHEM PLA2G1B protein P04054 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207633 PIK-90 chemical CID:6857685 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206229 Pyrin inflammasome complex SIGNOR-C226 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.2 SIGNOR-256383 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257984 CSNK2A1 protein P68400 UNIPROT XPC protein Q01831 UNIPROT up-regulates activity phosphorylation Ser94 VIKDEALsDGDDLRD 9606 BTO:0000552 29660033 YES miannu CK2 kinase mediates XPC phosphorylation at serine 94, and also promotes recruitment of ubiquitinated XPC to the chromatin after UVB irradiation. 0.2 SIGNOR-277389 NEDD9 protein Q14511 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 9606 16184168 YES miannu HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins. 0.571 SIGNOR-262653 GLDN protein Q6ZMI3 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 9606 BTO:0000227 19840192 YES miannu Ankyrin-G is recruited to the nodes of Ranvier by gliomedin, which is produced by Schwann cells and accumulates in the perinodal extracellular matrix. As a ligand for neurofascin-186, gliomedin causes the nodal clustering of this cell adhesion molecule, which in turn recruits to the nodal plasma membrane an ankyrin-G protein network consisting of voltage-gated sodium or potassium channels (KCNQ2/3) and β4-spectrin. 0.41 SIGNOR-266725 BORA protein Q6PGQ7 UNIPROT AURKA protein O14965 UNIPROT up-regulates binding 9606 16890155 YES gcesareni Both drosophila and human bora can bind to aurora-a and activate the kinase in vitro. 0.728 SIGNOR-148661 MAVS protein Q7Z434 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity binding 9606 25636800 YES miannu Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1.  0.8 SIGNOR-260143 LDHA protein P00338 UNIPROT (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity chemical modification 9606 24929216 YES Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. 0.8 SIGNOR-266919 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates phosphorylation Tyr411 RVIEDNEyTAREGAK 9606 BTO:0000007 10934191 YES gcesareni Tyr(416) is the autophosphorylation site in the activation loop. Autophosphorylation of tyr(416) is required for hck activation. 0.2 SIGNOR-80340 hsa-miR-101-3p mirna URS00001230A0_9606 RNAcentral ACKR3 protein P25106 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005855 27904690 YES Overall, miR-101 exerts tumor-suppressive functions by targeting CXCR7, leading to inhibition of OSCC cell growth, invasion, and migration. 0.4 SIGNOR-277953 CDH24 protein Q86UP0 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.55 SIGNOR-265862 STK11 protein Q15831 UNIPROT ETV4 protein P43268 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 16912160 YES miannu LKB1 phosphorylated PEA3 and promoted its degradation through a proteasome-mediated mechanism. 0.62 SIGNOR-279293 TAF1C protein Q15572 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 YES lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. 0.805 SIGNOR-269564 NCKAP1 protein Q9Y2A7 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 9606 20332100 YES miannu We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge. 0.2 SIGNOR-253576 FYN protein P06241 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation 9606 24586768 YES miannu Taken together, these results suggest that p130Cas is directly phosphorylated by Fyn kinase in the cytoplasm of oligodendrocytes. 0.765 SIGNOR-279372 HCK protein P08631 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation 9606 26619401 YES miannu These results suggest that the interaction between Gli1 and Hck or the phosphorylation of Gli1 by Hck disrupts Sufu-Gli1 interaction.|We showed that tyrosine kinase Hck activates Gli1 and the kinase activity is required for its maximum effect. 0.299 SIGNOR-279374 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser108 DKYGQNEsFARIQVR -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276220 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser374 GLYSRSGsLSGRSSL -1 10467162 YES lperfetto Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect. 0.2 SIGNOR-249021 SMAD1 protein Q15797 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 22298955 YES gcesareni Smad1 interacts with runx2 on the promoter of target genes and controls osteoblast gene expression and differentiation 0.539 SIGNOR-195642 CSNK2A1 protein P68400 UNIPROT VDR protein P11473 UNIPROT up-regulates phosphorylation Ser208 SFSNLDLsEEDSDDP 9606 17368182 YES lperfetto Casein kinase ii (ckii) phosphorylates vdr both in vitro and in vivo at serine 208 within the hinge domain. This phosphorylation does not affect the ability of vdr to bind dna, but increases its ability to transactivate target promoters 0.337 SIGNOR-153711 AURKB protein Q96GD4 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser67 S-->K 9606 32049046 YES miannu AURKB directly phosphorylates MYC at serine 67, counteracting GSK3\u03b2-directed threonine 58 phosphorylation and subsequent FBXW7- mediated proteasomal degradation. 0.373 SIGNOR-279439 AKT1 protein P31749 UNIPROT ZRANB1 protein Q9UGI0 UNIPROT up-regulates activity phosphorylation Ser78 SARPRVKsSYSMENA 9606 BTO:0000007 29748601 YES miannu Our findings also identify an essential role for activation of Trabid by AKT-mediated phosphorylation at Ser78/Thr117 in negatively regulating Twist1 signaling, which further provides insights into the mechanisms by which Trabid regulates Twist1 ubiquitination. 0.2 SIGNOR-273483 PPP1R8 protein Q12972 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity binding -1 1322907 YES lperfetto We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity. 0.648 SIGNOR-264673 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT up-regulates activity phosphorylation Tyr387 SEEPEPDyEAIQTLN 9534 16920712 YES miannu Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn. 0.725 SIGNOR-262893 MFGE8 protein Q08431 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates activity binding 10116 BTO:0000452 31958465 YES miannu Milk fat globule-EGF factor 8 (MFGE8), a protein known as lactadherin in humans, contains C domains interacting with extracellular matrices and epidermal growth factor–like domains with an RGD motif binding to integrins αvβ3 and αvβ5. 0.525 SIGNOR-260645 KLKB1 protein P03952 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg494 CAKTKQLrVVNGIPT -1 12372819 YES miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. 0.324 SIGNOR-256512 CHEK1 protein O14757 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation Thr210 YDGERKKtLCGTPNY 9606 34197606 YES miannu These results suggest that both PLK1 S137 and T210 sites can be phosphorylated in vitro by CHK1, but that S137 is the major site.|We reason that PARG and CHK1 inhibitors should also cause synthetic lethality : PARG inhibition sustains PLK1 inhibition at the PAR forest , while CHK1 inhibition blocks PLK1 reactivation and RAD51 phosphorylation at S14 and T309 . 0.314 SIGNOR-279501 glutamine smallmolecule CHEBI:28300 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 NO Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. 0.8 SIGNOR-268012 CDK5 protein Q00535 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser191 SRHAIMRsPQMVSAI 9606 26509276 YES miannu By combining multiple network relations with PTM proteoform specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity.|CDK5 phosphorylates beta-catenin on Ser-191 and Ser-246 (PR:000037229) 0.371 SIGNOR-279515 MAP3K3 protein Q99759 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity phosphorylation Ser272 RSRLTPVsPESSSTE 9606 26279575 YES miannu MEKK3 overexpression, but not that of a kinase dead mutant, was able to induce the phosphorylation of p62 at T269 and S272 (XREF_FIG), which correlated with mTORC1 activation (XREF_FIG), suggesting that MEKK3 could be a bona fide regulator of p62 phosphorylation and mTORC1 activity. 0.555 SIGNOR-279533 MAPK9 protein P45984 UNIPROT ATP2A2 protein P16615 UNIPROT up-regulates activity phosphorylation 9606 33334123 YES miannu JNK2 Enhances SERCA2 Function in a CaMKII-Independent Manner..|We found that JNK2 and SERCA2 proteins are physically associated with each other, and that JNK2 directly elevates the maximal rate of the SERCA2 activity by phosphorylating SERCA2. 0.2 SIGNOR-279540 MAPKAPK2 protein P49137 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates activity phosphorylation Ser121 NIKRKVTsVSTLKSE 9606 16278218 YES miannu A potential mechanism for MK2-induced HSF1 inactivation is suggested by the findings that phosphorylation of serine 121 enhances HSF1 binding to HSP90, a major repressor of HSF1.|Phosphorylation of HSF1 by MAPK activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding. 0.517 SIGNOR-279541 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT up-regulates activity phosphorylation Ser72 PPRKRLKsKGSDKDF 9606 20663873 YES miannu We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. 0.341 SIGNOR-259819 IFNA10 protein P01566 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 10090 BTO:0000944 1632769 NO Regulation miannu Interleukin-1 and interferon-alpha and gamma induce lipolysis and decrease LPL activity but do not stimulate much PG production. These results demonstrate that cytokines enhance lipolysis and decrease LPL activity in 3T3 adipocytes by a PG independent mechanism. 0.2 SIGNOR-251859 BCKDK protein O14874 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation 9606 35070754 YES miannu BCKDK can activate ACLY and promote the cleavage of citric acid into acetyl-CoA, and oxaloacetate.|BCKDK can phosphorylate BCKDHA and ATP citrate lyase (ACLY), exerting opposing effects on both. 0.2 SIGNOR-280194 PTPRC protein P08575 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr508 YTATEGQyQQQP 10090 BTO:0000776 10415030 YES CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508) 0.665 SIGNOR-248354 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 YES gcesareni We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch). 0.967 SIGNOR-93313 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser251 GKLGGQDsFESIESY BTO:0003637 12475968 YES llicata Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1  0.31 SIGNOR-250684 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr575 SNSCRSStTTCPEQD 9606 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249299 CSNK2A2 protein P19784 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 YES llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified 0.374 SIGNOR-250986 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity sumoylation Lys608 LLAEEKSKPIPIMPA 9606 BTO:0000007 19638400 YES Barakat Through detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. 0.535 SIGNOR-274130 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by stabilization binding 9606 23438602 YES miannu XRCC3 activation is essential for the recruitment of RAD51 to the sites of DNA lesions. It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation. 0.748 SIGNOR-262667 AMPK complex SIGNOR-C15 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 10090 BTO:0000575 20577053 YES lperfetto Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 0.442 SIGNOR-216576 C1R protein P00736 UNIPROT Complement C1 complex complex SIGNOR-C309 SIGNOR form complex binding -1 29449492 YES lperfetto The complement system is part of our innate immune system. The classical complement pathway is triggered by activation of the C1 initiation complex upon binding to cell surfaces. C1, or C1qr2s2, consists of four proteases, C1r and C1s, that associate with C1q, which contains antibody-binding sites.|The reconstruction reveals densities for all C1q collagen-like triple helices and gC1q modules, C1r and C1s proteases 0.707 SIGNOR-263395 NEK5 protein Q6P3R8 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates activity binding 9606 BTO:0000815 30675923 YES miannu NEK5 promotes breast cancer cell proliferation through up-regulation of Cyclin A2 0.2 SIGNOR-273874 SLBP protein Q14493 UNIPROT H3C1 protein P68431 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265413 GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.278 SIGNOR-268601 TP53 protein P04637 UNIPROT FGF2 protein P09038 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10029407 NO miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. 0.44 SIGNOR-255431 GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268595 OLIG1 protein Q8TAK6 UNIPROT OLIG2 protein Q13516 UNIPROT up-regulates 9606 BTO:0000938 25206819 NO miannu During central nervous system development, olig1 assists olig2 in formation of the motor neuron progenitor domain (pmn), the area responsible for generation of motor neurons and oligodendrocytes 0.305 SIGNOR-205304 SRC protein P12931 UNIPROT PKP3 protein Q9Y446 UNIPROT up-regulates activity phosphorylation Tyr195 PGGLDDRySLVSEQL 9606 BTO:0000552 25501895 YES done miannu We have discovered that reactive oxygen species (ROS) trigger the c-Src kinase-mediated tyrosine (Tyr)-195 phosphorylation of PKP3. This modification is associated with a change in the subcellular distribution of the protein. Specifically, PKP3 bearing phospho-Tyr-195 is released from the desmosomes, suggesting that phospho-Tyr-195 is relevant for the control of desmosome disassembly and function, at least in cells exposed to ROS.  0.306 SIGNOR-273807 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25B protein P30305 UNIPROT down-regulates phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 YES lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.2 SIGNOR-124847 MAPKAPK2 protein P49137 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity phosphorylation 9606 35554104 YES miannu MK2 Phosphorylates Caspase-3, Facilitates Nuclear Translocation of Caspase 3, and Regulates Apoptosis.|Over-expression of MK2 led to an increase in nuclear caspase-3 activity. 0.311 SIGNOR-278960 STK25 protein O00506 UNIPROT CCM2 protein Q9BSQ5 UNIPROT up-regulates phosphorylation Ser384 GRGIITDsFGRHRRA 9606 BTO:0001757 22782892 YES miannu CCM2 can be phosphorylated by STK25, and the kinase activity of STK25 is required for death signaling. 0.501 SIGNOR-263144 PCM1 protein Q15154 UNIPROT PCNT protein O95613 UNIPROT up-regulates relocalization 9606 12403812 YES miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome 0.687 SIGNOR-95117 (RS)-Ppcc chemical CID:16726095 PUBCHEM SIGMAR1 protein Q99720 UNIPROT up-regulates activity chemical activation 9606 17328523 YES Federica We suggest that 4b may act as a ơ1/ơ2 agonist and that the ơ ligands may modulate TG-2 differently. 0.8 SIGNOR-261107 BCL9 protein O00512 UNIPROT PYGO1 protein Q9Y3Y4 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 YES miannu Here we report the identification of two segment polarity genes in drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human bcl9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking pygo to beta-catenin. 0.906 SIGNOR-116577 SEC16A protein O15027 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.72 SIGNOR-265293 NCK1 protein P16333 UNIPROT WASL protein O00401 UNIPROT up-regulates binding 9606 11340081 YES gcesareni Nck and cdc42 activate n-wasp by redundant mechanisms. 0.779 SIGNOR-107634 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-249684 hsa-miR-101-3p mirna URS00001230A0_9606 RNAcentral PTX3 protein P26022 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 39559327 YES miannu MiR-101-3p suppresses proliferation of orbital fibroblasts by targeting pentraxin-3 in thyroid eye disease 0.4 SIGNOR-279939 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT unknown phosphorylation Tyr564 SKHKEDVyENLHTKN -1 12468540 YES gcesareni Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect 0.414 SIGNOR-246240 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Thr5794 REFSGPStPTGTLEF 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.256 SIGNOR-262767 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000452 11983694 YES lperfetto In summary, this study describes a novel mechanism for metal-induced egfr transactivation, which is likely to be mediated by src through the phosphorylation site of tyr-845 on egfr. emanating from a variety of growth factor receptors, including egfry845 (e-e-k-e-y845-h-a-e) 0.624 SIGNOR-235921 hsa-miR-199a-5p mirna URS0000554A4F_9606 RNAcentral FZD6 protein O60353 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000391 25772759 YES Parnian Observations suggest that miR-199a-5p targeted the 3’-UTR of FZD6 mRNA directly, resulting in inhibition of its expression in CRC. 0.4 SIGNOR-277971 hsa-miR-100-3p mirna URS00001A405B_9606 RNAcentral FZD8 protein Q9H461 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000093 26537584 YES Parnian These findings suggest that miR-100 suppresses the migration and invasion of breast cancer cells by targeting FZD-8 and inhibiting Wnt/β-catenin signaling pathway and manipulation of miR-100 may provide a promoting therapeutic strategy for cancer breast treatment 0.4 SIGNOR-277972 PPP2CB protein P62714 UNIPROT ELF1 protein P32519 UNIPROT down-regulates activity dephosphorylation Thr231 CPKYIKWtQREKGIF 9606 18714041 YES Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response 0.2 SIGNOR-248591 MAPK3 protein P27361 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 YES miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. 0.276 SIGNOR-277854 sunitinib chemical CHEBI:38940 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 20185585 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-163956 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190152 NBEAL2 protein Q6ZNJ1 UNIPROT VWF protein P04275 UNIPROT up-regulates 9606 BTO:0000132 28082341 NO lperfetto Recent in vitro megakaryopoiesis studies using HSCs from GPS patients with NBEAL2 mutations showed normal MK differentiation with defective proplatelet formation and reduced α-granule proteins such as von Willebrand factor (VWF), thrombospondin and P-selectin. 0.273 SIGNOR-261884 Tiospirone chemical CID:55752 PUBCHEM HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258863 PI4KA protein P42356 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269104 FZD5 protein Q13467 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 18077588 YES areggio Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. 0.737 SIGNOR-258966 PTK2 protein Q05397 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation 9606 33498611 YES miannu Then, FAK phosphorylates and activates YAP, leading to the activation and nuclear translocation of YAP/TAZ transcription factor, which is known to be involved in such cellular mechanoresponses [ xref , xref ]. 0.284 SIGNOR-280099 AEP complex complex SIGNOR-C117 SIGNOR HOXA9 protein P31269 UNIPROT up-regulates quantity by expression 9606 20854876 NO irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. 0.407 SIGNOR-255879 GABPB1 protein Q06547 UNIPROT HCFC1 protein P51610 UNIPROT down-regulates activity binding 9606 BTO:0000567 10675337 YES miannu The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation 0.329 SIGNOR-221377 RAB38 protein P57729 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR up-regulates activity relocalization 9606 23247405 YES lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. 0.2 SIGNOR-260701 MECP2 protein P51608 UNIPROT CREB1 protein P16220 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 BTO:0000614 18511691 YES Luana Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) | In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1 0.532 SIGNOR-264682 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser659 WPNVPDPsKSHIAQW -1 8511589 YES lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. 0.2 SIGNOR-238621 domperidone chemical CHEBI:31515 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258720 GSK3B protein P49841 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by destabilization phosphorylation Ser41 EYYPYLSsDGESHSD 9606 BTO:0002181 33188146 YES miannu We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7. 0.2 SIGNOR-277541 POU4F3 protein Q15319 UNIPROT LHX3 protein Q9UBR4 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000630 17331196 YES lperfetto Using oligonucleotide microarrays to generate expression profiles of inner ears of Pou4f3(ddl/ddl) mutant and wild-type mice, we have identified and validated Lhx3, a LIM domain transcription factor, as an in vivo target gene regulated by Pou4f3. Lhx3 is a hair cell-specific gene expressed in all hair cells of the auditory and vestibular system as early as embryonic day 16. The level of Lhx3 mRNA is greatly reduced in the inner ears of embryonic Pou4f3 mutant mice. Our data also show that the expression of Lhx3 is regulated differently in auditory and vestibular hair cells. 0.399 SIGNOR-262586 PAK1 protein Q13153 UNIPROT FXR1 protein P51114 UNIPROT up-regulates activity phosphorylation Ser420 SERKDELsDWSLAGE 9534 BTO:0000298 20417602 YES done miannu Identification of Ser420 in FXR1 as a PAK1 Kinase Target. During zebrafish muscle development, FXR1 Ser420 phosphorylation is needed for protein function. 0.271 SIGNOR-273713 CSF1R protein P07333 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr904 TKSLDNNySTPNERG 9606 21049007 YES miannu In our study, CSF-1R induced the tyrosine phosphorylation of p120 Y904 and Y228 in a SRC-dependent manner ( xref ). 0.27 SIGNOR-278929 midostaurin chemical CHEBI:63452 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258248 IL21R protein Q9HBE5 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 BTO:0000876 BTO:0000763;BTO:0001253 15667561 NO gcesareni Interleukin 24 (il-24) is a new member of the il-10 family of cytokines and it signals through two heterodimeric receptors: il-20r1/il-20r2 and il-22r1/il-20r2. Upon binding to its receptors, il-24 induces rapid activation of stat-1 and stat-3 transcription factors, 0.608 SIGNOR-133379 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr95 DKTQLNPtSLQKLFR 9606 15319445 YES gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. 0.419 SIGNOR-128268 E2F2 protein Q14209 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8649818 NO gcesareni We have found that cell cycle regulation of cyclin e transcription is mediated by e2f binding sites present in the promoter 0.606 SIGNOR-42020 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10230394 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.541 SIGNOR-67379 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates activity binding 9606 14607242 YES It turned out that RGS domain of p115RhoGEF is specific for Gα12 and Gα13, and does not bind Gαi, Gαs and Gαq (Kozasa et al., 1998). The binding of Gα13 but not Gα12 stimulated GEF activity for Rho 0.607 SIGNOR-256521 CCKAR protein P32238 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.484 SIGNOR-257410 CRYAA protein P02489 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 22982024 NO miannu Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin. 0.7 SIGNOR-252156 IKBKB protein O14920 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser132 GDYFRYLsEVASGDN 9606 16024783 YES gcesareni We provide a mechanism for these observations through the phosphorylation of 14-3-3beta by ikkbeta and pkcdelta on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm. 0.37 SIGNOR-138608 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC9 protein Q93079 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271991 RNF41 protein Q9H4P4 UNIPROT VPS52 protein Q8N1B4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28542518 YES miannu RNF41 ubiquitinates and relocates VPS52 away from VPS53, another shared subunit of the GARP and EARP complexes, towards RNF41-positive structures. 0.434 SIGNOR-278597 UPF3B protein Q9BZI7 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity binding -1 18066079 YES miannu UPF2 and UPF3b increase UPF1 ATPase activity 0.957 SIGNOR-265247 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 11988172 NO miannu Ca(2+) influx through voltage-gated channels initiates the exocytotic fusion of synaptic vesicles to the plasma membrane. 0.7 SIGNOR-264355 SMARCA4 protein P51532 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.862 SIGNOR-270756 CACNA1C protein Q13936 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 YES miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). 0.8 SIGNOR-264325 CSNK2B protein P67870 UNIPROT CACNA1S protein Q13698 UNIPROT up-regulates activity phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 YES miannu To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. 0.2 SIGNOR-263115 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7535768 YES We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively 0.805 SIGNOR-248464 TAF8 protein Q7Z7C8 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.54 SIGNOR-269573 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one chemical CHEBI:91348 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258294 KDM1A protein O60341 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 BTO:0000567 15620353 YES miannu Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. 0.2 SIGNOR-265332 STYX protein Q8WUJ0 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity binding 9606 28007894 YES STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti-correlated in breast cancer patients, 0.347 SIGNOR-251663 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Ser368 NTSPRAIsRVDRERK 9606 BTO:0000007 10542239 YES llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T 0.2 SIGNOR-250808 MAPKAP1 protein Q9BPZ7 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates activity binding 9606 21806543 YES miannu In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC.  0.263 SIGNOR-276348 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 25309941 NO Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6). 0.373 SIGNOR-255485 2',2'-difluoro-2'-deoxyuridine chemical CHEBI:83486 ChEBI TYMS protein P04818 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003207 25562513 YES miannu 2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000. The specific TS inhibitor Raltitrexed (RTX) was included as a positive control. Using the in situ TS activity assay measuring the intracellular conversion of [5-(3)H]-2'-deoxyuridine or [5-(3)H]-2'-deoxycytidine to dTMP and tritiated water, it was observed that dFdC and dFdU inhibited TS. 0.8 SIGNOR-259351 IL33 protein O95760 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 BTO:0006111 36660926 YES miannu IL-33 secreted by pericytes and CAFs promotes M2 polarization and induced MMP9 expression in M2 TAMs facilitating metastasis development via the IL-33-ST2-NF-κB-MMP9-laminin pathway in a mouse model of pancreatic cancer 0.7 SIGNOR-277712 CPSF3 protein Q9UKF6 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 BTO:0000007 19224921 YES lperfetto The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30. 0.883 SIGNOR-268333 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277669 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 14679200 YES lperfetto Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro 0.734 SIGNOR-120347 PARP1 protein P09874 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity relocalization 9606 19629035 YES PARP1 collaborates with Mre11 to promote replication fork restart after release from replication blocks, most likely by recruiting Mre11 to the replication fork to promote resection of DNA. 0.2 SIGNOR-272478 CARM1 protein Q86X55 UNIPROT MDH1 protein P40925 UNIPROT down-regulates activity acetylation Arg230 FVTTVQQrGAAVIKA 9606 27840030 YES lperfetto Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization 0.355 SIGNOR-267639 CRX protein O43186 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 NO miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 0.38 SIGNOR-253821 APH1A protein Q96BI3 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR form complex binding 9606 25610395 YES lperfetto -Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2) 0.959 SIGNOR-209714 WNT3A protein P56704 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 22653731 YES gcesareni Structural basis of wnt recognition by frizzled. 0.797 SIGNOR-197638 TJP1 protein Q07157 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 10090 19447104 YES miannu NHS-A is a novel interactor of ZO-1 and is expected to have a role at tight junctions. Its recruitment to these junctions is dependent upon their assembly. 0.2 SIGNOR-253567 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser24 APIRRRSsNYRAYAT 9606 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.421 SIGNOR-134609 EPHA8 protein P29322 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates activity phosphorylation Tyr616 FYAEPHTyEEPGRAG 9606 BTO:0000007 10498895 YES Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites. 0.2 SIGNOR-251120 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275754 Aldolase proteinfamily SIGNOR-PF75 SIGNOR beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266490 RB1 protein P06400 UNIPROT E2F2 protein Q14209 UNIPROT down-regulates binding 9606 22569856 YES gcesareni Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins. 0.914 SIGNOR-197328 DDB1 protein Q16531 UNIPROT RAD23B protein P54727 UNIPROT up-regulates 24086044 NO lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). 0.643 SIGNOR-275689 TFEB protein P19484 UNIPROT NAGLU protein P54802 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.324 SIGNOR-276543 CDK1 protein P06493 UNIPROT RAB11FIP3 protein O75154 UNIPROT up-regulates quantity phosphorylation Ser102 GPRGQLAsPDAPGPG 9606 BTO:0000567 22401586 YES done miannu FIP3 is phosphorylated on S102 in a cell cycle-dependent manner. We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase. 0.2 SIGNOR-273588 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000574 10837024 YES lperfetto Expression analysis of known notch ligands suggests that dll4 is the only ligand that exhibits spatial and temporal expression consistent with the activation of notch1 and notch4 during vascular development. The identification of dll4 reveals a candidate ligand for notch receptors involved in blood vessel biology 0.643 SIGNOR-77973 CDK1 protein P06493 UNIPROT STIL protein Q15468 UNIPROT down-regulates activity phosphorylation 9606 27112295 YES miannu Importantly, we show that CDK1 and CyclinB phosphorylates the N-terminal domain of STIL, but not the region encompassing the CC or STAN motifs. 0.32 SIGNOR-279145 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Ser329 LGGLCDLsSRY 9606 12639913 YES miannu Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA 0.309 SIGNOR-250016 SPART protein Q8N0X7 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity binding 9606 19580544 YES miannu Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins. 0.2 SIGNOR-261306 Complement C1 complex complex SIGNOR-C309 SIGNOR C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.642 SIGNOR-263433 CHEK1 protein O14757 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates phosphorylation Ser328 INITKPAsVFVQLRR 9606 22152481 YES llicata Taken together, the above findings suggest that chk1 phosphorylates p50 at s329 and further, that this phosphorylation blocks p50 dna binding. 0.275 SIGNOR-195208 SRC protein P12931 UNIPROT VAMP7 protein P51809 UNIPROT up-regulates activity phosphorylation Tyr45 SENNKLTySHGNYLF 9534 BTO:0000298 23471971 YES done miannu We found that TI-VAMP is phosphorylated in vitro by c-Src kinase on tyrosine 45 of the Longin domain.Mimicking tyrosine 45 phosphorylation activates both t-SNARE binding and exocytosis of TI-VAMP. 0.287 SIGNOR-273819 CSNK1D protein P48730 UNIPROT DCK protein P27707 UNIPROT up-regulates activity phosphorylation Ser74 EFEELTMsQKNGGNV 20637175 YES lperfetto We showed that recombinant CKI delta phosphorylated several residues of bacterially overexpressed dCK: Ser-74, but also Ser-11, Ser-15, and Thr-72. Phosphorylation of dCK by CKI delta correlated with increased activity reaching at least 4-fold. Site-directed mutagenesis demonstrated that only Ser-74 phosphorylation was involved in dCK activation by CKI delta, 0.339 SIGNOR-275799 beta-D-fructofuranose smallmolecule CHEBI:28645 ChEBI beta-D-fructofuranose 1-phosphate(2-) smallmolecule CHEBI:138881 ChEBI up-regulates activity precursor of 9606 38971308 YES miannu KHK catalyzes the phosphorylation of the C1 hydroxyl of fructose to generate fructose-1-phosphate (F-1P) 0.8 SIGNOR-280239 KHK protein P50053 UNIPROT beta-D-fructofuranose 1-phosphate(2-) smallmolecule CHEBI:138881 ChEBI up-regulates quantity chemical modification 9606 38971308 YES miannu KHK catalyzes the phosphorylation of the C1 hydroxyl of fructose to generate fructose-1-phosphate (F-1P) 0.8 SIGNOR-280240 EIF2B5 protein Q13144 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.734 SIGNOR-269133 ceramide smallmolecule CHEBI:17761 ChEBI ceramide 1-phosphate(2-) smallmolecule CHEBI:84404 ChEBI up-regulates quantity precursor of 9606 34202192 YES miannu Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). 0.8 SIGNOR-268501 RPL8 protein P62917 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.86 SIGNOR-262453 DRD2 protein P14416 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.517 SIGNOR-256980 GCM2 protein O75603 UNIPROT CASR protein P41180 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004712 BTO:0000975 18712808 NO miannu we show that both promoters (P1 and P2) of the calcium-sensing receptor (CASR) gene, a differentiation marker for the parathyroid gland, are transactivated by wild-type GCM2. 0.458 SIGNOR-254199 TIMP3 protein P35625 UNIPROT MMP14 protein P50281 UNIPROT down-regulates activity binding 10090 BTO:0005300 28709001 YES FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. 0.569 SIGNOR-255908 MMP9 protein P14780 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272376 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation 9606 20230789 YES inferred from 70% family members lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity 0.2 SIGNOR-270114 CSNK1D protein P48730 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates activity phosphorylation 9606 22123863 YES miannu We further show that casein kinase 1\u03b4 binds and phosphorylates EB1 and promotes microtubule growth. 0.503 SIGNOR-279165 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000093 16582606 YES lperfetto In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue. 0.302 SIGNOR-216729 PPP1R3B protein Q86XI6 UNIPROT GYS1 protein P13807 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 YES miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) 0.714 SIGNOR-271734 ARHGAP35 protein Q9NRY4 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.723 SIGNOR-260493 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr830 PLEEQCEyLSYDASQ 9606 20431062 YES lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. 0.511 SIGNOR-165047 KPNB1 protein Q14974 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates relocalization 9606 10846168 YES gcesareni Here we show that the isolated smad 3 mh1 domain displays significant specific binding to importin beta. we propose that activation of all of the pathway-specific smad proteins (smads 1, 2, 3, 5, 8, and 9) exposes the conserved nls motif, which then binds directly to importin beta and triggers nuclear translocation. 0.522 SIGNOR-78191 PBX2 protein P40425 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.251 SIGNOR-265778 FTL protein P02792 UNIPROT Ferritin complex SIGNOR-C563 SIGNOR form complex 9606 39534872 YES miannu Ferritin is a spherical protein complex composed of 24 subunits, which include two types: the heavy chain (FTH1) and the light chain (FTL). 0.603 SIGNOR-279858 PRKCA protein P17252 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.392 SIGNOR-275954 NEK11 protein Q8NG66 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser82 GSSESTDsGFCLDSP 9606 19734889 YES lperfetto Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites 0.418 SIGNOR-187867 PKC proteinfamily SIGNOR-PF53 SIGNOR KLHL3 protein Q9UH77 UNIPROT up-regulates quantity by stabilization phosphorylation Ser433 PMNTRRSsVGVGVVE 9534 BTO:0000298 25313067 YES done miannu We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. 0.2 SIGNOR-273780 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB4 protein Q9UN71 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265701 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity phosphorylation Tyr78 SSISTPHyEDIPFTR 10090 25368164 YES We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ. 0.341 SIGNOR-255912 PRKCD protein Q05655 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates activity phosphorylation Ser58 VVGARRSsWRVVSSI 9606 12861023 YES lperfetto We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. | Experimentally, S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1. 0.447 SIGNOR-249222 MAML1 protein Q92585 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 11101851 YES inferred from 70% of family members gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4 0.923 SIGNOR-269934 TRIM38 protein O00635 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22323536 YES miannu As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6.  0.431 SIGNOR-272009 FGFR1 protein P11362 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation 9606 22195962 YES miannu Y105 phosphorylation of PKM2, which is involved in FGFR1-regulated PDHK1 expression, appears to be an upstream event that precedes FGFR1-dependent phosphorylation and activation of PDHK1 in cancer cell metabolism. 0.2 SIGNOR-279174 DHCR24 protein Q15392 UNIPROT DHCR7 protein Q9UBM7 UNIPROT up-regulates activity binding 10029 BTO:0000246 25637936 YES miannu DHCR7 coimmunoprecipitates DHCR24. Overexpression of functional DHCR24 increases DHCR7 activity. Because knockdown of DHCR24 has no effect on DHCR7 mRNA (Fig. 3A), this implies that this phenomenon is occurring posttranscriptionally. Thus, the interaction between the two terminal steps of cholesterol synthesis appears to have functional consequences. 0.651 SIGNOR-267249 KIF3B protein O15066 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272516 BTF3 protein P20290 UNIPROT EPHB2 protein P29323 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 17312387 NO In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. 0.2 SIGNOR-253949 CDK2 protein P24941 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C16 12676926 YES gcesareni Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. 0.574 SIGNOR-99746 CREB1 protein P16220 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000783 12842910 YES miannu Taken together, these results indicate that the IRS2 gene is a direct target for CREB action in vivo 0.342 SIGNOR-278145 DAD1 protein P61803 UNIPROT OST-B complex complex SIGNOR-C536 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.714 SIGNOR-272067 2-[4-[3-(6-quinolinylmethyl)-5-triazolo[4,5-b]pyrazinyl]-1-pyrazolyl]ethanol chemical CHEBI:91425 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205968 HECTD3 protein Q5T447 UNIPROT RAF1 protein P04049 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 28636940 YES miannu  By western blot, we observed robust degradation of endogenous native CRAF in untransformed HEK293 cells treated with control siRNA 24 hr after the addition of AUY922, but this was substantially reduced in cells in which HECTD3 was knocked down, confirming that endogenous CRAF is a bona fide degradation target of HECTD3  0.2 SIGNOR-272328 MUL1 protein Q969V5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity ubiquitination 9606 26018823 YES miannu MUL1 promotes ubiquitination of ULK1.|Overexpression of MUL1 and treatment with selenite promotes ULK1 degradation through the proteasome pathway. 0.347 SIGNOR-278759 ADRA1D protein P25100 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.583 SIGNOR-257080 CEBPA protein P49715 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001056 11283671 YES apalma Here, we demonstrate that C/EBPα indeed activates its promoter in transient transfection assays in myeloid cells. 0.2 SIGNOR-255673 RARA protein P10276 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 15650024 YES inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.536 SIGNOR-267801 GNG12 protein Q9UBI6 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 YES gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. 0.398 SIGNOR-252681 CAK complex complex SIGNOR-C456 SIGNOR RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser79 EMVPSSPsPPPPPRV 9534 BTO:0000298 10748061 YES miannu Retinoic acid receptor gamma (RARgamma) is phosphorylated in COS-1 cells at two conserved serine residues located in the N-terminal region (serines 77 and 79 in RARgamma1 and serines 66 and 68 in RARgamma2) that contains the activation function AF-1. These serines are phosphorylated in vitro by cdk7, a cyclin-dependent kinase associated to cyclin H and MAT1 in the CAK complex (cdk7.cyclin H. MAT1), that is found either free or as a component of the transcription/DNA repair factor TFIIH.  0.417 SIGNOR-275968 AMPK complex SIGNOR-C15 SIGNOR HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Thr1116 AALGSTGtVAHLVAS 23871434 YES Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro 0.249 SIGNOR-275484 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258462 KIT protein P10721 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 21135090 YES KIT is responsible for the permanent phosphorylation of all three STAT proteins. STAT1, -3, and -5 were phosphorylated on their activation-specific Tyr701, Tyr704, and Tyr694, respectively, following KIT stimulation. 0.724 SIGNOR-251365 SMARCA4 protein P51532 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18234970 NO miannu An increased association of the chromatin remodeling factor, Brg-1, to the ABCG2 promoter was observed consistently in S1 and H460 cells where ABCG2 expression was activated by romidepsin treatment 0.305 SIGNOR-255150 GSK3B protein P49841 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 23685991 YES miannu Invitro, both GSK3alpha and GSK3beta phosphorylate IRF3 at the linker region. 0.346 SIGNOR-279182 Ub:E2 complex SIGNOR-C497 SIGNOR SHPRH protein Q149N8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271119 HASPIN protein Q8TF76 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Thr3 T-->R 9606 20705812 YES miannu Here we show that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is necessary for CPC accumulation at centromeres and that the CPC subunit Survivin binds directly to H3T3ph. 0.2 SIGNOR-275418 SNX9 protein Q9Y5X1 UNIPROT EGFR protein P00533 UNIPROT down-regulates 9606 11799118 NO gcesareni We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation. 0.573 SIGNOR-114167 LAS1L protein Q9Y4W2 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR up-regulates activity binding 9606 BTO:0000007 22190735 YES miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. 0.849 SIGNOR-265467 Hypoxia stimulus SIGNOR-ST25 SIGNOR NPTX1 protein Q15818 UNIPROT up-regulates 10090 BTO:0000938 15115814 NO lperfetto We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. 0.7 SIGNOR-261431 CHKB protein Q9Y259 UNIPROT choline smallmolecule CHEBI:15354 ChEBI down-regulates quantity chemical modification 27149373 YES lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes 0.8 SIGNOR-275635 PEX12 protein O00623 UNIPROT UBE2D1 protein P51668 UNIPROT up-regulates activity binding -1 19687296 YES miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 0.625 SIGNOR-253024 PLCG1 protein P19174 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation 9606 12645577 YES gcesareni Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199. 0.554 SIGNOR-99310 NMDA receptor_2A complex SIGNOR-C347 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor 0.8 SIGNOR-264222 KLHL25 protein Q9H0H3 UNIPROT ACLY protein P53396 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002552 27664236 YES miannu Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells.  0.345 SIGNOR-272333 RAB22A protein Q9UL26 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR up-regulates activity relocalization 9606 30404817 YES lperfetto Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. 0.2 SIGNOR-260696 coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity precursor of 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271825 PRKCA protein P17252 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation 9606 22031842 YES miannu PKC\u03b1 then phosphorylates and activates endothelial cell protein tyrosine phosphatase 1B (PTP1B) , . 0.249 SIGNOR-279257 PRKX protein P51817 UNIPROT SMAD6 protein O43541 UNIPROT up-regulates activity phosphorylation 9606 16491121 YES miannu In vitro phosphorylation assays demonstrated that PrKX phosphorylates Smad6 at a serine residue. 0.432 SIGNOR-279270 CCL5 protein P13501 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000584 38339310 NO miannu This suggests CCL5 not only remodels the PDAC TME to benefit tumor cells, but can also enhance the tumor cell’s metastatic potential. 0.7 SIGNOR-277729 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser266 FGYGGRAsDYKSAHK -1 2413024 YES miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-163 0.347 SIGNOR-250013 LYN protein P07948 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1125 APSRDPHyQDPHSTA 9606 22430206 YES miannu Taken together, our findings demonstrate that Yes and Lyn phosphorylate EGFR at Y1101 which influences EGFR nuclear translocation in this model of cetuximab resistance. 0.585 SIGNOR-279205 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP 9606 8657103 YES lperfetto Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771. 0.774 SIGNOR-246576 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser784 GVEKCSDsQSWEDIA 9606 12697768 YES llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 0.873 SIGNOR-100653 PUF60 protein Q9UHX1 UNIPROT SCF(TBL1) complex SIGNOR-C533 SIGNOR form complex binding 9606 BTO:0000007 20181957 YES miannu Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC).  0.32 SIGNOR-271951 sirolimus chemical CHEBI:9168 ChEBI IRS1 protein P35568 UNIPROT up-regulates 9606 16452206 NO gcesareni The mtor inhibitory drug rapamycin up-regulates irs-1 protein levels and induces akt phosphorylation, protein kinase activity, and downstream signaling. 0.8 SIGNOR-144159 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR WNK4 protein Q96J92 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23838290 YES miannu We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body. 0.389 SIGNOR-272123 SMARCD2 protein Q92925 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.724 SIGNOR-270603 POLR2E protein P19388 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.887 SIGNOR-266167 JUN protein P05412 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 10090 BTO:0000725 17041602 NO miannu These results show that restoration of c-Jun expression rescues the myelomonocytic differentiation block in preleukemic PU.1-knockdown bone marrow cells, suggesting that c-Jun is a critical downstream target in PU.1-knockdown HSCs. 0.7 SIGNOR-256066 Av/b2 integrin complex SIGNOR-C176 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269025 NEK2 protein P51955 UNIPROT SRSF1 protein Q07955 UNIPROT down-regulates activity phosphorylation 9606 24369428 YES miannu First, NEK2 interacts with and phosphorylates SRSF1. 0.385 SIGNOR-279344 TFAP4 protein Q01664 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0001109 19505873 YES miannu We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads. 0.357 SIGNOR-226593 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.2 SIGNOR-275957 EDA protein Q92838 UNIPROT EDA2R protein Q9HAV5 UNIPROT up-regulates binding 9606 BTO:0001253 12084975 YES gcesareni Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed. 0.677 SIGNOR-90040 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM BMX protein P51813 UNIPROT down-regulates activity chemical inhibition -1 24556163 YES miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 0.8 SIGNOR-262232 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization ubiquitination Lys344 NLEEVTMkQICKKVY 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). 0.3 SIGNOR-272833 BLOC-1 complex SIGNOR-C381 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 BTO:0000847 22203680 NO lperfetto Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes 0.7 SIGNOR-265939 VCB-Cul2 complex SIGNOR-C524 SIGNOR EGFR protein P00533 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 15590694 YES miannu SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation. 0.3 SIGNOR-271521 ADRM1 protein Q16186 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.831 SIGNOR-263342 TBP protein P20226 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.893 SIGNOR-263933 AMPK complex SIGNOR-C15 SIGNOR SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser122 YRNTGSIsGPKVNRP 10090 BTO:0003946 17341212 YES miannu In the present study, we demonstrate that the metabolic sensing kinase AMPK (AMP-activated protein kinase) phosphorylates NKCC2 on Ser126 in vitro. Activation of AMPK in the MMDD1 (mouse macula densa-derived 1) cell line resulted in an increase in Ser126 phosphorylation in situ, suggesting that AMPK may phosphorylate NKCC2 in vivo. The functional significance of Ser126 phosphorylation was examined by mutating the serine residue to an alanine residue resulting in a marked reduction in co-transporter activity when exogenously expressed in Xenopus laevis oocytes under isotonic conditions. 0.2 SIGNOR-263103 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser807 PGGNIYIsPLKSPYK 9606 1756735 YES lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. 0.687 SIGNOR-21552 FAS protein P25445 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates 9606 22830020 NO gcesareni It was also shown that the fas active receptor induces rassf1a to compete with raf1 in binding to mst2, thus promoting the formation of a lats1 complex. 0.257 SIGNOR-198435 AURKB protein Q96GD4 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity phosphorylation Ser1342 GPLRGKTsGTEPADF 9606 BTO:0001938 28415769 YES lperfetto Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores. 0.409 SIGNOR-264411 RPS6 protein P62753 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 10090 23318442 NO Luana Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program 0.7 SIGNOR-264619 ERBB2 protein P04626 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 12648465 YES Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers. gcesareni Although ErbB-2 binds no known ligand, when recruited into heterodimers it increases ligand binding affinity 0.587 SIGNOR-99569 PRKN protein O60260 UNIPROT PACRG protein Q96M98 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12150907 YES miannu In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6).  0.2 SIGNOR-272889 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 11904305 YES gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1. 0.643 SIGNOR-116166 DUSP3 protein P51452 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity dephosphorylation 9606 33777934 YES lperfetto In the absence of DUSP3, these three residues remain phosphorylated and favor the dissociation equilibrium of NPM homo-oligomerization and/or its association with ARF, therefore promoting an early nuc|Therefore, here we focused on the molecular mechanisms used by DUSP3-NPM interaction to affect the abovementioned cellular responses and found out that DUSP3 dephosphorylates three tyrosine residues (Y29, Y67, and Y271) of NPM. 0.2 SIGNOR-277005 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.267 SIGNOR-268608 MAOB protein P27338 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-264000 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0001538 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.73 SIGNOR-252757 apraclonidine chemical CHEBI:2788 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation -1 8784451 YES miannu we describe full details of our studies with 2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline (AGN 193080, 3), a potent, selective α2 adrenoceptor agonist that does not cross the blood−brain barrier. 0.8 SIGNOR-258497 chloride smallmolecule CHEBI:17996 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO miannu GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-264989 MYCBP2 protein O75592 UNIPROT Skp1-Pam E3 complex SIGNOR-C537 SIGNOR form complex binding 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.417 SIGNOR-272184 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser623 NRHSLPFsLPSQMEP 9606 BTO:0000782 11024037 YES lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  0.322 SIGNOR-249055 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp349 RVASTMTdGANTMIE 9534 BTO:0004055 11517310 YES lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. 0.616 SIGNOR-109878 APOBEC3D protein Q96AK3 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 NO lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). 0.7 SIGNOR-261328 KREMEN1 protein Q96MU8 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 12050670 NO gcesareni Dkk1 has been shown to inhibit wnt signalling by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. 0.64 SIGNOR-88891 CCP110 protein O43303 UNIPROT CALM1 protein P0DP23 UNIPROT up-regulates activity binding 9606 16760425 YES miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. 0.32 SIGNOR-265965 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr95 DKTQLNPtSLQKLFR 9606 15319445 YES gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. 0.2 SIGNOR-259430 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA1 protein Q9Y5H4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265708 CSNK1D protein P48730 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 YES miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. 0.807 SIGNOR-267999 NF90-NF45 complex SIGNOR-C443 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 21969602 NO miannu The NF90/NF45 complex participates in DNA break repair via nonhomologous end joining 0.7 SIGNOR-268490 CTH protein P32929 UNIPROT L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275824 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 YES lperfetto Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability. 0.2 SIGNOR-244622 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12226093 YES The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. 0.762 SIGNOR-92603 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Tyr341 GQRDSSYyWEIEASE 10090 BTO:0001482 8876196 YES  JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process. 0.616 SIGNOR-251362 GOLPH3 protein Q9H4A6 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity 9606 BTO:0000018;BTO:0005011 19553991 NO Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. 0.292 SIGNOR-253556 PRKCZ protein Q05513 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization phosphorylation Ser45 GATTTAPsLSGKGNP 9606 BTO:0002181 25660024 YES miannu  Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). 0.597 SIGNOR-276878 pemetrexed disodium chemical CHEBI:63722 ChEBI ATIC protein P31939 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 YES miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). 0.8 SIGNOR-259292 MARK2 protein Q7KZI7 UNIPROT RAB11FIP2 protein Q7L804 UNIPROT up-regulates phosphorylation Ser227 QRLSSAHsMSDLSGS 9606 BTO:0000671 16775013 YES lperfetto We identified the kinase that phosphorylated rab11-fip2 as mark2/emk1/par-1balpha (mark2), and recombinant mark2 phosphorylated rab11-fip2 only on serine 227. In calcium switch assays, cells expressing rab11-fip2(s227a) showed a defect in the timely reestablishment of p120-containing junctional complexes. 0.42 SIGNOR-147118 SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR STAT3 protein P40763 UNIPROT down-regulates 9606 26194464 YES mrosina In summary, the TGF-b/IL-6/TCR-pERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation 0.629 SIGNOR-255036 PCDHAC1 protein Q9H158 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-269037 ETS1 protein P14921 UNIPROT BAX protein Q07812 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 17213822 NO miannu Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo. 0.2 SIGNOR-254204 BCL7B protein Q9BQE9 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.451 SIGNOR-270721 WNT9A protein O14904 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.639 SIGNOR-132076 PAX3 protein P23760 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 23384562 NO gcesareni Direct molecular regulation of the myogenic determination gene myf5 by pax3, with modulation by six1/4 factors, is exemplified by the -111 kb-myf5 enhancer. 0.473 SIGNOR-200862 MARCHF9 protein Q86YJ5 UNIPROT ICAM1 protein P05362 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17174307 YES miannu MARCH-IX expression causes ubiquitination and downregulation of ICAM-1 and a short alternative transcript of MARCH-IX lacking the RING-CH domain, termed MARCH-IX RINGless, is shown to act as a positive regulator of MARCH-IX activity.|MARCH-IX mediates ubiquitination and downregulation of ICAM-1. 0.2 SIGNOR-278821 ATM protein Q13315 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser490 QSTEPALsQIVMAPS 9606 15916964 YES lperfetto Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif) 0.567 SIGNOR-137619 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR GINS1 protein Q14691 UNIPROT up-regulates quantity by expression transcriptional regulation 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276578 PAX7 protein P23759 UNIPROT KMT2D protein O14686 UNIPROT up-regulates binding 9606 SIGNOR-C88 22863532 YES miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.304 SIGNOR-198629 MYC protein P01106 UNIPROT HLA-E protein P13747 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 NO miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. 0.2 SIGNOR-254604 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Thr1410 STHPHFMtQRALYLA 9606 BTO:0000938 19824698 YES lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. 0.2 SIGNOR-188437 ADAM10 protein O14672 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 BTO:0000782 28624438 YES miannu ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development 0.781 SIGNOR-259838 GSK3B protein P49841 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity phosphorylation Ser186 APRTHPYsPKSEAPR 9606 BTO:0001583 21873430 YES miannu  Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. 0.287 SIGNOR-276354 SOCS4 protein Q8WXH5 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates activity binding 9534 BTO:0000298 24210661 YES miannu SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. 0.493 SIGNOR-272141 PTPRJ protein Q12913 UNIPROT PLCG1 protein P19174 UNIPROT unknown dephosphorylation 9606 11259588 YES Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation 0.369 SIGNOR-248706 PRKCA protein P17252 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates phosphorylation Ser39 FMRLRRLsTKYRTEK 9606 7520867 YES miannu Ptp-pest is phosphorylated in vitro by both cyclic amp-dependent protein kinase (pka) and protein kinase c (pkc) at two major sites, which we have identified as ser39 and ser435 / phosphorylation of ser39 in vitro decreases the activity of ptp-pest by reducing its affinity for substrate. 0.322 SIGNOR-27300 CRBN protein Q96SW2 UNIPROT SALL4 protein Q9UJQ4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 32071327 YES miannu Thalidomide-induced teratogenicity is dependent on its binding to cereblon (CRBN), the substrate receptor of the Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide binding to CRBN elicits subsequent ubiquitination and proteasomal degradation of CRBN neosubstrates including SALL4, a transcription factor of which polymorphisms phenocopy thalidomide-induced limb defects in humans. 0.2 SIGNOR-272206 NDFIP1 protein Q9BT67 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity relocalization 9606 BTO:0002181 26363003 YES SARA Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. 0.59 SIGNOR-260997 FGD4 protein Q96M96 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.618 SIGNOR-260554 GSK3B protein P49841 UNIPROT NEFH protein P12036 UNIPROT down-regulates phosphorylation Ser503 GGEEETKsPPAEEAA 9606 12130654 YES lperfetto Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment 0.302 SIGNOR-90668 FRK protein P42685 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr336 NKDKANRyFSPNFKV 9606 19345329 YES miannu Rak Phosphorylates PTEN on Tyrosine Residue 336.|Together, these results suggested that phosphorylation on Y336 by Rak prevents PTEN degradation; loss of Rak markedly decreased the ability of PTEN to inhibit tumor cell growth. 0.597 SIGNOR-278244 AP1G2 protein O75843 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity binding 9606 BTO:0001950 18772139 YES miannu Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination. 0.402 SIGNOR-272636 RNF41 protein Q9H4P4 UNIPROT USP8 protein P40818 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 23750007 YES irozzo RNF41 redistributes and ubiquitylates USP8, and reduces USP8 levels. 0.879 SIGNOR-259106 AKT1 protein P31749 UNIPROT PAWR protein Q96IZ0 UNIPROT down-regulates activity phosphorylation 9606 21555373 YES miannu Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy 0.39 SIGNOR-279668 PKA proteinfamily SIGNOR-PF17 SIGNOR CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser40 PKRRRASsLSRDAER 27149373 YES lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. 0.2 SIGNOR-275631 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1001 SKESEHDsDESSDDD 9606 10066810 YES gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, 0.442 SIGNOR-65281 TIMM9 protein Q9Y5J7 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 YES lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). 0.573 SIGNOR-267704 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser585 RLPKNRHsPSWSPDG 9606 20864540 YES lperfetto Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability. 0.252 SIGNOR-168053 nisoxetine chemical CHEBI:73410 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18487050 YES Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  0.8 SIGNOR-257797 POU5F1 protein Q01860 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 BTO:0004180 23041284 YES flangone Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription. 0.457 SIGNOR-242103 AURKB protein Q96GD4 UNIPROT CDCA2 protein Q69YH5 UNIPROT down-regulates activity phosphorylation Ser981 RRKSFCIsTLANTKA 9606 BTO:0000567 32938714 YES done miannu This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin. 0.447 SIGNOR-274001 CTBP1 protein Q13363 UNIPROT UBE2D3 protein P61077 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 21044962 NO miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. 0.2 SIGNOR-255174 MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 21408055 NO andrea cerquone perpetuini We have demonstrated that following muscle damage, phosphorylated STAT3 (p-STAT3) in SCs increases early (within one hour), inducing downstream target genes (i.e. GP130 and SOCS3), which further regulate the increase in STAT3 production and response (as induced via IL-6), leading to increased cMyc expression, which drives cell proliferation 0.7 SIGNOR-255414 PRKACA protein P17612 UNIPROT PACSIN2 protein Q9UNF0 UNIPROT down-regulates activity phosphorylation Ser313 ADLNRTLsRREKKKA 9606 BTO:0000007 31801866 YES done miannu PKCα phosphorylates PACSIN2 at serine 313 in the linker region and decreases its membrane binding and tubulation activities. Phosphorylation of PACSIN2 at S313 negatively regulated protein interaction between NS5A and core, which affected viral assembly 0.2 SIGNOR-273799 GNAS protein P63092 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates activity binding 9606 12145344 YES lperfetto HETEROTRIMERIC G PROTEINS are essential for cell signaling throughout the body. The stimulatory G protein, Gs, couples activation of a host of different transmembrane receptors to adenylyl cyclase stimulation, leading to intracellular generation of cAMP 0.741 SIGNOR-268693 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 YES gcesareni Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. 0.2 SIGNOR-188139 CUL3 protein Q13618 UNIPROT HSF2 protein Q03933 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 19768582 YES 1 miannu Here we show that the PEST sequences of a short-lived protein called HSF2 interact with Cullin3, a subunit of a Cullin-RING E3 ubiquitin ligase, and that this interaction mediates the Cul3-dependent ubiquitination and degradation of HSF2 0.327 SIGNOR-239129 GOLGA2 protein Q08379 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 16489344 YES Giulio Previous studies have implicated the GM130–GRASP65 complex in diverse Golgi functions. Therefore, GM130–GRASP65 interactions are required for Golgi ribbon formation.|A surprising clue came from the observation that GM130 was required for stability of GRASP65. 0.878 SIGNOR-260601 PFN1 protein P07737 UNIPROT CDH4 protein P55283 UNIPROT up-regulates activity 9606 BTO:0000815 22820501 YES lperfetto Taken together, data obtained from MCF10A cells were consistent with the idea that Rho signaling to Dia1 and profilin-1 was essential for R-cadherin adherens junction formation. 0.335 SIGNOR-253111 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser530 DGPPSPRsPVIGSEV 9606 BTO:0001271 15093545 YES The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). 0.36 SIGNOR-124056 AMPK complex SIGNOR-C15 SIGNOR FOXO1 protein Q12778 UNIPROT up-regulates phosphorylation 9606 18394876 YES lperfetto The energy sensor AMP-activated protein kinase (AMPK) has been shown to directly phosphorylate FoxO factors at six regulatory sites that are distinct from the Akt phosphorylation sites, resulting in FoxO activation. 0.369 SIGNOR-216478 Monobutylphthalate chemical CHEBI:88522 ChEBI AHR protein P35869 UNIPROT up-regulates activity chemical activation -1 25081364 YES miannu BBP affected hepatocellular carcinoma progression through the aryl hydrocarbon receptor (AhR) and that benzyl butyl phthalate (BBP) stimulated AhR at the cell surface, which then interacted with G proteins and triggered a downstream signaling cascade. BBP activated AhR through a nongenomic action involving G-protein signaling rather than the classical genomic AhR action. 0.8 SIGNOR-268791 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207935 ITGB1BP1 protein O14713 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.314 SIGNOR-257650 GDNF protein P39905 UNIPROT PAFAH1B1 protein P43034 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. 0.2 SIGNOR-252171 DISC1 protein Q9NRI5 UNIPROT KIF5B protein P33176 UNIPROT up-regulates activity binding 9606 BTO:0000938 17202468 YES miannu We identified Kinesin-1, a microtubule-dependent and plus-end directed motor, as a DISC1-interacting molecule. Our results show that DISC1 links Kinesin-1 to the NUDEL/LIS1/14-3-3ε complex, serves as the cargo receptor, and regulates the transport of the complex to axons, leading to axon elongation. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3ε complex through DISC1 0.2 SIGNOR-252161 KIF5A protein Q12840 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 NO miannu The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue. 0.7 SIGNOR-264067 1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanol chemical CHEBI:91549 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). 0.8 SIGNOR-258849 NFE2L2 protein Q16236 UNIPROT SLC7A11 protein Q9UPY5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. NFE2L2 directly binds to the promoter region of SLC7A11, leading to increased expression of this transporter, which in turn contributes to the resistance to ferroptosis and to radiotherapy 0.424 SIGNOR-279867 GRIN2D protein O15399 UNIPROT NMDA receptor_2D complex SIGNOR-C350 SIGNOR form complex binding 9606 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits 0.663 SIGNOR-264127 IL10RA protein Q13651 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 26260587 YES lperfetto IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes. 0.431 SIGNOR-249545 ZRSR2 protein Q15696 UNIPROT ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR form complex binding 9606 9237760 YES miannu Recognition of a functional 3' splice site in pre-mrna splicing requires a heterodimer of the proteins u2af65/u2af35. 0.766 SIGNOR-50176 IRF7 protein Q92985 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16612387 NO miannu Ikkalfa can also phosphorylate and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production. 0.2 SIGNOR-263128 KNL1 protein Q8NG31 UNIPROT KNL1 complex complex SIGNOR-C363 SIGNOR form complex binding 27881301 YES lperfetto KNL1C (known as Spc105 complex in S. cerevisiae) contains the KNL1 and ZWINT subunits. 0.2 SIGNOR-265193 CALM2 protein P0DP24 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 BTO:0001009 14701738 YES miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. 0.2 SIGNOR-266326 RBM42 protein Q9BTD8 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.309 SIGNOR-270645 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr983 AAPPAPPtPPPPTLP -1 19448668 YES miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. 0.38 SIGNOR-262882 PAK1 protein Q13153 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser305 IKRSKKNsLALSLTA 9606 BTO:0000149 12374744 YES lperfetto Pak1 directly phosphorylated the activation function-2 domain of the er at the n-terminal residue ser305, and its mutation to ala (s305a) abolished the pak1-mediated phosphorylation and transactivation functions of the er 0.535 SIGNOR-94206 Ub:E2 complex SIGNOR-C497 SIGNOR DTX3L protein Q8TDB6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270952 CSNK1G1 protein Q9HCP0 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 YES llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR 0.493 SIGNOR-250821 FZD1 protein Q9UP38 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 NO fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) 0.2 SIGNOR-80595 PAK proteinfamily SIGNOR-PF13 SIGNOR MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser298 RTPGRPLsSYGMDSR 9606 BTO:0000567 16129686 YES gcesareni Inhibition of pak kinase activity dramatically decreased phosphorylation of mek1 at ser(298) in response to either pdgf or egf. 0.2 SIGNOR-140039 MAPK14 protein Q16539 UNIPROT PIP4K2B protein P78356 UNIPROT down-regulates phosphorylation Ser326 SYGTPPDsPGNLLSF 9606 16949365 YES gcesareni Inhibition of pip4kbeta activity occurs through the direct phosphorylation of pip4kbeta at ser326 by the p38 stress-activated protein kinase. 0.2 SIGNOR-149359 SGK3 protein Q96BR1 UNIPROT GSK3A protein P49840 UNIPROT down-regulates activity phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000007 16543730 YES lperfetto Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3. 0.355 SIGNOR-249165 RACK1 protein P63244 UNIPROT PTK7 protein Q13308 UNIPROT up-regulates binding 9606 21350015 YES gcesareni Here, we identify rack1 as a novel interaction partner of ptk7. Mechanistically, rack1 is necessary for the ptk7-mediated membrane localization of dishevelled (dsh). Rack1 facilitates the ptk7-dsh interaction by recruiting pkcdelta1, a known effector of dsh membrane translocation. 0.2 SIGNOR-172322 SRC protein P12931 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 11641791 YES gcesareni Src can thus directly tyrosine-phosphorylate the activation site of stat5 (tyr 694 in stat5a), and src may contribute to epo-induced signal transduction via stat5. 0.749 SIGNOR-111078 PTPN11 protein Q06124 UNIPROT CSF2RB protein P32927 UNIPROT up-regulates dephosphorylation 9606 phosphorylation:Tyr628 PPPGSLEyLCLPAGG 9162089 YES gcesareni Shp2 is thought to act as a positive mediator of growth factor signals.. Hp2 could act as an adaptor between the activated c and grb2, thus leading to activation of the ras/mitogen-activated protein kinase pathway, known to be activated by il-3 0.51 SIGNOR-48557 CSNK1A1 protein P48729 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 16341017 YES gcesareni We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin. 0.551 SIGNOR-143037 NPAS1 protein Q99742 UNIPROT TH protein P07101 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003945 17457889 YES lperfetto Overexpression and siRNA experiments revealed that NPAS1, in concert with ARNT, negatively regulates the expression of TH and that this regulation is mediated by a direct binding of NPAS1 on the TH promoter. 0.252 SIGNOR-253702 AARS1 protein P49588 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 32314272 YES miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). 0.8 SIGNOR-270448 TRPM6 protein Q9BX84 UNIPROT TRPM7 protein Q96QT4 UNIPROT down-regulates quantity phosphorylation 9606 24858416 YES miannuccelli We found TRPM6 and TRPM7 both autophosphorylate threonine residues, but only TRPM6 crossphosphorylates TRPM7, and not the reverse . 0.497 SIGNOR-279770 IRS2 protein Q9Y4H2 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 12850284 YES gcesareni There was a high level of irs-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust pi3k binding and activation 0.557 SIGNOR-103174 RIPK1 protein Q13546 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity phosphorylation 9606 36198273 YES miannu Additionally, RIPK1-dependent hyper-phosphorylation of TBK1 in Casp8 Ripk3 cells occurred during MNV-1 infection (Figure 4F).|RIPK1 and its kinase activity were required to promote increased TBK1 phosphorylation in the absence of caspase-8 (Figure 3E), suggesting that RIPK1 may promote TBK1 activation. 0.373 SIGNOR-279278 CNTFR protein P26992 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 10582086 NO gcesareni Clc/clf activates stat1 and stat3. 0.339 SIGNOR-72774 NF2 protein P35240 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 24012335 YES The opposite changes in Lats/YAP and Mst1/2 phosphorylation upon loss of NF2 therefore argue against the generally assumed linear model in which NF2 signals through activation of Mst1/2 flangone As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2 0.695 SIGNOR-202607 hydromorphone chemical CHEBI:5790 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258143 SRC protein P12931 UNIPROT PROM1 protein O43490 UNIPROT unknown phosphorylation Tyr852 GYHKDHVyGIHNPVM 9606 19296573 YES llicata Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src 0.501 SIGNOR-184776 CPS1 protein P31327 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI down-regulates quantity chemical modification 9606 15096496 YES CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules 0.8 SIGNOR-267198 AKT1 protein P31749 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates activity phosphorylation Thr100 LRARDIItAWHPPAP 9606 BTO:0000007 11976320 YES gcesareni CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation. 0.387 SIGNOR-252551 MAP3K11 protein Q16584 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation 9606 12738796 YES miannu Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells. 0.335 SIGNOR-280019 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR AKT1S1 protein Q96B36 UNIPROT down-regulates binding 9606 SIGNOR-C3 20006481 YES gcesareni Akt can phosphorylate pras40, a raptor binding protein that also acts as an inhibitor of torc1. Akt-mediated phosphorylation of pras40 again promotes 14-3-3 binding, in this case leading to relief from pras40-mediated inhibition. 0.2 SIGNOR-162003 flutamide chemical CHEBI:5132 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition 9606 18571420 YES Luana Among the compounds obtained, N-[4-[(benzyl)(4-nitrophenyl)amino]-1-methylpyrrole-2-carbonyl]pyrrolidine (22) is as potent an AR antagonist as the typical anilide-type AR antagonists hydroxyflutamide and bicalutamide.  0.8 SIGNOR-257807 WYE-687 chemical CID:25229450 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;ATP-competitive inhibitor mTOR gcesareni 0.8 SIGNOR-207818 hsa-miR-26a-5p mirna URS000019B0F7_9606 RNAcentral SLC7A11 protein Q9UPY5 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 37776596 YES miannu Hsa-miR-26a-5p improves OSCC sensitivity to ferroptosis by inhibiting SLC7A11 0.4 SIGNOR-279951 BACH1 protein O14867 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity transcriptional regulation 9606 31257027 YES inferred from family member BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. 0.2 SIGNOR-270266 PGK1 protein P00558 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation 9606 32646968 YES miannu PGK1 is an important enzyme in the metabolic glycolysis pathway, but PGK1 also phosphorylates and activates PDK1 through its protein kinase activity ( xref ).|PGK1 is an important enzyme in the metabolic glycolysis pathway, but PGK1 also phosphorylates and activates PDK1 through its protein kinase activity. 0.2 SIGNOR-280064 PLK2 protein Q9NYY3 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT up-regulates activity phosphorylation 9606 21382555 YES miannu Here, we report that Plk2 phosphorylates a quartet of Ras and Rap regulators : SynGAP, PDZGEF1, RasGRF1 and SPAR, resulting in powerful bidirectional control over Rap and Ras activity.|Thus, Plk2 was sufficient to promote the activities of both SynGAP and PDZGEF1 in mammalian cells. 0.357 SIGNOR-280066 HIP1 protein O00291 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 11007801 NO miannu Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain. 0.7 SIGNOR-82463 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192458 PRKCZ protein Q05513 UNIPROT MAPK7 protein Q13164 UNIPROT down-regulates activity phosphorylation 9606 20538799 YES miannu Furthermore, PKC\u03b6 phosphorylates ERK5, and mutation analysis showed that the preferred site is S486.|PKCzeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5 0.576 SIGNOR-280090 PRKD1 protein Q15139 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates quantity by destabilization phosphorylation Ser112 APLSRSIsTVSSGSR 9606 37045830 YES miannu PKD negatively affects the stability of Spry2 WT but not of mutant Spry2 S112A.|Using in vitro and in vivo assays, we show that protein kinase D (PKD) phosphorylates Spry2 at serine 112 and interacts in vivo with the C-terminal half of this protein. 0.324 SIGNOR-280091 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MAGEA6 protein P43360 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002806 31267705 YES miannu  The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6 0.2 SIGNOR-272266 SYK protein P43405 UNIPROT HUWE1 protein Q7Z6Z7 UNIPROT up-regulates activity phosphorylation 9606 26212014 YES miannu Collectively, these data suggest that TNF induced tyrosine phosphorylation of Mule by Syk contributes to its E3 ligase activity. 0.2 SIGNOR-280150 PMCH protein P20382 UNIPROT MCHR2 protein Q969V1 UNIPROT up-regulates binding 9606 BTO:0000142 10471841 YES gcesareni Upon several purification steps, followed by mass spectrometric analysis and peptide sequencing, the ligand was identified as melanin concentrating hormone (mch), revealing that the orphan slc-1 is the mch receptor. 0.612 SIGNOR-70520 NEU1 protein Q99519 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0003554 32164705 NO miannu Our data showed that NEU1 inhibited cancer cell proliferation, induced apoptosis, and suppressed tumor formation both in vitro and in vivo, by disrupting interaction of FN and integrin β1 and inhibiting the Akt signaling pathway. 0.7 SIGNOR-260657 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 9606 SIGNOR-C15 19584320 YES gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.503 SIGNOR-186637 PRKCA protein P17252 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 9606 BTO:0001271 9738012 YES gcesareni Purified pkca can efficiently and directly phosphorylate bcl2 at serine 70 0.35 SIGNOR-60120 SNCAIP protein Q9Y6H5 UNIPROT SNCA protein P37840 UNIPROT up-regulates activity binding 9606 19224863 YES miannu Synphilin-1 interacts in vivo with α-synuclein, and their coexpression promotes the formation of Lewy body-like inclusions 0.799 SIGNOR-272597 EPHA2 protein P29317 UNIPROT YES1 protein P07947 UNIPROT up-regulates activity phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 BTO:0001007 33941853 YES miannu EphA2 interacts with YES1 and phosphorylates YES1 at Tyr426 site. 0.421 SIGNOR-277556 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser645 RPASVPPsPSLSRHS -1 2117608 YES llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. 0.33 SIGNOR-250879 CDK1 protein P06493 UNIPROT CPEB1 protein Q9BZB8 UNIPROT up-regulates activity phosphorylation 9606 21145160 YES miannu Combined, our results suggest that XGef is involved in XRINGO and CDK1 mediated activation of CPEB and that an XGef, XRINGO, ERK2, and CPEB complex forms in ovo to facilitate this process.|Notably, specific inhibition of XRINGO and CDK1 activity in CPEB phosphorylation-competent extracts completely blocks phosphorylation of CPEB, which suggests that XRINGO and CDK1 directly phosphorylates CPEB. 0.58 SIGNOR-280205 CDK2 protein P24941 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation Thr210 YDGERKKtLCGTPNY 9606 33402344 YES miannu Thus, CycA2-CDK2 can stimulate phosphorylation of PLK1 T210 in vitro and the interactions required for CycA2-mediated PLK1 T210 phosphorylation are detected in the cytoplasm, but not in the nucleus.|We find that Cyclin A2-CDK2 can activate the mitotic kinase PLK1 through phosphorylation of Bora, and that only cytoplasmic Cyclin A2 interacts with Bora and PLK1. 0.375 SIGNOR-280212 CDK2 protein P24941 UNIPROT RAD51 protein Q06609 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 25927241 YES miannu Phosphorylation of the BRCA2 C-terminal RAD51 binding site by CDK2 promotes RAD51 filament disassembly, leading to nucleolitic cleavage of newly synthesized DNA and compromised fork integrity. 0.593 SIGNOR-280213 CHUK protein O15111 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 23343355 YES miannu In the nucleus, IKKalpha enhances p53 mediated GADD45 and BAD gene expressions by phosphorylating p53 at Ser20 and stabilizing p53 protein levels , leading to the induction of apoptosis in response to ROS exposure.|PKC-activated nuclear I\u03baB kinase\u03b1 promotes the stability of p53 protein and mediates reactive oxygen species-induced apoptosis [ ]. 0.429 SIGNOR-280231 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. 0.569 SIGNOR-164471 KRAS protein P01116 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 BTO:0003104 10082541 NO lperfetto A constitutively active Ras protein [Ras(G12V)] regulates the stable expression of the NFIL3 transcription factor through both the Raf-MAPK and PI3-K pathways. 0.2 SIGNOR-242757 USP7 protein Q93009 UNIPROT CHFR protein Q96EP1 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 17442268 YES miannu In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell.  USP7 mediates deubiquitination of Chfr. 0.433 SIGNOR-271462 GYS1 protein P13807 UNIPROT α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR up-regulates quantity chemical modification 9606 26882899 YES miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. 0.2 SIGNOR-267940 E2F1 protein Q01094 UNIPROT MCPH1 protein Q8NEM0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22136275 NO miannu Overexpression of E2F1 led to the upregulation of MCPH1 transcription, and knocking down the endogenous E2F1 resulted in the inhibition of the MCPH1 promoter activity. 0.348 SIGNOR-253848 LEPR protein P48357 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 9606 11085989 YES miannu Because the long leptin receptor lacking tyrosine 985 exhibits a significantly reduced ability to activate ERK phosphorylation, this residue is at least in part mediating stimulation of the ERK pathway by ObRb. This residue binds SHP-2 and is required for tyrosine phosphorylation of SHP-2 0.472 SIGNOR-263506 PTGS2 protein P35354 UNIPROT prostaglandin G2(1-) smallmolecule CHEBI:82629 ChEBI up-regulates quantity chemical modification -1 7592599 YES Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, 0.8 SIGNOR-269770 TFEB protein P19484 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 NO lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) 0.2 SIGNOR-276796 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser256 ESWLGARsSRPASPC 9606 BTO:0001061 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276768 CDK16 protein Q00536 UNIPROT PRC1 protein O43663 UNIPROT up-regulates activity phosphorylation Thr481 RRGLAPNtPGKARKL 9606 BTO:0000815 35449080 YES lperfetto Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis.|Indeed, immunoblot analysis showed that PRC1 phosphorylation at the T481 site (CDK-dependent major phosphorylation site) fluctuated with the abundance of CDK16 protein in the cell cycle process 0.345 SIGNOR-273017 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.407 SIGNOR-275774 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr2 tAKMETTF 9606 BTO:0000848 21177766 YES lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) 0.268 SIGNOR-170760 ponatinib chemical CHEBI:78543 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001271;BTO:0000184 23526464 YES miannu The RET tyrosine kinase encoding gene acts as a dominantly transforming oncogene in thyroid carcinoma and other malignancies. Ponatinib (AP24534) is an oral ATP-competitive tyrosine kinase inhibitor that is in advanced clinical experimentation in leukemia.Ponatinib is a potent inhibitor of RET kinase and has promising preclinical activity in models of RET-driven medullary thyroid carcinoma. 0.8 SIGNOR-259275 CHEK1 protein O14757 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation 9606 20068082 YES gcesareni Chk1 directly phosphorylates essential s-phase kinases cdc7. 0.733 SIGNOR-163161 CTNNB1 protein P35222 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity binding 9606 20492721 YES FFerrentino Hypophosphorylation of β-catenin and translocation into the nucleus leads to binding with members of the lymphoid-enhancer-binding factor/T-cell-specific transcription factor (LEF/TCF) family and activation of WNT target genesAs a member of LEF/TCF family, transcription factor 7 like 2 (Tcf7l2, formerly called Tcf4) is an important transcription factor triggering the downstream responsive genes of WNT signaling 0.9 SIGNOR-85757 CASP1 protein P29466 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp348 GTGGLEPdLARGRWA 9606 BTO:0005111 32122970 YES miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. 0.2 SIGNOR-272192 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH3 protein Q9UM47 UNIPROT up-regulates activity cleavage 9606 25610395 YES lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins. 0.575 SIGNOR-209726 OPRK1 protein P41145 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.474 SIGNOR-256710 RUNX3 protein Q13761 UNIPROT TXN2 protein Q99757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255093 PIAS3 protein Q9Y6X2 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR form complex binding 9606 26194464 YES mrosina In summary, the TGF-b/IL-6/TCR-ERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation 0.596 SIGNOR-255035 BTF3 protein P20290 UNIPROT MADCAM1 protein Q13477 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 17312387 NO In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. 0.2 SIGNOR-253945 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA3 protein Q9Y5H0 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265677 MAPK12 protein P53778 UNIPROT NUP62 protein P37198 UNIPROT down-regulates quantity by destabilization phosphorylation Thr269 GAASGTStTTSTAAT 9606 BTO:0000007 30401435 YES miannu We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1).  0.2 SIGNOR-277415 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr21 ENLEQEEyEDPDIPE -1 10942405 YES The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton 0.452 SIGNOR-251411 PGAM proteinfamily SIGNOR-PF78 SIGNOR 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI down-regulates quantity chemical modification 9606 24786789 YES miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. 0.8 SIGNOR-266513 VAV3 protein Q9UKW4 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.711 SIGNOR-260584 FBXW10 protein Q5XX13 UNIPROT GAPDH protein P04406 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000578 37450367 YES miannu Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation.  0.2 SIGNOR-277841 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 NO apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. 0.7 SIGNOR-255579 FUBP1 protein Q96AE4 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26490982 NO irozzo The human far upstream element (FUSE) binding protein 1 (FUBP1) belongs to an ancient family which is required for proper regulation of the c-Myc proto-oncogene. Our results indicated that FUBP1 may potentially stimulate c-Myc expression in ESCC and its expression may promote ESCC progression. 0.413 SIGNOR-259123 UVRAG protein Q9P2Y5 UNIPROT RINT1 protein Q6NUQ1 UNIPROT up-regulates activity binding 9606 BTO:0000007 24056303 YES lperfetto We further show that UVRAG interacts with RINT-1, and acts as an integral component of the RINT-1-containing ER tethering complex, which couples phosphoinositide metabolism to COPI-vesicle tethering. Displacement or knockdown of UVRAG profoundly disrupted COPI cargo transfer to the ER and Golgi integrity 0.498 SIGNOR-265028 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251597 AKT proteinfamily SIGNOR-PF24 SIGNOR HMOX1 protein P09601 UNIPROT unknown phosphorylation Ser188 LYRSRMNsLEMTPAV 9606 BTO:0000007 15581622 YES llicata We have identified a putative consensus sequence for phosphorylation by akt/pkb of ho-1 at ser188. although the changes in activity are small, this study provides the first evidence for a role of the survival kinase akt in the regulation of ho-1. 0.2 SIGNOR-161283 GSK3B protein P49841 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 33081032 YES miannu GSK3β regulates S6K1 activity positively through modulating phosphorylation of S6K1 at p.Ser371. 0.36 SIGNOR-263513 PTEN protein P60484 UNIPROT DVL2 protein O14641 UNIPROT down-regulates activity dephosphorylation Ser143 FHPNVSSsHENLEPE 9606 26399523 YES miannu This showed that while both PTEN WT and the lipid phosphatase-inactive G129E mutant suppressed phosphorylation of DVL2 on serine 143 that accumulated upon PTEN knockdown, the C124S and Y138L mutants did not .|Finally, it is important to point out that while our studies show that PTEN can directly dephosphorylate DVL2 in vitro, it is possible that regulation of serine 143 phosphorylation of DVL2 by PTEN in cells may require additional protein factors, or post-translational modifications. 0.318 SIGNOR-277035 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257931 INPP5D protein Q92835 UNIPROT PLCG2 protein P16885 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 32323266 YES scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. 0.312 SIGNOR-268455 dactolisib chemical CHEBI:71952 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 YES ATP-competitive inhibitor of PI3K and mTOR gcesareni While the pi3k inhibitors, ly294002 or wortmannin, in the presence of plx4032 were individually inactive against pprm cell lines (fig. S4), the dual pi3k and mtorc1/2 inhibitor bez235 was highly specific (vs. parental lines) and potent in growth-inhibiting pprm cell lines 0.8 SIGNOR-175712 RYK protein P34925 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 15454084 YES gcesareni Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled. 0.42 SIGNOR-129571 PPM1A protein P35813 UNIPROT CDK9 protein P50750 UNIPROT down-regulates activity dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 18829461 YES gcesareni Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function 0.494 SIGNOR-248490 PPAT protein Q06203 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 9914248 YES miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. 0.8 SIGNOR-267294 indisulam chemical CHEBI:145431 ChEBI DCAF15 protein Q66K64 UNIPROT up-regulates activity chemical activation 9606 BTO:0001109 31819272 YES miannu Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. 0.8 SIGNOR-272204 EGFR protein P00533 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity phosphorylation Tyr179 SVYGTEEyLHPDMYE 9606 27287717 YES miannu To understand the mechanism by which IKBKE is activated by mutant EGFR, we first investigated if activating mutation of EGFR is able to form a complex with IKBKE.|While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179. 0.258 SIGNOR-278222 SIRT1 protein Q96EB6 UNIPROT NCOR2 protein Q9Y618 UNIPROT up-regulates 9606 22395773 YES FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. 0.494 SIGNOR-253506 PPM1D protein O15297 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity dephosphorylation Ser131 DESLANLsEDEYYSE 9606 BTO:0002181 25999347 YES miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. 0.466 SIGNOR-276904 RIPK1 protein Q13546 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 18545270 YES lperfetto The death domain of the rip1 kinase binds to death receptors such as fas that is required for caspase 8 activation and apoptosis 0.65 SIGNOR-177949 GSK3B protein P49841 UNIPROT GCM1 protein Q9NP62 UNIPROT down-regulates quantity by destabilization phosphorylation Ser322 NYPFPLTsWPCSFSP 9606 20855292 YES miannu We demonstrated that GSK-3beta mediates phosphorylation of GCM1 on Ser322, which is recognized by the F-box protein, FBW2, to promote GCM1 ubiquitination and degradation. 0.2 SIGNOR-278940 HIF1A protein Q16665 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.262 SIGNOR-271569 CHL1 protein O00533 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 YES miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. 0.413 SIGNOR-266723 LONP1 protein P36776 UNIPROT STAR protein P49675 UNIPROT down-regulates quantity by destabilization cleavage 10116 BTO:0000542 17579211 YES lperfetto Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by Lon protease: the unexpected effect of proteasome inhibitors 0.268 SIGNOR-265726 XRCC4 protein Q13426 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR up-regulates activity binding 9606 BTO:0002137 26774286 YES miannu In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.  0.821 SIGNOR-277201 EIF3E protein P60228 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity translation regulation 9606 BTO:0000815; BTO:0001938 20453879 NO irozzo Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. 0.2 SIGNOR-259156 FYN protein P06241 UNIPROT BSG protein P35613-2 UNIPROT up-regulates activity phosphorylation Tyr183 MEADPGQyRCNGTSS 9606 BTO:0000849 32291412 YES miannu Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment. 0.269 SIGNOR-274000 ADRA1D protein P25100 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.278 SIGNOR-256951 WNT5A protein P41221 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.757 SIGNOR-131841 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser82 HSISYTLsRAQTVVV -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.657 SIGNOR-276132 MYC protein P01106 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150;BTO:0000782 BTO:0000887;BTO:0001260 11313917 NO amattioni P27(kip1) gene is a target of transcriptional repression by c-myc. 0.533 SIGNOR-107032 STK39 protein Q9UEW8 UNIPROT SLC12A3 protein P55017 UNIPROT down-regulates activity phosphorylation Thr55 SSTFCMRtFGYNTID 10090 25651566 YES lperfetto SPAK directly phosphorylates NCC and its effects on NCC are universally associated with phosphorylation|This adds to the evidence that SPAK-mediated phosphorylation acts primarily to increase activity of individual cotransporters without affecting the amount of NCC on the surface| the kinase (SPAK) that phosphorylates NCC at T53 0.485 SIGNOR-264623 MAPK14 protein Q16539 UNIPROT SNX27 protein Q96L92 UNIPROT down-regulates activity phosphorylation Ser51 VRIVKSEsGYGFNVR 9606 33605979 YES miannu Altogether, our study suggests that MAPK11 and MAPK14 mediate the phosphorylation of SNX27 at Ser51 in vitro and in vivo. 0.2 SIGNOR-279069 CAMK1 protein Q14012 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS 9606 7523419 YES flangone Ser-52 in k18 is not glycosylated and matches consensus sequences for phosphorylation by cam kinase..these kinases can phosphorylate k18 in vitro predominantly at that site 0.2 SIGNOR-27398 IL1B protein P01584 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 NO inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b. 0.2 SIGNOR-267812 Ub:E2 complex SIGNOR-C497 SIGNOR CBLL2 protein Q8N7E2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271198 dothiepin chemical CHEBI:36798 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258877 axitinib chemical CHEBI:66910 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258074 isoleucine smallmolecule CHEBI:24898 ChEBI Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270426 EGFR protein P00533 UNIPROT HGS protein O14964 UNIPROT up-regulates activity phosphorylation Tyr334 ARYLNRNyWEKKQEE 9606 12953068 YES lperfetto We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation 0.636 SIGNOR-100246 FOXA1 protein P55317 UNIPROT SFTPB protein P07988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12161428 NO miannu A homeodomain and a forkhead transcription factor, NKX2.1 and HNF-3, respectively, are known activators of Sp-B transcription 0.283 SIGNOR-254181 belinostat chemical CHEBI:61076 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257959 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk. 0.309 SIGNOR-186959 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Thr213 SASFPHTtPSMCLNP 9606 BTO:0000664 17475908 YES miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 0.319 SIGNOR-262913 SREBF2 protein Q12772 UNIPROT SQLE protein Q14534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000759 31848472 YES miannu The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription 0.594 SIGNOR-265162 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NR3C1 protein P04150 UNIPROT down-regulates phosphorylation -1 9199329 YES inferred from 70% family members lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. 0.2 SIGNOR-270098 COPS5 protein Q92905 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 27866850 YES Barakat The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization. 0.2 SIGNOR-274977 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 8974401 YES Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif. gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subgroups of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subgroups of map kinases, respectively. here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). 0.743 SIGNOR-45360 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser32 RSRERSPsPLRGNVV 9606 BTO:0000671 15910284 YES lperfetto Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells. 0.26 SIGNOR-137478 MYT1L protein Q9UL68 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005949 30312684 YES miannu Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth. 0.2 SIGNOR-266778 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 21059642 YES The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.58 SIGNOR-273030 JAK1 protein P23458 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr327 NSKPKKSyIATQGCL 9534 8995399 YES lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 0.767 SIGNOR-236274 Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 24311584 NO miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. 0.7 SIGNOR-263713 PTGER3 protein P43115 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 12038972 YES gcesareni Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i) 0.497 SIGNOR-88192 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Thr123 RLLQQCEtLKVPPKK 9606 BTO:0000567 25670858 YES lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 0.587 SIGNOR-265231 NME1 protein P15531 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 NO miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 0.33 SIGNOR-255164 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane chemical CHEBI:125354 ChEBI CXCR4 protein P61073 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206268 GSK3B protein P49841 UNIPROT DCX protein O43602 UNIPROT up-regulates activity phosphorylation Ser332 STPKSKQsPISTPTS 9606 21159948 YES lperfetto Gsk3b phosphorylates dcx at the distinct site of ser327 and thereby contributes to dcx function in the restriction of axon branching. Together, our data define a jip3-regulated gsk3_/dcx signaling pathway that restricts axon branching in the mammalian brain.Gsk3_ induces the phosphorylation of dcx at ser327, which contributes to dcx function in the inhibition of axon branching and self-contact. 0.271 SIGNOR-170755 DTL protein Q9NZJ0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates binding 9606 BTO:0000567 27906959 YES miannu Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction. The cleaved SDE2 products need to be degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner, and failure to degrade SDE2 impairs S phase progression and cellular survival. 0.694 SIGNOR-272808 sorafenib tosylate chemical CHEBI:50928 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). 0.8 SIGNOR-259220 MAPK3 protein P27361 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 BTO:0000599 10915800 YES lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. 0.444 SIGNOR-80096 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 YES miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. 0.372 SIGNOR-250392 Gbeta proteinfamily SIGNOR-PF4 SIGNOR IL16 protein Q14005 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 14768064 YES inferred from 70% family members lperfetto The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response. 0.2 SIGNOR-270056 MAML1 protein Q92585 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 16510869 YES gcesareni Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin). 0.393 SIGNOR-144913 SAGA complex complex SIGNOR-C465 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR up-regulates 9606 15970593 NO lperfetto Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs).|this observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools. 0.7 SIGNOR-269570 GATA1 protein P15976 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17688409 NO miannu Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells. Mutation of the GATA-1 and the Ets-1 motifs amplified the expression of HOXA10 in HEL and K562 cells, confirming the importance of these cis-acting elements in regulating HOXA10 expression in megakaryocytic cells. Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. 0.306 SIGNOR-254470 HDAC4 protein P56524 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 25726523 YES lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 0.287 SIGNOR-275663 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 17151142 YES These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling 0.93 SIGNOR-253592 SERPINE1 protein P05121 UNIPROT F12 protein P00748 UNIPROT down-regulates activity binding 9606 BTO:0000131 26707513 YES lperfetto C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). 0.306 SIGNOR-263516 BRCC3 protein P46736 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates deubiquitination 9606 20656690 YES gcesareni Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a 0.2 SIGNOR-265312 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1714 SPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248822 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Ser623 RDSENLAsPSEYPEN 9606 21335236 YES gcesareni We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks. 0.398 SIGNOR-172221 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 14765127 YES Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation. gcesareni Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner. 0.45 SIGNOR-121803 TBK1 protein Q9UHD2 UNIPROT OPTN protein Q96CV9 UNIPROT up-regulates activity phosphorylation Ser473 AQMEVYCsDFHAERA 9606 26365381 YES miannu Given that TBK1 can phosphorylate OPTN on S177, S473 and S513 in response to mitochondrial depolarization, we explored the function of these events in vivo.|Phosphorylation of OPTN on S473 and S513 promotes TBK1 activation and recruitment of OPTN to depolarized mitochondria. 0.788 SIGNOR-278170 ATR protein Q13535 UNIPROT USP28 protein Q96RU2 UNIPROT up-regulates activity phosphorylation Ser714 ESSTNSSsQDYSTSQ 31938050 YES lperfetto Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity.|Representative immunoblots of n = 3. C Immunoblotting of total and phosphorylated USP28 at serine 67 and 714 in A431 cells exposed to indicated concentrations of CPPD for 6 h. 0.2 SIGNOR-275851 fluoxymesterone chemical CHEBI:5120 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 10077001 YES miannu The anabolic steroids, oxandrolone and fluoxymesterone, have high inhibition constants for binding, yet induce the N/C interaction and stabilize AR at relatively low ligand concentrations and are AR agonists in vivo. 0.8 SIGNOR-259264 PAK1 protein Q13153 UNIPROT RPA1 protein P27694 UNIPROT up-regulates activity phosphorylation Thr180 LSHTSGGtQSKVVPI 9606 33704464 YES miannu In this article, we found that Ser-135 and Thr-180 of RPA1 are directly phosphorylated by PAK1 in a DOCK7-Rac1/Cdc42-dependent manner.|We further explored the biological role of PAK1 in replication stress and found that depletion of PAK1 resulted in decreased RPA1 and RPA2 chromatin loading and RPA2 foci formation ( Figure 4I-K ) . 0.2 SIGNOR-279379 TBK1 protein Q9UHD2 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity phosphorylation Thr189 TAKKNGGtLYYMAPE 9606 30146158 YES miannu Our data clearly indicate that TBK1 can directly phosphorylate RIPK1 at T189.|TBK1 inhibits RIPK1 by direct phosphorylation. 0.373 SIGNOR-279388 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR SLC24A2 protein Q9UI40 UNIPROT up-regulates quantity phosphorylation Tyr364 LAEELGSyGKLKYYD 9606 BTO:0000938 23431067 YES miannu Src family kinase-mediated Tyr-365 phosphorylation of NCKX2 regulates its surface expression. PP2 facilitated the endocytosis of NCKX2 in both the somatodendritic and axonal compartments, suggesting that tyrosine phosphorylation of NCKX2 by SFK negatively regulates its endocytosis. Supporting this idea, activation of SFK enhanced the NCKX activity in the proximal dendrites of dentate granule cells (GCs). These results suggest that endocytosis of somatodendritic NCKX2 is regulated by SFK-dependent phosphorylation of Tyr-365. 0.2 SIGNOR-264387 IKBKE protein Q14164 UNIPROT REL protein Q04864 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C68 16888014 YES miannu The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel. 0.355 SIGNOR-148620 ATR protein Q13535 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser68 EELDTLAsQALSQCP 9606 15451423 YES lperfetto When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro. 0.878 SIGNOR-129469 MEIS2 protein O14770 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21746878 YES miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. 0.2 SIGNOR-267240 WASF1 protein Q92558 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 YES miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems. 0.897 SIGNOR-253572 HACD1 protein B0YJ81 UNIPROT FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 YES Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, 0.2 SIGNOR-267760 GSK3B protein P49841 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 16885213 YES lperfetto Gli2 and Gli3 (in vertebrates) are phosphorylated by protein kinase A and glycogen synthase kinase-3_ and are proteolytically processed 0.535 SIGNOR-148475 ERBB2 protein P04626 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 23576562 YES miannu Second, ErbB2 phosphorylates \u03b2-catenin at Tyr 654, leading to dissociation of the E-cadherin-\u03b2-catenin membrane complex and increased signaling to Wnt target genes such as cyclin D1 ( ). 0.765 SIGNOR-279041 okadaic acid chemical CHEBI:44658 ChEBI STK3 protein Q13188 UNIPROT up-regulates 9606 23493077 NO gcesareni Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway. 0.8 SIGNOR-201551 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.272 SIGNOR-268609 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR JUN protein P05412 UNIPROT up-regulates binding 9606 18174238 YES lperfetto Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment 0.577 SIGNOR-216337 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Thr2153 LDIPLQThrPHKLVD -1 26051540 YES irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. 0.472 SIGNOR-259117 HARS1 protein P12081 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 10430027 YES miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. 0.8 SIGNOR-270489 VAMP8 protein Q9BV40 UNIPROT STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR form complex binding 9606 BTO:0000132 22767500 YES lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  0.562 SIGNOR-261896 17beta-estradiol smallmolecule CHEBI:16469 ChEBI GPER1 protein Q99527 UNIPROT up-regulates chemical activation 9606 18262661 YES gcesareni Recent studies have revealed the contribution of a novel estrogen receptor gpr30, which belongs to the family of seven-transmembrane g-protein-coupled receptors, to many of the rapid biological responses to estrogen. 0.8 SIGNOR-160778 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser283 RSVPEPLsPVSSLQA 9606 16027724 YES llicata Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. 0.476 SIGNOR-138825 CDK2 protein P24941 UNIPROT NR1I2 protein O75469 UNIPROT down-regulates quantity by destabilization phosphorylation Ser350 MQAISLFsPDRPGVL 9606 35053380 YES miannu PXR Phosphorylation at S350 by CDK2 Triggers PXR Degradation via the Ubiquitin-Proteasome Pathway. 0.373 SIGNOR-279397 FYN protein P06241 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates activity phosphorylation 9606 17371836 YES miannu The tyrosine kinase Fyn modulates Sam68 mediated alternative splicing of Bcl-x mRNA.|Tyrosine phosphorylation of Sam68 by Fyn inverted this effect and favored the Bcl-x(L) splice site selection. 0.545 SIGNOR-279462 IL31 protein Q6EBC2 UNIPROT OSMR protein Q99650 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 BTO:0001253 15184896 YES gcesareni Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor. 0.613 SIGNOR-125347 DBH protein P09172 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 10090 7961964 YES brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. 0.8 SIGNOR-264005 CDK2 protein P24941 UNIPROT RPL12 protein P30050 UNIPROT unknown phosphorylation Ser38 KIGPLGLsPKKVGDD 9606 18847512 YES llicata Finally, we selected one novel substrate, the ribosomal protein rl12, for further study: site-directed mutagenesis and phosphopeptide mapping confirmed that cdk2 phosphorylates rl12 in vitro and in vivo on the same site determined by our methods. 0.2 SIGNOR-181603 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 YES gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction. 0.2 SIGNOR-244180 cyclosporin A chemical CHEBI:4031 ChEBI PPP3CC protein P48454 UNIPROT down-regulates chemical inhibition 9606 15276472 YES gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-127231 ponatinib chemical CHEBI:78543 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 23563700 YES miannu Ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1. 0.8 SIGNOR-259276 PSMC1 protein P62191 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.872 SIGNOR-263373 MTOR protein P42345 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 NO gcesareni In differentiated myofibres, we observed that wnt7a binding to fzd7 directly activates the akt/mtor growth pathway, thereby inducing myofibre hypertrophy. 0.7 SIGNOR-191564 RUNX2 protein Q13950 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15765505 NO gcesareni Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development 0.494 SIGNOR-134515 TOPBP1 protein Q92547 UNIPROT ATR protein Q13535 UNIPROT up-regulates activity binding 9606 BTO:0001938 SIGNOR-C298 16530042 YES lperfetto These results establish that TopBP1 can activate both Xenopus and human ATR. Furthermore, these experiments provide conclusive evidence that the kinase activity that is induced by TopBP1 is intrinsic to the ATR protein itself and is not due to a kinase that associates with ATR. 0.813 SIGNOR-263232 FZD1 protein Q9UP38 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 23151663 YES areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  0.677 SIGNOR-258952 CYP19A1 protein P11511 UNIPROT testosterone smallmolecule CHEBI:17347 ChEBI down-regulates quantity chemical modification 9606 BTO:0000975 27702664 YES lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively 0.8 SIGNOR-268671 SYK protein P43405 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr768 HSEDEIEyENQKRLE 9606 24525236 YES miannu Only two mutants, FLT3-KD (V5) Y768A and Y955A, were resistant to SYK-mediated FLT3 phosphorylation, suggesting that SYK directly phosphorylates FLT3 at sites Y768 and Y955 ( ).|SYK Enhances FLT3 WT and Mutant Activation by Phosphorylation of Residues Y768 and Y955. 0.408 SIGNOR-278431 PRKG1 protein Q13976 UNIPROT RGS2 protein P41220 UNIPROT up-regulates activity phosphorylation Ser46 KDWKTRLsYFLQNSS -1 14608379 YES lperfetto Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.  0.679 SIGNOR-249240 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates binding 9534 7629118 YES Tyrosine phosphorylation of insulin receptor substrate-1 in vivo depends upon the presence of its pleckstrin homology region. 0.757 SIGNOR-253604 LHX3 protein Q9UBR4 UNIPROT FSHB protein P01225 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23766128 NO miannu we also demonstrated that LHX3 bound with greater affinity to the wild-type human FSHB promoter compared with the -211 G/T mutation and that LHX3 binding was more effectively competed with excess wild-type oligonucleotide than with the SNP. Finally, we showed that FSHB transcription was decreased in gonadotrope cells with the -211 G/T mutation compared with the wild-type FSHB promoter. 0.369 SIGNOR-254557 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR Caspase 3 complex complex SIGNOR-C221 SIGNOR down-regulates activity 9606 BTO:0002882 11684015 NO lperfetto BCR/ABL Tyrosine Kinase Enhances Expression of RAD51 by Stimulation of STAT5-Mediated Transactivation and Inhibition of Caspase-3-Dependent Degradation| 0.2 SIGNOR-271705 NFIX protein Q14938 UNIPROT ANOS1 protein P23352 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268884 RARA protein P10276 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11788593 NO gcesareni We show that retinoic acid receptor (rar)-selective ligands reduce egfr level and the magnitude and duration of egfr activation in egf-stimulated cells 0.395 SIGNOR-114087 DRD5 protein P21918 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.405 SIGNOR-257311 SEC23B protein Q15437 UNIPROT UBA52 protein P62987 UNIPROT unknown binding 30605680 YES lperfetto We validate the genotype-specific differential SEC23B–UBA52 (ribosomal protein RPL40) interaction. 0.2 SIGNOR-265305 KMT5B protein Q4FZB7 UNIPROT EID3 protein Q8N140 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 23720823 YES miannu Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene. 0.2 SIGNOR-266640 T_cell_activation phenotype SIGNOR-PH73 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 NO miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. 0.7 SIGNOR-261022 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates activity relocalization 9606 15221015 YES lperfetto We found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor. 0.731 SIGNOR-126578 MYOG protein P15173 UNIPROT MYOG protein P15173 UNIPROT up-regulates transcriptional regulation 9606 SIGNOR-C92 17194702 YES miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle 0.2 SIGNOR-151694 SHH protein Q15465 UNIPROT SMO protein Q99835 UNIPROT up-regulates activity 10090 16885213 NO lperfetto Binding of Hh to Ptch relieves the repression of Smo, allowing Smo to signal. 0.748 SIGNOR-148481 CBL protein P22681 UNIPROT KIT protein P10721 UNIPROT down-regulates activity ubiquitination 9606 15315962 YES miannu KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. 0.617 SIGNOR-260104 CSNK2A1 protein P68400 UNIPROT IGFBP3 protein P17936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser138 PPAPGNAsESEEDRS 9606 BTO:0000093 10650937 YES llicata The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment. 0.339 SIGNOR-250903 DUSP6 protein Q16828 UNIPROT MAPK7 protein Q13164 UNIPROT down-regulates activity dephosphorylation 9606 18280112 YES lperfetto However, whilst the interaction itself might be difficult to monitor, DUSP6 should still be able to promote the de-phosphorylation of ERK5 in cells if it is an ERK5 phosphatase.To test this HEK293 cells were transiently transfected with HA-ERK2 or HA-ERK5 together with EGFP-MEK1E (a constitutively active version of MEK1) or EGFP-MEK5D (a constitutively active version of MEK5).|Whilst one can envisage scenarios in which the interaction between DUSPs and their substrates might be transient, DUSP6 should still be able to promote the de-phosphorylation and inactivation of ERK5. 0.645 SIGNOR-277007 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 BTO:0001130 18511414 YES lperfetto Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126 0.2 SIGNOR-244606 PEA15 protein Q15121 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates 9606 11702783 NO gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. 0.768 SIGNOR-111502 MAPK3 protein P27361 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 YES gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. 0.459 SIGNOR-134841 p38 proteinfamily SIGNOR-PF16 SIGNOR BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Ser87 AAAGPALsPVPPVVH 9606 19336399 YES gcesareni The protein's reduced antiapoptotic capacity was related to phosphorylation of its threonine 56 and serine 87 residues by virally activated p38mapk 0.2 SIGNOR-260450 HTR2C protein P28335 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.567 SIGNOR-257221 DMTF1 protein Q9Y222 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 YES Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  0.2 SIGNOR-261584 ZW10 protein O43264 UNIPROT NRZ complex complex SIGNOR-C358 SIGNOR form complex binding 25364732 YES lperfetto NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay. 0.846 SIGNOR-265023 SB 505124 chemical CHEBI:100922 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206742 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 11904305 YES gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1. 0.643 SIGNOR-116158 ACTB protein P60709 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.436 SIGNOR-269788 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Thr451 PIPKALGtPVLTPPT 10090 11689711 YES gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. 0.2 SIGNOR-252984 JAK2 protein O60674 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1069 EDSFLQRySSDPTGA 9534 9363897 YES Tyrosine at residue 1,068 of the EGFR is proposed to be one of the principal phosphorylation sites and Grb2-binding sites stimulated by growth hormone via Jak2. Our results indicate that the role of EGFR in signalling by growth hormone is to be phosphorylated by Jak2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression, independently of the intrinsic tyrosine kinase activity of EGFR.¬† 0.611 SIGNOR-251347 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser385 RYSDTTDsDPENEPF 9606 21779440 YES gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity 0.679 SIGNOR-89822 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.252 SIGNOR-268605 ABL1 protein P00519 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation 9606 BTO:0000567;BTO:0001271 12944467 YES gcesareni We thus hypothesized that wrn may interact with the abl tyrosine kinase in the dna damage response. Here, we provide evidence for a functional and physical interaction between wrn and c-abl, including wrn relocalization in response to dna damage, suggesting that this protein-protein interaction participates in a shared pathway of genome surveillance. 0.411 SIGNOR-86497 MARCHF8 protein Q5T0T0 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 33540066 YES miannu Inhibiting proteasome activity with MG132 prevented CDH1 and beta2M degradation, indicating that MARCH8 might be targeting CDH1 and beta2M for proteasomal degradation.|We demonstrated that MARCH8 interacts with and ubiquitinates CDH1 and beta2M. 0.2 SIGNOR-278820 ARHGAP20 protein Q9P2F6 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.445 SIGNOR-260474 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr112 EGMQIPStQFDAAHP 9606 BTO:0000007 12432063 YES llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin 0.555 SIGNOR-250848 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates activity phosphorylation Tyr594 TYVDPHTyEDPNQAV 9606 18387945 YES lperfetto The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells. 0.2 SIGNOR-178173 GFs stimulus SIGNOR-ST12 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates 9606 23863153 NO lperfetto Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease. 0.7 SIGNOR-219382 AKT proteinfamily SIGNOR-PF24 SIGNOR CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 YES lperfetto The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1. 0.2 SIGNOR-244206 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser41 LRGNVVPsPLPTRRT 9606 21177848 YES gcesareni Ser41 is known to be phosphorylated by a dyrk isoform in serum-fed or -starved cells (21). A phosphomimetic mutation of ser41 to asp resulted in complete loss of human crhsp-24 binding ability whether in the oxidative state or not 0.26 SIGNOR-170781 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 10090 BTO:0000944 10978177 YES HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin 0.501 SIGNOR-251315 STUB1 protein Q9UNE7 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23256568 YES miannu Taken together, our data suggest that CHIP interacts with c-FLIP L in vivo and promotes the ubiquitination of c-FLIP L.|When we knocked down CHIP, c-FLIP L degradation was inhibited after treatment with 17-AAG, which indicated that CHIP modulated c-FLIP L degradation in the NSCLC cell lines. 0.357 SIGNOR-278783 MARCHF9 protein Q86YJ5 UNIPROT HLA-DQB1 protein P01920 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271539 TFE3 protein P19532 UNIPROT GBA protein P04062 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.2 SIGNOR-276822 TEC protein P42680 UNIPROT MAF protein O75444 UNIPROT up-regulates activity phosphorylation Tyr21 TSPLAMEyVNDFDLM 9606 25993510 YES miannu We subsequently investigated whether Tec phosphorylated c-Maf at Tyr21/92/131.|We found that overexpression of Tec enhanced the binding of c-Maf to the MARE site derived from the IL-4 promoter (XREF_FIG).|As shown in xref , tyrosine phosphorylation of c-Maf was strongly enhanced by Tec and this Tec-induced tyrosine phosphorylation was completely mitigated by Ptpn22. 0.2 SIGNOR-279433 CRYBB2 protein P43320 UNIPROT CRYBB2 protein P43320 UNIPROT up-regulates activity binding 9606 16319073 YES miannu βB2-crystallin is the major component of β-crystallin and is a dimer at low concentrations. At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency. 0.2 SIGNOR-252154 ATM protein Q13315 UNIPROT ACTR8 protein Q9H981 UNIPROT down-regulates activity phosphorylation Ser412 MTTLQHRsQGDPEDP 9606 29759113 YES miannu These findings indicate that ATM dependent phosphorylation on ARP8-S412 reduces ARP8 INO80 interaction.|These findings raised the possibility that ATM negatively regulates the interaction of ARP8 with INO80 after etoposide treatment. 0.2 SIGNOR-279437 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser15 SGGAGRLsMQELRSQ 9606 20471944 YES lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). 0.847 SIGNOR-165554 MAPK14 protein Q16539 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates quantity by destabilization phosphorylation Thr339 STDKAEYtFYEGMGP 9606 BTO:0000007 22302987 YES miannu P38 MAPK phosphorylates RBP-Jk at Thr339 by physical binding, which subsequently induces the degradation and ubiquitylation of the RBP-Jk protein.  0.247 SIGNOR-276403 PAK1 protein Q13153 UNIPROT SORT1 protein Q99523 UNIPROT down-regulates activity phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 YES miannu PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. 0.2 SIGNOR-273718 SARS1 protein P49591 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270802 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Thr345 GADSDVEtPSNFGKY 9606 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.312 SIGNOR-262985 CDK1 protein P06493 UNIPROT SLC9A3R1 protein O14745 UNIPROT down-regulates activity phosphorylation Ser280 LAEAALEsPRPALVR 9606 20937695 YES miannu During the early stages of mitosis in HeLa cells, Cdc2 phosphorylates EBP50 on serine residues 280 and 302.|Phosphorylation by Cdc2 inhibits EBP50's role in forming microvilli in interphase but not mitotic cells. (A) Results from scoring JEG-3 cells for the presence of microvilli; error bars indicate mean \u00b1 SD. (B) Representative images from the microvillar rescue assay. 0.276 SIGNOR-278305 CDK2 protein P24941 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates activity phosphorylation 9606 18838553 YES miannu Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.|Cdk2 phosphorylates SMRT at consensus Cdk motifs to generate Pin1 binding sites and consequently targets SMRT for degradation, the latter also requiring the PPIase activity of Pin1 (XREF_FIG). 0.43 SIGNOR-278306 ritonavir chemical CHEBI:45409 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258154 NOTCH1 protein P46531 UNIPROT TCFL5 protein Q9UL49 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 NO gcesareni Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene. 0.2 SIGNOR-149807 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr418 LSGEDDAyCTFPSRD -1 10214954 YES Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. 0.643 SIGNOR-251378 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB6 protein P18564 UNIPROT up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.2 SIGNOR-259007 PLK1 protein P53350 UNIPROT TPT1 protein P13693 UNIPROT down-regulates phosphorylation Ser46 TEGNIDDsLIGGNAS 9606 12167714 YES lperfetto Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase 0.715 SIGNOR-91344 CDK4 protein P11802 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity phosphorylation 9606 32662822 YES miannu CDK4 and CDK6 phosphorylate TFEB and TFE3. 0.2 SIGNOR-279450 TBK1 protein Q9UHD2 UNIPROT OPTN protein Q96CV9 UNIPROT up-regulates activity phosphorylation Ser177 SSGSSEDsFVEIRMA 9606 26365381 YES miannu Given that TBK1 can phosphorylate OPTN on S177, S473 and S513 in response to mitochondrial depolarization, we explored the function of these events in vivo.|Phosphorylation of OPTN on S473 and S513 promotes TBK1 activation and recruitment of OPTN to depolarized mitochondria. 0.788 SIGNOR-278169 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 BTO:0000150 23562856 YES gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, 0.964 SIGNOR-201666 PRKACA protein P17612 UNIPROT RARA protein P10276 UNIPROT down-regulates activity phosphorylation Ser369 YVRKRRPsRPHMFPK 9606 20215566 YES miannu  Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity.  0.403 SIGNOR-276282 RET protein P07949 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 27994058 YES miannu In detail, RET and PTC3 induced STAT1 overexpression and phosphorylation at Ser 727 and Tyr 701. 0.275 SIGNOR-279276 JAK2 protein O60674 UNIPROT ITGAL protein P20701 UNIPROT up-regulates activity phosphorylation 9606 25624455 YES miannu PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role. 0.269 SIGNOR-254739 S protein P59594 UNIPROT EIF3F protein O00303 UNIPROT down-regulates activity binding 9606 18231581 YES lperfetto Coronavirus spike protein inhibits host cell translation by interaction with eIF3f 0.2 SIGNOR-260255 2'-deoxyguanosine smallmolecule CHEBI:17172 ChEBI 2'-deoxyguanosine 5'-monophosphate(2-) smallmolecule CHEBI:57673 ChEBI up-regulates quantity precursor of 20637175 YES lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis 0.8 SIGNOR-275812 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates 9606 BTO:0000007;BTO:0000782 11073940 NO gcesareni Mekk2 activated bmk1/erk5 to a greater extent, which might correlate with a higher affinity mekk2-mek5 interaction. A dominant negative form of mek5 blocked the activation of bmk1/erk5 by mekk2 0.762 SIGNOR-84184 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP -1 15241418 YES llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo. 0.757 SIGNOR-250766 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser60 PHVLEALsPPQTSGL 9606 20516213 YES lperfetto The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. 0.479 SIGNOR-217149 HTR6 protein P50406 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.501 SIGNOR-256801 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 YES Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. 0.842 SIGNOR-99725 CDK5 protein Q00535 UNIPROT DBN1 protein Q16643 UNIPROT up-regulates activity phosphorylation Ser142 NGLARLSsPVLHRLR 9606 23979715 YES miannu Phosphorylation of drebrin at S142 by Cdk5 relieves the intramolecular inhibition of F-actin bundling. 0.54 SIGNOR-279452 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Thr207 TPPTLSStVLIVRNE 9606 BTO:0001938 12815053 YES lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 0.54 SIGNOR-102502 KIF18B protein Q86Y91 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272525 NPEPPS protein P55786 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 11062501 YES The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides| We performed in vitro peptide digests using recombinant PSA | PSA behaved exclusively as an aminopeptidase |BH and PSA act as complementary and redundant systems responsible for the final trimming of the correct NH2 terminus. 0.8 SIGNOR-272467 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18339811 YES Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. 0.318 SIGNOR-248649 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 18682241 YES flangone We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity. 0.552 SIGNOR-242044 PLAG1 protein Q6DJT9 UNIPROT IGF2 protein P01344 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14695992 NO miannu Plag1 has been shown be a transcriptional activator of igf2 0.417 SIGNOR-120363 PRKCG protein P05129 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 YES inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.452 SIGNOR-270279 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 14711813 YES gcesareni Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation 0.2 SIGNOR-121161 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser396 SSSSSSHsLSASDTG 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity 0.2 SIGNOR-236764 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 YES lperfetto The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. 0.372 SIGNOR-105251 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0002181 SIGNOR-C3 10942774 YES lperfetto PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1. 0.926 SIGNOR-226714 DAB2IP protein Q5VWQ8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity binding 9606 27858941 YES miannu DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit. 0.498 SIGNOR-254751 TGIF1 protein Q15583 UNIPROT WWP1 protein Q9H0M0 UNIPROT up-regulates binding 9606 15359284 YES gcesareni We demonstrate that tiul1 degrades not only the activated type i receptor in association with smad7 but also smad2 in association with tgif.the steady-state levels of tgif are not affected by tiul1, but the interaction of tiul1 with tgif allows this ubiquitin ligase to target smad2 for degradation. 0.331 SIGNOR-128854 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT up-regulates activity phosphorylation Tyr193 EDEESEDyQNSASIH 10090 BTO:0001930 14722116 YES miannu Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases. 0.591 SIGNOR-273575 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ 9606 15946941 YES Luana Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. 0.2 SIGNOR-260840 TNF protein P01375 UNIPROT GCH1 protein P30793 UNIPROT up-regulates activity 9606 9204951 NO miannu The de novo synthesis of 6-BH4 depends on the induction of GTP-CH-1, e.g., by tumor necrosis factor-alpha (TNF alpha). 0.248 SIGNOR-252210 GSK690693 chemical CHEBI:90677 ChEBI AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258118 BCOR protein Q6W2J9 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 BTO:0004850 26847029 NO irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. 0.7 SIGNOR-256010 PTPRJ protein Q12913 UNIPROT LAT protein O43561 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11259588 YES flangone We propose that cd148 negatively regulates tcr signaling by interfering with the phosphorylation and function of plcgamma1 and lat 0.353 SIGNOR-105787 hsa-mir-146a-5p mirna URS000050B527_9606 RNAcentral IRAK1 protein P51617 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004602 25623956 YES Tiberia MiR-146a has anti-inflammatory action by directly targeting IRAK to inhibit NF-κB signaling, which exerts negative feedback control on the biogenesis of this miR. 0.4 SIGNOR-279893 L-thyroxine smallmolecule CHEBI:18332 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 10116 BTO:0000759 2158622 YES inferred from family member miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 0.8 SIGNOR-267808 AMPK complex SIGNOR-C15 SIGNOR Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 20640476 NO lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. 0.7 SIGNOR-209929 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 BTO:0000007 SIGNOR-C3 9465032 YES lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.926 SIGNOR-55697 EGR1 protein P18146 UNIPROT PCSK2 protein P16519 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9359835 NO miannu we show that the transcription factor EGR-1 interacts with two distinct elements within the proximal human PC2 promoter region. Transfection experiments also demonstrate that EGR-1 is able to enhance PC2 promoter activity. 0.2 SIGNOR-253896 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 BTO:0000887;BTO:0001103 12058061 YES lperfetto Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. 0.509 SIGNOR-236571 FIP1L1 protein Q6UN15 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates binding 9606 14749727 YES miannu Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. 0.791 SIGNOR-121700 NEK2 protein P51955 UNIPROT CEP68 protein Q76N32 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 25704143 YES miannu In this study we show phosphorylation of Cep68 by Nek2 creates a potential phosphodegron that directs Cep68 destruction through the activity of SCF-beta-Trcp.|Our above results showed that Nek2 promoted mitotic degradation of Cep68. 0.252 SIGNOR-279471 PPARG protein P37231 UNIPROT GLS protein O94925 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005871 33754076 NO Luana Furthermore, the protein level of the rate-limiting enzyme GLS1 but not GLUD1, GOT1, or GPT2 was consistently reduced by PPARγ agonists 0.247 SIGNOR-268043 IL11 protein P20809 UNIPROT IL11RA protein Q14626 UNIPROT up-regulates binding 9606 10948192 YES gcesareni Il-11 has been shown to induce gp130-dependent signaling through the formation of a high affinity complex with the il-11 receptor (il-11r) and gp130 0.736 SIGNOR-81102 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM4 protein Q14833 UNIPROT up-regulates activity chemical activation 9606 25042998 YES miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate 0.8 SIGNOR-264074 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23431053 YES lperfetto This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap. 0.375 SIGNOR-217187 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT unknown phosphorylation Ser70 EAMNYEGsPIKVTLA 9606 19933706 YES gcesareni Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c. 0.519 SIGNOR-161801 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT up-regulates quantity phosphorylation Ser187 LRELLSIsSESLQAR 9606 BTO:0000007 23649622 YES done miannu TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.Serines are listed from left to right: 133, 185, 187, 188, 190, and 198. 0.717 SIGNOR-273814 RBX1 protein P62877 UNIPROT CUL3-RBX1-KEAP1 complex SIGNOR-C562 SIGNOR form complex binding 9606 24138990 YES miannu KEAP1/CUL3/RBX1 E3-ligase protein complex exert different functions under physiological and oxidative conditions. 0.819 SIGNOR-279843 PAX5 protein Q02548 UNIPROT TLE4 protein Q04727 UNIPROT down-regulates activity binding 9606 BTO:0002291 10811620 YES Gianni Grg4 efficiently represses the transcriptional activity of Pax5 in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were also observed between distantly related members of both the Pax2/5/8 and Groucho protein families 0.564 SIGNOR-269083 RNF19B protein Q6ZMZ0 UNIPROT UCKL1 protein Q9NWZ5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000914 16709802 YES miannu We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and has as one of its substrates, URKL-1, thus defining this cytolytic protein as an E3 ubiquitin ligase. 0.584 SIGNOR-271590 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr119 AGTAGALtPQHVRAH 9606 24101154 YES miannu Specifically, we found that YAP is phosphorylated in vitro and in vivo by the cell cycle kinase CDK1 at T119, S289, and S367 during G2/M phase of the cell cycle. 0.425 SIGNOR-279361 CSNK2A1 protein P68400 UNIPROT CEBPD protein P49716 UNIPROT up-regulates activity phosphorylation Ser57 PAMYDDEsAIDFSAY -1 25680545 YES miannu Here, we have identified the CCAAT/enhancer binding protein δ (C/EBPδ) as a new substrate for CK2. Using point mutants of C/EBPδ the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPδ. For proper functioning as a transcription factor C/EBPδ has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPδ nor its interaction with C/EBPβ, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPδ.  0.2 SIGNOR-276886 CSNK2A2 protein P19784 UNIPROT IL16 protein Q14005 UNIPROT up-regulates activity phosphorylation Ser743 MPLQPNAsLNEEEGT -1 12450396 YES llicata We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation. 0.326 SIGNOR-251009 NRF1 protein Q16656 UNIPROT RETREG3 protein Q86VR2 UNIPROT up-regulates 9606 BTO:0000934 23939472 NO lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  0.2 SIGNOR-261489 SMO protein Q99835 UNIPROT ARRB1 protein P49407 UNIPROT up-regulates binding 9606 23074268 YES The binding occours if Smo is phosphorylated gcesareni Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2 0.634 SIGNOR-199150 adenosine 5'-monophosphate smallmolecule CHEBI:16027 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 BTO:0001103 1631143 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. 0.8 SIGNOR-269774 ELP5 protein Q8TE02 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 YES miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. 0.707 SIGNOR-269712 CSNK2A1 protein P68400 UNIPROT HMOX2 protein P30519 UNIPROT up-regulates activity phosphorylation Ser79 TALYFTYsALEEEME 10116 BTO:0003036 14527438 YES llicata Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. | CK2 activation is abolished by the S79A mutation but preserved in S179A and T248A mutations, indicating that S79 is the target of CK2-dependent activation of HO2 0.336 SIGNOR-250895 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation -1 8929531 YES lperfetto The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL. 0.2 SIGNOR-244497 IL10 protein P22301 UNIPROT IL1RN protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20032313 NO miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. 0.614 SIGNOR-254793 CTNND2 protein Q9UQB3 UNIPROT CDH3 protein P22223 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.294 SIGNOR-252130 PPP1CA protein P62136 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members fstefani P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases 0.447 SIGNOR-269927 ETFBKMT protein Q8IXQ9 UNIPROT ETFB protein P38117 UNIPROT down-regulates activity methylation Lys203 PNIMKAKkKKIEVIK -1 25416781 YES miannu Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases. 0.2 SIGNOR-269451 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 15489227 YES gcesareni Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. 0.439 SIGNOR-129939 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258461 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT down-regulates activity binding 9606 BTO:0001271 11283671 YES apalma Here we show that AML1–ETO blocks C/EBPα –dependent activation of its own promoter and thereby inhibits autoregulation. 0.2 SIGNOR-255672 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MAGEA3 protein P43357 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002806 31267705 YES miannu  The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6 0.2 SIGNOR-272265 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270432 CARS1 protein P49589 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 11347887 YES miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. 0.8 SIGNOR-270473 LMO2 protein P25791 UNIPROT TAL1 protein P17542 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 9020185 YES miannu Transcriptional activity of tal1 in t cell acute lymphoblastic leukemia (t-all) requires rbtn1 or -2 0.926 SIGNOR-46161 SRC protein P12931 UNIPROT DNM2 protein P50570 UNIPROT up-regulates activity phosphorylation Tyr231 LLPLRRGyIGVVNRS 9606 32457704 YES miannu Here, Dyn2 is activated by Src and promotes the induction of endocytosis of the integrins, thus, easing the invasion of the cells.|Src tyrosine kinases are themselves activated by phosphorylation at Y424 residue and phosphorylates its substrate Dyn2 at the residues Y231 and Y597. 0.558 SIGNOR-279485 CSK protein P41240 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9534 BTO:0001538 9624175 YES miannu We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances. 0.549 SIGNOR-262741 NOXA1 protein Q86UR1 UNIPROT NOX3 protein Q9HBY0 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 YES lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation 0.631 SIGNOR-264711 TBXA2R protein P21731 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256744 SPI1 protein P17947 UNIPROT TAL2 protein Q16559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24086757 NO irozzo We show that Tal2 is a direct target gene of the myeloid transcription factor PU.1, which is a key transcription factor for osteoclast gene expression 0.2 SIGNOR-259086 AKT proteinfamily SIGNOR-PF24 SIGNOR PHF20 protein Q9BVI0 UNIPROT down-regulates phosphorylation Ser291 ELRRRKIsKGCEVPL 9606 22334668 YES llicata Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function. 0.2 SIGNOR-196112 CAPN2 protein P17655 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 YES lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain 0.563 SIGNOR-251610 FOXD2 protein O60548 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 12621056 YES Luana Elevating the amounts of FOXD2 expression vector up to 12-fold relative to the RIα1b reporter construct demonstrated that maximal induction of the RIα1b promoter by FOXD2 was at least 5.8-fold 0.2 SIGNOR-261605 LPCAT1 protein Q8NF37 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI down-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272763 Caspase 3 complex complex SIGNOR-C221 SIGNOR NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization cleavage -1 9367996 YES lperfetto The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues. 0.422 SIGNOR-256456 ZNF804A protein Q7Z570 UNIPROT CLIC2 protein O15247 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23434502 YES miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 0.2 SIGNOR-269465 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser15 NVIKMKSsDFLESAE -1 18408713 YES miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) 0.2 SIGNOR-276162 CFHR1 protein Q03591 UNIPROT CFH protein P08603 UNIPROT down-regulates activity binding -1 27814381 YES lperfetto Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b 0.505 SIGNOR-263476 PSMB2 protein P49721 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.892 SIGNOR-263358 AURKB protein Q96GD4 UNIPROT CASP2 protein P42575 UNIPROT up-regulates activity phosphorylation Ser384 MRNTKRGsWYIEALA 9606 32811973 YES miannu Furthermore, in vitro phosphorylation using GST-Casp2 363-423 WT or S384A confirmed that S384 of caspase-2 is phosphorylated by AURKB. 0.244 SIGNOR-279496 BMX protein P51813 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 22348200 YES miannu BMX activates STAT3 in glioblastoma stem cells.|BMX has previously been identified as an activator of STAT3, and BMX can phosphorylate STAT3 in vitro. 0.601 SIGNOR-279497 CDK5 protein Q00535 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates activity phosphorylation Ser444 SIKSEPVsPSRERSP 9606 19812325 YES miannu In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity. 0.415 SIGNOR-279509 TRIM25 protein Q14258 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity ubiquitination Lys172 ENWPKTLkLALEKER 9606 24493797 YES miannu Lys63 linked polyubiquitination of RIG-I at Lys 172 catalyzed by TRIM25 is an important step for RIG-I activation. 0.802 SIGNOR-278730 GLI1/GLI2 complex SIGNOR-C450 SIGNOR MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 32766732 YES GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells 0.399 SIGNOR-269212 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser365 IVDQRPSsRASSRAS 9606 16474210 YES lperfetto We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity. 0.44 SIGNOR-144461 Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI down-regulates quantity chemical modification 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. 0.8 SIGNOR-266276 CSNK2A1 protein P68400 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 YES llicata A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity. 0.53 SIGNOR-250889 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000599 10915800 YES inferred from 70% family members lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. 0.2 SIGNOR-270081 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 YES milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) 0.42 SIGNOR-230728 cabazitaxel chemical CHEBI:63584 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 21770474 YES miannu Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization 0.8 SIGNOR-259341 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.27 SIGNOR-248496 CDK1 protein P06493 UNIPROT SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser48 KLDPVFDsPRMSRRS 9606 BTO:0000567 25482198 YES miannu Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. 0.358 SIGNOR-263099 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates activity acetylation Lys19 VKRLLGWkKSAGGSG 9606 BTO:0000567;BTO:0002181;BTO:0000552 17074756 YES lperfetto We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. To identify the specific lysine residue acetylated by p300, lys19, and lys20 in smad2(fl) were mutated individually and subjected to p300-mediated acetylation following expression in 293t cells. Mutation of lys19 blocked the p300-mediated acetylation of smad2(fl), whereas mutation of lys20 had no effect (fig. 2b), suggesting that lys19 is the preferred site for p300-mediated acetylation of smad2(fl). 0.66 SIGNOR-235899 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.488 SIGNOR-251208 CDK5RAP2 protein Q96SN8 UNIPROT APP protein P05067 UNIPROT up-regulates quantity by stabilization phosphorylation Thr743 VEVDAAVtPEERHLS 9606 15178331 YES Manara The APPcyt is phosphorylated at Thr668 in vivo specifically in the brain. Cyclin‐dependent kinase 5 (Cdk5), a unique member of the Cdk family that is implicated in central nervous system development, participates in this phosphorylation. | In the present study, we demonstrate that APP phosphorylated at Thr668 is less vulnerable to cytoplasmic cleavage by caspase-3 and caspase-8. 0.2 SIGNOR-260818 RACK1 protein P63244 UNIPROT PKC proteinfamily SIGNOR-PF53 SIGNOR up-regulates activity binding 6239 BTO:0005677 25280016 YES Marta Tosoni The scaffolding protein RACK1 recruits and activates PKC in the cytoplasm 0.2 SIGNOR-278067 ZRANB1 protein Q9UGI0 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates activity deubiquitination 9606 BTO:0000007 30686098 YES miannu Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux.  0.2 SIGNOR-273651 MAPK1 protein P28482 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 YES gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.733 SIGNOR-163242 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr1008 LNANDEAtVSVLGEL 9606 17376779 YES gcesareni Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1 0.84 SIGNOR-153863 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 BTO:0000567 10411906 YES Ser-967 is a critical component of the 14-3-3 interaction site of ASK1 and suggest that phosphorylation of this residue may be the major mode of regulation of 14-3-3 binding to ASK1 gcesareni 14-3-3 may suppress ask1-induced cell death by directly inhibiting the catalytic activity of ask1. 0.2 SIGNOR-69408 LIF protein P15018 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 10212267 NO Regulation of expression miannu Increase of protein synthesis rate and β-MHC gene expression in cardiac myocytes by ET-1 and LIF. 0.2 SIGNOR-251959 INPP5D protein Q92835 UNIPROT SYK protein P43405 UNIPROT down-regulates activity dephosphorylation 9606 32323266 YES scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. 0.419 SIGNOR-268456 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120164 NEDD4 protein P46934 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates activity ubiquitination 9606 25879670 YES miannu Nedd4 monoubiquitinates IRS-2, which promotes its association with Epsin1, a ubiquitin binding protein. 0.374 SIGNOR-278659 CCKAR protein P32238 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.458 SIGNOR-257361 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr955 ADAEEAMyQNVDGRV 10090 BTO:0001516 16627759 YES lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. 0.2 SIGNOR-271923 EGF protein P01133 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9168989 NO Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. 0.2 SIGNOR-251785 XIAP protein P98170 UNIPROT AIFM1 protein O95831 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22103349 YES miannu Notably, cotransfection of XIAP along with AIF resulted in the complete inhibition of DNA degradation (21.2% degraded nuclei), suggesting that XIAP directly abrogates the ability of AIF to induce chromatin degradation.|XIAP binds and ubiquitinates AIF, and in this study, we determined the functional consequences of XIAP-mediated AIF ubiquitination. 0.435 SIGNOR-278537 MGRN1 protein O60291 UNIPROT TSG101 protein Q99816 UNIPROT up-regulates activity monoubiquitination 9606 BTO:0000567 17229889 YES miannu In the present study, we identified the first substrate of the Mahogunin E3 ubiquitin–protein ligase: TSG101, a key component of the endosomal sorting ESCRT machinery.We find that Mahogunin interacts with the ubiquitin E2 variant (UEV) domain of TSG101 via its PSAP motif and that it catalyzes monoubiquitylation of TSG101 both in vivo and in vitro.  Consistent with the results of the biochemical characterization and subcellular localization studies of Mahogunin, our functional studies provide direct evidence that Mahogunin plays an essential role in regulation of endosome-to-lysosome trafficking. We found that siRNA-mediated depletion of Mahogunin in HeLa cells causes enlargement and clustering of EEA1-positive endosomes and LAMP2-positive late endosomes/lysosomes (Figure 8B) and inhibits the endosomal trafficking of internalized EGF–EGFR complexes to lysosomes for degradation (Figures 9 and ​and10,10, A and B). These results are strikingly similar to the phenotypes that resulted from depletion of TSG101 0.493 SIGNOR-271635 TBXA2R protein P21731 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.573 SIGNOR-257139 GSK3B protein P49841 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser303 RVKEEPPsPPQSPRV 9606 8940068 YES gcesareni Sequential phosphorylation by mitogen-activated protein kinase and glycogen synthase kinase 3 represses transcriptional activation by heat shock factor-1. 0.556 SIGNOR-44995 clonidine chemical CHEBI:46631 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258904 CSNK2A1 protein P68400 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser249 LSPIDMEsQERIKAE 9606 1516134 YES lperfetto Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii). 0.591 SIGNOR-19603 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248369 ACSS2 protein Q9NR19 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271828 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR GDF3 protein Q9NR23 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.442 SIGNOR-269250 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser824 LVDKEHDsAEGSHTS 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.369 SIGNOR-276511 MAP2K3 protein P46734 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Tyr182 ADAEMTGyVVTRWYR 9606 BTO:0000007 10066767 YES done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. 0.606 SIGNOR-273949 mRNA_capping phenotype SIGNOR-PH178 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 NO lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. 0.7 SIGNOR-268317 NPTX1 protein Q15818 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity binding 10090 BTO:0000938 15115814 YES lperfetto We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. 0.296 SIGNOR-261430 SNAI2 protein O43623 UNIPROT UBE2D3 protein P61077 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 21044962 NO miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. 0.2 SIGNOR-255173 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 9372954 YES llicata We have mapped a major site of phosphorylation by cak to ser-33 of p53 and have demonstrated as well that p53 is phosphorylated at this site in vivo. 0.436 SIGNOR-269326 Non-structural protein 10 protein P0C6X7-PRO_0000037317 UNIPROT IFTAP protein Q86VG3 UNIPROT unknown binding 4932 18433331 YES lperfetto In our previous work, we isolated a gene from a cDNA library of human embryo lung tissue, which en- coded a novel protein that specifically interacted with nsp-10 of SARS-CoV in a yeast trap experiment.|Since nsp- 10 of SARS-CoV is involved in viral genomic replica- tion and was observed to interact with ATF5, the cellular initiation factor of the RNA pol II complex (13), we in- ferred that HEPIS may also be involved in cellular gene transcription. Therefore, the significance of HEPIS ex- pression in cells needed to be further investigated. The work we describe here suggests that HEPIS represses cel- lular transcription initiation through interaction with a component of the RNA pol II complex 0.2 SIGNOR-260251 MMP9 protein P14780 UNIPROT Cellular_extravasation phenotype SIGNOR-PH225 SIGNOR up-regulates 9606 BTO:0000584 38339310 NO miannu Given that MMP-9 is able to degrade the ECM, which is an essential step in tumor cell extravasation and metastasis, and it is highly expressed in PDAC, CXCL12 may be playing a similar role in upregulating MMPs in PDAC 0.7 SIGNOR-277734 TAF1 protein P21675 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 15053879 YES llicata Phosphorylation on thr-55 by taf1 mediates degradation of p53 0.68 SIGNOR-123651 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1023 DLVDAEEyLVPQQGF 9606 1706616 YES Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. 0.2 SIGNOR-251129 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RGCC protein Q9H4X1 UNIPROT up-regulates activity phosphorylation Thr111 ALLSATVtPQKAKLG 9606 BTO:0001685 11687586 YES miannu RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity. 0.445 SIGNOR-262725 CDK2 protein P24941 UNIPROT ING5 protein Q8WYH8 UNIPROT up-regulates quantity phosphorylation Thr152 RRTSEEDtPKKKKHK 9606 25860957 YES miannu We report that ING5 is phosphorylated in a cell cycle dependent manner by CDK2 at T152 (Figs 1 and 3). 0.401 SIGNOR-279447 ZEB1 protein P37275 UNIPROT EPCAM protein P16422 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150;BTO:0000584 23667256 NO miannu We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter. 0.43 SIGNOR-255622 EDNRA protein P25101 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.475 SIGNOR-256780 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0000007 8955135 YES lperfetto In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1. 0.368 SIGNOR-45343 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr88 AVSPLLLtTTNSSEG 9606 11152499 YES tpavlidou Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites. 0.2 SIGNOR-85781 MAPK8 protein P45983 UNIPROT YWHAB protein P31946 UNIPROT down-regulates phosphorylation Ser186 FYYEILNsPEKACSL 9606 15696159 YES llicata The c-jun n-terminal kinase (jnk) protein is activated in the cellular response to dna damage and phosphorylates 14-3-3 on ser 184 these results support a role for 14-3-3 proteins in inhibiting c-abl-mediated apoptosis by sequestering c-abl into the cytoplasm. these findings support a model in which jnk phosphorylation of 14-3-3 proteins induces dissociation of the c-abl_14-3-3 complex and thereby targeting of c-abl to the nucleus. 0.2 SIGNOR-133875 PPM1G protein O15355 UNIPROT USP7 protein Q93009 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser18 KAGEQQLsEPEDMEM 22361354 YES lperfetto We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. |After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. 0.511 SIGNOR-276531 CRYBB2 protein P43320 UNIPROT CRYBB1 protein P53674 UNIPROT up-regulates activity binding 9606 16319073 YES miannu At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency. 0.2 SIGNOR-252153 2-[[(1R)-1-[7-methyl-2-(4-morpholinyl)-4-oxo-9-pyrido[1,2-a]pyrimidinyl]ethyl]amino]benzoic acid chemical CHEBI:91359 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190200 PRKCA protein P17252 UNIPROT ARHGDIB protein P52566 UNIPROT down-regulates phosphorylation Ser31 YKPPPQKsLKELQEM 9606 22469974 YES llicata These results reveal a mechanism of downregulation of rhogdi2 activity through pkc-mediated phosphorylation of ser31. 0.2 SIGNOR-196765 PRKACA protein P17612 UNIPROT ARHGEF6 protein Q15052 UNIPROT down-regulates activity phosphorylation Ser684 GSSTRKDsIPQVLLP 9606 BTO:0000132 26507661 YES lperfetto Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex. 0.2 SIGNOR-272159 RUNX1 protein Q01196 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23817177 NO irozzo RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity. 0.686 SIGNOR-255709 PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24367090 YES AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Insulin activation of phosphoinositide 3-kinase (pi3k) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (pip3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (pten) blocks pi3k signaling by dephosphorylating pip3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent rac exchanger 2 0.8 SIGNOR-147948 PRKCQ protein Q04759 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 YES inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.291 SIGNOR-270273 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 10116 BTO:0001556 14636580 YES miannu In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function. 0.296 SIGNOR-249990 AKT1 protein P31749 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC -1 27784766 YES miannu Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. 0.293 SIGNOR-276461 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr227 KVDATADyICKVKWG 9606 BTO:0000007 32420483 YES done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. 0.265 SIGNOR-274108 SMAD1 protein Q15797 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR form complex binding 9606 9436979 YES lperfetto Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription. 0.67 SIGNOR-103615 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR ACTL6B protein O94805 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.269 SIGNOR-136212 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPSTGGV 9606 11278789 YES Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription. miannu In the present study, ERK1, ERK2, or p38 kinase strongly phosphorylated H3 at serine 28 in vitro. JNK1 or JNK2 was able also to phosphorylate H3 at serine 28 in vitro but to a lesser degree. Histone H3 phosphorylation is related closely to chromatin remodeling and chromosome condensation. H3 phosphorylation at serine 28 is coupled with mitotic chromosome condensation in diverse mammalian cell lines. 0.2 SIGNOR-263068 CD79B protein P40259 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323266 YES scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. 0.656 SIGNOR-268193 SDC4 protein P31431 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 9606 BTO:0002314 BTO:0001103 23290138 YES apalma Rac1 is associated with Sdc4 and is activated by FN binding […] We observed that over-expression of Fzd7, or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts 0.501 SIGNOR-255849 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.794 SIGNOR-249133 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 16495336 YES lperfetto Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit. 0.2 SIGNOR-144779 gamma-secretase complex SIGNOR-C98 SIGNOR APP protein P05067 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 19958215 YES lperfetto The production and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer's disease (AD). A multi-subunit enzyme complex, referred to as gamma (gamma) secretase, plays a pivotal role in the generation of Abeta from its parent molecule, the amyloid precursor protein (APP). 0.587 SIGNOR-251576 nicotine smallmolecule CHEBI:18723 ChEBI CHRNB3 protein Q05901 UNIPROT up-regulates activity chemical activation 9606 BTO:0000227 28901280 YES miannu Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. 0.8 SIGNOR-264259 RPS6KA1 protein Q15418 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 YES llicata Rsk phosphorylates serine 58 of ranbp3 in vitro and in vivo 0.319 SIGNOR-160904 SRC protein P12931 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.575 SIGNOR-273920 FBXO8 protein Q9NRD0 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000675 31024008 YES miannu Here, we show that loss of FBX8 accelerates chemical-induced colon tumorigenesis. FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC. 0.379 SIGNOR-272307 COQ10B protein Q9H8M1 UNIPROT coenzyme Q10 smallmolecule CHEBI:46245 ChEBI up-regulates activity binding 9606 19120452 YES miannu It has been widely accepted that most coenzyme Q (CoQ) exists freely in the mitochondrial membrane as a CoQ pool. However, the recent identification of a mitochondrial CoQ-binding protein, termed Coq10, in budding yeast has the potential to change our current view of CoQ status in membranes. A human Coq10 ortholog was able to functionally compensate for the absence of coq10 in fission yeast, suggesting that Coq10 is important for proper respiration in a variety of organisms. 0.8 SIGNOR-280282 COQ10A protein Q96MF6 UNIPROT coenzyme Q10 smallmolecule CHEBI:46245 ChEBI up-regulates activity binding 9606 19120452 YES miannu It has been widely accepted that most coenzyme Q (CoQ) exists freely in the mitochondrial membrane as a CoQ pool. However, the recent identification of a mitochondrial CoQ-binding protein, termed Coq10, in budding yeast has the potential to change our current view of CoQ status in membranes. A human Coq10 ortholog was able to functionally compensate for the absence of coq10 in fission yeast, suggesting that Coq10 is important for proper respiration in a variety of organisms. 0.8 SIGNOR-280283 FPR1 protein P21462 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.453 SIGNOR-256825 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCD protein Q05655 UNIPROT up-regulates activity binding 9606 14967450 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. 0.8 SIGNOR-242587 NFE2L2 protein Q16236 UNIPROT Purine biosynthesis phenotype SIGNOR-PH186 SIGNOR up-regulates 9606 BTO:0000018 22789539 NO miannu Nrf2 promotes purine nucleotide synthesis and glutamine use in proliferating cells 0.7 SIGNOR-267352 CDK4 protein P11802 UNIPROT WDR77 protein Q9BQA1 UNIPROT up-regulates activity phosphorylation Thr5 tPPPLVPP 9606 20951943 YES miannu Phosphorylation of MEP50 on Thr 5 by D1T286A and CDK4 is necessary and sufficient to increase the intrinsic methyltransferase activity of PRMT5, resulting in increased H4R3 and H3R8 methylation and repression of the CUL4A/B expression. 0.699 SIGNOR-279019 CIITA protein P33076 UNIPROT HLA-G protein P17693 UNIPROT unknown transcriptional regulation 9606 BTO:0000776 11137218 NO The X1 box is the binding site for the ubiquitous RFX complex consisting of three subunits; the X2 box is bound by the X2BP/ATF/CREB family factors. The basic S-X-Y regulatory module interacts with CIITA, which is expressed constitutively in APCs, but may be inducible in others cell types by IFN-gamma|We propose that the X region in the HLA-G gene promoter might participate to the combination of factors which play a role in HLA-G gene activation 0.479 SIGNOR-254021 CHEK2 protein O96017 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates activity phosphorylation Ser331 HPWVRANsRRVLPPS 9606 24798733 YES miannu Because Chk1 and Chk2 can share substrates ( ), we investigated whether Chk2 phosphorylates Aurora B-B-serine 331 in nocodazole.|In addition, Chk2 promotes proper chromosome alignment through Aurora B-B-serine 331 phosphorylation. 0.325 SIGNOR-278906 BDKRB2 protein P30411 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.385 SIGNOR-257199 CCKAR protein P32238 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.265 SIGNOR-256763 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr249 APGPQDIyDVPPVRG 9606 12601080 YES lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. 0.256 SIGNOR-98492 MED14 protein O60244 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.838 SIGNOR-266676 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-252977 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Thr509 PVCEVSVtPKTVTPA 9606 phosphorylation:Ser522 PASSAKTsPAKQQAP 25040932 YES lperfetto Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition 0.723 SIGNOR-264839 BTG1 protein P62324 UNIPROT HOXB9 protein P17482 UNIPROT up-regulates activity binding 9606 BTO:0000567 10617598 YES miannu The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. 0.443 SIGNOR-221019 MAPK1 protein P28482 UNIPROT ETV3 protein P41162 UNIPROT down-regulates activity phosphorylation Ser139 SSGVVPQsAPPVPTA 10090 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. Among the ERK2 substrates, we identified the E-twenty six (ETS) domain-containing protein ETV3. We determined that phosphorylation of this protein by ERK2 was functionally relevant, abrogating the DNA-binding activity of ETV3 at thousands of targets across the genome, thereby providing an additional mechanism for transcriptional regulation downstream of ERK2 activation. 0.404 SIGNOR-262758 KDM2B protein Q8NHM5 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 25533466 NO miannu Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage. 0.7 SIGNOR-252243 CBL protein P22681 UNIPROT SORBS2 protein O94875 UNIPROT down-regulates ubiquitination 9606 12475393 YES gcesareni Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl 0.513 SIGNOR-96325 FLT3 protein P36888 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by repression transcriptional regulation 16146838 NO lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. 0.296 SIGNOR-250563 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck lperfetto 0.8 SIGNOR-244871 CDK4 protein P11802 UNIPROT CELF1 protein Q92879 UNIPROT up-regulates activity phosphorylation Ser302 TSSGSSPsSSSSNSV 10090 16931514 YES miannu These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein. 0.398 SIGNOR-262735 DTNB protein O60941 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.433 SIGNOR-255990 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 YES lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87. 0.2 SIGNOR-244610 RET protein P07949 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 11360177 YES gcesareni Tyrosine 1062 in ret provides a site for the interaction of multiple signaling molecules and that the balance of shc and snt/frs2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated ret 0.677 SIGNOR-108244 Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR hydron chemical CHEBI:15378 ChEBI up-regulates quantity relocalization 9606 10563795 YES miannu Cytochrome c oxidase catalyzes the reduction of molecular oxygen to water, a process in which four electrons, four protons, and one molecule of oxygen are consumed. The reaction is coupled to the pumping of four additional protons across the membrane. According to the currently accepted concept, the pumping of all four protons occurs after the binding of oxygen to the reduced enzyme and is exclusively coupled to the last two electron transfer steps.  0.8 SIGNOR-280293 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.257 SIGNOR-159470 PTAFR protein P25105 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257262 MAPK1 protein P28482 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 23024368 YES miannu We demonstrate that oct4a interacts with erk1/2 by using both in vitro gst pulldown and in vivo co-immunoprecipitation assays. Ms analysis identified phosphorylation of oct4a at ser-111. / serine 111 phosphorylation regulates oct4a protein subcellular distribution and degradation. 0.38 SIGNOR-192097 imatinib chemical CHEBI:45783 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193375 EDNRA protein P25101 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.406 SIGNOR-257052 COX5B protein P10606 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.793 SIGNOR-267749 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity 16037825 NO miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-263127 SART1 protein O43290 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.756 SIGNOR-270623 ABL1 protein P00519 UNIPROT SRCIN1 protein Q9C0H9 UNIPROT unknown phosphorylation Tyr264 IYRKEPLyAAFPGSH 9606 BTO:0000142 23383002 YES llicata Furthermore, we identify abl as the major tyrosine kinase that can trigger p140cap phosphorylation on these sequences. 0.2 SIGNOR-200854 WWTR1 protein Q9GZV5 UNIPROT YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR up-regulates 30224758 YES lperfetto The transcription coactivators YAP/TAZ are ideal candidates to mediate cancer-specific transcriptional addictions. In fact, YAP/TAZ are genetically dispensable for homeostasis in many adult tissues9–17 while YAP/TAZ activation is a hallmark of many human malignancies13,17–19. Here we show that tumor transcriptional dependencies in fact overlap with tumor reliance on YAP/TAZ. 0.55 SIGNOR-276573 STC2/HMOX1 complex SIGNOR-C244 SIGNOR heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity by destabilization 22503972 YES lperfetto Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme. 0.8 SIGNOR-260405 PLRG1 protein O43660 UNIPROT HNRNPM protein P52272 UNIPROT up-regulates activity binding 9606 BTO:0000567 20467437 YES 1 miannu hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay. 0.747 SIGNOR-239444 NCAPG protein Q9BPX3 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.963 SIGNOR-263902 KIF7 protein Q2M1P5 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity by stabilization binding 9606 19549984 YES lperfetto Kif7 physically interacted with Gli transcription factors and controlled their proteolysis and stability, and acted both positively and negatively in Hh signaling. 0.585 SIGNOR-209611 ATP6AP1 protein Q15904 UNIPROT RAB7A protein P51149 UNIPROT up-regulates activity binding 22467241 YES lperfetto We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A). In addition, a co-immunoprecipitation assay revealed that Ac45 directly interacted with Rab7| Therefore, Ac45’s role in extracellular acidification, lysosomal trafficking, and cathepsin K exocytosis may be through the Rab7 pathway. 0.29 SIGNOR-261484 PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT down-regulates activity binding 9606 14556242 YES lperfetto In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. 0.785 SIGNOR-118609 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser276 AAQQTKGsYMEVEDN 9615 BTO:0000837 11742978 YES llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. 0.338 SIGNOR-250974 Aflibercept chemical SID:134445687 PUBCHEM PGF protein P49763 UNIPROT down-regulates activity chemical inhibition 9606 22813448 YES miannu Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor. 0.8 SIGNOR-259385 HUWE1 protein Q7Z6Z7 UNIPROT NEIL1 protein Q96FI4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27924031 YES miannu Mule and TRIM26 ubiquitylate NEIL1 in vitro within C-terminal lysine residues. 0.2 SIGNOR-278695 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PGR protein P06401 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 10655479 YES inferred from 70% family members gcesareni Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation. 0.2 SIGNOR-270157 heme smallmolecule CHEBI:30413 ChEBI HBB protein P68871 UNIPROT up-regulates activity chemical activation 9606 26557657 YES miannu Heme is a prosthetic group comprising ferrous iron (Fe2+) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins. 0.8 SIGNOR-251908 quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258270 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT up-regulates activity phosphorylation Thr211 TVGGKLDtFCGSPPY 9606 BTO:0000568 12879020 YES lperfetto Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211. 0.315 SIGNOR-104063 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Ile) smallmolecule CHEBI:29174 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269501 TRAPPC9 protein Q96Q05 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity binding 9606 BTO:0000007 15951441 YES miannu We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates. 0.478 SIGNOR-269672 baicalein chemical CHEBI:2979 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258158 TWIST1 protein Q15672 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.25 SIGNOR-255531 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11163210 YES miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  0.709 SIGNOR-272938 (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide chemical CHEBI:92629 ChEBI HTR2B protein P41595 UNIPROT up-regulates activity chemical activation 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258688 DLG3 protein Q92796 UNIPROT NMDA receptor_2A complex SIGNOR-C347 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 YES lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. 0.719 SIGNOR-266006 SLC2A1 protein P11166 UNIPROT Ankyrin complex complex SIGNOR-C383 SIGNOR form complex binding 9606 BTO:0000424 22465511 YES lperfetto The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB))  0.301 SIGNOR-266017 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr8 MSSILPFtPPVVKRL 9606 BTO:0000763 12193595 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-91746 CSNK2A2 protein P19784 UNIPROT ACACA protein Q13085 UNIPROT unknown phosphorylation Ser29 GSVSEDNsEDEISNL -1 2900140 YES llicata Phosphorylation at site 6 by casein kinase-2 is in good agreement with previous studies on the specificity of this kinase, which is known to phosphorylate serine residues followed by an acidic cluster 0.307 SIGNOR-250973 SSH1 protein Q8WYL5 UNIPROT LIMK1 protein P53667 UNIPROT down-regulates activity dephosphorylation 9606 23153585 YES miannu In addition to its cofilin\u2013phosphatase activity, SSH1 can also dephosphorylate LIMK1 and LIMK2, although LIMK1 is a better substrate than LIMK2  [63] .|SSH1 suppresses the kinase activity of LIMK1 toward cofilin by dephosphorylation at Thr 508 in the kinase catalytic domain and other autophosphorylated residues [63]. 0.598 SIGNOR-277096 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR TP73 protein O15350 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277668 SMURF1 protein Q9HCE7 UNIPROT MINDY3 protein Q9H8M7 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272675 carbachol chemical CHEBI:3385 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258619 MAPK1 protein P28482 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser43 RNPEAALsPTFRSDS 9606 BTO:0000007 33217317 YES miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.274 SIGNOR-265950 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 YES inferred from 70% family members gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.2 SIGNOR-270065 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18378770 YES gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). 0.787 SIGNOR-178150 MAPK1 protein P28482 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Ser18 ANRTPPKsPGDPSKD -1 17693641 YES miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. 0.355 SIGNOR-262929 MAPK3 protein P27361 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000567 18211802 YES gcesareni Activates rhoa and as a result regulates actin assembly. 0.29 SIGNOR-160420 HES1 protein Q14469 UNIPROT NEUROG2 protein Q9H2A3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 NO lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 0.319 SIGNOR-265142 17beta-estradiol smallmolecule CHEBI:16469 ChEBI GPER1 protein Q99527 UNIPROT up-regulates chemical activation 9534 BTO:0000298 15705806 YES Luana Competition binding assays of E2-Alexa 633 binding with 17β-estradiol demonstrated a Ki for 17β-estradiol of approximately 6.6 nM for GPR30 (Fig. 2F). These results demonstrate that a classic GPCR superfamily member directly binds a sex steroid hormone and that GPR30 is an estrogen-binding receptor. |Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. 0.8 SIGNOR-269752 DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme , indicat-ing that dlx5 can work as an upstream gene of runx2. 0.484 SIGNOR-195576 CDK18 protein Q07002 UNIPROT CyclinA2/CDK18 complex SIGNOR-C547 SIGNOR form complex binding 33781185 YES lperfetto PCTAIRE kinases (PCTKs) are a CDK subfamily, characterized by serine to cysteine mutation in the consensus PSTAIRE motif, involved in binding to the cyclin. One member of this class is PCTK3, which has two isoforms (a and b) and is also known as CDK18. After being activated by cyclin A2 or phosphorylation at Ser12 by PKA, PCTK3 can perform several functions. 0.393 SIGNOR-273436 GRK5 protein P34947 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 20124405 YES llicata Grk5, but not grk2 or grk6, phosphorylates p53 at thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage. 0.37 SIGNOR-163707 ATM protein Q13315 UNIPROT SMC1A protein Q14683 UNIPROT up-regulates phosphorylation Ser966 GEDSVSGsQRISSIY 9606 11877377 YES lperfetto Here we report that smc1 is a component of the dna damage response network that functions as an effector in the atm/nbs1-dependent s-phase checkpoint pathway. Smc1 associates with brca1 and is phosphorylated in response to ir in an atm- and nbs1-dependent manner. Using mass spectrometry, we established that atm phosphorylates s957 and s966 of smc1 in vivo. 0.704 SIGNOR-115496 MRGBP protein Q9NV56 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.781 SIGNOR-269296 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr279 PPLEYQPyQSIYVGG 9606 BTO:0000007 8955135 YES lperfetto In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1. 0.368 SIGNOR-45334 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001023 17072343 NO miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 0.383 SIGNOR-255614 MAPK3 protein P27361 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 28646232 YES Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels 0.349 SIGNOR-262520 FUS protein P35637 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 NO This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease 0.254 SIGNOR-262805 HLTF protein Q14527 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 11756191 NO Regulation of transcription miannu DNA-dependent adenosine triphosphatase (helicaselike transcription factor) activates beta-globin transcription in K562 cells. Overexpression of HLTF in K562 cells does not affect the endogenous levels of gamma- and epsilon-globin message, but it markedly activates beta-globin transcription. 0.2 SIGNOR-251812 PP1 proteinfamily SIGNOR-PF54 SIGNOR SLC4A4 protein Q9Y6R1 UNIPROT up-regulates activity dephosphorylation 10090 BTO:0000988 21317537 YES lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, 0.2 SIGNOR-264647 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 9143707 YES gcesareni Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44). 0.759 SIGNOR-48111 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser119 GAAAAPPsPAWSEPE 10090 37029927 YES miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. 0.2 SIGNOR-277810 CNR1 protein P21554 UNIPROT HCRTR1 protein O43613 UNIPROT up-regulates activity binding 9606 29751001 YES miannu Another example is the heteromer between CB1 and orexin 1 receptor (OX1R). The CB1 activation potentiated the OX1R signaling (218), suggesting the interaction of these two receptors. Interaction of their surface distribution was also reported.  0.389 SIGNOR-264269 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000459 18621737 YES amattioni c-IAPs are ubiquitin ligases capable of promoting polymerization of non-degradative Lys-63-linked polyubiquitin chains on the critical adapter in the canonical NF-_B signaling pathway, RIP1. c-IAPs are E3 ligases and RIP1 ubiquitination is critical for propagation of TNF_-induced NF-_B activation 0.767 SIGNOR-179439 F2RL1 protein P55085 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254839 RNA Polymerase I complex SIGNOR-C390 SIGNOR ribosomal RNA smallmolecule CHEBI:18111 ChEBI up-regulates quantity chemical modification 9606 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).¬† 0.8 SIGNOR-266159 SOSTDC1 protein Q6X4U4 UNIPROT WNT5A protein P41221 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.302 SIGNOR-242736 SRC protein P12931 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 NO gcesareni C-src was suggested to be involved in bmk1 activation from the experiments with herbimycin a and pp2, specific inhibitors of src family kinases. 0.345 SIGNOR-113779 TRiC complex SIGNOR-C539 SIGNOR STAT3 protein P40763 UNIPROT up-regulates quantity by stabilization binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.419 SIGNOR-272870 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 YES lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. 0.877 SIGNOR-147327 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 9858528 YES The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain 0.695 SIGNOR-62788 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1696 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248810 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser422 RFHSLPFsLTKMPNT 9606 BTO:0000938 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.542 SIGNOR-204692 CARD11 protein Q9BXL7 UNIPROT CBM complex SIGNOR-C555 SIGNOR form complex binding 9606 15122200 YES miannu CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways. 0.824 SIGNOR-276296 STUB1 protein Q9UNE7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24578159 YES miannu CHIP promotes TRAF6 ubiquitination and degradation.|These results suggest that CHIP negatively regulates the stability of TRAF6. 0.467 SIGNOR-278670 CYC1 protein P08574 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.93 SIGNOR-262192 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr57 GKGVTVEtVFSVDEF -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.374 SIGNOR-263595 PELI1 protein Q96FA3 UNIPROT MDM4 protein O15151 UNIPROT up-regulates activity ubiquitination 9606 29523541 YES miannu We found that Peli1 induces Mdmx ubiquitination without promoting its degradation, which leads to the cytoplasmic localization of Mdmx and subsequent activation of p53 function. 0.435 SIGNOR-278773 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1763 TPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248825 CREBBP protein Q92793 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 SIGNOR-C6 10944526 YES gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo. 0.615 SIGNOR-81050 AARS1 protein P49588 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI down-regulates quantity chemical modification 9606 32314272 YES miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). 0.8 SIGNOR-270446 PRKD2 protein Q9BZL6 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 34010649 YES lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-275941 NOTCH2 protein Q04721 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity binding 9606 BTO:0003960 31699119 YES miannu  NOTCH2 attenuated the TRAF6-AKT signaling axis via an interaction between the NOTCH2 intracellular domain (N2ICD) and TRAF6, which inhibited epithelial-mesenchymal transition (EMT) and eventually suppressed NPC metastasis. 0.311 SIGNOR-265562 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120036 PFKM protein P08237 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266467 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser352 SSNNFSSsPSTPVGS 9606 19801649 YES llicata Mlk2 inhibits e47 transactivation activity on the trkb promote 0.2 SIGNOR-161527 SIRT1 protein Q96EB6 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 14976264 NO lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress 0.7 SIGNOR-217878 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr192 AGMGHDIyQVPPSMD 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246393 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257987 IPA-3 chemical CHEBI:101355 ChEBI PKN1 protein Q16512 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003897 23894351 YES lperfetto In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. 0.8 SIGNOR-262017 CAPN3 protein P20807 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity cleavage 9606 25969760 YES lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase 0.272 SIGNOR-251607 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr759 LYDVSRMyVDPSEIN 9606 BTO:0000776 11507089 YES lperfetto These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2. 0.777 SIGNOR-109758 MMP2 protein P08253 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Gly702 YEMHGPEgLRVGFYE -1 9344465 YES lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.635 SIGNOR-261780 tamoxifen citrate chemical CHEBI:9397 ChEBI ESR2 protein Q92731 UNIPROT down-regulates activity chemical inhibition 9606 20512796 YES miannu Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. 0.8 SIGNOR-259300 ZFHX3 protein Q15911 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14654895 NO miannu these results corroborated the previous reports that ATBF1 regulated AFP expression and inhibited transcription. 0.416 SIGNOR-255625 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 24352507 YES lperfetto We finally confirmed that in the absence of HIF-1α there was a significant reduction at the protein level in pro-caspase-1, activated caspase-1, pro-IL-1β, and ultimately active IL-1β (Fig. 4g and h). These data show that adenosine induced up-regulation of IL-1β is dependent on a CREB/HIF-1α pathway which is distinct from the NF-kB pathway used for initial production of IL-1β in response to LPS. 0.336 SIGNOR-251718 ARAP3 protein Q8WWN8 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.469 SIGNOR-260456 TOB2 protein Q14106 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR down-regulates activity binding 9606 BTO:0000567 18377426 YES miannu We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob.  0.347 SIGNOR-273615 Ub:E2 complex SIGNOR-C497 SIGNOR ZNF341 protein Q9BYN7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271277 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRB protein P10828 UNIPROT up-regulates activity chemical activation 10116 BTO:0000759 2158622 YES miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 0.8 SIGNOR-258384 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 15367694 YES Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes 0.893 SIGNOR-248627 HOXB7 protein P09629 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity binding 9606 BTO:0002419 SIGNOR-C106 17308091 YES miannu Ku70 and Ku80 associated with HOXB7 in vivo. Ku70/Ku80 heterodimer formation is a prerequisite for HOXB7 binding. interaction between Ku70/80 and HOXB7 may affect the catalytic activity of DNA-PK. HOXB7 stimulates DNA-PK activity 0.333 SIGNOR-226063 PTH2 protein Q96A98 UNIPROT PTH2R protein P49190 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671 11861531 YES gcesareni Subsequent efforts led to the isolation and definition of the primary structure of a novel peptide, referred to as tip39, from bovine hypothalamus and the synthetic peptide was shown to efficiently activate human, rat, and zebrafish pth2 receptors 0.762 SIGNOR-115124 LAG3 protein P18627 UNIPROT Class II MHC:Antigen complex SIGNOR-C429 SIGNOR down-regulates activity binding 9606 BTO:0000782 35413245 YES Barakat Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity 0.2 SIGNOR-275412 CDK2 protein P24941 UNIPROT RNF157 protein Q96PX1 UNIPROT up-regulates activity phosphorylation 9606 28655764 YES miannu CDK2 promotes phosphorylation of RNF157 at the same Ser 660-663 residues that become phosphorylated downstream of combined PI3K and MAPK pathway activity. 0.287 SIGNOR-279016 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates sumoylation Lys65 QQCQAEAkCPKLLPC 9534 9756909 YES lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation. 0.779 SIGNOR-261788 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Thr1394 SQSDILTtQQRDTMQ 9606 BTO:0002181 11114888 YES llicata Although no single mutation eliminated the GST–BRCA1 (1314–1863) electrophoretic mobility shift, a quadruple mutant (GST–BRCA14A) containing Ala substitutions at Ser 1387, Thr 1394, Ser 1423, and Ser 1457 showed no alteration in electrophoretic mobility after phosphorylation by ATR-containing immune complexes (Fig.2D). The total incorporation of 32Pi into the GST–BRCA14Asubstrate was reduced by 70% relative to that obtained with wild-type GST–BRCA1 (1314–1863), suggesting that these four residues account for most, but not all of the phosphorylation sites in this fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. 0.8 SIGNOR-250583 PRKCB protein P05771 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 11325528 YES lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. 0.283 SIGNOR-249093 AURKA protein O14965 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 9606 BTO:0001225 19060929 YES lperfetto The recombinant human aurka protein phosphorylated the gsk-3beta protein at ser 9 in a concentration-dependent manner, in vitro. The phosphorylation of beta-catenin (ser33/37/thr41) by gsk-3beta is known to target beta-catenin towards degradation. In line with our findings, the increase in phospho-gsk-3beta level was accompanied by a significant decrease in beta-catenin phosphorylation (ser33/37/thr41) and accumulation of beta-catenin protein. 0.353 SIGNOR-227923 linifanib chemical CHEBI:91435 ChEBI CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258241 PRKAA1 protein Q13131 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 9606 26816379 YES gcesareni A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. 0.2 SIGNOR-245953 SCN9A protein Q15858 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 NO miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. 0.7 SIGNOR-253449 CREB1 protein P16220 UNIPROT CEBPB protein P17676 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 14593102 NO lperfetto Expression of constitutively active CREB strongly activated C/EBPbeta promoter-reporter genes, induced expression of endogenous C/EBPbeta, and caused adipogenesis in the absence of the hormonal inducers normally required 0.561 SIGNOR-250573 NFATC3 protein Q12968 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 YES miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. 0.2 SIGNOR-264024 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 BTO:0001271 17318191 YES lperfetto Bcr-abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylationthe notion that y86 and y654 are located respectively within the n_ and c_terminal transcriptional domains of __catenin suggests that one or both residues might regulate the transactivating function of __catenin. In this regard, phosphorylation of y654 was reported to strengthen __catenin association with the basal transcription factor tata_binding protein (tbp) 0.2 SIGNOR-153431 OPRD1 protein P41143 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.276 SIGNOR-256962 MTA3 protein Q9BTC8 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.771 SIGNOR-263840 Ub:E2 complex SIGNOR-C497 SIGNOR NEDD4 protein P46934 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271300 PRKCE protein Q02156 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.396 SIGNOR-249288 AMPK complex SIGNOR-C15 SIGNOR TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 16959574 YES lperfetto We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels. Phosphorylation of tsc2 by ampk is required for translation regulation and cell size control in response to energy deprivation. 0.534 SIGNOR-216438 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 BTO:0004245 10217147 YES Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. 0.762 SIGNOR-252569 MEN1 protein O00255 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates activity binding 9606 BTO:0000567 15640349 YES irozzo However, menin dramatically increases the amount of MLL bound at the p27Kip1 and p18Ink4c loci, suggesting that it either directly or indirectly promotes MLL recruitment to these targets. Once recruited, MLL could enhance transcription by a number of mechanisms.Overall, the data suggest that transcriptional regulation by menin involves increasing MLL protein association with target loci. 0.725 SIGNOR-255890 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273067 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr307 MRHVSISyDIPPTPG -1 10734310 YES lperfetto Gab1 is also phosphorylated in response to epidermal growth factor (egf) but is unable to induce tubule formation. nine tyrosines are phosphorylated by both receptors. Three of them (y307, y373, y407) bind phospholipase c-gamma (plc-gamma). 0.76 SIGNOR-233233 GRK2 protein P25098 UNIPROT TBXA2R protein P21731-2 UNIPROT down-regulates activity phosphorylation Ser357 RLPGSSDsRASASRA 9606 16956790 YES done miannu  These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization. 0.2 SIGNOR-274089 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 23431053 YES milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation 0.608 SIGNOR-201278 NOS2 protein P35228 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates 9606 7537672 NO apalma Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline 0.8 SIGNOR-255381 FGFR1 protein P11362 UNIPROT ACAT1 protein P24752 UNIPROT up-regulates activity phosphorylation Tyr407 HALKQGEyGLASICN 9606 BTO:0002552 27867011 YES lperfetto Treatment with the FGFR1 inhibitor TKI258 in FGFR1-expressing H1299 cells led to decreased Y407 phosphorylation of ACAT1 in the mitochondrial fraction, where both ACAT1 and a fraction of FGFR1 were detected|Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, 0.2 SIGNOR-264423 SMURF1 protein Q9HCE7 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates activity monoubiquitination 9615 BTO:0000837 32010791 YES miannu  Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. 0.2 SIGNOR-277507 MED15 protein Q96RN5 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.8 SIGNOR-266660 FYN protein P06241 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates activity phosphorylation Tyr446 DQSRQMKyQSFNEYR -1 24970799 YES miannu We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity. FYN and LYN kinases phosphorylate COX2 on two distinct residues in vitro. 0.389 SIGNOR-276644 CHIR-124 chemical CID:11502647 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190976 PRKCZ protein Q05513 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 BTO:0002181 25660024 YES miannu  Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). 0.597 SIGNOR-276879 PKA proteinfamily SIGNOR-PF17 SIGNOR GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Thr374 PGCTKRYtDPSSLRK 9534 BTO:0000298 16293631 YES miannu Here, we report that activation of PKA retains Gli1 in the cytoplasm.Mutation analysis identifies Thr374 as a major PKA site determining Gli1 protein localization.  0.2 SIGNOR-276044 FOXO3 protein O43524 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14981546 NO Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim 0.77 SIGNOR-261528 STK33 protein Q9BYT3 UNIPROT AKAP4 protein Q5JQC9 UNIPROT up-regulates quantity by stabilization phosphorylation -1 37146716 YES lperfetto Differential phosphoproteomic analysis and in vitro kinase assay identified novel phosphorylation substrates of STK33, fibrous sheath components AKAP3 and AKAP4, whose expression levels decreased in testis after deletion of Stk33. 0.2 SIGNOR-272956 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 YES miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. 0.74 SIGNOR-267996 CSNK2A1 protein P68400 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates phosphorylation Ser253 DNLVVDVsNEDPSSP 9606 22354967 YES lperfetto These results show that tle1 is necessary for the maintenance of neuronal survival. Experiments using pharmacological inhibitors as well as expression of point mutants indicate that phosphorylation of tle1 by casein kinase-2 (ck2) at ser-239 and ser-253 is necessary for its survival-promoting activity. 0.32 SIGNOR-196146 CHKA protein P35790 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 BTO:0000093 21822308 YES miannu We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines 0.402 SIGNOR-266352 CKB protein P12277 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265787 Ub:E2 complex SIGNOR-C497 SIGNOR RNF139 protein Q8WU17 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271026 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21389315 NO irozzo Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. 0.7 SIGNOR-255872 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC4 protein Q9Y5F7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265693 MAPK1 protein P28482 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 16554440 YES lperfetto Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002). 0.382 SIGNOR-249411 EGR1 protein P18146 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22431919 NO miannu Overexpression or short interfering RNA (siRNA)-mediated down-regulation of EGR1 or NAB2, and chromatin immunoprecipitations indicated that EGR1 and NAB2 act in concert to positively regulate p130(Cas)/BCAR1 expression in breast cancer cells. 0.2 SIGNOR-253890 EGR2 protein P11161 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 20506119 NO miannu In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2. 0.577 SIGNOR-253883 F2RL1 protein P55085 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu PAR2 expression is up-regulated following PAR2 activation. This is logical for PAR2, as endogenous activators for the receptor are serine proteases, which irreversibly activate PAR2 through N-terminal cleavage. 0.2 SIGNOR-254840 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr680 RDIYSTDyYRVGGRT 9606 9099755 YES gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 0.2 SIGNOR-47175 SL1 complex complex SIGNOR-C464 SIGNOR UBTF protein P17480 UNIPROT up-regulates activity binding 9606 15970593 YES lperfetto Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. 0.664 SIGNOR-269567 FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.427 SIGNOR-236540 metformin chemical CHEBI:6801 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression 9606 17909097 NO inferred from family member gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. 0.8 SIGNOR-270254 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 YES lperfetto Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites 0.61 SIGNOR-130736 TAL1 protein P17542 UNIPROT FUBP1 protein Q96AE4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30653565 YES irozzo TAL1 directly activates the FUBP1 promoter, leading to increased FUBP1 expression during erythroid differentiation. 0.2 SIGNOR-259131 SUZ12 protein Q15022 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23836662 NO miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. 0.489 SIGNOR-254150 EIF4E2 protein O60573 UNIPROT EIF4E2/GIGYF2 complex complex SIGNOR-C257 SIGNOR form complex binding 9606 BTO:0000568 22751931 YES SARA A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated. 0.693 SIGNOR-261008 NTSR1 protein P30989 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 10030 BTO:0000457 28341345 YES Marta Tosoni Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways 0.268 SIGNOR-278059 Caspase 3 complex complex SIGNOR-C221 SIGNOR DFFA protein O00273 UNIPROT up-regulates activity cleavage 9606 9108473 YES lperfetto DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3. 0.754 SIGNOR-256464 DRD3 protein P35462 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.453 SIGNOR-256845 CSNK2A2 protein P19784 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser11 DFGFFSSsESGAPEA -1 3128543 YES llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. 0.309 SIGNOR-250983 SIRT5 protein Q9NXA8 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31815138 NO Monia Western blot showed that Sirt5 overexpression upregulated Nrf2. Sirt5 attenuates apoptosis through Nrf2/HO-1 and Bcl-2. 0.307 SIGNOR-261208 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser726 IDPASPQsPESVDLV 9606 18701649 YES gcesareni Such results suggest that during apoptosis, oxidative stress could activate p38 mapk, phosphorylating nhe1 at s726 and s729. 0.57 SIGNOR-180044 Pac-1 chemical CID:135421197 PUBCHEM CASP3 protein P42574 UNIPROT up-regulates activity chemical activation -1 16936720 YES lperfetto Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. W 0.8 SIGNOR-262016 FGF13 protein Q92913 UNIPROT SCN1A protein P35498 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.278 SIGNOR-253419 LTB4R2 protein Q9NPC1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256674 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.764 SIGNOR-252864 MC2R protein Q01718 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.515 SIGNOR-268694 MAP3K12 protein Q12852 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 28111074 YES miannu Collectively, these data suggest the hypothesis that ApoE activates DLK by increasing its levels 0.554 SIGNOR-279630 ASIP protein P42127 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.501 SIGNOR-268708 Diprenorphine chemical CHEBI:4650 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258791 CEP290 protein O15078 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 18694559 NO miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110 0.7 SIGNOR-252147 metformin chemical CHEBI:6801 ChEBI CRTC2 protein Q53ET0 UNIPROT down-regulates 9606 16308421 NO gcesareni It has been proposed that metformin stimulates crtc2 phosphorylation in response to metabolic signals such as energy stress through the lkb1-ampk/sik1 pathways, which promotes binding to 14-3-3 proteins, thereby sequestering crtc2 from the nucleus to the cytoplasm 0.8 SIGNOR-142207 PHB protein P35232 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 16964284 NO lperfetto We now present evidence that PHB, which has 54% homology at the protein level to the oestrogen receptor corepressor REA (repressor of oestrogen receptor activity), can repress androgen receptor (AR)-mediated transcription and androgen-dependent cell growth. 0.45 SIGNOR-268977 PRKAA2 protein P54646 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Ser121 LMRRSTVsLLDTYQK 23871434 YES Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro 0.2 SIGNOR-275486 SCF-betaTRCP complex SIGNOR-C5 SIGNOR COMMD1 protein Q8N668 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 20068069 YES miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. 0.466 SIGNOR-271430 MDM4 protein O15151 UNIPROT MDM4 protein O15151 UNIPROT down-regulates quantity by destabilization ubiquitination -1 12393902 YES miannu Here we demonstrate that MdmX acts as a ubiquitin ligase in vitro, being capable of autoubiquitination, as well as mediating the ubiquitination of p53.  0.2 SIGNOR-271390 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.291 SIGNOR-275779 CREBBP protein Q92793 UNIPROT MYB protein P10242 UNIPROT up-regulates activity binding 9534 BTO:0004055 8654374 YES 2 miannu the nuclear co-activator CREB binding protein (CBP). This protein interacts directly with both c-Myb and v-Myb and potentiates Myb-specific transcription 0.806 SIGNOR-240994 MET protein P08581 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation Tyr907 MVSKSANyCHTSQGD 9606 26779812 YES miannu Here we show that the receptor tyrosine kinase c-Met associates with and phosphorylates PARP1 at Tyr907 (PARP1 pTyr907 or pY907).|To address whether c-Met activates PARP1, we exposed MDA-MB-231 cells expressing control shRNA or c-Met shRNA to H 2 O 2 and subjected them to a comet assay to evaluate the extent of DNA damage. 0.388 SIGNOR-279470 MDM2 protein Q00987 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 BTO:0000149 21402876 YES gcesareni We demonstrate that the intracellular domain of notch 4 is targeted for ubiquitylation and hence degradation by the ubiquitin ligase mdm2. 0.371 SIGNOR-172826 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr207 TPPTLSStVLIVRNE 9606 BTO:0001938 12815053 YES lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. 0.54 SIGNOR-249221 PSPN protein O60542 UNIPROT GFRA4 protein Q9GZZ7 UNIPROT up-regulates binding 9606 BTO:0000938 11116144 YES gcesareni Glial cell line-derived neurotrophic factor (gdnf) family ligands signal through receptor complex consisting of a glycosylphosphatidylinositol-linked gdnf family receptor (gfr) alpha subunit and the transmembrane receptor tyrosine kinase ret. 0.746 SIGNOR-85162 bisphenol A chemical CHEBI:33216 ChEBI AHR protein P35869 UNIPROT up-regulates activity chemical activation -1 31995776 YES miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs. 0.8 SIGNOR-268735 Wnt proteinfamily SIGNOR-PF40 SIGNOR LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES inferred from 70% family members gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.2 SIGNOR-269961 HAUS complex complex SIGNOR-C281 SIGNOR NEDD1 protein Q8NHV4 UNIPROT up-regulates activity relocalization 9606 19369198 YES lperfetto We further found coprecipitation of HA-tagged NEDD1 [also called GCP-WD, a component of gamma-TuRC (12, 22)] with endogenous hDgt6|A link between augmin and gamma-TuRC is likely critical for these functions, because a gamma-TuRC mutant that attenuates interaction with augmin does not restore function in vivo 0.544 SIGNOR-262332 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys218 EIFLLCDkVQKEDIE 9606 SIGNOR-C13 20080798 YES miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. 0.463 SIGNOR-163454 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR6 protein P43657 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257533 PHF10 protein Q8WUB8 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.72 SIGNOR-270614 LYN protein P07948 UNIPROT RGS16 protein O15492 UNIPROT up-regulates activity phosphorylation Tyr168 TLMEKDSyPRFLKSP -1 12588871 YES Lyn kinase phosphorylated recombinant RGS16 in vitro. Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes. 0.347 SIGNOR-251410 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 SIGNOR-C17 21059642 YES The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.342 SIGNOR-169322 PRKCA protein P17252 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 YES lperfetto Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. 0.2 SIGNOR-249058 CAMK2G protein Q13555 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity phosphorylation Ser645 LTVERMVsPIESAED BTO:0000007 7877986 YES llicata In this study, CaM-kinase II enhanced kainate currents of expressed glutamate receptor 6 in 293 cells and of wild-type glutamate receptor 1, but not the Ser-627 to Ala mutant, in Xenopus oocytes. | This CaM-kinase II regulatory phosphorylation site is conserved in all AMPA/kainate-type glutamate receptors, and its phosphorylation may be important in enhancing postsynaptic responsiveness as occurs during synaptic plasticity. 0.629 SIGNOR-250697 tRNA(Thr) smallmolecule CHEBI:29180 ChEBI Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates quantity precursor of 9606 25824639 YES miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 0.8 SIGNOR-270507 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR G0/G1_transition phenotype SIGNOR-PH219 SIGNOR up-regulates 37104883 NO lperfetto Among them, CDK3 is critically important because it triggers the transitions of G0 to G1 and G1 to S phase through binding to cyclin C and cyclin E1, respectively. 0.7 SIGNOR-273190 BBC3 protein Q9BXH1 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 YES lperfetto Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis. 0.76 SIGNOR-133811 PRKCE protein Q02156 UNIPROT GLS protein O94925 UNIPROT up-regulates activity phosphorylation Ser314 RYVGKEPsGLRFNKL 9606 BTO:0002552 29515166 YES miannu PKCε is the kinase that phosphorylates GAC at Ser314. 0.2 SIGNOR-277387 IL4 protein P05112 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 12757709 NO miannu These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth 0.7 SIGNOR-255896 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI PTGER2 protein P43116 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257570 RORA protein P35398 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 YES miannu Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. 0.687 SIGNOR-267982 CUL5 protein Q93034 UNIPROT ARIH2 protein O95376 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 YES miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. 0.533 SIGNOR-268843 ZBTB20 protein Q9HC78 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 29748916 NO miannu The transcription factor (TF) Zbtb20 is important for the hippocampal specification and the regulation of neurogenesis of neocortical projection neurons. Herein, we show a critical involvement of the TF Zbtb20 in the neurogenesis of both projection neurons and interneurons of the olfactory bulb during embryonic stages 0.7 SIGNOR-266866 PAK1 protein Q13153 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates activity phosphorylation Ser158 REGTRVQsVEQIREV 9606 12872159 YES lperfetto Pak1 phosphorylates ctbp selectively on ser158 within a putative regulatory loop, triggering ctbp cellular redistribution and blocking ctbp ak1 superphosphorylates ctbp and inhibits ctbp dehydrogenase activitycorepressor functions. 0.403 SIGNOR-103943 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1354 DFVPSDAsPPKTKTS 9606 BTO:0000567 7635160 YES llicata We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated. 0.526 SIGNOR-30248 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCH protein P24723 UNIPROT up-regulates activity binding 9606 14967450 YES PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. 0.8 SIGNOR-242593 MLLT10 protein P55197 UNIPROT SS18/MLLT10 complex SIGNOR-C75 SIGNOR form complex binding 9606 11423977 YES miannu Based on these results, a model is proposed in which the syt and af10 proteins act in concert as bipartite transcription factors 0.427 SIGNOR-108924 CSNK2A1 protein P68400 UNIPROT G3BP1 protein Q13283 UNIPROT down-regulates activity phosphorylation Ser149 VTEPQEEsEEEVEEP 9606 BTO:0001938 27920254 YES miannu We also show that casein kinase 2 phosphorylates G3BP1 at serine 149 in vitro and in cells. These data support a role for casein kinase 2 in regulation of protein synthesis by downregulating stress granule formation through G3BP1.CK2 regulates SG disassembly during stress recovery.G3BP1 is among the strongest SG nucleating proteins, and previous work indicated that G3BP1 phosphorylation at S149 restricts stress granule assembly by partly inhibiting G3BP1 oligomerization 0.239 SIGNOR-260748 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR arginine smallmolecule CHEBI:29016 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270365 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Thr2620 QGTLQTRtQEGSLSA -1 12186630 YES lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. 0.2 SIGNOR-249158 AKT2 protein P31751 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 YES lperfetto the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate 0.292 SIGNOR-249582 FGF2 protein P09038 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 22298955 YES gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts. 0.82 SIGNOR-195588 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser106 SQKTYQGsYGFRLGF 9606 23201157 YES gcesareni Ser-106 phosphorylation of p53 decreases its interaction with mdm2 and prolongs the half-life of p53 0.778 SIGNOR-199939 CNR2 protein P34972 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257095 TACR3 protein P29371 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257179 WWTR1 protein Q9GZV5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 21084559 YES lperfetto Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. 0.592 SIGNOR-169838 NF2 protein P35240 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity binding 10090 BTO:0003324 27402866 YES Hippo pathway Gianni NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart. 0.412 SIGNOR-261956 PTPN11 protein Q06124 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates dephosphorylation 9606 19022774 YES fspada We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions. 0.373 SIGNOR-182475 ATP5MG protein O75964 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261408 MYOG protein P15173 UNIPROT mir-133a2 mirna URS00005675D3_9606 RNAcentral up-regulates quantity transcriptional regulation 10090 18619954 NO We found that directed expression of MRFs in the neural tube of chicken embryos induced ectopic expression of miR-1 and miR-206. Conversely, the lack of Myf5 but not of MyoD resulted in a loss of miR-1 and miR-206 expression. 0.4 SIGNOR-255919 MMP28 protein Q9H239 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272395 ZFP91 protein Q96JP5 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates ubiquitination 9606 20682767 YES gcesareni Zfp91 interacts with and promotes the lys(63)-linked ubiquitination of nik and subsequent processing of p100 to p52. 0.501 SIGNOR-167331 RPL15 protein P61313 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.874 SIGNOR-262483 SOX9 protein P48436 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 NO miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. 0.503 SIGNOR-251756 EIF2B5 protein Q13144 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.84 SIGNOR-269123 PHGDH protein O43175 UNIPROT 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI up-regulates activity chemical modification 9606 25406093 YES lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. 0.8 SIGNOR-268568 GNAZ protein P19086 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 7108 BTO:0001240 7829508 YES Marta Tosoni Activated a z inhibits the activity of type I and type V adenylyl cyclases. 0.466 SIGNOR-278044 RASGEF1C protein Q8N431 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.2 SIGNOR-161508 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257471 HTR7 protein P34969 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.519 SIGNOR-256783 JNJ-28312141 free base chemical CID:11676971 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259749 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser333 NLKSVQNsHFKEPLV -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276197 ITGB5 protein P18084 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.597 SIGNOR-257722 PIK3R1 protein P27986 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 YES lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.851 SIGNOR-242640 PCDH11X protein Q9BZA7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000227 25687328 NO miannu Our previous research found that protocadherin 11 X-linked protein (Pcdh11x) is predominantly expressed in neurons and has an influence on dendritic branching. In this study, gain-of-function and loss-of-function experiments revealed that Pcdh11x acts as a negative regulator of dendritic branching in cultured cortical neurons derived from embryonic day 16 mice. Overexpression of wild-type Pcdh11x (Pcdh11x-GFP) reduced dendritic complexity, whereas knockdown of Pcdh11x increased dendritic branching. 0.7 SIGNOR-265163 STAT6 protein P42226 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity binding 9606 BTO:0000801 10982806 YES lperfetto STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site 0.486 SIGNOR-249552 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 9606 14636580 YES lperfetto In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues.  0.289 SIGNOR-249243 SMAD7 protein O15105 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 BTO:0001130 15684397 NO gcesareni In the current study, our data indicate that both smad7 and p38 map kinase positively contributed to the accumulation of -catenin 0.699 SIGNOR-133447 CSF1 protein P09603 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000801 39416792 YES miannu CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK 0.938 SIGNOR-277713 CLOCK protein O15516 UNIPROT NR0B2 protein Q15466 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20674862 YES lperfetto CLOCK knockdown activated MTP promoter and reduced small heterodimer partner (SHP, NROB2). CLOCK upregulated SHP by binding to its E box. 0.388 SIGNOR-253698 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 YES lperfetto Thrombin cleaved PAR1E at the Arg41-Ser42 activation site at concentrations known to induce cellular activation, supporting a native conformation of the recombinant polypeptide. 0.887 SIGNOR-263569 OSM protein P13725 UNIPROT AHR protein P35869 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24127753 NO gcesareni The il-6-type cytokine oncostatin m induces ahr expression in a stat3-ependent manner in human hepg2 hepatoma cells. 0.341 SIGNOR-202963 PRKCI protein P41743 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.265 SIGNOR-275446 MLLT3 protein P42568 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005545 20159978 NO Regulation miannu AF9/MLLT3 contributes to the regulation of the gene encoding the epithelial sodium channel alpha, ENaCalpha, in renal tubular cells. Specifically, increases in AF9 protein lead to a reduction in ENaCalpha expression and changes in AF9 activity appear to be an important component of aldosterone signaling in the kidney. 0.272 SIGNOR-251944 PRPF3 protein O43395 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and L√ºhrmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.775 SIGNOR-271967 ANKRD26 protein Q9UPS8 UNIPROT PIDD1 protein Q9HB75 UNIPROT up-regulates activity relocalization 9606 BTO:0004790 33350486 YES lperfetto Here, we demonstrate that PIDD1 is recruited to mature centrosomes by the centriolar distal appendage protein ANKRD26.|We propose that PIDDosome activation can in both cases be promoted by an ANKRD26-dependent local increase in PIDD1 concentration close to the centrosome. 0.2 SIGNOR-266068 COL4A1 protein P02462 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 YES lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. 0.53 SIGNOR-272353 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr304 SSHKGFHyKH 9606 BTO:0000567 19059208 YES miannu We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. 0.416 SIGNOR-262852 MAPK1 protein P28482 UNIPROT IER3 protein P46695 UNIPROT up-regulates phosphorylation Thr18 MTILQAPtPAPSTIP 9606 12356731 YES lperfetto Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors. 0.551 SIGNOR-93740 PAK1 protein Q13153 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser246 QACARTFsRMSLLHK 9606 BTO:0000150 15833848 YES lperfetto Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions. 0.4 SIGNOR-135605 PHF12 protein Q96QT6 UNIPROT TLE5 protein Q08117 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 YES miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. 0.2 SIGNOR-266990 MAML3 protein Q96JK9 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 12370315 YES gcesareni We report here the cloning and characterization of two new genes, maml2 and maml3, that also function as transcriptional coactivators for notch receptors. 0.881 SIGNOR-94100 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT down-regulates activity phosphorylation Tyr120 SETKKGFySLSVRHR 9534 24284075 YES miannu Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity 0.2 SIGNOR-263140 AKT proteinfamily SIGNOR-PF24 SIGNOR ZYX protein Q15942 UNIPROT down-regulates phosphorylation Ser142 PQPREKVsSIDLEID 9606 17572661 YES lperfetto Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation 0.2 SIGNOR-244389 Ac-Asp-Glu(3-) smallmolecule CHEBI:76931 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 10085079 YES miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. 0.8 SIGNOR-267540 KRT14 protein P02533 UNIPROT TRADD protein Q15628 UNIPROT down-regulates activity binding 9606 11684708 YES Regulation of binding miannu TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD. 0.347 SIGNOR-251907 RNF128 protein Q8TEB7 UNIPROT CD83 protein Q01151 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys177 SIFPDFSkAGMERAF 9606 BTO:0000007 19542455 YES miannu In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83. 0.353 SIGNOR-271850 PRKCA protein P17252 UNIPROT PLEK protein P08567 UNIPROT up-regulates phosphorylation Ser117 ARKSTRRsIRLPETI 9606 8615792 YES gcesareni To determine the role of pkc-dependent phosphorylation in pleckstrin function, we mapped the phosphorylation sites in vivo of wild-type and site-directed mutants of pleckstrin expressed in cos cells. Phosphorylation was found to occur almost exclusively on ser-113 and ser-117. Replacing all these sites with glycine decreased phosphorylation by > 90% and reduced pleckstrin's ability to inhibit phosphoinositide hydrolysis by as much as 80%. 0.28 SIGNOR-40048 LYN protein P07948 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates activity phosphorylation Tyr397 EDEPEGDyEEVLEPE 9606 9104825 YES Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252 0.713 SIGNOR-251401 LCK protein P06239 UNIPROT ACP1 protein P24666 UNIPROT up-regulates activity phosphorylation Tyr132 QLIIEDPyYGNDSDF 9534 BTO:0004055 9038134 YES In co-transfected COS cells, Lck and Fyn caused phosphorylation of LMPTP. Most of the phosphate was located at Tyr-131, and some was also located at Tyr-132. Site-directed mutagenesis showed that Tyr-131 is important for the catalytic activity of LMPTP, and that thiophosphorylation of Tyr-131, and to a lesser degree Tyr-132, is responsible for the activation. 0.355 SIGNOR-251366 PRKCA protein P17252 UNIPROT ARX protein Q96QS3 UNIPROT up-regulates activity phosphorylation Ser174 VSISRSKsYRENGAP 9606 BTO:0002181 30419043 YES miannu We confirm that ARX is phosphorylated by PRKCA and demonstrate phosphorylation at serine 174. We demonstrate that phosphorylation is required for correct transcriptional activity of the ARX protein using transcriptome-wide analysis of gene expression of phospho-null mutants (alanines replacing serines) compared to ARX wild-type (ARX-WT) overexpressed in pancreatic alpha TC cells. 0.2 SIGNOR-277418 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser503 KENIFGEsRASTFCG 9606 19366211 YES llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. 0.2 SIGNOR-185299 PRKCB protein P05771 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser41 AATKIQAsFRGHITR -1 2140056 YES lperfetto We conclude that serine-41 is the protein kinase C phosphorylation site of neuromodulin and that phosphorylation of this amino acid residue blocks binding of calmodulin to neuromodulin. 0.347 SIGNOR-248859 TFDP1 protein Q14186 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity binding 9606 14618416 YES miannu DP-1 is a heterodimerization partner for members of the E2F family of transcription factors; E2F/DP-1 regulates the expression of various cellular promoters, particularly gene products that are involved in the cell cycle. 0.814 SIGNOR-253865 FYN protein P06241 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity phosphorylation Tyr70 HKETGNHyAMKILDK -1 30274258 YES miannu We found that the Src family kinase Fyn phosphorylates the catalytic subunit of PKA (PKA-C) at Y69, thereby increasing PKA kinase activity.  0.457 SIGNOR-277410 DDX3X protein O00571 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 21883093 YES miannu In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival. 0.571 SIGNOR-269201 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR F3 protein P13726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001949 12744731 NO miannu In conclusion, NF-kappaB could be activated promptly after HUVEC incubated with TNF-alpha, then it was bound to TF promotor to start the TF transcription, TF mRNA expression was upregulated, that leaded to the increase of TF expression on the HUVEC surface and activated the coagulation cascade. 0.249 SIGNOR-254810 SRP54 protein P61011 UNIPROT SRPRA protein P08240 UNIPROT up-regulates activity binding -1 30649417 YES miannu The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site. 0.2 SIGNOR-261163 STK4 protein Q13043 UNIPROT SIRT1 protein Q96EB6 UNIPROT down-regulates activity phosphorylation 9606 21212262 YES miannu We found that MST1 increases p53 acetylation and transactivation by inhibiting the deacetylation of Sirtuin 1 (Sirt1) and its interaction with p53 and that Sirt1 can be phosphorylated by MST1 leading to the inhibition of Sirt1 activity. 0.345 SIGNOR-279574 oxybutynin chemical CHEBI:7856 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 22243489 YES Luana  Compared to the reference compound oxybutynin, an antagonist used for the treatment of OAB,(5) the newly synthesized 1,4-dioxane derivatives exhibit a higher potency. 0.8 SIGNOR-258329 CCNA1 protein P78396 UNIPROT WT1 protein P19544 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19082485 NO irozzo This study identified WT1 as a repressed target of cyclin A1 and suggests that the suppression of WT1 in cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells. 0.389 SIGNOR-255905 MARK2 protein Q7KZI7 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 22072711 YES The effect has been demonstrated using Q92974-2 gcesareni We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation 0.504 SIGNOR-177096 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 16051226 YES gcesareni Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44). 0.759 SIGNOR-139102 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CFI protein P05156 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10630630 NO miannu The production of CFI by Hep G2 cells was enhanced in a dose- and time-dependent fashion by 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), a potent PKC activator. The enhancement of the activity of transfected chimeric CAT constructs by TPA was abrogated by calphostin C and by pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB and AP-1 transactivation). These results indicate that TPA regulation of CFI gene requires PKC signalling and is mediated by via a TPA response element (TRE) in the CFI promoter region located at -136/-130 and involves the transactivation of AP-1 and NF-kappaB transcription factors 0.2 SIGNOR-254786 IGF2 protein P01344 UNIPROT INSR protein P06213 UNIPROT up-regulates binding 9606 9281335 YES fspada Therefore, these results provide genetic evidence that the growth-promoting function of igf-ii during mouse embryogenesis is mediated in part by signaling through the insulin receptor. 0.706 SIGNOR-50719 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 24142698 YES Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis 0.371 SIGNOR-268148 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.91 SIGNOR-249627 KDM4C protein Q9H3R0 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-263865 MAP3K5 protein Q99683 UNIPROT ZNF622 protein Q969S3 UNIPROT up-regulates phosphorylation Ser314 WCNEKGKsFYSTEAV 9606 21771788 YES gcesareni Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis. 0.488 SIGNOR-175113 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT down-regulates activity phosphorylation Ser277 QAVSRRRsEVRVPWL 10090 11751901 YES miannu PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.‚  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276) 0.503 SIGNOR-250029 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr502 TTANVVYyVGENVVN 9606 12637538 YES lperfetto Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation. 0.412 SIGNOR-247328 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19797526 NO We therefore conclude that PML-RARα–mediated repression of C/EBPα is driven through a DNA methylation pathway. In accordance with this finding, a recent study in human APL samples described increased C/EBPα promoter methylation, consistent with the ability of PML-RARα to recruit corepressor complexes. Moreover, the PML-RARα effect on C/EBPα repression does not seem to be mediated via direct binding. 0.2 SIGNOR-255726 HDAC2 protein Q92769 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23836662 NO miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. 0.571 SIGNOR-254156 CALM2 protein P0DP24 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 YES miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.465 SIGNOR-266331 CTTNBP2NL protein Q9P2B4 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10116 23015759 NO miannu Through alternative splicing, a single CTTNBP2 gene encodes three different transcripts, namely short (S), long (L), and intron forms. The interaction with cortactin is required for the function of CTTNBP2-S in dendritic spine formation because the CTTNBP2-S mutant, which no longer interacts with cortactin, is unable to rescue the spine defects resulting from CTTNBP2 knockdown. Thus CTTNBP2-S may control cortactin–F-actin cytoskeletons and regulate the formation and maintenance of dendritic spines in neurons. 0.7 SIGNOR-261694 PRKD1 protein Q15139 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 YES lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. 0.2 SIGNOR-123226 CyclinC/CDK19 complex SIGNOR-C544 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.39 SIGNOR-273161 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr588 QLKPLKTyVDPHTYE -1 21538645 YES gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates 0.659 SIGNOR-246035 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT up-regulates activity phosphorylation Tyr535 LKTQPKKyAKSKYDF 9606 BTO:0000007 28214294 YES miannu Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. 0.358 SIGNOR-263191 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273063 PRKCA protein P17252 UNIPROT STXBP1 protein P61764 UNIPROT unknown phosphorylation Ser306 VSQEVTRsLKDFSSS -1 12519779 YES lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. 0.379 SIGNOR-249182 PPARG protein P37231 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates relocalization 9606 16431920 YES fspada These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome 0.616 SIGNOR-143961 ROCK1 protein Q13464 UNIPROT LIMK2 protein P53671 UNIPROT up-regulates activity phosphorylation Thr526 NGKSYDEtVDIFSFG 9534 BTO:0000298 11018042 YES lperfetto Specific Activation of LIM kinase 2 via Phosphorylation of Threonine 505 by ROCK, a Rho-dependent Protein Kinase 0.631 SIGNOR-249053 CXCL1 protein P09341 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 16885213 NO gcesareni The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i). 0.2 SIGNOR-148454 BIRC6 protein Q9NR09 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 15200957 YES gcesareni Bruce binds and thereby inhibits caspases, in particular effector caspase-3. 0.465 SIGNOR-125956 PLK1 protein P53350 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr197 ASTETYStPALLAPS 9606 BTO:0002181 35437307 YES miannu We observed that PLK1 could significantly promote the ubiquitination and degradation of Smad4 wild type, Smad4 S171A, Smad4 S187A, Smad4 S191A, respectively, but PLK1-induced the ubiquitination and degradation of Smad4 T197A were obviously inhibited (Fig. 1M). 0.255 SIGNOR-277591 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser407 DSQGRNCsTNDSLL -1 8662852 YES we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 0.693 SIGNOR-251197 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT up-regulates activity phosphorylation Thr389 RVITQREtENNQMTS -1 21423175 YES miannu In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h). 0.2 SIGNOR-276325 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation -1 8454633 YES gcesareni Intrinsic activity was demonstrated in vitro against a variety of phosphotyrosine-containing substrates including BIRK, the autophosphorylated cytoplasmic kinase domain of the insulin receptor beta subunit. 0.378 SIGNOR-39155 MAVS protein Q7Z434 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 25636800 YES miannu After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively. 0.912 SIGNOR-260145 Starvation stimulus SIGNOR-ST4 SIGNOR SIRT1 protein Q96EB6 UNIPROT up-regulates activity 9606 BTO:0000759 15744310 NO AMPK pathway Gianni We show here that the Sir2 homologue, SIRT1—which modulates ageing in several species —controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. 0.7 SIGNOR-261951 FBXW7 protein Q969H0 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002524 17298674 YES miannu Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme 0.568 SIGNOR-271643 TCF12 protein Q99081 UNIPROT PTCRA protein Q6ISU1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22577461 NO miannu Hebalt positively regulates t-cell genes, such as pt_ and notch3 0.326 SIGNOR-197520 VAV1 protein P15498 UNIPROT SYK protein P43405 UNIPROT up-regulates binding 9606 11331248 YES lperfetto Vav interacts with the tyrosine kinase syk 0.92 SIGNOR-107049 CHN1 protein P15882 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.665 SIGNOR-260499 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 YES lperfetto Recently, Liu et al. [3] identified CyclinE/CDK2 to be the kinase phosphorylating OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) by elegantly combining genetics and biochemistry. Knockout of all five G1 cyclins (D1, D2, D3, E1 and E2) in mESCs (coined Q-KO cells) and consequent inactivation of CDK2/4/ 6 leads to perturbation of the pluripotent state and to the adaption of the trophectoderm cell fate. This was attributed to reduced phosphorylation of OCT4 (as well as SOX2 and NANOG) leading to an increase of protein turnover [3]. 0.319 SIGNOR-264438 EIF5B protein O60841 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates activity relocalization 9606 30551605 YES lperfetto EIF5B was also shown to deliver Met-tRNAi into the P-site of the ribosome in an eIF2-independent translation initiation mechanism utilized by the CSFV and HCV IRESs  0.8 SIGNOR-269119 PAFAH1B1 protein P43034 UNIPROT DYNC1H1 protein Q14204 UNIPROT up-regulates activity binding 10090 BTO:0000938 11163259 YES miannu We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex 0.886 SIGNOR-252158 PTPN6 protein P29350 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr654 RNEGVATyAAAVLFR 9606 20840866 YES lperfetto Because SHP-1 can dephosphorylate residues Y86 and Y654 on the \u03b2-catenin protein, these residues were therefore mutated into phenylalanine and the transcriptional activity of the subsequent \u03b2-catenin mutants analyzed: \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F. As shown in  Fig.\u00a03 B, the mutants \u03b2-catenin/Y86F, \u03b2-catenin/Y654F and \u03b2-catenin/Y86F/Y654F had a significantly reduced transcriptional activity in comparison to wild-type \u03b2-catenin.|SHP-1 inhibits \u03b2-catenin function by inducing its degradation and interfering with its association with TATA-binding protein. 0.557 SIGNOR-277014 HOOK3 protein Q86VS8 UNIPROT MARCO protein Q9UEW3 UNIPROT down-regulates binding 9606 BTO:0000801 17237231 YES miannu We have identified a microtubule-binding protein, hook3, as a novel interacting partner of sr-a. / by transfecting small interfering rna targeting hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of sr-a were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that hook3 may participate in the turnover of the endocytosed scavenger receptor 0.2 SIGNOR-152268 PRC1 protein O43663 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity binding 9606 15297875 YES miannu These data indicate that PRC1 binds to KIF4, MKLP1 and CENP-E during late mitosis; however, it apparently does not interact simultaneously with more than one of these motor proteins. 0.585 SIGNOR-265990 EEF1A1 protein P68104 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269512 PPP2R2A protein P63151 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR form complex binding 9606 23454242 YES gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. 0.901 SIGNOR-243430 lurasidone chemical CHEBI:70735 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10030 20404009 YES Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. 0.8 SIGNOR-257838 GSC protein P56915 UNIPROT EVX1 protein P49640 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 22178155 NO miannu We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin. 0.253 SIGNOR-254140 CTBP1 protein Q13363 UNIPROT CLDN7 protein O95471 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 19277896 YES lperfetto ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1. 0.2 SIGNOR-254105 RPS6KA3 protein P51812 UNIPROT ATF4 protein P18848 UNIPROT up-regulates phosphorylation Ser245 TRGSPNRsLPSPGVL 9606 15109498 YES lperfetto Here, we show that rsk2 is required for osteoblast differentiation and function. We identify the transcription factor atf4 as a critical substrate of rsk2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression 0.632 SIGNOR-124436 HDAC3 protein O15379 UNIPROT ATP6V0E2 protein Q8NHE4 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000801 30375985 YES lperfetto Consistent with previous data, HDAC3 only bound to the ATP6V0E2 promoter in the presence of ALDH2.|Taken together, our data demonstrate that in the macrophages of LDLR-KO or ALDH2 rs671 mutant, AMPK phosphorylates ALDH2 at T356, which enables its nuclear translocation. Once in the nucleus, ALDH2 binds to HDAC3 and suppresses the transcription and protein expression of ATP6V0E2. 0.2 SIGNOR-271868 KLF2 protein Q9Y5W3 UNIPROT NPNT protein Q6UXI9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005787 BTO:0001103 23612709 NO miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 0.265 SIGNOR-255456 PRKAA1 protein Q13131 UNIPROT ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr356 GNPFDSKtEQGPQVD 10090 BTO:0000801 30375985 YES lperfetto Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. 0.2 SIGNOR-271863 CRHR1 protein P34998 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 22869609 YES lperfetto Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3 0.286 SIGNOR-268619 PTK2 protein Q05397 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates phosphorylation Tyr12 DSQQTNDyMQPEEDW 9606 23454549 YES lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin . 0.573 SIGNOR-192126 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 YES gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. 0.616 SIGNOR-131311 TFIIF complex SIGNOR-C394 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity relocalization 9606 18218714 YES lperfetto Transcription processes in eukaryotes begin with the formation of a pre-initiation complex (PIC), composed of RNA polymerase II (Pol II) associated with five general transcription factors: TFIIB, TFIID, TFIIE, TFIIF, and TFIIH 0.729 SIGNOR-266199 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity 0.2 SIGNOR-236772 DRD2 protein P14416 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.481 SIGNOR-256701 LRFN5 protein Q96NI6 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 NO miannu These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength. 0.7 SIGNOR-264085 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000725 21389315 NO irozzo Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. 0.7 SIGNOR-256650 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val55 VTGKGVTvETVFSVD -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.374 SIGNOR-263599 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270396 C3 protein P01024 UNIPROT C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR form complex binding 9606 BTO:0000089 cleavage:Arg748 ASHLGLArSNLDEDI 26489954 YES complement C3b fragment: PRO_0000005911 lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). 0.2 SIGNOR-263480 ETS2 protein P15036 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 11175361 NO miannu Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis 0.7 SIGNOR-259870 CHEK1 protein O14757 UNIPROT NEK6 protein Q9HC98 UNIPROT down-regulates activity phosphorylation -1 18728393 YES miannu Nek6 is also directly phosphorylated by the checkpoint kinases Chk1 and Chk2 in vitro . 0.237 SIGNOR-279403 AURKA protein O14965 UNIPROT NEDD9 protein Q14511 UNIPROT up-regulates activity phosphorylation Ser296 PVARRHQsLSPNHPP 9606 BTO:0000093 16184168 YES miannu HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins. 0.571 SIGNOR-262654 CSMD1 protein Q96PZ7 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 22538441 YES miannu CSMD1 co-immunoprecipitated with SMAD3, confirming our results that CSMD1 interacts with Smad3 in A375 cells. CSMD1 interacts with Smad3 and induces phosphorylation (p-Smad3). Phosphorylated Smad3 promotes Smad2 phosphorylation and Smad2/3/4 complex formation. 0.2 SIGNOR-265151 PTPN6 protein P29350 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation 9606 18508557 YES gcesareni Stat3 may also be a substrate of shp1 0.457 SIGNOR-178699 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr102 RAAMFPEtLDEGMQI 9606 BTO:0000007 12432063 YES llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin 0.555 SIGNOR-250847 PDK1 protein Q15118 UNIPROT PDH complex SIGNOR-C402 SIGNOR down-regulates activity phosphorylation 9606 BTO:0003291 16517405 YES miannu PDK1 is a direct HIF-1 target gene. We found that the gene encoding pyruvate dehydrogenase kinase 1 (PDK1) is a direct target of HIF-1. PDK1 phosphorylates the pyruvate dehydrogenase (PDH) E1α subunit and inactivates the PDH enzyme complex that converts pyruvate to acetyl-coenzyme A, thereby inhibiting pyruvate metabolism via the tricarboxylic acid (TCA) cycle 0.643 SIGNOR-267445 YWHAE protein P62258 UNIPROT GRIN2C protein Q14957 UNIPROT up-regulates quantity by stabilization binding 10090 19477150 YES miannu Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells. 0.318 SIGNOR-262622 ATM protein Q13315 UNIPROT SMC1A protein Q14683 UNIPROT up-regulates phosphorylation Ser957 ISQEEGSsQGEDSVS 9606 11877377 YES lperfetto Here we report that smc1 is a component of the dna damage response network that functions as an effector in the atm/nbs1-dependent s-phase checkpoint pathway. Smc1 associates with brca1 and is phosphorylated in response to ir in an atm- and nbs1-dependent manner. Using mass spectrometry, we established that atm phosphorylates s957 and s966 of smc1 in vivo. 0.704 SIGNOR-115492 SIRT1 protein Q96EB6 UNIPROT EP300 protein Q09472 UNIPROT down-regulates deacetylation Lys1020 EERSTELkTEIKEEE 9606 BTO:0000150 19047049 YES gcesareni Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024 0.835 SIGNOR-182507 HTATSF1 protein O43719 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.43 SIGNOR-270652 ATM protein Q13315 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 21149446 YES gcesareni In human cells, the activation process involves autophosphorylation on three sites (ser367, ser1893, and ser1981) and acetylation on lys3016. We now describe the identification of a new atm phosphorylation site, thr(p)1885 and an additional autophosphorylation site, ser(p)2996, that is highly dna damage-inducible. 0.2 SIGNOR-170469 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation -1 16326050 YES miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast 0.8 SIGNOR-268749 ARPC3 protein O15145 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 YES The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc 0.964 SIGNOR-251516 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 17386267 YES gcesareni These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3 0.62 SIGNOR-153935 PHKG2 protein P15735 UNIPROT PYGL protein P06737 UNIPROT up-regulates activity phosphorylation Ser15 QEKRRQIsIRGIVGV 9606 BTO:0002049 22225877 YES It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 0.655 SIGNOR-267401 AGT protein P01019 UNIPROT AGTR2 protein P50052 UNIPROT up-regulates 9606 BTO:0001130 16597412 NO gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. 0.824 SIGNOR-145680 SNTA1 protein Q13424 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.525 SIGNOR-255991 ABCA7 protein Q8IZY2 UNIPROT APOA1 protein P02647 UNIPROT up-regulates activity binding 9606 BTO:0000007 12917409 YES miannu ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux. HEK293 cells overexpressing ABCA7 showed specific binding and cross-linking of lipid-poor apoA-I. ABCA7 expression increased cellular phosphatidylcholine and sphingomyelin efflux to apoA-I in a manner similar to ABCA1 but had no effect on cholesterol efflux. 0.47 SIGNOR-265178 PRKACA protein P17612 UNIPROT ARHGEF6 protein Q15052 UNIPROT down-regulates activity phosphorylation Ser640 RKTERKPsEEEYVIR 9606 BTO:0000132 26507661 YES lperfetto ARHGEF6 is a Rho guanine nucleotide exchange factor for Rac1 and constitutively bound to GIT1. NO and PGI2 activate PKG and PKA, respectively and both kinases phosphorylate ARHGEF6 on Ser-684 and possibly on Ser-640. Phosphorylation of ARHGEF6 results in the assembly of a GIT1-ARHGEF6–14-3-3 complex. These changes might contribute to PGI2- and NO-mediated Rac1 inhibition. 0.2 SIGNOR-272162 PPP2CA protein P67775 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Thr641 TRHPPVLtPPDQEVI 10116 8749392 YES Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. 0.445 SIGNOR-248622 OPRL1 protein P41146 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.457 SIGNOR-256865 AKT1 protein P31749 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000192 31435020 YES inferred from family member K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization 0.484 SIGNOR-270267 FOXO3 protein O43524 UNIPROT MIR1-1 mirna URS000075CF56_9606 RNAcentral up-regulates quantity transcriptional regulation 10090 25477897 YES miannu The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC 0.4 SIGNOR-255798 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 10454565 YES The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2. 0.829 SIGNOR-248482 XPA protein P23025 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 9606 30327428 NO A coordinated repair process mediated by the xeroderma pigmentosum complementation group proteins (XPs), which include XPA through XPG. XPA is indispensable in this pathway and has reported functions in DNA damage verification, stabilization of repair intermediates and positioning of NER factors 0.7 SIGNOR-258984 CCR4-NOT complex complex SIGNOR-C439 SIGNOR RC3H1 protein Q5TC82 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 YES lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins 0.33 SIGNOR-268348 TWIST1 protein Q15672 UNIPROT FAP protein Q12884 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20646316 NO miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. 0.242 SIGNOR-255523 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser274 RSKSQSSsNCSNPIS -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251291 pictrelisib chemical CHEBI:65326 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 BTO:0000149 21876152 YES gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed 0.8 SIGNOR-176301 SMURF1 protein Q9HCE7 UNIPROT HOMER2 protein Q9NSB8 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272699 MYO5A protein Q9Y4I1 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates activity binding 9606 21077886 YES miannu Another potential role of myosin Va in LDCV exocytosis lies in facilitating the formation of the SNARE complex, which is needed for fusion of the vesicle with the plasma membrane. Notably, myosin Va binds to at least two SNARE proteins in a Ca2+-dependent manner: at micromolar Ca2+-levels, it binds to VAMP2 located in the membrane of the cargo vesicle via its globular tail domain 0.482 SIGNOR-269281 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 12832520 YES gcesareni Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity. 0.498 SIGNOR-102717 SMARCD1 protein Q96GM5 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.885 SIGNOR-132939 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI KEAP1 protein Q14145 UNIPROT up-regulates activity chemical modification CYS226 EFFNLSHcQLVTLIS 9606 32284348 YES miannu In response to oxidative stress, the direct binding of stressors to reactive cysteine residues results in a conformation change in KEAP1, which inhibits the ubiquitination of NRF2. the sensor for H2O2 consists of four residues within KEAP1: Cys226, Cys613, Cys622, and Cys624.KEAP1 uses multiple sensing mechanisms to coordinate the NRF2-dependent oxidative stress response. 0.8 SIGNOR-279845 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI KEAP1 protein Q14145 UNIPROT up-regulates activity chemical modification CYS613 VAVTMEPcRKQIDQQ 9606 32284348 YES miannu In response to oxidative stress, the direct binding of stressors to reactive cysteine residues results in a conformation change in KEAP1, which inhibits the ubiquitination of NRF2. the sensor for H2O2 consists of four residues within KEAP1: Cys226, Cys613, Cys622, and Cys624.KEAP1 uses multiple sensing mechanisms to coordinate the NRF2-dependent oxidative stress response. 0.8 SIGNOR-279846 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation -1 22306293 YES PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In¬†vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor 0.2 SIGNOR-268149 ARID1B protein Q8NFD5 UNIPROT Histone H2B proteinfamily SIGNOR-PF68 SIGNOR down-regulates activity ubiquitination -1 20086098 YES miannu The immunopurified BAF250b E3 ubiquitin ligase was found to target histone H2B at lysine 120 for monoubiquitination in vitro.  0.2 SIGNOR-271442 L-arginine chemical CHEBI:16467 ChEBI ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 NO apalma In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT) 0.8 SIGNOR-255555 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT up-regulates activity phosphorylation Tyr174 YPTDNEDyEHDDEDD 9534 12709437 YES lperfetto By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk. 0.553 SIGNOR-246587 PIAS1 protein O75925 UNIPROT RPA2 protein P15927 UNIPROT up-regulates sumoylation 9606 20016603 YES gcesareni Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair 0.2 SIGNOR-162153 BAG5 protein Q9UL15 UNIPROT HSPA1B protein P0DMV9 UNIPROT down-regulates activity binding 9606 BTO:0000142 15603737 YES Monia Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction. 0.683 SIGNOR-261197 FOXC1 protein Q12948 UNIPROT MMP10 protein P09238 UNIPROT up-regulates quantity by expression transcriptional regulation 31650548 YES lperfetto Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX13|MMP10 was demonstrated as the direct target and mediator of FOXC1. 0.2 SIGNOR-275915 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser237 SFHFKSGsLENVPNV 22584576 YES lperfetto LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation. 0.2 SIGNOR-275526 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Tyr397 SVSETDDyAEIIDEE 17828307 YES gcesareni Fak y397 phosphorylation promotes src sh2 domain binding to fak, presumably leading to conformational src activation with a fak-src complex. 0.648 SIGNOR-157767 PLK1 protein P53350 UNIPROT SVIL protein O95425 UNIPROT up-regulates activity phosphorylation Ser238 SFSGRDSsFTEVPRS 9606 BTO:0000007 23750008 YES miannu PLK1 phosphorylates Ser238 of SVIL, which can promote the localization of SVIL to the central spindle and association with PRC1. Expression of a PLK1 phosphorylation site mutant, S238A-SVIL, inhibited myosin II activation at the equatorial cortex and induced aberrant furrowing.  0.2 SIGNOR-273729 PECAM1 protein P16284 UNIPROT CD38 protein P28907 UNIPROT up-regulates activity binding 9606 18626062 YES miannu As a receptor, CD38 interacts with its ligand CD31 [15,16]. CD31, also known as platelet endothelial cell adhesion molecule-1 (PECAM-1), is a 130 kDa type I transmembrane glycoprotein that consists of six extracellular immunoglobulin-like homology domains, a 19-residue transmembrane domain, and a 118-residue cytoplasmic tail 0.484 SIGNOR-264254 USP4 protein Q13107 UNIPROT PRPF3 protein O43395 UNIPROT down-regulates activity deubiquitination 9606 20595234 YES miannu Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site. 0.488 SIGNOR-271975 AKT1 protein P31749 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 15806160 YES lperfetto Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102 0.559 SIGNOR-252475 KAT2B protein Q92831 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.671 SIGNOR-269592 SKP2 protein Q13309 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10790373 YES miannu  Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3. 0.706 SIGNOR-272566 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by stabilization phosphorylation 9606 24142698 YES Manara Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. 0.371 SIGNOR-268151 PRKCA protein P17252 UNIPROT KCNJ13 protein O60928 UNIPROT down-regulates phosphorylation Ser201 TRPSPLTsVRVSAVL 9606 18976636 YES gcesareni After pharmacological pkc activation, kir7.1 currents were strongly inhibited. Co-application of pkc inhibitors attenuated this effect. Inactivation of pkc consensus sites also strongly attenuated the effect with a single site ((201)s) being essential for almost the total pkc sensitivity. 0.2 SIGNOR-181863 Ub:E2 complex SIGNOR-C497 SIGNOR CGRRF1 protein Q99675 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270960 pimozide chemical CHEBI:8212 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258378 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity acetylation 9606 9865691 YES lperfetto The closely related CBP and p300 proteins are also important coactivators for Smad activity. CBP and p300 act as coactivators of several transcription factors by bringing the sequence-specific activators within proximity of the general transcription machinery and by modifying the chromatin structure through histone acetylation.In response to TGF-b, Smad3 associates with CBP/p300 and TGF-b-induced C-terminal phosphorylation of Smad3 promotes this association. This association with CBP/p300 is likely to be essential for transcriptional activity of Smad3. 0.693 SIGNOR-227553 EGFR protein P00533 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 YES gcesareni These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity 0.613 SIGNOR-106500 RNF5 protein Q99942 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys362 RAGMVPSkVPTSMVL 9606 BTO:0000007 20483786 YES miannu In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase.  0.457 SIGNOR-271488 IQSEC2 protein Q5JU85 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 27009485 YES miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. 0.2 SIGNOR-264912 CDK1 protein P06493 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 9524113 YES lperfetto With regard to k8 phosphorylation at ser-431, it increases dramatically upon stimulation of cells with epidermal growth factor (egf) or after mitotic arrest and is the major k8 phosphorylated residue after incubating k8 immunoprecipitates with mitogen-activated protein or cdc2 kinases. 0.248 SIGNOR-56054 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -1 9677319 YES llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. 0.313 SIGNOR-250946 serotonin smallmolecule CHEBI:28790 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264297 MAPK3 protein P27361 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates activity phosphorylation Ser1051 NRSEIGHsPPPAYTP 9606 BTO:0000007 31053301 YES miannu We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation.  0.532 SIGNOR-277449 MAPK3 protein P27361 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser530 DGPPSPRsPVIGSEV 9606 BTO:0001271 15093545 YES The effect has been demonstrated using P29590-4 gcesareni Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. 0.339 SIGNOR-124317 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation 21613606 YES lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs 0.445 SIGNOR-264629 OFD1 protein O75665 UNIPROT IFT88 protein Q13099 UNIPROT up-regulates activity binding 9606 BTO:0001086 20230748 YES Regulation of binding miannu Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length. 0.412 SIGNOR-251973 CSNK1E protein P49674 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 YES miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. 0.842 SIGNOR-267997 NRAS protein P01111 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 21779497 YES lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k 0.677 SIGNOR-252700 CPSF6 protein Q16630 UNIPROT CFI complex complex SIGNOR-C388 SIGNOR form complex binding 9606 BTO:0000567 8626397 YES lperfetto We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity. 0.819 SIGNOR-266123 GAR1 protein Q9NY12 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 YES lperfetto A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP 0.444 SIGNOR-263333 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser262 DSEDYSLsEEGQELS 9606 12167711 YES gcesareni Hypophosphorylation of mdm2 augments p53 stability. 0.346 SIGNOR-91199 IL3RA protein P26951 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15795318 YES gcesareni Indeed, only upon fibronectin adhesion is janus kinase 2 (jak2) recruited to the beta1 integrin-il-3r complex and triggers il-3r beta common phosphorylation, leading to the formation of docking sites for activated stat5a. 0.614 SIGNOR-134859 HBB protein P68871 UNIPROT EDN1 protein P05305 UNIPROT down-regulates activity 9606 8573884 NO Regulation of localization miannu Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury. 0.275 SIGNOR-251766 JUN protein P05412 UNIPROT GLS protein O94925 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28111979 YES Luana The transcription factor c-Jun can directly bind to the GLS gene promoter and enhance expression 0.35 SIGNOR-268035 ACSS2 protein Q9NR19 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; 0.2 SIGNOR-276562 CASP7 protein P55210 UNIPROT Caspase 7 complex complex SIGNOR-C232 SIGNOR form complex binding cleavage:Asp206 SGPINDTdANPRYKI 11701129 YES lperfetto The quaternary structure of caspase-7 comprises two closely associated heterodimers, with each heterodimer consisting of a large and a small subunit. 0.2 SIGNOR-256394 glycine smallmolecule CHEBI:15428 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264745 ATP smallmolecule CHEBI:15422 ChEBI PRKAG1 protein P54619 UNIPROT down-regulates chemical inhibition 9606 SIGNOR-C15 21680840 YES gcesareni AMPK is an ___ heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations. 0.8 SIGNOR-228607 N-[2-(4-bromocinnamylamino)ethyl]isoquinoline-5-sulfonamide chemical CHEBI:47495 ChEBI PRKACA protein P17612 UNIPROT down-regulates activity chemical inhibition 10116 2156866 YES Simone Vumbaca Kinetic analysis indicated that H-89 inhibits protein kinase A, in competitive fashion against ATP. 0.8 SIGNOR-261087 PRKCA protein P17252 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates activity phosphorylation Ser34 YKPPAQKsIQEIQEL 9606 25924946 YES miannu PKCalpha phosphorylates RhoGDIalpha at Ser34 to reduce its affinity for RhoA (but not for Rac1 or Cdc42) . 0.447 SIGNOR-279097 STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25787076 NO miannu P-Stat3 stimulates C/EBPδ expression and activity, which increases myostatin and MAFbx/Atrogin-1 and MuRF-1. Both pathways result in protein losses in muscle. 0.61 SIGNOR-255334 UVB radiation stimulus SIGNOR-ST17 SIGNOR TNF protein P01375 UNIPROT up-regulates 9606 19005488 NO miannu UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts. 0.7 SIGNOR-252208 ALK protein Q9UM73 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 11850821 YES miannu Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death.|We show here that expression of activated ALK induces the constitutive phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs. 0.44 SIGNOR-279319 SPAG5 protein Q96R06 UNIPROT CENPF protein P49454 UNIPROT up-regulates activity 9606 BTO:0000567 17664331 NO lperfetto Furthermore, although both the core kinetochore protein Hec1 and the spindle checkpoint kinase Bub1 were unaffected (Fig. 3 C), the kinetochore resident motor protein CENP-E (Yen et al., 1992) and its interaction partner CENP-F (Chan et al., 1998) were delocalized from the kinetochore in the absence of astrin. These cells remained cyclin B1 positive (unpublished data), confirming that they were still in mitosis. These data suggest that the presence of astrin is required for the kinetochore recruitment or maintenance of CENP-E and CENP-F. 0.339 SIGNOR-252042 CREB1 protein P16220 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 NO amattioni beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state 0.7 SIGNOR-229777 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 15950189 YES lperfetto It has been shown previously that ribosomal protein s3 (rps3) 0.2 SIGNOR-137967 THR proteinfamily SIGNOR-PF84 SIGNOR RARB protein P10826 UNIPROT up-regulates binding 9606 15650024 YES inferred from family member gcesareni Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs 0.2 SIGNOR-270314 SRC protein P12931 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr248 EESEDPDyYQYNIQA 9534 BTO:0004055 11934902 YES lperfetto c-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling 0.454 SIGNOR-247185 KAR proteinfamily SIGNOR-PF57 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264940 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.2 SIGNOR-249645 PRKACA protein P17612 UNIPROT RGS10 protein O43665 UNIPROT down-regulates activity phosphorylation Ser176 QTAAKRAsRIYNT 9606 11443111 YES lperfetto We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel. 0.335 SIGNOR-109173 EGR1 protein P18146 UNIPROT HYAL1 protein Q12794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004796 18718911 NO miannu In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription. 0.2 SIGNOR-253878 CDK5 protein Q00535 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Ser279 KSKTLDNsDLHPGPP 9606 BTO:0000938;BTO:0000527 18487454 YES lperfetto Here, we demonstrate that cyclin dependent kinase 5 (cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates pike-a at ser-279 in its gtpase domain in glioblastoma cells. This phosphorylation event stimulates pike-a gtpase activity and the activity of its downstream effector akt. 0.262 SIGNOR-178660 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 YES gcesareni Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. 0.2 SIGNOR-151449 BTF3 protein P20290 UNIPROT ABL2 protein P42684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 17312387 NO In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. 0.2 SIGNOR-253947 Av/b1 integrin complex SIGNOR-C175 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.313 SIGNOR-253273 PPP1R9B protein Q96SB3 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity binding 10090 BTO:0001976 15996550 YES miannu The Rho Family GEF Lfc Interacts with Neurabin and Spinophilin. Neurabin and spinophilin are homologous protein phosphatase 1 and actin binding proteins that regulate dendritic spine function. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc 0.397 SIGNOR-269176 JUN protein P05412 UNIPROT SMAD4/JUN complex SIGNOR-C10 SIGNOR form complex binding 9606 9312063 YES gcesareni Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter. 0.675 SIGNOR-51110 PBK protein Q96KB5 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser380 EPDHYRYsDTTDSDP 9606 BTO:0000567 24012691 YES miannu PTEN is phosphorylated by TOPK and is required for mitotic entry. In addition, reduced PTEN phosphorylation levels upon TOPK knockdown correlated with decreased Akt activation (Fig. 4e) suggesting that TOPK mediated phosphorylation may lead to PTEN inactivation. By using various PTEN mutants in a kinase assay we concluded that TOPK phosphorylates PTEN at S380 residue in vitro (Fig. 4c). 0.505 SIGNOR-271472 AKT2 protein P31751 UNIPROT SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 YES gcesareni Overexpression of posh induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase akt. We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac 0.389 SIGNOR-155233 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM64 protein A6NGJ6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271138 CDK1 protein P06493 UNIPROT DLG1 protein Q12959 UNIPROT unknown phosphorylation Ser158 FVSHSHIsPIKPTEA 9606 19066288 YES llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. 0.393 SIGNOR-182753 MAST3 protein O60307 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation 9606 15951562 YES gcesareni Furthermore, binding of PTEN to the PDZ domains from microtubule-associated serine/threonine kinases facilitated PTEN phosphorylation at its C terminus by these kinases. 0.57 SIGNOR-138080 CSNK2A1 protein P68400 UNIPROT CERS4 protein Q9HA82 UNIPROT up-regulates activity phosphorylation Ser342 QMEKDIRsDVEESDS 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273981 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273094 CLK1 protein P49759 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 YES lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 0.259 SIGNOR-181031 PLK3 protein Q9H4B4 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation 9606 19490146 YES miannu In this study, we found that Plk3 inhibits pro-apoptotic activity of p73 through physical interaction and phosphorylation.|Plk3 inhibits pro-apoptotic activity of p73 through physical interaction and phosphorylation. 0.409 SIGNOR-279647 dacomitinib chemical CHEBI:132268 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 23405260 YES gcesareni The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor. 0.8 SIGNOR-200905 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7326 RAGSRASsRRGSDAS 9606 BTO:0004905 21295697 YES lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. 0.436 SIGNOR-264434 progesterone smallmolecule CHEBI:17026 ChEBI Corticotropin protein P01189-PRO_0000024969 UNIPROT down-regulates 24631756 NO lperfetto ACTH and corticosterone responses to the same acute stress stimulus are higher in the pro-estrus phase of the cycle, when the serum concentrations of estrogen are the highest (Viau and Meaney, 1991). In the same study, it was shown that progesterone inhibits the sensitizing effects of estrogen on ACTH release during stress, as the ACTH levels and HPA output decreased with increasing amounts of progesterone in the estrous and diestrous phases. 0.8 SIGNOR-268727 MAPK11 protein Q15759 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation 9606 9199504 YES miannu Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in its ability to promote microtubule assembly.|Tau phosphorylated by SAPK2b and SAPK2a also reacted with AT8, whereas AT8 failed to recognise tau phosphorylated by SAPK1gamma. 0.342 SIGNOR-279637 CEBPB protein P17676 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates quantity transcriptional regulation 10090 22355693 YES These results show that GSK3β is involved in regulating phosphorylation and activation of C/EBPβ and that this transcription factor is required to transactivate srebf1a expression, leading to the early steps of adipogenesis 0.411 SIGNOR-251645 Av/b1 integrin complex SIGNOR-C175 SIGNOR TERT protein O14746 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.319 SIGNOR-253274 PRKACA protein P17612 UNIPROT SLC2A2 protein P11168 UNIPROT down-regulates activity phosphorylation Ser505 EFQKKSGsAHRPKAA 9534 BTO:0004055 8626492 YES miannu GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity. 0.31 SIGNOR-250051 CDC25A protein P30304 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000093 11154267 YES lperfetto Cyclin E-Cdk2 complexes from p16INK4a-expressing MCF-7 cells are activated in vitro and in vivo by Cdc25A 0.745 SIGNOR-245452 FKBP5 protein Q13451 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 30685540 NO Luana Loss of FKBP5 Affects Neuron Synaptic Plasticity | In this study, a reduction in LTP in Fkbp5 knockout (KO) mice was observed when compared to WT mice, which correlated with changes to the glutamatergic and GABAergic signaling pathways. 0.7 SIGNOR-265798 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF7 protein Q6Q0C0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271096 UTS2R protein Q9UKP6 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.25 SIGNOR-256779 SLC2A4 protein P14672 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 17403369 YES Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis 0.8 SIGNOR-267291 DNMT3A protein Q9Y6K1 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19786833 NO irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. 0.504 SIGNOR-255808 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR GORASP1 protein Q9BQQ3 UNIPROT down-regulates activity phosphorylation Ser373 FEVSFLDsPGAQAQA 10116 15678101 YES Giulio The pS376 antibody gave the strongest staining when Golgi apparatus fragmentation is initiated during prophase and in metaphase when it has become converted into a haze of small vesicles and some larger tubulovesicular remnants (Figure 4A). Therefore, GRASP65, like GM130, is phosphorylated in mitotic entry on Cdk1–cyclin B sites during the period when the Golgi apparatus is fragmented. 0.574 SIGNOR-260606 LTK protein P29376 UNIPROT PREB protein Q9HCU5 UNIPROT down-regulates activity phosphorylation Tyr10 RRRAPELyRAPFPLY 9606 BTO:0000567 31227593 YES miannu Furthermore, we show that LTK interacts with and phosphorylates Sec12. Expression of a phosphoablating mutant of Sec12 reduces the efficiency of ER export. Thus, LTK-to-Sec12 signaling represents the first example of an ER-resident signaling module with the potential to regulate proteostasis.Altogether, we propose that Sec12 is phosphorylated in a manner dependent on LTK and that this phosphorylation affects ERES function. 0.2 SIGNOR-273650 CHFR protein Q96EP1 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 19182791 YES miannu Histone deacetylase 1 (HDAC1), which represses transcription by deacetylating histones, was newly isolated as a Chfr-interacting protein. Chfr binds and downregulates HDAC1 by inducing its polyubiquitylation, both in vitro and in vivo. Together, these results suggest that the ubiquitin ligase activity of Chfr targets HDAC1 for degradation. 0.395 SIGNOR-271465 SKI protein P12755 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 BTO:0000848 12793438 YES lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway 0.821 SIGNOR-236074 EGFR protein P00533 UNIPROT MYC protein P01106 UNIPROT up-regulates activity 10090 26592448 NO Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC 0.466 SIGNOR-252092 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser76 ISNKDQHsISYTLSR 9606 BTO:0000007 12496252 YES lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation 0.767 SIGNOR-96739 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity acetylation Lys19 VKRLLGWkKGEQNGQ 9606 BTO:0000567;BTO:0002181;BTO:0000552 17074756 YES lperfetto We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfb-dependent manner. the p300-dependent acetylation of smad3 was attenuated when lys19 was mutated, whereas mutation of lys20 had no effect, suggesting that lys19 is acetylated also in smad3. 0.693 SIGNOR-236126 AKAP12 protein Q02952 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity relocalization 14657015 YES lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. 0.46 SIGNOR-271836 GNAQ protein P50148 UNIPROT ARHGEF25 protein Q86VW2 UNIPROT up-regulates activity binding -1 17606614 YES P63RhoGEF is autoinhibited by the Dbl homology (DH)-associated pleckstrin homology (PH) domain; activated Galpha(q) relieves this autoinhibition by interacting with a highly conserved C-terminal extension of the PH domain 0.586 SIGNOR-256493 IKBKB protein O14920 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser122 CPMEHPLsADIAMAT -1 28689659 YES miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  0.366 SIGNOR-277364 3-[[6-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]phenol chemical CHEBI:91384 ChEBI GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207474 6-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthalenecarboxamide chemical CHEBI:94965 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207141 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT down-regulates activity dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 12138178 YES Upon interferon (IFN) stimulation, Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to DNA to activate transcription. The activity of Stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (PTP). We have now purified a Stat1 PTP activity from HeLa cell nuclear extract and identified it as TC45, the nuclear isoform of the T-cell PTP (TC-PTP). 0.733 SIGNOR-248402 D-glucitol smallmolecule CHEBI:17924 ChEBI HNRNPA1 protein P09651 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 NO We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne 0.8 SIGNOR-262814 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Tyr9 ARTTSQLyDAVPIQS 9606 11481331 YES lperfetto Using site-directed mutants, we show that, although phosphorylation on tyr-373/376 is important for pdk1 activity, phosphorylation on tyr-9 has no effect on the activity of the kinase. Both of these residues can be phosphorylated by v-src tyrosine kinase in vitro, and co-expression of v-src leads to tyrosine phosphorylation and activation of pdk1. 0.584 SIGNOR-109533 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Thr540 KRLSRSVtMRKSQRS 9606 24505490 YES llicata A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498. 0.2 SIGNOR-204554 MLL2 complex complex SIGNOR-C88 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.2 SIGNOR-268798 UMPS protein P11172 UNIPROT orotic acid smallmolecule CHEBI:16742 ChEBI down-regulates quantity chemical modification 9606 18020427 YES miannu Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate). 0.8 SIGNOR-253580 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2280 LSPSKSerPAKLN -1 26051540 YES irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. 0.472 SIGNOR-259121 SKP2 protein Q13309 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 SIGNOR-C136 20852628 YES gcesareni The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain 0.735 SIGNOR-243548 panobinostat chemical CHEBI:85990 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257756 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1668 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248772 HK3 protein P52790 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266457 PIK-75 Hydrochloride chemical CID:45265864 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206211 4-[2-[(1R)-1-(N-(4-chlorophenyl)sulfonyl-2,5-difluoroanilino)ethyl]-5-fluorophenyl]butanoic acid chemical CHEBI:94983 ChEBI PSEN1 protein P49768 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 18032377 YES gcesareni We employed a combination of chimeric constructs and point mutants to identify structural determinants for ps1-selective inhibition by eln318463. Our studies identified amino acid residues leu(172), thr(281), and leu(282) in ps1 as necessary for ps1-selective inhibition by eln318463. These residues also contributed in part to the ps1-selective inhibition by bms299897. 0.8 SIGNOR-159344 PIM3 protein Q86V86 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity phosphorylation Ser339 GKRGGHSsVSTESES 9606 26075720 YES miannu Pim-1 and Pim-3 enhance phosphorylation and cell surface expression of CXCR4.|The intracellular tail of CXCR4 can be phosphorylated in vitro at Ser339 by Pim-1 kinase and by Pim-3, as shown here, but not by Pim-2. 0.263 SIGNOR-279092 SNAI1 protein O95863 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 19055748 NO lperfetto Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status. 0.7 SIGNOR-252259 TAK-901 chemical CID:16124208 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207191 UVRAG protein Q9P2Y5 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 YES lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.82 SIGNOR-260322 CHEK1 protein O14757 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates phosphorylation Ser331 HPWVRANsRRVLPPS 9606 17276342 YES lperfetto Chk1 phosphorylates aurora-b and enhances its catalytic activity in vitro. 0.361 SIGNOR-152926 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1113 VREAEAAsIKIRTDA -1 11741957 YES lperfetto PKC Phosphorylates Serines 1033 and 1045 in Helix H5 0.391 SIGNOR-249129 PRKCB protein P05771 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.354 SIGNOR-249279 PTPRE protein P23469 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9534 15522235 YES llicata PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src. 0.402 SIGNOR-238074 PRKCA protein P17252 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr41 GIHSGATtTAPSLSG 9606 25058461 YES miannu As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha. 0.414 SIGNOR-278494 HIVEP2 protein P31629 UNIPROT SSTR2 protein P30874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 10207097 YES Luana Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain. 0.411 SIGNOR-261617 NCF1 protein P14598 UNIPROT Phagocyte NADPH oxidase complex complex SIGNOR-C557 SIGNOR form complex binding 9606 37263099 YES miannu NADPH oxidase is composed of essential protein components in its active state: membranous subunits, including p22-phox and gp91-phox, and cytoplasmic subunits, including p47-phox, p67-phox, p40-phox, and RAC2 (in neutrophils), among which NCF4 encodes the cytoplasmic subunit p40-phox 0.749 SIGNOR-277630 MAPK1 protein P28482 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation Ser189; Ser283 SGILGITsPSADTNK;DMKANLAsPTPADIG 9606 BTO:0003079 22593617 YES Gianni In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5. 0.352 SIGNOR-269087 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser295 TKRRKSMsGASPKES 9606 23708659 YES lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. 0.2 SIGNOR-252776 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT up-regulates quantity phosphorylation Ser190 LLSISSEsLQARKEN 9606 BTO:0000007 23649622 YES done miannu TBK1 phosphorylates SIKE on six serine residues that mimic the IRF3 phosphorylation sequence.Serines are listed from left to right: 133, 185, 187, 188, 190, and 198. 0.717 SIGNOR-273817 UBE2I protein P63279 UNIPROT CEBPA protein P49715 UNIPROT down-regulates activity sumoylation Lys161 ALRPLVIkQEPREED -1 12511558 YES miannu C/EBPalpha interacts directly with the E2 SUMO-conjugating enzyme Ubc9 and can be SUMOylated in vitro using purified recombinant components. Our results indicate that SUMO modification of SC motifs provides a means to rapidly control higher order interactions among transcription factors and suggests that SUMOylation may be a general mechanism to limit transcriptional synergy. 0.2 SIGNOR-256334 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation 9606 21620960 YES lperfetto Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. 0.605 SIGNOR-233529 SPOP protein O43791 UNIPROT CUL3 protein Q13618 UNIPROT up-regulates activity binding 9606 BTO:0000007 34599168 YES miannu Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. 0.921 SIGNOR-268927 ML240 chemical CHEBI:143014 ChEBI VCP protein P55072 UNIPROT down-regulates activity chemical inhibition -1 23316025 YES Monia Inhibition of p97 by ML240 and ML241 is ATP competitive. To determine the mechanism by which ML240 and ML241 inhibited p97 ATPase, we evaluated rates of ATP hydrolysis at different concentrations of ATP. ML240 and ML241 inhibited p97competitively with respect to ATP with a Kivalues of 0.22 mm and 0.35 mm respectively. 0.8 SIGNOR-261066 Integrator complex complex SIGNOR-C265 SIGNOR JUNB protein P17275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 25675981 NO lperfetto The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes. 0.2 SIGNOR-261479 PPM1F protein P49593 UNIPROT CAMK4 protein Q16566 UNIPROT down-regulates activity dephosphorylation 9606 11726284 YES miannu Calmodulin-dependent protein kinase phosphatase (CaMKP) dephosphorylates and concomitantly deactivates multifunctional Ca(2+)/calmodulin-dependent protein kinases , such as CaMKI, CaMKII, and CaMKIV. 0.348 SIGNOR-277157 RPN1 protein P04843 UNIPROT OPRM1 protein P35372 UNIPROT up-regulates binding 9606 19289571 YES miannu Ribophorin i (rpni), a component of the oligosaccharide transferase complex, could directly interact with mor. Rpni can be shown to participate in mor export by the intracellular retention of the receptor after small interfering rna knockdown of endogenous rpni. 0.252 SIGNOR-184651 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 YES inferred from 70% family members gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. 0.2 SIGNOR-270024 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258255 FCER1G/FCER1G complex SIGNOR-C199 SIGNOR FCER1 complex SIGNOR-C200 SIGNOR form complex binding 9606 BTO:0000830 16470226 YES Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. 0.61 SIGNOR-254962 SIAH1 protein Q8IUQ4 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 18536714 YES miannu  Here we demonstrate that HIPK2 is an unstable protein that colocalizes and interacts with the E3 ubiquitin ligase Siah-1 in unstressed cells. Siah-1 knockdown increases HIPK2 stability and steady-state levels, whereas Siah-1 expression facilitates HIPK2 polyubiquitination, degradation and thereby inactivation.  0.515 SIGNOR-276166 SRC protein P12931 UNIPROT WBP2 protein Q969T9 UNIPROT up-regulates activity phosphorylation Tyr231 AEAAASAyYNPGNPH 9606 BTO:0000093 21642474 YES miannu Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα. 0.297 SIGNOR-273568 SMURF proteinfamily SIGNOR-PF29 SIGNOR BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 YES inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.2 SIGNOR-270212 ELOC protein Q15369 UNIPROT H1-1 protein Q02539 UNIPROT up-regulates phosphorylation Ser183 KPKKVAKsPAKAKAV 9606 BTO:0000567 20551309 YES lperfetto Our results also show the potential function of p-tefb phosphorylation of h1, namely, to increase h1 dissociation from actively transcribed dna. P-tefb preferentially phosphorylates the ser-183 phosphorylation site of histone h1.1 0.2 SIGNOR-166120 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 BTO:0000567 20543138 YES fstefani Maf1, a repressor that binds and inhibits pol iii, is phosphorylated in a mtor-dependent manner both in vitro and in vivo at serine 75 0.711 SIGNOR-166054 ITCH protein Q96J02 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17463226 YES miannu Interaction with the ErbB-4 receptors occurs via the WW domains of AIP4/Itch. Functional analyses demonstrate that AIP4/Itch is recruited to the ErbB-4 receptor to promote its polyubiquitination and degradation, thereby regulating stability of the receptor and access of receptor intracellular domains to the nuclear compartment.  0.605 SIGNOR-272618 PRKAR1A protein P10644 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.885 SIGNOR-258751 SPTA1 protein P02549 UNIPROT Erythrocytic spectrin complex SIGNOR-C384 SIGNOR form complex binding 9606 BTO:0000424 24302288 YES lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell 0.741 SIGNOR-266025 ATR protein Q13535 UNIPROT ZDHHC13 protein Q8IUH4 UNIPROT up-regulates activity phosphorylation Ser8 MEGPGLGsQCRNHSH 10090 BTO:0000847 28869973 YES miannu Collectively these results suggest that ZDHHC13 phosphorylation by ATR following UVB irradiation promotes its interaction with MC1R to stimulate MC1R palmitoylation. 0.2 SIGNOR-273517 ATM protein Q13315 UNIPROT L3MBTL2 protein Q969R5 UNIPROT up-regulates activity phosphorylation 9606 31225475 YES miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. 0.2 SIGNOR-266785 DAPK1 protein P53355 UNIPROT STX1A protein Q16623 UNIPROT down-regulates activity phosphorylation Ser188 IIMDSSIsKQALSEI 9606 BTO:0000007;BTO:0000356 12730201 YES llicata Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking. 0.34 SIGNOR-251083 IYD protein Q6PHW0 UNIPROT L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI up-regulates quantity chemical modification 9606 28153798 YES scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. 0.8 SIGNOR-267033 MAP3K4 protein Q9Y6R4 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 9606 21152872 NO lperfetto We found that mekk1/mekk4 as opposed to ask1, are responsible for trail-induced c-jun nh2-terminal kinase (jnk) or p38 activation, 0.388 SIGNOR-170534 1-[6-(2-hydroxypropan-2-yl)-2-pyridinyl]-6-[4-(4-methyl-1-piperazinyl)anilino]-2-prop-2-enyl-3-pyrazolo[3,4-d]pyrimidinone chemical CHEBI:91414 ChEBI WEE1 protein P30291 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194423 SDC3 protein O75056 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 10090 BTO:0002314 20696709 YES gcesareni Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. 0.379 SIGNOR-244072 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 20068082 YES gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). 0.856 SIGNOR-163146 ritonavir chemical CHEBI:45409 ChEBI CYP3A4 protein P08684 UNIPROT down-regulates activity chemical inhibition -1 18285471 YES Luana Ritonavir is the most potent and efficacious inhibitor of cytochrome P4503A (CYP3A 0.8 SIGNOR-257769 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr723 SSQGVDTyVEMRPVS 9606 BTO:0001271 15297464 YES lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. 0.2 SIGNOR-127614 PPARG protein P37231 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20303941 NO gcesareni The results from mammalian one-hybrid experiments showed that functional ppar gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation. 0.539 SIGNOR-164516 BRD2 protein P25440 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity relocalization 9606 BTO:0001938 29018219 YES lperfetto BRD2 is required to recruit 53BP1 to DSBs.|When BRD2 recruitment was blocked with shRNA or JQ1 (Fig. 3a and Supplementary Figure 3c) or a panel of BRD2 siRNAs (Supplementary Figure 3a), the recruitment of 53BP1 to DSBs was significantly delayed. 0.269 SIGNOR-262035 MAP3K2 protein Q9Y2U5 UNIPROT PXN protein P49023 UNIPROT down-regulates quantity phosphorylation 9606 25190348 YES miannu As MEKK2 kinase activity is required for this function, our findings support a model of paxillin modification wherein MEKK2 directly phosphorylates and targets paxillin for ubiquitylation. 0.362 SIGNOR-278955 AXIN1 protein O15169 UNIPROT RNF111 protein Q6ZNA4 UNIPROT up-regulates binding 9606 16601693 YES gcesareni Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia. 0.641 SIGNOR-145845 BRD4 protein O60885 UNIPROT KDM5C protein P41229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30921702 NO miannu  KDM5C was transcriptionally upregulated by bromodomain-containing protein 4 (BRD4), and knockdown KDM5C sensitized the therapeutic effects of CRPC cells to the bromodomain and extraterminal (BET) inhibitor.  0.328 SIGNOR-264311 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr106 SGNSAEEyYENVPCK -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.356 SIGNOR-273570 ALDOC protein P09972 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266489 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 18498746 YES lperfetto We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival. 0.819 SIGNOR-178676 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.333 SIGNOR-248551 Ub:E2 complex SIGNOR-C497 SIGNOR CBLB protein Q13191 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271055 prostaglandin D2(1-) smallmolecule CHEBI:57406 ChEBI PTGDR protein Q13258 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257568 ARAP1 protein Q96P48 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.53 SIGNOR-260452 LYN protein P07948 UNIPROT NMT1 protein P30419 UNIPROT unknown phosphorylation Tyr180 YTLLNENyVEDDDNM -1 11594778 YES Human NMT was found to be phosphorylated by non-receptor tyrosine kinase family members of Lyn. a site-directed mutagenesis study indicated that substitution of tyrosine 100 with phenylalanine served NMT as a poor substrate for the Lyn kinase. 0.348 SIGNOR-251404 MC4R protein P32245 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257440 HAX1 protein O00165 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18971376 NO miannu HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels. 0.37 SIGNOR-254222 HIF1A protein Q16665 UNIPROT KDM2B protein Q8NHM5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271567 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 YES lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Atm resides in a complex with brca1 and phosphorylated brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a brca1-deficient cell line.Atm-dependent phosphorylation of ser1423 or ser1524 also occurred in vivo, 0.819 SIGNOR-72079 DTNA protein Q9Y4J8 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.445 SIGNOR-255989 AMPK complex SIGNOR-C15 SIGNOR TXNIP protein Q9H3M7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser308 GLSSRTSsMASRTSS 10116 BTO:0000575 23453806 YES miannu AMPK phosphorylation of TXNIP on S308 accelerates its degradation 0.282 SIGNOR-276489 CYSLTR1 protein Q9Y271 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256740 AKT1 protein P31749 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 KGWEVVEsDLYAMNF 9606 BTO:0000007 31358653 YES miannu Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.  0.37 SIGNOR-276868 CASP8 protein Q14790 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9727491 YES gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. 0.735 SIGNOR-59857 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPD protein P49716 UNIPROT down-regulates binding 9606 12524424 YES fspada C/ebpbeta and c/ebpdelta were found to physically interact with smad3 and smad4, and smad3 cooperated with smad4 and tgf-beta signaling to repress the transcriptional activity of c/ebps. 0.323 SIGNOR-97120 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI CADPS2 protein Q86UW7 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 24363652 YES miannu CAPS exhibits low affinity but functionally significant interactions with plasma membrane PIP2 via its central PH (pleckstrin homology) domain (82, 111). PIP2 enhanced CAPS stimulation of SNARE-dependent liposome fusion with wild-type but not with mutant PH domain CAPS proteins 0.8 SIGNOR-264335 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR PRDM14 protein Q9GZV8 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.514 SIGNOR-269242 IKBKB protein O14920 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser454 PSPAPGGs -1 28689659 YES miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  0.366 SIGNOR-277365 AURKA protein O14965 UNIPROT TPX2 protein Q9ULW0 UNIPROT up-regulates activity phosphorylation Ser121 PAQPQRRsLRLSAQK 9606 BTO:0000567 26240182 YES lperfetto Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells 0.965 SIGNOR-265089 nilotinib chemical CHEBI:52172 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258256 CYP26A1 protein O43174 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI down-regulates quantity chemical modification 9606 31963453 YES lperfetto Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development 0.8 SIGNOR-265139 CDC42BPA protein Q5VT25 UNIPROT LIMK2 protein P53671 UNIPROT up-regulates activity phosphorylation Thr505 NDRKKRYtVVGNPYW 9534 BTO:0004055 11340065 YES lperfetto These results indicate that mrckalpha phosphorylates and activates lim kinases downstream of cdc42, which in turn regulates the actin cytoskeletal reorganization through the phosphorylation and inactivation of adf/cofilin. 0.395 SIGNOR-107584 ADRA2C protein P18825 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.486 SIGNOR-256842 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 21808241 YES gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. 0.635 SIGNOR-175821 EP300 protein Q09472 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates acetylation Lys57 TIVRRRAkGAMGLEH 9606 BTO:0000801 20626350 YES gcesareni A recent report shows that mkp1 may also be regulated by acetylation. When raw macrophages are stimulated with lps, mkp1 becomes acetylated on lys57 by p300 0.31 SIGNOR-166581 CAMK2D protein Q13557 UNIPROT TPD52 protein P55327 UNIPROT unknown phosphorylation Ser176 KNSPTFKsFEEKVEN 9606 20946871 YES gcesareni Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation 0.2 SIGNOR-168550 MYOCD protein Q8IZQ8 UNIPROT ACTG2 protein P63267 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19797053 NO miannu  These results demonstrate the ability of MYOCD to discriminate among several juxtaposed CArG elements, presumably through its novel partnership with NKX3.1, to optimally transactivate the human ACTG2 promoter. 0.426 SIGNOR-254620 KLHL21 protein Q9UJP4 UNIPROT EB1/MLL protein Q5UEC6 UNIPROT up-regulates activity binding 9606 BTO:0000567 27641145 YES miannu Indeed, KLHL21 localizes to FA structures preferentially at the leading edge, and in complex with Cul3, ubiquitylates EB1 within its microtubule-interacting CH-domain. Cells lacking CRL3(KLHL21) activity or expressing a non-ubiquitylatable EB1 mutant protein are unable to migrate and exhibit strong defects in FA dynamics, lamellipodia formation and cortical plasticity. Our study thus reveals an important mechanism to regulate cortical dynamics during cell migration that involves ubiquitylation of EB1 at focal adhesions. 0.2 SIGNOR-272407 MAPK11 protein Q15759 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21757713 YES llicata Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation. 0.353 SIGNOR-174874 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 YES miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. 0.2 SIGNOR-251570 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR FGFR4 protein P22455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 NO miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. 0.2 SIGNOR-251565 CKM complex complex SIGNOR-C406 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. 0.2 SIGNOR-273172 CALU protein O43852 UNIPROT GGCX protein P38435 UNIPROT down-regulates activity binding 10116 BTO:0000759 15075329 YES lperfetto Results are presented that demonstrate that the endoplasmic reticulum chaperone protein calumenin is associated with gamma-carboxylase and inhibits its activity. 0.401 SIGNOR-265910 CTDP1 protein Q9Y5B0 UNIPROT CDK1 protein P06493 UNIPROT down-regulates activity dephosphorylation 9606 26653855 YES miannu Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.|We can not exclude that, in addition to S90 and S453, other Cdk1 phosphorylation sites in Gwl are dephosphorylated by Fcp1; nevertheless, assaying S67-Ensa kinase activity of V5-GwlS90A and V5-GwlS453A mutant proteins, isolated from transfected and prometaphase arrested HeLa cells, revealed that both mutants had significantly reduced S67-Ensa kinase activity compared to V5-GwlWT (XREF_FIG).|We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells. 0.333 SIGNOR-277141 CSNK1E protein P49674 UNIPROT PER1 protein O15534 UNIPROT down-regulates phosphorylation 9606 15917222 YES miannu Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1. 0.842 SIGNOR-137706 USP28 protein Q96RU2 UNIPROT UCK1 protein Q9HA47 UNIPROT up-regulates quantity by stabilization deubiquitination Lys81 EQKAKALkGQYNFDH 31938050 YES lperfetto We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. 0.2 SIGNOR-275855 PRKACA protein P17612 UNIPROT SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation Ser9 NYLRRRLsDSNFMAN -1 10571231 YES miannu Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I 0.339 SIGNOR-250058 DHPS protein P49366 UNIPROT EIF5A protein P63241 UNIPROT up-regulates activity post translational modification -1 32142284 YES miannu Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation. 0.933 SIGNOR-266374 DYRK1B protein Q9Y463 UNIPROT ID2 protein Q02363 UNIPROT down-regulates activity phosphorylation Thr27 LGISRSKtPVDDPMS 9606 26735018 YES miannu Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2Œ± ubiquitylation.|We report that DYRK1A and DYRK1B kinases phosphorylate ID2 on Threonine-27 (T27). 0.2 SIGNOR-279033 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000142 20308788 YES The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. 0.2 SIGNOR-164659 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 YES gcesareni The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. 0.372 SIGNOR-105766 KLHL12 protein Q53G59 UNIPROT DVL1 protein O14640 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 16547521 YES miannu  KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation. 0.619 SIGNOR-271558 SCF-betaTRCP complex SIGNOR-C5 SIGNOR MYC protein P01106 UNIPROT up-regulates quantity ubiquitination 9606 20852628 YES gcesareni Here we show that SCF²-TrCP binds to Myc by means of a characteristic phosphodegron and ubiquitylates Myc; this results in enhanced Myc stability. 0.47 SIGNOR-243542 AKT1 protein P31749 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity phosphorylation Tyr47 KTGQAPGySYTAANK -1 32781572 YES miannu Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. 0.465 SIGNOR-277237 CSNK1D protein P48730 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser396 ELSPPHAsEASQMS 9606 BTO:0002552 28581525 YES lperfetto CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. 0.2 SIGNOR-264892 ID2 protein Q02363 UNIPROT TCF4 protein P15884 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C129 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.597 SIGNOR-241376 CDH13 protein P55290 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.533 SIGNOR-265853 GTF2H3 protein Q13889 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 YES lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.904 SIGNOR-269314 EPHA2 protein P29317 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation 9606 32753469 YES miannu EphA2 activates PLC\u03b31 in human lung cancer cells.|The result here showed that only wild-type EphA2, but not K646M\nor Y588F mutants, could phosphorylate PLC\u03b31, demonstrating that\nPLC\u03b31 phosphorylation is dependent on the kinase activity of EphA2. 0.276 SIGNOR-279708 POU3F4 protein P49335 UNIPROT POU3F2 protein P20265 UNIPROT up-regulates activity binding -1 9105675 YES miannu POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes. 0.312 SIGNOR-220080 suprofen chemical CHEBI:9362 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001061 18667313 YES Luana Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2.  0.8 SIGNOR-257809 RUVBL1 protein Q9Y265 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.719 SIGNOR-270855 ERBB4 protein Q15303 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 15863494 YES miannu ERBB4 directly activates STAT5A, in part, through phosphorylation of STAT5A at the regulatory Tyr-694.|ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events. 0.811 SIGNOR-279711 DNMT3A protein Q9Y6K1 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24280869 NO miannu HOXA9 is significantly upregulated in both categories of DNMT3A modifications and this has been associated with poor prognosis in AML before (Figure 3d). In fact, almost the entire HOXA and HOXB cluster were significantly upregulated in AML samples with either epimutation or mutation in DNMT3A. 0.338 SIGNOR-256128 NEK11 protein Q8NG66 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 19734889 YES lperfetto Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites 0.418 SIGNOR-187871 CASP8 protein Q14790 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.333 SIGNOR-261744 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr1967 QQDKASLtRTLQHRI 9606 BTO:0000938 19824698 YES lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. substitution of thr1969 located in close proximity to thr1967 had little effect on its kinase activity 0.2 SIGNOR-188417 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser357 DGSGDTSsNEEIGST -1 12107178 YES llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. 0.415 SIGNOR-250992 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-252921 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser391 RSSMNNGsPTALSGS 9606 BTO:0000007 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249309 USP11 protein P51784 UNIPROT EEF1A1 protein P68104 UNIPROT up-regulates activity deubiquitination Lys439 TVAVGVIkAVDKKAA 9606 BTO:0000608 37973952 YES Marta Tosoni USP11 interacted with and deubiquitinated eEF1A1 on Lys439, thereby inhibiting its ubiquitin-mediated degradation. Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription 0.2 SIGNOR-278107 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120236 HMGB1 protein P09429 UNIPROT HOXB3 protein P14651 UNIPROT up-regulates activity binding -1 8890171 YES miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. 0.298 SIGNOR-219902 PKA proteinfamily SIGNOR-PF17 SIGNOR PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr34 MIRRRRPtPAMLFRL 9606 BTO:0000938 10604473 YES miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  0.2 SIGNOR-264956 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates activity phosphorylation Tyr754 LLAVSEEyLDLRLTF -1 8576110 YES Analysis of the major autophosphorylation site Y754F mutant of FGFR-4 showed that binding of p85 and its serine phosphorylation were independent of receptor autophosphorylation at this site. 0.2 SIGNOR-251140 AKT2 protein P31751 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000586 SIGNOR-C110 16293724 YES lperfetto We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase Akt by free G protein betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. 0.622 SIGNOR-235718 TRIM5 protein Q9C035 UNIPROT TRIM5 protein Q9C035 UNIPROT up-regulates quantity monoubiquitination 9606 BTO:0000567 18312418 YES miannu Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B. Thus, the ubiquitination of TRIM5alpha is catalyzed by itself and Ro52. Unexpectedly, although TRIM5alpha is ubiquitinated, our results have revealed that the proteasome inhibitors MG115 and MG132 do not stabilize it in HeLa cells, suggesting that the ubiquitination of TRIM5alpha does not lead to proteasomal degradation. Importantly, TRIM5alpha is clearly conjugated by a single ubiquitin molecule (monoubiquitination). Our monoubiquitin-fusion assay suggests that monoubiquitination is a signal for TRIM5alpha to translocate from cytoplasmic bodies to the cytoplasm. 0.2 SIGNOR-271671 AKT3 protein Q9Y243 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity phosphorylation Tyr47 KTGQAPGySYTAANK -1 32781572 YES miannu Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. 0.265 SIGNOR-277235 AKT proteinfamily SIGNOR-PF24 SIGNOR FLNC protein Q14315 UNIPROT up-regulates quantity by stabilization phosphorylation Ser2233 LGRERLGsFGSITRQ 10090 BTO:0000165 32444788 YES miannu We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236. 0.2 SIGNOR-262616 GLE1 protein Q53GS7 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.589 SIGNOR-262096 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 16603398 YES amattioni In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein. 0.746 SIGNOR-145855 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. 0.75 SIGNOR-235960 DCAF1 protein Q9Y4B6 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0005907 25026211 YES miannu CRL4 DCAF1 ubiquitylates and inhibits Lats. 0.2 SIGNOR-272228 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT down-regulates quantity relocalization 9606 BTO:0000007 22575959 YES Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. 0.802 SIGNOR-260113 ABL1 protein P00519 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000150 15138294 YES llicata C-abl activation by apoptotic agents specifically promotes phosphorylation of lasp-1 at tyrosine 171, which is associated with the loss of lasp-1 localization to focal adhesions and induction of cell death. Thus, lasp-1 is a dynamic focal adhesion protein necessary for cell migration and survival in response to growth factors and ecm proteins. 0.343 SIGNOR-124719 IFNA1 protein P01562 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 8181059 YES fspada The present study describes a novel type i ifn receptor having the ability to bind and respond to several subtypes of ifn-a as well as to ifn-8. This 102 kda-51 kda receptor is essential for the activity of many type i ifns, as demonstrated with anti-receptor antibodies. 0.65 SIGNOR-36622 RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 BTO:0000007 15327770 YES lperfetto TNF_ induced the polyubiquitination of RIP and the association of polyubiquitinated RIP with TAB2. 0.863 SIGNOR-128406 PIK3R3 protein Q92569 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9415396 YES gcesareni The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha 0.846 SIGNOR-53597 MYH9 protein P35579 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000498 32685004 YES miannu  Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo. 0.274 SIGNOR-278896 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR BSG protein P35613 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 28117675 YES miannu FBXO22 mediates poly-ubiquitination and degradation of CD147. Classically, F-box protein together with Skp1 and Cullin 1 constitute Skp-Cullin-F box ubiquitin E3 ligase (SCFs) 0.2 SIGNOR-272789 MAPK1 protein P28482 UNIPROT PDE4B protein Q07343-2 UNIPROT up-regulates activity phosphorylation Ser487 YQSMIPQsPSPPLDE -1 11030732 YES miannu The short-form PDE4B2 isoenzyme was activated by Erk2 phosphorylation. These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid. 0.269 SIGNOR-275971 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr402 CSIESDIyAEIPDET 10116 11337490 YES Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation|CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity. 0.545 SIGNOR-248662 FZD2 protein Q14332 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 23151663 YES areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  0.649 SIGNOR-258959 MAPK3 protein P27361 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Thr891 NSETSSDtPEMSLSA 10090 BTO:0000944 11581251 YES lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. 0.416 SIGNOR-249470 P2RY2 protein P41231 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256902 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser393 NLQIRETsLDTKSVS -1 7822264 YES llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. 0.428 SIGNOR-250629 MAPK8 protein P45983 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 BTO:0000671 19234442 YES gcesareni The stress-response kinase jnk1, activated by dna damage and initiating a pro-apoptotic program, has been recently shown to translocate into the nucleus upon activation where it phosphorylates substrates including h2ax s139, an event critical for dna degradation mediated by caspase-activated dnase (cad) in apoptotic cells 0.2 SIGNOR-184146 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Phe619 EVKMDAEfRHDSGYE -1 8943232 YES lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261769 RNF26 protein Q9BY78 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 27368102 YES miannu SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors. 0.358 SIGNOR-269830 ATXN2L protein Q8WWM7 UNIPROT DDX6 protein P26196 UNIPROT unknown binding 9606 23209657 YES miannu Ataxin-2-like associates with known interaction partners of ataxin-2, the rna helicase ddx6 0.54 SIGNOR-199948 ITGA10 protein O75578 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.69 SIGNOR-253185 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 12690203 YES miannu P53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Purified p300 exhibited intrinsic ubiquitin ligase activity that was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300. 0.912 SIGNOR-271418 AKT1 protein P31749 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 20693286 YES miannu AKT1 stimulated PLD activity via activation of ERK.|AKT1 actually phosphorylated ERK2 as a substrate (K(m) 1 \u03bcm). 0.532 SIGNOR-279136 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu68 VEETCSYeEAFEALE -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263681 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 YES gcesareni Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth. 0.759 SIGNOR-252601 PRKD2 protein Q9BZL6 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 34010649 YES lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-275949 MAPK1 protein P28482 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates activity phosphorylation 9606 12809513 YES inferred from family member llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. 0.443 SIGNOR-270303 DLG3 protein Q92796 UNIPROT NMDA receptor_2C complex SIGNOR-C349 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 YES lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. 0.682 SIGNOR-266008 SLBP protein Q14493 UNIPROT H2BC14 protein Q99879 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265390 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 20233713 YES flangone Employing an mtor active-site inhibitor wye-125132 (wye-132), we have performed quantitative phospho-proteomics and identified a ser-75-containing phosphopeptide from maf1, a known repressor of rna polymerase iii (pol iii) transcriptionmaf1 mutant proteins carrying s75a alone or with s60a, t64a, and s68a (maf1-s75a, maf1-4a) progressively enhanced basal repression of trna in actively proliferating cells and attenuated amino acid-induced trna transcription 0.711 SIGNOR-164352 GSK3A protein P49840 UNIPROT NOL3 protein O60936 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 28670266 YES miannu The present study provided evidence that GSK3alpha and beta directly phosphorylates Arc, resulting in its subsequent degradation. 0.2 SIGNOR-279179 PRKCB protein P05771 UNIPROT NRGN protein Q92686 UNIPROT up-regulates activity phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 YES lperfetto Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM. 0.362 SIGNOR-248914 TGFB1 protein P01137 UNIPROT ACTA2 protein P62736 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000764 20846954 NO Regulation miannu We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes. 0.419 SIGNOR-251923 TYSND1 protein Q2T9J0 UNIPROT SCP2 protein P22307 UNIPROT up-regulates activity cleavage -1 17255948 YES miannu Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1. 0.502 SIGNOR-261055 MAP2K4 protein P45985 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Tyr182 ADAEMTGyVVTRWYR 9606 BTO:0000007 10066767 YES done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. 0.457 SIGNOR-273955 TNIK protein Q9UKE5 UNIPROT NF2 protein P35240 UNIPROT up-regulates activity phosphorylation Ser13 ASRMSFSsLKRKQPK 9606 33495197 YES miannu Consistently with TNIK modulating Merlin, we also observed reduced YAP levels following TNIK knockdown in LK2 and NCI-H520 cells (Supplementary Fig. S7B).|Using in vitro kinase assays followed by phosphopeptide mapping, and mass spectrometry analysis on Merlin isolated from cells co-expressing TNIK and Merlin, we determined that TNIK could phosphorylate Merlin at S13, T272, S315, and T576 (Fig. 4B, Supplementary Fig. S4D, and Supplementary Table S3). 0.2 SIGNOR-278388 SREBF1 protein P36956 UNIPROT LRP1 protein Q07954 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980003 NO miannu In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression. 0.277 SIGNOR-254462 MAPK1 protein P28482 UNIPROT MYLK protein Q15746 UNIPROT up-regulates activity phosphorylation 9606 24116218 YES miannu Inhibition of ERK2 impaired phosphorylation of MLCK and insulin stimulated glucose uptake.|These findings suggest that ERK2 activates MLCK which then mediates the phosphorylation of RLC of MyoIIA. 0.476 SIGNOR-279226 DOK1 protein Q99704 UNIPROT Av/b2 integrin complex SIGNOR-C176 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.297 SIGNOR-257684 PTPRB protein P23467 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation 9606 27314562 YES miannu Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2. 0.446 SIGNOR-277132 CTCF protein P49711 UNIPROT BCL6 protein P41182 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001690 20733034 NO miannu Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription. 0.278 SIGNOR-253824 PPM1G protein O15355 UNIPROT SNRPN protein P63162 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 17984321 YES lperfetto Dephosphorylation of survival motor neurons (SMN) by PPM1G and PP2Cgamma governs Cajal body localization and stability of the SMN complex.|This indicates that the catalytic activity of PPM1G promotes accumulation of the SMN complex in CBs and suggests that PPM1G is a major determinant of the SMN-complex localization in the nucleus. 0.2 SIGNOR-277021 FGF2 protein P09038 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8142649 NO Regulation miannu Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. 0.2 SIGNOR-251795 CHUK protein O15111 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser454 PSPAPGGs -1 28689659 YES miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  0.429 SIGNOR-277363 PSEN1 protein P49768 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 2195779 YES gcesareni Importantly, our data show that binding of ps1 to cadherin mediates the effects of ps1 on the phosphorylation, ubiquitination, and destabilization of beta-catenin. Thus, cadherins mediate both the association of ps1 and beta-catenin and the effects of ps1 on the cellular levels of beta-catenin 0.808 SIGNOR-22837 BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 YES amattioni Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim) 0.676 SIGNOR-55546 FBXL18 protein Q96ME1 UNIPROT ERCC3 protein P19447 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 30762924 YES miannu These results led us to propose a model that spironolactone may trigger the phosphorylation of XPB at Ser90 by CDK7, which promotes the recognition and polyubiquitination of XPB by SCFFBXL18 for proteasomal degradation. 0.2 SIGNOR-277434 VAV1 protein P15498 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 9013873 NO lperfetto Vav may link gp130 activation to downstream mapk activation in hematopoietic cells. 0.509 SIGNOR-244640 ECM stimulus SIGNOR-ST20 SIGNOR Av/b6 integrin complex SIGNOR-C179 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259039 FAS protein P25445 UNIPROT FAS protein P25445 UNIPROT up-regulates activity binding 9606 BTO:0000776 19305384 YES lperfetto Fas/FasL, TRAIL/DR4, TRAIL/DR5 and TNF-alpha/TNFR1 are ligand/receptor pairs of the tumor necrosis factor/nerve growth factor family, which are able to induce apoptosis by trimerization of the receptor by its corresponding ligand. 0.2 SIGNOR-217809 Ub:E2 complex SIGNOR-C497 SIGNOR WDR59 protein Q6PJI9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271115 FOXO3 protein O43524 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity transcriptional regulation 22848740 YES We show that FOXO3 binds and activates its own promoter via a positive autoregulatory feedback loop 0.2 SIGNOR-255757 MKRN1 protein Q9UHC7 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 31640799 YES miannu We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1.Our data show that MKRN1 associates with polysomes and ubiquitylates RPS10, indicating a role in translational control. We hypothesize that ribosomes encountering the MKRN1-PABPC1 complex are stalled, possibly via ubiquitylation of RPS10 on K107 and other MKRN1 substrates. 0.351 SIGNOR-272215 SRC protein P12931 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates activity phosphorylation 9606 23804646 YES miannu Further, we show here that c-Src dramatically stimulates IRF4 phosphorylation and activity and that Y61 and Y124 are two key sites responding to c-Src-mediated activation.|We have further shown that inhibition of c-Src activity reduces p-IRF4(Y121/124) and significantly represses transcription of the IRF4 target B cell integration cluster in Epstein-Barr virus-transformed cells. 0.273 SIGNOR-279287 SRC protein P12931 UNIPROT LMNA protein P02545 UNIPROT up-regulates activity phosphorylation Tyr45 LNDRLAVyIDRVRSL 9606 34385357 YES miannu In this study, we found that the constitutively active Src Y527F mutant caused the disassembly of lamin A/C. We demonstrate that Src directly phosphorylates lamin A mainly at Tyr45 both in vitro and in intact cells. 0.508 SIGNOR-279288 NR3C1/STAT5A complex SIGNOR-C84 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 12540601 NO fspada We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner. 0.7 SIGNOR-97562 STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR up-regulates 9606 BTO:0000782 22767500 NO lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. 0.7 SIGNOR-261901 MARCHF1 protein Q8TCQ1 UNIPROT INSR protein P06213 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27577745 YES miannu MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation. 0.2 SIGNOR-278819 TBX22 protein Q9Y458 UNIPROT MSX2 protein P35548 UNIPROT down-regulates quantity by repression transcriptional regulation 9031 BTO:0005956 20033915 YES miannu the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22. 0.309 SIGNOR-265567 CSNK2A1 protein P68400 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser1037 IGNSNHGsQSPRNVE 23858473 YES phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. 0.2 SIGNOR-273427 PPAT protein Q06203 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 9914248 YES miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. 0.8 SIGNOR-267293 GNAL protein P38405 UNIPROT RIC8B protein Q9NVN3 UNIPROT up-regulates activity binding 9606 BTO:0000552 33802009 YES Marta Tosoni In the olfactory sensory neurons located in the nasal epithelium, OR activation by odorants or other stimuli can switch on a specific olfactory G-protein (GNAL), which in turn stimulatesand ADCY3 and Ric8b leads to cyclic adenosine monophosphate (cAMP) generation from adenosine triphosphate (ATP) 0.493 SIGNOR-278071 HIF-1 complex complex SIGNOR-C418 SIGNOR BNIP3 protein Q12983 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 YES miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 0.38 SIGNOR-267454 HOPX protein Q9BPY8 UNIPROT LORICRIN protein P23490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 21256618 NO miannu In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation. 0.2 SIGNOR-254464 TNFRSF10C protein O14798 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 BTO:0000671 20103630 YES amattioni Albeit on binding the ligand, dcr1 and dcr2 do not transduce the apoptogenic signal, 0.898 SIGNOR-163611 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser113 SPAPPAIsPIIKNAI 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262765 tazarotene chemical CHEBI:32184 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9534 19058965 YES Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  0.8 SIGNOR-258028 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 11691836 YES lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 0.658 SIGNOR-249394 TGFA protein P01135 UNIPROT NKD2 protein Q969F2 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 18757723 YES miannu Here, we show that Naked2 is a short-lived protein with a half-life of 60 min caused by its rapid ubiquitin-mediated proteasomal degradation. Overexpression of TGF-alpha stabilizes Naked2 protein in an EGF receptor (EGFR)-independent manner; a physical interaction between the cytoplasmic tail of TGF-alpha and Naked2 is necessary and sufficient for this protection. We have identified a RING finger protein, AO7/RNF25, as a ubiquitin ligase for Naked2, and we have shown that overexpression of TGF-alpha reduces binding of AO7 to Naked2. 0.45 SIGNOR-271739 THR proteinfamily SIGNOR-PF84 SIGNOR RARA protein P10276 UNIPROT up-regulates binding 9606 15650024 YES inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.2 SIGNOR-270313 antigen smallmolecule CHEBI:59132 ChEBI BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 YES scontino The recognition of antigen by the BCR initiates BCR signaling cascade. 0.8 SIGNOR-268203 sabcomeline chemical CHEBI:134846 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10116 9399977 YES miannu SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes 0.8 SIGNOR-258674 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser756 HSCLEQAs 9606 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251284 DYRK3 protein O43781 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 23415227 YES miannu Thus, DYRK3 directly phosphorylates PRAS40 at Thr246, a phosphorylation site responsible for regulation of PRAS40, resulting in decreased binding of PRAS40 to mTORC1, allowing activation of mTORC1 signaling in unstressed cells and reactivation of mTORC1 during stress recovery.Finally, we studied the dynamics of how DYRK3 couples SG partitioning with mTORC1 regulation. 0.34 SIGNOR-279167 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.68 SIGNOR-249362 GRK5 protein P34947 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.488 SIGNOR-251210 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAPN1 protein P07384 UNIPROT up-regulates activity chemical activation 9606 BTO:0000590 25969760 YES lperfetto The data obtained from those studies suggest that the mechanisms leading to the formation of the hallmark lesions of AD might be linked. One of such mechanisms seems to be the dysregulation of calcium homeostasis that results in the abnormal activation of calpains. Calpains are a family of Ca2+-dependent cysteine proteases that play a key role in multiple cell functions including cell development, differentiation and proliferation, axonal guidance, growth cone motility, and cell death, among others. 0.8 SIGNOR-251580 FLT1 protein P17948 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr155 LNDSAAYyLNDLDRI -1 33139573 YES miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. 0.257 SIGNOR-277229 serotonin smallmolecule CHEBI:28790 ChEBI HTR3B protein O95264 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264290 STK11 protein Q15831 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates activity phosphorylation Thr80 LPKLYLPtGPRRGRD 9606 25329316 YES miannu Mass spectrometry analysis of the phosphorylated CDKN1A identified Thr80 as the residue phosphorylated by LKB1 in vitro (Figure 4A and S5A).|UVB induced phosphorylation of LKB1 T366 mediates CDKN1A degradation. 0.488 SIGNOR-278253 PRKAR2A protein P13861 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.876 SIGNOR-258752 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 BTO:0000763 20861316 YES lperfetto We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity 0.3 SIGNOR-167993 CDK5 protein Q00535 UNIPROT SOX6 protein P35712 UNIPROT down-regulates quantity phosphorylation 9606 24662752 YES miannu GST-Sox6 was phosphorylated in vitro by Cdk5 and p35 (XREF_FIG).|Inhibition of Cdk5 activity by DN Cdk5 and roscovitine increases the Sox6 expression in primary cortical neurons. 0.367 SIGNOR-279365 HRH2 protein P25021 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257049 farnesol chemical CHEBI:28600 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258159 Activated PSC phenotype SIGNOR-PH224 SIGNOR TGFB1 protein P01137 UNIPROT up-regulates quantity 9606 BTO:0000988 38540204 YES miannu Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction 0.7 SIGNOR-277673 GNRHR protein P30968 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.476 SIGNOR-257331 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr234 PNFYDETyDYGGFTM 9606 12052863 YES lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). 0.603 SIGNOR-88907 TOMM70 protein O94826 UNIPROT HSP90AA1 protein P07900 UNIPROT up-regulates activity binding 9534 12526792 YES miannu The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting. 0.2 SIGNOR-261379 SEC23IP protein Q9Y6Y8 UNIPROT SEC23A protein Q15436 UNIPROT up-regulates activity binding 10090 BTO:0000142 10400679 YES lperfetto The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway. 0.571 SIGNOR-265307 POLR2H protein P52434 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.82 SIGNOR-266172 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.564 SIGNOR-89182 DYRK1A protein Q13627 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation 9606 22110360 YES miannu Moreover, Dyrk1A appears to directly phosphorylate the C-terminal domain of ASK1.|The current finding that Dyrk1A enhances the activities of ASK1 and JNK1, it could act as a pro-apoptotic player. 0.396 SIGNOR-279366 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity phosphorylation Ser283 PERSQEEsPPGSTKR 9606 34363019 YES miannu DYRK2 depletion by siRNA substantially increased CDC25A protein levels (Fig.\u00a01C) and led to an extension of its half-life (Supplementary Fig.\u00a01C).|Phosphorylation of CDC25A on S283 by DYRK2 could suggest a role for DYRK2 complementary to the CDK/cyclin complexes\u2019 action during mitotic exit. 0.2 SIGNOR-279367 KDM5C protein P41229 UNIPROT BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 31691806 NO miannu The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. 0.274 SIGNOR-264315 PIWIL1 protein Q96J94 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates binding 9606 BTO:0003081 32203416 YES miannu PIWIL1 leads to the constitutive activation of APC/C in PDAC cells. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. Collectively, these results demonstrate that Pinin is an authentic substrate of APC/CPIWIL1 in PDAC cells. 0.2 SIGNOR-272202 CDK5 protein Q00535 UNIPROT CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser313 RCRTLSGsPRPKNFK 9534 11733001 YES miannu P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed. 0.741 SIGNOR-112418 SRC protein P12931 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 BTO:0000150;BTO:0000567 9500442 YES tpavlidou Although the molecular mechanisms underlying ligand-independent activation of era are not completely understood, phosphorylation of a serine residue in af1 has been implicated in the response to epidermal growth factor. Era is also a target for tyrosine phosphorylation, anda single tyrosine residue located immediately adjacent to af2 has been identified as a substrate for src-family tyrosine kinases. 0.777 SIGNOR-55857 AURKC protein Q9UQB9 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-98361 MAPK14 protein Q16539 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates phosphorylation Ser211 PGKETNEsPWRSDLL 10090 20660302 YES We demonstrate here that AMPK differentially modulates glucocorticoid action by phosphorylating the human GR at serine 211 indirectly through the activation of p38 MAPK 0.509 SIGNOR-255952 TCF4 protein P15884 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18852287 YES Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription. 0.371 SIGNOR-253324 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser150 PELCGPGsPPVLTPG 9606 15952796 YES lperfetto We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling. 0.374 SIGNOR-138163 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9534 BTO:0004055 12023018 YES miannu We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity. 0.852 SIGNOR-272611 SGF29 protein Q96ES7 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.2 SIGNOR-269572 TSC1 protein Q92574 UNIPROT TSC complex SIGNOR-C101 SIGNOR form complex binding 9606 12172553 YES lperfetto TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). 0.934 SIGNOR-217910 SOCS4 protein Q8WXH5 UNIPROT DAB1 protein O75553 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0000298 24210661 YES miannu SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. 0.2 SIGNOR-272139 SMARCA5 protein O60264 UNIPROT WICH complex SIGNOR-C449 SIGNOR form complex binding 9606 16603771 YES miannu We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling. 0.925 SIGNOR-268827 ADSS2 protein P30520 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-267343 CTNNB1 protein P35222 UNIPROT SOX2 protein P48431 UNIPROT up-regulates activity binding 10090 BTO:0002572 BTO:0002181 24482235 YES flangone The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes. 0.708 SIGNOR-242087 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 9606 22778263 YES lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. 0.273 SIGNOR-198142 obinutuzumab antibody DB08935 DRUGBANK MS4A1 protein P11836 UNIPROT down-regulates activity binding 9606 BTO:0001546;BTO:0004656 28584136 YES miannu Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL). 0.4 SIGNOR-259896 PDIK1L protein Q8N165 UNIPROT STK35/PDIK1L complex SIGNOR-C552 SIGNOR form complex binding 9606 BTO:0002181 35021089 YES miannu Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport. 0.2 SIGNOR-273771 IL15RA protein Q13261 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation 9606 30029643 YES areggio Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 0.5 SIGNOR-256225 CRB3 protein Q9BUF7 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR up-regulates binding 10090 BTO:0000150 21145499 YES milica Interestingly, knockdown of crb3, which facilitates crumbs complex assembly and localization to the apical junctions disrupted taz/yap interaction with multiple components of the complex, whereas the other knockdowns only disrupted their respective interaction. 0.538 SIGNOR-170399 ADSS1 protein Q8N142 UNIPROT N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI up-regulates quantity chemical modification 9606 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-267348 cysteine smallmolecule CHEBI:15356 ChEBI Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates quantity precursor of 9606 11347887 YES miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. 0.8 SIGNOR-270476 CBLB protein Q13191 UNIPROT TYRO3 protein Q06418 UNIPROT up-regulates activity ubiquitination 9606 31531847 YES miannu Consistent with these data, we also found that Tyro3 is ubiquitinated by Cbl-b.|These data suggest that not only was Tyro3 a ubiquitination target of Cbl-b, but also that Cbl-b was a phosphorylation target of Tyro3. 0.351 SIGNOR-278807 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI LATS1 protein O95835 UNIPROT down-regulates 9606 BTO:0000007 22863277 NO milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. 0.8 SIGNOR-198550 NFYB protein P25208 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 NO miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 0.2 SIGNOR-254431 ATAT1 protein Q5SQI0 UNIPROT TUBA4A protein P68366 UNIPROT up-regulates quantity by stabilization acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 YES lperfetto Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules 0.262 SIGNOR-272249 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 6958488 YES nasal polyposys gcesareni 0.8 SIGNOR-251688 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258443 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser853 SSLNSSEsDKDQDYD 10090 10671552 YES llicata Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | Under these conditions, phosphorylation of the E-cadherin double mutant S853A/S855A was reduced by 25% as compared with wt E-cadherin. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion. 0.402 SIGNOR-250841 TBK1 protein Q9UHD2 UNIPROT PRPS2 protein P11908 UNIPROT up-regulates activity phosphorylation Thr228 DMADTCGtICHAADK -1 34343500 YES miannu Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis.  0.2 SIGNOR-277317 APBA1 protein Q02410 UNIPROT STXBP1 protein P61764 UNIPROT up-regulates activity binding 10116 9395480 YES miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. 0.701 SIGNOR-264035 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Ser14 PFSCHYPsRLRRDPF 9606 BTO:0000887 11342557 YES lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation 0.307 SIGNOR-107684 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.497 SIGNOR-248316 CSNK2A1 protein P68400 UNIPROT CERS4 protein Q9HA82 UNIPROT up-regulates activity phosphorylation Ser350 DVEESDSsEEAAAAQ 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273982 AR protein P10275 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates binding 9606 11518799 YES gcesareni Ar suppresses transcription of the lhbeta subunit by interacting with steroidogenic factor-1. 0.41 SIGNOR-109996 MAP4K5 protein Q9Y4K4 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 9606 16914735 YES lperfetto Gckr can phosphorylate an n-terminal recombinant fusion protein of gsk3beta and enhance the in vivo phosphorylation of gsk3beta on serine 9reduction of gckr expression inhibits wnt3a-induced phosphorylation of gsk3beta at serine 9 and decreases the accumulation of cytosolic _-catenin. 0.2 SIGNOR-228006 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR up-regulates 25838379 NO lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules. 0.7 SIGNOR-262600 CCT128930 chemical CID:17751819 PUBCHEM AKT2 protein P31751 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;ATP-competitive inhibitor of Akt2 gcesareni 0.8 SIGNOR-190868 CSNK1A1 protein P48729 UNIPROT ZRANB1 protein Q9UGI0 UNIPROT up-regulates activity phosphorylation Ser209 RWRGSCSsGNSQRRS 9606 BTO:0000007 30686098 YES miannu Interestingly, ZRANB1 is phosphorylated at Thr35, and Ser209 residues by CSNK1A1, and this phosphorylation activates its deubiquitinating activity. 0.2 SIGNOR-273621 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120216 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 BTO:0000150 19085255 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase. 0.595 SIGNOR-182804 CASP3 protein P42574 UNIPROT ACIN1 protein Q9UKV3 UNIPROT up-regulates cleavage 9606 10490026 YES amattioni Induces apoptotic chromatin condensation after activation by casp3 0.627 SIGNOR-70800 MOV10 protein Q9HCE1 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity binding 9606 27016603 YES miannu MOV10 has been shown to promote mRNA degradation by associating with UPF1, this activity requires the helicase activity of MOV10. 0.522 SIGNOR-261139 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 8940173 YES miannu The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.2 SIGNOR-246248 MAPK9 protein P45984 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 YES The effect has been demonstrated using P45984-2 gcesareni Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. 0.482 SIGNOR-179275 SKP2 protein Q13309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 15998794 YES gcesareni Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3). 0.766 SIGNOR-138493 PPP2R1A protein P30153 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR form complex binding 9606 23454242 YES gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. 0.909 SIGNOR-243436 MAPK1 protein P28482 UNIPROT SORBS3 protein O60504 UNIPROT unknown phosphorylation Ser530 DGPQLPTsPRLTAAA 9606 15184391 YES The effect has been demonstrated using O60504-2 llicata Vinexin was directly phosphorylated by erk2 upon stimulation with egf at the serine 189 of vinexin _. 0.388 SIGNOR-125221 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR BHLHE40 protein O14503 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19032342 NO lperfetto DEC1 (BHLHB2/Stra13/Sharp2)-a basic helix-loop-helix transcription factor-is known to be involved in various biological phenomena including clock systems and metabolism. In the clock systems, Dec1 expression is dominantly up-regulated by CLOCK : BMAL1 heterodimer, and it exhibits circadian rhythm in the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and other peripheral tissues. 0.664 SIGNOR-253707 BIRC2 protein Q13490 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. 0.676 SIGNOR-272711 PRKCA protein P17252 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.301 SIGNOR-251620 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 15996096 YES miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). 0.8 SIGNOR-266532 CAMK2A protein Q9UQM7 UNIPROT PDC protein P20941 UNIPROT unknown phosphorylation Ser73 ERVSRKMsIQEYELI 11331285 YES llicata In this study, we report that Pd was rapidly phosphorylated by Ca(2+)/calmodulin-dependent kinase II, resulting in 100-fold greater inhibition of Gbetagamma binding than cAMP-dependent protein kinase phosphorylation. Furthermore, Pd phosphorylation by Ca(2+)/calmodulin-dependent kinase II at Ser-54 and Ser-73 led to binding of the phosphoserine-binding protein 14-3-3. 0.307 SIGNOR-250637 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr170 ARILNHDtSFAKTFV 9606 17197699 YES gcesareni Thus, it appears that autophosphorylation of thr-170 and/or ser-171 in nek2 may fine-tune overall activity of nek2 in vivo. regardless, the importance of thr-175 suggested by its conservation in many other kinases is underlined by the t175a mutant that shows reduced kinase activity and a significant reduction in efficiency of cs. 0.2 SIGNOR-151759 MLL1 complex complex SIGNOR-C89 SIGNOR PAX7/MLL1 complex complex SIGNOR-C90 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 YES miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.2 SIGNOR-198620 PRKDC protein P78527 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation 9606 23620287 YES gcesareni Dna-dependentprotein_ kinase_ (dna-pk) that phosphorylate h2ax at dsbs 0.2 SIGNOR-192443 APC-c complex SIGNOR-C150 SIGNOR KIFC1 protein Q9BW19 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24510915 YES miannu Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). 0.257 SIGNOR-266109 BCOR protein Q6W2J9 UNIPROT HOXA7 protein P31268 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 26847029 NO irozzo Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation. 0.2 SIGNOR-256013 ARHGEF28 protein Q8N1W1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.754 SIGNOR-260546 DOK1 protein Q99704 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.325 SIGNOR-257696 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 19282669 YES inferred from 70% family members lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.2 SIGNOR-270070 IKK-complex complex SIGNOR-C14 SIGNOR IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser376 PPAPAYLsSPLALPS 9606 SIGNOR-C14 12657630 YES lperfetto Phosphopeptide-mapping experiments with metabolically radiolabeled cells indicate that ikkbeta phosphorylates human ikkgamma at ser-31, ser-43, and ser-376 0.93 SIGNOR-209792 MAPK1 protein P28482 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser122 CPMEHPLsADIAMAT -1 28689659 YES miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  0.475 SIGNOR-277360 GSK3B protein P49841 UNIPROT TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation 10116 BTO:0003293 16959574 YES lperfetto Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation. 0.73 SIGNOR-149380 AKT2 protein P31751 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates activity phosphorylation Thr346 APRPRVEtSRAVPLA -1 27505672 YES miannu  Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex.  0.376 SIGNOR-277271 CDK2 protein P24941 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 20080565 YES gcesareni We report that grk2 protein levels are transiently down-regulated during the g2/m transition by a mechanism involving cdk2-mediated phosphorylation of grk2 at serine670, which triggers binding to the prolyl-isomerase pin1 and subsequent degradation. 0.2 SIGNOR-163279 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR BAG3 protein O95817 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 34215846 YES miannu We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377. 0.279 SIGNOR-277320 Ub:E2 complex SIGNOR-C497 SIGNOR RNF128 protein Q8TEB7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270953 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 22124607 YES lperfetto Moreover, we reported that TCPTP knockdown in PTP1B deficient MEFS further enhanced IR activation, consistent with the two PTPs acting in a coordinated manner to attenuate insulin signalling .|Therefore, the inhibition of PTPs such as PTP1B that attenuate IR activation and signalling might be particularly effective in alleviating insulin resistance.|The prototypic family member PTP1B (encoded by PTPN1) dephosphorylates the IR beta subunit Y1162 and Y1163 activation loop autophosphorylation site to attenuate insulin signalling in vivo . 0.788 SIGNOR-276947 PAK6 protein Q9NQU5 UNIPROT SLC25A5 protein P05141 UNIPROT up-regulates quantity phosphorylation Thr107 LGGVDKRtQFWLYFA 9606 32194820 YES miannu In the present study, it was demonstrated that ANT2 was phosphorylated by PAK6 at T107.|Moreover, PAK6 overexpression upregulated the protein expression of ANT2, while PAK6 knockdown led to opposing effects. 0.2 SIGNOR-279473 SIRT7 protein Q9NRC8 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity deacetylation Lys37 APSTGGVkKPHRYRP 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275878 MLL2 complex complex SIGNOR-C88 SIGNOR CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates activity binding 9606 28669924 YES miannu KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. KMT2D is a major mammalian H3K4 mono-methyltransferase and co-localizes with lineage determining transcription factors on transcriptional enhancers. It is required for the binding of histone H3K27 acetyltransferases CBP and p300 on enhancers, enhancer activation and cell-type specific gene expression during differentiation. 0.2 SIGNOR-268814 ITCH protein Q96J02 UNIPROT LATS1 protein O95835 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21212414 YES miannu Furthermore, ITCH mediated degradation of LATS1 was associated with enhanced cell growth, induction of epithelial-mesenchymal transition, and increased tumorigenicity.|Ubiquitination of LATS1 catalyzed by ITCH stimulated the proteasomal degradation of LATS1. 0.517 SIGNOR-278816 USP24 protein Q9UPU5 UNIPROT EP300 protein Q09472 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000018 27991932 YES lperfetto In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. |Knockdown of USP24 decreases Bax and p300 levels 0.271 SIGNOR-275607 UBAC1 protein Q9BSL1 UNIPROT KPC complex SIGNOR-C523 SIGNOR form complex binding 10090 BTO:0000944 15531880 YES miannu  We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation.  0.881 SIGNOR-271512 ILK protein Q13418 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA -1 11313365 YES miannu ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner. 0.778 SIGNOR-250261 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr220 PETEENIyQVPTSQK 10090 11279201 YES lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. 0.421 SIGNOR-247080 DUSP3 protein P51452 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates activity dephosphorylation 9534 BTO:0004055 10224087 YES inferred from 70% of family members Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2 0.2 SIGNOR-269907 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 12058066 YES lperfetto Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. 0.408 SIGNOR-216749 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.257 SIGNOR-159466 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 10116 7535768 YES We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively 0.805 SIGNOR-248465 UCHL5 protein Q9Y5K5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity deubiquitination 9606 16027725 YES lperfetto Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases 0.398 SIGNOR-232101 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Thr345 GADSDVEtPSNFGKY 9606 BTO:0000007 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.2 SIGNOR-262986 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 7961936 YES We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. 0.618 SIGNOR-251395 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 YES lperfetto Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation 0.364 SIGNOR-216546 FZD3 protein Q9NPG1 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 YES amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. 0.657 SIGNOR-134288 PIN1 protein Q13526 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization binding 9606 16699525 YES lperfetto Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication. 0.641 SIGNOR-252256 DYRK1A protein Q13627 UNIPROT IRS1 protein P35568 UNIPROT up-regulates quantity phosphorylation Ser312 TESITATsPASMVGG 9606 31723029 YES miannu DYRK1A interacts with IRS-1 and phosphorylates IRS-1 at Ser-312 and Ser-616.|We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing the turnover of IRS-1 protein. 0.2 SIGNOR-279520 clofarabine chemical CHEBI:681569 ChEBI POLG protein P54098 UNIPROT down-regulates activity chemical inhibition 9606 1707752 YES miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. 0.8 SIGNOR-258361 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser58 ESETNQNsSSDSEAE -1 11711551 YES llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 0.359 SIGNOR-250962 CNOT7 protein Q9UIV1 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.836 SIGNOR-268307 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Thr1179 NYGTNPGtPPASTSP 9606 10660621 YES lperfetto Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. 0.365 SIGNOR-74880 STK11 protein Q15831 UNIPROT NUAK2 protein Q9H093 UNIPROT up-regulates phosphorylation Thr208 HQGKFLQtFCGSPLY 9606 14976552 YES llicata A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold. 0.273 SIGNOR-122717 ROCK1 protein Q13464 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Thr696 ARQSRRStQGVTLTD 9606 8662509 YES Rho-associated kinase (Rho-kinase) is activated by GTP-RhoA gcesareni Rho-associated kinase (rho-kinase) phosphorylated mbs and consequently inactivated myosin phosphatase. Rho appears to inhibit myosin phosphatase through the action of rho-kinase. 0.774 SIGNOR-42354 risperidone chemical CHEBI:8871 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258526 EGFR protein P00533 UNIPROT PKM protein P14618 UNIPROT down-regulates activity phosphorylation Tyr148 KITLDNAyMEKCDEN 9606 BTO:0001570 26759242 YES miannu EGFR binds to and phosphorylates PKM2 to inhibit its activity.  0.45 SIGNOR-277197 risperidone chemical CHEBI:8871 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258528 IFNGR2 protein P38484 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation 0.7 SIGNOR-249504 BRCA1-C complex complex SIGNOR-C299 SIGNOR TP53BP1 protein Q12888 UNIPROT up-regulates activity relocalization 25400280 YES lperfetto Additional to the role of the BRCA1–C complex in 53BP1 repositioning and initiation of resection, end resection is extended to facilitate RPA loading and subsequent RPA‐Rad51 exchange prior to sister strand invasion 0.624 SIGNOR-263230 PRKCA protein P17252 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser371 AHSSHLKsKKGQSTS -1 9571186 YES lperfetto Here, we demonstrate that cotransfection of p53 with either PKC alpha or PKC zeta increases p53's transcriptional activity. Mutagenesis of p53 indicates that serine 371 is the major site for phosphorylation by PKC alpha in vitro. 0.438 SIGNOR-248999 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr71 VAFSVDNtIKRPNPA 29383184 YES lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. 0.2 SIGNOR-275568 PTPRT protein O14522 UNIPROT PXN protein P49023 UNIPROT down-regulates activity dephosphorylation Tyr88 PQSSSPVyGSSAKTS 9606 BTO:0000182 27447856 YES brain lperfetto To this end, using a phospho-proteomics approach, we identified and validated paxillin and STAT3 as the substrates of PTPRT [15, 16]|the PTPRT target site on paxillin is a previously uncharacterized tyrosine-88 residue (paxillin Y88)|In this study, we also show how pY88 paxillin transduces a signal to activate Akt 0.463 SIGNOR-263978 LRRK2 protein Q5S007 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation 9606 22998870 YES miannu We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association. 0.468 SIGNOR-192068 GRB2 protein P62993 UNIPROT KIT protein P10721 UNIPROT down-regulates 9606 BTO:0001271 17904548 NO miannu Grb2 mediates c-kit degradation through recruitment of cbl to c-kit, leading to ubiquitination of c-kit followed by internalization and degradation 0.649 SIGNOR-157956 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser510 KKVDRKAsKGRKLRF 9606 BTO:0001109 17157788 YES lperfetto Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability. 0.359 SIGNOR-264418 NRF1 protein Q16656 UNIPROT BRK1 protein Q8WUW1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23939472 NO miannu We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. 0.2 SIGNOR-261369 RAB6B protein Q9NRW1 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 20360680 NO miannu We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles. 0.7 SIGNOR-266881 N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide chemical CHEBI:91370 ChEBI PTK2B protein Q14289 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206070 TGFB1 protein P01137 UNIPROT PAX8 protein Q06710 UNIPROT down-regulates activity binding 9606 14623893 YES miannu DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3. 0.2 SIGNOR-251993 IRS1 protein P35568 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000156 11259577 YES lperfetto Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis. 0.803 SIGNOR-236614 AKT1 protein P31749 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser345 ELLCLRRsSLKAYGN 9606 11809767 YES lperfetto Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation. 0.355 SIGNOR-252469 EGFR protein P00533 UNIPROT ZNRF1 protein Q8ND25 UNIPROT up-regulates activity phosphorylation Tyr103 TYAHGNGyQETGGGH 9606 26572619 YES miannu Together, these results demonstrate that EGFR-dependent phosphorylation of ZNRF1 at Y103 promotes degradation of AKT and resultant activation of GSK3\u03b2, which mediates oxidative stress\u2013induced neuronal apoptosis ( xref ). 0.27 SIGNOR-279522 FYN protein P06241 UNIPROT NPHS1 protein O60500 UNIPROT up-regulates activity phosphorylation 9606 12668668 YES miannu Fyn directly bound Nephrin via its SH3 domain, and Fyn directly phosphorylated Nephrin.|Similar to Fyn deletion, simultaneous deletion of Fyn and Yes reduced Nephrin phosphorylating activity. 0.737 SIGNOR-279523 CHEK1 protein O14757 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser178 LFTQRQNsAPARMLS 9606 20068082 YES gcesareni The signal for ubiquitination after uv and ir exposure is created by phosphorylation of cdc25a mediated by chk1 and chk2, respectively. Chk1 is a major kinase phosphorylating cdc25a (ser76/124) and cdc25c (ser216). regulation;btrc(induces);14-3-3 beta(induces);apoptosis, altered;14-3-3 beta(induces);ccna1(disrupts);cdk2(disrupts);cdk1(disrupts);ccnb1(disrupts); 0.856 SIGNOR-163138 NEK2 protein P51955 UNIPROT LRRC45 protein Q96CN5 UNIPROT down-regulates activity phosphorylation Ser661 VLAYVQAsPVRTLSP 9606 BTO:0000567 24035387 YES miannu  Moreover, LRRC45 interacts with both C-Nap1 and rootletin and is phosphorylated by Nek2A at S661 during mitosis. After phosphorylation, both LRRC45 centrosomal localization and fiber-like structures are significantly reduced, which subsequently leads to centrosome separation.  0.37 SIGNOR-273707 KIF1C protein O43896 UNIPROT RAB6C protein Q9H0N0 UNIPROT up-regulates quantity relocalization -1 20360680 YES miannu Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. 0.245 SIGNOR-266879 ruxolitinib phosphate chemical CHEBI:66917 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition 9606 23061804 YES miannu Ruxolitinib is a selective inhibitor of Janus kinases (JAK) 1 and 2, which are involved in the signalling pathway of various cytokines and growth factors essential to haematopoiesis. 0.8 SIGNOR-259171 GRM2 protein Q14416 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264349 AKT2 protein P31751 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates activity phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 YES miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively 0.2 SIGNOR-276196 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 20679343 YES The effect has been demonstrated using P10636-8 lperfetto Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3? 0.738 SIGNOR-167294 MAPK12 protein P53778 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR form complex binding 29681515 YES apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated 0.362 SIGNOR-255981 EZH2 protein Q15910 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23836662 NO miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. 0.527 SIGNOR-254146 histamine smallmolecule CHEBI:18295 ChEBI HRH2 protein P25021 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257513 PDPK1 protein O15530 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007;BTO:0001914 23887393 YES gcesareni Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency 0.2 SIGNOR-243519 nintedanib chemical CHEBI:85164 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 18559524 YES Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. 0.8 SIGNOR-257800 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 19701891 YES miannu The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway) 0.811 SIGNOR-254361 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 SIGNOR-C17 8626512 YES lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. 0.389 SIGNOR-41319 NRF1 protein Q16656 UNIPROT SPAST protein Q9UBP0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22574173 NO miannu we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11. 0.337 SIGNOR-254885 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189933 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition 9606 31908417 YES miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. 0.8 SIGNOR-262251 MAP3K7 protein O43318 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation 9606 19136967 YES miannu Here we showed that TAK1 directly phosphorylated RCAN1 at two novel sites (serine 94 and -136), resulting in activation of calcineurin-NFAT signaling.|Indeed, low doses of RCAN1 facilitated calcineurin-nuclear factor of activated T cells signaling in the presence of TGF-\u03b2-activated kinase 1+TAB1 ( ), suggesting that TGF-\u03b2-activated kinase 1 augments calcineurin-nuclear factor of activated T cells signaling through RCAN1. 0.2 SIGNOR-279535 PRKACA protein P17612 UNIPROT AANAT protein Q16613 UNIPROT up-regulates activity phosphorylation Thr31 PSCQRRHtLPASEFR -1 11336675 YES miannu AANAT1201 is phosphorylated at Thr-31 by PKA, it binds to 14-3-3. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations.  0.321 SIGNOR-250325 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 9606 9840932 YES lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk4 0.715 SIGNOR-217264 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT up-regulates activity phosphorylation Ser330 AGSTISNsHAQPFDF 10116 BTO:0000067 12270943 YES lperfetto We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation). 0.6 SIGNOR-249331 PAK2 protein Q13177 UNIPROT MYC protein P01106 UNIPROT down-regulates activity phosphorylation Thr358 ISNNRKCtSPRSSDT 9606 14749374 YES miannu Here we demonstrate that Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo. 0.648 SIGNOR-278489 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Ala36 PESKATNaTLDPRSF -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus 0.42 SIGNOR-263575 CSNK2A1 protein P68400 UNIPROT IFI16 protein Q16666 UNIPROT up-regulates activity phosphorylation Ser132 GAQKRKKsTKEKAGP 9606 BTO:0000567 11115400 YES llicata Here we examine the functionality of the interferon-induced factor 16 (IFI 16) CcN motif, demonstrating its ability to target a heterologous protein to the nucleus, and to be phosphorylated specifically by the CcN-motif-phosphorylating protein kinase CK2 (CK2). | Specific phosphorylation of IFI 16 Ser132 in HeLa cell extracts and by purified CK2 in vitro 0.322 SIGNOR-250902 FBXW11 protein Q9UKB1 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates ubiquitination 9606 16885021 YES gcesareni Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbetatrcp ubiquitin ligase. 0.346 SIGNOR-148438 AURKA protein O14965 UNIPROT MAP9 protein Q49MG5 UNIPROT up-regulates phosphorylation Ser625 RKQKKRHsFLESEAL 9606 17925329 YES llicata Asap is a novel substrate of the oncogenic mitotic kinase aurora-a: phosphorylation on ser625 is essential to spindle formation and mitosis. 0.326 SIGNOR-158210 C3 convertase complex complex SIGNOR-C310 SIGNOR C3 protein P01024 UNIPROT up-regulates activity cleavage Arg671 QPAARRRrSVQLTEK 31331124 YES lperfetto This forms the C4b2a complex, which is a classical pathway C3 convertase. C4b2a cleaves C3, which is the central component of the complement cascade, to C3a, and anaphylatoxin, and C3b results in the activation of the lytic pathway 0.557 SIGNOR-263449 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR LTC4S protein Q16873 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001433 12574384 NO miannu activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism. 0.257 SIGNOR-254799 LYN protein P07948 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity phosphorylation Tyr313 PSDKQRFyTNQLLDV 9606 BTO:0002181 27521268 YES miannu Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity. 0.329 SIGNOR-277247 ATF4 protein P18848 UNIPROT YARS2 protein Q9Y2Z4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269432 sorafenib chemical CHEBI:50924 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258285 MITF protein O75030 UNIPROT MLANA protein Q16655 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 12819038 NO miannu The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels. 0.469 SIGNOR-254590 APC-c complex SIGNOR-C150 SIGNOR SKIL protein P12757 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11741538 YES miannu  We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC.  0.324 SIGNOR-272622 CNKSR1 protein Q969H4 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates activity binding 26319181 YES lperfetto The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration. 0.293 SIGNOR-275921 NGLY1 protein Q96IV0 UNIPROT RAD23B protein P54727 UNIPROT up-regulates activity binding 9606 16401726 YES miannu The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome. 0.82 SIGNOR-261061 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser711 EEEEESDsSETEKED -1 21296876 YES miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis 0.2 SIGNOR-276251 ANGPT1 protein Q15389 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 NO lperfetto Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. 0.265 SIGNOR-241529 AMPK complex SIGNOR-C15 SIGNOR GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser8 MPLNRTLsMSSLPGL -1 22233421 YES miannu Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations). 0.488 SIGNOR-263102 MARCHF5 protein Q9NX47 UNIPROT FIS1 protein Q9Y3D6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16874301 YES miannu MITOL associates with and ubiquitinates mitochondrial fission protein hFis1. (A) Ubiquitination of hFis1 by MITOL. Thus, MITOL may control the protein expression level of hFis1 through the ubiquitin–proteasome pathway. 0.2 SIGNOR-271896 SEMA3B protein Q13214 UNIPROT PLXNA4 protein Q9HCM2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 YES miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  0.65 SIGNOR-261810 ROCK1 protein Q13464 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates activity phosphorylation 9606 27302366 YES miannu We then engineered the T653A NHE1 mutant (ROCKA mutant), which can not be phosphorylated by p160ROCK.|p160ROCK has also been shown to activate NHE1 at threonine 653 , in close vicinity to the Akt phosphorylation site at serine 648. 0.684 SIGNOR-279566 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser528 KPRSSRGsIFTFRRR -1 12242273 YES miannu These results demonstrate that the effect of PKA stimulation to increase cardiac INa requires at least 2 processes: phosphorylation of consensus sites in the I-II interdomain linker, and one or more additional molecular events mediated by the kinase, that could include phosphorylation of other substrates/proteins. 0.2 SIGNOR-275992 SIRT7 protein Q9NRC8 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates activity deacetylation Lys37 APATGGVkKPHRYRP 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275881 bexarotene chemical CHEBI:50859 ChEBI RXRB protein P28702 UNIPROT up-regulates activity chemical activation 9606 BTO:0002058 17483357 YES miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. 0.8 SIGNOR-259231 AMPK complex SIGNOR-C15 SIGNOR HNF4A protein P41235 UNIPROT down-regulates activity phosphorylation Ser303 DPDAKGLsDPGKIKR -1 12740371 YES miannu Here we demonstrate that AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. 0.307 SIGNOR-263106 STAT3 protein P40763 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 32454942 NO miannu IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS 0.7 SIGNOR-263821 LINC complex complex SIGNOR-C303 SIGNOR NXF1 protein Q9UBU9 UNIPROT up-regulates activity binding 9606 BTO:0000567 28831067 YES lperfetto SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1. 0.301 SIGNOR-263297 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr249 APGPQDIyDVPPVRG 9606 12972425 YES lperfetto We tested synthetic peptides modeled on cas phosphorylation sites, and found that the sequence containing tyrosine 253 was phosphorylated by src most efficiently. Using cells derived from cas-deficient mice, we confirmed that cas greatly enhanced the ability of src to transform cells. 0.802 SIGNOR-100363 MTSS1 protein O43312 UNIPROT GLI1 protein P08151 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 YES gcesareni Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex 0.542 SIGNOR-130542 GDP smallmolecule CHEBI:17552 ChEBI GNAQ protein P50148 UNIPROT down-regulates chemical inhibition 9606 12040175 YES gcesareni Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of gdp from the alfa subunit followed by gtp-binding to galfa and the dissociation of galfa from gbetagamma subunits1. 0.8 SIGNOR-88229 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity dephosphorylation Ser227 DHEKKAYsFCGTVEY 10090 15206906 YES RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity 0.361 SIGNOR-248320 PTPRZ1 protein P23471 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity dephosphorylation 9606 23100427 YES miannu PTPRZ1 constitutively promotes the tyrosine dephosphorylation of \u03b2-catenin, and thus \u03b2-catenin participation in TCF-mediated transcription. 0.379 SIGNOR-277044 MYOG protein P15173 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 YES P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells 0.331 SIGNOR-251575 RAB5C protein P51148 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates activity binding -1 12493736 YES Federica The Rab5 effector early endosome antigen 1 (EEA1) is a parallel coiled coil homodimer with an N-terminal C(2)H(2) Zn(2+) finger and a C-terminal FYVE domain. Rab5 binds to independent sites at the N and C terminus of EEA1.|The results demonstrate that the C(2)H(2) Zn(2+) finger is both essential and sufficient for the N-terminal interaction with Rab5. 0.829 SIGNOR-261266 RNF8 protein O76064 UNIPROT L3MBTL2 protein Q969R5 UNIPROT up-regulates activity ubiquitination 9606 31225475 YES miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. 0.242 SIGNOR-266787 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates quantity precursor of 9606 21173190 YES lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† 0.8 SIGNOR-267013 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates phosphorylation Ser394 EDAVHEDsGDEDGED 9606 20388487 YES gcesareni Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation. 0.619 SIGNOR-164795 EGFR protein P00533 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 25164010 YES miannu One possible explanation is that activation of \u03b2-catenin by EGFR mutants may \u201cprime\u201d pulmonary cells to be susceptible to other downstream signaling aberrations and subsequent transformation into tumor cells.|beta-catenin is phosphorylated at Y86 by Src and oncogenic Bcr-Abl and at Y654 by activated wild type EGFR and oncogenic FLT3-ITD. 0.773 SIGNOR-278308 hsa-miR-320a-5p mirna URS000042A57E_9606 RNAcentral GNAI1 protein P63096 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003227 23691483 YES Parnian GNAI1 was a target of miR-320a/c/d in HCC cells.| Western blot assays revealed that miR-320a/c/d dramatically down-regulated the endogenous GNAI1 protein level, which indicates that these miRNAs may directly target GNAI1 in HCC cells. 0.4 SIGNOR-278026 PLK1 protein P53350 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 19889641 YES lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. 0.319 SIGNOR-176079 CS protein O75390 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 3013232 YES miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. 0.8 SIGNOR-266238 PRKDC protein P78527 UNIPROT POLL protein Q9UGP5 UNIPROT up-regulates activity phosphorylation Thr204 EASDGEEtQVSAADL 9606 BTO:0000007 28109743 YES done miannu  We show that Polλ is efficiently phosphorylated by DNA-PKcs in vitro and predominantly by ATM after DSB induction with ionizing radiation (IR) in vivo. We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ.  0.465 SIGNOR-273835 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation 0.713 SIGNOR-249505 PRKACA protein P17612 UNIPROT HSPB6 protein O14558 UNIPROT down-regulates phosphorylation Ser16 PSWLRRAsAPLPGLS 9606 10196226 YES llicata Hosphorylation of hsp20 at ser16 is not only associated with cyclic nucleotide-dependent vasorelaxation but also inhibits agonist-induced contractile responses. 0.2 SIGNOR-66493 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Ser332 LSRSRTAsLTSAASV 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 YES llicata Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344 0.395 SIGNOR-129672 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 9315650 YES llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. 0.459 SIGNOR-51288 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr332 ILAIHDSyKPEFHSD 10029 12907755 YES PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 0.5 SIGNOR-248418 TUBA1C protein Q9BQE3 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 NO miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. 0.7 SIGNOR-269728 RAD51 protein Q06609 UNIPROT SYCP3 protein Q8IZU3 UNIPROT up-regulates activity binding 10090 SIGNOR-C351 10525529 YES miannu The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. 0.362 SIGNOR-264205 IKK-complex complex SIGNOR-C14 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 YES lperfetto Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. 0.543 SIGNOR-252950 AMPK complex SIGNOR-C15 SIGNOR PPP1R12C protein Q9BZL4 UNIPROT down-regulates phosphorylation Ser452 AGLQRSAsSSWLEGT 9606 22137581 YES lperfetto Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo. 0.257 SIGNOR-216600 PIM1 protein P11309 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity phosphorylation 9606 27281612 YES miannu Interestingly, Pim1 phosphorylated Notch1 and Notch3, but not Notch2 ICD (Figure xref ), which was in line with the observed Pearson correlations ( xref ).|Our data indicate that endogenous Pim1 and Notch1 interact already in the cytoplasm, which supports the notion that Pim1 enhances nuclear localization and activity of Notch1. 0.27 SIGNOR-279643 HIF1AN protein Q9NWT6 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates hydroxylation Asn2022 INSHADVnAVDDLGK 9606 18299578 YES gcesareni We show that fih-1 hydroxylates notch icd at two residues (n(1945) and n(2012)) that are critical for the function of notch icd as a transactivator within cells and during neurogenesis and myogenesis in vivo. Fih-1 negatively regulates notch activity and accelerates myogenic differentiation. 0.552 SIGNOR-161061 CHRM5 protein P08912 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256873 BCL2L1 protein Q07817 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity binding -1 10949026 YES lperfetto Bad dimerizes with bcl-xl at the mitochondrial membrane where it exert its killing effects. Phosphorylation of bad promotes its binding to 14-3-3 protein, which may sequester bad from bcl-xl, thus promoting cell cells survival. 0.848 SIGNOR-81125 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 7493944 YES lperfetto Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. 0.2 SIGNOR-26586 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr203 HQHYYYDtHTNTYYL 9606 16669787 YES miannu We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1 0.525 SIGNOR-146513 EPRS1 protein P07814 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.2 SIGNOR-270356 ABL1 protein P00519 UNIPROT MICAL1 protein Q8TDZ2 UNIPROT up-regulates activity phosphorylation 9606 28689759 YES miannu Biochemical assays revealed Abl phosphorylates Mical to directly amplify Mical Redox-mediated F-actin disassembly.|We now find that the Abl non receptor protein tyrosine kinase and oncoprotein signaling pathway activates Mical to direct multiple cellular effects - including extending and shaping cellular processes, guiding axons, and orchestrating cancer cell invasion, colony formation, and survival. 0.312 SIGNOR-279674 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 24614225 YES lperfetto Purified camkii phosphorylates cyld on at least three residues (s-362, s-418, and s-772 on the human cyld protein q9nqc7-1) and promotes its deubiquitinase activity. 0.2 SIGNOR-25329 LARP4B protein Q92615 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 20573744 YES miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex. 0.558 SIGNOR-260940 PKA proteinfamily SIGNOR-PF17 SIGNOR IQGAP2 protein Q13576 UNIPROT up-regulates activity phosphorylation Thr716 EYMHRRQtFIDNTDS 9606 21776420 YES miannu We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP. 0.2 SIGNOR-273742 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1715686 YES gcesareni Dephosphorylation of autophosphorylated insulin and epidermal-growth-factor receptors by two major subtypes of protein-tyrosine-phosphatase from human placenta. 0.305 SIGNOR-21303 PPARG protein P37231 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 17681149 NO lperfetto This mechanism is mainly operative in native monocytes that, in the presence of an appropriate M2 stimulus such as IL-4, can be primed by PPARg ligands to an enhanced M2 phenotype. 0.7 SIGNOR-249542 CSNK2A1 protein P68400 UNIPROT GBF1 protein Q92538 UNIPROT down-regulates quantity by destabilization phosphorylation Ser297 TDSGLEFsSQTTSKE 9606 BTO:0002181 29898406 YES miannu We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation. 0.2 SIGNOR-277398 PRKCD protein Q05655 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 15972820 YES Manara The present study showed that shear stress, but not stretch, activates PKC delta and phosphorylates K8 Ser-73, which then mediates the disassembly/reorganization of keratin IF in AEC. 0.322 SIGNOR-260887 LNPEP protein Q9UIQ6 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT down-regulates quantity by destabilization cleavage 9606 25767437 YES miannu It has been shown that the steady state of the mature OT form can be controlled by an oxytocinase (P-LAP) that is produced in periphery and centrally by the OT-magnocellular neurons. Noticeably, P-LAP is also expressed in parvocellular OT neurons and in other brain structures| The OT intermediate forms are produced from E16.5 (see above) but the mature amidated OT form is detected only from birth. The released mature form is then degraded by an oxytocinase (PLAP) 0.2 SIGNOR-268552 NEFL protein P07196 UNIPROT Neurofilament L/M complex SIGNOR-C207 SIGNOR form complex binding 9606 19468066 YES miannu Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H 0.523 SIGNOR-255270 ATM protein Q13315 UNIPROT ABRAXAS1 protein Q6UWZ7 UNIPROT up-regulates activity phosphorylation Ser404 MKGFGEYsRSPTF 9606 BTO:0000007 26778126 YES In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. 0.2 SIGNOR-255587 CDK1 protein P06493 UNIPROT USP1 protein O94782 UNIPROT up-regulates activity phosphorylation Ser313 ATSDTLEsPPKIIPK -1 23116119 YES miannu In this study, we show that Ser313 phosphorylation in USP1 is required for its interaction with UAF1 and for the stimulation of USP1's activity. We further demonstrated that CDK1 is responsible for Ser313 phosphorylation, and protein phosphatase treatment of USP1 can lead to inactivation of USP1/UAF1. 0.371 SIGNOR-276423 LMO1 protein P25800 UNIPROT TAL1 protein P17542 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 9020185 YES miannu Transcriptional activity of tal1 in t cell acute lymphoblastic leukemia (t-all) requires rbtn1 or -2 0.735 SIGNOR-46114 CSNK1D protein P48730 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser212 SVKLRGSsLFMDTEK -1 24817118 YES miannu Casein kinase 1-mediated N-terminal Weee1 phosphorylation is required for interaction with the F-box protein β-TrCP.MS/MS spectra of human Wee1 identifying serine 212 as phosphorylated after incubation with recombinant CK1δ. 0.308 SIGNOR-276631 TTI1 protein O43156 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 YES miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. 0.604 SIGNOR-272002 Ub:E2 complex SIGNOR-C497 SIGNOR LONRF3 protein Q496Y0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271162 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 21454478 YES gcesareni In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner 0.329 SIGNOR-172993 SMAD5 protein Q99717 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. 0.674 SIGNOR-255266 GADD45G protein O95257 UNIPROT CDK11A protein Q9UQ88 UNIPROT down-regulates activity binding 9606 BTO:0000007 26885618 YES lperfetto Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58. 0.2 SIGNOR-273025 PAN3 protein Q58A45 UNIPROT PAN2-PAN3 deadenylation complex complex SIGNOR-C553 SIGNOR form complex binding 9606 34280615 YES miannu There are two major deadenylase complexes, Ccr4-Not and Pan2-Pan3, which shorten the 3′ poly(A) tail of mRNA and are conserved from yeast to human.The Ccr4-Not complex has two catalytic subunits including the Ccr4 (Carbon catabolite repressor 4) and Pop2 (PGK promoter directed overproduction). The Pan2-Pan3 complex comprises the catalytic subunit Pan2, a member of the RNase D family, and the regulatory subunit Pan3. Degradation of mRNA begins with either shortening of the poly(A) tail by deadenylases or removal of 5′ cap structure by the decapping enzyme Dcp1-Dcp2. 0.827 SIGNOR-273871 PRKCD protein Q05655 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 16377624 YES llicata Here, we show that the pro-apoptotic kinase, protein kinase c delta (pkcdelta), is involved in phosphorylation of p53 on ser(46). pkcdelta potentiates p53-dependent apoptosis by ser(46) phosphorylation in response to genotoxic stress. 0.676 SIGNOR-143382 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.384 SIGNOR-129268 WWP1 protein Q9H0M0 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity ubiquitination 9606 16924229 YES miannu Unlike other E3 ligases, WWP1 increases p53 stability; inhibition of WWP1 expression or expression of a ligase-mutant form results in decreased p53 expression.|WWP1 associates with p53 and induces p53 ubiquitylation. 0.319 SIGNOR-278649 FANCL protein Q9NW38 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity ubiquitination 9606 22653977 YES miannu Here we provide evidence that FANCL increases the activity and expression of beta-catenin, a key pluripotency factor in hematopoietic stem cells.|We show that FANCL ubiquitinates \u03b2-catenin with atypical ubiquitin chain extension known to have nonproteolytic functions. 0.2 SIGNOR-278651 HUWE1 protein Q7Z6Z7 UNIPROT KAT7 protein O95251 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 32555450 YES miannu Moreover, we determined that Huwe1 is a novel E3 ligase for Myst2 degradation in mESCs, and Brpf3 disturbs Huwe1 mediated ubiquitination of Myst2 via interaction with Huwe1 and Myst2. 0.2 SIGNOR-278652 UNC80 protein Q8N2C7 UNIPROT NALCN protein Q8IZF0 UNIPROT up-regulates activity binding 9606 BTO:0000007 19535918 YES miannu UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex.  0.809 SIGNOR-265180 CAD protein P27708 UNIPROT N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI up-regulates quantity chemical modification 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267425 zotepine chemical CHEBI:32316 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258551 IRS2 protein Q9Y4H2 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 22810696 YES lperfetto These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients. 0.685 SIGNOR-251492 hsa-miR-382-5p mirna URS000035E174_9606 RNAcentral ROR1 protein Q01973 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000948 26575700 YES Parnian Collectively, these data suggest that miR‑382 may inhibit ROR1 expression by targeting its 3'-UTR.| these findings suggested that miR‑382 inhibited migration and invasion by directly targeting ROR1 in SKOV3 and COV434 cells. 0.4 SIGNOR-278845 hsa-miR-148a-3p mirna URS00003BBF48_9606 RNAcentral WNT1 protein P04628 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002745 33026174 YES Parnian These findings indicated that miR-148a-3p could inhibit Wnt/β-catenin signalling pathway by directly targeting Wnt1. 0.4 SIGNOR-278851 HRH1 protein P35367 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.455 SIGNOR-257425 STK11 protein Q15831 UNIPROT STRADA protein Q7RTN6 UNIPROT up-regulates activity phosphorylation Thr419 SGIFGLVtNLEELEV 9606 BTO:0000007 12805220 YES lperfetto Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419 0.939 SIGNOR-247564 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G1 protein Q04637 UNIPROT up-regulates activity stabilization 9606 17581632 YES lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 0.638 SIGNOR-269155 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr77 RASRLGTtRTPSSYG 9606 BTO:0000971 10574968 YES lperfetto We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin 0.317 SIGNOR-249033 Netrin proteinfamily SIGNOR-PF97 SIGNOR NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 21558366 YES miannu In mammals, three secreted netrins, netrin 1, 3 and 4, and two membrane-tethered glycophosphatidylinositol (GPI)-linked (see Glossary, Box 1) netrins, netrin G1 and G2, have been identified. In mammals, receptors for the secreted netrins include deleted in colorectal cancer (DCC), the DCC paralogue neogenin, the UNC-5 homologues UNC5A-D, and Down syndrome cell adhesion molecule (DSCAM). 0.2 SIGNOR-268172 MAP3K3 protein Q99759 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG 9606 14636585 YES miannu Genetic analysis showed that MEKK3, which is thought to activate IKK2 through phosphorylation (Yang et al., 2001), is necessary for TNF-alpha-induced NF-kappaB activation.|Our results also suggest that IKK2 is phosphorylated on S177 and S181 on its activation loop by MEKK3. 0.568 SIGNOR-279467 VAPB-PTPIP51 complex complex SIGNOR-C275 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 10116 BTO:0000142 30841933 NO lperfetto Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. 0.7 SIGNOR-262120 DYRK1A protein Q13627 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 32587776 YES miannu Furthermore, DYRK1A likely directly bound and phosphorylated Mcl-1, thereby enhancing Mcl-1 protein stability and contributing to the development of acquired resistance to Bcl-2 inhibitors.|DYRK1A upregulates Mcl-1 expression in NSCLC cells.|We demonstrated that DYRK1A suppression by siRNA or harmine decreased the phosphorylation of Mcl-1 at Ser159/Thr163. 0.2 SIGNOR-279704 MTHFD2 protein P13995 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity chemical modification 9606 16100107 YES lperfetto Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase|One of the enzymes in this pathway, the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC),5 catalyzes the interconversion of 5,10-methylenetetrahydrofolate (methylene-THF) and 10-formyltetrahydrofolate (formyl-THF) in mammalian mitochondria. 0.8 SIGNOR-268256 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates phosphorylation 9606 15209375 YES gcesareni One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.462 SIGNOR-126236 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 10454565 YES The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2. 0.829 SIGNOR-248481 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation 9606 32420483 YES miannuccelli ACLY is phosphorylated on tyrosine residues by Lyn in AML.|These findings show that SFK dependent pathway, Lyn in AML cells, induces the ACLY activity in protein tyrosine kinase dependent manner. 0.2 SIGNOR-279743 MAPK1 protein P28482 UNIPROT PHF8 protein Q9UPP1 UNIPROT down-regulates activity phosphorylation 9606 28100697 YES miannuccelli Upon IFNgamma treatment, PHF8 is phosphorylated by ERK2 and evicted from the promoters, which correlates with an increase in H4K20me1 and H3K4me3 levels. 0.2 SIGNOR-279745 GARS1 protein P41250 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 24898252 YES miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 0.8 SIGNOR-270479 SF3A2 protein Q15428 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.815 SIGNOR-270667 SEMA3A protein Q14563 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates binding 9606 10679438 YES gcesareni Plexins form stable complexes with neuropilin-1 or -2. 0.858 SIGNOR-75168 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267880 KMT2D protein O14686 UNIPROT HMT complex SIGNOR-C19 SIGNOR form complex binding 9606 17500065 YES lperfetto The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes. 0.835 SIGNOR-154763 LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 YES lperfetto Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling 0.38 SIGNOR-252598 DOK1 protein Q99704 UNIPROT ITGB4 protein P16144 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.2 SIGNOR-257689 MAPKAPK5 protein Q8IW41 UNIPROT PARK7 protein Q99497 UNIPROT up-regulates activity phosphorylation 9606 25383140 YES miannuccelli PRAK preferentially colocalizes with DJ-1 and leads to DJ-1 activation, which in turn facilitates DJ-1 to sequester Daxx in the nucleus, preventing oxidative stress induced cell death.|These data clearly demonstrate a PRAK dependent phosphorylation of DJ-1. 0.47 SIGNOR-279746 (R)-carnitine smallmolecule CHEBI:16347 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267117 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 1939237 YES lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. 0.503 SIGNOR-22424 EGLN3 protein Q9H6Z9 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization hydroxylation 9606 24990963 YES lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization 0.796 SIGNOR-262000 GPR183 protein P32249 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256994 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser952 DSRSHQNsPTELNKD 9606 BTO:0001938 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104691 RAD18 protein Q9NS91 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 26871286 YES miannu In summary, these findings suggest a model, where Rad18 promotes monoubiquitination of FANCD2, and associates with a functional complex involving Rad51, BRCA2, and FANCD2 in the repair of CPT induced stalled or collapsed forks.|In this study we focused on the role of Rad18 mediated activation of FANCD2 and its functional relationship with BRCA2 and Rad51 proteins in repair of CPT induced lesions. 0.521 SIGNOR-278712 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser670 SKVRGPVsGSPDSMN 9606 BTO:0000007 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251274 CNR2 protein P34972 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256979 SP1 protein P08047 UNIPROT SLC5A8 protein Q8N695 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20082847 YES Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription. 0.2 SIGNOR-254059 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity phosphorylation Ser147 EDLCQAFsDVILAVN 9606 BTO:0000567 11242082 YES lperfetto Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation. 0.922 SIGNOR-105719 ULK1 protein O75385 UNIPROT PRKAG3 protein Q9UGI9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 YES gcesareni Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity phosphorylation of ampk by ulk1 represents a negative feedback circuit. 0.405 SIGNOR-173053 carbamazepine chemical CHEBI:3387 ChEBI SCN2A protein Q99250 UNIPROT down-regulates activity chemical inhibition 10116 1658608 YES miannu This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. 0.8 SIGNOR-258353 degarelix chemical CHEBI:135961 ChEBI GNRHR protein P30968 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001033 22416801 YES miannu  Two GnRH antagonists are currently available: abarelix and degarelix.  0.8 SIGNOR-259160 PTPN12 protein Q05209 UNIPROT PSTPIP1 protein O43586 UNIPROT down-regulates activity dephosphorylation Tyr345 PERNEGVyTAIAVQE 10090 11711533 YES We also demonstrate that PTP-PEST dephosphorylates PSTPIP at tyrosine 344. Importantly, we identified tyrosine 344 as the main phosphorylation site of PSTPIP by performing tryptic phosphopeptide maps. |The biological functions of the complexes formed between PSTPIP and SH2 domain-containing tyrosine kinases may be to transmit the signals from activated EGF and PDGF receptor.|Furthermore, we show that PSTPIP is phosphorylated downstream of the activated PDGF and EGF receptors. This phosphorylation of PSTPIP is most likely mediated by c-Abl 0.611 SIGNOR-248656 PRKACA protein P17612 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 YES llicata Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.  0.256 SIGNOR-188177 PCDH19 protein Q8TAB3 UNIPROT GABRA5 protein P31644 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C335 29360992 YES miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  0.258 SIGNOR-267219 CDK1 protein P06493 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Thr269 GGKRSRLtPVSPESS 9606 SIGNOR-C17 20974803 YES gcesareni Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. 0.344 SIGNOR-169016 IRX2 protein Q9BZI1 UNIPROT CCL5 protein P13501 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003885 26560478 NO Luana Our results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression.  0.2 SIGNOR-266043 PRKCZ protein Q05513 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 8810272 YES gcesareni These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc. 0.2 SIGNOR-43834 ALPK1 protein Q96QP1 UNIPROT TIFA protein Q96CG3 UNIPROT up-regulates activity phosphorylation 9606 30308148 YES lperfetto The authors proposed that binding of ADP-Hep caused a conformational change exposing the catalytic cleft and allowing for ALPK1 to phosphorylate and activate TIFA leading to downstream NF-kB activation. 0.248 SIGNOR-279789 TRIM28 protein Q13263 UNIPROT FBP1 protein P09467 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000594 28394358 YES lperfetto In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. 0.31 SIGNOR-267591 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 19667122 YES lperfetto Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta. 0.2 SIGNOR-187578 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 11278991 YES lperfetto We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. 0.405 SIGNOR-216674 PPP1R3B protein Q86XI6 UNIPROT GYS2 protein P54840 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 YES miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) 0.769 SIGNOR-271732 vandetanib chemical CHEBI:49960 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258308 SMO protein Q99835 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 17251915 YES gcesareni As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp. 0.2 SIGNOR-152817 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Thr830 DSAEGSHtSGQSNGR 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.369 SIGNOR-276510 CDK1 protein P06493 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser251 MIQFAINsTERKRMT 9606 SIGNOR-C17 19737929 YES lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1the phosphorylation at ser-251 is critical for the activation of foxm1. 0.761 SIGNOR-187876 PXDN protein Q92626 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000567 29305973 NO miannu Our findings show that Snai1 mediates repression of PXDN and consolidate a role for this ECM-modifier during EMT. 0.7 SIGNOR-265253 miR-155 mirna URS000062749E_9606 RNAcentral INPP5D protein Q92835 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 24708856 YES miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. 0.4 SIGNOR-255764 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248747 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR AR protein P10275 UNIPROT down-regulates quantity by destabilization phosphorylation Ser310 TEDTAEYsPFKGGYT 9534 17698582 YES phosphorylation site remapping based on Fig 7D lperfetto We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1). 0.598 SIGNOR-273130 ATAT1 protein Q5SQI0 UNIPROT TUBA3D protein P0DPH8 UNIPROT up-regulates quantity by stabilization acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 YES lperfetto Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules 0.242 SIGNOR-272246 TIGIT protein Q495A1 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates activity binding 9606 BTO:0000914 24817116 YES lperfetto With TIGIT/PVR engagement, cytoplasmic TIGIT was phosphorylated at Tyr-225 and Tyr-231 residues. Phosphorylated Tyr-225 recruits adaptor protein beta arrestin 2|TIGIT/PVR signaling mediates suppression of IFN- gamma production via the NF-kappaB pathway. We identified a new adaptor β-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells. 0.2 SIGNOR-261482 PRKCD protein Q05655 UNIPROT EP300 protein Q09472 UNIPROT down-regulates phosphorylation Ser89 SELLRSGsSPNLNMG 9606 12379484 YES lperfetto Inhibition of histone acetyltransferase function of p300 by pkcdeltawe found that pkcdelta but not classical pkc, specifically phosphorylates p300 at serine 89 in vitro and in vivo. This phosphorylation causes inhibition of p300 intrinsic hat activity. 0.367 SIGNOR-94263 lysophosphatidylinositol 22:6 smallmolecule CHEBI:138556 ChEBI GPR55 protein Q9Y2T6 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257507 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr265 KDCGSQKyAYFNGCS 9606 16916748 YES lperfetto The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites. 0.59 SIGNOR-148917 PIAS4 protein Q8N2W9 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates sumoylation 9606 20016603 YES gcesareni Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation 0.635 SIGNOR-162167 CPT1B protein Q92523 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267133 ACO2 protein Q99798 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity chemical modification 9606 24068518 YES miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. 0.8 SIGNOR-266246 PPP4C protein P60510 UNIPROT HDAC3 protein O15379 UNIPROT down-regulates activity dephosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 YES Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c). 0.379 SIGNOR-248548 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 YES lperfetto Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. 0.789 SIGNOR-235475 CDK1 protein P06493 UNIPROT NUP210 protein Q8TEM1 UNIPROT up-regulates activity phosphorylation Ser1881 SPPSGLWsPAYASH -1 8672508 YES miannu In vitro phosphorylation of GST fusion protein containing the carboxyl-terminal domain of gp210 by cyclin B-p34cdc2 protein kinase generates a phosphopeptide that comigrates with a mitosis-specific phosphopeptide. Ser1880 Is the Mitotic Phosphorylation Site of Gp210. 0.548 SIGNOR-262699 TGFB3 protein P10600 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252284 MAPK3 protein P27361 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 BTO:0000150 10931950 YES gcesareni These data suggest that increased signaling by erbb receptors up-regulates mapk activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression. 0.376 SIGNOR-80234 FBXL18 protein Q96ME1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 10090 BTO:0002268 25654763 YES miannu F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18. 0.559 SIGNOR-272449 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr107 GNSAEEYyENVPCKA -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.245 SIGNOR-273557 PTGIR protein P43119 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.529 SIGNOR-256806 PGK1 protein P00558 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates activity phosphorylation Thr338 LFNYMYStAPRPRVE 9606 26942675 YES miannu Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex. 0.429 SIGNOR-278365 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Thr566 NTRQQMDtPMVSCGN -1 12361598 YES miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) 0.516 SIGNOR-265959 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROD4 protein Q9HD90 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19028584 NO miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. 0.247 SIGNOR-254631 APLNR protein P35414 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256824 FGFR3 protein P22607 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 10918587 YES Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. 0.67 SIGNOR-251138 GNAQ protein P50148 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 17606614 YES gcesareni Recently, the dbl-family guanine nucleotide exchange factor (gef) p63rhogef/geft has been described as a novel mediator of galpha(q/11) signaling to rhoa based on its ability to synergize with galpha(q/11) resulting in enhanced rhoa signaling in cells. 0.578 SIGNOR-156534 LEF1 protein Q9UJU2 UNIPROT OCA2 protein Q04671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22234890 NO miannu the SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression. 0.253 SIGNOR-254555 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser362 PVHPKPLsPDSRASS 9606 BTO:0001033 23188829 YES miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. 0.2 SIGNOR-263062 Ub:E2 complex SIGNOR-C497 SIGNOR UBE3B protein Q7Z3V4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271281 PBK protein Q96KB5 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity phosphorylation 9606 29896413 YES miannu TOPK overexpression promotes HDAC1 and HDAC2 phosphorylation and Histone 3 and Histone 4 acetylation in BV2 cells.|The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells. 0.245 SIGNOR-279086 LPAR6 protein P43657 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256868 ERBB2 protein P04626 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 1676673 YES gcesareni Activated egfr binds the sh2 domain of phospholipase c-gamma (plc-gamma), activating plc-gamma-mediated downstream signaling. 0.648 SIGNOR-20815 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser238 SEESWTDsEVDSSCS 9606 BTO:0000007 26885618 YES lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| 0.356 SIGNOR-273126 APH1A protein Q96BI3 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 YES Gamma secretase subunit that leads to PS1/PS2 eterodimer complex stabilisation. gcesareni By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. 0.947 SIGNOR-93262 LCK protein P06239 UNIPROT TCR complex SIGNOR-C153 SIGNOR up-regulates activity phosphorylation 10090 2470098 YES Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. 0.2 SIGNOR-259932 PREX1 protein Q8TCU6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.718 SIGNOR-260569 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser436 LRTKNGTsGKDSATT 9606 BTO:0000567 34198826 YES miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. 0.25 SIGNOR-276666 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 NO lperfetto STAT3 signaling controls satellite cell expansion and skeletal muscle repair 0.7 SIGNOR-245048 aspartic acid smallmolecule CHEBI:22660 ChEBI Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270378 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr519 EDPYAGStDENTDSE 9606 20471329 YES lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 0.396 SIGNOR-165431 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation Ser820 VSSAYTVsRRSSGIS 9606 BTO:0000007 16611981 YES lperfetto The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. 0.561 SIGNOR-148472 ADORA2A protein P29274 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.301 SIGNOR-257239 MAP2K1 protein Q02750 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates quantity by stabilization phosphorylation Ser1107 VLNNFIEsPSKLLDT 9606 BTO:0004082 38461173 YES miannu TET2 was stabilized by MEK1 phosphorylation at Ser 1107, while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7FBXW11. 0.247 SIGNOR-277891 KLF4 protein O43474 UNIPROT MEIS2 protein O14770 UNIPROT up-regulates activity binding 9606 21746878 YES miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. 0.268 SIGNOR-267238 MAP4K1 protein Q92918 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR down-regulates 9606 BTO:0000661 17353368 NO phosphorilation: Ser376 Barakat Thus, our study reveals the mechanism of a novel negative feedback loop initiated from SLP-76 to modulate signal intensity during T cell activation. 0.7 SIGNOR-274563 BLVRA protein P53004 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr500 WDGVTTKtFCGTPDY 9606 17227757 YES llicata Human biliverdin reductase, a previously unknown activator of protein kinase c ?II the phosphorylation of thr500 was confirmed by immunoblotting of hbvr.pkc betaii immunocomplex. 0.307 SIGNOR-152181 SP3 protein Q02447 UNIPROT MAOB protein P27338 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11259630 NO miannu Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. 0.2 SIGNOR-253870 SAV1 protein Q9H4B6 UNIPROT STK3 protein Q13188 UNIPROT up-regulates binding 9606 21084559 YES Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2. gcesareni Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. 0.834 SIGNOR-169829 ROCK1 protein Q13464 UNIPROT FHOD3 protein Q2V2M9 UNIPROT up-regulates activity phosphorylation 9606 23052206 YES miannu In addition we were able to throw light on the mechanism of activation of FHOD3 by ROCK1 and could demonstrate the effects of constitutively active FHOD3 on actin filament synthesis in cardiomyocytes.|ROCK1 can directly phosphorylate FHOD3 and FHOD3 seems to be the downstream mediator of the exaggerated actin filament formation phenotype that is induced in cardiomyocytes upon the overexpression of constitutively active ROCK1. 0.275 SIGNOR-278903 PPM1G protein O15355 UNIPROT USP7 protein Q93009 UNIPROT down-regulates activity dephosphorylation 9606 22361354 YES miannu Here, we report that in response to DNA damage USP7 is downregulated by the ATM dependent protein phosphatase PPM1G, thus downregulating Mdm2 and activating the p53 response.|We have now shown that when DNA damage is detected, PPM1G is activated and dephosphorylates USP7 isoform protein that leads to its degradation and consequently to Mdm2 degradation and accumulation of p53 ( A). 0.511 SIGNOR-277159 SENP1 protein Q9P0U3 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by destabilization desumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 YES gcesareni Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. 0.28 SIGNOR-252738 AMPK complex SIGNOR-C15 SIGNOR NR2C2 protein P49116 UNIPROT down-regulates phosphorylation Ser351 HVISRDQsTPIIEVE 9606 21478464 YES lperfetto Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression 0.2 SIGNOR-216537 STAT3 protein P40763 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR form complex binding 10090 BTO:0000667 15284024 YES lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. 0.614 SIGNOR-235664 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR -1 9139719 YES lperfetto In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33. 0.58 SIGNOR-248971 RNF216 protein Q9NWF9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16968706 YES miannu Triad3A promotes proteolytic degradation of adapter proteins. Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins. 0.504 SIGNOR-271608 hexestrol chemical CHEBI:31669 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258593 AP1 complex SIGNOR-C154 SIGNOR CXCL8 protein P10145 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 NO miannu The up-regulation of the CXCL8 gene expression, could be due to a direct effect of the virus at the cellular level. Indeed, intestinal and lung cells lines infected by SARS-CoV, promptly increase their secretion of CXCL8 [88]. This observation would fit with the notion that the expression of CXCL8 is dependent on the tran-scription factor Activator protein 1 (AP-1), which was shown to bestrongly up-regulated by SARS-CoV 0.56 SIGNOR-261029 lipopolysaccharide smallmolecule CHEBI:16412 ChEBI TLR4 protein O00206 UNIPROT up-regulates activity chemical activation 10090 9851930 YES The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. 0.8 SIGNOR-252075 PRKAA1 protein Q13131 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 SIGNOR-C15 11069105 YES gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. 0.464 SIGNOR-84061 LAT protein O43561 UNIPROT VAV1 protein P15498 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr255;Tyr220 EEEGAPDyENLQELN;SLDGSREyVNVSQEL 11368773 YES lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. 0.751 SIGNOR-246045 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9534 11445557 YES lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. 0.676 SIGNOR-252620 Netrin proteinfamily SIGNOR-PF97 SIGNOR UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 25881791 YES miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. 0.853 SIGNOR-268174 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser653 PSLSRHSsPHQSEDE 11427888 YES Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II. 0.685 SIGNOR-251241 RAB6A protein P20340 UNIPROT VPS13B protein Q7Z7G8 UNIPROT up-regulates activity binding 10116 BTO:0003102 25492866 YES miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization. 0.372 SIGNOR-266869 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI glycine zwitterion smallmolecule CHEBI:57305 ChEBI up-regulates quantity precursor of 9606 11802770 YES miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. 0.8 SIGNOR-269691 GGCX protein P38435 UNIPROT PROS1 protein P07225 UNIPROT up-regulates activity carboxylation 9606 28125048 YES lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z 0.612 SIGNOR-265924 pazopanib chemical CHEBI:71219 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 YES Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. 0.8 SIGNOR-257739 RBBP5 protein Q15291 UNIPROT MLL/SET subcomplex complex SIGNOR-C87 SIGNOR form complex binding 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complexincluding wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.904 SIGNOR-204825 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity dephosphorylation Tyr742 KQADTTQyVPMLERK -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.25 SIGNOR-254713 POMC protein P01189 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.65 SIGNOR-258410 HSPA8 protein P11142 UNIPROT CFTR protein P13569 UNIPROT down-regulates quantity binding 9606 BTO:0000007 21148293 YES miannu JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex 0.671 SIGNOR-271492 APBB1 protein O00213 UNIPROT TSHZ3 protein Q63HK5 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 19343227 YES miannu We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex. 0.367 SIGNOR-264813 CTNNB1 protein P35222 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 10937998 NO fspada Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma). 0.397 SIGNOR-80589 PRKCE protein Q02156 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 BTO:0000007 11085981 YES lperfetto In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism. 0.365 SIGNOR-249064 SYK protein P43405 UNIPROT TUBA4A protein P68366 UNIPROT up-regulates activity phosphorylation Tyr432 MAALEKDyEEVGIDS 9606 BTO:0000776 9490415 YES lperfetto Syk, Activated by Cross-linking the B-cell Antigen Receptor, Localizes to the Cytosol Where It Interacts with and Phosphorylates alpha-Tubulin on Tyrosine 0.331 SIGNOR-246626 NKX2-5 protein P52952 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003265 19479054 NO Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5. 0.346 SIGNOR-253653 APC-c complex SIGNOR-C150 SIGNOR KIF4A protein O95239 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24510915 YES miannu Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). 0.287 SIGNOR-266112 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser225 ARLGSQHsPGRTASL 9606 21419341 YES gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. 0.443 SIGNOR-172877 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser252 DIWSMGLsLVEMAVG -1 8413257 YES lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. 0.789 SIGNOR-39062 GH1 protein P01241 UNIPROT GHR protein P10912 UNIPROT up-regulates binding 9606 7862673 YES gcesareni The hghr only binds primate gh. Arg43 in hghr interacts with asp171 of hgh. 0.859 SIGNOR-34129 RPS6KA1 protein Q15418 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 11500364 YES lperfetto We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity 0.514 SIGNOR-109708 LDHB protein P07195 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000164 34929314 NO lperfetto LDHB is a glycolytic enzyme that catalyzes the conversion of lactic acid and NAD+ into pyruvate, NADH and H+.  0.7 SIGNOR-267654 P2RY11 protein Q96G91 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257328 UCHL3 protein P15374 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity deubiquitination Lys58 AVAYAPKkELINIKG 27941124 YES lperfetto Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. 0.326 SIGNOR-275908 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 YES inferred from 70% family members gcesareni Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus 0.2 SIGNOR-270005 ATG14 protein Q6ZNE5 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 YES lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.91 SIGNOR-260318 OS9 protein Q13438 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 17932042 YES miannu Here we report that OS-9, a ubiquitously expressed endoplasmic reticulum (ER)-associated protein, interacts with the cytosolic N-terminal tail of TRPV4.Thus, OS-9 regulates the secretory transport of TRPV4 and appears to protect TRPV4 subunits from the precocious ubiquitination and ER-associated degradation. Our data suggest that OS-9 functions as an auxiliary protein for TRPV4 maturation. 0.375 SIGNOR-261064 CUDC-101 chemical CID:24756910 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262258 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser153 SWTRVFQsWWDRNLG 9606 BTO:0000007 10837486 YES lperfetto We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites. 0.2 SIGNOR-252767 BBS4 protein Q96RK4 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 YES lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 0.784 SIGNOR-262560 CD79B protein P40259 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 32323266 YES scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. 0.656 SIGNOR-268197 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity precursor of 9606 23000145 YES scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). 0.8 SIGNOR-268450 GNAI1 protein P63096 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity binding 9606 15922020 YES miannu Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated. 0.633 SIGNOR-267853 desloratadine chemical CHEBI:291342 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257784 CSNK2A1 protein P68400 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates quantity by stabilization phosphorylation Ser388 RTANSEDsDEQDPEE -1 17911614 YES miannu Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. It seems that phosphorylation of 3DL1 by CK does not significantly affect receptor inhibitory function or turnover, at least in the assays that we have used so far. 0.2 SIGNOR-276078 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser99 NRQAAKLsKPTLENL 9606 15703181 YES lperfetto We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195. 0.2 SIGNOR-133888 KDM4C protein Q9H3R0 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-263867 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr92 FYEEIKKyEKLETEE 9606 BTO:0000007 16725308 YES miannu Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.  0.2 SIGNOR-266305 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser55 NKFLENKsPWRKMVH 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.249 SIGNOR-275598 DOK1 protein Q99704 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257670 SMARCD2 protein Q92925 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.763 SIGNOR-270693 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr653 RDIHHIDyYKKTTNG 10116 BTO:0002809;BTO:0001009 8622701 YES lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses. 0.2 SIGNOR-236195 PTK6 protein Q13882 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 26247733 YES miannu 29 PTK6 promotes activating phosphorylation of STAT3 at tyrosine residue 705.|STAT3 has been shown to promote tumor initiation of different tumor types, including those of the gastrointestinal tract and skin, and PTK6 was previously shown to promote STAT3 activation and tumorigenesis in mouse models of colon and skin cancer. 0.621 SIGNOR-278346 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258537 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity precursor of 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267416 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2S protein Q16763 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.771 SIGNOR-271309 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX10 protein P56693 UNIPROT down-regulates activity phosphorylation Thr244 GPPTPPTtPKTELQS 9606 BTO:0002806 29295999 YES miannu Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity.ERK2 directly phosphorylates SOX10 at T240 and T244. 0.2 SIGNOR-277820 NEDD4L protein Q96PU5 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 YES miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 0.318 SIGNOR-253459 Ub:E2 complex SIGNOR-C497 SIGNOR RNF17 protein Q9BXT8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270965 SGCG protein Q13326 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.455 SIGNOR-255987 CDC25B protein P30305 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity dephosphorylation 9606 26474275 YES miannu CDC25B is also able to dephosphorylate and activate CDK2-Cyclin A and CDK2-Cyclin E complexes [ xref \u2013 xref ]. 0.766 SIGNOR-277140 PIGG protein Q5H8A4 UNIPROT PIGO protein Q8TEQ8 UNIPROT up-regulates quantity by stabilization binding 10029 BTO:0000246 15632136 YES miannu We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O. 0.399 SIGNOR-261359 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR VRK3 protein Q8IV63 UNIPROT up-regulates activity phosphorylation Ser108 RPPTPKSsPQKTRKS 27346674 YES lperfetto Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation| 0.356 SIGNOR-275545 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser153 SWTRVFQsWWDRNLG 9606 BTO:0000007 10837486 YES lperfetto We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites. 0.396 SIGNOR-249045 KDM4B protein O94953 UNIPROT BBC3 protein Q96PG8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 NO miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. 0.2 SIGNOR-263733 JAK2 protein O60674 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates activity binding 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation 0.7 SIGNOR-249489 HCK protein P08631 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.551 SIGNOR-249363 TRIM23 protein P36406 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 25905670 YES miannu In this study, we showed that TRIM23 mediates atypical polyubiquitin conjugation including M1- and K27 linked ubiquitin chains to PPARgamma and that ubiquitination of PPARgamma by TRIM23 causes reduced recognition of PPARgamma by 26S proteasome. 0.2 SIGNOR-278577 PTPN2 protein P17706 UNIPROT FKBP4 protein Q02790 UNIPROT down-regulates dephosphorylation 9606 BTO:0000567 12552015 YES tpavlidou We have documented that a cellular protein that binds the immunosuppressant drug fk506, termed the fk506-binding protein (fkbp52), interacts with the single-stranded d sequence within the aav inverted terminal repeats, inhibits viral second-strand dna synthesis, and consequently limits high-efficiency transgene expression. Deliberate overexpression of the murine wild-type (wt) tc-ptp gene, but not that of a cysteine-to-serine (c-s) mutant, caused tyrosine dephosphorylation of fkbp52, leading to efficient viral second-strand dna synthesis and resulting in a significant increase in aav-mediated transduction efficiency in hela cells in vitro. 0.4 SIGNOR-97794 FOXO3 protein O43524 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity transcriptional regulation 10090 BTO:0002314 24749067 NO gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. 0.375 SIGNOR-254320 CEBPA protein P49715 UNIPROT Basophil_diff phenotype SIGNOR-PH116 SIGNOR up-regulates activity 10090 BTO:0000725 23990620 NO Notably, enforced overexpression of C/EBP-α in BMCPs results in exclusive differentiation into basophils, whereas conditional deletion of C/EBP-α in these same cells promotes mast cell differentiation,1 suggesting that C/EBP-α is an essential “switch factor” for basophil lineage choice 0.7 SIGNOR-259968 IL7R protein P16871 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000776 18445337 YES milica For instance, jak1 is associated with the ? Subunits of ?c Cytokines such as il-7r? And IL-4R. jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation. 0.637 SIGNOR-178494 NTF4 protein P34130 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 YES gcesareni Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb. 0.692 SIGNOR-85117 AURKB protein Q96GD4 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser265 QKVAERRsSPLLRRK 9606 22865920 YES lperfetto We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions 0.264 SIGNOR-198646 GADD45B protein O75293 UNIPROT CDK11A protein Q9UQ88 UNIPROT down-regulates activity binding 9606 BTO:0000007 26885618 YES lperfetto Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58. 0.2 SIGNOR-273024 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr813 GDNVLINtYSGVLKI 9606 17937911 YES lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. 0.2 SIGNOR-158423 PRKAA1 protein Q13131 UNIPROT ACSS2 protein Q9NR19 UNIPROT up-regulates activity phosphorylation Ser659 PGLPKTRsGKIMRRV 28820290 YES lperfetto This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin α5 for binding. In the nucleus, ACSS2 forms a complex with TFEB (transcription factor EB) and utilizes the acetate generated from histone deacetylation to locally produce acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes. 0.275 SIGNOR-271822 RHOA protein P61586 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0000132 35267019 YES miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. 0.612 SIGNOR-268431 COX5A protein P20674 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.802 SIGNOR-267751 MYC protein P01106 UNIPROT CDC25A protein P30304 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11154267 YES lperfetto Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen 0.626 SIGNOR-245465 GABRA6 protein Q16445 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.611 SIGNOR-263762 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.2 SIGNOR-248569 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation 9606 16023596 YES gcesareni Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation. 0.331 SIGNOR-138592 NMDA proteinfamily SIGNOR-PF56 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 YES miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. 0.2 SIGNOR-266598 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser537 GTFSPGAsPGSEART 9606 BTO:0000567 31981797 YES miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. 0.434 SIGNOR-276833 CCR4-NOT complex complex SIGNOR-C439 SIGNOR NANOS2 protein P60321 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 YES lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins 0.481 SIGNOR-268349 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Thr388 VYFKPSLtPSGEFRK 9606 19767751 YES llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. 0.389 SIGNOR-188127 cinolazepam chemical CHEBI:59514 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). 0.8 SIGNOR-263801 MDM2 protein Q00987 UNIPROT RPL6 protein Q02878 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24174547 YES miannu Furthermore, we also demonstrated that RPL6 is a substrate for HDM2-mediated ubiquitination and proteasomal degradation.|The interaction of RPL6 and HDM2 drives HDM2 mediated RPL6 polyubiquitination and proteasomal degradation. 0.433 SIGNOR-278630 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr875 GLITTLHyPAPKRNK 9606 16912036 YES Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 0.2 SIGNOR-260816 ITGB1BP1 protein O14713 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.279 SIGNOR-257655 KDM3A protein Q9Y4C1 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 YES miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  0.2 SIGNOR-276843 SIAH1 protein Q8IUQ4 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20940030 YES gcesareni The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation 0.26 SIGNOR-168460 CDK19 protein Q9BWU1 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.302 SIGNOR-273136 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 21749389 YES The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert. 0.2 SIGNOR-252795 ATM protein Q13315 UNIPROT IPO9 protein Q96P70 UNIPROT up-regulates activity phosphorylation 9606 26943034 YES miannu In line with our previous results, IR exposure induced the nuclear accumulation of RanBP9, which was prevented by ATM inhibition using KU-55933.|Taken together these data indicate that RanBP9 is a novel target of ATM and that ATM phosphorylates at least two different residues (S181 and S603) of RanBP9 following IR exposure. 0.2 SIGNOR-278910 EGLN2 protein Q96KS0 UNIPROT ADSL protein P30566 UNIPROT up-regulates activity hydroxylation Pro24 LASRYASpEMCFVFS 9606 BTO:0000007 31729379 YES miannu ADSL is hydroxylated by EglN2 on Proline 24. An integrated transcriptomics and metabolomics analysis reveals that ADSL activates the oncogenic cMYC pathway by regulating cMYC protein level via a mechanism requiring ADSL proline 24 hydroxylation. ADSL regulates cMYC protein level through adenosine levels 0.2 SIGNOR-266613 STX11 protein O75558 UNIPROT Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR up-regulates 9606 22767500 NO lperfetto In contrast to previous studies,13,15,16,19 the results of the present study show that syntaxin-2 and syntaxin-4 are not required for release, but that syntaxin-11 is critical for platelet exocytosis. 0.7 SIGNOR-261893 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.708 SIGNOR-249642 RELA protein Q04206 UNIPROT CD80 protein P33681 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12860928 NO Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. 0.296 SIGNOR-253935 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser203 APAPDEGsDLFYDDY 9606 BTO:0000567 11546811 YES lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. 0.395 SIGNOR-110383 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP53 protein P04637 UNIPROT up-regulates 9606 17700533 YES miannu Nutlin, a class of small molecule antagonist of HDM2, binds to the p53-binding pocket of HDM2, preventing p53 from binding to HDM2 and thus, resulting in stabilization and activation of p53 0.8 SIGNOR-255471 PHLPP2 protein Q6ZVD8 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 19261608 YES The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. 0.772 SIGNOR-248732 JAK3 protein P52333 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 YES Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 0.792 SIGNOR-256254 DTL protein Q9NZJ0 UNIPROT SDE2 protein Q6IQ49 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 27906959 YES miannu Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction. The cleaved SDE2 products need to be degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner, and failure to degrade SDE2 impairs S phase progression and cellular survival. 0.282 SIGNOR-272807 STAT5A protein P42229 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates quantity transcriptional regulation 9606 26059451 YES … these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells 0.326 SIGNOR-255631 AUTS2 protein Q8WXX7 UNIPROT PREX1 protein Q8TCU6 UNIPROT up-regulates activity binding 10090 BTO:0001909 25533347 YES miannu Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells. 0.252 SIGNOR-266817 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RUNX3 protein Q13761 UNIPROT down-regulates phosphorylation Ser356 SSSGGDRsPTRMLAS 9606 19351720 YES lperfetto Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation. 0.529 SIGNOR-216980 SLC1A3 protein P43003 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 YES miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). In glia or in neurons, EAATs mediate the re-uptake of synaptically released glutamate via the coupled co-transport of three Na+, one H+, and one glutamate, in counter-transport to one K+. 0.8 SIGNOR-264802 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.939 SIGNOR-253679 NDUFS4 protein O43181 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.847 SIGNOR-262178 STT3A protein P46977 UNIPROT OST-A complex complex SIGNOR-C535 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.778 SIGNOR-272064 SHOX protein O15266 UNIPROT NPPB protein P16860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17881654 NO miannu The ability of SHOX to transactivate the NPPB endogenous promoter was demonstrated in luciferase reporter assays using serial deletions of the NPPB promotor region. Binding of SHOX to the NPPB promoter was also demonstrated in vivo by chromatin fixation and immunoprecipitation. We also demonstrate the lack of promoter activation in two SHOX mutants from patients with Leri-Weill syndrome. 0.291 SIGNOR-255138 RNF115 protein Q9Y4L5 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination Thr58 T-->P 9606 22844532 YES miannu These results suggest that Rabring7 antagonizes function of c-Myc possibly through degradation of c-Myc.|Unexpectedly, we found that Rabring7 more strongly binds to c-Myc than to MM-1 (XREF_FIG) and that Rabring7 stimulates poly-ubiquitination of c-Myc in a T58 dependent manner (XREF_FIG). 0.449 SIGNOR-278662 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 YES lperfetto Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts 0.614 SIGNOR-249145 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation 9606 14988395 YES inferred from 70% family members lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. 0.2 SIGNOR-270141 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0000567 11337501 YES lperfetto Taken together, our findings support the idea that binding of pkr to dsrna increases autophosphorylation in the activation loop of the kinase domain (fig. 9). Because dsrna binding promotes dimerization, this would facilitate trans-autophosphorylation of thr-446 and thr-451 by the two kinase moieties in a pkr dimer 0.2 SIGNOR-107511 MAP3K1 protein Q13233 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 10647776 YES miannu As yet, the apparent discrepancy between these and above data is not clear, but obviously the type of cell under study and the cellular context may play an important role.In endothelial cells, Smad2 activity is stimulated by MEKK1, a component of the Stress Activated Protein Kinase and c-Jun N terminal kinase (SAPK and JNK) pathway.|Phosphorylation of Smad2 by MEKK1 increased its association with Smad4, its nuclear accumulation and its transcription induction activity . 0.472 SIGNOR-279064 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.708 SIGNOR-252878 AKT1 protein P31749 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 12588998 YES gcesareni Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro 0.2 SIGNOR-265320 RNF5 protein Q99942 UNIPROT ATG4B protein Q9Y4P1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23093945 YES miannu These results substantiate the notion that RNF5 negatively regulates ATG4B availability with concomitant effect on LC3 processing and autophagy under normal growth conditions.|These results suggest that RNF5 directly induces ATG4B ubiquitination. 0.405 SIGNOR-278664 USP36 protein Q9P275 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates quantity by stabilization deubiquitination Lys222 PRKFPSDkIFEAISS 9606 BTO:0002030 31434700 YES miannu We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination.  Furthermore, we identify USP36 as the deubiquitinating enzyme that deubiquitinates EZH2 at K222. 0.2 SIGNOR-277481 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 BTO:0000017 10358079 YES gcesareni We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5. 0.821 SIGNOR-68159 TEAD1 protein P28347 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22286761 NO gcesareni Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. 0.272 SIGNOR-194371 RUNX2 protein Q13950 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 9182762 NO gcesareni Osf2/cbfa1 as an osteoblast-specific transcription factor and as a regulator of osteoblast differentiation 0.7 SIGNOR-48940 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258093 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CRY2 protein Q49AN0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17463251 YES miannu  We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex. This regulation by SCF(Fbxl3) is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. HEK293T cells were transfected with Cry2, Skp1, Cul1, and Roc1 in the absence or presence of either FLAG-tagged Fbxl3 or a FLAG-tagged Fbxl3(ΔF-box) mutant. Fbxl3, but not an inactive Fbxl3(ΔF-box) mutant (4), induced the ubiquitination of Cry2 (Fig. 2D), which supports the notion that the effect of Fbxl3 on Cry2 is direct. 0.385 SIGNOR-271650 PRKDC protein P78527 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization phosphorylation Ser636 SRRPRYDsYEEYQHE 9606 BTO:0005949 36696363 YES miannu Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34.  0.2 SIGNOR-277911 FBXO33 protein Q7Z6M2 UNIPROT EIF3F protein O00303 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000165 18354498 YES miannu Mediation of eIF3-f polyubiquitination by the SCFMAFbx. The association of MAFbx with the essential Skp1, Roc 1 and Cul1 proteins, specific components of an E3 ubiquitin–protein ligase (SCFMAFbx), was previously described. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome. 0.2 SIGNOR-271768 SYK protein P43405 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates phosphorylation Ser361 LAEGTPRsNHSAQDS 9606 BTO:0001271 23071339 YES miannu Syk phoshorylatesikarosat unique c-terminal serine phosphorylation sites s358 and s361, thereby augmenting its nuclear localization and sequence-specific dna binding activity. Mechanistically, we establish that syk-inducedikarosactivation is essential for its nuclear localization and optimal transcription factor function. 0.404 SIGNOR-199096 PRKD3 protein O94806 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 34010649 YES lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-275940 FGF13 protein Q92913 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 BTO:0001103 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.252 SIGNOR-253431 COA1 protein Q9GZY4 UNIPROT MITRAC complex complex SIGNOR-C538 SIGNOR form complex binding 9606 BTO:0000007 23260140 YES By analyzing MITRAC12 interaction partners, we show that recently identified assembly factors, such as c12orf62, CMC1, and the novel assembly factor MITRAC15, are constituents of MITRAC complexes 0.38 SIGNOR-272483 TNF protein P01375 UNIPROT SCN1A protein P35498 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.258 SIGNOR-253487 EPHA2 protein P29317 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 12400011 YES gcesareni We also show that the interaction of epha2 with grb2 is indirect and mediated by shc and that this complex is necessary for epha2-mediated activation of erk kinases. 0.615 SIGNOR-94804 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway 0.691 SIGNOR-252947 Calcineurin complex SIGNOR-C155 SIGNOR DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 YES CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). 0.266 SIGNOR-252317 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3). 0.8 SIGNOR-257854 STAT6 protein P42226 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 NO lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. 0.515 SIGNOR-249533 125-L-serine-2-133-interleukin 2 (human reduced) smallmolecule SID:46508054 PUBCHEM IL2RB protein P14784 UNIPROT up-regulates activity chemical activation 9606 18031103 YES miannu Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. 0.8 SIGNOR-259389 GSK3B protein P49841 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity 10090 24260231 NO miannu Involvement of GSK3 Inhibition by the PI3K/Akt Pathway in Regulation of Etoposide-induced Chk1 Activation. GSK3ß regulates etoposide-induced Chk1 activation. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. Thus, proteasomal degradation of Chk1 as well as GSK3 activation may be involved in negative regulation of etoposide-induced Chk1 by imatinib in these cells. 0.298 SIGNOR-263050 DLX5 protein P56178 UNIPROT Osteoblast_differentiation phenotype SIGNOR-PH9 SIGNOR up-regulates 10090 12000792 NO Giulio Giuliani In conclusion, Dlx5 and Dlx6 are dynamic regulators of mammalian development, which are absolutely required for proper craniofacial and skeletal development and which display overlapping genetic functions in all tissues in which they are expressed. In addition, they appear to act as essential regulators of chondrogenesis and osteogenesis. 0.7 SIGNOR-255450 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258081 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18211802 YES inferred from 70% family members gcesareni Activates rhoa and as a result regulates actin assembly. 0.2 SIGNOR-270007 SNRPA protein P09012 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.826 SIGNOR-270678 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser149 TNVNFGRsRSAQEPA 9606 24309468 YES lperfetto Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1. 0.461 SIGNOR-203456 MAP2K6 protein P52564 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates activity phosphorylation Ser721 PSDLLPMsPSVYAVL 10090 BTO:0000944 10961885 YES MKK6, phosphorylate STAT4 on serine 721. IL-12 induces STAT4 phosphorylation on serine 721 and that mutation of serine 721 interferes with STAT4 transcriptional activity. 0.342 SIGNOR-251425 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser66 GVYATRSsAVRLRSS -1 11895474 YES miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.  0.307 SIGNOR-250241 WWTR1 protein Q9GZV5 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 YES YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. 0.698 SIGNOR-201415 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 YES lperfetto These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase 0.744 SIGNOR-40423 PRKCZ protein Q05513 UNIPROT MARK2 protein Q7KZI7 UNIPROT down-regulates phosphorylation Thr596 RGVSSRStFHAGQLR 9606 15084291 YES lperfetto Hpar-1b is phosphorylated by apkc on threonine 595 importantly, phosphorylation of hpar-1b on t595 negatively regulates the kinase activity and plasma membrane localization of hpar-1b in vivo. 0.266 SIGNOR-124217 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser700 FGEKRKNsILNPINS -1 1377674 YES miannu CFTR is phosphorylated directly by PKA and PKC in vivo. phosphorylation by PKA is necessary to allow ATP hydrolysis by CFTR and that ATP hydrolysis is necessary for channel opening. CF-2 was phosphorylated by PKA in vitro on serines 660,700, 737, 813 and most likely on both serines 768 and 795. 0.484 SIGNOR-250348 UBE3A protein Q05086 UNIPROT SOX9 protein P48436 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 24155239 YES miannu We show that E6-AP ubiquitinates SOX9 in vitro and in vivo and that SOX9 levels are enhanced after addition of the proteasome inhibitor bortezomib. Similar, siRNA knockdown of E6-AP and the E2 ligase Ubc9 increased cellular SOX9 amounts, supporting the notion that SOX9 may be ubiquitinated in hypertrophic chondrocytes by E6-AP and degraded by proteasomes. 0.261 SIGNOR-272134 ITGB3 protein P05106 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.666 SIGNOR-257718 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2L2 protein Q92843 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189156 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001056 23409026 YES miannu Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. 0.8 SIGNOR-259270 pomalidomide chemical CHEBI:72690 ChEBI CRBN protein Q96SW2 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 22552008 YES miannu Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. 0.8 SIGNOR-259283 HNF4G protein Q14541 UNIPROT AKR1C4 protein P17516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003846 2044952 NO 2 miannu Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C. 0.2 SIGNOR-240013 FLT3 protein P36888 UNIPROT HK2 protein P52789 UNIPROT up-regulates activity 9606 BTO:0002144 28194038 NO FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity 0.259 SIGNOR-261322 PTPN11 protein Q06124 UNIPROT CDC73 protein Q6P1J9 UNIPROT up-regulates activity dephosphorylation 9606 21726809 YES miannu We found in this work that SHP2 dephosphorylates parafibromin and Cdc73, a component of the nuclear RNA polymerase II associated factor (PAF) complex, which can function as a tumor suppressor or oncoprotein in a context dependent manner. 0.495 SIGNOR-277036 RET protein P07949 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 16153436 YES inferred from 70% of family members gcesareni We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1). 0.2 SIGNOR-269894 CCNO protein P22674 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity binding 9606 BTO:0000007 25364462 YES lperfetto Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O 0.454 SIGNOR-275616 RUNX2/EP300 complex SIGNOR-C211 SIGNOR BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002648 12697832 NO Giulio Giuliani In agreement with our studies in ROS 17/2.8 cells, coexpression of p300 and Runx2/Cbfa1 resulted in marked enhancement of the OC promoter activity, further indicating that both factors cooperate to stimulate this promoter. 0.424 SIGNOR-255420 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr823 DIKNDSNyVVKGNAR 9606 12824176 YES lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth. / tyr-823 is the last tyrosine residue to be autophosphorylated 0.2 SIGNOR-102641 Caspase 3 complex complex SIGNOR-C221 SIGNOR CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 YES lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. 0.638 SIGNOR-256440 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 NO lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F 0.7 SIGNOR-245480 AKT proteinfamily SIGNOR-PF24 SIGNOR AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 YES gcesareni Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40 0.2 SIGNOR-236929 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18339811 YES Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. 0.2 SIGNOR-248606 AXIN1 protein O15169 UNIPROT APC protein P25054 UNIPROT up-regulates activity binding 9606 BTO:0000038 9734785 YES amattioni Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level. 0.944 SIGNOR-60043 FBXW7 protein Q969H0 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0002524 17298674 YES miannu Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme 0.891 SIGNOR-271640 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 10068651 YES lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. 0.952 SIGNOR-236254 AR protein P10275 UNIPROT UCN protein P55089 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001509 23801677 YES lperfetto When cells were treated with DHT alone, AR was upregulated and translocated into the nuclei, which might repress UCN1 expression via a potential androgen-responsive element found in human CRF family promoter|These data suggest that DHT differentially influences UCN1 levels under normal and inflammatory conditions in human umbilical vein endothelial cells, which involves AR-dependent and -independent mechanisms respectively. 0.2 SIGNOR-253688 HIF-1 complex complex SIGNOR-C418 SIGNOR LDHA protein P00338 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 YES miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 0.656 SIGNOR-267456 GIPR protein P48546 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000783 35065096 YES miannu The GPCRs are allocated in five families where the GLP-1R and GIPR are found within the secretin family, also classified as class B [31,32]. Upon stimulation by an extracellular stimuli (ligand), GPCRs undergo conformational changes, and triggers downstream intracellular signals by coupling with G proteins (or other intracellular proteins such as arrestins), causing a wide range of both physiological and pathological processes.To stimulate insulin secretion, and in the presence of elevated blood glucose concentrations, GLP-1R activation in pancreatic beta cells promote recruitment and activation of Gαs protein leading to adenylate cyclase-mediated cAMP production, elevation of Ca2+, and ERK1/2 phosphorylation (Fig. 3) 0.442 SIGNOR-278138 Ub:E2 complex SIGNOR-C497 SIGNOR PJA2 protein O43164 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271143 RPS6KA3 protein P51812 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 10464286 YES gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-265347 CREB1 protein P16220 UNIPROT PAX3 protein P23760 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 NO gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. 0.314 SIGNOR-176539 CCND3 protein P30281 UNIPROT CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR form complex binding -1 12082095 YES lperfetto We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1). 0.651 SIGNOR-273120 HIF-1 complex complex SIGNOR-C418 SIGNOR BNIP3L protein O60238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 YES miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 0.301 SIGNOR-267455 MAPK1 protein P28482 UNIPROT DUSP16 protein Q9BY84 UNIPROT up-regulates quantity by stabilization phosphorylation Ser446 TNKLCQFsPVQELSE 9534 15689616 YES lperfetto Phosphorylation of Ser-446 determines stability of MKP-7.|We also determined that MKP-7 phosphorylated at Ser-446 has a longer half-life than unphosphorylated form of the wild type protein, as does a phospho-mimic mutant of MKP-7. These results indicate that activation of the ERK pathway strongly blocks JNK activation through stabilization of MKP-7 mediated by phosphorylation. 0.808 SIGNOR-249389 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1647 SPSYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248806 ROS stimulus SIGNOR-ST2 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates 9534 BTO:0004055 12646569 NO lperfetto We have also provided evidence that the mitochondrial GSTA4-4 level markedly increases in COS cells under oxidative stress conditions, suggesting its critical role in maintaining the GSH homeostasis under conditions of chemical and oxidative stress 0.7 SIGNOR-264797 AVPR1A protein P37288 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.271 SIGNOR-256948 miR-155 mirna URS000062749E_9606 RNAcentral MYC protein P01106 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 19933931 YES On the basis of bioinformatics tools, biochemical assays, and in vivo models, we demonstrate that (1) insulin-like growth factor-1 (IGF-1) and IGF-1 receptor are targets of miR-1 0.4 SIGNOR-255721 NF2 protein P35240 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 24012335 YES The opposite changes in Lats/YAP and Mst1/2 phosphorylation upon loss of NF2 therefore argue against the generally assumed linear model in which NF2 signals through activation of Mst1/3 flangone As expected, the nf2-/- fc-912 cells were defective in lats1/2 phosphorylation (figure s2e-f). Subcellular fractionation revealed a significant increase of endogenous lats1/2 in the cytoplasmic relative to the membrane fraction in the nf2-/- fc-912 schwann cells compared to the nf2+/+ fh-912 schwann cells (figure 2e). This localization defect was rescued by re-expression of nf2 0.691 SIGNOR-202604 TGFB1 protein P01137 UNIPROT LPL protein P06858 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 11742878 NO Regulation of expression miannu TGF-β1 inhibited gene expression and cell surface activity of LPL. TGF-β1 did not have an effect on LPL activity when it was added directly to the LPL activity assay (data not shown); however, as shown in the Table, TGF-β1 significantly reduced LPL mRNA by 55.0% 0.265 SIGNOR-251847 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 YES gcesareni In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. 0.2 SIGNOR-83217 PPM1D protein O15297 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity dephosphorylation Thr68 SSLETVStQELYSIP -1 16311512 YES an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C. 0.573 SIGNOR-248318 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr937 ADEEPEStPVPLLGS 9606 18055457 YES lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta 0.272 SIGNOR-159582 MAPK1 protein P28482 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates activity phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 YES miannu Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events. 0.27 SIGNOR-262841 MED22 protein Q15528 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.746 SIGNOR-266661 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9606 18321241 YES miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). 0.8 SIGNOR-259236 SRC protein P12931 UNIPROT INPPL1 protein O15357 UNIPROT up-regulates phosphorylation Tyr987 SFNNPAYyVLEGVPH 9606 12235291 YES lperfetto Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo. 0.536 SIGNOR-92935 SCARB1 protein Q8WTV0 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding 10090 26059978 YES Giulio Importantly, coimmunoprecipitation of SR-BI and Src demonstrated that the two proteins are directly associated in WT macrophages (Fig. 7B), suggesting that SR-BI plays a direct role in activation of Src in macrophages. 0.369 SIGNOR-260314 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser31 LKLGSGPsIKALDGR 9606 BTO:0000567 24781523 YES miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase 0.31 SIGNOR-276382 CSNK2A1 protein P68400 UNIPROT ACE protein P12821 UNIPROT up-regulates activity phosphorylation Ser1299 SHGPQFGsEVELRHS 9823 BTO:0001176 12386153 YES lperfetto CK2 coprecipitated with ACE from endothelial cells, and CK2 phosphorylated both ACE and a peptide corresponding to the cytoplasmic tail. Mutation of serine(1270) within the CK2 consensus sequence almost abolished ACE phosphorylation.|These results indicate that the CK2-mediated phosphorylation of ACE regulates its retention in the plasma membrane and may determine plasma ACE levels. 0.303 SIGNOR-264425 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Ror1 and ror2 bind wnt5a. 0.746 SIGNOR-199644 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates phosphorylation Ser337 FVQLRRKsDLETSEP 9606 SIGNOR-C13 17959673 YES llicata In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab. 0.508 SIGNOR-158595 INPP5D protein Q92835 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI down-regulates quantity chemical modification 9606 12421919 YES gcesareni Two inositol phosphatases implicated in the degradation of PI(3, 4, 5)P3, namely the 5_ phosphatase Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and the 3_ phosphatase and tensin homolog deleted on chromosome ten 0.8 SIGNOR-252428 ATM protein Q13315 UNIPROT RAD17 protein O75943 UNIPROT unknown phosphorylation Ser656 SASELPAsQPQPFSA 9606 10608806 YES lperfetto We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself. 0.846 SIGNOR-73524 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 YES lperfetto In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway 0.2 SIGNOR-252811 RPS6KB1 protein P23443 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser286 LRSCSLGsLGALGPA -1 27407113 YES miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  0.322 SIGNOR-274068 SMARCD1 protein Q96GM5 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.795 SIGNOR-269822 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 34674502 YES scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† 0.8 SIGNOR-268126 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr539 RGLDKVItVLTRSKR 9606 16216881 YES lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. 0.2 SIGNOR-141034 RAB6C protein Q9H0N0 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9534 20360680 NO miannu We show that BICDR-1 interacts with the dynein/dynactin motor complex, binds to kinesin-3 motor protein Kif1C and controls the pericentrosomal localization of Rab6-positive secretory vesicles. 0.7 SIGNOR-266882 1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one chemical CHEBI:93578 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258851 PRKG2 protein Q13237 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr430 LEIIRGRtKQHGQFS -1 35226996 YES miannu Recombinant PKG II inhibited the epidermal growth factor (EGF)-induced activation of the EGF receptor via phosphorylating the T406 of the extracellular domain and blocked EGF-triggered proliferation of various cancer cells. 0.2 SIGNOR-277589 NMUR2 protein Q9GZQ4 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256874 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249317 CARM1 protein Q86X55 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates methylation 10090 BTO:0001103 29163212 YES FFerrentino The first evidence alluding to a role of PRMTs in mediating skeletal muscle plasticity, specifically myogenesis, arose from the identification of CARM1 as a glucocorticoid receptor-interacting protein 1 (GRIP1) binding protein. (Chen et al., 2000). Here, GRIP1 and MEF2 were co-expressed in the nucleus during skeletal muscle differentiation. These initial findings led to an investigation that revealed that this methyltransferase was responsible for coactivating the transcription of myocyte enhancer factor-2C (MEF2C) via GRIP1  0.388 SIGNOR-255964 UBE2K protein P61086 UNIPROT RNF138 protein Q8WVD3 UNIPROT up-regulates activity binding 9606 BTO:0000007 16714285 YES miannu NARF exhibits E3 ubiquitin-ligase activity in cooperation with the ubiquitin conjugating enzyme, E2-25K. These data show that the auto-ubiquitylating activity of NARF is coordinated with E2-25K, and that the RING finger domain of NARF is indispensable for this reaction. 0.535 SIGNOR-271594 GSK3B protein P49841 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser184 GKTTTTNsKREEKLF 9606 BTO:0002548 27572267 YES miannu We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. 0.307 SIGNOR-277275 MRPL46 protein Q9H2W6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.65 SIGNOR-262350 CDK8 protein P49336 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 29239838 YES lperfetto We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. 0.392 SIGNOR-273179 NPBWR1 protein P48145 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256675 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 YES lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. 0.272 SIGNOR-275789 BLOC-3 complex SIGNOR-C253 SIGNOR RAB32 protein Q13637 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23174301 YES lperfetto HPS1/HPS4 was active exclusively for RAB32 and RAB38. Moreover, when overexpressed with HPS1 in HeLa cells, a mitochondrially restricted form of HPS4 preferentially recruited GFP-tagged RAB32 or RAB38 – but not the related RAB7 or RAB9 – to mitochondria. Activity in both assays required both HPS1 and HPS4. Finally, depletion of HPS1 or HPS4 by siRNA in a pigmented human melanoma cell line, MNT-1, resulted in the mislocalization of RAB32. These data provide strong evidence that BLOC-3 is a selective GEF for RAB32 and RAB38  0.562 SIGNOR-260693 MFGE8 protein Q08431 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21901532 NO miannu In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production 0.346 SIGNOR-260653 STUB1 protein Q9UNE7 UNIPROT ATXN1 protein P54253 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 16831871 YES miannu CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation|Interestingly, CHIP also interacts with and ubiquitinates unexpanded ataxin-1 0.442 SIGNOR-278666 POMC protein P01189 UNIPROT MC1R protein Q01726 UNIPROT up-regulates activity binding 9606 BTO:0000847 19656324 YES miannu Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses. 0.765 SIGNOR-252370 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser408 GPLPRAPsISTVEPK 26190112 YES Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. 0.297 SIGNOR-253541 SHC1 protein P29353 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 YES gcesareni The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. 0.695 SIGNOR-66949 5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin chemical CID:122187 PUBCHEM HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258865 CLCC1 protein Q96S66 UNIPROT PIGBOS1 protein A0A0B4J2F0 UNIPROT up-regulates activity binding 9606 31653868 YES Simone The PIGBOS microprotein interacts with the ER protein CLCC1. PIGBOS localizes to the mitochondrial outer membrane where itinteracts with the ER protein CLCC1 at ER–mitochondria contact sites. PIGBOS-CLCC1 interaction is necessary for PIGBOS function 0.2 SIGNOR-261040 ADAM10 protein O14672 UNIPROT CD44 protein P16070 UNIPROT up-regulates activity cleavage 9606 26284334 YES miannu The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. 0.347 SIGNOR-259847 XL765 chemical CHEBI:71958 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207881 MARCHF5 protein Q9NX47 UNIPROT MFN2 protein O95140 UNIPROT up-regulates activity ubiquitination 9606 23727017 YES miannu Taken together, these results suggested that MITOL regulates endoplasmic reticulum tethering to mitochondria by activating Mfn2 via K192 ubiquitination.|Therefore, MITOL specifically ubiquitinates mitochondrial Mfn2. 0.2 SIGNOR-278553 MDM2 protein Q00987 UNIPROT DDX24 protein Q9GZR7 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0001109 24980433 YES miannu MDM2 mediates nonproteolytic polyubiquitylation of the DEAD-Box RNA helicase DDX24. Unexpectedly, however, the polyubiquitylation of DDX24 did not elicit its proteasomal degradation but rather promoted its association with preribosomal ribonucleoprotein (pre-rRNP) processing complexes that are required for the early steps of pre-rRNA processing. 0.334 SIGNOR-272845 PIK3CA protein P42336 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000899 10201980 YES lperfetto Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation 0.512 SIGNOR-249610 APEX1 protein P27695 UNIPROT CYP11B2 protein P19099 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22652909 NO miannu We conclude that APEX1 is a novel transcriptional repressor of CYP11B2 and that differential APEX1 binding at -1651 of CYP11B2 results in altered gene expression. 0.343 SIGNOR-253736 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR SMURF1 protein Q9HCE7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25721664 YES miannu F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway. 0.502 SIGNOR-272443 GRIK5 protein Q16478 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264946 EFNA3 protein P52797 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 YES gcesareni The eph family of receptors. 0.813 SIGNOR-52309 CHRM5 protein P08912 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257351 CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1270 YQQKPYPsPKTIEDL 9606 11584018 YES lperfetto Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter. 0.357 SIGNOR-110912 indometacin chemical CHEBI:49662 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition -1 9057869 YES miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 0.8 SIGNOR-258607 GNAL protein P38405 UNIPROT ADCY3 protein O60266 UNIPROT up-regulates activity binding 9606 BTO:0004345 23817016 YES Marta Tosoni Subsequently, the Gaolf subunit activates the integral membrane protein adenylyl cyclase type III (AC3), leading to the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP) 0.64 SIGNOR-278072 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). 0.868 SIGNOR-157734 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT up-regulates activity phosphorylation Thr27 KFRFRKEtNNAAIIM -1 9030586 YES miannu Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82. 0.307 SIGNOR-249984 SMARCA2 protein P51531 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.823 SIGNOR-270610 FYN protein P06241 UNIPROT APP protein P05067 UNIPROT up-regulates quantity phosphorylation Tyr757 SKMQQNGyENPTYKF 9606 18089558 YES miannu Fyn induced phosphorylation of APP at Tyr-757 of the (757)YENPTY(762) motif and increased cell surface expression of APP. 0.451 SIGNOR-278378 CSNK2A1 protein P68400 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 YES llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  0.345 SIGNOR-250952 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization phosphorylation Ser54 ILSSGAYsPITVWTT 9606 24662826 YES miannu At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. 0.287 SIGNOR-276628 ODC1 protein P11926 UNIPROT spermidine smallmolecule CHEBI:16610 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) 0.8 SIGNOR-256038 AKT proteinfamily SIGNOR-PF24 SIGNOR HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 YES lperfetto Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212 0.2 SIGNOR-153323 HRH2 protein P25021 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257162 MPO protein P05164 UNIPROT APOA1 protein P02647 UNIPROT down-regulates activity oxidation 9606 20043647 YES miannu When apolipoprotein A-I (apoA-I), the major HDL protein, was oxidized by MPO, its ability to promote cellular cholesterol efflux by ABCA1 was impaired. Moreover, oxidized apoA-I was unable to activate lecithin:cholesterol acyltransferase (LCAT), which rapidly converts free cholesterol to cholesteryl ester, a critical step in HDL maturation 0.407 SIGNOR-252102 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI RAPGEF4 protein Q8WZA2 UNIPROT up-regulates activity binding 9606 BTO:0000783 24843404 YES miannu Both GIP and GLP‐1 exert their insulinotropic effects by binding to GIP and GLP‐1 receptors expressed on pancreatic β cells. Incretin‐bound receptors increase intracellular cAMP levels thereby activating protein kinase A (PKA)65 and exchange protein activated by cAMP2 (EPAC2)/cAMP‐guanine nucleotide exchange factor (GEF) II 0.8 SIGNOR-278139 CSNK1A1 protein P48729 UNIPROT JADE1 protein Q6IE81 UNIPROT down-regulates activity phosphorylation Ser20 SDDNGSLsTTWSQNS 9606 BTO:0000007 25100726 YES done miannu We demonstrate that the destruction complex component casein kinase 1α (CK1α) phosphorylates Jade-1 at a conserved SLS motif and reduces the ability of Jade-1 to inhibit β-catenin signaling.  0.277 SIGNOR-273617 GAS2L1 protein Q99501 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 24706950 NO miannu Previous work has shown that members of the growth-arrest-specific 2 (GAS2) family mediate the crosstalk between filamentous actin (F-actin) and MTs, but the molecular basis of this process remained unclear. By using fluorescence microscopy, we demonstrate that three members of this family, GAS2-like 1, GAS2-like 2 and GAS2-like 3 (G2L1, G2L2 and G2L3, also known as GAS2L1, GAS2L2 and GAS2L3, respectively) are differentially involved in mediating the crosstalk between F-actin and MTs.  0.7 SIGNOR-273700 RTKs proteinfamily SIGNOR-PF38 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 17306385 YES miannu The adaptor protein Grb2 can bind with activated RTKs through an SH2 domain-phosphotyrosine interaction, while through the SH3 domain (a binding domain specific to proline-rich sequences) Grb2 interacts with the guanine nucleotide exchange factor, Sos. 0.2 SIGNOR-256167 EEF1A1P5 protein Q5VTE0 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269549 PRKAA1 protein Q13131 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates quantity phosphorylation Ser30 EDLQEVLsSDENGGT 9606 27650555 YES miannu Here, we report that phosphorylation of CHOP at Ser30 by AMPK\u03b11 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo .|XREF_FIG showed the deletion of Ampkalpha1 but not Ampkalpha2 significantly increased CHOP protein levels in macrophages. 0.265 SIGNOR-278381 FGF12 protein P61328 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.317 SIGNOR-253412 NUP50 protein Q9UKX7 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.586 SIGNOR-262068 clozapine chemical CHEBI:3766 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258514 FZD5 protein Q13467 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates activity binding 9606 23151663 YES areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  0.639 SIGNOR-258963 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr445 QKQQREKtRWLNSGR 9606 BTO:0000671 10209029 YES lperfetto Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480 0.377 SIGNOR-66992 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.2 SIGNOR-159373 ANGPT1 protein Q15389 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 NO lperfetto Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. 0.2 SIGNOR-241557 TRIM32 protein Q13049 UNIPROT DBNDD1 protein Q9H9R9 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 19349376 YES miannu TRIM32 is an E3 ubiquitin ligase for dysbindin. TRIM32 targets dysbindin for degradation. 0.2 SIGNOR-271422 RPS6K proteinfamily SIGNOR-PF26 SIGNOR Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 17360704 NO gianni Mutation of rpS6 at Ser(235/236) reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery. 0.7 SIGNOR-268527 SYVN1 protein Q86TM6 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29233968 YES miannu HRD1 overexpression also decreased the expression of eIF2alpha and p-eIF2alpha in HKC-8 cells.|HRD1 promoted eIF2alpha ubiquitylation and degradation, thereby providing a protective mechanism that suppressed tubular epithelial cell apoptosis. 0.2 SIGNOR-278671 MZF1 protein P28698 UNIPROT PRKCA protein P17252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16297876 NO irozzo We demonstrated that both Elk-1 and MZF-1 were highly expressed in human poor differentiated HCC cells and involved in the up-regulation of PKCa, which was essential for cell migration and invasion. Over-expression assay confirmed that the PKCa expression may be modulated by these two factors at the transcriptional level. 0.384 SIGNOR-256283 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR2 protein P34972 UNIPROT up-regulates activity chemical activation 9606 BTO:0000142 29751001 YES miannu Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana. 0.8 SIGNOR-264268 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000298 8974401 YES lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. 0.751 SIGNOR-236110 Ub:E2 complex SIGNOR-C497 SIGNOR NSMCE1 protein Q8WV22 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270994 TWIST1 protein Q15672 UNIPROT SRPX protein P78539 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255534 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT up-regulates quantity by stabilization sumoylation Lys626 KKKSKALkEEKMEID 9606 BTO:0000007 23686912 YES miannu Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. 0.453 SIGNOR-263901 AKT3 protein Q9Y243 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 38402584 NO miannu Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells.  0.288 SIGNOR-277224 ETV6 protein P41212 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002883 16828711 NO miannu Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma. 0.339 SIGNOR-254138 FLT3 protein P36888 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 10090 BTO:0002882 phosphorylation:Tyr599 VDFREYEyDLKWEFP 16684964 YES gcesareni Y599 was additionally found to interact with the protein tyrosine phosphatase SHP2 in a phosphorylation-dependent manner. As Y599F-Flt3-32D was unable to associate with and to phosphorylate SHP2 and since silencing of SHP2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3 phenotype, we hypothesize that recruitment of SHP2 to pY599 contributes to FL-mediated Erk activation and proliferation. 0.526 SIGNOR-245057 DACT2 protein Q5SW24 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates binding 9606 17197390 YES lpetrilli Here, we provide evidence that unlike dpr1 that modulates wnt signaling, mdpr2 negatively regulates tgf-? Signaling and promotes tgf-? Receptor degradation in lysosomes. these results suggest that mdpr2 interferes with tgf-? By directly binding to and targeting the receptors for lysosomal inhibitor-sensitive degradation. 0.392 SIGNOR-151750 CSNK2A1 protein P68400 UNIPROT BMI1 protein P35226 UNIPROT down-regulates quantity by destabilization phosphorylation Ser110 SADAANGsNEDRGEV 9606 28270146 YES miannu Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. e-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function. 0.269 SIGNOR-277345 lurasidone chemical CHEBI:70735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10030 20404009 YES Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. 0.8 SIGNOR-259463 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.91 SIGNOR-252828 CREBBP protein Q92793 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates activity acetylation Lys288 CAHPGCGkSYTKSSH 9606 11259590 YES Regulation miannu EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain. 0.491 SIGNOR-251826 ASPA protein P45381 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI down-regulates quantity chemical modification 9606 17194761 YES miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. 0.8 SIGNOR-267526 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR THBD protein P07204 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15677570 NO miannu We further show evidence suggesting that NF-κB inhibits TM expression indirectly by competition for the coactivator p300/CBP. 0.2 SIGNOR-253909 TLE4 protein Q04727 UNIPROT PAX2 protein Q02962 UNIPROT down-regulates activity binding 9606 BTO:0000007 25631048 YES In cell culture, Grg4 suppresses Pax2-mediated transcriptional activation and inhibits phosphorylation of the Pax2 activation domain by WNT signaling and JNK 0.456 SIGNOR-251710 MARK2 protein Q7KZI7 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.706 SIGNOR-275437 PTPRK protein Q15262 UNIPROT EGFR protein P00533 UNIPROT unknown dephosphorylation Tyr1197 STAENAEyLRVAPQS 10029 BTO:0000246 16263724 YES RPTP-kappa also reduced epidermal growth factor-dependent EGFR tyrosine phosphorylation in CHO cells. Purified RPTP-kappa preferentially dephosphorylated EGFR tyrosines 1068 and 1173 in vitro. 0.616 SIGNOR-248723 HIC1 protein Q14526 UNIPROT STAT3 protein P40763 UNIPROT down-regulates quantity by repression binding 9606 BTO:0000815 24067369 YES miannu HIC1 interacts with the DNA binding domain of STAT3 and suppresses the binding of STAT3 to its target gene promoters. HIC1 C-terminal domain binds to STAT3. HIC1 mutant defective in STAT3 interaction reduced its repressive effect on STAT3 DNA binding activity, the reporter activity and gene expression of the VEGF and c-Myc genes, and cell growth in MDA-MB 231 cells. 0.368 SIGNOR-254246 CDK2 protein P24941 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 YES gcesareni In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2 0.735 SIGNOR-144000 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 YES inferred from 70% family members gcesareni Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms 0.2 SIGNOR-270018 VKORC1L1 protein Q8N0U8 UNIPROT vitamin K epoxide smallmolecule CHEBI:28371 ChEBI down-regulates quantity chemical modification 9606 31226734 YES lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) 0.8 SIGNOR-265906 IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 21240265 NO Among the genes with differences in expression in the M1 and M2 subsets are those regulated by IRF5, including IL12A, IL12B, IL23A, IL1B, TNF, CCL3(encoding MIP-1α), RANTES, CD1A, CD40, CD86 and CCR7 0.292 SIGNOR-254510 DAB2IP protein Q5VWQ8 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity binding 9606 27858941 YES miannu DAB2IP inhibits the PI3K–AKT axis by directly interacting with both proteins, reducing phosphorylation and activation of AKT. The GAP activity of DAB2IP can further enforce inhibition of the PI3K–AKT axis by reducing Ras-dependent activation of PI3K p110α subunit. 0.2 SIGNOR-254750 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WEE1 protein P30291 UNIPROT down-regulates binding 9606 15340381 YES lperfetto Scfb-trcp continues to have a role in this phase, however, through its induced degradation of the cdk1 inhibitor, wee1. 0.387 SIGNOR-217184 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 SIGNOR-C110 11955436 YES gcesareni Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). 0.86 SIGNOR-116528 PPP3CC protein P48454 UNIPROT FLNA protein P21333 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 YES Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation. 0.2 SIGNOR-248507 OTUD7A protein Q8TE49 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000007 18178551 YES lperfetto NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination. 0.2 SIGNOR-268410 PRKAA1 protein Q13131 UNIPROT CPT1C protein Q8TCG5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21892142 NO gcesareni In 2010, bungard et al., reported that ampk can target transcriptional regulation through phosphorylation of histone h2b on serine3681. Cells expressing a mutant h2b s36a blunted the induction of stress genes upregulated by ampk including p21 and cpt1c. 0.26 SIGNOR-176422 PRKACA protein P17612 UNIPROT RAP1B protein P61224 UNIPROT up-regulates phosphorylation Ser179 PGKARKKsSCQLL 9606 19651783 YES llicata These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation 0.521 SIGNOR-187410 RAP1A protein P62834 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates quantity binding 9606 BTO:0000783 21478675 YES miannu  The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε. 0.49 SIGNOR-278142 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.636 SIGNOR-143692 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR G0/G1_transition phenotype SIGNOR-PH219 SIGNOR up-regulates 12640120 NO lperfetto Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0. 0.7 SIGNOR-273193 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 10116 11287630 YES lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten 0.766 SIGNOR-106586 SATB1 protein Q01826 UNIPROT TAF11 protein Q15544 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17343824 NO miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. 0.2 SIGNOR-255130 pazopanib hydrochloride chemical CHEBI:71217 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-201250 CHEK1 protein O14757 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation 9606 26658951 YES miannu Chk1 inhibition with small interfering RNA (siRNA) reduces Rad9A stabilization and accumulation.|In the case of DNA damage, an activated Chk1 phosphorylates Rad9A or other proteins (TLK1) as a feedback mechanism to prevent Rad9A (poly) ubiquitination and degradation. 0.668 SIGNOR-279503 UBE3A protein Q05086 UNIPROT NELFCD protein Q8IXH7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 17131388 YES miannu In this paper, we identify here trihydrophobin 1 (TH1), an integral subunit of the human negative transcription elongation factor (NELF) complex, as a novel E6-AP interaction protein and a target of E6-AP-mediated degradation. Overexpression of E6-AP results in degradation of TH1 in a dose-dependent manner, whereas knock-down of endogenous E6-AP elevates the TH1 protein level.  0.327 SIGNOR-271404 FANCL protein Q9NW38 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination SIGNOR-C300 18985065 YES lperfetto Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding 0.9 SIGNOR-263264 PRKCG protein P05129 UNIPROT CYTH2 protein Q99418 UNIPROT down-regulates activity phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 BTO:0000567 10531036 YES lperfetto ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'. 0.333 SIGNOR-249025 CPT1A protein P50416 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR up-regulates activity 9606 31900483 NO As the key rate-limiting enzyme of FAO, carnitine palmitoyltransferase I (CPT1) regulates FAO and facilitates adaptation to the environment, both in health and in disease, including cancer. The CPT1 family of proteins contains 3 isoforms: CPT1A, CPT1B, and CPT1C. This review focuses on CPT1A, the liver isoform that catalyzes the rate-limiting step of converting acyl-coenzyme As into acyl-carnitines, which can then cross membranes to get into the mitochondria 0.7 SIGNOR-267757 KDM3A protein Q9Y4C1 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 YES miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  0.2 SIGNOR-276847 MYC protein P01106 UNIPROT SHMT1 protein P34896 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 YES miannu Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis 0.276 SIGNOR-267379 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates phosphorylation Ser328 VLPSISLsPGPQPPK 9606 18940270 YES llicata Tlk1b phosphorylates hrad9 at s328 after the induction of dsb, occupancy of rad9 adjacent to the break increased during repair while that of asf1 decreased, and the effect was more pronounced in tlk1b-overexpressing cells. We propose that following genotoxic stress, tlk1/1b is first recruited to the dsb in a complex with rad9. It then exchanges with asf1 to promote nucleosomes eviction at the dsb and access of the repair machinery to unencumbered dna. 0.448 SIGNOR-181748 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates 9606 23994464 YES apalma Activation of those receptors triggers the dissociation of the GPCR-specific GŒ± subunit from the shared GŒ≤Œ≥ dimer and concomitant activation of various signal transduction pathways by both G-protein fragments 0.2 SIGNOR-255009 meloxicam chemical CHEBI:6741 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9083488 YES miannu Meloxicam (5),an NSAID in the enol−carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. This favorable therapeutic index has been confirmed in clinical trials. In subsequent studies we and others discovered that it possessed a selectivity profile for COX-2 superior to several other marketed NSAIDs.1 A comparison of 5 with piroxicam (6) revealed different inhibitory profiles for the two enzymes 0.8 SIGNOR-258609 Sincalide smallmolecule CID:9833444 PUBCHEM CCKBR protein P32239 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257467 IRAK1 protein P51617 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 8837778 YES lperfetto Il-1 treatment of 293 cells induces the association of traf6 with irak. 0.913 SIGNOR-44234 NatA complex SIGNOR-C415 SIGNOR CHEK2 protein O96017 UNIPROT down-regulates activity acetylation 9606 BTO:0001109 21351257 YES miannu The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer.  lack of acetylation by hNatA activated H2A.X and Chk2 in both HCT116 cell lines independent of TP53 status (Fig. 6). 0.2 SIGNOR-267228 CEP250 protein Q9BV73 UNIPROT Centrosome_separation phenotype SIGNOR-PH177 SIGNOR down-regulates 9606 BTO:0000567 24035387 YES miannu C-Nap1 and rootletin have been previously reported to be the important centrosome linker components involved in centrosome cohesion. 0.7 SIGNOR-273705 DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 15494734 YES miannu Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling. 0.719 SIGNOR-268371 ASXL1 protein Q8IXJ9 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity binding 9606 BTO:0001271 22897849 YES irozzo These data led us to hypothesize that ASXL1 interacts with the PRC2 complex; co-immunoprecipitation studies revealed that ASXL1 associates with members of the PRC2 complex including EZH2 and SUZ12 but not with the PRC1 repressive complex. Importantly, ASXL1 downregulation resulted in loss of EZH2 recruitment to the HOXA locus indicating a role of ASXL1 in recruiting the PRC2 complex to known leukemogenic loci. 0.562 SIGNOR-255923 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser376 LKSKKGQsTSRHKKL 9606 9315650 YES llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. 0.436 SIGNOR-269328 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 17015473 YES The effect has been demonstrated using Q01196-8 lperfetto Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a. 0.2 SIGNOR-217340 NAT8L protein Q8N9F0 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI down-regulates quantity chemical modification 9606 19524112 YES miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. 0.8 SIGNOR-267522 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9534 7839144 YES lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. 0.727 SIGNOR-232156 CREB1 protein P16220 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001009 10753867 NO lperfetto Creb activity by akt signaling leads to increased bcl-2 promoter activity and cell survival. 0.459 SIGNOR-76558 MDM2 protein Q00987 UNIPROT KAT5 protein Q92993 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 11927554 YES miannu Furthermore, we provide evidence that Mdm2, the ubiquitin ligase of the p53 tumour suppressor, interacts physically with Tip60 and induces its ubiquitylation and proteasome-dependent degradation. 0.653 SIGNOR-272613 AKT2 protein P31751 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 11504915 YES lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. 0.558 SIGNOR-109732 RAPGEF4 protein Q8WZA2 UNIPROT RAP1A protein P62834 UNIPROT up-regulates quantity binding 9606 BTO:0000783 21478675 YES miannu  The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε. 0.794 SIGNOR-278143 SAGA complex complex SIGNOR-C465 SIGNOR H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269642 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.67 SIGNOR-156848 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates phosphorylation Thr212 TYSNEHFtPGNPPPH 9606 12556497 YES llicata Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. 0.771 SIGNOR-97873 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates activity dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 16778204 YES The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels 0.277 SIGNOR-248700 KAT2A protein Q92830 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269602 CAMK2A protein Q9UQM7 UNIPROT RIMS1 protein Q86UR5 UNIPROT up-regulates phosphorylation Ser242 PSAPPDRsKGAEPSQ 9606 BTO:0000938 BTO:0000142 12871946 YES gcesareni Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3, 0.348 SIGNOR-103886 SCF-FBW7 complex SIGNOR-C135 SIGNOR BLM protein P54132 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26028025 YES miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. 0.275 SIGNOR-276912 CDK1 protein P06493 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 SIGNOR-C17 20937773 YES lperfetto In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387 0.362 SIGNOR-168446 AKT proteinfamily SIGNOR-PF24 SIGNOR SRPK2 protein P78362 UNIPROT up-regulates phosphorylation Thr492 PSHDRSRtVSASSTG 9606 BTO:0000938 BTO:0000142 19592491 YES lperfetto Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis. 0.2 SIGNOR-244341 lovastatin chemical CHEBI:40303 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0000318 9727070 YES miannu The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C). 0.8 SIGNOR-258828 FAM13A protein O94988 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.433 SIGNOR-260502 FOXP1 protein Q9H334 UNIPROT PITX3 protein O75364 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000596 20175877 YES Gianni We identified FoxP1 as a novel marker for midbrain dopamine neurons. Enforced expression of FoxP1 in embryonic stem cells actuates the expression of Pitx3, a homeobox protein that is exclusively expressed in midbrain dopaminergic neurons and is required for their differentiation and survival during development and from embryonic stem cells in vitro. We show that FoxP1 can be recruited to the Pitx3 locus in embryonic stem cells and regulate Pitx3 promoter activity in a dual-luciferase assay. 0.292 SIGNOR-269049 STK35 protein Q8TDR2 UNIPROT STK35/PDIK1L complex SIGNOR-C552 SIGNOR form complex binding 9606 BTO:0002181 35021089 YES miannu Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport. 0.2 SIGNOR-273770 ARID1A protein O14497 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.808 SIGNOR-269818 NFIX protein Q14938 UNIPROT GAS6 protein Q14393 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.205 SIGNOR-268888 NEMF protein O60524 UNIPROT RQC complex complex SIGNOR-C559 SIGNOR form complex binding 28528489 YES lperfetto The ribosome-bound quality control (RQC) complex is a multi-protein complex conserved throughout eukaryotes and composed of the E3 ubiquitin ligase Ltn1/Listerin, the ATPase Cdc48/p97 with its co-factors Ufd1/UFD1L and Npl4/NPLOC4, as well as the factors Rqc1/TCF25 and Rqc2/NEMF (Fig. 1). 0.515 SIGNOR-277693 ROCK1 protein Q13464 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 19386264 YES lperfetto Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. We performed an in vitro kinase assay with 80 selected kinases on an ezrin peptide containing the t567 phosphorylation site (figure 3a). In this screen, we identified the mst and rock kinases as the most potent kinases for the ezrin peptide 0.732 SIGNOR-185567 PLK1 protein P53350 UNIPROT TOPORS protein Q9NS56 UNIPROT up-regulates activity phosphorylation Ser718 KDRDGYEsSYRRRTL 9606 19473992 YES lperfetto Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. 0.446 SIGNOR-185838 ATM protein Q13315 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Ser498 QIVMAPSsQSQPSGS 9606 15916964 YES lperfetto Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif) 0.567 SIGNOR-137623 GSK3A protein P49840 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser381 RKFNILTsNQKTLTP 9606 BTO:0002181 31843895 YES miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. 0.263 SIGNOR-276760 PIK3CA protein P42336 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity 9606 11160134 NO lperfetto Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307 0.721 SIGNOR-104911 flumazenil chemical CHEBI:5103 ChEBI GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto Receptors containing the alpha4 or alpha6 subunits, together with beta and gamma2, do not bind the traditional BZ agonists, including zolpidem, but demonstrate high affinity for some ligands, notably the imidazobenzodiazepines such as flumazenil and Ro15-4513, or bretazenil 0.8 SIGNOR-263806 PRKACA protein P17612 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Ser10 MTGSTPCsSMSNHTK -1 22142472 YES miannu GSK-3β phosphorylated STK38 on residues S6 and T7 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively.  Our results indicate that that GSK-3β inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress. 0.295 SIGNOR-276391 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE8A protein O60658 UNIPROT up-regulates activity phosphorylation Ser359 HKDRRKGsLDVKAVA 9606 BTO:0000567 22673573 YES done miannu  We show that under elevated cAMP conditions, PKA acts to phosphorylate PDE8A on serine 359 and this action serves to enhance the activity of the enzyme.  0.2 SIGNOR-273783 ADAM10 protein O14672 UNIPROT BTC protein P35070 UNIPROT up-regulates activity cleavage 9606 26284334 YES miannu Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin 0.373 SIGNOR-259839 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 10116 BTO:0000575 15738637 YES In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. 0.286 SIGNOR-248445 FOXC1 protein Q12948 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 21871448 YES gcesareni We demonstrate that physical interactions occur between wt1, foxc1/2 and rbpj, suggestive of the formation of multimeric transcriptional complexes. 0.276 SIGNOR-176183 ECM stimulus SIGNOR-ST20 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259034 PDX1 protein P52945 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000627 8866550 NO inferred from family member miannu The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. 0.604 SIGNOR-270264 PTEN protein P60484 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 NO miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 0.2 SIGNOR-260052 CSNK1A1 protein P48729 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates phosphorylation Ser253 ETNVKMEsEGGADDS 9606 15687492 YES gcesareni A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c. 0.355 SIGNOR-133528 LAT protein O43561 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 YES lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. 0.408 SIGNOR-246050 DZIP3 protein Q86Y13 UNIPROT ATXN1 protein P54253 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 24326307 YES miannu HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation. 0.483 SIGNOR-272078 NCBP3 protein Q53F19 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 26382858 YES lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 0.8 SIGNOR-268364 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys373 SSHLKSKkGQSTSRH 9606 BTO:0000567 11070080 YES gcesareni P300 acetylates and activates the tumor suppressor p53 after dna damage. 0.912 SIGNOR-84070 alvocidib chemical CHEBI:47344 ChEBI CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258172 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 YES llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  0.307 SIGNOR-250936 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser108 WKLRARPsLTVTPRR 9606 BTO:0000567 21658950 YES miannu Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. 0.2 SIGNOR-263137 MAPK3 protein P27361 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 12169099 YES gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. 0.78 SIGNOR-91383 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 YES The effect has been demonstrated using Q01196-8 lperfetto We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.2 SIGNOR-244711 HIF1A protein Q16665 UNIPROT NT5E protein P21589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000414 12370277 NO miannu Examination of the CD73 gene promoter identified at least one binding site for hypoxia-inducible factor-1 (HIF-1) and inhibition of HIF-1alpha expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 expression 0.291 SIGNOR-254423 CHEK1 protein O14757 UNIPROT SYK protein P43405 UNIPROT down-regulates phosphorylation Ser295 GIISRIKsYSFPKPG 9606 22585575 YES llicata We found that chk1 phosphorylated the tumor suppressor spleen tyrosine kinase (l) (syk[l]) and identified the phosphorylation site at ser295. Furthermore, chk1 phosphorylation of syk(l) promoted its subsequent proteasomal degradation. 0.311 SIGNOR-197528 GRM4 protein Q14833 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264352 RAPGEF4 protein Q8WZA2 UNIPROT ABCC8 protein Q09428 UNIPROT up-regulates quantity binding 9606 21478675 YES miannu  The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε. 0.714 SIGNOR-278141 CDK1 protein P06493 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser272 RSRLTPVsPESSSTE 9606 SIGNOR-C17 20974803 YES gcesareni Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. 0.344 SIGNOR-169012 DNA_damage stimulus SIGNOR-ST1 SIGNOR ATR protein Q13535 UNIPROT up-regulates 9606 21034966 NO lperfetto the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. 0.7 SIGNOR-242609 MDFI protein Q99750 UNIPROT MYF5 protein P13349 UNIPROT down-regulates activity binding 10090 BTO:0000944 8797820 YES 2 miannu We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals. 0.371 SIGNOR-240433 KDM6A protein O15550 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 YES miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase 0.2 SIGNOR-260033 AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 20640476 YES lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. 0.405 SIGNOR-209947 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR SPI1 protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0000318 18519037 YES We found that AML1-ETO is able to inhibit Sp1 transactivity. We also found that this inhibition of Sp1 transactivity by AML1-ETO is achieved by interaction between Sp1 and RUNT domain of AML1 0.2 SIGNOR-255671 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation 0.2 SIGNOR-252350 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 YES lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. 0.365 SIGNOR-74296 TRIM23 protein P36406 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 28871090 YES miannu TRIM23 interacts with TBK1 and p62. TRIM23 GTPase activates TBK1 to phosphorylate p62. Biochemical characterization showed that TRIM23 binds with its C-terminal ARF domain to the N-terminal KD of TBK1, and that GTP hydrolysis activity of the ARF stimulates TBK1-mediated phosphorylation of p62 at S403 in its ubiquitin-associated (UBA) domain, which was shown to promote cargo recruitment and autophagic flux 0.52 SIGNOR-266654 CHD8 protein Q9HCK8 UNIPROT NEUROG1 protein Q92886 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.2 SIGNOR-268919 BBS2 protein Q9BXC9 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 YES lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 0.813 SIGNOR-262557 CFHR1 protein Q03591 UNIPROT C3 protein P01024 UNIPROT up-regulates activity binding -1 cleavage:Arg748 ASHLGLArSNLDEDI 27814381 YES complement C3b fragment: PRO_0000005911 lperfetto Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b 0.832 SIGNOR-263475 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 YES gcesareni Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation. 0.68 SIGNOR-158328 ALDOC protein P09972 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266485 MAPK1 protein P28482 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 YES The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation. 0.704 SIGNOR-75030 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates activity dephosphorylation Ser988 PPLFPIKsFVKTKCK 9606 BTO:0000007 17603999 YES Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524. 0.377 SIGNOR-248560 SRC protein P12931 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr682 SRTTDGVyEGVAIGG 9606 BTO:0000007 32420483 YES done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. 0.265 SIGNOR-274106 CASK protein O14936 UNIPROT TBR1 protein Q16650 UNIPROT up-regulates binding 9534 BTO:0000298 10749215 YES miannu Here we report that, through its guanylate kinase domain, CASK interacts with Tbr-1, a T-box transcription factor that is involved in forebrain development. CASK enters the nucleus and binds to a specific DNA sequence (the T-element) in a complex with Tbr-1. CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development. 0.459 SIGNOR-266835 PAMPs stimulus SIGNOR-ST11 SIGNOR MPO-ANCA complex SIGNOR-C474 SIGNOR up-regulates quantity 9606 BTO:0000133 15972951 NO lperfetto In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. |using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus. 0.7 SIGNOR-270586 CCR5 protein P51681 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. 0.322 SIGNOR-255119 PRKCZ protein Q05513 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG 9606 10022904 YES lperfetto Activation of IkappaB kinase beta by protein kinase C isoforms. | Interestingly, recombinant active zetaPKC and alphaPKC are able to stimulate in vitro the activity of IKKbeta but not that of IKKalpha. In addition, evidence is presented here that recombinant zetaPKC directly phosphorylates IKKbeta in vitro, involving Ser177 and Ser181. Collectively, these results demonstrate a critical role for the PKC isoforms in the NF-kappaB pathway at the level of IKKbeta activation and IkappaB degradation. 0.515 SIGNOR-249015 PPP1CA protein P62136 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity dephosphorylation 9606 29335436 YES miannu To address whether PP1\u03b1 activates B-Raf through these inhibitory sites, we made use of B-Raf protein mutants in which an individual inhibitory site, as well as all four sites (4A), were mutated to alanine.|We confirmed that GST-B-Raf was phosphorylated by ERK2 in vitro  xref  , mainly on S151 and T753 (Fig.\u00a0 xref ), and found that PP1\u03b1 dephosphorylated B-Raf on both ERK phosphorylation sites (Fig.\u00a0 xref ). 0.295 SIGNOR-277160 LRP5 protein O75197 UNIPROT LPR5/6 complex SIGNOR-C219 SIGNOR form complex binding 9606 27821587 YES miannu Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands. 0.405 SIGNOR-256176 CSNK1A1 protein P48729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates activity binding 9606 22083140 YES lperfetto In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] 0.67 SIGNOR-227967 oxotremorine M chemical CHEBI:38322 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258656 ACE protein P12821 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT up-regulates quantity cleavage 9606 32201502 YES MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I 0.2 SIGNOR-260236 WIPF1 protein O43516 UNIPROT WASL protein O00401 UNIPROT up-regulates activity binding 9606 10878810 YES lperfetto Recruitment of N-WASP to vaccinia is mediated by WASP-interacting protein (WIP), whereas in Shigella WIP is recruited by N-WASP. Our observations show that vaccinia and Shigella activate the Arp2/3 complex to achieve actin-based motility, by mimicking either the SH2/SH3-containing adaptor or Cdc42 signalling pathways to recruit the N-WASP-WIP complex. 0.933 SIGNOR-261880 ASPG protein Q86U10 UNIPROT L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI down-regulates quantity chemical modification 9606 24657844 YES miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. 0.8 SIGNOR-267537 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15306821 YES lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulates insulin. 0.787 SIGNOR-127904 HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates binding 9606 8380735 YES gcesareni Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene. 0.928 SIGNOR-38429 BBS7 protein Q8IWZ6 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 YES lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 0.848 SIGNOR-262556 valine smallmolecule CHEBI:27266 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264747 FGF13 protein Q92913 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.407 SIGNOR-253411 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide chemical CHEBI:94489 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207681 Shikonin chemical CHEBI:81068 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000093;BTO:0000018 21516121 YES inferred from family member lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. 0.8 SIGNOR-270289 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.2 SIGNOR-248567 IL1B protein P01584 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005760 15755725 NO Regulation of transcription miannu Interleukin-1beta decreases expression of the epithelial sodium channel alpha-subunit in alveolar epithelial cells via a p38 MAPK-dependent signaling pathway. 0.2 SIGNOR-251947 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr162 QLAAKLAyLQILSEE 9606 BTO:0001282 16373505 YES PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation. 0.2 SIGNOR-251113 SMAD5 protein Q99717 UNIPROT HAND1 protein O96004 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.2 SIGNOR-268941 TP73 protein O15350 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 17700533 NO miannu Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death. 0.7 SIGNOR-256665 putrescine smallmolecule CHEBI:17148 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 NO apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism 0.7 SIGNOR-255551 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269341 COMMD5 protein Q9GZQ3 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 30021164 NO miannu In this study, we identified a specific and crucial role for COMMD5 in the endocytic trafficking machinery, and especially we determined COMMD5 as an actin- and tubulin-binding protein. Our results provide further insight into the essential role of COMMD5 on every aspect of cellular processes, from membrane receptor trafficking to cytoskeleton organization, cell migration, and junctions. Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. 0.7 SIGNOR-261693 LNX1 protein Q8TBB1 UNIPROT ZBTB8A protein Q96BR9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 19668196 YES miannu LNX (ligand of Numb protein-X) is a RING finger and four PDZ domain-containing E3 ubiquitin ligase. Lnx-l induced K48-linked polyubiquitylation of Boz, leading to its proteasomal degradation in human 293T cells and in zebrafish embryos. 0.2 SIGNOR-272777 CSNK2A1 protein P68400 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Ser263 PEIEDVGsDEEEEKK 9606 BTO:0000567 2492519 YES llicata Both hsp 90 proteins are phosphorylated at two homologous sites. For the alpha protein, these sites correspond to serine 231 and serine 263. | Dephosphorylated hsp 90 is phosphorylated at both sites by casein kinase II from HeLa cells, calf thymus, or rabbit reticulocytes; no other hsp 90 residues were phosphorylated by casein kinase II in vitro. 0.532 SIGNOR-250900 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys102 GVFICRGkEDALVTK 30540930 YES lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) 0.27 SIGNOR-275898 OBSCN protein Q5VST9 UNIPROT ANK2 protein Q01484 UNIPROT up-regulates quantity relocalization 9606 BTO:0003324 19840192 YES miannu Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. 0.499 SIGNOR-266726 CAMK2A protein Q9UQM7 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser656 RAEFLNKsVQKSSGV 9606 2170388 YES gcesareni Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii 0.2 SIGNOR-22635 apomorphine chemical CHEBI:48538 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258374 GHSR protein Q92847 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257429 WNK3 protein Q9BYP7 UNIPROT SLC12A7 protein Q9Y666 UNIPROT down-regulates activity phosphorylation 21613606 YES lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs 0.452 SIGNOR-264630 Caspase 3 complex complex SIGNOR-C221 SIGNOR DFFB protein O76075 UNIPROT up-regulates cleavage 9606 9108473 YES gcesareni Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation 0.683 SIGNOR-256463 UBE3A protein Q05086 UNIPROT RAD23A protein P54725 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 10373495 YES miannu  Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B. 0.486 SIGNOR-272550 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 NO Alessandro Palma It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits 0.608 SIGNOR-254957 PKI-402 chemical CID:44187953 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206256 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates activity phosphorylation Tyr596 KLPGLRTyVDPHTYE 9606 11870224 YES Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3 0.2 SIGNOR-251115 ACSS1 protein Q9NUB1 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI up-regulates quantity chemical modification 10843999 YES lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. 0.8 SIGNOR-271829 PTPN1 protein P18031 UNIPROT NTRK2 protein Q16620 UNIPROT down-regulates activity dephosphorylation Tyr706 RDVYSTDyYRVGGHT 9606 BTO:0000793 26214522 YES Luana Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling 0.381 SIGNOR-264554 buspirone chemical CHEBI:3223 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258837 UBE2T protein Q9NPD8 UNIPROT FANCL protein Q9NW38 UNIPROT up-regulates activity ubiquitination -1 24389026 YES lperfetto Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex|Our structural and biochemical analyses suggest that, in a cellular environment with multiple E2s present, FANCL will preferentially select Ube2T. 0.901 SIGNOR-263263 CNTN6 protein Q9UQ52 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 BTO:0000938 15082708 YES gcesareni Here, we establish that nb-3, a member of the f3/contactin family, acts as a novel notch ligand to participate in oligodendrocyte generation. Nb-3 triggers nuclear translocation of the notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via deltex1. 0.586 SIGNOR-254318 nintedanib chemical CHEBI:85164 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 18559524 YES Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. 0.8 SIGNOR-257801 EGFR protein P00533 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity 10090 BTO:0000667 15284024 NO JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs. lperfetto Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion 0.611 SIGNOR-235870 IPP complex complex SIGNOR-C380 SIGNOR ACTB protein P60709 UNIPROT up-regulates activity relocalization 27590440 YES lperfetto Apart from binding with integrins on the membrane, IPP complex can interact with the cytoskeleton as well as many signaling proteins inside the cell. Up to now, dozens of IPP complex-related proteins have been identified. One of these proteins is parvin that binds to F-actin, thus connecting ECM with cytoskeleton.17 In the following, we will discuss PINCH-interacting proteins and their roles. 0.363 SIGNOR-265768 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCC8 protein Q09428 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000783 35065096 YES miannu Activated PKA and EPAC enhance insulin granular exocytosis by insulin granular priming and phosphorylates sulfonylurea receptor (SUR1) KATP channel subunit and thereby closes KATP-channels in the plasma membrane [13,43,82], leading to membrane depolarization, and opening of the voltage gated Ca2+-channels. This leads to an increased influx of extracellular Ca2+, which triggers fusion of intracellular insulin-containing granules with the plasma membrane and thereby insulin secretion. 0.2 SIGNOR-278146 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr222 TSHNSLTtPCYTPYY 9606 BTO:0000130 14499342 YES lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. 0.769 SIGNOR-118040 WWP1 protein Q9H0M0 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates activity ubiquitination 9606 34035464 YES miannu WWP1 and Smurf2 were adopted to induce ubiquitination of endogenous KLF5 protein in cells.|WWP1 or Smurf2 degrades KLF5 by ubiquitination to repress fracture healing. 0.459 SIGNOR-278683 Viral protein proteinfamily SIGNOR-PF88 SIGNOR Ubiquitinated-Viral_Protein complex SIGNOR-C427 SIGNOR form complex binding 9606 25688236 YES scontino MHC class I antigen presentation pathway. Proteins with ubiquitin tags (red spheres) are degraded by proteasomes and the resulting peptides are transported into the endoplasmic reticulum (ER) by TAP|Many viruses have mechanisms of interfering with MHC class I processing, including direct interaction of viral proteins with immunoproteasome subunits. 0.2 SIGNOR-267765 SLC35A1 protein P78382 UNIPROT sialic acid smallmolecule CHEBI:26667 ChEBI up-regulates quantity relocalization 9606 34384782 YES miannu The CMP-sialic acid transporter SLC35A1 and UDP-galactose transporter SLC35A2 are two well-characterized nucleotide sugar transporters with distinctive substrate specificities. Nucleotide sugar transporters (NSTs) transport nucleotide sugars from the cytosol into the lumen of the endoplasmic reticulum or the Golgi apparatus, where the nucleotide sugars serve as substrates for protein glycosylation and glycosphingolipid synthesis. 0.8 SIGNOR-268466 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Ser175 SFVTPPQsHFVRVST 9606 BTO:0002181 26028025 YES miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. 0.429 SIGNOR-276910 SRC protein P12931 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation 9606 26677978 YES miannu Dasatinib sensitivity in samples from patients with TNK2 mutations ( xref ) could result from either direct inhibition of TNK2 kinase activity itself, or indirectly through inhibition of SRC kinases by dasatinib, since SRC can activate TNK2 by directly phosphorylating the TNK2 activation loop ( xref ).|In addition to phosphorylation in response to EGFR signaling, TNK2 can also be activated by other receptor tyrosine kinases ( xref ), and phosphorylation of the TNK2 activation loop by SRC is required for its kinase activity ( xref ). 0.385 SIGNOR-279082 Ub:E2 complex SIGNOR-C497 SIGNOR RAPSN protein Q13702 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270996 SREBF2 protein Q12772 UNIPROT ABCG8 protein Q9H221 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21123766 NO miannu these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α. 0.42 SIGNOR-254456 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR ABL1 protein P00519 UNIPROT down-regulates phosphorylation 9606 18794806 YES inferred from 70% family members lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 0.2 SIGNOR-270219 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser1217 PIKNLHSsHSSGLMD 9606 BTO:0000565 28630147 YES miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 0.371 SIGNOR-266420 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 12793438 YES lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway 0.886 SIGNOR-236152 AKT1 protein P31749 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 YES llicata Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis. 0.438 SIGNOR-164884 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 26194464 YES MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). 0.853 SIGNOR-255030 AKT proteinfamily SIGNOR-PF24 SIGNOR DLC1 protein Q96QB1 UNIPROT unknown phosphorylation Ser766 VTRTRSLsACNKRVG 10116 BTO:0000443 16338927 YES gcesareni We have demonstrated that Ser-322 is phosphorylated upon insulin stimulation of intact cells and that this site is directly phosphorylated in vitro by PKB and ribosomal S6 kinase, members of the AGC (protein kinases A, G, and C) family of insulin-stimulated protein kinases 0.2 SIGNOR-247997 SLC9A9 protein Q8IVB4 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265608 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Thr705 WKLQRAItILDTEKS 9534 BTO:0000298 14523239 YES lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 0.2 SIGNOR-249235 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT down-regulates activity phosphorylation Ser81 EPVVRRLsTQFTAAN 10090 BTO:0000944 11751901 YES miannu PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276) 0.503 SIGNOR-250492 CLP1 protein Q92989 UNIPROT CFII complex complex SIGNOR-C387 SIGNOR form complex binding 9606 BTO:0000567 30139799 YES lperfetto Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. 0.889 SIGNOR-266120 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 22252525 YES gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. 0.659 SIGNOR-195414 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR STK4 protein Q13043 UNIPROT up-regulates 9606 22683405 NO milica In response to growth inhibitory signal (e.g. cell–cell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127. 0.7 SIGNOR-230693 EDN1 protein P05305 UNIPROT EDNRB protein P24530 UNIPROT up-regulates binding 9606 16597412 YES gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. 0.946 SIGNOR-145762 PRKCA protein P17252 UNIPROT MEP1B protein Q16820 UNIPROT down-regulates quantity phosphorylation Ser687 KKYRERMsSNRPNLT 9534 BTO:0001538 12941954 YES miannu These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate. 0.2 SIGNOR-263172 ALDH1A1 protein P00352 UNIPROT D-glyceraldehyde smallmolecule CHEBI:17378 ChEBI down-regulates quantity chemical modification 9606 23444097 YES miannu Aldehyde dehydrogenases (ALDHs) couple the oxidation of aldehydes to the reduction of NAD(P)(+) . These enzymes have gained importance as they have been related to the detoxification of aldehydes generated in several diseases involving oxidative stress. 0.8 SIGNOR-280249 JAK1 protein P23458 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity phosphorylation 9606 9020188 YES lperfetto The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-?, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. 0.767 SIGNOR-88285 GDF6 protein Q6KF10 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 16049014 YES gcesareni We found that transfection of small hairpin rna for bmprii and actriia in mc3t3 cells suppressed the signaling of gdf6, gdf7, and bmp10. 0.595 SIGNOR-139090 CLU protein P10909 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR up-regulates activity binding 9606 BTO:0001321 20068069 YES miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. 0.314 SIGNOR-271429 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Thr305 TDAATMKtFCGTPEY 9606 18160256 YES llicata Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.493 SIGNOR-248611 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DUSP1 protein P28562 UNIPROT down-regulates phosphorylation 9606 16286470 YES inferred from 70% family members lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain 0.2 SIGNOR-270189 PAK3 protein O75914 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser714 EGVRNIKsMWEKGNV 9606 BTO:0000887;BTO:0001260 20858431 YES gcesareni We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin. 0.2 SIGNOR-167976 MIF protein P14174 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates activity binding 10090 BTO:0000876 17435771 YES gcesareni We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. 0.372 SIGNOR-252062 NEDD4 protein P46934 UNIPROT SAG protein P10523 UNIPROT down-regulates quantity ubiquitination 9606 25216516 YES miannu These data collectively indicate that NEDD4-1 negatively regulates the SAG protein levels.|Third, NEDD4-1 promotes SAG poly-ubiquitylation and degradation, as demonstrated by both in vitro and in vivo ubiquitylation assays. 0.374 SIGNOR-278610 RUNX3 protein Q13761 UNIPROT IKBKB protein O14920 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255089 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8702662 YES lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function 0.804 SIGNOR-42968 ADCY4 protein Q8NFM4 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-265006 QRICH1 protein Q2TAL8 UNIPROT FARSB protein Q9NSD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269404 KLF10 protein Q13118 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 YES miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. 0.447 SIGNOR-222394 etoposide chemical CHEBI:4911 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 16101488 YES miannu Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II. 0.8 SIGNOR-259326 PTK2 protein Q05397 UNIPROT WASL protein O00401 UNIPROT up-regulates activity phosphorylation 9606 24290759 YES miannu In addition, FAK can phosphorylate N-WASP and promote actin polymerization, and inhibition of FAK kinase activity suppresses N-WASP activity. 0.689 SIGNOR-278977 pyridoxal 5'-phosphate(2-) smallmolecule CHEBI:597326 ChEBI PSAT1 protein Q9Y617 UNIPROT up-regulates activity chemical activation 3702 30034403 YES lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. 0.8 SIGNOR-268561 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252336 SLC4A1 protein P02730 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 YES lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] 0.377 SIGNOR-266036 hsa-miR-326 mirna URS00000A939F_9606 RNAcentral MYCN protein P04198 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002035 25173582 NO Parnian The upregulation of miR-326 not only inhibited the activity of the Hh pathway but also reduced the expression of additional Hh signaling components, including GLI1, N-myc, and CyclinD1. 0.4 SIGNOR-277980 RAC1 protein P63000 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity binding 9606 39000072 YES miannu Activated RAC1 interacts with GIT1, a GAP protein of ARF6, and causes the inactivation of ARF6 [78]. As ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane [78], the inactivation of ARF6 by RAC1 reduces the recycling of macropinosomes. 0.655 SIGNOR-277783 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Thr292 PQLQAHStPHPDDFA 9606 12734188 YES lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. 0.362 SIGNOR-101055 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258782 PLK3 protein Q9H4B4 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates phosphorylation Ser49 ESEMETPsAINGNPS 9606 21336504 YES lperfetto Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest. 0.391 SIGNOR-172230 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 10702794 YES HePTP efficiently dephosphorylated active ERK2 on the tyrosine residue in the activation loop in vitro. Together, these data identify ERK2 as a specific and direct target of HePTP and are consistent with a model in which HePTP negatively regulates ERK2 activity as part of a feedback mechanism 0.812 SIGNOR-248484 SIRT6 protein Q8N6T7 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR up-regulates activity binding 9606 BTO:0000007 25083875 YES miannu SIRT6 is involved in circadian control of gene expression and metabolism. SIRT6 Interacts with CLOCK:BMAL1 and Controls Their Chromatin Recruitment. SIRT6 physically interacts with CLOCK and BMAL1, individually or together, as shown by coimmunoprecipitation (co-IP) (Figures 4A and 4B). SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1. 0.368 SIGNOR-268157 CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR ZNF652 protein Q9Y2D9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 20116376 YES Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. 0.51 SIGNOR-253955 POLR1A protein O95602 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.843 SIGNOR-266152 NTN3 protein O00634 UNIPROT NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 28245592 YES miannu Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins. 0.719 SIGNOR-268171 BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates activity phosphorylation 10090 BTO:0004058 19620713 YES ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). 0.781 SIGNOR-255831 PKMYT1 protein Q99640 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Thr14 IEKIGEGtYGVVYKG 9606 BTO:0000567 9001210 YES Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2 gcesareni Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory. 0.751 SIGNOR-45725 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT up-regulates activity phosphorylation Tyr81 EQGAAAIyTTQMDDF 9606 BTO:0000567 15342783 YES lperfetto These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton 0.364 SIGNOR-247441 RNF111 protein Q6ZNA4 UNIPROT SKIL protein P12757 UNIPROT down-regulates ubiquitination 9606 17591695 YES gcesareni Arkadia interacts with snon and induces its ubiquitination irrespective of tgf-beta/activin signaling, but snon is efficiently degraded only when it forms a complex with both arkadia and phosphorylated smad2 or smad3 0.723 SIGNOR-156430 MMP3 protein P08254 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage His31 LDHDRAIhIQAENGP -1 7694569 YES miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. 0.384 SIGNOR-256330 CEBPA protein P49715 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates activity 10090 BTO:0000725 19706798 NO Conditional cebpa deficiency in adult mice blocks the transition from common myeloid progenitors (CMP) to granulocyte monocyte progenitors (GMP) resulting in the accumulation of myeloid blasts 0.7 SIGNOR-259965 CHKA protein P35790 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 21577200 YES miannu First, by using purified recombinant SRC-3 (XREF_FIG) and CKI proteins, we found that CKI is able to phosphorylate SRC-3 (XREF_FIG). 0.2 SIGNOR-280229 CSNK2A1 protein P68400 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Thr16 DVSVSVEtQGDDWDT 9606 10806407 YES llicata The in vivo Ser/Thr phosphorylation of HS1 is enhanced by okadaic acid and reduced by specific inhibitors of casein kinase (CK)2. In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme | It is likely therefore that Thr16 and/or Thr23 account for the phosphate incorporated into HS1 threonyl residue(s) upon incubation with CK2. 0.307 SIGNOR-250885 TOMM6 protein Q96B49 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 YES lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. 0.634 SIGNOR-267676 PDGFRB protein P09619 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr154 QLNDSAAyYLNDLDR -1 33139573 YES miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. 0.2 SIGNOR-277233 FLCN protein Q8NFG4 UNIPROT RRAGD protein Q9NQL2 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000007 24095279 YES The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur 0.682 SIGNOR-256504 ARNTL protein O00327 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR form complex binding -1 22653727 YES lperfetto Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock. 0.779 SIGNOR-253708 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 15747065 YES gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex. Ck1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. 0.303 SIGNOR-134500 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RRM1 protein P23921 UNIPROT up-regulates activity phosphorylation Ser559 PYETYEGsPVSKGIL 9606 32712628 YES miannu Here, we report that RRM1 is phosphorylated at Ser 559 by CDK2/cyclin A during S/G2 phase. And this S559 phosphorylation of RRM1enhances RNR enzymatic activity and is required for maintaining sufficient dNTPs during normal DNA replication. 0.322 SIGNOR-277522 ULK1 protein O75385 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity phosphorylation Ser74 EATWESVsMMLQLGG 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274035 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination 10090 BTO:0002572 15175328 YES miannu Taken together, these data suggest that Traf2 may be the E3 ubiquitin ligase that initiates TNF-α signaling, potentially by ubiquitinating Rip1. In the absence of Traf2, TNF-alpha-induced ubiquitination of Rip1 is impaired, suggesting that Traf2 may be the E3 ubiquitin ligase responsible for the TNF-alpha-dependent, ubiquitination of Rip1. Finally, recruitment of the ubiquitinated Tak1 complex is dependent on the presence of Rip1, suggesting that Rip1 ubiquitination rather than its phosphorylation is critical in signaling. 0.895 SIGNOR-271423 HTR1A protein P08908 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257197 CDK1 protein P06493 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Thr345 LTAERIKtPPKRPGG 9606 21659531 YES lperfetto Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome 0.576 SIGNOR-174054 POU4F1 protein Q01851 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000931 24493753 NO miannu In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression. 0.298 SIGNOR-253465 NFIL3 protein Q16649 UNIPROT CYP3A4 protein P08684 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 18004209 NO miannu The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock. 0.2 SIGNOR-253836 ATM protein Q13315 UNIPROT RAD17 protein O75943 UNIPROT unknown phosphorylation Ser646 ETWSLPLsQNSASEL 9606 10608806 YES lperfetto We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself. 0.846 SIGNOR-73520 MAPK1 protein P28482 UNIPROT DOCK1 protein Q14185 UNIPROT unknown phosphorylation Thr1772 QQTPPPVtPRAKLSF 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.252 SIGNOR-262769 DOK1 protein Q99704 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257679 USF1 protein P22415 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 9731700 NO miannu Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription. 0.41 SIGNOR-255595 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr514 TTTPKGGtPAGSARG 10116 16611631 YES lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.473 SIGNOR-146015 OST4 protein P0C6T2 UNIPROT OST-A complex complex SIGNOR-C535 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.593 SIGNOR-272061 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr66 ATRKALGtVNRATEK 9606 BTO:0000567 24781523 YES miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase 0.295 SIGNOR-276376 PRKD1 protein Q15139 UNIPROT RABEP1 protein Q15276 UNIPROT up-regulates activity phosphorylation Ser407 DGLRRAQsTDSLGTS 9606 22975325 YES miannu PKD phosphorylates Rabaptin-5 at Ser407, and this controls alphavbeta3 and alpha5beta1 integrin and EGFR recycling. 0.382 SIGNOR-278192 TFEB protein P19484 UNIPROT APOA4 protein P06727 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) 0.2 SIGNOR-276783 PRR5 protein P85299 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 YES lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) 0.676 SIGNOR-205621 SKP1 protein P63208 UNIPROT Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR form complex binding 9606 BTO:0001109 phosphorylation:Thr286 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1  0.838 SIGNOR-271627 HIF-1 complex complex SIGNOR-C418 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11744734 YES PFKFB3, is highly induced by hypoxia and the hypoxia mimics cobalt and desferrioxamine. This induction could be replicated by the use of an inhibitor of the prolyl hydroxylase enzymes responsible for the von Hippel Lindau (VHL)-dependent destabilization and tagging of HIF-1α. The absolute dependence of the PFKFB3 gene on HIF-1 was confirmed by its overexpression in VHL-deficient cells and by the lack of hypoxic induction in mouse embryonic fibroblasts conditionally nullizygous for HIF-1α 0.347 SIGNOR-267388 GRK5 protein P34947 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 16957079 YES llicata Grk5 phosphorylated ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. Grk5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein. 0.635 SIGNOR-149372 AKT proteinfamily SIGNOR-PF24 SIGNOR AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Ser985 THLSRVRsLDLDDWP 9606 BTO:0001130 19176382 YES lperfetto In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2. 0.2 SIGNOR-244132 ZNHIT1 protein O43257 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20473270 YES gcesareni We show that the srcap subunit named znhit1 or p18hamlet, which is a substrate of p38 mapk, is recruited to the myogenin promoter at the onset of muscle differentiation, in a p38 mapk-dependent manner. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation. 0.259 SIGNOR-165613 Camostat chemical CID:2536 PUBCHEM TMPRSS2 protein O15393 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000195 32142651 YES miannu Indeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells (Figure 4 A). Full inhibition was attained when camostat mesylate and E-64d, an inhibitor of CatB/L, were added (Figure 4A; Figure S3B), indicating that SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines. 0.8 SIGNOR-260284 dothiepin chemical CHEBI:36798 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258696 AURKA protein O14965 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 23993973 YES miannu The results of the in vitro kinase assay, using purified human recombinant AURKA and IkappaBalpha proteins, confirmed that AURKA can directly phosphorylate IkappaBalpha (Ser32) at a concentration as low as 2.5 ng/mul (XREF_FIG).|While an earlier study suggested that AURKA down-regulates IkappaBalpha indirectly through activation of the PI3K and AKT pathway 35, our data demonstrate, for the first time, that AURKA directly binds and phosphorylates the IkappaBalpha subunit, leading to activation of NF-kappaB. 0.54 SIGNOR-278912 YAP1 protein P46937 UNIPROT MCM3 protein P25205 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276568 CSNK2A1 protein P68400 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates phosphorylation Ser2110 PEPSTKVsEEAESQQ 9606 17088250 YES miannu We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment. 0.334 SIGNOR-150467 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 YES Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. 0.64 SIGNOR-248831 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120256 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000007 11970898 YES Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner 0.796 SIGNOR-248404 CCR4-NOT complex complex SIGNOR-C439 SIGNOR RC3H2 protein Q9HBD1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 YES lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins 0.315 SIGNOR-268353 CUDC-101 chemical CID:24756910 PUBCHEM HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262260 PRTN3 protein P24158 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 YES miannu Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen. 0.259 SIGNOR-256314 FBXO2 protein Q9UK22 UNIPROT STUB1 protein Q9UNE7 UNIPROT up-regulates activity binding 10116 BTO:0001009 16682404 YES miannu Through this novel interaction, which is mediated by the TPR domain of CHIP and an N-terminal PEST domain of Fbx2, CHIP facilitates the ubiquitination and degradation of Fbx2-bound glycoproteins. This study highlights a novel mechanism of F-box protein-mediated ubiquitination that contributes to glycoprotein homeostasis. 0.589 SIGNOR-271589 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.561 SIGNOR-270879 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-75009 FOSL2 protein P15408 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004603 13679379 YES Luana Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.  0.402 SIGNOR-261602 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 9606 23337587 YES gcesareni Interestingly, sufu stability is regulated via dual phosphorylation at ser342/ser346 by pka and gsk3, and blocking sufu phosphorylation either by mutating ser346 to ala or by treating cultured cells with pka inhibitors attenuates sufu ciliary accumulation, whereas phospho-mimetic forms of sufu exhibits increased ciliary localization 0.466 SIGNOR-119099 mTORC2 complex SIGNOR-C2 SIGNOR RRM1 protein P23921 UNIPROT up-regulates activity phosphorylation Ser631 IYTRRVLsGEFQIVN 9606 BTO:0002552 34126361 YES miannu Mechanistically, mTORC2 directly interacted and phosphorylated RNR large subunit RRM1 at Ser 631. Ser631 phosphorylation of RRM1 enhanced its interaction with small subunit RRM2 to maintain sufficient RNR enzymatic activity for efficient DNA replication. 0.304 SIGNOR-277566 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates activity phosphorylation Ser746 RRSVRIGsYIERDVT 9823 7539802 YES lperfetto We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling. 0.53 SIGNOR-248899 methiothepin chemical CHEBI:64203 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258892 SNAI1 protein O95863 UNIPROT SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19055748 NO lperfetto We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. 0.417 SIGNOR-252262 PAK1 protein Q13153 UNIPROT DYNLL1 protein P63167 UNIPROT down-regulates phosphorylation Ser88 VAILLFKsG 9606 BTO:0000149 18084006 YES lperfetto Dlc1 phosphorylation on ser(88) by p21-activated kinase 1 (pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with bim and the stability of bim. Here we discovered that phosphorylation of ser(88), which juxtapose each other at the interface of the dlc dimer, disrupts dlc1 dimer formation and consequently impairs its interaction with bim 0.378 SIGNOR-159995 CyclinY/CDK14 complex SIGNOR-C541 SIGNOR CCNY protein Q8ND76 UNIPROT down-regulates quantity by destabilization phosphorylation Ser71 RASTIFLsKSQTDVR 9606 BTO:0000599 24794231 YES lperfetto Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation|Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex 0.829 SIGNOR-273010 5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide chemical CHEBI:91333 ChEBI PLK1 protein P53350 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258221 DNMT3A protein Q9Y6K1 UNIPROT FGF21 protein Q9NSA1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29091029 NO Gianni Unbiased gene profiling studies revealed Fgf21 as a key negatively regulated Dnmt3a target gene in adipocytes with concordant changes in DNA methylation at the Fgf21 promoter region. 0.2 SIGNOR-262200 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 YES inferred from 70% family members miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. 0.2 SIGNOR-269953 RAB14 protein P61106 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 20534812 YES Giulio Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn. 0.629 SIGNOR-261279 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 18486448 YES gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus 0.879 SIGNOR-178655 NANOG protein Q9H9S0 UNIPROT PAX6 protein P26367 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.435 SIGNOR-253164 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT unknown phosphorylation Ser453 PRQEMGRsPVDSLSS 9606 BTO:0000938 BTO:0000887 12586839 YES lperfetto Thr-312 and thr-319 are known phosphorylation sites important for the increased transcriptional activation of mef2a by p38 mapk. Ser-453 and ser-479 are phosphorylated in vitro but were not important functionally 0.66 SIGNOR-98228 Cohesin complex complex SIGNOR-C304 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 30544080 NO miannu Cohesin, one of structural maintenance of chromosomes (SMC) complexes, forms a ring-shaped protein complex, and mediates sister chromatid cohesion for accurate chromosome segregation and precise genome inheritance. 0.7 SIGNOR-264523 F2RL1 protein P55085 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257028 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 16085715 YES miannu  In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms.  S123 phosphorylation creates a PBD-binding motif and accelerates S53 phosphorylation by Plk1. 0.641 SIGNOR-276040 COLEC11 protein Q9BWP8 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding -1 20956340 YES lperfetto On the basis of the significant concentration of CL-11 in circulation and CL-11's interaction with various microorganisms and MASP-1 and/or MASP-3, it is conceivable that CL-11 plays a role in activation of the complement system and in the defense against invading microorganisms. 0.62 SIGNOR-263409 CCKBR protein P32239 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257150 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 14968113 YES lperfetto Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation 0.73 SIGNOR-122094 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2A protein P49459 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.786 SIGNOR-271327 FLI1 protein Q01543 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR up-regulates 9606 BTO:0000565 28052010 NO irozzo The ETS-related transcription factor Fli-1 affects many developmental programs including erythroid and megakaryocytic differentiation, and is frequently de-regulated in cancer. 0.7 SIGNOR-256087 PIK3CA protein P42336 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser608 ENTEDQYsLVEDDED -1 14729945 YES miannu We find that p110 alpha phosphorylates p85 alpha Ser608 in vivo with significant stoichiometry. However, p110 beta is far less efficient at phosphorylating p85 alpha Ser608, identifying a potential difference in the mechanisms by which these two isoforms are regulated. The p85 alpha Ser608 phosphorylation was increased by treatment with insulin, platelet-derived growth factor, and the phosphatase inhibitor okadaic acid. The functional effects of this phosphorylation are highlighted by mutation of Ser608, which results in reduced lipid kinase activity and reduced association of the p110 alpha catalytic subunit with p85 alpha.  0.936 SIGNOR-276004 JAK2 protein O60674 UNIPROT PDP1 protein Q9P0J1 UNIPROT down-regulates activity phosphorylation Tyr94 SILKANEySFKVPEF 10090 BTO:0000944 24962578 YES miannu Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.  0.264 SIGNOR-276642 PTEN protein P60484 UNIPROT MAPT protein P10636 UNIPROT up-regulates activity dephosphorylation 9606 27221467 YES miannu Reduced phosphorylation of PTEN can dramatically increase tau phosphorylation and impair the ability of tau to bind to microtubules . 0.382 SIGNOR-277079 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser41 SLSESEEsQDSSDSI 9606 20730097 YES lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf2 0.2 SIGNOR-167568 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser289 PPPLAPQsPQGGVMG 9606 24101154 YES miannu Specifically, we found that YAP is phosphorylated in vitro and in vivo by the cell cycle kinase CDK1 at T119, S289, and S367 during G2/M phase of the cell cycle. 0.425 SIGNOR-279362 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258001 LYN protein P07948 UNIPROT CD22 protein P20273 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino LYN is a BCR-associated SRC kinase involved in the positive regulation of BCR, but it also functions as a negative regulator by phosphorylating the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of CD22. 0.742 SIGNOR-268443 ESR2 protein Q92731 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 NO miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice 0.2 SIGNOR-253474 PRKACA protein P17612 UNIPROT PDE4D protein Q08499 UNIPROT up-regulates phosphorylation 9606 8663227 YES llicata Phosphorylation and activation of a camp-specific phosphodiesterase by the camp-dependent protein kinase. 0.569 SIGNOR-42515 GATA1 protein P15976 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21853041 YES miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. 0.441 SIGNOR-256060 ITCH protein Q96J02 UNIPROT DTX1 protein Q86Y01 UNIPROT down-regulates ubiquitination 9606 17028573 YES gcesareni Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains. 0.699 SIGNOR-150002 PCDH15 protein Q96QU1 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 YES lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. 0.55 SIGNOR-262575 COL4A3 protein Q01955 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 YES Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) 0.7 SIGNOR-254667 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 12056906 YES esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. 0.448 SIGNOR-89221 USP16 protein Q9Y5T5 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity deubiquitination 9606 17914355 YES miannu  Here we report the identification and functional characterization of the major deubiquitinase for histone H2A, Ubp-M (also called USP16). Ubp-M prefers nucleosomal substrates in vitro, and specifically deubiquitinates histone H2A but not H2B in vitro and in vivo.  This study identifies the major deubiquitinase for histone H2A and demonstrates that H2A deubiquitination is critically involved in cell cycle progression and gene expression. 0.2 SIGNOR-277348 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser249 GLSLSRFsWGAEGQR -1 2413024 YES lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 0.49 SIGNOR-248872 EPHB1 protein P54762 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates activity phosphorylation Tyr594 GSPGMKIyIDPFTYE 10029 BTO:0000246 12223469 YES  Co-immunoprecipitation was used to confirm the interaction of Grb7 with the cytoplasmic domain of EphB1 as well as the full-length receptor in intact cells. This interaction is mediated by the SH2 domain of Grb7 and requires tyrosine autophosphorylation of EphB1. We also found that EphB1 could phosphorylate Grb7 and mutation of either Tyr-928 or Tyr-594 to Phe decreased this activity. 0.2 SIGNOR-251122 BMPR1A protein P36894 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR up-regulates activity phosphorylation 10090 19620713 YES ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). 0.699 SIGNOR-255786 PRKCD protein Q05655 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 11085981 YES lperfetto In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism. 0.307 SIGNOR-249063 IL10 protein P22301 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 NO miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. 0.2 SIGNOR-253498 MAPK14 protein Q16539 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates activity phosphorylation 10090 20682789 YES ggiuliani We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes 0.408 SIGNOR-255791 RORA protein P35398 UNIPROT NPAS2 protein Q99743 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20817722 YES miannu Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. 0.664 SIGNOR-267980 MRE11 protein P49959 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR form complex binding 17713585 YES lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. 0.2 SIGNOR-251504 SCRIB protein Q14160 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity binding 9606 BTO:0000007 20622900 YES miannu These two KIM sites are found at N- and C-terminal locations on hScrib, and both are essential for directing the interaction between ERK and hScrib, but with the C-terminal site having the strongest affinity for ERK. One of the most likely consequences of this interaction is to inhibit ERK translocation to the nucleus. 0.367 SIGNOR-263067 MAPK1 protein P28482 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation Ser167 FLISPPAsPPVGWKQ 10090 BTO:0000165 12063245 YES lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 0.27 SIGNOR-249198 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 YES gcesareni Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1. 0.385 SIGNOR-111507 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001103 9551976 NO Federica Ferrentino A role for STAT1 in regulation of the CIITA promoter is shown by the rescue of IFN-gamma induction by expression of STAT1 in STAT1-defective U3A cells 0.538 SIGNOR-255752 PPARGC1A protein Q9UBK2 UNIPROT ESRRA protein P11474 UNIPROT up-regulates activity 10090 18074631 NO lperfetto The PGC1 transcriptional coactivators are major regulators of several crucial aspects of energy metabolism. PGC1alpha controls many aspects of oxidative metabolism, including mitochondrial biogenesis and respiration through the coactivation of many nuclear receptors, and factors outside the nuclear receptor family. ERRalpha, NRF1 and NRF2 are key targets of the PGC1s in mitochondrial biogenesis. 0.923 SIGNOR-253392 PRKCZ protein Q05513 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser978 KRPSSVKsLRSERLI -1 15081397 YES lperfetto PKCzeta phosphorylates KIBRA at serine 975 and 978 0.705 SIGNOR-249263 MBTPS2 protein O43462 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates activity cleavage 10029 BTO:0000246 10419520 YES In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted 0.672 SIGNOR-267498 BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0001938 11463392 YES lperfetto Puma localizes to the mitochondria, interacts with bcl-2, and function to induce cytochrome c release 0.663 SIGNOR-109506 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 1310351 NO gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.668 SIGNOR-16469 HIF-1 complex complex SIGNOR-C418 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 27692180 YES miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 0.355 SIGNOR-267500 RBBP8 protein Q99708 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001130 22832221 NO gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. 0.828 SIGNOR-198473 MAPK1 protein P28482 UNIPROT LIFR protein P42702 UNIPROT down-regulates phosphorylation Ser1044 WNLVSPDsPRSIDSN 9606 7777512 YES gcesareni Indeed, phosphorylation of the cytoplasmic domain of the low-affinity lif receptor alpha-subunit (lifr) in mono q-fractionated, lif-stimulated 3t3-l1 extracts occurred only in those fractions containing activated mapk;ser-1044 served as the major phosphorylation site in the human lifr for mapk both in agonist-stimulated 3t3-l1 lysates and by recombinant extracellular signal-regulated kinase 2 in vitro 0.37 SIGNOR-32753 erlotinib hydrochloride chemical CHEBI:53509 ChEBI JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 17178722 YES JAK2(V617F), a mutant of tyrosine kinase JAK2. Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. gcesareni This study shows that the anti-cancer drug erlotinib (tarceva) is a potent inhibitor of jak2(v617f) activity 0.8 SIGNOR-151274 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 YES gcesareni Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. 0.2 SIGNOR-89411 PCBD1 protein P61457 UNIPROT HNF1B protein P35680 UNIPROT up-regulates activity binding 9606 BTO:0000482 24204001 YES miannu Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT. 0.582 SIGNOR-254910 SPART protein Q8N0X7 UNIPROT WWP1 protein Q9H0M0 UNIPROT up-regulates activity binding 9606 19580544 YES miannu Cytosolic endogenous spartin is mono-ubiquitinated and we demonstrate that it interacts via a PPXY motif with the ubiquitin E3 ligases AIP4 [atrophin-interacting protein 4; ITCH (itchy E3 ubiquitin protein ligase homologue] [corrected] and AIP5 (WWP1). Surprisingly, the PPXY motif, AIP4 and AIP5 are not required for spartin's ubiquitination, and so we propose that spartin acts as an adaptor for these proteins. 0.2 SIGNOR-261307 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UBTF protein P17480 UNIPROT up-regulates phosphorylation Ser389 INKKQATsPASKKPA 9606 11698641 YES lperfetto Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity 0.372 SIGNOR-216678 GTP smallmolecule CHEBI:15996 ChEBI Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR form complex binding 9606 29735640 YES miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. 0.8 SIGNOR-275394 RFX1 protein P22670 UNIPROT HLA-DOB protein P13765 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11823510 NO Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. 0.2 SIGNOR-254022 SCF-FBW7 complex SIGNOR-C135 SIGNOR SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001225 30177679 YES miannu  We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.  0.28 SIGNOR-277409 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 17204478 YES lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). 0.798 SIGNOR-263434 TFE3 protein P19532 UNIPROT GAA protein P10253 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.278 SIGNOR-276820 ACTB protein P60709 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.502 SIGNOR-270748 CXCL2 protein P19875 UNIPROT Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000130 35022267 NO miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. 0.7 SIGNOR-277722 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser118 EPDNRRFsSYSQMEN -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273486 CDK5 protein Q00535 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Thr138 PAVTSAGtPKRVIVQ 9606 18326489 YES lperfetto P35 phosphorylation by cdk5 interferes with the microtubule-binding and polymerizing activities of p35. Using a mutational approach, we found that only phosphorylation at thr-138, one of the two residues primarily phosphorylated in vivo, inhibits the polymerizing activity 0.943 SIGNOR-177967 CENPH protein Q9H3R5 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.764 SIGNOR-265198 CDC25C protein P30307 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 BTO:0001938 10913154 YES lperfetto Cyclin B-Cdc2 complexes are maintained in an inactive state until the end of G2 by phosphorylation of the Thr14/Tyr15 residues. Around the time of nuclear translocation of the complex, these residues are dephosphorylated, resulting in the formation of an active cyclin B-Cdc2 complex (2). As mentioned, this dephosphorylation occurs by a Cdc25 protein phosphatase. Three Cdc25 family members have been identified to date, A, B and C, the last one being the active one at the onset of mitosis. The activity of Cdc25C itself can be enhanced through phosphorylation by cyclin B-Cdc2 (9, 10). Therefore, activation of cyclin B-Cdc2 has been proposed to result in an autocatalytic feedback loop to ensure rapid activation of these complexes at the G2/M transition 0.844 SIGNOR-251509 GSK3B protein P49841 UNIPROT AREL1 protein O15033 UNIPROT down-regulates quantity by destabilization phosphorylation Thr783 IAAPTHStLPTAHTC 27162139 YES lperfetto These experiments suggested that GSK3beta phosphorylation of FIEL1 is required for PIAS4 targeting, and FIEL1 residues P779 and phosphorylated T783 are both required for PIAS4 interaction |FIEL1 T783A mutant overexpression completely failed to decrease PIAS4 protein level. 0.317 SIGNOR-275528 MARCHF9 protein Q86YJ5 UNIPROT HLA-DQA1 protein P01909 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271538 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.276 SIGNOR-253484 BRD8 protein Q9H0E9 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.656 SIGNOR-269304 DUSP1 protein P28562 UNIPROT JUN protein P05412 UNIPROT down-regulates activity dephosphorylation 9606 26734995 YES miannu However, adenovirus mediated overexpression of MKP-1 only slightly decreased JNK and c-Jun phosphorylation compared with the severe inactivation of JNK activities induced by MKK7 knockdown.|The results suggested that HDACI-induced MKP-1 contributes to inactivation of JNK instead of ERK, consistent with the previous reports in other cell types 0.455 SIGNOR-277102 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCC8 protein Q09428 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000783 35065096 YES miannu Activated PKA and EPAC enhance insulin granular exocytosis by insulin granular priming and phosphorylates sulfonylurea receptor (SUR1) KATP channel subunit and thereby closes KATP-channels in the plasma membrane [13,43,82], leading to membrane depolarization, and opening of the voltage gated Ca2+-channels. This leads to an increased influx of extracellular Ca2+, which triggers fusion of intracellular insulin-containing granules with the plasma membrane and thereby insulin secretion. 0.2 SIGNOR-278147 PPP1CA protein P62136 UNIPROT CASP2 protein P42575 UNIPROT up-regulates activity dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 YES llicata nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. 0.2 SIGNOR-248564 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser272 EEPSPLPsPTASPNH -1 11113134 YES llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  0.355 SIGNOR-250644 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 YES lperfetto Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity 0.2 SIGNOR-244521 AFAP1L2 protein Q8N4X5 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 BTO:0000007 19060924 YES miannu RET/PTC induced robust tyrosine phosphorylation of XB130, which promoted its subsequent association with the p85alpha subunit of phosphatidylinositol 3-kinase (PI 3-kinase). We identified tyrosine 54 of XB130 as the major target of RET/PTC-mediated phosphorylation and a critical binding site for the SH2 domains of p85alpha. 0.2 SIGNOR-263193 TFEB protein P19484 UNIPROT TPP1 protein O14773 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.288 SIGNOR-276548 BMP2 protein P12643 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates 9606 22298955 NO inferred from 70% of family members lperfetto Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation. 0.699 SIGNOR-269848 mir-143 mirna URS0000008A99_9606 RNAcentral IGFBP5 protein P24593 UNIPROT down-regulates quantity post transcriptional regulation 9606 29506532 YES gianni The results indicated that CADM2 is a direct target of miR-10b in HCC cells and miR-10b/CADM2 modulates EMT process and migration ability via focal adhesion kinase (FAK) /AKT signaling pathway in HCC 0.4 SIGNOR-268853 MAPK1 protein P28482 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Ser780 DSLDSRLsPPAGLFT 9606 BTO:0000975 10194762 YES lperfetto Gh treatment of chinese hamster ovary cells stably transfected with the gh receptor (choa cells) led to rapid and transient activation of both stat5a and erk1 and erk2. these observations show, for the first time, direct physical interaction between erk and stat5a and also clearly identify serine 780 as a target for erk. 0.759 SIGNOR-66239 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CBX5 protein P45973 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23431138 YES miannu As expected, the SKP1 and CUL1 proteins, subunits of all F-box-containing E3 ligases, were also present in the immune complexes containing FBXO10 and BCL2. To test for FBXO10-induced ubiquitination of BCL2, 293T cells were transduced with retroviral vectors expressing Flag-tagged FBXO10, MYC-tagged BCL2, and HA-tagged ubiquitin, and cells were treated with the proteasome inhibitor PS-341 to enhance the detection of ubiquitinated proteins.Together, these data suggest that FBXO10 is a component of a ubiquitin ligase that can target BCL2 protein for degradation. 0.2 SIGNOR-271934 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 YES gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. 0.819 SIGNOR-187591 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT up-regulates activity phosphorylation Ser486 DDAFVGFsYAPPSED 10548550 YES miannu SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. 0.462 SIGNOR-250278 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 BTO:0000782 15623513 YES lperfetto Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus. 0.479 SIGNOR-132894 PTPN11 protein Q06124 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity dephosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 23420874 YES lperfetto Using an in vitro experiment in which purified full-length wild-type Shp2 (WT Shp2) was incubated with phosphorylated C-SH3 domain of Grb2 we demonstrated that Shp2 can dephosphorylate Grb2 on residue Y209 (XREF_FIG). 0.736 SIGNOR-276995 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1190 DIYETDYyRKGGKGL -1 2449432 YES lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; 0.2 SIGNOR-106518 TAB1 protein Q15750 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. 0.384 SIGNOR-205437 PRKACA protein P17612 UNIPROT TRPM8 protein Q7Z2W7 UNIPROT up-regulates activity phosphorylation Ser9 SFRAARLsMRNRRND 9606 BTO:0000007 20110357 YES done miannu Using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. the intracellular serine/threonine protein phosphatase 2A (PP2A) dephosphorylates TRPM8 Ser-9 and Thr-17 inhibiting the channel activity. 0.2 SIGNOR-273792 PTEN protein P60484 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 BTO:0001271 20596030 NO lperfetto Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfralpha was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. 0.635 SIGNOR-252638 RFWD3 protein Q6PCD5 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0002552 20173098 YES miannu RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage.  0.361 SIGNOR-271944 BCR-Ml complex SIGNOR-C434 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 YES scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). 0.714 SIGNOR-268440 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser285 MEVEDNRsQVETDDL 9615 BTO:0000837 11742978 YES llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. 0.416 SIGNOR-250827 CDR2 protein Q01850 UNIPROT TTK protein P33981 UNIPROT up-regulates quantity by expression transcriptional regulation 20383333 NO lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology 0.2 SIGNOR-252021 LRRC45 protein Q96CN5 UNIPROT CEP250 protein Q9BV73 UNIPROT up-regulates activity binding 9606 BTO:0000567 24035387 YES miannu Here, we show that LRRC45 is a centrosome linker that localizes at the proximal ends of the centrioles and forms fiber-like structures between them. Depletion of LRRC45 results in centrosome splitting during interphase. LRRC45 interacts with C-Nap1 and rootletin 0.408 SIGNOR-273703 GSK3B protein P49841 UNIPROT PAX3 protein P23760 UNIPROT up-regulates quantity phosphorylation Ser197 GILSERAsAPQSDEG 9606 22679108 YES miannu The ubiquitously expressed CK2 often provides the priming phosphorylation for GSK-3, however, we found that GSK-3beta alone was sufficient to phosphorylate PAX3 at both Ser205 and Ser197 and Ser201 in-vitro. 0.334 SIGNOR-278482 RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17011493 YES miannu We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod. 0.419 SIGNOR-149967 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120132 NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys6 kGGKGLGK 9606 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8. 0.2 SIGNOR-267167 SRMS protein Q9H3Y6 UNIPROT FKBP5 protein Q13451 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr54 PMIGDKVyVHYKGKL 9606 BTO:0000567 34077419 YES miannu SRMS binds FKBP51 and phosphorylates tyrosine 54. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. 0.268 SIGNOR-277564 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 YES lperfetto Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3 0.2 SIGNOR-244630 AKT proteinfamily SIGNOR-PF24 SIGNOR BAX protein Q07812 UNIPROT down-regulates activity phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 BTO:0003473 14766748 YES lperfetto Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members 0.2 SIGNOR-209651 PEX6 protein Q13608 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity binding 10029 16314507 YES Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner. 0.57 SIGNOR-253619 GSK3A protein P49840 UNIPROT ARHGAP31 protein Q2M1Z3 UNIPROT up-regulates activity phosphorylation Thr789 PPAPPPPtPLEESTP 10090 BTO:0000944 17158447 YES miannu We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. 0.337 SIGNOR-262878 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser865 YLSSRRSsGISPCFS 9606 10693759 YES lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. 0.467 SIGNOR-75347 STAT3 protein P40763 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. 0.566 SIGNOR-255024 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 YES gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. 0.791 SIGNOR-156353 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR TDG protein Q13569 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24962565 YES miannu TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner 0.298 SIGNOR-272849 MGluR proteinfamily SIGNOR-PF55 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264690 nintedanib chemical CHEBI:85164 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 18559524 YES Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. 0.8 SIGNOR-257804 HTR2C protein P28335 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.294 SIGNOR-256734 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT up-regulates quantity by stabilization phosphorylation Ser725 CLSSERMsLPLLAGG 9606 BTO:0000007 15987997 YES miannu Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life. 0.75 SIGNOR-262650 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000007 19126544 YES lperfetto Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. 0.486 SIGNOR-236667 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr288 SVIPDSGyISEVRNF 9606 BTO:0002181 37977223 YES miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. 0.566 SIGNOR-277865 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 SIGNOR-C16 12058066 YES gcesareni Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. 0.562 SIGNOR-89609 PRKCZ protein Q05513 UNIPROT ATP1A1 protein P05023 UNIPROT up-regulates activity phosphorylation Ser16 KYEPAAVsEQGDKKG 9606 BTO:0000018 12671055 YES miannu Na,K-ATPase alpha(1) subunit was phosphorylated by PKC in hypoxia-treated AEC. In AEC treated with a PKC-zeta antagonist peptide or with the Na,K-ATPase alpha(1) subunit lacking the PKC phosphorylation site (Ser-18), hypoxia failed to decrease Na,K-ATPase abundance and function. 0.2 SIGNOR-263181 LPCAT2 protein Q7L5N7 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272765 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT unknown phosphorylation Tyr691 PKGTQADyAEVKFQ 9606 11733002 YES lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691 0.2 SIGNOR-112487 PKA proteinfamily SIGNOR-PF17 SIGNOR HDAC4 protein P56524 UNIPROT up-regulates activity phosphorylation -1 30661366 YES miannu  In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. 0.2 SIGNOR-277425 GART protein P22102 UNIPROT N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity chemical modification 9606 34283828 YES miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 0.8 SIGNOR-267300 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 YES lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity 0.91 SIGNOR-252859 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249327 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9507002 YES gcesareni Our present study established that n-shc and sck are expressed in a region-specific manner in the brain and that n-shc is a higher affinity adapter molecule than sck for trka and trkb receptors 0.755 SIGNOR-55864 JUN protein P05412 UNIPROT RACK1 protein P63244 UNIPROT up-regulates quantity by expression 9606 BTO:0002806 17482134 YES Marta Tosoni In turn, c-Jun induces expression of RACK1, which is required for JNK activation by PKC, pointing to a c-Jun/RACK1/PKC/JNK feedback loop. 0.2 SIGNOR-278066 SMAD4 protein Q13485 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 YES lperfetto Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. 0.639 SIGNOR-251493 ROCK1 protein Q13464 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser181 YQPRRRKsVKNGQAE 9606 20039424 YES lperfetto Rho kinase-dependent activation of sox9 in chondrocytes. In vitro, rock directly phosphorylated sox9 at ser(181), and the overexpression of rock or the activation of the rhoa pathway in sw1353 chondrosarcoma cells increased sox9(ser181) phosphorylation 0.305 SIGNOR-162643 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser697 QPSTASNsLPEPAKK 9606 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251282 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu72 MEEKCSFeEAREVFE 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263692 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT up-regulates activity phosphorylation His118 QVGRNIIhGSDSVKS -1 8132589 YES miannu Using site-directed mutagenesis of the cDNA encoding NM23-H2, we have created a mutant substituting for the amino acid histidine 118, the presumed site of phosphorylation in the formation of the phosphoenzyme intermediate, the nonphosphorylatable amino acid phenylalanine. The H118F mutant protein is shown to be catalytically inactive 0.2 SIGNOR-250304 CXCL1 protein P09341 UNIPROT PRKACA protein P17612 UNIPROT down-regulates binding 9606 17251915 YES gcesareni As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp. 0.2 SIGNOR-152594 GRPR protein P30550 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.25 SIGNOR-256774 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser100 DEDSGKGsQPPSPPS 9606 20305697 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-164613 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Ser329 LGGLCDLsSRY 9606 12639913 YES Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA and GRK phosphorylation and the subsequent recruitment of β-arrestin to the activated receptor. Replacement by alanine(s) of Thr312 and Ser329/330 in the C-terminal tail resulted in an impaired sequestration of mutated receptors to agonist, whereas mutations of Thr232 or Ser306 did not. This indicates that phosphorylation of these residues by kinases is critical for the internalization of MC4R. 0.2 SIGNOR-251453 FLT3 protein P36888 UNIPROT ACAT1 protein P24752 UNIPROT up-regulates activity phosphorylation Tyr407 HALKQGEyGLASICN 9606 BTO:0001545 34289383 YES in mitochondria lperfetto We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)  0.2 SIGNOR-267628 EIF2AK2 protein P19525 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr4 yTKIEKIG 9606 20395957 YES lperfetto Our findings demonstrate that (i) pkr, ser/thr kinase, phosphorylates its new substrate cdc2 at the tyr 4 residue, (ii) pkr-mediated tyr 4-phosphorylation facilitates cdc2 ubiquitination and proteosomal degradation 0.329 SIGNOR-164809 romidepsin chemical CHEBI:61080 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257994 PPM1L protein Q5SGD2 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity dephosphorylation 9606 24327956 YES miannu Overall, our study establishes that PP2Ce mediated IRE1 regulation in ER stress signaling is a potentially important molecular basis for its genetic contribution to metabolic syndrome.Lin et al. [36] have reported that different durations and composition of ER stress signaling pathways can dictate cell fate and the balance between survival and death.|Recombinant wildtype PP2Ce, but not a phosphatase-dead mutant (PP2Ce-D302A), effectively dephosphorylated the phosphor-Ser724 site of IRE1\u03b1 protein (p-IRE1\u03b1)  (A). 0.31 SIGNOR-277074 CSNK2A2 protein P19784 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -1 9045708 YES llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  0.307 SIGNOR-251038 FAM13B protein Q9NYF5 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.45 SIGNOR-260504 PHA-665752 chemical CHEBI:90197 ChEBI MET protein P08581 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258265 NDUFS5 protein O43920 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 0.823 SIGNOR-262179 MAP2K1 protein Q02750 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 NO gcesareni Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. 0.673 SIGNOR-178636 CYCS protein P99999 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR up-regulates activity 9606 10563795 YES miannu Cytochrome c oxidase catalyzes the reduction of molecular oxygen to water, a process in which four electrons, four protons, and one molecule of oxygen are consumed. The reaction is coupled to the pumping of four additional protons across the membrane. According to the currently accepted concept, the pumping of all four protons occurs after the binding of oxygen to the reduced enzyme and is exclusively coupled to the last two electron transfer steps.  0.763 SIGNOR-280292 PLK1 protein P53350 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates phosphorylation Ser195 LTKTASEsISNLSEA 9606 20664522 YES gcesareni Furthermore, we provide evidence that plk1 phosphorylation of clip-170 at s195 enhances its association with ck2 0.702 SIGNOR-167172 ATM protein Q13315 UNIPROT TTC5 protein Q8N0Z6 UNIPROT up-regulates activity phosphorylation Ser203 TGQNPKIsQQALSAY 9606 15448695 YES miannu Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. 0.536 SIGNOR-262645 CIITA protein P33076 UNIPROT HLA-DMB protein P28068 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 9300700 NO The class II transactivator (CIITA) is a highly specific transcription factor that activates only genes known to be involved in the class II MHC processing pathway, including class II MHC, invariant chain, and HLA-DMA/B genes. 0.352 SIGNOR-254014 hsa-miR-326 mirna URS00000A939F_9606 RNAcentral CCND1 protein P24385 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002035 25173582 NO Parnian The upregulation of miR-326 not only inhibited the activity of the Hh pathway but also reduced the expression of additional Hh signaling components, including GLI1, N-myc, and CyclinD1. 0.4 SIGNOR-277981 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser51 LRPSTSRsLYASSPG -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248883 TGM2 protein P21980 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16407273 YES gcesareni Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells. 0.2 SIGNOR-265369 NPEPPS protein P55786 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 11062501 YES The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides| We performed in vitro peptide digests using recombinant PSA | PSA behaved exclusively as an aminopeptidase |BH and PSA act as complementary and redundant systems responsible for the final trimming of the correct NH2 terminus. 0.8 SIGNOR-272468 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258628 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.383 SIGNOR-189137 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 15448698 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-129414 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258922 RPL39 protein P62891 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.844 SIGNOR-262490 NEDD4L protein Q96PU5 UNIPROT OGG1 protein O15527 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 33282879 YES miannu We demonstrate that recombinant NEDD4L stimulates ubiquitylation of OGG1 in vitro, particularly on lysine 341, and that NEDD4L and OGG1 interact in U2OS cells. 0.2 SIGNOR-278639 AURKB protein Q96GD4 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates phosphorylation Thr117 KNKIAKEtNNKKKEF 9606 17457057 YES lperfetto Phosphorylation by aurora-b negatively regulates survivin function . hat survivin is phosphorylated at t117 during mitosis, and once phosphorylated, dephosphorylation is crucial for chromosome congression and progression into anaphaseduring mitosis 0.794 SIGNOR-154569 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b8 integrin complex SIGNOR-C185 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.326 SIGNOR-259013 PTPN1 protein P18031 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 24590766 YES miannu Here, we show that PTP1B regulates CD40 and BAFF-R signaling and dephosphorylates the mitogen-activated protein kinase p38.|Specifically, PTP1B counteracts p38 mitogen-activated protein kinase activation by directly dephosphorylating Tyr182 of this kinase. 0.444 SIGNOR-277167 SP1 protein P08047 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000944 23936544 YES lperfetto MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-β mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-β production 0.296 SIGNOR-251740 HTR6 protein P50406 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257073 MMP3 protein P08254 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Ser240 ISRVDAAsLKGLNNL -1 9148753 YES miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. 0.672 SIGNOR-256353 P2RY11 protein Q96G91 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.383 SIGNOR-256788 trimetrexate chemical CHEBI:9737 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 7981057 YES miannu We examined the cytotoxicity and biochemical effects of the lipophilic antifol trimetrexate (TMQ) in two human colon carcinoma cell lines, SNU-C4 and NCI-H630, with different inherent sensitivity to TMQ. Dihydrofolate reductase (DHFR) and thymidylate synthase were quantitatively and qualitatively similar in both lines. During drug exposure, DHFR catalytic activity was inhibited by > or = 85% in both cell lines 0.8 SIGNOR-258482 TSC1 protein Q92574 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity 9606 BTO:0000007;BTO:0001938 12271141 NO lperfetto These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mtor. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mtor)-mediated signaling to eukaryotic initiation factor 4e-binding protein 1 (4e-bp1) and ribosomal protein s6 kinase 1 (s6k1). 0.705 SIGNOR-93130 SGK3 protein Q96BR1 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser664 GARQRALsAVSVLTS 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.276 SIGNOR-275768 PARP1 protein P09874 UNIPROT POLA1 protein P09884 UNIPROT up-regulates activity binding 9606 BTO:0000567 9518481 YES Federica We provide evidence that in proliferating cells: (i) PARP is physically associated with the catalytic subunit of the DNA polymerase α–primase tetramer, an association confirmed by confocal microscopy, demonstrating that both enzymes are co-localized at the nuclear periphery of HeLa cells.|(iii) PARP-deficient cells derived from PARP knock-out mice exhibited reduced DNA polymerase activity, 0.343 SIGNOR-261270 PRKD1 protein Q15139 UNIPROT REM1 protein O75628 UNIPROT up-regulates activity phosphorylation Ser18 TPLHRRAsTPLPLSP 9606 BTO:0000567 22076634 YES done miannu We found that activation of protein kinase D1, a protein kinase downstream of α(1)-adrenergic signaling, leads to direct phosphorylation of Rem1 at Ser18. This results in an increase of the channel activity and plasma membrane expression observed by using a combination of electrophysiology, live cell confocal microscopy, and immunohistochemistry in heterologous expression system and neonatal cardiomyocytes.  0.356 SIGNOR-273832 RPS6KA3 protein P51812 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 20385620 YES miannu Here, we show that RSK2 is activated by treatment with tumor necrosis factor-alpha (TNF-alpha) and directly phosphorylates IkappaBalpha at Ser 32, leading to IkappaBalpha degradation. 0.369 SIGNOR-279108 dexamethasone chemical CHEBI:41879 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258710 ABL1 protein P00519 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Tyr78 RAIDFSPyLEPLGAP 9606 BTO:0000007 19563810 YES gcesareni The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells 0.399 SIGNOR-186423 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr80 DQHSISYtLSRAQTV -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.657 SIGNOR-276131 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 10116 11287630 YES lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten 0.766 SIGNOR-106582 TWIST2 protein Q8WVJ9 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 NO miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells 0.472 SIGNOR-255517 SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 YES lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. 0.665 SIGNOR-44870 COX6C protein P09669 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.747 SIGNOR-267750 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser513 NLESHLMsPAEIPGQ 9606 22966201 YES llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. 0.322 SIGNOR-198992 STK39 protein Q9UEW8 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates activity phosphorylation Thr203 QGHVRTHtGEKPFSC 9606 34335956 YES miannu In this study, we found that STK39 also enhances SNAI1 stability by its phosphorylation at T203.|STK39 interacts with SNAI1 and phosphorylates SNAI1 on T203. 0.2 SIGNOR-279128 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR ST7 protein Q9NRC1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0004297 30945288 YES miannu We found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). 0.2 SIGNOR-272309 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-266281 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr599 VDFREYEyDLKWEFP 9606 BTO:0001271 11971190 YES lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation 0.2 SIGNOR-117583 TBK1 protein Q9UHD2 UNIPROT ELF4 protein Q99607 UNIPROT up-regulates activity phosphorylation 9606 24185615 YES miannu Taken together, these results suggest that in response to viral infection, ELF4 was phosphorylated by TBK1 and translocated to the nucleus in a MAVS- and STING dependent manner.|We speculate that overexpressed ELF4 may recruit and be activated by TBK1. 0.361 SIGNOR-279130 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0001271 18174237 YES gcesareni Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome. 0.758 SIGNOR-160326 CDK1 protein P06493 UNIPROT NUP35 protein Q8NFH5 UNIPROT down-regulates activity phosphorylation 9606 29065306 YES miannu Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association. 0.561 SIGNOR-278917 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248365 CD3E protein P07766 UNIPROT CD3 complex SIGNOR-C432 SIGNOR form complex binding 9606 12507424 YES miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules. 0.807 SIGNOR-255294 DGC complex SIGNOR-C217 SIGNOR GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265434 hsa-miR-326 mirna URS00000A939F_9606 RNAcentral SMO protein Q99835 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002035 25173582 YES Parnian These data indicated that miR-326 directly modulated SMO expression by binding to the 3′UTR. 0.4 SIGNOR-277978 CDK13 protein Q14004 UNIPROT SERINC5 protein Q86VE9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser360 ARCCFCFsPGGEDTE 9606 34380030 YES miannu In addition, CDK13-KD disrupted Nef downregulation of SERINC5 from the cell surface, whereas CDK12-KD did not (Figures 2D and 2E).|Thus, S360 phosphorylation increases interactions between Nef and SERINC5 and initiates the destruction of SERINC5 by the endocytic machinery.|Thus, we conclude that CycK/CDK13 phosphorylates the S360 residue of SERINC5. 0.2 SIGNOR-278918 LRFN4 protein Q6PJG9 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 21736948 NO miannu The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons. 0.7 SIGNOR-264092 oxaprozin chemical CHEBI:7822 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132;BTO:0003652 9650852 YES miannu We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively. 0.8 SIGNOR-258930 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 YES inferred from 70% family members gcesareni Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus 0.2 SIGNOR-270137 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 YES lperfetto We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. 0.2 SIGNOR-244662 DAPK2 protein Q9UIK4 UNIPROT DAPK2 protein Q9UIK4 UNIPROT down-regulates activity phosphorylation Ser318 VRRRWKLsFSIVSLC 9606 BTO:0000007;BTO:0000356 11230133 YES llicata Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding. | It comprises a single autophosphorylation event mapped to Ser308 within the CaM regulatory domain. 0.2 SIGNOR-251084 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1404 EEIKSQNsQESTADE 9606 12086603 YES lperfetto These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint 0.788 SIGNOR-90113 MRPL51 protein Q4U2R6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.664 SIGNOR-262337 ATM protein Q13315 UNIPROT BUB3 protein O43684 UNIPROT up-regulates activity phosphorylation Ser135 PCNAGTFsQPEKVYT 9606 BTO:0000567 35085551 YES miannu Taken together, we highlight the functional significance of the crosstalk between the kinetochore-oriented signal and double-strand break repair pathways via ATM phosphorylation of Bub3 on Ser135. 0.313 SIGNOR-277582 KREMEN2 protein Q8NCW0 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 12050670 YES gcesareni Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane. 0.638 SIGNOR-88894 PTPRG protein P23470 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity dephosphorylation Tyr701 DGPKGTGyIKTELIS -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254727 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 9405416 YES Phosphorylation of c-Jun on Ser73 by JNK is sufficient to protect c-Jun from ubiquitination. lperfetto Phosphorylation by activated jnk protects c-jun from ubiquitination. 0.2 SIGNOR-53788 TET1 protein Q8NFU7 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27708339 YES irozzo Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. 0.306 SIGNOR-259094 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser257 PERPGILsPATSEAV 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.742 SIGNOR-262719 ponatinib chemical CHEBI:78543 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 23468082 YES miannu Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. 0.8 SIGNOR-259277 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 10090 BTO:0002882 16122376 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work 0.2 SIGNOR-236531 CLCF1 protein Q9UBD9 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 YES gcesareni Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-6 0.559 SIGNOR-47959 ACSS2 protein Q9NR19 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; 0.2 SIGNOR-276561 IL1A protein P01583 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 NO miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 0.2 SIGNOR-254807 Degranulation phenotype SIGNOR-PH92 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity 9606 BTO:0000830 24232182 NO apalma Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6 0.7 SIGNOR-255349 CDH8 protein P55286 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000567 17938208 YES gianni CHD8 binds to histone H3 di- and trimethylated on lysine 4. It resides on the human U6 promoter as well as the mRNA IRF3 promoter in vivo and contributes to efficient transcription from both these promoters 0.2 SIGNOR-266898 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14623893 YES miannu I– uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane 0.38 SIGNOR-251995 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 YES areggio These findings present new insights into the role of the GR and FOXO family of transcription factors in the transcriptional regulation of the MuRF1 gene, a direct target of the GR in skeletal muscle. 0.2 SIGNOR-254991 SRC protein P12931 UNIPROT INPPL1 protein O15357 UNIPROT up-regulates phosphorylation Tyr986 NSFNNPAyYVLEGVP 9606 12235291 YES lperfetto Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo. 0.536 SIGNOR-92931 Skp1-Pam E3 complex SIGNOR-C537 SIGNOR ZEB1 protein P37275 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.25 SIGNOR-272186 ATIC protein P31939 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 33179964 YES miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. 0.8 SIGNOR-267329 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258821 SF3B6 protein Q9Y3B4 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 YES lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). 0.864 SIGNOR-268408 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249343 PROC protein P04070 UNIPROT F7 protein P08709 UNIPROT down-regulates activity cleavage 9606 BTO:0000131 29880919 YES lperfetto Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes 0.237 SIGNOR-263527 MET protein P08581 UNIPROT GLMN protein Q92990 UNIPROT down-regulates relocalization 9606 11571281 YES gcesareni Significantly, nonphosphorylated hgf receptor prevents fap68 from stimulating p70s6k. fap68 binding to met requires the last 30 amino acids of the c-terminal tail, which are unique to the hgf receptor. 0.331 SIGNOR-110726 PRKAB1 protein Q9Y478 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 YES gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. 0.87 SIGNOR-139164 RAD23B protein P54727 UNIPROT PAX3 protein P23760 UNIPROT down-regulates activity binding -1 17662948 YES llicata Monoubiquitinated Pax3 was shuttled to the intrinsic proteasomal protein S5a by interacting specifically with the ubiquitin-binding protein Rad23B. 0.294 SIGNOR-237667 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL -1 6772446 YES Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. 0.685 SIGNOR-253005 HTR1F protein P30939 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-256673 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR isoleucine smallmolecule CHEBI:24898 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270421 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 18073771 YES amattioni Active caspase-8 then proteolytically processes and activates caspase-7 0.741 SIGNOR-256454 THRAP3 protein Q9Y2W1 UNIPROT SFPQ protein P23246 UNIPROT down-regulates binding 9606 20932480 YES miannu Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion. 0.436 SIGNOR-168441 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RARA protein P10276 UNIPROT up-regulates activity chemical activation 9606 18321241 YES miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). 0.8 SIGNOR-259234 NUMA1 protein Q14980 UNIPROT TUBA1B protein P68363 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.263 SIGNOR-116472 GSK3B protein P49841 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 15276472 YES lperfetto Gsk3 was previously shown to directly phosphorylate the n-terminal regulatory domain of nfatc1, thus antagonizing the action of calcineurin and inhibiting nuclear shuttling of nfat. 0.56 SIGNOR-179784 A-966492 chemical CID:16666333 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-203622 AURKA protein O14965 UNIPROT MBD3 protein O95983 UNIPROT up-regulates phosphorylation Ser24 REEVPRRsGLSAGHR 9606 BTO:0000567 12354758 YES llicata These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3 0.286 SIGNOR-93693 HIF1A protein Q16665 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 9606 17415528 NO HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate 0.7 SIGNOR-256591 FGA protein P02671 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 NO lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. 0.7 SIGNOR-253372 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.394 SIGNOR-89280 propranolol chemical CHEBI:8499 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9205951 YES miannu The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. 0.8 SIGNOR-258614 EIF2AK2 protein P19525 UNIPROT KDM4C protein Q9H3R0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser918 MFDDGSFsRDTFPED 9606 BTO:0003016 31888886 YES miannu In the absence of Wnt3a, protein kinase R phosphorylated KDM4C at Ser918, inducing KDM4C ubiquitination and degradation. 0.2 SIGNOR-277497 FHIT protein P49789 UNIPROT MMP14 protein P50281 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 NO miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. 0.277 SIGNOR-159876 GSK3B protein P49841 UNIPROT MYO1C protein O00159 UNIPROT up-regulates activity phosphorylation 9606 24901984 YES miannu Here, we report that at early G1 the glycogen synthase kinase 3\u03b2 phosphorylates and stabilizes Nuclear myosin 1c, allowing for Nuclear myosin 1c association with the chromatin. 0.2 SIGNOR-279184 TUBA3D protein P0DPH8 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 NO miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. 0.7 SIGNOR-269723 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr255 DLPDMKEtKYTVDKR 9606 11152499 YES tpavlidou We previously identified four autophosphorylated amino acids and elucidated their participation in pkr activation.Replacement Of all four of these residues in pkr with alanines did not dramatically affect kinase activity in vitro or in yeast saccharomyces cerevisiae.However, when coupled with mutations of serine 242 and threonines 255 and 258 in the central region, these mutations increased pkr protein expression in mammalian cells, consistent with diminished kinase activity. 0.2 SIGNOR-85773 PTPN6 protein P29350 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity dephosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 18086677 YES Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. 0.355 SIGNOR-248477 SMO protein Q99835 UNIPROT MBP protein P02686 UNIPROT up-regulates quantity transcriptional regulation 10090 35082605 NO Non-canonical pathway (Gli1-indipendent): SMO/AMPK SimoneGraziosi We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. 0.2 SIGNOR-269226 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR USP7 protein Q93009 UNIPROT up-regulates activity phosphorylation Tyr243 NQLRKAVyMMPTEGD 24317448 YES lperfetto In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity.|The HAUSP Y243F mutant showed significantly reduced BCR-ABL-induced HAUSP phosphorylation, which in turn was completely abrogated by imatinib treatment 0.2 SIGNOR-276532 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0002035 11948419 YES miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). 0.537 SIGNOR-275982 TNF protein P01375 UNIPROT SCN11A protein Q9UI33 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.2 SIGNOR-253492 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr454 PTPPHLKyLYLVVSD 12441334 YES JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 0.811 SIGNOR-251350 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT up-regulates phosphorylation Ser342 SSRLRSCsVTDAVAE 9606 11742982 YES lperfetto Here we show by expression studies in xenopus laevis oocytes that the aldosterone-induced sgk1 kinase interacts with the ubiquitin protein ligase nedd4-2 in a py motif-dependent manner and phosphorylates nedd4-2 on ser444 and, to a lesser extent, ser338. Such phosphorylation reduces the interaction between nedd4-2 and enac, leading to elevated enac cell surface expression. 0.787 SIGNOR-113052 COL1A1 protein P02452 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates binding 9606 7688313 YES gcesareni Both a2b1- and a1b1- inegrins are implicated in chondrocyte adhesion to native collagene i and ii 0.637 SIGNOR-31787 LATS1 protein O95835 UNIPROT TAZ protein Q16635 UNIPROT down-regulates activity phosphorylation 9606 25592648 YES miannu When the inhibitory Hippo kinase module is ' on ', LATS1 and LATS2 phosphorylate and inactivate YAP and TAZ, and the output gene production is therefore turned off.|When the inhibitory Hippo kinase module is \u2018on\u2019, LATS1 and LATS2 phosphorylate and inactivate YAP and TAZ, and the output gene production is therefore turned off. 0.388 SIGNOR-279200 KIF5C protein O60282 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272518 PRKAA1 protein Q13131 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Ser121 LMRRSTVsLLDTYQK -1 23871434 YES miannu These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J). 0.2 SIGNOR-276467 OTX2 protein P32243 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20530484 NO miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. 0.351 SIGNOR-255186 VAV2 protein P52735 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.749 SIGNOR-260582 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser406 RSQSRKDsLDDSGSC 9534 BTO:0000298 9353340 YES lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  0.391 SIGNOR-248987 DICER1 protein Q9UPY3 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR form complex binding 9606 16142218 YES lperfetto Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer. 0.94 SIGNOR-140223 CLOCK protein O15516 UNIPROT PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.731 SIGNOR-253633 TGFB1 protein P01137 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates 9606 21212736 NO gcesareni Skp2, a f-box protein that determines the substrate specificity for scf ubiquitin ligase, has recently been demonstrated to be degraded by cdh1/apc in response to tgfbeta signaling. 0.258 SIGNOR-171013 cyclosporin A chemical CHEBI:4031 ChEBI PP2B proteinfamily SIGNOR-PF18 SIGNOR down-regulates chemical inhibition 9606 15276472 YES inferred from 70% of family members gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-269889 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI up-regulates quantity precursor of 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267423 MMP2 protein P08253 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Glu30 GLFDFMLeDEASGIG -1 9148753 YES miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. 0.694 SIGNOR-256349 P4HA1 protein P13674 UNIPROT HMGCS1 protein Q01581 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000192 36702290 YES miannu In this study, we found that the prolyl 4-hydroxylase (P4H) subunit P4HA1 protects NPC cells from erastin-induced ferroptosis by activating HMGCS1, a key enzyme in the mevalonate pathway. Our results show that HMGCS1 and HMGCR are regulated by P4HA subunits at the transcriptional level (Fig. S4). 0.2 SIGNOR-279853 CDKN1B protein P46527 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 8033212 NO gcesareni p27Kip1, a cyclin-dependent kinase inhibitor implicated in G1 phase arrest by TGF beta and cell-cell contact. p27Kip1 associates with cyclin E-Cdk2 complexes in vivo and in vitro, prevents their activation, and inhibits previously activated complexes, and p27Kip1 overexpression obstructs cell entry into S phase. 0.7 SIGNOR-241967 CLOCK protein O15516 UNIPROT PER3 protein P56645 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.571 SIGNOR-253635 TBX1 protein O43435 UNIPROT FLT4 protein P35916 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001176 20439995 NO Regulation of expression miannu Tbx1 plays a critical role in lymphatic vessel development and regulates the expression of Vegfr3, a gene that is essential for lymphangiogenesis. Tbx1 activates Vegfr3 transcription in endothelial cells (ECs) by binding to an enhancer element in the Vegfr3 gene. 0.307 SIGNOR-251869 LPCAT2 protein Q7L5N7 UNIPROT 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI down-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272766 LYN protein P07948 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity phosphorylation Tyr313 PSDKQRFyTNQLLDV 9606 30515152 YES miannu Lyn kinase phosphorylates IRF5 at Y313 and Y335 but this modification was dispensable as transactivation ability of the double mutant IRF5 (YY313, 335FF) was still inhibited by Lyn (116).|These data show that Lyn negatively regulates IRF5 transcriptional activity via a mechanism independent of its kinase activity and possibly via a direct interaction of Lyn with IRF5. 0.329 SIGNOR-279206 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24145166 YES miannu Here we show that RhoBTB3, a Golgi-associated, Rho-related ATPase, regulates the S/G2 transition of the cell cycle by targeting cyclin E for ubiquitylation. Depletion of RhoBTB3 arrested cells in S phase, triggered Golgi fragmentation, and elevated cyclin E levels. On the Golgi, RhoBTB3 bound cyclin E as part of a Cullin3 (CUL3)-dependent RING-E3 ubiquitin ligase complex comprised of RhoBTB3, CUL3, and RBX1. 0.502 SIGNOR-272133 PAK1 protein Q13153 UNIPROT PXN protein P49023 UNIPROT unknown phosphorylation Ser272 ELDELMAsLSDFKIQ 9606 16717130 YES llicata We show that p21-activated kinase (pak)-induced phosphorylation of serine 273 in paxillin is a critical regulator of this turnover. 0.663 SIGNOR-146842 ANXA1 protein P04083 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0004136 17464329 NO miannu We next focused on the pro-apoptotic function of ANXA1 in AML1-ETO-expressing AML cells. In this regard, FK228 was found to increase the protein levels of both the full-length and 33 kDa N-terminal cleavage products of ANXA1, which led to the localization of ANXA1 on the plasma membrane. Conversely, the inhibition of ANXA1 function (by ANXA1 neutralizing antibody, which blocked ANXA1 localization on the plasma membrane) or expression (by siRNA) significantly reduced FK228-induced apoptosis, indicating that ANXA1 is involved in apoptosis induction in response to FK228. 0.7 SIGNOR-261689 PF-03814735 chemical CID:49830590 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205956 RPS19 protein P39019 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.921 SIGNOR-262432 PCNA protein P12004 UNIPROT NCR2 protein O95944 UNIPROT down-regulates activity binding 9606 22021614 YES miannu NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. 0.307 SIGNOR-260043 NFIX protein Q14938 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.265 SIGNOR-268904 glycine smallmolecule CHEBI:15428 ChEBI Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates quantity precursor of 9606 24898252 YES miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 0.8 SIGNOR-270484 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF -1 21457715 YES Giulio Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation. 0.645 SIGNOR-260308 TRIM25 protein Q14258 UNIPROT ZFHX3 protein Q15911 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002999 22452784 YES miannu In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels. 0.451 SIGNOR-272048 CKM complex complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.383 SIGNOR-273160 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser174 LSPASSGsSASFISD 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248512 GNAI1 protein P63096 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 10090 BTO:0000944 11099498 YES These findings indicate that both G alpha(i) and G beta gamma stimulate Rac and Cdc42 pathways with lysophosphatidic acid-induced cell spreading on fibronectin 0.469 SIGNOR-256530 MAPK3 protein P27361 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 YES fstefani We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1. 0.437 SIGNOR-179812 C8A protein P07357 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 YES lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer 0.596 SIGNOR-263445 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269499 PRKCZ protein Q05513 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 16116087 YES gcesareni We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta. 0.275 SIGNOR-139914 alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI up-regulates quantity precursor of 9606 24769394 YES miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress 0.8 SIGNOR-267049 GSK3B protein P49841 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser183 SNLLQSPsSILSTLD 9606 BTO:0000567 21757741 YES miannu Here, we demonstrate that glycogen synthase kinase-3β (GSK3β) phosphorylates securin to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase. 0.2 SIGNOR-276345 AKT proteinfamily SIGNOR-PF24 SIGNOR DOCK6 protein Q96HP0 UNIPROT up-regulates activity phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 YES lperfetto Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching 0.2 SIGNOR-275667 AKT2 protein P31751 UNIPROT ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 YES miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively 0.2 SIGNOR-276192 BRK1 protein Q8WUW1 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 9606 20332100 YES miannu We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge. 0.2 SIGNOR-253574 GEM protein P55040 UNIPROT CACNB2 protein Q08289 UNIPROT down-regulates activity binding 9606 14701738 YES miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. 0.2 SIGNOR-261710 BAD protein Q92934 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002418;BTO:0002552;BTO:0000018; BTO:0002207;BTO:0002203 23725574 NO irozzo Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. 0.7 SIGNOR-256260 PGM2 protein Q96G03 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 17804405 YES miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. 0.8 SIGNOR-267076 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR PPP2R5B protein Q15173 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23135275 YES miannu Here, we report that KLHL15-Cul3 specifically targets B'β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B'β. 0.395 SIGNOR-272019 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 30552988 NO miannu Oncogenic, constitutively active mutants of FLT3 are known to be expressed in acute myeloid leukemia and to correlate with poor prognosis. Activation of the receptor mediates cell survival, cell proliferation and differentiation of cells. Several of the signal transduction pathways downstream of FLT3 have been shown to include various members of the SRC family of kinases (SFKs). They are involved in regulating the activity of RAS/ERK pathways through the scaffolding protein GAB2 and the adaptor protein SHC. 0.292 SIGNOR-260132 CSNK1D protein P48730 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates phosphorylation Ser388 RTANSEDsDEQDPEE 9606 17911614 YES gcesareni In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover. 0.2 SIGNOR-158125 C5 convertase complex complex SIGNOR-C312 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg677 KEILRPRrTLQKKIE 31331124 YES lperfetto Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b 0.557 SIGNOR-263452 STAT6 protein P42226 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 NO lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. 0.352 SIGNOR-249534 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248734 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JUND protein P17535 UNIPROT up-regulates phosphorylation 9606 22327296 YES inferred from 70% family members gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. 0.2 SIGNOR-270083 GPR174 protein Q9BXC1 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256900 EIF2AK2 protein P19525 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG 9606 20685959 YES miannu First, PKR induces phosphorylation of IRS1 at Ser312 and suppresses tyrosine phosphorylation of IRS1, mediated by the insulin receptor substrates kinases, JNK and I\u03baB kinase.|These results suggest that PKR induces the inhibitory phosphorylation of IRS1 at Ser312 in HepG2 cells, thereby suppressing the phosphorylation at Tyr941. 0.339 SIGNOR-278310 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.55 SIGNOR-270884 PSEN1 protein P49768 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates cleavage 9606 SIGNOR-C98 10593990 YES Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. gcesareni Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. 0.796 SIGNOR-72886 MC1R protein Q01726 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.346 SIGNOR-256956 MAPK14 protein Q16539 UNIPROT EWSR1 protein Q01844 UNIPROT unknown phosphorylation Thr79 QPPTGYTtPTAPQAY 9606 19076070 YES lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 . but the p38_/p38_ mapks were the major kinases phosphorylating ews-fli1. It will be important to investigate how the p38_/p38_-stimulated phosphorylation of ews-fusion proteins affects their ability to transactivate and their oncogenic potential. 0.2 SIGNOR-182778 MAPK10 protein P53779 UNIPROT ATN1 protein P54259 UNIPROT down-regulates activity phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 YES lperfetto Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment, 0.2 SIGNOR-102394 MRPL9 protein Q9BYD2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.745 SIGNOR-262343 betamethasone chemical CHEBI:3077 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 17561562 YES dermatitis gcesareni 0.8 SIGNOR-251686 CH5132799 chemical CID:49784945 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190937 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258794 GSK3A protein P49840 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser280 FHCCQCTsVETVTEL 9606 30745182 YES miannu GSK-3alpha phosphorylates PPARalpha at Ser280, located in the ligand binding domain.|These results suggest that GSK-3alpha positively regulates PPARalpha activity through Ser280 phosphorylation. 0.2 SIGNOR-278515 DCC protein P43146 UNIPROT CACNA1A protein O00555 UNIPROT up-regulates activity 9606 12827203 YES miannu DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER. 0.2 SIGNOR-268293 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 YES miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. 0.8 SIGNOR-262252 PCM1 protein Q15154 UNIPROT NEK2 protein P51955 UNIPROT up-regulates relocalization 9606 15659651 YES miannu Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1 0.423 SIGNOR-133337 MAS1 protein P04201 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 23488800 NO miannu The discovery that Ang-(1-7) offsets the major biological effects of Ang II has contributed to the realization that the RAS is composed of two opposing axes. The first axis is constituted by the enzyme ACE, with Ang II as the end product, and the AT1 receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to production of Ang-(1-7), with Mas receptor as the main effector conveying the vasodilator, antiproliferative, anti-inflammatory and anti-fibrotic effects of Ang-(1-7). Activation of the ACE2/Ang-(1-7)/Mas axis decreases inflammatory cell function and fibrogenesis in diverse models of human diseases. 0.7 SIGNOR-260228 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser2624 QTRTQEGsLSARWPV -1 12186630 YES lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. 0.2 SIGNOR-249156 PRKACA protein P17612 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 9660950 YES lperfetto The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka). 0.511 SIGNOR-217364 MAPK8 protein P45983 UNIPROT JUNB protein P17275 UNIPROT up-regulates activity phosphorylation Thr104 GVITTTPtPPGQYFY 10090 9889198 YES miannu JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. 0.719 SIGNOR-250121 Ub:E2 complex SIGNOR-C497 SIGNOR DZIP3 protein Q86Y13 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271191 PPP2R1A protein P30153 UNIPROT MAPT protein P10636 UNIPROT down-regulates dephosphorylation 9606 15525651 YES gcesareni Galpha12 directly interacts with pp2a: evidence for galpha12-stimulated pp2a phosphatase activity and dephosphorylation of microtubule-associated protein, tau. 0.2 SIGNOR-130136 HIPK2 protein Q9H2X6 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser38 EGRQPSPsPSPTERA 9606 19015637 YES llicata In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death. 0.439 SIGNOR-182428 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 YES gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. 0.641 SIGNOR-139473 MEF2C protein Q06413 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 9418854 YES lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. 0.742 SIGNOR-54089 NFYA protein P23511 UNIPROT PHGDH protein O43175 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18378410 NO miannu Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. 0.2 SIGNOR-255209 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT down-regulates activity binding 9606 BTO:0000567 9099724 YES 2 miannu Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function. 0.421 SIGNOR-240915 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates binding 9606 23400686 YES gcesareni Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1. 0.2 SIGNOR-200875 KIF3A protein Q9Y496 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272538 NF1 protein P21359 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates 9606 BTO:0000938 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.399 SIGNOR-267846 TP53 protein P04637 UNIPROT GMPS protein P49915 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599;BTO:0003477;BTO:0001670 27939741 YES miannu Herein, we identified GMP synthetase (GMPS), a key enzyme of de novo purine biosynthesis, as an important p53 repression target using a large-scale proteomics approach. This p53-mediated repression of GMPS could be validated by immunoblotting in Sk-Hep1, HepG2, and HuH6 cells. 0.379 SIGNOR-267342 AKT proteinfamily SIGNOR-PF24 SIGNOR YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 YES lperfetto Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102 0.2 SIGNOR-182493 SMAD3 protein P84022 UNIPROT PAX6 protein P26367 UNIPROT down-regulates activity binding 9606 BTO:0001874 17251190 YES Regulation miannu The paired domain of Pax6 interacts with the MH1 domain of Smad3. Smad3 prevents Pax6 paired domain from binding DNA 0.4 SIGNOR-251875 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR NFKBIB protein Q15653 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0004055 10514424 YES miannu Interaction with beta-TrCP is also necessary for ubiquitination of IkappaBbeta upon stimulation of cells, and deletion of the F-box in beta-TrCP abolishes its ability to ubiquitinate IkappaBbeta. Therefore, these results indicate that beta-TrCP plays a critical role in the activation of NF-kappaB by assembling the ubiquitin ligase complex for both phosphorylated IkappaBalpha and IkappaBbeta.β-TrCP recognizes IκBα phosphorylated at Ser-32 and Ser-36 through its WD40 domain, whereas the F-box motif recruits additional proteins including Skp1 and Cullin to form the Skp1-cullin-F-box (SCF) ubiquitin ligase complex 0.467 SIGNOR-272556 NHLRC1 protein Q6VVB1 UNIPROT PPP1R3B protein Q86XI6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18029386 YES miannu Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. We show here that laforin and malin play a crucial role in the regulation of glycogen biosynthesis in FTO2B hepatoma cells. In these cells, the laforin–malin complex counteracts the glycogenic effect of PTG because it promotes its ubiquitination and degradation. 0.399 SIGNOR-271728 CLK4 protein Q9HAZ1 UNIPROT MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr360 ILKASVDyIRKLQRE 9606 BTO:0002427 35092699 YES done miannu Mechanistically, wild type CLK4 (WT-CLK4) but not kinase-dead CLK4-K189R mutant phosphorylated MITF at Y360. This modification promoted its interaction with E3 ligase COP1 and its K63-linked ubiquitination at K308/K372, leading to sequestosome 1 recognition and autophagic degradation.  0.2 SIGNOR-274116 CFAP53 protein Q96M91 UNIPROT DNAH11 protein Q96DT5 UNIPROT up-regulates activity binding 10090 BTO:0000379 33347437 YES miannu CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). 0.2 SIGNOR-265545 CD38 protein P28907 UNIPROT cyclic ADP-ribose smallmolecule CHEBI:31445 ChEBI up-regulates quantity chemical modification 9606 18626062 YES miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. 0.8 SIGNOR-264244 FOXO3 protein O43524 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates activity 9606 BTO:0000007 22931788 NO AMPK signaling Gianni Forkhead box O (FOXO) transcriptional protein family members, including FOXO1 and FOXO3, are involved in the modulation of autophagy. However, whether there is redundancy between FOXO1 and FOXO3 in the ability to induce autophagy remains unclear. In this study, we showed that FOXO3 induced a transcription-dependent autophagy, and FOXO1 was required for this process. 0.7 SIGNOR-261952 PEX2 protein P28328 UNIPROT PEX5 protein P50542 UNIPROT down-regulates quantity by destabilization ubiquitination -1 19687296 YES miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 0.58 SIGNOR-253021 SYK protein P43405 UNIPROT PIP5K1B protein O14986 UNIPROT down-regulates activity phosphorylation Tyr105 FGIKPDDyLYSICSE 9534 BTO:0004055 19553680 YES miannu We identified spleen tyrosine kinase (Syk), which is activated by oxidants, as a candidate PIP5Kbeta kinase in this pathway, and mapped the oxidant-sensitive tyrosine phosphorylation site to residue 105. The PIP5KbetaY105E phosphomimetic is catalytically inactive and cytosolic, whereas the Y105F non-phosphorylatable mutant has higher intrinsic lipid kinase activity and is much more membrane associated than wild type PIP5Kbeta.  0.2 SIGNOR-276227 AURKA protein O14965 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 19060929 YES miannu The recombinant human AURKA protein phosphorylated the GSK-3beta protein at Ser 9 in a concentration-dependent manner, in vitro. 0.558 SIGNOR-279357 PLK1 protein P53350 UNIPROT KIF2A protein O00139 UNIPROT up-regulates activity phosphorylation Thr554 ANRVKELtVDPTAAG 9606 25660017 YES miannu Taken together, KIF2A is phosphorylated at T554 by PLK1 in the subdistal appendages of the mother centriole, which enhances MT depolymerization to disassemble primary cilia in a growth-signal-dependent manner.|Thus, PLK1 and APC/C mediated dual regulation connect the MT depolymerizing activity of KIF2A to a physiological primary cilia disassembly during the proliferative phase. 0.683 SIGNOR-278380 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763 12193595 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-91730 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS2 protein Q9NRM7 UNIPROT down-regulates 10090 BTO:0002572 22863277 NO milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. 0.8 SIGNOR-198520 JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 8977526 YES irozzo JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation. 0.584 SIGNOR-256001 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser337 DPRGRLRsADSENAL 9534 BTO:0001538 12392720 YES miannu It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3. 0.2 SIGNOR-250005 CSNK2A1 protein P68400 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Thr231 ALKEEPQtVPEMPGE 9606 1516134 YES lperfetto Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii). 0.591 SIGNOR-19607 arformoterol chemical CHEBI:408174 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation -1 20655218 YES Luana Table 1. Human β2- and β1-adrenoceptor binding and calculated log D7.4 values for formoterol, indacaterol, salmeterol, S1319 and the representative library members 11–41 0.8 SIGNOR-257881 HIC1 protein Q14526 UNIPROT VLDLR protein P98155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001938;BTO:0000815 24076391 NO miannu The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1. ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. 0.2 SIGNOR-254244 MAPK3 protein P27361 UNIPROT CAPN2 protein P17655 UNIPROT up-regulates phosphorylation Ser50 GTLFQDPsFPAIPSA 9606 14993287 YES lperfetto Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo. 0.564 SIGNOR-123083 ABL1 protein P00519 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276187 PRKD2 protein Q9BZL6 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 21525957 YES gcesareni Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1. 0.291 SIGNOR-173441 LCK protein P06239 UNIPROT CD3G protein P09693 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000782 2470098 YES Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. 0.559 SIGNOR-259931 PRKCZ protein Q05513 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.371 SIGNOR-249284 ABL1 protein P00519 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr352 TEVYESPyADPEEIR 9606 23100514 YES miannu Abl kinases modulate Syk kinase activation.|Expression of constitutively active Abl (AblPP) increased Syk Y346 phosphorylation, whereas the phosphorylation was unaffected in cells expressing kinase inactive form of Abl (AblKR) (XREF_FIG). 0.253 SIGNOR-279665 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 0.2 SIGNOR-260127 TRIM25 protein Q14258 UNIPROT GPI protein P06744 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 24810856 YES miannu Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. 0.25 SIGNOR-272178 CARS1 protein P49589 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 11347887 YES miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. 0.8 SIGNOR-270471 CDKN2A protein P42771 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 10648628 NO Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics 0.7 SIGNOR-259286 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser99 PFRGRSRsAPPNLWA -1 10195903 YES lperfetto Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.| Bcl-xL did not coimmunoprecipitate with BAD(S75E, S99E) protein (Fig. 2A), regardless of whether it was coexpressed with DCnA/B¬† 0.47 SIGNOR-263740 GDNF protein P39905 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.266 SIGNOR-252188 PYY protein P10082 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 7592911 YES gcesareni Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid. 0.668 SIGNOR-29767 STUB1 protein Q9UNE7 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12239347 YES miannu We now show that the chaperone-binding ubiquitin ligase CHIP efficiently ubiquitinates and down-regulates ErbB2. CHIP expression shortens the half-life of both nascent and mature ErbB2 protein. In vitro ubiquitination assay shows that CHIP serves as a ubiquitin ligase for ErbB2, and both exogenously expressed and endogenous CHIP coprecipitate with the kinase.  0.626 SIGNOR-272586 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity 9606 23151663 NO gcesareni Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization. 0.659 SIGNOR-199539 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263814 CDK5 protein Q00535 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates activity phosphorylation Thr1152 LDEEGYMtPMRDKPK 9606 24142862 YES miannu Cdk5 Promotes ErbB4 and PI3-Kinase Activity In Vivo.|Cdk5 phosphorylates ErbB4 at T1152, situated in close proximity to the PI3-kinase-binding site (Y1056), and in turn promotes ErbB4 tyrosine phosphorylation. 0.278 SIGNOR-278436 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 BTO:0000038 11279024 YES lperfetto beta-catenin is a good substrate of pp60c- srctyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation. 0.76 SIGNOR-106458 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2T protein Q9NPD8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.694 SIGNOR-271316 MEF2C protein Q06413 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.383 SIGNOR-238754 CSNK1A1L protein Q8N752 UNIPROT GLIS2 protein Q9BZE0 UNIPROT up-regulates 9606 17289029 NO gcesareni We decided to focus on the interaction between _-catenin and glis2. the critical role of the first zinc finger motif was confirmed by the observation that a point mutation in the first zinc finger motif, that destroys its tetrahedral configuration, abolished the interaction. _-catenin contains several functional domains, the amino terminus interacts with gsk3_ and casein kinase i_ (ck1) binding sites while its 12 armadillo repeats provides an interface for tcf/lefs, the co-activator cbp, and several other proteins 0.2 SIGNOR-152962 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr666 GWMEDYDyVHLQGKE 9606 11604500 YES lperfetto The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding. 0.802 SIGNOR-111060 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 YES Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. 0.636 SIGNOR-248412 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM22 protein Q8IYM9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271080 PPP1R1B protein Q9UD71 UNIPROT PPP1CB protein P62140 UNIPROT down-regulates activity binding 9606 BTO:0000938 10604473 YES miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚  0.444 SIGNOR-264959 MAP4K4 protein O95819 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity phosphorylation Thr1061 KMDWIFHtIKQHALN -1 38060450 YES miannu MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061  0.2 SIGNOR-277921 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 10318843 YES lperfetto Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation 0.618 SIGNOR-67443 TFE3 protein P19532 UNIPROT CLCN3 protein P51790 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.2 SIGNOR-276813 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 YES lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity 0.757 SIGNOR-232138 SIRT1 protein Q96EB6 UNIPROT TP53 protein P04637 UNIPROT down-regulates deacetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0000150 19047049 YES gcesareni Sirt1 has been shown to regulate cell fate in part by deacetylating the p53 protein at lysine 382 and inhibiting p53-mediated transcriptional activation and apoptosis. 0.803 SIGNOR-182515 SMC6 protein Q96SB8 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 YES miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks 0.9 SIGNOR-265482 SENP1 protein Q9P0U3 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization desumoylation Lys276 NVVYRDLkLENLMLD 10090 BTO:0002572 23884910 YES gcesareni Although multiple sites on Akt could be SUMOylated, K276 was identified as a major SUMO acceptor site. K276R or E278A mutation reduced SUMOylation of Akt but had little effect on its ubiquitination. Strikingly, these mutations also completely abolished Akt kinase activity. In support of these results, we found that expression of PIAS1 and SUMO1 increased Akt activity, whereas expression of SENP1 reduced Akt1 activity. 0.28 SIGNOR-252736 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192871 CDK5 protein Q00535 UNIPROT VIM protein P08670 UNIPROT up-regulates activity phosphorylation Ser56 SRSLYASsPGGVYAT 9606 21465480 YES miannu Cdk5 mediates vimentin Ser56 phosphorylation during GTP-induced secretion by neutrophils. 0.27 SIGNOR-278922 CDK7 protein P50613 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Ser159 GIPVRCYsAEVVTLW 9606 14586172 YES miannu In addition, the Cdk7 substrate, CTD of RNAPII, causes a dose-dependent decline in Cdk5 activation by Cdk7.|Likewise, Cdk7 or cyclin H immunoprecipitate from mouse brain specifically phosphorylates wt Cdk5 at Ser159 and enhances Cdk5 and p25 activity. 0.516 SIGNOR-278923 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.361 SIGNOR-273165 DYRK1A protein Q13627 UNIPROT IRS1 protein P35568 UNIPROT up-regulates quantity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 31723029 YES miannu DYRK1A interacts with IRS-1 and phosphorylates IRS-1 at Ser-312 and Ser-616.|We found that DYRK1A overexpression up-regulated IRS-1 expression by slowing the turnover of IRS-1 protein. 0.2 SIGNOR-279521 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001109 phosphorylation:Thr286 EEVDLACtPTDVRDV 17205132 YES miannu FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1. We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8. 0.539 SIGNOR-271634 RPL22L1 protein Q6P5R6 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.737 SIGNOR-262498 GSK3B protein P49841 UNIPROT OGT protein O15294 UNIPROT up-regulates activity phosphorylation 9606 23395175 YES miannu But OGT activity is modulated by GSK3beta (XREF_FIG) and GSK3beta activity is known to oscillate through Ser9 phoshorylation.|Here, we found that OGT is phosphorylated at serines 3 or 4 by GSK3beta and that O GlcNAcylation of OGT also occurs on the same or neighboring serine residues, suggesting interacting phosphorylation and O GlcNAcylation events on OGT itself. 0.516 SIGNOR-279528 MAPKAPK2 protein P49137 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates phosphorylation Thr366 FTVYRNRtLQKWHDK 9606 22909821 YES lperfetto Upon genotoxic stress, aatf is phosphorylated by the checkpoint kinase mk2. Phosphorylation results in the release of aatf from cytoplasmic mrlc3 and subsequent nuclear translocation where aatf binds to the puma, bax and bak promoter regions to repress p53-driven expression of these pro-apoptotic genes. 0.327 SIGNOR-191935 PRKCZ protein Q05513 UNIPROT AQP9 protein O43315 UNIPROT up-regulates phosphorylation Ser11 EGAEKGKsFKQRLVL 9606 21873454 YES lperfetto Wt-pkc_-mediated phosphorylation of wt aqp9 in vitro. In the experiments, substitution of ser11 to ala markedly inhibited phosphorylation. the s11a mutation in fibroblasts caused a smoother cell periphery with fewer aqp9-induced filopodia 0.2 SIGNOR-176278 ARAP2 protein Q8WZ64 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.512 SIGNOR-260453 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP -1 16481012 YES miannu Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.  0.834 SIGNOR-276053 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 NO PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype. 0.7 SIGNOR-254373 GPR34 protein Q9UPC5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256967 HERC1 protein Q15751 UNIPROT PSMC5 protein P62195 UNIPROT down-regulates quantity ubiquitination 9606 34446601 YES miannu HERC1 interacts with and ubiquitinates nascent PSMC5.|PSMC5 produced in the absence of PAAF1 is presumably misfolded (consistent with its aggregation in the PURE system), triggering PSMC5 degradation by a HERC1-independent pathway. 0.2 SIGNOR-278812 MIIP protein Q5JXC2 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity binding 9606 BTO:0001109 29038521 YES done miannu Here, we show that EGF stimulation induces PKCε-dependent phosphorylation of migration and invasion inhibitory protein (MIIP) at Ser303; this phosphorylation promotes the interaction between MIIP and RelA in the nucleus, by which MIIP prevents histone deacetylase 6 (HDAC6)-mediated RelA deacetylation, and thus enhances transcriptional activity of RelA and facilitates tumor metastasis.  0.2 SIGNOR-273829 SNRPF protein P62306 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.705 SIGNOR-270658 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 YES gcesareni Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation. 0.355 SIGNOR-88724 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr1108 TYVNTTLyEKFTYAG 9606 BTO:0001176 20973951 YES miannu This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor. 0.2 SIGNOR-259833 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Ser547 TMRKSQRsSKGSEIL -1 21642394 YES miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. 0.2 SIGNOR-276332 ADRB3 protein P13945 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.447 SIGNOR-256896 DUSP4 protein Q13115 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 9020184 YES lperfetto Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2 0.713 SIGNOR-27756 AKT1 protein P31749 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 10559253 YES esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. 0.56 SIGNOR-252587 ADAM17 protein P78536 UNIPROT MUC1 protein P15941 UNIPROT down-regulates cleavage 9606 12441351 YES gcesareni These characteristics along with studies conducted with cell lines genetically deficient in various adams (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (tace)/adam 17 as a muc1 sheddase. 0.308 SIGNOR-95630 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Tyr221 HQYFMTEyVATRWYR 9606 BTO:0000567 20667468 YES miannu ERK5 is a member of the mitogen-activated protein kinase (MAPK) family that, after stimulation, is activated selectively by dual phosphorylation in the TEY motif by MAPK kinase 5 (MEK5). ERK5 is activated selectively by dual phosphorylation on Thr218 and Tyr220 in the TEY motif by its only upstream kinase, MEK5, a member of the MEK 0.702 SIGNOR-259825 CCKBR protein P32239 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.274 SIGNOR-257037 HCK protein P08631 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC -1 12244095 YES Activation of STAT3 by the Src family kinase Hck requires a functional SH3 domain. Direct Phosphorylation of STAT3 on Tyr-705 by Src Family Kinases 0.617 SIGNOR-251267 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF8 protein Q5T0T0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271098 ABL1 protein P00519 UNIPROT GMFG protein O60234 UNIPROT down-regulates activity phosphorylation Tyr104 KPEQQMMyAGSKNRL 9606 BTO:0001660 24818551 YES miannu Acetylcholine stimulation also increased GMF-γ phosphorylation at Tyr-104. GMF-γ phosphorylation at this residue was mediated by c-Abl tyrosine kinase. The GMF-γ mutant Y104F (phenylalanine substitution at Tyr-104) had higher association with Arp2 in HASM cells upon contractile activation.Furthermore, expression of mutant Y104F GMF-γ attenuated actin polymerization and contraction in smooth muscle. 0.2 SIGNOR-273536 MAPK14 protein Q16539 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 15879307 YES gcesareni Conversely, constitutively active mkk6 induced p38 mapk activation that recapitulated the effects of polyphenols by inducing eralpha phosphorylation and downstream activation of akt, and enos. The key role of eralpha ser-118 phosphorylation was confirmed in enos-transfected cos-7 cells 0.624 SIGNOR-136950 TAB2 protein Q9NYJ8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. 0.575 SIGNOR-205446 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT up-regulates activity phosphorylation Ser204 HLDSSKIsVLEPPQE 9606 22535524 YES lperfetto We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors. 0.659 SIGNOR-252050 IL1RL1 protein Q01638 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 YES miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  0.593 SIGNOR-277707 FOXO3 protein O43524 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12913110 NO lperfetto In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. 0.77 SIGNOR-209657 SKP1 protein P63208 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR form complex binding 9606 BTO:0000007 16547521 YES miannu KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation. 0.903 SIGNOR-271620 NFE2L2 protein Q16236 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000599 26194347 NO irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. 0.7 SIGNOR-259285 ACTL6B protein O94805 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.693 SIGNOR-270600 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR EIF4B protein P23588 UNIPROT up-regulates activity phosphorylation Ser422 RERSRTGsESSQTGT 9606 BTO:0001109 36882522 YES lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. 0.276 SIGNOR-273116 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 BTO:0000661 8960373 YES lperfetto Functional analysis of phosphorylation at serine 532 of human c-myb by map kinase. expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. Our data suggest that the mapk-dependent state of phosphorylation modifies the cellular function of c-myb by modulating its interaction with a putative inhibitory factor 0.2 SIGNOR-244569 MRPL24 protein Q96A35 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.721 SIGNOR-262369 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 10090 BTO:0002883 11684015 YES gcesareni Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance 0.772 SIGNOR-247599 HIF1A protein Q16665 UNIPROT KDM3A protein Q9Y4C1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.416 SIGNOR-271568 KAT2A protein Q92830 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269595 CDK5 protein Q00535 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Ser10 NVRVSNGsPSLERMD 9606 26146988 YES miannu CDK5 knockdown in HEY cells significantly prolonged the half-life of TP53 and p27 Kip1 proteins (XREF_FIG).|During neural stem cell differentiation, CDK5 can phosphorylate p27 at Thr187 and at Ser10, promoting neurite outgrowth as neurons differentiate . 0.645 SIGNOR-279681 GFPT1 protein Q06210 UNIPROT D-fructofuranose 6-phosphate(2-) smallmolecule CHEBI:61527 ChEBI down-regulates quantity chemical modification 9606 21310273 YES miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans 0.8 SIGNOR-267815 CLIP1 protein P30622 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates binding 17889670 YES lperfetto Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170) 0.7 SIGNOR-264832 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 BTO:0000782 15280374 YES gcesareni Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2. 0.296 SIGNOR-127198 MAPK1 protein P28482 UNIPROT TTN protein Q8WZ42 UNIPROT up-regulates quantity phosphorylation 9606 26682816 YES miannu ERK2 phosphorylates three serines in titin\u2019s N2B-Us: S3918, S3960, and S4010 (the latter of which is well conserved) (). 0.387 SIGNOR-279636 Crenolanib chemical CID:10366136 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191121 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12950161 YES lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases 0.404 SIGNOR-86585 NLGN4X protein Q8N0W4 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 YES brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. 0.754 SIGNOR-264192 MAPKAPK3 protein Q16644 UNIPROT HSPB1 protein P04792 UNIPROT unknown phosphorylation Ser78 PAYSRALsRQLSSGV -1 8774846 YES miannu MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15) 0.684 SIGNOR-250160 PRKAA2 protein P54646 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0000876 21673972 YES lperfetto These results demonstrate that the ikk is a direct substrate of ampk_2 and that its phosphorylation on ser177 and ser181no initiates the activation of the ampk_2 in endothelial cells which in turn phosphorylates and activates the _-subunit of the ikk. The latter also induces a higher rate of ikk auto-inactivation and thus attenuates the activation of nf_b and the expression of inflammatory genes 0.256 SIGNOR-217457 CAMK2A protein Q9UQM7 UNIPROT ATP2A2 protein P16615 UNIPROT up-regulates activity phosphorylation Ser38 KLKERWGsNELPAEE 9606 BTO:0000007 7929371 YES llicata SERCA2 and SERCA2 mutants S38A, S167A, and S531A were expressed in HEK-293 cells and tested for phosphorylation with CaM kinase. Mutant S38A was not phosphorylated, while mutants S167A and S531A were phosphorylated, suggesting that Ser38 is the site of CaM kinase phosphorylation in SERCA2. This conclusion was supported by the observation that phosphorylation of SERCA2 and mutants S167A and S531A by CaM kinase increased the Vmax for Ca2+ transport, while the Vmax for Ca2+ transport by mutant S38A was unaffected by exposure to a phosphorylation reaction mix. 0.398 SIGNOR-250616 CCT2 protein P78371 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.759 SIGNOR-272860 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Ser357 REFCIPTsSNIEQQN 9606 12123746 YES GRK2-mediated phosphorylation is involved in the development of agonist-induced μ-opioid receptor desensitization. two C-terminal amino acids, Ser355 and Thr357, are required for short-term homologous desensitization of μ-opioid receptors expressed in HEK 293 cells. 0.2 SIGNOR-251458 STK38L protein Q9Y2H1 UNIPROT FLNA protein P21333 UNIPROT up-regulates activity phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 30568657 YES miannu Activated Ndr2 Promotes FLNa Release From LFA-1.|Taken together the data depicted in Figures xref and xref indicate that Ndr2 phosphorylates FLNa at S2152 both in vitro and in vivo . 0.2 SIGNOR-278501 CDK5 protein Q00535 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 26146988 YES miannu CDK5 knockdown in HEY cells significantly prolonged the half-life of TP53 and p27 Kip1 proteins (XREF_FIG).|During neural stem cell differentiation, CDK5 can phosphorylate p27 at Thr187 and at Ser10, promoting neurite outgrowth as neurons differentiate [ xref ]. 0.645 SIGNOR-279680 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR GEN1 protein Q17RS7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31409866 YES miannu (WDR23) isoforms differentially ubiquitinate (GEN1). In the presence of the necessary components for a successful ubiquitination reaction (CUL4A-DDB1-WDR23 complex, UBE1, UBE2D1, ubiquitin, and ATP) GEN1 receives the addition of ubiquitin in a time dependent manner. 0.287 SIGNOR-272263 CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 7557387 YES Andrea Cerquone Perpetuini  Induction of C/EBP beta DNA-binding activity in NIH-3T3 beta 2 cells exposed to dexamethasone in the presence of insulin and fetal bovine serum activates the expression of an adipocyte-specific nuclear hormone receptor, PPAR gamma, that stimulates the conversion of these fibroblasts into committed preadipocytes 0.728 SIGNOR-255730 IL15 protein P40933 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 YES gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex. 0.853 SIGNOR-108815 H2AC4 protein P04908 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR form complex binding -1 23324462 YES miannu In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro. 0.2 SIGNOR-263700 IL15 protein P40933 UNIPROT IL15RA protein Q13261 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 YES Interleukin-15 specificity and high affinity binding are conferred by the IL-5-specific but nonsignaling IL-15R alpha subunit, which is structurally similar (but not homologous) to the alpha receptor subunit of IL-2 0.868 SIGNOR-157415 PRKACA protein P17612 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT down-regulates phosphorylation Ser557 SGKFRRGsGSACSLL 9606 17988215 YES llicata The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1. 0.2 SIGNOR-158946 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser287 EPLSPVSsLQASVPG -1 16027724 YES GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) 0.381 SIGNOR-251228 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR BTRC protein Q9Y297 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002419 31406304 YES miannu Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1.  0.798 SIGNOR-277477 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.34 SIGNOR-273145 MAS1 protein P04201 UNIPROT FLNA protein P21333 UNIPROT up-regulates activity binding 9606 26460884 YES miannu We further determined that GPCRs, AT1R, and MAS directly recruited FLNa and promoted its phosphorylation by cellular S/T kinases in an agonist-dependent manner. Our studies thus provide a structural framework for filamin in GPCR signaling, potentially regulating a variety of cellular responses. MAS likely binds filamin constitutively and hence leads to constitutive filamin phosphorylation. These results emphasize that it is the active receptor that mediates filamin phosphorylation by PKA or other cellular S/T kinases 0.2 SIGNOR-260627 CDK7 protein P50613 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 21157430 YES acerquone Here, we show that the transcription factor tfiih, via its cdk7 kinase, phosphorylates the androgen receptor (ar) at position ar/s515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the mdm2 e3 ligase, the subsequent ubiquitination of ar at the promoter of target genes and its degradation by the proteasome machinery 0.377 SIGNOR-170599 TNF protein P01375 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004914 22190977 NO Exposure of RA FLSs to TNF-α (10 ng/ml) led to increase of Hes-1, a target gene of Notch signaling, and a marked upregulation of Notch 2, Delta-like 1, and Delta-like 3 mRNA levels. 0.2 SIGNOR-253605 CHKA protein P35790 UNIPROT VANGL2 protein Q9ULK5 UNIPROT down-regulates activity phosphorylation 9606 31090542 YES miannu CKI\u03b5-dependent phosphorylation increases Stbm turnover at junctions, and thus promotes complex sorting, while phosphorylation of Dsh decreases its turnover.|Interestingly, CKI\u03b5 has been implicated in phosphorylation of both Stbm and Dsh. 0.2 SIGNOR-278925 CHUK protein O15111 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates activity phosphorylation Ser90 SPMPATLsPSTIPQL 9606 17540171 YES miannu In addition, we show that IKKalpha is associated with PIAS1 and mediates the S90 phosphorylation of PIAS1.|Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription. 0.381 SIGNOR-278926 CSNK1E protein P49674 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1420 YVVHGPAsVPLGYVP 9606 16513652 YES gcesareni We find that ckiepsilon binds to lrp5 and lrp6 in vitro and in vivo and identify three ckiepsilon-specific phosphorylation sites in lrp6. Two of the identified phosphorylation sites, ser1420 and ser1430, influence wnt signaling in vivo, 0.262 SIGNOR-145049 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI up-regulates quantity precursor of 9606 34775382 YES miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. 0.8 SIGNOR-267059 AGTR1 protein P30556 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.488 SIGNOR-257133 IRX1 protein P78414 UNIPROT BPI protein P17213 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.2 SIGNOR-261652 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB5 protein P18084 UNIPROT up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.2 SIGNOR-259005 NEDD4 protein P46934 UNIPROT SQSTM1 protein Q13501 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28085563 YES miannu Depletion of NEDD4 dramatically reduced the LC3 protein level and elevated the SQSTM1 protein level.|Furthermore, SQSTM1 is ubiquitinated by NEDD4 while LC3 functions as an activator of NEDD4 ligase activity. 0.277 SIGNOR-278637 P2RY11 protein Q96G91 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257060 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193612 CDK1 protein P06493 UNIPROT PTPN2 protein P17706 UNIPROT unknown phosphorylation Ser304 LSPAFDHsPNKIMTE 9606 15030318 YES llicata Our studies identify ser-304 as a major phosphorylation site in human tcptp, and the tc45 variant as a novel mitotic cdk substrate. 0.351 SIGNOR-123467 ALK protein Q9UM73 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 YES lperfetto Two phosphorylation sites on Grb2 have been identified thus far at position Tyr209 in BCR-ABL-expressing cells (16) and Tyr160 by pp60c-src (18)Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation. 0.467 SIGNOR-247142 CHEK1 protein O14757 UNIPROT RHOB protein P62745 UNIPROT up-regulates activity phosphorylation Thr173 GVREVFEtATRAALQ 9606 30297842 YES miannuccelli We identified that Thr173 and Thr175 of RhoB was phosphorylated by Chk1 using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) (Supplementary Fig.\u00a06f). 0.328 SIGNOR-279727 MYC protein P01106 UNIPROT DKK1 protein O94907 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17485441 NO gcesareni C-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity 0.387 SIGNOR-245355 KLF4 protein O43474 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000801 22378047 NO miannu KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPARγ) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-κB activation. 0.332 SIGNOR-254520 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 YES inferred from 70% family members gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3. 0.2 SIGNOR-270142 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-209986 VPS33B protein Q9H267 UNIPROT CHEVI complex complex SIGNOR-C269 SIGNOR form complex binding 9606 BTO:0000007 29778605 YES lperfetto It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named "CHEVI") 0.758 SIGNOR-261830 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR DPPA4 protein Q7L190 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.606 SIGNOR-269235 Sound_vibration stimulus SIGNOR-ST27 SIGNOR TIP-LINK complex complex SIGNOR-C291 SIGNOR up-regulates 10090 BTO:0000630 23217710 NO lperfetto Sound induced vibrations or motion lead to deflection of the stereociliary bundles, which directly control the activity of the mechanotransduction channels in stereocilia. It is thought that tip links, fine extracellular filaments that connect the tips of neighboring stereocilia, transmit tension force onto the transduction channels 0.7 SIGNOR-262581 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 16146838 YES lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. 0.376 SIGNOR-249621 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser65 PCSSVPSsPSFCAPS 9606 BTO:0000567 11416124 YES miannu In the present study, we provide the first evidence that MafA is phosphorylated and that its biological properties strongly rely upon phosphorylation of serines 14 and 65, two residues located in the transcriptional activating domain within a consensus for phosphorylation by mitogen-activated protein kinases and which are conserved among Maf proteins. These residues are phosphorylated by ERK2 but not by p38, JNK, and ERK5 in vitro.  0.335 SIGNOR-275977 CSNK2A1 protein P68400 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates phosphorylation Ser122 RIQEQESsGEEDSDL 9606 9405437 YES gcesareni Recombinant inh2 was phosphorylated by kinases in cytosols prepared from g1 and s phase cells. The amount of inh2 kinase attributed to casein kinase 2, based on inhibition by heparin, increased 2.6-fold from g1 to s phase 0.307 SIGNOR-53861 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity dephosphorylation Tyr319 TSVYESPySDPEELK -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.261 SIGNOR-254734 TTC36 protein A6NLP5 UNIPROT HPD protein P32754 UNIPROT up-regulates quantity by stabilization binding 10090 BTO:0003036 31537781 YES lperfetto Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. 0.27 SIGNOR-272960 DDC protein P20711 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity chemical modification 7955 23940784 YES brain lperfetto AADC is responsible for the decarboxylation step in the catecholamine and dopamine biosynthesis. Dopamine and serotonin can be synthesized by AADC from L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively [7]. A deficiency in AADC will lead to reduced biogenic monoamines, including dopamine, norepinephrine, epinephrine, and serotonin 0.8 SIGNOR-263986 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser397 EQKFRMLsQDAPTVK 9606 10839545 YES lperfetto We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. 0.855 SIGNOR-78030 CSNK2A1 protein P68400 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000661 15818404 YES lperfetto Akt/pkb ser129 is phosphorylated by ck2 in vitro and in vivo;(4) such a phosphorylation of activated akt/pkb correlates with a further increase in catalytic activity. 0.372 SIGNOR-244400 IPO5 protein O00410 UNIPROT DSCAML1 protein Q8TD84 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 30745319 YES miannu DSCAM and DSCAML1 specifically interacted with the importin beta IPO5, whereas deletion of the identified NLSs abolished this specific interaction and suppressed nuclear translocation of the DSCAM/L1 ICDs in cell lines and cultured neurons. This suggests a direct role of IPO5 in the nuclear import of the DSCAM/L1 ICDs. 0.2 SIGNOR-264274 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HSD11B2 protein P80365 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15659537 NO miannu Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50. 0.2 SIGNOR-253877 MIB1 protein Q86YT6 UNIPROT DLL4 protein Q9NR61 UNIPROT up-regulates activity ubiquitination 9606 16140393 YES lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. 0.551 SIGNOR-209626 BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates activity binding 9534 SIGNOR-C29 7791754 YES lperfetto Under our assay conditions, bmp-2 binds better to bmpr-ii in combination with actr-i or bmpr-ib than in combination with bmpr-ia 0.799 SIGNOR-144101 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267905 BCL3 protein P20749 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates binding 9606 15469820 YES gcesareni We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, 3 and 6. 0.349 SIGNOR-129804 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT down-regulates activity phosphorylation Ser314 DLEESSSsDHAERPP 10029 BTO:0000246 7876239 YES The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization. 0.2 SIGNOR-251443 Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity chemical modification 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. 0.8 SIGNOR-266277 3C-like proteinase protein P0C6X7-PRO_0000037312 UNIPROT ATP6V1G1 protein O75348 UNIPROT down-regulates activity cleavage -1 16226257 YES lperfetto Cleavage of the V-ATPase G1 fusion protein by SARS-CoV 3CLpro was found in this study (Fig. 3), implying that 3CLpro potentially cleaves the cellular V-ATPase G1, and affects the function of vacuolar H(+)-ATPase. Meanwhile, a significant intracellular acidification has been demonstrated in the 3CLpro-expressing cells (Fig. 4D). The result correlated well with previous reports in that V-ATPase-specific inhibitors cause acidic pHi [28], [29], and influences cell apoptosis 0.2 SIGNOR-260264 PHF12 protein Q96QT6 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR form complex binding 9606 BTO:0000007 21041482 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.795 SIGNOR-266969 CXCL12 protein P48061 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 11859124 YES gcesareni To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells. 0.809 SIGNOR-115029 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176805 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 YES fspada We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130 0.918 SIGNOR-42866 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr221 KDEILPTtPISEQKG 9606 19059439 YES gcesareni Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. Phosphorylated rps3 was only detected in non-ribosomal rps3 and the repair endonuclease activity of rps3 was increased by its phosphorylation. 0.2 SIGNOR-182623 MEF2A protein Q02078 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.355 SIGNOR-238748 FFAR4 protein Q5NUL3 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.458 SIGNOR-257420 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 BTO:0000887;BTO:0001260 8702756 YES gcesareni Rho-kinase phosphorylates the mlc of intact myosin and activates its mgatpase activity in a gtp_?Rho-dependent manner. 0.645 SIGNOR-43031 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 NO gcesareni Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence 0.578 SIGNOR-107160 KDM6A protein O15550 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 YES miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase 0.2 SIGNOR-260034 CAMK2B protein Q13554 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 YES miannu ERK1/2 and CaMKIIβ mediated phosphorylation of GABAB1 at serine 867 (S867) and threonine 872 (T872). We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. 0.2 SIGNOR-277851 PRKCD protein Q05655 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Ser297 GLRYNRLsAIPRSLA 29383184 YES lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. 0.2 SIGNOR-275565 MCM2 protein P49736 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 YES The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. 0.778 SIGNOR-198428 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 11381136 YES miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. 0.8 SIGNOR-267302 FFAR3 protein O14843 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256821 PPP1CB protein P62140 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 23277204 YES Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. 0.2 SIGNOR-248577 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates activity phosphorylation Ser82 RKMKDTDsEEEIREA -1 26675311 YES miannu Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. We found that in the complex between CaM and CaMKII, residue E115 of CaM is strongly interacting with K299 of the kinase through forming a salt-bridge (PDB entry 1WEL), it is quite likely that the phosphorylation induced structural change can disrupt this interaction and negatively affect the binding between the two proteins 0.423 SIGNOR-266353 TOMM7 protein Q9P0U1 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 YES lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. 0.77 SIGNOR-267680 PTPRG protein P23470 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity dephosphorylation Tyr690 NLQERRKyLKHRLIV -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254728 MAPK3 protein P27361 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Thr43 KVTTVVAtPGQGPDR 9606 BTO:0000150;BTO:0000680 16039586 YES lperfetto Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin. 0.294 SIGNOR-138898 ERRFI1 protein Q9UJM3 UNIPROT EGFR protein P00533 UNIPROT down-regulates binding 10116 11003669 YES gcesareni These data indicate that the gene 33 protein is a feedback inhibitor of ErbB-2 mitogenic function and a suppressor of ErbB-2 oncogenic activity. We propose that the gene 33 protein be renamed with the acronym RALT (receptor-associated late transducer) 0.643 SIGNOR-186198 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 NO miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 0.2 SIGNOR-254805 TRBC1 protein P01850 UNIPROT TCR complex SIGNOR-C153 SIGNOR form complex binding 9606 12507424 YES miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ 0.2 SIGNOR-255298 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4C protein Q9H3R0 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273474 ESR1 protein P03372 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11477071 NO lperfetto Er_ mutants unable to bind coactivators drastically decrease estradiol regulation of ap-1-mediated transcription and overexpression of the coactivator grip1 0.818 SIGNOR-109520 AKT proteinfamily SIGNOR-PF24 SIGNOR ATG4B protein Q9Y4P1 UNIPROT up-regulates activity phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000586 29165041 YES lperfetto In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity. 0.2 SIGNOR-275836 WAVE complex complex SIGNOR-C271 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000132 27871158 YES lperfetto Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex 0.545 SIGNOR-261876 FYN protein P06241 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Tyr529 TITKTVEyLHAQGVV 9606 18156174 YES llicata Epidermal growth factor stimulates rsk2 activation through activation of the mek/erk pathway and src-dependent tyrosine phosphorylation of rsk2 at tyr-529. By mass spectroscopy-based studies, we identified src tyrosine kinase family members src and fyn as upstream kinases of rsk2 tyr-529. 0.327 SIGNOR-160048 TERF2 protein Q15554 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR down-regulates 10116 27117401 NO miannu During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. 0.7 SIGNOR-266805 ARHGEF9 protein O43307 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 NO miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. 0.7 SIGNOR-264976 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Thr363 IEDDIIYtQDFTVPG 9606 BTO:0000007;BTO:0000567 12805220 YES lperfetto It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity. 0.2 SIGNOR-101848 CDK1 protein P06493 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 YES gcesareni Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1. 0.512 SIGNOR-178202 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Thr271 RQRKSRRtI 9606 BTO:0000782 2303462 YES lperfetto The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site. 0.264 SIGNOR-22988 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Thr100 LKRLFSGtQISTIAE 9606 15073328 YES lperfetto Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp) 0.523 SIGNOR-124051 SLK protein Q9H2G2 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates phosphorylation 9606 BTO:0000671 16316999 YES gcesareni Induction of apoptosis by the ste20-like kinase slk, a germinal center kinase that activates apoptosis signal-regulating kinase and p38 0.253 SIGNOR-142665 TBCK protein Q8TEA7 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000142 33240423 NO miannu TBCK included two types of alternatively spliced isoforms (long TBCK and short TBCK). Although there is a long way to go to fully understand the function of TBCK, recent research indicates that TBCK plays an important role in brain development. BCK deficiency would disturb activation of the mTOR complex 1 (mTORC1), thus, affecting the autophagy process and further leading to autophagosomal-lysosomal dysfunction 0.252 SIGNOR-266699 RAD21 protein O60216 UNIPROT ERG protein P11308 UNIPROT down-regulates activity relocalization 9606 BTO:0001545 26607380 YES miannu Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity. 0.2 SIGNOR-261515 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser402 LSGSKTNsPKNSVHK 9606 BTO:0000007 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249304 C5AR2 protein Q9P296 UNIPROT CR1 protein P17927 UNIPROT up-regulates quantity by expression 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.339 SIGNOR-263465 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr94 ATADLDItEINKLTA 9606 19530738 YES lperfetto First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form. 0.462 SIGNOR-186155 ILK protein Q13418 UNIPROT ILK protein Q13418 UNIPROT up-regulates activity phosphorylation Ser343 SMADVKFsFQCPGRM 9606 11313365 YES lperfetto Although ilk has been shown to autophosphorylate serine 343 (s343) is in the hydrophobic motif fsf within the activation loop of the kinase domain and has previously been suggested to be the target of autophosphorylation (9). Mutation of serine 343 to alanine (s343a) resulted in the inability of ilk to stimulate phosphorylation of pkb/akt in cos cells (9). 0.2 SIGNOR-106838 SPAG5 protein Q96R06 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 YES lperfetto By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically. 0.465 SIGNOR-271719 DUSP5 protein Q16690 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 20626350 YES gcesareni The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues. 0.537 SIGNOR-166574 LRRC4 protein Q9HBW1 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 NO miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. 0.2 SIGNOR-264056 BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 YES lperfetto Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. 0.663 SIGNOR-133808 MED29 protein Q9NX70 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.769 SIGNOR-266658 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11016919 YES lperfetto The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway. 0.2 SIGNOR-253263 MMP7 protein P09237 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 YES miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. 0.322 SIGNOR-256329 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii 0.777 SIGNOR-203508 Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 10090 BTO:0001086 19279220 NO miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.7 SIGNOR-270728 CDK5 protein Q00535 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity phosphorylation Ser687 TEKSHPRsPNVLSVA 9606 27027353 YES miannu In conclusion, we obtained compelling evidence that CDK5 directly stabilizes the transcription factor hypoxia inducible factor-1\u03b1 by phosphorylation, and thus promotes the formation of blood vessels.|Mass spectrometry and site directed mutagenesis revealed a stabilizing phosphorylation of HIF-1\u03b1 at Ser687 by CDK5. 0.259 SIGNOR-279020 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 16679294 YES gcesareni Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action 0.261 SIGNOR-146676 MBTPS2 protein O43462 UNIPROT CREB3L1 protein Q96BA8 UNIPROT up-regulates cleavage 9606 16417584 YES miannu Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes 0.567 SIGNOR-143820 DLGAP2 protein Q9P1A6 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 YES miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. 0.704 SIGNOR-264210 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity phosphorylation Ser346 FAQTVMTsRIVGTTA 9606 BTO:0000876 24567333 YES lperfetto We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity 0.2 SIGNOR-204653 sertindole chemical CHEBI:9122 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258543 MT-CO2 protein P00403 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.766 SIGNOR-267748 RPS3 protein P23396 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.895 SIGNOR-262421 PARL protein Q9H300 UNIPROT PINK1 protein Q9BXM7 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000007 22354088 YES miannu Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. 0.614 SIGNOR-261364 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI formate smallmolecule CHEBI:15740 ChEBI up-regulates quantity precursor of 9606 18767138 YES lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate 0.8 SIGNOR-268248 ATP13A1 protein Q9HD20 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004093 29650961 NO doi.org/10.1101/185272 francesca Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions 0.7 SIGNOR-261216 COL14A1 protein Q05707 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known 0.7 SIGNOR-254672 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates phosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000149 1706616 YES gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. 0.2 SIGNOR-21211 GSK3B protein P49841 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser373 VQARLERsSSKSLER 9606 17991736 YES gcesareni Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B 0.347 SIGNOR-158959 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 YES Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. 0.2 SIGNOR-248600 BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding -1 18937504 YES ggiuliani Here we report the high-resolution NMR structure of BMPR-IA ECD in solution, revealing that a large part of the ligand-binding epitope is unfolded and flexible before formation of the complex. The binding beta4beta5 loop of BMPR-IA passes through a structural rearrangement upon BMP-2 binding. 0.928 SIGNOR-255771 SRC protein P12931 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Tyr785 STFTNITyRGT 9606 11723131 YES lperfetto The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength. 0.66 SIGNOR-247207 GLI2 protein P10070 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16880529 NO gcesareni The zinc finger transcription factor gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling 0.429 SIGNOR-148346 PLCG2 protein P16885 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI down-regulates quantity chemical modification 9606 23000145 YES scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). 0.8 SIGNOR-268452 DRD1 protein P21728 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.269 SIGNOR-257269 BMP7 protein P18075 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003858 12734180 NO miannu In the present study we investigated the inhibitory effects of IGF-1 and OP-1 on MMP-13 expression in human chondrocytes. We found that the suppressive effect of IGF-1 and OP-1 on the MMP-13 promoter activity was dose-dependent at the transcriptional level with a corresponding decrease in the level of MMP-13 protein. 0.35 SIGNOR-254801 PIK-75 Hydrochloride chemical CID:45265864 PUBCHEM PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206214 PCGF1 protein Q9BSM1 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 YES miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. 0.702 SIGNOR-255279 FOXP1 protein Q9H334 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 18640093 NO Notably, we demonstrate that FOXP1 directly interacts with AR and negatively regulates AR signaling ligand-dependently, as exemplified by the transcriptional repression of PSA gene regulated by androgen-dependent FOXP1 recruitment on its enhancer region. 0.274 SIGNOR-253660 THBD protein P07204 UNIPROT Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR form complex binding 9606 BTO:0000131 29880919 YES lperfetto Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). 0.905 SIGNOR-267726 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI CADPS protein Q9ULU8 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 24363652 YES miannu CAPS exhibits low affinity but functionally significant interactions with plasma membrane PIP2 via its central PH (pleckstrin homology) domain (82, 111). PIP2 enhanced CAPS stimulation of SNARE-dependent liposome fusion with wild-type but not with mutant PH domain CAPS proteins 0.8 SIGNOR-264334 tamsulosin chemical CHEBI:9398 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258474 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263810 ATM protein Q13315 UNIPROT BRD7 protein Q9NPI1 UNIPROT down-regulates activity phosphorylation Ser263 QKDGTDTsQSGEDGG 9606 33101843 YES miannuccelli ATM Directly Phosphorylates BRD7 at Ser 263 Site. 0.2 SIGNOR-279780 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258071 AKT proteinfamily SIGNOR-PF24 SIGNOR CCNF protein P41002 UNIPROT up-regulates activity phosphorylation Ser577 TKRKRENsLQEDRGS 9606 BTO:0001938 28954236 YES miannu AKT phosphorylation of cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes. 0.2 SIGNOR-266361 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). 0.8 SIGNOR-267320 Class II MHC:Antigen complex SIGNOR-C429 SIGNOR T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 31810556 NO scontino Once they are formed, peptide/MHC class II molecules complexes are very stable and allow for sustained antigen presentation increasing the chances to encounter the matching CD4+ T lymphocytes. Once CD4+ T cells have become acti- vated, they in turn trigger macrophages to eliminate pathogens that have been previously internalized, and B lymphocytes to produce pathogen- specific antibodies. 0.7 SIGNOR-267873 CRCP protein O75575 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.8 SIGNOR-266134 HIF-1 complex complex SIGNOR-C418 SIGNOR BID protein P55957 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27692180 YES miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 0.2 SIGNOR-267457 MYOD1 protein P15172 UNIPROT CCND3 protein P30281 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 10373569 YES gcesareni Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator. 0.374 SIGNOR-238526 PRKACA protein P17612 UNIPROT CIITA protein P33076 UNIPROT down-regulates activity phosphorylation Ser834 QELPGRLsFLGTRLT 9606 BTO:0000984 11416140 YES lperfetto Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylationphosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription. 0.31 SIGNOR-108573 CHGA protein P10645 UNIPROT Secretory_granule_organization phenotype SIGNOR-PH87 SIGNOR up-regulates 10090 12456801 NO CgA was initially identified as the major soluble matrix protein of secretory vesicles formed in neuroendocrine cells. Its functions include modulation of secretory granule stability, prohormone processing, and regulation of peptide sorting into secretory pathways 0.7 SIGNOR-254274 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr290 RQSVLVPyEPPQVGT 9606 19783996 YES Manara In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. 0.541 SIGNOR-260933 SNRPF protein P62306 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.8 SIGNOR-270631 MAPK3 protein P27361 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser257 ESHPKPSsPRQESTR 10090 BTO:0000944 15060146 YES miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. 0.318 SIGNOR-260085 GSK3A protein P49840 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates activity phosphorylation Thr586 HNTPVDVtPCMSPLP -1 24879152 YES lperfetto The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. 0.323 SIGNOR-261794 PPM1D protein O15297 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity dephosphorylation Ser369 TAKTPKDsPGIPPSA 10090 15206906 YES RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity 0.361 SIGNOR-248321 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 10377430 YES lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. 0.764 SIGNOR-252871 MARCHF9 protein Q86YJ5 UNIPROT PVR protein P15151 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271530 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PML protein P29590 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 15093545 YES The effect has been demonstrated using P29590-4 gcesareni Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. 0.2 SIGNOR-270153 SUZ12 protein Q15022 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 SIGNOR form complex binding 9606 16712789 YES miannu Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2. 0.961 SIGNOR-146764 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 10973958 YES lperfetto The pathway restricted (r)Smads (e.g. Smad1, 2, 3, and 5) are serine/threonine kinase activated proteins that interact in an unphosphorylated state with a TGF-b superfamily receptor. Upon ligand binding they are phosphorylated by the receptor and released. 0.824 SIGNOR-249549 C5AR2 protein Q9P296 UNIPROT ITGAM protein P11215 UNIPROT up-regulates quantity by expression 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.295 SIGNOR-263463 AKT1 protein P31749 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 YES lperfetto Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102 0.559 SIGNOR-252521 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2V2 protein Q15819 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.56 SIGNOR-271335 FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 22890322 YES lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 0.79 SIGNOR-191781 MYCL protein P12524 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002891 27546534 NO irozzo Our findings demonstrate that stable expression of the L-MYC gene in NSC008 cells promotes their survival and proliferation while preserving their migration and differentiation properties in vitro and in vivo. 0.7 SIGNOR-259109 SNAI2 protein O43623 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 NO miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. 0.678 SIGNOR-255155 MEF2A protein Q02078 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.326 SIGNOR-238703 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser318 SRTNSNAsTVSGRLS 9606 20110348 YES lperfetto Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export 0.416 SIGNOR-252899 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Ser1252 QPTLPSSsPVPIPVS 9606 BTO:0000567 37584777 YES phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. 0.257 SIGNOR-272969 PRKCA protein P17252 UNIPROT PITPNC1 protein Q9UKF7 UNIPROT up-regulates activity phosphorylation Ser299 KDRPRKKsAPETLTL 9534 BTO:0000298 21728994 YES done miannu Only BIM-I caused a reduction in 14-3-3 binding (Figure 3B), suggesting that PKC could be responsible for one or both of the serine phosphorylations, pSer274 and pSer299. 0.32 SIGNOR-273801 Degranulation phenotype SIGNOR-PH92 SIGNOR IL5 protein P05113 UNIPROT up-regulates quantity 9606 BTO:0000830 17259966 NO apalma The array of mediators released by human mast cells is enormous and explains how mast cells can be involved in so many different physiological and pathophysiological functions. Of particular relevance [...] cytokines, such as IL-3 -basophil recruitment and activation-, IL-5 -eosinophil recruitment and activation- and IL-13 -induction of IgE synthesis by B cells. 0.7 SIGNOR-255346 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR MEIS1 protein O00470 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14701735 NO irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. 0.2 SIGNOR-255862 SLC1A6 protein P48664 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 YES miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). 0.8 SIGNOR-264805 PIM2 protein Q9P1W9 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 YES lperfetto Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo 0.402 SIGNOR-164646 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser362 QGRSGCSsQSISPMR -1 28130417 YES lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. 0.264 SIGNOR-264870 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR LASP1 protein Q14847 UNIPROT unknown phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000664 24913448 YES phosphorylation blocks localization at focal adhesion sites and induces binding to CRLK lperfetto LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia|We demonstrate that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients 0.2 SIGNOR-271703 NDN protein Q99608 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates activity binding 10090 BTO:0000920 24392139 YES lperfetto Necdin interacts with E2F transcription factors and suppresses E2F1-dependent transcriptional activation of the cyclin-dependent kinase Cdk1 gene. Here we show that necdin serves as a suppressor of NPC proliferation in the embryonic neocortex. 0.6 SIGNOR-253382 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000590 11578751 NO lperfetto Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death 0.7 SIGNOR-251640 CSNK2A1 protein P68400 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Ser231 KERDKEVsDDEAEEK 9606 BTO:0000567 2492519 YES llicata Both hsp 90 proteins are phosphorylated at two homologous sites. For the alpha protein, these sites correspond to serine 231 and serine 263. | Dephosphorylated hsp 90 is phosphorylated at both sites by casein kinase II from HeLa cells, calf thymus, or rabbit reticulocytes; no other hsp 90 residues were phosphorylated by casein kinase II in vitro. 0.532 SIGNOR-250899 JQ1 chemical CHEBI:137113 ChEBI BRD3 protein Q15059 UNIPROT down-regulates activity chemical inhibition -1 20871596 YES lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. 0.8 SIGNOR-261988 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser216 SKSKAPGsPLSSEGA -1 15850461 YES miannu CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.286 SIGNOR-263087 rizatriptan chemical CHEBI:48273 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 10193663 YES Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  0.8 SIGNOR-258342 AATF protein Q9NY61 UNIPROT BAX protein Q07812 UNIPROT down-regulates quantity transcriptional regulation 9606 22909821 YES We identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes. 0.2 SIGNOR-259916 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1005 EHDSDESsDDDSDSE 9606 BTO:0000661 10066810 YES llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  0.435 SIGNOR-251030 CSNK2A1 protein P68400 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates activity phosphorylation Ser335 SDLGDAMsEEDMLQA 9606 BTO:0000007 19542537 YES miannu Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs. 0.2 SIGNOR-276226 GSK3B protein P49841 UNIPROT CREB3L3 protein Q68CJ9 UNIPROT down-regulates activity phosphorylation 9606 27507854 YES lperfetto It is possible that phosphorylation of CREBH by GSK3beta leads to altered CREBH conformation with a resulting decreased affinity toward the COPII coated transport complex.|Similarly, expression of dominant negative GSK3beta can rescue the decreased CREBH cleavage activity in the Bmal1 knockdown hepatocytes under the circadian clock (XREF_FIG), thus confirming that BMAL1 controls circadian regulated CREBH cleavage and activation through AKT and GSK3beta signaling in hepatocytes. 0.548 SIGNOR-279785 P2RY1 protein P47900 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257394 ARHGAP31 protein Q2M1Z3 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.672 SIGNOR-260490 SLC25A12 protein O75746 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity relocalization 9606 12084073 YES miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 0.8 SIGNOR-265154 WLS protein Q5T9L3 UNIPROT WNT3A protein P56704 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 20826466 YES WNT secretion requires its binding to the carrier protein wntless (WLS); 0.64 SIGNOR-256599 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 19864431 YES lperfetto Our data that insulin-stimulated raptor ser863 phosphorylation requires kinase-active mtorc1 and displays rapamycin sensitivity in intact cells, together with the data of wang et al. (67) that mtor phosphorylates raptor ser863 in vitro, strongly suggest that mtor itself mediates raptor ser863 phosphorylation. / strikingly, raptor ser863 phosphorylation is absolutely required for raptor ser859 and ser855 phosphorylation. These data suggest that mtorc1 activation leads to raptor multisite phosphorylation and that raptor ser863 phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation 0.989 SIGNOR-188924 Shikonin chemical CHEBI:81068 ChEBI PKM protein P14618 UNIPROT down-regulates activity chemical inhibition 9606 21516121 YES lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. 0.8 SIGNOR-262008 TWIST1 protein Q15672 UNIPROT RAP1A protein P62834 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255533 ERBB4 protein Q15303 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16729043 YES gcesareni Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength. 0.829 SIGNOR-146876 SRC protein P12931 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr34 KDQFPEVyVPTVFEN 9606 BTO:0000567 23027962 YES lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity 0.667 SIGNOR-271702 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF5 protein O00463 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271084 [4,5,6,7-Tetrabromo-2-(Dimethylamino)-1h-Benzimidazol-1-Yl]acetic Acid chemical CID:46943415 PUBCHEM CSNK2A2 protein P19784 UNIPROT down-regulates activity chemical inhibition -1 22115617 YES Federica 4,5,6,7-tetrabromo- and 4,5,6,7-tetraiodo-1H-benzimidazoles and their newly obtained N1- and 2-S-carboxyalkyl derivatives showed potent inhibitory activity against both these subunits. CK2α was up to 6 times more sensitive to the studied compounds than CK2α. 0.8 SIGNOR-261112 RNF111 protein Q6ZNA4 UNIPROT SKIL protein P12757 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23530057 YES miannu Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4. 0.723 SIGNOR-272885 CDK9 protein P50750 UNIPROT UBE2A protein P49459 UNIPROT up-regulates activity phosphorylation Ser120 LDEPNPNsPANSQAA 9606 22722497 YES miannu CDK9 phosphorylates RNA polymerase II CTD at serine 2 to recruit the RNF20/40 E3 ubiquitin ligase, which is required for H2Bub1, and phosphorylates UBE2A at serine 120 to increase its activity in regulating H2Bub1. 0.449 SIGNOR-279025 SCN2A protein Q99250 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 YES miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. 0.8 SIGNOR-253404 JUNB protein P17275 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 21799768 NO Our results suggest that the prolonged IL-4 expression in NFAT1 deficient Th2 cells is mediated by preferential binding of JUNB/SATB1 to the IL-4 promoter with permissive chromatin architecture 0.49 SIGNOR-254503 GSK3B protein P49841 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by stabilization phosphorylation Ser903 KTTSQAHsLPLSPAS 10090 BTO:0000452 12871932 YES GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α. 0.389 SIGNOR-251251 PLK1 protein P53350 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Ser146 LLTFPNSsPGLRRQK phosphorylation:Ser36;Thr40 HPGFDAEsYTFTVPR;DAESYTFtVPRRHLE 23972993 YES For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP 0.297 SIGNOR-274054 R2SP co-chaperone complex SIGNOR-C517 SIGNOR Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 29844425 NO miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. 0.7 SIGNOR-270941 CDK1 protein P06493 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Thr767 ESFKRLVtPRKKSKS 9606 BTO:0000007 23063527 YES lperfetto Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis. 0.322 SIGNOR-271839 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 YES Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. 0.2 SIGNOR-248598 GABRB2 protein P47870 UNIPROT GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.476 SIGNOR-263744 ATM protein Q13315 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates activity phosphorylation Thr172 SDGEFLRtSCGSPNY 23871434 YES lperfetto ATM phosphorylates AMPKalpha2 to induce inhibitory phosphorylation of HIPK2| 0.264 SIGNOR-275488 4-aminopyridine smallmolecule CHEBI:34385 ChEBI KCNJ13 protein O60928 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9620703 YES miannu Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations 0.8 SIGNOR-258924 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIA2 protein P42262 UNIPROT up-regulates activity chemical activation 9606 30825796 YES miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses 0.8 SIGNOR-264609 pimozide chemical CHEBI:8212 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258841 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR SEC31B protein Q9NQW1 UNIPROT up-regulates activity monoubiquitination lys641 9606 BTO:0000567 22358839 YES miannu By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division. 0.298 SIGNOR-272015 PRKACA protein P17612 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 20110267 YES llicata We identified ser-282 as target of mapk and ser-172 as target of pkc and pka in vitro and in a transfected human embryonic kidney 293 (hek293) cell model using site directed mutagenesis and phosphopeptide mapping analysis. In hek293 cells, phosphorylation of these sites occurred at a basal level and down-regulated constitutive nox1 activity. I 0.325 SIGNOR-163663 FER protein P16591 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr374 ELKGRGEyFAIKALK 9606 BTO:0002548 33411917 YES miannu We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface. 0.2 SIGNOR-277546 romidepsin chemical CHEBI:61080 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257995 MAP3K3 protein Q99759 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates 9606 10347227 NO gcesareni However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2. 0.428 SIGNOR-68020 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268584 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain 0.2 SIGNOR-263622 AP2M1 protein Q96CW1 UNIPROT SLC24A2 protein Q9UI40 UNIPROT down-regulates quantity binding 9606 BTO:0000938 SIGNOR-C245 23431067 YES miannu  we report that the first tyrosine motif of NCKX2 interacts with AP2M1 and that the interaction is required for endocytosis of NCKX2 from the dendritic surface. Furthermore, we show that a Src family kinase (SFK) modulates the endocytosis of NCKX2 by tyrosine-phosphorylation of the AP-2 recognition motif in NCKX2. 0.2 SIGNOR-264388 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258097 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 YES miannu We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. 0.578 SIGNOR-263130 SCAND1 protein P57086 UNIPROT MZF1 protein P28698 UNIPROT up-regulates activity binding -1 10777584 YES miannu Co-immunoprecipitation and yeast two-hybrid analyses demonstrate that MZF1B and RAZ1 associate in vitro via a SCAN box-dependent mechanism. The interaction between MZF1B and RAZ1 might be necessary for mediating MZF1B function 0.365 SIGNOR-221561 FBXL17 protein Q9UF56 UNIPROT SUFU protein Q9UMX1 UNIPROT down-regulates quantity by destabilization ubiquitination 27234298 YES Here, we show that Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction 0.42 SIGNOR-253545 CENPQ protein Q7L2Z9 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.787 SIGNOR-265207 STK39 protein Q9UEW8 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 21317537 YES miannu SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. 0.345 SIGNOR-263134 FOXP3 protein Q9BZS1 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 38339310 YES miannu FOXP3 expression additionally increased programmed death ligand 1 (PD-L1) expression, which, when inhibited with CCL5, decreased the tumor burden and Treg infiltration in orthotopic murine, Pan-02 PDAC tumors 0.468 SIGNOR-277728 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS 9606 BTO:0002552 11331603 YES lperfetto Atm phosphorylates mdm2 on s395 in vitro. Moreover, s395 appears to be phosphorylated in an atm-dependent manner in vivo the precise mechanism through which s395 phosphorylation attenuates mdm2 function is unclear. 0.755 SIGNOR-107256 SRC protein P12931 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1267 PATGEQVyQQDWAQN -1 10195142 YES lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. 0.568 SIGNOR-247167 GOT1 protein P17174 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-268064 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR BRD4 protein O60885 UNIPROT up-regulates activity relocalization 30224758 YES lperfetto BRD4 is recruited to chromatin by YAP/TAZ 0.2 SIGNOR-276574 PRKCA protein P17252 UNIPROT RORA protein P35398 UNIPROT unknown phosphorylation Ser35 ETPLNQEsARKSEPP 9606 20122401 YES llicata Wnt5a/pkcalpha-dependent phosphorylation on serine residue 35 of roralpha is crucial to link roralpha to wnt/beta-catenin signaling, which exerts inhibitory function of the expression of wnt/beta-catenin target genes. 0.252 SIGNOR-163702 CDK2 protein P24941 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Ser59 GGQESQPsPLALLAA 10090 BTO:0000944 11598016 YES gcesareni Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation 0.424 SIGNOR-248232 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 9606 12356758 YES lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase 0.263 SIGNOR-93989 PBK protein Q96KB5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser495 GVLARKMsLGGGRPY 9606 BTO:0002181 31378785 YES miannu We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.  0.2 SIGNOR-277473 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation 9606 21808241 YES The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. 0.2 SIGNOR-270221 AMPK complex SIGNOR-C15 SIGNOR TSC complex SIGNOR-C101 SIGNOR up-regulates activity phosphorylation 10090 BTO:0002572 SIGNOR-C15 16959574 YES lperfetto GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation 0.484 SIGNOR-217749 LYN protein P07948 UNIPROT SOCS1 protein O15524 UNIPROT down-regulates activity phosphorylation Tyr80 LLDACGFyWGPLSVH -1 31101761 YES miannu These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors. 0.301 SIGNOR-277888 PRKG1 protein Q13976 UNIPROT CREB1 protein P16220 UNIPROT unknown phosphorylation Ser119 EILSRRPsYRKILND -1 11175347 YES lperfetto G-kinase phosphorylated GST-CREB, albeit less efficiently than A-kinase, but GST was not phosphorylated by either kinase (Figure 5a). GST-CREB purified from bacteria was similarly phosphorylated by G-kinase, whereas GST-CREB containing a serine 133 to alanine mutation was not (Figure 5b). These results demonstrate that G-kinase can directly phosphorylate CREB on serine 133. 0.644 SIGNOR-249076 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT down-regulates dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 12138178 YES miannu Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to dna to activate transcription. The activity of stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (ptp). We have now purified a stat1 ptp activity from hela cell nuclear extract and identified it as tc45, the nuclear isoform of the t-cell ptp (tc-ptp). Tc45 can dephosphorylate stat1 both in vitro and in vivo. 0.733 SIGNOR-90814 CSNK1D protein P48730 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1493 NPPPSPAtERSHYTM 9606 35487243 YES miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 0.2 SIGNOR-275403 GALR1 protein P47211 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256966 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275757 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB3 protein Q01970 UNIPROT up-regulates 23994464 YES apalma However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits 0.392 SIGNOR-255016 EXT1 protein Q16394 UNIPROT WNT8A protein Q9H1J5 UNIPROT up-regulates activity 9606 24860992 NO miannu Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern. 0.2 SIGNOR-264019 CENPE protein Q02224 UNIPROT BUB1B protein O60566 UNIPROT up-regulates activity binding 10090 BTO:0000452 12925705 YES lperfetto Without CENP-E, diminished levels of BubR1 are recruited to kinetochores and BubR1 kinase activity remains at basal levels. CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. Thus, CENP-E is required for enhancing recruitment of its binding partner BubR1 to each unattached kinetochore and for stimulating BubR1 kinase activity, implicating it as an essential amplifier of a basal mitotic checkpoint signal. 0.845 SIGNOR-252043 chlorpromazine chemical CHEBI:3647 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258371 CYLD protein Q9NQC7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates deubiquitination 9606 BTO:0001253 12917689 YES lperfetto The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6. 0.788 SIGNOR-117856 BMP7 protein P18075 UNIPROT PRDM16 protein Q9HAZ2 UNIPROT up-regulates transcriptional regulation 9606 18719589 NO fspada Bmp7 activates a full program of€š brown€š adipogenesis€š including induction of early regulators of€š brown€š fat fate prdm16 (pr-domain-containing 16; ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha; ref. 5), increased expression of the€š brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways 0.404 SIGNOR-210053 ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 YES inferred from 70% family members gcesareni Like erbb1, erbb4 recruits grb2, shc and stat5. 0.2 SIGNOR-269962 YIF1B protein Q5BJH7 UNIPROT HTR1A protein P08908 UNIPROT up-regulates activity relocalization 10116 BTO:0000938 18685031 YES nucleus lperfetto Together, our results provide strong evidence that Yif1B is a member of the ER/Golgi trafficking machinery, which plays a key role in specific targeting of 5-HT(1A)R to the neuronal dendrites. This finding opens up new pathways for the study of 5-HT(1A)R regulation by partner proteins and for the development of novel antidepressant drugs.|We confirmed 5-HT(1A)R-Yif1B interaction by glutathione S-transferase pull-down experiments using rat brain extracts and transfected cell lines. 0.399 SIGNOR-268299 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS3 protein P23396 UNIPROT unknown phosphorylation 9606 15950189 YES inferred from 70% family members llicata Erk phosphorylates threonine 42 residue of ribosomal protein s3. 0.2 SIGNOR-270019 MAJIN protein Q3KP22 UNIPROT TTM complex complex SIGNOR-C305 SIGNOR form complex binding 9606 BTO:0000007 30718482 YES lperfetto Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE 0.2 SIGNOR-263303 TNF protein P01375 UNIPROT SCN4A protein P35499 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. VGSCs were up-regulated at both the mRNA and protein levels. 0.257 SIGNOR-253481 felodipine chemical CHEBI:585948 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18250364 YES Luana Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression.  0.8 SIGNOR-257766 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Thr110 PRSGVRGtPVRQRPD 9606 BTO:0000567 12714602 YES lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. 0.699 SIGNOR-217352 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4B protein P23588 UNIPROT up-regulates activity stabilization 9606 17581632 YES lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit 0.638 SIGNOR-269158 UVB radiation stimulus SIGNOR-ST17 SIGNOR cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI down-regulates quantity chemical modification 9606 BTO:0001253 30080183 YES lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin 0.7 SIGNOR-270563 CAMK2A protein Q9UQM7 UNIPROT RIMS1 protein Q86UR5 UNIPROT up-regulates phosphorylation Ser288 NGKGALKsERKRVPK 9606 BTO:0000938 BTO:0000142 12871946 YES gcesareni Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3, 0.348 SIGNOR-103890 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Glu) smallmolecule CHEBI:29175 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269486 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 9889196 YES lperfetto Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2. 0.942 SIGNOR-217332 PRKACA protein P17612 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 15228085 YES gcesareni Site-directed mutagenesis analysis indicated that serine 2152 is the unique substrate in the c-terminal region of abp for endogenously activated pka. 0.2 SIGNOR-126659 CD22 protein P20273 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 YES scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. 0.2 SIGNOR-268444 belinostat chemical CHEBI:61076 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257952 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0001538 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.73 SIGNOR-252755 MAPK3 protein P27361 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 15192708 YES The effect has been demonstrated using O43561-2 gcesareni Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway. 0.304 SIGNOR-125770 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Ser193 AEVDPDMsWSSSLAT 9606 BTO:0001938 12815053 YES lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 0.54 SIGNOR-102486 SMAD3 protein P84022 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000165 11711431 YES azuccotti We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors. 0.73 SIGNOR-252071 PPP2CB protein P62714 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7780739 YES Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts. 0.478 SIGNOR-248590 MST1 protein P26927 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation Thr183 DTMAKRNtVIGTPFW 9606 11805089 YES llicata We directly show that okadaic acid induces phosphorylation in the activation loop of mst, and, once phosphorylated, mst is rapidly translocated to the nucleus. when thr183 in mst1 was mutated to ala, no band could be detected by oa treatment,2 indicating that thr183 was the site of phosphorylation. 0.525 SIGNOR-114289 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser8 MESEMLQsPLLGLGE 9606 SIGNOR-C3 21071439 YES llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.518 SIGNOR-169518 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR NFKB2 protein Q00653 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0002572 22388891 YES miannu Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α 0.443 SIGNOR-272909 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10606744 YES gcesareni Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. 0.577 SIGNOR-73266 ABL1 protein P00519 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Tyr170 LHSEPPVyANLSNFN -1 10637231 YES Active nuclear Abl efficiently phosphorylate c-Jun. After phosphorylation of c-Jun by Abl on Tyr170, both proteins interacted via the SH2 domain of Abl. 0.527 SIGNOR-251428 HOXA10 protein P31260 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000661 21261500 NO miannu Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC 0.284 SIGNOR-254212 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF4 protein Q9BUZ4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271081 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120160 GFs stimulus SIGNOR-ST12 SIGNOR AKT3 protein Q9Y243 UNIPROT up-regulates activity 9606 23300340 NO lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation 0.7 SIGNOR-245408 RNF183 protein Q96D59 UNIPROT ATP1B1 protein P05026 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31732153 YES miannu RNF183 promotes the degradation of Na, K-ATPas.  We confirmed that RNF183 interacted with both α1 and β1 subunits; however, we found that RNF183 ubiquitinated only the β1 subunit, not the α1 subunit.  0.2 SIGNOR-272218 taurine smallmolecule CHEBI:15891 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 BTO:0000007 9009272 YES inferred from family member miannu For each mutant GlyR we examined the agonist efficacies of taurine and beta-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where beta-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human alpha-1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and beta-alanine act as full agonists of huma nalpha-1 GlyRs when expressed in this system. 0.8 SIGNOR-267793 HNF4A protein P41235 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 9792724 NO miannu AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP. 0.404 SIGNOR-254446 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268653 SMURF2 protein Q9HAU4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11016919 YES miannu The ability of Smurf2 to promote Smad2 destruction required the HECT catalytic activity of Smurf2 and depended on the proteasome-dependent pathway. Consistent with these results, Smurf2 potently reduced the transcriptional activity of Smad2.  0.778 SIGNOR-272935 PPP1CC protein P36873 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 YES Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. 0.2 SIGNOR-248504 PKA proteinfamily SIGNOR-PF17 SIGNOR FRAT1 protein Q92837 UNIPROT down-regulates activity phosphorylation Ser188 RLQQRRGsQPETRTG 9606 BTO:0002181 16982607 YES miannu Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells.  Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription. 0.2 SIGNOR-276058 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser955 KDLCRRAsYISQDMI 9606 19144650 YES llicata We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade 0.2 SIGNOR-183449 GPR174 protein Q9BXC1 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257029 MAML1 protein Q92585 UNIPROT NOTCH4 protein Q99466 UNIPROT up-regulates binding 9606 11101851 YES gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4 0.709 SIGNOR-84916 CDK1 protein P06493 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation Ser332 TDSATIVsPPPSSPP 9606 8087847 YES lperfetto Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro. 0.699 SIGNOR-36022 AKT1 protein P31749 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 YES gcesareni In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. 0.636 SIGNOR-252589 PURB protein Q96QR8 UNIPROT MYH6 protein P13533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12933792 NO miannu In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene. 0.364 SIGNOR-253901 WWP2 protein O00308 UNIPROT WWP1 protein Q9H0M0 UNIPROT up-regulates activity binding 9606 BTO:0000007 25071155 YES miannu WWP1 in complex with WWP2 specifically regulates ΔNp73.  In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.  0.2 SIGNOR-272231 PAK1 protein Q13153 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 YES lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, 0.644 SIGNOR-159764 PRKCG protein P05129 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 YES gcesareni Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. 0.325 SIGNOR-115726 DLGAP3 protein O95886 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264594 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI up-regulates quantity precursor of 25406093 YES lperfetto Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG). 0.8 SIGNOR-268573 ZNF165 protein P49910 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26567849 YES Luana ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1. 0.2 SIGNOR-266093 AURKB protein Q96GD4 UNIPROT MAPRE3 protein Q9UPY8 UNIPROT up-regulates phosphorylation Ser176 MQTSGRLsNVAPPCI 9606 23712260 YES lperfetto Phosphorylation of eb3 at s176 by aurora b ensures successful cytokinesis completion by promoting midbody mt stability and midbody stabilization. 0.473 SIGNOR-202130 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277672 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser442 STFLAFPsPEKLLRL 9606 15037602 YES lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain. 0.468 SIGNOR-216785 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249348 NFIX protein Q14938 UNIPROT ID3 protein Q02535 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268885 GADD45A protein P24522 UNIPROT CDK11A protein Q9UQ88 UNIPROT down-regulates activity binding 9606 BTO:0000007 26885618 YES lperfetto GADD45alpha inhibits CDK11p58 kinase activity|We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58. 0.2 SIGNOR-273023 NR3C1 protein P04150 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity 10090 BTO:0000944 11742987 NO gcesareni Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity. 0.622 SIGNOR-251678 FOXL2 protein P58012 UNIPROT CYP19A1 protein P11511 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 NO miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. 0.499 SIGNOR-254179 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 16829981 YES Cbl binds directly to Tyr1045 receptors gcesareni Likewise, cbl is recruited to erbb1 either directly (tyr1045), or indirectly, trough grb2 0.886 SIGNOR-147826 RAB7A protein P51149 UNIPROT Late macropinosomes phenotype SIGNOR-PH229 SIGNOR up-regulates 9606 19693279 NO miannu Rab7 is localized on later macropinosomes. Rab21 is localized on macropinosomes at an intermediate stage partially overlapping with Rab5 and Rab7, and then dissociates from the macropinosomes prior to Lamp1 acquisition by fusing with lysosomes. 0.7 SIGNOR-277779 nintedanib chemical CHEBI:85164 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 18559524 YES Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. 0.8 SIGNOR-257799 HTR2A protein P28223 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.447 SIGNOR-257227 CSNK2A1 protein P68400 UNIPROT HES6 protein Q96HZ4 UNIPROT up-regulates activity phosphorylation Ser183 GPGDDLCsDLEEAPE -1 12972610 YES llicata Hes6 inhibits the interaction of Hes1 with its transcriptional corepressor Gro/TLE. Moreover, it promotes proteolytic degradation of Hes1. This effect is maximal when both Hes1 and Hes6 contain the WRPW motif and is reduced when Hes6 is mutated to eliminate a conserved site (Ser183) that can be phosphorylated by protein kinase CK2.  0.499 SIGNOR-250890 TSPOAP1 protein O95153 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.2 SIGNOR-264363 XBP1 protein P17861-2 UNIPROT Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 15598891 NO miannu ATF6 and XBP1 are transcription factors activated specifically in response to endoplasmic reticulum (ER) stress. Three cis-acting elements capable of binding to ATF6, XBP1 or both have been identified to date, namely ER stress-response element (ERSE), unfolded protein response element (UPRE) and ERSE-II. ERSE controls the expression of ER-localized molecular chaperones such as BiP that can refold unfolded proteins in the ER; transcription from ERSE is fully activated by ATF6 even in the absence of XBP1. In contrast, transcription from UPRE depends solely on XBP1 and it has been suggested that UPRE may control the expression of components of the ER-associated degradation system that can degrade unfolded proteins in the ER. 0.7 SIGNOR-260185 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser206 SSSTYPHsPTSSDPG 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.497 SIGNOR-248800 AGTR1 protein P30556 UNIPROT PAX2 protein Q02962 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15569307 NO Ang II up-regulated Pax-2 gene expression via AT2R in IRPTC (immortalized rat renal proximal tubular cells) 0.256 SIGNOR-252294 PPP2CA protein P67775 UNIPROT DDHD1 protein Q8NEL9 UNIPROT up-regulates activity dephosphorylation Ser711 NPAKEPTsVSENEGI -1 11328814 YES miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity 0.2 SIGNOR-262975 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser44 GKSSVLEsLVGRDLL 9606 BTO:0000007 25192600 YES miannu  We identified glycogen synthase kinase (GSK)3β-dependent Drp1 phosphorylation at Ser(40) and Ser(44), which increases Drp1 GTPase activity and its mitochondrial distribution and could induce mitochondrial fragmentation. 0.389 SIGNOR-276848 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates activity chemical activation 10116 10617617 YES We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation. 0.8 SIGNOR-261141 TIMM17A protein Q99595 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.706 SIGNOR-267695 Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT ACE protein P12821 UNIPROT up-regulates activity binding 9606 32201502 YES MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I 0.2 SIGNOR-260231 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg1046 HHAPLSPrTFHPLRS -1 10026263 YES lperfetto Factor VIIa/tissue factor generates a form of factor V with unchanged specific activity, resistance to activation by thrombin, and increased sensitivity to activated protein C| In this study, we found that TF/VIIa was able to cleave multiple peptide bonds in the coagulation cofactor, factor V. SDS-PAGE analysis and sequencing indicated the factor V was cleaved at Arg679, Arg709, Arg1018, and Arg1192 0.499 SIGNOR-263645 AMOT protein Q4VCS5 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates relocalization 9606 23431053 YES AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity. gcesareni Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms. 0.677 SIGNOR-201132 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7780739 YES Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts. 0.62 SIGNOR-248625 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates quantity by destabilization phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 19833968 YES miannu We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1 0.364 SIGNOR-268046 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 BTO:0000567 17615152 YES lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. 0.2 SIGNOR-244655 MAPK3 protein P27361 UNIPROT MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation Ser180 PGSSAPNsPMAMLTL 10841026 YES lperfetto More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis. 0.541 SIGNOR-249620 IER3 protein P46695 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates binding 9606 16456541 YES gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. 0.541 SIGNOR-144309 OPRM1 protein P35372 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.509 SIGNOR-257106 metformin chemical CHEBI:6801 ChEBI G6PC1 protein P35575 UNIPROT up-regulates quantity by expression 9606 17909097 NO gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. 0.8 SIGNOR-158056 MAP2K7 protein O14733 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Tyr182 ADAEMTGyVVTRWYR 9606 BTO:0000007 10066767 YES done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. 0.434 SIGNOR-273953 FER protein P16591 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Tyr142 AVVNLINyQDDAELA -1 12640114 YES Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases.  Transfection of these kinases to epithelial cells disrupted the association between both catenins. 0.72 SIGNOR-251131 ROCK1 protein Q13464 UNIPROT KCNK3 protein O14649 UNIPROT up-regulates activity phosphorylation Ser393 GLMKRRSsV 9606 21838752 YES lperfetto Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway. 0.2 SIGNOR-176029 CCKBR protein P32239 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.453 SIGNOR-257305 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 10617468 YES gcesareni The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1. 0.786 SIGNOR-73617 FYN protein P06241 UNIPROT PTPRT protein O14522 UNIPROT down-regulates activity phosphorylation Tyr915 Y-->K 19816407 YES lperfetto Synapse formation by PTPRT was inhibited by phosphorylation of tyrosine 912 within the membrane-proximal catalytic domain of PTPRT by Fyn. This tyrosine phosphorylation reduced phosphatase activity of PTPRT 0.415 SIGNOR-275543 Complement C1 complex complex SIGNOR-C309 SIGNOR C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.642 SIGNOR-263436 PTEN protein P60484 UNIPROT GLI1 protein P08151 UNIPROT down-regulates 9606 17845852 NO PTEN is a suppressor of RAS-AKT function gcesareni Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code 0.354 SIGNOR-157776 SRP19 protein P09132 UNIPROT SRP68 protein Q9UHB9 UNIPROT up-regulates activity binding -1 30649418 YES miannu Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. 0.95 SIGNOR-261167 NOG protein Q13253 UNIPROT BMPR1B protein O00238 UNIPROT down-regulates activity binding 9606 22298955 YES lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285) 0.598 SIGNOR-192802 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268583 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 YES flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. 0.622 SIGNOR-75918 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr487 SQKVVVTtPLHRDKT 9606 9840932 YES lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk2 0.715 SIGNOR-217260 GLI1/GLI2 complex SIGNOR-C450 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 32766732 YES GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells 0.401 SIGNOR-269211 NFE2L2 protein Q16236 UNIPROT TKT protein P29401 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 NO miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). 0.267 SIGNOR-267356 EGF protein P01133 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9168989 NO Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. 0.259 SIGNOR-251782 MRPL41 protein Q8IXM3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.711 SIGNOR-262355 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268592 CDK2 protein P24941 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser428 FAQSAPGsPLSSQPV 9606 20810654 YES gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. 0.369 SIGNOR-167834 Ub:E2 complex SIGNOR-C497 SIGNOR RNF113A protein O15541 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270986 CBL protein P22681 UNIPROT PDGFRA protein P16234 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10347229 YES lperfetto Cbl overexpression in nih3t3 cells enhanced the ubiquitination and degradation of the platelet-derived growth factor receptor-alpha (pdgfralpha) 0.478 SIGNOR-68024 CTNNB1 protein P35222 UNIPROT YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR down-regulates activity binding 9606 24976009 YES miannu YAP/TAZ Are Transcriptionally Inactivated by Sequestration in the Destruction Complex.  YAP and TAZ Are Sequestered in the Cytoplasm by the β-Catenin Destruction Complex.  This analysis revealed that Axin1 not only bound established elements of the destruction complex (such as GSK3β, β-catenin and β-TrCP) but, remarkably, also strongly associated to endogenous YAP and TAZ (Figure 1A). To further confirm YAP/TAZ association to the destruction complex, we carried out immunoprecipitations for endogenous YAP/TAZ from extracts of control or Axin1/2-depleted HEK293 cells. As shown in Figure 1B, YAP and TAZ associate with endogenous Axin1, β-catenin, GSK3, and β-TrCP. mplex 0.532 SIGNOR-277656 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Thr302 PEPEVLStQEDLFDQ 9606 22621922 YES gcesareni Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm. 0.873 SIGNOR-197619 MAPK14 protein Q16539 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser937 FLGGSQVsPSRAKAP 9606 BTO:0002181 38307877 YES miannu Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1's proteasomal degradation and negates the transcription of SHH signaling.  0.271 SIGNOR-277916 SYP protein P08247 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 26903854 YES miannu Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs. 0.601 SIGNOR-264117 Ub:E2 complex SIGNOR-C497 SIGNOR HECW2 protein Q9P2P5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271289 SIAH2 protein O43255 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates 9606 17003045 NO gcesareni The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha 0.361 SIGNOR-149893 PRKAA1 protein Q13131 UNIPROT NRF1 protein Q16656 UNIPROT up-regulates 9606 15509864 NO gcesareni In muscle, it causes increased dna binding by the transcription factors nrf1 (bergeron et al., 2001) and mef2 (zheng et al., 2001), which may be involved in regulation of mitochondrial genes and glut4, respectively. 0.2 SIGNOR-130076 LEF1 protein Q9UJU2 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 17081971 NO amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. 0.7 SIGNOR-229770 ATM protein Q13315 UNIPROT DCK protein P27707 UNIPROT up-regulates activity phosphorylation Ser74 EFEELTMsQKNGGNV 9606 22850745 YES miannu Here we report that ATM phosphorylation of dCK on Serine 74 is essential to activate the G2/M checkpoint in response to DNA damage.|Together, these results indicate that the dCK-Cdk1 interaction is enhanced in response to DNA damage and that ATM mediated dCK Serine 74 phosphorylation is required for the interaction. 0.4 SIGNOR-278221 SMC2 protein O95347 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.82 SIGNOR-263908 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 BTO:0002181 11238441 NO fspada Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m). 0.378 SIGNOR-105494 RAG1 protein P15918 UNIPROT MTOR protein P42345 UNIPROT up-regulates relocalization 9606 22790199 YES gcesareni Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated. 0.256 SIGNOR-198242 tRNA(Asn) smallmolecule CHEBI:29172 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270467 CSNK1G2 protein P78368 UNIPROT IRS4 protein O14654 UNIPROT down-regulates quantity by destabilization phosphorylation Ser859 KDAASKPsGEGSFSK 9606 BTO:0002181 30026872 YES miannu IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP). 0.2 SIGNOR-277615 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT down-regulates quantity by destabilization cleavage Leu92 QLIKAIQlTYNPDES -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain 0.2 SIGNOR-263617 Wnt proteinfamily SIGNOR-PF40 SIGNOR Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 23290138 YES miannu Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.839 SIGNOR-256173 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 YES C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315 0.772 SIGNOR-251434 PRKCE protein Q02156 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates phosphorylation Ser415 QRKITRPsQRPKTPP 9606 17911614 YES gcesareni Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover. 0.2 SIGNOR-158129 FOXP2 protein O15409 UNIPROT FOXP2 protein O15409 UNIPROT up-regulates activity binding -1 16407075 YES miannu Our studies also reveal that the FOXP2 forkhead domain can form a domain-swapped dimer. The most surprising finding from these studies is that the FOXP2 forkhead domain can form a domain-swapped dimer. Disease-related mutations, sequence comparison, and biochemical analyses argue strongly that this domain swapping is a physiologically relevant function evolved in the P branch of FOX proteins. 0.2 SIGNOR-225738 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1802 SNVSSSGsINLLESP -1 8631898 YES miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 0.419 SIGNOR-250168 TNIP1 protein Q15025 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity binding 21885437 YES lperfetto ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. 0.433 SIGNOR-275736 romidepsin chemical CHEBI:61080 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257997 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.91 SIGNOR-252823 RAD51 protein Q06609 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR up-regulates activity binding 10090 BTO:0001275 10525529 YES miannu The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. 0.319 SIGNOR-264207 DYRK2 protein Q92630 UNIPROT KATNA1 protein O75449 UNIPROT down-regulates quantity by destabilization phosphorylation Ser109 VPVERRPsPGPRKRQ 9606 BTO:0000007 19287380 YES miannu DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d). 0.51 SIGNOR-262847 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT up-regulates activity phosphorylation Ser334 PLGDDEAsATVSKTE -1 8617805 YES That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated. 0.923 SIGNOR-251189 SMURF1 protein Q9HCE7 UNIPROT KRT36 protein O76013 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272695 PRDM16 protein Q9HAZ2 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 NO fspada Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells. 0.7 SIGNOR-180301 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC7 protein O00311 UNIPROT up-regulates activity phosphorylation Thr376 QVAPRAGtPGFRAPE 10846177 YES llicata Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks. 0.602 SIGNOR-250725 PPARGC1A protein Q9UBK2 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO inferred from family member miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.255 SIGNOR-270226 SLC18A2 protein Q05940 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 YES miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. 0.8 SIGNOR-269190 STON2 protein Q8WXE9 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 26903854 YES miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. 0.562 SIGNOR-264113 DOK1 protein Q99704 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257674 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser491 IQDVGAFsTVKGVAF -1 1527025 YES The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase. 0.2 SIGNOR-251187 Naltrindole chemical CHEBI:81528 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258816 LY2940680 chemical CID:49848070 PUBCHEM SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193805 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser637 VDLSKVTsKCGSLGN -1 10090741 YES miannu We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. 0.43 SIGNOR-250173 CUDC-101 chemical CID:24756910 PUBCHEM HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262263 STAT1 protein P42224 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000249 17179173 NO miannu IFNgamma, through its receptor, activates STAT1, which binds with CBP/p300 coactivator, sequesters it from the cell system, and thus inhibits transcriptional induction of the MMP13 gene in chondrocytes. 0.29 SIGNOR-255235 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21524151 YES lperfetto P53 then transcriptionally upregulates the expression of target genes, of which p21 is critical for inhibiting G1/S entry. 0.876 SIGNOR-173425 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser25 PGTASRPsSSRSYVT -1 2500966 YES miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. 0.309 SIGNOR-250066 BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 7834748 YES lperfetto Bad binds more strongly to Bcl-x, than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-x,, but not that of Bcl-2. When Bad dimerized with Bcl-x,, Bax was displaced and apoptosis was restored. 0.848 SIGNOR-249617 ATM protein Q13315 UNIPROT KHDC3L protein Q587J8 UNIPROT up-regulates activity phosphorylation Thr156 VEVREAGtQRSVEVQ 9606 BTO:0001086 31609975 YES miannu Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions.  0.2 SIGNOR-273504 AKT proteinfamily SIGNOR-PF24 SIGNOR RGCC protein Q9H4X1-2 UNIPROT up-regulates activity phosphorylation Ser47 MKRRSSAsVSDSSGF 9606 BTO:0000567 19162005 YES miannu Akt phosphorylated GST-RGC-32 in vitro, and CDC2 was also able to phosphorylate RGC-32.  Akt failed to phosphorylate RGC-32 S45A-S47A mutant. These data indicate that Ser 45 and Ser 47 may be the RGC-32 phosphorylation sites for Akt kinase. 0.2 SIGNOR-262628 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser160 PVRLLGHsPVLRNIT 9606 12107172 YES lperfetto We demonstrate that serine 146 is required for two crucial features of cdc25b1. It is essential for cdc25b1 to function as a mitotic inducer and to prevent cdc25b1 export from the nucleus. We also show that serine 146 is phosphorylated in vitro by cdk1-cyclin b. Serine 146 phosphorylation is proposed to be a key event in the regulation of the cdc25b function 0.767 SIGNOR-216753 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr473 RNPKGFGyVTFMHLE 9606 BTO:0002181 37977223 YES miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. 0.566 SIGNOR-277867 CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 395188 YES lperfetto Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors, androstenedione and testosterone, to yield estrone and estradiol, respectively. In men, the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species. 0.8 SIGNOR-251528 CAMK1 protein Q14012 UNIPROT SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation Ser9 NYLRRRLsDSNFMAN -1 10571231 YES miannu Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I 0.562 SIGNOR-250615 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT up-regulates activity phosphorylation Tyr1226 GGSHISGyATLRRGP -1 20417104 YES miannu Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C). 0.285 SIGNOR-262605 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation 9606 12792650 YES inferred from 70% family members lperfetto Inhibition of caspase-9 through phosphorylation at thr 125 by erk mapk 0.2 SIGNOR-270084 AURKA protein O14965 UNIPROT WDR62 protein O43379 UNIPROT up-regulates activity phosphorylation Ser32 VPARRGQsSPPPAPP -1 25501809 YES lperfetto AURKA activity promotes WDR62 spindle localization|We next purified recombinant full-length WDR62 (GST–WDR62-FL) for in vitro kinase assays with active AURKA and demonstrated that WDR62 was a direct phosphorylation target of AURKA|In addition, our quantitative phosphoproteomic analysis of in-vitro-phosphorylated WDR62 identified S32 and S33 as significantly phosphorylated in the presence of active AURKA|Alanine replacement of the five putative phosphorylation sites (S32/S33/S49/T50/S52-AAAAA) of WDR62 attenuated interphase microtubule association induced by AURKA coexpression 0.352 SIGNOR-271712 AMPK complex SIGNOR-C15 SIGNOR HAT1 protein O14929 UNIPROT up-regulates activity phosphorylation Ser190 MWFIETAsFIDVDDE -1 28143904 YES lperfetto Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314 0.306 SIGNOR-264787 RFX4 protein Q33E94 UNIPROT IFT172 protein Q9UG01 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19887680 NO miannu We find that Ift172, which encodes an intraflagellar transport protein necessary for ciliogenesis, is a direct transcriptional target of Rfx4 0.346 SIGNOR-223319 CPT1B protein Q92523 UNIPROT O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267130 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 YES amattioni Casp8 induces apoptosis by directly activating casp3. 0.726 SIGNOR-149420 PLG protein P00747 UNIPROT APOH protein P02749 UNIPROT down-regulates activity cleavage Lys336 HSSLAFWKTDASDVK 9606 BTO:0000131 9596664 YES lperfetto Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI. 0.458 SIGNOR-266996 TEK protein Q02763 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr1102 MLEERKTyVNTTLYE 14665640 YES gcesareni Our results identified a novel interaction between Tie2 with the adapter molecule ShcA and suggested that this interaction may play a role in the regulation of migration and three-dimensional organization of endothelial cells induced by angiopoietin-1. Furthermore, Tyr-1101 of Tie2 was identified as the primary binding site for the SH2 domain of ShcA. 0.579 SIGNOR-242573 KLHL20 protein Q9Y2M5 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 20389280 YES miannu Here, we identify the BTB-Kelch protein KLHL20 as a negative regulator of DAPK. KLHL20 binds DAPK and Cullin 3 (Cul3) via its Kelch-repeat domain and BTB domain, respectively. The KLHL20-Cul3-ROC1 E3 ligase complex promotes DAPK polyubiquitination, thereby inducing the proteasomal degradation of DAPK. 0.396 SIGNOR-271960 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates activity phosphorylation Tyr602 TYVDPHTyEDPTQAV 9606 11870224 YES Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3 0.2 SIGNOR-251116 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 0.2 SIGNOR-260126 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR PROX1 protein Q92786 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 36433955 YES miannu Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. 0.2 SIGNOR-277610 Ub:E2 complex SIGNOR-C497 SIGNOR PCGF2 protein P35227 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271089 PIM1 protein P11309 UNIPROT CDC25C protein P30307 UNIPROT up-regulates activity phosphorylation 9606 16356754 YES miannu First, Pim-1 activates the Cdc25C phosphatase directly through phosphorylation, very probably at the N-terminal part of the protein.|We find that phosphorylation by Pim-1 enhances the phosphatase activity of Cdc25C and in transfected cells that are arrested in G2/M by bleomycin, Pim-1 can enhance progression into G1. 0.349 SIGNOR-278298 USP36 protein Q9P275 UNIPROT NPM1 protein P06748 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000567 19208757 YES lperfetto USP36 deubiquitylated the nucleolar proteins nucleophosmin/B23 and fibrillarin, and stabilized them by counteracting ubiquitylation-mediated proteasomal degradation.  0.391 SIGNOR-272290 FYN protein P06241 UNIPROT FYB1 protein O15117 UNIPROT up-regulates activity phosphorylation Tyr651 LDMGDEVyDDVDTSD 9606 10570256 YES  two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription. 0.2 SIGNOR-251164 STK11 protein Q15831 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 14657655 NO gcesareni Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent. 0.379 SIGNOR-119892 PRKCI protein P41743 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity phosphorylation Ser18 KRRRTGGsLRGNPSS 9606 BTO:0000567 28850619 YES miannu Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation. 0.267 SIGNOR-277250 ING2 protein Q9H160 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 14522900 NO miannu ING1b and ING2 also repressed the AFP promoter in Hep3B p53-null cell lines, and p53 coexpression enhanced this transcriptional repression. Suppression of AFP gene transcription by ING was strongly dependent on AT-motifs that bind to the hepatocyte nuclear factor 1 (HNF1) transcription factor. 0.2 SIGNOR-254485 RUBCNL protein Q9H714 UNIPROT STX17 protein P56962 UNIPROT up-regulates activity binding 9606 BTO:0000007 30704899 YES miannu Under nutrient-rich conditions, mTORC1 phosphorylates Pacer at serine157 to disrupt the association of Pacer with Stx17 and the HOPS complex and thus abolishes Pacer-mediated autophagosome maturation. These results demonstrate that mTORC1-mediated Pacer phosphorylation at S157 inhibits autophagosome maturation by disrupting the association of Pacer with Stx17 and the HOPS complex 0.2 SIGNOR-273684 CTTNBP2NL protein Q9P2B4 UNIPROT STRN protein O43815 UNIPROT up-regulates activity binding 9606 23015759 YES miannu Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A. 0.646 SIGNOR-261702 GLI3 protein P10071 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 NO lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. 0.708 SIGNOR-209641 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr371 LLAKLEEtKEYQEPE -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.2 SIGNOR-276211 RFX complex complex SIGNOR-C104 SIGNOR HLA-DPA1 protein P20036 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.264 SIGNOR-253995 Dynorphin B chemical CHEBI:80347 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258797 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258713 CDK1 protein P06493 UNIPROT VCPIP1 protein Q96JH7 UNIPROT down-regulates activity phosphorylation Ser768 TPTKAPYsPTTSKEK 23500464 YES lperfetto We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.  0.536 SIGNOR-265038 BIRC3 protein Q13489 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 12525502 YES miannu  Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac. 0.791 SIGNOR-271391 lapatinib chemical CHEBI:49603 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 17892419 YES gcesareni Recently, lapatinib, a small molecule dual inhibitor of both her2 and egf receptors, has been developed to expand the options for treating her-positive breast cancer. 0.8 SIGNOR-157867 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 12801888 YES inferred from 70% family members llicata Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4. 0.2 SIGNOR-270107 MAPK1 protein P28482 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 28646232 YES Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels 0.32 SIGNOR-262521 NADPH(4-) smallmolecule CHEBI:57783 ChEBI NADP(3-) smallmolecule CHEBI:58349 ChEBI up-regulates quantity precursor of 9606 15507492 YES miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-268088 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18617643 YES gcesareni We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf. 0.479 SIGNOR-179430 SPI1 protein P17947 UNIPROT FCGR1A protein P12314 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12393465 NO apalma In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPŒ±-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia. 0.552 SIGNOR-255697 ARHGAP6 protein O43182 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.579 SIGNOR-260462 RFNG protein Q9Y644 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000975 12486116 YES gcesareni We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1. 0.646 SIGNOR-96561 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 21059642 YES The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.614 SIGNOR-169334 (-)-anisomycin chemical CHEBI:338412 ChEBI FOS protein P01100 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-189626 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser76 ISNKDQHsISYTLSR -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.657 SIGNOR-276127 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.497 SIGNOR-248314 EGFR protein P00533 UNIPROT SHC2 protein P98077 UNIPROT up-regulates binding 9606 11350724 YES miannu Shc exists in three different isoforms, p46shc, p52shc and p66shc which are tyrosine phosphorylated upon egf stimulation and bind to the activated egfr and grb2. Interestingly, while the 46 and 52 kda isoforms increase mitogenic signalling after egf stimulation and are able to transform nih3t3 cells (pelicci et al. 1992), p66shc has no transforming potential and negatively influences egf-induced c-fos transcription 0.61 SIGNOR-107750 AMER1 protein Q5JTC6 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C110 21304492 YES gcesareni Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6. 0.417 SIGNOR-171892 iodide smallmolecule CHEBI:16382 ChEBI 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI up-regulates quantity precursor of 9606 16098474 YES scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 0.8 SIGNOR-268120 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 12530968 NO �The present data provide a direct link between insulin signaling through Irs _ PI 3-kinase _ Akt and adipogenesis through Foxo1 phosphorylation. Inhibition of Foxo1 via phosphorylation appears to be required during the clonal expansion phase, and our data show that unrestrained Foxo1 activity prevents terminal differentiation. 0.7 SIGNOR-254981 serotonin smallmolecule CHEBI:28790 ChEBI AANAT protein Q16613 UNIPROT up-regulates activity chemical activation -1 22775292 YES miannu Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS. 0.8 SIGNOR-265477 SRC protein P12931 UNIPROT ENO1 protein P06733 UNIPROT up-regulates phosphorylation Tyr44 SGASTGIyEALELRD 9606 7629021 YES lperfetto The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways 0.411 SIGNOR-30126 NOS2 protein P35228 UNIPROT L-citrulline smallmolecule CID:9750 PUBCHEM up-regulates 9606 7537672 NO apalma Activation with lipopolysaccharide induces macrophages to produce the enzymes arginase and nitric oxide (NO) synthase. Both enzymes use as a substrate the ammino acid L-arginine, which can be either hydrolyzed by arginase to urea and ornithine or oxidized by NO synthase to NO and citrulline 0.8 SIGNOR-255382 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates phosphorylation Tyr284 LPQNDDHyVMQEHRK 9606 14506255 YES llicata Purified ack1 undergoes autophosphorylation, and autophosphorylation enhances kinase activity. We identified tyr284 in the activation loop of ack1 as the primary autophosphorylation site using mass spectrometry. 0.2 SIGNOR-118201 ponatinib chemical CHEBI:78543 ChEBI STAT5A protein P42229 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000830 23539538 YES miannu Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells 0.8 SIGNOR-259274 CLTB protein P09497 UNIPROT AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.769 SIGNOR-260677 MMP13 protein P45452 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain 0.2 SIGNOR-263612 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). 0.2 SIGNOR-252352 CAMK1 protein Q14012 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates activity phosphorylation Ser47 YAKHIYSsEDKNAQR 9606 BTO:0000007 21791615 YES miannu We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation. 0.388 SIGNOR-262680 DYRK1A protein Q13627 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates activity phosphorylation Ser251 NKVIPAKsPPPPTHS 9606 BTO:0000007 34109727 YES miannu DYRK1A phosphorylates MEF2D and decreases its transcriptional activity 0.411 SIGNOR-277901 TFE3 protein P19532 UNIPROT RRAGC protein Q9HB90 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.337 SIGNOR-276827 Ub:E2 complex SIGNOR-C497 SIGNOR MIB1 protein Q86YT6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271133 BRSK2 protein Q8IWQ3 UNIPROT WDR45 protein Q9Y484 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 28561066 YES miannu WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes. 0.248 SIGNOR-268482 TLN1 protein Q9Y490 UNIPROT ITGB6 protein P18564 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.577 SIGNOR-257631 DROSHA protein Q9NRR4 UNIPROT Microprocessor complex complex SIGNOR-C356 SIGNOR form complex binding 9606 BTO:0000552 24581491 YES lperfetto Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA. 0.924 SIGNOR-264848 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251594 DYRK2 protein Q92630 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 17349958 YES llicata Here, we demonstrate that the dual-specificity tyrosine-phosphorylation-regulated kinase 2 (dyrk2) directly phosphorylates p53 at ser46. these findings indicate that dyrk2 regulates p53 to induce apoptosis in response to dna damage. 0.669 SIGNOR-153544 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr312 QATQPLAtPVVSVTT 9606 BTO:0000567 10849446 YES lperfetto We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. 0.71 SIGNOR-236583 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Thr173 DTFWKGTtRTRPRNG 9606 17420447 YES lperfetto We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin. 0.41 SIGNOR-154307 ATM protein Q13315 UNIPROT PPP2R5C protein Q13362-3 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 21460856 YES miannu In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth. 0.379 SIGNOR-276320 GRK5 protein P34947 UNIPROT ST13 protein P50502 UNIPROT up-regulates activity phosphorylation Ser346 AQNPANMsKYQSNPK 9606 BTO:0000007 21728385 YES miannu An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303-319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells.we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4. 0.268 SIGNOR-262877 PLK1 protein P53350 UNIPROT RAP1GAP protein P47736 UNIPROT down-regulates phosphorylation Ser525 AGQKTPDsGHVSQEP 9606 25329897 YES lperfetto Plk1 phosphorylates ser525 in conserved 524dsghvs529 degron of rap1gap and promotes its interaction with _-trcp. Together, these results further support a model in which plk1, but not cdk1 or gsk-3_-mediated phosphorylation of rap1gap is a prerequisite for mitotic degradation. 0.453 SIGNOR-205577 ELE1-RET fusion protein SIGNOR-FP10 SIGNOR SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 16946010 YES miannu RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade 0.2 SIGNOR-251985 FOXO1 protein Q12778 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17873901 NO gcesareni Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity 0.273 SIGNOR-157839 NFYA protein P23511 UNIPROT OGG1 protein O15527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14688259 NO miannu these results demonstrate that MMS can up-regulate hOGG1 expression through the induction of the transcription factor, NF-YA, and increased transcription level of the hOGG1 gene correlates with an increase in enzyme activity providing functional protection from MMS. 0.265 SIGNOR-254817 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.2 SIGNOR-244681 MTOR protein P42345 UNIPROT NRBF2 protein Q96F24 UNIPROT up-regulates activity phosphorylation Ser113 AEDAEGQsPLSQKYS 9606 BTO:0001938 28059666 YES miannu Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. 0.2 SIGNOR-265874 GSK3B protein P49841 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity phosphorylation Ser49 GSPGQLHsPISTLSS 9606 BTO:0000007 29137318 YES miannu GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.  0.275 SIGNOR-277372 STK11 protein Q15831 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates phosphorylation Thr109 QWARLLQtSNITKSE 9606 20400510 YES esanto Lkb1 suppresses p21-activated kinase-1 (pak1) by phosphorylation of thr109 in the p21-binding domain. 0.247 SIGNOR-164814 GPIb-IX-V complex complex SIGNOR-C270 SIGNOR FLNA protein P21333 UNIPROT up-regulates activity relocalization 9606 16293600 YES lperfetto The cytoplasmic domain of GPIbα of the GPIb-IX-V complex binds to actin filaments through FLNa|This immediately means that clustering of the GPIb-IX-V complex and anchoring of FLNa to actin filaments by activation could also increase avidity, which could withstand high shear stress. 0.577 SIGNOR-261846 TFDP1 protein Q14186 UNIPROT TYMS protein P04818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.434 SIGNOR-253861 glutamine smallmolecule CHEBI:28300 ChEBI Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270394 RPS27A protein P62979 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.794 SIGNOR-262424 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 16582879 YES Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR 0.788 SIGNOR-248410 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 10942774 YES lperfetto Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies. 0.755 SIGNOR-236702 TGFBR2 protein P37173 UNIPROT USP2 protein O75604 UNIPROT up-regulates activity phosphorylation Ser207 ENYGRKGsASQVPSQ -1 29490279 YES miannu Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. 0.2 SIGNOR-273604 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 20626350 YES lperfetto The activity of MAPKs can be also regulated by a family of DUSPs (dual-specificity phosphatases)/MKPs (MAPK phosphatases), which dephosphorylate both phosphotyrosine and phosphothreonine residues MKPs 1, 4, 5 and 7 can dephosphorylate p38_ and p38_ in addition to JNK MAPKs. Importantly, some MKPs are transcriptionally up-regulated by stimuli that activate MAPK signalling, and are thought to play an important role limiting the extent of MAPK activation 0.804 SIGNOR-166571 DDX58 protein O95786 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 19052324 YES miannu Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. 0.937 SIGNOR-260139 PRKACA protein P17612 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9534 1545828 YES miannu Human c-Fos protein is phosphorylated in vitro by PKA. phosphorylation of Fos occurs at serine residue 362. Modification of the Fos protein by phosphorylation with PKA then allows it to act as a regulator of its own synthesis by downregulating fos gene expression at a transcriptional level 0.518 SIGNOR-250356 CDC14A protein Q9UNH5 UNIPROT CDC25A protein P30304 UNIPROT down-regulates activity dephosphorylation 9606 20956543 NO miannu Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).|Indeed, in vitro dephosphorylation of Cdk1-cyclin B1-phosphorylated Cdc25A by Cdc14A did not inhibit its catalytic activity (data not shown).|Taken together, our results suggest that at the G2/M transition Cdc14A acts on an unknown protein, which in turn inhibits Cdc25A phosphatase activity. 0.504 SIGNOR-277065 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 SIGNOR-C110 23151663 YES gcesareni Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. 0.86 SIGNOR-199504 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr393 RNLSDAAtKQEGMEG 9534 BTO:0000298 12700239 YES llicata The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability. 0.555 SIGNOR-250849 SYK protein P43405 UNIPROT USP25 protein Q9UHP3 UNIPROT down-regulates quantity phosphorylation Tyr740 QAAGDPEyLEQPSRS 9606 19909739 YES miannu Altogether, these data strengthen our results that SYK specifically phosphorylates USP25 and suggest that Y740 is the most probable phosphorylated tyrosine on USP25.We also assessed whether the SYK mediated phosphorylation of USP25 alters its protease activity.|Preliminary data indicate that proteasome inhibition by MG132 treatment did not modify the SYK dependent decrease of USP25 levels in contrary to accumulation of USP25 protein by MG132 treatment in the absence of SYK overexpression. 0.386 SIGNOR-278458 CCAN complex complex SIGNOR-C365 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 18007590 NO lperfetto Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis. 0.7 SIGNOR-265219 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr1217 LNNQLFLyDTHQNLR 9606 11507089 YES lperfetto These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2. 0.777 SIGNOR-109750 MPHOSPH10 protein O00566 UNIPROT IMP3 protein Q9NV31 UNIPROT up-regulates activity binding -1 28813493 YES miannu Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA. 0.881 SIGNOR-261173 DNA polymerase gamma complex SIGNOR-C378 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 19837034 NO lperfetto DNA Pol gamma, in contrast to the many nuclear DNA polymerases (DNAPs) that have specialized functions, is solely responsible for DNA replication and repair in mitochondria.  0.7 SIGNOR-265723 LRRK2 protein Q5S007 UNIPROT RAB5B protein P61020 UNIPROT up-regulates activity phosphorylation Thr6 tARPNGQP 9606 BTO:0000567 25605758 YES miannu  Using recombinant proteins, we show here that LRRK2 phosphorylates Rab5b at its Thr6 residue in in vitro kinase assays with mass spectrophotometry analysis. Phosphorylation of Rab5b by LRRK2 on the threonine residue was confirmed by western analysis using cells stably expressing LRRK2 G2019S. The phosphomimetic T6D mutant exhibited stronger GTPase activity than that of the wild-type Rab5b. In addition, phosphorylation of Rab5b by LRRK2 also exhibited GTPase activity stronger than that of the unphosphorylated Rab5b protein. 0.6 SIGNOR-276873 LY294002 chemical CHEBI:65329 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates chemical inhibition 9534 BTO:0001444 22253445 YES lperfetto From these results, we conclude that LY294002 and wortmannin inhibit SARS pseudovirus entry by targeting PI4KB and that PI4KB is involved in SARS-CoV S-mediated entry into VeroE6 cells. 0.8 SIGNOR-260731 FBXL15 protein Q9H469 UNIPROT SMURF1 protein Q9HCE7-2 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 21572392 YES miannu Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation.  FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells. 0.558 SIGNOR-271909 GTF2I protein P78347 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity relocalization 17970752 YES lperfetto We demonstrate that Suz12, a component of the polycomb repressor complex 2, is recruited to the beta-globin gene.| Our data suggest that TFII-I contributes to the recruitment of the polycomb repressor complex 2 complex to the beta-globin gene. 0.362 SIGNOR-268543 SMAD3 protein P84022 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9534 9670020 YES lperfetto Smad2 and Smad3 form homo-oligomers upon phosphorylation by the constitutively active TGF-beta type I receptor, and this oligomerization does not require Smad4 0.2 SIGNOR-217227 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 9606 18819921 YES Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. 0.5 SIGNOR-248387 GSK3B protein P49841 UNIPROT AKAP11 protein Q9UKA4 UNIPROT down-regulates activity phosphorylation Thr1136 AKEFAPAtPPSTPHN 9606 BTO:0000007 26088133 YES lperfetto A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles. 0.373 SIGNOR-264816 ATM protein Q13315 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 YES lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively 0.403 SIGNOR-180751 CHUK protein O15111 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000567 SIGNOR-C14 SIGNOR-C13 10521409 YES lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. 0.847 SIGNOR-71270 HSP90AB1 protein P08238 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 15861399 YES miannu The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes. 0.703 SIGNOR-251535 torin 2 chemical CHEBI:90682 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 23436801 YES ATP-competitive inhibitor gcesareni Torin2, a second generation atp-competitive inhibitor that is potent and selective for mtor.. 0.8 SIGNOR-201499 EPB41 protein P11171 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 33187473 YES lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] 0.407 SIGNOR-266035 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser376 LQESQAGsDTDVEEG 9606 18678890 YES gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. 0.347 SIGNOR-179879 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 19279133 YES flangone Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs. 0.552 SIGNOR-242049 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates chemical inhibition 9606 11717429 YES inferred from 70% of family members gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor. 0.8 SIGNOR-269885 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr449 IIQHCSNySTQELLR 9606 29022905 YES miannu Interestingly, we found that Drp1 was a substrate of c-Abl kinase and ectopic expression of c-Abl increased Drp1 's mitochondrial localization and GTPase activity.|c-Abl phosphorylates Drp1 at Y266, Y368 and Y449. 0.26 SIGNOR-278463 GRIN2A protein Q12879 UNIPROT NMDA receptor_2A complex SIGNOR-C347 SIGNOR form complex binding 9606 BTO:0000938 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits 0.726 SIGNOR-264121 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9712898 YES lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1 0.729 SIGNOR-236376 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 YES amattioni Casp8 induces apoptosis by directly activating casp3. 0.726 SIGNOR-256458 PRKAA1 protein Q13131 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 19262508 NO gcesareni The acute actions of ampk on lipid oxidation alter the balance between cellular nad+ and nadh, which acts as a messenger to activate sirt1 0.395 SIGNOR-184473 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PKM protein P14618 UNIPROT down-regulates activity phosphorylation Ser37 MCRLDIDsPPITARN 9606 BTO:0001106 28607489 YES miannu We show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity, which was not further affected by pre-incubation with cyclin D3-CDK6 (Extended Data Fig. 3a, b). 0.259 SIGNOR-276453 MAPK8 protein P45983 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 BTO:0000793 24610780 YES lperfetto Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1 0.709 SIGNOR-204679 CDK1 protein P06493 UNIPROT NIFK protein Q9BYG3 UNIPROT up-regulates activity phosphorylation Thr238 QGPTPVCtPTFLERR -1 16244663 YES miannu The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1. 0.28 SIGNOR-262696 DYRK1A protein Q13627 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 9534 BTO:0000298 14593110 YES miannu DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity. 0.268 SIGNOR-260632 Ub:E2 complex SIGNOR-C497 SIGNOR MEX3D protein Q86XN8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271189 DNA polymerase delta complex SIGNOR-C376 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 24035200 NO lperfetto Analysis of the subcellular localization of Pol subunits in response to UV indicates that Pol delta3 is present at sites of DNA damage long before repair is complete, so that Pol delta3 is the form of Pol activity that is likely involved in gap filling reactions during DNA repair 0.7 SIGNOR-265721 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNA4 protein P22459 UNIPROT down-regulates quantity by destabilization phosphorylation Thr601 LKKFRSStSSSLGDK 9606 BTO:0000007 15955806 YES miannu In parallel experiments, it was shown that recombinant PKA catalytic subunits (Fig. 3A) or cell extracts from GIP-stimulated GIPR-HEK293-KV cells (Fig. 3B) increased phosphorylation of KV1.4, and active PKA phosphorylated Thr-601 in the C terminus of KV1.4 (Fig. 3D). These results therefore provide compelling evidence for a role for GIP-induced down-regulation of KV1.4, via phosphorylation-dependent endocytosis of the channel protein, in the modulation of insulin secretion. 0.2 SIGNOR-276037 1-[4-[1-(1,4-dioxaspiro[4.5]decan-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-pyrazolo[3,4-d]pyrimidinyl]phenyl]-3-methylurea chemical CHEBI:91364 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;ATP-competitive inhibitor mTOR gcesareni 0.8 SIGNOR-207800 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 YES gcesareni MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt 0.642 SIGNOR-252438 ACVR2A protein P27037 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12682303 YES acerquone In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase 0.686 SIGNOR-99995 MSH2/MSH6 complex SIGNOR-C60 SIGNOR BLM protein P54132 UNIPROT up-regulates binding 9606 15064730 YES lperfetto We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro 0.592 SIGNOR-217223 NFATC2 protein Q13469 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15130492 YES lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA 0.2 SIGNOR-251729 PTGER4 protein P35408 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.49 SIGNOR-256760 CDC14B protein O60729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates dephosphorylation 9606 18662541 YES lperfetto The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1 0.253 SIGNOR-227927 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser768 EPLERRLsLVPDSEQ 9606 19095655 YES Luana AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites. 0.484 SIGNOR-18141 KCNQ3 protein O43525 UNIPROT KCNQ2 protein O43526 UNIPROT up-regulates activity binding 10116 BTO:0000938 9836639 YES The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current. 0.514 SIGNOR-268832 MFNG protein O00587 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11346656 YES gcesareni These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch (30, 31). It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2. 0.686 SIGNOR-107708 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck lperfetto 0.8 SIGNOR-244854 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248509 NTRK1 protein P04629 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 10092678 YES gcesareni The signaling adapter frs-2 competes with shc for binding to the nerve growth factor receptor trka:a model for discriminating proliferation and differentiation 0.778 SIGNOR-65955 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA -1 11121119 YES lperfetto In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation. 0.344 SIGNOR-249066 MTHFD2L protein Q9H903 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity chemical modification 10116 21163947 YES lperfetto Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH(2)-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified.  0.8 SIGNOR-268253 PYGL protein P06737 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267392 CTSG protein P08311 UNIPROT C3 protein P01024 UNIPROT up-regulates activity cleavage Leu751 LGLARSNlDEDIIAE 9606 BTO:0001412 1861080 YES miannu Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752. 0.598 SIGNOR-256348 PTPN6 protein P29350 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity dephosphorylation Tyr448 TILTEVNyEVSNKDD 9606 18086677 YES Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. 0.355 SIGNOR-248478 (S,S)-asenapine chemical CHEBI:71257 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258566 MYCN protein P04198 UNIPROT ABCC1 protein P33527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7923112 NO miannu Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. 0.274 SIGNOR-254617 MAPK14 protein Q16539 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates activity phosphorylation Thr66 EPICSVNtPREVTLH -1 10206983 YES miannu The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP. 0.59 SIGNOR-250110 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248682 ORC4 protein O43929 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 YES lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA 0.966 SIGNOR-267564 CDK11A protein Q9UQ88 UNIPROT SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser242 WTDSEVDsSCSGQPI 9606 BTO:0000007 26885618 YES lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| 0.356 SIGNOR-273021 PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 YES lperfetto Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, 24647478 0.8 SIGNOR-252712 TNFSF11 protein O14788 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT up-regulates activity binding 9606 12897775 YES miannu RANKL, a member of the tumour necrosis factor superfamily, is most abundantly expressed as a cell-surface protein by bone-marrow stromal cells. It interacts with its receptor RANK (which is encoded by Tnfrsf11a) on macrophages and mature osteoclasts. 0.895 SIGNOR-253042 RAP1GDS1 protein P52306 UNIPROT RHOB protein P62745 UNIPROT up-regulates binding 9606 21242305 YES miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob 0.279 SIGNOR-171615 IKBKE protein Q14164 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 11815618 YES lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. |TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha. 0.485 SIGNOR-249367 PPM1A protein P35813 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity dephosphorylation Ser276 SMQLRRPsDRELSEP 9606 23812431 YES lperfetto 23 Here we show that PPM1A directly dephosphorylated RelA at S536 and S276, with resultant inhibition of NF-kappaB transactivation and decreased expression of target genes, notably including MCP-1 and CCL2.|Taken together, these data suggest that dephosphorylation of S276 by PPM1A may contribute to inhibit RelA transcriptional activity, but the majority of PPM1A activity to inhibit RelA transcription relies on dephos phorylation of S536 of RelA.|We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited Nuclear factor-\u03baB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis. 0.353 SIGNOR-276963 CDK1 protein P06493 UNIPROT CLN3 protein Q13286 UNIPROT down-regulates activity phosphorylation 9606 23217712 YES miannu (D) Phosphorylation of Cln3 by Cdk1 is independent of Ssa1 T36.|Thereby, both Cdk1 and Pho85can promote Cln3 degradation, though under distinct circumstances. 0.257 SIGNOR-279013 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120096 EGLN3 protein Q9H6Z9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates activity hydroxylation 9606 BTO:0000567 21620138 YES Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1Œ± and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. 0.436 SIGNOR-268147 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252343 RET protein P07949 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 21454698 YES gcesareni The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation. 0.638 SIGNOR-173013 ID1 protein P41134 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000222 8380166 YES 2 miannu Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.478 SIGNOR-240265 CENPX protein A8MT69 UNIPROT FANCM protein Q8IYD8 UNIPROT up-regulates binding 9606 20347429 YES gcesareni We also provide biochemical evidence that mhf1 and mhf2 assemble into a heterodimer that binds dna and enhances the dna branch migration activity of fancm. These findings reveal critical roles of the mhf1-mhf2 dimer in dna damage repair and genome maintenance through fancm. 0.2 SIGNOR-164729 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates chemical activation 9606 16794003 YES gcesareni The evidence suggests that s1p acting on s1p receptors coupled to gq. 0.8 SIGNOR-147230 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity dephosphorylation Tyr754 ERKEVSKySDIQRSL -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.25 SIGNOR-254714 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI IDH2 protein P48735 UNIPROT up-regulates activity chemical activation 9606 32943735 YES Wild-type IDH1 and IDH2 catalyze the reaction by converting isocitrate and NADP+ into α-KG and CO2 with the concomitant generation of NADPH in the cytosol and mitochondrial matrix 0.8 SIGNOR-267370 CCDC6-RET fusion protein SIGNOR-FP9 SIGNOR SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 16946010 YES miannu RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade 0.2 SIGNOR-251986 CDK1 protein P06493 UNIPROT ELAVL1 protein Q15717 UNIPROT down-regulates activity phosphorylation Ser202 LLSQLYHsPARRFGG 9606 22936947 YES miannu Cdk1 inhibition promoted a cytoplasmic accumulation of HuR, while a predominately nuclear localization of HuR was observed under conditions of high Cdk1 activity.|Kim et al. further showed that Cdk1-dependent Ser-202 phosphorylation of HuR was essential for 14-3-3\u03b8 binding to HuR. 0.407 SIGNOR-279014 SYN2 protein Q92777 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 NO miannu Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. 0.7 SIGNOR-264106 GOLPH3 protein Q9H4A6 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity 9606 BTO:0000018;BTO:0005011 19553991 NO Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. 0.331 SIGNOR-253554 TKT protein P29401 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI down-regulates quantity chemical modification 9606 24929114 YES miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. 0.8 SIGNOR-267086 MYC protein P01106 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 11804592 YES gcesareni Through its direct interaction with smads, c-myc binds to the sp1-smad complex on the promoter of the p15(ink4b) gene, thereby inhibiting the tgf-beta-induced transcriptional activity of sp1 and smad/sp1-dependent transcription of the p15(ink4b) gene. These results suggest that oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads. 0.684 SIGNOR-114284 PTPN6 protein P29350 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr86 VADIDGQyAMTRAQR 9606 20840866 YES lperfetto In the present investigation, we demonstrate that SHP-1 dephosphorylates \u03b2-catenin on tyrosines 86 and 654 and promotes its proteasomal degradation.|SHP-1 inhibits \u03b2-catenin function by inducing its degradation and interfering with its association with TATA-binding protein. 0.557 SIGNOR-277013 GPR174 protein Q9BXC1 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256757 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser877 CFSSRRSsEASQAEG 9606 10693759 YES lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. 0.467 SIGNOR-75351 KDM5A protein P29375 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264299 ACE2 protein Q9BYF1 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage His42 RVYIHPFhLVIHNES -1 11815627 YES miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. 0.758 SIGNOR-256317 clomipramine chemical CHEBI:47780 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  0.8 SIGNOR-258874 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 YES The effect has been demonstrated using P10636-8 gcesareni Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase. 0.434 SIGNOR-60659 CDC34 protein P49427 UNIPROT SCF-FBW2 complex SIGNOR-C525 SIGNOR up-regulates activity binding 9606 25425648 YES miannu The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. 0.717 SIGNOR-277332 TFEB protein P19484 UNIPROT NDUFAF2 protein Q8N183 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). 0.2 SIGNOR-276703 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206841 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.397 SIGNOR-275771 DBP protein Q10586 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 21633182 NO miannu In addition to NHRs, Dbp, a known clock target gene, regulates expression of key metabolic genes involved in gluconeogenesis and lipogenesis (60). Because DBP levels change 100-fold in response to CLOCK/BMAL1 activation, it is conceivable that DBP generates circadian oscillation in metabolic processes such as gluconeogenesis. 0.7 SIGNOR-268028 PKA proteinfamily SIGNOR-PF17 SIGNOR KLHL3 protein Q9UH77 UNIPROT up-regulates activity phosphorylation Ser433 PMNTRRSsVGVGVVE -1 26435498 YES done miannu Consistent with the fact that S433 is a component of Akt and PKA phosphorylation motifs, in vitro kinase assay demonstrated that Akt and PKA can phosphorylate KLHL3 at S433, that was previously reported to be phosphorylated by PKC.  0.2 SIGNOR-273824 MAPK1 protein P28482 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by stabilization phosphorylation Ser566 PTWKEPVsPMELTGP 9606 BTO:0001109 28945223 YES miannu In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.  0.2 SIGNOR-276742 G6PC2 protein Q9NQR9 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266565 PINK1 protein Q9BXM7 UNIPROT RHOT2 protein Q8IXI1 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000007 22078885 YES miannu PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C). 0.718 SIGNOR-272727 adenosine smallmolecule CHEBI:16335 ChEBI inosine smallmolecule CHEBI:17596 ChEBI up-regulates quantity precursor of -1 15926889 YES Luana Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates 0.8 SIGNOR-269736 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Thr1404 GREEFYStHPHFMTQ 9606 BTO:0000938 19824698 YES lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. 0.2 SIGNOR-188433 ethanol chemical CHEBI:16236 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 8355 BTO:0000964 8700149 YES miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. 0.8 SIGNOR-258495 SDC4 protein P31431 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR form complex binding 9606 BTO:0002314 BTO:0001103 23290138 YES apalma We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells. 0.556 SIGNOR-255847 PAK1 protein Q13153 UNIPROT ARPC1B protein O15143 UNIPROT up-regulates phosphorylation Thr21 HAWNKDRtQIAICPN 9606 14749719 YES lperfetto The formation of new branched actin filament networks at the cell cortex of migrating cells is choreographed by the actin-related protein (arp) 2/3 complex. Despite the fundamental role of the arp2/3 complex in actin nucleation and branching, upstream signals that control the functions of p41-arc, a putative regulatory component of the mammalian arp2/3 complex. Pak1 phosphorylation of p41-arc regulates its localization with the arp2/3 complex in the cortical nucleation regions of cells. Pak1 phosphorylates p41-arc on threonine 21 0.532 SIGNOR-121642 AKT1 protein P31749 UNIPROT CDCA7 protein Q9BWT1 UNIPROT down-regulates phosphorylation Thr163 SRRPRRRtFPGVASR 9606 23166294 YES llicata The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus. 0.338 SIGNOR-252533 PTEN protein P60484 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR down-regulates quantity by destabilization 16055704 NO lperfetto PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex 0.278 SIGNOR-269645 MAT2B protein Q9NZL9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001938 30942439 NO miannu MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen 0.7 SIGNOR-261243 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid chemical CHEBI:91366 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194518 PRKACA protein P17612 UNIPROT APOBEC3B protein Q9UH17 UNIPROT down-regulates activity phosphorylation Thr214 LVLRRRQtYLCYEVE -1 31165764 YES miannu Here we show that protein kinase A (PKA) physically binds to A3B and phosphorylates Thr214. 0.2 SIGNOR-277455 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 SIGNOR-C110 23151663 YES gcesareni Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. 0.86 SIGNOR-199512 MAP3K7 protein O43318 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity phosphorylation Ser452 STNTHTQsSSSSSDG 9606 BTO:0000007 22216226 YES miannu We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.  0.929 SIGNOR-276364 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 18174237 YES gcesareni Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome. 0.636 SIGNOR-250136 Caspase 1 complex complex SIGNOR-C220 SIGNOR IL18 protein Q14116 UNIPROT up-regulates activity cleavage Asp36 DDENLESdYFGKLES 9606 BTO:0001370 9334240 YES lperfetto We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. 0.79 SIGNOR-256377 AKT1 protein P31749 UNIPROT CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Ser282 FFAKRKRsAPEKSSG 9606 BTO:0000150 23421998 YES lperfetto Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination 0.448 SIGNOR-252535 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 16896351 YES lperfetto In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1 0.852 SIGNOR-252015 CSNK2A1 protein P68400 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 YES gcesareni In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2 0.26 SIGNOR-144004 androgen smallmolecule CHEBI:50113 ChEBI AR protein P10275 UNIPROT up-regulates activity binding 9606 27057074 YES miannu The actions of androgens such as testosterone and dihydrotestosterone are mediated via the androgen receptor (AR), a ligand-dependent nuclear transcription factor and member of the steroid hormone nuclear receptor family.  0.8 SIGNOR-277992 LARP4B protein Q92615 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 20573744 NO miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. 0.7 SIGNOR-260939 CTSB protein P07858 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 YES miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 0.33 SIGNOR-256318 UBE2N protein P61088 UNIPROT H2AX protein P16104 UNIPROT up-regulates ubiquitination 9606 18077395 YES gcesareni In an h2ax- and mdc1-dependent manner , rnf8/ubc13 complexes go to sites of dna damage through their fha domain and initiate the synthesis of k63 polyubiquitin chains on chromatin that recruit the brca1 a complex through the uim domains of rap80. 0.2 SIGNOR-159880 CAMKK1 protein Q8N5S9 UNIPROT CAMK1 protein Q14012 UNIPROT up-regulates activity phosphorylation Thr177 DPGSVLStACGTPGY 8253780 YES llicata Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase. 0.415 SIGNOR-250717 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 BTO:0000567 16371512 YES gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell 0.876 SIGNOR-143285 PRKD1 protein Q15139 UNIPROT KIDINS220 protein Q9ULH0 UNIPROT unknown phosphorylation Ser918 RTITRQMsFDLTKLL 10116 10998417 YES lperfetto Our results provide the first physiological substrate for PKD and indicate that Kidins220 is phosphorylated by PKD at serine 919 in vivo. 0.519 SIGNOR-249052 HP protein P00738 UNIPROT APOA1 protein P02647 UNIPROT up-regulates quantity by stabilization binding 9606 17824618 YES miannu Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase. haptoglobin, when circulating at enhanced levels with free Hb during the acute phase of inflammation, might protect ApoA-I structure and function against hydroxyl radicals. 0.726 SIGNOR-252106 PRKAA1 protein Q13131 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Thr119 HNLMRRStVSLLDTY -1 23871434 YES miannu These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J). 0.2 SIGNOR-276468 RANBP3 protein Q9H6Z4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity relocalization 9606 19289081 YES lperfetto RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner. 0.436 SIGNOR-217634 SLBP protein Q14493 UNIPROT H2BC5 protein P58876 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265378 PP2B proteinfamily SIGNOR-PF18 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation 9606 18838687 YES inferred from 70% family members When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. 0.2 SIGNOR-269994 NEK2 protein P51955 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 30968157 YES miannu NEK2 silencing reduced the phosphorylation of beta-catenin at Ser33 and Ser37, but did not decrease the level of total beta-catenin.|NEK2 slightly decreased the level of total beta-catenin (XREF_FIG). 0.47 SIGNOR-278173 DFFA protein O00273 UNIPROT DFFB protein O76075 UNIPROT down-regulates binding 9606 BTO:0000567 9108473 YES amattioni Dff is a heterodimer of 40 kda and 45 kda subunits. 0.928 SIGNOR-29729 PLK1 protein P53350 UNIPROT DCTN1 protein Q14203 UNIPROT up-regulates phosphorylation Ser179 SASAGELsSSEPSTP 9606 20679239 YES lperfetto Plk1-mediated phosphorylation of p150(glued) at ser-179 positively regulates its accumulation at the nuclear envelope during prophase. 0.524 SIGNOR-167281 TYK2 protein P29597 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 YES lperfetto Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity. 0.774 SIGNOR-246943 HIF1A protein Q16665 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0001336 28623342 NO Our results demonstrate that SF(synovial fibroblasts) are highly dependent on glycolytic metabolism and that HIF-1α plays a regulatory role in glycolysis even under aerobic conditions. 0.7 SIGNOR-259380 CAV1 protein Q03135 UNIPROT SLC1A1 protein P43005 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 YES miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. 0.2 SIGNOR-264807 CSNK2A1 protein P68400 UNIPROT IGFBP3 protein P17936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser140 APGNASEsEEDRSAG 9606 BTO:0000093 10650937 YES llicata The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment. 0.339 SIGNOR-250904 LCK protein P06239 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP 10090 BTO:0000782 8114715 YES Two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. . 0.612 SIGNOR-251387 GRM3 protein Q14832 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. 0.8 SIGNOR-264934 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 23486913 YES lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation 0.755 SIGNOR-217137 ROCK1 protein Q13464 UNIPROT PPP1R12B protein O60237 UNIPROT down-regulates phosphorylation Thr646 ARQTRRStQGVTLTD 9606 22937917 YES lperfetto Phosphorylation of ppp1r12b on threonine 646 by rho kinase inhibits the activity of the pp1c-ppp1r12b complex. 0.585 SIGNOR-198812 RAB1A protein P62820 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity binding 9606 BTO:0000567 27334615 YES Giulio Thus, these data show ULK1–Rab1a interaction in intact cells and reveal that this interaction is C9orf72 dependent. 0.374 SIGNOR-261283 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 23151663 YES lperfetto Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells. 0.894 SIGNOR-227866 CTDNEP1 protein O95476 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity dephosphorylation Ser106 IPMHLATsPILSEGA 9606 BTO:0001131 17420445 YES Dullard significantly dephosphorylates mouse lipin 1b only in BHK cells (Fig. 5A). This is most clearly seen by using the antibody prepared against the phosphorylation site Ser-106.|Dephosphorylation of lipin results in its translocation to the nuclear envelope and endoplasmic reticulum membranes from the cytosol and generation of diacylglycerol 0.779 SIGNOR-248346 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 BTO:0000007 10022832 YES The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. 0.353 SIGNOR-64326 OPRD1 protein P41143 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.541 SIGNOR-256683 FBXL21P protein Q9UKT6 UNIPROT TCAP protein O15273 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 32937135 YES lperfetto FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. 0.2 SIGNOR-264853 ZBTB16 protein Q05516 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 BTO:0002882 9710637 NO fcortellessa PLZF overexpression leads to apoptosis. 0.7 SIGNOR-261686 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11018021 YES Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. 0.748 SIGNOR-244952 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRA protein P01903 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys244 FIIKGLRkSNAAERR 9606 19117940 YES miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. 0.2 SIGNOR-271411 vilanterol chemical CHEBI:75037 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20462258 YES Luana A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. | Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo 0.8 SIGNOR-257843 ABL2 protein P42684 UNIPROT GPX1 protein P07203 UNIPROT up-regulates activity phosphorylation Tyr98 EILNSLKyVRPGGGF 9606 12893824 YES lperfetto GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress. 0.323 SIGNOR-104328 RSPO3 protein Q9BXY4 UNIPROT LGR5 protein O75473 UNIPROT up-regulates binding 9606 21693646 YES gcesareni Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation 0.656 SIGNOR-174535 PRKCE protein Q02156 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.331 SIGNOR-251632 CTDSPL2 protein Q05D32 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20932329 NO Regulation of transcription miannu CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood. 0.2 SIGNOR-251779 LPAR4 protein Q99677 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-256928 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 21807946 YES miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). 0.378 SIGNOR-276353 APC-c complex SIGNOR-C150 SIGNOR KIF2C protein Q99661 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24510915 YES miannu Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). 0.278 SIGNOR-266111 STAT3 protein P40763 UNIPROT STAT1 protein P42224 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 22693070 YES miannu In summary, we report in this study that STAT1 expression is upregulated by nuclear EGFR, EGFRvIII and HER2, and that STAT3 synergizes with the three receptors to further enhance STAT1 expression. These novel findings establish a novel link between the mitogenic ErbB signaling pathway and the inflammatory pathway mediated by STAT1. The oncogenic transcription factor STAT3 binds to the STAT1 promoter and synergizes with nuclear EGFR to significantly enhance STAT1 gene expression. 0.614 SIGNOR-263650 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 YES gcesareni Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab). 0.906 SIGNOR-58122 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 10737616 YES lperfetto Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease. 0.564 SIGNOR-249416 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.41 SIGNOR-249682 MTMR2 protein Q13614 UNIPROT 1-phosphatidyl-1D-myo-inositol 3-phosphate(3-) smallmolecule CHEBI:58088 ChEBI down-regulates quantity chemical modification 9606 18429927 YES miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns 0.8 SIGNOR-269807 RPS6KB2 protein Q9UBS0 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser286 LRSCSLGsLGALGPA -1 27407113 YES miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  0.334 SIGNOR-274069 tRNA(Met) smallmolecule CHEBI:29173 ChEBI Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270401 CHEK1 protein O14757 UNIPROT MDM4 protein O15151 UNIPROT down-regulates activity phosphorylation Ser342 SKLTHSLsTSDITAI 9606 BTO:0000971 16163388 YES llicata MDMX is a direct substrate for Chk1 and Chk2 in vitro. Phosphorylation of MDMX leads to increased binding to MDM2 and more efficient ubiquitination, providing an explanation for the enhanced degradation of MDMX after DNA damage. | Western blot showed that Chk1 modified S342 and S367, but with strong preference for S342. 0.521 SIGNOR-250770 GREB1 protein Q4ZG55 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 30154312 NO miannu GREB1 is an early estrogen-responsive gene, and its expression is correlated with estrogen levels in breast cancer patients. Additionally, GREB1 responds to androgen in prostate cancer cells, and can stimulate the proliferation of breast, ovarian, and prostate cancer cells. 0.7 SIGNOR-265886 KIF3A protein Q9Y496 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272531 ABL1 protein P00519 UNIPROT SRCIN1 protein Q9C0H9 UNIPROT unknown phosphorylation Tyr396 LVKGEGLyADPYGLL 9606 BTO:0000142 23383002 YES llicata Mapping of p140cap phosphorylation sites: the eplya and eglya motifs have a key role in tyrosine phosphorylation and csk binding, and are substrates of the abl kinase 0.2 SIGNOR-200858 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 17108107 YES gcesareni We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392 0.755 SIGNOR-150834 PP2 chemical CHEBI:78331 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 BTO:0001760 12351660 YES gcesareni Treatment of l6 cells with pp2 or su6656, specific inhibitors of src family kinases, and transient transfection of dominant-inhibitory src inhibited the formation of myotubes and expression of myogenin. 0.8 SIGNOR-93549 KLF2 protein Q9Y5W3 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12426306 NO fspada Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta. 0.418 SIGNOR-95519 DYRK1A protein Q13627 UNIPROT SRSF1 protein Q07955 UNIPROT unknown phosphorylation Ser238 SRGSPRYsPRHSRSR 9606 BTO:0000142 18658135 YES gcesareni Here, we demonstrate that dyrk1a, a kinase encoded by a gene in the ds critical region, phosphorylates alternative splicing factor (asf) at ser-227, ser-234, and ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. 0.392 SIGNOR-179615 HERC2 protein O95714 UNIPROT NEURL4 protein Q96JN8 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 22261722 YES miannu NEURL4 is a substrate of HERC2, and together these results indicate that the NEURL4-HERC2 complex participates in the ubiquitin-dependent regulation of centrosome architecture. 0.457 SIGNOR-272921 methysergide chemical CHEBI:584020 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9205951 YES miannu The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. 0.8 SIGNOR-258616 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Thr28 AELLGADtQGSEFEF 9606 23356578 YES lperfetto Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively 0.971 SIGNOR-200793 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 YES lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.384 SIGNOR-217577 H2AC11 protein P0C0S8 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 phosphorylation:Thr121 AVLLPKKtESHHKAK phosphorylation:Thr346 LEEGVHLtPFRQKVS 24055156 YES lperfetto The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl.|The centromeric localization of Sgo1 requires histone H2A phosphorylation at T120 (H2A-pT120) by the kinase Bub1. 0.2 SIGNOR-265262 CXCL2 protein P19875 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 38309677 YES miannu CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively 0.739 SIGNOR-277718 AKT1 protein P31749 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser652 LERPFRPsVTSVGHV -1 24548923 YES miannu Here we show that Akt-mediated NF-κB activation is mediated at least in part through direct phosphorylation of the adaptor protein Carma1, which we previously demonstrated could interact with Akt in a TCR ligation-dependent manner. The putative Akt phosphorylation sites in Carma1 are distinct from known PKC consensus sites. Mutation of S551, S637 and S645 in Carma1 to non-phosphorylatable residues decreased phosphorylation of GST-Carma1-linker construct by Akt in vitro.  0.523 SIGNOR-276256 FBXW12 protein Q6X9E4 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT down-regulates quantity by destabilization binding -1 26171402 YES miannu FBXW12 causes depletion of endogenous and plasmid-derived IL-22R in lung epithelia, binds the E3 ligase constituent Skp-1, and facilitates ubiquitination of IL-22R in vitro. 0.343 SIGNOR-272426 PDHX protein O00330 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates activity binding 9606 BTO:0000120 12783165 YES miannu In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. 0.2 SIGNOR-254904 PLK1 protein P53350 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser216 IPLMLNDsGSAHSMP 9606 18794143 YES lperfetto Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway. 0.444 SIGNOR-180915 TNC protein P24821 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 BTO:0001521 38058842 YES miannu TNC is shown to bind to integrin receptors expressed in adjacent PAAD cells, thereby inducing EMT. In addition, TNC expression in CAFs had significant positive correlations with ITGαV, ITGβ1, or ITGβ3 expression in cancer cells, which supports our speculations that the TNC-integrin signaling axis promotes the EMT pathway in cancer cells. 0.429 SIGNOR-277736 TRIM72 protein Q6ZMU5 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23965929 YES miannu Here, we demonstrate that MG53 induces IRS-1 ubiquitination with the help of the E2 enzyme UBE2H during skeletal myogenesis by examining MG53 disrupted skeletal muscle cells and tissues.|The IRS-1 protein level was decreased by MG53 in a concentration dependent manner and was restored by the addition of MG132, a proteasome inhibitor (XREF_FIG; XREF_SUPPLEMENTARY). 0.478 SIGNOR-278520 USF1 protein P22415 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 NO miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. 0.2 SIGNOR-222554 MYOG protein P15173 UNIPROT ITGA7 protein Q13683 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8798472 YES lperfetto Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development. 0.283 SIGNOR-241521 UCHL3 protein P15374 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity deubiquitination Lys64 KKELINIkGISEAKA 27941124 YES lperfetto Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. 0.326 SIGNOR-275909 EIF1AX protein P47813 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity relocalization 9606 12514125 YES lperfetto Translation initiation factor 1A (eIF1A) is predicted to bind in the decoding site of the 40S ribosome and has been implicated in recruitment of the eIF2-GTP-Met-tRNA i Met ternary complex (TC) and ribosomal scanning.  0.724 SIGNOR-269147 perfluorooctanoic acid chemical CHEBI:35549 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 YES miannu Human, mouse, and rat PPARα were activated by PFOA isomers and PFOS. 0.8 SIGNOR-268790 ARHGAP33 protein O14559 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.443 SIGNOR-260491 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates binding 9606 15767678 YES gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. 0.663 SIGNOR-134561 PLAU protein P00749 UNIPROT PLAUR protein Q03405 UNIPROT up-regulates binding 9606 16456079 YES gcesareni The urokinase plasminogen activator binds to its cellular receptor with high affinity and initiates signaling cascades that are implicated in pathological processes including tumor growth, metastasis, and inflammation. 0.89 SIGNOR-144306 TRADD protein Q15628 UNIPROT TRAF5 protein O00463 UNIPROT up-regulates binding 9606 19632174 YES gcesareni Upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor-associated factor 2 ,traf2. 0.606 SIGNOR-187058 AGRN protein O00468 UNIPROT LRP4 protein O75096 UNIPROT up-regulates activity binding 9606 BTO:0000887 23458718 YES miannu AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer. 0.848 SIGNOR-273849 PLK1 protein P53350 UNIPROT TEX14 protein Q8IWB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser437 QKAATVKsDIYSFSM 9606 BTO:0001363 22405274 YES miannu We show that phosphorylation of Tex14 by Plk1 during metaphase is required for proteosome dependent degradation of Tex14 and transition from metaphase to anaphase. Phosphorylation of Tex14 Ser431 by Plk1 promotes Tex14 depletion. 0.354 SIGNOR-273529 HNRNPA1 protein P09651 UNIPROT TRA2B protein P62995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31311954 YES lperfetto HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells. 0.698 SIGNOR-262288 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 10090 BTO:0004052 23996074 YES irozzo In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL. The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1 0.2 SIGNOR-255870 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser330 SFRVRASsDGEGTMS -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.34 SIGNOR-250908 hsa-miR-183-5p mirna URS0000528CBC_9606 RNAcentral LRP6 protein O75581 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001596 29402412 YES Parnian Taken together, these data indicate that miR-183 down-regulates LRP6 expression by directly targeting its 3'-UTR. 0.4 SIGNOR-278842 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 YES gcesareni We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling. 0.2 SIGNOR-252789 STK11 protein Q15831 UNIPROT CPS1 protein P31327 UNIPROT down-regulates quantity transcriptional regulation 9606 BTO:0002553 28538732 NO Luana LKB1 negatively regulates CPS1 transcription 0.295 SIGNOR-267919 selumetinib chemical CHEBI:90227 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck lperfetto 0.8 SIGNOR-244823 AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 YES lperfetto We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity 0.2 SIGNOR-244236 DIO proteinfamily SIGNOR-PF83 SIGNOR L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity chemical modification 9606 34674502 YES scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† 0.8 SIGNOR-267043 Adechlorin chemical CID:125913 PUBCHEM ADA protein P00813 UNIPROT down-regulates activity chemical inhibition 9606 2433905 YES miannu 2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin. 0.8 SIGNOR-259262 LPAR4 protein Q99677 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257432 TGFBI protein Q15582 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 26387839 YES lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers 0.439 SIGNOR-253270 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR ABCB1 protein P08183 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 26299618 YES miannu Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation.Purified in vitro translated FLAG-tagged P-gp along with E2 (UbcH5c), E3 ligase FBXO21, Cul1, Skp1, Roc1 purified from Sf-9 insect cells were incubated in vitro. 0.2 SIGNOR-272425 UXT protein Q9UBK9 UNIPROT URI1 prefoldin co-chaperone complex SIGNOR-C514 SIGNOR form complex binding 9606 30484151 YES miannu In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR93 0.609 SIGNOR-270916 MLL3 complex complex SIGNOR-C446 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 34156443 YES miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 0.2 SIGNOR-268812 SP1 protein P08047 UNIPROT RLIM protein Q9NVW2 UNIPROT up-regulates quantity by expression transcriptional regulation 23650532 YES lperfetto Thus, RLIM is a novel target of p53, and p53 exerts its inhibitory effect on RLIM expression by interfering with Sp1-mediated transcriptional activation on RLIM.|Although p53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter. 0.2 SIGNOR-268980 FBN1 protein P35555 UNIPROT EFEMP2 protein O95967 UNIPROT down-regulates activity binding 9606 19570982 YES Regulation of binding miannu Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin. 0.394 SIGNOR-251860 L-ornithine smallmolecule CHEBI:15729 ChEBI M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates activity 24669294 NO apalma While investigating the factors that regulate macrophage arginine metabolism, Mills and colleagues found that macrophages activated in mouse strains with Th1 and Th2 backgrounds differed qualitatively in their ability to respond to the classic stimuli IFN-γ or lipopolysaccharide (LPS) or both and defined an important metabolic difference in the pathway: M1 macrophages made the toxic nitric oxide (NO), whereas M2 macrophages made the trophic polyamines 0.7 SIGNOR-256076 CALM2 protein P0DP24 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 BTO:0001853 24379783 YES miannu Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer 0.506 SIGNOR-266323 CDH1 protein P12830 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 15601859 NO lperfetto A hallmark characteristic of epithelial tumor progression as well as some processes of normal development is the loss of the epithelial phenotype and acquisition of a motile or mesenchymal phenotype. Such epithelial to mesenchymal transitions are accompanied by the loss of E-cadherin function by either transcriptional or posttranscriptional mechanisms. 0.7 SIGNOR-252261 Quazepam chemical CHEBI:8694 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). 0.8 SIGNOR-263800 FBLN5 protein Q9UBX5 UNIPROT ELN protein P15502 UNIPROT up-regulates binding 9606 19570982 YES miannu Our data show that fibulin-5 can interact with tropoelastin or with fibrillin-1, implying a chaperone role for fibulin-5 in directing elastin onto microfibrils 0.76 SIGNOR-186603 (R)-(+)-sulpiride chemical CHEBI:64122 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258735 TAF3/TRF3 complex SIGNOR-C23 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 10090 BTO:0000165 17704303 NO llicata Here we report that differentiation of myoblast to myotubes involves the disruption of the canonical holo-TFIID and replacement by a novel TRF3/TAF3 (TBP-related factor 3/TATA-binding protein-associated factor 3) complex. 0.7 SIGNOR-237621 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser199 PRPEHTKsVYTRSVI 9534 9032240 YES miannu Cdc42 and Rac1 cause alpha-PAK autophosphorylation and kinase activation. 0.2 SIGNOR-250216 FGFR1 protein P11362 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates activity phosphorylation 10116 BTO:0002809 9182757 YES fspada In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. 0.867 SIGNOR-236944 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser66 TSLVEGRsCGWVPPP -1 14688255 YES miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. 0.698 SIGNOR-250154 FGFR2 protein P21802 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 22891331 YES llicata Fgfrs phosphorylate pten at tyrosine 240 0.428 SIGNOR-191793 SLC6A4 protein P31645 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity relocalization 9606 BTO:0000132 17506858 YES miannu Serotonin (5HT) is a platelet-stored vasoconstrictor. Altered concentrations of circulating 5HT are implicated in several pathologic conditions, including hypertension. The actions of 5HT are mediated by different types of receptors and terminated by a single 5HT transporter (SERT). Therefore, SERT is a major mechanism that regulates plasma 5HT levels to prevent vasoconstriction and thereby secure a stable blood flow. 0.8 SIGNOR-263952 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0000848 23450633 YES gcesareni Thrombin, actin through par1 promotes tumor cell proliferation, migration and contributes to the metastatic potenital of breast, prostate, gastrointestinal cancers and melanoma. 0.887 SIGNOR-199788 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.621 SIGNOR-161589 CHD4 protein Q14839 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.817 SIGNOR-263844 TFAP2C protein Q92754 UNIPROT ECM1 protein Q16610 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 NO miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 0.286 SIGNOR-255396 PRKACA protein P17612 UNIPROT TPH2 protein Q8IWU9 UNIPROT up-regulates phosphorylation Ser19 YWARRGFsLDSAVPE 9606 18339632 YES llicata We also demonstrate that phosphorylation of serine 19, a protein kinase a consensus site located in this n-terminal domain, results in increased tph2 stability and consequent increases in enzyme output in cell culture systems 0.255 SIGNOR-178018 Oxatomide chemical CHEBI:31943 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257791 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11314020 NO miannu We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1. 0.329 SIGNOR-254435 TLN1 protein Q9Y490 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.698 SIGNOR-257624 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr93 TSSLPEGyYEEAVPL 9534 9655255 YES lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. 0.573 SIGNOR-246359 DYRK1A protein Q13627 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Thr75 KPAPRPStQHKHERL 9606 18678649 YES gcesareni We identify dyrk1a as one of the protein kinases of sprouty2. We show that dyrk1a interacts with and regulates the phosphorylation status of sprouty2. Moreover, we identify thr75 on sprouty2 as a dyrk1a phosphorylation site in vitro and in vivo. 0.304 SIGNOR-179828 IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity -1 8511589 NO lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. 0.869 SIGNOR-238617 ULK1 protein O75385 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C15 21460634 YES lperfetto Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. 0.571 SIGNOR-173047 RPL28 protein P46779 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.827 SIGNOR-262472 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide chemical CHEBI:95082 ChEBI BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition -1 24015967 YES Gianni This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation 0.8 SIGNOR-262202 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr75 VLTGKLTtVFLPIVY -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.374 SIGNOR-263597 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 YES inferred from 70% family members lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.392 SIGNOR-270150 LPAR6 protein P43657 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257004 dabrafenib chemical CHEBI:75045 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 24720932 YES miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations 0.8 SIGNOR-259215 SOX2 protein P48431 UNIPROT ABCC6 protein O95255 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21531766 NO miannu ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. 0.283 SIGNOR-255182 MAPK1 protein P28482 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 YES lperfetto Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity 0.37 SIGNOR-161855 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 YES llicata Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo 0.68 SIGNOR-135696 YARS1 protein P54577 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 16429158 YES miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr 0.8 SIGNOR-270519 PRRX1 protein P54821 UNIPROT MAF protein O75444 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.354 SIGNOR-221893 DZIP3 protein Q86Y13 UNIPROT H2AC12 protein Q96KK5 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271760 MECP2 protein P51608 UNIPROT MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR form complex binding 10116 9620804 YES Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. 0.7 SIGNOR-265070 DAPK1 protein P53355 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates activity phosphorylation Ser308 ARKKWKQsVRLISLC 9606 BTO:0000007 11579085 YES lperfetto The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism.These results are consistent with a molecular model in which phosphorylation on ser(308) stabilizes a locked conformation of the cam-regulatory domain within the catalytic cleft and simultaneously also interferes with cam binding. 0.2 SIGNOR-110807 GAST protein P01350 UNIPROT SLC4A2 protein P04920 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000269 22228178 NO Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation. 0.277 SIGNOR-254251 SYK protein P43405 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr281 LEETNNDyETADGGY -1 8756631 YES lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. 0.672 SIGNOR-247590 DRD3 protein P35462 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.547 SIGNOR-256702 AKT3 protein Q9Y243 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 YES lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta 0.417 SIGNOR-217466 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT up-regulates phosphorylation Ser172 NRVKRRPsPYEMEIT 9606 22310283 YES llicata The phosphorylation of serine 172 of tal1 specifically destabilizes tal1 interaction with histone demethylase lsd1 and, therefore, leads to the activation of the certain tal1 target genes in differentiated erythroid cells or t-cell leukemia. 0.2 SIGNOR-195983 FOXA1 protein P55317 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19486887 NO miannu The results showed overexpression of Foxa1 promoted the expression of HSP72, while Foxa1 depletion, induced by antisense oligonucleotides, decreased the expression of HSP72 in MCF-7 cells under normal and heat stress condition. 0.2 SIGNOR-254164 pentazocine chemical CHEBI:7982 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258766 MAPK14 protein Q16539 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 12058028 YES gcesareni The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro. 0.446 SIGNOR-89436 MARK4 protein Q96L34 UNIPROT ODF2 protein Q5BJF6 UNIPROT up-regulates activity phosphorylation 9606 23400999 YES miannu Collectively, our data indicate that MARK4 interacts with ODF2 in vivo and phosphorylates ODF2 in vitro.|Collectively, our data support the model that MARK4 promotes ciliogenesis by acting upstream of ODF2. 0.515 SIGNOR-278961 Non-structural protein 6 protein P0DTD1-PRO_0000449624 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 32979938 YES miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). 0.2 SIGNOR-262510 JUN protein P05412 UNIPROT CFI protein P05156 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10630630 NO miannu The production of CFI by Hep G2 cells was enhanced in a dose- and time-dependent fashion by 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), a potent PKC activator. The enhancement of the activity of transfected chimeric CAT constructs by TPA was abrogated by calphostin C and by pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB and AP-1 transactivation). These results indicate that TPA regulation of CFI gene requires PKC signalling and is mediated by via a TPA response element (TRE) in the CFI promoter region located at -136/-130 and involves the transactivation of AP-1 and NF-kappaB transcription factors 0.2 SIGNOR-254787 DLGAP2 protein Q9P1A6 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.756 SIGNOR-264589 DCTPP1 protein Q9H773 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0001033 29874556 NO miannu Autophagy Induced by Overexpression of DCTPP1 Promotes Tumor Progression and Predicts Poor Clinical Outcome in Prostate Cancer 0.7 SIGNOR-261177 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 1689310 YES llicata We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation. 0.84 SIGNOR-20984 AHCYL1 protein O43865 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates activity relocalization 10090 BTO:0000988 21317537 YES lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, 0.2 SIGNOR-264645 EREG protein O14944 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000150 22891299 YES gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4. 0.705 SIGNOR-191788 HSPA1B protein P0DMV9 UNIPROT PACRG protein Q96M98 UNIPROT up-regulates quantity by stabilization binding -1 12150907 YES miannu Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo. 0.2 SIGNOR-272891 STAT4 protein Q14765 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 22740693 NO miannu It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. 0.307 SIGNOR-255246 BRCA1 protein P38398 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 BTO:0003323 SIGNOR-C297 12485996 YES lperfetto The major genetic evidence supporting ubiquitin ligase function for BRCA1 in vivo comes from studies on the FANCD2 protein. Whereas in wild‐type cells the FANCD2 protein co‐localizes with BRCA1 in nuclear foci and becomes monoubiquitylated in response to DNA damage, HCC1937 cells, which encode a mutated form of BRCA1, are largely defective for both monoubiquitylation of FANCD2 and foci formation 0.845 SIGNOR-263236 PGAM5 protein Q96HS1 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000007 19590015 YES miannu PGAM5 Is a Protein Ser/Thr Phosphatase That Activates ASK1. PGAM5 Dephosphorylates ASK1. This dephosphorylation unleashes phosphorylation ofThr-838 in the kinase domain, with activation of ASK1. 0.438 SIGNOR-277984 ECM stimulus SIGNOR-ST20 SIGNOR AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259051 NR1I3 protein Q14994 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 12896978 YES gcesareni Therefore, both car-rxr heterodimers and car monomers can contribute to the gene activating function of pbrems in car target genes. 0.469 SIGNOR-104441 CRABP2 protein P29373 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000551 30696915 NO Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. 0.7 SIGNOR-259371 hsa-mir-126-5p mirna URS00001D69F6_9606 RNAcentral VCAM1 protein P19320 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004465 25015105 YES Parnian In this study, we show that miR-126 transferred to endothelial cells via LAMA84 exosomes directly targets the 3’ UTR of CXCL12 and VCAM1 mRNA, significantly down-regulating the expression and function of both proteins. 0.4 SIGNOR-278010 PDCD1 protein Q15116 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000782 16227604 NO Barakat Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation. 0.344 SIGNOR-275408 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr686 VKDSQVGtVNYMPPE 9606 19120698 YES llicata Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity, autophosphorylation at the p+1 loop (t686) is associated with the active kinase. 0.2 SIGNOR-183030 FGF6 protein P10767 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 YES gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. 0.731 SIGNOR-18570 RPS6KA2 protein Q15349 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates activity phosphorylation Ser351 GRRGRLPsKPKQPPD 10116 11883936 YES From PMID 9395454: We have shown that the in vitro phosphorylation of Ser350 located within the "A-box," a motif necessary for DNA binding by NGFI-B, results in a decrease in the binding of NGFI-B to its response element lperfetto Phosphorylation of a residue in the DNA-binding region (Ser-350 of NGFI-B and 354 of Nur77) has been described in detail to have effect on the transcriptional function of the protein [11, 24]. Growth-related kinase pp90rsk, but not ERK1 (pp44mapk), was shown to phosphorylate recombinant Nur77 in vitro in the DNA binding domain, but not the amino-terminus, using an immune complex kinase as- say [11]. 0.367 SIGNOR-249429 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr286 LQIDDNEyAYLKAII 9606 22308320 YES lperfetto Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function. 0.365 SIGNOR-195896 2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide chemical CID:121427831 PUBCHEM BRD3 protein Q15059 UNIPROT down-regulates quantity chemical inhibition 9606 29764999 YES Monia DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells 0.8 SIGNOR-261096 SMURF1 protein Q9HCE7 UNIPROT UBXN6 protein Q9BZV1 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272702 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser689 SQEFPYKsEMDSMPY 9606 BTO:0000567 34198826 YES miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. 0.25 SIGNOR-276660 INSR protein P06213 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates activity phosphorylation 9606 11604231 YES miannu Thus, Tyr phosphorylation of Sam68 by IR could modulate its association with the splicing machinery in a similar way to that described for p59 fyn, and this way, it could influence splice site selection. 0.363 SIGNOR-278946 CSNK2A1 protein P68400 UNIPROT HOXB7 protein P09629 UNIPROT down-regulates activity phosphorylation Ser133 IYPWMRSsGTDRKRG 10090 BTO:0002882 11290787 YES llicata Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation. 0.345 SIGNOR-250896 M1_polarization phenotype SIGNOR-PH54 SIGNOR IFNG protein P01579 UNIPROT up-regulates 9606 BTO:0000801 32454942 NO miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ 0.7 SIGNOR-263827 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 23663276 YES milica In classical il-6 signaling, the cytokine first binds to the membrane-bound il-6 receptor (il-6r;cd126) that is induced to associate with a homodimer of gp130 which then transmits the intracellular signal. 0.751 SIGNOR-202033 PRKACA protein P17612 UNIPROT ACADVL protein P49748 UNIPROT up-regulates activity phosphorylation Ser586 VVVLSRAsRSLSEGH -1 19889959 YES lperfetto As shown in Fig. 2C, an in vitro kinase assay carried out using PKA and a GST fusion protein containing the COOH-terminal 258 amino acids showed the protein to be efficiently phosphorylated in a time-dependent manner. |Furthermore, a phosphorylation-negative mutant (S586A) VLCAD shows reduced electron transfer activity and a strong dominant-negative effect on fatty acid beta-oxidation. 0.2 SIGNOR-264422 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2279 PVQPNPMsPQQHMLP 9606 17623675 YES lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. 0.466 SIGNOR-156887 DSCAM protein O60469 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR down-regulates 9606 BTO:0000938 30745320 NO miannu The DSCAM/L1 transcriptome data sets also contained a significant number of genes known to regulate synapse formation or function.Increased nuclear DSCAM levels inhibit synapse formation 0.7 SIGNOR-264321 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000785 15084608 YES lperfetto We report here that one important mechanism of nik regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (traf3). Traf3 physically associates with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome. 0.585 SIGNOR-124233 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser795 SPYKFPSsPLRIPGG 9606 SIGNOR-C18 23336272 YES gcesareni Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression. 0.929 SIGNOR-200487 BRK1 protein Q8WUW1 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 23939472 NO lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  0.7 SIGNOR-261491 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser545 PTSATKTsPLNSSGS 10090 BTO:0000964 34048556 YES lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. 0.258 SIGNOR-268339 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203584 FYN protein P06241 UNIPROT ACP1 protein P24666 UNIPROT up-regulates activity phosphorylation Tyr132 QLIIEDPyYGNDSDF 9534 BTO:0004055 9038134 YES We identify Tyr-131 as the major phosphorylation site and Tyr-132 as a minor site and the Src family PTKs Lck and Fyn as enzymes capable of phosphorylating these sites in vivo and in vitro. Both Tyr-131 and Tyr-132 are located next to the catalytic pocket of LMPTP, and especially, Tyr-131 seems to be important for the activity of LMPTP. Phosphorylation of Tyr-131 or Tyr-132, particularly the former, caused an increase in the activity of LMPTP. 0.383 SIGNOR-251149 TRPV1 protein Q8NER1 UNIPROT PRKCB protein P05771 UNIPROT up-regulates activity binding 9606 BTO:0000007 24920628 YES miannu  In the present study, we report that the sensitivity of TRPV1 channels is determined by PKCβII. TRPV1 binds directly to PKCβII and subsequently activates PKCβII. Activated PKCβII then enhances the responsiveness of TRPV1 to thermal and chemical stimuli through a phosphorylation-dependent mechanism. 0.2 SIGNOR-276639 mTORC1 complex SIGNOR-C3 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 YES azuccotti Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain [..]. Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. 0.465 SIGNOR-255842 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248521 ATP7B protein P35670 UNIPROT copper(1+) smallmolecule CHEBI:49552 ChEBI up-regulates quantity relocalization 24706876 YES lperfetto WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper out of cells by trafficking from the TGN to the plasma membrane. 0.8 SIGNOR-272297 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 10882715 YES gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. 0.846 SIGNOR-78911 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr1102 MLEERKTyVNTTLYE 9606 BTO:0001176 20973951 YES miannu This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor. 0.2 SIGNOR-259834 PIN1 protein Q13526 UNIPROT KLF10 protein Q13118 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000018 23994618 YES miannu RAF1 phosphorylates the Thr93 site of KLF10 in vivo. Since the phosphorylation of Thr93 enables KLF10 and PIN1 to bind, it seems likely that RAF-1 will have an effect on KLF10 stability that is similar to that of PIN1.PIN1 facilitates KLF10 protein degradation. ( 0.2 SIGNOR-276503 NFIA protein Q12857 UNIPROT RBFOX3 protein A6NFN3 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.261 SIGNOR-268911 Caspase 3 complex complex SIGNOR-C221 SIGNOR Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000142 10200555 NO amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation 0.7 SIGNOR-256481 PKC proteinfamily SIGNOR-PF53 SIGNOR ARHGEF6 protein Q15052 UNIPROT down-regulates activity phosphorylation Ser640 RKTERKPsEEEYVIR 9606 BTO:0000132 26507661 YES lperfetto ARHGEF6 is a Rho guanine nucleotide exchange factor for Rac1 and constitutively bound to GIT1. NO and PGI2 activate PKG and PKA, respectively and both kinases phosphorylate ARHGEF6 on Ser-684 and possibly on Ser-640. Phosphorylation of ARHGEF6 results in the assembly of a GIT1-ARHGEF6–14-3-3 complex. These changes might contribute to PGI2- and NO-mediated Rac1 inhibition. 0.2 SIGNOR-272164 Certolizumab (Cimzia) antibody DB08904 DRUGBANK TNF protein P01375 UNIPROT down-regulates activity binding 9606 32207094 YES Certolizumab pegol (Cimzia®) is a PEGylated, Fab'-only, recombinant humanized antibody against TNF-α.  0.4 SIGNOR-272492 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 YES milica In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. 0.839 SIGNOR-197647 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser114 EETRTPEsQPDTPPG 9606 21824916 YES lperfetto We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro. 0.648 SIGNOR-176016 CHEK1 protein O14757 UNIPROT ASF1A protein Q9Y294 UNIPROT up-regulates activity phosphorylation Ser166 KLEDAESsNPNLQSL 9606 BTO:0002181 33503415 YES miannu Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. 0.415 SIGNOR-277620 WASF2 protein Q9Y6W5 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 YES lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  0.91 SIGNOR-261871 A4/b1 integrin complex SIGNOR-C162 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269011 PK proteinfamily SIGNOR-PF80 SIGNOR pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 15996096 YES miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). 0.8 SIGNOR-266540 Ub:E2 complex SIGNOR-C497 SIGNOR MAP3K1 protein Q13233 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271008 SPI1 protein P17947 UNIPROT CD14 protein P08571 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12393465 NO apalma In patients with t(8;21), expression of the cell surface markers CD11b, CD14, and CD64 was less in comparison to patients without t(8;21) (Figure 5B). CD14 and CD64 promoters have putative PU.1 binding sites but not AML1-, C/EBPα-, or MEF-binding sites suggesting that down-regulation of the function of PU.1 by AML1-ETO could possibly be an important step in progression toward leukemia. 0.424 SIGNOR-255696 AKT1 protein P31749 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 12535517 YES gcesareni One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. 0.594 SIGNOR-252593 ARHGAP39 protein Q9C0H5 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.575 SIGNOR-260495 LRRFIP1 protein Q32MZ4 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 14522076 YES Luana GC-binding factor 2 (GCF2) is a transcriptional repressor that decreases activity of the epidermal growth factor receptor (EGFR) and other genes. |Deletion mutants of GCF2 revealed that amino acids 429–528 are required for both DNA binding and repression of the EGFR promoter. 0.293 SIGNOR-266057 CTDSPL2 protein Q05D32 UNIPROT STK35/PDIK1L complex SIGNOR-C552 SIGNOR up-regulates quantity by stabilization dephosphorylation 9606 BTO:0002181 35021089 YES miannu Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport.We provide evidence that SCP4 regulates STK35/PDIK1L through two distinct mechanisms: catalytic removal of inhibitory phosphorylation and by promoting kinase stability. 0.319 SIGNOR-273772 KDM6A protein O15550 UNIPROT ELF4 protein Q99607 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 YES miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase 0.279 SIGNOR-260031 NRBF2 protein Q96F24 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates activity binding 9606 BTO:0001938 phosphorylation:Ser113;Ser120 AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL 28059666 YES miannu NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. 0.687 SIGNOR-265879 CNTN6 protein Q9UQ52 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 BTO:0000938 15082708 YES gcesareni Here, we establish that nb-3, a member of the f3/contactin family, acts as a novel notch ligand to participate in oligodendrocyte generation. Nb-3 triggers nuclear translocation of the notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via deltex1. 0.586 SIGNOR-124151 GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity transcriptional regulation 9606 19772889 YES These findings indicate that fatty marrow replacement in AA patients can be explained by downregulation of GATA-2 and overexpression of PPARgamma in MSCs. Decreased expression of GATA-2 might be responsible for the pathogenesis and development of the clinical features of the disease. 0.369 SIGNOR-259949 PRKCA protein P17252 UNIPROT FLNC protein Q14315 UNIPROT up-regulates quantity by stabilization phosphorylation Ser2236 ERLGSFGsITRQQEG 10090 BTO:0000165 32444788 YES miannu We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236. 0.339 SIGNOR-262617 SAR1A protein Q9NR31 UNIPROT SEC23B protein Q15437 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 YES lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 0.677 SIGNOR-265298 PAMPs stimulus SIGNOR-ST11 SIGNOR AIM2 protein O14862 UNIPROT up-regulates activity 16037825 NO lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-256423 EEF1A1P5 protein Q5VTE0 UNIPROT Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269547 ABL1 protein P00519 UNIPROT NCK1 protein P16333 UNIPROT up-regulates phosphorylation Tyr105 VDPGERLyDLNMPAY 9606 22327338 YES lperfetto Activated c-abl reduces the amplitude of mitogen-activated protein kinases (erk1/2, jnks and p38) activation in a dose-dependent manner by a negative feedback mechanism. By analysis of the adaptor proteins nck1 and grb2 mutants we further show that the negative loop on p38 is mediated by c-abl phosphorylation at tyrosine 105 of the adaptor protein nck1 0.401 SIGNOR-196043 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT up-regulates phosphorylation Tyr265 MTYVSSFyHAFSGAQ 9606 23454549 YES lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin 0.557 SIGNOR-192191 VARS1 protein P26640 UNIPROT valine smallmolecule CHEBI:27266 ChEBI down-regulates quantity chemical modification 9606 30755602 YES miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 0.8 SIGNOR-270526 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr4 yHAANQSY 9606 23454549 YES lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin 0.557 SIGNOR-192199 SCF-FBW7 complex SIGNOR-C135 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity ubiquitination 9606 20852628 YES gcesareni We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. 0.577 SIGNOR-243757 NFASC protein O94856 UNIPROT ANK2 protein Q01484 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 YES miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. 0.693 SIGNOR-266716 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 10567369 YES lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 0.758 SIGNOR-244858 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation 9606 12832467 YES lperfetto Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. 0.718 SIGNOR-102648 TAL1 protein P17542 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 NO miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. 0.277 SIGNOR-253924 DCC protein P43146 UNIPROT MYO10 protein Q9HD67 UNIPROT up-regulates activity binding 10090 BTO:0000938 17237772 YES miannu Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin. 0.686 SIGNOR-268281 C3 protein P01024 UNIPROT C3 protein P01024 UNIPROT up-regulates activity cleavage Arg748 ASHLGLArSNLDEDI 9606 26806831 YES lperfetto C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion. 0.2 SIGNOR-263484 CSNK2A1 protein P68400 UNIPROT CAV2 protein P51636 UNIPROT up-regulates activity phosphorylation Ser36 DPEKFADsDQDRDPH 9606 BTO:0001130 12743374 YES lperfetto We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae 0.321 SIGNOR-101110 NR3C1 protein P04150 UNIPROT NR2F2 protein P24468 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14739255 NO gcesareni Gralpha, but not grbeta, enhanced coup-tfii-induced transactivation of the simple coup-tfii-responsive 7alpha-hydroxylase promoter through the transcriptional activity of its activation function-1 domain, whereas coup-tfii repressed gralpha-induced transactivation of the glucocorticoid-responsive promoter by attracting the silencing mediator for retinoid and thyroid hormone receptors. 0.352 SIGNOR-121422 BUB1 protein O43683 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity relocalization 11402067 YES lperfetto Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity 0.96 SIGNOR-252018 PRKCA protein P17252 UNIPROT UNC5A protein Q6ZN44 UNIPROT down-regulates quantity phosphorylation Ser532 EPSPDSWsLRLKKQS 10116 BTO:0003036 16554470 YES miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. 0.2 SIGNOR-268179 CDC25B protein P30305 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation 9606 SIGNOR-C17 7880537 YES gcesareni Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex 0.828 SIGNOR-34541 HK2 protein P52789 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates activity 9606 18350175 NO The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase. 0.7 SIGNOR-259980 POU2F1 protein P14859 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23836662 NO miannu This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. 0.267 SIGNOR-254149 Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 27487822 YES miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. 0.8 SIGNOR-266269 Degranulation phenotype SIGNOR-PH92 SIGNOR TPSAB1 protein Q15661 UNIPROT up-regulates quantity by expression 9606 24232182 NO apalma Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6 0.7 SIGNOR-255348 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Thr151 RSYSRLEtLGSASTS -1 23901111 YES miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  0.71 SIGNOR-276121 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.91 SIGNOR-252826 SGK1 protein O00141 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser214 GGKERPGsKEEVDED 9606 16982696 YES lperfetto Second, sgk1 indirectly depolymerized mts through the phosphorylation of tau at ser214 0.331 SIGNOR-161288 LINC complex complex SIGNOR-C303 SIGNOR TTM complex complex SIGNOR-C305 SIGNOR up-regulates activity relocalization 30718482 YES lperfetto Together, we conclude that both the TTM complex and SUN1 (the LINC complex) contribute to the stable telomere–NE association. 0.2 SIGNOR-263305 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser426 VNKGSDEsIGKGDGF 9606 BTO:0000567 19509060 YES lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. 0.617 SIGNOR-272992 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000782;BTO:0001271 8125092 YES gcesareni Phosphorylation of either serine 16 or 63 is sufficient to inhibit stathmin in vitro. Phosphorylation at ser-63 reduces tubulin binding 10-fold and suppresses the mt polymerization inhibition activity. 0.31 SIGNOR-36370 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates activity phosphorylation Ser870 KEDSAYGsQSVEQEA 9606 BTO:0000007 11239468 YES lperfetto NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870 0.676 SIGNOR-105557 TEX10 protein Q9NXF1 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 YES miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. 0.878 SIGNOR-265472 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr299 PERRRLKtTRLKEYT 9606 15611134 YES lperfetto Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311.Abrogation of phosphorylation of thr299, thr306, and ser311 had little effect on enzyme activity, but mutation of thr299 and thr300 to alanine resulted in redistribution of zipk from the cytosol to the nucleus 0.2 SIGNOR-132471 GH1 protein P01241 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 15665309 YES Luana Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells 0.2 SIGNOR-261628 USF1 protein P22415 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 9677331 NO inferred from family member miannu Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element 0.289 SIGNOR-267797 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser22 FGGPGTAsRPSSSRS -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248878 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 23151663 YES gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane. 0.655 SIGNOR-199656 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR NABP2 protein Q9BQ15 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25249620 YES miannu Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation.  0.293 SIGNOR-272462 GTF2E1 protein P29083 UNIPROT TFIIE complex SIGNOR-C458 SIGNOR form complex binding 9606 31064989 YES lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. 0.942 SIGNOR-269360 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser394 TRQTPVDsPDDSTLS 9606 BTO:0000567 12586835 YES gcesareni A physical interaction exists between cdc2 and s6k1, and this interaction is enhanced in mitotic cells. These results suggest that cdc2 provides a signal that triggers inactivation of s6k1 in mitosis, presumably serving to spare energy for costly mitotic processes at the expense of ribosomal protein synthesis. 0.385 SIGNOR-98211 PPM1B protein O75688 UNIPROT MPRIP protein Q6WCQ1 UNIPROT down-regulates activity dephosphorylation 9606 25751141 YES lperfetto Ppm1b prevents Rip3 auto-activation in resting cells.|Together, these data demonstrate that Ppm1b dephosphorylates Rip3 and thus negatively regulates TNF induced necroptosis in L929 cells. 0.2 SIGNOR-277019 RET protein P07949 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 12242309 YES lperfetto Overexpressed rai resulted in the potentiation of the ret-dependent activation of phosphatidylinositol 3-kinase (pi3k) and akt. The ret/ptc receptor tyrosine kinase that responds to glial cell-line-derived neurotrophic factor also phosphorylated akt tyrosine residue 315 promoting activation of akt 0.323 SIGNOR-244443 NFATC2 protein Q13469 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21871017 YES miannu NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration 0.372 SIGNOR-264025 P2RY4 protein P51582 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257288 COL18A1 protein P39060 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium 0.7 SIGNOR-254679 MAP3K20 protein Q9NYL2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 12220515 YES gcesareni This result suggests that ZAK activates JNK/SAPK mediated by downstream target, MKK7 0.2 SIGNOR-243342 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr19 GAVPSEAtKRDQNLK 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.2 SIGNOR-262925 NFIA protein Q12857 UNIPROT NEUROD4 protein Q9HD90 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268891 MAPK1 protein P28482 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15001544 YES lperfetto Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation. 0.679 SIGNOR-123173 MAPKAPK2 protein P49137 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates activity phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 12861023 YES miannu We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. Mutation analysis showed that MAPKAPK2 phosphorylated 14-3-3zeta at Ser-58. S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1. 0.624 SIGNOR-250151 HOTAIR ncrna URS000075C808_9606 RNAcentral DZIP3 protein Q86Y13 UNIPROT up-regulates activity binding 9606 BTO:0000567 24326307 YES miannu HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation. 0.2 SIGNOR-272091 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA5 protein Q9Y5G8 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265717 CDK5 protein Q00535 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Ser1232 SGHFTMRsPFKCDAC 10116 BTO:0000938 11675505 YES llicata Here, we demonstrate that cyclin dependent kinase-5 (Cdk5) associates with and phosphorylates NR2A subunits at Ser-1232 in vitro and in intact cells. Moreover, we show that roscovitine, a selective Cdk5 inhibitor, blocks both long-term potentiation induction and NMDA-evoked currents in rat CA1 hippocampal neurons. These results suggest that Cdk5 plays a key role in synaptic transmission and plasticity through its up-regulation of NMDARs. 0.526 SIGNOR-250666 MYOM1 protein P52179 UNIPROT OBSCN protein Q5VST9 UNIPROT up-regulates quantity relocalization 9606 BTO:0003324 19840192 YES miannu Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. 0.3 SIGNOR-266727 SIRT2 protein Q8IXJ6 UNIPROT PGAM2 protein P15259 UNIPROT up-regulates activity deacetylation Lys100 GGLTGLNkAETAAKH 9606 24786789 YES miannu Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. 0.2 SIGNOR-266518 PGM2 protein Q96G03 UNIPROT alpha-D-ribose 1-phosphate(2-) smallmolecule CHEBI:57720 ChEBI down-regulates quantity chemical modification 9606 17804405 YES miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. 0.8 SIGNOR-267075 SP4 protein Q02446 UNIPROT MAOB protein P27338 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11259630 NO miannu Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. 0.2 SIGNOR-253869 PLEKHG4 protein Q58EX7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.361 SIGNOR-260564 CALM1 protein P0DP23 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 YES lperfetto The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases 0.754 SIGNOR-232178 CDK2 protein P24941 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C16 21902831 YES gcesareni Cyclin e/cdk2 can phosphorylate myod at serine 200, which causes ubiquitination and degradation of this transcription factor during g1, preventing its accumulation and a commitment to differentiation. 0.523 SIGNOR-176509 DNMT3B protein Q9UBC3 UNIPROT GSTM2 protein P28161 UNIPROT down-regulates quantity by repression transcriptional regulation 21246532 NO lperfetto Knockdown of Sp1 in normal lung cells reduced GST-M2 expression, and silencing of DNMT-3b increased GST-M2 expression in lung cancer cells. 0.327 SIGNOR-271687 U0126 chemical CHEBI:90693 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 11160424 YES gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. U0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. 0.8 SIGNOR-104942 KLF16 protein Q9BXK1 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 YES miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. 0.465 SIGNOR-222460 NBR1 protein Q14596 UNIPROT GABARAPL1 protein Q9H0R8 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 YES gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family 0.74 SIGNOR-184264 VPS8 protein Q8N3P4 UNIPROT CORVET tethering complex complex SIGNOR-C550 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.75 SIGNOR-273693 SCF-betaTRCP complex SIGNOR-C5 SIGNOR PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 0.541 SIGNOR-272751 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR1 protein P30872 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257581 EP300 protein Q09472 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity acetylation 9606 BTO:0003292 28045112 YES lperfetto Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3|Importantly, Brd3 promotes the recruitment of IRF3/p300 complex to the promoter of Ifnb1, and increases the acetylation of histone3/histone4 within the Ifnb1 promoter, leading to the enhancement of type I interferon production. 0.2 SIGNOR-262045 PRKCZ protein Q05513 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser109 KSHSRQAsTDAGTAG 9606 BTO:0002181 25660024 YES miannu  Yap and β-catenin are direct substrates of PKCζ.We show here that PKCζ suppresses intestinal stem cell function by promoting the downregulation of β-catenin and Yap through direct phosphorylation.Consistent with MS/MS analysis, mutation to alanine of these two sites completely abolished Yap phosphorylation by PKCζ. Interestingly, S109 and T110 sites were highly conserved among species (Figure S3B), which suggested an important role in Yap regulation. 0.277 SIGNOR-276876 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation 9606 14500912 YES �Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. 0.2 SIGNOR-254978 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Thr252 LLYMCLEtGAISFVQ 9606 15979581 YES miannu The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity 0.691 SIGNOR-138355 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. 0.8 SIGNOR-268128 PSTPIP1 protein O43586 UNIPROT PTPN18 protein Q99952 UNIPROT up-regulates activity binding 9534 BTO:0004055 9422760 YES lperfetto These data confirm the importance of these residues to the binding interaction, and they suggest that much of the COOH-terminal region of PTP HSCF may be required for highest affinity binding to PST PIP.|Because this protein-protein interaction appears to be required for the dephosphorylation of PST PIP phosphotyrosines (20), it may be a potentially important new mechanism for the regulation of the cytoskeleton. 0.566 SIGNOR-262594 EEA1 protein Q15075 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto Early endosomal antigen-1 (EEA1) is a well-characterized effector of Rab5 and one of the most widely used markers for EE due to its specific localization to this compartment. EEA1, in coordination with members of the SNARE family, is essential for EE fusion in vivo 0.527 SIGNOR-260623 ACOX1 protein Q15067 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization binding 9606 31401980 YES miannu Downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. ACOX1 reduced p73 expression by destabilizing p73 protein. We also found that ACOX1 interacted with p73 protein 0.2 SIGNOR-261056 TLN1 protein Q9Y490 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.657 SIGNOR-257611 AKT1 protein P31749 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 YES gcesareni When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. 0.768 SIGNOR-252549 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263775 PDE1C protein Q14123 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 YES PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values 0.8 SIGNOR-253399 SARS1 protein P49591 UNIPROT MYC protein P01106 UNIPROT down-regulates activity binding 9606 BTO:0000007 24940000 YES Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation. 0.2 SIGNOR-259368 PRKCZ protein Q05513 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276016 SHANK3 protein Q9BYB0 UNIPROT NMDA proteinfamily SIGNOR-PF56 SIGNOR up-regulates quantity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264701 SAFB protein Q15424 UNIPROT FUS protein P35637 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 27731383 YES P35637:p.Pro525Leu (mutation disrupting interaction) SAFB1 as well as Matrin3 to regulate splicing and ligand-mediated transcription| In addition, depletion of SAFB1 reduced FUS's localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif. 0.363 SIGNOR-262821 SEC61 complex complex SIGNOR-C368 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 33925740 YES lperfetto The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol.  0.8 SIGNOR-265284 PRKCD protein Q05655 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Ser28 LEEGASGsTPPEELP 9606 16963224 YES llicata Activated pkc delta was able to phosphorylate shca at ser29, as determined by mass spectrometry. 0.567 SIGNOR-149402 EPX protein P11678 UNIPROT EPX protein P11678 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 YES miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. 0.2 SIGNOR-261706 AV412 chemical CID:11700696 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190053 RPL32 protein P62910 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.833 SIGNOR-262468 romidepsin chemical CHEBI:61080 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257992 TRIM4 protein Q9C037 UNIPROT RTN2 protein O75298 UNIPROT down-regulates quantity ubiquitination 9606 35637527 YES miannu 2: TRIM4 ubiquitinates and degrades the NSP2 protein.|Mechanistic studies showed that TRIM4 ubiquitinated modified NSP2 and down-regulated NSP2 expression. 0.2 SIGNOR-278793 HNF4A protein P41235 UNIPROT LDLR protein P01130 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000398 21123766 NO miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. 0.346 SIGNOR-254454 TPO protein P07202 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI up-regulates quantity chemical modification 9606 28153798 YES scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. 0.8 SIGNOR-267040 APOA1 protein P02647 UNIPROT LCAT protein P04180 UNIPROT up-regulates activity binding 9606 19860440 YES miannu Activation of LCAT by apolipoprotein (apo) A-I on nascent (discoidal) high density lipoproteins (HDL) is essential for formation of mature (spheroidal) HDL during the antiatherogenic process of reverse cholesterol transport. After attachment of LCAT to discoidal HDL, the helix 5/5 domains in apoA-I form amphipathic presentation tunnels for migration of hydrophobic acyl chains and amphipathic UC from the bilayer to the phospholipase A2-like and esterification active sites of LCAT, respectively. 0.781 SIGNOR-252103 ROS stimulus SIGNOR-ST2 SIGNOR NFE2L2 protein Q16236 UNIPROT up-regulates 9606 BTO:0000018 22789539 NO miannu Nrf2 is a master transcriptional activator of cytoprotective genes. It activates transcription in response to electrophiles and reactive oxygen species (ROS) (Itoh et al., 1997, Uruno and Motohashi, 2011). Under normal conditions, Nrf2 is constantly ubiquitinated by Keap1 and degraded by the proteasome. Exposure to the stimuli inactivates Keap1 and stabilizes Nrf2. 0.7 SIGNOR-267353 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR DDX1 protein Q92499 UNIPROT up-regulates 10090 21703541 NO miannu We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA. 0.7 SIGNOR-260190 ARID3A protein Q99856 UNIPROT Immunoglobulin mu heavy chain protein P0DOX6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 16738337 YES lperfetto In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure ​3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene. 0.2 SIGNOR-268532 GSK3B protein P49841 UNIPROT ARNTL protein O00327 UNIPROT down-regulates phosphorylation Thr21 DFMSPGPtDLLSSSL 9606 20049328 YES lperfetto Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened. 0.382 SIGNOR-162790 ANAPC2 protein Q9UJX6 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.875 SIGNOR-252002 SLC4A3 protein P48751 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 26136660 YES miannu Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride 0.8 SIGNOR-264917 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NHEJ1 protein Q9H9Q4 UNIPROT down-regulates quantity by destabilization ubiquitination Thr181 LIRDRLKtEPFEENS 9606 BTO:0000567 25661488 YES miannu Here we report that Akt phosphorylates XLF (XRCC4 like factor, also called NHEJ1) at T181, to dissociate XLF from the XRCC4 (X-ray repair cross-complementing protein 4)/DNA ligase IV (LIG4) complex and subsequently triggers XLF cytoplasmic translocation, leading to XLF ubiquitination by SCFβ-TRCP in a CKI-dependent manner. 0.322 SIGNOR-276882 TGFB1 protein P01137 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11331591 NO lperfetto Tgf-b caused a 50% reduction of cbfa1 mrna. 0.344 SIGNOR-235998 SALL4 protein Q9UJQ4 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001883 24051379 NO miannu In primary human AML cells, downregulation of SALL4 led to decreased HOXA9 expression and enhanced apoptosis. We found that SALL4 bound a specific region of the HOXA9 promoter in leukemic cells. SALL4 overexpression led to enhanced binding of histone activation markers at the HOXA9 promoter region, as well as increased HOXA9 expression in these cells. 0.38 SIGNOR-255125 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Thr577 AENGLLMtPCYTANF 9606 10980595 YES lperfetto We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway 0.2 SIGNOR-244696 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 24692351 NO scontino Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form. 0.7 SIGNOR-267619 miR-155 mirna URS000062749E_9606 RNAcentral AP1 complex SIGNOR-C154 SIGNOR up-regulates quantity by expression post transcriptional regulation 9606 19219026 YES Luana Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.  0.4 SIGNOR-268039 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249351 EXOC6B protein Q9Y2D4 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.742 SIGNOR-270781 carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI up-regulates quantity precursor of 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267422 SMAD7 protein O15105 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 9606 30017632 NO miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. 0.7 SIGNOR-260433 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 YES fspada Using ghr hyper-phosphorylated by elk kinase, we have identified tc-ptp, ptp- , pyst-2, sap1, meg-2, ptp1b, and ptph1 as having substrate specificity for this receptor. In addition, we have shown that these same ptps (or rather their nonmutated counterparts) can dephosphorylate the ghr. 0.315 SIGNOR-104577 L-serine chemical CHEBI:17115 ChEBI D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity precursor of 10090 BTO:0000142 12393813 YES lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. 0.8 SIGNOR-268271 N-(6-fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide chemical CHEBI:91332 ChEBI ROCK1 protein Q13464 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 19740074 YES miannu We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2. 0.8 SIGNOR-262229 MRE11 protein P49959 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 17713585 YES esanto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. 0.2 SIGNOR-157475 ADRA2C protein P18825 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.436 SIGNOR-257094 frovatriptan chemical CHEBI:134991 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation -1 9986723 YES miannu As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold). 0.8 SIGNOR-259074 AUTS2 protein Q8WXX7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 25533347 NO miannu AUTS2 is involved in neurite outgrowth and branch formation in neurons. 0.7 SIGNOR-266818 MTA2 protein O94776 UNIPROT FSHR protein P23945 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001238 23086931 NO miannu Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. 0.248 SIGNOR-254226 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PKM protein P14618 UNIPROT down-regulates activity phosphorylation Ser37 MCRLDIDsPPITARN 9606 BTO:0000782 28607489 YES lperfetto Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3–CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.|Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity 0.259 SIGNOR-273032 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser628 LSLGSGIsQCGYSST 9534 BTO:0000298 11865049 YES llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  0.74 SIGNOR-250817 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CACNB1 protein Q02641 UNIPROT up-regulates activity phosphorylation Ser161 CEVGFIPsPVKLDSL 9534 BTO:0000298 16406008 YES miannu Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs. 0.2 SIGNOR-262966 SDHD protein O14521 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 30030361 YES lperfetto Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites 0.927 SIGNOR-262187 KDM6A protein O15550 UNIPROT HOXC13 protein P31276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.267 SIGNOR-260027 LNX1 protein Q8TBB1 UNIPROT GRIN1 protein Q05586 UNIPROT down-regulates quantity by destabilization ubiquitination -1 22889411 YES miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. 0.289 SIGNOR-272901 HUNK protein P57058 UNIPROT ITM2A protein O43736 UNIPROT up-regulates activity phosphorylation Thr35 TVRTQILtGKELRVA 9606 BTO:0000007 31438969 YES miannu ITM2A is phosphorylated at T35 and the phosphorylation status of ITM2A contributes to breast cancer proliferation. Moreover, we found that ITM2A was phosphorylated at T35 by HUNK, a serine/threonine kinase significantly correlated with human breast cancer overall survival and HER2-induced mammary tumorigenesis. 0.2 SIGNOR-273640 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT up-regulates activity phosphorylation Ser338 DEASATVsKTETSQV -1 8617805 YES That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated. 0.923 SIGNOR-251190 RELA protein Q04206 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates activity relocalization 10090 14982881 YES Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. This indicates that shuttling of p65 was necessary for Flt3-ITD-mediated SMRT nuclear export. 0.405 SIGNOR-261539 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SP1 protein P08047 UNIPROT up-regulates phosphorylation 9606 11904305 YES inferred from 70% family members gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. sa-perk1/2 activates the transcription factor, sp1, via ser59 phosphorylation downstream of pkc_, leading to transcription of p21sdi1 and resulting in replicative senescence of hdf cells. 0.2 SIGNOR-270104 PRKAA1 protein Q13131 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity phosphorylation Ser433 PEKELPVsPGHRKTP -1 31805502 YES miannu MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected. 0.2 SIGNOR-277495 ARHGEF25 protein Q86VW2 UNIPROT CDC42 protein P60953 UNIPROT up-regulates guanine nucleotide exchange factor 10090 BTO:0000165;BTO:0000222 16314529 YES lperfetto Exogenous expression of geft promotes myogenesis of c2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process. 0.668 SIGNOR-235391 GRIN2A protein Q12879 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 20950656 YES lperfetto In addition, neurons also possess unique systems for local Ca2+ signaling at synapses including; presynaptic voltage-gated Ca2+ channels coupled to the synaptic vesicle membrane fusion machinery [39]; postsynaptic excitatory glutamate receptor channels which flux either Na+ (AMPA receptors) or Ca2+ (NMDA receptors) [40] and [41]; and Ca2+-binding proteins 0.8 SIGNOR-251578 AGRN protein O00468 UNIPROT CHRNB3 protein Q05901 UNIPROT up-regulates activity binding 9606 BTO:0002916 14502292 YES miannu Treatment of muscle cells with neural agrin causes tyrosine phosphorylation of the AChR β subunit and induces AChR clustering by promoting anchoring of the receptor protein to postsynaptic cytoskeleton. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. By showing a direct requirement for APC in AChR clustering, our present study suggests that the Wnt/β-catenin pathway may crosstalk with the agrin signaling cascade during the formation of mammalian neuromuscular junction. 0.2 SIGNOR-264260 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr502 TPGTGLGtSPALAGD -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.34 SIGNOR-250906 BDKRB1 protein P46663 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257362 PRKAA1 protein Q13131 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity phosphorylation Ser408 GDMVQPLsPSQGQST -1 31805502 YES miannu MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected. 0.2 SIGNOR-277496 AKT1 protein P31749 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 38402584 NO miannu Jagged1 is upregulated by Akt upon activation by R-Ras. All three Akt isoforms influence Jagged1 expression in ECs, but Akt3 is the most prominent Akt isoform in this role, despite its low expression level compared with Akt1. Jagged1 then activates Notch to upregulate Hey1, Hes1, p21, p53, and Unc5b in adjacent cells.  0.409 SIGNOR-277222 RARA protein P10276 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 YES gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.43 SIGNOR-133231 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 7867073 YES gcesareni Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. 0.905 SIGNOR-34339 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270416 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9606 19433246 YES miannu Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic. 0.8 SIGNOR-268747 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 18794899 YES lperfetto E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. 0.484 SIGNOR-181078 PTPN6 protein P29350 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation Tyr681 DIYSTDYyRVGGRTM 10116 phosphorylation: tyr496 HIIENPQyFSDACVH 14662744 YES Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. 0.477 SIGNOR-248469 ARID1A protein O14497 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.808 SIGNOR-270611 TYMS protein P04818 UNIPROT dTMP(2-) smallmolecule CHEBI:63528 ChEBI up-regulates quantity chemical modification 9606 21876188 YES lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. 0.8 SIGNOR-268235 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Ser14 PFSCHYPsRLRRDPF 9606 22721717 YES lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation 0.307 SIGNOR-197940 SLBP protein Q14493 UNIPROT H2AZ2 protein Q71UI9 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265410 TFE3 protein P19532 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells 0.266 SIGNOR-276807 MAPK14 protein Q16539 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 BTO:0001255 12839928 NO miannu Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes. 0.673 SIGNOR-263511 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 NO miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. 0.7 SIGNOR-261021 LSM3 protein P62310 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.801 SIGNOR-270633 POLR1H protein Q9P1U0 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.2 SIGNOR-266156 CBLB protein Q13191 UNIPROT CLEC6A protein Q6EIG7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27432944 YES miannu Furthermore, we found that Cbl-b, an E3 ubiquitin ligase, mediates the ubiquitination and degradation of the activated Dectin-2 and Dectin-3 to negatively regulate CLR mediated innate immune responses against fungal infections. 0.2 SIGNOR-278625 DYRK2 protein Q92630 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 18455992 YES miannu DYRK2 directly phosphorylated Gli2 sequences and resulted in the loss of coexpressed GLI proteins, indicating that DYRK2 acts by inducing the phosphorylation and degradation of GLI proteins via the ubiquitin and proteasome pathway. 0.3 SIGNOR-279034 DYRK2 protein Q92630 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 31605148 YES miannu We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism. 0.288 SIGNOR-279035 SIRT3 protein Q9NTG7 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity deacetylation Lys321 SDPIMLLkDRMVNSN 9606 BTO:0000007 25152236 YES lperfetto SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells|SIRT3 deacetylates PDHA1 lysine 321 (K321) 0.48 SIGNOR-267636 PRKACA protein P17612 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 BTO:0000007 33110360 YES miannu We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence. 0.2 SIGNOR-277537 NLGN3 protein Q9NZ94 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.825 SIGNOR-264162 AKT2 protein P31751 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 YES lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta 0.458 SIGNOR-217463 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL -1 20044479 YES lperfetto IGF-1R Directly Interacts with and Phosphorylates PDK1 in Vitro 0.341 SIGNOR-236548 OXSR1 protein O95747 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr105 LQTFGHNtMDAVPKI 9606 BTO:0000007 21321328 YES miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). 0.503 SIGNOR-276310 SEC31A protein O94979 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.763 SIGNOR-265292 ITGB3BP protein Q13352 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.753 SIGNOR-265206 CAMK2G protein Q13555 UNIPROT ADCY3 protein O60266 UNIPROT down-regulates activity phosphorylation Ser1076 NVASRMEsTGVMGNI 9606 BTO:0000007 8798667 YES llicata Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. | Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo. 0.354 SIGNOR-250691 DAPK1 protein P53355 UNIPROT MCM3 protein P25205 UNIPROT unknown phosphorylation Ser160 KTIERRYsDLTTLVA 9606 18283219 YES lperfetto Mcm3 was efficiently and specifically phosphorylated by dapk on a unique site, ser160 / the functional effects of dapk-mediated phosphorylation and any connection to these functions remain to be determined 0.331 SIGNOR-160958 CFLAR protein O15519 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity binding 9606 9794838 YES amattioni Flip can be incorporated into the disc complex and blocks processing and activation of pro-caspase8 0.77 SIGNOR-61122 EGFR protein P00533 UNIPROT USP8 protein P40818 UNIPROT up-regulates activity phosphorylation Tyr717 PSKLKRSySSPDITQ 9606 29472535 YES miannu EGFR activates USP8 by phosphorylating Tyr-717 and Tyr-810.|Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr 717 and Tyr 810 in RPE1 cells. 0.71 SIGNOR-279037 imatinib chemical CHEBI:45783 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258225 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207944 CNOT9 protein Q92600 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.2 SIGNOR-268303 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 NO Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA) 0.574 SIGNOR-254304 PYCARD protein Q9ULZ3 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.796 SIGNOR-256401 IGF1 protein P05019 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003858 12734180 NO miannu In the present study we investigated the inhibitory effects of IGF-1 and OP-1 on MMP-13 expression in human chondrocytes. We found that the suppressive effect of IGF-1 and OP-1 on the MMP-13 promoter activity was dose-dependent at the transcriptional level with a corresponding decrease in the level of MMP-13 protein. 0.356 SIGNOR-254802 miR-155 mirna URS000062749E_9606 RNAcentral CEBPB protein P17676 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 25477897 YES miannu The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT3 0.4 SIGNOR-255795 SF3A3 protein Q12874 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.74 SIGNOR-270663 SCF-betaTRCP complex SIGNOR-C5 SIGNOR TOP2B protein Q02880 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 32015321 YES miannu Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.ATM binds with and phosphorylates TOP2β at Ser1134 to promote its degradation by VM-26. 0.2 SIGNOR-277511 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267885 FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 10080542 YES gcesareni Flt3 ligand (fl) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor flt3/flk2 belongs to class iii receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1 0.884 SIGNOR-65564 RPA1 protein P27694 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 NO lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.7 SIGNOR-275705 axitinib chemical CHEBI:66910 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258076 PRKAA1 protein Q13131 UNIPROT CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 SIGNOR-C15 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 YES gcesareni Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation 0.383 SIGNOR-176472 RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 19222999 YES lperfetto Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1. 0.798 SIGNOR-232208 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 12853467 YES 14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling. 0.2 SIGNOR-251485 TBX5 protein Q99593 UNIPROT NPPA protein P01160 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000562 18451335 NO miannu TBX5 is expressed, among others, in the embryonic heart and forelimbs.8 In the heart, it regulates transcription of downstream genes such as the atrial natriuretic factor (NPPA) and fibroblast growth factor 10 (FGF10) by the binding to T-box binding elements (TBEs),11 often in combination with the NKX2-5 transcription factor. 0.589 SIGNOR-255384 CAPN3 protein P20807 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity cleavage 9606 25969760 YES lperfetto Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains 0.324 SIGNOR-251605 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser380 EPDHYRYsDTTDSDP 9606 21779440 YES gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity 0.679 SIGNOR-152348 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR WNK2 protein Q9Y3S1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23838290 YES miannu We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body. 0.296 SIGNOR-272125 MITF protein O75030 UNIPROT TPSAB1 protein Q15661 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000830 20513998 YES lperfetto The transcription of tryptase gene in human mast cells is regulated by mi transcription factor |Using mutant constructs of tryptase promoter, we observed that two E-box (CANNTG) motifs including between -817 to -715 and -421 to -202 are able to involve in the transactivation of tryptase gene by MITF-A. 0.2 SIGNOR-251725 TRAF3 protein Q13114 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26085207 YES miannu TRAF2 and TRAF3 mediate NIK ubiquitination by forming a complex with the E3 ligase cIAP (cIAP1 or cIAP2).|We demonstrated further that TRAF3 mediates the degradation of NIK and thereby serves as a pivotal negative regulator of noncanonical NF-kappaB signaling. 0.667 SIGNOR-278673 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser499 MSPGVAGsPRIPPSQ 9606 BTO:0000801 29170386 YES Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. 0.246 SIGNOR-256099 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCND3 protein P30281 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189975 NMS protein Q5H8A3 UNIPROT NMUR1 protein Q9HB89 UNIPROT up-regulates binding 9606 BTO:0000142 15635449 YES gcesareni Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus. 0.728 SIGNOR-133074 HBB protein P68871 UNIPROT Hemoglobin complex SIGNOR-C209 SIGNOR form complex binding 9606 18179859 YES miannu AHSP does not bind to β-hemoglobin (βHb) or the hemoglobin tetramer, instead, it specifically binds to free αHb, avoiding its precipitation and its pro-oxidant activity. In the presence of βHb, the αHb-AHSP complex is dismembered and βHb displaces AHSP to generate the quaternary structure of hemoglobin 0.709 SIGNOR-255275 LPAR1 protein Q92633 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12393875 YES gcesareni We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac. 0.554 SIGNOR-94635 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 YES gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.738 SIGNOR-163258 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT down-regulates activity dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000586 19115206 YES the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431 0.272 SIGNOR-248341 AKT proteinfamily SIGNOR-PF24 SIGNOR PIK3R6 protein Q5UE93 UNIPROT up-regulates activity phosphorylation Thr607 SHRPREVtVSLRATG 25753393 YES lperfetto P84 forms a negative regulatory complex with p110gamma to control PI3Kgamma signalling during cell migration|However, phosphorylation at this site was confirmed using an in vitro kinase assay in which Akt kinase was shown to readily phosphorylate Thr607 using a p84 peptide (Figure 1e), where Thr607 in conjunction with surrounding residues forms an Akt kinase consensus sequence|In contrast, although p84-T607A exhibited basal p110γ dimerisation, this interaction could not be further induced with stimulation 0.2 SIGNOR-275723 SRC protein P12931 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Tyr289 MELQTYRyHGHSMSD 9606 BTO:0000007 26848621 YES miannu Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1).  0.349 SIGNOR-277204 BIRC3 protein Q13489 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 9545235 YES gcesareni Xiap, birc2 and birc3 were shown to bind pro-casp9. Iaps may suppress casp9 by direct auto-activation of pro-caspase-11 0.759 SIGNOR-56481 Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR Neutrophil_degranulation phenotype SIGNOR-PH212 SIGNOR up-regulates 9606 BTO:0000133 2161532 NO lperfetto ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. 0.7 SIGNOR-270582 MAPK1 protein P28482 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation Ser102 LQTVIRTsPSSLVAF -1 35831023 YES miannu We conclude that multisite phosphorylation of GLI1 by ERK2 or other MAP kinases weakens GLI1-SUFU binding, thereby facilitating GLI1 activation and contributing to both physiological and pathological crosstalk. 0.323 SIGNOR-277601 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr821 KISEGLPtPTKMTPR 9606 9139732 YES lperfetto We demonstrate that phosphorylation by either cdk2-cyclin a, which phosphorylates t821, or cdk4-cyclin d1, which phosphorylates threonine 826, can disable prb for subsequent binding of an lxcxe protein. 0.805 SIGNOR-217324 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 NO lperfetto We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 0.679 SIGNOR-235625 FYN protein P06241 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates activity phosphorylation 9606 29790812 YES miannu Our results demonstrate Fyn -mediated upregulation of Nav1.7 protein expression and tyrosine phosphorylation and identify two tyrosine residues within the DIII-DIV linker (L3) as Fyn phosphorylation sites. 0.363 SIGNOR-279614 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity phosphorylation Ser1236 PKPKPRPsITKATWE 9534 BTO:0000298 19103606 YES miannu these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells 0.414 SIGNOR-276176 O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI L-serine chemical CHEBI:17115 ChEBI up-regulates quantity precursor of 9606 BTO:0000142 12213811 YES lperfetto Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP 0.8 SIGNOR-268569 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp546 ALQTDIVdLQRSPMG 9606 11741536 YES gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. 0.365 SIGNOR-256435 GNAO1 protein P09471 UNIPROT NDN protein Q99608 UNIPROT up-regulates activity 9606 BTO:0002036 25012566 NO lperfetto We subsequently analyzed whether Gαo modulates the cellular activities of Necdin. Notably, expression of Gαo significantly augmented Necdin-mediated cellular responses, such as proliferation and differentiation. Moreover, activation of type 1 cannabinoid receptor (CB1R), a Gi/oα-coupled receptor, augmented cell growth suppression, which was mediated by Gαo and Necdin in U87MG cells containing CB1R, Gαo, and Necdin as normal components. 0.239 SIGNOR-253388 FER protein P16591 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates activity phosphorylation 9606 21122136 YES miannu Fer interferes with binding of RhoGDI\u03b1 and Rac. (A) GST-RhoGDI\u03b1 was pre-incubated with Rac, after which GST-Fer (G-Fer) or GST (G) was added and GST fusion proteins were pulled down with glutathione agarose, followed by kinase reactions. (B) GST-RhoGDI\u03b1 was pre-incubated with GST-Fer or GST in kinase buffer, after which Rac was added and RhoGDI\u03b1 was immunoprecipitated. 50 pmol of RhoGDI\u03b1 and Rac1, with 25 pmol of GST and GST-Fer were used.|These results identify tyrosine phosphorylation of RhoGDIalpha by Fer as a mechanism to regulate binding of RhoGDIalpha to Rac. 0.2 SIGNOR-279042 GRK2 protein P25098 UNIPROT C3AR1 protein Q16581 UNIPROT down-regulates activity phosphorylation 9606 21799898 YES miannu These findings indicated that agonist-induced C3aR phosphorylation by GRK2 promotes C3aR desensitization. 0.2 SIGNOR-279044 MYD88 protein Q99836 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity binding 9606 BTO:0000776 17548806 YES lperfetto St2825 interfered with recruitment of irak1 and irak4 by myd88, causing inhibition of il-1beta-mediated activation of nf-kappab transcriptional activity. 0.946 SIGNOR-155385 RCOR1 protein Q9UKL0 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 YES miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells 0.829 SIGNOR-264498 AURKA protein O14965 UNIPROT SECISBP2L protein Q93073 UNIPROT up-regulates quantity phosphorylation Thr573 IAKLKRPtALKKVIL 9606 BTO:0000007 31314582 YES miannu To explore the underlying mechanisms, we found that SLAN, a potential tumor suppressor, served as a substrate of Aurora-A and knockdown of SLAN induced immature cytokinesis. Aurora-A phosphorylates SLAN at T573 under the help of the scaffold protein 14-3-3η. Intriguingly, SLAN T573D or T573E inactivated and T573A activated the key cytokinesis regulator RhoA. 0.2 SIGNOR-273547 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 10673502 YES The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert. 0.2 SIGNOR-252791 SOSTDC1 protein Q6X4U4 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates activity 9606 BTO:0000815 21113658 NO lperfetto For example, SOSTDC1 decreases Wnt signaling by impeding the binding of Wnt8 to the LRP6 receptor 0.372 SIGNOR-242742 LYN protein P07948 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates phosphorylation 9606 11517336 YES gcesareni Gadd34 was tyrosine-phosphorylated in vivo in a lyn-dependent manner. 0.335 SIGNOR-109934 ZNRF4 protein Q8WWF5 UNIPROT RIPK2 protein O43353 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28656966 YES miannu Collectively, ZNRF4 degrades RIP2 protein by targeting the RIP2CARD domain in an E3-ubiquitin ligase activity dependent manner.|Here we show that ZNRF4 induces K48-linked ubiquitination of RIP2 and promotes RIP2 degradation. 0.2 SIGNOR-278684 HNF4A protein P41235 UNIPROT C1QTNF5 protein Q9BXJ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000224 20621834 NO miannu Here we demonstrate the mechanism by which the CTRP5 gene is transcriptionally activated in the liver. CTRP5 is activated by HNF4alpha via the region -206/-167 of the human CTRP5 promoter. 0.2 SIGNOR-254448 BCOR protein Q6W2J9 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 26847029 NO irozzo Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation. 0.251 SIGNOR-256014 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Ser323 RMGQLRGsATRALPP 9606 BTO:0000007 10542239 YES llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T 0.2 SIGNOR-250807 MAOA protein P21397 UNIPROT (R)-adrenaline smallmolecule CHEBI:28918 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 YES Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. 0.8 SIGNOR-269744 HIF1A protein Q16665 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR form complex binding 9606 27692180 YES miannu HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life 0.786 SIGNOR-267447 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 9606 11781100 YES lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. 0.331 SIGNOR-249139 PRKCZ protein Q05513 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.371 SIGNOR-251637 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC5 protein P58876 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271985 APBA2 protein Q99767 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9534 BTO:0000298 11036064 YES miannu Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa. 0.635 SIGNOR-264039 TP53 protein P04637 UNIPROT MMP2 protein P08253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 NO miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. 0.445 SIGNOR-255432 PRKCZ protein Q05513 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0002181 25660024 YES miannu  Yap and β-catenin are direct substrates of PKCζ. Similar MS/MS analysis to map the sites phosphorylated in β-catenin by PKCζ identified S45 and several sites of low abundance that included S552 and S675 (Figure S3C). 0.597 SIGNOR-276880 CLK4 protein Q9HAZ1 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 YES lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 0.272 SIGNOR-181052 WASF3 protein Q9UPY6 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 9534 17623672 NO We have also shown that Abl targets and phosphorylates four tyrosine residues in WAVE3 and that the Abl-dependent phosphorylation of WAVE3 is critical for the stimulation of lamellipodia formation and cell migration. 0.7 SIGNOR-259078 CSNK2A1 protein P68400 UNIPROT TSPY1 protein Q01534 UNIPROT up-regulates activity phosphorylation Thr300 PPEEGTEtSGDSQLL -1 16426576 YES llicata CK2-dependent C-terminal phosphorylation at T300 directs the nuclear transport of TSPY protein 0.2 SIGNOR-250969 CDK5 protein Q00535 UNIPROT MAPK10 protein P53779 UNIPROT down-regulates activity phosphorylation Thr131 ISLLNVFtPQKTLEE 9606 BTO:0000007 11823425 YES llicata Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation. 0.346 SIGNOR-250668 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000667 15866158 YES Induction of the p21WAF1/Cip1 gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-J_ protein to the p21 promoter. 0.338 SIGNOR-252033 PRKDC protein P78527 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser27 QEENLEAsGDYKYSG 9606 BTO:0001546 26337656 YES done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. 0.94 SIGNOR-274022 GATA1 protein P15976 UNIPROT AGGF1 protein Q8N302 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19556247 NO miannu Overexpression of GATA1 increased expression of AGGF1. Knockdown of GATA1 expression by siRNA reduced expression of AGGF1, and resulted in endothelial cell apoptosis and inhibition of endothelial capillary vessel formation and cell migration, which was rescued by purified recombinant human AGGF1 protein. 0.373 SIGNOR-254188 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270422 CDK1 protein P06493 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity phosphorylation Thr287 KIGFPSTtPAKAKAN 19687009 YES lperfetto Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression. 0.488 SIGNOR-275470 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 YES lperfetto To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells 0.396 SIGNOR-160635 FLI1 protein Q01543 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity binding 10090 BTO:0000944 12556498 YES irozzo On the other hand, our data demonstrate that FLI-1 also interacts with GATA-1. However, FLI-1 does not repress but enhances GATA-1 activity. 0.519 SIGNOR-256045 THPO protein P40225 UNIPROT MPL protein P40238 UNIPROT up-regulates binding 9606 11784712 YES miannu Thrombopoietin(tpo) controls the formation of megakaryocytes and platelets from hematopoietic stem cells via activation of the c-mplreceptorand multiple downstream signal transduction pathways. 0.78 SIGNOR-113955 WNT1 protein P04628 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 10116 11149923 NO gcesareni Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that wnt-1-mediated cell survival was dependent on the activation of beta-catenin/t cell factor (tcf) transcription 0.743 SIGNOR-85760 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates phosphorylation Ser1386 FVDSGEMsESFPYRT 9606 BTO:0000551 17434128 YES lperfetto Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities 0.519 SIGNOR-154333 CGA protein P01215 UNIPROT TSHR protein P16473 UNIPROT up-regulates binding 9606 12045258 YES miannu Human thyrotropin (tsh), follitropin (fsh), lutropin (lh), and chorionic gonadotropin (cg) are members of the glycoprotein hormone family derived from heterodimerization of a common ? Subunit with hormone-specific ? Subunits. These hormones were originally purified from the anterior pituitary (tsh, lh, and fsh) and placenta (human cg) and shown to activate specific g protein_coupled receptors in the thyroid (tsh receptor) and gonads (lh and fsh receptors), respectively 0.432 SIGNOR-88519 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 YES lperfetto The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity. 0.817 SIGNOR-252354 F2 protein P00734 UNIPROT Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR form complex binding 9606 BTO:0000131 29880919 YES lperfetto Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC). 0.905 SIGNOR-263549 IKK-complex complex SIGNOR-C14 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 YES lperfetto Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway 0.543 SIGNOR-252951 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 YES lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. 0.407 SIGNOR-233441 CSNK1A1 protein P48729 UNIPROT SRPK2 protein P78362 UNIPROT up-regulates activity phosphorylation Ser497 SRTVSASsTGDLPKA 9606 BTO:0000007 29153836 YES no miannu  Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. 0.25 SIGNOR-275460 STK4 protein Q13043 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation 9606 26456820 YES miannu MST kinase phosphorylates and activates LATS kinase. 0.2 SIGNOR-279661 PRKCA protein P17252 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Ser262 SPAKDCGsQKYAYFN 9606 14702389 YES gcesareni Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes. 0.536 SIGNOR-120907 DYRK1A protein Q13627 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. 0.507 SIGNOR-183670 FOXO1 protein Q12778 UNIPROT PDHX protein O00330 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12488434 YES miannu Our genetic analysis indicates that Foxo1 is an effector of Irs2 signaling in pancreatic β cells. Foxo1 inactivation leads to increased Pdx1 expression and β cell proliferation. Since Foxo1 is expressed in a subset of cells embedded within pancreatic ducts, we propose that, in quiescent duct-associated cells that are not committed to a β cell fate, Foxo1 acts as a transcriptional brake on Pdx1. We propose the following mechanism of Foxo1 regulation: small quantities of insulin are released in the pancreatic duct (31), where they activate signaling (32) in the Foxo1-positive duct cell subset, leading to Foxo1 nuclear exclusion and Pdx1 expression. 0.2 SIGNOR-278151 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 YES gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. 0.819 SIGNOR-72064 ARAP1 protein Q96P48 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.453 SIGNOR-260451 MITRAC complex complex SIGNOR-C538 SIGNOR NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR up-regulates quantity relocalization 23260140 YES Each association relies on the supply of subunits from either the cytosol or the mitochondrial matrix, suggesting that human TIM21 ushers nuclear-encoded proteins to assembly intermediates. In agreement with this, assembly of the early cytochrome c oxidase subunit COX4-1 requires TIM21, whereas it is dispensable for late-assembling subunits. The finding that TIM21 also interacts with complex I intermediates points to a more general role of TIM21 in respiratory-chain assembly. Furthermore, TIM21 appears to be tightly connected to MITRAC15, which, in contrast to TIM23 and MITRAC12, coimmunoprecipitates with TIM21 under all tested conditions. MITRAC15 associates with MITRAC and is required for complex IV but also complex I assembly. 0.2 SIGNOR-272486 EXOC8 protein Q8IYI6 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.94 SIGNOR-270791 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 10531062 YES lperfetto Thus, SnoN can interact with Smad4 and Smad2 and inhibit their abilities to activate transcription. 0.886 SIGNOR-71633 SMARCE1 protein Q969G3 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.818 SIGNOR-270731 PPY protein P01298 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 7592911 YES gcesareni Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid. 0.651 SIGNOR-24230 MFGE8 protein Q08431 UNIPROT IL1B protein P01584 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 23454767 NO Giorgia We show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1β production. MFGE8 inhibited necrotic cell–induced and ATP-dependent IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions in primed cells. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1β production. 0.264 SIGNOR-260649 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 18650425 YES gcesareni Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun. 0.37 SIGNOR-179555 F2RL1 protein P55085 UNIPROT TXNIP protein Q9H3M7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254857 GTF2H2C protein Q6P1K8 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 YES lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.715 SIGNOR-269317 RORC protein P51449 UNIPROT IL17A protein Q16552 UNIPROT up-regulates transcriptional regulation 9606 16990136 YES mrosina We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells 0.541 SIGNOR-255029 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT up-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.366 SIGNOR-254704 SNRPF protein P62306 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.921 SIGNOR-270682 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000007 11154276 YES lperfetto Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1. 0.2 SIGNOR-104646 GNB1 protein P62873 UNIPROT SRC protein P12931 UNIPROT up-regulates activity 15345719 NO In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation 0.48 SIGNOR-251107 progesterone smallmolecule CHEBI:17026 ChEBI 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 25855791 YES lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively 0.8 SIGNOR-268631 BRCA1 protein P38398 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 19074868 YES gcesareni The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation 0.507 SIGNOR-252435 FLT3 protein P36888 UNIPROT SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12468433 NO We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling 0.281 SIGNOR-261546 SOSTDC1 protein Q6X4U4 UNIPROT BMP7 protein P18075 UNIPROT down-regulates activity 10090 18032587 NO lperfetto SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7 0.768 SIGNOR-242752 HCFC1 protein P51610 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. 0.603 SIGNOR-267165 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 YES lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 0.713 SIGNOR-235933 CEBPB protein P17676 UNIPROT C3 protein P01024 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25617152 YES Gianni CCAAT/enhancer binding protein β directly regulates the expression of the complement component 3 gene in neural cells: implications for the pro-inflammatory effects of this transcription factor 0.259 SIGNOR-261927 GSK3B protein P49841 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization phosphorylation Thr180 QVLSGKTtTTNSKRE 9606 BTO:0002548 27572267 YES miannu We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. 0.307 SIGNOR-277276 Ub:E2 complex SIGNOR-C497 SIGNOR UBE3C protein Q15386 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271296 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral LRP6 protein O75581 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 25240815 YES Parnian These results provided strong evidence that LRP6 is a target of miR-126-3p in HCC and mediates the metastasis function of miR-126-3p in HCC. | MiR-126-3p inhibits HCC metastasis by directly targeting LRP6. 0.4 SIGNOR-278836 SRC protein P12931 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr860 KVSSTHYyLLPERPS -1 36178070 YES miannu We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity.  0.385 SIGNOR-276341 EIF2B3 protein Q9NR50 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.847 SIGNOR-269131 PLK1 protein P53350 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 27003818 YES miannu An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (XREF_FIG).|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation. 0.289 SIGNOR-278190 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 33875769 YES miannu In the absence of Wnt and Wnt signalling GSK3\u03b2 phosphorylates MITF, targeting MITF for proteasomal degradation. 0.436 SIGNOR-279050 PCDHA12 protein Q9UN75 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265673 MAP2K1 protein Q02750 UNIPROT MYT1 protein Q01538 UNIPROT down-regulates activity phosphorylation 9606 23241949 YES miannu Altogether our findings reveal that Myt1 is inactivated by MEK1 mediated phosphorylation to fragment the Golgi complex in G2 and for the entry of cells into mitosis.|MEK1 inactivates Myt1 to regulate Golgi membrane fragmentation and mitotic entry in mammalian cells. 0.261 SIGNOR-279052 PRKCB protein P05771 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates activity phosphorylation Thr728 MPSVSRStSRSSANW -1 19805577 YES miannu  This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload. 0.2 SIGNOR-276266 DYRK1A protein Q13627 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser278 NGRQPPYsPHHSPTP 9606 28235034 YES miannu DYRK1A phosphorylation of NFATc1 and alphaA at S261, S278, S403 and S409 interfered with NFATc1 ubiquitination and ubiquitin-proteasome degradation.|Here, we demonstrated that DYRK1A increased NFATc1 (NFATc1 and alphaA isoform) protein stability, in contrast to the decrease of NFATc2 protein stability by DYRK1A. 0.429 SIGNOR-278278 WRC complex complex SIGNOR-C191 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 20332100 YES miannu The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex 0.543 SIGNOR-253573 GATA1 protein P15976 UNIPROT CYBB protein P04839 UNIPROT up-regulates quantity transcriptional regulation 9606 10734088 YES These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils. 0.279 SIGNOR-259947 ACVR1 protein Q04771 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 18801898 NO gcesareni Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle. 0.248 SIGNOR-252463 LGALS3 protein P17931 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000664 21821001 NO miannu The aim of this study was to investigate the role of inducible galectin-3 in leukemic cells escape of apoptotic stimuli. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. 0.7 SIGNOR-261904 AGTR1 protein P30556 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256738 PP1 proteinfamily SIGNOR-PF54 SIGNOR CAD protein P27708 UNIPROT down-regulates activity dephosphorylation Ser1406 GAGGRRLsSFVTKGY -1 4092695 YES lperfetto Cyclic AMP-dependent protein kinase phosphorylates two serine residues on the protein termed sites 1 and 2| Site 1: Arg-Leu-Ser(P)-Ser-Phe-Val-Thr-Lys Site 2: Ile-His-Arg-Ala-Ser(P)-Asp-Pro-Gly-Leu-Pro-Ala-Glu-Glu-Pro-Lys | Both phosphorylation and activation can be reversed using purified preparations of the catalytic subunits of protein phosphatases 1- and -2A, and inactivation also correlates better with dephosphorylation of site 1 rather than site 2. 0.2 SIGNOR-264653 MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 NO miannu The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enhancers. 0.7 SIGNOR-37455 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120008 BAD protein Q92934 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity binding 9606 BTO:0002552 17000778 YES lperfetto We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis 0.328 SIGNOR-149815 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr242 FFQQQMIyDSPPSRA 9606 19881549 YES lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis 0.703 SIGNOR-236314 Ub:E2 complex SIGNOR-C497 SIGNOR HECTD3 protein Q5T447 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271280 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25901680 NO lperfetto Ribosomes are translational machineries that catalyse protein synthesis. 0.7 SIGNOR-262413 iron(3+) smallmolecule CHEBI:29034 ChEBI TFRC protein P02786 UNIPROT up-regulates quantity relocalization 9606 39534872 YES miannu Fe3+ is taken up by TFRC and exported by SLC40A1. Inside the cell, Fe3+ is reduced to Fe2+, with excess iron stored in ferritin (composed of FTH1 and FTL) or sequestered by MT1G. 0.8 SIGNOR-279856 E2F2 protein Q14209 UNIPROT TFDP1 protein Q14186 UNIPROT up-regulates activity binding 10029 BTO:0000246 8832394 YES 2 miannu The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3. 0.737 SIGNOR-240550 HCRTR1 protein O43613 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256733 MYLIP protein Q8WY64 UNIPROT AR protein P10275 UNIPROT down-regulates quantity ubiquitination 9606 29707137 YES miannu MYLIP knockdown increased AR protein levels whereas CNPY2 knockdown increased MYLIP and reduced AR protein expression levels.|These results showed that the E3 ligase MYLIP could ubiquitinate lysine 845 and 847 residues of AR. 0.2 SIGNOR-278766 TTL protein Q8NG68 UNIPROT TUBA1A protein Q71U36 UNIPROT down-regulates tyrosination 9606 22020298 YES miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization 0.531 SIGNOR-176912 MAPK13 protein O15264 UNIPROT CDC25B protein P30305 UNIPROT down-regulates 9606 11333986 NO gcesareni P38 map k can also induce a g2/m checkpoint through the phosphorylation and the phosphatase cdc25b. 0.478 SIGNOR-85999 CREB5 protein Q02930 UNIPROT STAT1 protein P42224 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002817 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253810 MDK protein P21741 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 18469519 YES gcesareni We showed that mk binds to the notch2 receptor in hacat keratinocytes. We further found that mk activates notch2 0.489 SIGNOR-161427 SYVN1 protein Q86TM6 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27417417 YES miannu The E3 ligase activity of Hrd1 is required for p27 kip1 ubiquitination, because co-expression of Hrd1 containing an alanine point mutation at the critical cysteine within the RING E3 ligase region (Hrd1/CA) failed to enhance p27 kip1 ubiquitination (XREF_FIG).|Therefore, our study identifies Hrd1 as an E3 ligase of p27 kip1 and establishes that Hrd1 mediated p27 kip1 degradation plays an important role in T-cell immunity. 0.2 SIGNOR-278786 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.552 SIGNOR-89158 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 YES Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. 0.569 SIGNOR-248337 ILK protein Q13418 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Ser474 RTHFPQFsYSASIRE 9606 19460343 YES miannu ILK mediated activation of Akt2 is required for Tbeta4 inducible expression of MMP-2 and EC motility.|Our experiments suggest that ILK phosphorylates Akt2 at Ser474, that Akt2 is a better substrate than Akt1, and that a post-translational modification to ILK is required for its activity. 0.614 SIGNOR-279055 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAK1 protein Q13153 UNIPROT down-regulates phosphorylation 9606 14993270 YES inferred from 70% family members gcesareni Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation. 0.2 SIGNOR-270186 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR PSEN1 protein P49768 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 12354302 YES miannu SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production SEL-10 protein is a homologue of yeast Cdc4, a member of the SCF (Skp1-Cdc53/CUL1-F-box protein) E2-E3 ubiquitin ligase family. In this study, we show that human SEL-10 interacts with PS1 and enhances PS1 ubiquitination, thus altering cellular levels of unprocessed PS1 and its N- and C-terminal fragments. These observations suggest that SEL-10 mediated ubiquitination of PS1-CTF and PS1-NTF leads to their degradation. 0.267 SIGNOR-272601 DCAF12 protein Q5T6F0 UNIPROT MAGEA6 protein P43360 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002806 31267705 YES miannu  The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6 0.2 SIGNOR-272255 WWP2 protein O00308 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25071155 YES miannu WWP2 ubiquitinates p73 and controls its protein stability. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.  0.283 SIGNOR-272233 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2R2 protein Q712K3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.764 SIGNOR-271324 SIRT5 protein Q9NXA8 UNIPROT GLS protein O94925 UNIPROT up-regulates activity binding 9606 BTO:0006301 30910998 YES Monia Immunoprecipitation assays of interaction between GLS and SIRT5 in HepG2 cells infected with lentivirus containing empty or BAG3 construct. Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. It has been reported that SIRT5 is responsible for desuccinylation of GLS35, immunoprecipitation (IP) was then performed. 0.449 SIGNOR-261207 RAB5A protein P20339 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 0.553 SIGNOR-260616 PIKFYVE protein Q9Y2I7 UNIPROT PAS complex complex SIGNOR-C190 SIGNOR form complex binding 9606 BTO:0000007 17556371 YES miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. 0.934 SIGNOR-253529 GNB1 protein P62873 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 23074268 NO gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. 0.406 SIGNOR-199129 TLR4 protein O00206 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 YES gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.771 SIGNOR-252065 GSK3B protein P49841 UNIPROT IL17RA protein Q96F46 UNIPROT down-regulates quantity by destabilization phosphorylation Thr780 MVLTDPHtPYEEEQR 9606 BTO:0000007 26871944 YES miannu Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.  0.2 SIGNOR-277205 ULK1 protein O75385 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates phosphorylation 9606 19597335 YES gcesareni Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks. 0.913 SIGNOR-186992 MEF2C protein Q06413 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 10082551 NO lperfetto During embryogenesis, the MEF2 genes are expressed throughout developing skeletal and cardiac muscle lineages, as well as in the nervous system (19, 42, 65, 68).MEF2C is the first member of the family to be expressed in developing muscle cell lineages, with transcripts appearing in precardiac cells by about embryonic day 7.75 and in skeletal muscle precursor cells within the myotome of the developing somites by embryonic day 8.5. Soon thereafter, the other MEF2 genes are expressed in overlapping patterns (19). After birth, the expression of MEF2A, -B, and -Dbecomes ubiquitous, whereas the expression of MEF2C becomes restricted to skeletal muscle, brain, and spleen 0.7 SIGNOR-219368 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF2 protein Q9P0N8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271245 PRKCZ protein Q05513 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Thr309 SDGATMKtFCGTPEY -1 9512493 YES lperfetto The activation of PKBbeta and PKBgamma by PDK1 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma). PKBgamma which had been activated by PDK1 possessed a substrate specificity identical with that of PKBalpha and PKBbeta towards a range of peptides. The activation of PKBgamma and its phosphorylation at Thr305 was triggered by insulin-like growth factor-1 in 293 cells. 0.497 SIGNOR-248997 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser206 ATPPTLSsTVLIVRN 9606 BTO:0001938 12815053 YES lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. 0.54 SIGNOR-249219 CNTFR protein P26992 UNIPROT STAT1 protein P42224 UNIPROT up-regulates 9606 10582086 NO gcesareni Signal transduction by cntf requires that it bind first to cntfr alpha, permitting the recruitment of gp130 and lifr beta, forming a tripartite receptor complex. Cntf-induced heterodimerization of the beta receptor subunits leads to tyrosine phosphorylation (through constitutively associated jaks), and the activated receptor provides docking sites for sh2-containing signaling molecules, such as stat proteins. 0.272 SIGNOR-72771 UBA2 protein Q9UBT2 UNIPROT SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR form complex binding -1 15660128 YES lperfetto E1 enzymes facilitate conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins. Structures of human heterodimeric Sae1/Sae2-Mg.ATP and Sae1/Sae2-SUMO-1-Mg.ATP complexes were determined at 2.2 and 2.75 A resolution, respectively. 0.824 SIGNOR-263004 STK4 protein Q13043 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates -1 16930133 YES lperfetto In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav 0.886 SIGNOR-217833 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 18612045 NO lperfetto Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity 0.2 SIGNOR-252927 STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24011072 NO miannu To assess whether Stat3 affects C/EBPŒ¥ expression, we co-transfected C2C12 myoblasts with a plasmid expressing a C/EBPŒ¥promoter-driven luciferase plus a lentivirus expressing the constitutively active Stat3C-GFP. Overexpression of Stat3C increased C/EBPŒ¥promoter activity compared to that in lentivirus expressing GFP control 0.61 SIGNOR-255333 SRC protein P12931 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr334 MQDNSGTyGKIWEGS 9606 17658731 YES miannu Inhibition of Src decreased the cleavage of PKCdelta and modified the apoptotic responses of the cells to TRAIL and cisplatin, similar to effect of the PKCdeltaY332F mutant.|These results demonstrate that the phosphorylation of tyrosine 332 by Src modulates the cleavage of PKCdelta and the sensitivity of glioma cells to TRAIL and cisplatin. 0.601 SIGNOR-278164 TP53 protein P04637 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 11714700 YES gcesareni This study identifies the anti-apoptotic survivin gene as a p53-repressed gene;notably, survivin repression by p53 is shown to be distinct from p53-dependent growth arrest. 0.56 SIGNOR-111971 FOXO1 protein Q12778 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001103 21798082 YES FoxO factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF1), leading to the ubiquitylation of myosin and other muscle proteins (see below), and their degradation via the proteasome 0.248 SIGNOR-256268 PKA proteinfamily SIGNOR-PF17 SIGNOR MOS protein P00540 UNIPROT down-regulates activity phosphorylation Ser73 LGAGGFGsVYKATYR 9606 8622681 YES Manara The purified PKA catalytic subunit was able to phosphorylate recombinant p37v-mos in vitro, suggesting that the mechanism of in vivo inhibition of v-Mos kinase involves direct phosphorylation by PKA. 0.2 SIGNOR-260819 LYN protein P07948 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates activity phosphorylation 9606 27206658 YES miannu In this line, Lyn has been demonstrated to tyrosine-phosphorylate and activate SHIP1, thereby constituting a negative feedback control of PI3K-mediated signals. 0.51 SIGNOR-279060 NEUROG3 protein Q9Y4Z2 UNIPROT VSX2 protein P58304 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19028584 NO miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. 0.273 SIGNOR-254635 mTORC1 complex SIGNOR-C3 SIGNOR Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 23863160 NO lperfetto Cellular energy and nutrient status will dictate whether mTORC1 takes over and drives cell growth or conversely whether AMPK becomes active once again to drive consecutive waves of autophagy thorough ULK1. 0.7 SIGNOR-209919 PRKCB protein P05771 UNIPROT ORAI1 protein Q96D31 UNIPROT down-regulates phosphorylation Ser27 GGSTTSGsRRSRRRS 9606 20534587 YES llicata We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30. 0.2 SIGNOR-166040 ACVR1B protein P36896 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by stabilization 9606 2920215 NO Regulation miannu Activin, also named FSH-releasing protein, was previously shown to induce hemoglobin accumulation in K562 cells and potentiate the proliferation and differentiation of CFU-E in human bone marrow cultures. 0.2 SIGNOR-251768 DDB1 protein Q16531 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR form complex binding 9606 17452440 YES lperfetto Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes 0.895 SIGNOR-154505 ARAF protein P10398 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000567 8621729 YES lperfetto Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222. 0.739 SIGNOR-235944 NRARP protein Q7Z6K4 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR down-regulates binding 8355 11485984 YES lperfetto Overexpression of nrarp in embryos blocks notch signaling and inhibits the activation of notch target genes by icd. We show that nrarp forms a ternary complex with the icd of xnotch1 and the csl protein xsu(h) and that in embryos nrarp promotes the loss of icd. 0.408 SIGNOR-219228 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1214 VCDPKFHyDNTAGIS 9606 BTO:0000007 18840653 YES We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well. 0.565 SIGNOR-248401 SKP2 protein Q13309 UNIPROT IDH1 protein O75874 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Thr157 GKVEITYtPSDGTQK 34929314 YES lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome 0.2 SIGNOR-267625 LYN protein P07948 UNIPROT PRKDC protein P78527 UNIPROT down-regulates activity phosphorylation 9606 9748231 YES miannu The interaction between Lyn and DNA-PKcs inhibits DNA-PKcs activity and the ability of DNA-PKcs to form a complex with Ku/DNA.|We also show that Lyn phosphorylates DNA-PKcs but not Ku in vitro. 0.467 SIGNOR-279061 CORVET tethering complex complex SIGNOR-C550 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.2 SIGNOR-273699 TP53 protein P04637 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates 9606 15073170 NO gcesareni Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb. 0.357 SIGNOR-124038 SAR1A protein Q9NR31 UNIPROT SEC24D protein O94855 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 YES lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 0.713 SIGNOR-265301 PTK6 protein Q13882 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000150 17997837 YES llicata Phosphospecific antibodies, mutational analysis, and in vitro kinase assays demonstrated that brk specifically mediated stat5b phosphorylation at the activating tyrosine, y699. 0.43 SIGNOR-159066 tRNA(Leu) smallmolecule CHEBI:29169 ChEBI Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270417 PPARGC1A protein Q9UBK2 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 20404331 NO lperfetto Capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression 0.393 SIGNOR-217966 AKT1 protein P31749 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates quantity by stabilization phosphorylation Thr152 AARARLLtEIHGGAG 9606 BTO:0000007 27593939 YES lperfetto Mechanistically, Akt1 physically interacted with and phosphorylated UBE2S at Thr 152, enhancing its stability by inhibiting proteasomal degradation. 0.438 SIGNOR-265078 MAP2K7 protein O14733 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 15001534 YES gcesareni The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells 0.496 SIGNOR-123164 NCR2 protein O95944 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 BTO:0000914 22021614 NO miannu NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. In this study, we show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through NKp44/ITIM. 0.7 SIGNOR-260044 Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 NO miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.7 SIGNOR-270910 ALDOA protein P04075 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266483 SARS1 protein P49591 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270800 MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 21902831 YES lperfetto Tak1 can phosphorylate and activate map kinase kinase 3/6 (mkk3/6), and numerous studies have demonstrated a requirement for mkk3/6 activity in the initiation of myoblast differentiation, again in a p38-dependent manner. 0.764 SIGNOR-236145 MC5R protein P33032 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257441 POLR1F protein Q3B726 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.2 SIGNOR-266157 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser33 TQSQGSSsQSQGISS 9606 BTO:0000007 10973490 YES lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir 0.834 SIGNOR-81399 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-266282 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269359 RNF43 protein Q68DV7 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25996295 YES miannu Moreover, RNF43 polyubiquitinates p53 which further leads to its destabilization resulting in a decrease in induction of the p53 apoptotic pathway, a hitherto unknown process targeted by NP for p53 stabilization and accumulation. 0.452 SIGNOR-278714 PPP1CA protein P62136 UNIPROT AURKA protein O14965 UNIPROT down-regulates dephosphorylation 9606 11551964 YES gcesareni Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro. 0.437 SIGNOR-110411 NANOG protein Q9H9S0 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 NO flangone Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes. 0.7 SIGNOR-242076 DLX5 protein P56178 UNIPROT MSX1 protein P28360 UNIPROT down-regulates activity binding 10090 BTO:0000946 9111364 YES 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. 0.39 SIGNOR-240921 C3 protein P01024 UNIPROT C3 protein P01024 UNIPROT up-regulates activity cleavage Arg671 QPAARRRrSVQLTEK 9606 BTO:0000089 26806831 YES lperfetto C3 autoactivates in a process known as “tick-over,” which is characterized by spontaneous hydrolysis of a reactive thiol-ester to generate C3(H2O). Although C3(H2O)Bb produces only relatively small amounts of C3b compared to the other C3 convertases, it nevertheless generates enough C3b to set the C3 convertase amplification loop in motion. 0.2 SIGNOR-263483 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RRAS protein P10301 UNIPROT up-regulates activity phosphorylation Ser186 S-->L 9606 BTO:0002181 27086924 YES miannu  In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo.  0.2 SIGNOR-277220 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Thr884 SKTSSSDtLSEEKNS 9606 BTO:0000567 31167143 YES miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  0.2 SIGNOR-276732 HSPA8 protein P11142 UNIPROT Chaperone-mediated autophagy phenotype SIGNOR-PH118 SIGNOR up-regulates activity -1 2799391 NO A 73-kilodalton (kD) intracellular protein was found to bind to peptide regions that target intracellular proteins for lysosomal degradation in response to serum withdrawal. This protein cross-reacted with a monoclonal antibody raised to a member of the 70-kD heat shock protein (hsp70) family, and sequences of two internal peptides of the 73-kD protein confirm that it is a member of this family. 0.7 SIGNOR-259991 SGK1 protein O00141 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser824 LRRDRWSsVVPRVVE 9606 25972993 YES miannu Recently, we identified that TRPV4 is also one of SGK1 substrate proteins (Fig. . , and the phosphorylation on serine 824 by SGK1 regulates the binding affinity to actin or tubulin [31].|Therefore, we propose the hypothesis that the SGK1 phosphorylation may enhance TRPV4 channel density in the plasma membrane through the dissociation from STIM1, similar with the regulation mechanism of GLUT4 or AQP2 by insulin or vasopressin, respectively , ]. 0.362 SIGNOR-279386 BMP2 protein P12643 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates 9606 22298955 NO lperfetto Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation. 0.652 SIGNOR-195561 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity dephosphorylation Thr842 CTETFTGtLQYMAPE 10090 11689443 YES llicata After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845. 0.596 SIGNOR-248540 raloxifene chemical CHEBI:8772 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258582 NEK6 protein Q9HC98 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser403 DDSTLSEsANQVFLG -1 12023960 YES miannu Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation. 0.368 SIGNOR-262953 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Ala617 ISEVKMDaEFRHDSG -1 8943232 YES lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261737 FUS protein P35637 UNIPROT GEMIN4 protein P57678 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 23022481 YES lperfetto Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells 0.2 SIGNOR-262105 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR1 protein P03372 UNIPROT up-regulates chemical activation 9606 BTO:0000150 17478088 YES gcesareni Oestrogen receptors (er)alpha and beta modify the expression of genes involved in cell growth, proliferation and differentiation through binding to oestrogen response elements (eres) located in a number of gene promoters. 0.8 SIGNOR-154660 BCL7B protein Q9BQE9 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.426 SIGNOR-269783 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 18337751 YES gcesareni The phosphorylation of eef2k at ser359 is of particular interest. First, the phosphorylation of this site strongly decreases the activity of eef2k even at high calcium concentrations (knebel et al, 2001), that is, desensitizes eef2k to the activating effects of elevated ca2+ levels. third, although p38 map kinase (also termed sapk4 can phosphorylate ser359 in vitro (knebel et al, 2001), this enzyme is not known to be active basally or to be regulated by amino acids. 0.577 SIGNOR-177986 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 BTO:0000671 15533987 YES gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. 0.348 SIGNOR-130269 PTPRO protein Q16827 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 27345410 YES lperfetto In this study, our co-immunoprecipitation experiment along with the results derived from in vivo , cultured cells and clinical specimen confirm that PTPRO dephosphorylates ERBB2 at Y1248.|PTPRO overexpression remarkably accelerated degradation of ERBB2 (XREF_FIG). 0.403 SIGNOR-276979 HIF-1 complex complex SIGNOR-C418 SIGNOR SLC2A3 protein P11169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 YES miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 0.359 SIGNOR-267451 MAP3K11 protein Q16584 UNIPROT GOLGA3 protein Q08378 UNIPROT up-regulates activity phosphorylation 9606 14734651 YES miannu In vitro kinase assays demonstrated that MLK3 directly phosphorylates golgin-160 in the N-terminal head region between residues 96 and 259. 0.361 SIGNOR-279065 DYRK1A protein Q13627 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 24119401 YES lperfetto Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells. 0.396 SIGNOR-202838 FGFR1 protein P11362 UNIPROT LDHA protein P00338 UNIPROT up-regulates phosphorylation Tyr10 TLKDQLIyNLLKEEQ 9606 21969607 YES gcesareni We found that the oncogenic receptor tyrosine kinase fgfr1 directly phosphorylates ldh-a. Phosphorylation at y10 and y83 enhances ldh-a activity by enhancing the formation of active, tetrameric ldh-a and the binding of ldh-a substrate nadh, respectively. 0.367 SIGNOR-176730 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 12510059 YES gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.771 SIGNOR-96944 NPC complex SIGNOR-C263 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 28831067 NO lperfetto The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export. 0.7 SIGNOR-263295 ELP6 protein Q0PNE2 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 YES miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. 0.769 SIGNOR-269713 PTAFR protein P25105 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257061 TP53 protein P04637 UNIPROT FNTA protein P49354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26469958 NO lperfetto In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs. 0.2 SIGNOR-242408 TRIB3 protein Q96RU7 UNIPROT COP1 protein Q8NHY2 UNIPROT up-regulates activity binding 9606 BTO:0000007 16794074 YES miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). 0.2 SIGNOR-271603 FGF2 protein P09038 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15564063 NO miannu Increased expression of RUNX2 in OA cartilage may contribute to increased expression of MMP-13. FGF2, which is present in OA synovial fluid, activated RUNX2 via the MEK/ERK pathway and increased MMP-13 expression. 0.42 SIGNOR-255079 TP53 protein P04637 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 24737129 NO simone vumbaca We have identified a novel role for p53 that is specific to the regulation of several pro-inflammatory genes in human macrophages, including IL-6, IL-8 and CXCL1. Importantly, NF-κB co-activation is essential for this regulation 0.466 SIGNOR-255969 TFIIH complex SIGNOR-C457 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 30860024 NO lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair. 0.7 SIGNOR-269323 UBN1 protein Q9NPG3 UNIPROT HIRA complex 1 complex SIGNOR-C461 SIGNOR form complex binding 9606 30285846 YES miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. 0.724 SIGNOR-269433 ZBTB46 protein Q86UZ6 UNIPROT LIF protein P15018 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 30962287 YES miannu ZBTB46 binds directly to the LIF regulatory sequence and enhances its transcription. Our study confirmed a novel positive association between ZBTB46 activity and LIF levels in prostate cancer tissues and cells. Under androgen regulation, low levels of ZBTB46 are an essential transcriptional factor for maintaining LIF-STAT3 signaling, while the loss of androgen signaling or inhibition of AR signaling causes LIF-enhanced therapeutic resistance and CRPC characteristics through the upregulation of ZBTB46. We also found that LIF activation drives malignant progression and NE-like reprogramming in prostate cancer by activating STAT3 signaling. 0.2 SIGNOR-277988 NEK7 protein Q8TDX7 UNIPROT TERF1 protein P54274 UNIPROT up-regulates quantity by stabilization phosphorylation Ser114 AIIHGLSsLTACQLR 9606 BTO:0000567 28216227 YES done miannu Mechanistically, Nek7 interacts with and phosphorylates TRF1 on Ser114, which prevents TRF1 from binding to Fbx4, an Skp1-Cul1-F box E3 ligase subunit, thereby alleviating proteasomal degradation of TRF1, leading to a stable association of TRF1 with Tin2 to form a shelterin complex. 0.343 SIGNOR-273903 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr239 APRSSDLtDRVKVWT 9606 BTO:0000671 17522053 YES llicata Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc). 0.2 SIGNOR-155106 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 12242151 YES gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members. 0.822 SIGNOR-92942 cisapride chemical CHEBI:3720 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9395068 YES miannu A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. cisapride displays specific, high affinity block of the human cardiac K+ channel HERG. It is likely that this interaction underlies the proarrhythmic effects of the drug observed under certain clinical settings. 0.8 SIGNOR-258672 PLCE1 protein Q9P212 UNIPROT PRKCA protein P17252 UNIPROT up-regulates 9606 12645577 NO miannu TNF-alpha Binds to tnfr1 and activates pc-plc to induce pkc? And c-src activation 0.446 SIGNOR-99307 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.8 SIGNOR-258663 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser761 DSLGRRSsLSRLEPS 9606 25009260 YES lperfetto Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome 0.2 SIGNOR-205238 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Thr356 PLEEERQtQRSKPQP 9606 BTO:0000130 17217339 YES lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation. 0.38 SIGNOR-152027 ROCK1 protein Q13464 UNIPROT PFN1 protein P07737 UNIPROT down-regulates phosphorylation Ser138 MASHLRRsQY 9606 22479341 YES lperfetto We previously identified pfn1 as a huntingtin aggregation inhibitor, and others have implicated it as a tumor-suppressor. Rho-associated kinase (rock) directly phosphorylates pfn1 at ser-137 to prevent its binding to polyproline sequences. This negatively regulates its anti-aggregation activity. 0.272 SIGNOR-196820 ZNF384 protein Q8TF68 UNIPROT MMP1 protein P03956 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000944 10669742 YES Luana Luciferase activity driven by the MMP-1 promoter also increased by 2.5- to 3-fold. In contrast, CIZ had no effect on the luciferase activity from the MMP-1 promoter that was mutated at the CIZ binding consensus sequence. These results show that the CIZ transactivates the MMP-1 promoter through this sequence. 0.307 SIGNOR-266229 AURKB protein Q96GD4 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-70420 TERF2 protein Q15554 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 YES lperfetto It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex 0.684 SIGNOR-263323 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity phosphorylation 9606 23431053 YES miannu The thousand-and-one (TAO) amino acids kinase or TAOK1 – 3 has been shown to directly phosphorylate and activate Hpo or MST1/2. 0.371 SIGNOR-256182 EBV gH:gL:gp42 complex SIGNOR-C403 SIGNOR HLA-DRA protein P01903 UNIPROT up-regulates activity binding 9606 BTO:0000776 11864610 YES scontino The EBV gp42 glycoprotein binds MHC class II molecules, playing a critical role in infection of B lymphocytes. The gp42 binds HLA-DR1 using a surface site 0.2 SIGNOR-266628 AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity 9606 16293724 NO lperfetto We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. 0.2 SIGNOR-244225 MAP3K21 protein Q5TCX8 UNIPROT CHUK protein O15111 UNIPROT down-regulates activity phosphorylation 9606 26859459 YES miannu Immunoprecipitation and in vitro kinase analysis revealed that MLK4 physically interacts with both IKKalpha and beta, but preferentially phosphorylates IKKalpha over IKKbeta (XREF_FIG 0.2 SIGNOR-279067 AURKA protein O14965 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates activity phosphorylation 7227 16824953 YES lperfetto INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop 0.694 SIGNOR-252047 Tert-butyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate chemical CID:46907787 PUBCHEM BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition 9606 30080437 YES Simone Vumbaca Through the integrative analyses of ChIP-seq and CAGE data, we elucidate the involvement of BRD2 in gene regulation upon BET inhibition by JQ1 in H23 cells. 0.8 SIGNOR-261124 NEUROG3 protein Q9Y4Z2 UNIPROT NHLH1 protein Q02575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19028584 NO miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. Ngn3 overexpression increased the NSCL1-expressing domain corresponding to young ganglion cells 0.264 SIGNOR-254634 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 8622669 YES lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways. 0.727 SIGNOR-40356 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser281 SGTPSSAsPALSRRG 10090 17213202 YES lperfetto Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo. 0.385 SIGNOR-234465 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Thr531 PNATGTGtFSPGASP -1 10467162 YES lperfetto Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect. 0.2 SIGNOR-249020 KEAP1 protein Q14145 UNIPROT CUL3 protein Q13618 UNIPROT up-regulates activity binding 9534 BTO:0001538 15983046 YES miannu Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome.  The N-terminal BTB domain and central linker region of Keap1 bind Cul3, whereas the C-terminal Kelch domain of Keap1 binds Nrf2 via residues located within loops that extend out from the bottom of the Kelch domain 0.95 SIGNOR-268925 IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 26178471 YES lperfetto Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (Œ±-KG) 0.8 SIGNOR-261827 DZIP3 protein Q86Y13 UNIPROT H2AC21 protein Q8IUE6 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHKP 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271758 S1PR2 protein O95136 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22863277 YES gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. 0.588 SIGNOR-198559 KDM5A protein P29375 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264301 FYN protein P06241 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates quantity phosphorylation Tyr576 RDEDGKPySPSEYSL 9606 23434765 YES miannu Fyn phosphorylates Nrf2 Y568, resulting in nuclear export and degradation of Nrf2.|Fyn phosphorylates Nrf2Y568 resulting in nuclear export and degradation of Nrf2. 0.401 SIGNOR-278358 RAB9A protein P51151 UNIPROT RABEPK protein Q7Z6M1 UNIPROT up-regulates activity 9230071 YES lperfetto P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking. 0.58 SIGNOR-253088 NR3C1 protein P04150 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 NO areggio Consistent with these findings, DEX-induced upregulation of MuRF1 is significantly attenuated in mice expressing a homodimerization-deficient GR despite no effect on the degree of muscle loss in these mice vs. their wild-type counterparts. Finally, chromatin immunoprecipitation analysis reveals that both GR and FOXO1 bind to the endogenous MuRF1 promoter in C(2)C(12) myotubes, and IGF-I inhibition of DEX-induced MuRF1 expression correlates with the loss of FOXO1 binding. 0.33 SIGNOR-254992 UBE2J1 protein Q9Y385 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by destabilization ubiquitination 9606 BTO:0001379 29892818 YES inferred from family member scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. 0.379 SIGNOR-270242 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1009 LDTSSVLyTAVQPNE 9606 18567737 YES gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. 0.69 SIGNOR-179064 MOS protein P00540 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 10090 7731726 YES Manara Our data indicate that Mos activated MEK1 in vitro as well as in vivo by phosphorylating Ser 222. 0.484 SIGNOR-260920 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY4 protein P51582 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257564 CSNK2A1 protein P68400 UNIPROT FHOD3 protein Q2V2M9 UNIPROT down-regulates phosphorylation 9606 BTO:0000887 21149568 YES tpavlidou We have identified a novel striated muscle-specific splice variant of the formin fhod3 that introduces a casein kinase 2 (ck2) phosphorylation site. The specific targeting of muscle fhod3 to the myofibrils in cardiomyocytes is abolished in phosphomutants or by the inhibition of ck2. Phosphorylation of muscle fhod3 also prevents its interaction with p62/sequestosome 1 and its recruitment to autophagosomes. 0.31 SIGNOR-170525 Ub:E2 complex SIGNOR-C497 SIGNOR PCGF3 protein Q3KNV8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271159 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser138 MEDLTNVsSLLNMER 9606 25670858 YES lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 0.587 SIGNOR-265228 TRAF6 protein Q9Y4K3 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity ubiquitination Lys24 ETFSDLWkLLPENNV 9606 27818144 YES miannu Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK.|We mutated every conserved lysine (K) residue on p53 and found that TRAF6 preferentially ubiquitinates p53 at K24 in the in vivo ubiquitination assay (XREF_FIG, XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY). 0.608 SIGNOR-278728 CSNK1A1L protein Q8N752 UNIPROT GLI2 protein P10070 UNIPROT up-regulates phosphorylation 9606 16481469 YES gcesareni Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed 0.333 SIGNOR-144551 AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser227 GARRRGGsASRSLPL 9606 10224060 YES lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. 0.2 SIGNOR-244361 SLC4A10 protein Q6U841 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI up-regulates quantity relocalization 9606 26136660 YES miannu Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride 0.8 SIGNOR-264919 lovastatin chemical CHEBI:40303 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 6933445 YES miannu Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. 0.8 SIGNOR-258403 USF1 protein P22415 UNIPROT B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 NO miannu Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation. 0.2 SIGNOR-254655 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.765 SIGNOR-252746 WNT5A protein P41221 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates 9606 21078818 NO lperfetto We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3). 0.423 SIGNOR-227958 MAPK4 protein P31152 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 20734105 YES miannu ERK3, ERK4 and p38 MAPK can all phosphorylate MK5 at Thr 182 , , , - ], but it is not known whether these enzymes also can phosphorylate Ser 115 and whether this modification contributes to ERK3-, ERK4-, or p38 MAPK -regulated subcellular localization of MK5. 0.629 SIGNOR-279072 PASK protein Q96RG2 UNIPROT PASK protein Q96RG2 UNIPROT up-regulates activity phosphorylation Thr1161 ERGKLFYtFCGTIEY -1 11459942 YES lperfetto We present evidence that the activity of pask is regulated by two mechanisms. Autophosphorylation at two threonine residues located within the activation loop significantly increases catalytic activity. 0.2 SIGNOR-109481 PTPRG protein P23470 UNIPROT SHC1 protein P29353 UNIPROT down-regulates activity dephosphorylation Tyr350 EPPDHQYyNDFPGKE -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254724 FOXP1 protein Q9H334 UNIPROT SEMA5B protein Q9P283 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001176 24023716 YES Gianni FoxP1 stimulates angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells. 0.33 SIGNOR-269050 ABL1 protein P00519 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 BTO:0001271 8441409 YES lperfetto Sh1 domain autophosphorylation of p210 bcr/abl is required for transformation but not growth factor independence. 0.2 SIGNOR-39142 MST1 protein P26927 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Ser226 LNPQWNEsFTFKLKP 9606 BTO:0002181 26414765 YES miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  0.2 SIGNOR-277179 hsa-miR-139-5p mirna URS000025D232_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000976 24318902 YES Our results showed that miR-139 expression inhibits proliferation and metastasis of LSCC by repressing the functional expression of CXCR4 and CXCR4 was directly targeted by miR-139. 0.4 SIGNOR-277934 MTNR1B protein P49286 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256986 tyrosine smallmolecule CHEBI:18186 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264757 MAPK9 protein P45984 UNIPROT ELK3 protein P41970 UNIPROT down-regulates activity phosphorylation 11042694 YES miannu JNK binds to the J box in the middle of the protein, and binding is required for phosphorylation of the adjacent EXport motif. Both the binding and phosphorylation sites (the JEX element) are important for Net export. 0.323 SIGNOR-250138 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM6B protein O15054 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273461 TP53 protein P04637 UNIPROT GADD45A protein P24522 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23576563 NO gcesareni P53 acetylated at k120 subsequently bound to the promoters of its target apoptotic genes, bax and gadd45, to promote their expression and lead to apoptosis. 0.658 SIGNOR-201679 Fibrin complex SIGNOR-C317 SIGNOR Fibrin_clot_formation phenotype SIGNOR-PH153 SIGNOR up-regulates binding 9606 BTO:0000131 18544683 YES lperfetto A fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel.|Fibrin clots were formed as described for turbidity experiments, in which the fibrinogen, calcium, and polyP (when included) were preincubated for 15 minutes before adding thrombin. 0.7 SIGNOR-263531 MAPK1 protein P28482 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 9606 15486195 YES lperfetto In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel 0.715 SIGNOR-129874 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248374 vorinostat chemical CHEBI:45716 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257918 PIM1 protein P11309 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 YES tpavlidou Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene. 0.388 SIGNOR-179304 RAB38 protein P57729 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR up-regulates activity relocalization 9606 23247405 YES lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. 0.299 SIGNOR-260699 TGFB1 protein P01137 UNIPROT ACTA2 protein P62736 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452 11988769 YES miannu A TGF-β1 response element that has a sequence different to that known for Smad binding has been identified in the α- SM actin promoter and seems to be essential for expression of α-SM actin in both SM cells 72 and myofibroblasts73 . How TGF-β1 activates expression of α-SM actin through this TGF-β1 control element is, as yet, unknown 0.419 SIGNOR-277681 DACH1 protein Q9UI36 UNIPROT Six1/Dach complex SIGNOR-C122 SIGNOR form complex binding 10090 14628042 YES llicata The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, 0.596 SIGNOR-238026 MRPL53 protein Q96EL3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.662 SIGNOR-262345 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15695813 YES gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. 0.2 SIGNOR-133865 SRC protein P12931 UNIPROT RAC1 protein P63000 UNIPROT up-regulates phosphorylation 9606 17991704 YES gcesareni N attractive hypothesis consistent with our present data is that the gef responsible for rac activation in mce cells may be activated by src family kinase tyrosine phosphorylationour results present a novel mechanism by which the pi3k and src signaling cascades cooperate to activate rac and promote intestinal epithelial cell migration downstream of egfr. 0.613 SIGNOR-158954 CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1237 TEYSQGAsPQPQHQL 9606 11584018 YES lperfetto Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter. 0.357 SIGNOR-110908 TRAF6 protein Q9Y4K3 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity binding 9606 10075662 YES miannu RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK. 0.63 SIGNOR-253048 MYOCD protein Q8IZQ8 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 21673106 NO miR-143 and miR-145 target KLF4 gcesareni These results further confirm that bmp4 requires mrtf-a, whereas tgf-_ requires myocd for the induction of pri-mir-143/145 and down-regulation of klf4. 0.465 SIGNOR-174319 ACP1 protein P24666 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 17353188 YES Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3 0.322 SIGNOR-248455 EIF2S1 protein P05198 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 YES lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. 0.946 SIGNOR-269114 PRKD1 protein Q15139 UNIPROT NOS1 protein P29475 UNIPROT up-regulates activity phosphorylation Ser1417 TNRLRSEsIAFIEES 9606 24740233 YES miannu In addition, we demonstrate that protein kinase D1 activates nNOS by phosphorylating the activatory residue Ser1412, leading to increased \u00b7NO production, hence establishing a novel role of PKD in the regulation of \u00b7NO synthesis.|PKD1 phosphorylates nNOS at activatory Ser 1412 in vitro and in live cells. 0.386 SIGNOR-278426 TRIM68 protein Q6AZZ1 UNIPROT TFG protein Q92734 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24999993 YES miannu Our results suggest that TRIM68 degrades TFG at a point of pathway convergence in which downstream events lead to the activation of both NF-kappaB and IRF3.|TRIM68 polyubiquitinates TFG leading to its degradation via its RING domain which also plays an important role in TRIM68 negative inhibition on IFN-beta production. 0.452 SIGNOR-278737 PP1 proteinfamily SIGNOR-PF54 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases 0.493 SIGNOR-269923 TNKS2 protein Q9H2K2 UNIPROT RNF146 protein Q9NTX7 UNIPROT up-regulates activity 9606 BTO:0000007 21478859 NO lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.612 SIGNOR-263337 APP protein P05067 UNIPROT NAE1 protein Q13564 UNIPROT up-regulates activity binding 9606 BTO:0000590 25568892 YES lperfetto Alzheimer's disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis. 0.731 SIGNOR-251577 MAPK8 protein P45983 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 25077544 YES miannu (b) Phosphorylation of Bid at Thr59 by JNK1 and JNK2 (in vitro kinase assay). 0.593 SIGNOR-279076 MAPK9 protein P45984 UNIPROT EGLN2 protein Q96KS0 UNIPROT up-regulates activity phosphorylation Ser162 SSGSGEAsAGLMEEA 9606 27263528 YES miannu Interestingly, we found that docetaxel induced JNK2 activation increased phosphorylation of PHD1 at Ser 74 and Ser 162 in hypoxic cancer cells (XREF_FIG). 0.2 SIGNOR-279077 PPBP protein P02775 UNIPROT OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.383 SIGNOR-258412 PPARGC1A protein Q9UBK2 UNIPROT COX4I1 protein P13073 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000443 23021218 NO lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). 0.399 SIGNOR-253098 FBXO25 protein Q8TCJ0 UNIPROT ELK1 protein P19419 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23940030 YES miannu The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1 protein. FBXO25 is one of the 69 known human F-box proteins that serve as specificity factors for a family of ubiquitin ligases composed of SKP1, Rbx1, Cullin1, and F-box protein (SCF1) that are involved in targeting proteins for degradation across the ubiquitin proteasome system. FBXO25 interacted with and mediated the ubiquitination and proteasomal degradation of ELK-1 in HEK293T cells. 0.2 SIGNOR-272127 KLF1 protein Q13351 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0000725 28026072 NO irozzo Activation of KLF1 at day 10 of the differentiation process when hematopoietic progenitor cells were present, enhanced erythroid commitment and differentiation. 0.7 SIGNOR-256086 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.278 SIGNOR-276086 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser421 DNCASVSsPYESAIG 9534 BTO:0000298 12756254 YES miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. 0.879 SIGNOR-250126 GSK3B protein P49841 UNIPROT EIF2B1 protein Q14232 UNIPROT down-regulates binding 9606 21798082 YES gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). 0.2 SIGNOR-175436 ESR2 protein Q92731 UNIPROT TFF1 protein P04155 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 NO ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression 0.351 SIGNOR-253939 CARD11 protein Q9BXL7 UNIPROT BCL10 protein O95999 UNIPROT up-regulates binding 9606 12356734 YES gcesareni Card11 cooperates with bcl10 in a card domain-dependent manner.;These results implicate card11 in factor- specific activation of nf-kappab 0.845 SIGNOR-93869 XIAP protein P98170 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity ubiquitination 9606 28666324 YES miannu HIF1alpha is ubiquitinated by XIAP.|Lys 63 -linked ubiquitination of HIF1alpha by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13.|We find that XIAP and Ubc13 dependent Lys 63 -linked polyubiquitination promotes HIF1alpha nuclear retention leading to an increase in the expression of HIF1 responsive genes.|The data indicate that XIAP promotes the formation of the non-degradative Lys63-linked ubiquitin chains onto hypoxia inducible factor1\u03b1, but does not affect the formation of Lys48-linked chains. 0.284 SIGNOR-278740 BIRC2 protein Q13490 UNIPROT PACS2 protein Q86VP3 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24633224 YES miannu The principal findings indicate that (i) PACS-2 is constitutively polyubiquitinated and degraded via the proteasome pathway in liver cells; (ii) Cellular Inhibitor of Apoptoses bind to and directly ubiquitinate PACS-2; (iii) pharmacological depletion (by SMAC mimetics) or genetic deletion of both cIAP-1 and cIAP-2 impairs PACS-2 ubiquitination and results in its intracellular accumulation; and (iv) PACS-2 accumulation facilitates its translocation to the lysosomes following TRAIL treatment, promoting TRAIL-induced lysosomal membrane permeabilization and apoptosis.|Therefore, it appears that cIAP-1 and cIAP-2 act coordinately and redundantly to ubiquitinate PACS-2. 0.304 SIGNOR-278742 GDNF protein P39905 UNIPROT ID2 protein Q02363 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.247 SIGNOR-252180 MAPK9 protein P45984 UNIPROT EGLN2 protein Q96KS0 UNIPROT up-regulates activity phosphorylation Ser74 TATSTTAsPLRDGFG 9606 27263528 YES miannu Interestingly, we found that docetaxel induced JNK2 activation increased phosphorylation of PHD1 at Ser 74 and Ser 162 in hypoxic cancer cells (XREF_FIG). 0.2 SIGNOR-279078 MET protein P08581 UNIPROT CAV1 protein Q03135 UNIPROT up-regulates activity phosphorylation 9606 25148256 YES miannu Findings obtained using SNU-449 cells suggested that c-Met positively regulated CAV1 activity.|Inhibition of c-Met activation abolished phosphorylation of CAV1 on Tyrosine 14. 0.424 SIGNOR-279080 CYP19A1 protein P11511 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification 9606 BTO:0000975 27702664 YES lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively 0.8 SIGNOR-268670 CFL2 protein Q9Y281 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR down-regulates quantity binding 9606 BTO:0000132 27871158 YES lperfetto Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. 0.7 SIGNOR-261837 PRKCA protein P17252 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates activity phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 YES lperfetto Protein kinase A negatively modulates the nuclear accumulation of NF-ATc1. | Here we show that overexpression of PKA causes phosphorylation and cytoplasmic accumulation of NF-ATc1 in direct opposition to calcineurin by phosphorylating Ser-245, Ser-269, and Ser-294 in the conserved serine-proline repeat domain, and that mutation of these serines blocks the effect of PKA. Activation of endogenous PKA is similarly able to promote phosphorylation of these sites on NF-ATc1 in two lymphoid cell lines. 0.384 SIGNOR-249175 ARRB2 protein P32121 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 16908539 YES gcesareni We demonstrate that _-arrestins mediate the activity-dependent interaction of smo and the kinesin motor protein kif3a. 0.637 SIGNOR-148773 Av/b3 integrin complex SIGNOR-C177 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.683 SIGNOR-257719 PRKCD protein Q05655 UNIPROT PLSCR1 protein O15162 UNIPROT up-regulates phosphorylation Thr161 CGPSRPFtLRIIDNM 9606 10770950 YES lperfetto Following the induction of apoptosis, however, phosphorylation of serine residues decreased and it increased on threonine, consistent with the predicted pkc phosphorylation site at thr-161. Transfection of cho cells with scramblase and pkc_, but not scramblase or pkc_ alone, increased scramblase activity 0.425 SIGNOR-76904 INSR protein P06213 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Tyr607 NENTEDQySLVEDDE 9534 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. 0.669 SIGNOR-251322 MET-enkephalin smallmolecule CHEBI:6618 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257551 GATAD2B protein Q8WXI9 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.784 SIGNOR-263857 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP 9606 BTO:0001412 8692915 YES gcesareni Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. 0.414 SIGNOR-246227 PRKACA protein P17612 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser305 IKRSKKNsLALSLTA 9606 15193262 YES lperfetto We show that phosphorylation of serine-305 in the hinge region of er_ by protein kinase a (pka) induced resistance to tamoxifenactivation of pka prevents tamoxifen-mediated inhibition of er transactivation 0.485 SIGNOR-125779 CREB1 protein P16220 UNIPROT CHGA protein P10645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007 12456801 YES Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. 0.265 SIGNOR-254276 ATP5PD protein O75947 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261404 midostaurin chemical CHEBI:63452 ChEBI FGR protein P09769 UNIPROT down-regulates activity chemical inhibition -1 30069632 YES Gianni Midostaurin (PKC412, Rydapt®) is an oral multiple tyrosine kinase inhibitor. Main targets are the kinase domain receptor, vascular endothelial-, platelet derived-, and fibroblast growth factor receptor, stem cell factor receptor c-KIT, as well as mutated and wild-type FLT3 kinase 0.8 SIGNOR-261976 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248368 BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000165;BTO:0002974; BTO:0002809 9442019 YES ggiuliani In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus. 0.781 SIGNOR-255830 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB7 protein P26010 UNIPROT up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.2 SIGNOR-259009 USF1 protein P22415 UNIPROT GCK protein P35557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9677331 NO miannu Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element 0.289 SIGNOR-255597 CLTCL1 protein P53675 UNIPROT AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.73 SIGNOR-260673 ARID5B protein Q14865 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 NO miannu We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). 0.2 SIGNOR-256159 precursor messenger RNA smallmolecule CHEBI:139356 ChEBI messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity precursor of 9606 19224921 YES lperfetto Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation. 0.8 SIGNOR-268314 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000527;BTO:0000017 9890893 YES lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). 0.76 SIGNOR-236400 HBA1 protein P69905 UNIPROT CD163 protein Q86VB7 UNIPROT up-regulates activity binding 9606 16522161 YES Regulation miannu These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells. 0.259 SIGNOR-251747 Ub:E2 complex SIGNOR-C497 SIGNOR ITCH protein Q96J02 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271301 iron(2+) smallmolecule CHEBI:29033 ChEBI Ferritin complex SIGNOR-C563 SIGNOR down-regulates quantity binding 9606 39534872 YES miannu Fe3+ is taken up by TFRC and exported by SLC40A1. Inside the cell, Fe3+ is reduced to Fe2+, with excess iron stored in ferritin (composed of FTH1 and FTL) or sequestered by MT1G. 0.8 SIGNOR-279882 TH protein P07101 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). 0.8 SIGNOR-263990 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr603 PCCIVTStYGWTANM 9606 24117238 YES lperfetto Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity. 0.258 SIGNOR-202820 MAPK8 protein P45983 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11781324 YES lperfetto Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. 0.376 SIGNOR-113645 PAK5 protein Q9P286 UNIPROT AIFM1 protein O95831 UNIPROT down-regulates activity phosphorylation Thr281 GAEVKSRtTLFRKIG 9606 33867848 YES miannu Our results show that PAK5 can phosphorylate Thr-281 of AIF, which is included in its NLS1 sequence.|These results suggested that PAK5 inhibited AIF from entering the nucleus through phosphorylation of AIF T281 site, thus inhibiting cell apoptosis. 0.2 SIGNOR-279085 F2RL1 protein P55085 UNIPROT CTSD protein P07339 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254860 SLC27A5 protein Q9Y2P5 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264466 ESR2 protein Q92731 UNIPROT SCN1A protein P35498 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 NO miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice 0.2 SIGNOR-253472 WNT5A protein P41221 UNIPROT GSK3B protein P49841 UNIPROT up-regulates 9606 21078818 NO gcesareni We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3) 0.396 SIGNOR-169669 PBK protein Q96KB5 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation 9606 29896413 YES miannu The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells.|These results indicated that TOPK overexpression resulted in the phosphorylation of HDAC1 and HDAC2, which might inactivate them and promote the acetylation of Histone 3 and Histone 4. 0.2 SIGNOR-279087 MCF2 protein P10911 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.663 SIGNOR-260557 GNAO1 protein P09471 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates activity binding -1 10224115 YES G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. 0.2 SIGNOR-256540 MAPKAPK2 protein P49137 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation 9606 17292828 YES amattioni Mk2 was required for the degradation of cdc25a. Mk2 phosphorylates cdc25a in vitro. Phosphorylation of cdc25a in vivo has been shown to facilitate its ubiquitin-mediated proteolysis 0.365 SIGNOR-152996 PRKACA protein P17612 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation. 0.2 SIGNOR-70424 GRM6 protein O15303 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264354 DAB2IP protein Q5VWQ8 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity relocalization 10090 20080667 YES miannu DAB2IP prevents β-catenin nuclear translocation. 0.299 SIGNOR-254755 HTR2C protein P28335 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.502 SIGNOR-257355 PIM1 protein P11309 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 29472550 YES miannu We further showed that PIM1 could interact with and phosphorylate Smad2 or Smad3 in the nucleus to induce transcription factor (ZEB1, ZEB2, Snail1, Snail2 and Twist) expression and EMT. 0.2 SIGNOR-279090 DIO2 protein Q92813 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity chemical modification 9606 8755651 YES scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T4 0.8 SIGNOR-266949 AURKB protein Q96GD4 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser539 TSLSPRSsLSSPSPP 9606 21878642 YES llicata We identified the highly conserved ser(539) as the primary phosphorylation site for aurora kinases. 0.25 SIGNOR-176363 NANOG protein Q9H9S0 UNIPROT GATA6 protein Q92908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 NO miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 0.459 SIGNOR-254627 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser103 RGLKRSLsEMEIGMV 10753652 YES llicata Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors. 0.37 SIGNOR-250638 UBE3A protein Q05086 UNIPROT PSMB1 protein P20618 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28559284 YES lperfetto Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits. 0.355 SIGNOR-265131 triazolopyridazine chemical CHEBI:48384 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). 0.8 SIGNOR-263803 PA2G4 protein Q9UQ80 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 16254079 YES Ectopic expression of ebp1, a member of the PA2G4 family, inhibits the proliferation and induces the differentiation of human breast and prostate cancer cell lines. Ebp1 inhibits transcription of E2F1 and androgen receptor regulated genes such as prostate specific antigen (PSA) through its interactions with histone deacetylases (HDACs) 0.2 SIGNOR-253662 PSPH protein P78330 UNIPROT L-serine chemical CHEBI:17115 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 12213811 YES lperfetto Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP 0.8 SIGNOR-268571 PPP2CA protein P67775 UNIPROT HDAC2 protein Q92769 UNIPROT down-regulates activity dephosphorylation Ser394 EDAVHEDsGDEDGED 9606 30050113 YES miannu In contrast, in the present work, PPP2CA reduced HDAC2 S394 phosphorylation.|We postulated that PPP2CA would negatively regulate phospho dependent HDAC2 activity. 0.281 SIGNOR-277049 NRXN3 protein Q9HDB5 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 YES miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 0.2 SIGNOR-265462 LHX3 protein Q9UBR4 UNIPROT ISL2 protein Q96A47 UNIPROT up-regulates activity binding 9606 BTO:0000007 9452425 YES lperfetto a direct NLI-independent interaction between Lhx3 and the related proteins Isl1 and Isl2 was observed. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity 0.434 SIGNOR-236836 ERMP1 protein Q7Z2K6 UNIPROT UPR phenotype SIGNOR-PH131 SIGNOR up-regulates activity 9606 BTO:0000093 27566589 NO Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation. 0.7 SIGNOR-261295 ADA protein P00813 UNIPROT ADORA1 protein P30542 UNIPROT up-regulates activity binding -1 18680557 YES miannu The results show that human ADA, apart from reducing the adenosine concentration and thus preventing A(1)R desensitization, binds to A(1)R behaving as an allosteric effector that markedly enhances agonist affinity and increases receptor functionality. 0.572 SIGNOR-269105 MSL2 protein Q9HCI7 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002552 19033443 YES miannu Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization. MSL2 ubiquitination of p53 is required for p53 cytoplasmic localization. 0.371 SIGNOR-271774 DNA_damage stimulus SIGNOR-ST1 SIGNOR SLX4 protein Q8IY92 UNIPROT up-regulates -1 10542278 NO miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. 0.7 SIGNOR-259063 PPP3CB protein P16298 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 NO gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.464 SIGNOR-84044 SP3 protein Q02447 UNIPROT PCYT1A protein P49585 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 10744779 YES Luana Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter 0.2 SIGNOR-266232 PLK1 protein P53350 UNIPROT CELSR1 protein Q9NYQ6 UNIPROT down-regulates activity phosphorylation 9606 26004507 YES miannu In contrast to the non autonomous polarity defects caused by transgenic expression of Celsr1 LLtoAA, Plk1 inhibition did not cause a significant alteration in Celsr1 interphase polarity (XREF_FIG).|Plk1 phosphorylates the Celsr1 cytoplasmic domain in\nvitro . 0.2 SIGNOR-279094 TGFBI protein Q15582 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity 10090 BTO:0004093 25786978 YES lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. 0.369 SIGNOR-253284 ACTL6A protein O96019 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.827 SIGNOR-270699 GPR183 protein P32249 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.249 SIGNOR-257110 Ub:E2 complex SIGNOR-C497 SIGNOR MEX3B protein Q6ZN04 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271174 NLRC4 inflammasome complex SIGNOR-C223 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.2 SIGNOR-256384 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0002035 11948419 YES miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). 0.374 SIGNOR-275984 BIRC7 protein Q96CA5 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates binding 9606 BTO:0000848 15485396 YES gcesareni These results suggest that ml-iap might regulate apoptosis by sequestering smac and preventing it from antagonizing xiap-mediated caspases, rather than by direct caspases. 0.667 SIGNOR-129869 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser189 DEEFREPsTGKTCLP 9606 19661060 YES Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.379 SIGNOR-260884 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser19 KGFRRAVsELDAKQA -1 11359875 YES miannu MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. 0.519 SIGNOR-250149 ITGB1 protein P05556 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR form complex binding 9606 BTO:0000222;BTO:0002319 10199978 YES lperfetto The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle. 0.772 SIGNOR-241512 CASP3 protein P42574 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity cleavage Asp1405 CPGYPETdHGLFEDP 9606 12907805 YES lperfetto Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain. 0.321 SIGNOR-104585 FBXO3 protein Q9UK99 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 25721664 YES miannu F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway. 0.464 SIGNOR-272442 TACR1 protein P25103 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.29 SIGNOR-257316 CD38 protein P28907 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000078 18626062 NO miannu CD38 knockdown was found to increase apoptosis in normal microglia, but played a protective role in LPS-stimulated microglia and reduced proinflammatory cytokine secretion (Figure 1) 0.7 SIGNOR-264255 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 11073979 NO ggiuliani As shown in Fig. 8A, overexpression of Smad5 by itself induced Runx2 expression even in the absence of BMP-2 (lane 5). Western blot analysis also confirmed the induced level of Runx2 protein in C2C12-Sm5 cells (Fig. 8B) 0.593 SIGNOR-255835 PGD protein P52209 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 YES miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle 0.8 SIGNOR-267053 SMURF1 protein Q9HCE7 UNIPROT CCDC69 protein A6NI79 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272704 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr502 TPGTGLGtSPALAGD -1 8349691 YES llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. 0.32 SIGNOR-251077 ZMIZ1 protein Q9ULJ6 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 BTO:0001321 14609956 YES miannu Our results demonstrate that hZimp10 is a novel AR interacting protein that augments AR-mediated transcription. Moreover, hZimp10 co-localized with AR and SUMO-1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo. 0.708 SIGNOR-263935 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM37 protein O94972 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271082 PIM1 protein P11309 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates activity phosphorylation Thr362 GEKKKKItVFKEISY 9606 BTO:0001130 18056989 YES lperfetto Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells|This is further corroborated by our finding that the plasma membrane localization and drug-resistant activity of BCRP were compromised by T362A mutation. 0.36 SIGNOR-264420 FANCL protein Q9NW38 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.909 SIGNOR-263245 AKT proteinfamily SIGNOR-PF24 SIGNOR BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser694 QTSKRHDsDTFPELK 9606 BTO:0000150 20085797 YES lperfetto We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation 0.2 SIGNOR-244164 KIRREL3 protein Q8IZU9 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 10090 BTO:0004032 28381988 YES miannu We here report that, through its C-terminal PDZ domain-binding motif, Neph2 directly interacts with postsynaptic density (PSD)-95, an abundant excitatory postsynaptic scaffolding protein. Moreover, Neph2 protein is detected in the brain PSD fraction and interacts with PSD-95 in synaptosomal lysates. Functionally, loss of Neph2 in mice leads to age-specific defects in the synaptic connectivity of DG neurons. 0.373 SIGNOR-269079 RARA protein P10276 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 15322262 YES lperfetto Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter. 0.2 SIGNOR-268989 CALM1 protein P0DP23 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 YES gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.578 SIGNOR-252337 EPHB2 protein P29323 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates quantity phosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 33661095 YES miannu In addition, EPHB2 signaling leads to phosphorylation of GluN2B at tyrosine residue 1472 preventing clathrin dependent endocytosis, and increasing the surface retention of GluN2B containing NMDARs. 0.444 SIGNOR-279710 MECP2 protein P51608 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR up-regulates 10090 BTO:0000601 17532643 NO Luana Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis. 0.7 SIGNOR-264968 STAT1 protein P42224 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19482358 NO miannu Socs1 expression is induced in the human keratinocytes HaCaT cell line through sequential activation of STAT1 and IRF-1 0.625 SIGNOR-226484 PRKCA protein P17252 UNIPROT FMNL2 protein Q96PY5 UNIPROT up-regulates activity phosphorylation 9606 26256210 YES miannu In contrast, endogenous FMNL2 or FMNL2-GFP remained membrane associated, arguing that PKCalpha activation triggers FMNL2 relocation into intracellular membranes.|We demonstrate that PKCalpha phosphorylates the FMNL2 C terminus to control its localization and autoinhibition, thus uncovering a mode of formin activation by PKCs. 0.2 SIGNOR-279098 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 YES llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. 0.313 SIGNOR-250948 HBP1 protein O60381 UNIPROT NCF1 protein P14598 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 15024088 YES Luana Together, these results indicate that HBP1 may contribute to the regulation of NADPH oxidase-dependent superoxide production through transcriptional repression of the p47phox gene.  0.265 SIGNOR-261614 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr813 NSLFTPDyELLTEND 9606 BTO:0000007 15121872 YES 16705160:The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. lperfetto Tyrosine 813 is a site of jak2 autophosphorylation critical for activation of jak2 by sh2-b betawe show that phosphorylation of tyrosine 813 is required for the sh2 domain-containing adapter protein sh2-b beta to bind jak2 and to enhance the activity of jak2 and stat5b. 0.2 SIGNOR-235910 PCDHA10 protein Q9Y5I2 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265664 CLTA protein P09496 UNIPROT AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.765 SIGNOR-260672 CSNK1A1 protein P48729 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation Ser844 GSGSEAAsLSSLNSS 17353278 YES lperfetto Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846 0.312 SIGNOR-274045 KDM3B protein Q7LBC6 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005964 19194461 YES miannu We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. 0.2 SIGNOR-266637 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000567 15642743 YES lperfetto Recombinant p38 phosphorylated recombinant p53 on serine 46 in vitro. Inhibition of p38 MAPK by pharmacological inhibitors, dominant-negative p38, or small interfering RNA, suppressed p53S46P 0.772 SIGNOR-226620 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19808903 YES lperfetto We report a Notch signal-induced pathway that leads to transcriptional activation of HIF1-alpha gene. 0.459 SIGNOR-209720 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Thr501 QMDSGYNtQNCGSNI 9606 18521620 YES gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). 0.787 SIGNOR-178807 IKK-complex complex SIGNOR-C14 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 15084260 YES lperfetto Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. 0.541 SIGNOR-216407 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT down-regulates activity phosphorylation Thr352 PSEPMMStPPPASEL 9606 BTO:0000567 26080397 YES miannu ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. 0.2 SIGNOR-266204 CBL protein P22681 UNIPROT ABL1 protein P00519 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001271 20675402 YES lperfetto We found that while c-cbl e3 ligase induced ubiquitin-dependent degradation of mature and phosphorylated bcr-abl proteins 0.614 SIGNOR-167194 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser696 KKRARRGsSSDEEGG -1 14657015 YES lperfetto Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin. 0.2 SIGNOR-271843 JAK2 protein O60674 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity phosphorylation 9606 15007095 YES miannu Jak2 and Lyn coimmunoprecipitated with Btk and phosphorylated Btk on tyrosine (XREF_FIG C). 0.445 SIGNOR-279196 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser49 REQQEQLsLQQTIID 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.742 SIGNOR-262722 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr544 FDPGQDTyQHPPKDS -1 17997986 YES miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. 0.2 SIGNOR-262869 SCF-FBW7 complex SIGNOR-C135 SIGNOR DLGAP5 protein Q15398 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 15145941 YES miannu We show here that Fbx7, an F-box protein without WD repeats and leucine-rich repeats, is required for the proteasome-mediated proteolysis of the hepatoma up-regulated protein (HURP).Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. In the SCFFbx7 complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner. 0.273 SIGNOR-271508 PRKCD protein Q05655 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 9606 10698949 YES miannu As shown for serum, phosphorylation of 4E-BP1 by PKCdelta inhibits the interaction between 4E-BP1 and eIF4E and stimulates cap-dependent translation.|Here we demonstrate that protein kinase Cdelta (PKCdelta) associates with RAFT1 and that PKCdelta is required for the phosphorylation and inactivation of 4E-BP1. 0.2 SIGNOR-279100 BIRC2 protein Q13490 UNIPROT CSE1L protein P55060 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 26668314 YES miannu We find that TRAIL induces up-regulation of CAS in a posttranscriptional, caspase-8-dependent manner through degradation of cIAP1, an E3 ligase that targets CAS for ubiquitin-dependent proteasomal degradation.  0.334 SIGNOR-272812 RPS6K proteinfamily SIGNOR-PF26 SIGNOR PPP1R3A protein Q16821 UNIPROT up-regulates activity phosphorylation Ser46 PQPSRRGsDSSEDIY -1 10648825 YES lperfetto The protein G(M), which targets protein phosphatase 1 (PP1) to the glycogen particles and sarcoplasmic reticulum (SR) of striated muscles, is known to be phosphorylated at Ser48 and Ser67 in vitro by adenosine 3',5' cyclic monophosphate-dependent protein kinase (PKA) and at Ser48 by MAP kinase-activated protein kinase-1 (MAPKAP-K1, also called p90 RSK). The phosphorylation of Ser48 increases the rate at which the glycogen-associated PP1.G(M) complex dephosphorylates (activates) glycogen synthase, but the phosphorylation of Ser67 has the opposite effect, suppressing the activity of PP1 toward glycogen-bound substrates. 0.2 SIGNOR-252777 PTPN1 protein P18031 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 16291744 YES gcesareni We show that coexpression of wild-type alpha-actinin and ptp 1b causes dephosphorylation at tyr-397 in fak. 0.346 SIGNOR-141637 MTOR protein P42345 UNIPROT TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000567 SIGNOR-C3 22692423 YES gcesareni Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB. 0.477 SIGNOR-248270 PRKCE protein Q02156 UNIPROT ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Ser296 KSPNIIMsDADMDWA -1 28056995 YES lperfetto Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. 0.281 SIGNOR-271864 MAML1 protein Q92585 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation 9606 17300219 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 gcesareni The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. 0.2 SIGNOR-153038 EIF3A protein Q14152 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.921 SIGNOR-266400 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr263 NKSESVVyADIRKN 9606 11751924 YES lperfetto Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr 0.469 SIGNOR-113410 MYC protein P01106 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates quantity transcriptional regulation 10116 10823814 YES inferred from family member miannu C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. 0.412 SIGNOR-267785 CHFR protein Q96EP1 UNIPROT KIF22 protein Q14807 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 19321445 YES miannu Chfr ubiquitinates Kif22 and promotes its degradation. 0.4 SIGNOR-271469 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257457 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr487 SLSNIDFyAQVSDIT 10029 12907755 YES PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates 0.5 SIGNOR-248419 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 20871233 NO Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. 0.7 SIGNOR-255343 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT unknown phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Within the Jak2 kinase domain, there is a region that has considerable sequence homology to the regulatory region of the insulin receptor and contains two tyrosines, Y1007 and Y1008, that are potential regulatory sites. Y1007 and Y1008 are sites of trans- or autophosphorylation in vivo and in in vitro kinase reactions. Mutation of Y1007, or both Y1007 and Y1008, to phenylalanine essentially eliminated kinase activity, whereas mutation of Y1008 to phenylalanine had no detectable effect on kinase activity 0.2 SIGNOR-251358 CASP3 protein P42574 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates cleavage 9606 11283607 YES gcesareni Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity. 0.733 SIGNOR-106546 RAF1 protein P04049 UNIPROT XIAP protein P98170 UNIPROT up-regulates activity phosphorylation 9606 16964381 YES miannu Interaction and stabilization of X-linked inhibitor of apoptosis by Raf-1 protein kinase.|We also demonstrate that Raf-1 phosphorylates XIAP in vitro and in vivo. 0.505 SIGNOR-279105 NOS1 protein P29475 UNIPROT HDAC2 protein Q92769 UNIPROT down-regulates activity s-nitrosylation 10090 BTO:0001103 19047631 YES gcesareni we found that restoration of NO signaling in vivo, by adenoviral-mediated expression of a constitutively active endothelial NOS mutant in MDX muscles, and in vitro, by exposing MDX-derived satellite cells to NO donors, resulted in HDAC2 blockade by cysteine S-nitrosylation 0.265 SIGNOR-236919 ARID1A protein O14497 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.791 SIGNOR-132919 ADRA2A protein P08913 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.398 SIGNOR-256977 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser443 ATGSGIKsHNSALYS 9606 15574499 YES amattioni Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility. 0.253 SIGNOR-131451 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR Degranulation phenotype SIGNOR-PH92 SIGNOR up-regulates 9606 16470226 NO Alessandro Palma So, the association of aggregated FcεRI with the preferentially activated LYN in lipid rafts might be sufficient to shift the equilibrium of FcεRI from a nonphosphorylated state to a phosphorylated state, thereby initiating FcεRI-mediated degranulation 0.7 SIGNOR-254956 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194545 MAML1 protein Q92585 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000887 18758483 YES gcesareni Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin). 0.31 SIGNOR-180136 KDM4C protein Q9H3R0 UNIPROT H2AX protein P16104 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29207681 NO miannu Knockdown of JMJD2C gene led to the up-regulation of basal γ-H2AX expression. and γ-H2AX together with its phosphorylated C-terminal (Sre residues 139–140, γ-H2AX) are crucial for DNA repair 0.2 SIGNOR-263872 IKZF1 protein Q13422 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 NO miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 0.276 SIGNOR-255403 CDC23 protein Q9UJX2 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.916 SIGNOR-252008 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000782 10702316 YES lperfetto We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase). 0.682 SIGNOR-217000 CB-5083 chemical CID:73051434 PUBCHEM VCP protein P55072 UNIPROT down-regulates activity chemical inhibition -1 26565666 YES miannu Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-5083. 0.8 SIGNOR-260189 EGR1 protein P18146 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 17715378 NO Isochaihulactone treatment increased the luciferase activity of NAG-1 in A549 cells transfected with the NAG-1 promoter construct. This induction increased expression of NAG-1 that was p53-independent and Sp1-dependent. Our findings suggest that NAG-1 expression is up-regulated by isochaihulactone through an ERK-dependent pathway involving the activation of EGR-1. 0.38 SIGNOR-254266 NME1 protein P15531 UNIPROT NETO2 protein Q8NC67 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17671192 NO miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 0.257 SIGNOR-255166 AD/b2 integrin complex SIGNOR-C172 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269021 arachidonic acid smallmolecule CHEBI:15843 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 1357097 YES miannu These results suggest that the activation of protein kinase c by both arachidonic acid and phorbol esters may play a role in the potentiation of glutamate exocytosis. 0.8 SIGNOR-17809 dUMP(2-) smallmolecule CHEBI:246422 ChEBI dTMP(2-) smallmolecule CHEBI:63528 ChEBI up-regulates quantity precursor of 9606 21876188 YES lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. 0.8 SIGNOR-268236 MRPS18A protein Q9NVS2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.72 SIGNOR-262334 Fibrinogen complex SIGNOR-C311 SIGNOR Fibrin complex SIGNOR-C317 SIGNOR form complex cleavage 9606 BTO:0000131 18544683 YES lperfetto A fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel.|Fibrin clots were formed as described for turbidity experiments, in which the fibrinogen, calcium, and polyP (when included) were preincubated for 15 minutes before adding thrombin. 0.2 SIGNOR-263551 vorinostat chemical CHEBI:45716 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257947 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT unknown phosphorylation Ser216 SGLYRSPsMPENLNR -1 10557092 YES lperfetto The physical association and phosphorylation of Cdc25C protein phosphatase by Prk. | Further studies reveal that His6-Prk phosphorylates Cdc25C on serine216, a residue also phosphorylated by Chk1 and Chk2. Together, these observations strongly suggest that Prk's role in mitosis is at least partly mediated through direct regulation of Cdc25C. 0.73 SIGNOR-249030 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257998 ziprasidone chemical CHEBI:10119 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258504 RPS6KA5 protein O75582 UNIPROT ATXN1 protein P54253 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 23719381 YES miannu In summary, the data from the cell based screen, biochemical studies and genetic interactions strongly suggest that MSK1 phosphorylates ATXN1 and regulates its stability. 0.26 SIGNOR-279109 HOXB8 protein P17481 UNIPROT PBX3 protein P40426 UNIPROT up-regulates activity binding 9606 BTO:0001545 11571641 YES miannu the ability of HoxB8 to heterodimerizes with endogenous Pbx proteins on DNA alters gene transcription in a manner that prevents progression through an intrinsic genetic differentiation program. In conjunction with Pbx, HoxB8 could alter transcription of Pbx target genes by direct or indirect mechanisms. 0.485 SIGNOR-223149 CDKN1B protein P46527 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity binding 9606 17409098 YES lperfetto P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e). 0.882 SIGNOR-217505 MAPK10 protein P53779 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 17686459 YES gcesareni Here we demonstrate that jnk3 can phosphorylate smac. Phosphorylation of smac by jnk3 attenuates its interaction with xiap. These results suggest that jnk3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between smac and xiap. 0.341 SIGNOR-157280 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 10581361 YES lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function 0.507 SIGNOR-72724 EEF1A1 protein P68104 UNIPROT Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269517 KHSRP protein Q92945 UNIPROT SRC protein P12931 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 9858532 YES lperfetto We show here that this component of the DCS complex is hnRNP H and that, like hnRNP F and KSRP, hnRNP H is needed for src N1 splicing in vitro. 0.271 SIGNOR-261274 Guanfacine chemical CHEBI:5558 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258918 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 BTO:0000887 11940578 YES gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. 0.616 SIGNOR-116489 ZEB2 protein O60315 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 NO miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. 0.488 SIGNOR-255159 RRAGB protein Q5VZM2 UNIPROT RAGBD complex SIGNOR-C116 SIGNOR form complex binding 9606 20381137 YES gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant 0.78 SIGNOR-228179 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258066 AKT proteinfamily SIGNOR-PF24 SIGNOR HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser199 SQRGRSGsGNFGGGR 9606 18562319 YES gcesareni Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199. 0.2 SIGNOR-179059 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273076 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser100 DEDSGKGsQPPSPPS 9606 15448698 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-129398 SGK1 protein O00141 UNIPROT MLLT3 protein P42568 UNIPROT down-regulates activity phosphorylation 9606 25817867 YES miannu In addition to Nedd4-2, Sgk1 also phosphorylates Af9, forkhead like transcription factor FOXO3a and several other substrates.|Sgk1 impairs the ability of Af9 to interact with Dot1a at these subregions without impacting Af9 DNA binding activity, leading to targeted histone H3 K79 hypomethylation. 0.51 SIGNOR-279111 SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR PPARG protein P37231 UNIPROT down-regulates activity 10090 21952300 NO FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1). SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3-L1 cells 0.454 SIGNOR-253524 STK11 protein Q15831 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates activity phosphorylation Thr183 SDGEFLRtSCGSPNY -1 16054095 YES lperfetto The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase. 0.598 SIGNOR-139297 Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 NO miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.7 SIGNOR-270914 CPM protein P14384 UNIPROT HBA1 protein P69905 UNIPROT down-regulates activity cleavage Tyr141 STVLTSKyR -1 8635221 YES miannu Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity. 0.2 SIGNOR-256507 PTGS2 protein P35354 UNIPROT Prostacycline smallmolecule CID:159 PUBCHEM up-regulates chemical modification 9606 11751058 YES gcesareni Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2 0.8 SIGNOR-113300 MMP25 protein Q9NPA2 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272369 FBXL5 protein Q9UKA1 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization binding -1 24157836 YES miannu FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. To demonstrate that FBXL5 has a direct activity on Snail1, we carried out polyubiquitination reactions in vitro. For this we purified Snail1 and the SCFFBXL5 complex from Sf9 insect cells infected with different baculoviruses corresponding to Flag-FBXL5, His-Skp1, HA-Cullin1 and Rbx1 (Supplementary Figure S3C). 0.51 SIGNOR-272135 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser932 CDSGVETsFRKLSFT 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 YES lperfetto The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. 0.746 SIGNOR-235442 CDK1 protein P06493 UNIPROT RRM2 protein P31350 UNIPROT unknown phosphorylation Ser20 DPQQLQLsPLKGLSL 9606 9990288 YES llicata Ribonucleotide reductase r2 protein is phosphorylated at serine-20 by p34cdc2 kinase. comparison of ribonucleotide reductase activities between wild type and mutated forms of the r2 proteins suggested that mutation at serine-20 did not significantly affect enzyme activity. 0.505 SIGNOR-64312 FARSA protein Q9Y285 UNIPROT Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR form complex binding 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.994 SIGNOR-270436 NMDA receptor_2C complex SIGNOR-C349 SIGNOR CAMK2A protein Q9UQM7 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD 0.6 SIGNOR-264216 NLGN1 protein Q8N2Q7 UNIPROT NRXN3 protein Q9HDB5 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.828 SIGNOR-264169 PPP3CA protein Q08209 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR form complex binding 9606 14623295 YES miannu Calcineurin is a heterodimer consisting of a catalytic subunit with a molecular mass of about 59 kDa (calcienurin A or CNA) and a regulatory subunit with a molecular mass of 19 kDa (calcineurin B or CNB). 0.954 SIGNOR-255291 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation 10090 11730323 YES Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs 0.742 SIGNOR-258997 RPL3 protein P39023 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.857 SIGNOR-262495 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248752 INSR protein P06213 UNIPROT PIK3R3 protein Q92569 UNIPROT unknown phosphorylation Tyr341 NEDADENyFINEEDE 9606 BTO:0000142;BTO:0000671 7542745 YES llicata This pattern of 32p-tyr release unambiguously identified tyr-341 in p55pik as a major in vitro phosphorylation site. 0.614 SIGNOR-28791 STUB1 protein Q9UNE7 UNIPROT EIF4E protein P06730 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28852129 YES miannu This collaborative activity of cIAP1 and CHIP directs eIF4E toward degradation, controlling its levels and suppressing tumorigenesis.|We next sought to investigate whether eIF4E ubiquitination is enhanced by the collaborative activity of cIAP1 and CHIP, which we define as both the E3 ligase activity of cIAP1 alone and the E3 ligase activity of cIAP1 and CHIP together. 0.333 SIGNOR-278669 RNGTT protein O60942 UNIPROT mRNA_capping phenotype SIGNOR-PH178 SIGNOR up-regulates quantity chemical modification 9606 9512541 NO lperfetto The human mRNA 5'-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNAcappingenzyme1), HCE1A and HCE1B , were isolated from a HeLa cDNA library. The HCE1 cDNA has the longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3'-half of the HCE1 ORF was missing in HCE1A and HCE1B , and, additionally, HCE1B has an early translation termi 0.7 SIGNOR-268356 bradykinin smallmolecule CHEBI:3165 ChEBI BDKRB1 protein P46663 UNIPROT up-regulates chemical activation 9606 BTO:0001130;BTO:0000189 17251915 YES gcesareni Neuropeptides such as grp, endothelin, bradykinin, neuromedin b (nmb), cholecystokinin (cck) and angiotensin ii activate their cognate gpcrs to stimulate cell proliferation in various cell types, and have a crucial role in many aggressive human cancers, including small-cell lung cancer (sclc), pancreatic cancer, hnscc and prostate cancer. 0.8 SIGNOR-152588 CREB1 protein P16220 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 NO gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. 0.462 SIGNOR-176536 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 1716180 YES lperfetto Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response. 0.484 SIGNOR-21312 MAPK14 protein Q16539 UNIPROT TCF3 protein P15923 UNIPROT up-regulates activity phosphorylation Ser139 LNSPGPLsPSGMKGT 9606 BTO:0000887 15719023 YES lperfetto Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription 0.479 SIGNOR-134194 SNRPB2 protein P08579 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.703 SIGNOR-270654 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser400 AKTSTRSsAKTLKNR 9606 BTO:0000590 20679343 YES lperfetto Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3? 0.738 SIGNOR-167290 SNX9 protein Q9Y5X1 UNIPROT EGFR protein P00533 UNIPROT down-regulates 9606 16316319 NO gcesareni We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation. 0.573 SIGNOR-142566 SCNN1B protein P51168 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 26772908 YES miannu The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. 0.8 SIGNOR-269276 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 16782899 YES llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain 0.496 SIGNOR-147187 FRS2 protein Q8WU20 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 11997436 YES gcesareni Complex formation between grb2 and frs2_ is mediated by y196, y306, y349, and y392 of frs2_ (designated direct grb2-binding sites;ref. 1). In addition, frs2_ recruits grb2 indirectly by means of the protein tyrosine phosphatase shp2 by way of residues y436 and y471 (designated shp2-binding sites;ref. 2). 0.34 SIGNOR-87169 SP1 protein P08047 UNIPROT UGCG protein Q16739 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000738 15342415 NO miannu the results suggest that transcriptional up-regulation of GCS through DOX-induced activation of Sp1 is one potential mechanism to regulate ceramide increase and apoptosis in HL-60/ADR cells. 0.2 SIGNOR-255205 AR protein P10275 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 15861399 NO miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation 0.7 SIGNOR-251539 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates activity 9606 18350175 NO inferred from family member The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase. 0.7 SIGNOR-270310 PTEN protein P60484 UNIPROT RAB7A protein P51149 UNIPROT up-regulates activity dephosphorylation Tyr183 QETEVELyNEFPEPI -1 26869029 YES lperfetto PTEN dephosphorylates Rab7 on two conserved residues S72 and Y183, which are necessary for GDP dissociation inhibitor (GDI)-dependent recruitment of Rab7 on to late endosomes and subsequent maturation. 0.373 SIGNOR-276959 MYC protein P01106 UNIPROT CCND2 protein P30279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7526316 YES gcesareni C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation. 0.45 SIGNOR-27446 CDK1 protein P06493 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates activity phosphorylation -1 12556484 YES done miannu We found that Nudel and NudE were also phosphorylated in M phase (Fig. ​(Fig.22 and ​and3).3). First, Nudel and NudE were specifically phosphorylated in M phase. Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro.Due to conservation of the S/TP motifs, NudE may also be phosphorylated at similar sites by these kinases, though it contains an additional potential Cdk site at S282 (SPNR). 0.653 SIGNOR-274077 SPEG protein Q15772 UNIPROT RYR2 protein Q92736 UNIPROT down-regulates activity phosphorylation 9606 32683896 YES miannu Conclusions : Unlike other kinases (PKA, CaMKII) that increase RyR2 activity, SPEG phosphorylation reduces RyR2 mediated SR Ca 2+ -release.|Further, we show that SPEG phosphorylates RyR2 at a previously uncharacterized serine (S2367) located in the central domain of the channel. xref Importantly, in contrast to previously studied phosphorylation sites that activate RyR2 (e.g. S2808, S2814), we show that SPEG mediated RyR2-S2367 phosphorylation suppresses pathogenic diastolic SR Ca 2+ -leak. 0.248 SIGNOR-279114 SRC protein P12931 UNIPROT ADAM17 protein P78536 UNIPROT up-regulates activity phosphorylation 9606 25371038 YES miannu These data suggests that Src mediates TACE activation in mechanically stressed cardiomyocytes and this mechanism could be exploited for specific blockade of TNFalpha secretion and its detrimental effects in congestive heart failure.|We found that the non receptor tyrosine kinase Src mediates TACE activation in mechanically stretched rat cardiomyocytes by phosphorylating the Tyr 702 residue within the intracellular tail of TACE. 0.459 SIGNOR-279115 SERPINC1 protein P01008 UNIPROT F11 protein P03951 UNIPROT down-regulates activity cleavage 31030036 YES lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 0.656 SIGNOR-264137 SIRT7 protein Q9NRC8 UNIPROT DDX21 protein Q9NR30 UNIPROT up-regulates activity deacetylation Lys137 PKKMKKEkEMNGETR 28790157 YES lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. 0.26 SIGNOR-275903 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 8798643 YES lperfetto Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation 0.618 SIGNOR-43659 TRIM21 protein P19474 UNIPROT SHMT2 protein P34897 UNIPROT down-regulates quantity ubiquitination 9606 30367038 YES miannu The expression of TRIM21, but not the expression of the ligase-dead (LD) mutant TRIM21 (C16A, C31A and H33W) 36, increased SHMT2 ubiquitylation, which suggests that TRIM21 is the E3 ligase for SHMT2 and that the E3 ligase activity of TRIM21 is required for SHMT2 ubiquitylation.|We found that the overexpression of TRIM21 increased the degradation of SHMT2 in high glucose conditions by binding more K63-ubiquitin. 0.2 SIGNOR-278792 CDK2 protein P24941 UNIPROT CDK7 protein P50613 UNIPROT unknown phosphorylation Ser164 GLAKSFGsPNRAYTH 9606 11113184 YES amattioni Cdk2 phosphorylates serine-164 in the cdk7 t loop. 0.57 SIGNOR-84832 ABL1 protein P00519 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates phosphorylation 9606 9144171 YES gcesareni We also report that the amino-terminal domain of rin1 contains sequences that can mediate interactions with the abl tyrosine kinase and that rin1 is itself tyrosine phosphorylated by c-abl. 0.75 SIGNOR-48142 CEBPE protein Q15744 UNIPROT LTF protein P02788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 15588942 NO miannu C/EBP_ interacts with C/EBP_ through the leucine-zipper–containing domain. C/EBP_ and C/EBP_ synergistically activate transcription of lactoferrin promoter 0.369 SIGNOR-225012 PPP2CB protein P62714 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000176 19607706 YES Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac) 0.26 SIGNOR-248581 RET protein P07949 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 16153436 YES gcesareni We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1). 0.434 SIGNOR-140298 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 20463034 YES Gianni We show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them. 0.888 SIGNOR-268868 GABARAPL1 protein Q9H0R8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000567 17580304 YES lperfetto P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha 0.79 SIGNOR-156304 SHMT2 protein P34897 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity chemical modification 9606 32439610 YES lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 0.8 SIGNOR-268224 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 12645577 YES gcesareni These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. 0.363 SIGNOR-99314 PPARGC1A protein Q9UBK2 UNIPROT GPX1 protein P07203 UNIPROT up-regulates 10090 18074631 NO lperfetto In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat. 0.316 SIGNOR-253396 MMP13 protein P45452 UNIPROT FGG protein P02679 UNIPROT down-regulates quantity by destabilization cleavage Tyr27 LSSTCVAyVATRDNC -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain 0.2 SIGNOR-263614 POLR3H protein Q9Y535 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.865 SIGNOR-266126 SRC protein P12931 UNIPROT VAV1 protein P15498 UNIPROT up-regulates activity phosphorylation 9606 28930674 YES miannu These interactions are required for SRC-induced activation of VAV and the subsequent engagement of a JIP1-tethered JNK signaling module.|These interactions are required for SRC-induced tyrosine phosphorylation and activation of VAV and the subsequent engagement of a JIP1-tethered JNK signaling module ( xref ). 0.368 SIGNOR-279124 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr199 VKKSIRDtPAKNAQK 9606 SIGNOR-C17 12058066 YES llicata However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation. 0.519 SIGNOR-89605 CDKN1A protein P38936 UNIPROT CDK3 protein Q00526 UNIPROT down-regulates binding 9606 7626805 YES gcesareni P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. We have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases. 0.664 SIGNOR-29954 PHF2 protein O75151 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. 0.2 SIGNOR-264521 ARVCF protein O00192 UNIPROT CDH3 protein P22223 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.327 SIGNOR-252127 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation Thr404 SSMSTEQtLASDTDS -1 11062067 YES MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. 0.636 SIGNOR-251418 ARID1A protein O14497 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.766 SIGNOR-270751 AXL protein P30530 UNIPROT AXL protein P30530 UNIPROT up-regulates activity phosphorylation Tyr821 QEPDEILyVNMDEGG -1 9178760 YES llicata Our data showed that various receptor substrates are at least associated with the C-terminal tyrosine pY821. Two additional potential autophosphorylation sites (pY866 and pY779) may play a minor role in binding of e€ector proteins 0.2 SIGNOR-250592 FABP6 protein P51161 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264460 SRC protein P12931 UNIPROT VHL protein P40337 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr185 LDIVRSLyEDLEDHP 9606 21212839 YES miannu We have found that elevated Src can trigger a drastic reduction in VHL stability even under normoxic conditions, through phosphorylation of VHL tyrosine residue 185, leading to ubiquitination and proteasome mediated degradation of VHL. 0.29 SIGNOR-279125 SRC protein P12931 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation 9606 34161759 YES miannu In the cluster, Zap70 will be rapidly phosphorylated by active Src and slowly phosphorylated by autoinhibited, inactive Src.|We provide evidence that clusters harbor a positive feedback loop among Zap70, LAT, and Src-family kinases that binds phosphorylated LAT and further activates Zap70. 0.477 SIGNOR-279126 STK24 protein Q9Y6E0 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates activity phosphorylation 9606 26910843 YES miannu In addition, MST3 can phosphorylate PTP-PEST and inhibit the tyrosine phosphatase activity of PTP-PEST.|MST3 directly phosphorylates and inactivates protein tyrosine phosphatase PTP-PEST, which enhances cell migration by enhancing the tyrosine phosphorylation of paxillin Y31 and Y118 [ ]. 0.272 SIGNOR-279127 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269340 SLC24A4 protein Q8NFF2 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264402 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser189 DEEFREPsTGKTCLP 9606 19661060 YES Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.2 SIGNOR-260883 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 YES lperfetto The activation of PKBbeta and PKBamma by PDK11 was accompanied by the phosphorylation of the residues equivalent to Thr308 in PKBalpha, namely Thr309 (PKBbeta) and Thr305 (PKBgamma) 0.748 SIGNOR-244480 APC-c complex SIGNOR-C150 SIGNOR PNN protein Q9H307 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003081 32203416 YES miannu Apo-PIWIL1 functions as a co-activator for APC/C ubiquitin ligase. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. 0.205 SIGNOR-272201 ABL1 protein P00519 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates quantity phosphorylation Tyr43 PGACGLRyRNPVSQC 9606 36552734 YES miannu The phosphorylation of tyrosine 43 of TDP-43 by c-Abl led to increased TDP-43 levels in the cytoplasm and increased the formation of G3BP1-positive stress granules in SH-SY5Y cells. 0.2 SIGNOR-279135 HCK protein P08631 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 24396067 YES llicata We also showed that ctla-4 receptor signaling mediates tyrosine phosphorylation in the c3g protein, and that this is required for augmented activation of rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (lfa-1). ctla-4 signaling leads to phosphorylation of c3g tyrosine 504. the src family member hck phosphorylates c3g downstream of ctla-4. 0.499 SIGNOR-203613 CDKN2B protein P42772 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0001056 14681685 NO The Ink4b gene (Cdkn2b) encodes p15Ink4b, a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice. 0.7 SIGNOR-259407 terazosin chemical CHEBI:9445 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001260 9379432 YES miannu Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication 0.8 SIGNOR-258671 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Ser198 TRKSAPSsPTLDCEK 10090 BTO:0000142 12796778 YES llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. 0.771 SIGNOR-250675 AMPK complex SIGNOR-C15 SIGNOR RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser792 LTQSAPAsPTNKGVH 10090 SIGNOR-C15 SIGNOR-C3 18439900 YES lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK 0.52 SIGNOR-263044 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273095 CDK1 protein P06493 UNIPROT NCKAP5L protein Q9HCH0 UNIPROT down-regulates activity phosphorylation 9606 26549230 YES miannu Inhibiting Cdk1 with purvalanol A in nocodazole arrested cells increased fluorescent intensity of Cep169 at centrosomes relative to the value at the cytosol (2.36 +/- 0.12), while control cells indicated 1.13 +/- 0.03.|Taken together, these results suggest that the Cdk1-dependent phosphorylation of Cep169 mediates the dissociation from centrosomes during mitosis. 0.2 SIGNOR-279144 CDK2 protein P24941 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation 9606 22948662 YES miannu CDK2 dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells.|Hormone dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities. 0.358 SIGNOR-279146 AMPK complex SIGNOR-C15 SIGNOR PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser486 DDEITEAKsGTATPQRS -1 17023420 YES We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators 0.829 SIGNOR-256113 CDK4 protein P11802 UNIPROT GATA4 protein P43694 UNIPROT up-regulates activity phosphorylation Ser160 GFAGSYSsPYPAYMA 9606 25241353 YES miannu In addition, we have shown that CDK4 can enhance cardiogenic activity of GATA4 (XREF_FIG).|The physical and functional interactions between GATA4 and Cyclin D2 depend on phosphorylation of Ser 160 of GATA4, which can be mediated in vitro by CDK4. 0.356 SIGNOR-279148 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0001939 15520018 YES miannu Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways. 0.538 SIGNOR-250113 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 21880741 YES gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. 0.649 SIGNOR-252311 RNF5 protein Q99942 UNIPROT PXN protein P49023 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 12861019 YES miannu Here we demonstrate that the human homologue of RNF5 associates with the amino-terminal domain of paxillin, resulting in its ubiquitination. RNF5 requires intact RING and C-terminal domains to mediate paxillin ubiquitination.  Concomitantly, RNF5 expression results in inhibition of cell motility. Via targeting of paxillin ubiquitination, which alters its localization, RNF5 emerges as a novel regulator of cell motility. 0.407 SIGNOR-271479 CDK5 protein Q00535 UNIPROT DLG4 protein P78352 UNIPROT down-regulates activity phosphorylation Ser35 HLPNQANsPPVIVNT 9606 28502042 YES miannu Cdk5 was shown to phosphorylate PSD-95 at three sites, Thr19, Ser25, and Ser35, in PSD fractions, which reduces the ability of PSD-95 to multimerize, resulting in decreased NMDAR clustering (Table 2). 0.654 SIGNOR-279151 CDK5 protein Q00535 UNIPROT DLG4 protein P78352 UNIPROT down-regulates activity phosphorylation Thr19 YRYQDEDtPPLEHSP 9606 28502042 YES miannu Cdk5 was shown to phosphorylate PSD-95 at three sites, Thr19, Ser25, and Ser35, in PSD fractions, which reduces the ability of PSD-95 to multimerize, resulting in decreased NMDAR clustering (Table 2). 0.654 SIGNOR-279152 CDK5 protein Q00535 UNIPROT DLGAP1 protein O14490 UNIPROT down-regulates quantity by destabilization phosphorylation Ser77 FPRRHYTsQQELKDE 9606 21829588 YES miannu Taken together, these sets of data suggest that Abeta triggers the phosphorylation of GKAP by cdk5 at the serine residues S77 and S111 that in turn are crucial for GKAP degradation. 0.408 SIGNOR-279153 NR2F1 protein P10589 UNIPROT LHCGR protein P22888 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 10644740 YES Luana Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription. 0.275 SIGNOR-266218 CDK5 protein Q00535 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation 9606 26509276 YES miannu Since Tyr-654 is the ERBB2 phosphorylation site on beta-catenin, this result is consistent with our hypothesis that CDK5 activates ERBB2 , which in turn phosphorylates beta-catenin on Tyr-654, leading to a shift of beta-catenin away from the adherens junction and into the nucleus where it can serve as a transcriptional co-activator.|Taken together with the results of our kinase analysis, these observations suggest that CDK5 phosphorylation of both ERBB2 and ERBB3 and AR could drive a feedback loop, in which ERBB2 and ERBB3 promotes beta-catenin transcriptional activity that then contributes to higher expression of ERBB3. 0.274 SIGNOR-279155 CDK5 protein Q00535 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation 9606 26912996 YES miannu CDK5 increases recombinant SYNGAP1 activity on Ras-GAP by 98% and its Rap-GAP activity by 20%.|Interestingly, phosphorylation of SYNGAP1 by CDK5 and CaMKII increases overall SYNGAP1 activity, but also alters the ratio of its GAP activity towards Ras- and Rap-GTPases. 0.384 SIGNOR-279157 CDK6 protein Q00534 UNIPROT PKM protein P14618 UNIPROT down-regulates activity phosphorylation 9606 28607489 YES miannu Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. 0.26 SIGNOR-279158 CHEK1 protein O14757 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation 9606 15736430 YES miannu Chkl binds and phosphorylates BAD protein.|Taken together, our results suggest that Chk1 may inactivate BAD by associating with and phosphorylating residues critical for BAD function in response to DNA damage. 0.2 SIGNOR-279159 TMC1 protein Q8TDI8 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 YES lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). 0.391 SIGNOR-262569 ATF6 protein P18850 UNIPROT NUCB1 protein Q02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17686766 NO miannu we identified nucleobindin 1 (NUCB1) as a novel repressor of the S1P-mediated ATF6 activation. NUCB1 is an ER stress-inducible gene with the promoter region having functional cis-elements for transcriptional activation by ATF6. 0.352 SIGNOR-253753 CALM1 protein P0DP23 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates binding 9606 11796223 YES inferred from 70% of family members gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.762 SIGNOR-269892 ARF4 protein P18085 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 NO lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface 0.7 SIGNOR-272151 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 11815618 YES lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator. 0.922 SIGNOR-249365 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT down-regulates activity phosphorylation Ser113 TELCRTFsESGRCRY -1 14688255 YES miannu We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated. 0.698 SIGNOR-250156 CHKA protein P35790 UNIPROT TUT1 protein Q9H6E5 UNIPROT up-regulates activity phosphorylation 9606 21729869 YES miannu Our data indicate that the kinase activities of both the isoforms of CKI -- alpha and epsilon modulate Star-PAP polyadenylation activity and target mRNAs.|Taken together, these data suggest that phosphorylation of Star-PAP by CKI modulates the Star-PAP polyadenylation activity downstream of stimulation by oxidant stress and phosphorylation primes Star-PAP, so that it can be stimulated by PI4,5 P 2. 0.2 SIGNOR-279162 CSK protein P41240 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Tyr281 EVYQVTVyQAGESDT 9606 25624478 YES miannu Here we show that activated c-Src kinase phosphorylates Y281 and Y302 of Mdm2, resulting in an increase in Mdm2 stability and its association with Ubc12, the E2 enzyme of the neddylating complex. 0.2 SIGNOR-279163 CSK protein P41240 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Tyr302 PEISLADyWKCTSCN 9606 25624478 YES miannu Here we show that activated c-Src kinase phosphorylates Y281 and Y302 of Mdm2, resulting in an increase in Mdm2 stability and its association with Ubc12, the E2 enzyme of the neddylating complex. 0.2 SIGNOR-279164 DYRK1A protein Q13627 UNIPROT SRSF6 protein Q13247 UNIPROT up-regulates activity phosphorylation 9606 27049307 YES miannu These results suggest that Dyrk1A enhances SRp55 promoted cTnT exon 5 inclusion.|These results supported the finding that phosphorylation of SRp55 by Dyrk1A promotes cTnT exon 5 inclusion.Alternative splicing of cTnT exon 5 is regulated developmentally. 0.432 SIGNOR-279166 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates activity dephosphorylation Tyr491 CAAWHGYySVAKALC 9606 BTO:0002181 17803936 YES miannu  Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.  0.2 SIGNOR-276075 GNAI3 protein P08754 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 19703466 YES Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma) 0.594 SIGNOR-256500 COMT protein P21964 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI up-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-263998 PRKCA protein P17252 UNIPROT KCNE1 protein P15382 UNIPROT down-regulates activity phosphorylation Ser102 VQARVLEsYRSCYVV -1 1553557 YES lperfetto Inhibition of the current was not seen in channels in which Ser103 was replaced by Ala, although other properties of the current were unchanged. These results indicate that inhibition of the potassium current results from direct phosphorylation of the channel subunit protein at Ser103. 0.307 SIGNOR-248852 AKT2 protein P31751 UNIPROT PPIF protein P30405 UNIPROT up-regulates activity phosphorylation Ser31 LPAARACsKGSGDPS 9606 BTO:0002004 25650317 YES miannu In turn, mitochondrial Akt2 phosphorylates Ser31 in cyclophilin D (CypD), a regulator of organelle functions. Akt2-phosphorylated CypD supports mitochondrial bioenergetics and opposes tumor cell death, conferring resistance to PI3K therapy. 0.2 SIGNOR-276875 PKC proteinfamily SIGNOR-PF53 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser671 RKRSTRRsVRGSQAQ 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.2 SIGNOR-272514 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser711 EEEEESDsSETEKED 21296876 YES lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. 0.2 SIGNOR-275501 B3GNT3 protein Q9Y2A9 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates activity glycosylation Asn200 VTSTLRINTTTNEIF 9606 BTO:0002548 29438695 YES Barakat These results further suggested that B3GNT3 mediates PD-L1 and PD-1 interaction through N-linked glycosylation instead of O-linked glycosylation 0.2 SIGNOR-275390 EPHB2 protein P29323 UNIPROT MYO1B protein O43795 UNIPROT up-regulates activity phosphorylation 9606 26195670 YES miannu EphB2 kinase activity is required for Myo1b-EphB2 interaction and induced Myo1b phosphorylation. 0.2 SIGNOR-279171 EPHB4 protein P54760 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation 9606 26817610 YES miannu These results suggest that activation of Eph-B4 with Ephrin-B2/Fc stimulates eNOS phosphorylation in vitro (XREF_FIG), eg, eNOS may be a downstream mediator of Eph-B4 signaling in endothelial cells. 0.311 SIGNOR-279172 FAM20C protein Q8IXL6 UNIPROT STIM1 protein Q13586 UNIPROT up-regulates activity phosphorylation Ser88 GDVDVEEsDEFLRED 9606 30520731 YES miannu Similarly, STIM1 is phosphorylated on S88 by FAM20C both in vitro and in vivo. 0.2 SIGNOR-279173 FGFR1 protein P11362 UNIPROT PGAM1 protein P18669 UNIPROT up-regulates activity phosphorylation 9606 23653202 YES miannu Nevertheless, these data suggest that FGFR1 dependent tyrosine phosphorylation " further " enhances PGAM1 activation.|Phosphorylation of PGAM1 WT by FGFR1 resulted in a significant increase in the amount of bound 2,3-BPG analogue, whereas substitution of PGAM1 Y26 abolished enhanced binding of cofactor in the presence of rFGFR1 (XREF_FIG). 0.33 SIGNOR-279175 FGFR3 protein P22607 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation 9606 24466111 YES miannu Indeed, we found that TAK1 was tyrosine phosphorylated in HEK293 cells transiently expressing constitutively active FGFR3 (K650E), but not the kinase-dead receptor (K508M), indicating that activated FGFR3 can either directly or indirectly tyrosine phosphorylate TAK1 (XREF_FIG). 0.294 SIGNOR-279176 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23431053 YES lperfetto Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ 0.425 SIGNOR-230750 RNF146 protein Q9NTX7 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21478859 YES lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.67 SIGNOR-263336 PP1 proteinfamily SIGNOR-PF54 SIGNOR MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 YES lperfetto P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases 0.2 SIGNOR-264665 GSK3B protein P49841 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates activity phosphorylation Ser711 PLPSPPTsDSDSDSE 9606 26999213 YES miannu More recently, phosphorylation of S707 and S711 by GSK3beta has been shown to promote complete proteasomal degradation of p100 involving the E3 ligase Fbw7 .|These studies suggest that a pool of p100 is constitutively phosphorylated by GSK3beta at S707 and S711, triggering the Fbw7 mediated ubiquitination and proteasomal degradation of p100 which controls the levels of p100 available for the non canonical pathway. 0.271 SIGNOR-279187 TCF4 protein P15884 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20459685 NO miannu Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. 0.34 SIGNOR-255388 PLK1 protein P53350 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007;BTO:0001914 23887393 YES gcesareni Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency 0.533 SIGNOR-243522 MVD protein P53602 UNIPROT NRAS protein P01111 UNIPROT up-regulates quantity by stabilization 9534 12646231 NO miannu An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B) 0.2 SIGNOR-265889 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr53 KEPSEVPtPKRPRGR 9606 17960875 YES gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. 0.384 SIGNOR-158608 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000142 20308788 YES The effect has been demonstrated using P10636-8 lperfetto Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells. 0.738 SIGNOR-164651 MTOR protein P42345 UNIPROT PRKN protein O60260 UNIPROT down-regulates activity phosphorylation Ser127 AVILHTDsRKDSPPA 9606 BTO:0002181 35191952 YES miannu MTOR phosphorylates PARK2 at Ser127 Through biochemical, mutational, and genetic studies, we identified PARK2 as a mTORC1 substrate. mTORC1 phosphorylates PARK2 at Ser127, which blocks its cellular ubiquitination activity, thereby hindering its tumor suppressor effect on eIF4B's stability. 0.2 SIGNOR-277586 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 BTO:0000848 BTO:0001253 20959475 YES lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). 0.2 SIGNOR-168766 SYVN1 protein Q86TM6 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29958993 YES miannu Secondly, HRD1 promotes PTEN ubiquitination and degradation. 0.2 SIGNOR-278724 GSK3B protein P49841 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates activity phosphorylation 9606 21757741 YES miannu Glycogen synthase kinase-3beta (GSK3beta) negatively regulates PTTG1 and human securin protein stability, and GSK3beta inactivation correlates with securin accumulation in breast tumors.|Here, we demonstrate that glycogen synthase kinase-3\u03b2 (GSK3\u03b2) phosphorylates securin to promote its proteolysis via SCF(\u03b2TrCP) E3 ubiquitin ligase. 0.2 SIGNOR-279188 HIPK1 protein Q86Z02 UNIPROT MYB protein P10242 UNIPROT down-regulates activity phosphorylation 9606 19646965 YES miannu C-Myb appears to be phosphorylated by HIPK1 in its negative regulatory domain as supported by both in vivo and in vitro data. 0.2 SIGNOR-279189 HIPK2 protein Q9H2X6 UNIPROT BCHE protein P06276 UNIPROT down-regulates quantity phosphorylation 9606 25210797 YES miannu As shown in XREF_FIG, HIPK2 overexpression strongly reduced Myc-Che-1 levels, whereas it produced little effect on Che-1 T144A expression.|Notably, we found that HIPK2 phosphorylates a specific residue of Che-1, which is required for its interaction with Pin1 and for its degradation through the proteasome pathway. 0.2 SIGNOR-279190 SMO protein Q99835 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.427 SIGNOR-199165 HIPK2 protein Q9H2X6 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates activity phosphorylation 9606 26247811 YES miannu Moreover, we show that HIPK2 strongly potentiates the transcriptional activity of CREB-binding protein.|We show that HIPK2 interacts with and phosphorylates several regions of CBP. 0.425 SIGNOR-279191 HIPK2 protein Q9H2X6 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates activity phosphorylation 9606 23620283 YES miannu HIPK2 associates with the MEF2C\u2013HDAC4 complex and phosphorylates MEF2C. 0.4 SIGNOR-279192 HIPK2 protein Q9H2X6 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity phosphorylation 9606 21285352 YES miannu This result provides a mechanistic explanation for the context-dependent function of HIPK2 in Wnt signaling 0.2 SIGNOR-279193 PRKG1 protein Q13976 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The 1 IC-loop does not have consensus sequences for PKG, but we found that this enzyme phosphorylated the same sites as PKA: S422, S423 (Fig. 5A).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.317 SIGNOR-262757 IKBKB protein O14920 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation 9606 26603838 YES miannu Active IKKbeta promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma.|Herein, we demonstrate that IKKbeta phosphorylates GLI1 in DLBCL. 0.357 SIGNOR-279194 IKBKE protein Q14164 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity phosphorylation Ser11 ASVTPPGsLELLQPG 9606 24362534 YES miannu IKKepsilon phosphorylates TRAF2 at Ser11 to activate NF-kappaB and promote malignant transformation. 0.685 SIGNOR-279195 N protein P0DTC9 UNIPROT G3BP1 protein Q13283 UNIPROT down-regulates activity binding 9606 32353859 YES miannu N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms SIGNOR-260749 PTTG1 protein O95997 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 10090 BTO:0000093 22002306 NO Overexpressed hPTTG1 promotes breast cancer cell invasion and metastasis by regulating GEF-H1/RhoA signalling 0.7 SIGNOR-256535 DRD3 protein P35462 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.316 SIGNOR-257097 TRIM33 protein Q9UPN9 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 BTO:0000574;BTO:0002625;BTO:0000414 16751102 YES lperfetto The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses. 0.637 SIGNOR-236064 CALM2 protein P0DP24 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 BTO:0000782 BTO:0000142 9822657 YES miannu The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk. 0.542 SIGNOR-266329 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 29955047 YES lperfetto Collectively, our findings indicate that TC-PTP negatively regulates Flk-1 and JNK signaling via direct dephosphorylation of Flk-1 on its Y1173 residue, which contributes to increased epidermal apoptosis in response to UVB exposure.|TC-PTP dephosphorylates activated Flk-1 at Y1173 after UVB irradiation, which is followed by the suppression of JNK phosphorylation.|TC-PTP promotes UVB induced apoptosis in keratinocytes by dephosphorylating Flk-1 tyrosine residue 1173. 0.565 SIGNOR-276961 TAB3 protein Q8N5C8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. 0.461 SIGNOR-205452 ATM protein Q13315 UNIPROT PPP2R5D protein Q14738 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 21460856 YES miannu In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth. 0.297 SIGNOR-276319 LCK protein P06239 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 10617281 YES miannu Lck was able to induce tyrosine phosphorylation of STAT3 to a level equal to or greater than that induced by Jak2.|This finding, along with the previous data, gives strong evidence that Lck can directly and positively affect STAT3 activity.Our data provide strong evidence that Lck can activate STAT3 via phosphorylation in baculovirus infected insect cells. 0.698 SIGNOR-279201 LRRK2 protein Q5S007 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation 9606 17447891 YES miannu LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558. 0.411 SIGNOR-279202 CDK1 protein P06493 UNIPROT NME1 protein P15531 UNIPROT up-regulates phosphorylation Ser120 GRNIIHGsDSVESAE 9606 SIGNOR-C17 18234856 YES gcesareni Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates. 0.266 SIGNOR-160493 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 YES lperfetto Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity 0.2 SIGNOR-244688 LRRK2 protein Q5S007 UNIPROT RDX protein P35241 UNIPROT up-regulates activity phosphorylation 9606 17447891 YES miannu LRRK2 also phosphorylated ezrin and radixin, which are related to moesin, at the residue equivalent to Thr558, as well as a peptide (LRRKtide: RLGRDKYKTLRQIRQ) encompassing Thr558. 0.365 SIGNOR-279203 LYN protein P07948 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity phosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 8806683 YES miannu We also show that Lyn phosphorylates Tyr15 of Cdk2 and that incubation of Lyn with Cdk2 results in inhibition of Cdk2 activity. 0.354 SIGNOR-279204 LCK protein P06239 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9534 9624175 YES miannu We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances. 0.587 SIGNOR-262742 LSM5 protein Q9Y4Y9 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.802 SIGNOR-270649 CSNK1D protein P48730 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr224 MSRFSSStEQSSASR 9606 22609948 YES lperfetto Ck1_/__dependent phosphorylation of dvl2 at s143 and t224and that this event is critical to interact with plk1 in early stages of the cell cycle 0.533 SIGNOR-197551 STOML2 protein Q9UJZ1 UNIPROT MFN2 protein O95140 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 NO Giorgia Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion. 0.336 SIGNOR-260380 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser350 ELKAIVSsSNQALLR 9606 20643644 YES Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. 0.2 SIGNOR-260794 ESR2 protein Q92731 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 NO miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice 0.2 SIGNOR-253473 A9/b1 integrin complex SIGNOR-C166 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.577 SIGNOR-257708 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr154 NRMPVAPyWTSPEKM 9606 8443592 YES lperfetto Tyrosine residues 154 and 307, which are in the extracellular domain of transmembrane receptor isoforms and are in an unusual sequence context for tyrosine phosphorylation, were also phosphorylated. 0.2 SIGNOR-98622 CBFB protein Q13951 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 10090 11179217 YES irozzo We observed previously that the RUNX proteins are susceptible to proteolytic degradation (Ogawa et al., 1993b). In this study, we show that the ubiquitin‚proteasome system is largely responsible for this degradation. We also show that when PEBP2Œ≤ dimerizes with RUNX it inhibits the ubiquitylation of RUNX, which is necessary for the protein to be targeted for proteolysis by the proteasome. 0.847 SIGNOR-255712 MAP2K1 protein Q02750 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser241 VHGSGPYsAPSPAYS 9606 35080342 YES miannu This study indicates that mTORC1, MEK1, p38 and DYRK2 induce HSF1 activity to a similar level but phosphorylate HSF1 primarily at S326 as well as S363, a known inhibitory site [71,72], S221, also thought to be an inhibitory site [70], or at S241 and S344, which are two novel phosphorylation sites with unknown function.|While AKT1, mTORC1, MEK1, p38 and DYRK2 can all activate HSF1, the current study indicates that activity of only AKT1 and mTORC1 maintains a strong association with HSF1 activity in tumours (Fig. 4). 0.287 SIGNOR-279208 vorinostat chemical CHEBI:45716 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257948 IHH protein Q14623 UNIPROT BMP2 protein P12643 UNIPROT up-regulates 9606 14973297 NO gcesareni Ihh is found to be required for bmp-induced os-teogenesis of a limb-bud cell line in culture. Ihh sig-naling is directly required for the osteoblast lineage in developing long bones. Ihh functions in conjunction with other factors such as bmps to induce osteoblast differentiation. In vivo, ihh acts on potential progeni-tor cells to promote osteoblast differentiation and prevent chondrocyte differentiation. 0.517 SIGNOR-122200 CSNK2B protein P67870 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1572 ESGISLFsDDPESDP -1 10403822 YES llicata Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity. 0.345 SIGNOR-251055 CSNK2A1 protein P68400 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser121 WEEEGFGsSSPVKSP 9606 BTO:0000567 16085715 YES miannu  In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms.  S123 phosphorylation creates a PBD-binding motif and accelerates S53 phosphorylation by Plk1. 0.409 SIGNOR-276038 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROG2 protein Q9H2A3 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19028584 NO miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. 0.2 SIGNOR-254633 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Ser582 LNKLQQHsDKIIRLY 9606 18680479 YES miannu We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / autophosphorylation outside the activation segment was also important for activity in vitro, since s582a/s582d and y811f mutants exhibited decreased activity 0.2 SIGNOR-179896 MAP2K1 protein Q02750 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser326 SSVDTLLsPTALIDS 9606 35080342 YES miannu This study indicates that mTORC1, MEK1, p38 and DYRK2 induce HSF1 activity to a similar level but phosphorylate HSF1 primarily at S326 as well as S363, a known inhibitory site [71,72], S221, also thought to be an inhibitory site [70], or at S241 and S344, which are two novel phosphorylation sites with unknown function.|While AKT1, mTORC1, MEK1, p38 and DYRK2 can all activate HSF1, the current study indicates that activity of only AKT1 and mTORC1 maintains a strong association with HSF1 activity in tumours (Fig. 4). 0.287 SIGNOR-279209 MAP2K1 protein Q02750 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser344 ESEPAPAsVTALTDA 9606 35080342 YES miannu This study indicates that mTORC1, MEK1, p38 and DYRK2 induce HSF1 activity to a similar level but phosphorylate HSF1 primarily at S326 as well as S363, a known inhibitory site [71,72], S221, also thought to be an inhibitory site [70], or at S241 and S344, which are two novel phosphorylation sites with unknown function.|While AKT1, mTORC1, MEK1, p38 and DYRK2 can all activate HSF1, the current study indicates that activity of only AKT1 and mTORC1 maintains a strong association with HSF1 activity in tumours (Fig. 4). 0.287 SIGNOR-279210 CSNK2A1 protein P68400 UNIPROT HNRNPC protein P07910 UNIPROT down-regulates activity phosphorylation Ser260 SEGGADDsAEEGDLL 9606 15687492 YES gcesareni In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C. 0.358 SIGNOR-133540 CD40 protein P25942 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000782;BTO:0000776 19904719 NO fstefani Cd40 has been found to be essential in mediating a broad variety of immune and inflammatory responses including t cell-dependent immunoglobulin class switching, memory b cell development 0.7 SIGNOR-189109 PRKCA protein P17252 UNIPROT CSPG4 protein Q6UVK1 UNIPROT up-regulates activity phosphorylation Thr2252 YLRKRNKtGKHDVQV 9606 BTO:0002035 15504744 YES miannu Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility. 0.2 SIGNOR-263162 PRLR protein P16471 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 17975019 NO miannu We also show that activation of RS represses the expression of the transcription factor Forkhead box O3 (FOXO3) and that of the enzyme galactose-1-phosphate uridyltransferase (Galt), two proteins known to be essential for normal follicular development. 0.2 SIGNOR-254187 ELP2 protein Q6IA86 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 YES miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. 0.782 SIGNOR-269709 SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000938 11560935 YES lperfetto Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras 0.779 SIGNOR-110566 Vincristine sulfate chemical CHEBI:79401 ChEBI TUBB protein P07437 UNIPROT down-regulates activity chemical inhibition 9606 30599272 YES miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 0.8 SIGNOR-259251 SP1 protein P08047 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19781662 NO The 5-LO promoter possesses a unique GC-rich region which contains consensus sequences for the transcription factors Sp1 and Egr-1 (GC-boxes) which are important for basal transcriptional activity 0.25 SIGNOR-254032 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser81 AAGSGAAsPSAAEKG -1 8034575 YES lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites. 0.729 SIGNOR-248910 SYN3 protein O14994 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates activity binding 9606 BTO:0000938 15265865 YES miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. 0.7 SIGNOR-269186 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 21443865 YES The MAPT H1 haplotype and subhaplotypes may be associated with sporadic tauopathies including AD. And that, tau's phosphorylation is regulated by many protein kinases, including glycogen synthase kinase 3beta (GSK3B). 0.738 SIGNOR-255486 SMAD3 protein P84022 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity binding 9606 BTO:0000007 11331591 YES lperfetto Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence. 0.737 SIGNOR-235902 SRC protein P12931 UNIPROT ENG protein P17813 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr612 LLTAALWyIYSHTRS 9606 BTO:0002828 25070888 YES miannu We identified epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as Src-activators that induce endoglin turnover following (612)YIY(614) phosphorylation.  0.385 SIGNOR-276655 PRKACA protein P17612 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Ser27 SFGFTRTsARRRLAD -1 21880142 YES miannu PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. 0.307 SIGNOR-266309 IKBKE protein Q14164 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR up-regulates phosphorylation 9606 16888014 YES lperfetto The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel. 0.397 SIGNOR-217664 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22470139 NO miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. 0.554 SIGNOR-255607 MAPK7 protein Q13164 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates activity phosphorylation 9606 17020917 YES miannu Activation of MEK, which in turns activates ERK5, does enhance the ERK5 induced nurr1 activity, while no increase is observed in the presence of a dn MEK5 or of the unphosphorylated ERK5 AEF, in which amino acids phosphorylated by MEK5 are mutated.|The A/B domain of nurr1 is highly phosphorylated in the presence of ERK5 and mutations of two amino acids in this same domain decrease significantly the ERK5 mediated nurr1 transcriptional response.|These data would suggest once again that the basal activity of ERK5 is responsible for the phosphorylation of nurr1.|As shown in XREF_FIG, nurr1 A/B domain was significantly phosphorylated by ERK5, while the GST protein alone was not a substrate for this kinase. 0.2 SIGNOR-279215 SETD5 protein Q9C0A6 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity methylation Lys37 APATGGVkKPHRYRP -1 31515109 YES miannu SETD5 Exhibits Intrinsic Methyltransferase Activity on H3K36. This assay showed that SETD5 has specific histone methyltransferase activity toward K36 but not for other residues such as K4 and K27 (Figure 8B). we revealed that SETD5 is endowed with H3K36 methyltransferase, which is necessary for RNA elongation and processing and, ultimately, correct gene transcription. 0.2 SIGNOR-264621 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates activity phosphorylation Ser511 RREERSLsAPGNLLT 9534 BTO:0000298 32913128 YES miannu  Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues.  0.2 SIGNOR-277240 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CALD1 protein Q05682 UNIPROT down-regulates phosphorylation 9606 BTO:0001260 10514499 YES inferred from 70% family members lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. 0.2 SIGNOR-270049 ITCH protein Q96J02 UNIPROT TNFAIP3 protein P21580 UNIPROT up-regulates activity binding 9606 BTO:0000782;BTO:0001271 18246070 YES lperfetto Here we demonstrate that the regulatory molecule tax1bp1 recruited the e3 ligase itch to a20 via two 'ppxy' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling a20-mediated recruitment and inactivation of rip1. (abstract) 0.28 SIGNOR-160621 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC1R protein Q01726 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.2 SIGNOR-268701 MAP3K5 protein Q99683 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Ser98 GGRRPGTsPALLQGT 9606 17325029 YES lperfetto P21cip1 is phosphorylated in vitro by both ask1 and jnk1 at s98. /phosphorylation of p21cip1 at s98, which in vivo appears to be regulated by ask1, may therefore mediate negative feedback in the ask1 signaling pathway. 0.588 SIGNOR-153440 PRKCB protein P05771 UNIPROT EEF1A1 protein P68104 UNIPROT up-regulates activity phosphorylation Ser53 AAEMGKGsFKYAWVL 10090 20923971 YES miannu PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein. 0.2 SIGNOR-263167 LRRK2 protein Q5S007 UNIPROT NSF protein P46459 UNIPROT up-regulates activity phosphorylation Thr645 RKLLIIGtTSRKDVL 9606 BTO:0002181 26758690 YES miannu LRRK2 phosphorylates full-length NSF at threonine 645 in the ATP binding pocket of D2 domain. Functionally, NSF phosphorylated by LRRK2 displays enhanced ATPase activity and increased rate of SNARE complex disassembling. 0.367 SIGNOR-277196 CDK2 protein P24941 UNIPROT ARID4A protein P29374 UNIPROT down-regulates phosphorylation Ser864 RKILGQSsPEKKIRI 9606 21148318 YES gcesareni In the present study we identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation 0.427 SIGNOR-170455 MAPK7 protein Q13164 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates activity phosphorylation 9606 16626623 YES miannu This suggested that ERK5 may directly activate RSKs.|In vitro active ERK5 also phosphorylated RSK2 that had been immunoprecipitated from transfected cells using an anti-HA antibody ( Fig. 2 B).|Phosphorylation of RSK2 by ERK5 in vitro increased its activity towards GST-S6 as much as 8-fold (Figs. 2 C and E). 0.56 SIGNOR-279216 MAPK8 protein P45983 UNIPROT TP73 protein O15350 UNIPROT up-regulates activity phosphorylation 9606 23516355 YES miannu Therefore, it is likely that p73 recruitment to the \u0394Np73 promoter is mediated by its JNK-1-dependent phosphorylation. 0.421 SIGNOR-279219 MAPK9 protein P45984 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 25077544 YES miannu (c) The phosphorylation of recombinant Bid by JNK2 (in vitro kinase assay) prevents its cleavage by caspase-8 0.405 SIGNOR-279220 AKT1 protein P31749 UNIPROT PALLD protein Q8WX93 UNIPROT unknown phosphorylation Ser1118 VRRPRSRsRDSGDEN 9606 20471940 YES llicata Akt1, but not akt2, phosphorylates palladin at ser507 in a domain that is critical for f-actin bundling. 0.406 SIGNOR-252510 MAPK9 protein P45984 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation 9606 25377781 YES miannu Activation of c-Src by JNK2 was accompanied by the phosphorylation of c-Src on threonine residue (s).|JNK2 directly phosphorylates c-Src and activates its auto phosphorylation. 0.356 SIGNOR-279222 NEDD4 protein P46934 UNIPROT AP1G2 protein O75843 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0001950 18772139 YES miannu Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination. 0.402 SIGNOR-272635 CBLB protein Q13191 UNIPROT STAT6 protein P42226 UNIPROT down-regulates quantity ubiquitination Lys398 SFTLGPGkLPIQLQA 9606 24508458 YES miannu Having shown that Cbl-b negatively regulates Stat6, we further investigated the mechanism of this regulation by determining whether Cbl-b associates with Stat6.|Our data demonstrate that Stat6 is ubiquitinated at K108 and K398 by Cbl-b, and that Stat6 ubiquitination is a critical post-translational regulatory mechanism for Stat6. 0.2 SIGNOR-278806 CUL9 protein Q8IWT3 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity ubiquitination 9606 24793696 YES miannu CUL9 promotes the ubiquitylation and degradation of survivin and is inhibited by CUL7.|Together, these results demonstrate the specificity of survivin ubiquitylation by CUL9 E3 ligase complex. 0.487 SIGNOR-278808 BZW2 protein Q9Y6E2 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 31643092 NO miannu WB showed that BZW2 silence significantly decreased p‐ERK protein level in Colo205 cells, whereas BZW2 overexpression upregulated p‐ERK protein expression in HCT116 cells (Figure 3a,b) 0.2 SIGNOR-261219 THOC5 protein Q13769 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 YES miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. 0.929 SIGNOR-268506 LATS1 protein O95835 UNIPROT PPP1R12A protein O14974 UNIPROT up-regulates activity phosphorylation Ser445 LGLRKTGsYGALAEI 9606 22641346 YES miannu LATS1 directly and preferentially phosphorylated serine 445 (S445) of MYPT1.|This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity. 0.471 SIGNOR-278184 LATS1 protein O95835 UNIPROT PPP1R12A protein O14974 UNIPROT up-regulates activity phosphorylation Ser473 GVTRSASsPRLSSSL 9606 22641346 YES miannu The present study identified S473 as a one of the significant LATS1 phosphorylation sites within MYPT1 (Fig. 3, B and E).|This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity. 0.471 SIGNOR-278185 IL17A protein Q16552 UNIPROT IL17R complex complex SIGNOR-C260 SIGNOR up-regulates activity binding 9606 BTO:0001946 32024054 YES lperfetto Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response. 0.805 SIGNOR-261337 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser622 KHVPGGGsVQIVYKP -1 8999860 YES miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules 0.314 SIGNOR-250286 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 11085989 NO miannu We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation. 0.866 SIGNOR-263499 PPP6C protein O00743 UNIPROT CGAS protein Q8N884 UNIPROT down-regulates activity dephosphorylation Ser435 KHLDKFSsYHVKTAF 9606 32474700 YES lperfetto In this study, we found that PPP6C suppressed phosphorylation of human cGAS (hcGAS) at S435 or mouse cGAS (mcGAS) at S420 in its substrate-binding pocket, thus preventing its binding to GTP and inhibiting the synthesis of cGAMP.|These data suggest that PPP6C inhibits cGAS activity. 0.2 SIGNOR-276990 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 BTO:0000007 18204439 YES lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. 0.716 SIGNOR-252959 FGF11 protein Q92914 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253426 CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR BORA protein Q6PGQ7 UNIPROT up-regulates activity phosphorylation 9606 29870721 YES lperfetto The active cyclin A/cdk1 complex phosphorylates Bora and promotes Plx1 activation 0.444 SIGNOR-267573 RPS6KA4 protein O75676 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000782 17668895 YES gcesareni Msk1 and msk2 directly phosphorilate and activete transcription factors such as creb1, atf1 msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. 0.604 SIGNOR-157158 MELK protein Q14680 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation 9606 24885567 YES miannu As the aforementioned results showed that MELK promotes FAK phosphorylation, and it is well known that FAK is an important regulator of cell migration and invasion, we speculated that MELK could regulate cell migration and invasion via the FAK/Paxillin pathway.|Finally, knockdown of MELK decreased the phosphorylation of the FAK and paxillin, and prevented gastrin stimulated FAK and paxillin phosphorylation. 0.2 SIGNOR-279230 MTOR protein P42345 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity phosphorylation 9606 12742166 YES miannu By contrast to the phosphorylation of p150 Glued by PKA, inhibition of mTOR by rapamycin inhibited the ability of CLIP-170 to bind to microtubules, suggesting that phosphorylation by mTOR promotes CLIP-170 microtubule binding.|The new study confirms this physical interaction in animal cells and suggests that mTOR phosphorylates CLIP-170 on some, but not all, of the sites that are phosphorylated in vivo. 0.566 SIGNOR-279231 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT up-regulates quantity by stabilization sumoylation Lys159 TFDGSFVkEENAEQA 9606 BTO:0000007 23686912 YES miannu Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. 0.453 SIGNOR-263899 MEF2A protein Q02078 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 19725819 NO areggio In response to increases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin 0.7 SIGNOR-255957 COPS8 protein Q99627 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.921 SIGNOR-270763 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Thr157 VLYSQKAtPGSSRKT 9606 BTO:0000567 15525512 YES llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  0.992 SIGNOR-250609 zotepine chemical CHEBI:32316 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 9534 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258556 MTOR protein P42345 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates activity phosphorylation 9606 20602111 YES miannu Subsequently, mTOR phosphorylates and activates the 70-kDa ribosomal protein S6 kinase (p70S6K), which results in increased translation either directly or indirectly by activating initiation and elongation factors, eIF-2, eIF-4E (through 4E-BP) and eEF-2 (Bodine et al. xref 0.393 SIGNOR-279232 MYLK protein Q15746 UNIPROT MYL2 protein P10916 UNIPROT up-regulates activity phosphorylation 9606 18166657 YES miannu MLCK directly phosphorylates MLC2 and is a substrate for ERK1/2 ( ), thus providing a direct link between the Raf-MEK1/2-ERK1/2 module and MLC2.|These findings strongly suggest that the phosphorylation of MLC2 stimulated by MLCK and ROCK1/2 is an integral component of the biochemical signal transduction program that promotes noninvasive motility. 0.719 SIGNOR-279233 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 YES gcesareni Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm 0.855 SIGNOR-181631 EFNA1 protein P20827 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9576626 YES gcesareni Ephrins are cell-surface tethered guidance cues that bind to eph receptor tyrosine kinases in trans on opposing cells. 0.817 SIGNOR-56968 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 SIGNOR-C15 19584320 YES gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. 0.503 SIGNOR-186641 AKT2 protein P31751 UNIPROT ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 YES gcesareni Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B. 0.287 SIGNOR-245263 LETM1 protein O95202 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR up-regulates 9606 BTO:0000567 18628306 NO lperfetto LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected. 0.253 SIGNOR-262547 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser85 PLPDAGAsPAPSRCC 9606 27308327 YES miannu HIPK2 phosphorylates WIP1 at Ser54 and Ser85, and phosphorylated WIP1 is subject to proteasomal degradation so that WIP1 is maintained at low levels. 0.42 SIGNOR-278230 ATRX protein P46100 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity binding 9606 25417162 YES lperfetto ATRX is a required specificity determinant for PRC2 targeting and function. 0.336 SIGNOR-241890 FBXW7 protein Q969H0 UNIPROT MED13 protein Q9UHV7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 SIGNOR-C135 SIGNOR-C406 23322298 YES miannu The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. 0.372 SIGNOR-266690 NEK6 protein Q9HC98 UNIPROT EML4 protein Q9HC35 UNIPROT down-regulates activity phosphorylation Ser146 PQIRASPsPQPSSQP 9606 31409757 YES miannu In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules.|The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser 144 and Ser 146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. 0.253 SIGNOR-279236 NPR1 protein P16066 UNIPROT ART1 protein P52961 UNIPROT down-regulates activity phosphorylation 9606 33024932 YES miannu Art1 is a substrate for the kinase Npr1, which phosphorylates Art1 and, thereby, causes its inactivation by limiting its plasma membrane association. 0.2 SIGNOR-279239 DGC complex SIGNOR-C217 SIGNOR NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 YES miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. 0.36 SIGNOR-265446 NUMB protein P49757 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 12682059 YES lperfetto Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain 0.797 SIGNOR-99762 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI WASL protein O00401 UNIPROT up-regulates activity chemical activation 9606 10219243 YES lperfetto In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules. 0.8 SIGNOR-261870 GATA1 protein P15976 UNIPROT SPI1 protein P17947 UNIPROT down-regulates activity binding 9606 BTO:0004826 10753833 YES irozzo GATA-1 represses PU.1 activity.We have in this report found that the GATA-1 transcription factor is capable of functionally interfering with the PU.1 protein and have provided evidence that this interference is mediated through interaction between the PU.1 ETS domain and the GATA-1 C-finger region. 0.621 SIGNOR-256050 RPS6KA3 protein P51812 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity 9606 BTO:0000567 20383198 NO lperfetto We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions. 0.2 SIGNOR-252037 hsa-miR-1-5p mirna URS000075C105_9606 RNAcentral CXCL12 protein P48061 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000196 21752897 YES We also show that miR-1 transfection down-regulates the luciferase activity of a reporter construct carrying the 3′-UTR-CXCR4 or 3′-UTR-SDF-1α sequence. 0.4 SIGNOR-277927 hsa-mir-494-3p mirna URS0000535FDD_9606 RNAcentral CDH1 protein P12830 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 BTO:0000150 25955111 YES In the present study, significant upregulation of E-cadherin and downregulation of N-cadherin, vimentin and α-SMA were observed in the miR-494 mimic-transfected cells compared to the control cells, indicating suppression of EMT following miR-494 transfection in breast cancer cells. 0.4 SIGNOR-277944 PAK4 protein O96013 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation 9606 23125951 YES miannu PAK4 specifically phosphorylates GefH1, and this is thought to inhibit its ability to activate Rho, consequently inhibiting stress fiber formation. 0.519 SIGNOR-279245 PLK1 protein P53350 UNIPROT BUB1 protein O43683 UNIPROT up-regulates activity phosphorylation 9606 25540073 YES miannu Note that PLK1 phosphorylates and activates BUB1 to localize it to the kinetochore, phosphorylates and inhibits the negative regulator PKMYTI and interacts with the G1/S kinase Cdc7p to target it to initiation complexes late in G1. 0.864 SIGNOR-279251 GRM2 protein Q14416 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 YES miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. 0.356 SIGNOR-264079 TNKS protein O95271 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 19759537 YES lperfetto Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin. 0.773 SIGNOR-263379 GSK3B protein P49841 UNIPROT EIF2B4 protein Q9UI10 UNIPROT down-regulates binding 9606 21798082 YES gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). 0.2 SIGNOR-175572 PKC proteinfamily SIGNOR-PF53 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL -1 19661060 YES miannu Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.2 SIGNOR-276229 PP2B proteinfamily SIGNOR-PF18 SIGNOR DNM2 protein P50570 UNIPROT unknown dephosphorylation 10116 20496096 YES inferred from 70% family members CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). 0.2 SIGNOR-269990 PTK2 protein Q05397 UNIPROT TRIO protein O75962 UNIPROT up-regulates activity phosphorylation Tyr2796 KDNFDSFySEVAELG 9534 12551902 YES lperfetto A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity. 0.508 SIGNOR-249188 ARHGAP30 protein Q7Z6I6 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.447 SIGNOR-260485 MYC protein P01106 UNIPROT BCR protein P11274 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664;BTO:0004465 26179066 YES lperfetto In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer. 0.363 SIGNOR-272144 FOXO1 protein Q12778 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22521266 YES gcesareni Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase). 0.428 SIGNOR-197200 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser370 TSVTPDVsDNEPDHY -1 12297295 YES llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  0.704 SIGNOR-251025 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 15456867 YES gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation 0.715 SIGNOR-129589 SCF-FBW7 complex SIGNOR-C135 SIGNOR MED13 protein Q9UHV7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 SIGNOR-C406 23322298 YES miannu The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. 0.295 SIGNOR-266691 ziprasidone chemical CHEBI:10119 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 YES miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). 0.8 SIGNOR-258833 PLK1 protein P53350 UNIPROT YBX1 protein P67809 UNIPROT up-regulates quantity phosphorylation Ser176 EKNEGSEsAPEGQAQ 9606 36805592 YES miannu Here we identify that PLK1 inhibition can induce apoptosis and DNA damage of GSCs, we have also delineat the possible underlying molecular mechanisms: PLK1 interacts with YBX1 and directly phosphorylates serine 174 and serine 176 of YBX1.|Inhibition of PLK1 reduces the phosphorylation level of YBX1, and decreased phosphorylation of YBX1 prevents its nuclear translocation, thereby inducing apoptosis and DNA damage of GSCs. 0.253 SIGNOR-279255 GNB3 protein P16520 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Furthermore, this work suggested that the g subunits released upon gi activation activated phospholipase c (plc- ) to produce inositol 3-phosphate (ip3), which would subsequently increase intracellular ca2+ abundance. 0.2 SIGNOR-199135 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser345 DDRSDIEsSSDEEDS 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273991 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9858528 YES The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain 0.695 SIGNOR-62792 phenytoin chemical CHEBI:8107 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258160 PAK3 protein O75914 UNIPROT SORT1 protein Q99523 UNIPROT down-regulates activity phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 YES miannu PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. 0.2 SIGNOR-273719 PRKD1 protein Q15139 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates quantity phosphorylation Ser325 TSVSRGSsLKILSKG 9606 27127886 YES miannu Inhibition of PKD activity restores membrane expression of CXCR4 and migration towards CXCL12 in BCR responsive cells in vitro.|This cascade consisted on a novel BCR dependent pathway in which PI3K-delta phosphorylates PKD, which in turn phosphorylates CXCR4 at Ser 324/325. 0.2 SIGNOR-279263 PRKD1 protein Q15139 UNIPROT TFAP2B protein Q92481 UNIPROT down-regulates activity phosphorylation Ser258 GEVQRRLsPPECLNA 9606 31492751 YES miannu Mechanistically, we observed that PKD phosphorylates AP2beta at Ser 258 and Ser 277 and suppresses its nuclear accumulation.|Using ChIP analyses, here we found that PKD knockdown in HUVECs increases binding of AP2beta to the VEGFR-2 promoter. 0.295 SIGNOR-279266 PRKD1 protein Q15139 UNIPROT TFAP2B protein Q92481 UNIPROT down-regulates activity phosphorylation Ser277 GVLRRAKsKNGGRSL 9606 31492751 YES miannu Mechanistically, we observed that PKD phosphorylates AP2\u03b2 at Ser-258 and Ser-277 and suppresses its nuclear accumulation.|Using ChIP analyses, here we found that PKD knockdown in HUVECs increases binding of AP2beta to the VEGFR-2 promoter. 0.295 SIGNOR-279267 PRKG1 protein Q13976 UNIPROT PLN protein P26678 UNIPROT up-regulates activity phosphorylation Ser16 RSAIRRAsTIEMPQQ 9606 22199120 YES miannu Phosphorylation of PLB by PKA or cGKI at Ser 16 relieves the inhibition of SERCA2a and results in increased contractility through enhanced Ca 2+ i reuptake into the SR. 0.407 SIGNOR-279269 WNT5A protein P41221 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 YES gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. 0.706 SIGNOR-141434 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser746 AMRFARRsVSDNDIR 9606 BTO:0000150 16551632 YES llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I 0.509 SIGNOR-252492 TTL protein Q8NG68 UNIPROT TUBA1C protein Q9BQE3 UNIPROT down-regulates tyrosination 9606 22020298 YES miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization 0.472 SIGNOR-176918 ARRB2 protein P32121 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Betaarrestin 2 was subsequentialy shown to bridge smo to the kinestesin motor kif3 to promote ciliary accumulation of smo in mammalian cells 0.637 SIGNOR-199107 PSMD1 protein Q99460 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.906 SIGNOR-263354 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 BTO:0000938 12040039 YES lperfetto Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Thus, neuronal stress selectively activates JNK2/3 in the presence of mechanisms maintaining constitutive JNK1 activity, and this JNK2/3 activity selectively targets c-Jun, which is isolated from constitutive JNK1 activity. 0.2 SIGNOR-236149 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser202 EEDSRPRsQSSKAAI 9534 BTO:0001538 23519612 YES miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. Clk1 promotes SPF45-induced exon 6 exclusion 0.318 SIGNOR-262705 PTK2 protein Q05397 UNIPROT ARHGEF28 protein Q8N1W1 UNIPROT up-regulates activity phosphorylation 9606 21643014 YES miannu Importantly, FAK promotes p190RhoGEF tyrosine phosphorylation and enhances activation of RhoA ( ).|Importantly, FAK promotes p190RhoGEF tyrosine phosphorylation and enhances activation of RhoA. 0.457 SIGNOR-279271 PTK2B protein Q14289 UNIPROT PXN protein P49023 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 15263022 YES miannu P130Cas and paxillin can be phosphorylated by Fak or Pyk2, and bind directly to these kinases. 0.94 SIGNOR-279272 PTK6 protein Q13882 UNIPROT CDC73 protein Q6P1J9 UNIPROT down-regulates activity phosphorylation 9606 27650679 YES miannu PTK6 impairs the coactivator function of parafibromin.|To study the functional consequence of parafibromin phosphorylation by PTK6, we examined the effect of PTK6 inhibition on Wnt signal activation. 0.368 SIGNOR-279273 PTK6 protein Q13882 UNIPROT CNTNAP1 protein P78357 UNIPROT up-regulates activity phosphorylation 9606 18829532 YES miannu As a consequence, Brk stimulates p190 and attenuates p120 functions, leading to RhoA inactivation and Ras activation, respectively.|Brk phosphorylates p190 at the Y (1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120RasGAP (p120). 0.2 SIGNOR-279274 EP300 protein Q09472 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR form complex binding 9606 11559745 YES lperfetto P300/cbp proteins: hats for transcriptional bridges and scaffolds 0.544 SIGNOR-110562 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AM/b2 integrin complex SIGNOR-C170 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.406 SIGNOR-259025 PRKG1 protein Q13976 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 YES gcesareni Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.  0.276 SIGNOR-188185 TFEB protein P19484 UNIPROT ACOT2 protein P49753 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) 0.2 SIGNOR-276781 FGF9 protein P31371 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1. gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts. 0.375 SIGNOR-195591 PRKAA1 protein Q13131 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser385 RRRKKRTsIETNIRV 9606 9368058 YES lperfetto Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites. 0.2 SIGNOR-53254 PIK3CG protein P48736 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates chemical modification 9606 16847462 YES gcesareni The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) 0.8 SIGNOR-147954 ATP6V0C protein P27449 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.742 SIGNOR-277750 CHMP3 protein Q9Y3E7 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.742 SIGNOR-265523 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 15818404 YES gcesareni Akt/pkb ser129 is phosphorylated by ck2 in vitro and in vivo;(4) such a phosphorylation of activated akt/pkb correlates with a further increase in catalytic activity. 0.372 SIGNOR-135203 FLT3 protein P36888 UNIPROT SIRT3 protein Q9NTG7 UNIPROT down-regulates activity phosphorylation Tyr226 KGLLLRLyTQNIDGL -1 34289383 YES lperfetto We also hypothesize that, besides activating ACAT1 through Y407 phosphorylation (Fan et al., 2016), FLT3 might simultaneously phosphorylate and regulate SIRT3. Our mutational studies on all of the seven tyrosine sites of SIRT3 revealed that purified rFLT3 directly phosphorylated purified rSIRT3 in an in vitro kinase assay, leading to decreased SIRT3 deacetylase activity that was assessed by ability to deacetylate K413 of mIDH2 (Figure 4H, first three samples in left, middle, and right panels), whereas replacement of Y226 completely abolished inhibition of SIRT3 by FLT3 (Figure 4H, right). 0.2 SIGNOR-267631 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 YES lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. 0.2 SIGNOR-244747 UBAP2L protein Q14157 UNIPROT RNF2 protein Q99496 UNIPROT up-regulates activity binding 9606 BTO:0000007 25185265 YES Sara UBAP2L associates with BMI1 and RNF2. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex 0.383 SIGNOR-261316 TRPC6 protein Q9Y210 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 12032305 YES Members of the transient receptor potential channel (TRPC) family have been characterized as molecular substrates mediating receptor-activated cation influx 0.8 SIGNOR-253339 SRC protein P12931 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity phosphorylation Thr288 APSSRRTtLCGTLDY 9606 25501815 YES miannu We report here that Src phosphorylates and activates AURA at T288, and AURA also activates focal adhesion kinase (FAK, also known as PTK2), leading to initiation of cell movement. 0.309 SIGNOR-279286 SRC protein P12931 UNIPROT LRP6 protein O75581 UNIPROT down-regulates activity phosphorylation 9606 25391905 YES miannu Both Src and Fer associate with LRP6 and phosphorylate LRP6 directly.|Wnt3a treatment of cells enhances tyrosine phosphorylation of endogenous LRP6 and, mechanistically, Src reduces cell surface LRP6 levels and disrupts LRP6 signalosome formation. 0.397 SIGNOR-279289 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition 25309440 YES lperfetto Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway. 0.8 SIGNOR-262010 SRC protein P12931 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates activity phosphorylation 9606 20219970 YES miannu Direct phosphorylation of TrkA by Src family kinases has been demonstrated in vitro, and our studies suggest that Src may lead to selective activation of TrkA. 0.292 SIGNOR-279291 TBX21 protein Q9UL17 UNIPROT IL2 protein P60568 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003432 10761931 YES Luana T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells 0.473 SIGNOR-266233 CIB2 protein O75838 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR up-regulates activity binding 9606 35408910 YES miannu So far, two integrins have been found to interact with CIB2: αIIbβ3 is expressed by platelets and megakaryocytes and, apparently, a common target for all CIB family members, at odds with α7Bβ1D, which seems to be CIB2-specific and is expressed in skeletal muscles. 0.2 SIGNOR-269669 MAP3K21 protein Q5TCX8 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 9606 23319808 YES Manara These experiments showed that MEK1 is phosphorylated by MLK4 on Ser217/221 0.2 SIGNOR-260767 bremazocine chemical CHEBI:3171 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258779 AKAP5 protein P24588 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity relocalization 10116 10939335 YES In this report, we demonstrate that glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150 0.56 SIGNOR-261292 YES1 protein P07947 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276185 amitriptyline chemical CHEBI:2666 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258703 GSK3B protein P49841 UNIPROT DROSHA protein Q9NRR4 UNIPROT up-regulates activity phosphorylation Ser302 RDNRRSPsLERSYKK -1 25699712 YES lperfetto Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.  0.278 SIGNOR-264846 PCM1 protein Q15154 UNIPROT CETN2 protein P41208 UNIPROT up-regulates relocalization 9606 12403812 YES miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome 0.529 SIGNOR-94990 EGFR protein P00533 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Tyr142 AVVNLINyQDDAELA 9606 22558232 YES miannu EGFR and TRKA effect on WNT3a mediated Topflash induction was abolished by U0126 or expression of dominant negative LRP6-5A mutant (XREF_FIG), demonstrating that both EGFR and TRKA signal via ERK and LRP6 pathway to upregulate WNT and beta-catenin signaling.|FGFR2, FGFR3, EGFR and TRKA Phosphorylate beta-catenin at Tyr142. 0.773 SIGNOR-278309 SRC protein P12931 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 28943431 YES miannu Although the role of ERK in mediating phosphorylation of Smad2/3 remains to be investigated, our data indicate that early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release, whereas Src mediated chronic EGFR transactivation and ERK1/2 activation involve late Smad3 activation induced by TGF-beta1.|Inhibition of Src not only decreases Smad3 phosphorylation but also decreases phosphorylation dependent nuclear translocation of Smad2/3, suggesting that Src kinase could modulate Smad3 activity. 0.377 SIGNOR-279292 STK25 protein O00506 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation 9606 30948712 YES miannu In sum, these data reveal that STK25 activates LATS kinases through a mechanism that is distinct from what has been characterized for the MAP4K/MST kinases (Fig.\u00a0 xref ).|Mechanistically, we demonstrate that STK25 promotes LATS phosphorylation at the activation loop in the absence of hydrophobic motif phosphorylation, which distinguishes it from all of the other known LATS-activating kinases discovered to date. 0.2 SIGNOR-279294 LCK protein P06239 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9973379 YES Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218. Phosphorylation of Y201 correlated with accumulation of CTLA-4 on the cell surface. 0.748 SIGNOR-251370 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser43 RNPEAALsPTFRSDS 9606 BTO:0000007 33217317 YES miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.2 SIGNOR-265953 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser576 VSDKGSDsEEEETNR 9606 BTO:0000599 23287549 YES lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. 0.2 SIGNOR-265268 TEK protein Q02763 UNIPROT GRB14 protein Q14449 UNIPROT up-regulates activity phosphorylation 9606 20973951 YES miannu Together these results suggest a role for the Grb14 SH2 domain in Tie2 mediated Grb14 signaling.|Tyrosine phosphorylation of Grb14 by Tie2. 0.649 SIGNOR-279300 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe709 ENPTYKFfEQMQN -1 10605825 YES lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. 0.489 SIGNOR-261778 TNFSF4 protein P23510 UNIPROT TNFRSF4 protein P43489 UNIPROT up-regulates binding 9606 BTO:0000007 9488716 YES gcesareni Activation of nf-kappab in ox40-transfected hsb-2 cells was detected by electrophoretic mobility shift assay within 30 min after the binding of the ligand gp34. 0.92 SIGNOR-54927 PRKCQ protein Q04759 UNIPROT ICAM3 protein P32942 UNIPROT up-regulates activity phosphorylation Ser518 REHQRSGsYHVREES 9606 BTO:0000661 9268366 YES lperfetto Ser489 was a phosphorylation site in vitro for recombinant protein kinase Ctheta. Finally, treatment of Jurkat cells with chelerythrine chloride, a protein kinase C inhibitor, prevented ICAM-3-triggered spreading.  0.334 SIGNOR-248979 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 YES lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. 0.485 SIGNOR-248924 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr156 GSRNALKyEHKEIEY -1 21840312 YES miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. 0.389 SIGNOR-263037 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 YES lperfetto Rsk1, and survival factor signaling stimulate phosphorylation of bad at ser-155, blocking the binding of bad to bcl-xl. 0.2 SIGNOR-252786 AKT1 protein P31749 UNIPROT METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 3627513 YES lperfetto The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells 0.336 SIGNOR-24994 ILK protein Q13418 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 12144526 YES miannu Phosphopeptide mapping, phospho amino acid analysis and immunoblotting using phospho-specific antibodies indicated that ilk predominantly phosphorylated the site critical for potent inhibition, i.e. Thr(38) of cpi-17 0.548 SIGNOR-90828 DNA_damage stimulus SIGNOR-ST1 SIGNOR TTK protein P33981 UNIPROT up-regulates 9606 19151762 NO lperfetto Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68 0.7 SIGNOR-242619 HLA-G protein P17693 UNIPROT KIR2DL4 protein Q99706 UNIPROT up-regulates binding 9606 10190900 YES gcesareni Recombinant soluble kir2dl4 binds to cells expressing hla-g but not to cells expressing other hla class i molecules. 0.763 SIGNOR-66132 PRKCD protein Q05655 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates activity phosphorylation Ser153 LRTGLYKsQRPCVTH 9606 BTO:0003038 12682370 YES lperfetto Phosphorylation of Kruppel-like factor 5 (KLF5/IKLF) at the CBP interaction region enhances its transactivation function. | Inhibition of protein kinase activity by H7 or calphostin C blocked both full-length and N-terminal fragment (amino acids 1-238) KLF5 activities. Mutation at a potential protein kinase C phosphorylation site within the CBP interaction domain of KLF5 reduces its transactivation function. Furthermore, using the GST pull-down approach, we showed that phosphorylation of KLF5 enhances its interaction with CBP. The results of the present study provide a mechanism for KLF5 transactivation function. | We found that KLF5€™s activity was reduced to half when the serine in the potential PKC phosphorylation site was mutated to alanine (Fig. 6B, S153A) Nonetheless, the S153A mutant still retains significant transactivation activity. 0.336 SIGNOR-249206 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 YES gcesareni Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. 0.344 SIGNOR-76001 PTPN2 protein P17706 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000782 22080863 YES lperfetto Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks 0.325 SIGNOR-177113 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PFKM protein P08237 UNIPROT down-regulates activity phosphorylation -1 28607489 YES miannu In vitro kinase reactions revealed that all three PFK1 isoforms (PFKP, PFKL, PFKM) and PKM2 were phosphorylated by cyclin D3-CDK6 (Extended Data Fig. 2a–d, Supplementary Table 4). 0.2 SIGNOR-276452 UBE2D1 protein P51668 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity ubiquitination -1 19687296 YES miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 0.388 SIGNOR-253022 PAK1 protein Q13153 UNIPROT MID1 protein O15344 UNIPROT up-regulates activity phosphorylation 9606 32421151 YES miannu Pak1 phosphorylates the N-terminus of Mid1 to promote its association with cortical nodes.|Pak1 promotes Mid1 localization to cortical nodes. 0.2 SIGNOR-279307 PRKCE protein Q02156 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates activity phosphorylation 9606 17851107 YES miannu At least two TIP60 residues, Thr298 and Ser300, can be targeted in vitro by PKCepsilon.|In vitro, protein kinase C epsilon phosphorylates Tat-interactive protein 60 kDa on at least two sites within the acetyltransferase domain. 0.366 SIGNOR-279309 BLK protein P51451 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 YES lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. 0.437 SIGNOR-249312 HOXD11 protein P31277 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 YES 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. 0.408 SIGNOR-241229 AKT proteinfamily SIGNOR-PF24 SIGNOR SLC2A4 protein P14672 UNIPROT up-regulates 9606 9415393 NO Translocation from intracellular compartment to cell surface in muscle and adipose tissue gcesareni Akt is not only capable of stimulating the translocation of glut4 to the cell surface. Endogenous akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue 0.2 SIGNOR-53968 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 7651411 YES lperfetto However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. 0.511 SIGNOR-236432 TNK2 protein Q07912 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 28739485 YES miannu Since STAT1 and STAT3 are structurally related [3], we also assessed if ACK1 could induce the phosphorylation of STAT3 at residue Y705 (p-STAT3).|Our work demonstrates that catalytically active ACK1 can promote the activation of STAT1 and STAT3.|Here we demonstrate that catalytically active ACK1 induces the tyrosine phosphorylation of STAT1 and STAT3. 0.286 SIGNOR-279312 TTBK1 protein Q5TCY1 UNIPROT DPYSL2 protein Q16555 UNIPROT up-regulates activity phosphorylation Thr514 SVTPKTVtPASSAKT 9606 32019603 YES miannu TTBK1 induces complex formation of pCRMP2 with pTau.|These data suggest that TTBK1-induced T514 CRMP2 phosphorylation is dependent on both S522 phosphorylation by Cdk5 and T555 phosphorylation by RhoK. 0.243 SIGNOR-279313 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19028584 NO miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. 0.469 SIGNOR-254630 TRiC complex SIGNOR-C539 SIGNOR MYC protein P01106 UNIPROT up-regulates quantity by stabilization binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.268 SIGNOR-272872 CIB2 protein O75838 UNIPROT TMC1 protein Q8TDI8 UNIPROT up-regulates activity binding 10090 BTO:0004744 28663585 YES miannu  Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia. 0.334 SIGNOR-269664 CEP152 protein O94986 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 YES lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. 0.278 SIGNOR-271724 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 YES Luana AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions 0.492 SIGNOR-259858 GABRB1 protein P18505 UNIPROT GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.645 SIGNOR-263751 KPNA1 protein P52294 UNIPROT KPNB1 protein Q14974 UNIPROT up-regulates activity binding 9534 17596301 YES lperfetto Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization. 0.86 SIGNOR-260273 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24817118 YES miannu Casein kinase 1-mediated N-terminal Weee1 phosphorylation is required for interaction with the F-box protein β-TrCP.MS/MS spectra of human Wee1 identifying serine 212 as phosphorylated after incubation with recombinant CK1δ. 0.387 SIGNOR-276633 TNK2 protein Q07912 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 28739485 YES miannu Hence, ACK1 activates STAT1 through its kinase activity.|We found that wild-type ACK1 and to a larger extent constitutively active ACK1 increased the phosphorylation of cytoplasmic STAT1 at Y701. 0.358 SIGNOR-278348 TTK protein P33981 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Thr4 tNMSVPTD 9606 26531827 YES miannu In support, the MDM2 Ser307 to Ala mutant was less stable than the wild-type protein when coexpressed with hMps1 (Supplementary Figure S2B and C). hMps1 promotes MDM2-mediated H2B ubiquitination. (A) wild-type but not kinase-dead mutant hMps1 promotes MDM2-mediated H2B ubiquitination. 293T cells were transfected with the indicated plasmids and lysates were prepared for the Ni-NTA bead pulldown assay. 46999999="S307A"}|MDM2 Thr4 and Thr306 are phosphorylated by hMps1 upon oxidative stress. 0.264 SIGNOR-279314 ABL1 protein P00519 UNIPROT ERCC6 protein P0DP91 UNIPROT up-regulates activity phosphorylation 9606 17626041 YES miannu These data raise the possibility that tyrosine phosphorylation of CSB by c-Abl promotes redistribution of CSB in the nucleus and enrichment of CSB in the nucleolus in response to oxidative stress 0.271 SIGNOR-279317 POLA2 protein Q14181 UNIPROT DNA polymerase alpha:primase complex complex SIGNOR-C262 SIGNOR form complex binding -1 24043831 YES lperfetto At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation  0.98 SIGNOR-261342 PRKAG3 protein Q9UGI9 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 16054041 YES gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. 0.72 SIGNOR-139179 PTPA protein Q15257 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 YES gcesareni Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473) 0.2 SIGNOR-252607 RTKs proteinfamily SIGNOR-PF38 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 YES miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase 0.2 SIGNOR-256166 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM1 protein Q13255 UNIPROT up-regulates activity chemical activation 9606 25042998 YES miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate 0.8 SIGNOR-264069 Ribonucleotide reductase complex SIGNOR-C233 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 14583450 NO miannu Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2. 0.7 SIGNOR-259365 BMP1 protein P13497 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates activity cleavage 9534 BTO:0000298 11283002 YES miannu BMP-1myc Expressed in COS-7 Cells Exhibits Procollagen C-proteinase Activity. Bone morphogenetic protein (BMP)-1, which belongs to the tolloid subgroup of astacin-like zinc metalloproteinases, cleaves the C-propeptides of procollagen at the physiologic site and is, therefore, a procollagen C-proteinase (PCP). Cleavage occurs between a specific alanine or glycine residue (depending on the procollagen chain) and an invariant aspartic acid residue in each of the three chains of procollagen. 0.68 SIGNOR-256342 ALK protein Q9UM73 UNIPROT MAPT protein P10636 UNIPROT up-regulates quantity phosphorylation 9606 33452442 YES miannu All these results point to the critical role played by ALK in the phosphorylation and accumulation of tau and in the associated memory impairment seen in 3xTg-AD mice. 0.2 SIGNOR-279318 ATR protein Q13535 UNIPROT FANCI protein Q9NVI1 UNIPROT up-regulates activity phosphorylation 9606 23723247 YES miannu Alternatively, the locally accumulated ATRIP-ATR might have sufficient activity to phosphorylate FANCI without TOPBP1 stimulation.|The results described above and our previous studies clearly indicated that FANCI phosphorylation is mediated by ATR kinase in a manner dependent on the FA core complex and FANCD2 protein. 0.622 SIGNOR-279320 PIK3R4 protein Q99570 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates binding 9606 8999962 YES gcesareni Recombinant p150 associated with ptdins 3-kinase in vitro in a stable manner, resulting in a 2-fold increase in lipid kinase activity. 0.939 SIGNOR-45664 CDK5 protein Q00535 UNIPROT CTNND2 protein Q9UQB3 UNIPROT up-regulates activity phosphorylation 9606 20573893 YES miannu Cdk5 mediated delta-catenin phosphorylation regulates delta-catenin subcellular localization into two distinct pools : a cytoplasmic or intraneurite state as well as a pool that is localized to the membrane.|Cdk5 phosphorylates delta-catenin on serines 300 and 357. 0.327 SIGNOR-279323 CHEK1 protein O14757 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 25486478 YES miannu Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21 Waf1 on T145 and S146 residues and induces its proteasome-dependent proteolysis. 0.532 SIGNOR-279324 SMAD1 protein Q15797 UNIPROT HAND1 protein O96004 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.2 SIGNOR-268936 ATM protein Q13315 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by destabilization phosphorylation Thr166 KNLKLTEtQVKIWFQ 9606 BTO:0002181 23890999 YES miannu ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction. 0.362 SIGNOR-276500 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 21440011 YES lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs 0.91 SIGNOR-252858 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 YES lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 0.2 SIGNOR-252797 DYRK1A protein Q13627 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 19016842 YES miannu Depletion of DYRK1A from human cells by short interfering RNA inhibits the basal phosphorylation of caspase 9 at an inhibitory site, Thr125. DYRK1A-dependent phosphorylation of Thr125 is also blocked by harmine, confirming the use of this beta-carboline alkaloid as a potent inhibitor of DYRK1A in cells.|When co-expressed in cells, DYRK1A interacts with caspase 9, strongly induces Thr125 phosphorylation and inhibits caspase 9 auto-processing. 0.388 SIGNOR-279326 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 YES lperfetto Our data show that BCR-ABL also phosphorylates Grb2 in Tyr160Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation. 0.2 SIGNOR-247146 EGR1 protein P18146 UNIPROT HSD11B2 protein P80365 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15659537 NO miannu Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50. 0.276 SIGNOR-253876 HTR2A protein P28223 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.313 SIGNOR-257021 GFPT1 protein Q06210 UNIPROT Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 21310273 NO miannu GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. 0.7 SIGNOR-267820 IGF1 protein P05019 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates 10090 BTO:0000165;BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 10448861 NO lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. 0.275 SIGNOR-235645 MBTPS1 protein Q14703 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity cleavage 10029 BTO:0000246 10644685 YES We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2 0.56 SIGNOR-267497 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 YES lperfetto Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. 0.684 SIGNOR-251494 PRKAA1 protein Q13131 UNIPROT ULK1 protein O75385 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 SIGNOR-C15 21460634 YES lperfetto Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition. 0.571 SIGNOR-173038 MAPK1 protein P28482 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser178 EENVSDGsPNAGSVE 9606 10831586 YES lperfetto Indeed, p27kip1 was phosphorylated by p42 mapk (erk2) in vitrothese results suggest that ser(10) is the major site of phosphorylation of p27(kip1) and that phosphorylation at this site, like that at thr(187), contributes to regulation of p27(kip1) stability. 0.346 SIGNOR-77655 SATB2 protein Q9UPW6 UNIPROT NR4A2 protein P43354 UNIPROT down-regulates quantity transcriptional regulation 9606 31666685 YES gianni Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development 0.295 SIGNOR-268930 DYRK1A protein Q13627 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates quantity phosphorylation Ser1048 NRTHSLKsPRYLPEE 9606 25368549 YES miannu DYRK1A enhances the surface expression of GluN1 and GluN2A receptors.|Mechanistically, the DYRK1A-dependent phosphorylation of GluN2A at Ser 1048 hinders the internalization of GluN1/GluN2A, causing an increase of surface GluN1/GluN2A in heterologous systems, as well as in primary cortical neurons. 0.398 SIGNOR-279327 EGFR protein P00533 UNIPROT DOCK1 protein Q14185 UNIPROT up-regulates activity phosphorylation Ser1250 HAKLLKWsEDVCVAH 9606 23728337 YES miannu Here we report that EGFRvIII induces serine phosphorylation at serine residue 1250 (S1250) of Dock180 (p-Dock180 S1250 ) and that p-Dock180 S1250 is required for EGFRvIII-promoted Rac1 activation, glioblastoma cell growth, survival and invasion in vitro and in vivo .|We demonstrate that EGFRvIII induces serine phosphorylation of Dock180, stimulates Rac1 activation and glioma cell migration. 0.308 SIGNOR-279329 FAM20C protein Q8IXL6 UNIPROT SDF4 protein Q9BRK5 UNIPROT up-regulates activity phosphorylation 9606 32422653 YES miannu Together, these results indicate that Fam20C kinase activity drives the sorting and secretion of the Cab45 dependent client LyzC.|We show that Fam20C phosphorylates Cab45 on distinct residues and thereby decreases Cab45 retention in the TGN. 0.2 SIGNOR-279330 FGR protein P09769 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation 9606 21746961 YES miannu Fgr associates with Fc\u03b5RI and phosphorylates Syk in antigen-stimulated mast cells.|The overexpression of Fgr stimulates Syk, Syk dependent signaling molecules, and degranulation in RBL-2H3 cells and BMMCs. 0.593 SIGNOR-279332 SATB1 protein Q01826 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000725 23563689 NO miannu Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc 0.396 SIGNOR-224831 LCMT1 protein Q9UIC8 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity methylation Leu309 RRTPDYFl -1 18394995 YES lperfetto Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1) 0.908 SIGNOR-265749 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM65 protein Q6PJ69 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271171 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EWSR1 protein Q01844 UNIPROT unknown phosphorylation 9606 19076070 YES inferred from 70% family members lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2. 0.2 SIGNOR-270172 IKBKB protein O14920 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 11971985 YES We demonstrated the in vitro phosphorylation of SRC-3 by the two catalytic subunits of the IKK complex, IKKα and IKKβ.  IKK kinase activity is required for synergistic activation with SRC-3 0.379 SIGNOR-251298 HIPK2 protein Q9H2X6 UNIPROT DAZAP2 protein Q15038 UNIPROT down-regulates activity phosphorylation 9606 33591310 YES miannu In response to DNA damage, HIPK2 phosphorylates DAZAP2 at several Ser/Thr residues including Ser77, which inhibits its HIPK2-degrading function and targets it to the cell nucleus. 0.2 SIGNOR-279335 GNAS protein P63092 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates activity binding -1 10224115 YES G protein alpha subunits Gi1alpha, Gsalpha, and Goalpha are shown to activate the GTPase activity of tubulin, inhibit microtubule assembly, and accelerate microtubule dynamics. 0.2 SIGNOR-256539 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21157483 YES lperfetto Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism 0.642 SIGNOR-217004 LRRK2 protein Q5S007 UNIPROT NLRC4 protein Q9NPP4 UNIPROT up-regulates activity phosphorylation Ser533 RPLWRQEsLQSVKNT 9606 28821568 YES miannu LRRK2 phosphorylates NLRC4 at Ser533 upon inflammasome activation.|These data suggest that LRRK2 promotes NLRC4 inflammasome activation through its kinase activity. 0.359 SIGNOR-279338 MAP3K14 protein Q99558 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 17543278 YES miannu Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays.|When we transfected NIK into LNCaP cells, NIK was able to phosphorylate Stat3 at both tyrosine 705 and serine 727 residues ( Fig. 3 A). 0.26 SIGNOR-279341 PLK1 protein P53350 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation 9606 28102733 YES miannu Of note, MYC-PLK1 (WT) overexpression strongly enhanced MTOR and RPTOR signals in PLK1 IPs, whereas the LAMP2 signal was strongly decreased (XREF_FIG).|Thus, we conclude that PLK1 can directly phosphorylate RPTOR in vitro. 0.33 SIGNOR-279346 CCNH protein P51946 UNIPROT CAK complex complex SIGNOR-C456 SIGNOR form complex binding 9606 30860024 YES lperfetto CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.961 SIGNOR-269321 SMAD2 protein Q15796 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR form complex binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 YES gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 0.721 SIGNOR-235188 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.708 SIGNOR-252877 CDK1 protein P06493 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 SIGNOR-C17 21902831 YES gcesareni Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis. 0.365 SIGNOR-176505 DYRK2 protein Q92630 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser320 ASPGRPSsVDTLLSP 9606 33268814 YES miannu To test whether in a similar way DYRK2 phosphorylates and activates HSF1 in human cancer cells, we overexpressed DYRK2 and, by use of phosphospecific antibodies, we observed that the levels of endogenous HSF1 phosphorylated at S326 and S320 (two main phosphorylation events linked to HSF1 activation) were increased (Fig.\u00a0 xref ).|Together, these results show that DYRK2 phosphorylates HSF1 in cells and in vitro at S320 and also at S326, which is critical for HSF1 activation.Next, to test whether endogenous DYRK2 plays a role in HSF1 activation by proteotoxic stress, we used the prototypical HSF1 inducer heat shock (HS), in the absence or in the presence of harmine, observing that the inhibitor clearly impaired the phosphorylation of HSF1 upon HS (Fig S1F). 0.318 SIGNOR-278355 DYRK2 protein Q92630 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser326 SSVDTLLsPTALIDS 9606 33268814 YES miannu To test whether in a similar way DYRK2 phosphorylates and activates HSF1 in human cancer cells, we overexpressed DYRK2 and, by use of phosphospecific antibodies, we observed that the levels of endogenous HSF1 phosphorylated at S326 and S320 (two main phosphorylation events linked to HSF1 activation) were increased (Fig.\u00a0 xref ).|Together, these results show that DYRK2 phosphorylates HSF1 in cells and in vitro at S320 and also at S326, which is critical for HSF1 activation.Next, to test whether endogenous DYRK2 plays a role in HSF1 activation by proteotoxic stress, we used the prototypical HSF1 inducer heat shock (HS), in the absence or in the presence of harmine, observing that the inhibitor clearly impaired the phosphorylation of HSF1 upon HS (Fig S1F). 0.318 SIGNOR-278356 ADP chemical CHEBI:16761 ChEBI P2RY12 protein Q9H244 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257560 RPS6KA3 protein P51812 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity phosphorylation Ser140 GKKATQAsQEY 9606 21224359 YES miannu Herein, we found that ribosomal S6 kinase 2 (RSK2) directly phosphorylates histone H2AX at Ser139 and also at a newly discovered site, Ser16.|Phosphorylated RSK2 and histone H2AX colocalized in the nucleus following EGF treatment, and the phosphorylation of histone H2AX by RSK2 enhanced the stability of histone H2AX and prevented cell transformation induced by EGF. 0.2 SIGNOR-279349 TUT7 protein Q5VYS8 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 NO lperfetto Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails. 0.7 SIGNOR-268354 EEF1A2 protein Q05639 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269533 LPAR5 protein Q9H1C0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.413 SIGNOR-256718 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr842 DIMSDSNyVVRGNAR 10090 BTO:0001516 16627759 YES lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. 0.2 SIGNOR-271925 RPS6KA3 protein P51812 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity phosphorylation Ser17 KARAKAKsRSSRAGL 9606 21224359 YES miannu Phosphorylated RSK2 and histone H2AX colocalized in the nucleus following EGF treatment, and the phosphorylation of histone H2AX by RSK2 enhanced the stability of histone H2AX and prevented cell transformation induced by EGF.|Phosphorylation of H2AX at Ser139 and a new phosphorylation site Ser16 by RSK2 decreases H2AX ubiquitination and inhibits cell transformation. 0.2 SIGNOR-279350 STK33 protein Q9BYT3 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 9606 30760631 YES miannu In vitro kinase assay results indicated that STK33 can phosphorylate ERK2.|STK33 phosphorylated ERK2 and increased the activity of ERK2 and promote the tumorigenesis of colorectal cancer HCT15 cells. 0.273 SIGNOR-279351 TTK protein P33981 UNIPROT ARHGEF17 protein Q96PE2 UNIPROT down-regulates activity phosphorylation 9606 26953350 YES miannu Because Mps1 also phosphorylates ARHGEF17, the Mps1\u2013ARHGEF17 complex is short lived and promotes its own dissociation, which in turn releases Mps1 and ARHGEF17 from the kinetochore.|ARHGEF17 and Mps1 interact during mitosis and Mps1 phosphorylates ARHGEF17. 0.2 SIGNOR-279352 CDC7 protein O00311 UNIPROT CLSPN protein Q9HAW4 UNIPROT up-regulates activity phosphorylation 9606 27401717 YES miannu Cdc7 phosphorylates Claspin in a manner dependent on AP and inhibits N\u2013C interaction.|Thus, Cdc7-ASK may activate DNA and PCNA bindings of Claspin through AP-mediated phosphorylation. 0.742 SIGNOR-279360 PRKCD protein Q05655 UNIPROT DAP3 protein P51398 UNIPROT up-regulates phosphorylation Thr237 ITRVRNAtDAVGIVL 9606 18227431 YES amattioni Dap3 is phosphorylated by protein kinase cdelta on thr237. Dap3 was originally identified as a pro-apoptotic protein. The mutation of the phosphorylation site thr237 to alanine reversed the cell death caused by the wild-type dap3 0.2 SIGNOR-160488 AKT proteinfamily SIGNOR-PF24 SIGNOR DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 22298955 YES lperfetto Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. 0.2 SIGNOR-244228 PTMS protein P20962 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 BTO:0000567 16150697 YES miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells. 0.322 SIGNOR-268461 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser2 sLKNEPRV 9606 10441128 YES gcesareni Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells. 0.713 SIGNOR-69930 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser424 CDEEFSDsEDEGEGG 9606 BTO:0000567 12082111 YES llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. 0.619 SIGNOR-250888 TNIK protein Q9UKE5 UNIPROT NF2 protein P35240 UNIPROT up-regulates activity phosphorylation Thr272 SYSDKEFtIKPLDKK 9606 33495197 YES miannu Consistently with TNIK modulating Merlin, we also observed reduced YAP levels following TNIK knockdown in LK2 and NCI-H520 cells (Supplementary Fig. S7B).|Using in vitro kinase assays followed by phosphopeptide mapping, and mass spectrometry analysis on Merlin isolated from cells co-expressing TNIK and Merlin, we determined that TNIK could phosphorylate Merlin at S13, T272, S315, and T576 (Fig. 4B, Supplementary Fig. S4D, and Supplementary Table S3). 0.2 SIGNOR-278386 MAPK14 protein Q16539 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates activity phosphorylation 10090 20551513 YES ggiuliani Mechanistic analysis revealed that the TAK1–MKK3/6–p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38β and establish that MAPK signaling is essential for bone formation in vivo. 0.367 SIGNOR-255777 AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT down-regulates activity phosphorylation Ser792 CVRMRHLsQEFGWLQ 9534 BTO:0001538 11404460 YES lperfetto Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790 0.2 SIGNOR-244136 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM74 protein Q86UV6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271186 E2F1 protein Q01094 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 NO lperfetto In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F 0.7 SIGNOR-245477 (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity precursor of 9606 18767138 YES lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate 0.8 SIGNOR-268247 8-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:91845 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258860 ECM stimulus SIGNOR-ST20 SIGNOR A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259045 MELK protein Q14680 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity phosphorylation 9606 28938528 YES miannu Further analysis indicated that FOXO1 and FOXO3, two known transcriptional regulators of p21, were phosphorylated by MELK and thus be involved in the induction of p21 after MELK inhibition.|Our findings revealed that siRNA mediated MELK knockdown increased protein levels of FOXO1 and FOXO3, which might increase p21 transcriptional level in a p53 independent manner. 0.362 SIGNOR-279375 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Tyr424 GQVGTARyMAPEVLE -1 9169454 YES lperfetto Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor. 0.2 SIGNOR-48867 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0001538 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.718 SIGNOR-219353 A3/b1 integrin complex SIGNOR-C161 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.617 SIGNOR-257703 GRIPAP1 protein Q4V328 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 BTO:0002181;BTO:0000142 17761173 YES Giorgia To examine whether GRASP‐1 interacts with MEKK1 and JNK1 in neurons, co‐immunoprecipitation experiments were performed with detergent‐solubilized extracts from cultured cortical neurons. Both antiJNK1 and anti‐MEKK1 antibodies immunoprecipitated GRASP‐1 from neuronal lysates. These results suggest that GRASP‐1 interacts with MEKK1 and JNK1 in neurons. GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1. 0.311 SIGNOR-260639 CAMKK2 protein Q96RR4 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 15980064 YES gcesareni These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. 0.619 SIGNOR-138364 PLK1 protein P53350 UNIPROT REST protein Q13127 UNIPROT down-regulates activity phosphorylation Ser1030 MSEGSDDsGLHGARP 9606 25453754 YES miannu Mass spectrometry revealed that PLK1 phosphorylates REST on serine-1030 ( xref and xref ).|Notably, PLK1 depletion significantly increased REST protein half-life (XREF_FIG, XREF_SUPPLEMENTARY), indicating PLK1 antagonizes REST abundance by restraining REST protein stability. 0.309 SIGNOR-279380 PLK1 protein P53350 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity phosphorylation Ser486 SRGMLDRsRLALCTL 9606 27579997 YES miannu As illustrated in , the turnover of nuclear SREBP1a was attenuated in the presence of Plk1, confirming that Plk1 stabilizes nuclear SREBP1 by reducing its degradation.|Figure 2.Plk1 phosphorylates threonine 424, serine 467 and serine 486 in nuclear SREBP1 during mitosis. (A) In vitro kinase assay with recombinant nuclear SREBP1a and Plk1. 0.442 SIGNOR-279383 PRKCA protein P17252 UNIPROT DOCK8 protein Q8NF50 UNIPROT down-regulates activity phosphorylation 9606 28028151 YES miannu In response to chemokine stimulation, PKC\u03b1 phosphorylates DOCK8 at its three serine sites, promoting DOCK8 separation from LRCH1 and translocation to the leading edge to guide T cell migration.|Taken our data together, we suggest that PKC\u03b1 phosphorylates DOCK8 at the Ser2077/2082/2087 sites to promote T cell migration. 0.2 SIGNOR-279384 PTPN6 protein P29350 UNIPROT CD72 protein P21854 UNIPROT down-regulates dephosphorylation 9606 BTO:0000776 9740800 YES gcesareni Our work clearly identifies cd72 as both an shp-1 binding protein (figure 1,figure 2) and a direct substrate for shp-1 in vivo (figure 3). As tyrosine phosphorylation of cd72 strongly correlates with the ability of the bcr to deliver growth-inhibitory/apoptosis-inducing signals (figure 4), our results suggest that shp-1-catalyzed dephosphorylation of cd72 may antagonize these signals. 0.622 SIGNOR-60155 DYRK1B protein Q9Y463 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr288 VDLACTPtDVRDVDI 9606 BTO:0000567 17046823 YES lperfetto Further, we found that not only gsk-3beta but also dyrk1b modulates cyclin d1 subcellular localization by the phosphorylation of thr(288). These results suggest that dif-3 induces degradation of cyclin d1 through the gsk-3beta- and dyrk1b-mediated threonine phosphorylation in hela cells 0.411 SIGNOR-150126 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser38 EGRQPSPsPSPTERA 9606 BTO:0001271 15093545 YES The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). 0.36 SIGNOR-124244 ABL1 protein P00519 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity phosphorylation Tyr211 QLTFALRyLNFFTKA 9606 23542172 YES miannu In the current study, we are able to establish a new pathway in which the Ron receptor tyrosine kinase activates c-Abl which in turn catalyzes Y211 phosphorylation of PCNA.|We previously showed that Y211 phosphorylation stabilized chromatin bound PCNA, which in turn promoted cell proliferation, and that c-Abl functioned to enhance chromatin association of PCNA in cancer cells. 0.334 SIGNOR-279389 ABL1 protein P00519 UNIPROT WASF2 protein Q9Y6W5 UNIPROT up-regulates activity phosphorylation Tyr150 GKEALKFyTDPSYFF 9606 16899465 YES miannu Furthermore, Abl phosphorylates WAVE2 on tyrosine 150, and WAVE2 deficient cells rescued with a Y150F mutant fail to regain their ability to ruffle and form microspikes, unlike cells rescued with wild-type WAVE2.|Together, these data show that c-Abl activates WAVE2 via tyrosine phosphorylation to promote actin remodeling in vivo and that Abi-1 forms the crucial link between these two factors. 0.697 SIGNOR-279390 ARAF protein P10398 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 23591895 YES miannu Araf promotes Smad2 linker phosphorylation through S253.|In this study, we demonstrate that Araf can directly bind to and phosphorylate the linker of Smad2, leading to degradation of activated Smad2. 0.37 SIGNOR-279391 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR IKZF1 protein Q13422 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0003933 24292625 YES miannu We found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. 0.371 SIGNOR-272083 AKT1 protein P31749 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 YES lperfetto Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212 0.323 SIGNOR-252500 IRX1 protein P78414 UNIPROT COL9A3 protein Q14050 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.2 SIGNOR-261653 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser313 QRVPSFEsFEDDCSQ 9606 19182667 YES lperfetto Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters 0.2 SIGNOR-183604 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1766 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248778 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PARP10 protein Q53GL7 UNIPROT up-regulates activity phosphorylation Thr101 QGLPPGTtPQRLEQH -1 16455663 YES miannu The PARP activity of PARP10 depends on phosphorylation by CDK2-cyclin E in vitro. CDK-phosphorylated PARP10 is absent in growth-arrested cells. These results suggest that PARP10 functions in cell proliferation and may serve as a marker for proliferating cells.our results suggest that nucleolar PARP10 acquires CDK2-cyclin E-dependent phosphorylation at the Thr-101 residue. 0.3 SIGNOR-273594 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL 26933062 YES lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. 0.389 SIGNOR-276590 RFX2 protein P48378 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 10090 32725242 NO miannu RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process. 0.7 SIGNOR-266928 ATM protein Q13315 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by stabilization phosphorylation Ser140 PKTDPSDsQTGLAEQ 9606 27611996 YES miannu We also uncovered that ATM phosphorylates p27Kip1 on a previously uncharacterized residue (Ser-140), which leads to its stabilization after induction of DNA double-strand breaks. 0.419 SIGNOR-279392 BUB1B protein O60566 UNIPROT APC protein P25054 UNIPROT up-regulates activity phosphorylation 9606 17709426 YES miannu These findings support a model in which BubR1 kinase may directly regulate APC function involved in stable kinetochore microtubule attachment.|Using purified components, BubR1 directly phosphorylates APC and forms a ternary complex with APC and microtubules. 0.429 SIGNOR-279393 CDK1 protein P06493 UNIPROT SIRT3 protein Q9NTG7 UNIPROT up-regulates activity phosphorylation Thr150 MVGAGIStPSGIPDF 9606 26141949 YES miannu Both SIRT3 T150 and S159 phosphorylated by CDK1 indicates that CDK1-SIRT3 pathway may play a role in the overall mitochondrial protein acetylation involved in mitochondrial homeostasis and apoptosis. 0.315 SIGNOR-279395 CDK1 protein P06493 UNIPROT SIRT3 protein Q9NTG7 UNIPROT up-regulates activity phosphorylation Ser159 SGIPDFRsPGSGLYS 9606 26141949 YES miannu Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. 0.315 SIGNOR-279396 α-D-glucose smallmolecule CHEBI:17925 ChEBI GCG protein P01275-PRO_0000011258 UNIPROT up-regulates quantity 9606 BTO:0000783 31693916 YES miannu GIP and GLP-1 were classified as incretin1 hormones since they are secreted in response to glucose ingestion and augment glucose-induced insulin secretion 0.8 SIGNOR-278135 α-D-glucose smallmolecule CHEBI:17925 ChEBI GIP protein P09681 UNIPROT up-regulates quantity 9606 BTO:0000783 31693916 YES miannu GIP and GLP-1 were classified as incretin1 hormones since they are secreted in response to glucose ingestion and augment glucose-induced insulin secretion 0.8 SIGNOR-278136 Inflammation phenotype SIGNOR-PH12 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 NO miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. 0.7 SIGNOR-261036 SP3 protein Q02447 UNIPROT CADM1 protein Q9BY67 UNIPROT up-regulates quantity by expression transcriptional regulation 18794147 NO lperfetto Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation. 0.27 SIGNOR-268959 ETV6 protein P41212 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15958056 NO Regulation of expression miannu Upon erythropoietin exposure, overexpressed TEL stimulated hemoglobin synthesis 0.2 SIGNOR-251794 NEFM protein P07197 UNIPROT Neurofilament bundle assembly phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 8376466 NO miannu Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons. 0.7 SIGNOR-252391 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BW2 protein P0C1H6 UNIPROT down-regulates activity monoubiquitination Lys35 ANSTKAQkQKRRGCR 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271981 CHEK2 protein O96017 UNIPROT NEK6 protein Q9HC98 UNIPROT down-regulates activity phosphorylation -1 18728393 YES miannu Nek6 is also directly phosphorylated by the checkpoint kinases Chk1 and Chk2 in vitro . 0.229 SIGNOR-279404 CNOT9 protein Q92600 UNIPROT GIGYF1 protein O75420 UNIPROT up-regulates activity binding 9606 BTO:0000007 20878056 YES miannu Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2 0.2 SIGNOR-260059 AMPK complex SIGNOR-C15 SIGNOR PPP1R3C protein Q9UQK1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser33 MRLCLAHsPPVKSFL 9606 BTO:0000007 19171932 YES miannu We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.  0.284 SIGNOR-276237 WEE1 protein P30291 UNIPROT PTP4A1 protein Q93096 UNIPROT down-regulates activity phosphorylation 9606 33450002 YES miannu In this study , we found that WEE1 phosphorylates PRL1 and promotes PRL1 degradation .|In this study, we demonstrated that WEE1 phosphorylates and inhibits PRL1 to regulate alternative splicing of CYCD1;1 and CYCD3;1 , which may represent a new cell cycle control mechanism. 0.2 SIGNOR-278434 MAPK14 protein Q16539 UNIPROT JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10330170 NO gcesareni Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. 0.501 SIGNOR-67535 CDK5 protein Q00535 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation 9606 26894912 YES miannu TNF-alpha overexpression increased Cdk5-mediated phosphorylation of TRPV1 at T407.|These results suggest that the activation of Cdk5 by p35 enhances the response of TRPV1 to capsaicin, probably by phosphorylation of the channel [34]. 0.2 SIGNOR-278437 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI L-alanine zwitterion smallmolecule CHEBI:57972 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. 0.8 SIGNOR-268122 PTPN5 protein P54829 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates activity dephosphorylation Tyr26 IPEGSHQyELLKHAE 9606 28675297 YES miannu PTPN5 dephosphorylates\nMob1a at Y26 residue. 0.2 SIGNOR-277058 dimethyloxalylglycine chemical CHEBI:102218 ChEBI EGLN2 protein Q96KS0 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000018 28900510 YES lperfetto We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1. 0.8 SIGNOR-261992 sorafenib chemical CHEBI:50924 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258283 ERBB2 protein P04626 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation 9606 19275932 YES miannu In this study, we show that Abl kinase SH2 domains bind directly to Her-2, and like PDGFR-beta, Her-2 directly phosphorylates c-Abl. 0.374 SIGNOR-279407 FYN protein P06241 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates activity phosphorylation 9606 16860569 YES miannu Here, we demonstrate that Fyn can directly phosphorylate the intracellular domain of TrkA and that its kinase activity towards Trk is increased by GPCR stimulation ( Fig. 4 ). 0.254 SIGNOR-279410 GRK2 protein P25098 UNIPROT PDC protein P20941 UNIPROT down-regulates activity phosphorylation 9606 10884381 YES miannu Phosphorylation of phosducin by GRK2 markedly reduces its G beta gamma binding ability|The phosphorylation of purified phosducin and PhLP by recombinant GRK2 proceeds rapidly and stoichiometrically (0.82 +/- 0.1 and 0.83 +/- 0.09 mol of P(i)/mol of protein, respectively). 0.2 SIGNOR-279411 NPLOC4 protein Q8TAT6 UNIPROT RQC complex complex SIGNOR-C559 SIGNOR form complex binding 28528489 YES lperfetto The ribosome-bound quality control (RQC) complex is a multi-protein complex conserved throughout eukaryotes and composed of the E3 ubiquitin ligase Ltn1/Listerin, the ATPase Cdc48/p97 with its co-factors Ufd1/UFD1L and Npl4/NPLOC4, as well as the factors Rqc1/TCF25 and Rqc2/NEMF (Fig. 1). 0.537 SIGNOR-277697 GRK6 protein P43250 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation 9606 19801552 YES miannu In contrast to the GRK5 and GRK6 stimulated activity of wild-type LRP6, the LRP6 M5 mutant failed to respond to the expression of GRK5 or GRK6 (XREF_FIG C) by increased TOPflash reporter activity, indicating that PPPSP motifs are indispensable for GRK5- and GRK6 mediated LRP6 activation.|Our findings that GRK5 and GRK6 phosphorylate the single membrane-spanning receptor LRP6 on defined serine/threonine sites ( i.e. serine 1490) within proline-rich PPPSP motifs and thereby activate LRP6 are important and interesting in two respects. 0.345 SIGNOR-279412 AREL1 protein O15033 UNIPROT SEPTIN4 protein O43236 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23479728 YES lperfetto Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists 0.2 SIGNOR-267670 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation Ser52 MILLSELsRRRIRSI 9606 30070006 YES gcesareni The integrated stress response is characterized by the phosphorylation of eukaryotic initiation factor-2α (eIF2α) on serine 51 by one out of four specific kinases (EIF2AK1 to 4) 0.765 SIGNOR-246153 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 19115199 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-182992 NR3C1 protein P04150 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9600 BTO:0000567 26652733 YES inferred from family member Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB 0.2 SIGNOR-270258 MAP2K1 protein Q02750 UNIPROT MYRF protein Q9Y2G1 UNIPROT down-regulates activity phosphorylation 9606 30496175 YES miannu Mek1 phosphorylation of Ndt80 therefore provides an elegant way for cells to know when it is safe to enter the first meiotic division.|These observations suggest that phosphorylation of the DBD by Mek1 prevents Ndt80 from binding to MSEs and explains how Mek1 phosphorylation can inhibit Ndt80 activity. 0.258 SIGNOR-279416 MAP3K11 protein Q16584 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser204 TKSVYTRsVIEPLPV 9606 30664689 YES miannu Although, MLK3 can phosphorylate PAK1 on Ser133 and Ser204 sites, PAK1S133A mutant is constitutively active, whereas, PAK1S204A is not activated by MLK3.|MLK3 was able to directly phosphorylate PAK1 on two Serine residues of which Ser204 is critical for MLK3-induced PAK1 activation and downstream functions. 0.304 SIGNOR-279417 MAP3K11 protein Q16584 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser133 DVLEFYNsKKTSNSQ 9606 30664689 YES miannu Although, MLK3 can phosphorylate PAK1 on Ser133 and Ser204 sites, PAK1S133A mutant is constitutively active, whereas, PAK1S204A is not activated by MLK3.|MLK3 was able to directly phosphorylate PAK1 on two Serine residues of which Ser204 is critical for MLK3-induced PAK1 activation and downstream functions. 0.304 SIGNOR-279418 GNAS protein P63092 UNIPROT HCK protein P08631 UNIPROT up-regulates activity binding -1 11007482 YES Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases. 0.2 SIGNOR-256529 PLK2 protein Q9NYY3 UNIPROT APP protein P05067 UNIPROT up-regulates activity phosphorylation Thr743 VEVDAAVtPEERHLS 9606 28257888 YES miannu Here we show that Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic plasticity, directly binds and phosphorylates threonine-668 and serine-675 of APP in\u00a0vitro and associates with APP in\u00a0vivo.|Plk2 was necessary and sufficient to induce BACE-1-mediated APP amyloidogenic processing following overexcitation, associated intimately with APP, and directly phosphorylated the APP C-terminus. 0.348 SIGNOR-279424 SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 YES lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. 0.665 SIGNOR-44866 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation 9606 BTO:0000130 16778989 YES inferred from 70% family members gcesareni Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells. 0.2 SIGNOR-270091 RAPGEF4 protein Q8WZA2 UNIPROT INS protein P01308 UNIPROT up-regulates quantity relocalization 9606 BTO:0000783 24843404 YES miannu Activation of EPAC2 has recently been shown to increase the density of insulin‐containing granules near the plasma membrane, facilitating insulin secretion from the β cells 0.377 SIGNOR-278140 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14585074 NO Nuclear p53 amattioni Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53 0.646 SIGNOR-113707 RPL10A protein P62906 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.851 SIGNOR-262489 CDX1 protein P47902 UNIPROT VIL1 protein P09327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19371634 NO miannu We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter. 0.296 SIGNOR-185483 SRC protein P12931 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity phosphorylation 9606 24582588 YES miannu Given that VPS34 is activated by Src mediated tyrosine phosphorylation, we next determined if VPS34 was tyrosine phosphorylated following insulin treatment.|These data indicate that VPS34 is an effector of insulin-mediated signal transduction and that Src phosphorylation of VPS34 is required for this function. 0.42 SIGNOR-278456 PRKCA protein P17252 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity phosphorylation Ser111 TPEGRRTsRRKRAKV 9606 29395062 YES miannu Together, these data indicate that LPS-induced LSD1 phosphorylation by PKC\u03b1 is required for its interaction with p65 in the nucleus.|We have previously reported that LSD1 is phosphorylated by PKCalpha on serine 112 site, and knockin mice bearing phosphorylation defective Lsd1 SA/SA alleles show altered circadian rhythms and impaired phase resetting (Nam et al., 2014). 0.352 SIGNOR-279425 PRKCD protein Q05655 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 23473759 YES miannu This pathway is triggered by activation of PKCdelta, and activated PKCdelta enhanced the phosphorylation of C/EBPalpha, which consequently led to its cytoplasmic translocation, transcriptional inactivation, ubiquitination and degradation. 0.2 SIGNOR-279426 PRKD1 protein Q15139 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation 9606 28716882 YES miannu PKD at the Golgi phosphorylates NLRP3 to release it from mitochondria-associated endoplasmic reticulum membranes, allowing for assembly of the mature inflammasome in the cytosol.|These data thus suggest that PKD activity at the Golgi is sufficient to activate the NLRP3 inflammasome. 0.332 SIGNOR-279428 DUOX2 protein Q9NRD8 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.8 SIGNOR-264727 PLK3 protein Q9H4B4 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Thr80 RMGSSEStDSGFCLD 9606 18167338 YES lperfetto Here, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cdc25a to promote its proteolysis in early cell-cycle phases. Phosphorylation by gsk-3beta requires priming of cdc25a, and this can be catalyzed by polo-like kinase 3 (plk-3) 0.384 SIGNOR-160228 EGFR protein P00533 UNIPROT KRT14 protein P02533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11875647 NO Regulation of expression miannu UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK. 0.459 SIGNOR-251901 calcium(2+) smallmolecule CHEBI:29108 ChEBI Cadherins proteinfamily SIGNOR-PF71 SIGNOR up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265811 FBXO4 protein Q9UKT5 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates binding 9606 BTO:0000007 29142209 YES miannu Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinomaThe Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4.  0.627 SIGNOR-272796 RBPJ protein Q06330 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression binding 9606 BTO:0000938 10520600 YES gcesareni These results indicate that the two Hes genes are essential effectors for the Notch pathway and that neuronal differentiation is controlled by the pathway Notch-Hes1/Hes5-|Mash1. 0.598 SIGNOR-71168 CSNK2A2 protein P19784 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Ser45 LFRLSEHsSPEEEAS -1 2557337 YES llicata Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase 0.376 SIGNOR-251019 PRKCE protein Q02156 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 YES miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 0.2 SIGNOR-276050 ULK1 protein O75385 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser792 DKMRRASsYSSLNSL 9606 25761126 YES miannu ULK1 phosphorylates RPTOR at S792, S855, and S859.|When active, ULK1 inhibits MTOR complex 1 through phosphorylation of RPTOR, which has the effect of limiting RPTOR-mediated recruitment of MTOR substrates to MTOR complex 1 [ ]. 0.703 SIGNOR-278461 vorinostat chemical CHEBI:45716 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257922 YES1 protein P07947 UNIPROT ANXA2 protein P07355 UNIPROT up-regulates activity phosphorylation Tyr24 HSTPPSAyGSVKAYT 9606 33941853 YES miannu Activated YES1 interacts with ANXA2 andphosphorylates ANXA2 at Tyr24 site that induces ANXA2 activation and increases ANXA2 nuclear distribution , leading to activation of the tumorpromoting transcription factors ( such as Myc , Stat3 , Stat6 ) that promotes GC invasion and metastasis .|YES1 phosphorylates ANXA2 at Tyr24 site that leads to ANXA2 activation and increased ANXA2 nuclear distribution. 0.2 SIGNOR-279435 GDF11 protein O95390 UNIPROT ACTR2 protein P61160 UNIPROT up-regulates binding 9606 16446785 YES gcesareni Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2. 0.2 SIGNOR-144147 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.411 SIGNOR-252884 GSK3B protein P49841 UNIPROT CLASP2 protein O75122 UNIPROT down-regulates activity phosphorylation Ser533 QGCSREAsRESSRDT 9534 BTO:0004055 19638411 YES lperfetto GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells 0.516 SIGNOR-264825 AURKA protein O14965 UNIPROT ARPC1B protein O15143 UNIPROT up-regulates activity phosphorylation Thr21 HAWNKDRtQIAICPN 9606 20603326 YES miannu Aurora A phosphorylates Arpc1b on threonine 21, and expression of Arpc1b but not a nonphosphorylatable Arpc1b mutant in mammalian cells leads to Aurora A kinase activation and abnormal centrosome amplification in a Pak1-independent manner. 0.46 SIGNOR-279438 NTSR1 protein P30989 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 10030 BTO:0000457 28341345 YES Marta Tosoni Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways 0.47 SIGNOR-278058 PPP2CA protein P67775 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates dephosphorylation Ser24 APIRRRSsNYRAYAT 9606 BTO:0000887 15769444 YES lperfetto The major phosphatase thought to dephosphorylate ctni and phospholamban is type 2a protein phosphatase (pp2a) [61]. Activation of pp2a and ensuing dephosphorylation of regulatory proteins is involved in the anti-adrenergic effects of adenosine and muscarinic receptor activation see also fig2. 0.4 SIGNOR-134601 CDK7 protein P50613 UNIPROT ERCC3 protein P19447 UNIPROT down-regulates quantity by destabilization phosphorylation Ser90 HIFLEAFsPVYKYAQ 9606 BTO:0000567 30762924 YES miannu These results led us to propose a model that spironolactone may trigger the phosphorylation of XPB at Ser90 by CDK7, which promotes the recognition and polyubiquitination of XPB by SCFFBXL18 for proteasomal degradation. 0.895 SIGNOR-277433 MECP2 protein P51608 UNIPROT TFF1 protein P04155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 15870696 NO miannu Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters 0.2 SIGNOR-254572 DRAP1 protein Q14919 UNIPROT NC2 complex complex SIGNOR-C108 SIGNOR form complex binding 9606 BTO:0000567 18838386 YES miannu NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex 0.751 SIGNOR-226402 NDUFB6 protein O95139 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 0.829 SIGNOR-262169 BTK protein Q06187 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates activity phosphorylation Ser215 RSYKQRSsLEEHKER 9606 23977012 YES miannu We demonstrate that BTK phosphorylates Ikaros at unique phosphorylation sites S214 and S215 in the close vicinity of its zinc finger 4 (ZF4) within the DNA binding domain, thereby augmenting its nuclear localization and sequence-specific DNA binding activity. 0.432 SIGNOR-279442 CDK1 protein P06493 UNIPROT CHMP7 protein Q8WUX9 UNIPROT down-regulates activity phosphorylation Ser441 GLVPSSKsPKRQLEP 9606 34286694 YES miannu We found that recombinant CHMP7 could be directly phosphorylated by CDK1/CCNB1 in vitro and that CDK1-phosphorylation reduced the capacity of CHMP7 to sediment (Figure 4A and B).|We identified direct CDK1 phosphorylation of CHMP7 at Ser3 and Ser441 as a suppressor of both CHMP7\u2019s ability to interact with LEM2 and its ability to assemble, as judged by sedimentation assays. 0.2 SIGNOR-279445 DARS1 protein P14868 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.2 SIGNOR-270362 CDK1 protein P06493 UNIPROT CHMP7 protein Q8WUX9 UNIPROT down-regulates activity phosphorylation Ser3 sPEREAEA 9606 34286694 YES miannu We found that recombinant CHMP7 could be directly phosphorylated by CDK1/CCNB1 in vitro and that CDK1-phosphorylation reduced the capacity of CHMP7 to sediment (Figure 4A and B).|We identified direct CDK1 phosphorylation of CHMP7 at Ser3 and Ser441 as a suppressor of both CHMP7\u2019s ability to interact with LEM2 and its ability to assemble, as judged by sedimentation assays. 0.2 SIGNOR-279446 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr95 KFPECGFyGMYDKIL 9606 17804414 YES llicata Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation. 0.412 SIGNOR-157716 PKA proteinfamily SIGNOR-PF17 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000783 35065096 YES miannu Additionally, PKA activates transducer of regulated CREB (TORC2) and cAMP response element-binding protein (CREB), which leads to beta cell proliferation through CREB- and TORC2-mediated IRS2 gene expression 0.346 SIGNOR-278149 mTORC2 complex SIGNOR-C2 SIGNOR IRS2 protein Q9Y4H2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000783 35065096 YES miannu Additionally, PKA activates transducer of regulated CREB (TORC2) and cAMP response element-binding protein (CREB), which leads to beta cell proliferation through CREB- and TORC2-mediated IRS2 gene expression 0.402 SIGNOR-278150 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.546 SIGNOR-270908 8-OH-DPAT chemical CHEBI:73364 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258890 OGDH protein Q02218 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 YES miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. 0.741 SIGNOR-266255 FYN protein P06241 UNIPROT CYTH1 protein Q15438 UNIPROT up-regulates activity phosphorylation 9606 26224309 YES miannu Fyn directly binds, phosphorylates, and activates cytohesin-1. 0.395 SIGNOR-280015 RARG protein P13631 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 15650024 YES lperfetto We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs 0.417 SIGNOR-133237 CDK5 protein Q00535 UNIPROT PPP1R9B protein Q96SB3 UNIPROT down-regulates quantity phosphorylation Ser17 GGPLRSAsPHRSAYE 9606 29786422 YES miannu CDK5 decreased the expression of both spinophilin (30%) and neurabin (64%).|This suggests that CDK5 phosphorylation of spinophilin at Ser17 is not responsible for the CDK5 dependent increase in the spinophilin and PP1 association. 0.396 SIGNOR-279453 CDK7 protein P50613 UNIPROT CDK9 protein P50750 UNIPROT up-regulates activity phosphorylation Thr186 NSQPNRYtNRVVTLW 9606 23064645 YES miannu Cdk7 activates Cdk9 in vitro .|Cdk7 phosphorylates wild-type Cdk9 on Thr186, resulting in increased activity towards a recombinant GST-Spt5 substrate. 0.549 SIGNOR-279455 SKP2 protein Q13309 UNIPROT NUDT1 protein P36639 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0005713 28947420 YES miannu Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination.  0.253 SIGNOR-272790 CSNK1A1 protein P48729 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1248 AADSGRGsWTSCSSG 9606 BTO:0002181 24290981 YES miannu Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. 0.2 SIGNOR-276604 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser439 SIGHSPLsLSAQSVM 9606 BTO:0000938 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.542 SIGNOR-204704 CDK1 protein P06493 UNIPROT RPA2 protein P15927 UNIPROT up-regulates activity phosphorylation Ser23 GAGGYTQsPGGFGSP 9606 1318195 YES llicata Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell 0.508 SIGNOR-16971 Ub:E2 complex SIGNOR-C497 SIGNOR MKRN1 protein Q9UHC7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271234 EGFR protein P00533 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr542 SKRKGHEyTNIKYSL 9606 19427850 YES miannu EGFRvIII transformation may be due to the enhanced PTPase activity from higher basal SHP-2 Tyr542 phosphorylation induced by EGFRvIII ( xref ).|These results suggest that EGFRvIII expression recruits SHP-2 to an activated complex and induces SHP-2 Tyr542 and its PTPase activity in GBM cells. 0.869 SIGNOR-279460 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 YES lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. 0.2 SIGNOR-244743 N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity precursor of 9606 22812634 YES miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case 0.8 SIGNOR-268067 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity cleavage 9606 25610395 YES lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins. 0.677 SIGNOR-254328 ADRB2 protein P07550 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 14500986 YES We have found that signaling via the erythrocyte beta2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (Galphas) regulated the entry of the human malaria parasite Plasmodium falciparum. 0.659 SIGNOR-256149 ATR protein Q13535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates phosphorylation Ser179 FRPEYSAsQLKGFSL 9606 33811702 YES miannu Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments.|These data suggest that the phosphorylation of S179 is necessary and sufficient for ATR inhibition of PARP1 PARylation activity. 0.357 SIGNOR-278506 GRK2 protein P25098 UNIPROT ADIPOR1 protein Q96A54 UNIPROT down-regulates activity phosphorylation 9606 25696921 YES miannu AdipoR1 is Directly Phosphorylated by GRK2.|In summary, our study demonstrates for the first time that cardiometabolic-regulatory, anti-inflammatory, and cardioprotective functions of APN are significantly impaired by GRK2 mediated AdipoR1 phosphorylative desensitization during a critical period of post-MI HF development. 0.2 SIGNOR-279463 MAP4K1 protein Q92918 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 YES gcesareni Hpk1 binds and phosphorylates mekk1 directly, 0.453 SIGNOR-43996 ATM protein Q13315 UNIPROT DYRK2 protein Q92630 UNIPROT up-regulates quantity by stabilization phosphorylation Thr106 NKRTVLTtQPNGLTT 19965871 YES Phosphosites were derived from Figure 3 lperfetto ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. 0.556 SIGNOR-275576 SIRT7 protein Q9NRC8 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity deacetylation Lys19 TGGKAPRkQLATKAA 22722849 YES lperfetto SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation.|Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. 0.2 SIGNOR-275874 double-stranded DNA chemical CHEBI:4705 ChEBI BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 YES lperfetto The BRCA1‚ÄìC complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 0.8 SIGNOR-269477 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258098 GSK3B protein P49841 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr7 tPCSSMSN 9606 22142472 YES miannu Our results indicate that that GSK-3\u03b2 inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress.|Second, we demonstrated that GSK-3beta interacted with STK38, that GSK-3beta phosphorylated residues S6 and T7 of STK38 (and did so efficiently following PKA pretreatment), and that mutations at two priming phosphorylation sites (S10 and S11) attenuated the phosphorylation of two other sites S6/T7 by GSK-3 in vitro. 0.278 SIGNOR-279464 HOPX protein Q9BPY8 UNIPROT FLG protein P20930 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 21256618 NO miannu In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation. 0.2 SIGNOR-254463 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser1934 LFRQQAGsGLSEEDA 28882890 YES Phosphosite is derived from Figure 2 lperfetto C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation| Of 19 native NaV1.5 phosphorylation sites identified, two C-terminal phosphoserines at positions 1938 and 1989 showed increased phosphorylation in the CaMKIIδc-Tg compared with the WT ventricles. 0.491 SIGNOR-275782 EZH2 protein Q15910 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 NO miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. 0.33 SIGNOR-254151 RASSF5 protein Q8WWW0 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity binding 9606 22195963 YES lperfetto NORE1A can bind K-Ras.GTP through its RA domain and regulate the proapoptotic activity of MST1/2 kinases 0.69 SIGNOR-249586 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 12213813 YES lperfetto In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E 0.67 SIGNOR-262992 tRNA(Arg) smallmolecule CHEBI:29171 ChEBI Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270369 MAPK14 protein Q16539 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 20626350 YES gcesareni Fgfr1 translocation requires p38 mapk activation which phosphorylates the c-term tail of fgfr1 on ser777 0.275 SIGNOR-166598 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR up-regulates activity ubiquitination -1 12485996 YES lperfetto Auto‐ubiquitylation stimulates the ubiquitin ligase activity of BRCA1/BARD1|Secondly, BRCA1/BARD1 catalyses the formation of multiple polyubiquitin chains on itself. Remarkably, this auto‐polyubiquitylation potentiates the E3 ubiquitin ligase activity of the BRCA1/BARD1 complex >20‐fold. 0.795 SIGNOR-263233 AURKA protein O14965 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser305 IKRSKKNsLALSLTA 9606 24166501 YES miannu Based on these findings, we conclude that ER\u03b1-Ser167 and -Ser305 are phosphorylated by Aurora-A in vitro and in vivo .|These data suggest that Aurora-A not only activates ER\u03b1 activity but also enhances E2 action and that Aurora-A-induced ER\u03b1 activation could not be inhibited by tamoxifen. 0.358 SIGNOR-278507 AURKA protein O14965 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser167 GGRERLAsTNDKGSM 9606 24166501 YES miannu Based on these findings, we conclude that ER\u03b1-Ser167 and -Ser305 are phosphorylated by Aurora-A in vitro and in vivo .|These data suggest that Aurora-A not only activates ER\u03b1 activity but also enhances E2 action and that Aurora-A-induced ER\u03b1 activation could not be inhibited by tamoxifen. 0.358 SIGNOR-278508 PAK4 protein O96013 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser305 IKRSKKNsLALSLTA 9606 26554417 YES miannu Further, PAK4 phosphorylated ER\u03b1-Ser305, a phosphorylation event needed for the PAK4 activation of ER\u03b1-dependent transcription.|Further, PAK4 phosphorylated ERalpha-Ser305, a phosphorylation event needed for the PAK4 activation of ERalpha dependent transcription. 0.277 SIGNOR-279472 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr227 PAPPEGAtPTSPVGH 9606 BTO:0000848 BTO:0001253 20959475 YES lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). 0.2 SIGNOR-168758 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr597 FYVDFREyEYDLKWE 9606 BTO:0001271 11971190 YES lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation 0.2 SIGNOR-117579 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR MAP3K5 protein Q99683 UNIPROT up-regulates activity dephosphorylation Ser966 NEYLRSIsLPVPVLV 9606 27858941 YES miannu DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1 0.287 SIGNOR-254756 5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine chemical CHEBI:91338 ChEBI ALK protein Q9UM73 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258293 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005787 BTO:0001103 23612709 YES miannu The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion 0.702 SIGNOR-255453 HSP90AB1 protein P08238 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 27353360 YES miannu Heat shock protein-90 (Hsp90) is an essential molecular chaperone in eukaryotes involved in maintaining the stability and activity of numerous signalling proteins, also known as clients. Hsp90 ATPase activity is essential for its chaperone function and it is regulated by co-chaperones. Here we show that the tumour suppressor FLCN is an Hsp90 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones. FNIPs decelerate the chaperone cycle, facilitating FLCN interaction with Hsp90, consequently ensuring FLCN stability. 0.2 SIGNOR-261417 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr500 RLAYVAPtIPRRLAS -1 12030846 YES miannu MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition 0.583 SIGNOR-262884 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates activity dephosphorylation Tyr490 HCAAWHGyYSVAKAL 9606 BTO:0002181 17803936 YES miannu  Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation.  0.2 SIGNOR-276076 CDK1 protein P06493 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser684 IGIPQFHsPVGSPLK 9606 SIGNOR-C17 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. 0.483 SIGNOR-164487 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr387 RPGPGTLyDVPRERV 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246413 PLK2 protein Q9NYY3 UNIPROT LRPAP1 protein P30533 UNIPROT up-regulates activity phosphorylation 9606 21382555 YES miannu Inhibition of Ras and activation of Rap by Plk2.|Plk2 phosphorylation of Ras and Rap regulators controls surface AMPARs. 0.3 SIGNOR-279476 PRKCE protein Q02156 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity phosphorylation Ser188 ARRGKKKsGCLVL 9606 24191200 YES miannu Our laboratory reported that PKCepsilon modulates RhoA activity in HNSCC presumably through posttranslation phosphorylation .|Phosphopeptide mapping revealed that PKCepsilon phosphorylates RhoA at T127 and S188. 0.439 SIGNOR-279477 CHEK2 protein O96017 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr288 SPDCDVKtDDSVVPC 9606 19151762 YES llicata Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir 0.292 SIGNOR-242665 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 10816598 YES miannu Fak autophosphorylation site, tyr397. / extracellular matrix (ecm)-induced autophosphorylation of fak on tyr397 creates a high affinity binding site for the sh2 domain of c-src, and mutation (tyr to phe) of this residue inhibits association 0.2 SIGNOR-77434 TNFRSF6B protein O95407 UNIPROT TNFSF15 protein O95150 UNIPROT down-regulates binding 9606 BTO:0000782 11911831 YES amattioni Tl1a, is a ligand for dr3 and decoy receptor tr6/dcr3. Tr6-fc protein antagonizes nf-kappab activation and apoptosis induced by tl1a 0.71 SIGNOR-116256 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EGR1 protein P18146 UNIPROT up-regulates binding 9606 10671503 YES lperfetto The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo 0.398 SIGNOR-216328 TYSND1 protein Q2T9J0 UNIPROT ACOX1 protein Q15067 UNIPROT up-regulates activity cleavage -1 17255948 YES miannu Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1. 0.693 SIGNOR-261057 MAPK1 protein P28482 UNIPROT AKAP4 protein Q5JQC9 UNIPROT unknown phosphorylation Thr265 KERISPRtPASKIAS 9606 BTO:0001277 27901058 YES lperfetto Here we demonstrate that ERK1/2 phosphorylates proAKAP4 on Thr265 in human spermatozoa in vitro and in vivo 0.26 SIGNOR-271861 Caspase 3 complex complex SIGNOR-C221 SIGNOR GOLGB1 protein Q14789 UNIPROT down-regulates activity cleavage Asp1881 LSQISTKdGELKMLQ 9606 14970262 YES miannu Giantin and syntaxin 5 are cleaved by caspase-3. Given that both giantin and syntaxin 5 are cleaved at an early stage during apoptosis, we anticipated that, at the very least, the delivery of ER-derived transport intermediates to the Golgi would be impaired in apoptotic cells. 0.253 SIGNOR-261235 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 YES Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. 0.569 SIGNOR-248335 F2RL1 protein P55085 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256752 AKT2 protein P31751 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000093 11504915 YES lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.. Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. 0.558 SIGNOR-109736 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr694 DSPSDGGtPGRMPPQ 9606 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104707 PRKCE protein Q02156 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity phosphorylation Thr127 DLRNDEHtRRELAKM 9606 24191200 YES miannu Our laboratory reported that PKCepsilon modulates RhoA activity in HNSCC presumably through posttranslation phosphorylation .|Phosphopeptide mapping revealed that PKCepsilon phosphorylates RhoA at T127 and S188. 0.439 SIGNOR-279478 PRKCE protein Q02156 UNIPROT STXBP1 protein P61764 UNIPROT down-regulates quantity phosphorylation 9606 29946239 YES miannu These results show that nPKC\u03b5 induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKC\u03b5 downregulates Munc18-1 levels, induced by the nerve stimulation.|These results show that nPKCepsilon induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKCepsilon downregulates Munc18-1 levels, induced by the nerve stimulation. 0.273 SIGNOR-279479 PTK2 protein Q05397 UNIPROT PLD2 protein O14939 UNIPROT up-regulates activity phosphorylation 9606 32843133 YES miannu The kinase domain of FAK interacts with PLD2-PH and induces tyrosine phosphorylation and activation of PLD2. 0.32 SIGNOR-279480 RAF1 protein P04049 UNIPROT RB1 protein P06400 UNIPROT down-regulates activity phosphorylation 9606 9819434 YES miannu Further, Raf-1 was able to phosphorylate Rb in vitro quite efficiently.|Raf-1 can inactivate Rb function and can reverse Rb mediated repression of E2F1 transcription and cell proliferation efficiently. 0.577 SIGNOR-279481 ROCK2 protein O75116 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity phosphorylation 9606 16574662 YES miannu Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase.|p300 acetyltransferase activity is dependent on its phosphorylation status in cells, and p300 phosphorylation by ROCK2 results in an increase in its acetyltransferase activity in vitro. 0.297 SIGNOR-279482 P2RY14 protein Q15391 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257118 CADM2 protein Q8N3J6 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 BTO:0000007 29506532 NO Gianni The results indicated that CADM2 […} modulates EMT process and migration ability via focal adhesion kinase (FAK) /AKT signaling pathway in HCC. 0.2 SIGNOR-268855 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 20966922 NO APL cells closely resemble normal promyelocytes, a specific stage of the granulocytic differentiation pathway, suggesting that PML–RARα blocks the normal myeloid differentiation programme. 0.7 SIGNOR-255724 GPT2 protein Q8TD30 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9606 11863375 YES Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2 0.8 SIGNOR-266926 GSK3A protein P49840 UNIPROT BCL3 protein P20749 UNIPROT down-regulates quantity by destabilization phosphorylation Ser406 PSSSPSQsPPRDPPG 9606 BTO:0000007 15469820 YES miannu In this report, we show that BCL-3 is a substrate for the protein kinase GSK3 and that GSK3-mediated BCL-3 phosphorylation, which is inhibited by Akt activation, targets its degradation through the proteasome pathway. 0.393 SIGNOR-276012 TNFRSF21 protein O75509 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR down-regulates 9606 32454942 NO miannu Next to inhibition of sTNF/TNFR1 signaling, specific activation of TNFR2 may hold promise as a new MS therapy. Indeed, TNF promotes proliferation of oligodendrocyte progenitors and remyelination via TNFR2 0.7 SIGNOR-263832 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEP76 protein Q8TAP6 UNIPROT down-regulates activity phosphorylation Ser83 VEQELPSsPKQPICF 9606 BTO:0001938 27065328 YES miannu Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. we conclude that Cep76 inhibits centriole disengagement and consequently amplification by blocking Plk1 activation at the centrosome. 0.3 SIGNOR-262730 Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 YES lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. 0.74 SIGNOR-256471 ATM protein Q13315 UNIPROT APLF protein Q8IW19 UNIPROT up-regulates activity phosphorylation 9606 18077224 YES miannu We show that APLF undergoes ATM dependent hyperphosphorylation following IR and that APLF is directly phosphorylated by ATM in vitro. 0.401 SIGNOR-279492 ATM protein Q13315 UNIPROT HMGA1 protein P17096 UNIPROT up-regulates activity phosphorylation 9606 18783938 YES miannu 21 As shown in Fig. 2 b, ATM was able to phosphorylate in vitro the C-terminal peptide of HMGA1. 0.2 SIGNOR-279493 ATR protein Q13535 UNIPROT DCK protein P27707 UNIPROT up-regulates activity phosphorylation Ser74 EFEELTMsQKNGGNV 9606 26620371 YES miannu Since activation of dCK by IR was not prevented by KU-60019 at longer times, but could be suppressed if the ATR inhibitor was combined with the ATM inhibitor, we propose that dCK is activated by ATR when ATM is inhibited.|Taken together, these data indicate that ATR, like ATM [15], can directly phosphorylate dCK at Ser 74 in vitro and thereby increase its activity.Most dCK activators share the feature of inducing DNA damage followed by DNA damage response, a complex signaling network aimed to preserve genome integrity. 0.2 SIGNOR-279494 NLK protein Q9UBE8 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates activity phosphorylation 9606 14720327 YES miannu In vitro kinase assay showed that NLK could phosphorylate the C-terminal domain of CBP. 0.556 SIGNOR-280048 PKA proteinfamily SIGNOR-PF17 SIGNOR SYN2 protein Q92777 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 10571231 YES miannu Synapsins are exclusively localized to synaptic vesicles, which they coat as peripheral membrane proteins; they probably constitute one of the most abundant neuronal PKA substrates. Our study reveals an unexpectedly dynamic state of synapsins in nerve terminals: any changes in PKA or CaM Kinase I activity will modulate the amount of synapsin on synaptic vesicles. PKA Activation Triggers Synapsin Dissociation 0.2 SIGNOR-264109 PELI2 protein Q9HAT8 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity ubiquitination 9606 29674674 YES miannu Pellino2 promotes ubiquitination of NLRP3.|We now demonstrate that Pellino2 can promote increased production of mature bioactive IL-1beta by facilitating activation of the NLRP3 inflammasome. 0.2 SIGNOR-278525 SUGT1 protein Q9Y2Z0 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR up-regulates activity binding 9606 BTO:0000567 22869522 YES lperfetto Here we identify Sgt1, a cochaperone for Hsp90, as a novel Plk1 substrate during mitosis|This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone with the MIS12 complex to stabilize this complex at the kinetochores and thus coordinates the recruitment of the NDC80 complex to form efficient microtubule-binding sites. 0.303 SIGNOR-265223 CDK4 protein P11802 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 YES gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.284 SIGNOR-176515 AR protein P10275 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16281084 NO After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. 0.26 SIGNOR-253678 SCF-betaTRCP complex SIGNOR-C5 SIGNOR PER2 protein O15055 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17876059 YES miannu Here, the authors show that the F-box protein beta-transducin repeat containing protein 1 (beta-TrCP1) as part of the E3 ubiquitin ligase complex is an essential component of the mammalian circadian oscillator. Down-regulation of endogenous beta-TrCP1 as well as expression of a dominant-negative form both result in lengthening of the circadian period in oscillating fibroblasts. These phenotypes are due to an impaired degradation of PERIOD (PER) proteins, since expression of beta-TrCP interaction-deficient PER2 variants--but not wild-type PER2--results in a dramatic stabilization of PER2 protein as well as in the disruption of circadian rhythmicity. 0.487 SIGNOR-268055 MYC protein P01106 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 23175188 NO miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. 0.466 SIGNOR-255146 CHEK1 protein O14757 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation Ser137 LELCRRRsLLELHKR 9606 34197606 YES miannu These results suggest that both PLK1 S137 and T210 sites can be phosphorylated in vitro by CHK1, but that S137 is the major site.|We reason that PARG and CHK1 inhibitors should also cause synthetic lethality : PARG inhibition sustains PLK1 inhibition at the PAR forest , while CHK1 inhibition blocks PLK1 reactivation and RAD51 phosphorylation at S14 and T309 . 0.314 SIGNOR-279502 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu433 REYHTEKlVTSKGDK -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain 0.2 SIGNOR-263620 AURKB protein Q96GD4 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates activity phosphorylation Ser275 RLAQICSsIRTHK 9606 17483322 YES miannu AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells.|Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis. 0.819 SIGNOR-279506 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1038 STSATQSsPAPGQSK 9606 BTO:0000551 24530506 YES miannu In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels.  0.2 SIGNOR-276455 CDK1 protein P06493 UNIPROT HEXIM1 protein O94992 UNIPROT down-regulates activity phosphorylation 9606 22918952 YES miannu Given that Cdk1 phosphorylation promotes Clp1 nucleoplasmic accumulation upon genotoxic stress and Cdk1 phosphorylation inhibits Clp1 activity, Clp1 may be only primed by its nucleolar release but not actually active under these circumstances.|In addition, Cdk1 directly phosphorylates Clp1 on TP sites primarily in early mitosis and inhibits Clp1 catalytic activity. 0.257 SIGNOR-279508 CDK11B protein P21127 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation 9606 23519612 YES miannu However, Clk1 enhanced SPF45 protein expression, but not mRNA expression, whereas inhibition of Clk1 increased SPF45 degradation through a proteasome dependent pathway.|In the present work, we show that Clk1 phosphorylates SPF45 in vitro on eight serine residues, all of which are N-terminal to the RRM domain required for splicing. 0.207 SIGNOR-279510 CDK16 protein Q00536 UNIPROT NSF protein P46459 UNIPROT down-regulates activity phosphorylation Ser569 FPFIKICsPDKMIGF 9606 16461345 YES miannu Moreover, inhibition of Pctaire1 activity by transfecting its kinase-dead (KD) mutant into COS-7 cells enhances the self association of NSF.|We demonstrate that the D2 domain of NSF, which is required for the oligomerization of NSF subunits, binds directly to and is phosphorylated by Pctaire1 on serine 569. 0.44 SIGNOR-279511 alvocidib chemical CHEBI:47344 ChEBI CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192446 RALGAPB protein Q86X10 UNIPROT RalGAP2 complex SIGNOR-C469 SIGNOR form complex binding 10090 BTO:0000011 21148297 YES miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. 0.604 SIGNOR-269794 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.357 SIGNOR-259014 Unii-2ewn8Z05CN chemical CID:129138801 PUBCHEM EIF4A1 protein P60842 UNIPROT down-regulates activity chemical inhibition 9606 32470302 YES Simone Vumbaca Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase 0.8 SIGNOR-261120 PTPN14 protein Q15678 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9534 35259601 YES miannu Moreover, dephosphorylation of STAT3 by PTPN14 might occur in the cytoplasm but not in nucleus.|The tyrosine phosphatase PTPN14 inhibits the activation of STAT3 in PEDV infected Vero cells. 0.272 SIGNOR-277088 captopril chemical CHEBI:3380 ChEBI ACE2 protein Q9BYF1 UNIPROT down-regulates activity chemical inhibition -1 9187274 YES Monia The interaction of captopril at one active site of wild-type ACE impeding substrate interaction with the other active site. 0.8 SIGNOR-261069 NRZ complex complex SIGNOR-C358 SIGNOR Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 25364732 NO lperfetto NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay. 0.7 SIGNOR-265026 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-267504 TRPM6 protein Q9BX84 UNIPROT TRPM6 protein Q9BX84 UNIPROT down-regulates activity phosphorylation Thr1851 FNQVKPQtIPYTPRF 9606 18258429 YES Manara Autophosphorylation of Threonine1851 in the Kinase Domain Is Essential for the Inhibitory Effect of RACK1 0.2 SIGNOR-260922 CDK4 protein P11802 UNIPROT TFE3 protein P19532 UNIPROT up-regulates activity phosphorylation 9606 32662822 YES miannu CDK4 and CDK6 interact with TFEB and TFE3 in the nucleus We next investigated how CDK4 and CDK6 activate TFEB and TFE3 .|We found that CDK4 and CDK6 interact with and phosphorylate nuclear TFEB and TFE3, thereby promoting their shuttling to the cytoplasm. 0.2 SIGNOR-279514 CDK5 protein Q00535 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser246 ALVKMLGsPVDSVLF 9606 26509276 YES miannu By combining multiple network relations with PTM proteoform specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity.|CDK5 phosphorylates beta-catenin on Ser 191 and Ser 246 (PR :000037229) 0.371 SIGNOR-279516 CDK6 protein Q00534 UNIPROT TFE3 protein P19532 UNIPROT up-regulates activity phosphorylation 9606 32662822 YES miannu CDK4 and CDK6 interact with TFEB and TFE3 in the nucleus We next investigated how CDK4 and CDK6 activate TFEB and TFE3 .|CDK4 and CDK6 phosphorylate TFEB and TFE3. 0.2 SIGNOR-279517 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR SQSTM1 protein Q13501 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25721664 YES miannu F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway. 0.298 SIGNOR-272446 GAP43 protein P17677 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 21938722 NO miannu Growth associated protein 43 (Gap43) is a neuron-specific phosphoprotein, which plays critical role in axon growth and synapses functions during neurogenesis.  0.7 SIGNOR-266769 YWHAQ protein P27348 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 14701738 YES miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase 0.267 SIGNOR-261714 CIC protein Q96RK0 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR up-regulates activity binding 10090 BTO:0000142 32229723 YES miannu Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1-containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. CIC interacts with mSWI/SNF complex during neurogenesis. CIC tethers SIN3-HDAC corepressor complex and mSWI/SNF complex to VGF promoter during neurogenesis. 0.336 SIGNOR-269206 PAK5 protein Q9P286 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000150 29041983 YES lperfetto PAK5-mediated phosphorylation and nuclear translocation of NF-κB-p65 promotes breast cancer cell proliferation in vitro and in vivo|We characterized that PAK5 could promote the phosphorylation and the nuclear translocation of p65 subunit of nuclear factor-kappaB, and demonstrated that p65 could directly bind to the promoter of Cyclin D1 0.2 SIGNOR-275657 PRKCA protein P17252 UNIPROT NF2 protein P35240 UNIPROT down-regulates activity phosphorylation 9606 24481838 YES miannu PKC\u03b1\nnormally phosphorylates and inactivates NF2.|PKCalpha normally phosphorylates and inactivates NF2. 0.329 SIGNOR-280081 GTF2H1 protein P32780 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates quantity by destabilization phosphorylation Ser403 PEEFISLsPPHEALD -1 10428966 YES TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase. 0.435 SIGNOR-251259 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 19709076 YES lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. 0.389 SIGNOR-216904 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248688 CXCL5 protein P42830 UNIPROT Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000130 34237033 NO miannu  We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. 0.7 SIGNOR-277732 MAP4K4 protein O95819 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity phosphorylation Ser35 LEAKYLCsACRNVLR 9606 25098764 YES miannu A key finding of our study is that HGK induces lysosomal degradation of TRAF2 by directly phosphorylating TRAF2 Ser35.|Conversely, TRAF2 levels were decreased by ectopically expressed HGK in an overexpression system (XREF_FIG). 0.519 SIGNOR-279536 MAPK1 protein P28482 UNIPROT RASGRP2 protein Q7LDG7 UNIPROT down-regulates activity phosphorylation Ser394 RSKSSPTsPTSCTPP 9606 27107697 YES miannu ERK2 phosphorylates RasGRP2 at Ser394 located in the linker region implicated in its autoinhibition. 0.396 SIGNOR-279537 MAPK1 protein P28482 UNIPROT SHANK3 protein Q9BYB0 UNIPROT down-regulates activity phosphorylation 9606 30696942 YES miannu Interestingly, we discovered that several kinases in the MEK and ERK2 pathway destabilize Shank3 and that genetic deletion and pharmacological inhibition of ERK2 increases Shank3 abundance in vivo.|We also determined that phosphorylation of Shank3 by ERK2 at selective residues promotes its ubiquitination and degradation. 0.2 SIGNOR-279538 MAPKAPK2 protein P49137 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates activity phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 32409685 YES miannu MK2 mediated OCT4 transcriptional activation is a novel mechanism for activating the MYC oncogene in progressive disease neuroblastoma that provides a therapeutic target.|OCT4 phosphorylation at the S111 residue by MK2 was upstream of MYC transcriptional activation. 0.2 SIGNOR-279542 MELK protein Q14680 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates quantity phosphorylation 9606 28938528 YES miannu Direct phosphorylation of FOXO1 and FOXO3 by MELK.|Our findings revealed that siRNA mediated MELK knockdown increased protein levels of FOXO1 and FOXO3, which might increase p21 transcriptional level in a p53 independent manner. 0.257 SIGNOR-279543 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR H2AX protein P16104 UNIPROT up-regulates activity ubiquitination -1 12485996 YES lperfetto Strikingly, as well as H2AX, the nucleosome core histones H2A, H2B, H3 and H4 were all ubiquitylated efficiently by BRCA1/BARD1, while the linker histone H1 was not (Figure 3).| Generally, histone proteins are required for compaction of nuclear DNA into chromatin, and their modification is thought to loosen this compaction. Therefore, one might envisage that ubiquitylation of γH2AX by BRCA1/BARD1 at DNA breaks modulates local chromatin packaging to facilitate the action of DNA repair enzymes. 0.2 SIGNOR-263235 PRKCA protein P17252 UNIPROT KCNMA1 protein Q12791 UNIPROT up-regulates phosphorylation Ser1200 SHSSQSSsKKSSSVH 9606 19592459 YES gcesareni Results showed that mutating s1076 altered the effect of pkc activation on bk(ca) channels in hek-293 cells 0.2 SIGNOR-186755 JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30029643 NO areggio Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway. 0.7 SIGNOR-256231 PP1 proteinfamily SIGNOR-PF54 SIGNOR AURKA protein O14965 UNIPROT down-regulates dephosphorylation 9606 11551964 YES lperfetto Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro. 0.2 SIGNOR-264651 MARK2 protein Q7KZI7 UNIPROT TNK1 protein Q13470 UNIPROT down-regulates activity phosphorylation Ser502 RMKGISRsLESVLSL 9606 BTO:0000018 34504101 YES miannu We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.Phosphorylation of TNK1 at S502 within the proline rich domain is required for TNK1 binding to 14-3-3.MARKs mediate phosphorylation at S502 and 14-3-3 binding to TNK1, which restrains the movement of TNK1 into heavy membrane-associated clusters. 0.2 SIGNOR-273867 NEK2 protein P51955 UNIPROT CNTROB protein Q8N137 UNIPROT down-regulates activity phosphorylation 9606 23291182 YES miannu The opposite outcomes in NEK2- and centrobin-depleted cells suggest that NEK2 antagonizes biological functions of centrobin.|These results suggest that NEK2 phosphorylates specific sites of centrobin, which are distinct from the PLK1 phosphorylation sites. 0.35 SIGNOR-279545 PAK6 protein Q9NQU5 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation 9606 24352566 YES miannu Moreover, we find that \u03b2-catenin is also localized with PAK6 in cell-cell junctions and is a novel PAK6 substrate.|PAK6 binds to and phosphorylates beta-catenin. 0.2 SIGNOR-279546 PRKCD protein Q05655 UNIPROT NR2F6 protein P10588 UNIPROT down-regulates phosphorylation Ser83 CKSFFKRsIRRNLSY 9606 BTO:0000782 18701084 YES esanto Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6. 0.2 SIGNOR-180017 PIM1 protein P11309 UNIPROT RUNX3 protein Q13761 UNIPROT up-regulates quantity phosphorylation 9606 24266874 YES miannu Inhibition of Pim1 kinase prevents peanut allergy by enhancing Runx3 expression and suppressing T (H) 2 and T (H) 17 T-cell differentiation.|Pim1 kinase phosphorylates and stabilizes Runx3 and alters its subcellular localization. 0.353 SIGNOR-279547 PINK1 protein Q9BXM7 UNIPROT RHOT1 protein Q8IXI2 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 28973175 YES miannu PINK1 also phosphorylates Miro1 which targets Miro1 for degradation in a Parkin dependent manner. 0.774 SIGNOR-279549 PLK1 protein P53350 UNIPROT BEX4 protein Q9NWD9 UNIPROT up-regulates activity phosphorylation Thr107 RHYMRFQtPEPDNHY 9606 30367032 YES miannu In addition, the inhibition of PLK1 activity by BI2536 treatment sharply reduced BEX4 protein, which was localized at the centrosomes in the HeLa cells or the GFP-BEX4 stable cell lines.|PLK1 directly phosphorylates BEX4 at T107 and contributes to BEX4-induced aneuploidy. 0.2 SIGNOR-279550 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 18267068 YES gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. 0.616 SIGNOR-160787 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258540 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr333 NIMRTYTyEKLLWTT 9606 22056988 YES lperfetto Egfr activation induces translocation of pkm2 into the nucleus, where k433 of pkm2 binds to c-src-phosphorylated y333 of _-cateninthese findings reveal that egf induces _-catenin transactivation via a mechanism distinct from that induced by wnt/wingless and highlight the essential non-metabolic functions of pkm2 in egfr-promoted _-catenin transactivation, cell proliferation and tumorigenesis 0.76 SIGNOR-177086 EGFR protein P00533 UNIPROT CALM2 protein P0DP24 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 YES miannu Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. 0.346 SIGNOR-266319 PLK1 protein P53350 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT down-regulates activity phosphorylation Ser393 VCHDSDEsDTAKAVE 9606 34051063 YES miannu 2.11 Plk1 Directly Phosphorylates DNMT3a at S393.|Elevated Plk1 further inhibited DNMT3a via phosphorylation at S393 in mitosis in accord with its mitotic role during cell cycle. 0.269 SIGNOR-279552 PLK1 protein P53350 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates quantity phosphorylation 9606 20214750 YES miannu As GRASP65 is a substrate of cdc2 and polo-like kinase, manipulation of GRASP65 level may affect the localization and activity of these kinases in cell cycle progression, as suggested by a previous study ( ).|During mitosis, GRASP65 is phosphorylated by two mitotic kinases, cdc2 and polo-like kinase (plk), which leads to GRASP65 deoligomerization and thus Golgi unstacking ( xref , xref ). 0.728 SIGNOR-279554 PRKCA protein P17252 UNIPROT RND3 protein P61587 UNIPROT down-regulates activity phosphorylation 9606 19723022 YES miannu PKCalpha dependent Rnd3 phosphorylation downregulates Rnd3 inhibitory activity and leads to increased signaling through the Rho-ROCK pathway.|We further show that PKC\u03b1 directly phosphorylates Rnd3 in an in vitro kinase assay. 0.2 SIGNOR-279557 PRKCA protein P17252 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser423 GRAGPFSsSRCGASV 9606 30154410 YES miannu ULK1 is phosphorylated by PKCalpha at S423 in vivo and in vitro.|PKC\u03b1 phosphorylation of ULK1 does not change its kinase activity 0.2 SIGNOR-279558 PRKCD protein Q05655 UNIPROT TRPC1 protein P48995 UNIPROT up-regulates activity phosphorylation 9606 32627185 YES miannu Taken together, these results indicate that store depletion induces interactions between TRPC1 and PKC\u03b4 in VSMCs, and that these interactions cause PKC\u03b4\u2010dependent phosphorylation of TRPC1. 0.2 SIGNOR-279559 PRKD2 protein Q9BZL6 UNIPROT SET protein Q01105 UNIPROT down-regulates activity phosphorylation Ser171 S-->I 9606 23251465 YES miannu In conclusion, the roles of protein kinase D2 and its substrate SET in T cell activation were investigated and we found that protein kinase D2 phosphorylates Ser171 of SET, which resulted in the reduction of its inhibitory effect on PP2A phosphatase activity. 0.2 SIGNOR-279560 moclobemide chemical CHEBI:83531 ChEBI MAOB protein P27338 UNIPROT down-regulates activity chemical inhibition -1 21680183 YES Luana Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5–16) were found to be potent inhibitors of hMAO-A isoform with SIMAO-A in the order 103 and 104.  0.8 SIGNOR-258315 AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 9829964 YES The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. |When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. 0.2 SIGNOR-251474 MAP3K7 protein O43318 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates activity 9606 9890973 NO lperfetto These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. 0.294 SIGNOR-63979 FBXO22 protein Q8NEZ5 UNIPROT BSG protein P35613 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007;BTO:0003227;BTO:0005816 28117675 YES lperfetto F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells 0.428 SIGNOR-273452 miR-132 mirna URS00001F4E81_9606 RNAcentral MECP2 protein P51608 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 23132946 NO irozzo In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability. 0.4 SIGNOR-256649 TGFB1 protein P01137 UNIPROT MYOG protein P15173 UNIPROT down-regulates 10090 14739161 NO lperfetto Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12. 0.258 SIGNOR-235728 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273102 FZD3 protein Q9NPG1 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 14977528 YES gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. 0.2 SIGNOR-122886 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR PPARG protein P37231 UNIPROT down-regulates activity 9606 17139329 NO fferrentino Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter 0.41 SIGNOR-253537 PRKG2 protein Q13237 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity phosphorylation Ser152 LAGQPRKsSSSRRNA 9606 22393355 YES miannu Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2.|We found that cGKII also phosphorylates FoxO1 at S152\u2013155 and that these residues are major sites of phosphorylation in FoxO-N (Fig. 0.356 SIGNOR-279563 PHC1 protein P78364 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 YES miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b 0.819 SIGNOR-266809 PRKG2 protein Q13237 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 22393355 YES miannu Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2. 0.356 SIGNOR-279564 AURKA protein O14965 UNIPROT SKI protein P12755 UNIPROT down-regulates quantity by destabilization phosphorylation Ser383 LSAFRPWsPAVSASE -1 26138431 YES miannu Here we show that AURKA phosphorylates in vitro the transcripcional co-repressor Ski on aminoacids Ser326 and Ser383. Phosphorylations on these aminoacids decreased Ski protein half-life 0.2 SIGNOR-276917 AIFM1 protein O95831 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 21210296 NO gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. 0.435 SIGNOR-170960 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.2 SIGNOR-253482 TWIST2 protein Q8WVJ9 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255503 NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR NADH(2-) smallmolecule CHEBI:57945 ChEBI down-regulates quantity chemical modification 9606 12231006 YES miannu The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H(+) (or Na(+)) ions across the membrane, resulting in a significant contribution to energy production. Complex I is located at an entry point of the electron transport chain and initiates electron transfer by oxidizing NADH and the electrons are transferred to a lipid-soluble electron carrier quinone (coenzyme Q) as an electron acceptor. 0.8 SIGNOR-280279 SRC protein P12931 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates activity phosphorylation 9606 23115189 YES miannu Indeed, activated Src can directly phosphorylate recombinant TrkB protein in a cell-free system.|We found that both exogenous H 2 O 2 and endogenous ROS activate TrkB signaling by a Src family kinase dependent but brain derived neurotrophic factor independent mechanism in cultured rat cortical neurons. 0.458 SIGNOR-280130 STOML2 protein Q9UJZ1 UNIPROT CD3E protein P07766 UNIPROT up-regulates activity binding 9606 BTO:0000661 18641330 YES Giorgia We observed that SLP-2 steadily associated with the CD3-epsilon chain of the TCR complex under resting conditions and during the 60 min of stimulation|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. 0.2 SIGNOR-260375 NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR hydron chemical CHEBI:15378 ChEBI up-regulates quantity relocalization 9606 12231006 YES miannu The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H(+) (or Na(+)) ions across the membrane, resulting in a significant contribution to energy production. Complex I is located at an entry point of the electron transport chain and initiates electron transfer by oxidizing NADH and the electrons are transferred to a lipid-soluble electron carrier quinone (coenzyme Q) as an electron acceptor. 0.8 SIGNOR-280280 NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR coenzyme Q10 smallmolecule CHEBI:46245 ChEBI down-regulates quantity chemical modification 9606 12231006 YES miannu The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H(+) (or Na(+)) ions across the membrane, resulting in a significant contribution to energy production. Complex I is located at an entry point of the electron transport chain and initiates electron transfer by oxidizing NADH and the electrons are transferred to a lipid-soluble electron carrier quinone (coenzyme Q) as an electron acceptor. 0.8 SIGNOR-280281 NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR NAD(1-) smallmolecule CHEBI:57540 ChEBI up-regulates quantity chemical modification 9606 12231006 YES miannu The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H(+) (or Na(+)) ions across the membrane, resulting in a significant contribution to energy production. Complex I is located at an entry point of the electron transport chain and initiates electron transfer by oxidizing NADH and the electrons are transferred to a lipid-soluble electron carrier quinone (coenzyme Q) as an electron acceptor. 0.8 SIGNOR-280284 NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR ubiquinol-10 smallmolecule CHEBI:64183 ChEBI up-regulates quantity chemical modification 9606 12231006 YES miannu The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H(+) (or Na(+)) ions across the membrane, resulting in a significant contribution to energy production. Complex I is located at an entry point of the electron transport chain and initiates electron transfer by oxidizing NADH and the electrons are transferred to a lipid-soluble electron carrier quinone (coenzyme Q) as an electron acceptor. 0.8 SIGNOR-280285 NADH(2-) smallmolecule CHEBI:57945 ChEBI NAD(1-) smallmolecule CHEBI:57540 ChEBI up-regulates quantity precursor of 9606 12231006 YES miannu The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H(+) (or Na(+)) ions across the membrane, resulting in a significant contribution to energy production. Complex I is located at an entry point of the electron transport chain and initiates electron transfer by oxidizing NADH and the electrons are transferred to a lipid-soluble electron carrier quinone (coenzyme Q) as an electron acceptor. 0.8 SIGNOR-280286 miR-3191 mirna URS0000116F83_9606 RNAcentral PAK6 protein Q9NQU5 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0001950 39696440 YES miannu MiR-3191 promotes the proliferation and metastasis of hepatocellular carcinoma via regulating PAK6 0.4 SIGNOR-279971 coenzyme Q10 smallmolecule CHEBI:46245 ChEBI ubiquinol-10 smallmolecule CHEBI:64183 ChEBI up-regulates quantity precursor of 9606 12231006 YES miannu The energy-transducing NADH: quinone (Q) oxidoreductase (complex I) is the largest and most complicated enzyme complex in the oxidative phosphorylation system. Complex I is a redox pump that uses the redox energy to translocate H(+) (or Na(+)) ions across the membrane, resulting in a significant contribution to energy production. Complex I is located at an entry point of the electron transport chain and initiates electron transfer by oxidizing NADH and the electrons are transferred to a lipid-soluble electron carrier quinone (coenzyme Q) as an electron acceptor. 0.8 SIGNOR-280287 CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR ubiquinol-10 smallmolecule CHEBI:64183 ChEBI down-regulates quantity chemical modification 9606 14977419 YES miannu The bc1 complexes are intrinsic membrane proteins that catalyze the oxidation of ubihydroquinone and the reduction of cytochrome c in mitochondrial respiratory chains and bacterial photosynthetic and respiratory chains. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis. 0.8 SIGNOR-280288 CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR hydron chemical CHEBI:15378 ChEBI up-regulates quantity relocalization 9606 14977419 YES miannu The bc1 complexes are intrinsic membrane proteins that catalyze the oxidation of ubihydroquinone and the reduction of cytochrome c in mitochondrial respiratory chains and bacterial photosynthetic and respiratory chains. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis. 0.8 SIGNOR-280289 CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR CYCS protein P99999 UNIPROT up-regulates activity chemical modification 9606 14977419 YES miannu The bc1 complexes are intrinsic membrane proteins that catalyze the oxidation of ubihydroquinone and the reduction of cytochrome c in mitochondrial respiratory chains and bacterial photosynthetic and respiratory chains. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis. 0.848 SIGNOR-280290 STUB1 protein Q9UNE7 UNIPROT GLYCTK protein Q8IVS8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002036 40467571 YES miannu Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. ERK1 phosphorylates GLYCTK2 at S220 to promotes its stability 0.2 SIGNOR-280258 SNX5 protein Q9Y5X3 UNIPROT IGF2R protein P11717 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 YES miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. 0.568 SIGNOR-269442 STK4 protein Q13043 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Ser226 LNPQWNEsFTFKLKP 9606 26414765 YES miannu Mst1 and Mst2 activate PKC\u03b1 to disrupt the LyGDI-Rac complex.|Thus, the phosphorylation of PKC\u03b1 at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKC\u03b1. 0.2 SIGNOR-280146 CHUK protein O15111 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 SIGNOR-C14 15494311 YES Translocation from Nucleus to Cytoplasm gcesareni Nf-kappab transcription requires ikkalpha to phosphorylate smrt on chromatin, stimulating the exchange of corepressor for coactivator complexes. Ikk directly phosphorylates smrt to stimulate nuclear export. Ikkalpha orchestrates smrt derepression, a prerequisite for nf-kappab transcription and survival. 0.417 SIGNOR-129956 HTR6 protein P50406 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.345 SIGNOR-257340 CBLB protein Q13191 UNIPROT KIT protein P10721 UNIPROT down-regulates activity ubiquitination 9606 15315962 YES miannu KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. 0.329 SIGNOR-260105 NatA complex SIGNOR-C415 SIGNOR HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization acetylation 9606 BTO:0001282 12464182 YES miannu In this report, we reveal an important function for ARD1 in mammalian cells as a protein acetyltransferase by direct binding to HIF-1alpha to regulate its stability. We present further evidence showing that ARD1-mediated acetylation enhances interaction of HIF-1alpha with pVHL and HIF-1alpha ubiquitination, suggesting that the acetylation of HIF-1alpha by ARD1 is critical to proteasomal degradation. 0.513 SIGNOR-267226 RANBP3 protein Q9H6Z4 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity relocalization 9606 19289081 YES lperfetto RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner. 0.39 SIGNOR-232116 PAX8 protein Q06710 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14623893 YES miannu Pax8 has an essential role in thyroid organogenesis and differentiation, being the main mediator of thyroid gene transcription, including the NIS gene. 0.408 SIGNOR-251990 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Lys) smallmolecule CHEBI:29185 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269490 hsa-mir-200b-3p mirna URS000014D9C1_9606 RNAcentral PMAIP1 protein Q13794 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000007 38503887 YES miannu Noxa inhibits oncogenesis through ZNF519 in gastric cancer and is suppressed by hsa-miR-200b-3p 0.4 SIGNOR-279972 TACR1 protein P25103 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256776 CHEK1 protein O14757 UNIPROT BLM protein P54132 UNIPROT up-regulates phosphorylation Ser646 LKHERFQsLSFPHTK 9606 20719863 YES llicata Hese results indicated that chk1-mediated phosphorylation on blm at ser(646) might be a determinant for regulating subnuclear localization and could act as a marker for the activation status of blm in response to dna damage. 0.78 SIGNOR-167534 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 10090 BTO:0000944 15367694 YES Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes 0.893 SIGNOR-252606 MECP2 protein P51608 UNIPROT miR-199a mirna URS0000759977_9606 RNAcentral up-regulates quantity by expression post transcriptional regulation 9606 24708856 YES miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. 0.4 SIGNOR-255765 PRKD3 protein O94806 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity phosphorylation Ser358 WPLSRTRsEPLPPSA 18692497 YES Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7 lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. 0.2 SIGNOR-275934 CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR coenzyme Q10 smallmolecule CHEBI:46245 ChEBI up-regulates quantity chemical modification 9606 14977419 YES miannu The bc1 complexes are intrinsic membrane proteins that catalyze the oxidation of ubihydroquinone and the reduction of cytochrome c in mitochondrial respiratory chains and bacterial photosynthetic and respiratory chains. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis. 0.8 SIGNOR-280291 Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR dioxygen smallmolecule CHEBI:15379 ChEBI down-regulates quantity chemical modification 9606 10563795 YES miannu Cytochrome c oxidase catalyzes the reduction of molecular oxygen to water, a process in which four electrons, four protons, and one molecule of oxygen are consumed. The reaction is coupled to the pumping of four additional protons across the membrane. According to the currently accepted concept, the pumping of all four protons occurs after the binding of oxygen to the reduced enzyme and is exclusively coupled to the last two electron transfer steps.  0.8 SIGNOR-280294 Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR water smallmolecule CHEBI:15377 ChEBI up-regulates quantity chemical modification 9606 10563795 YES miannu Cytochrome c oxidase catalyzes the reduction of molecular oxygen to water, a process in which four electrons, four protons, and one molecule of oxygen are consumed. The reaction is coupled to the pumping of four additional protons across the membrane. According to the currently accepted concept, the pumping of all four protons occurs after the binding of oxygen to the reduced enzyme and is exclusively coupled to the last two electron transfer steps.  0.8 SIGNOR-280295 ULK2 protein Q8IYT8 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates activity phosphorylation 9606 33135781 YES miannu When mTOR is inhibited, ULK1 and ULK2 activate and phosphorylate ATG13 and FIP200. 0.746 SIGNOR-280159 HCCS protein P53701 UNIPROT CYCS protein P99999 UNIPROT up-regulates activity chemical modification 9606 10563795 YES miannu Cytochrome c oxidase catalyzes the reduction of molecular oxygen to water, a process in which four electrons, four protons, and one molecule of oxygen are consumed. The reaction is coupled to the pumping of four additional protons across the membrane. According to the currently accepted concept, the pumping of all four protons occurs after the binding of oxygen to the reduced enzyme and is exclusively coupled to the last two electron transfer steps.  0.44 SIGNOR-280296 heme b smallmolecule CHEBI:26355 ChEBI CYCS protein P99999 UNIPROT up-regulates activity chemical modification 9606 23150584 YES miannu Spectroscopic analyses of HCCS alone and complexes of HCCS with site-directed variants of cytochrome c revealed the fundamental steps of heme attachment and maturation. A conserved histidine in HCCS (His154) provided the key ligand to the heme iron. Formation of the HCCS:heme complex served as the platform for interaction with apocytochrome c.  0.8 SIGNOR-280297 HCCS protein P53701 UNIPROT heme b smallmolecule CHEBI:26355 ChEBI up-regulates activity binding 9606 23150584 YES miannu Spectroscopic analyses of HCCS alone and complexes of HCCS with site-directed variants of cytochrome c revealed the fundamental steps of heme attachment and maturation. A conserved histidine in HCCS (His154) provided the key ligand to the heme iron. Formation of the HCCS:heme complex served as the platform for interaction with apocytochrome c.  0.8 SIGNOR-280298 Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates 9606 28185716 YES miannu CII (SDH) comprises four subunits (SDHA, SDHB, SDHC, and SDHD) encoded by nuclear DNA (nDNA). In additional to its role in OXPHOS, SDH is a component of the TCA cycle, making a functional link between these two essential processes [2–6]. In the TCA cycle, SDH oxidizes succinate to fumarate [3,7]. As part of OXPHOS, SDH transfers electrons from succinate via its [Fe–S] clusters to ubiquinone (UbQ) 0.7 SIGNOR-280301 Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR ubiquinol-10 smallmolecule CHEBI:64183 ChEBI up-regulates quantity chemical modification 9606 28185716 YES miannu CII (SDH) comprises four subunits (SDHA, SDHB, SDHC, and SDHD) encoded by nuclear DNA (nDNA). In additional to its role in OXPHOS, SDH is a component of the TCA cycle, making a functional link between these two essential processes [2–6]. In the TCA cycle, SDH oxidizes succinate to fumarate [3,7]. As part of OXPHOS, SDH transfers electrons from succinate via its [Fe–S] clusters to ubiquinone (UbQ) 0.8 SIGNOR-280300 ABL1 protein P00519 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation 9606 29025973 YES miannu SFKs and Abl differentially phosphorylate DCBLD1 and DCBLD2 at distinct tyrosine phosphorylation sites.|We report that Src family kinases and Abl differentially promote the interaction between the CRKL-SH2 domain and DCBLD1 and DCBLD2, and while Src family kinases and Abl each promote DCBLD1 and DCBLD2 binding to the CRKL-SH2 domain, the effect of Abl is more pronounced for DCBLD1. 45999997={Domain=45999998 LikeProtein=1399} 45999998="sh2 domain" 45999999="sh2 domain"} 0.2 SIGNOR-280167 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 16778204 YES gcesareni Ptprj expression induces dephosphorylation of the ret(c634r) and, probably via an indirect mechanism, ret/ptc1 oncoproteins on two key ret autophosphorylation sites (tyr1062 and tyr905). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret 0.277 SIGNOR-147161 KAT6A/KAT6B complex SIGNOR-C54 SIGNOR TP53 protein P04637 UNIPROT up-regulates acetylation Lys120 FLHSGTAkSVTCTYS 9606 BTO:0001271 23431171 YES lperfetto We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression 0.495 SIGNOR-217194 UBE2I protein P63279 UNIPROT PLAG1 protein Q6DJT9 UNIPROT down-regulates sumoylation Lys244 NQELLKVkTEPVDFL 9606 15208321 YES miannu Sumoylation decreases the transcriptional activity of plag1 / plag1 is sumoylated at 2 specific lysine residues (lys-244 and lys-263) 0.277 SIGNOR-126044 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr288 QCPVGFNtLAFPSMK -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.767 SIGNOR-276136 MYO1E protein Q12965 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 10116 BTO:0000142 17257598 NO miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. 0.7 SIGNOR-265426 MAPK1 protein P28482 UNIPROT PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation Ser337 QLAKCVSsPHFQVAE 9606 16456541 YES gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. 0.512 SIGNOR-144313 TWIST1 protein Q15672 UNIPROT FN1 protein P02751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20646316 NO miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. 0.411 SIGNOR-255521 SIRT1 protein Q96EB6 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity 10090 BTO:0000165 12887892 YES gcesareni Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation 0.62 SIGNOR-241963 DZIP3 protein Q86Y13 UNIPROT H2AC18 protein Q6FI13 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271755 ALK protein Q9UM73 UNIPROT HES1 protein Q14469 UNIPROT up-regulates activity phosphorylation 9606 35640677 YES miannu NPM-ALK also directly phosphorylates HES1 protein. 0.267 SIGNOR-280181 CSNK1E protein P49674 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr50 FSTTPGGtRIIYDRK 9606 BTO:0000150 24247720 YES lperfetto Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation. 0.2 SIGNOR-203276 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Ser2056 VQSYSYSsQDPRPAT 9606 17189255 YES llicata Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, in addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair. 0.2 SIGNOR-151445 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9823 BTO:0001840 SIGNOR-C3 23486913 YES lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation 0.926 SIGNOR-219273 WWTR1 protein Q9GZV5 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 NO gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. 0.7 SIGNOR-199211 BTK protein Q06187 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT BTO:0000776 10880360 YES lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. 0.671 SIGNOR-249313 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-264179 GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 9606 BTO:0001412 10570290 YES GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. 0.912 SIGNOR-236792 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH19 protein Q9H159 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265836 PRKAA1 protein Q13131 UNIPROT ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 SIGNOR-C15 17097062 YES gcesareni Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp. 0.2 SIGNOR-150590 IL1B protein P01584 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 NO miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. 0.2 SIGNOR-254806 ATR protein Q13535 UNIPROT CHKA protein P35790 UNIPROT up-regulates activity phosphorylation 9606 16085356 YES miannu In particular, ATR phosphorylates Chk 1 and ATM signals to Chk 2. 0.248 SIGNOR-280184 CAMK2G protein Q13555 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser605 AGPTRQAsQAGPVPR 3118371 YES llicata Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II. 0.447 SIGNOR-250708 TAF3 protein Q5VWG9 UNIPROT TAF3/TRF3 complex SIGNOR-C23 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 18851836 YES lperfetto We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation 0.664 SIGNOR-181611 AKT proteinfamily SIGNOR-PF24 SIGNOR INSIG2 protein Q9Y5U4 UNIPROT down-regulates activity 10090 BTO:0000759 21723501 NO MTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. 0.2 SIGNOR-256212 NTRK1 protein P04629 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9856458 YES lperfetto Two substrates of trk kinases, raps and sh2-b. raps and sh2-b mediate trk signaling in developing neurons 0.546 SIGNOR-62619 MAPK8 protein P45983 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates activity phosphorylation Ser6 sWLSRSVT 9606 25310587 YES miannu JNK1\u2011mediated phosphorylation of Smac/DIABLO at the serine 6 residue is functionally linked to its mitochondrial release during TNF\u2011\u03b1-\u2011induced apoptosis of HeLa cells. 0.371 SIGNOR-280029 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR up-regulates relocalization 9606 25627476 YES lperfetto One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP.  0.2 SIGNOR-280302 CSF3 protein P09919 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252287 Sin3B_complex complex SIGNOR-C409 SIGNOR H3C15 protein Q71DI3 UNIPROT down-regulates activity binding 9606 BTO:0000007 21041486 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.2 SIGNOR-266974 SREBF1 protein P36956 UNIPROT ELOVL proteinfamily SIGNOR-PF93 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 18226595 YES Luana These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c. 0.452 SIGNOR-267944 SKI protein P12755 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates activity binding 9606 12793438 YES lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway 0.774 SIGNOR-253301 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 22710723 YES lperfetto Furthermore, we demonstrate that src phosphorylates p130cas y128. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation 0.802 SIGNOR-197927 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr112 EGMQIPStQFDAAHP -1 12432063 YES miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  0.555 SIGNOR-275997 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFKL protein P17858 UNIPROT up-regulates activity binding 9606 19454274 YES The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux 0.8 SIGNOR-267266 MAPK1 protein P28482 UNIPROT RGS19 protein P49795 UNIPROT up-regulates phosphorylation Ser151 EDYVSILsPKEVSLD 9606 15488168 YES gcesareni Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation. 0.475 SIGNOR-129883 EHF protein Q9NZC4 UNIPROT SPRR1B protein P22528 UNIPROT up-regulates quantity by expression transcriptional regulation 12682075 NO Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3 0.239 SIGNOR-254280 RAB1A protein P62820 UNIPROT ULK1 protein O75385 UNIPROT up-regulates activity relocalization 9606 27334615 YES Sara C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation 0.532 SIGNOR-261299 THRA protein P10827 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 15650024 YES gcesareni Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs 0.414 SIGNOR-133243 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18997794 YES gcesareni A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution. 0.892 SIGNOR-182137 CBL protein P22681 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 10514377 YES miannu Ubiquitination of the PDGF β-receptor (Rβ) by the c-Cbl RING in an SH2-dependent manner. 0.628 SIGNOR-272553 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1196 GAVENPEyLTPQGGA 9606 BTO:0000007 25081058 YES lperfetto PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. 0.67 SIGNOR-262596 ADNP protein Q9H2P0 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 24365867 NO miannu Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes. 0.25 SIGNOR-266760 PRKN protein O60260 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28038320 YES miannu In cells, we found BCL-XL levels were reduced by overexpression of PARK2, but this catalytic activity was blocked by the proteasome inhibitor MG132, suggesting degradation of BCL-XL protein by PARK2 is dependent on the proteasome system (XREF_FIG A).|PARK2 directly binds to and ubiquitinates BCL-XL. 0.2 SIGNOR-278661 GNB2 protein P62879 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 23074268 NO gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. 0.2 SIGNOR-199132 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser138 SLQLGAVsPGTLTPT 9606 BTO:0001938 21364637 YES miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells 0.2 SIGNOR-277642 CREB5 protein Q02930 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 9534 BTO:0000318 8378084 YES miannu CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription 0.511 SIGNOR-219634 UBQLN4 protein Q9NRR5 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity binding 9606 BTO:0001938 30612738 YES lperfetto These data suggest that MRE11 is one of probably many UBQLN4 interaction partners. >Particularly HRR is dependent on ATM activity (Dietlein et al., 2014). Here, we showed that UBQLN4 is an ATM substrate and that DSB sealing is markedly impaired in UBQLN4-depleted cells. HRR depends on a 5′-3′ DSB end resection, which is initiated by the MRE11 nuclease 0.2 SIGNOR-265077 threonine smallmolecule CHEBI:26986 ChEBI Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates quantity precursor of 9606 25824639 YES miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 0.8 SIGNOR-270508 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2E2 protein Q96LR5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.628 SIGNOR-271351 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249320 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr583 RRPPGLEyCYNPSHN 10116 BTO:0003293 19224897 YES lperfetto Autophosphorylation of Y653 is followed by the ordered autophosphorylation of several key tyrosine residues within binding sites for the SH2 or PTB domains of signaling proteins that bind to and are phosphorylated by activated FGFR1. This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region 0.2 SIGNOR-235906 NUDT21 protein O43809 UNIPROT CFI complex complex SIGNOR-C388 SIGNOR form complex binding 9606 8626397 YES lperfetto We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity. 0.949 SIGNOR-266122 ZFPM2 protein Q8WW38 UNIPROT GATA4 protein P43694 UNIPROT down-regulates activity binding 10090 BTO:0000944 9927675 YES miannu FOG-2 associates physically with the N-terminal zinc finger of GATA-4 both in vitro and in vivo. This interaction appears to modulate specifically the transcriptional activity of GATA-4 because overexpression of FOG-2 in both NIH 3T3 cells and primary rat cardiomyocytes represses GATA-4-dependent transcription from multiple cardiac-restricted promoters. 0.782 SIGNOR-236959 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAG3 protein O95817 UNIPROT up-regulates activity phosphorylation Ser289 RSSTPLHsPSPIRVH 9606 BTO:0000016 27659916 YES miannu ERK-dependent phosphorylation of BIS following H2O2 treatment. 0.2 SIGNOR-274070 FOXO proteinfamily SIGNOR-PF27 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000007 14976264 NO lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress 0.7 SIGNOR-252938 TEK protein Q02763 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 NO lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. 0.272 SIGNOR-241532 CDK5 protein Q00535 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates quantity by destabilization phosphorylation Ser789 QSVDKVTsPTKV 9606 21791703 YES miannu Together, these data demonstrate that phosphorylation of caldesmon on Ser527 by Cdk5 serves to down regulate its stability. 0.341 SIGNOR-280215 MYT1 protein Q01538 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005949 30312684 YES miannu Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth. 0.2 SIGNOR-266777 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT up-regulates activity phosphorylation Tyr525 NRHIDRNyEPLKTQP 9606 28214294 YES miannu Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. 0.358 SIGNOR-263190 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr95 AYDSHTNtYYLQTFG 9606 BTO:0000007 21321328 YES miannu We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. 0.578 SIGNOR-263132 COL1A1 protein P02452 UNIPROT DDR1 protein Q08345 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 YES lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  0.336 SIGNOR-272340 ETV2 protein O00321 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0001086 24583263 NO irozzo Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation. 0.7 SIGNOR-256009 PLCB1 protein Q9NQ66 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification -1 23880553 YES miannu Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. 0.8 SIGNOR-256496 HK2 protein P52789 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266456 MRPL33 protein O75394 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.697 SIGNOR-262364 NIPBL protein Q6KC79 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates activity binding 9606 28914604 YES miannu Scc2 (Nipbl) stimulates cohesin’s ABC-like ATPase and is essential for loading cohesin onto chromosomes. However, it is possible that the stimulation of cohesin’s ATPase by Scc2 also has a post-loading function, for example driving loop extrusion. Using fluorescence recovery after photobleaching (FRAP) and single-molecule tracking in human cells, we show that Scc2 binds dynamically to chromatin, principally through an association with cohesin. 0.846 SIGNOR-264522 ROCK1 protein Q13464 UNIPROT KCNK3 protein O14649 UNIPROT down-regulates phosphorylation Ser336 IPRDLSTsDTCVEQS 9606 21838752 YES lperfetto Task1 channels contain two putative rho kinase phosphorylation sites, ser(336) and ser(393) . Mutation of ser(393) rendered task1 channels insensitive to et(a) - or et(b)-mediated current inhibition. In contrast, removal of ser(336) selectively attenuated et(a) -dependent task1 regulation without affecting the et(b) pathway. 0.2 SIGNOR-176025 IC-87114 chemical CHEBI:90686 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252662 MAPK8 protein P45983 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser422 AHPPHAPsPGQTVKP 9606 BTO:0000551 16984892 YES lperfetto In this study, we found that c-jun nh2-terminal kinase 1 activation triggered ctbp phosphorylation on ser-422 and subsequent degradation, 0.358 SIGNOR-149721 TUBB protein P07437 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 17429065 YES lpetrilli Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. 0.2 SIGNOR-154319 CSNK2B protein P67870 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 YES lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. 0.27 SIGNOR-275745 DNMT3B protein Q9UBC3 UNIPROT HOXB13 protein Q92826 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 22808286 NO miannu EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. 0.256 SIGNOR-254145 MED24 protein O75448 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.781 SIGNOR-266666 HIF1A protein Q16665 UNIPROT P4HA1 protein P13674 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003081 40332386 YES miannu Hypoxia upregulates P4HA1 expression in PDAC PDOs through HIF1α. Our results show that the treatment of PDO4 and PDO11 cells with 10 μmol/L of PX-478 for 24 hours reduced the levels of P4HA1 in hypoxia (Fig. 2F), suggesting P4HA1 expression in hypoxia is regulated by HIF1α expression. 0.314 SIGNOR-279840 KAT2B protein Q92831 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates acetylation 9606 BTO:0000887 10944526 YES gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo 0.646 SIGNOR-81056 MAPK1 protein P28482 UNIPROT HNRNPH1 protein P31943 UNIPROT unknown phosphorylation Ser104 LKHTGPNsPDTANDG 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262776 NFATC1 protein O95644 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001260 17079331 YES lperfetto The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. 0.415 SIGNOR-251730 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser109 KERRRTEsINSAFAE 9606 14636580 YES lperfetto In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues.  0.289 SIGNOR-249242 DOT1L protein Q8TEK3 UNIPROT MYC protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0001939 26199140 YES 1 miannu Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1 0.334 SIGNOR-239362 RPS6KA5 protein O75582 UNIPROT H2AC11 protein P0C0S8 UNIPROT up-regulates phosphorylation Ser2 sGRGKQGG 9606 15010469 YES gcesareni We found that msk1 phosphorylated histone h2a on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by msk1. 0.2 SIGNOR-123383 pazopanib hydrochloride chemical CHEBI:71217 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 17620431 YES miannu Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases.  0.8 SIGNOR-259165 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr585 PPGLEYCyNPSHNPE 10116 BTO:0002809;BTO:0001009 8622701 YES lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 0.2 SIGNOR-236187 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser89 KTEESPAsDEAGEKE 9606 10739259 YES lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. 0.2 SIGNOR-76274 PPP2R5C protein Q13362 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 16456541 YES gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk 0.512 SIGNOR-144325 PPP1CA protein P62136 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 YES Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. 0.357 SIGNOR-248566 LIMS1 protein P48059 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 YES lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. 0.749 SIGNOR-265763 FANCD2 protein Q9BXW9 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates activity relocalization 9606 15199141 YES lperfetto FANCD2-Ub then promotes BRCA2 loading into a chromatin complex. 0.812 SIGNOR-263253 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Phe55 PNDKYEPfWEDEEKN -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.582 SIGNOR-263563 DENR protein O43583 UNIPROT JAK2 protein O60674 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004163 35440133 YES miannu DENR directly regulates JAK2 expression. 0.2 SIGNOR-269675 SMAD6 protein O43541 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates binding 9606 19352540 YES gcesareni Mad6-pellino-1 interaction abrogated signaling mediated by a complex of irak1. 0.333 SIGNOR-185128 SP1 protein P08047 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000552 12954631 NO miannu these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter. 0.2 SIGNOR-253903 Cyclopamine chemical CHEBI:4021 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191227 EAF2 protein Q96CJ1 UNIPROT ELL protein P55199 UNIPROT up-regulates binding 9606 16006523 YES miannu The eaf1-related eaf2 protein is also a positive regulator of ell elongation activity 0.745 SIGNOR-138540 H3C1 protein P68431 UNIPROT CPC complex SIGNOR-C554 SIGNOR up-regulates quantity binding 9606 BTO:0000567 24413556 YES miannu Histone modifications coordinate the chromatin localization of key regulatory factors in mitosis. For example, mitotic phosphorylation of Histone H3 threonine-3 (H3T3ph) by Haspin creates a binding site for the chromosomal passenger complex (CPC). 0.2 SIGNOR-275422 GATA6 protein Q92908 UNIPROT CYP17A1 protein P05093 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002850 BTO:0000975 15284005 NO miannu The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells. 0.345 SIGNOR-254198 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUND protein P17535 UNIPROT up-regulates phosphorylation 9606 22327296 YES inferred from 70% family members gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. 0.2 SIGNOR-270183 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser291 PVSSLQAsVPGSVPG 9606 16027724 YES miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation 0.415 SIGNOR-250094 cabozantinib chemical CHEBI:72317 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 21606412 YES miannu XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. 0.8 SIGNOR-259321 CSNK2A1 protein P68400 UNIPROT BRMS1 protein Q9HCU9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser30 MNGEEEEsEEERSGS -1 26980766 YES miannu We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2α') phosphorylation of nuclear BRMS1 on serine 30 (S30), resulting in 14-3-3ε-mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome-induced BRMS1 degradation. 0.472 SIGNOR-266407 USF1 protein P22415 UNIPROT JMJD1C protein Q15652 UNIPROT up-regulates activity binding 9606 BTO:0000759 32034158 YES miannu We show that, by direct interaction with USF-1, JMJD1C is recruited to lipogenic promoters. We also show that JMJD1C is phosphorylated at T505 by mammalian target of rapamyci (mTOR) to be recruited to lipogenic genes in response to insulin/feeding. 0.2 SIGNOR-265167 KLHL12 protein Q53G59 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 32433973 YES miannu   Lunapark Is Ubiquitylated by the CRL3KLHL12 Ubiquitin Ligase Complex. Taken together, these results demonstrate that Lunapark is ubiquitylated by the CRL3KLHL12 ubiquitin ligase, and the CRL3KLHL12-dependent ubiquitylation of Lunapark does not lead to its proteasomal degradation. Inhibition of Lunapark Ubiquitylation Affects Lysosomal Recruitment of mTORC2 0.532 SIGNOR-272198 NKX2-5 protein P52952 UNIPROT ANKRD1 protein Q15327 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003265 9043061 NO Finally, a carp promoter-lacZ transgene, which displays cardiac-specific expression in wild-type and Nkx2-5(+/-) background, was also significantly reduced in Nkx2-5(-/-) embryos, indicating that Nkx2-5 either directly or indirectly regulates carp promoter activity during in vivo cardiogenesis as well as in cultured cardiac myocytes 0.336 SIGNOR-253646 MAPK1 protein P28482 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser544 RSVTMRKsQRSSKGS 9606 21297032 YES The effect has been demonstrated using Q96PH1-4 gcesareni These results suggest that the mek/erk1/2 pathway is necessary but not sufficient to regulate the pma-dependent activation of nox5. 0.326 SIGNOR-171847 FASN protein P49327 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization 9606 BTO:0001130 18838960 NO lperfetto Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer 0.268 SIGNOR-242878 CDH1 protein P12830 UNIPROT FBXO31 protein Q5XUX0 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 YES miannu Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT. 0.2 SIGNOR-277377 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0001412 8692915 YES The SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites. The functional significance of the c-Abl-SHPTP1 interaction is supported by the demonstration that, like c-Abl, SHPTP1 regulates the induction of Jun kinase activity following DNA damage. 0.414 SIGNOR-251433 PPP1CA protein P62136 UNIPROT SP3 protein Q02447 UNIPROT down-regulates activity dephosphorylation 9606 12684058 YES miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. 0.2 SIGNOR-251953 PTK2B protein Q14289 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation 9606 15263022 YES miannu Pyk2 knockdown also decreased p130Cas.|p130Cas and paxillin can be phosphorylated by Fak or Pyk2, and bind directly to these kinases. 0.781 SIGNOR-280100 TACR1 protein P25103 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257249 RNA Polymerase III complex SIGNOR-C389 SIGNOR small nuclear RNA smallmolecule CHEBI:74035 ChEBI up-regulates quantity chemical modification 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-266144 hsa-miR-451a mirna URS00002E857A_9606 RNAcentral IL6R protein P08887 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004602 25623956 YES Tiberia Transfection of endothelial cells with pre-miR-451 reduced the protein and mRNA levels of IL-6R, compared to control groups. 0.4 SIGNOR-279896 SRC protein P12931 UNIPROT HK2 protein P52789 UNIPROT up-regulates activity phosphorylation 9606 28054552 YES miannu Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate limiting enzymes in glycolysis.|Moreover, c-Src could efficiently stimulate the catalytic activities of HK1 and HK2, but failed to stimulate their corresponding mutants (XREF_FIG and XREF_SUPPLEMENTARY). 0.362 SIGNOR-278499 eIF4F_complex complex SIGNOR-C44 SIGNOR 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.847 SIGNOR-269166 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2L3 protein P68036 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.474 SIGNOR-271360 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser758 TSTETRSsSSESSHS 9606 15568999 YES lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. 0.2 SIGNOR-131407 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Thr142 DSVTKLLtDVQLMKG -1 35080342 YES miannu Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9. 0.405 SIGNOR-277579 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQA2 protein P01906 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.27 SIGNOR-253996 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEP76 protein Q8TAP6 UNIPROT down-regulates activity phosphorylation Ser83 VEQELPSsPKQPICF 9606 BTO:0000007 27065328 YES miannu Cep76 is phosphorylated by cyclin A/CDK2 at a single site S83. These data suggest that the phosphomimetic mutant is functional and that phosphorylation at S83 is critical for Cep76 to suppress centriole amplification. 0.3 SIGNOR-262603 JAG1 protein P78504 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 18660822 YES Binding Calcium-dependent. gcesareni Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch. 0.638 SIGNOR-179622 NDUFS6 protein O75380 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.844 SIGNOR-262180 PPP1CA protein P62136 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 YES Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. 0.314 SIGNOR-248556 tiotropium chemical CHEBI:90960 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition -1 8441333 YES miannu A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors. 0.8 SIGNOR-258486 U50488 chemical CHEBI:73358 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258826 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Ser1107 SQIDVALsQDSTYQG 9606 23356578 YES lperfetto Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively 0.971 SIGNOR-200789 DAMPS stimulus SIGNOR-ST18 SIGNOR AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates 9606 25720354 NO scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 0.7 SIGNOR-267856 ASCL1 protein P50553 UNIPROT DKK1 protein O94907 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000527 23707066 YES gcesareni We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. 0.306 SIGNOR-245885 SKP1 protein P63208 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR form complex binding 9606 15340381 YES gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. 0.936 SIGNOR-243760 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 YES miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 0.2 SIGNOR-268220 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr743 PQAHYNMyPQNPDSV 9606 BTO:0000007;BTO:0000150 11751923 YES llicata Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor. 0.829 SIGNOR-113401 CSNK2A1 protein P68400 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser739 EIIVLSDsD 9606 21474068 YES lperfetto Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors. 0.327 SIGNOR-173109 KCNH2 protein Q12809 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 35442831 YES miannu One such mechanism is operant in colorectal cancer (CRC) cells. On integrin-dependent CRC cell adhesion, the Kv11.1/β1 integrin complex recruits the PI3K p85 subunit, which stimulates AKT phosphorylation and thus regulates autophagy 0.2 SIGNOR-277613 glutamic acid smallmolecule CHEBI:18237 ChEBI KAR proteinfamily SIGNOR-PF57 SIGNOR up-regulates activity chemical activation 9606 15919192 YES miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. 0.8 SIGNOR-264694 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr179 LGSKGQKtTQNRYSF -1 23444369 YES miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. 0.267 SIGNOR-273489 TRAF7 protein Q6Q0C0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15001576 NO miannu Overexpression of traf7 induced caspase-dependent apoptosis. 0.7 SIGNOR-123218 hsa-mir-148b-3p mirna URS0000521626_9606 RNAcentral CYBB protein P04839 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0003292 28235791 YES Tiberia MiR-148b can regulate the expression of CYBB and its downstream products in human and murine macrophages. In vitro and in vivo studies in mice have confirmed that PK3-miRNA particles can inhibit the expression and activity of CYBB and significantly improve infarct size and acute cardiac function after myocardial infarction. 0.4 SIGNOR-279899 hsa-mir-204-5p mirna URS000029D9F1_9606 RNAcentral CYBB protein P04839 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0003292 28235791 YES Tiberia MiR-204 can regulate the expression of CYBB and its downstream products in human and murine macrophages. In vitro and in vivo studies in mice have confirmed that PK3-miRNA particles can inhibit the expression and activity of CYBB and significantly improve infarct size and acute cardiac function after myocardial infarction. 0.4 SIGNOR-279900 Riluzole chemical CHEBI:8863 ChEBI KCNN4 protein O15554 UNIPROT up-regulates activity chemical activation 9606 18955585 YES Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  0.8 SIGNOR-258022 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity deacetylation 9606 20640476 YES lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 0.798 SIGNOR-209962 CCR1 protein P32246 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 25230753 NO CCL3, an eosinophil precursor-produced chemokine that signals through CCR1, promotes terminal differentiation of CCR1-positive eosinophil precursors in the absence of IL-5, highlighting an autocrine loop capable of sustaining eosinophil differentiation 0.7 SIGNOR-254369 MYC protein P01106 UNIPROT ITGA7 protein Q13683 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14525975 NO lperfetto This report provides evidence that alpha7 gene expression during muscle differentiation is regulated by the c-Myc transcription factor. In myoblasts, alpha7 is expressed at basal levels, but following conversion to myotubes the expression of the integrin is strongly elevated. The increased alpha7 mRNA and protein levels following myogenic differentiation are inversely correlated with c-Myc expression. Transfection of myoblasts with the c-Myc transcription factor down-regulated alpha7 expression 0.2 SIGNOR-241769 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 19433246 YES miannu Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic. 0.8 SIGNOR-268745 SRC protein P12931 UNIPROT CD46 protein P15529 UNIPROT up-regulates activity phosphorylation Tyr321 ASGPRPTyKPPVSNY 9606 11901164 YES miannu Src kinase phosphorylates CD46 at Y354 of the Cyt2 isoform in vitro. 0.458 SIGNOR-280127 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -1 2413024 YES lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 0.49 SIGNOR-248871 IL4 protein P05112 UNIPROT IL13RA1 protein P78552 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 YES milica It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1. 0.781 SIGNOR-100759 PLK1 protein P53350 UNIPROT STK38 protein Q15208 UNIPROT down-regulates activity phosphorylation Thr407 EIKSIDDtSNFDEFP 9606 BTO:0000567 26057687 YES miannu Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis.  0.316 SIGNOR-276915 FGF12 protein P61328 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.301 SIGNOR-253440 SMURF1 protein Q9HCE7 UNIPROT SLAIN2 protein Q9P270 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272696 FYN protein P06241 UNIPROT TXK protein P42681 UNIPROT up-regulates activity phosphorylation Tyr420 RYVLDDEyVSSFGAK 11353545 YES lperfetto We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association. 0.348 SIGNOR-249341 MAPK3 protein P27361 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9606 16705159 YES 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner 0.521 SIGNOR-146747 PTPRB protein P23467 UNIPROT TEK protein Q02763 UNIPROT down-regulates activity dephosphorylation 9606 34417472 YES miannu Simultaneous inhibition of Tie2 cleavage and VE-PTP synergistically enhances Tie2 activation by up to 10-fold (Fig. 7A).|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects  .|Tie2 activation is also importantly regulated by vascular endothelial protein tyrosine phosphatase (VE-PTP), which dephosphorylates Tie2 to inhibit its vascular stabilizing effects. 0.556 SIGNOR-277059 TBK1 protein Q9UHD2 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 11815618 YES lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha. 0.457 SIGNOR-246643 FOXS1 protein O43638 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by repression transcriptional regulation 9913 18288644 YES Luana Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4. 0.2 SIGNOR-261610 PAX8 protein Q06710 UNIPROT TG protein P01266 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11786384 YES miannu The transcription factor Pax8 plays an important role in the expression of the differentiated phenotype of thyroid follicular cells. It has recently been shown that Pax8 is necessary for thyroglobulin (Tg) gene expression. 0.458 SIGNOR-251998 SOD3 protein P08294 UNIPROT hydrogen peroxide smallmolecule CHEBI:16240 ChEBI up-regulates quantity chemical modification 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272273 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI PIN1 protein Q13526 UNIPROT down-regulates activity chemical inhibition 9606 30093655 YES ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. 0.8 SIGNOR-259925 STK4 protein Q13043 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Thr253 PDPGMSLtDRGVMSY 9606 32174922 YES miannu Beyond that, another investigation demonstrated that MST1 directly phosphorylated IRF3 at T75 and T253, which disrupted the dimerization of IRF3 and restrained RLRs and cGAS-mediated innate antiviral response. 0.2 SIGNOR-280144 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT down-regulates quantity by destabilization phosphorylation Ser146 PALEVSDsESDEALV 9606 BTO:0000567 10618498 YES llicata Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo 0.307 SIGNOR-251041 CPN1 protein P15169 UNIPROT HBA1 protein P69905 UNIPROT down-regulates activity cleavage Tyr141 STVLTSKyR -1 8635221 YES miannu Both human plasma carboxypeptidase N (CPN) and membrane-bound carboxypeptidase M (CPM) released the C-terminal arginine (alpha-Arg141) of the alpha chain of human adult hemoglobin. Thus, the hydrolysis of hemoglobin by CPM and CPN demonstrated the contribution of the alpha-Arg141 residue to sustaining the tetrameric structure of hemoglobin and its normal oxygen affinity and vasoactivity. 0.2 SIGNOR-256508 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UBTF protein P17480 UNIPROT up-regulates phosphorylation Ser389 INKKQATsPASKKPA 9606 11698641 YES lperfetto Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity 0.364 SIGNOR-217304 RalGAP2 complex SIGNOR-C469 SIGNOR RALA protein P11233 UNIPROT down-regulates activity guanine nucleotide exchange factor 10090 BTO:0000011 21148297 YES miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. RGC2 negatively regulates RalA activity in adipocytes. When immunoprecipitated from cell lysates of 3T3-L1 adipocytes by an anti-RGC2 antibody, RGC proteins efficiently enhanced GTP hydrolysis of recombinant RalA in vitro, compared with RalA alone or RalA incubated with various control immunoprecipitates (Figure 2C). 0.516 SIGNOR-269796 tipifarnib chemical CHEBI:141969 ChEBI FNTA protein P49354 UNIPROT down-regulates activity chemical inhibition 9606 11196150 YES lperfetto In vitro, using isolated human farnesyl protein transferase, R115777 competitively inhibited the farnesylation of lamin B and K-RasB peptide substrates, with IC50s of 0.86 nM and 7.9 nM, respectively. In a panel of 53 human tumor cell lines tested for growth inhibition, approximately 75% were found to be sensitive to R115777. 0.8 SIGNOR-262033 MAPK3 protein P27361 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser291 TYVNNSPsPGFNSSH 9606 19237534 YES lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. 0.2 SIGNOR-184176 GFPT1 protein Q06210 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 21310273 YES miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans 0.8 SIGNOR-267818 SOX9 protein P48436 UNIPROT COL11A2 protein P13942 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 NO miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. 0.388 SIGNOR-251758 LRRK2 protein Q5S007 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 20067578 YES miannu LRRK2 phosphorylates MKK3 and MKK7 in vitro but has a relatively minor effect on MKK6 phosphorylation. 0.393 SIGNOR-279057 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248740 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser477 PQFSYSAsGTA 9606 BTO:0000093 24670654 YES gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation 0.416 SIGNOR-252450 mir-137 ncrna URS000232FB78_9606 RNAcentral SHANK2 protein Q9UPX8 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000793 29665782 YES miannu MiR-137 regulates SHANK2 expression by repressing protein translation rather than inducing mRNA degradation.  0.2 SIGNOR-279979 CSNK2A1 protein P68400 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser543 SIADMDFsALLSQIS 9606 10938077 YES llicata We demonstrate that casein kinase II (CKII) interacts with p65 in vivo and can phosphorylate p65 at serine 529 in vitro. A CKII inhibitor (PD144795) inhibited TNFalpha-induced p65 phosphorylation in vivo. Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential.  0.444 SIGNOR-250942 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI L-thyroxine smallmolecule CHEBI:18332 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. 0.8 SIGNOR-267038 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 23431053 YES milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity 0.85 SIGNOR-201282 MED13 protein Q9UHV7 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 YES miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. 0.802 SIGNOR-266684 MAPK3 protein P27361 UNIPROT MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 BTO:0000661 8960373 YES lperfetto Functional analysis of phosphorylation at serine 532 of human c-myb by map kinase. expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. Our data suggest that the mapk-dependent state of phosphorylation modifies the cellular function of c-myb by modulating its interaction with a putative inhibitory factor 0.301 SIGNOR-45348 glucose chemical CHEBI:17234 ChEBI PRKAA1 protein Q13131 UNIPROT down-regulates activity 10090 BTO:0000222 18477450 NO Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). 0.8 SIGNOR-256136 FOXO proteinfamily SIGNOR-PF27 SIGNOR PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22521266 YES gcesareni Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase). 0.2 SIGNOR-252924 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser380 EPDHYRYsDTTDSDP 9606 21779440 YES gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity 0.605 SIGNOR-161118 PRKN protein O60260 UNIPROT PHGDH protein O43175 UNIPROT down-regulates quantity by destabilization ubiquitination Lys330 SAFSPHTkPWIGLAE 9606 BTO:0000018;BTO:0003885 32478681 YES Luisa Parkin binds to PHGDH and degrades it through ubiquitination to inhibit serine synthesis, which contributes greatly to the tumor-suppressive function of Parkin. 0.2 SIGNOR-269075 NAE1 protein Q13564 UNIPROT NAE complex SIGNOR-C131 SIGNOR form complex binding 9606 25504797 YES lperfetto the NEDD8 E1-activating enzyme (NAE) is a heterodimer of APPBP1 and UBA3 corresponding to the N-terminal and C-terminal of the single polypeptide of the ubiquitin E1 respectively 0.966 SIGNOR-242907 PDPK1 protein O15530 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000007 15175348 YES lperfetto In vitro kinase assay revealed that the direct targets of pdk1 in the mapk pathway were the upstream mapk kinases mek1 and mek2. The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation 0.27 SIGNOR-236633 SUGT1 protein Q9Y2Z0 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 22869522 YES lperfetto Here we identify Sgt1, a cochaperone for Hsp90, as a novel Plk1 substrate during mitosis|This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone with the MIS12 complex to stabilize this complex at the kinetochores and thus coordinates the recruitment of the NDC80 complex to form efficient microtubule-binding sites. 0.272 SIGNOR-265224 AAK1 protein Q2M2I8 UNIPROT NUMB protein P49757 UNIPROT up-regulates phosphorylation Thr102 LRVVDEKtKDLIVDQ 9606 18657069 YES llicata Collectively, these observations demonstrate that numb endocytic activity is regulated by aak1 and that phosphorylation may be a critical step in promoting coated pit maturation. 0.46 SIGNOR-179606 PTCRA protein Q6ISU1 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 BTO:0000782 1717999 YES lperfetto Stimulation of the T-cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including phospholipase C (PLC) gamma 1 and the TCR zeta chain. We describe here a 70-kDa tyrosine phosphoprotein (ZAP-70) that associates with zeta within 15 sec following TCR stimulation. The phosphorylation of ZAP-70 and its association with zeta is independent of the other TCR chains 0.285 SIGNOR-134325 ITK protein Q08881 UNIPROT ITK protein Q08881 UNIPROT up-regulates activity phosphorylation Tyr180 ETVVIALyDYQTNDP 9606 BTO:0000782 12842872 YES lperfetto In this study, we present evidence for another mode of regulation for itk, the autophosphorylation of tyr-180 in the src homology 3 (sh3) domain. 0.2 SIGNOR-103170 ERBB3 protein P21860 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.719 SIGNOR-252673 hydromorphone chemical CHEBI:5790 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258037 PI4K2B protein Q8TCG2 UNIPROT 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI up-regulates quantity chemical modification 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269101 U0126 chemical CHEBI:90693 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 YES gcesareni Pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity and neuronal survival. Interestingly, erk5 activation by egf in cos7 cells is also blocked by these inhibitors suggesting that the erk5 pathway may also regulate cellular processes credited previously to erk1/2. 0.8 SIGNOR-104945 CALM1 protein P0DP23 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 YES gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.696 SIGNOR-114101 GRK2 protein P25098 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates phosphorylation Thr123 IVKCQKLtDDHVQFL 9606 BTO:0000801 17055984 YES lperfetto Phosphorylation of p38 by grk2 at the docking groove unveils a novel mechanism for inactivating p38mapk p38 associates with grk2 endogenously and is phosphorylated by grk2 at thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by mkk6 and diminishes the capacity of p38 to bind and phosphorylate its substrates 0.2 SIGNOR-150152 UNC13B protein O14795 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 YES miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. 0.717 SIGNOR-263972 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr447 SEELDENyVPMNPNS 10090 10978177 YES HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin 0.501 SIGNOR-251313 Skp1-Pam E3 complex SIGNOR-C537 SIGNOR TWIST1 protein Q15672 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.25 SIGNOR-272190 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 YES inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.2 SIGNOR-270214 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH9 protein Q9ULB4 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265849 SRP54 protein P61011 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR up-regulates activity binding -1 8816452 YES Monia We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65). 0.335 SIGNOR-261162 Netrin proteinfamily SIGNOR-PF97 SIGNOR DSCAM protein O60469 UNIPROT up-regulates activity binding 10090 BTO:0001279 18585357 YES miannu Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1. 0.2 SIGNOR-268173 CSRP3 protein P50461 UNIPROT MYOG protein P15173 UNIPROT up-regulates activity binding 10090 BTO:0004058 9234731 YES 2 miannu we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. 0.52 SIGNOR-241113 FYN protein P06241 UNIPROT IFITM3 protein Q01628 UNIPROT up-regulates quantity phosphorylation Tyr20 NSGQPPNyEMLKEEH 10090 BTO:0000452 24627473 YES miannu We determined that both mouse and human IFITM3 are phosphorylated by the protein-tyrosine kinase FYN on tyrosine 20 (Tyr(20)). Phosphorylation of IFITM3 on Tyr20 Leads to Plasma Membrane Accumulation. 0.453 SIGNOR-266304 PKA proteinfamily SIGNOR-PF17 SIGNOR PPM1B protein O75688 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 MIQRVNGsLAVSRAL 9606 BTO:0000007 23756813 YES miannu Here, we show that protein kinase A (PKA) phosphorylates the PP2Cβ, which was inhibited by PKA-specific inhibitor, H89. Mutation analysis of serine residues in PP2Cβ revealed that Ser-195 in PP2Cβ is phosphorylated by PKA. Importantly, PKA inhibition by H89 abrogated the Forskolin-induced destabilization of PP2Cβ against ubiquitin-dependent proteosomal degradation pathway. 0.2 SIGNOR-276494 FZD2 protein Q14332 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23151663 YES areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  0.666 SIGNOR-258956 AXL protein P30530 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates activity binding 9606 BTO:0000130 35022267 YES miannu Gas6 and its main receptor AXL are overexpressed in pancreatic cancer and their expression correlates with poor prognosis.Gas6/AXL signalling in cancer cells is associated with tumour cell proliferation, epithelial mesenchymal transition and metastases. 0.7 SIGNOR-277723 hsa-mir-431-5p mirna URS000043908D_9606 RNAcentral XIAP protein P98170 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004060 33023644 YES Tiberia MiR-431-5p directly targeted XIAP in RA FLS and showed an inverse correlation with XIAP levels in synovial tissues. Notably, XIAP silencing partially reversed the effects of miR-431-5p inhibition in RA FLS. 0.4 SIGNOR-279901 miR-130a mirna URS000039E12D_9606 RNAcentral PPARG protein P37231 UNIPROT down-regulates quantity post transcriptional regulation 9606 24057258 YES miannu MiR-142-3p downregulated MLL-AF4 expression in the RS4;11 leukemic cell line. the downregulation of MLL-AF4 by ectopically expressed miR-142-3p reduced the expression of MLL-AF4 downstream target genes, including HOXA7, HOXA9, and HOXA10, which may contribute to miR-142-3p-induced apoptosis and growth inhibition. 0.4 SIGNOR-255760 PBX1 protein P40424 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 21746878 YES miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. 0.308 SIGNOR-267239 FZD7 protein O75084 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 BTO:0004050 24018051 NO Parnian Knockdown of FZD7 led to decrease the expressions of the MDR1 mRNA and P-gp protein, indicating that FZD7 is involved in the regulation of multidrug resistance in HCC. 0.272 SIGNOR-277983 TBK1 protein Q9UHD2 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 YES miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. 0.59 SIGNOR-260157 NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 9606 7566092 YES Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. 0.95 SIGNOR-254381 ATM protein Q13315 UNIPROT TOP2B protein Q02880 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1135 HDDSSSDsGTPSGPD 9606 32015321 YES miannu Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation.ATM binds with and phosphorylates TOP2β at Ser1134 to promote its degradation by VM-26. 0.412 SIGNOR-277510 hsa-miR-138-5p mirna URS000040780F_9606 RNAcentral ADGRA2 protein Q96PE1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005518 24582749 YES Parnian MiR-138-5p reverses gefitinib resistance in non-small cell lung cancer cells via negatively regulating G protein-coupled receptor 124 0.4 SIGNOR-277982 ERBB2 protein P04626 UNIPROT hsa-miR-139-5p mirna URS000025D232_9606 RNAcentral down-regulates quantity by repression deacetylation 9606 BTO:0002392 21925125 NO HER2 stabilizes CD44 and activates MTA1/HDAC2 signaling, epigenetically silencing miR-139, leading to CXCR4 upregulation, promoting cancer cell invasion and metastasis 0.4 SIGNOR-277933 Ub:E2 complex SIGNOR-C497 SIGNOR RNF4 protein P78317 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271016 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 18042541 YES gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). 0.679 SIGNOR-252613 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258204 POLR2F protein P61218 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.867 SIGNOR-266139 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity phosphorylation Thr342 ASEKFAQtVMTSRIV 9606 BTO:0000876 24567333 YES lperfetto We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity 0.2 SIGNOR-204657 RELA protein Q04206 UNIPROT NPPB protein P16860 UNIPROT unknown transcriptional regulation 15837525 NO In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription. 0.2 SIGNOR-253651 (R)-carnitine smallmolecule CHEBI:16347 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-268108 RIPK1 protein Q13546 UNIPROT TAB3 protein Q8N5C8 UNIPROT up-regulates activity binding 9606 19927120 YES lperfetto Tab2 and tab3 activate the jun n-terminal kinase and nuclear factor-kappab pathways through the specific recognition of lys 63-linked polyubiquitin chains by its npl4 zinc-finger (nzf) domain. 0.573 SIGNOR-161787 WT1 protein P19544 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23042785 YES irozzo Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression. 0.38 SIGNOR-255904 EXOSC1 protein Q9Y3B2 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.959 SIGNOR-261381 YAP1 protein P46937 UNIPROT RRM2 protein P31350 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276569 tacedinaline chemical CHEBI:90195 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258008 MAPK9 protein P45984 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 YES gcesareni Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-188 0.2 SIGNOR-124031 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 8755651 YES scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3 0.8 SIGNOR-268127 Ub:E2 complex SIGNOR-C497 SIGNOR RBX1 protein P62877 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270993 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser450 SHNSALYsQVQKSGA 9606 15574499 YES amattioni Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility. 0.253 SIGNOR-131556 LCK protein P06239 UNIPROT LAX1 protein Q8IWV1 UNIPROT up-regulates activity phosphorylation Tyr268 SSQISNDyVNMTGLD 9606 BTO:0000007 12359715 YES miannu Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85.  0.4 SIGNOR-273526 THOC6 protein Q86W42 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 YES miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. 0.912 SIGNOR-268510 hydron chemical CHEBI:15378 ChEBI ATP synthase complex SIGNOR-C264 SIGNOR up-regulates activity chemical modification 9606 31115493 YES miannu The mammalian mitochondrial electron transport chain (ETC) includes complexes I‑IV, as well as the electron transporters ubiquinone and cytochrome c. There are two electron transport pathways in the ETC: Complex I/III/IV, with NADH as the substrate and complex II/III/IV, with succinic acid as the substrate. The electron flow is coupled with the generation of a proton gradient across the inner membrane and the energy accumulated in the proton gradient is used by complex V (ATP synthase) to produce ATP. 0.8 SIGNOR-280303 Complement C1 complex complex SIGNOR-C309 SIGNOR C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.642 SIGNOR-263424 SYK protein P43405 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 YES lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. 0.672 SIGNOR-246551 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Ser231 LSTSSSSsPPGTPSP 9606 phosphorylation:Ser237 SSPPGTPsPADAKAP 22369944 YES fspada However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs. 0.458 SIGNOR-196377 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.384 SIGNOR-129272 SBDS protein Q9Y3A5 UNIPROT EIF6 protein P56537 UNIPROT up-regulates 9606 BTO:0001271 21536732 NO miannu Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits 0.516 SIGNOR-173536 ANK3 protein Q12955 UNIPROT SPTBN1 protein Q01082 UNIPROT up-regulates activity binding 9606 BTO:0000007 17620337 YES miannu Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton. 0.643 SIGNOR-266711 AKT proteinfamily SIGNOR-PF24 SIGNOR SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8940145 NO gcesareni The constitutively active akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3t3-l1 adipocytes directed lipid but not glycogen synthesis 0.2 SIGNOR-45064 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid chemical CHEBI:94640 ChEBI MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates chemical activation 9606 Other YES Selleck|inferred from family member gcesareni 0.8 SIGNOR-270281 Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR coenzyme Q10 smallmolecule CHEBI:46245 ChEBI down-regulates quantity chemical modification 9606 28185716 YES miannu CII (SDH) comprises four subunits (SDHA, SDHB, SDHC, and SDHD) encoded by nuclear DNA (nDNA). In additional to its role in OXPHOS, SDH is a component of the TCA cycle, making a functional link between these two essential processes [2–6]. In the TCA cycle, SDH oxidizes succinate to fumarate [3,7]. As part of OXPHOS, SDH transfers electrons from succinate via its [Fe–S] clusters to ubiquinone (UbQ) 0.8 SIGNOR-280299 CD27 protein P26842 UNIPROT BIK protein Q13323 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12324477 NO gcesareni Bik expression was weakly but significantly down-regulated by cd27 but up-regulated by cd40. 0.2 SIGNOR-93323 RANBP2 protein P49792 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity relocalization 9606 BTO:0002932 28882106 YES irozzo RanBP2 can increase the sumoylation of p27kip1. In our study, the target protein p27kip1 mainly acts as a tumor-suppressor gene in the nucleus, RanBP2 and SUMO1 act as oncogenes by promoting the nuclear-cytoplasmic translocation and debilitate the G1-arrest brought by p27kip1 accumulation in the nucleus. 0.2 SIGNOR-259115 hsa-mir23a3p mirna URS00005540D2_9606 RNAcentral XIAP protein P98170 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000093 29113338 YES Tiberia Forced expression of miR-23a significantly reduced XIAP expression and promoted autophagy, whereas down-regulation of miR-23a increased XIAP expression and suppressed autophagy in breast cancer cells. XIAP was confirmed as a direct target of miR-23a by a reporter assay using the 3'UTR of XIAP 0.4 SIGNOR-279903 TFEB protein P19484 UNIPROT ACACB protein O00763 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) 0.2 SIGNOR-276780 MECP2 protein P51608 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 23242655 NO Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells. 0.39 SIGNOR-254024 SPC25 protein Q9HBM1 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR form complex binding 27881301 YES lperfetto Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits 0.974 SIGNOR-265186 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr736 FGMSRNLySGDYYRI 9606 16186108 YES gcesareni Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues. 0.381 SIGNOR-140728 N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:17311 ChEBI 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI up-regulates quantity precursor of 9606 11431483 YES miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 0.8 SIGNOR-269685 GOT2 protein P00505 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity chemical modification 9606 31422819 YES Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. 0.8 SIGNOR-266923 metformin chemical CHEBI:6801 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression 9606 17909097 NO inferred from family member gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. 0.8 SIGNOR-267789 RNF38 protein Q9H0F5 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 23973461 YES miannu Here we demonstrate that RNF38 is a functional ubiquitin protein ligase (E3). We show that RNF38 isoform 1 is localized to the nucleus by a bipartite nuclear localization sequence (NLS). We confirm that RNF38 is a binding partner of p53 and demonstrate that RNF38 can ubiquitinate p53 in vitro and in vivo. Finally, we show that overexpression of RNF38 in HEK293T cells results in relocalization of p53 to discrete foci associated with PML nuclear bodies.  0.364 SIGNOR-272130 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner 0.329 SIGNOR-195687 IL10 protein P22301 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 YES milica Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling. 0.714 SIGNOR-68007 AFDN protein P55196 UNIPROT RIN1 protein Q13671 UNIPROT up-regulates activity binding 9606 10545207 YES miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. 0.2 SIGNOR-220926 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT up-regulates activity phosphorylation Thr369 KRSFAPStPLTGRRY 9606 BTO:0001938 12006580 YES llicata Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.  0.806 SIGNOR-250765 KAT6A protein Q92794 UNIPROT KAT6A/PML complex SIGNOR-C55 SIGNOR form complex binding 9606 BTO:0001271 23431171 YES miannu We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression 0.522 SIGNOR-201478 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser203 APAPDEGsDLFYDDY 9606 BTO:0000567 11546811 YES llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  0.352 SIGNOR-251057 linifanib chemical CHEBI:91435 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 16648571 YES Gianni ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families 0.8 SIGNOR-262206 dexamethasone chemical CHEBI:41879 ChEBI PPARG protein P37231 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-106475 ATM protein Q13315 UNIPROT BTRC protein Q9Y297 UNIPROT up-regulates quantity by stabilization phosphorylation Ser158 EFVEHLIsQMCHYQH 9606 BTO:0000093 33676897 YES miannu ATM phosphorylates and stabilizes β-TrCP1 upon DNA damage. 0.299 SIGNOR-277549 GSK3B protein P49841 UNIPROT H1-5 protein P16401 UNIPROT up-regulates phosphorylation Thr11 TAPAETAtPAPVEKS 9606 BTO:0000567 19136008 YES lperfetto We found that threonine 10 of h1.5 can be phosphorylated by glycogen synthase kinase-3 in vitro. We have generated an antiserum specific for human h1.5 phosphorylated at threonine 10. Immunofluorescence labeling of hela cells with this antiserum revealed that the phosphorylation at this site appears in prometaphase and disappears in telophase, and that this hyperphosphorylated form of h1.5 is mainly chromatin-bound in metaphase when chromatin condensation is maximal. 0.2 SIGNOR-183325 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 YES lperfetto Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. 0.2 SIGNOR-244337 KU-60019 chemical CID:15953870 PUBCHEM ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193597 BAK1 protein Q16611 UNIPROT AIFM1 protein O95831 UNIPROT up-regulates relocalization 9606 23003569 YES gcesareni First, bax/bak-mediated momp leads to the release of a significant part of the cyt c, smac/diablo and htra2/omi proteins. in a third step, cyt c, smac/diablo and htra2/omi, which were released into the cytosol, trigger caspase activation. This is necessary to alter the physical association of aif and endog with the im to enable their relocation to the cytosol. 0.297 SIGNOR-192092 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser205 GAEGDVSsEREP -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.285 SIGNOR-273980 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9576626 YES tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm 0.936 SIGNOR-56901 WNT1 protein P04628 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 BTO:0000007 21078818 YES gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling. 0.788 SIGNOR-169645 hsa-mir-149-5p mirna URS00001C770D_9606 RNAcentral XIAP protein P98170 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005772 29731888 YES Tiberia XIAP was identified as a direct target gene of miR-149 in ovarian cancer cells. It was further shown that XIAP expression was upregulated in ovarian cancer tissues and cell lines, while it was negatively correlated with miR-149 in these tissues and cells. 0.4 SIGNOR-279904 hsa-mir-146a-5p mirna URS000050B527_9606 RNAcentral SLAMF1 protein Q13291 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002417 25743066 YES Tiberia Slamf1 was further tested for direct repression by miR-146a using luciferase reporter assays. Therefore, Slamf1 is likely to be the novel direct target of miR-146a. 0.4 SIGNOR-279907 hsa-mir-146a-5p mirna URS000050B527_9606 RNAcentral ICOS protein Q9Y6W8 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002417 25743066 YES Tiberia MiR-146a represses several Tfh cell-expressed messenger RNAs, and among these, ICOS is the most strongly autonomically upregulated target in miR-146a-deficient T cells. 0.4 SIGNOR-279908 SMAD4 protein Q13485 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. 0.684 SIGNOR-255269 ATR protein Q13535 UNIPROT WRN protein Q14191 UNIPROT down-regulates quantity phosphorylation Ser1141 PEKAYSSsQPVISAQ 9606 26695548 YES miannu Importantly, ATR-mediated phosphorylation targets Werner syndrome protein for ubiquitination and degradation.|WRN is phosphorylated at serine 1141 by ATR in response to replication-associated DSBs A. WRN is heavily phosphorylated at S1141 in response to CPT treatment of cells. 0.794 SIGNOR-278159 MTOR protein P42345 UNIPROT NRBF2 protein Q96F24 UNIPROT up-regulates activity phosphorylation Ser120 SPLSQKYsPSTEKCL 9606 BTO:0001938 28059666 YES miannu Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. 0.2 SIGNOR-265875 ITGA2 protein P17301 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.758 SIGNOR-253171 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1616 TPQSPSYsPTSPSYS -1 17157258 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248767 SRC protein P12931 UNIPROT CLTC protein Q00610 UNIPROT up-regulates phosphorylation Tyr1477 LFITEEDyQALRTSI 9606 10089883 YES gcesareni Egf-mediated clathrin phosphorylation is followed by clathrin redistribution to the cell periphery and is the product of downstream activation of src kinase by egf receptor (egfr) signaling 0.407 SIGNOR-65714 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser788 PIPHIPRsPYKFPSS -1 9139732 YES llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. 0.862 SIGNOR-250759 dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 21876184 YES lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. 0.8 SIGNOR-268259 CHD3 protein Q12873 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.817 SIGNOR-263855 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-119229 histamine smallmolecule CHEBI:18295 ChEBI HRH1 protein P35367 UNIPROT up-regulates activity chemical activation 10029 7925364 YES miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. 0.8 SIGNOR-258483 PDHX protein O00330 UNIPROT PAX6 protein P26367 UNIPROT down-regulates activity binding 9606 BTO:0000120 12783165 YES miannu In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. 0.2 SIGNOR-254903 PRKCZ protein Q05513 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.371 SIGNOR-249291 MAPK8 protein P45983 UNIPROT NEIL1 protein Q96FI4 UNIPROT up-regulates activity phosphorylation Ser306 KSKATQLsPEDRVED 9606 27518429 YES miannu These data confirm that NEIL1 can be phosphorylated by JNK1 in vitro at S207, S306, and S61. 0.2 SIGNOR-278315 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser540 KVMARSLsPPPELEE 10090 15851026 YES lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. 0.693 SIGNOR-249458 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000007 SIGNOR-C13 11158290 YES lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. 0.853 SIGNOR-104811 MEF2A protein Q02078 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates quantity by expression transcriptional regulation 14630949 NO lperfetto Neither GEF nor MEF2A alone significantly activated GLUT4 promoter activity, but increased promoter activity 4- to 5-fold when expressed together. 0.362 SIGNOR-271692 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser444 PLSLSAQsVMEELNT 9606 BTO:0000938 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.542 SIGNOR-204712 HOXD12 protein P35452 UNIPROT MAFG protein O15525 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.377 SIGNOR-221958 IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 17063185 YES flangone Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively 0.702 SIGNOR-150194 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Thr2074 VTPSPPGtVLTSALS 9606 BTO:0000007 12794074 YES lperfetto We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093. 0.482 SIGNOR-101574 Ub:E2 complex SIGNOR-C497 SIGNOR RNF175 protein Q8N4F7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271196 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI MST1R protein Q04912 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194346 MYF5 protein P13349 UNIPROT MIR1-1 mirna URS000075CF56_9606 RNAcentral up-regulates quantity transcriptional regulation 10090 21730352 NO miannu We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation. 0.4 SIGNOR-256241 CSNK2A1 protein P68400 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser13 GFFSSSEsGAPEAAE -1 3128543 YES llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. 0.309 SIGNOR-250843 CSNK1A1 protein P48729 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 16061179 YES gcesareni FADD is essential for death receptor (DR)-induced apoptosis.|Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities 0.333 SIGNOR-139307 bexarotene chemical CHEBI:50859 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity chemical activation 9606 BTO:0002058 17483357 YES miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. 0.8 SIGNOR-259233 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser447 SQRSSYVsMRIDTHA -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.336 SIGNOR-262754 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH20 protein Q9HBT6 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265837 PAK4 protein O96013 UNIPROT RAN protein P62826 UNIPROT unknown phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 20805321 YES llicata We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis. our study suggests that pak4-mediated phosphorylation of gdp- or gtp-bound ran regulates the assembly of ran-dependent complexes on the mitotic spindle 0.308 SIGNOR-167671 C3 convertase complex complex SIGNOR-C310 SIGNOR C3 protein P01024 UNIPROT up-regulates activity cleavage Arg748 ASHLGLArSNLDEDI 31331124 YES lperfetto This forms the C4b2a complex, which is a classical pathway C3 convertase. C4b2a cleaves C3, which is the central component of the complement cascade, to C3a, and anaphylatoxin, and C3b results in the activation of the lytic pathway 0.557 SIGNOR-263450 GC protein P02774 UNIPROT vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity relocalization 9606 BTO:0000759 30080183 YES lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. 0.8 SIGNOR-270566 C3 protein P01024 UNIPROT C5 convertase complex complex SIGNOR-C312 SIGNOR form complex binding cleavage:Arg748 ASHLGLArSNLDEDI 31331124 YES complement C3b fragment: PRO_0000005911 lperfetto C3b associates with C3 convertase to form C5 convertase and cleaves C5. 0.2 SIGNOR-263448 SRC protein P12931 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity phosphorylation Tyr198 IDEAEVIySELMSDF 9606 BTO:0002181 31420453 YES miannu Src activates GEF-H1. 0.414 SIGNOR-277478 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activi-ties of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manne 0.344 SIGNOR-195690 PRKCD protein Q05655 UNIPROT ENOX2 protein Q16206 UNIPROT up-regulates phosphorylation Ser504 ENLKEKEsCASRLCA 9606 22659163 YES lperfetto Tnox is phosphorylated by protein kinase c_ (pkc_) both in vitro and in vivo. Replacement of serine-504 with alanine significantly reduces phosphorylation by pkc_. C. overexpression of the s504a tnox mutant leads to diminished cell proliferation and migration, reflecting reduced stability of the unphosphorylatable tnox mutant protein. 0.2 SIGNOR-197706 UBE2D2 protein P62837 UNIPROT UBR5 protein O95071 UNIPROT up-regulates activity ubiquitination -1 11714696 YES miannu Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks. 0.509 SIGNOR-272668 sedoheptulose smallmolecule CHEBI:16802 ChEBI sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity precursor of 9606 22682222 YES miannu The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose 0.8 SIGNOR-268137 FBXW2 protein Q9UKT8 UNIPROT SCF-FBW2 complex SIGNOR-C525 SIGNOR form complex binding 9606 BTO:0000007 15640526 YES miannu FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system 0.724 SIGNOR-271525 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 YES lperfetto Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7. 0.367 SIGNOR-248860 UV stress stimulus SIGNOR-ST7 SIGNOR RRM2B protein Q7LG56 UNIPROT up-regulates 9606 BTO:0001061 14583450 NO miannu Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3. 0.7 SIGNOR-259362 PRKD3 protein O94806 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 34010649 YES lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-275945 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr130 PAQLLCStPNGLDRG 9606 10864927 YES lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. 0.844 SIGNOR-216769 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24577401 YES miannu A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription. 0.669 SIGNOR-268005 JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 30029643 NO areggio In summary, our results indicate IL-15 can stimulate the proliferation of FAPs through Jak-STAT pathway. 0.7 SIGNOR-256230 5-[1-(2-hydroxyethyl)-3-pyridin-4-yl-4-pyrazolyl]-2,3-dihydroinden-1-one oxime chemical CHEBI:91434 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258112 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT up-regulates activity cleavage Arg391 SPSFIQIrSVAKKHP -1 10350471 YES lperfetto Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689. 0.754 SIGNOR-263640 FAS protein P25445 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates binding 9606 11495919 YES amattioni Ask1 binds fas 0.693 SIGNOR-109676 SMARCC2 protein Q8TAQ2 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.848 SIGNOR-270754 DVL1P1 protein P54792 UNIPROT PRKCB protein P05771 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Taken together, these results suggest that site-specific dvl2 phosphorylation is required for dvl2 association with pkc_. This interaction is likely to be one of the mechanisms essential for wnt3a-dependent neurite outgrowth. 0.2 SIGNOR-199457 FBXO44 protein Q9H4M3 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization binding -1 23086937 YES miannu The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. 0.369 SIGNOR-272037 STAT5A protein P42229 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 22025054 NO lperfetto The activation of receptors for both GM-CSF and IFN-g stimulates the Jak kinaseSTAT transcription factor pathway, and an ISRE in the Irf5 promoter can bind STAT1 and STAT2, which suggests a possible mechanism for IRF5 expression induced by GM-CSF and IFN-g. Consequently, high expression of IRF5 results in polarization of the macrophage phenotype toward M1. 0.7 SIGNOR-249510 GFPT1 protein Q06210 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 21310273 YES miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans 0.8 SIGNOR-267816 hsa-miR-143-3p mirna URS00005C2A6D_9606 RNAcentral MAP3K7 protein O43318 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0003292 26391398 YES Tiberia To establish that Map3k7 is a true target of miR-143, we used classical luciferase assays on the 3'-UTR. Consistent with previous findings, Ac 2 PIM mimetics, or co-treatment of Ac 2 PIM with MDP or transfection with miR-143 (in the case of Map3k7) significantly reduced luciferase activity on the 3'-UTR of Map3k7 WT 0.4 SIGNOR-279920 RARB protein P10826 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 YES inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs 0.421 SIGNOR-270299 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 21059642 YES The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.58 SIGNOR-273029 MTOR protein P42345 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Ser455 PAPSRTAsFSESRAD -1 27015560 YES miannu Biochemical studies indicated that mTOR directly and specifically phosphorylated ACL on Ser 455 in vitro. 0.332 SIGNOR-278962 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2U protein Q5VVX9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.6 SIGNOR-271371 NR2F2 protein P24468 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 YES lperfetto Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site 0.281 SIGNOR-79446 UPF1 protein Q92900 UNIPROT Upf-EJC complex SIGNOR-C367 SIGNOR form complex binding 9606 BTO:0000567 17803942 YES miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1 0.968 SIGNOR-265237 RORB protein Q92753 UNIPROT OPN1MW protein P04001 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001175 19381306 YES miannu These observations indicate that RORβ is required for the induction of S opsin and support the conclusion that RORβ regulates Opn1sw transcription in a direct manner through ROREs within its proximal promoter region. In addition, they explain the greatly diminished expression of Opn1sw observed in the retina of RORβ-/- mice. 0.2 SIGNOR-266851 2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol chemical CHEBI:93773 ChEBI ARAF protein P10398 UNIPROT down-regulates chemical inhibition 9606 12970777 YES gcesareni At drug concentrations around the reported ic(50) for the raf inhibitor l-779,450, it suppressed dna synthesis and induced apoptosis in hematopoietic fdc-p1 cells transformed to grow in response to either raf-1 or a-raf (fd/deltaraf-1:er and fd/deltaa-raf:er) 0.8 SIGNOR-100355 SP1 protein P08047 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 YES lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. 0.2 SIGNOR-251739 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser551 ELQAPVRsPITRSFA 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.601 SIGNOR-249397 paliperidone chemical CHEBI:82978 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258560 UBR5 protein O95071 UNIPROT EDVP complex SIGNOR-C530 SIGNOR form complex binding 9606 BTO:0000007 19287380 YES miannu We named this E3 ligase complex containing EDD, DDB1 and VPRBP proteins as EDVP complex to distinguish it from the previously identified Cul4-Roc1-DDB1-VPRBP E3 ligase complex.  0.385 SIGNOR-271790 EP300 protein Q09472 UNIPROT SMAD2/STAT3/EP300 complex SIGNOR-C203 SIGNOR form complex binding 9606 26194464 YES MARCO ROSINA Thus, pSmad2L (Ser255) forms complex with p300 and STAT3 to bind to the proximal promoter of the Rorc and Il17a genes. 0.686 SIGNOR-255025 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257902 EFNA2 protein O43921 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 YES gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. Therefore, eph receptors mediate signals that can override cell adhesion. 0.749 SIGNOR-52269 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.91 SIGNOR-252522 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11158580 YES miannu Here, we report the identification of Smurf2, a new member of the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation. At higher expression levels, Smurf2 also decreases the protein levels of Smad2, but not Smad3.  0.725 SIGNOR-272936 mTORC1 complex SIGNOR-C3 SIGNOR ISCU protein Q9H1K1 UNIPROT up-regulates phosphorylation Ser14 FRLRRAAsALLLRSP 9606 23508953 YES lperfetto Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein. 0.2 SIGNOR-217082 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 9732876 YES lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos 0.643 SIGNOR-253332 CDK1 protein P06493 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation Ser386 LRGAQAAsPAKGEPS 9606 BTO:0000567 8491187 YES llicata Ptp1b is phosphorylated on ser386 by p34cdc2 in vivo. 0.503 SIGNOR-39233 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARHGAP31 protein Q2M1Z3 UNIPROT up-regulates activity phosphorylation Thr789 PPAPPPPtPLEESTP 9534 BTO:0000298 16024771 YES miannu CdGAP interacts with and is phosphorylated by ERK-1 and RSK-1 in vitro. A putative DEF (docking for ERK FXFP) domain located in the proline-rich region of CdGAP is required for efficient binding and phosphorylation by ERK1/2. We identify Thr776 as an in vivo target site of ERK1/2 and as an important regulatory site of CdGAP activity. Together, these data suggest that CdGAP is a novel substrate of ERK1/2 and mediates cross talk between the Ras/mitogen-activated protein kinase pathway and regulation of Rac1 activity. 0.2 SIGNOR-263057 Naltriben chemical CID:5486827 PUBCHEM OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258424 LY96 protein Q9Y6Y9 UNIPROT HMGB1 protein P09429 UNIPROT up-regulates activity binding 10090 BTO:0000801 25559892 YES gcesareni Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling. 0.629 SIGNOR-252058 FOXA1 protein P55317 UNIPROT NFIX protein Q14938 UNIPROT up-regulates binding 9606 BTO:0001129 24801505 YES miannu Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex. 0.335 SIGNOR-205082 CDCA5 protein Q96FF9 UNIPROT WAPL protein Q7Z5K2 UNIPROT down-regulates activity binding 7227 21111234 YES lperfetto We show that DNA replication and cohesin acetylation promote binding of Sororin to cohesin, and that Sororin displaces Wapl from its binding partner Pds5.  0.2 SIGNOR-265266 FST protein P19883 UNIPROT GDF11 protein O95390 UNIPROT down-regulates activity binding 10090 24627466 YES lperfetto Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. 0.665 SIGNOR-251716 CDC25A protein P30304 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates activity dephosphorylation 9606 16682204 YES miannu Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1  [4,5] . 0.691 SIGNOR-277136 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr846 RAFSFSKtPKRALRR 9606 BTO:0001938 16247472 YES lperfetto Thr-814 to ala greatly diminished the ability of p34cdk1/cyclin b to phosphorylate recombinant ect2-c protein (figure 1b, left panel). These data suggest that thr-814 is a major cdk1 phosphorylation site in ect2-c in vitrothe sequence thr-pro-lys-arg (tpkr) starting at amino acid 814we found that the t814a mutation slightly reduces the exchange activity of ect2 on rac1 0.488 SIGNOR-216928 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser526 MSGTGMRsVTGTPYW 9606 20448038 YES lperfetto Pp2ac binds to the phosphorylated mekk3 and subsequently dephosphorylate mekk3 at thr-516, ser-520, and ser-526 residues to terminate mekk3-mediated ikkbeta/Nf-kappaB Activation 0.372 SIGNOR-165233 ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 10090 14517293 YES gcesareni ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway 0.801 SIGNOR-235157 BMPR1B protein O00238 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 YES lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). 0.56 SIGNOR-33431 CDC25A protein P30304 UNIPROT CDK6 protein Q00534 UNIPROT up-regulates activity dephosphorylation Tyr24 AEIGEGAyGKVFKAR 9606 BTO:0000007 23429262 YES lperfetto Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs. 0.703 SIGNOR-267569 E2F1 protein Q01094 UNIPROT HIC1 protein Q14526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19491197 NO miannu expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. 0.289 SIGNOR-253844 SMARCB1 protein Q12824 UNIPROT CSF1 protein P09603 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 16267391 NO miannu Ini1/hsnf5/baf47 is involved in activation of the csf1 promoter. 0.2 SIGNOR-141047 SRC protein P12931 UNIPROT SH3PXD2A protein Q5TCZ1 UNIPROT up-regulates activity phosphorylation 20943948 YES lperfetto  Recently, we have shown that tyrosine kinase c-Src substrate Tks4 and Tks5 proteins are novel members of the organizer superfamily 0.64 SIGNOR-264706 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275759 BRD4 protein O60885 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 32544088 YES lperfetto In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. |Together, these studies suggest that Brd4 enhances p300-mediated histone acetylation. 0.427 SIGNOR-262064 [5-fluoro-1-(4-isopropylbenzylidene)-2-methylinden-3-yl]acetic acid chemical CHEBI:59660 ChEBI RXRA protein P19793 UNIPROT down-regulates activity chemical inhibition 9606 20541701 YES Luana NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling 0.8 SIGNOR-258031 ORC complex SIGNOR-C419 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 32808929 NO lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA 0.7 SIGNOR-267561 CTCF protein P49711 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12032779 NO miannu Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. 0.648 SIGNOR-253827 CCT239065 chemical CID:44131523 PUBCHEM BRAF protein P15056 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190907 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 15688006 YES milica We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity. 0.622 SIGNOR-133555 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 YES gcesareni Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. 0.729 SIGNOR-184583 TGFB1 protein P01137 UNIPROT ITGA3 protein P26006 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001596 1744142 NO lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. 0.352 SIGNOR-253353 IRF3 protein Q14653 UNIPROT ABCC2 protein Q92887 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15185298 NO miannu Expression of recombinant human IRF3 increased MRP2 promoter activity.  0.2 SIGNOR-254533 CDK3 protein Q00526 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation Ser63 GILARRPsYRKILKD 9606 BTO:0000527 BTO:0000142 18794154 YES lperfetto Cyclin-dependent kinase 3-mediated activating transcription factor 1 phosphorylation enhances cell transformationwe found that cdk3 phosphorylates activating transcription factor 1 (atf1) at serine 63 and enhances the transactivation and transcriptional activities of atf1. 0.2 SIGNOR-180920 CD38 protein P28907 UNIPROT nicotinic acid-adenine dinucleotide phosphate smallmolecule CHEBI:76072 ChEBI up-regulates quantity chemical modification 9606 18626062 YES miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. 0.8 SIGNOR-264245 IL6R protein P08887 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0000785 11238858 YES gcesareni Part of the receptor for interleukin 6. Binds to il6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with il6st. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis. 0.751 SIGNOR-105504 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation 9606 8816480 YES inferred from 70% family members gcesareni In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1 0.2 SIGNOR-270112 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG -1 9111318 YES Multiple autophosphorylation sites on Jak2, including Y1007 and Y1008. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. 0.2 SIGNOR-251357 UBE4B protein O95155 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 21317885 YES miannu We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis.  0.397 SIGNOR-271907 TFEB protein P19484 UNIPROT LAMP1 protein P11279 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants 0.441 SIGNOR-276555 nintedanib chemical CHEBI:85164 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190305 LARP6 protein Q9BRS8 UNIPROT DHX9 protein Q08211 UNIPROT up-regulates activity binding 9606 BTO:0000007 22190748 YES miannu  La ribonucleoprotein domain family member 6 (LARP6) is the protein that binds 5' SL with high affinity and specificity and coordinates their translation. Here we show that RNA helicase A (RHA) is tethered to the 5' SL of collagen mRNAs by interaction with the C-terminal domain of LARP6.  0.41 SIGNOR-273500 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 10090 BTO:0000782 15735648 YES miannu Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323. 0.474 SIGNOR-276030 FOLR1 protein P15328 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity relocalization 9606 10787414 YES lperfetto The differential polarized distribution of the reduced-folate transporter (RFT-1) and folate receptor alpha (FRalpha), the two proteins involved in the transport of folate, has been characterized in normal mouse retinal pigment epithelium (RPE) and in cultured human RPE cells. 0.8 SIGNOR-268267 SIRT3 protein Q9NTG7 UNIPROT CYP11A1 protein P05108 UNIPROT up-regulates quantity by stabilization deacetylation Lys149 KKSAAWKkDRVALNQ 9606 BTO:0002588 22585829 YES lperfetto Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis. 0.2 SIGNOR-268718 NR0B2 protein Q15466 UNIPROT THRA protein P10827 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11368516 NO gcesareni Shp (short heterodimer partner) is an orphan nuclear receptor lacking a dna binding domain that interacts with nuclear receptors (nr) including thyroid receptor (tr), retinoic acid receptors (rar and rxr), and estrogen receptors alpha and beta (eralpha and erbeta). Shp acts as a negative regulator of these receptors by inhibiting dna binding and transcriptional activation. 0.371 SIGNOR-108248 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity binding 9534 15537544 YES lperfetto Here we report that HDAC4, which is expressed in prehypertrophic chondrocytes, regulates chondrocyte hypertrophy and endochondral bone formation by interacting with and inhibiting the activity of Runx2, a transcription factor necessary for chondrocyte hypertrophy.PDPK1 0.525 SIGNOR-226680 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates binding 9606 17429065 YES lpetrilli Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. 0.2 SIGNOR-154316 PRKACA protein P17612 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT up-regulates activity phosphorylation Ser685 KLGRSIVsSPQGKSG -1 29230552 YES miannu PKD2L1 channel activation by PKA phosphorylation. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of β2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation. 0.2 SIGNOR-273562 LRRK1 protein Q38SD2 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity phosphorylation Ser140 SLAEAGGsEIQRVKE 9606 BTO:0000567 26192437 YES lperfetto Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its gamma-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with gamma-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation. 0.506 SIGNOR-275468 BRCA1 protein P38398 UNIPROT CTSD protein P07339 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 11244506 NO miannu BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. 0.276 SIGNOR-253759 AR protein P10275 UNIPROT SERPINB5 protein P36952 UNIPROT down-regulates quantity by repression transcriptional regulation 16304843 YES lperfetto In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter 0.401 SIGNOR-253685 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR IGF1R protein P08069 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20663909 YES lperfetto We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma. 0.2 SIGNOR-249595 ixabepilone chemical CHEBI:63605 ChEBI TUBB3 protein Q13509 UNIPROT down-regulates activity chemical inhibition 9606 18945860 YES miannu Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy. 0.8 SIGNOR-259349 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser23 ITDESLEsTRRILGL 9606 12930825 YES lperfetto Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion. 0.33 SIGNOR-249228 Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 11376933 YES miannu To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis. 0.8 SIGNOR-267844 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT down-regulates activity phosphorylation Ser1073 KAQAKVGsLDNVGHL -1 8631898 YES miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 0.438 SIGNOR-250169 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr93 GHITTTPtPTQFLCP 9606 BTO:0000848 21177766 YES lperfetto P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286) 0.268 SIGNOR-170776 LNX1 protein Q8TBB1 UNIPROT PBK protein Q96KB5 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22889411 YES miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. 0.376 SIGNOR-272898 vorapaxar chemical CHEBI:82702 ChEBI F2R protein P25116 UNIPROT down-regulates activity chemical inhibition -1 18447380 YES Luana The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described.  0.8 SIGNOR-257792 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Ser239 WRSPGRGsWFVQALC 9606 BTO:0000150 21555521 YES gcesareni Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. 0.351 SIGNOR-173655 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2E3 protein Q969T4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.719 SIGNOR-271330 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR COIL protein P38432 UNIPROT up-regulates phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 BTO:0000567;BTO:0000938 11102515 YES lperfetto In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1__†€ †_248) was observed 0.382 SIGNOR-216733 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0000782 8325880 YES gcesareni Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase. 0.412 SIGNOR-25826 LCK protein P06239 UNIPROT SSBP3 protein Q9BWW4 UNIPROT up-regulates activity phosphorylation Tyr25 EKLALYVyEYLLHVG 9606 BTO:0000007 18080319 YES miannu  The Src tyrosine kinase inhibitor PP2 blocked the nuclear translocation of Ssdp1. Western blot analysis showed that co-expression of Ssdp1 and Lck in 293T cells induces Ssdp1 phosphorylation. Mutation of the Ssdp1 N terminal tyrosine residues 23 and 25 markedly reduced both the phosphorylation and the nuclear localization of Ssdp1.  Lck enhanced the transcriptional activity of Ssdp1 in the context of known components of a LIM-homeodomain (LIM-HD)/cofactor complex. 0.2 SIGNOR-273648 CCIN protein Q13939 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 BTO:0001277 11090452 YES miannu The results suggest that the affinity of calicin to F-actin allows targeting of calicin at the subacrosomal space of round spermatids, and that its ability to form homomultimers contributes to the formation of a rigid calyx. 0.7 SIGNOR-268503 CKM complex complex SIGNOR-C406 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. 0.2 SIGNOR-273170 PRKAA2 protein P54646 UNIPROT INSR protein P06213 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C15 22207502 YES gcesareni Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway. 0.372 SIGNOR-195324 CLTC protein Q00610 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 YES lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  0.745 SIGNOR-260665 FAF1 protein Q9UNN5 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity binding 9606 BTO:0002181 30472208 YES miannu We find that the scaffold protein FAF1 forms aggregates that negatively regulate MAVS.FAF1 antagonizes the poly-ubiquitination and aggregation of MAVS by competing with TRIM31 for MAVS association. 0.2 SIGNOR-277619 2-(4-(4,4-Bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxylic acid methyl ester chemical CID:127728 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). 0.8 SIGNOR-258949 CCL2 protein P13500 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity binding 9606 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  0.786 SIGNOR-255113 BTRC protein Q9Y297 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization ubiquitination Lys800 LNPILPPkAPAVSPL 9606 BTO:0000938 17283082 YES lperfetto Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage. 0.67 SIGNOR-249578 YAP1 protein P46937 UNIPROT MYF6 protein P23409 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 NO gcesareni Myf6 (mrf4) is repressed by hyap1 s127a overexpression. 0.2 SIGNOR-199075 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258004 NEFH protein P12036 UNIPROT Neurofilament L/H complex SIGNOR-C208 SIGNOR form complex binding 9606 BTO:0000938 19468066 YES miannu Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H 0.437 SIGNOR-255273 PRKACA protein P17612 UNIPROT GNA13 protein Q14344 UNIPROT down-regulates activity phosphorylation Thr203 ILLARRPtKGIHEYD 9534 12399457 YES miannu PKA directly phosphorylates Galpha(13). Galpha(13)-T203A mutant (in COS-7 cells) could not be phosphorylated by PKA. PKA blocks Rho activation by phosphorylation of Galpha(13) Thr(203). 0.366 SIGNOR-249985 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Tyr432 KEGWMVHyTSKDTLR 9606 BTO:0000567 12637538 YES lperfetto Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation. 0.412 SIGNOR-247320 EGR1 protein P18146 UNIPROT SLC4A2 protein P04920 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000269 22228178 NO Cellular and molecular experiments indicated that AE2 expression promoted proliferation of colon cancer cells. In addition, we found that transcription factor EGR1 underlies AE2 upregulation and the AE2 sequester p16INK4a (P16) in the cytoplasm of colon cancer cells 0.2 SIGNOR-254250 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.432 SIGNOR-273151 ELOB protein Q15370 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR form complex binding 9606 11574546 YES miannu The von Hippel-Lindau tumor-suppressor protein (pVHL) forms a protein complex (VCB-Cul2) with elongin C, elongin B, Cul-2, and Rbx1, which functions as a ubiquitin-protein ligase (E3). The alpha-subunits of the hypoxia-inducible factors have been identified as targets for the VCB-Cul2 ubiquitin ligase.  0.2 SIGNOR-271517 RIMS3 protein Q9UJD0 UNIPROT RAB3C protein Q96E17 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 YES miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle 0.26 SIGNOR-264380 ELOC protein Q15369 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 YES miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro 0.2 SIGNOR-271438 L-serine zwitterion smallmolecule CHEBI:33384 ChEBI L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI up-regulates quantity precursor of 9606 23981774 YES lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 0.8 SIGNOR-275827 CDK14 protein O94921 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity 24794231 YES lperfetto Compared with the wild-type CDK14, CDK14D256A mutant showed 2-fold reduced phosphorylation of LRP6 at Ser-1490, a known substrate of the CDK14/CCNY complex| It is also reported to be required for maximal phosphorylation of LRP6 on Ser 1490 and activation of Wnt signaling  0.333 SIGNOR-273019 TDGF1 protein P13385 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0002314 BTO:0000887;BTO:0001103 23129614 NO miannu Cripto, a regulator of early embryogenesis, is a novel regulator of muscle regeneration and satellite cell progression toward the myogenic lineage. 0.7 SIGNOR-192439 FYN protein P06241 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 15537652 YES gcesareni Here we provide evidence that fyn kinase, a member of the src kinase family, is involved in the uvb-induced phosphorylation of histone h3 at serine 10 0.2 SIGNOR-265330 PML protein P29590 UNIPROT KAT6A/PML complex SIGNOR-C55 SIGNOR form complex binding 9606 BTO:0001271 23431171 YES miannu We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression 0.522 SIGNOR-201489 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 BTO:0001271 12835716 YES lperfetto Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2 0.529 SIGNOR-217172 ERRFI1 protein Q9UJM3 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity binding -1 18046415 YES The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 0.708 SIGNOR-252077 ATR protein Q13535 UNIPROT ETV1 protein P50549 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 23284306 YES miannu Collectively, the results described above indicate that ATR phosphorylates ETV1 and stabilizes it from proteolytic degradation. 0.2 SIGNOR-279355 CBL protein P22681 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 phosphorylation:Ser2;Tyr182 sAEVIHQV;VQGAGTSyRNVLQAA 19597496 YES CFLAR has to be phosphorylated on Tyr211 and Ser4 by c-Abl and p38, respectively. This phosphorylation facilitated specific interaction between FLIPS and the ubiquitin E3 ligase c-Cbl gcesareni We therefore conclude that c-cbl is a e3 ubiquitin ligase for flips and that the interaction of flips with c-cbl requires phosphorylation of both ser4 and tyr211 of flips.This interaction triggered proteasomal degradation of FLIP(S), which promoted activation of caspase-8 and apoptosis. 0.2 SIGNOR-186998 ATM protein Q13315 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates phosphorylation Thr434 TPPPSPNtQTPVQPP 9606 BTO:0000551 23108047 YES miannu Phosphorylation of ccdc6 at thr434 by atm during dna damage response prevents fbxw7-mediated ccdc6 degradation. 0.274 SIGNOR-199276 HSPA5 protein P11021 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity binding 9606 31226023 YES miannu In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation. 0.725 SIGNOR-260164 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IL16 protein Q14005 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 14768064 YES inferred from 70% family members lperfetto The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response. 0.2 SIGNOR-270168 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TGFB1 protein P01137 UNIPROT up-regulates quantity BTO:0000801 22933625 NO apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype 0.7 SIGNOR-255444 CUDC-101 chemical CID:24756910 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191145 PRKACA protein P17612 UNIPROT SLC8B1 protein Q6J4K2 UNIPROT up-regulates activity phosphorylation Ser258 YQRQRRGsLFCPMPV 36476859 YES Phosphosite is derived from the graphical abstract lperfetto However, the PDE2-inhibitory effect is eliminated when the mitochondrial S258A NCLX mutant that mimics a non-PKA phosphorylated state of NCLX is expressed. Altogether, our findings indicate that NCLX is regulated by the mitochondrial PDE2A2 form.|We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. |Moreover, PDE2 acts by diminishing mitochondrial cAMP, thus promoting NCLX phosphorylation at its PKA site. 0.2 SIGNOR-275727 ATF4 protein P18848 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 YES miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. 0.655 SIGNOR-260172 dopamine smallmolecule CHEBI:18243 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258716 STUB1 protein Q9UNE7 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14701756 YES miannu We demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process.  0.397 SIGNOR-272947 RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 9606 23661684 NO lperfetto 0.7 SIGNOR-255323 Complement C1 complex complex SIGNOR-C309 SIGNOR C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.642 SIGNOR-263430 P2RY2 protein P41231 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-265342 EPHB2 protein P29323 UNIPROT NRCAM protein Q92823 UNIPROT up-regulates activity phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 YES miannu EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase.  0.298 SIGNOR-262863 BRK1 protein Q8WUW1 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 YES miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems 0.864 SIGNOR-253570 PIAS1 protein O75925 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation 9606 15028714 YES lperfetto These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4 0.395 SIGNOR-123462 PRKCA protein P17252 UNIPROT CYBA protein P13498 UNIPROT up-regulates phosphorylation Thr147 ERPQIGGtIKQPPSN -1 19948736 YES Manara Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding. | Threonine 147 of p22phox Is Phosphorylated by PKC-α and PKC-δ in Vitro 0.2 SIGNOR-260891 MTR protein Q99707 UNIPROT methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity chemical modification 9606 10520212 YES lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. 0.8 SIGNOR-253143 ESR1 protein P03372 UNIPROT SCN1A protein P35498 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 BTO:0001264 22169964 NO miannu 17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice 0.267 SIGNOR-253468 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2047 QRVSDQNsPVLPKKS 9606 BTO:0000018 27991932 YES lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. 0.258 SIGNOR-275610 NGFR protein P08138 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14699954 NO amattioni Neurotrophin binding to p75ntrhas also been shown to induce apoptosis 0.7 SIGNOR-120558 RIPK1 protein Q13546 UNIPROT TNFRSF10A protein O00220 UNIPROT up-regulates 9606 18545270 NO gcesareni The death domain of the rip1 kinase binds to death receptors such as tumor necrosis factor-related apoptosis-inducing ligand receptor 1,trailr1. 0.628 SIGNOR-177952 phenylalanine smallmolecule CHEBI:28044 ChEBI GCHFR protein P30047 UNIPROT down-regulates activity chemical inhibition 9606 11361142 YES miannu The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine 0.8 SIGNOR-252205 MAP2K3 protein P46734 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9534 BTO:0000298 7839144 YES Luana Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. 0.727 SIGNOR-260723 PPP1R3C protein Q9UQK1 UNIPROT GYS2 protein P54840 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 YES miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) 0.752 SIGNOR-271731 MED31 protein Q9Y3C7 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.71 SIGNOR-266668 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 10101032 YES Translocation from Endosome to Lysosome fspada Ser396 and ser398 are also potential phosphorylation sites for capk, cgmp-dependent protein kinase, and camk ii. Elevation of intracellular camp content has been shown to attenuate histamine-induced accumulation of ip in c6 glioma cells (peakman and hill, 1994) and in ddt1 mf-2 smooth muscle cells (sipma et al., 1995 0.2 SIGNOR-66019 TFEB protein P19484 UNIPROT CLCN7 protein P51798 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.328 SIGNOR-276536 PTPN21 protein Q16825 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 15143158 YES Dephosphorylation of Y527 was more pronounced in cells expressing PTPD1 at each time point tested. PTPD1C1108S drastically inhibited Y527 dephosphorylation|Activation of src requires dephosphorylation of src residue Y527. This promotes displacement of the SH2 domain from this residue and subsequent autophosphorylation of residue Y416 within the activation loop 0.642 SIGNOR-248725 PPARGC1A protein Q9UBK2 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates 9606 19491292 NO gcesareni Nuclear pgc-1alpha and foxo3a respond in a reciprocal manner following aicar treatment. 0.393 SIGNOR-186058 IL1B protein P01584 UNIPROT LPL protein P06858 UNIPROT down-regulates activity 9606 1572904 NO Regulation miannu IL-1 beta also depressed adipoconversion, inhibited markedly LPL activity, and partially reduced GPDH activity. 0.29 SIGNOR-251856 SPSB2 protein Q99619 UNIPROT NANOS2 protein P60321 UNIPROT down-regulates quantity by destabilization binding -1 20603330 YES miannu We have identified SPRY domain-containing SOCS (suppressor of cytokine signaling) box protein 2 (SPSB2) as a novel negative regulator that recruits an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in its proteasomal degradation. A cell-free ubiquitination assay was established to demonstrate SPSB2-dependent ubiquitination of iNOS. LPS/IFN-γ–stimulated macrophage lysates from Spsb2−/− mice were used as a source of iNOS and incubated with ubiquitin and a trimeric SPSB2/elongin BC complex in the presence of E1 and E2 (UbcH5a) enzymes, Rbx2, and Cullin5 for various times. 0.2 SIGNOR-271901 PKN1 protein Q16512 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 BTO:0000150 12560069 YES lperfetto Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1. 0.2 SIGNOR-252968 RNF216 protein Q9NWF9 UNIPROT TLR9 protein Q9NR96 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15107846 YES miannu Here we describe how a RING finger protein, Triad3A, acts as an E3 ubiquitin-protein ligase and enhances ubiquitination and proteolytic degradation of some TLRs. Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling.  0.406 SIGNOR-271505 bortezomib chemical CHEBI:52717 ChEBI PSMD2 protein Q13200 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 YES miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. 0.8 SIGNOR-259313 GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263815 valrubicin chemical CHEBI:135876 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000096 16019763 YES miannu Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis. 0.8 SIGNOR-259384 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM77 protein I1YAP6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271273 AMPK complex SIGNOR-C15 SIGNOR PPP1R3C protein Q9UQK1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser33 MRLCLAHsPPVKSFL 10029 BTO:0000246 19171932 YES miannu AMPK induces the phosphorylation of residues Ser-8 and Ser-268 in R5/PTG. We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity. Thus, our results define a novel role of AMPK in glycogen homeostasis. 0.284 SIGNOR-273739 INSR protein P06213 UNIPROT DOK4 protein Q8TEW6 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 NO gcesareni Irs5/dok4 and irs6/dok5 represent two new signaling proteins with potential roles in insulin and igf-1 action. 0.371 SIGNOR-101005 SUN1 protein O94901 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.514 SIGNOR-263282 POLR2J protein P52435 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.822 SIGNOR-266161 SPI1 protein P17947 UNIPROT TAL1 protein P17542 UNIPROT down-regulates activity binding 9606 BTO:0000567 16298389 YES irozzo PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity.By expressing a mutant protein containing only the ETS domain of PU.1 in human erythroleukemic HEL cells, we demonstrated that PU.1 mediates the transcriptional repression activity of the silencer. Our data clearly demonstrate that PU.1 mediates TAL-1 silencer activity 0.439 SIGNOR-256048 DKK1 protein O94907 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 11448771 YES gcesareni We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6. 0.904 SIGNOR-109247 NRF1 protein Q16656 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 NO lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC 0.557 SIGNOR-268997 CAMK2A protein Q9UQM7 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 18978352 YES lperfetto Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export|We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques|Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca2+/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO. 0.2 SIGNOR-264408 FGFR1 protein P11362 UNIPROT PCDH15 protein Q96QU1 UNIPROT up-regulates activity phosphorylation 9606 30061390 YES miannu FGFR1 mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia.|We find that on activation, FGFR1 binds and phosphorylates Pcdh15. 0.2 SIGNOR-280014 MAPK1 protein P28482 UNIPROT RSPH3 protein Q86UC2 UNIPROT up-regulates activity phosphorylation Thr243 QEQLRPQtPEPVEGR 9606 19684019 YES miannu ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D). inhibiting ERK1/2 activity appears to negatively regulate the AKAP function of RSPH3. 0.2 SIGNOR-262839 hsa-let-7a-5p mirna URS0000416056_9606 RNAcentral CCR7 protein P32248 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000007 22251626 YES miannu MicroRNA let-7a suppresses breast cancer cell migration and invasion through downregulation of C-C chemokine receptor type 7 0.4 SIGNOR-279938 Melanin-concentrating hormone smallmolecule CHEBI:80254 ChEBI MCHR1 protein Q99705 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257540 miR-335-5p mirna URS0000237AF9_9606 RNAcentral SP1 protein P08047 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 35931409 YES miannu We identified SP1 as a miR-335-5p target gene by using the dual-luciferase reporter assay. 0.4 SIGNOR-279953 NUAK1 protein O60285 UNIPROT PPP1R10 protein Q96QC0 UNIPROT up-regulates activity phosphorylation 9606 32006464 YES miannu Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1.|Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis. 0.2 SIGNOR-280051 MAPK14 protein Q16539 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 YES lperfetto All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). 0.719 SIGNOR-154779 PLK1 protein P53350 UNIPROT KIF4A protein O95239 UNIPROT down-regulates activity phosphorylation 9606 28817632 YES miannu Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome. 0.468 SIGNOR-280069 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr231 NQDDVGVyTCLVVNG 9606 BTO:0000763 20861316 YES lperfetto Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity 0.3 SIGNOR-167989 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 19114990 YES lperfetto in immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K 0.449 SIGNOR-217830 CDK1 protein P06493 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser425 NREKVAAsPKSPTAA 9606 16198290 YES lperfetto Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis. 0.451 SIGNOR-140882 PRKCA protein P17252 UNIPROT TRPM2 protein O94759 UNIPROT up-regulates activity phosphorylation Ser39 NLRRSNSsLFKSWRL 9606 24337049 YES miannu ROS production in endothelial cells or directly applying ROS induced PKC\u03b1 activation and phosphorylation of TRPM2 at Ser 39.|ROS production in endothelial cells or directly applying ROS induced PKCalpha activation and phosphorylation of TRPM2 at Ser 39. 0.2 SIGNOR-280082 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR1B protein P31321 UNIPROT down-regulates activity chemical inhibition 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.8 SIGNOR-258760 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser238 QGTPLTCsPNVENRG 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.35 SIGNOR-276112 CTCF protein P49711 UNIPROT APP protein P05067 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11706010 NO miannu Depleting HeLa cell nuclear extract of endogenous CTCF specifically reduced transcriptional activity from the APP promoter. CTCF activates transcription from the APP promoter and that the activation domain is located on the N-terminal side of the zinc finger domain. 0.264 SIGNOR-253823 miRNA30b mirna URS00002152A8_9606 RNAcentral ADAM12 protein Q5JRP2 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000815 39742357 YES miannu Dual-luciferase assays confirmed the presence of a binding site between miRNA30b and ADAM12. Western blot analysis revealed that overexpression of miRNA30b downregulated ADAM12 expression in MDA-MB-231 cells. 0.4 SIGNOR-279961 PRKCB protein P05771 UNIPROT RAB11A protein P62491 UNIPROT unknown phosphorylation Ser177 TEIYRIVsQKQMSDR -1 22188018 YES miannu This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. 0.2 SIGNOR-263169 GCSH protein P23434 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 YES lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. 0.737 SIGNOR-268241 cyclosporin A chemical CHEBI:4031 ChEBI PPP3CB protein P16298 UNIPROT down-regulates chemical inhibition 9606 15276472 YES gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-127228 RIPK3 protein Q9Y572 UNIPROT PYGL protein P06737 UNIPROT up-regulates binding 9606 19632174 YES gcesareni Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro. 0.52 SIGNOR-186939 AURKA protein O14965 UNIPROT SOX8 protein P57073 UNIPROT up-regulates activity phosphorylation 9606 32550913 YES miannu Therefore, Aurora-A not only directly phosphorylates SOX8 but also promotes SOX8 transcription indirectly by regulating c-Myc protein. 0.2 SIGNOR-280189 Bafetinib chemical CID:24853523 PUBCHEM LYN protein P07948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190227 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys205 RDLINLAkKRTNIIP 30540930 YES lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) 0.271 SIGNOR-275892 FBXL2 protein Q9UKC9 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000018 26037928 YES miannu LPS exposure reduces the ubiquitin-mediated proteasomal processing of NALP3 by inducing levels of an E3 ligase component, FBXO3, which targets FBXL2. The latter is an endogenous mediator of NALP3 degradation. FBXL2 recognizes Trp-73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation.  0.622 SIGNOR-272433 CAV1 protein Q03135 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 16890161 YES gcesareni Overall, our data suggest that wnt-3a triggers the interaction of lrp6 with caveolin and promotes recruitment of axin to lrp6 phosphorylated by glycogen synthase kinase-3beta and that caveolin thereby inhibits the binding of beta-catenin to axin. 0.675 SIGNOR-148665 PTPRC protein P08575 UNIPROT TYK2 protein P29597 UNIPROT down-regulates activity dephosphorylation Tyr1054 AVPEGHEyYRVREDG 10090 11201744 YES CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 0.407 SIGNOR-248357 CSNK2A1 protein P68400 UNIPROT CERS5 protein Q8N5B7 UNIPROT up-regulates activity phosphorylation Ser350 KVSKDDRsDVESSSE 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273988 lysine smallmolecule CHEBI:25094 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264755 PRKCA protein P17252 UNIPROT HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser95 RAVSREDsQRPGAHL 9606 7727389 YES gcesareni A survey of seven protein kinases showed that a1 was heavily phosphorylated by protein kinase c (pkc) and also was phosphorylated by casein kinase iiamino acid sequencing revealed that these sites were ser95, ser192, and ser199;phosphorylation at ser192 was more abundant than at ser95 and ser199. Phosphorylation by pkc inhibited the strand annealing activity of a1. 0.2 SIGNOR-32291 GSK3B protein P49841 UNIPROT NFE2L1 protein Q14494 UNIPROT down-regulates phosphorylation Ser379 SQDFLLFsPEVESLP 9606 BTO:0000938 23623971 YES lperfetto Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (nrf1) and inhibits pro-survival function of nrf1 0.401 SIGNOR-193450 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC20P protein Q6DN03 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271988 PTN protein P21246 UNIPROT ALK protein Q9UM73 UNIPROT up-regulates binding 9606 11278720 YES gcesareni We conclude from this series of experiments that ptn specifically binds to the alk orphan receptor as a high affinity ligand at least in part via the putative ligand binding domain described above. 0.548 SIGNOR-106411 FLT3 protein P36888 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression 9606 25280219 NO MYC expression was relatively higher (P <0Æ1) in theFLT3/ITD-positive AML samples compared to non-mutant FLT3 AML. 0.363 SIGNOR-261556 VCB-Cul2 complex SIGNOR-C524 SIGNOR USP20 protein Q9Y2K6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 12056827 YES miannu VDU1 and VDU2 could be important substrates of pVHL E3 ligase complex. Finally, we demonstrate that VDU2 can also be ubiquitinated and degraded in a pVHL-dependent manner.pVHL mediates the degradation of hVDU2 by proteasome. we have demonstrated that both VDU1 and VDU2 also bind to the β-domain of pVHL and several naturally occurring mutations in the β-domain disrupt the interaction between VDU1/VDU2 and pVHL. If pVHL is mutated either in the α-domain or β-domain, VDU1 and VDU2 would not be ubiquitinated and degraded properly. This could lead to accumulation of these two proteins in the cells. Together, our results suggest that VDU1 and VDU2 might be relevent to pVHL-related tumorigenesis. 0.362 SIGNOR-272606 ACO1 protein P21399 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI down-regulates quantity chemical modification 9606 24068518 YES miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. 0.8 SIGNOR-266242 GAL protein P22466 UNIPROT GALR2 protein O43603 UNIPROT up-regulates binding 9606 10601261 YES gcesareni Galanin showed high affinity for the galr1 (ic(50) = 0.097 nm) and galr2 receptors (ic(50) = 0.48 nm). 0.862 SIGNOR-73125 PRKACA protein P17612 UNIPROT KCNK3 protein O14649 UNIPROT up-regulates activity phosphorylation Ser393 GLMKRRSsV 9606 21357689 YES lperfetto Mutation of the ser393 to alanine, which can neither be phosphorylated nor mimic a phosphorylated residue, resulted in the channel failing to pass current all of our findings support the conclusion that camp-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both k2p3.1 and k2p9.1. 0.2 SIGNOR-172430 OXTR protein P30559 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 30739093 YES miannu OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). 0.448 SIGNOR-270330 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 YES The effect has been demonstrated using P07101-3 gcesareni Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax 0.267 SIGNOR-95483 MAPK8 protein P45983 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 19245816 YES gcesareni In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed. 0.705 SIGNOR-184194 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Tyr301 LGYRDSGyYWEVPPS 9534 BTO:0004055 9020159 YES lperfetto A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation. Activation of Raf-1 and A-Raf by Src requires tyrosine phosphorylation at residues 340 and 341 in Raf-1 and 301 and 302 in A-Raf. 0.487 SIGNOR-236037 AMPK complex SIGNOR-C15 SIGNOR CDC27 protein P30260 UNIPROT unknown phosphorylation Ser379 NALPRRSsRLFTSDS 9606 22137581 YES lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379, respectively) resulted in an almost complete loss of ampk phosphorylation in these proteins 0.271 SIGNOR-216434 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI up-regulates quantity precursor of 9606 BTO:0000050 25855791 YES lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively 0.8 SIGNOR-268642 HGS protein O14964 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates 9606 11094085 NO gcesareni Hgs and sara, are prerequisites for receptor-mediated activation of smad2 0.363 SIGNOR-84616 CAMK2A protein Q9UQM7 UNIPROT ITPKA protein P23677 UNIPROT up-regulates phosphorylation Thr311 EHAQRAVtKPRYMQW 9606 BTO:0000938 BTO:0000975;BTO:0000142 9155020 YES lperfetto D-myo-inositol 1,4,5-trisphosphate 3-kinase a is activated by receptor activation through a calcium:calmodulin-dependent protein kinase ii phosphorylation mechanism. the phosphorylated residue was thr311. 0.33 SIGNOR-48387 JAK1 protein P23458 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr304 PNEPVSDyINANIIM 9534 8995399 YES lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2. 0.767 SIGNOR-236282 QRICH1 protein Q2TAL8 UNIPROT VARS1 protein P26640 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269408 MAP2K2 protein P36507 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 YES lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. 0.746 SIGNOR-244637 PIM2 protein Q9P1W9 UNIPROT PFKFB3 protein Q16875 UNIPROT up-regulates quantity by stabilization phosphorylation Ser478 TKKPRINsFEEHVAS 9606 BTO:0002181 33931981 YES miannu We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin-proteasome pathway. 0.2 SIGNOR-277554 INTS7 protein Q9NVH2 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.788 SIGNOR-261464 DAB2IP protein Q5VWQ8 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity binding 9606 BTO:0001176 27858941 YES miannu DAB2IP binds IRE1α, and was shown to be required for activation of this signaling cascade in endothelial cells. IRE1α can trigger pro-apoptotic JNK signaling through recruitment of the TRAF2–ASK1 complex. DAB2IP facilitates IRE1α activation, and participates in a signaling complex required to induce TRAF2-dependent ASK1 activation and JNK phosphorylation. 0.381 SIGNOR-254749 BAIAP2 protein Q9UQB8 UNIPROT WASF2 protein Q9Y6W5 UNIPROT up-regulates activity binding 10090 BTO:0000944 11130076 YES miannu Here we demonstrate that IRSp53, a substrate for insulin receptor with unknown function, is the 'missing link' between Rac and WAVE. Activated Rac binds to the amino terminus of IRSp53, and carboxy-terminal Src-homology-3 domain of IRSp53 binds to WAVE to form a trimolecular complex. From studies of ectopic expression, we found that IRSp53 is essential for Rac to induce membrane ruffling, probably because it recruits WAVE, which stimulates actin polymerization mediated by the Arp2/3 complex. 0.801 SIGNOR-265556 SOSTDC1 protein Q6X4U4 UNIPROT WNT2 protein P09544 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.304 SIGNOR-242724 GRM6 protein O15303 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. 0.8 SIGNOR-264937 TP53 protein P04637 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 NO miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. 0.573 SIGNOR-255430 TRAF6 protein Q9Y4K3 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates activity binding 9606 BTO:0001370 29733298 YES miannu Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways.  0.2 SIGNOR-273656 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser422 IACDEEFsDSEDEGE 9606 BTO:0000567 12082111 YES llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. 0.39 SIGNOR-251002 docetaxel anhydrous chemical CHEBI:4672 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 23337758 YES miannu Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called "dynamic instability," which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer. 0.8 SIGNOR-259343 PRKCD protein Q05655 UNIPROT PLSCR3 protein Q9NRY6 UNIPROT up-regulates phosphorylation Thr21 PPPPYPVtPGYPEPA 9606 16267027 YES gcesareni Ad198-activated pkc-delta induces phosphorylation of mitochondrial pls3 at thr21;pls3 is a critical downstream effector of pkc-delta in ad198-induced apoptosis. 0.458 SIGNOR-140759 AKT1 protein P31749 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates activity phosphorylation Thr346 APRPRVEtSRAVPLA -1 27505672 YES miannu  Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex.  0.602 SIGNOR-277272 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 16817901 YES miannu These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities. 0.643 SIGNOR-147707 CDK1 protein P06493 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates phosphorylation Thr159 DGSEPTKtPGRTSST 9606 20513426 YES llicata We show that vps34 is phosphorylated on thr159 by cdk1, thr159 phosphorylation negatively regulates the ptdins3 kinase activity of vps34 and autophagy 0.42 SIGNOR-165768 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity BTO:0001103 7532173 NO Simone Vumbaca These results suggest that at least initially, the muscle-forming regions contained cells with myogenic potential, and that this potential is lost in the myogenin mutants as development proceeds. 0.7 SIGNOR-255644 BMX protein P51813 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 23716717 YES llicata Bmx phosphorylated focal adhesion kinase (fak) at tyr577 subsequent to its src-mediated phosphorylation at tyr576. Loss of bmx by rna interference or by genetic deletion in mouse embryonic fibroblasts (mefs) markedly impaired fak activity. 0.549 SIGNOR-202139 HOXD3 protein P31249 UNIPROT ITGA5 protein P08648 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14610084 YES Luana The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis. 0.25 SIGNOR-261649 AKT1 protein P31749 UNIPROT PEA15 protein Q15121 UNIPROT up-regulates activity phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 BTO:0000007 12808093 YES lperfetto Protein kinase b/akt binds and phosphorylates ped/pea-15, stabilizing its antiapoptotic action. 0.518 SIGNOR-102092 BAZ2B protein Q9UIF8 UNIPROT H3-2 protein Q5TEC6 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 YES miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. 0.2 SIGNOR-266618 ETS1 protein P14921 UNIPROT MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22270366 NO miannu VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. 0.377 SIGNOR-254083 GSK3B protein P49841 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Thr66 NVNTKCItIPRSLDG 9606 18172167 YES lpetrilli Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation. 0.489 SIGNOR-160318 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000150;BTO:0000551 12475979 YES gcesareni Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase dep-1 0.607 SIGNOR-96347 CSNK2A1 protein P68400 UNIPROT HIF1A protein Q16665 UNIPROT unknown phosphorylation Thr796 ESGLPQLtSYDCEVN -1 17382325 YES llicata These results implied that only Thr-796 was phosphorylated CK2.  0.341 SIGNOR-250891 ERBB2 protein P04626 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 27638858 YES miannu HER2, EGFR, and additional RTKs directly phosphorylate FAK FERM at Y397.|To further confirm the mechanism of direct FAK activation by HER2, we performed a series of GST pull-down assays with purified recombinant proteins. 0.656 SIGNOR-278475 LNX1 protein Q8TBB1 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 11782429 YES esanto Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation. 0.74 SIGNOR-112201 KLHL2 protein O95198 UNIPROT WNK3 protein Q9BYP7 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23838290 YES miannu We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body. 0.477 SIGNOR-272121 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 YES lbriganti Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. 0.752 SIGNOR-210176 Kindlin proteinfamily SIGNOR-PF48 SIGNOR FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 YES inferred from 70% family members miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 0.2 SIGNOR-269956 YWHAQ protein P27348 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 12042314 YES miannu 14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue. 0.523 SIGNOR-88300 TAF6L protein Q9Y6J9 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.721 SIGNOR-269587 NOL9 protein Q5SY16 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 YES miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. 0.797 SIGNOR-265470 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr791 LAQAPPVyLDVLG 9606 9099755 YES gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 0.2 SIGNOR-47183 Av/b1 integrin complex SIGNOR-C175 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269024 MYCN protein P04198 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000931 23175188 NO miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. 0.376 SIGNOR-255145 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. 0.8 SIGNOR-267031 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248516 JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates phosphorylation Tyr457 KAPTSFGyDKPHVLV 9606 7615558 YES lperfetto Interferon gamma activation of stat1alpha requires both jak1 and jak2 as well as tyrosine phosphorylation of the alpha chain of the ifngamma receptor. 0.702 SIGNOR-29866 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193775 PAK3 protein O75914 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 9823899 YES llicata The protein kinase pak3 positively regulates raf-1 activity through phosphorylation of serine 338. 0.555 SIGNOR-62043 MAP3K11 protein Q16584 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Ser257 ISGQLVDsIAKTRDA 9606 BTO:0001538 9003778 YES lperfetto These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo. 0.624 SIGNOR-48574 BORA protein Q6PGQ7 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation 9606 18615013 YES gcesareni Bora/aurora-a-dependent phosphorylation is a prerequisite for plk1 to promote mitotic entry after a checkpoint-dependent arrest. 0.787 SIGNOR-179425 hsa-miR-23b-3p mirna URS00004E57E7_9606 RNAcentral RRAS2 protein P62070 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001109 22109528 YES Parnian MiR-23b, which is downregulated in human colon cancer samples, potently mediates the multiple steps of metastasis, including tumour growth, invasion and angiogenesis in vivo . | Mutation of the putative miR-23b site(s) in the 3′-UTR of FZD7, MAP3K1 (MEKK1), PAK2, TGFβR2, RRAS2 or uPA resulted in an abrogated responsiveness to miR-23b. 0.4 SIGNOR-277963 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Ser2032 CRMGIKTsEGTPGFR 9606 BTO:0000938 20595391 YES lperfetto Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2. 0.2 SIGNOR-166466 MORF4L1 protein Q9UBU8 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR form complex binding 9606 BTO:0000007 21041482 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. our data suggest that the tethering of HDAC1, as part of this complex, to these loci promotes histone deacetylation within the coding region and prevents uncontrolled RNAP II progression at transcribed loci. 0.8 SIGNOR-266966 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7314 KSASRPGsRAGSRAG 9606 BTO:0004905 21295697 YES lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. 0.436 SIGNOR-264431 hsa-miR-23b-3p mirna URS00004E57E7_9606 RNAcentral PAK2 protein Q13177 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001109 22109528 YES Parnian MiR-23b, which is downregulated in human colon cancer samples, potently mediates the multiple steps of metastasis, including tumour growth, invasion and angiogenesis in vivo . | Mutation of the putative miR-23b site(s) in the 3′-UTR of FZD7, MAP3K1 (MEKK1), PAK2, TGFβR2, RRAS2 or uPA resulted in an abrogated responsiveness to miR-23b. 0.4 SIGNOR-277961 PRKN protein O60260 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000793 20871098 YES miannu Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2.  Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy. 0.2 SIGNOR-272780 hsa-miR-23b-3p mirna URS00004E57E7_9606 RNAcentral TGFBR2 protein P37173 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001109 22109528 YES Parnian MiR-23b, which is downregulated in human colon cancer samples, potently mediates the multiple steps of metastasis, including tumour growth, invasion and angiogenesis in vivo . | Mutation of the putative miR-23b site(s) in the 3′-UTR of FZD7, MAP3K1 (MEKK1), PAK2, TGFβR2, RRAS2 or uPA resulted in an abrogated responsiveness to miR-23b. 0.4 SIGNOR-277962 hsa-miR-124-5p mirna URS00003AA409_9606 RNAcentral ABCB1 protein P08183 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0006204 25861751 NO Parnian The current study showed that miR-124 was downregulated in vinblastine- and doxorubicin-resistant renal cancer cells, accompanied by increased levels of FZD5 and P-gp. | Meanwhile, miR-124 targeted FZD5 and abolished its presentation 0.4 SIGNOR-277970 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 BTO:0000944 11689711 YES gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. 0.2 SIGNOR-252985 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR UFL1 protein O94874 UNIPROT up-regulates activity relocalization 9606 BTO:0001938 30886146 YES lperfetto UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage. 0.2 SIGNOR-265074 DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 9606 23661684 NO lperfetto To test small RNA processing by such PACT-containing complexes, we tested the substrates described above for cleavage rates (pre-let-7a, pre-miR-34c and dsRNA W1) and product length specificity (pre-miR-200a and pre-miR-34c). The results of these experiments showed that Dicer–Ago2–TRBP and Dicer–Ago2–PACT produce the same miRNA products from pre-miR-200a and pre-miR-34c substrates as observed for Dicer–TRBP and Dicer–PACT, respectively (Figure 3A). 0.7 SIGNOR-255322 MAPK3 protein P27361 UNIPROT STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation Ser25 QAFELILsPRSKESV 9606 9731215 YES lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. 0.576 SIGNOR-249482 NLRP1 inflammasome complex SIGNOR-C224 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 NO miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. 0.7 SIGNOR-260355 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR FBXO15 protein Q8NCQ5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0005816 24703837 YES miannu Fbxo15 Targets CLS1 Protein for Ubiquitination and Degradation to Disrupt Mitochondrial Function. S. aureus infection induces expression of a kinase, PINK1, that phosphorylates an indispensable protein CLS1, which in turn triggers CLS1 ubiquitination and degradation by the F box protein (SCFFbxo15). 0.524 SIGNOR-272172 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser402 ISNSHPLsLTSDQYK -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.822 SIGNOR-178407 belinostat chemical CHEBI:61076 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257960 HSPA9 protein P38646 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.684 SIGNOR-267693 CS protein O75390 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 3013232 YES miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. 0.8 SIGNOR-266239 PTPN11 protein Q06124 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 YES miannu Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. 0.672 SIGNOR-255754 TWIST1 protein Q15672 UNIPROT AKR1C2 protein P52895 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255510 YBX1 protein P67809 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001023 17072343 NO miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. 0.322 SIGNOR-255610 KHK protein P50053 UNIPROT beta-D-fructofuranose smallmolecule CHEBI:28645 ChEBI down-regulates quantity chemical modification 9606 38971308 YES miannu KHK catalyzes the phosphorylation of the C1 hydroxyl of fructose to generate fructose-1-phosphate (F-1P) 0.8 SIGNOR-280238 PAK1 protein Q13153 UNIPROT ELF3 protein P78545 UNIPROT up-regulates phosphorylation Ser207 GTGASRSsHSSDSGG 9606 BTO:0000150 17491012 YES lperfetto Phosphorylation-dependent regulation of stability and transforming potential of ets transcriptional factor ese-1 by p21-activated kinase 1. Pak1 selectively phosphorylates ese-1 at ser(207). Intriguingly, pak1 phosphorylation inactive mutant ese1-s207a is more unstable 0.457 SIGNOR-154743 GALNT8 protein Q9NY28 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity glycosylation 9606 35220009 YES miannu Interestingly, the O-GalNAcylation of EGFR, which is the key factor related to the metastasis cascade, was impacted by GALNT8. Furthermore, our results suggested that the GALNT8-mediated O-GalNAcylation led to the suppression of the EGFR signaling pathway and metastatic potential in breast cancer cells.  0.2 SIGNOR-269679 CSNK1D protein P48730 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 11165242 YES miannu Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). 0.869 SIGNOR-268000 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Thr63 LSSAWPGtLRSGMVP 9606 BTO:0000887 11342557 YES lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation 0.307 SIGNOR-107688 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 YES We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B 0.578 SIGNOR-251237 Ub:E2 complex SIGNOR-C497 SIGNOR UHRF1 protein Q96T88 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271020 ANKRD11 protein Q6UB99 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 BTO:0000142 29274743 NO miannu We showed that ANKRD11 regulates dendrite outgrowth, arborization, and spine formation via Trkb transcription and activation of its downstream effectors in the developing mouse brain. 0.7 SIGNOR-266733 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI PHF8 protein Q9UPP1 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273477 KLF5 protein Q13887 UNIPROT PPARG protein P37231 UNIPROT up-regulates transcriptional regulation 10090 16054042 NO fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. 0.622 SIGNOR-210010 EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 31226023 NO miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation.The resulting global attenuation of protein synthesis reduces the ER protein influx and allows the ER to reprogram for preferential expression of UPR genes. 0.7 SIGNOR-260166 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266478 MMP14 protein P50281 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272359 NR2F6 protein P10588 UNIPROT LHCGR protein P22888 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 BTO:0000318 10644740 YES Luana Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription. 0.302 SIGNOR-266216 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Thr185 TRNKVRKtFVGTPCW 9606 17190791 YES gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1) 0.485 SIGNOR-151663 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide chemical CHEBI:95082 ChEBI BRD3 protein Q15059 UNIPROT down-regulates activity chemical inhibition -1 24015967 YES Gianni This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation 0.8 SIGNOR-262203 PLG protein P00747 UNIPROT PLAT protein P00750 UNIPROT up-regulates activity cleavage Arg310 QYSQPQFrIKGGLFA 9606 BTO:0000131 1447176 YES lperfetto The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme 0.572 SIGNOR-263534 WRN protein Q14191 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 9606 19652551 NO Our work provides the first demonstration of the major importance of WRN in repair of a specific class of DSB in human cells. 0.7 SIGNOR-258983 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 8816480 YES gcesareni In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1 0.634 SIGNOR-43951 EGFR protein P00533 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr102 YDLKLQEyQSAIKVE 9606 26718225 YES miannu  Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase.  0.514 SIGNOR-277190 TBK1 protein Q9UHD2 UNIPROT IKBKB protein O14920 UNIPROT up-regulates binding 9606 14743216 YES fstefani A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway. 0.404 SIGNOR-121576 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR DDX17 protein Q92841 UNIPROT down-regulates activity binding 9606 26045258 YES miannu In addition, nuclear YAP has also been found to regulate miRNA processing. Nuclear YAP/TAZ bind and sequester DEAD box helicase 17 (DDX17) (also known as p72) to repress its association with Microprocessor, a complex that regulates miRNA processing (Figure 3B). 0.2 SIGNOR-277659 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates activity acetylation Lys19 VKRLLGWkKSAGGSG 9606 17074756 YES lperfetto Acetylation of the short isoform of Smad2 improves its DNA binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity. Smad2(FL) and Smad2(_E3) were also acetylated by P/CAF in vivo and the acetylation of both proteins was lost following mutation of Lys19 (Fig. 2D), suggesting that Lys19 in Smad2 is also targeted by P/CAF. 0.632 SIGNOR-217607 TNFSF14 protein O43557 UNIPROT TNFRSF14 protein Q92956 UNIPROT up-regulates binding 9606 BTO:0000763 10894944 YES gcesareni A member of the tumor necrosis factor (tnf) superfamily, human tnfsf14 (htnfsf14)/hvem-l (herpes virus entry mediator ligand) was isolated as a cellular ligand for hvem/tr2 and human lymphotoxin beta receptor (ltbetar). Tnfsf14 induces apoptosis and suppresses tumor formation 0.857 SIGNOR-79328 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser688 SKGVDFEsSEDDDDD -1 28436950 YES miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. 0.2 SIGNOR-265893 CAMK2G protein Q13555 UNIPROT PEA15 protein Q15121 UNIPROT unknown phosphorylation Ser116 KDIIRQPsEEEIIKL BTO:0000099 9721757 YES llicata Partly purified PEA-15 was a substrate in vitro for CaMKII, but not for casein kinase II. Two-dimensional phosphopeptide mapping demonstrated that the site phosphorylated in vitro by CaMKII was also phosphorylated in intact astrocytes in response to endothelin. CaMKII phosphorylated selectively Ser116 and had no effect on Ser104, but in vitro phosphorylation by CaMKII appeared to facilitate further phosphorylation by protein kinase C.  0.346 SIGNOR-250701 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K12 protein Q12852 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 YES gcesareni One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks 0.377 SIGNOR-97060 MT-ND6 protein P03923 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 0.766 SIGNOR-262149 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr700 EGEEDTEyMTPSSRP 10090 11997497 YES Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation. 0.526 SIGNOR-251305 FUS protein P35637 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates quantity post transcriptional regulation 10090 BTO:0000142 32118033 YES lperfetto These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition. 0.2 SIGNOR-262104 MAPK9 protein P45984 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Ser319 NSKYNAEsTERESQD 9606 18667537 YES llicata This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity. 0.376 SIGNOR-179676 KLHL8 protein Q9P2G9 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 10090 BTO:0000944 19158078 YES miannu We found that rapsyn was polyubiquitinated by KLHL8-containing E3 ligase, but not by KEAP1-containing E3 ligase, clearly indicating that rapsyn is a direct substrate of KLHL8-containing E3 ligase in mammals. We next examined the effect of KLHL-8 depletion on the ubiquitination of rapsyn by performing RNAi experiments in mammalian cells. We found that knockdown of KLHL8 in 3T3 cells reduced the level of rapsyn ubiquitination (Fig. 5C), again indicating that the maintenance mechanism for rapsyn stability is conserved in mammals.The in vitro ubiquitination of mammalian rapsyn by CUL3-containing E3 ligase and the effect of KLHL8 knockdown on the ubiquitination of rapsyn. 0.403 SIGNOR-271783 DUSP6 protein Q16828 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity dephosphorylation Ser256 SPRRRAAsMDNNSKF 9606 22848439 YES lperfetto It has been previously demonstrated that MKP-3 dephosphorylates FOXO1 on Ser256 and promotes nuclear translocation of FOXO1 , which subsequentially binds to the promoters of gluconeogenic genes and turns on the gluconeogenic program.|We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256, one of the Akt phosphorylation sites xref . 0.428 SIGNOR-276983 HTR1E protein P28566 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.377 SIGNOR-256984 CDK5 protein Q00535 UNIPROT HTR6 protein P50406 UNIPROT down-regulates activity phosphorylation Ser350 ERQASLAsPSLRTSH 10090 BTO:0000942 32047117 YES lperfetto Cdk5 phosphorylates the 5-HT6R on serine 350 (Ser350)|This suggests that the 5-HT6R is unable to interact with GPRIN1 when it is phosphorylated by Cdk5. 0.374 SIGNOR-264407 N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide chemical CHEBI:91389 ChEBI PDGFRA protein P16234 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189528 IGF1R protein P08069 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity phosphorylation Tyr133 LGIPEQEySCVVKMP -1 28924044 YES miannu In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination. 0.2 SIGNOR-277254 PTPN6 protein P29350 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 10458769 YES miannu We propose that shp1 can dephosphorylate sites in zap-70 and syk that are involved in coupling these kinases to downstream signaling cascades, including erk2 and elements of the il-2 gene. 0.587 SIGNOR-70237 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 17204478 YES lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). 0.798 SIGNOR-263422 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.289 SIGNOR-251205 NOTCH4 protein Q99466 UNIPROT MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 12370315 YES gcesareni Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo 0.867 SIGNOR-94109 RASSF1 protein Q9NS23 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 21808241 YES Mst1/2 are pro-apoptotic kinases that are activated by caspase cleavage milica Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization. 0.806 SIGNOR-175793 CHD8 protein Q9HCK8 UNIPROT MAP2 protein P11137 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.2 SIGNOR-268916 SLC36A2 protein Q495M3 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity relocalization 9606 12748860 YES lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. 0.8 SIGNOR-264742 CREB3 protein O43889 UNIPROT HERPUD1 protein Q15011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16940180 NO miannu Luman/creb3 induces transcription of the endoplasmic reticulum (er) stress response protein herp through an er stress response element. 0.316 SIGNOR-149268 eribulin mesylate chemical CHEBI:70710 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 16940412 YES miannu The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. 0.8 SIGNOR-259444 DRD2 protein P14416 UNIPROT GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 21303898 YES miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC 0.602 SIGNOR-264993 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Thr694 LPDMSVKtPKISMPD 10090 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.256 SIGNOR-262768 ACSS2 protein Q9NR19 UNIPROT GUSB protein P08236 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants 0.262 SIGNOR-276554 MRPL17 protein Q9NRX2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.713 SIGNOR-262340 MAPK3 protein P27361 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 23024368 YES gcesareni Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5. 0.343 SIGNOR-192101 EPHB1 protein P54762 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity relocalization 26319181 YES lperfetto The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration. 0.2 SIGNOR-275922 MAP3K7 protein O43318 UNIPROT ATAT1 protein Q5SQI0 UNIPROT up-regulates activity phosphorylation Ser237 GDIKPYSsSDREFLK 9534 BTO:0004055 29703898 YES lperfetto Here we report TGF-beta-activated kinase 1 (TAK1) as a key activator of alphaTAT1. TAK1 directly interacts with and phosphorylates alphaTAT1 at Ser237 to critically enhance its catalytic activity 0.2 SIGNOR-272243 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258629 AKT proteinfamily SIGNOR-PF24 SIGNOR NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser134 ANLNRSTsVPENPKS 9606 BTO:0000731 24291004 YES lperfetto Akt1 impairs glucocorticoid-induced gene expression by direct phosphorylation of nr3c1 at position s134 and blocking glucocorticoid-induced nr3c1 translocation to the nucleus 0.2 SIGNOR-236216 NPY protein P01303 UNIPROT NPY1R protein P25929 UNIPROT up-regulates binding 9606 9549761 YES gcesareni Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors. 0.857 SIGNOR-56522 F2R protein P25116 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.25 SIGNOR-254851 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 9606 19917253 YES gcesareni Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation 0.804 SIGNOR-161713 MTR protein Q99707 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI down-regulates quantity chemical modification 9606 10520212 YES lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. 0.8 SIGNOR-253144 acetyl-CoA smallmolecule CHEBI:15351 ChEBI citrate(3-) smallmolecule CHEBI:16947 ChEBI up-regulates quantity precursor of 9606 3013232 YES miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. 0.8 SIGNOR-266236 Blood vessel damage stimulus SIGNOR-ST26 SIGNOR VWF protein P04275 UNIPROT up-regulates 9606 NBK559062 NO lperfetto Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VW|VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain. 0.7 SIGNOR-261862 SRC protein P12931 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr797 TLMSVPRyLPRPANP 31286874 YES lperfetto Activated c-Src phosphorylated E-cadherin at the tyrosine 797 site to initiate RNF43-mediated E-cadherin ubiquitination at lysine 816 and subsequent degradation 0.754 SIGNOR-274048 PKA proteinfamily SIGNOR-PF17 SIGNOR MFN2 protein O95140 UNIPROT up-regulates activity phosphorylation Ser442 AEEIRRLSVLVDDYQ 10090 BTO:0004578 20303493 YES Barakat Mitofusin 2 (Mfn2) is an important suppressor of vascular smooth muscle cell (VSMC) proliferation. It contains a protein kinase A (PKA) phosphorylation site at serine 442 (S442) and can be phosphorylated by PKA 0.2 SIGNOR-274137 PLK3 protein Q9H4B4 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser657 ETTSATSsPYRDTQS 9606 BTO:0000567 18519666 YES lperfetto Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation 0.349 SIGNOR-178743 TRH protein P20396 UNIPROT TRHR protein P34981 UNIPROT up-regulates activity binding 9606 BTO:0001379 27515033 YES scontino When TRH reaches the pars distalis of the pituitary, it regulates cells that express TRH receptor-1 (TRH-R1), such as the thyrotrophs. These cell types are subject to a multifactorial regulation that determines the extent and specificity of their response to TRH. 0.761 SIGNOR-267200 MAPK1 protein P28482 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 9606 BTO:0000130 16709866 NO gcesareni The role of members of the arrestin family to mediate kinase activation is also a well-established phenomenon, including activation of members of the src family, erk1/2, and jnk3. Activation often includes the recruitment and interaction of arrestins with upstream mapks (ask1, mek3, mkk3, and mek kinase-2). 0.32 SIGNOR-146751 risperidone chemical CHEBI:8871 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258840 FBXO22 protein Q8NEZ5 UNIPROT BACH1 protein O14867 UNIPROT down-regulates quantity ubiquitination 9606 31257023 YES Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. 0.282 SIGNOR-259331 RAF1 protein P04049 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Thr268 PNVHMVStTLPVDSR -1 8349614 YES lperfetto Furthermore, we find that Thr268 is the predominant Raf-1 residue phosphorylated in in vitro autokinase assays. 0.2 SIGNOR-248917 DAPK1 protein P53355 UNIPROT PKD1 protein P98161 UNIPROT up-regulates activity phosphorylation 9606 28361035 YES miannu In addition, the tumor suppressor death-associated protein kinase phosphorylates and activates PKD1 in response to oxidative damage ( xref ). 0.2 SIGNOR-279985 LDHB protein P07195 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI down-regulates quantity chemical modification 9606 24929216 YES lperfetto Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. 0.8 SIGNOR-267656 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral TEAD1 protein P28347 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 38681790 YES miannu Bioinformatics prediction identified 37 potential miR-30a-3p target genes, including transcriptional enhanced associate domain 1 (TEAD1). After transfection of HK-2 cells with miR-30a-3p mimics and miR-30a-3p inhibitor, TEAD1 transcript was significantly up- and down-regulated, respectively (both P <0.05). 0.4 SIGNOR-279976 MAPK11 protein Q15759 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation 9606 10330143 YES miannu In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2. 0.537 SIGNOR-280025 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser316 EKKGKDQsGEVLSSV 9615 BTO:0000837 11742978 YES llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. 0.416 SIGNOR-250828 GTF2B protein Q00403 UNIPROT FOXF2 protein Q12947 UNIPROT up-regulates activity binding 9534 BTO:0004055 9722567 YES miannu The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. FREAC-2 dependent activation of transcription by TFIIB. 0.492 SIGNOR-220317 PINK1 protein Q9BXM7 UNIPROT CRLS1 protein Q9UJA2 UNIPROT down-regulates quantity phosphorylation 9606 24703837 YES miannu In vitro kinase assays using recombinant proteins under various control conditions indicated that PINK1 directly phosphorylates CLS1 (XREF_FIG).|Similar to Fbxo15, knockdown of PINK1 kinase using shRNA increased CLS1 levels, whereas overexpression of PINK1 plasmid decreased CLS1 levels . 0.43 SIGNOR-280065 PRKCA protein P17252 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 24909179 YES miannu Phosphorylation of BAD at ser112 and ser136 in the setting of lapatinib treatment was fully restored by PRKACA expression in BT474, SKBr3, and ZR-75-30 cells (XREF_FIG).|We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro apoptotic protein BAD, thereby permitting survival signaling through BCL-XL. 0.2 SIGNOR-280080 PTK2B protein Q14289 UNIPROT LSR protein Q86X29 UNIPROT up-regulates activity phosphorylation 9606 31574128 YES miannu Pyk2 enhances LSR and tricellulin localization to tTJs.|Pyk2-dependent phosphorylation of LSR enhances localization of LSR and tricellulin at tricellular tight junctions. 0.2 SIGNOR-280101 ROR2 protein Q01974 UNIPROT VANGL2 protein Q9ULK5 UNIPROT down-regulates activity phosphorylation 9606 23140626 YES miannu In support of this, ror2 mutants abolish Vangl2 activity gradient and localization, and ror2; vangl2 double mutants phenocopy the wnt5a limb phenotype (Gao et al., 2011).4.6.|This process is mediated by its receptor Ror2, which in turn phosphorylates Vangl2 and induces asymmetric localization of Vangl2, propagating an activity gradient of Vangl2 in the proximal direction (Gao et al., 2011). 0.588 SIGNOR-280111 RPS6KB1 protein P23443 UNIPROT SRPK2 protein P78362 UNIPROT up-regulates activity phosphorylation 9606 35674408 YES miannu Altogether, these results identify S6K1-phosphorylated SRPK2 as an essential mediator of IGF1-stimulated SG formation in hPDAC cells.|The nodes of the core SG network are known to contribute to SG formation to varying degrees and it is possible that S6K1-stimulated SRPK2 may impact their contribution; this is consistent with the predicted model whereby SG assembly is subject to regulation by positive and negative cooperativity of extrinsic factors with the core network interactions (14). 0.356 SIGNOR-280121 CSNK2A1 protein P68400 UNIPROT CERS4 protein Q9HA82 UNIPROT up-regulates activity phosphorylation Ser349 SDVEESDsSEEAAAA 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273984 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr846 RAFSFSKtPKRALRR 9606 SIGNOR-C17 16247472 YES lperfetto Thr-814 to ala greatly diminished the ability of p34cdk1/cyclin b to phosphorylate recombinant ect2-c protein (figure 1b, left panel). These data suggest that thr-814 is a major cdk1 phosphorylation site in ect2-c in vitrothe sequence thr-pro-lys-arg (tpkr) starting at amino acid 814we found that the t814a mutation slightly reduces the exchange activity of ect2 on rac1 0.578 SIGNOR-141179 CAMK2A protein Q9UQM7 UNIPROT GFPT1 protein Q06210 UNIPROT up-regulates phosphorylation Ser261 CNLSRVDsTTCLFPV 9606 17941647 YES gcesareni Amp-activated protein kinase and calcium/calmodulin-dependent kinase ii were identified to phosphorylate specifically ser243 in vitro. Phosphorylation by these two kinases results in an increase of enzymatic activity by 1.4-fold. These findings suggest for the first time that hgfat1 may be regulated by kinases other than pka. 0.2 SIGNOR-158486 PRRX1 protein P54821 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.306 SIGNOR-221899 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates activity phosphorylation Ser284 RRDYDDMsPRRGPPP 11231586 YES miannu Mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) efficiently phosphorylates hnRNP-K both in vitro and in vivo at serines 284 and 353. Our results establish the role of MAPK/ERK in phosphorylation-dependent cellular localization of hnRNP-K, which is required for its ability to silence mRNA translation. 0.339 SIGNOR-250082 SMARCA4 protein P51532 UNIPROT SMARCC2 protein Q8TAQ2 UNIPROT up-regulates binding 9606 10078207 YES miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. 0.939 SIGNOR-65444 PTBP1 protein P26599 UNIPROT Alternative_Splicing_Regulation phenotype SIGNOR-PH204 SIGNOR up-regulates 9606 20010808 NO We show that three heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, polypyrimidine tract binding protein (PTB, also known as hnRNPI), hnRNPA1 and hnRNPA2, bind repressively to sequences flanking exon 9, resulting in exon 10 inclusion. 0.7 SIGNOR-268688 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. 0.2 SIGNOR-183664 BIRC2 protein Q13490 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. 0.651 SIGNOR-272712 PBRM1 protein Q86U86 UNIPROT RARB protein P10826 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15601824 NO miannu We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues. 0.419 SIGNOR-132378 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser733 TVREQDQsFTALDWS 9606 SIGNOR-C14 SIGNOR-C14 10195894 YES lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response 0.2 SIGNOR-66344 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1672 SPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248820 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270382 PPP2CB protein P62714 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity dephosphorylation Ser87 AAAGPALsPVPPVVH 9606 15225643 YES The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A. 0.384 SIGNOR-248589 CDC25B protein P30305 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 25384584 YES lperfetto CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G 2 /M transition ( xref ).|CDC25B facilitates dephosphorylation of the key cell cycle regulator CDC2 (also called CDK1) at Tyr15 or Thr14, thereby initiating the G2/M transition ( ). 0.828 SIGNOR-276969 FLCN protein Q8NFG4 UNIPROT RRAGC protein Q9HB90 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000007 24095279 YES The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur 0.694 SIGNOR-256503 ULK1 protein O75385 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity phosphorylation Ser108 SLTRVDLsSSVLPGD 9606 33827825 YES miannu Furthermore, the Parkin band shift induced by catalytically active WT ULK1 was diminished by treatment of cell lysates with lambda-phosphatase, as was the mobility of ULK1 itself (XREF_FIG).|Parkin is phosphorylated by ULK1 at Ser 108 in its recently described nine amino acid ACT element at this early time point 0.2 SIGNOR-279663 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 YES llicata Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.  0.246 SIGNOR-188181 DAPT chemical CHEBI:86193 ChEBI PSEN1 protein P49768 UNIPROT down-regulates chemical inhibition 9606 16569643 YES gcesareni The catalytic aspartates are necessary for binding of the transition state analogue inhibitor, l-685,458, to ps1. It is possible that these catalytic aspartates also contribute to the direct interaction of ps with dapt. 0.8 SIGNOR-145385 MECP2 protein P51608 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 BTO:0000614 18511691 YES Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. 0.272 SIGNOR-264677 BUB1 protein O43683 UNIPROT H2AC11 protein P0C0S8 UNIPROT unknown phosphorylation Thr121 AVLLPKKtESHHKAK 9606 19965387 YES lperfetto the localization of hBub1 kinase usually defines the centromere-specific phosphorylation of H2A-T120. Accordingly, hSgo1 localized along the whole chromosome length in H2B-hBub1deltaN cells (Fig. 6D), indicating that H2A-pT120 plays a predominant role in defining shugoshin localization sites on the human chromosomes 0.2 SIGNOR-265261 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Ser625 PIVGSNGsSRLQDSR 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.2 SIGNOR-262924 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000742 15568017 YES gcesareni We demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for Wnt-directed myogenic gene expression. 0.58 SIGNOR-255799 JUN protein P05412 UNIPROT TCF4 protein P15884 UNIPROT up-regulates binding 9606 16007074 YES gcesareni Phosphorylation-dependent interaction between c-jun and tcf4;c-jun and tcf4 cooperatively activated the c-jun promoter in reporter assays 0.393 SIGNOR-138544 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Ser475 IDIEGVQsEGQDNGA 10029 BTO:0002640 15066279 YES llicata We show that inhibiting XRCC1 phosphorylation by mutation of the CK2 phosphorylation sites or preventing CK2 activity using a highly specific inhibitor ablates the rapid repair of cellular DNA single-strand breaks by XRCC1. | 0.396 SIGNOR-250972 JARID2 protein Q92833 UNIPROT NKX2-5 protein P52952 UNIPROT down-regulates activity binding 10116 BTO:0003324 15542826 YES miannu JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4. 0.456 SIGNOR-224787 PAFAH1B1 protein P43034 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity binding 9606 BTO:0000567 11940666 YES miannu Here we demonstrate colocalization and direct interaction between CLIP-170 and LIS1. In mammalian cells, LIS1 recruitment to kinetochores is dynein/dynactin dependent, and recruitment there of CLIP-170 is dependent on its site of binding to LIS1, located in the distal zinc finger motif. 0.792 SIGNOR-252166 PRKAA1 protein Q13131 UNIPROT TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation 9606 31235817 YES miannu However, AMP-activated protein kinase (AMPK), an essential cellular energy sensor, phosphorylates and activates TSC2 [ xref ]. 0.681 SIGNOR-278981 PCNT protein O95613 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity binding 9606 BTO:0001938 18042621 YES Giulio Our observation that Cep215 may function downstream of pericentrin suggests that the two proteins affect centrosome cohesion through a common mechanism. |Finally, depletion of pericentrin caused an almost complete loss of Cep215 from centrosomes, a detectable reduction in centrosomal levels of Cep68 and rootletin, but no significant effect on C-Nap1 (Fig. 6C and Table 1). Taken together, these results point to functional (and perhaps molecular) interactions between (1) Cep68 and rootletin and (2) Cep215 and pericentrin. 0.818 SIGNOR-260309 vandetanib chemical CHEBI:49960 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258307 JAK2 protein O60674 UNIPROT STAM protein Q92783 UNIPROT up-regulates phosphorylation 9606 9133424 YES gcesareni Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2. 0.616 SIGNOR-47834 SMARCD1 protein Q96GM5 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.794 SIGNOR-270694 RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 YES lperfetto Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology 0.668 SIGNOR-105454 CDK2 protein P24941 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C16 21902831 YES gcesareni Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation. 0.884 SIGNOR-176512 TFEB protein P19484 UNIPROT WDFY3 protein Q8IZQ1 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 NO lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 0.27 SIGNOR-276804 ELOC protein Q15369 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR form complex binding 9606 11574546 YES miannu The von Hippel-Lindau tumor-suppressor protein (pVHL) forms a protein complex (VCB-Cul2) with elongin C, elongin B, Cul-2, and Rbx1, which functions as a ubiquitin-protein ligase (E3). The alpha-subunits of the hypoxia-inducible factors have been identified as targets for the VCB-Cul2 ubiquitin ligase.  0.2 SIGNOR-271518 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr795 AAERPGGtPTPVIAY -1 19448668 YES miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. 0.38 SIGNOR-262880 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 9606 23450633 NO inferred from 70% of family members gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. 0.7 SIGNOR-269861 glutamic acid smallmolecule CHEBI:18237 ChEBI MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity chemical activation 9606 25042998 YES miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate 0.8 SIGNOR-264688 LCK protein P06239 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr735 LKGPTCQyRAAQSGP 9606 11741929 YES lperfetto Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling. 0.35 SIGNOR-112935 ponatinib chemical CHEBI:78543 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 23430109 YES lperfetto AP24534 also inhibited SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (Table 1 and Table S1) 0.8 SIGNOR-261985 WNT1 protein P04628 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.788 SIGNOR-131574 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity transcriptional regulation 9606 30017632 YES miannu The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression 0.612 SIGNOR-260437 OPA1 protein O60313 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 NO lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria 0.7 SIGNOR-272987 MAPK11 protein Q15759 UNIPROT MAPK11 protein Q15759 UNIPROT down-regulates activity phosphorylation Ser243 MEVVGTPsPEVLAKI -1 26976637 YES miannu P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261 0.2 SIGNOR-277215 PAK2 protein Q13177 UNIPROT PRL protein P01236 UNIPROT up-regulates phosphorylation Ser207 LHCLRRDsHKIDNYL 9606 19555049 YES gcesareni Phosphorylated form of prolactin has a higher affinity for heparin. 0.338 SIGNOR-186211 NR3C1 protein P04150 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity 10090 BTO:0000944 11742987 NO gcesareni Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. 0.54 SIGNOR-251677 F2RL3 protein Q96RI0 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.427 SIGNOR-257419 COL4A3 protein Q01955 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 YES lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. 0.433 SIGNOR-272351 furtrethonium chemical CHEBI:134764 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258642 PLK3 protein Q9H4B4 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity phosphorylation Thr273 DAGALTTtFEELHFE 27325299 YES lperfetto Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. 0.338 SIGNOR-272995 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 10931950 YES inferred from 70% family members gcesareni These data suggest that increased signaling by erbb receptors up-regulates mapk activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression. 0.2 SIGNOR-270087 MYCT1 protein Q8N699 UNIPROT BCL2 protein P10415 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 NO miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 0.2 SIGNOR-261735 RET protein P07949 UNIPROT DOK5 protein Q9P104 UNIPROT up-regulates binding 9606 11470823 YES gcesareni Dok-4 and dok-5 enhance c-ret-dependent activation of mitogen-activated protein kinase 0.623 SIGNOR-109516 leukotriene D4(1-) smallmolecule CHEBI:63166 ChEBI CYSLTR2 protein Q9NS75 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257476 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 9649584 YES gcesareni This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation. 0.2 SIGNOR-58502 GATA1 protein P15976 UNIPROT FCER1A protein P12319 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000732 11971001 NO Transcriptional regulation of the gene-encoding human Fc epsilon RI alpha-chain was analyzed in detail. EMSA revealed that either YY1 or PU.1 bound to the region close to that recognized by Elf-1. The alpha-chain promoter activity was up-regulated approximately 2-fold by exogenously expressed YY1 or PU.1 and approximately 7-fold by GATA-1, respectively, in KU812 cells 0.31 SIGNOR-254288 AMOT protein Q4VCS5 UNIPROT YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR down-regulates activity binding 9606 21205866 YES miannu AMOT inhibits YAP/TAZ by regulating YAP/TAZ localization via physical interaction and promoting YAP/TAZ phosphorylation by the Hippo pathway. 0.733 SIGNOR-277657 PTGER1 protein P34995 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.263 SIGNOR-257278 sorafenib tosylate chemical CHEBI:50928 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 0.8 SIGNOR-259225 ARNT protein P27540 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR form complex binding 9606 27692180 YES miannu HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life 0.786 SIGNOR-267448 SORT1 protein Q99523 UNIPROT APOE protein P02649 UNIPROT up-regulates quantity binding 10029 BTO:0000246 23283348 YES miannu Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms. 0.428 SIGNOR-273721 CHFR protein Q96EP1 UNIPROT AURKA protein O14965 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 17442268 YES miannu Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A. 0.472 SIGNOR-271463 LETM1 protein O95202 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR up-regulates 9606 BTO:0000567 18628306 NO lperfetto LETM1 knockdown obviously reduced the formation of the supercomplexes (Fig. 5C, arrowhead). Complexes I and IV failed to form, and the assembly of complex III was significantly decreased. By contrast, the assembly of complex II (succinate dehydrogenase) and complex V (ATP synthase) – which are not proton pumps – was unaffected. 0.29 SIGNOR-262548 PRKD1 protein Q15139 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity phosphorylation Thr677 YKVLATStKHGFMQF 9606 22095288 YES miannu PKD phosphorylates Vps34, leading to activation of Vps34, phosphatydilinositol-3-phosphate formation, and autophagosome formation.|Therefore, PKD phosphorylates Vps34 on multiple sites, including Thr677 within the catalytic domain. 0.371 SIGNOR-278495 NFATC3 protein Q12968 UNIPROT TFF1 protein P04155 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16219765 NO miannu Overexpression of NFAT3 enhanced both ERalpha and ERbeta transcriptional activities in a ligand-independent manner and up-regulated downstream estrogen-responsive genes including pS2 and cathepsin D. Reduction of endogenous NFAT3 with NFAT3 small interfering RNA or overexpression of NFAT3 deletion mutants that lack the ER-binding sites reduced the NFAT3 coactivation of ERalpha and ERbeta. 0.2 SIGNOR-254639 DCLK1 protein O15075 UNIPROT MACC1 protein Q6ZN28 UNIPROT up-regulates activity phosphorylation 9606 32756469 YES miannu Subsequently, MACC1 gets phosphorylated by DCLK1.|This might be attributed to the higher activation of MACC1 by DCLK1 in the MACC1-positive cell lines SW620/Control and SW480/MACC1 used in this study. 0.2 SIGNOR-279031 PPP2CA protein P67775 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity dephosphorylation Ser87 AAAGPALsPVPPVVH 9606 15225643 YES The phosphorylation of Bcl-2 resulted in a reduction in anti-apoptotic function, implying that dephosphorylation promoted the anti-apoptotic activity of Bcl-2 protein in human tumor cell lines. Thus, the present findings suggest that ERK and PP2A are physiological regulators of Bcl-2 phosphorylation, and these enzymes exert an influence on the anti-apoptotic function of Bcl-2.phosphorylation of Bcl2 at Ser70 is proposed to be a dynamic process regulated by the sequential action of an agonist-activated Bcl2 kinase and PP2A. 0.469 SIGNOR-248624 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 17386266 YES gcesareni Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity. 0.673 SIGNOR-153931 ESRRA protein P11474 UNIPROT NR2F1 protein P10589 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000155 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.246 SIGNOR-253795 IMPDH2 protein P12268 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30518405 NO miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. 0.2 SIGNOR-260959 SGK3 protein Q96BR1 UNIPROT TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation 9606 34911733 YES miannu SGK3 phosphorylates six sites on TSC2 to activate mTORC1 in an AKT-independent manner. 0.435 SIGNOR-279284 SYK protein P43405 UNIPROT LAX1 protein Q8IWV1 UNIPROT up-regulates activity phosphorylation Tyr294 AFQCCRDyENVPAAD 9606 BTO:0000007 12359715 YES miannu Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85.  0.378 SIGNOR-273534 Ub:E2 complex SIGNOR-C497 SIGNOR RNF183 protein Q96D59 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271209 DYRK1A protein Q13627 UNIPROT SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr434 PARKLTAtPTPLGGM 9606 BTO:0000007 16512921 YES llicata The present data show that the splicing factor sf3b1 is a substrate of the protein kinase dyrk1a and suggest that dyrk1a may be involved in the regulation of pre mrna-splicing. by mass spectrometry and mutational analysis of sf3b1, thr434 was identified as the major phosphorylation site for dyrk1a. 0.501 SIGNOR-144975 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide chemical CHEBI:91433 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-195675 EPHA4 protein P54764 UNIPROT STAT5B protein P51692 UNIPROT up-regulates activity phosphorylation 9606 28686668 YES miannu We have shown here that EphA4 can phosphorylate STAT5B, but it is not yet clear whether the nuclear translocation of phosphorylated STAT5B is enhanced by EphA4. 0.375 SIGNOR-278934 UBE2I protein P63279 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity sumoylation Lys452 EKSLVLVkLEPWLCR 9606 BTO:0002181 22951831 YES scontino One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452. 0.287 SIGNOR-266837 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 YES gcesareni Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130. 0.2 SIGNOR-244618 MYOD/E12E47 complex SIGNOR-C127 SIGNOR VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 18094043 YES lperfetto we further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter. 0.332 SIGNOR-241545 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr228 GPSSSLNtPGSFRRG 9606 BTO:0000007 16682949 YES done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 0.543 SIGNOR-274085 PIK3C3 protein Q8NEB9 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 YES lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.918 SIGNOR-260316 FYN protein P06241 UNIPROT CD300LF protein Q8TDQ1 UNIPROT up-regulates activity phosphorylation Tyr236 VDQVEVEyVTMASLP 17202342 YES lperfetto Y236 (YVTM) and Y263 (YCNM) fit with the consensus motif reported to bind the p85α regulatory subunit of PI3K (16). |The association between IREM-1 and p85α was only perceived in the presence of c-Fyn, suggesting that tyrosine phosphorylation of IREM-1 cytoplasmic tail of IREM-1 was required for the interaction. 0.343 SIGNOR-275619 FYN protein P06241 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Tyr1495 TEEQKKYyNAMKKLG 9606 15831816 YES llicata This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site. 0.293 SIGNOR-135600 MAPK8 protein P45983 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 YES gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress. 0.317 SIGNOR-166694 PKA proteinfamily SIGNOR-PF17 SIGNOR SI protein P14410 UNIPROT unknown phosphorylation Ser7 sGLEISLI -1 8521865 YES miannu This paper reports the phosphorylation of the intracellular N-terminal tail of sucrase-isomaltase by protein kinase A and shows that this phosphorylation is targeted to Ser6 within a sequence Arg/Lys/Lys-Phe-Ser, which is conserved in all sucrase-isomaltase sequences known so far. 0.2 SIGNOR-263157 GSK3B protein P49841 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser302 APGSGPSsPNNSSGS 9606 21118993 YES lperfetto The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation 0.364 SIGNOR-170148 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr59 GETRFTDtRKDEQER 9606 8386634 YES gcesareni Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58. 0.787 SIGNOR-38556 MAPK8IP3 protein Q9UPT6 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10629060 YES gcesareni These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3jip3 increases mlk3-stimulated jnk activity. 0.551 SIGNOR-73909 FBXW7 protein Q969H0 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization ubiquitination 26971449 YES lperfetto We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system. 0.399 SIGNOR-253394 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257928 PHF2 protein O75151 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2‚ÄìARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. 0.2 SIGNOR-265343 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates activity sumoylation Lys65 QQCQAEAkCPKLLPC 9534 BTO:0000298 9756909 YES lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins |We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. 0.779 SIGNOR-270542 PYGM protein P11217 UNIPROT glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267948 CEBPB protein P17676 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 16319681 NO lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. 0.7 SIGNOR-250572 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT down-regulates activity ubiquitination 10090 16862145 YES gcesareni Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15. 0.2 SIGNOR-243282 SRC protein P12931 UNIPROT TGFA protein P01135 UNIPROT up-regulates cleavage 9606 17251915 YES lperfetto Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network. 0.3 SIGNOR-235888 PIM1 protein P11309 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 YES done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  0.2 SIGNOR-273895 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser602 INKKLDLsNVQSKCG -1 8999860 YES miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules 0.314 SIGNOR-250285 MDM2 protein Q00987 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 30425162 YES miannu We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation.  0.357 SIGNOR-277421 GNA14 protein O95837 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9534 BTO:0000298 1334487 YES This suggests that both Gal4 and Gal6 can activate PLC b1. 0.466 SIGNOR-278119 Starvation stimulus SIGNOR-ST4 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates 9606 BTO:0001760 20810907 NO lperfetto L6 myotubes were incubated in serum-containing or serum-free medium for 3 h. Levels of phosphorylated AMPK, Akt, and ATM were greater in serum-starved cells than in control cells. 0.7 SIGNOR-209894 LRRK2 protein Q5S007 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation 9606 22998870 YES miannu We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association. 0.472 SIGNOR-192075 ADCY3 protein O60266 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 YES miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. 0.8 SIGNOR-265000 AMPK complex SIGNOR-C15 SIGNOR CCNY protein Q8ND76 UNIPROT up-regulates activity phosphorylation Ser326 SARKRSAsADNLTLP 9606 32723157 YES lperfetto Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16 0.2 SIGNOR-273001 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR down-regulates 9606 21364186 NO Lowering the extent of costimulation of P2X in T cells diminishes the extent of ERK phosphorylation without affecting TCR-mediated nuclear translocation of NFAT (10). In Tregs, this mechanism would favor the stability of their transcriptional program through the stabilization of nuclear complexes of NFAT and Foxp3 (47). 0.7 SIGNOR-254687 KIT protein P10721 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr703 DHAEAALyKNLLHSK 10377264 YES gcesareni We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936. 0.649 SIGNOR-248283 AKT proteinfamily SIGNOR-PF24 SIGNOR INSIG2 protein Q9Y5U4 UNIPROT down-regulates quantity by repression 10090 21723501 NO miannu MTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2. 0.2 SIGNOR-256211 CDK1 protein P06493 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser301 IQSNLDFsPVNSASS 9606 21765472 YES lperfetto Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency 0.411 SIGNOR-175075 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser467 IDLTIDSsSDEEEEE 9606 19217413 YES llicata Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process. 0.332 SIGNOR-184043 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser243 DKRKDPSsVDIKKVL -1 10480872 YES llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. 0.323 SIGNOR-250776 Telatinib chemical CID:9808844 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207224 PTGER3 protein P43115 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.45 SIGNOR-256716 SRC protein P12931 UNIPROT CHKA protein P35790 UNIPROT up-regulates activity phosphorylation Tyr333 LMLIDFEySSYNYRG 9606 BTO:0000093 21822308 YES miannu We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. 0.337 SIGNOR-266350 TESK2 protein Q96S53 UNIPROT CFL2 protein Q9Y281 UNIPROT down-regulates activity phosphorylation Ser3 sGVTVNDE 9606 BTO:0001363 11418599 YES lperfetto Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin 0.321 SIGNOR-246711 BCAR1 protein P56945 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22431919 NO miannu In MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression. 0.2 SIGNOR-253892 ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates phosphorylation Ser446 PYPGIDLsQVYELLE 9606 BTO:0000938 9168116 YES lperfetto Ataxia telangiectasia mutant protein activates c-abl tyrosine kinase in response to ionizing radiation. Atm kinase domain corrects this defect, as it phosphorylates the c-abl tyrosine kinase in vitro at ser 465, leading to the activation of c-abl. 0.743 SIGNOR-48818 ESR1 protein P03372 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 BTO:0001264 24493753 NO miannu The effects of β-oestradiol (E2), the biologically active form of oestrogen, are classically mediated by two types of oestrogen receptor (ER): ERα and ERβ. E2 has both non-genomic and genomic effects upon VGSC expression/activity; and (ii) transcriptionally, E2 (via ERα) downregulates functional VGSC (nNav1.5) expression in BCa cells. 0.2 SIGNOR-253467 pazopanib hydrochloride chemical CHEBI:71217 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-201037 PGS1 protein Q32NB8 UNIPROT 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) smallmolecule CHEBI:60110 ChEBI up-regulates chemical modification 9606 29034233 YES lperfetto After activation of PA by the CDP-DAG synthase TAMM41 (Kutik et al., 2008), the phosphatidylglycerol phosphate synthase (PGS1) catalyzes the committed step by converting CDP-DAG to phosphatidylglycerol phosphate (PGP) 0.8 SIGNOR-267023 PRKDC protein P78527 UNIPROT PNPT1 protein Q8TCS8 UNIPROT up-regulates activity phosphorylation Ser776 IVMGEPIsQSSSNSQ 9606 22815474 YES miannu We also demonstrated that DNAPK phosphorylates PNPase at Ser-776, which is critical for its ribonuclease activity. 0.2 SIGNOR-263182 PRKCA protein P17252 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 YES inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.553 SIGNOR-270278 MMP14 protein P50281 UNIPROT ADAM9 protein Q13443 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000007 22632802 YES Giulio Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9|Western blotting using antibodies against ectodomain of ADAM9 detected a fragment (around 26 kDa) of ADAM9 in the conditioned culture medium from cells cotransfected with wild-type MT1-MMP, but not in that with catalytic activity-dead MT1-MMP (Figure 6A, top). 0.341 SIGNOR-260301 MAP4K1 protein Q92918 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser559 QPPRSRSsIMSITAE -1 19706536 YES miannu HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. 0.493 SIGNOR-276258 PLCG2 protein P16885 UNIPROT Macrophage_differentiation phenotype SIGNOR-PH99 SIGNOR up-regulates 9606 24890514 NO apalma Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway 0.7 SIGNOR-255571 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR glutamine smallmolecule CHEBI:28300 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270389 LEPR protein P48357 UNIPROT NPY protein P01303 UNIPROT down-regulates quantity 27154742 NO lperfetto Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production 0.457 SIGNOR-253075 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264921 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000562 23457334 YES lperfetto Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (pfkfb2) isoenzyme by amino acids. 0.653 SIGNOR-252528 CDK1 protein P06493 UNIPROT EPN1 protein Q9Y6I3 UNIPROT down-regulates activity phosphorylation Ser382 FSDPWGGsPAKPSTN 10029 BTO:0000246 10764745 YES miannu Phosphorylation of POB1 and Epsin by p34cdc2 kinase. Their phosphorylation sites (Ser411 of POB1 and Ser357 of Epsin) were determined. Phosphorylated Epsin and EpsinS357D formed a complex with α-adaptin less efficiently than wild type Epsin. 0.323 SIGNOR-262723 VEGFC protein P49767 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 YES gcesareni Vegf-c is also a ligand for vegfr-2 (12), but the functional significance of this potential interaction in vivo is unknown 0.916 SIGNOR-55208 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258290 TFEB protein P19484 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.432 SIGNOR-276537 CDK8 protein P49336 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. 0.2 SIGNOR-273171 PIK3C3 protein Q8NEB9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates relocalization 9606 10698680 YES lperfetto One of the best characterized targets of pi3k lipid products is the protein kinase akt or protein kinase b (pkb). In quiescent cells, pkb resides in the cytosol in a low-activity conformation. Upon cellular stimulation, pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1). 0.435 SIGNOR-75370 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000944 15851026 YES inferred from 70% family members lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. 0.2 SIGNOR-270108 USP7 protein Q93009 UNIPROT UBA52 protein P62987 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.734 SIGNOR-270823 MRPS30 protein Q9NP92 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.716 SIGNOR-262342 CAMK2D protein Q13557 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 19725819 NO areggio In the cytoplasm where the activated CaMKII localises it induces signalling pathways that are mainly involved in mitochondrial biogenesis and expression of contractile protein 0.7 SIGNOR-255955 LATS2 protein Q9NRM7 UNIPROT PRPS2 protein P11908 UNIPROT down-regulates quantity by destabilization phosphorylation Thr285 EDKMKHCtKIQVIDI -1 34465890 YES miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. 0.2 SIGNOR-276507 TFEB protein P19484 UNIPROT FGF21 protein Q9NSA1 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 NO lperfetto On the contrary, proteins increasing the most included those degraded by autophagy (e.g., SQSTM1/p62 and GABARAPL2 0.274 SIGNOR-276791 GRK2 protein P25098 UNIPROT PDE6G protein P18545 UNIPROT up-regulates activity phosphorylation Thr62 PGMEGLGtDITVICP 9606 BTO:0000007 12624098 YES gcesareni Mutation of Thr-62 (to Ala) in PDEgamma produced a GRK2 phosphorylation-resistant mutant that was less effective in associating with GRK2 in response to epidermal growth factor and did not potentiate the stimulation of p42/p44 mitogen-activated protein kinase by this growth factor. 0.2 SIGNOR-247823 CNOT6 protein Q9ULM6 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.819 SIGNOR-268309 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 11959862 YES amattioni Activation of mkk7 by ask1 0.593 SIGNOR-117264 RAB39B protein Q96DA2 UNIPROT PICK1 protein Q9NRD5 UNIPROT up-regulates activity binding 9534 BTO:0000298 25784538 YES miannu GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above. 0.375 SIGNOR-264045 ATR protein Q13535 UNIPROT CDC25C protein P30307 UNIPROT up-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 28264028 YES miannu We also found that activated ATR phosphorylates CDC25C (Cell Division Cycle 25C) at serine 216, which in turn inactivates the cyclin B1/Cyclin-Dependent Kinase 1(CDK1) complex and induces G2-phase arrest. 0.642 SIGNOR-279008 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser527 DYHSLYQsHL 9606 BTO:0000848 10347209 YES llicata We conclude that pkc-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein. our results strongly suggest that direct phosphorylation of tyrosinase by pkc-_ leads to its activation. 0.44 SIGNOR-67870 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Ser93 RVPKDRPsLTVTPKR 9606 BTO:0000567 21658950 YES miannu Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. 0.2 SIGNOR-263139 Ub:E2 complex SIGNOR-C497 SIGNOR TTC3 protein P53804 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271087 CAMK2D protein Q13557 UNIPROT KCNJ11 protein Q14654 UNIPROT down-regulates phosphorylation Thr224 MQVVRKTtSPEGEVV 9606 23223335 YES lperfetto Results showed that activation of camkii triggered dynamin-dependent internalization of k(atp) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)yskf(333) endocytosis motif of the k(atp) channel kir6.2 pore-forming subunit. 0.2 SIGNOR-200027 PRKCD protein Q05655 UNIPROT CDK5 protein Q00535 UNIPROT down-regulates activity phosphorylation Thr77 LHSDKKLtLVFEFCD 9606 BTO:0001332 29511352 YES miannu This generates a binding site for the C2 domain of PKCδ, which in turn phosphorylates CDK5 on T77. The resulting dissociation of the CDK5R1/CDK5 complex abolishes the activity of CDK5.  0.2 SIGNOR-277386 Ub:E2 complex SIGNOR-C497 SIGNOR UBE4A protein Q14139 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271274 JUN protein P05412 UNIPROT TNFAIP6 protein P98066 UNIPROT up-regulates quantity by expression transcriptional regulation 8454627 YES Tumor necrosis factor (TNF)-stimulated gene 6 (TSG-6) encodes a protein expressed during inflammation. We have previously shown that transcription factors of the NF-IL6 and AP-1 families cooperatively modulate activation of the TSG-6 gene by TNF or interleukin 1 (IL-1) through a promoter region that contains an NF-IL6 site (-106 to -114) and an AP-1 element 0.308 SIGNOR-254052 OAT protein P04181 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) 0.8 SIGNOR-256033 hsa-mir-519d-3p mirna URS0000298BA3_9606 RNAcentral XIAP protein P98170 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005152 24790458 YES Tiberia Overexpression of miR-519d reduced XIAP expression at both the protein and mRNA levels. 0.4 SIGNOR-279905 HECW2 protein Q9P2P5 UNIPROT AMOTL1 protein Q8IY63 UNIPROT up-regulates activity ubiquitination 9606 27498087 YES miannu These results clearly indicate that HECW2 ubiquitinates AMOTL1 with K63-linked polyubiquitin chains.|Unlike NEDD4.2, HECW2 targeted AMOTL1 and promoted its stability. 0.42 SIGNOR-278811 domperidone chemical CHEBI:31515 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258380 MAPK12 protein P53778 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser421 SKSQSSTsPEGQALE -1 15158451 YES miannu Activated SAPK3 phosphorylates the mitochondrial protein Sab. we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391 0.443 SIGNOR-250141 CACNA1G protein O43497 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10090 33393208 YES miannu Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG) 0.8 SIGNOR-264032 CDK5 protein Q00535 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Ser518 KGGTPAGsARGSPTR 9606 16611631 YES lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.602 SIGNOR-145963 TFEB protein P19484 UNIPROT MTM1 protein Q13496 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 NO lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 0.2 SIGNOR-276800 WNT2 protein P09544 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.61 SIGNOR-131727 MTOR protein P42345 UNIPROT MKNK2 protein Q9HBH9 UNIPROT down-regulates activity phosphorylation Ser74 KRGRATDsFSGRFED 9606 BTO:0000007 32170339 YES miannu MTOR phosphorylates MNK2a on Ser74. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. 0.274 SIGNOR-277516 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser111 SPPSPAPsSFSSTSV 9606 20305697 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-164625 1-(3-chlorophenyl)piperazine chemical CHEBI:10588 ChEBI HTR2B protein P41595 UNIPROT up-regulates activity chemical activation 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258684 KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates binding 9606 24997453 YES miannu Keap1 is an oxidative stress-sensing protein and is a negative regulator of nuclear factor-erythroid-2-related factor 2 (nrf2). 0.813 SIGNOR-205229 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267125 GALR2 protein O43603 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.401 SIGNOR-257020 WT1 protein P19544 UNIPROT PODXL protein O00592 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11719225 YES Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself. 0.41 SIGNOR-252300 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity transcriptional regulation 9606 BTO:0000007 28195531 YES While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus. 0.422 SIGNOR-252030 USF1 protein P22415 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001363; BTO:0000142 11058604 NO miannu We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs. 0.313 SIGNOR-254882 AKT1 protein P31749 UNIPROT S1PR1 protein P21453 UNIPROT up-regulates activity phosphorylation Thr236 RTRSRRLtFRKNISK 9606 11583630 YES lperfetto Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis 0.703 SIGNOR-252467 SRC protein P12931 UNIPROT RHOU protein Q7L0Q8 UNIPROT down-regulates activity phosphorylation Tyr254 SKSWWKKyCCFV 9606 BTO:0002552 20547754 YES miannu Regulation of the Rho family small GTPase Wrch-1/RhoU by C-terminal tyrosine phosphorylation requires Src. Phosphorylation at Y254 negatively regulates Wrch-1-mediated biological functions.Serum-stimulated tyrosine phosphorylation and relocalization of Wrch-1 decreases its activation of downstream effectors in a Y254-dependent manner. 0.534 SIGNOR-259814 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 17245430 YES A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis 0.589 SIGNOR-248618 PRKCA protein P17252 UNIPROT DDX5 protein P17844 UNIPROT down-regulates activity phosphorylation Ser557 VSAGIQTsFRTGNPT -1 7525583 YES lperfetto We report that p68 is phosphorylated by protein kinase C in vitro and binds calmodulin in a Ca(2+)-dependent manner. Both phosphorylation and calmodulin binding inhibited p68 ATPase activity | In addition, a 20-amino acid peptide corresponding to residues 549-568 of p68 was phosphorylated in a Ca- and phospholipid-dependent manner hy PKC 0.336 SIGNOR-248896 UQCRC1 protein P31930 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.894 SIGNOR-262198 GLI2 protein P10070 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 33125874 NO SimoneGraziosi Inhibition of Gli1 with simultaneous increase in Gli2 promotes migration of vNSC-derived cells to demyelinated lesions 0.7 SIGNOR-269223 tofacitinib chemical CHEBI:71200 ChEBI JAK3 protein P52333 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258302 ID1 protein P41134 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.554 SIGNOR-241125 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268777 MAPK8 protein P45983 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 YES lperfetto Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. 0.376 SIGNOR-114083 PKA proteinfamily SIGNOR-PF17 SIGNOR SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization phosphorylation Ser247 KYQCKNCsKTFSRMS 9606 BTO:0001950 37596321 YES miannu  PKA-dependent phosphorylation is pivotal for FBXO28-mediated SNAI2 degradation.  0.2 SIGNOR-277905 S1PR3 protein Q99500 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0000007 10488065 YES gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13. 0.528 SIGNOR-70710 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Thr207 FLTEYVAtRWYRAPE 9606 BTO:0000562 19060905 YES lperfetto Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. 0.2 SIGNOR-182628 Ub:E2 complex SIGNOR-C497 SIGNOR MID1 protein O15344 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271142 Membrane attack complex complex SIGNOR-C313 SIGNOR Cell_killing phenotype SIGNOR-PH149 SIGNOR up-regulates -1 30552328 NO lperfetto Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions. 0.7 SIGNOR-263454 DLK2 protein Q6UY11 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 10090 BTO:0002572 21419176 YES lperfetto Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts. 0.291 SIGNOR-219377 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270372 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr252 EAYPEEAyIADLDAK 9606 BTO:0000007 32420483 YES done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. 0.2 SIGNOR-274105 MAP4K1 protein Q92918 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser558 MQPPRSRsSIMSITA -1 19706536 YES miannu HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. 0.493 SIGNOR-276257 PRKG1 protein Q13976 UNIPROT TRPC6 protein Q9Y210 UNIPROT down-regulates activity phosphorylation Ser322 KNDYKKLsMQCKDFV -1 19961855 YES miannu PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q).  0.489 SIGNOR-276271 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 YES PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. 0.559 SIGNOR-248319 androsta-1,4,6-triene-3,17-dione chemical CHEBI:131190 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates activity chemical inhibition -1 7083195 YES miannu Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes. 0.8 SIGNOR-258408 AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity relocalization 9606 25720354 YES scontino APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place. 0.8 SIGNOR-267860 CDK5 protein Q00535 UNIPROT AMFR protein Q9UKV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser516 SIRPALNsPVERPSS 9606 BTO:0000007 28528366 YES miannu We found that GP78 expression is decreased in MPTP-based cellular and animal PD models, and CDK5 directly phosphorylated GP78 at Ser516, which promoted the ubiquitination and degradation of GP78.  0.248 SIGNOR-277356 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 10409765 NO lperfetto Nf-kappab regulation of cyclin d1 occurs at the transcriptional level and is mediated by direct binding of nf-kappab to multiple sites in the cyclin d1 promoter. 0.486 SIGNOR-235648 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 9534 BTO:0001538 7509796 YES Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells 0.72 SIGNOR-255949 TNFRSF1B protein P20333 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 8069916 YES lperfetto Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. 0.707 SIGNOR-34645 ATAT1 protein Q5SQI0 UNIPROT TUBA4B protein Q9H853 UNIPROT up-regulates quantity by stabilization acetylation -1 29703898 YES lperfetto Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules 0.2 SIGNOR-272252 PRKAA1 protein Q13131 UNIPROT HAT1 protein O14929 UNIPROT up-regulates activity phosphorylation Ser190 MWFIETAsFIDVDDE -1 28143904 YES lperfetto Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314 0.2 SIGNOR-264782 lenalidomide chemical CHEBI:63791 ChEBI CRBN protein Q96SW2 UNIPROT down-regulates activity chemical inhibition 9606 22552008 YES miannu Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. 0.8 SIGNOR-259284 blinatumomab antibody DB09052 DRUGBANK CD33 protein P20138 UNIPROT down-regulates activity binding 9606 25883042 YES miannu Blinatumomab, a bispecific antibody construct targeting CD19, is the most advanced member of bispecific T-cell engager (BiTE®) molecules. all data strongly suggest CD33 as a suitable target antigen for BiTE® therapy in AML. 0.4 SIGNOR-259889 NFKB1 protein P19838 UNIPROT NPPB protein P16860 UNIPROT unknown transcriptional regulation 15837525 NO In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription. 0.2 SIGNOR-253648 TBK1 protein Q9UHD2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 YES lperfetto Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling. 0.408 SIGNOR-172132 SMAD3 protein P84022 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 14638857 YES gcesareni Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd 0.727 SIGNOR-254325 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Ser1089 GLSQPELsQDSYLGD 9606 23356578 YES lperfetto Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively 0.971 SIGNOR-200785 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation 9606 16837009 YES gcesareni A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinasesa key step in the activation process is the phosphorylation of the activation loop of one pak kinase domain by another, but little is known about the underlying recognition events that make this phosphorylation specific. 0.2 SIGNOR-147874 NEDD4 protein P46934 UNIPROT KIF26B protein Q2KJY2 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22768111 YES miannu Nedd4 polyubiquitinates Kif26b and thus targets it for degradation via the ubiquitin-proteasome pathway. 0.316 SIGNOR-278767 MAP3K20 protein Q9NYL2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 11416147 YES gcesareni We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling. 0.2 SIGNOR-243345 MBD2 protein Q9UBB5 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001412 19781662 NO Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. 0.2 SIGNOR-254026 STX11 protein O75558 UNIPROT STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR form complex binding 9606 BTO:0000132 22767500 YES lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  0.648 SIGNOR-261897 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 SIGNOR-C83 10428798 YES gcesareni Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. 0.478 SIGNOR-69714 DYRK1A protein Q13627 UNIPROT MAP1A protein P78559 UNIPROT up-regulates activity phosphorylation 9606 22514676 YES miannu The phosphorylation of MAP1A and MAP2 by Dyrk1A was further confirmed by immunoprecipitating these proteins from the soluble fraction obtained after phosphorylating MTs (XREF_FIG). 0.2 SIGNOR-279032 ERG protein P11308 UNIPROT CLDN5 protein O00501 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22235125 YES Luana ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. 0.224 SIGNOR-261596 AKT proteinfamily SIGNOR-PF24 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16982699 NO Protein kinase B (PKB/Akt) is an important modulator of insulin signaling, cell proliferation, and survival. Using small interfering RNA duplexes in nontransformed mammalian cells, we show that only Akt1 is essential for cell proliferation 0.7 SIGNOR-254353 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176821 CDK2 protein P24941 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 10550055 YES gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. 0.676 SIGNOR-72091 ERBB2 protein P04626 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 8816440 YES Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers. gcesareni Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3. 0.587 SIGNOR-43841 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARRB1 protein P49407 UNIPROT down-regulates phosphorylation 9606 10347142 YES inferred from 70% family members gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation 0.2 SIGNOR-270190 SRC protein P12931 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Tyr1113 PSPVWMNySYSSLCL 9606 BTO:0002181 25805816 YES miannu Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4.  0.2 SIGNOR-276897 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD 9606 8576253 YES lperfetto Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta 0.722 SIGNOR-246732 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Thr5 tPRKTAAT -1 9139732 YES llicata In summary, we have shown evidence that CDK4-cyclin D1 phosphorylates Thr5, Ser249, Thr252, Thr356, Thr373, Ser788, Ser795, Ser807, Ser811, and Thr826 of pRB. 0.862 SIGNOR-250762 MAML1 protein Q92585 UNIPROT CDK8 protein P49336 UNIPROT up-regulates relocalization 9606 15546612 YES gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. 0.596 SIGNOR-130718 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT up-regulates activity phosphorylation Ser558 ESALRKQsLYLKFDP 9606 BTO:0001109 17545617 YES miannu We show that this conserved serine on human TACC3 (Ser(558)) is also phosphorylated by Aurora A. Moreover, phosphorylation of TACC3 by Aurora A in human cells is essential for its proper localization to centrosomes and proximal mitotic spindles. Inhibition of Aurora A with the selective small molecule inhibitor MLN8054 in cultured human tumor cells resulted in mislocalization of TACC3 away from mitotic spindles in a concentration-dependent manner. 0.936 SIGNOR-262655 GSK3B protein P49841 UNIPROT ARHGAP31 protein Q2M1Z3 UNIPROT up-regulates activity phosphorylation Thr789 PPAPPPPtPLEESTP 10090 BTO:0000944 17158447 YES miannu We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation. 0.302 SIGNOR-262879 1-phosphatidyl-1D-myo-inositol 3-phosphate smallmolecule CHEBI:17283 ChEBI Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto PtdIns(3)P-kinase/hVPS34/p150 (VPS34) is thought to be one of the first Rab5 effector proteins to be recruited to the EE . As suggested by its name, its primary role is to generate PtdIns(3)P, which is the most abundant phosphoinositide in the EE membrane. 0.8 SIGNOR-260622 LPAR3 protein Q9UBY5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.46 SIGNOR-257025 RUVBL1 protein Q9Y265 UNIPROT R2TP core co-chaperone complex SIGNOR-C515 SIGNOR form complex binding 9606 29662061 YES miannu  Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90.  0.813 SIGNOR-270928 IFNG protein P01579 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 10090 BTO:0000227 24507514 NO miannu Beside its wellknown antiviral and proinflammatory action, overexpression of IFN-g in the CNS could participate in demyelination. Transgenic overexpression of IFN-g in the mouse by CNS oligodendrocytes led to chronic demyelination that may be severe 0.7 SIGNOR-263833 PRKCD protein Q05655 UNIPROT PTPRA protein P18433 UNIPROT up-regulates activity phosphorylation Ser189 QAGSHSNsFRLSNGR 9606 BTO:0000017 11676480 YES lperfetto In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232. 0.329 SIGNOR-249113 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser15 SSYRGRKsGNKPPSK 9606 7993631 YES gcesareni We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type. 0.2 SIGNOR-35622 GSK3B protein P49841 UNIPROT FAAP20 protein Q6NZ36 UNIPROT down-regulates quantity phosphorylation Ser113 GAGGHLEsPARSLPQ 9606 27232758 YES miannu Furthermore, GSK3beta was able to decrease the cellular FAAP20 levels when overexpressed in wild-type, but not in FBW7 -/- HCT116 cells, indicating that GSK3beta requires downstream FBW7 to regulate the FAAP20 stability.|GSK3\u03b2 phosphorylates FAAP20 at Ser113. 0.2 SIGNOR-279048 FGF2 protein P09038 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 YES gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. 0.819 SIGNOR-18564 AKT proteinfamily SIGNOR-PF24 SIGNOR TKT protein P29401 UNIPROT up-regulates activity phosphorylation Thr382 GCATRNRtVPFCSTF 9606 BTO:0000567 24981175 YES lperfetto Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis. 0.2 SIGNOR-265102 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PBK protein Q96KB5 UNIPROT up-regulates activity phosphorylation Thr9 EGISNFKtPSKLSEK 15541388 YES llicata During mitosis, TOPK-Thr-9 was phosphorylated by cdk1/cyclin B and TOPK significantly associates with mitotic spindles. When TOPK expression was suppressed, formation of spindle midzone was thinned and dimmed and cytokinesis was disturbed. 0.553 SIGNOR-250720 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu66 EETCSYEeAREVFED -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263671 NCOR2 protein Q9Y618 UNIPROT SPEN protein Q96T58 UNIPROT up-regulates binding 9606 11331609 YES gcesareni Sharp is a potent transcriptional repressor whose repression domain (rd) interacts directly with smrt 0.468 SIGNOR-107260 Phenelzine chemical CHEBI:8060 ChEBI MAOA protein P21397 UNIPROT down-regulates activity chemical inhibition -1 18426226 YES Luana Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine. 0.8 SIGNOR-257777 UDP-N-acetyl-alpha-D-glucosamine smallmolecule CHEBI:16264 ChEBI N-acyl-D-mannosamine 6-phosphate(2-) smallmolecule CHEBI:57666 ChEBI up-regulates quantity precursor of 10745088 YES lperfetto UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate. 0.8 SIGNOR-266075 NFIA protein Q12857 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 32991581 YES brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, 0.2 SIGNOR-263983 TUBD1 protein Q9UJT1 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 NO miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation 0.7 SIGNOR-267177 AURKC protein Q9UQB9 UNIPROT TACC1 protein O75410 UNIPROT up-regulates activity phosphorylation Ser228 ELVPSRRsKLRKPKP -1 21531210 YES miannu Aurora-C interacts with and phosphorylates the transforming acidic coiled-coil 1 protein. The results demonstrated that TACC1 is phosphorylated by Aurora-C on a serine at position 228. although the patho-physiological meaning of TACC1 phosphorylation by Aurora-C in normal and in malignant somatic cells remains to be fully investigated, our observations suggest that Aurora-C has a role in the later stage of mitosis, when an interaction with TACC1 may be relevant for the correct progression of the cell cycle. 0.399 SIGNOR-262663 SLBP protein Q14493 UNIPROT H2BS1 protein P57053 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265384 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 YES lperfetto We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2. 0.791 SIGNOR-236010 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 14732063 YES miannu Tumour necrosis factor (TNF) exerts two main effects: a beneficial one as an anti-infection, anti-tumour cytokine, and a detrimental one in the systemic inflammatory response syndrome (SIRS). Two receptors (TNF-R) mediate these effects. two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b) 0.925 SIGNOR-253593 PPP3CB protein P16298 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000007 26000950 YES Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation. 0.377 SIGNOR-255306 WDR62 protein O43379 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates activity relocalization 10090 30566428 YES lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis 0.2 SIGNOR-271717 ROCK2 protein O75116 UNIPROT DPYSL2 protein Q16555 UNIPROT up-regulates phosphorylation Thr555 DNIPRRTtQRIVAPP 9606 BTO:0000938 10818093 YES lperfetto Rho-kinase phosphorylated crmp-2 at thr-555 in vitro.we demonstrated that crmp-2 is phosphorylated by rho-kinase in drg neurons during lpa-induced growth cone collapse. 0.383 SIGNOR-77543 IL4 protein P05112 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 YES gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex 0.858 SIGNOR-108861 MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 YES lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination 0.764 SIGNOR-109497 BAP1 protein Q92560 UNIPROT ASXL3 protein Q9C0F0 UNIPROT up-regulates activity binding 9606 BTO:0000189 32669118 YES miannu We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. 0.531 SIGNOR-266761 CP protein P00450 UNIPROT SMO protein Q99835 UNIPROT down-regulates binding 9606 16885213 YES gcesareni Genetic and biochemical studies imply that smo can adopt an active conformation but that it is normally repressed by patched (ptch), a 12-transmembrane protein considered the receptor for hh 0.2 SIGNOR-148451 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 BTO:0000562 12853467 YES lperfetto These findings suggest that pkb-dependent binding of 14-3-3s to phospho-ser483 of cardiac pfk-2 mediates the stimulation of glycolysis by growth factor. 0.2 SIGNOR-103462 PAK4 protein O96013 UNIPROT RAN protein P62826 UNIPROT up-regulates phosphorylation Ser135 DRKVKAKsIVFHRKK 9606 20805321 YES lperfetto We show that ran is a substrate for p21-activated kinase 4 (pak4) and that its phosphorylation on serine-135 increases during mitosis.Altogether, our findings strongly suggest that pak4-mediated phosphorylation of gdp- or gtp-bound ran modulates the assembly of complexes that are required at specific subcellular localizations for ran to carry out its functions during mitotic progression. 0.308 SIGNOR-167667 PRKCA protein P17252 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Ser625 PIVGSNGsSRLQDSR 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.332 SIGNOR-262923 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PAK1 protein Q13153 UNIPROT down-regulates phosphorylation 9606 14993270 YES inferred from 70% family members gcesareni Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation. 0.2 SIGNOR-270086 HIC1 protein Q14526 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001211 22184117 NO miannu The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). we observe that inactivation of endogenous HIC1 through RNA interference in normal breast epithelial cells results in the up-regulation of EphA2 and is correlated with increased cellular migration. chromatin immunoprecipitation (ChIP) and sequential ChIP experiments demonstrate that endogenous HIC1 proteins are bound, together with the MTA1 corepressor, to the EphA2 promoter in WI38 cells. 0.314 SIGNOR-254241 FCRL3 protein Q96P31 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding -1 12051764 YES miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. 0.384 SIGNOR-274014 ERG protein P11308 UNIPROT WNT11 protein O96014 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21242973 NO miannu ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. 0.2 SIGNOR-254071 LRRK2 protein Q5S007 UNIPROT RPS15 protein P62841 UNIPROT up-regulates activity phosphorylation Thr136 GRPGIGAtHSSRFIP 9606 24725412 YES miannu Taken together, these results suggest that phosphorylation of s15 on T136 by LRRK2 mediates enhanced cap-dependent and cap-independent reporter translation and that a stimulatory effect of LRRK2 on mRNA translation contributes to LRRK2 toxicity. 0.485 SIGNOR-279058 CTTN protein Q14247 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10116 23015759 NO miannu Through alternative splicing, a single CTTNBP2 gene encodes three different transcripts, namely short (S), long (L), and intron forms. The interaction with cortactin is required for the function of CTTNBP2-S in dendritic spine formation because the CTTNBP2-S mutant, which no longer interacts with cortactin, is unable to rescue the spine defects resulting from CTTNBP2 knockdown. Thus CTTNBP2-S may control cortactin–F-actin cytoskeletons and regulate the formation and maintenance of dendritic spines in neurons. 0.7 SIGNOR-261696 PLAU protein P00749 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 19055748 NO lperfetto Our data show that functional blockade of SNAI1 (SNAI1-dominant negative (DN)) leads to a partial re-expression of E-cadherin, and induces differential expression of EMT-related genes. This is confirmed by RT-PCR of PA system genes, where PAI-1 and uPA are decreased. 0.7 SIGNOR-252264 GFs stimulus SIGNOR-ST12 SIGNOR RTKs proteinfamily SIGNOR-PF38 SIGNOR up-regulates 9606 17306385 YES miannu Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. 0.7 SIGNOR-256169 Ub:E2 complex SIGNOR-C497 SIGNOR KMT2D protein O14686 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271136 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49D1 protein C9J1S8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271269 CDX2 protein Q99626 UNIPROT UGT1A8 protein Q9HAW9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 YES Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. 0.26 SIGNOR-253969 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249346 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr143 AVSPGTLtPTGVVSG 26933062 YES lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. 0.425 SIGNOR-276588 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-264963 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 17510057 YES lperfetto In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.595 SIGNOR-217074 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys126 DNEKDLVkLAKRLKK -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. 0.464 SIGNOR-272746 lofepramine chemical CHEBI:47782 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  0.8 SIGNOR-258881 PTK2B protein Q14289 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 26084289 YES miannu These results imply that following EGF stimulation, PYK2 enhances a STAT3-dependent IL8 expression, thus creating a positive feedback loop between ErbB receptors, PYK2, and IL8.|These results suggest that PYK2-induced STAT3 phosphorylation is crucial for IL8 secretion, while IL8 is crucial for EGF-induced MMP9 transcription (Figure xref ) and for SKBR3 invasion (Figure xref ). 0.429 SIGNOR-279429 AKT1 protein P31749 UNIPROT MST1R protein Q04912 UNIPROT up-regulates phosphorylation Ser1394 VRRPRPLsEPPRPT 9606 14505491 YES lperfetto Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing 0.558 SIGNOR-252471 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM24 protein O15164 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271034 SIRT1 protein Q96EB6 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization deacetylation 9606 25280219 YES SIRT1 overexpression was associated with down-modulation of p53 activity in FLT3-ITD AML CD34+ cells. SIRT1 can negatively regulate p53 by deacetylating several lysine sites 0.803 SIGNOR-261562 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT up-regulates 9606 BTO:0000934 23939472 NO lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  0.265 SIGNOR-261488 PTEN protein P60484 UNIPROT PPM1A protein P35813 UNIPROT up-regulates binding 9606 18482992 YES lpetrilli Upon complex formation with pten, ppm1a is protected from degradation induced by the tgf-? Signaling. this study establishes a novel role for nuclear pten in the stabilization of ppm1a. 0.308 SIGNOR-178643 pyruvate smallmolecule CHEBI:15361 ChEBI (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity precursor of 9606 24929216 YES Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. 0.8 SIGNOR-266920 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr515 QKYSMDNtPHTPTPF BTO:0000007 10593981 YES llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 0.718 SIGNOR-250739 A8/b1 integrin complex SIGNOR-C165 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269014 AMPK complex SIGNOR-C15 SIGNOR LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 YES lperfetto Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase. 0.397 SIGNOR-216507 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT up-regulates activity phosphorylation Tyr256 RETSKVIyDFIEKTG -1 16199863 YES Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation. 0.551 SIGNOR-251437 IFNL1 protein Q8IU54 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 YES gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. 0.873 SIGNOR-96174 GGCX protein P38435 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 31539109 NO miannu GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05). 0.299 SIGNOR-261230 kaempferol chemical CHEBI:28499 ChEBI AHR-ARNT complex SIGNOR-C125 SIGNOR down-regulates activity chemical inhibition 17012224 YES However, kaempferol inhibited the ability of BNF to induce formation of the AHR/ARNT DNA-binding complex at all concentrations tested 0.8 SIGNOR-253641 RAD50 protein Q92878 UNIPROT RINT1 protein Q6NUQ1 UNIPROT up-regulates activity binding 9606 BTO:0004784 16600870 YES lperfetto We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.  0.472 SIGNOR-265030 RAD21 protein O60216 UNIPROT APOB protein P04114 UNIPROT down-regulates quantity transcriptional regulation 9606 25575569 YES The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. 0.2 SIGNOR-259974 PRKAB1 protein Q9Y478 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates activity phosphorylation Ser257 GLHRAEQsLHDLQER 10090 BTO:0000452 31381180 YES miannu STIM1 is a novel exercise‐regulated AMPK substrate. Phosphorylation of STIM1 by AMPK suppresses SOCE 0.2 SIGNOR-277298 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 YES gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2). 0.761 SIGNOR-59635 ABL2 protein P42684 UNIPROT SIVA1 protein O15304 UNIPROT up-regulates phosphorylation Tyr34 RGVCAERySQEVFEK 9606 11278261 YES llicata Our results also demonstrate that mutation of the siva-1 tyr48 site abrogates the apoptotic function of siva-1 and that apoptosis induced by siva-1 is dependent on expression of kinase-active arg. 0.335 SIGNOR-104992 CHEK1 protein O14757 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser51 ADGHRGPsAAFAPAA 9606 29954829 YES miannu In this study, we show that Chk1 phosphorylates human Src at the newly identified site serine 51 to fully induce Src kinase activity. 0.338 SIGNOR-278332 LEPR protein P48357 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity 27154742 NO lperfetto Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production 0.465 SIGNOR-253074 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI RIOX1 protein Q9H6W3 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273475 MAPK1 protein P28482 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Thr185 HDHTGFLtEYVATRW 1712480 YES lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| 0.2 SIGNOR-249414 PRKCD protein Q05655 UNIPROT CREBBP protein Q92793 UNIPROT unknown phosphorylation Ser437 CLPLKNAsDKRNQQT 11463380 YES lperfetto This study demonstrates that transcriptional control of mitogen-responsive genes by AP-1 and Pit-1 response elements involves direct phosphorylation of CBP and that growth factor€“dependent phosphorylation of CBP within the GF box is indispensable for signaling via these sites.  0.367 SIGNOR-249104 MRPS10 protein P82664 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.755 SIGNOR-267731 PPP2CB protein P62714 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 19607706 YES Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac) 0.26 SIGNOR-248580 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120228 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Thr290 NKLKPPGtPPPSSRK 10090 19560418 YES These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 0.26 SIGNOR-248526 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BAD protein Q92934 UNIPROT down-regulates binding 9606 8929531 YES gcesareni 14-3-3 blocks bad activity by promoting ser-155 phosphorylation, which induces the dissociation of bad and bcl-xl. in the presence of survival factor il-3, cells phosphorylated bad on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated bad heterodimerized with bcl-x(l) at membrane sites to promote cell death. 0.2 SIGNOR-44855 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 19282669 YES inferred from 70% family members lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway 0.2 SIGNOR-270175 KNSTRN protein Q9Y448 UNIPROT KIF2B protein Q8N4N8 UNIPROT down-regulates activity relocalization 9606 BTO:0001938 22535524 YES lperfetto The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation. 0.407 SIGNOR-252053 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser280 RSPSPQPsSHVAPQD 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248691 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser371 AHSSHLKsKKGQSTS 9606 9315650 YES llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. 0.436 SIGNOR-269327 LYST protein Q99698 UNIPROT RAB5B protein P61020 UNIPROT down-regulates activity binding 7227 33725482 YES lperfetto Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment 0.2 SIGNOR-266002 NFKB1 protein P19838 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 NO gcesareni Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2 0.56 SIGNOR-59954 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.24 SIGNOR-268603 SHANK1 protein Q9Y566 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 28179641 NO miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. 0.7 SIGNOR-264605 brimonidine chemical CHEBI:3175 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258900 TAOK1 protein Q7L7X3 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 23431053 YES inferred from 70% of family members gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. 0.371 SIGNOR-269938 XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT down-regulates quantity by destabilization binding -1 11257231 YES lperfetto Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase. 0.859 SIGNOR-105732 MRPL10 protein Q7Z7H8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.663 SIGNOR-262383 TIMP3 protein P35625 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 NO lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 0.7 SIGNOR-252274 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr101 EGLSMGNyIGLINRI -1 16373505 YES Manara PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR. 0.2 SIGNOR-260782 NRCAM protein Q92823 UNIPROT ANK2 protein Q01484 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 YES miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. 0.736 SIGNOR-266719 IRX1 protein P78414 UNIPROT UGT8 protein Q16880 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. 0.2 SIGNOR-261665 PRKCZ protein Q05513 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 YES lperfetto A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis. 0.337 SIGNOR-249239 RHOA protein P61586 UNIPROT DIAPH1 protein O60610 UNIPROT up-regulates activity 9606 BTO:0000815 22820501 YES lperfetto We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells. 0.784 SIGNOR-253108 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu67 LERECMEeKCSFEEA 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263691 TIMM44 protein O43615 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.722 SIGNOR-267689 ADAM17 protein P78536 UNIPROT AREG protein P15514 UNIPROT up-regulates activity cleavage 9606 26284334 YES miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF 0.448 SIGNOR-259842 retinal smallmolecule CHEBI:15035 ChEBI all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity precursor of 9606 21621639 YES lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. 0.8 SIGNOR-265124 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1693 SPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248785 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation Ser63 GILARRPsYRKILKD 9606 8663317 YES lperfetto Camk ii phosphorylates only ser63 (corresponding to ser133 of creb), which is essential for the activation, and not ser72 (corresponding to ser142 of creb), which is a negative regulation site 0.297 SIGNOR-42565 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr310 YVGVWKKySLTVAVK -1 34144039 YES miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. 0.303 SIGNOR-277300 KATP channel complex SIGNOR-C274 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 BTO:0000783 35065096 NO miannu Activated PKA and EPAC enhance insulin granular exocytosis by insulin granular priming and phosphorylates sulfonylurea receptor (SUR1) KATP channel subunit and thereby closes KATP-channels in the plasma membrane [13,43,82], leading to membrane depolarization, and opening of the voltage gated Ca2+-channels. This leads to an increased influx of extracellular Ca2+, which triggers fusion of intracellular insulin-containing granules with the plasma membrane and thereby insulin secretion. 0.8 SIGNOR-278148 PHLPP2 protein Q6ZVD8 UNIPROT PRKCA protein P17252 UNIPROT down-regulates quantity dephosphorylation Ser657 QSDFEGFsYVNPQFV 9606 BTO:0000067 18162466 YES gcesareni In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha 0.253 SIGNOR-237051 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 YES gcesareni FOXO4 transcription factor, also referred to AFX, contains three putative phosphorylation motif sites for protein kinase B (PKB), Thr32, Ser197, and Ser262, and it is proposed that phosphorylated FOXO4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4 0.764 SIGNOR-252870 SSTR5 protein P35346 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-256833 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser440 DTSYVIEsDEDLEME 9606 BTO:0000007 24429382 YES llicata Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair. 0.642 SIGNOR-203737 NMDA receptor_2A complex SIGNOR-C347 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 YES miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  0.8 SIGNOR-264218 PRKD2 protein Q9BZL6 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 18692497 YES lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. 0.295 SIGNOR-275927 LEF1 protein Q9UJU2 UNIPROT IL4 protein P05112 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 18579517 NO We identified a high affinity LEF-1-binding site in the negative regulatory element of the IL-4 promoter. Knockdown LEF-1 expression by LEF-1-specific small interfering RNA resulted in an increase in the IL-4 mRNA expression 0.35 SIGNOR-254504 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser625 TAMLSLGsGISQCGY 9534 BTO:0000298 11865049 YES llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  0.74 SIGNOR-250816 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Tyr317 TEQDLQLyCDFPNII 9606 BTO:0000007 19364823 YES 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto Analysis of in vitro autophosphorylated jak2while cytokine receptor stimulation mediates the phosphorylation of both tyr317 and tyr637, these residues oppositely regulate jak2-dependent signaling: the mutation of tyr317 enhances jak2 function, suggesting a role for the phosphorylation of tyr317 in the inhibition of jak2. Conversely, mutation of tyr637 reduces jak2 signaling, suggesting a role for the phosphorylation of this residue in the activation of jak2. 0.2 SIGNOR-236502 GXYLT2 protein A0PJZ3 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22117070 YES Xylosylation in ER membrane gcesareni We have previously identified two human genes, gxylt1 and gxylt2, encoding glucoside xylosyltransferases responsible for the transfer of xylose to o-linked glucose. The identity of the enzyme further elongating the glycan to generate the final trisaccharide xylose-xylose-glucose, however, remained unknown. Here, we describe that the human gene c3orf21 encodes a udp-xylose:alfa-xyloside alfa1,3-xylosyltransferase, acting on xylose-alfa1,3-glucosebeta1-containing acceptor structures. We have, therefore, renamed it xxylt1 (xyloside xylosyltransferase 1). Xxylt1 cannot act on a synthetic acceptor containing an alfa-linked xylose alone, but requires the presence of the underlying glucose. Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. The enzyme was shown to be a typical type ii membrane-bound glycosyltransferase localized in the endoplasmic reticulum. 0.323 SIGNOR-177717 PRKACA protein P17612 UNIPROT IMMT protein Q16891 UNIPROT down-regulates activity phosphorylation Ser528 ELQFRRLsQEQVDNF -1 27153535 YES miannu PKA directly phosphorylated the Ser528 residue of MIC60. Phosphorylation of MIC60 Interrupts Parkin Recruitment and Formation of the MICOS Complex 0.2 SIGNOR-266302 SLC9A4 protein Q6AI14 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265594 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser242 MDKRKDPsSVDIKKV -1 10480872 YES llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. 0.323 SIGNOR-250775 DDIT3 protein P35638 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity transcriptional regulation 10090 7588595 YES We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process. 0.52 SIGNOR-255913 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 2155236 YES lperfetto Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7. 0.367 SIGNOR-248862 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser107 SQPPSPPsPAPSSFS 9606 15448698 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-129406 5-carboxamidotryptamine chemical CHEBI:48292 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258845 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266520 F2RL2 protein O00254 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257301 LEF1 protein Q9UJU2 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004850 14594802 NO miannu We find that LEF-1 and CBFalpha co-activate ELA2 expression. 0.256 SIGNOR-254550 IGF1R protein P08069 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 10090 11715022 NO lperfetto We show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy. 0.389 SIGNOR-235373 RAI1 protein Q7Z5J4 UNIPROT CLOCK protein O15516 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22578325 YES miannu RAI1 Transcriptionally Activates CLOCK via an Intron 1 Enhancer Element. data suggest that RAI1 binds, directly or in a complex, to the first intron of CLOCK and enhances its transcriptional activity in vitro, supporting RAI1 as a positive regulator of CLOCK and an important part of the circadian loop of transcription. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 0.478 SIGNOR-266839 ZDHHC5 protein Q9C0B5 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates activity palmitoylation 9606 BTO:0000526 28775165 YES Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2. 0.2 SIGNOR-261144 TAB2 protein Q9NYJ8 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. 0.415 SIGNOR-205443 fumarate(2-) smallmolecule CHEBI:29806 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates 9606 30090811 NO miannu Fumarase is a TCA cycle enzyme which catalyzes the conversion of fumarate to L-malate in the mitochondria. Upon DNA damage the cytosolic echoform of fumarase is localized to the nucleus, there, its enzymatic activity catalyzes the reverse conversion of malate to fumarate, so causing local accumulation of fumarate. 0.7 SIGNOR-267989 CCK protein P06307 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 10368033 YES gcesareni Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b 0.87 SIGNOR-66339 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 9890893 YES lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). 0.76 SIGNOR-236408 SNRPD3 protein P62318 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.828 SIGNOR-270637 MAPK3 protein P27361 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 YES llicata Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta 0.2 SIGNOR-187378 DPF2 protein Q92785 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity binding 9606 BTO:0000007 20460684 YES miannu REQ is required for the oncogenic activity induced by RelB/p52. . Through in vitro binding experiments, REQ was found to bind to several SWI/SNF complex subunits and also to the p52 NF-κB subunit through its nuclear localization signal containing the N-terminal region. In this study, we present evidence that REQ is a specific adaptor protein that links RelB/p52 with Brm-type SWI/SNF complexes and thereby plays pivotal roles at the most downstream stages of the noncanonical NF-κB pathway. We further show that REQ is required for oncogenesis in several human tumor cell lines in which the noncanonical NF-κB pathway is aberrantly regulated.REQ and Brm specifically promote RelB/p52-dependent transcriptional activity. 0.303 SIGNOR-261964 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273077 AMPD1 protein P23109 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 BTO:0001103 1631143 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. 0.8 SIGNOR-269773 HNF1A protein P20823 UNIPROT UGT1A9 protein O60656 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 YES Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. 0.267 SIGNOR-253973 CAMKK1 protein Q8N5S9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10833263 YES llicata Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway. 0.38 SIGNOR-250714 FFAR4 protein Q5NUL3 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.448 SIGNOR-257371 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 15262992 YES lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. 0.265 SIGNOR-126863 PLCG2 protein P16885 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates quantity chemical modification 9606 23000145 YES scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). 0.8 SIGNOR-268453 UHMK1 protein Q8TAS1 UNIPROT PIMREG protein Q9BSJ6 UNIPROT up-regulates phosphorylation Ser131 GAQKGSGsPTHSLSQ 9606 23419774 YES lperfetto Cats is a substrate of kis and mapped the phosphorylation site to cats serine 131 (s131). Kis enhances the transcriptional repressor activity of cats 0.2 SIGNOR-192702 LAMTOR3 protein Q9UHA4 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates binding 9606 9733512 YES gcesareni A protein called mp1 (mek partner 1) was identified that bound specifically to mek1 and erk1 and facilitated their activation. When overexpressed in cultured cells, mp1 enhanced activation of erk1 and activation of a reporter driven by the transcription factor elk-1. 0.605 SIGNOR-59877 ATF4 protein P18848 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11960987 NO miannu Transcription from the asparagine synthetase (A.S.) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. the results provide both in vitro and in vivo evidence for a role of ATF4 in the transcriptional activation of the A.S. gene in response to nutrient deprivation. 0.649 SIGNOR-253747 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser698 RARRGSSsDEEGGPK -1 14657015 YES lperfetto Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin. 0.2 SIGNOR-271844 CDK5 protein Q00535 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15741232 YES gcesareni Phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a cdk5 inhibitor, roscovitine, which does not inhibit the usual rb cyclin-d kinases cdk4 and cdk6. Furthermore, analyses of levels and subcellular localization of cdk-related cyclins did not reveal any change following cdk5 activation, arguing for a direct effect of cdk5 activity on rb protein. Rb phosphorylation was visualized using phosphorylation-dependent antibodies (p-rbser795 and p-rbser807/811). 0.337 SIGNOR-134468 FOXO3 protein O43524 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.413 SIGNOR-236551 MAPK8 protein P45983 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 20974802 YES gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. 0.383 SIGNOR-169007 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM9 protein Q9C026 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271085 KLHL22 protein Q53GT1 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding -1 23455478 YES miannu Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors.  0.536 SIGNOR-272109 EFNA5 protein P52803 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 YES gcesareni Efna5 are able to activate epha8 0.819 SIGNOR-52479 RORA protein P35398 UNIPROT NR1D1 protein P20393 UNIPROT down-regulates activity binding 9606 BTO:0000599 20817722 YES miannu Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. 0.459 SIGNOR-267979 DTX1 protein Q86Y01 UNIPROT TCF3 protein P15923 UNIPROT down-regulates 9606 BTO:0000776 9528794 NO gcesareni Our experiments indicate that deltex expression alone is suffcient to inhibit e47. 0.274 SIGNOR-56141 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr257 APSRQDVyGPQPQVR -1 11382764 YES lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 0.922 SIGNOR-246488 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR JUN protein P05412 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14739463 YES miannu  We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCF(Fbw7), which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.  0.383 SIGNOR-272949 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT up-regulates phosphorylation 9606 15209375 YES gcesareni One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.595 SIGNOR-126177 AURKA protein O14965 UNIPROT EIF4E protein P06730 UNIPROT up-regulates activity phosphorylation 9606 28073841 YES miannu In this study, we demonstrated for the first time that AURKA can phosphorylate and activate EIF4E. 0.278 SIGNOR-279495 Fibrin complex SIGNOR-C317 SIGNOR PLAT protein P00750 UNIPROT up-regulates 9606 BTO:0000131 1447176 NO lperfetto The presence of fibrin greatly accelerates the activation of plasminogen by tPA and hence can exert a regulatory influence over plasminogen activation 0.2 SIGNOR-263536 MAPK14 protein Q16539 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates 9606 17003045 NO gcesareni The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha. In the present study we determined the role of siah2 phosphorylation in the regulation of its activity toward phd3. We show that siah2 is subject to phosphorylation by p38 mapk, which increases siah2-mediated degradation of phd3. 0.307 SIGNOR-149887 oxotremorine M chemical CHEBI:38322 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258654 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser280 VDGTGDTsSEEDEDE -1 11278496 YES llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. 0.38 SIGNOR-250874 CCL2 protein P13500 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 NO miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. 0.7 SIGNOR-261027 ADA protein P00813 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity chemical modification -1 15926889 YES Luana Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates 0.8 SIGNOR-269735 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser109 KSHSRQAsTDAGTAG 9606 25601544 YES Luana We performed mass spectrometry to determine additional sites on YAP1 targeted by NDR, identifying three additional serines, namely S61, S109, and S164, to also be phosphorylated by NDR in vitro  0.383 SIGNOR-259856 1-(6,8-difluoro-2-methyl-4-quinolinyl)-3-[4-(dimethylamino)phenyl]urea chemical CHEBI:92941 ChEBI HCRTR1 protein O43613 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206733 CRP protein P02741 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity by repression translation regulation 9606 BTO:0000801 16917108 NO Regulation miannu CRP significantly decreased IL-10 mRNA stability 0.466 SIGNOR-251824 CHRM2 protein P08172 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.348 SIGNOR-256964 FBXW10 protein Q5XX13 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 23431138 YES miannu As expected, the SKP1 and CUL1 proteins, subunits of all F-box-containing E3 ligases, were also present in the immune complexes containing FBXO10 and BCL2. To test for FBXO10-induced ubiquitination of BCL2, 293T cells were transduced with retroviral vectors expressing Flag-tagged FBXO10, MYC-tagged BCL2, and HA-tagged ubiquitin, and cells were treated with the proteasome inhibitor PS-341 to enhance the detection of ubiquitinated proteins.Together, these data suggest that FBXO10 is a component of a ubiquitin ligase that can target BCL2 protein for degradation. 0.623 SIGNOR-271935 IL15RA protein Q13261 UNIPROT JAK1 protein P23458 UNIPROT up-regulates BTO:0000782 30029643 YES areggio Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 0.461 SIGNOR-256227 MAPK8 protein P45983 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Ser178 PPLPGALsPLYGVPE 10116 BTO:0004316 12853963 YES miannu JNK1 phosphorylates serine 178 on paxillin, a focal adhesion adaptor, both in vitro and in intact cells. NBT-II cells expressing the Ser 178 --> Ala mutant of paxillin (Pax(S178A)) formed focal adhesions and exhibited the limited movement associated with such contacts in both single-cell-migration and wound-healing assays. In contrast, cells expressing wild-type paxillin moved rapidly and retained close contacts as the predominant adhesion. 0.677 SIGNOR-250129 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 YES Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. 0.358 SIGNOR-248642 PIM1 protein P11309 UNIPROT AR protein P10275 UNIPROT down-regulates activity phosphorylation Ser215 SGRAREAsGAPTSSK 9606 22986532 YES miannu PIM1 Phosphorylates the Androgen Receptor at Serine 213. 0.381 SIGNOR-278177 zotepine chemical CHEBI:32316 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 20223878 YES Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. 0.8 SIGNOR-257828 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 NO apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. 0.677 SIGNOR-255354 PTPN1 protein P18031 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity dephosphorylation Tyr393 ASFNTDPyVREFGIM 9606 25175024 YES miannu Taken together, our results indicate that Tyr 393 of AGO2 is hyperphosphorylated in response to PTP1B inactivation and may contribute to H-RAS V12 -induced development of senescence.|We identified phospho-Tyr 393 of argonaute 2 (AGO2) as a direct substrate of PTP1B. 0.2 SIGNOR-277120 RPN1 protein P04843 UNIPROT OST-A complex complex SIGNOR-C535 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.802 SIGNOR-272063 SMURF1 protein Q9HCE7 UNIPROT ZFAND5 protein O76080 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272676 PLD3 protein Q8IV08 UNIPROT APP protein P05067 UNIPROT up-regulates quantity binding 9606 BTO:0000007 24336208 YES Monia Furthermore, PLD3 can be co-immunoprecipitated with APP in cultured cells (Extended Data Figure 4). Together, these studies demonstrate that PLD3 plays a role in APP processing. Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing. 0.373 SIGNOR-261200 PI3K complex SIGNOR-C156 SIGNOR IRS1 protein P35568 UNIPROT down-regulates activity 9606 11160134 NO lperfetto Ly294002 or wortmannin were used to determine whether pi 3-kinasedependent pathways mediate ser307 phosphorylation during insulin/igf-1 or TNF-alpha Stimulation. As expected, the pi-3 kinase inhibitors ly294002 or wortmannin inhibited activation of pkb/akt in insulin or igf-1 stimulated 3t3-l1 preadipocytes, but were without effect on erk1/2. these results suggest that elements of the pi 3-kinase cascade mediate insulin/igf-1stimulated phosphorylation of ser307 0.767 SIGNOR-252717 NCAPH2 protein Q6IBW4 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity binding 9606 BTO:0000567 31026066 YES miannu Taken together these observations suggest that NCAPH2 promotes telomere stability, possibly through a direct interaction with the TRF1 shelterin component, and prevents telomere dysfunction resulting from impaired DNA replication. 0.2 SIGNOR-263914 PRKG2 protein Q13237 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Ser556 HAKASRTsSKHKEDV 9606 BTO:0002181 21177494 YES miannu  PKGII directly phosphorylated and stimulated SHP-1 activity 0.2 SIGNOR-276286 PLK2 protein Q9NYY3 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 9606 20531387 YES lperfetto Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap 0.578 SIGNOR-166003 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser221 PRTSPIMsPRTSLAE 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248687 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser413 SVHKLDVsRSPPLMV 9606 BTO:0000007 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249306 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 21079800 YES gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. 0.706 SIGNOR-169694 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser613 EKKQITTsPITVRKN 9606 12372621 YES lperfetto Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition. 0.351 SIGNOR-216757 ATF2 protein P15336 UNIPROT PLAT protein P00750 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 8647095 NO lperfetto We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells. 0.2 SIGNOR-253724 PTPN1 protein P18031 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 15632081 YES gcesareni Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs 0.741 SIGNOR-132959 DMTF1 protein Q9Y222 UNIPROT JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 YES Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  0.265 SIGNOR-261585 BMPR1A protein P36894 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 10090 19620713 NO ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). 0.297 SIGNOR-255785 AKT proteinfamily SIGNOR-PF24 SIGNOR DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 21619873 YES gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. 0.2 SIGNOR-173976 Ub:E2 complex SIGNOR-C497 SIGNOR SIAH3 protein Q8IW03 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271264 SET protein Q01105 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates binding 9606 21806989 YES miannu Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac 0.282 SIGNOR-175722 ITCH protein Q96J02 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 12226085 YES miannu In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.  0.479 SIGNOR-272604 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 14522994 YES We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association 0.793 SIGNOR-248665 CAV1 protein Q03135 UNIPROT ANXA3 protein P12429 UNIPROT up-regulates quantity relocalization 9606 BTO:0000608 26095609 NO miannu There has been no study regarding the route of entry of exogenous ANXA3 in any cell type thus far. We found exogenous ANXA3 to be internalized into HCC cells through caveolin-1-mediated, but not HSPG-mediated, endocytosis. 0.291 SIGNOR-262215 MAPK14 protein Q16539 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates activity phosphorylation Thr158 VEVVSPAtPVPSETA 9606 25544752 YES miannu We found that phosphorylation of Tip60-T158 was increased by p38\u03b1 isolated from Dox- or \u03b3-radiation-treated cells over that from untreated cells (Figure xref ), indicating that DNA damage induces the protein kinase activity of p38\u03b1 towards Tip60-T158. 0.321 SIGNOR-278958 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.822 SIGNOR-178403 NAB2 protein Q15742 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22431919 NO miannu Overexpression or short interfering RNA (siRNA)-mediated down-regulation of EGR1 or NAB2, and chromatin immunoprecipitations indicated that EGR1 and NAB2 act in concert to positively regulate p130(Cas)/BCAR1 expression in breast cancer cells. 0.2 SIGNOR-253889 DCAF4 protein Q8WV16 UNIPROT OPTN protein Q96CV9 UNIPROT up-regulates activity binding 9606 BTO:0000567 32014991 YES miannu DCAF4-mediated ubiquitination of OPTN facilitates the degradation of DBR-exposed SOD1. OPTN is involved in degradation of DBR-exposed SOD1. These data demonstrate that DCAF4-including CRL4 complex mediates OPTN ubiquitination at lysine 501, and this ubiquitination is absent in the ALS-related OPTNmut. 0.2 SIGNOR-272210 PIK3CB protein P42338 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23504389 YES miannu In our cultures, both p110alpha and p110beta phosphorylated GSK-3beta at Ser9 confirming previous data.|Whereas p110alpha reduced the protein levels of the CDK2-inhibitor p27 Kip1, p110beta phosphorylated and inactivated GSK-3beta. 0.479 SIGNOR-279089 TWIST2 protein Q8WVJ9 UNIPROT PFDN4 protein Q9NQP4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255507 Ub:E2 complex SIGNOR-C497 SIGNOR RNF43 protein Q68DV7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271009 NUP160 protein Q12769 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.709 SIGNOR-262094 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Thr339 PVKSRKTtLEQPPSV 9606 BTO:0001061 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276771 GRK7 protein Q8WTQ7 UNIPROT GRK7 protein Q8WTQ7 UNIPROT unknown phosphorylation Ser490 YAKDIAEiDDFSEVR 9606 15946941 YES Manara In the absence of PKA, GRK1 and GRK7 are autophosphorylated | The mutants, S490A-GRK7 and S490E-GRK7, do not undergo autophosphorylation, indicating that Ser490 is the only autophosphorylation site in GRK7 0.2 SIGNOR-260838 ULK2 protein Q8IYT8 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Ser124 NIVHGSGsQLFDHVA 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274042 PINK1 protein Q9BXM7 UNIPROT RAB8A protein P61006 UNIPROT down-regulates activity phosphorylation Ser111 RNIEEHAsADVEKMI -1 31361120 YES lperfetto For Rab8a, it was shown that serine 111 phosphorylation (pS111) is dependent on the protein kinase PINK1 and that mimicking the phosphorylation at S111 by a serine/glutamate substitution (S111E) impaired Rab8a activation by its cognate nucleotide exchange factor (GEF) Rabin8. 0.271 SIGNOR-260268 PBK protein Q96KB5 UNIPROT PRDX1 protein Q06830 UNIPROT up-regulates phosphorylation Ser32 QFKDISLsDYKGKYV 9606 BTO:0000782;BTO:0000848;BTO:0001286 20647304 YES lperfetto We report that prx1 is newly discovered direct target of topk. Our results demonstrate that topk phosphorylation of prx1 at ser-32 inhibits uvb-induced apoptosis in rpmi7951 melanoma cells by increasing prx1 peroxidase activity and decreasing the intracellular accumulation of h2o2. 0.26 SIGNOR-166901 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates chemical activation 9606 10777564 YES gcesareni Wnt ligands working through frizzled receptors have a differential ability to stimulate release of intracellular calcium (ca(2+)) and activation of protein kinase c (pkc). 0.8 SIGNOR-76991 MAPK1 protein P28482 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 16282323 YES lperfetto Erk phosphorylation serves as a signal for bim ubiquitination and proteasomal degradation 0.715 SIGNOR-141584 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser21 VGVGRAGsVRMRDLR 22584576 YES lperfetto LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation. 0.2 SIGNOR-275525 miR-142-3p mirna URS000075AE07_9606 RNAcentral MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR down-regulates quantity by repression post transcriptional regulation 10090 23132946 NO irozzo In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability. 0.4 SIGNOR-255883 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser451 NGFYHFGsTSSSPPI 9606 BTO:0000007 16141410 YES In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity 0.398 SIGNOR-251245 CSNK2A1 protein P68400 UNIPROT RNF7 protein Q9UBF6 UNIPROT up-regulates phosphorylation Thr10 DVEDGEEtCALASHS 9606 BTO:0000567 12748192 YES lperfetto Ckbbp1 is phosphorylated in vivo and threonine to alanine mutation at residue 10 abrogates the phosphorylation of ckbbp1 observed in vivo, indicating that ckii is a major kinase that is responsible for in vivo phosphorylation of ckbbp1. As compared with the wild-type ckbbp1 or ckbbp1t10e (in which threonine 10 is replaced by glutamate), overexpression of nonphosphorylatable ckbbp1 (ckbbp1t10a) results in accumulation of ikappabalpha and p27kip1. 0.457 SIGNOR-101187 FLT3 protein P36888 UNIPROT PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 NO The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5.24 Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD. 0.337 SIGNOR-261541 CASK-Mint1-Veli complex complex SIGNOR-C561 SIGNOR Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 16842202 NO miannu The CASK-Mint1-Veli complex acts as an adaptor protein complex interacting with -neurexin, the current model proposes that the CASK- Mint1-Veli complex functions as a nucleation site for the assembly of proteins involved in synaptic junctions and synaptic vesicle exocytosis (Fig. 3a). 0.7 SIGNOR-278902 PKA proteinfamily SIGNOR-PF17 SIGNOR EVL protein Q9UI08 UNIPROT up-regulates activity phosphorylation 9606 15066263 YES miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts 0.2 SIGNOR-268287 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 YES inferred from 70% family members gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.2 SIGNOR-270117 MAP2K3 protein P46734 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation 9606 BTO:0000887;BTO:0001103 11980910 YES amattioni Mkk3 enhanced mirk kinase activity. Mkk3 possibly activates mirk by phosphorylating it. 0.348 SIGNOR-86731 SYCE2 protein Q6PIF2 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR form complex binding 9606 22394509 YES miannu The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region. 0.692 SIGNOR-264198 NFS1 protein Q9Y697 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 YES lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. 0.762 SIGNOR-262127 ATG7 protein O95352 UNIPROT ATG12 protein O94817 UNIPROT up-regulates binding 9606 18704115 YES gcesareni Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein. 0.936 SIGNOR-180132 PRSS21 protein Q9Y6M0 UNIPROT RAD21 protein O60216 UNIPROT up-regulates cleavage 9606 11875078 YES miannu Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation. 0.2 SIGNOR-115426 PKA proteinfamily SIGNOR-PF17 SIGNOR PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser83 YIGRKKIsPPTPKPR -1 21743495 YES miannu in vitro kinase assays using purified protein kinase A (PKA) and either GST fused full length p85 (GST-p85) or GST fused p85 peptide spanning amino acids 50-109 (GST-p85Δ2) as substrate.  Serine 83 phosphorylation on p85 is necessary for PI3K activation and membrane translocation in 14-3-3ζ overexpressing cells  0.2 SIGNOR-276343 PIK3CA protein P42336 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 NO lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.7 SIGNOR-242649 MAPK3 protein P27361 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser73 EAPRTLAsPKKKDLS 10116 BTO:0000142 9525956 YES lperfetto SCG10, a growth cone-enriched MT-destabilizing protein, has been recently characterized as an in vitro substrate for various serine/threonine kinases including PKA, MAP kinase, and CDK (19). We have found that SCG10 is phosphorylated in vivo in developing rat brain.| The sites for MAP kinase phosphorylation were identified as Ser-62 and Ser-73 of SCG10|By expressing a series of phosphorylation site mutants, we showed that the MT-destabilizing effect of SCG10 could be modulated. While the nonphosphorylatable mutant showed higher activity than the wild-type protein, the activity of the mutant in which phosphorylation on all four sites was mimicked by an aspartate residue was greatly reduced. These data suggest that the nonphosphorylated state of SCG10 represents the most active form of the protein. 0.353 SIGNOR-249116 P2RY1 protein P47900 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256943 ADAM10 protein O14672 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity cleavage 9606 26284334 YES miannu The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. 0.345 SIGNOR-259845 BHC complex complex SIGNOR-C353 SIGNOR SYN1 protein P17600 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 12032298 YES miannu We show that BHC interacts with the promoter of the synapsin gene and mediates its RE1-dependent repression. BHC is recruited to the endogenous synapsin gene. 0.27 SIGNOR-264504 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 YES lperfetto The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1 0.729 SIGNOR-236380 Ub:E2 complex SIGNOR-C497 SIGNOR TRIP12 protein Q14669 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271285 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 8846784 YES fstefani Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk. 0.508 SIGNOR-44347 CCT7 protein Q99832 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.754 SIGNOR-272867 dothiepin chemical CHEBI:36798 ChEBI CHRM5 protein P08912 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258695 CDC42BPA protein Q5VT25 UNIPROT MYL2 protein P10916 UNIPROT up-regulates activity phosphorylation Ser19 GANSNVFsMFEQTQI BTO:0000567 9418861 YES llicata These approximately 190-kDa myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs) preferentially phosphorylate nonmuscle myosin light chain at serine 19, which is known to be crucial for activating actin-myosin contractility. 0.649 SIGNOR-250723 MARCHF5 protein Q9NX47 UNIPROT MARCHF5 protein Q9NX47 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16874301 YES miannu Rapid degradation of MITOL by autoubiquitination activity. Taken together, these results suggested that MITOL strictly controls its protein expression level by rapid degradation of MITOL through the PHD-dependent autoubiquitination activity. 0.2 SIGNOR-271895 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr161 PSFDAILyYYQSGGR 9606 BTO:0000938 BTO:0000671 19166614 YES gcesareni Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein. 0.378 SIGNOR-183515 TRIP12 protein Q14669 UNIPROT NAE1 protein Q13564 UNIPROT down-regulates quantity by destabilization ubiquitination -1 SIGNOR-C131 18627766 YES miannu Our data suggest that that TRIP12 promotes degradation of APP-BP1 by catalyzing its ubiquitination, which in turn modulates the neddylation pathway. 0.433 SIGNOR-266780 UBE2D2 protein P62837 UNIPROT TRIM22 protein Q8IYM9 UNIPROT up-regulates activity binding 9606 BTO:0000007 18656448 YES miannu  It was found that TRIM22 underwent self-ubiquitylation in vitro in combination with the E2 enzyme UbcH5B and the ubiquitylation was dependent on its RING finger domain. Further evidences showed that TRIM22 could also be self-ubiquitylated in vivo. Importantly, TRIM22 was conjugated with poly-ubiquitin chains and stabilized by the proteasome inhibitor in 293T cells, suggesting that TRIM22 targeted itself for proteasomal degradation through the poly-ubiquitylation. We also found that TRIM22 was located in the nucleus, indicating that TRIM22 might function as a nuclear E3 ubiquitin ligase. 0.301 SIGNOR-271779 IRX1 protein P78414 UNIPROT NPTX1 protein Q15818 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.255 SIGNOR-261655 EGFR protein P00533 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity 10090 BTO:0000667 15284024 NO JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs. lperfetto Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion 0.631 SIGNOR-235655 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Ser518 GEDPYAGsTDENTDS 9606 BTO:0000567 15367657 YES llicata XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1. 0.461 SIGNOR-251050 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser289 PPPLAPQsPQGGVMG -1 29967145 YES miannu CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro. 0.322 SIGNOR-277650 CBP/p300 complex SIGNOR-C6 SIGNOR THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15677570 NO miannu We further show evidence suggesting that NF-κB inhibits TM expression indirectly by competition for the coactivator p300/CBP. 0.2 SIGNOR-253908 DUSP8 protein Q13202 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 23159405 YES gcesareni M3/6 (dusp8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of jnk and, to a lesser extent, p38 mapk 0.59 SIGNOR-199695 MAPK3 protein P27361 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 BTO:0000876 14701740 YES lperfetto Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21. 0.371 SIGNOR-120570 FBXO9 protein Q9UK97 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR down-regulates activity binding 9606 BTO:0000007 23263282 YES miannu Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins. 0.67 SIGNOR-271998 PPP2CA protein P67775 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 YES In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. 0.44 SIGNOR-248645 NEIL3 protein Q8TAT5 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275720 MAP3K7 protein O43318 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity phosphorylation Ser457 TQSSSSSsDGGLFRS 9606 BTO:0000007 22216226 YES miannu We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.  0.929 SIGNOR-276367 RPS6KB1 protein P23443 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates phosphorylation Thr1135 NRRIRTLtEPSVDFN 9606 19995915 YES gcesareni Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt 0.716 SIGNOR-161995 MAPK3 protein P27361 UNIPROT MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 8798443 YES llicata Here we describe that human c-myb can be phosphorylated by mitogen-activated protein kinases (mapk's) at serine 532 of the carboxy (c-) terminal regulatory domain in vitro. expression of a constitutively active form of ras together with c-myb in transient transfection experiments had no effect on the transcriptional activity of c-myb, while expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. 0.301 SIGNOR-43558 PCGF2 protein P35227 UNIPROT UBE2I protein P63279 UNIPROT down-regulates activity binding 9606 BTO:0000007 18211895 YES miannu Based on this finding of interaction between MEL-18 and UBC9, we envisioned a mechanism in which MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes that approach HSF2. 0.607 SIGNOR-226248 SOX2 protein P48431 UNIPROT ABCC3 protein O15438 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21531766 NO miannu ID4-mediated SOX2 induction enhanced ABCC3 and ABCC6 expression through direct transcriptional regulation, indicating that ID4 regulates the chemoresistance of iGSCs by promoting SOX2-mediated induction of ABC transporters. 0.294 SIGNOR-255181 PRKD1 protein Q15139 UNIPROT PIP4K2A protein P48426 UNIPROT down-regulates phosphorylation Thr376 KAAHAAKtVKHGAGA 9606 16563698 YES lperfetto We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases. 0.2 SIGNOR-145370 DMC1 protein Q14565 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR up-regulates activity binding 10090 BTO:0001275 10525529 YES miannu The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. 0.336 SIGNOR-264208 SP1 protein P08047 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001549 12359731 NO miannu Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter. 0.2 SIGNOR-254159 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 0.745 SIGNOR-161613 MAPKAPK5 protein Q8IW41 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001286 17254968 YES llicata Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37 0.759 SIGNOR-152847 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 0.2 SIGNOR-260129 GABRG2 protein P18507 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.637 SIGNOR-263758 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser36 AQQVSSLsESEESQD 9606 20730097 YES lperfetto Although the functional impact of ck-mediated atf1 phosphorylation is still unclear, we found that mutation of ser-36 and ser-41 increased cbp kix domain binding by up to four fold (fig. 2g). This result is consistent with the negative impact of ck-mediated phosphorylation on cbp binding affinity of creb that we previously reported 0.297 SIGNOR-167544 MYOD1 protein P15172 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 18094043 YES lperfetto We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter. 0.391 SIGNOR-257598 SIRT7 protein Q9NRC8 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275883 belinostat chemical CHEBI:61076 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257742 AURKB protein Q96GD4 UNIPROT CIT protein O14578 UNIPROT down-regulates activity phosphorylation 9606 27009191 YES miannu Finally, Aurora B phosphorylates CIT-K to control its localization and interaction with central spindle partners.|Together these findings indicate that CIT-K is an Aurora B substrate and that Aurora B phosphorylation at S699 dampens the association of CIT-K with KIF23 and the chromosomal passenger complex in order to reduce CIT-K accumulation at the spindle midzone in early cytokinesis. 0.283 SIGNOR-279140 MYC protein P01106 UNIPROT SURF1 protein Q15526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10858544 NO miannu We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response. 0.2 SIGNOR-254615 ZNF202 protein O95125 UNIPROT POMGNT1 protein Q8WZA1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22419172 NO miannu Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose β-1,2-N-acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83_-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202). 0.25 SIGNOR-255626 buprenorphine chemical CHEBI:3216 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.8 SIGNOR-258660 LTB4R protein Q15722 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257196 XL765 chemical CHEBI:71958 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207869 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp373 PATQCISdGKLNEGH 9606 11741536 YES gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. 0.365 SIGNOR-256436 PRKD1 protein Q15139 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates phosphorylation Ser294 SNLKRTAsNPKVENE 9606 16912074 YES The effect has been demonstrated using Q9UBF8-2 gcesareni Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity. 0.405 SIGNOR-148876 PLA2G4A protein P47712 UNIPROT arachidonic acid smallmolecule CHEBI:15843 ChEBI up-regulates chemical modification 9606 6810878 YES acerquone Alternatively, a phospholipase a2 may indeed deacylate the phosphatidylinositol, but the point of debate here is whether deacylation constitutes a significant component of the arachidonate liberation. 0.8 SIGNOR-25633 MITF protein O75030 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 12086670 YES lperfetto MITF directly occupies the BCL2 promoter in vivo and this suggest that BCL2 may be a direct transcriptional target of MITF 0.473 SIGNOR-249618 IFNL2 protein Q8IZJ0 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 12469119 YES gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. 0.696 SIGNOR-96209 CDK3 protein Q00526 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser104 FPPLNSVsPSPLMLL 26202215 YES lperfetto CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3 0.259 SIGNOR-273189 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates 10090 BTO:0001103 24003218 NO lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 0.911 SIGNOR-252997 ASB2 protein Q96Q27 UNIPROT FLNB protein O75369 UNIPROT down-regulates quantity by destabilization binding 19300455 YES miannu Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation.  Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb. 0.417 SIGNOR-271795 BMP4 protein P12644 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 26330344 YES fferrentino BMP interacts with specific receptors on the cell surface, BMP receptor types 1 and 2 (BMPr1 and BMPr2). 0.891 SIGNOR-253548 verapamil chemical CHEBI:9948 ChEBI SCN2A protein Q99250 UNIPROT down-regulates activity chemical inhibition 10116 1658608 YES miannu This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. 0.8 SIGNOR-258355 SEMA3A protein Q14563 UNIPROT NRP1 protein O14786 UNIPROT up-regulates activity binding 9606 25335892 YES miannu Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction. 0.913 SIGNOR-261815 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1644 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273042 AXL protein P30530 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 25873175 YES miannu AXL trans-actives EGFR in a ligand independent manner and induces phosphorylation of EGFR on tyrosine 1173.|In our models AXL seems to induce a re-wiring of the EGFR signaling towards the PLCgamma-PKC axis by receptor phosphorylation at tyrosine 1173. 0.431 SIGNOR-279141 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 NO We show that the ID1 and ID2 promoters are activated by PML-RARα but, unexpectedly, not by wild-type RARα/RXR. In contrast, PML-RARα transactivated the promoter more than 12-fold in an ATRA-dependent fashion. 0.2 SIGNOR-255728 CDK5 protein Q00535 UNIPROT CDK16 protein Q00536 UNIPROT up-regulates activity phosphorylation 9606 12084709 YES miannu Taken together, our findings demonstrate that Pctaire1 interacts with p35, both in vitro and in vivo, and that phosphorylation of Pctaire1 by Cdk5 enhances its kinase activity. 0.336 SIGNOR-279149 RIMS1 protein Q86UR5 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 YES miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle 0.804 SIGNOR-264381 CHEK1 protein O14757 UNIPROT WEE1 protein P30291 UNIPROT up-regulates phosphorylation 9606 20068082 YES gcesareni Chk1 also phosphorylates and stabilizes wee1. 0.61 SIGNOR-163164 SSTR2 protein P30874 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.581 SIGNOR-256684 TFEB protein P19484 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via Ppargc1α and Ppar1α. 0.381 SIGNOR-276708 COL4A2 protein P08572 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 YES Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) 0.7 SIGNOR-254666 EPHA7 protein Q15375 UNIPROT EPHA10 protein Q5JZY3 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000093 27566654 YES miannu By using co-immunoprecipitation, we demonstrated physical interaction between kinase-deficient EPHA10 with kinase-sufficient EPHA7 receptor. we speculate that the kinase activity of EPHA7 cross-phosphorylates EPHA10. 0.503 SIGNOR-273873 BCORL1 protein Q5H9F3 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates activity binding 9606 BTO:0000567 17379597 YES irozzo BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor. 0.428 SIGNOR-259112 OPRL1 protein P41146 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257117 PRKCA protein P17252 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser677 AIVSKIDsRLEQYTS 9606 BTO:0000887;BTO:0001260 8182108 YES gcesareni Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase. 0.357 SIGNOR-36796 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248738 PRKN protein O60260 UNIPROT RANBP2 protein P49792 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16332688 YES irozzo Our findings suggested that the intracellular levels of RanBP2 and its functional activity may be modulated by Parkin-mediated ubiquitination and proteasomal pathways. Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2. 0.2 SIGNOR-259116 PSMB8 protein P28062 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization 9606 BTO:0003445 19443843 YES Gianni Surprisingly, siRNA knockdown of PSMB8 (LMP7), an ‘immunoproteasome’ component, reversed IFNγ-induced sensitivity to Fas ligation and prevented Fas/IFNγ-induced degradation of Mcl-1, but did not protect p-Bcl-2 or p-Bcl-XL. Proteasome inhibition markedly increased Mcl-1, p-Bcl-2, and p-Bcl-XL levels after IFNγ treatment 0.2 SIGNOR-261974 CHEK2 protein O96017 UNIPROT MPEG1 protein Q2M385 UNIPROT up-regulates activity phosphorylation Thr288 VPFYPGItLQAWQQG 9606 24798733 YES miannu Chk2 phosphorylates Mps1-T288 after DNA damage.|In the present study, we show that Chk2 stabilizes Mps1 protein and phosphorylates Aurora B-B-serine 331 to prevent mitotic exit in vertebrate cells when the majority of kinetochores are unattached. 0.2 SIGNOR-279160 ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser317 ENVKYSSsQPEPRTG 9606 20068082 YES gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. 0.844 SIGNOR-163106 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258000 bromocriptine chemical CHEBI:3181 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258366 DLG4 protein P78352 UNIPROT DLGAP1 protein O14490 UNIPROT up-regulates activity relocalization 9606 18923512 YES brain lperfetto Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). 0.932 SIGNOR-264196 SLC16A2 protein P36021 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity relocalization 9606 28153798 YES scontino T4 and T3 are released from the thyroid cell through transporters present at the basolateral plasma membrane of thyrocytes (Fig. 1). The most important transporter known to be responsible for thyroid hormone transport is the SLC16A2 monocarboxylate transporter 8 (MCT8), which can promote both uptake and efflux of TH and is involved in the release of TH from the thyroid gland. 0.8 SIGNOR-267140 CAMKK2 protein Q96RR4 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates activity phosphorylation Thr200 EHQVLMKtVCGTPGY 7615569 YES llicata Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation. 0.619 SIGNOR-250718 STT3A protein P46977 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization glycosylation 9606 BTO:0001939 29765039 YES Barakat Together, these results support a notion that the two STT3 isoforms regulate EMT-mediated PD-L1 induction through PD-L1 protein N-glycosylation and stabilization. 0.2 SIGNOR-274975 SRPK1 protein Q96SB4 UNIPROT RBM8A protein Q9Y5S9 UNIPROT down-regulates phosphorylation Ser166 RRGGRRRsRSPDRRR 9606 16100109 YES gcesareni We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc. 0.261 SIGNOR-139551 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.289 SIGNOR-249006 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258277 CAPN2 protein P17655 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 BTO:0000590 25969760 YES lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain 0.568 SIGNOR-251608 XBP1 protein P17861 UNIPROT B-Lymphocyte_diff phenotype SIGNOR-PH113 SIGNOR up-regulates activity 9606 BTO:0000392 11460154 NO XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells. 0.7 SIGNOR-259957 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 YES Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs 0.752 SIGNOR-258992 NOX5 protein Q96PH1 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.7 SIGNOR-264718 CDK5 protein Q00535 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser73 PESPMLSsPPKKKDT -1 22577147 YES lperfetto Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta 0.323 SIGNOR-264894 SLBP protein Q14493 UNIPROT H2BC17 protein P23527 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265379 CDK1 protein P06493 UNIPROT SAMHD1 protein Q9Y3Z3 UNIPROT down-regulates phosphorylation Thr592 DVIAPLItPQKKEWN 9606 23602554 YES llicata Cyclin a2/cdk1 phosphorylates samhd1 at the threonine 592 residue both in vitro and in vivo. Phosphorylation of samhd1 thr592 correlates with loss of its ability to restrict hiv-1. 0.492 SIGNOR-201913 CDK5 protein Q00535 UNIPROT CLIC4 protein Q9Y696 UNIPROT up-regulates quantity by stabilization phosphorylation Ser108 PPKYLKLsPKHPESN 9606 30237421 YES miannu These results confirm that CDK5 phosphorylates CLIC4 at serine 108.|We found that activated CDK5 phosphorylated serine 108 in CLIC4, increasing CLIC4 protein stability, and accumulation. 0.2 SIGNOR-279451 TLK1 protein Q9UKI8 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Ser386 HENGAEDsNVALEKL 9606 BTO:0000007 35064619 YES miannu We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. 0.2 SIGNOR-276747 CDK8 protein P49336 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr119 AGTAGALtPQHVRAH -1 29967145 YES miannu CDK8 phosphorylates YAP and promotes its activation. Of interest, mutating four amino acid positions (T119, S128, S289, and S367) to alanines (YAP-4A) completely blocked phosphorylation (Fig. 6J), suggesting that CDK8 phosphorylates these sites in YAP in vitro. 0.322 SIGNOR-277648 CDC14A protein Q9UNH5 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser315 LPNNTSSsPQPKKKP 9606 10644693 YES The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification 0.402 SIGNOR-248828 BAZ2B protein Q9UIF8 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 YES miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. 0.2 SIGNOR-266622 TTF2 protein Q9UNY4 UNIPROT CDC5L protein Q99459 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 12927788 YES miannu HLodestar/HuF2 associates with CDC5L in cell lysates and HeLa nuclear extracts. It is possible that during the cell division cycle, hLodestar/HuF2’s associates with transcription/splicing complexes in order to inhibit transcription/splicing prior to the start of mitosis and/or functions in stabilizing nuclear complexes containing splicing factors (e.g., the CDC5L complex) so that these are available for re-initiation of splicing at the end of mitosis when gene expression is re-established in cells. 0.432 SIGNOR-224460 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269336 BST1 protein Q10588 UNIPROT cyclic ADP-ribose smallmolecule CHEBI:31445 ChEBI up-regulates quantity chemical modification 9606 18626062 YES miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. 0.8 SIGNOR-264248 GSK3B protein P49841 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates phosphorylation Ser346 SEEDRSKsAPTSPCD 9606 18604201 YES llicata Specifically, we have identified three phosphorylation sites within pkcepsilon that control its association with 14-3-3.kinase (ser 350), gsk3 (ser 346) and pkc itself (ser 368) 0.268 SIGNOR-179412 H2AC4 protein P04908 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 YES miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 0.2 SIGNOR-263724 CBX7 protein O95931 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000196 19706751 NO miannu We confirmed by coimmunoprecipitation that CBX7 physically interacts with the HDAC2 protein and is able to inhibit its activity. Then, we showed that both these proteins bind the E-cadherin promoter and that CBX7 up-regulates E-cadherin expression. 0.384 SIGNOR-253767 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 HPGFDAEsYTFTVPR 23972993 YES For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP 0.409 SIGNOR-274051 MAPK1 protein P28482 UNIPROT SP3 protein Q02447 UNIPROT up-regulates phosphorylation Ser73 CSKIGPPsPGDDEEE 9606 17685427 YES llicata Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73. in the inducible cell lines, expression of wild-type form of sp3 increases vegf production whereas the s73a form has a reduced potential reflecting its lower transcriptional activity. 0.305 SIGNOR-157272 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269022 creatine smallmolecule CHEBI:16919 ChEBI CKMT1A protein P12532 UNIPROT up-regulates activity chemical activation 9606 18502307 YES miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. 0.8 SIGNOR-265786 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr627 TPESWRLtPPAKVGG 9606 22094256 YES lperfetto We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627) 0.623 SIGNOR-177263 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 NO apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. 0.584 SIGNOR-255355 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 12052829 YES lperfetto Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms. 0.402 SIGNOR-249150 Class II MHC complex SIGNOR-C428 SIGNOR Class II MHC:Antigen complex SIGNOR-C429 SIGNOR form complex binding 9606 33374673 YES scontino The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). 0.2 SIGNOR-267872 HMGB1 protein P09429 UNIPROT HOXC6 protein P09630 UNIPROT up-regulates activity binding -1 8890171 YES miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. 0.298 SIGNOR-219937 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.322 SIGNOR-129316 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates binding 9606 21798082 YES gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). 0.578 SIGNOR-175621 Ub:E2 complex SIGNOR-C497 SIGNOR RNF126 protein Q9BV68 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270963 AHSA1 protein O95433 UNIPROT HSP90AA1 protein P07900 UNIPROT up-regulates activity binding 9606 16696853 YES miannu The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity 0.744 SIGNOR-252211 LYN protein P07948 UNIPROT LYN protein P07948 UNIPROT up-regulates activity phosphorylation Tyr397 RVIEDNEyTAREGAK -1 8530369 YES Lyn is a member of the Src family of protein-tyrosine kinases that can readily undergo autophosphorylation in vitro. The site of autophosphorylation is Tyr397. Autophosphorylation results in a 17-fold increase in protein-tyrosine kinase activity. 0.2 SIGNOR-251402 Liprin-alpha proteinfamily SIGNOR-PF82 SIGNOR KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 YES miannu Kinesin-3 Family Member KIF1A Interacts with Liprin-α and TANC2. TANC2 and Liprin-α Recruit KIF1A-Driven DCVs in Dendritic Spines. Upon Ca2+/CaM binding, KIF1A is activated, allowing for DCV loading and motility. KIF1A-driven DCVs are recruited in dendritic spines by liprin-α and TANC2, which ensure a precise mechanism of synaptic tagging for the vesicles. 0.2 SIGNOR-266892 RNMT protein O43148 UNIPROT mRNA_capping phenotype SIGNOR-PH178 SIGNOR up-regulates 9606 BTO:0000567 26942677 NO lperfetto The creation of translation-competent mRNA is dependent on RNA polymerase II transcripts being modified by addition of the 7-methylguanosine (m7G) cap. The factors that mediate splicing, nuclear export, and translation initiation are recruited to the transcript via the cap. The cap structure is formed by several activities and completed by RNMT (RNA guanine-7 methyltransferase), which catalyzes N7 methylation of the cap guanosine. 0.7 SIGNOR-265503 HIF-1 complex complex SIGNOR-C418 SIGNOR HK1 protein P19367 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 YES miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 0.352 SIGNOR-267452 JAK2 protein O60674 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr718 IPERDSRySQPLHEE 9606 BTO:0001963 19287004 YES miannu Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-718, leading to an enhanced association of ASK1 with SOCS1 and subsequent ASK1 degradation.  0.368 SIGNOR-276145 AKT1 protein P31749 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser939 SFRARSTsLNERPKS 10090 BTO:0000944 12150915 YES lperfetto We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. 0.816 SIGNOR-235511 TRAF6 protein Q9Y4K3 UNIPROT RUSC1 protein Q9BVN2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 19365808 YES miannu  We demonstrated that NESCA and NEMO interact by their N-terminal region. Beside to NEMO, we revealed that NESCA directly associates to the E3 ubiquitin ligase TRAF6, which in turn catalyzes NESCA polyubiquitination. Finally, we demonstrated that NESCA overexpression strongly inhibits TRAF6-mediated polyubiquitination of NEMO.  0.32 SIGNOR-272774 STUB1 protein Q9UNE7 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 18541707 YES miannu Here, we show that CHIP promotes Runx2 ubiquitination and degradation and thereby negatively regulates osteoblast differentiation. 0.408 SIGNOR-278600 ROCK1 protein Q13464 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 11283607 NO Cleaved by CASP3 amattioni Activation of rock i by caspase-3 seems to be responsible for bleb formation in apoptotic cells. 0.7 SIGNOR-106549 FGF11 protein Q92914 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.253 SIGNOR-253414 CADPS2 protein Q86UW7 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 YES miannu CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1 0.266 SIGNOR-264339 DCAF15 protein Q66K64 UNIPROT RBM39 protein Q14498 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001109 31819272 YES miannu Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation. 0.377 SIGNOR-272203 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates activity phosphorylation Thr442 KDIDKAItISSALQA -1 28193222 YES miannu AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.  0.372 SIGNOR-276748 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21761340 YES lperfetto The prostate-specific TMPRSS2 gene, while upregulated by AR activity in luminal cells, is also transcribed in basal populations, confirming that AR acts as an expression modulator. 0.576 SIGNOR-253687 FRK protein P42685 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation 9606 23318459 YES miannu Furthermore, Rak/Frk inhibited mutant EGFR phosphorylation at an activating site and dramatically decreased the levels of EGFR\u0394747-749/A750P from the plasma membrane.|Taken together, the results suggest that Rak and Frk inhibits EGFR signaling in cancer cells and has elevated activity against EGFR exon 19 mutants. 0.41 SIGNOR-279177 EDNRA protein P25101 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257320 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 18245089 YES gcesareni We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. 0.432 SIGNOR-160609 Ub:E2 complex SIGNOR-C497 SIGNOR RBCK1 protein Q9BYM8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271056 NME1 protein P15531 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates phosphorylation Ser406 TRLRRTEsVPSDINN 9606 12105213 YES gcesareni Autophosphorylated recombinant nm23-h1 phosphorylated ksr in vitro. Using site-directed mutagenesis, we found that nm23-h1 phosphorylated ksr serine 392, a 14-3-3-binding site, consistent with the recent identification of c-tak1 as a kinase for this site. 0.544 SIGNOR-90390 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser100 HLSGRKLsLQERSQG 9606 22778263 YES lperfetto Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity 0.2 SIGNOR-198146 EEF1A1 protein P68104 UNIPROT EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 YES miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. 0.2 SIGNOR-270809 PRKCD protein Q05655 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.29 SIGNOR-249248 CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 NO lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). 0.7 SIGNOR-262139 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 9606 16782899 YES llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain 0.496 SIGNOR-147191 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 YES Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [‚Ķ] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267394 CSNK1E protein P49674 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr41 YSTTPGGtLFSTTPG 9606 BTO:0000150 24247720 YES lperfetto Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation. 0.2 SIGNOR-203240 MKX protein Q8IYA7 UNIPROT SOX5 protein P35711 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001592 33115953 YES miannu MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2). 0.295 SIGNOR-267214 APC-c complex SIGNOR-C150 SIGNOR PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Ser40 PTAEEKPsPRRSLSQ 33309518 YES lperfetto Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20) 0.312 SIGNOR-275492 MRPL52 protein Q86TS9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.682 SIGNOR-262346 VEZF1 protein Q14119 UNIPROT CITED2 protein Q99967 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001086 29794136 YES miannu The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells 0.2 SIGNOR-266883 HDAC1 protein Q13547 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.825 SIGNOR-263851 serotonin smallmolecule CHEBI:28790 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264284 EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 30917308 NO lperfetto 4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression 0.7 SIGNOR-261012 MAPK14 protein Q16539 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates activity binding 9606 BTO:0000007 11062068 YES gcesareni Here we have shown that mkp-1 associates directly with p38 map kinase both in vivo and in vitro, and that this interaction enhances the catalytic activity of mkp-1. The point mutation asp-316-->asn in the c-terminus of p38, analogous to the erk2 (extracellular-signal-regulated kinase 2) sevenmaker mutation, dramatically decreases its binding to mkp-1 and substantially compromises its stimulatory effect on the catalytic activity of this phosphatase. 0.804 SIGNOR-83752 clofarabine chemical CHEBI:681569 ChEBI PRIM1 protein P49642 UNIPROT down-regulates activity chemical inhibition 9606 1707752 YES miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. 0.8 SIGNOR-258359 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. 0.8 SIGNOR-268121 WARS1 protein P23381 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270801 Erlin complex SIGNOR-C532 SIGNOR ITPR1 protein Q14643 UNIPROT down-regulates quantity by destabilization binding 10119 BTO:0003293 19240031 YES miannu Here we report that the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex that binds to IP(3)R tetramers immediately after their activation and is required for their processing. The complex is ring-shaped (diameter approximately 250A(),) and RNA interference-mediated depletion of SPFH1 and SPFH2 blocks IP(3)R polyubiquitination and degradation.  0.494 SIGNOR-271915 lurasidone chemical CHEBI:70735 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10030 20404009 YES Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. 0.8 SIGNOR-257841 terbutaline chemical CHEBI:9449 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 YES Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) 0.8 SIGNOR-257872 MYC protein P01106 UNIPROT HLA-B protein P01889 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 NO miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. We show here that transcription of the HLA-B locus, which is mainly affected by c-Myc, is downmodulated at the level of initiation of transcription. 0.265 SIGNOR-254606 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270366 ITGB1BP1 protein O14713 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257643 RAF1 protein P04049 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates binding 9606 15618521 YES inferred from 70% of family members gcesareni Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2) 0.361 SIGNOR-269942 GMIP protein Q9P107 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.51 SIGNOR-260507 copper(1+) smallmolecule CHEBI:49552 ChEBI SOD1 protein P00441 UNIPROT up-regulates activity chemical activation 1542024 YES lperfetto Copper as a cofactor and regulator of copper,zinc superoxide dismutase 0.8 SIGNOR-272299 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1064 KTVNESAsLRERIEF -1 7926007 YES lperfetto Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites. 0.348 SIGNOR-248906 STAR protein P49675 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity relocalization 17579211 YES lperfetto StAR transfers cholesterol from the outer to the inner mitochondrial membranes, where the enzyme complex of cholesterol side chain cleavage cytochrome P450 (P450scc) converts it to the first steroid, pregnenolone 0.8 SIGNOR-265727 EP400 protein Q96L91 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.704 SIGNOR-269289 CDK1 protein P06493 UNIPROT ANAPC1 protein Q9H1A4 UNIPROT up-regulates phosphorylation Ser355 AALSRAHsPALGVHS 9606 14657031 YES lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation 0.591 SIGNOR-119705 Ub:E2 complex SIGNOR-C497 SIGNOR CCNB1IP1 protein Q9NPC3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271052 TERB2 protein Q8NHR7 UNIPROT TTM complex complex SIGNOR-C305 SIGNOR form complex binding 9606 BTO:0000007 30718482 YES lperfetto Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE 0.2 SIGNOR-263304 NIM1K protein Q8IY84 UNIPROT WEE1 protein P30291 UNIPROT down-regulates activity phosphorylation 9606 8515817 YES miannu Furthermore, purified bacterially produced Nim1 kinase directly phosphorylates and inactivates Wee1 in vitro.|Phosphorylation and inactivation of the mitotic inhibitor Wee1 by the nim1 and cdr1 kinase. 0.48 SIGNOR-279238 GDNF protein P39905 UNIPROT ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.2 SIGNOR-252179 Ub:E2 complex SIGNOR-C497 SIGNOR SH3RF1 protein Q7Z6J0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271120 bilirubin(2-) smallmolecule CHEBI:57977 ChEBI biliverdin(2-) smallmolecule CHEBI:57991 ChEBI up-regulates quantity precursor of 9606 BTO:0000759 7929092 YES lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 0.8 SIGNOR-275522 PRKD1 protein Q15139 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 YES miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 0.2 SIGNOR-276046 ABL1 protein P00519 UNIPROT MTOR protein P42345 UNIPROT down-regulates phosphorylation 9606 10753870 YES gcesareni Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k). 0.454 SIGNOR-76562 CASP4 protein P49662 UNIPROT GSDMD protein P57764 UNIPROT up-regulates activity cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 YES lperfetto Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence | 0.646 SIGNOR-256417 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr337 PGPPTGAtANRLRSA 9606 BTO:0000007 10542239 YES llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T 0.2 SIGNOR-250813 SEMA7A protein O75326 UNIPROT PLXNC1 protein O60486 UNIPROT up-regulates binding 9606 10520995 YES gcesareni Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro. 0.913 SIGNOR-71260 FAM83B protein Q5T0W9 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273766 MTURN protein Q8N3F0 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR down-regulates activity binding 10090 BTO:0002572 28704656 YES miannu Here we report that viral infection induced upregulation of INKIT, an inhibitor for NF-κB and IRF3 that restricted innate antiviral responses by blocking phosphorylation of p65 and IRF3. Viral infection induced IKK-mediated phosphorylation of INKIT at Ser58, resulting in its dissociation from the IKKs. INKIT is associated with IKKα/β and TBK1/IKKɛ and inhibits the recruitment and phosphorylation of p65 and IRF3, respectively. IKKα and TBK1 phosphorylate INKIT at Ser58, which results in disassociation of INKIT from IKKα or TBK1 and thereby allows for the subsequent recruitment and phosphorylation of p65 and IRF3 0.2 SIGNOR-273663 KCNQ1 protein P51787 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 YES miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. 0.8 SIGNOR-265981 PBK protein Q96KB5 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16982762 YES gcesareni Pbk/topk could phosphorylate histone h3 at ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone h3 modification. 0.2 SIGNOR-265364 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12050114 YES gcesareni Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation. 0.352 SIGNOR-88732 MSN protein P26038 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 BTO:0000132 35267019 NO miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway. 0.7 SIGNOR-268434 TRIM33 protein Q9UPN9 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25639486 YES miannu TRIM33 ubiquitylates nuclear beta-catenin.|Tumour suppressor TRIM33 targets nuclear beta-catenin degradation. 0.457 SIGNOR-278578 PTEN protein P60484 UNIPROT PFKP protein Q01813 UNIPROT down-regulates activity dephosphorylation Ser386 AVRLRGRsFAGNLNT 9606 29038421 NO miannu In addition, AKT phosphorylation and PFKP S386 phosphorylation and PFKP expression levels were inversely correlated with PTEN expression levels, suggesting that PTEN inhibits PFKP S386 phosphorylation and reduces PFKP stability through inhibition of AKT.|These results indicate that AKT activation resulted from PTEN loss or EGFR dependent PI3K activation induces PFKP upregulation. 0.2 SIGNOR-277118 RUBCNL protein Q9H714 UNIPROT HOPS tethering complex complex SIGNOR-C549 SIGNOR up-regulates activity binding 9606 BTO:0000007 30704899 YES miannu Under nutrient-rich conditions, mTORC1 phosphorylates Pacer at serine157 to disrupt the association of Pacer with Stx17 and the HOPS complex and thus abolishes Pacer-mediated autophagosome maturation. These results demonstrate that mTORC1-mediated Pacer phosphorylation at S157 inhibits autophagosome maturation by disrupting the association of Pacer with Stx17 and the HOPS complex 0.2 SIGNOR-273685 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser554 RTPPKSPsSAKSRLQ -1 8999860 YES miannu Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules 0.314 SIGNOR-250283 CTNNB1 protein P35222 UNIPROT SOX2 protein P48431 UNIPROT down-regulates activity binding 9606 BTO:0000093 24291232 YES flangone The interaction between Sox2 and _-catenin provides a novel mechanism underlying the functional dichotomy of BC cells, which carries potential therapeutic implications. 0.708 SIGNOR-241994 idarubicin chemical CHEBI:42068 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 20824055 YES miannu Topoisomerase II (Top2) is a nuclear enzyme involved in several metabolic processes of DNA. Chemotherapy agents that poison Top2 are known to induce persistent protein-mediated DNA double strand breaks (DSB). In this report, by using knock down experiments, we demonstrated that Top2α was largely responsible for the induction of γH2AX and cytotoxicity by the Top2 poisons idarubicin and etoposide in normal human cells. 0.8 SIGNOR-259327 EXT2 protein Q93063 UNIPROT EXT1/EXT2 complex SIGNOR-C51 SIGNOR form complex binding 9606 11518722 YES miannu Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs 0.58 SIGNOR-109941 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 BTO:0000776 11507089 YES lperfetto These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2. 0.777 SIGNOR-109754 SMURF1 protein Q9HCE7 UNIPROT SMAD9 protein O15198 UNIPROT down-regulates ubiquitination 9606 22298955 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.668 SIGNOR-195669 CSNK2A1 protein P68400 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser608 ENTEDQYsLVEDDED -1 14729945 YES miannu Protein kinase CK2 phosphorylates p85α on Ser608 when p85α is free but not when it is complexed with p110α.  0.246 SIGNOR-276005 CAMK2A protein Q9UQM7 UNIPROT CD44 protein P16070 UNIPROT up-regulates phosphorylation Ser706 LNGEASKsQEMVHLV 9606 9580567 YES gcesareni We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase. 0.2 SIGNOR-57376 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser672 VRGPVSGsPDSMNAS 9606 BTO:0000007 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251275 STARD8 protein Q92502 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.509 SIGNOR-260520 ITGB1BP1 protein O14713 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.284 SIGNOR-257661 PTK6 protein Q13882 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity phosphorylation Tyr142 AVVNLINyQDDAELA 9606 20026641 YES miannu PTK6 directly phosphorylates beta-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64.|The ability of PTK6 to negatively regulate beta-catenin and TCF transcription by modulating levels of TCF4 and TLE and Groucho could contribute to its growth-inhibitory activities in vivo. 0.305 SIGNOR-278286 MYC protein P01106 UNIPROT miR-23b mirna URS0000283D0A_9606 RNAcentral down-regulates quantity by repression transcriptional regulation 10090 16731620 YES Moreover, both loci encoding miR-1, miR-1-1, and miR-1-2, and two of the three encoding miR-133, miR-133a-1 and miR-133a-2, are strongly induced during myogenesis.[…]By using CHIP analysis, we demonstrate that the myogenic factors Myogenin and MyoD bind to regions upstream of these microRNAs and, therefore, are likely to regulate their expression. 0.4 SIGNOR-255916 ADRB1 protein P08588 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257030 GNAS protein P63092 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 YES gcesareni Notably, the fzd7 receptor complex was associated with g_?(s) and pi(3)k and these components were required for wnt7a to activate the akt/mtor growth pathway in myotubes. These data led us to hypothesize that g_?s Mediates the activation of pi3kinase following wnt7a binding to fzd7. 0.356 SIGNOR-252678 GATA2 protein P23769 UNIPROT TSHB protein P01222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 9305891 YES scontino Pit-1, is necessary but not sufficient to allow basal transcription of the mTSHβ gene.The analysis of the mTSHβ gene described in this report provides evidence for the participation of a zinc finger factor, GATA-2, with a POU homeodomain partner, Pit-1, on a such a composite element.In summary, we have shown the requirement for at least two different classes of transcription factors to regulate mTSHβ gene expression. Both GATA-2 and Pit-1 can bind independently to the P1 region of the promoter, form a heteromeric complex with DNA, and functionally synergize to activate TSHβ promoter activity. 0.391 SIGNOR-267253 CDH3 protein P22223 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.85 SIGNOR-265865 adenosine smallmolecule CHEBI:16335 ChEBI ADORA3 protein P0DMS8 UNIPROT up-regulates activity binding -1 14662005 YES Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. 0.8 SIGNOR-268422 ITK protein Q08881 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 20519342 YES gcesareni In t cells, the predominant tec kinase is itk, which functions downstream of the t-cell receptor to regulate phospholipase c-gamma. 0.636 SIGNOR-165803 DAPK1 protein P53355 UNIPROT MAP1B protein P46821 UNIPROT up-regulates binding 9606 18806760 YES gcesareni Dapk-1 interacts with the microtubule-associated protein map1b, in particular in conditions of amino-acid starvation. 0.262 SIGNOR-181305 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys22 GPRDGLKkERLLDDR 9606 9990853 YES gcesareni We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. 0.541 SIGNOR-64321 9,11-Methanoepoxy PGH2 chemical CID:5311493 PUBCHEM TBXA2R protein P21731 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257589 Ub:E2 complex SIGNOR-C497 SIGNOR RBR E3 ligase proteinfamily SIGNOR-PF107 SIGNOR up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270945 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248751 TNK2 protein Q07912 UNIPROT KDM3A protein Q9Y4C1 UNIPROT down-regulates activity phosphorylation Tyr1114 ITPEDRKyGTTNLHL 9606 BTO:0000093 25148682 YES miannu We report that ACK1 phosphorylates the ER co-activator, KDM3A, a H3K9 demethylase, at an evolutionary conserved tyrosine 1114 site in a heregulin-dependent manner, even in the presence of tamoxifen. 0.37 SIGNOR-276842 PRKCB protein P05771 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 YES llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. 0.2 SIGNOR-97283 PIAS4 protein Q8N2W9 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 SIGNOR-C9 12904571 YES gcesareni Piasy binds most strongly with smad3 and also associates with other receptor-regulated smads and smad4. smad3, smad4, and piasy can form a ternary complex. Piasy does not inhibit smad complex binding to dna, but it represses smad transcriptional activity. 0.647 SIGNOR-104538 RARG protein P13631 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 15650024 YES inferred from family member lperfetto We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs 0.417 SIGNOR-267804 KIF5C protein O60282 UNIPROT TRAK2 protein O60296 UNIPROT up-regulates activity binding 9606 BTO:0000007 24161670 YES miannu Trafficking kinesin proteins (TRAKs) are kinesin adaptors. They bind the cargo binding domain of kinesin-1 motor proteins forming a link between the motor and their cargoes. This supports the idea that the KIF5A–TRAK2 interaction is multivalent and could act to ensure stable motor-cargo interaction during intracellular trafficking; dimerization of both motor and adaptor molecules further enhances this stability (Fig. 6). A similar multivalent profile was found for the TRAK2 binding site within the kinesin-1 isoform, KIF5C. 0.55 SIGNOR-264064 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120032 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 21215781 YES The effect has been demonstrated using P10636-8 lperfetto Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna 0.428 SIGNOR-171038 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 11404076 YES gcesareni Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip. 0.6 SIGNOR-86125 INS protein P01308 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 BTO:0000887 1851182 YES fspada Because of the sequence homology and tertiary structure similarities between proinsulin (pi) and insulin-like growth factor-i (igf-i), it is possible that pi interacts with the igf-i receptor with higher affinity than insulin. 0.89 SIGNOR-22083 WIPF1 protein O43516 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 19121306 NO lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. 0.7 SIGNOR-260609 ATR protein Q13535 UNIPROT WRN protein Q14191 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1141 PEKAYSSsQPVISAQ 9606 BTO:0000567 26695548 YES miannu A serine residue, S1141, in WRN is phosphorylated in vivo by the ATR kinase in response to replication stress. ATR-mediated WRN S1141 phosphorylation leads to ubiquitination of WRN, facilitating the reversible interaction of WRN with perturbed replication forks and subsequent degradation of WRN. 0.794 SIGNOR-277187 CDK5 protein Q00535 UNIPROT PIP5K1C protein O60331 UNIPROT down-regulates phosphorylation Ser650 DERSWVYsPLHYSAQ 9606 15738269 YES lperfetto The interaction of talin with phosphatidylinositol(4) phosphate 5 kinase type i gamma (pipki gamma) regulates pi(4,5)p2 synthesis at synapses and at focal adhesions. Here, we show that phosphorylation of serine 650 (s650) within the talin-binding sequence of human pipki gamma blocks this interaction. At synapses, s650 is phosphorylated by p35/cdk5 and mitogen-activated protein kinase at rest, and dephosphorylated by calcineurin upon stimulation. 0.364 SIGNOR-134455 UQCRH protein P07919 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.911 SIGNOR-262195 PTK6 protein Q13882 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 BTO:0001130 22084245 YES lperfetto Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro 0.598 SIGNOR-177242 SLBP protein Q14493 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265414 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser562 LGTDSDSsPQKSSRD 9606 BTO:0000567 31981797 YES miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. 0.434 SIGNOR-276831 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17108107 YES gcesareni We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392 0.755 SIGNOR-150830 PRKCQ protein Q04759 UNIPROT RASGRP3 protein Q8IV61 UNIPROT up-regulates phosphorylation Thr133 YDWMRRVtQRKKVSK 9606 BTO:0000776 15545601 YES lperfetto Activation of rasgrp3 by phosphorylation of thr-133 is required for b cell receptor-mediated ras activation. our data suggest that pkc, after being activated by diacylglycerol, phosphorylates rasgrp3, thereby contributing to its full activation. 0.329 SIGNOR-130490 CABIN1 protein Q9Y6J0 UNIPROT HIRA complex 2 complex SIGNOR-C462 SIGNOR form complex binding 9606 30285846 YES miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. 0.52 SIGNOR-269438 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser664 KKTSGPLsPPTGPPG 10090 BTO:0000944 15851026 YES lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. 0.693 SIGNOR-249457 COX8A protein P10176 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.524 SIGNOR-267753 AURKA protein O14965 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates activity phosphorylation Ser719 EQASRQIsSKKRPQ 9606 18434591 YES miannu In addition, we found that MCAK localization at spindle poles was regulated through another Aurora A phosphorylation site (S719), which positively enhances bipolar spindle formation. 0.585 SIGNOR-279139 NFKBIA protein P25963 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity binding 9606 SIGNOR-C13 1340770 YES lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b. 0.891 SIGNOR-17691 KDR protein P35968 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 16835467 YES gcesareni (vegfr) phosphorylated y1175 creates a binding site for phospholipase cgamma1 (plc-gamma1) 0.674 SIGNOR-147870 IKBKG protein Q9Y6K9 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity binding 9606 SIGNOR-C14 SIGNOR-C14 20300203 YES lperfetto The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation 0.962 SIGNOR-164512 YAP1 protein P46937 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 23178811 YES gcesareni Yap restricts elevated wnt independently of the axinapcgsk-3beta complex partly by limiting the activity of dishevelled (dvl). 0.334 SIGNOR-199806 BRAF protein P15056 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser467 GQRIGSGsFGTVYKG 9606 31929109 YES miannu We previously identified that BRAFWT can autophosphorylate its P-loop (Ser-465/Ser-467) to inactivate itself in the absence of native substrate MEK 0.2 SIGNOR-277499 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 BTO:0000801 16973330 YES The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. 0.353 SIGNOR-149570 PPP2CB protein P62714 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 YES miannu Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37. 0.435 SIGNOR-248584 PRKAR2B protein P31323 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 YES Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets 0.894 SIGNOR-258758 lapatinib chemical CHEBI:49603 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 YES Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. 0.8 SIGNOR-257899 BMP2 protein P12643 UNIPROT SHH protein Q15465 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19855020 NO gcesareni On the other hand, bmp activity negatively regulates shh transcription and a bmp-shh nega-tive-feedback loop serves to confine shh expression during limb development. 0.516 SIGNOR-188853 MAPK1 protein P28482 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 16778989 YES gcesareni Erk1/2 are the kinases involved in p47phox_ phosphorylation on ser345 in gm-csfprimed human neutrophils._ Phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells 0.45 SIGNOR-147170 ABL1 protein P00519 UNIPROT KAT5 protein Q92993 UNIPROT down-regulates activity phosphorylation Tyr294 HPPGNEIyRKGTISF 9606 BTO:0000007 24044023 YES miannu We present evidence that Tip60 is modified on tyrosine 327 by Abl kinase. We show that this causes functional changes in HAT activity and the subcellular localization of TIP60, which forms a complex with Abl kinase. The Tip60 mutation Y327F abolished tyrosine phosphorylation, reduced the inhibition of Tip60 HAT activity, and caused G0-G1 arrest and association with FE65.  0.646 SIGNOR-276598 GDF5 protein P43026 UNIPROT TRPS1 protein Q9UHF7 UNIPROT up-regulates activity relocalization 10090 BTO:0005092 18363966 YES Regulation of localization miannu Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1. 0.306 SIGNOR-251867 NHEJ1 protein Q9H9Q4 UNIPROT Lig4-Xrcc4 complex complex SIGNOR-C354 SIGNOR up-regulates activity binding 9606 BTO:0000567 25661488 YES miannu Here we report that Akt phosphorylates XLF (XRCC4 like factor, also called NHEJ1) at T181, to dissociate XLF from the XRCC4 (X-ray repair cross-complementing protein 4)/DNA ligase IV (LIG4) complex and subsequently triggers XLF cytoplasmic translocation, leading to XLF ubiquitination by SCFβ-TRCP in a CKI-dependent manner. 0.831 SIGNOR-276883 phosphatidylethanolamine chemical CHEBI:16038 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR form complex binding 9606 25627476 YES lperfetto The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition. 0.8 SIGNOR-266999 HIC1 protein Q14526 UNIPROT LRP8 protein Q14114 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001938;BTO:0000815 24076391 NO miannu The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1. ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. 0.2 SIGNOR-254243 THOC3 protein Q96J01 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 YES miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. 0.923 SIGNOR-268513 BBOX1 protein O75936 UNIPROT 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI down-regulates quantity chemical modification 9606 11802770 YES miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. 0.8 SIGNOR-269697 NCKAP1 protein Q9Y2A7 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 YES miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems 0.914 SIGNOR-253569 HIRA protein P54198 UNIPROT HIRA complex 2 complex SIGNOR-C462 SIGNOR form complex binding 9606 30285846 YES miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. 0.523 SIGNOR-269437 AKT1 protein P31749 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates quantity phosphorylation 9606 20361981 YES miannu Co-expression of Pc2 and Akt1 results in both phosphorylation and ubiquitylation of CtBP1, thereby targeting CtBP1 for degradation.|CtBP1 phosphorylation by Akt1 appears to both decrease dimerization and induce ubiquitylation. 0.484 SIGNOR-278304 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000007 SIGNOR-C13 11158290 YES lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. 0.853 SIGNOR-104803 MAG protein P20916 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 17241126 NO SimoneGraziosi The myelin-associated glycoprotein (MAG) is a type I transmembrane glycoprotein localized in periaxonal Schwann cell and oligodendroglial membranes of myelin sheaths where it functions in glia-axon interactions. 0.7 SIGNOR-269231 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2B protein P63146 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.663 SIGNOR-271368 RING1 protein Q06587 UNIPROT FHL1 protein Q13642 UNIPROT up-regulates binding 9606 14999091 YES gcesareni The polycombprotein ring1 interacts with the lim domains of kyot2 in yeast and mammalian cells. The interaction between kyot2 and ring1 was detected both in vitro and in vivo 0.358 SIGNOR-123150 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI PPARG protein P37231 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-106484 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 10629050 YES amattioni Bid, a bh3-domain-only protein which interacts with bax, was able to trigger a conformational change in bax. 0.824 SIGNOR-73902 MC4R protein P32245 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257182 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide chemical CHEBI:95008 ChEBI MCL1 protein Q07820 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207465 SMURF1 protein Q9HCE7 UNIPROT SRSF5 protein Q13243 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29942010 YES miannu K125 was also the major site of SRSF5 ubiquitylation mediated by Smurf1.|Smurf1 targets SRSF5 for degradation upon low glucose 0.262 SIGNOR-278665 KSR2 protein Q6VAB6 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 YES miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 0.605 SIGNOR-273879 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1004 SEHDSDEsSDDDSDS 9606 10066810 YES gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, 0.442 SIGNOR-65269 MAPK7 protein Q13164 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates quantity phosphorylation Ser910 KLQPQEIsPPPTANL 9606 32144580 YES miannu In conclusion, our data demonstrate that ERK5 is highly expressed in lung cancer, directly regulates FAK expression and its phosphorylation at the Ser 910 site and is required for cell proliferation, F-actin polymerization and epithelial-to-mesenchymal transition, which are associated with cell migration and invasion.|We found that the activation of ERK5 elevated the protein level of FAK, whereas the inactivation of ERK5 decreased the expression of FAK. 0.291 SIGNOR-279305 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2115 DIYKNDYyRKRGEGL 9606 17416557 YES gcesareni In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products. 0.374 SIGNOR-154207 PDE4DIP protein Q5VU43 UNIPROT PRKAR2A protein P13861 UNIPROT up-regulates binding 9606 21569246 YES miannu Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a. 0.455 SIGNOR-173831 AKT1 protein P31749 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 YES gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. 0.398 SIGNOR-252537 GATA1 protein P15976 UNIPROT TAL1 protein P17542 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 7632958 NO irozzo Moreover, GATA-1 but not GATA-2 or GATA-3 was able to transactivate SCL promoter 1a in a T-cell environment. These results suggest that inactivity of SCL promoter 1a in T cells reflected the absence of GATA-1 rather than the presence of trans-dominant negative regulators. 0.784 SIGNOR-256047 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 YES 14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling. 0.653 SIGNOR-252574 MCM10 protein Q7L590 UNIPROT RECQL4 protein O94761 UNIPROT down-regulates binding 9606 19696745 YES miannu Mcm10 inhibits recq4 helicase activity. 0.51 SIGNOR-187701 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT unknown phosphorylation Ser88 RSSIRRLsTRRR 9606 21220422 YES llicata We conclude that phosphorylation of plm increases its oligomerization into tetramers, decreases its binding to nka, and alters the structures of both the tetramer and nka regulatory complex. 0.449 SIGNOR-171188 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 21525957 YES gcesareni Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1. 0.479 SIGNOR-173437 AKT2 protein P31751 UNIPROT STXBP4 protein Q6ZWJ1 UNIPROT down-regulates activity phosphorylation Ser99 GAKLRLEsAWEIAFI 10029 BTO:0000246 15753124 YES miannu Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4. 0.421 SIGNOR-262635 C5AR1 protein P21730 UNIPROT CR1 protein P17927 UNIPROT up-regulates quantity by expression 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.45 SIGNOR-263466 ASAP3 protein Q8TDY4 UNIPROT ARHGEF6 protein Q15052 UNIPROT up-regulates activity binding 9606 BTO:0000599 23776207 YES lperfetto ArfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 4 (ACAP4) is an ADP-ribosylation factor 6 (ARF6) GTPase-activating protein essential for EGF-elicited cell migration. |The crystal structure of the catalytic core of ACAP4 in a complex with ARF6 reveals the structural determinants underlying ACAP4 selectivity and specificity as an ARF6 GTPase-activating protein 0.294 SIGNOR-272235 CHUK protein O15111 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation Ser111 PHLSPSLsPLGGQAA 9606 22196886 YES lperfetto Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression 0.2 SIGNOR-195316 MAF protein O75444 UNIPROT MYB protein P10242 UNIPROT down-regulates binding 9606 9566892 YES miannu Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity. 0.659 SIGNOR-56811 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity 0.651 SIGNOR-252891 GSK3B protein P49841 UNIPROT NEB protein P20929 UNIPROT down-regulates phosphorylation 9606 21798082 YES gcesareni Gsk3b is able to phosphorylate nebulin at two ser sites in the c-terminal region of nebulin localized to the z-disk, thus preventing the interaction of nebulin with neuronal wiscott-aldrich syndrome protein (nwasp), a ubiquitously expressed member of the wasp family, which is involved in actin assembly. 0.306 SIGNOR-175659 CSNK1A1 protein P48729 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 YES llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. 0.286 SIGNOR-250786 Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 NO miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.7 SIGNOR-270894 POU5F1 protein Q01860 UNIPROT DPPA4 protein Q7L190 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.628 SIGNOR-254941 LAMP2 protein P13473 UNIPROT Chaperone-mediated autophagy phenotype SIGNOR-PH118 SIGNOR up-regulates activity 10029 BTO:0000977 8662539 NO Here, the lysosomal membrane glycoprotein LGP96 was identified as a receptor for the selective import and degradation of proteins within lysosomes. Specific substrates of this proteolytic pathway bound to the cytosolic tail of a 96-kilodalton lysosomal membrane protein in two different binding assays. 0.7 SIGNOR-259990 IFNG protein P01579 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates binding 9606 10986460 YES fspada Molecular interactions among cytokines and cytokine receptors form the basis of many cell-signaling pathways relevant to immune function. Interferon-g (ifng) signals through a multimeric receptor complex consistingof two different but structurally related transmembrane chains: the high-affinityreceptor-binding subunit (ifn-gra) and a species-specific accessory factor (af-1 or ifn-grb). 0.886 SIGNOR-81804 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser215 DRNTFRHsVVVPYEP 9606 22611192 YES gcesareni We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma). 0.718 SIGNOR-197602 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 9534 BTO:0004055 12535517 YES milica One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. 0.2 SIGNOR-97481 PRKACA protein P17612 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17959673 YES lperfetto In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab. 0.511 SIGNOR-217391 U0126 chemical CHEBI:90693 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates 9606 11782488 NO gcesareni Bmk1activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2. 0.8 SIGNOR-113782 INS protein P01308 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 10090 12530968 NO lperfetto The forkhead transcription factor foxo1 is regulated by insulin via akt-dependent phosphorylation and nuclear exclusion. 0.752 SIGNOR-252627 PRKAA1 protein Q13131 UNIPROT CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser158 REGTRVQsVEQIREV 9606 SIGNOR-C15 23291169 YES lperfetto We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1 0.2 SIGNOR-200250 CDK5 protein Q00535 UNIPROT PPP1R2 protein P41236 UNIPROT unknown phosphorylation Thr73 MKIDEPStPYHSMMG -1 11320080 YES llicata Neuronal Cdc2-like protein kinase (Cdk5/p25) is associated with protein phosphatase 1 and phosphorylates inhibitor-2. | NCLK Phosphorylates Thr72 of I-2 0.357 SIGNOR-250672 phosphatidylcholine chemical CHEBI:64482 ChEBI Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR form complex binding 9606 25627476 YES lperfetto The lipid composition of the IMM varies from that of the OMM. PC and PE are still the most abundant phospholipids in the IMM, comprising about 75 % of total lipids.|One of the biggest differences between OMM and IMM lipid composition is the greater concentration of CL that is found in the IMM. Here, CL makes up about 15–20 % of the total phospholipid mass 0.8 SIGNOR-267003 RNF4 protein P78317 UNIPROT NFYB protein P25208 UNIPROT up-regulates activity binding 9606 15496512 YES miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. 0.2 SIGNOR-252230 FANCG protein O15287 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.924 SIGNOR-263243 GSK3B protein P49841 UNIPROT AR protein P10275 UNIPROT down-regulates activity phosphorylation 9606 14985354 YES miannu Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity.|In particular, we showed that glycogen synthase kinase-3 beta phosphorylates the androgen receptor, thereby inhibiting androgen receptor-driven transcription. 0.648 SIGNOR-279334 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258452 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.383 SIGNOR-189141 HSBP1 protein O75506 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates activity binding 9606 BTO:0000567 9649501 YES Monia HSBP1 is nuclear-localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock. During attenuation of HSF1 to the inert monomer, HSBP1 associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activity, and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. HSF1 interacts with HSBP1 in vivo and is a nuclear localized protein. 0.698 SIGNOR-261181 TNF protein P01375 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004914 14586405 NO We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. 0.475 SIGNOR-253606 WDR62 protein O43379 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 YES lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. 0.244 SIGNOR-271726 risperidone chemical CHEBI:8871 ChEBI HTR1F protein P30939 UNIPROT down-regulates activity chemical inhibition 9534 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258524 MDM2 protein Q00987 UNIPROT CDKN2AIP protein Q9NXV6 UNIPROT down-regulates ubiquitination 9606 18292944 YES amattioni Carf interacts with hdm2 and is ubiquitinated and negatively regulated by hdm2 by proteasome-dependent degradation. 0.371 SIGNOR-160974 CAMK2G protein Q13555 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887 11114197 YES gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation. 0.427 SIGNOR-85102 VHL protein P40337 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR form complex binding 9606 11574546 YES miannu The von Hippel-Lindau tumor-suppressor protein (pVHL) forms a protein complex (VCB-Cul2) with elongin C, elongin B, Cul-2, and Rbx1, which functions as a ubiquitin-protein ligase (E3). The alpha-subunits of the hypoxia-inducible factors have been identified as targets for the VCB-Cul2 ubiquitin ligase.  0.824 SIGNOR-272585 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.2 SIGNOR-275961 FBXO45 protein P0C2W1 UNIPROT ZEB1 protein P37275 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.285 SIGNOR-272179 RIMS1 protein Q86UR5 UNIPROT UNC13B protein O14795 UNIPROT up-regulates activity relocalization 9606 31679900 YES miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle 0.797 SIGNOR-264385 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR SEC31B protein Q9NQW1 UNIPROT up-regulates activity monoubiquitination lys1176 9606 BTO:0000567 22358839 YES miannu By analyzing mouse embryonic stem cell (mESC) division, we have identified Cul3Klhl12 as a regulator of COPII coat formation. Cul3Klhl12 monoubiquitinates Sec31 and drives assembly of large COPII-coats. As a result, ubiquitination by Cul3Klhl12 is essential for collagen export, a step that is required for integrin-dependent mESC division. 0.298 SIGNOR-272016 UTP(4-) smallmolecule CHEBI:46398 ChEBI UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity precursor of 9606 8631325 YES miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. 0.8 SIGNOR-267925 PRKCA protein P17252 UNIPROT SDC4 protein P31431 UNIPROT up-regulates activity phosphorylation Ser179 MKKKDEGsYDLGKKP 10116 BTO:0001176 11916978 YES lperfetto The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant. 0.731 SIGNOR-249149 calcium(2+) smallmolecule CHEBI:29108 ChEBI S100A8 protein P05109 UNIPROT up-regulates activity chemical activation 9606 BTO:0001044 16690079 YES miannu S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization. 0.8 SIGNOR-261935 TGFB1 protein P01137 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18586026 NO gcesareni These data show that tgf-beta-induced nf-kappab activation is through tak1/mek-mediated aktactivation, which is essential for tgf-beta to support of osteoclast survival 0.387 SIGNOR-179179 PTK6 protein Q13882 UNIPROT ARHGAP5 protein Q13017 UNIPROT up-regulates phosphorylation Tyr1109 KGYSDEIyVVPDDSQ 9606 BTO:0000150 18829532 YES lperfetto Breast tumor kinase phosphorylates p190rhogap to regulate rho and ras and promote breast carcinoma growth, migration, and invasion. Brk phosphorylates p190 at the y(1105) residue both in vitro and in vivo, thereby promoting the association of p190 with p120rasgap (p120). As a consequence, brk stimulates p190 and attenuates p120 functions, leading to rhoa inactivation and ras activation, respectively. 0.2 SIGNOR-181452 AKT2 protein P31751 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 YES gcesareni Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta 0.528 SIGNOR-187010 MAPK8 protein P45983 UNIPROT NEIL1 protein Q96FI4 UNIPROT up-regulates activity phosphorylation Ser207 ALQQHRPsPELTLSQ 9606 27518429 YES miannu The JNK1 protein kinase phosphorylates NEIL1 at S207, S306, and S61. 0.2 SIGNOR-278316 TP53 protein P04637 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 14586398 YES miannu We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. We show that ets-1 and p53 associate physically in vitro and in vivo and that their interaction, rather than a direct binding of p53 to the TXSA promoter, is required for transcriptional repression of TXSA by wild-type p53. 0.531 SIGNOR-254087 WWC1 protein Q8IX03 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 BTO:0000007 21233212 YES miannu Here, we show that KIBRA associates with and activates Lats (large tumor suppressor) 1 and 2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates the phosphorylation of Yes-associated protein (YAP), the Hippo pathway effector. 0.789 SIGNOR-263659 KMT2E protein Q8IZD2-8 UNIPROT NCR2 protein O95944 UNIPROT up-regulates activity binding 9606 BTO:0000737 23958951 YES miannu We identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. 0.506 SIGNOR-260042 FYN protein P06241 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Tyr1130 QGRTALFyARQAGSQ 9606 16841086 YES llicata We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival. 0.466 SIGNOR-147936 ALDH5A1 protein P51649 UNIPROT 4-oxobutanoate smallmolecule CHEBI:57706 ChEBI down-regulates quantity chemical modification 9606 19300440 YES miannu Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. 0.8 SIGNOR-266616 TJP2 protein Q9UDY2 UNIPROT ARVCF protein O00192 UNIPROT down-regulates activity relocalization 9615 15456900 YES Regulation of binding miannu We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. ZO-2, in contrast, relocated to the nucleus with ARVCF, and, given the interaction between the ZO-2 PDZ domains and ARVCF, raised the possibility that ZO-2 may play a role in nuclear localization of ARVCF. Such a role for ZO-2 is indeed supported by the ability of the ZO-2 PDZ domain to efficiently relocate ARVCF from the plasma membrane to the nucleus in a process that required the ability of the two proteins to interact and the presence of a functional NLS in the ZO-2 PDZ domains. Thus, ZO-2 could be involved in nuclear translocation and/or retention of ARVCF and play a role in regulating postulated functions of ARVCF in gene expression 0.369 SIGNOR-252122 UBE2G2 protein P60604 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys244 KIAYLGGkGPFSYNL 9606 BTO:0001379 29892818 YES scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. 0.2 SIGNOR-267484 CASP8 protein Q14790 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity -1 10988287 NO lperfetto One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway. 0.576 SIGNOR-81811 CDK16 protein Q00536 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 29344296 YES miannu In this study, we demonstrated that CDK16 phosphorylates p53 at Ser315 and promotes ubiquitination and subsequent degradation of p53.|Together, these results suggest that CDK16 negatively regulates p53 stability at the post-translational level. 0.387 SIGNOR-278354 GSK3B protein P49841 UNIPROT PDX1 protein P52945 UNIPROT down-regulates quantity phosphorylation Ser268 LPPGLSAsPQPSSVA 10090 BTO:0002284 19833727 YES We show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose 0.2 SIGNOR-255566 DNA polymerase gamma complex SIGNOR-C378 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates -1 19837034 NO lperfetto DNA Pol gamma, in contrast to the many nuclear DNA polymerases (DNAPs) that have specialized functions, is solely responsible for DNA replication and repair in mitochondria.  0.7 SIGNOR-265720 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 YES milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity 0.85 SIGNOR-201286 RTKN protein Q9BST9 UNIPROT SEPTIN9 protein Q9UHD8 UNIPROT down-regulates 9606 16007136 NO miannu We identified rhotekin, a downstream effector for rho, as a candidate regulator organizing septin structures through filament disruption. 0.2 SIGNOR-138578 EGFR protein P00533 UNIPROT PIK3C2B protein O00750 UNIPROT up-regulates phosphorylation 9606 BTO:0000017 10805725 YES gcesareni The n-terminal region of pi3k-c2beta was found to selectively interact with the egf receptor in vitro, suggesting that it mediates the association of this pi3k with the receptor. 0.441 SIGNOR-77195 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248372 MLL2 complex complex SIGNOR-C88 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 YES miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. 0.2 SIGNOR-268799 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser395 LKLSPSPsSRVTVSR -1 8034666 YES lperfetto Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo. 0.498 SIGNOR-248911 RBX1 protein P62877 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR form complex binding 9606 BTO:0000007 16547521 YES miannu  KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation. 0.93 SIGNOR-271561 AKT proteinfamily SIGNOR-PF24 SIGNOR YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 12535517 YES gcesareni One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. 0.2 SIGNOR-97485 SP1 protein P08047 UNIPROT TBXA2R protein P21731 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000565 19747485 NO Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein. 0.2 SIGNOR-254254 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity relocalization 9534 9637919 YES lperfetto In response to PDGF, binding of ptdlns (3,4,5)p3 and/or ptdlns(3,4)p2 to the PH domain of PDK-1 causes its translocation to the plasma membrane where it co-localises with PKB, significantly contributing to the scale of PKB activation. 0.8 SIGNOR-58313 HDAC1 protein Q13547 UNIPROT CLDN7 protein O95471 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 19277896 YES lperfetto ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1.|These data further suggest that HDAC1 is involved in the SNAI1P-mediated repression of the human CLDN7 gene promoter. 0.2 SIGNOR-254106 ETS1 protein P14921 UNIPROT TNC protein P24821 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15001984 YES Luana Sp1 and Ets1 are potent transactivators of the TN-C promoter. 0.2 SIGNOR-261599 TEAD1 protein P28347 UNIPROT MSLN protein Q13421 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17909009 NO miannu The presence of TEF-1 was required for MSLN protein overexpression as determined by TEF-1 knockdown experiments. 0.282 SIGNOR-255395 BMP7 protein P18075 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18719589 NO lperfetto Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways 0.321 SIGNOR-180311 EDNRB protein P24530 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.292 SIGNOR-256781 PRKACA protein P17612 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser685 VPLVQRGsANGL -1 11278469 YES miannu PKA directly phosphorylates GRK2 on serine 685. This modification increases G subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor. 0.2 SIGNOR-250334 TTC5 protein Q8N0Z6 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding 9606 BTO:0001938 15448695 YES miannu DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY 0.562 SIGNOR-262646 ATR protein Q13535 UNIPROT MCM6 protein Q14566 UNIPROT up-regulates phosphorylation 9606 21070963 YES gcesareni Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6. 0.561 SIGNOR-169450 SRC protein P12931 UNIPROT KCNB1 protein Q14721 UNIPROT up-regulates phosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000938 19622611 YES flangone In the present study we show that an n-terminal tyrosine of kv2.1 (y124), which is a known target of src kinase, is critical for the apoptotic current surge..Kv2.1-mediated k+ currents are also enhanced during non-injurious conditions through direct phosphorylation of intracellular n-terminal residue tyrosine 124 (y124) by src kinase 0.48 SIGNOR-187201 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT down-regulates phosphorylation Ser511 ENIIFGVsYDEYRYR 9606 21930781 YES lperfetto Serine 511 has been previously implicated in the regulation of cftr by ck2, as the mutant s511d was found to be insensitive to tbb in xenopus oocytes but to have no major impact on the single-channel behavior of cftr 0.278 SIGNOR-176623 C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR form complex binding 9606 BTO:0000089 26489954 YES lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). 0.2 SIGNOR-263479 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 YES miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. 0.2 SIGNOR-256188 Ub:E2 complex SIGNOR-C497 SIGNOR BIRC7 protein Q96CA5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271113 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203552 ESR1 protein P03372 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates quantity by expression transcriptional regulation 14764652 NO lperfetto Estrogen-induced transcriptional activities of both ERalpha and ERbeta and mRNA expression of estrogen-responsive genes, including pS2, c-myc, and cyclin D1, were suppressed by PP5 but enhanced by PP5 antisense oligonucleotide. 0.28 SIGNOR-271691 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser638 PQCSPQHsPLGAVKS 9606 BTO:0000007 16141410 YES In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity 0.398 SIGNOR-251250 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR FTH1 protein P02794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003212 19258503 NO miannu We show that inhibition of constitutively active NF-kappaB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS. 0.337 SIGNOR-254792 ASH2L protein Q9UBL3 UNIPROT Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR form complex binding 9606 BTO:0000567 12670868 YES miannu Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles. 0.911 SIGNOR-264479 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257930 PDPK1 protein O15530 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 YES miannu PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3. 0.472 SIGNOR-250266 LPAR3 protein Q9UBY5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.482 SIGNOR-257297 PTPRG protein P23470 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity dephosphorylation Tyr223 LKKVVALyDYMPMNA -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.263 SIGNOR-254694 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Tyr486 YPAEDSTyDEYENDL 9606 12601080 YES lperfetto Cortactin was first identified as a substrate of v-src (46) that mediates in vitro phosphorylation of residues tyr-421, tyr-466, and tyr-482 at the c terminus of the murine ortholog (47). Phosphorylation of these residues attenuates the f-actin cross-linking activity 0.801 SIGNOR-98720 DNMT3B protein Q9UBC3 UNIPROT BAG4 protein O95429 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 NO lperfetto In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+) 0.2 SIGNOR-254113 CDK2 protein P24941 UNIPROT SKP2 protein Q13309 UNIPROT up-regulates quantity by stabilization phosphorylation Ser64 SNLGHPEsPPRKRLK 18239684 YES lperfetto The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1). 0.799 SIGNOR-249173 MYO9B protein Q13459 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.561 SIGNOR-260511 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity dephosphorylation 9606 16751101 YES lperfetto Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. 0.621 SIGNOR-232110 FERMT3 protein Q86UX7 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 10090 BTO:0000132;BTO:0003292 18278053 YES lperfetto Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner 0.386 SIGNOR-266065 PLK1 protein P53350 UNIPROT PARP10 protein Q53GL7 UNIPROT up-regulates activity phosphorylation Thr601 EVRELLAtLEGLDLD 10090 BTO:0000578 32060423 YES miannu PLK1, an important regulator for cell mitosis, directly interacts with and phosphorylates PARP10 at T601. PARP10 phosphorylation at T601 significantly decreases its binding to NEMO and disrupts its inhibition to NEMO ubiquitination, thereby enhancing the transcription activity of NF-κB toward multiple target genes and promoting HCC development.  0.2 SIGNOR-273728 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr788 SLEKHSWyHGPVSRN 9606 16912036 YES Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 0.2 SIGNOR-260813 TP53INP2 protein Q8IXH6 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 19056683 YES gcesareni Tp53inp2 binds to lc3 as well as to lc3-related proteins gabarap and gabarap-like2. 0.601 SIGNOR-182611 AMOTL2 protein Q9Y2J4 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0001176 21937427 NO lperfetto Taking together, our data indicate that Amotl2 plays a pivotal role in polarity, migration and proliferation of angiogenic endothelial cells. 0.7 SIGNOR-271871 NFIA protein Q12857 UNIPROT SLIT1 protein O75093 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.257 SIGNOR-268892 arecoline chemical CHEBI:2814 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258638 calcidiol smallmolecule CHEBI:17933 ChEBI calcitriol smallmolecule CHEBI:17823 ChEBI up-regulates quantity precursor of 9606 BTO:0000671 12050193 YES lperfetto The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. 0.8 SIGNOR-270558 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES -1 17711846 YES done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). 0.41 SIGNOR-274093 PI3K complex SIGNOR-C156 SIGNOR PIK3CB protein P42338 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 YES lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.637 SIGNOR-252719 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1787 SPNYSPTsPSYSPTS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248815 belinostat chemical CHEBI:61076 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257741 PIM1 protein P11309 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001321 34697370 YES miannu PIM1 phosphorylates the AR and 14-3-3 ζ and coordinates their interaction. PIM1 phosphorylation of the AR and 14-3-3 ζ enhances their interaction and shifts their occupancy on chromatin, resulting in 14-3-3 ζ co-regulation of AR, likely by recruiting other AR co-regulators such as hnRNPK and TRIM28. 0.381 SIGNOR-277575 carvedilol chemical CHEBI:3441 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258165 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 22012619 YES miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna 0.783 SIGNOR-176797 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 10068651 YES lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. 0.952 SIGNOR-236262 KDM5A protein P29375 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264300 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269366 CoREST-HDAC complex complex SIGNOR-C105 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 32101746 NO miannu The CoREST complex is one of seven families of class I histone deacetylase complexes that have specialized physiological functions but are all thought to act as repressors of gene expression. CoREST is unique within these complexes in that it removes both acetyl and methyl modifications through the activity of its demethylase (LSD1) and deacetylase (HDAC1) enzymes. 0.7 SIGNOR-263861 MEF2C protein Q06413 UNIPROT MYH10 protein P35580 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.345 SIGNOR-238769 BRD4 protein O60885 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 32482868 YES lperfetto We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes. 0.563 SIGNOR-262046 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser187 LNSAAYSsPKLRGTL 9606 BTO:0000150 25726523 YES lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. 0.2 SIGNOR-275656 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259704 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19114991 YES lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity 0.757 SIGNOR-182979 TRHR protein P34981 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 9988720 YES Ga16 is phosphorylated in vivo by PMA and by TRH receptor stimulation 0.485 SIGNOR-278132 SHANK3 protein Q9BYB0 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates quantity binding 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264601 Glycine cleavage system complex SIGNOR-C437 SIGNOR glycine smallmolecule CHEBI:15428 ChEBI down-regulates quantity chemical modification 9606 16051266 YES lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. 0.8 SIGNOR-268238 CASK protein O14936 UNIPROT Exocytosis phenotype SIGNOR-PH157 SIGNOR up-regulates 9606 BTO:0000938 11036064 NO miannu As neurexins have been proposed to function in neuronal cell adhesion, it is possible that they define specific sites at the plasma membrane and that Mint complexes and Mint1-CASK complexes on neurexin are involved in the localized recruitment of Munc18 to the sites of exocytosis. In support of this hypothesis, both CASK and Mint1 have been reported to be localized at synapses 0.7 SIGNOR-264044 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu73 EEKCSFEeAREVFEN 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263693 Chaperone-mediated autophagy phenotype SIGNOR-PH118 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR down-regulates quantity by destabilization 9606 BTO:0004424 26323688 YES inferred from family member Our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability. 0.7 SIGNOR-270269 AR protein P10275 UNIPROT CRH protein P06850 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000931 16446741 YES lperfetto A direct androgenic involvement in the expression of human corticotropin-releasing hormone|A potential androgen-responsive element (ARE) in the human CRH promoter was subsequently analyzed with bandshifts and cotransfections in neuroblastoma cells. In the presence of testosterone, recombinant human AR bound specifically to the CRH-ARE. 0.305 SIGNOR-268723 IFNB1 protein P01574 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 10918594 NO gcesareni Early events in type i ifn signaling are tyrosine phosphorylation of the type i ifn receptor subunits (ifnar1 and ifnar2), and the activation of the receptor-associated tyk-2 and jak-1 janus kinases 0.539 SIGNOR-80100 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM54 protein Q9BYV2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270967 LCK protein P06239 UNIPROT CD3 complex SIGNOR-C432 SIGNOR up-regulates activity phosphorylation 9606 8626561 YES The binding of Lck to the tyrosine-phosphorylated zeta chain of the TcR would serve to strengthen the interaction of the associated CD4 and the TcR complex, leading to increased avidity for the antigen-major histocompatibility protein complex 0.645 SIGNOR-252305 PRKCZ protein Q05513 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 18250273 YES llicata We conclude that pkc-zeta phosphorylates lkb1 at ser428, resulting in lkb1 nuclear export and hence ampk activation. 0.321 SIGNOR-160681 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr690 PLNSDVQyTEVQVSS 9606 BTO:0000007 12972546 YES miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. 0.322 SIGNOR-262865 PSAT1 protein Q9Y617 UNIPROT 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI up-regulates activity chemical modification 3702 30034403 YES lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. 0.8 SIGNOR-268562 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation 12792650 YES inferred from 70% family members lperfetto Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2 0.2 SIGNOR-270222 TWIST1 protein Q15672 UNIPROT NF1 protein P21359 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.277 SIGNOR-255530 MAPK14 protein Q16539 UNIPROT CDKN1C protein P49918 UNIPROT up-regulates phosphorylation 9606 22820251 YES gcesareni G1-s control by p38/hog1 sapks upon osmostress. Upon osmostress, activated p38 and hog1 sapks phosphorylate the s/cdk inhibitor p57 or sic1 respectively at one single residue. In mammalian cells (left panel), p57 phosphorylation on thr143 leads to an increase of the affinity of p57 towards the cyclin a/cdk2 complex leading to a g1 arrest. 0.262 SIGNOR-198390 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 15809305 YES lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.755 SIGNOR-217067 RRN3 protein Q9NYV6 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 11250903 YES lperfetto HRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters|We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription. 0.781 SIGNOR-269648 ATP5MC1 protein P05496 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261399 TOP2B protein Q02880 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 NO lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development 0.2 SIGNOR-242311 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). 0.8 SIGNOR-267316 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity deubiquitination 9606 31226023 YES miannu Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-β and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3 0.2 SIGNOR-260246 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 10715136 YES Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif. gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). 0.743 SIGNOR-75792 POU1F1 protein P28069 UNIPROT GH1 protein P01241 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15998782 NO miannu Such findings are consistent with the existence, in humans, of an LHX4-driven pathway leading to the expression of GH through transcriptional activation of POU1F1. 0.358 SIGNOR-254559 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000782 18550856 YES gcesareni In this study, we present evidence that pkc isoforms are the major protein kinases that phosphorylate the c terminus of the integrin cd18 chain in leukocytes. Ser-745 is identified as a novel phosphorylation site in the integrin cytoplasmic domain. Additionally, we show that a thr-758-phosphorylated integrin peptide can interact with 14-3-3 proteins in leukocyte lysates 0.33 SIGNOR-178897 TLN1 protein Q9Y490 UNIPROT ITGB8 protein P26012 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.469 SIGNOR-257636 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 YES gcesareni Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death 0.541 SIGNOR-180780 AMPK complex SIGNOR-C15 SIGNOR SLC12A2 protein P55011 UNIPROT down-regulates activity phosphorylation Ser77 RPLGPTPsQSRFQVD -1 24702155 YES miannu  AMPK was found to directly phosphorylate a recombinant human-NKCC1 N-terminal fragment (1-293) with the phosphorylated site identified as S77. Mutation of Serine 77 to Alanine partially prevented the inhibitory effect of A-769662 on NKCC1 activity. In conclusion, AMPK can act to reduce NKCC1-mediated transport.  0.2 SIGNOR-276630 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR WWC1 protein Q8IX03 UNIPROT unknown phosphorylation 9606 BTO:0000149 24269383 YES inferred from 70% family members llicata We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro. 0.2 SIGNOR-270208 FHOD1 protein Q9Y613 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity by stabilization binding 9606 14576350 YES miannu Fhos, a mammalian formin, directly binds to F-actin via a region N-terminal to the FH1 domain and forms a homotypic complex via the FH2 domain to promote actin fiber formation 0.345 SIGNOR-276613 RARB protein P10826 UNIPROT RXRB protein P28702 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. 0.665 SIGNOR-16581 GSK3B protein P49841 UNIPROT APP protein P05067 UNIPROT unknown phosphorylation Thr743 VEVDAAVtPEERHLS -1 8764598 YES The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770). 0.543 SIGNOR-251220 ADORA2A protein P29274 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257306 AKT1 protein P31749 UNIPROT LONP1 protein P36776 UNIPROT up-regulates activity phosphorylation Ser173 VFLKRDDsNESDVVE 9606 BTO:0001061 31406245 YES lperfetto In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity. 0.253 SIGNOR-265724 CSNK2A2 protein P19784 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Ser102 NLNENQAsEEEDELG -1 2557337 YES llicata Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase 0.376 SIGNOR-251018 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr594 RLYDYEItDQYIYMV -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276221 MAP3K7 protein O43318 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity phosphorylation Ser456 HTQSSSSsSDGGLFR 9606 BTO:0000007 22216226 YES miannu We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.  0.929 SIGNOR-276365 STK26 protein Q9P289 UNIPROT ATG4B protein Q9Y4P1 UNIPROT up-regulates activity phosphorylation Ser383 RLERFFDsEDEDFEI 29232556 YES lperfetto ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. 0.2 SIGNOR-275833 MAP4K1 protein Q92918 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Ser376 SSFPQSAsLPPYFSQ 9606 BTO:0000782 17353368 YES lperfetto The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins 0.777 SIGNOR-153613 PPP3CC protein P48454 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 YES Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 0.397 SIGNOR-248528 MIB1 protein Q86YT6 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 12351649 YES miannu Transient expression of DIP-1 in HeLa cells antagonizes the anti-apoptotic function of DAPK to promote a caspase-dependent apoptosis. These studies also demonstrate that DAPK is an in vitro and in vivo target for ubiquitination by DIP-1, thereby providing a mechanism by which DAPK activities can be regulated through proteasomal degradation. 0.438 SIGNOR-272602 ILK protein Q13418 UNIPROT MYL12B protein O14950 UNIPROT up-regulates activity phosphorylation Ser20 KRPQRATsNVFAMFD 9606 11278951 YES lperfetto Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19). 0.314 SIGNOR-106423 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR UNG protein P13051 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20870715 YES miannu Using reconstituted CRL4(DCAF1) and CRL4(DCAF1-Vpr) E3 ubiquitin ligases in vitro reveals that UNG2 ubiquitination (ubiquitylation) is facilitated by Vpr. Co-expression of DCAF1 and Vpr causes down-regulation of UNG2 in a proteasome-dependent manner, with Vpr mutants that are defective in UNG2 or DCAF1 binding abrogating this effect. 0.375 SIGNOR-271905 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 9606 12510059 YES gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.771 SIGNOR-96940 CLASP2 protein O75122 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity binding 9534 BTO:0004055 19638411 YES lperfetto CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells|the C-terminal region of CLASP2 is known to interact with CLIP-170 0.771 SIGNOR-264827 R547 chemical CID:6918852 PUBCHEM CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206349 CHEK2 protein O96017 UNIPROT MDM4 protein O15151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 YES lperfetto The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes. 0.722 SIGNOR-178071 ACSL5 protein Q9ULC5 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI up-regulates quantity chemical modification 9606 24269233 YES ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity 0.8 SIGNOR-267712 TNFRSF14 protein Q92956 UNIPROT TRAF5 protein O00463 UNIPROT up-regulates activity binding 9606 9153189 YES lperfetto ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5|synergistic activation of NF-κB by ATAR and TRAF5 293 cells 0.625 SIGNOR-262592 RPS6KA3 protein P51812 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 7523419 YES lperfetto Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site. 0.3 SIGNOR-248895 CPS1 protein P31327 UNIPROT carbamoyl phosphate(2-) smallmolecule CHEBI:58228 ChEBI up-regulates quantity chemical modification 9606 15096496 YES CPSase catalyzes the synthesis of carbamoyl phosphate from glutamine, bicarbonate, and two ATP molecules 0.8 SIGNOR-267192 ZNF804A protein Q7Z570 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity binding 9606 BTO:0005397 34364876 YES miannu Together these results indicate the formation of ZNF804A:STAT2 protein complex and its translocation from the cytoplasm into the nucleus upon IFN stimulation, suggesting that it may function as a signal transducer that activates IFN-mediated gene expression programs. 0.2 SIGNOR-269460 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates phosphorylation Ser372 VAATPPPsTASAPAA 9606 BTO:0000938 BTO:0000142 16627622 YES lperfetto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. 0.2 SIGNOR-244669 MASP2 protein O00187 UNIPROT C2 protein P06681 UNIPROT up-regulates activity cleavage Ser20 LYPGLADsAPSCPQN 9606 BTO:0000392 11907111 YES lperfetto The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase 0.434 SIGNOR-263419 NR0B2 protein Q15466 UNIPROT NR1I2 protein O75469 UNIPROT down-regulates binding 9606 12805410 YES gcesareni Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments. 0.561 SIGNOR-101924 MYC protein P01106 UNIPROT MYCBP2 protein O75592 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 YES miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. 0.416 SIGNOR-267145 DYRK1B protein Q9Y463 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser279 KVAERRSsPLLRRKD 10090 15546868 YES lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent mannermirk phosphorylates hdac5 at ser-279 0.373 SIGNOR-235809 MAPK14 protein Q16539 UNIPROT FOXC1 protein Q12948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 SSLSSGSsPPGSLPS 31650548 YES lperfetto P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. 0.2 SIGNOR-275911 C3 protein P01024 UNIPROT C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR form complex binding 9606 BTO:0000089 cleavage:Arg748 ASHLGLArSNLDEDI 26489954 YES complement C3b fragment: PRO_0000005911 lperfetto Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over) 0.906 SIGNOR-263485 5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol chemical CID:104895 PUBCHEM CNR2 protein P34972 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257474 HNF1A protein P20823 UNIPROT CDH17 protein Q12864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972;BTO:0004168 20568120 YES The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC|we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L) 0.313 SIGNOR-253970 MK-2461 chemical CID:44137946 PUBCHEM MERTK protein Q12866 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194381 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPB protein P17676 UNIPROT down-regulates activity transcriptional regulation 9606 17139329 YES fferrentino Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter 0.578 SIGNOR-253538 GRK3 protein P35626 UNIPROT TBXA2R protein P21731-2 UNIPROT down-regulates activity phosphorylation Ser357 RLPGSSDsRASASRA 9606 16956790 YES done miannu  These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization. 0.2 SIGNOR-274091 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 15568999 YES gcesareni In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. 0.584 SIGNOR-131383 MYCN protein P04198 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18566016 NO miannu In primary neuroblastomas, high CTSD messenger RNA (mRNA) levels were associated with amplified MYCN, a strong predictive marker of adverse outcome. Chromatin immunoprecipitation and luciferase promoter assays revealed that MYCN protein binds to the CTSD promoter and activates its transcription, suggesting a direct link between deregulated MYCN and CTSD mRNA expression. 0.2 SIGNOR-254618 SMDT1 protein Q9H4I9 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.631 SIGNOR-270875 AKT2 protein P31751 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates activity binding 9606 BTO:0000222 16982699 YES gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation. 0.681 SIGNOR-149705 PTPRJ protein Q12913 UNIPROT FLT1 protein P17948 UNIPROT down-regulates dephosphorylation 9606 12771128 YES gcesareni Vegf acts by binding to two high affinity receptor tyrosine kinases: vegf receptor (vegfr)* 1 also called flt-1, and vegfr-2, also called flk-1/kdr a dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. 0.362 SIGNOR-101272 CNR1 protein P21554 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.54 SIGNOR-256867 CTBP1 protein Q13363 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21681822 YES irozzo Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. 0.599 SIGNOR-259197 CHD4 protein Q14839 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR form complex binding 10090 BTO:0002896 29795351 YES miannu Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP. 0.422 SIGNOR-266752 EIF5A protein P63241 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 15371445 YES miannu eIF5A regulated p53 protein expression. Further analysis by reverse transcription PCR showed eIF5A-activated p53 transcription. The effect of eIF5A on p53 transcriptional activity was further demonstrated by the increasing expressions of p21 and Bax, well known target genes of p53. 0.364 SIGNOR-266375 GATA1 protein P15976 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12432220 NO irozzo Closer examination revealed a cross-regulatory mechanism by which GATA-1 can control the expression of GATA-2 and vice versa, possibly via essential GATA binding sites in their cis-acting elements.In this model, GATA-2 activates GATA-1 gene expression, while GATA-1 represses GATA-2 gene expression. 0.441 SIGNOR-256058 ATM protein Q13315 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser27 QEENLEAsGDYKYSG 9606 BTO:0001546 26337656 YES done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. 0.712 SIGNOR-274020 PTPN11 protein Q06124 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation Tyr577 YMEDSTYyKASKGKL 9606 16920701 YES gcesareni Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner. 0.73 SIGNOR-148926 DYRK1A protein Q13627 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates phosphorylation Ser167 FLISPPAsPPVGWKQ 9606 BTO:0000782 16126726 YES gcesareni We show that rcan1 self-associates and forms multimers, and that this process is promoted by the dyrk1a-mediated phosphorylation of rcan1 at the thr(192) residue. these results suggest that the phosphorylation of rcan1 by dyrk1a stimulates the formation of insoluble aggregates upon aging. 0.563 SIGNOR-139958 PLK1 protein P53350 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation 9606 26280018 YES miannu Furthermore, PLK1 can directly phosphorylate FOXO3 in an in vitro kinase assay.|PLK1 induces translocation of FOXO3 from the nucleus to the cytoplasm and suppresses FOXO3 activity, measured by the decrease in the pro-apoptotic Bim protein levels and in the cell cycle inhibitor protein p27. 0.492 SIGNOR-279095 CDK7 protein P50613 UNIPROT CDK1 protein P06493 UNIPROT up-regulates phosphorylation Thr161 GIPIRVYtHEVVTLW 9606 8344251 YES lperfetto The mo15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (cdks) through phosphorylation of thr161 and its homologues 0.58 SIGNOR-38307 1-phospho-alpha-D-glucuronic acid smallmolecule CHEBI:681 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 YES miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1). 0.8 SIGNOR-258435 sertindole chemical CHEBI:9122 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258546 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0001950 21561061 YES Luana Activation of JNK pathway components in 3b-expressing cells was assessed by analyzing levels of active phosphorylated formsof JNK and its upstream kinase MEK4. An enhanced phosphor-ylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP 0.751 SIGNOR-260759 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 10090 15856019 YES milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. 0.459 SIGNOR-236988 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT down-regulates activity phosphorylation Thr337 VKSFSRRtPNSSSYC 9606 BTO:0000567 26080397 YES miannu ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. 0.2 SIGNOR-266377 CHUK protein O15111 UNIPROT MECP2 protein P51608 UNIPROT up-regulates activity phosphorylation Ser423 EKMPRGGsLESDGCP 9606 22848609 YES miannu Representative confocal micrographs of 4th day differentiating cultures are shown. (C) IKK\u03b1 promotes MeCP2-dependent BDNF expression.|The characterization of IKK\u03b1-mediated phosphorylation of MeCP2 at Ser421 and other residues and their effects on the activity of MeCP2 is a topic of current work in our laboratory. 0.2 SIGNOR-279459 PRKCD protein Q05655 UNIPROT SLC29A1 protein Q99808 UNIPROT up-regulates activity phosphorylation Ser281 QPTNESHsIKAILKN 9606 25725289 YES Manara Phosphorylation of hENT1 by PKC has effects on both the function and subcellular trafficking of hENT1 0.2 SIGNOR-260888 EPHA4 protein P54764 UNIPROT GHR protein P10912 UNIPROT up-regulates activity phosphorylation 9606 28686668 YES miannu EphA4 binds to growth hormone receptor at both its extracellular and intracellular domains and phosphorylates growth hormone receptor when stimulated with a ligand.|These findings suggest that EphA4 activates not only GHR, as shown above, but also JAK2 by direct phosphorylation. 0.2 SIGNOR-279461 PRKACA protein P17612 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 YES lperfetto Merlin localizes to the cell membrane where it links the actin cytoskeleton to membrane proteins.we identify a novel pka phosphorylation site, serine 10, in the n terminus of merlin. s10a reduces the amount of cellular f-actin and merlin s10d stabilizes f-actin filaments. 0.403 SIGNOR-159844 PRKDC protein P78527 UNIPROT HNRNPU protein Q00839 UNIPROT up-regulates phosphorylation Ser59 AMEPGNGsLDLGGDS 9606 19351595 YES lperfetto We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks 0.375 SIGNOR-185058 CACNA1D protein Q01668 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 YES miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). 0.8 SIGNOR-264326 SLC24A2 protein Q9UI40 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 YES miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) 0.8 SIGNOR-264389 IKBKB protein O14920 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates activity phosphorylation Ser446 DSIRLQIsNPDLKDR 9606 25326420 YES miannu Here we present evidence that the kinase IKKbeta phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll like receptors and retinoic acid inducible gene I like receptors.|Recombinant IKK\u03b2 phosphorylated IRF5 at Ser-445 in vitro, and a point mutation of this serine abolished IRF5 activation and cytokine production. 0.37 SIGNOR-279466 ALDOB protein P05062 UNIPROT beta-D-fructofuranose 1-phosphate(2-) smallmolecule CHEBI:138881 ChEBI down-regulates quantity chemical modification 9606 10970798 YES yes miannu Fructoaldolases (EC 4.1.2.13) catalyse the specific and reversible cleavage of fructose 1,6-bisphosphate (FBP) and fructose 1-phosphate (F1P) into dihydroxyacetone phosphate and -glyceraldehyde 3-phosphate or -glyceraldehyde respectively 0.8 SIGNOR-280241 beta-D-fructofuranose 1-phosphate(2-) smallmolecule CHEBI:138881 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates activity precursor of 9606 10970798 YES miannu Fructoaldolases (EC 4.1.2.13) catalyse the specific and reversible cleavage of fructose 1,6-bisphosphate (FBP) and fructose 1-phosphate (F1P) into dihydroxyacetone phosphate and -glyceraldehyde 3-phosphate or -glyceraldehyde respectively 0.8 SIGNOR-280242 beta-D-fructofuranose 1-phosphate(2-) smallmolecule CHEBI:138881 ChEBI D-glyceraldehyde smallmolecule CHEBI:17378 ChEBI up-regulates activity precursor of 9606 10970798 YES miannu Fructoaldolases (EC 4.1.2.13) catalyse the specific and reversible cleavage of fructose 1,6-bisphosphate (FBP) and fructose 1-phosphate (F1P) into dihydroxyacetone phosphate and -glyceraldehyde 3-phosphate or -glyceraldehyde respectively 0.8 SIGNOR-280243 ALDOB protein P05062 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 10970798 YES miannu Fructoaldolases (EC 4.1.2.13) catalyse the specific and reversible cleavage of fructose 1,6-bisphosphate (FBP) and fructose 1-phosphate (F1P) into dihydroxyacetone phosphate and -glyceraldehyde 3-phosphate or -glyceraldehyde respectively 0.8 SIGNOR-280244 ALDOB protein P05062 UNIPROT D-glyceraldehyde smallmolecule CHEBI:17378 ChEBI up-regulates quantity chemical modification 9606 10970798 YES miannu Fructoaldolases (EC 4.1.2.13) catalyse the specific and reversible cleavage of fructose 1,6-bisphosphate (FBP) and fructose 1-phosphate (F1P) into dihydroxyacetone phosphate and -glyceraldehyde 3-phosphate or -glyceraldehyde respectively 0.8 SIGNOR-280245 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser545 PTSATKTsPLNSSGS 10090 BTO:0000964 34048556 YES lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. 0.2 SIGNOR-268342 MAPK1 protein P28482 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 20230789 YES lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity 0.326 SIGNOR-164227 LYN protein P07948 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity phosphorylation Tyr335 QLQGQDLyAIRLCQC 9606 30515152 YES miannu Lyn kinase phosphorylates IRF5 at Y313 and Y335 but this modification was dispensable as transactivation ability of the double mutant IRF5 (YY313, 335FF) was still inhibited by Lyn ( xref ).|These data show that Lyn negatively regulates IRF5 transcriptional activity via a mechanism independent of its kinase activity and possibly via a direct interaction of Lyn with IRF5. 0.329 SIGNOR-279207 ANXA13 protein P27216 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates quantity relocalization -1 10871286 YES miannu Annexin XIII has two known isoforms, a and b, that are apically localized, although XIIIa is also found in the basolateral compartment. In vitro binding and coprecipitation experiments showed that the Nedd4-C2 domain interacts with both annexin XIIIa and b in the presence of Ca2+, and the interaction is direct and optimal at 1 μM Ca2+.These results suggest that the apical membrane localization of Nedd4 is mediated by an association of its C2 domain with the apically targeted annexin XIIIb. 0.345 SIGNOR-272571 MYOCD protein Q8IZQ8 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 YES gcesareni A coactivator of srf, myocd, interacts with srf and activates vsmc expression of contractile genes. 0.796 SIGNOR-174322 PINK1 protein Q9BXM7 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000793 20871098 NO Barakat Ubiquitination of MFN-1 or MFN-2 was induced in untransfected cells and cells transfected with control siRNA. However, ubiquitination of MFN-1 and MFN-2 was significantly reduced when treated with either PINK1 siRNA combination. These results suggest that PINK1 is required for the ubiquitination of MFN-1 and MFN-2. 0.696 SIGNOR-274135 JNK proteinfamily SIGNOR-PF15 SIGNOR MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation 9606 15767678 YES inferred from 70% family members gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.2 SIGNOR-269984 BECN1 protein Q14457 UNIPROT USP13 protein Q92995 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0003704 21962518 YES Giulio We found that endogenous Beclin1 can interact with USP13 and the interaction was reduced in the presence of spautin-1 (Figure 5C). Interestingly, the DUB activities were significantly increased when USP13 and USP10 coincubated together or with Beclin1 or all 3 proteins together, suggesting the DUB activity can be significantly enhanced when USP13 interacts with its substrate Beclin1 or USP10. 0.529 SIGNOR-260296 TKFC protein Q3LXA3 UNIPROT D-glyceraldehyde smallmolecule CHEBI:17378 ChEBI down-regulates quantity chemical modification 9606 24569995 YES miannu Triokinase (EC 2.7.1.28) catalyzes the third and final step of the classical Hers pathway for fructose metabolism: the 1-OH group of the sugar is phosphorylated by fructokinase, the product fructose 1-phosphate is converted to dihydroxyacetone phosphate and d-glyceraldehyde by aldolase B, and finally d-glyceraldehyde (GA)4 is phosphorylated to d-glyceraldehyde 3-phosphate by triokinase 0.8 SIGNOR-280246 D-glyceraldehyde smallmolecule CHEBI:17378 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates activity precursor of 9606 24569995 YES miannu Triokinase (EC 2.7.1.28) catalyzes the third and final step of the classical Hers pathway for fructose metabolism: the 1-OH group of the sugar is phosphorylated by fructokinase, the product fructose 1-phosphate is converted to dihydroxyacetone phosphate and d-glyceraldehyde by aldolase B, and finally d-glyceraldehyde (GA)4 is phosphorylated to d-glyceraldehyde 3-phosphate by triokinase 0.8 SIGNOR-280247 TKFC protein Q3LXA3 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 24569995 YES miannu Triokinase (EC 2.7.1.28) catalyzes the third and final step of the classical Hers pathway for fructose metabolism: the 1-OH group of the sugar is phosphorylated by fructokinase, the product fructose 1-phosphate is converted to dihydroxyacetone phosphate and d-glyceraldehyde by aldolase B, and finally d-glyceraldehyde (GA)4 is phosphorylated to d-glyceraldehyde 3-phosphate by triokinase 0.8 SIGNOR-280248 D-glyceraldehyde smallmolecule CHEBI:17378 ChEBI D-glycerate smallmolecule CHEBI:16659 ChEBI up-regulates activity precursor of 9606 23444097 YES miannu Aldehyde dehydrogenases (ALDHs) couple the oxidation of aldehydes to the reduction of NAD(P)(+) . These enzymes have gained importance as they have been related to the detoxification of aldehydes generated in several diseases involving oxidative stress. 0.8 SIGNOR-280250 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr68 DPPLESKyECPICLM 9606 BTO:0002181 37977223 YES miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. 0.566 SIGNOR-277862 ALDH1A1 protein P00352 UNIPROT D-glycerate smallmolecule CHEBI:16659 ChEBI up-regulates quantity chemical modification 9606 23444097 YES miannu Aldehyde dehydrogenases (ALDHs) couple the oxidation of aldehydes to the reduction of NAD(P)(+) . These enzymes have gained importance as they have been related to the detoxification of aldehydes generated in several diseases involving oxidative stress. 0.8 SIGNOR-280251 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT up-regulates activity phosphorylation Ser209 LQKQPQPsPAEGRAV 9606 BTO:0000567 25097229 YES miannu Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins.  0.2 SIGNOR-276671 F5 protein P12259 UNIPROT Factor Va-Xa complex SIGNOR-C318 SIGNOR form complex binding -1 2026608 YES lperfetto The binding of factor Xa to factor Va in the presence of Ca2+ ions and phospholipid is fundamental for the activation of prothrombin to thrombin. |Regardless of which protein was labeled, a factor Xa-Va complex (s20,w = 9.8) was formed. The interaction is specific and reversible. I 0.775 SIGNOR-263558 PTPN1 protein P18031 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation -1 10660596 YES lperfetto Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein. 0.778 SIGNOR-74852 BZW2 protein Q9Y6E2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 BTO:0003897 30805927 NO francesca Overexpression (or silence) of BZW2 in HCC cells significantly stimulates (or decreases) the activation of the PI3K/AKT/mTOR signaling pathway 0.2 SIGNOR-261218 LMX1B protein O60663 UNIPROT LMX1B/SFPQ/PSPC1 complex complex SIGNOR-C106 SIGNOR form complex binding 10090 23308148 YES miannu LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo. 0.343 SIGNOR-223966 Food intake phenotype SIGNOR-PH152 SIGNOR beta-D-fructofuranose smallmolecule CHEBI:28645 ChEBI up-regulates 9606 29388924 YES miannu Glucose is the predominant form of circulating sugar in animals, while sucrose, the disaccharide composed of equal portions of glucose and fructose, is the predominant circulating sugar in plants. As plants form the basis of the food chain, herbivores and omnivores are highly adapted to use sucrose for energetic and biosynthetic needs.  0.7 SIGNOR-280252 GLYCTK protein Q8IVS8 UNIPROT D-glycerate smallmolecule CHEBI:16659 ChEBI down-regulates quantity chemical modification 9606 40467571 YES miannu GLYCTK catalyzes the formation of 3-phosphate glycerol from glycerol in plants, fungi, and non autotrophic bacteria, while catalyzing the formation of 2-phosphate glycerol from glycerol in animals and methylotrophic bacteria 0.8 SIGNOR-280253 D-glycerate smallmolecule CHEBI:16659 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates activity precursor of 9606 40467571 YES miannu GLYCTK catalyzes the formation of 3-phosphate glycerol from glycerol in plants, fungi, and non autotrophic bacteria, while catalyzing the formation of 2-phosphate glycerol from glycerol in animals and methylotrophic bacteria 0.8 SIGNOR-280254 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 21248841 NO lperfetto The importance of polycomb function for stem cells is best illustrated by various PcG-knockout mice. Deletion of any of the PRC2 members results in embryonic lethality. In vitro studies with ES cells demonstrated that cells lacking EED or Suz12 could not maintain their pluripotency and were prone to differentiation. 0.7 SIGNOR-241910 RPS6KA1 protein Q15418 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 15342917 YES lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 0.722 SIGNOR-217900 GLYCTK protein Q8IVS8 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity chemical modification 9606 40467571 YES miannu GLYCTK catalyzes the formation of 3-phosphate glycerol from glycerol in plants, fungi, and non autotrophic bacteria, while catalyzing the formation of 2-phosphate glycerol from glycerol in animals and methylotrophic bacteria 0.8 SIGNOR-280255 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 29388924 YES miannu  Both fructose-derived DHAP and GA3P enter the glycolytic/gluconeogenic metabolite pool at the triose-phosphate level, and these metabolites have numerous metabolic fates. 0.7 SIGNOR-280256 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 YES gcesareni Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. 0.344 SIGNOR-75989 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys612 LFSFPAAkPKEPTMV 9606 BTO:0000007 28448495 YES miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 0.2 SIGNOR-272801 PTPN3 protein P26045 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity dephosphorylation Tyr537 CKNVVPLyDLLLEML 9606 26079946 YES miannu Our recent studies further demonstrated that PTPH1 dephosphorylates estrogen receptor at Y537, increases estrogen receptor stability and nuclear accumulation, and enhances breast cancer sensitivity to anti-estrogens [ ]. 0.2 SIGNOR-277127 HACE1 protein Q8IYU2 UNIPROT OPTN protein Q96CV9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 25026213 YES miannu Here we report that tumor suppressor HACE1, a ubiquitin ligase, ubiquitylates OPTN and promotes its interaction with p62 and SQSTM1 to form the autophagy receptor complex, thus accelerating autophagic flux.|Ubiquitylation of Autophagy Receptor Optineurin by HACE1 Activates Selective Autophagy for Tumor Suppression.|HACE1 mediated K48 linked poly-Ub chains targets OPTN for autophagic degradation. 0.402 SIGNOR-278748 sirolimus chemical CHEBI:9168 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 16452206 NO gcesareni We now show that mtor inhibition induces insulin receptor substrate-1 expression and abrogates feedback the pathway, resulting in akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, rad001. 0.8 SIGNOR-144156 PPP3CA protein Q08209 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18177723 NO lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy 0.25 SIGNOR-251733 KNL1 complex complex SIGNOR-C363 SIGNOR KMN network complex SIGNOR-C366 SIGNOR form complex binding 18007590 YES lperfetto The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, 0.2 SIGNOR-265217 NMI protein Q13287 UNIPROT SOX10 protein P56693 UNIPROT up-regulates activity binding 9606 BTO:0000007 16214168 YES miannu we identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific. 0.429 SIGNOR-225599 MAPK3 protein P27361 UNIPROT GLYCTK protein Q8IVS8 UNIPROT up-regulates quantity by stabilization phosphorylation Ser220 NTIRKALsQLKGGGL 9606 BTO:0002036 40467571 YES miannu Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. ERK1 phosphorylates GLYCTK2 at S220 to promotes its stability 0.2 SIGNOR-280257 GALM protein Q96C23 UNIPROT beta-D-galactose smallmolecule CHEBI:27667 ChEBI down-regulates quantity chemical modification 9606 12753898 YES miannu Aldose 1-epimerase or mutarotase (EC 5.1.3.3) is a key enzyme of carbohydrate metabolism catalysing the interconversion of the alpha- and beta-anomers of hexose sugars such as glucose and galactose. 0.8 SIGNOR-280259 beta-D-galactose smallmolecule CHEBI:27667 ChEBI alpha-D-galactose smallmolecule CHEBI:28061 ChEBI up-regulates activity precursor of 9606 12753898 YES miannu Aldose 1-epimerase or mutarotase (EC 5.1.3.3) is a key enzyme of carbohydrate metabolism catalysing the interconversion of the alpha- and beta-anomers of hexose sugars such as glucose and galactose. 0.8 SIGNOR-280260 GALM protein Q96C23 UNIPROT alpha-D-galactose smallmolecule CHEBI:28061 ChEBI up-regulates quantity chemical modification 9606 12753898 YES miannu Aldose 1-epimerase or mutarotase (EC 5.1.3.3) is a key enzyme of carbohydrate metabolism catalysing the interconversion of the alpha- and beta-anomers of hexose sugars such as glucose and galactose. 0.8 SIGNOR-280261 GALK1 protein P51570 UNIPROT alpha-D-galactose smallmolecule CHEBI:28061 ChEBI down-regulates quantity chemical modification 9606 12694189 YES miannu Galactokinase (EC 2.7.1.6) catalyzes the first committed step in the catabolism of galactose. The sugar is phosphorylated at position 1 at the expense of ATP. 0.8 SIGNOR-280262 alpha-D-galactose smallmolecule CHEBI:28061 ChEBI alpha-D-galactose 1-phosphate smallmolecule CHEBI:17973 ChEBI up-regulates activity precursor of 9606 12694189 YES miannu Galactokinase (EC 2.7.1.6) catalyzes the first committed step in the catabolism of galactose. The sugar is phosphorylated at position 1 at the expense of ATP. 0.8 SIGNOR-280263 GALK1 protein P51570 UNIPROT alpha-D-galactose 1-phosphate smallmolecule CHEBI:17973 ChEBI up-regulates quantity chemical modification 9606 12694189 YES miannu Galactokinase (EC 2.7.1.6) catalyzes the first committed step in the catabolism of galactose. The sugar is phosphorylated at position 1 at the expense of ATP. 0.8 SIGNOR-280264 GALT protein P07902 UNIPROT alpha-D-galactose 1-phosphate smallmolecule CHEBI:17973 ChEBI down-regulates quantity chemical modification 9606 2011574 YES miannu Cytosolic galactose-1-phosphate uridylyltransferase (GALT) catalyzes the reaction of alpha-D-galactose 1-phosphate and UDP glucose to form D-glucose 1-phosphate and UDP galactose 0.8 SIGNOR-280265 MAPK14 protein Q16539 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates activity phosphorylation Ser79 EVTSTSQsPHSPDSS 9606 8650547 YES lperfetto ...undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, chop is phosphorylated on these residues by p38 mitogen-activated protein kinase (map kinase). phosphorylation of chop on these residues enhanced its ability to function as a transcriptional activator. 0.609 SIGNOR-42200 alpha-D-galactose 1-phosphate smallmolecule CHEBI:17973 ChEBI UDP-alpha-D-galactose(2-) smallmolecule CHEBI:66914 ChEBI up-regulates activity precursor of 9606 2011574 YES miannu Cytosolic galactose-1-phosphate uridylyltransferase (GALT) catalyzes the reaction of alpha-D-galactose 1-phosphate and UDP glucose to form D-glucose 1-phosphate and UDP galactose 0.8 SIGNOR-280266 GALT protein P07902 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 2011574 YES miannu Cytosolic galactose-1-phosphate uridylyltransferase (GALT) catalyzes the reaction of alpha-D-galactose 1-phosphate and UDP glucose to form D-glucose 1-phosphate and UDP galactose 0.8 SIGNOR-280267 SMO protein Q99835 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 16885213 YES gcesareni We found that smo, by virtue of what appears to be constitutive activity, activates all members of the g(i) family but does not activate members of the g(s), g(q), and g(12) families. 0.2 SIGNOR-148484 TNF protein P01375 UNIPROT SCN4A protein P35499 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.257 SIGNOR-253490 GALT protein P07902 UNIPROT UDP-alpha-D-galactose(2-) smallmolecule CHEBI:66914 ChEBI up-regulates quantity chemical modification 9606 2011574 YES miannu Cytosolic galactose-1-phosphate uridylyltransferase (GALT) catalyzes the reaction of alpha-D-galactose 1-phosphate and UDP glucose to form D-glucose 1-phosphate and UDP galactose 0.8 SIGNOR-280269 UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates activity precursor of 9606 2011574 YES miannu Cytosolic galactose-1-phosphate uridylyltransferase (GALT) catalyzes the reaction of alpha-D-galactose 1-phosphate and UDP glucose to form D-glucose 1-phosphate and UDP galactose 0.8 SIGNOR-280270 GALE protein Q14376 UNIPROT UDP-alpha-D-galactose(2-) smallmolecule CHEBI:66914 ChEBI down-regulates quantity chemical modification 9606 15175331 YES miannu UDP-galactose 4'-epimerase (GALE) interconverts UDP-galactose and UDP-glucose in the final step of the Leloir pathway.  0.8 SIGNOR-280271 UDP-alpha-D-galactose(2-) smallmolecule CHEBI:66914 ChEBI UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates activity precursor of 9606 15175331 YES miannu UDP-galactose 4'-epimerase (GALE) interconverts UDP-galactose and UDP-glucose in the final step of the Leloir pathway.  0.8 SIGNOR-280272 GALE protein Q14376 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI up-regulates quantity chemical modification 9606 15175331 YES miannu UDP-galactose 4'-epimerase (GALE) interconverts UDP-galactose and UDP-glucose in the final step of the Leloir pathway.  0.8 SIGNOR-280273 AKR1B1 protein P15121 UNIPROT alpha-D-galactose smallmolecule CHEBI:28061 ChEBI down-regulates quantity chemical modification 9606 7851421 YES miannu Based on studies in mouse, ADKR1B1 catalyzes the conversion of alpha-D-galactose (a-Gal) to galactitol 0.8 SIGNOR-280274 alpha-D-galactose smallmolecule CHEBI:28061 ChEBI galactitol smallmolecule CHEBI:16813 ChEBI up-regulates activity precursor of 9606 7851421 YES miannu Based on studies in mouse, ADKR1B1 catalyzes the conversion of alpha-D-galactose (a-Gal) to galactitol 0.8 SIGNOR-280275 ABT-737 chemical CID:11228183 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189174 AKR1B1 protein P15121 UNIPROT galactitol smallmolecule CHEBI:16813 ChEBI up-regulates quantity chemical modification 9606 7851421 YES miannu Based on studies in mouse, ADKR1B1 catalyzes the conversion of alpha-D-galactose (a-Gal) to galactitol 0.8 SIGNOR-280276 AKR1B1 protein P15121 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI down-regulates quantity chemical modification 9606 7851421 YES miannu Based on studies in mouse, ADKR1B1 catalyzes the conversion of alpha-D-galactose (a-Gal) to galactitol 0.8 SIGNOR-280277 AKR1B1 protein P15121 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI up-regulates quantity chemical modification 9606 7851421 YES miannu Based on studies in mouse, ADKR1B1 catalyzes the conversion of alpha-D-galactose (a-Gal) to galactitol 0.8 SIGNOR-280278 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Ser146 LLTFPNSsPGLRRQK 23972993 YES For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP 0.289 SIGNOR-274055 CHKA protein P35790 UNIPROT LPIN1 protein Q14693 UNIPROT down-regulates activity phosphorylation 9606 28049764 YES miannu Because CKI is a constitutively active kinase and ubiquitously distributed in many cell types, high mTORC1 activity depending on nutritional status may be a physiological cue for Lipin1 degradation mediated by CKI and beta-TRCP.|Thus, we propose that mTORC1 may function as a priming kinase for CKI to promote the phosphorylation of the degron motif in Lipin1. 0.273 SIGNOR-280228 CHUK protein O15111 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity phosphorylation 9606 22435559 YES miannu Interestingly, while IKK2 negatively regulates beta-catenin stability similar to GSK3beta, IKK1 seems to increase beta-catenin protein level and downstream signal, such as cyclin D1 transcription.|These results suggested IKK1 may phosphorylate beta-catenin at different residues and protect it from ubiquitination mediated degradation. 0.486 SIGNOR-280230 CIT protein O14578 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates activity phosphorylation 9606 27009191 YES miannu Figure 5.CIT-K phosphorylates INCENP. (a) Schematic diagram of INCENP structure illustrating the phosphorylated sites identified by MS. 0.426 SIGNOR-280232 PAK1 protein Q13153 UNIPROT PGAM2 protein P15259 UNIPROT down-regulates quantity by destabilization phosphorylation Ser118 QVKIWRRsFDIPPPP 9606 24567357 YES miannu The ability of Pak1 to phosphorylate wild-type PGAM2 was increased after exposure of the cells to etoposide (XREF_FIG).|Bar, 20 \u00b5m. (E) Primary mouse embryonic fibroblasts at early passages were treated with 20 \u00b5M etoposide in the presence of 20 \u00b5M MG132, and cell lysates were immunoblotted with antibodies against Pak1 and phospho-Ser118 in phosphoglycerate mutase as indicated. (F) Pak1 kinase phosphorylates PGAM2 at Ser118 in vitro. 0.2 SIGNOR-280237 HDLBP protein Q00341 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity binding 9606 BTO:0000150 33941620 YES miannu We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. 0.2 SIGNOR-266698 DLK1 protein P80370 UNIPROT FN1 protein P02751 UNIPROT up-regulates binding 9606 20457810 YES fspada We show a direct interaction of pref-1 and fibronectin via the pref-1 juxtamembrane domain and fibronectin c-terminal domain 0.37 SIGNOR-165347 R547 chemical CID:6918852 PUBCHEM CCND1 protein P24385 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206352 ADRA1D protein P25100 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.291 SIGNOR-256808 SB-202190 chemical CHEBI:79090 ChEBI PCSK7 protein Q16549 UNIPROT down-regulates chemical inhibition 9606 BTO:0000876 9738669 YES gcesareni Sb202190, a selective inhibitor of p38 mitogen activated protein kinase, is a powerful regulator of lps-induced mrnas in monocytes. 0.8 SIGNOR-60130 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258889 SF3B5 protein Q9BWJ5 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.766 SIGNOR-270673 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.305 SIGNOR-249003 ADORA2B protein P29275 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.399 SIGNOR-257365 MRPS33 protein Q9Y291 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.693 SIGNOR-261444 NDUFA1 protein O15239 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 0.849 SIGNOR-262150 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 9020159 YES lperfetto We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src. 0.935 SIGNOR-235786 MYC protein P01106 UNIPROT SHMT2 protein P34897 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 YES miannu Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis 0.291 SIGNOR-267380 CDK20 protein Q8IZL9 UNIPROT CILK1 protein Q9UPZ9 UNIPROT up-regulates phosphorylation Thr157 IRSKPPYtDYVSTRW 9606 15988018 YES lperfetto Recombinant cak1p phosphorylates thr-157 in the tdy motif of recombinant ick and activates its activity in vitro. 0.2 SIGNOR-138420 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.289 SIGNOR-251206 PRKCG protein P05129 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 YES lperfetto We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function. 0.3 SIGNOR-249027 ZDHHC5 protein Q9C0B5 UNIPROT S1PR1 protein P21453 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000793 29185452 YES We propose that DHHC5-mediated palmitoylation of S1P1R determines Gi coupling and its signalling in a spatio/temporal manner. 0.2 SIGNOR-261140 SUFU protein Q9UMX1 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 20463034 YES Gianni We show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them. 0.909 SIGNOR-268867 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 YES gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways. 0.464 SIGNOR-106998 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269349 ER stress stimulus SIGNOR-ST9 SIGNOR QRICH1 protein Q2TAL8 UNIPROT up-regulates 9606 33384352 NO miannu QRICH1 promotes cell death under ER stress 0.7 SIGNOR-269398 ERBB4 protein Q15303 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.608 SIGNOR-146879 LATS2 protein Q9NRM7 UNIPROT VEPH1 protein Q14D04 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 NO In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 0.2 SIGNOR-177071 ING1 protein Q9UK53 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 15662138 NO miannu Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. 0.2 SIGNOR-254488 BBC3 protein Q9BXH1 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 17289999 YES gcesareni Bh3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding bax and bak enabler bh3-only proteins such as puma promote momp more indirectly. They activate bax and bak by forming inhibitory complexes with the anti-apoptotic bh1-4 proteins such as bcl2, bclxl and mcl1 that normally stabilize the outer membrane. 0.382 SIGNOR-152974 L-arginine chemical CHEBI:16467 ChEBI SLC38A9 protein Q8NBW4 UNIPROT up-regulates activity chemical activation 9606 29053970 YES SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins 0.8 SIGNOR-254895 BBC3 protein Q9BXH1 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 22492984 YES gcesareni Bim, and puma bind with high affinity to all pro-survival proteins 0.382 SIGNOR-196929 ITCH protein Q96J02 UNIPROT LAPTM5 protein Q13571 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22009753 YES miannu Here, we found that the level of LAPTM5 protein is regulated negatively by the degradation through ubiquitination by ITCH, an E3 ubiquitin ligase. ITCH directly binds to the PPxY motif of LAPTM5 via its WW domains and promotes ubiquitination through a HECT-type ligase domain. 0.412 SIGNOR-272721 PP2B proteinfamily SIGNOR-PF18 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0001103 11062529 YES inferred from 70% family members gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.2 SIGNOR-269989 HCFC1 protein P51610 UNIPROT Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR up-regulates activity binding 9606 BTO:0000567 12670868 YES miannu Our analysis of HCF-1-associated proteins suggests that a K4 histone H3 HMT complex has been conserved from yeast to humans in both structure and activity: the Set1/Ash2 HMT. The results presented here show that this Set1/Ash2 HMT complex, in mutually exclusive interactions, can associate with HCF-1 bound to the repressive Sin3 HDAC or the transcriptional activator VP16, indicating a diversity of transcriptional regulatory roles. 0.772 SIGNOR-264481 SIRT2 protein Q8IXJ6 UNIPROT NEDD4 protein P46934 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23175188 NO miannu SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. 0.262 SIGNOR-255144 F2R protein P25116 UNIPROT TNFRSF12A protein Q9NP84 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254846 PBRM1 protein Q86U86 UNIPROT CRABP2 protein P29373 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15601824 NO miannu We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues. 0.421 SIGNOR-131552 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM5 protein P08912 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257472 NFATC2 protein Q13469 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18676376 NO gcesareni € provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis. 0.284 SIGNOR-235006 NCBP1 protein Q09161 UNIPROT Cap-binding complex complex SIGNOR-C440 SIGNOR form complex binding 9606 26382858 YES lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 0.969 SIGNOR-268359 CSNK1E protein P49674 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation 9606 15747065 YES gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. 0.268 SIGNOR-134497 DYRK1B protein Q9Y463 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 NO lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner 0.284 SIGNOR-235816 SRC protein P12931 UNIPROT SIAH2 protein O43255 UNIPROT up-regulates activity phosphorylation 9606 23700162 YES miannu In human breast cancer cell lines, the protein kinase Src has been shown to activate Siah2 by phosphorylation of tyrosines 86, 140, and 263.|This function is promoted by Src phosphorylation of Siah2, which increases C/EBPdelta binding, ubiquitination, and degradation. 0.334 SIGNOR-279555 MDH2 protein P40926 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-266286 PRKCA protein P17252 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Ser518 VFRTNGVsDVPTSPT -1 27368100 YES miannu These results suggest that PKC activates JAK2 and thereby STAT3 by directly phosphorylating T174 and S518.  0.26 SIGNOR-277261 ADNP protein Q9H2P0 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates quantity binding 9606 BTO:0000007 17878164 YES miannu ADNP Co-precipitates with the SWI/SNF Complex through ADNP C-terminal Interaction. Down-regulation of ADNP by shRNA resulted in morphological changes that are in line with the fact that ADNP contains a homeodomain profile (2) and with the SWI/SNF complex function that is associated with cellular differentiation. Our results suggest that ADNP functionality plays a role in these changes. 0.354 SIGNOR-266757 KDM6A protein O15550 UNIPROT ELK3 protein P41970 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 YES miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase 0.2 SIGNOR-260037 FPR2 protein P25090 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-256745 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 YES miannu Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376 0.584 SIGNOR-166722 DEF6 protein Q9H4E7 UNIPROT RAP1B protein P61224 UNIPROT up-regulates activity binding 9606 BTO:0000782 26483383 YES lperfetto Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion. 0.2 SIGNOR-253366 hsa-mir-146a-5p mirna URS000050B527_9606 RNAcentral CD84 protein Q9UIB8 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002417 25743066 YES Tiberia Cd84 was further tested for direct repression by miR-146a using luciferase reporter assays. This target was specifically repressed by miR-146a 0.4 SIGNOR-279909 hsa-mir-146a-5p mirna URS000050B527_9606 RNAcentral SLAMF6 protein Q96DU3 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002417 25743066 YES Tiberia Luciferase assays, along with published reports, have shown that ectopic expression of miR-146a can lead to the repression of multiple mRNAs expressed by Tfh cells, including Slamf6. 0.4 SIGNOR-279910 PSMC5 protein P62195 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.883 SIGNOR-263372 MRGPRX1 protein Q96LB2 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256786 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 YES lperfetto Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization. 0.2 SIGNOR-244202 3-(9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione chemical CID:10029385 PUBCHEM GSK3B protein P49841 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000183 31562256 YES miannu Indeed, we demonstrated that the selective GSK3 inhibitor LY2090314 significantly reduced cell proliferation in control pancreatic cancer cell lines 0.8 SIGNOR-262539 OGA protein O60502 UNIPROT PFKP protein Q01813 UNIPROT up-regulates activity deglycosylation Ser540 VMVPATVsNNVPGSD 9606 26399441 YES lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 0.2 SIGNOR-267606 hsa-miR-150-5p mirna URS000016FD1A_9606 RNAcentral RIPK2 protein O43353 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0003292 26391398 YES Tiberia MiR-150 was identified as the Ac 2 PIM-sensitive miRNAs that targeted RIP2. Furthermore, macrophages transfected with specific miR-150 inhibitors either failed to reduce RIP2 expression and in the presence of Ac 2 PIM 0.4 SIGNOR-279919 CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser174 TPAVPPVsEDEDDDD 19520772 YES lperfetto CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression|We show that PAK1 is a substrate of CDK11p58 and can be strongly activated upon phosphorylation. 0.385 SIGNOR-273124 RIMS1 protein Q86UR5 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity binding 9606 BTO:0005822 28642685 YES miannu Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells. 0.365 SIGNOR-264358 PPP2CB protein P62714 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity dephosphorylation Ser129 NEAYEMPsEEGYQDY 9606 21562258 YES α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129 0.276 SIGNOR-248592 TLN1 protein Q9Y490 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.628 SIGNOR-257614 GCGR protein P47871 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 12626323 YES Glucagon signals through its receptor on the cell surface (Fig.1). The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gsα and Gq. The activation of Gsα leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA). 0.511 SIGNOR-267715 NR3C1 protein P04150 UNIPROT KLF15 protein Q9UIH9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 20956975 NO lperfetto We identified glucocorticoid response element sites in the first intron of KLF15 by bioinformatical promoter analysis and confirmed their functional relevance by demonstrating GR interaction by chromatin immunoprecipitation 0.376 SIGNOR-236212 SH3GLB1 protein Q9Y371 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 11894095 YES gcesareni Cbl rapidly recruits cin85 (cbl-interacting protein of 85k;ref. 6) and endophilins (regulatory components of clathrin-coated vesicles) to form a complex with activated egf receptors, thus controlling receptor internalization. 0.398 SIGNOR-115826 HCK protein P08631 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates activity phosphorylation Tyr752 GTSDQVLyGQLLGSP -1 9790917 YES Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. the ability of Hck to phosphorylate the G-CSF-R in vitro, both Y728 and Y763 fit the Src consensus phosphorylation site 0.386 SIGNOR-251263 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248750 HNRNPA1 protein P09651 UNIPROT TRA2B protein P62995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000586 31311954 YES lperfetto HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells. 0.698 SIGNOR-262280 SPRY4 protein Q9C004 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR down-regulates 9606 BTO:0002283 20501643 NO Re-expression of Spry4 inhibits migration and invasion in NSCLC cells. 0.7 SIGNOR-278111 PIM proteinfamily SIGNOR-PF34 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 17643117 YES gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. 0.2 SIGNOR-265365 GLI3 protein P10071 UNIPROT MYCN protein P04198 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17419683 NO gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1. 0.357 SIGNOR-154237 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Thr210 FTLGSPLtSPGGSPG 9606 BTO:0001131 9630228 YES lperfetto Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4. 0.589 SIGNOR-109776 LTK protein P29376 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000938 9223670 YES gcesareni Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85 0.254 SIGNOR-49622 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 17194702 NO miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes 0.357 SIGNOR-151688 BTRC protein Q9Y297 UNIPROT RAP1GAP protein P47736 UNIPROT down-regulates ubiquitination 9606 25329897 YES lperfetto Here, we demonstrated that rap1gap is ubiquitinated and degraded through proteasome pathway in mitosis. Proteolysis of rap1gap requires the plk1 kinase and _-trcp ubiquitin ligase complex. 0.343 SIGNOR-203548 NR3C2 protein P08235 UNIPROT ATP1B1 protein P05026 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000318 9694812 NO miannu Together these data indicate that the 21-base pair sequence represents a true MRE/GRE and that optimal activation of the human Na/K-ATPase beta1 promoter is controlled by mineralocorticoid and glucocorticoid hormones. It appears that an interaction of MR with GR on the beta1 promoter effectively down-regulates transcription. 0.238 SIGNOR-254865 FYN protein P06241 UNIPROT LRP8 protein Q14114 UNIPROT up-regulates quantity phosphorylation 9606 25340851 YES miannu Fyn phosphorylates ApoER2.|Together these data demonstrate that Fyn activity is necessary for its effects increasing ApoER2 levels. 0.634 SIGNOR-278197 PRKACA protein P17612 UNIPROT KCNN4 protein O15554 UNIPROT down-regulates activity phosphorylation Ser334 KHTRRKEsHAARRHQ 9606 BTO:0000007 25274816 YES miannu Mutating the single PKA site (S334A) in human KCa3.1 abolished the PKA-dependent regulation. CaM-affinity chromatography showed that CaM binding to KCa3.1 was decreased by PKA-dependent phosphorylation of S334, and this regulation was absent in the S334A mutant.The results above indicate that PKA activation led to a phosphorylation event that inhibited KCa3.1 channel activity 0.2 SIGNOR-276855 BAK1 protein Q16611 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates 9606 21210296 NO gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. 0.52 SIGNOR-170963 ZNRF3 protein Q9ULT6 UNIPROT FZD5 protein Q13467 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 YES Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. 0.513 SIGNOR-260118 SGK1 protein O00141 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates phosphorylation Thr366 GTRSRSHtSEGAHLD 9606 BTO:0000567 18787837 YES llicata Transient expression of active (sgk1-s422d) and inactive (sgk1-k127a) sgk1 mutants confirmed that activating sgk1 stimulates ndrg1-thr(346/356/366) phosphorylation. dexamethasone (0.2 mum) acutely activated sgk1 and the peak of this response (2-3 h) coincided with the induction of g (na), and both responses were pi3k-dependent. While these data suggest that sgk1 might mediate the rise in g (na), transient expression of the inactive sgk1-k127a mutant did not affect the hormonal induction of g (na) but did suppress the activation of sgk1. 0.57 SIGNOR-180829 CABIN1 protein Q9Y6J0 UNIPROT HIRA complex 1 complex SIGNOR-C461 SIGNOR form complex binding 9606 30285846 YES miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. 0.696 SIGNOR-269435 AVPR1B protein P47901 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257176 EP300 protein Q09472 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys28 LATKAARkSAPSTGG 9606 SIGNOR-C6 21131905 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 fspada These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. 0.2 SIGNOR-170266 HIPK2 protein Q9H2X6 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr53 KEPSEVPtPKRPRGR 9606 17960875 YES gcesareni Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation. 0.494 SIGNOR-158620 IL17RC protein Q8NAC3 UNIPROT IL17R complex complex SIGNOR-C260 SIGNOR form complex binding 9606 BTO:0001946 32024054 YES lperfetto Importantly, IL-17 was involved in increased collagen production in cardiac fibroblasts in response to HG, with both subunits of the IL-17RA and IL-17RC heterodimer complex being important to mediating this response. 0.548 SIGNOR-261336 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 YES lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). 0.914 SIGNOR-236752 CSAD protein Q9Y600 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 22718265 YES miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. 0.8 SIGNOR-267548 PKA proteinfamily SIGNOR-PF17 SIGNOR SLITRK1 protein Q96PX8 UNIPROT up-regulates activity phosphorylation Ser695 DCGSHSLsD -1 19640509 YES miannu In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides. 0.2 SIGNOR-273634 PPM1A protein P35813 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 9707433 YES lperfetto Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay 0.409 SIGNOR-59618 TAF11 protein Q15544 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.903 SIGNOR-263925 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser276 PLPSPTAsPNHTLAP 9606 BTO:0000142 15262992 YES lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd 0.396 SIGNOR-126847 SMURF1 protein Q9HCE7 UNIPROT PARD6/SMURF1 complex SIGNOR-C112 SIGNOR form complex binding 9606 BTO:0004183 15761148 YES lperfetto The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT. 0.637 SIGNOR-227562 TBX3 protein O15119 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 25211658 YES lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS 0.304 SIGNOR-249602 TNK2 protein Q07912 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr176 EKATGRYyAMKILKK 10090 BTO:0002021 20333297 YES gcesareni Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. 0.427 SIGNOR-252457 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MCL1 protein Q07820 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 18676833 YES inferred from 70% family members fstefani We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1. 0.2 SIGNOR-270158 sepantronium bromide chemical CHEBI:139608 ChEBI BIRC5 protein O15392 UNIPROT down-regulates activity chemical inhibition 9606 25659731 YES miannu The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation. 0.8 SIGNOR-262245 CAPN1 protein P07384 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Lys76 YRLVSINkSSPLQKQ -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.377 SIGNOR-263560 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 8668348 YES lperfetto We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. 0.789 SIGNOR-244843 SRMS protein Q9H3Y6 UNIPROT FKBP4 protein Q02790 UNIPROT down-regulates activity phosphorylation 9606 34077419 YES miannuccelli Together, these data indicate that SRMS inhibits the scaffolding function of its endogenous substrate FKBP51, thus antagonizing FKBP51-dependent inactivation of AKT (S4E Fig).|We demonstrate that SRMS phosphorylates FKBP51 to inhibit its scaffolding activity and promote its degradation through the ubiquitin-proteasome pathway. 0.268 SIGNOR-279764 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM7A protein Q6ZMT4 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273470 ATP6V1H protein Q9UI12 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR up-regulates activity binding 10090 BTO:0004122 29782852 YES miannu ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs. Lack of ATP6V1H function decreases bone formation in vivo 0.227 SIGNOR-266887 PF-03814735 chemical CID:49830590 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205953 NFE2L2 protein Q16236 UNIPROT ABCB6 protein Q9NP58 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Two critical enzymes in this pathway, ATP binding cassette subfamily B member 6 (ABCB6) and ferrochelatase (FECH), are regulated by the transcription factor NFE2L2 and play significant roles in inhibiting ferroptosis when upregulated. 0.2 SIGNOR-279864 CDK19 protein Q9BWU1 UNIPROT CyclinC/CDK19 complex SIGNOR-C544 SIGNOR form complex binding 9606 BTO:0004173 25344755 YES lperfetto We found that in MOLT-16 cells cyclin C physically interacts with CDK19 (Fig. 5a) and activates its kinase activity (Fig. 5e and Supplementary Fig. 4f,g). 0.913 SIGNOR-273155 ADSL protein P30566 UNIPROT SAICAR(4-) smallmolecule CHEBI:58443 ChEBI down-regulates quantity chemical modification 9606 22812634 YES miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case 0.8 SIGNOR-266611 GARS1 protein P41250 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates quantity chemical modification 9606 24898252 YES miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 0.8 SIGNOR-270482 NKX3-1 protein Q99801 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization 9606 16697957 NO miannu NKX3.1 stabilizes p53.NKX3.1 can physically associate with HDAC1 and promotes p53 acetylation by recruiting HDAC1 from p53-MDM2-HDAC1 complex 0.356 SIGNOR-251548 RALGAPB protein Q86X10 UNIPROT RalGAP1 complex SIGNOR-C468 SIGNOR form complex binding 10090 BTO:0000011 21148297 YES miannu Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA. 0.413 SIGNOR-269792 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser422 NNNNRKTsNGDDSLF 9606 21930781 YES lperfetto Cftr possesses two ck2 phosphorylation sites (s422 and t1471)this is consistent with an important role for s422 phosphorylation in increasing cftr activity. 0.278 SIGNOR-176619 TCEA1 protein P23193 UNIPROT UBR5 protein O95071 UNIPROT up-regulates binding 9606 21127351 YES miannu We show that the e3 ubiquitin ligase ubr5 associates with the cdk9 subunit of positive transcription elongation factor b to mediate its polyubiquitination in human cells. Tfiis also binds ubr5 to stimulate cdk9 polyubiquitination. 0.358 SIGNOR-170258 XL765 chemical CHEBI:71958 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207875 TNF protein P01375 UNIPROT SCN3A protein Q9NY46 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.2 SIGNOR-253485 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates activity phosphorylation Ser100 HLSGRKLsLQERSQG 9534 BTO:0000298 32913128 YES miannu  Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues.  0.2 SIGNOR-277239 PLK1 protein P53350 UNIPROT TERF1 protein P54274 UNIPROT up-regulates phosphorylation Ser435 KKLKLISsDSED 9606 18625707 YES lperfetto Plk1 phosphorylation of trf1 is essential for its binding to telomeres 0.373 SIGNOR-179461 SLC2A1 protein P11166 UNIPROT glucose chemical CHEBI:17234 ChEBI up-regulates quantity relocalization 9606 23506862 YES miannu GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells. 0.8 SIGNOR-267460 TNFRSF25 protein Q93038 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 YES amattioni Dr3 induces apoptosis by tradd-mediated recruitment of fadd and caspase-8 0.738 SIGNOR-100480 PSMD6 protein Q15008 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.89 SIGNOR-263350 AKT proteinfamily SIGNOR-PF24 SIGNOR TBX3 protein O15119 UNIPROT up-regulates activity phosphorylation Ser719 AEKEAATsELQSIQR 9606 25595898 YES lperfetto We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion. 0.2 SIGNOR-244353 AURKA protein O14965 UNIPROT MBD3 protein O95983 UNIPROT up-regulates phosphorylation Ser85 RQRVRYDsSNQVKGK 9606 BTO:0000567 12354758 YES llicata These results suggest that the biochemical changes of mbd3 may be intimately related to the targeting of mbd3 to centrosomes. aurora-a phosphorylates mbd3 0.286 SIGNOR-93697 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQB1 protein P01920 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.273 SIGNOR-253992 TAK-875 chemical CID:24857286 PUBCHEM FFAR1 protein O14842 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207182 AKT proteinfamily SIGNOR-PF24 SIGNOR PDE3B protein Q13370 UNIPROT up-regulates phosphorylation Ser295 VIRPRRRsSCVSLGE 9606 10454575 YES esanto Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b. 0.2 SIGNOR-70205 LCK protein P06239 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 9606 BTO:0000007 9973379 YES Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218.the role of Y218 in CTLA-4 biology is not known at the present 0.748 SIGNOR-251371 JAK2 protein O60674 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Tyr88 KGSLPEFyYRPPRPP 9606 21423214 YES miannu JAK2 phosphorylates tyrosine residue 88 (Y88) of p27(Kip1). 0.695 SIGNOR-278260 MLL2 complex complex SIGNOR-C88 SIGNOR ESR1 protein P03372 UNIPROT up-regulates binding 9606 16603732 YES miannu Eralpha directly binds to the mll2 complex through two lxxll motifs in a region of mll2 near the c terminus in a ligand-dependent manner. Disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity. 0.455 SIGNOR-145868 CDK1 protein P06493 UNIPROT NUP98 protein P52948 UNIPROT down-regulates activity phosphorylation Ser612 LNNSNLFsPVNRDSE 9606 21335236 YES gcesareni We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks. 0.398 SIGNOR-172217 PER2 protein O15055 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 NO miannu PER2 Suppresses TWIST1 and SLUG Transcription by Recruiting EZH2, SUZ12, and HDAC2. 0.2 SIGNOR-254147 RORA protein P35398 UNIPROT CAV3 protein P56539 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15199055 NO Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. 0.2 SIGNOR-254255 MECP2 protein P51608 UNIPROT DEAF1 protein O75398 UNIPROT up-regulates activity binding 10090 BTO:0000142 29636529 YES Gianni We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue.To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons. 0.2 SIGNOR-269063 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation 9606 17573348 YES gcesareni Here we show in vitro that lkb1 phosphorylates and activates mark2 0.587 SIGNOR-156126 BMP1 protein P13497 UNIPROT COL5A1 protein P20908 UNIPROT up-regulates activity cleavage Asp1549 IKTEEISeVKMDAEF 9606 BTO:0002974 11741999 YES miannu BMP-1 Can Efficiently Cleave Pro-α1(V) N-propeptides and Pro-α2(V) C-propeptides and Less Efficiently Cleave Pro-α1(V) C-propeptides in Vitro.NH2-terminal sequencing of an ∼35-kDa band in the BMP-1-treated material (N-α1(V), Fig. 3 B,lanes 2 and 3) showed it to correspond to the NH2-terminal portion of the pro-α1(V) N-propeptide previously shown to be cleaved in pro-α1(V)3 homotrimers by BMP-1 (39), whereas NH2-terminal sequencing of an ∼38-kDa band (C-α1(V)BMP-1, Fig. 3 B,lanes 2 and 3) showed it to correspond to pro-α1(V) C-propeptides cleaved between Asp-1594 and Asp-1595. 0.622 SIGNOR-256344 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 9606 10884684 YES lperfetto Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations 0.8 SIGNOR-78915 RSPO2 protein Q6UXX9 UNIPROT FZD4 protein Q9ULV1 UNIPROT down-regulates quantity ubiquitination 9606 22575959 YES miannu Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. 0.313 SIGNOR-260117 ADCYAP1 protein P18509 UNIPROT ADCYAP1R1 protein P41586 UNIPROT up-regulates binding 9606 8703026 YES gcesareni Type i pacap receptors bind pacap-27 and -38. the potencies of the two forms of pacap are similar for adenylate cyclase stimulation, whereas pacap-38 is more potent than pacap-27 in phospholipase c activation. 0.877 SIGNOR-43225 clozapine chemical CHEBI:3766 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258518 BTRC protein Q9Y297 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates ubiquitination 9606 BTO:0000007 BTO:0001253 18296647 YES gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. 0.425 SIGNOR-160985 ARF3 protein P61204 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 NO lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface 0.7 SIGNOR-272150 S1PR3 protein Q99500 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.492 SIGNOR-257062 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr768 MTSTYGRtPMYGSQT 9606 16427012 YES lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif 0.776 SIGNOR-143919 PKA proteinfamily SIGNOR-PF17 SIGNOR PDZK1 protein Q5T2W1 UNIPROT up-regulates activity phosphorylation Ser505 MAKERAHsTASHSSS 10029 BTO:0000457 16174736 YES done miannu Metabolic labeling experiments and phosphoamino acid analysis revealed that PDZK1 is phosphorylated at Ser residues within this region. Point-mutation analysis demonstrated that PDZK1 is phosphorylated at Ser-509. Interestingly, a mutant PDZK1, in which Ser-509 was replaced with Ala, lost the ability to up-regulate SR-BI protein. 0.2 SIGNOR-273784 HIPK2 protein Q9H2X6 UNIPROT CBX4 protein O00257 UNIPROT up-regulates activity phosphorylation 9606 17018294 YES miannu In addition, HIPK2 phosphorylates Pc2 at several sites, including threonine 495. 0.423 SIGNOR-278484 CAPN2 protein P17655 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity cleavage 9606 BTO:0000590 25969760 YES lperfetto Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains 0.434 SIGNOR-251611 NF1 protein P21359 UNIPROT ADCY6 protein O43306 UNIPROT up-regulates 9606 BTO:0000938 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.264 SIGNOR-204195 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 YES lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity 0.742 SIGNOR-182975 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18377662 YES Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175 0.667 SIGNOR-248474 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258780 GNAZ protein P19086 UNIPROT ADCY5 protein O95622 UNIPROT down-regulates activity binding 7108 BTO:0001240 7829508 YES Marta Tosoni Activated a z inhibits the activity of type I and type V adenylyl cyclases. 0.518 SIGNOR-278045 SWI/SNF complex complex SIGNOR-C92 SIGNOR MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR form complex binding 9606 BTO:0001103 17194702 YES miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes 0.2 SIGNOR-151703 VWF protein P04275 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 YES lperfetto Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury 0.687 SIGNOR-261853 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr207 YYDTHTNtYYLRTFG 9606 16669787 YES miannu We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1 0.525 SIGNOR-146517 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr106 SGNSAEEyYENVPCK -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.245 SIGNOR-273556 GADD45A protein P24522 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR down-regulates binding 9606 10362260 YES lperfetto Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex 0.689 SIGNOR-217508 PKN3 protein Q6P5Z2 UNIPROT ARHGAP18 protein Q8N392 UNIPROT up-regulates activity phosphorylation Thr154 AVQKRVEtVSQTLRK -1 33092266 YES lperfetto We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158. 0.2 SIGNOR-264570 ATF4 protein P18848 UNIPROT DYRK3 protein O43781 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000578 31066068 YES miannu Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop. 0.2 SIGNOR-275453 GNRH1 protein P01148 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 BTO:0000007 17202804 YES miannu GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5 0.459 SIGNOR-259267 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM7 protein Q14831 UNIPROT up-regulates activity chemical activation 9606 25042998 YES miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate 0.8 SIGNOR-264072 AKT1 protein P31749 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr120 IIRLRNKtLTEDEIA 9606 19940129 YES llicata Akt interacts with mst1 and phosphorylates a highly conserved residue threonine 120 of mst1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of thr(183). 0.398 SIGNOR-252507 SLC5A5 protein Q92911 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity relocalization 10116 28192058 YES scontino Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis.  0.8 SIGNOR-266960 IL1B protein P01584 UNIPROT IL1R2 protein P27930 UNIPROT down-regulates binding 9606 BTO:0000876 8332913 YES gcesareni Interleukin-1 (il-1) interacts with cells through two types of binding molecules, il-1 type i receptor (il-1r i) and il-1r ii. Il-1r ii inhibits il-1 activity by acting as a decoy target for il-1 0.878 SIGNOR-38302 PPM1D protein O15297 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Ser140 GKKATQAsQEY 9606 20118229 YES gcesareni Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-h2ax and suppresses dna double strand break repair. Here, we demonstrate that the wild-type p53-induced phosphatase 1 (wip1) also dephosphorylates gamma-h2ax at serine 139 in vitro and in vivo. 0.2 SIGNOR-163693 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7322 RAGSRAGsRASSRRG 9606 BTO:0004905 21295697 YES lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. 0.436 SIGNOR-264433 TFE3 protein P19532 UNIPROT CLCN7 protein P51798 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.284 SIGNOR-276814 TLR4 protein O00206 UNIPROT JUN protein P05412 UNIPROT up-regulates activity 9606 BTO:0000801 19592489 NO lperfetto The transcription factor AP-1 consists of a variety of dimers composed of members of the Jun, Fos, and ATF families of proteins. The Jun proteins can both homo- and heterodimerize with Fos members to form transcriptionally active complexes. The stimulation of macrophage TLR4 receptor rapidly activates not only the NF-kappaB pathway but also MAPK pathways, including JNK, ERK, and p38. Many of the downstream targets of MAPK pathways are transcription factors that include c-Jun. 0.443 SIGNOR-249518 N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester chemical CHEBI:94306 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000785 31016515 YES Gianni We explored the anti-tumor effect and the molecular mechanism of cay10603, a potent HDAC6 inhibitor in Burkitt's lymphoma cells. 0.8 SIGNOR-262205 HBEGF protein Q99075 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 9135143 YES gcesareni It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response. 0.749 SIGNOR-47881 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.257 SIGNOR-159454 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI up-regulates quantity precursor of 9606 31226734 YES lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form 0.8 SIGNOR-265913 PTK2 protein Q05397 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 15688067 YES miannu Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade. 0.705 SIGNOR-257733 G3BP1 protein Q13283 UNIPROT G3BP2 protein Q9UN86 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 YES miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. 0.46 SIGNOR-260862 RBX1 protein P62877 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000093 20130088 YES miannu I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERalpha protein. 0.344 SIGNOR-271434 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr184 GTACDIQtHMTNNKG -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. 0.2 SIGNOR-227544 DLX5 protein P56178 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity transcriptional regulation 9031 17335796 YES gcesareni Dlx5 initiates a complete osteogenic differentiation in these early primary cells, by triggering Runx2, osteopontin, alkaline phosphatase, and other gene expression according to the sequential temporal sequence observed during skull osteogenesis €œin vivo€. 0.373 SIGNOR-245340 CDK12 protein Q9NYV4 UNIPROT CyclinK/CDK12 complex SIGNOR-C37 SIGNOR form complex binding 9606 22012619 YES miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells 0.942 SIGNOR-176789 TBX21 protein Q9UL17 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 17541280 NO T-bet is crucially implicated in Th1 differentiation due to its strong promoting activity for IFN-gamma gene transcription 0.476 SIGNOR-254508 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. 0.817 SIGNOR-238638 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206313 G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0000007 23279204 NO miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. 0.7 SIGNOR-260864 TAF4 protein O00268 UNIPROT ATF7 protein P17544 UNIPROT down-regulates activity binding 9534 BTO:0004055 15735663 YES miannu These results not only demonstrate an interaction between ATF7 and TAF4 but also indicate, as in the case of TAF12 (see Figure 3e), that no additional cellular component is required for this binding. They also suggest that TAF4 may interfere with the formation of ATF7–TAF12 subcomplexes, thereby inhibiting ATF7-induced transactivation. 0.397 SIGNOR-225300 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. 0.894 SIGNOR-267967 ILK protein Q13418 UNIPROT NACA protein E9PAV3 UNIPROT up-regulates phosphorylation Ser1906 PELEEQDsTQATTQQ 9606 15299025 YES lperfetto The inactivation of gsk3? In response to adhesion and ilk activation (6) would then result in a thr-159-hypophosphorylated ?-Nac that would become unavailable for proteasome degradation but would become a substrate for the ilk kinase activity on residue ser-43. The ser-43-phosphorylated ?-Nac would preferentially interact with c-jun (30), translocate to the nucleus, and potentiate transcription 0.425 SIGNOR-127631 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258631 NLGN4Y protein Q8NFZ3 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.2 SIGNOR-264163 KRAS protein P01116 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner. 0.777 SIGNOR-175213 Frizzled proteinfamily SIGNOR-PF11 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity 18697834 NO Simone Vumbaca […] we suggest that Wnt1, Wnt3a and Wnt5a result in the accumulation of Act-β-Cat 0.2 SIGNOR-255652 NUP98 protein P52948 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 20498086 NO miannu The export of mRNAs is a multistep process, involving the packaging of mRNAs into messenger ribonucleoprotein particles (mRNPs), their transport through nuclear pore complexes, and mRNP remodeling events prior to translation. Ribonucleic acid export 1 (Rae1) and Nup98 are evolutionarily conserved mRNA export factors that are targeted by the vesicular stomatitis virus matrix protein to inhibit host cell nuclear export. these data suggest that the Rae1*Nup98 complex directly binds to the mRNP at several stages of the mRNA export pathway. 0.7 SIGNOR-260872 PKN3 protein Q6P5Z2 UNIPROT ARHGAP18 protein Q8N392 UNIPROT up-regulates activity phosphorylation Thr158 RVETVSQtLRKKNKQ -1 33092266 YES lperfetto We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158. 0.2 SIGNOR-264572 ZNF746 protein Q6NUN9 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000793 21376232 YES miannu PARIS represses the expression of the transcriptional coactivator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. 0.445 SIGNOR-277627 MECP2 protein P51608 UNIPROT GPRIN1 protein Q7Z2K8 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 18511691 YES Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. 0.298 SIGNOR-264679 MUTYH protein Q9UIF7 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 BTO:0000007 21615992 YES miannu Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis. 0.373 SIGNOR-173972 CENPS protein Q8N2Z9 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.2 SIGNOR-265205 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 11812650 YES gcesareni However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2. 0.521 SIGNOR-114597 5-azacytidine chemical CHEBI:2038 ChEBI DNMT1 protein P26358 UNIPROT down-regulates activity chemical inhibition 9606 14585280 YES miannu Both Azacitidine and Decitabine may also exert antitumor activity through induction of DNA hypomethylation, by forming a covalent complex with the major DNA methyltransferase (now termed DNMT1).Azacitidine and Decitabine effectively deplete the cell of functional DNA methylating activity, which results in profound hypomethylation after several rounds of DNA replication (Fig. 2). DNMT1 is considered a bona fide anticancer target at different levels 0.8 SIGNOR-259293 CSNK1A1 protein P48729 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 21695114 YES gcesareni We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation. 0.519 SIGNOR-174542 PRKCZ protein Q05513 UNIPROT YWHAB protein P31946 UNIPROT down-regulates activity phosphorylation Thr143 SGDNKQTtVSNSQQA 9534 BTO:0004055 10620507 YES lperfetto Our results with the 14-3-3 mutants indirectly imply a new phosphorylation site, 130Ser (and to a lesser extent 141Thr), in 14-3-3b that regulates the association}dissociation of 14-3-3b and PKC-f. 0.369 SIGNOR-249035 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 15328002 YES gcesareni Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes. 0.2 SIGNOR-128415 AHSP protein Q9NZD4 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by stabilization binding 9606 18179859 YES Regulation miannu α-Hemoglobin stabilizing protein (AHSP) binds α-hemoglobin (Hb), avoiding its precipitation and its pro-oxidant activity. 0.774 SIGNOR-251770 CDK5 protein Q00535 UNIPROT ATM protein Q13315 UNIPROT up-regulates phosphorylation Ser794 LSNCTKKsPNKIASG 9606 BTO:0000938 19151707 YES lperfetto Here we show that cdk5 (cyclin-dependent kinase 5), activated by dna damage, directly phosphorylates atm at ser 794 in post-mitotic neurons. Phosphorylation at ser 794 precedes, and is required for, atm autophosphorylation at ser 1981, and activates atm kinase activity 0.415 SIGNOR-183454 NLGN4X protein Q8N0W4 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.767 SIGNOR-264160 hexadecanoic acid smallmolecule CHEBI:15756 ChEBI palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI up-regulates quantity precursor of 9606 21242590 YES miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). 0.8 SIGNOR-267876 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr930 LAHGADPtMKNQEGQ 9606 BTO:0000567 21818122 YES miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  0.428 SIGNOR-276243 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 15735151 NO gcesareni Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1 0.8 SIGNOR-134216 ZDHHC13 protein Q8IUH4 UNIPROT MC1R protein Q01726 UNIPROT up-regulates activity palmitoylation 10090 BTO:0000847 28869973 YES miannu Collectively these results suggest that ZDHHC13 phosphorylation by ATR following UVB irradiation promotes its interaction with MC1R to stimulate MC1R palmitoylation.Activating MC1R palmitoylation rescues the defect of MC1R RHC variants 0.274 SIGNOR-273518 EPS15 protein P42566 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 YES lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth 0.691 SIGNOR-260713 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser68 GQNGEEKsPPNASHP -1 15850461 YES miannu CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.286 SIGNOR-263085 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 YES The effect has been demonstrated using P10636-8 lperfetto Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells. 0.738 SIGNOR-164655 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Thr316 GTASSRKtLWNQELY -1 21880142 YES miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. 0.307 SIGNOR-266310 NMDA receptor_2D complex SIGNOR-C350 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264135 CSNK1E protein P49674 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser45 GATTTAPsLSGKGNP 9606 BTO:0000007 12176352 YES gcesareni Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45). 0.656 SIGNOR-244102 PRKCA protein P17252 UNIPROT PRKG1 protein Q13976 UNIPROT up-regulates phosphorylation Thr59 THIGPRTtRAQGISA 9606 12609995 YES gcesareni Antibodies generated against phosphorylated threonine 58 were used to demonstrate phosphorylation in response to pma treatment of the cells with kinetics similar to vasodilator-stimulated phosphoprotein phosphorylation. A phospho-mimetic mutation at this site (t58e) generated a partially activated pkg that was more sensitive to cgmp levels. A phospho- mutation (t58a) revealed that this residue is important but not sufficient for pkg activation by pkc. 0.345 SIGNOR-98803 MARCHF5 protein Q9NX47 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 20103533 YES Barakat MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. 0.2 SIGNOR-274133 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.762 SIGNOR-252754 TRIM11 protein Q96F44 UNIPROT PHOX2B protein Q99453 UNIPROT down-regulates ubiquitination 9606 22307522 YES miannu The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b. 0.485 SIGNOR-195878 LPAR3 protein Q9UBY5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 12531543 YES gcesareni Lpa3couples to gq 0.482 SIGNOR-97400 PER1 protein O15534 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. 0.732 SIGNOR-267978 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266521 PPP2CA protein P67775 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates dephosphorylation 9606 20626350 YES gcesareni In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a. 0.558 SIGNOR-166649 CDK2 protein P24941 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates activity phosphorylation Ser19 QRVQAMKsPDHNGED 9606 BTO:0000815 28842430 YES miannu In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions. 0.383 SIGNOR-277366 ZBED1 protein O96006 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 7227 BTO:0001138 22021382 NO 1 miannu XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression. 0.2 SIGNOR-239736 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270390 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation -1 9525907 YES inferred from 70% family members miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. 0.2 SIGNOR-270170 PRKCA protein P17252 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 YES lperfetto In vitro kinase assays show that Ser-59 can be uniquely phosphorylated by mitogen-activated protein kinase and that Ser-42 can be phosphorylated by either protein kinase A or protein kinase C. 0.323 SIGNOR-248936 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269339 RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 BTO:0000007;BTO:0000661 16603398 YES lperfetto Taken together, these results indicate that polyubiquitination of RIP1 mediates the independent re- cruitment of TAB2 and NEMO, which in turn recruits TAK1 and IKK, respectively, to TNF-R1. 0.863 SIGNOR-145861 Ub:E2 complex SIGNOR-C497 SIGNOR MID2 protein Q9UJV3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270973 CDK2 protein P24941 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser224 APSVSHVsPRKNPSV 9606 17638878 YES lperfetto Atrip is a cdk2 substrate, and cdk2-dependent phosphorylation of s224 regulates the ability of atr-atrip to promote cell cycle arrest in response to dna damage./ One possibility is s224 phosphorylation creates a binding site for another protein involved in the g2-m checkpoint response 0.578 SIGNOR-156928 MAPK3 protein P27361 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation Ser982 KKKSEPSsPDHGSST -1 11287604 YES lperfetto Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 0.413 SIGNOR-106565 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 19914161 YES lpetrilli Phosphorylation of the linker region of Smads mediated by ERK2, GSK3β, and CDK2/4 negatively regulates Smad activity 0.745 SIGNOR-161609 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr273 LGQRIYQyIQSRFYR 9606 10910078 YES lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site 0.2 SIGNOR-79810 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Ser268 WQRRQRKsRRTI 9606 BTO:0000782 2303462 YES lperfetto The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site. 0.264 SIGNOR-22984 clobetasol chemical CHEBI:205919 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 9606 26658258 YES Non-canonical SMO pathway SimoneGraziosi Two of the top ranking compounds, Halcinonide and Clobetasol, act as Smoothened (Smo) agonists to up-regulate myelin gene expression in the Oli-neuM cell line.  0.8 SIGNOR-269216 BMP4 protein P12644 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 8006002 YES fspada Bmp-4 bound to alk-3 and alk-6 efficiently 0.78 SIGNOR-35763 ELK3 protein P41970 UNIPROT MYH6 protein P13533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 12933792 NO miannu From HeLa cells an Ets family of protein, Ets-related protein (ERP), binds to double-stranded PNR element. The ERP.PNR complex inhibited the activity of the basal transcription complex from homologous as well as heterologous promoters in a PNR position-independent manner, suggesting that ERP acts as a silencer of alpha-MHC gene expression in non-muscle cells. 0.2 SIGNOR-253900 ACE2 protein Q9BYF1 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT up-regulates activity cleavage Pro40 GDRVYIHpFHLVIHN -1 11815627 YES miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. 0.2 SIGNOR-260222 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 22944199 NO gcesareni In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Here we report that cells expressing wnt1 will preferentially activate myf5 while cells expressing wnt7a will preferentially activate myod 0.348 SIGNOR-198922 INCENP protein Q9NQS7 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 YES miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). 0.877 SIGNOR-275425 GATA4 protein P43694 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 YES miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter 0.25 SIGNOR-265815 MTTP protein P55157 UNIPROT APOB protein P04114 UNIPROT up-regulates activity lipidation 9606 23721961 YES miannu As ApoB is translated, it is lipidated by microsomal triglyceride transfer protein (MTP). MTP adds triglycerides to the nascent ApoB during its co-translational translocation into the lumen of the endoplasmic reticulum. 0.792 SIGNOR-252118 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1799 RRLSNVSsSGSINLL -1 8631898 YES miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. 0.419 SIGNOR-250167 PRKCG protein P05129 UNIPROT GRK2 protein P25098 UNIPROT up-regulates phosphorylation Ser29 ATPAARAsKKILLPE 9606 11042191 YES acerquone Phosphorylation of grk2 by protein kinase c abolishes its inhibition by calmodulinin vitro, grk2 was preferentially phosphorylated by pkc isoforms alpha, gamma, and delta 0.2 SIGNOR-83231 SLBP protein Q14493 UNIPROT H2BC9 protein Q93079 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265391 SYNGAP1 protein Q96PV0 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 26356309 YES miannu The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95. 0.597 SIGNOR-264229 LTF protein P02788 UNIPROT iron(3+) smallmolecule CHEBI:29034 ChEBI up-regulates quantity relocalization 9606 11747454 YES Lactoferrin (Lf), a major iron-binding protein in human milk, has been suggested to have multiple biological roles such as facilitating iron absorption, modulating the immune system, embryonic development, and cell proliferation. 0.8 SIGNOR-272473 ADSL protein P30566 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 22812634 YES miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case 0.8 SIGNOR-266607 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000586 16293724 YES lperfetto Because phosphorylation of β-catenin by GSK-3β leads to its rapid ubiquitination and subsequent degradation in the proteosome, inactivation of GSK-3β is often a prerequisite for stimulating the accumulation, nuclear translocation, and functional activity of β-catenin 0.894 SIGNOR-227893 CDK1 protein P06493 UNIPROT APLP2 protein Q06481 UNIPROT unknown phosphorylation Thr736 VEVDPMLtPEERHLN 9606 BTO:0000142 9109675 YES lperfetto A cytoplasmic domain peptide from aplp2 is phosphorylated in vitro by protein kinase c and cdc2 kinase. Aplp2 is phosphorylated by cdc2 kinase at a site homologous to the cdc2 kinase site phosphorylated in app. 0.334 SIGNOR-47483 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT up-regulates activity binding 9606 23020315 YES miannu Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF 0.788 SIGNOR-251967 MELK protein Q14680 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates activity phosphorylation Thr354 WENLHQQtPPKLTAY 9606 BTO:0000007 22544756 YES miannu The results showed that MPK38 interacted with and inhibited PDK1 activity via Thr(354) phosphorylation.  0.267 SIGNOR-276414 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity deubiquitination 9606 25481026 YES miannu Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response. 0.2 SIGNOR-260249 TPH1 protein P17752 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity chemical modification 9606 31024440 YES brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. 0.8 SIGNOR-264010 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 YES miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. 0.2 SIGNOR-251566 CLOCK protein O15516 UNIPROT CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR form complex binding 19605937 YES lperfetto Like BMAL1, its paralog BMAL2 dimerizes with CLOCK to activate the E-box-dependent transcription 0.683 SIGNOR-253711 RAD18 protein Q9NS91 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination 9606 19706603 YES gcesareni Rad5 interacts with the e3 ligase rad18, which is initially required to monoubiquitinate pcna 0.846 SIGNOR-187705 FLNA protein P21333 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity binding 10116 BTO:0000232 11102480 YES Luisa Filamin may function as a scaffold protein in the postsynaptic density, mediating a direct link between Kv4.2 and the actin cytoskeleton, and that this interaction is essential for the generation of appropriate Kv4.2 current densities. 0.353 SIGNOR-269003 MAP3K1 protein Q13233 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17563747 YES lperfetto Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna. 0.291 SIGNOR-236346 MMP3 protein P08254 UNIPROT HBEGF protein Q99075 UNIPROT up-regulates cleavage 9606 BTO:0000150 11043579 YES gcesareni It was concluded that mmp-3 cleaves hb-egf at a specific site in the jm domain and that this enzyme might regulate the conversion of hb-egf from being a juxtacrine to a paracrine/autocrine growth factor. 0.516 SIGNOR-83339 FAM83H protein Q6ZRV2 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273755 ID3 protein Q02535 UNIPROT TCF12 protein Q99081 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C128 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.466 SIGNOR-241152 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.771 SIGNOR-269237 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI down-regulates quantity chemical modification 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-268115 E2F4 protein Q16254 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12110166 NO fspada We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation 0.46 SIGNOR-90507 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Pro) smallmolecule CHEBI:29177 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270427 5'-S-methyl-5'-thioadenosine smallmolecule CHEBI:17509 ChEBI adenine smallmolecule CHEBI:16708 ChEBI up-regulates quantity precursor of 9606 3091600 YES miannu The reaction catalyzed by the enzyme is fully reversible with a Keq of 1.39 X 10(-2) (in the direction of phosphorolysis) at 37 degrees C and pH 7.4. The Km values for 5'-methylthioadenosine, phosphate, adenine, and 5-methylthioribose 1-phosphate are 5, 320, 23, and 8 microM, respectively. 0.8 SIGNOR-278891 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR IKBKB protein O14920 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 10321728 YES miannu We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.  0.45 SIGNOR-272547 BMP7 protein P18075 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 7644468 YES lperfetto In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7. 0.778 SIGNOR-217520 P-TEFb complex SIGNOR-C238 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001545 19516275 NO miannu Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) inhibits the positive transcription elongation factor b (P-TEFb), which is a key RNA polymerase II (Pol II) transcriptional regulator. In transfected cells, mutated NPM1 associated with, and sequestered, HEXIM1 in cytoplasm, resulting in higher transcription of RNA pol II target genes, among which were some positive regulators of cell-cycle progression such as cyclin D1 and anti-apoptotic proteins such as Mcl-1 0.7 SIGNOR-260137 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr2 tTSQKHRD 9606 16495336 YES lperfetto Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain 0.503 SIGNOR-144799 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 YES lperfetto The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. 0.79 SIGNOR-74835 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 YES miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. 0.8 SIGNOR-262248 ARRB2 protein P32121 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates activity binding 9606 24817116 YES lperfetto We identified a new adaptor beta-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells. 0.2 SIGNOR-261428 UIMC1 protein Q96RL1 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 YES lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  0.925 SIGNOR-263211 CRBN protein Q96SW2 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31591562 YES miannu CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs.When thalidomide binds to CRBN, substrate specificity of CRL4CRBN is altered and CRBN neomorphically binds to ∆Np63, TAp63 and other neosubstrates and ubiquitinates them for proteasomal degradation. 0.2 SIGNOR-272214 DPP6 protein P42658 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity relocalization 8355 BTO:0000964 17130523 YES Luisa DPPX-S reduced energy barriers of the voltage-dependent transitions; therefore, this auxiliary subunit may exert a catalytic effect on voltage-dependent gating of Kv4.2 channels. DPPX-S may also accelerate coupled inactivation indirectly 0.549 SIGNOR-269005 TGFB1 protein P01137 UNIPROT ITGA2 protein P17301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001596 1744142 NO lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. 0.285 SIGNOR-253354 PRKCA protein P17252 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates phosphorylation 9606 20577053 YES gcesareni The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex, 0.261 SIGNOR-166368 CDK6 protein Q00534 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 16160006 YES gcesareni Phosphorylation on ser-10 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.p27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization. 0.855 SIGNOR-140401 MAPK14 protein Q16539 UNIPROT CCND1 protein P24385 UNIPROT up-regulates phosphorylation 9606 20626350 YES gcesareni A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins 0.426 SIGNOR-166594 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr383 HYRYSDTtDSDPENE 9606 18321849 YES gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity 0.605 SIGNOR-161126 IL5RA protein Q01344 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 21106848 NO Human blood eosinophils exhibit a hyperactive phenotype in response to chemotactic factors after cell priming with IL-5 family cytokines. Earlier work has identified ERK1/2 as molecular markers for IL-5 priming 0.2 SIGNOR-254350 SRC protein P12931 UNIPROT HSP90AB1 protein P08238 UNIPROT up-regulates phosphorylation Tyr301 DDITQEEyGEFYKSL 9606 17855507 YES lperfetto C-src directly phosphorylates hsp90 on tyrosine 300 residue and that this event is essential for vegf-stimulated enos association to hsp90 and thus no release from endothelial cells. 0.586 SIGNOR-157781 FYN protein P06241 UNIPROT MAG protein P20916 UNIPROT up-regulates activity phosphorylation Tyr620 LTEELAEyAEIRVK 10090 BTO:0000142 7525550 YES Fyn constitutively binds to MAG in a latent form. Ligand stimulation of L-MAG would result in activation of Fyn kinase and phosphorylation of Tyr-620. Binding and activation of PLC y through this phosphotyrosine residue would contribute to the signaling pathway involved in the regulation of myelination. 0.426 SIGNOR-251178 ANO6 protein Q4KMQ2 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 24663380 NO francesca Ano6 deficiency significantly reduces ERK/AKT phosphorylation. Our data have also shown that Ano6-KD significantly attenuates ERK phosphorylation, which is implicated in the regulation of cancer cell proliferation by Ano1, suggesting that Ano6 is potentially involved in regulating myoblast proliferation through the ERK signaling pathway. 0.2 SIGNOR-261214 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782 8325880 YES gcesareni Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase|The present study shows that the MAP kinase has a 20-fold preference for Ser25 as opposed to Ser38 of Op18, while cdc2 kinases have a 5-fold preference for the Ser38 residue. 0.412 SIGNOR-37848 CDK1 protein P06493 UNIPROT REPS2 protein Q8NFH8 UNIPROT down-regulates activity phosphorylation Ser463 RPRSRSYsSTSIEEA 10029 10764745 YES miannu Phosphorylation of POB1 and Epsin by p34cdc2 kinase. Their phosphorylation sites (Ser411 of POB1 and Ser357 of Epsin) were determined. Phosphorylated Epsin and EpsinS357D formed a complex with α-adaptin less efficiently than wild type Epsin. 0.341 SIGNOR-262724 trimipramine chemical CHEBI:9738 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258741 TPR protein P12270 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.603 SIGNOR-262070 D-glucopyranose smallmolecule CHEBI:4167 ChEBI lactose smallmolecule CHEBI:17716 ChEBI up-regulates quantity precursor of 9606 16157350 YES miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 0.8 SIGNOR-268474 TGFB1 protein P01137 UNIPROT PAX6 protein P26367 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001874 17251190 NO Regulation miannu The effect of TGFbeta on Pax6 expression was studied in the FHL124 lens epithelial cell line and was found to cause up to a 50% reduction in Pax6 mRNA levels within 24 h. Pax6-stimulated activity of the Pax6 promoter is repressed by TGFβ signalling. 0.274 SIGNOR-251874 SLC27A2 protein O14975 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264462 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 YES lperfetto Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation 0.404 SIGNOR-181667 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 11717410 NO Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases 0.7 SIGNOR-255344 HSCB protein Q8IWL3 UNIPROT iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI up-regulates activity relocalization 27714045 YES lperfetto Cluster transfer from ISCU to recipient apoproteins is assisted by a dedicated chaperone/cochaperone (HSPA9/HSC20) system that facilitates cluster release from the primary scaffold ISCU and transfer to recipient apoproteins or to intermediate carriers 0.8 SIGNOR-262130 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT down-regulates dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000149 10993888 YES gcesareni A cytosolic protein-tyrosine phosphatase ptp1b specifically dephosphorylates and deactivates prolactin-activated stat5a and stat5b. 0.675 SIGNOR-82042 COLGALT1 protein Q8NBJ5 UNIPROT COL3A1 protein P02461 UNIPROT up-regulates activity glycosylation -1 19075007 YES Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. 0.402 SIGNOR-261154 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 17126298 YES gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. 0.333 SIGNOR-150875 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28138032 NO miannu Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Ras–MEK signaling transcriptionally activates Chk1, which appears to sustain cancer cell growth by maintaining DNA damage levels below a threshold that would otherwise drive apoptosis. 0.2 SIGNOR-263069 CAK complex complex SIGNOR-C456 SIGNOR CDK4 protein P11802 UNIPROT up-regulates phosphorylation Thr172 YSYQMALtPVVVTLW 9606 8139570 YES lperfetto Phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (cak).  therefore, formation of the cyclin d-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for cak activity, serum stimulation is required to promote assembly of the complexes in mammalian cells. 0.577 SIGNOR-269329 MMP1 protein P03956 UNIPROT COL1A1 protein P02452 UNIPROT down-regulates quantity by destabilization cleavage Gly776 IGPPGPAgAPGDKGE -1 17318226 YES lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  0.378 SIGNOR-272336 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 15209375 YES lperfetto Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. 0.649 SIGNOR-236637 RAB5A protein P20339 UNIPROT COMMD5 protein Q9GZQ3 UNIPROT up-regulates activity binding 9606 30021164 YES miannu The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. 0.2 SIGNOR-261691 BTK protein Q06187 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT -1 11524430 YES llicata We present a number of lines of evidence that in vivo, Src-type tyrosine kinases are responsible for the phosphorylation of tyrosine 139 in DAPP-1. | Although Btk appears to phosphorylate DAPP-1 relatively efficiently both in Sf9 cells and in vitro, we find no evidence that in either B cells or PAE cells Btk family kinases phosphorylate DAPP-1. 0.671 SIGNOR-250602 trichostatin A chemical CHEBI:46024 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258013 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 10581361 YES lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function 0.507 SIGNOR-72728 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 9606 15952796 YES lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation 0.298 SIGNOR-138175 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 12186630 YES lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. 0.2 SIGNOR-249154 GGNBP2 protein Q9H3C7 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity binding 9606 BTO:0001248 27357812 YES miannu We further demonstrate that GGNBP2 protein physically interacts with ERα, inhibits E2-induced activation of estrogen response element-driven reporter activity, and attenuates ER target gene expression in T47D cells. 0.2 SIGNOR-269076 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 14963330 YES lperfetto Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program 0.752 SIGNOR-178690 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.361 SIGNOR-273166 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 23336025 YES gcesareni Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol. 0.8 SIGNOR-200460 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 8119945 YES gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. 0.858 SIGNOR-36275 GSK3B protein P49841 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by destabilization phosphorylation Ser140 EEEGERQsPPLEVSD 9606 BTO:0002181 33188146 YES miannu We demonstrate that GSK3β phosphorylates PU.1 at Ser41 and Ser140 leading to its recognition and subsequent ubiquitin-mediated degradation by E3 ubiquitin ligase FBW7. 0.2 SIGNOR-277542 MAPK1 protein P28482 UNIPROT CDC42EP2 protein O14613 UNIPROT unknown phosphorylation Ser101 RELPDGPsPLLKNAI 10090 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.248 SIGNOR-262770 sirolimus chemical CHEBI:9168 ChEBI LILRB4 protein Q8NHJ6 UNIPROT down-regulates quantity by repression 9606 18652845 NO miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. 0.8 SIGNOR-255478 UQCR11 protein O14957 UNIPROT CoQ-cytochrome c reductase-Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 YES lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits 0.844 SIGNOR-262196 DNMT3A protein Q9Y6K1 UNIPROT DNMT1/DNMT3A complex SIGNOR-C42 SIGNOR form complex binding 9606 12145218 YES miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation 0.782 SIGNOR-90842 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10090 BTO:0000011 11279134 YES lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin 0.46 SIGNOR-250566 PI4K2B protein Q8TCG2 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI down-regulates quantity chemical modification 9606 10101268 YES miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. 0.8 SIGNOR-269099 KDM4C protein Q9H3R0 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-263869 PLK1 protein P53350 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser3205 TPLPEDNsMNVDQDG 9606 24844881 YES miannu Moreover, PLK1 phosphorylates DNA-PKcs directly on Ser 3205 invitro, suggesting that DNA-PKcs Ser 3205 is a direct target of PLK1 in mitosis. 0.425 SIGNOR-278188 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT up-regulates activity cleavage Arg759 KNNAIEPrSFSQNSR -1 10350471 YES lperfetto Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689. 0.754 SIGNOR-263641 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity binding -1 18025157 YES We show that PML-RARα physically interacts with Sp1 in the absence of DNA. In this report, we show that PML-RARα interacts with Sp1 and may interfere with the expression of genes that are not normally regulated by retinoic acid receptors. 0.2 SIGNOR-255729 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 8106516 YES Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù 0.8 SIGNOR-267189 TFDP1 protein Q14186 UNIPROT DHFR protein P00374 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.438 SIGNOR-253860 SEC61A2 protein Q9H9S3 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 YES lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER 0.656 SIGNOR-267728 BRCA2 protein P51587 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding 9606 17515904 YES We suggest that interactions of the BRCA2 C-terminal region with RAD51 may facilitate efficient nucleation of RAD51 multimers on DNA and thereby stimulate recombination-mediated repair. 0.946 SIGNOR-259905 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 YES gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2). 0.761 SIGNOR-59643 DOK4 protein Q8TEW6 UNIPROT FYN protein P06241 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 YES gcesareni Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells. 0.537 SIGNOR-100999 ATP5F1D protein P30049 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261402 CDH15 protein P55291 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.634 SIGNOR-265854 LAMTOR5 protein O43504 UNIPROT LIN28B protein Q6ZN17 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23494474 NO miannu We found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells. 0.25 SIGNOR-255251 PRKAA1 protein Q13131 UNIPROT ACACA protein Q13085 UNIPROT down-regulates activity phosphorylation Ser1201 IPTLNRMsFSSNLNH 10116 7907095 YES miannu We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase 0.699 SIGNOR-250400 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. 0.416 SIGNOR-252898 NR1D1 protein P20393 UNIPROT OPHN1 protein O60890 UNIPROT up-regulates activity binding 9606 BTO:0000132 35267019 YES miannu Rev-erbα regulates OPHN-1-mediated RhoA/ERM signalling in platelets., The results of the co-immunoprecipitation revealed that Rev-erbα coimmunoprecipitated with OPHN-1 in both mouse and human platelets and this interaction significantly increased upon stimulation with agonist U46619. 0.2 SIGNOR-268428 orantinib chemical CHEBI:91088 ChEBI FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207435 SEC61A1 protein P61619 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 YES lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER 0.766 SIGNOR-265279 SMAD1 protein Q15797 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C85 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common(co-Smad; Smad4 in mammals) and shuttle into the nucleus. 0.67 SIGNOR-168734 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270391 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 11591790 NO We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation 0.248 SIGNOR-254358 CAV1 protein Q03135 UNIPROT SLC1A3 protein P43003 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 YES miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. 0.2 SIGNOR-264808 PRKN protein O60260 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates quantity ubiquitination 9606 26627850 YES miannu Parkin induces the degradation of cav-1 through the proteasome dependent pathway.|We also demonstrated that WT parkin ubiquitinates cav-1 for degradation. 0.2 SIGNOR-278710 OPHN1 protein O60890 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000938 12932438 YES miannu OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro 0.636 SIGNOR-268398 CDKN1A protein P38936 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 BTO:0000222 16982699 YES gcesareni Considering that akt1 phosphorylates p21, this dissociation likely results from phosphorylation of p21 and release of cdk2. 0.954 SIGNOR-149711 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM63 protein Q969Q1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271117 LYN protein P07948 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.655 SIGNOR-249381 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 YES lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). 0.894 SIGNOR-227897 DAB2IP protein Q5VWQ8 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity gtpase-activating protein 9606 27858941 YES miannu The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP. 0.516 SIGNOR-254746 MAPK8 protein P45983 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 YES lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. 0.2 SIGNOR-264876 phosphatidic acid smallmolecule CHEBI:16337 ChEBI MTOR protein P42345 UNIPROT up-regulates chemical activation 9606 11729323 YES gcesareni Pa directly interacted with the domain in mtor that is targeted by rapamycin, and this interaction was positively correlated with mtor's ability to activate downstream effectors. 0.8 SIGNOR-112379 F2R protein P25116 UNIPROT SDC4 protein P31431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254852 BKM120 chemical CHEBI:71954 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190383 GATA3 protein P23771 UNIPROT TBX21 protein Q9UL17 UNIPROT down-regulates 9606 16386358 NO Conversely, T-bet is capable of inhibiting GATA-3 (Szabo et al., 2000). The mutual inhibition between GATA-3 and T-bet ensures that Th1 and Th2 cells express one or the other molecule (T-bet in Th1, and GATA-3 in Th2), but not both 0.756 SIGNOR-254296 DLGAP5 protein Q15398 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.453 SIGNOR-264599 CDKL1 protein Q00532 UNIPROT CDKN2B protein P42772 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001616 28352193 YES miannu We demonstrated that depletion of CDKL1 notably upregulated the protein expression of P15. P15 is shown to be a target of CDKL1 in CRC, either direct or indirect. 0.2 SIGNOR-273862 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization phosphorylation Thr286 EEVDLACtPTDVRDV 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 YES lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 0.783 SIGNOR-245437 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser520 RLQTICMsGTGMRSV 9606 20448038 YES lperfetto Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation. 0.372 SIGNOR-165229 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258774 FAM83B protein Q5T0W9 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.256 SIGNOR-273762 TRHR protein P34981 UNIPROT GNA11 protein P29992 UNIPROT up-regulates activity binding 9606 BTO:0001379 27515033 YES scontino Binding of TRH to TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C. 0.483 SIGNOR-267201 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser226 ATGKDVEsYLQPKAK 9606 20573420 YES lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. 0.362 SIGNOR-166325 PIM1 protein P11309 UNIPROT HBP1 protein O60381 UNIPROT up-regulates activity phosphorylation Ser372 SAVYVLSsMARQRRA 9606 BTO:0002181 28348080 YES miannu  Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it. 0.2 SIGNOR-277346 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates chemical activation 9606 23450633 YES gcesareni S1p action on yap in 293a (or hacat) cells is mediated by s1p2 rather than s1p1 or s1p3 (of ? Ve known s1p receptors) and lpa receptors 1 and 3 (of six). 0.8 SIGNOR-192117 LPAR1 protein Q92633 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 20331961 YES gcesareni The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits) 0.542 SIGNOR-164682 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT up-regulates activity phosphorylation Tyr281 EKKSLTIyAQVQKPG 9534 BTO:0000298 11806999 YES All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. 0.657 SIGNOR-251181 RPS6KA1 protein Q15418 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 21749389 YES The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert. 0.41 SIGNOR-174760 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 18593525 NO gcesareni Dag and ip3 initiate further signal transduction pathways through activation of protein kinase c (pkc) and intracellular calcium release. 0.8 SIGNOR-179288 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 SIGNOR-C15 21892142 YES gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) 0.342 SIGNOR-176479 TRIM24 protein O15164 UNIPROT TP53 protein P04637 UNIPROT down-regulates ubiquitination 9606 19844164 YES miannu New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation 0.532 SIGNOR-188726 hsa-miR-27b-5p mirna URS0000330617_9606 RNAcentral FZD7 protein O75084 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001007 26780940 YES Parnian The results showed that both the mRNA and protein expression of FZD7 that was upregulated by H. pylori infection was significantly decreased by miR-27b overexpression in AGS and BGC-823 cells. Taken together, these results demonstrated that miR-27b regulated FZD7 expression. 0.4 SIGNOR-277968 DDIT3 protein P35638 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity transcriptional regulation 10090 7588595 YES We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process. 0.668 SIGNOR-255914 p38 proteinfamily SIGNOR-PF16 SIGNOR TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 YES lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 0.2 SIGNOR-264445 AMOT protein Q4VCS5 UNIPROT YAP1 protein P46937 UNIPROT down-regulates relocalization 9606 21808241 YES gcesareni Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms. 0.733 SIGNOR-175779 DNMT3A protein Q9Y6K1 UNIPROT CDKN2D protein P55273 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 NO miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family 0.2 SIGNOR-261510 AKT1 protein P31749 UNIPROT DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 22298955 YES gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. 0.264 SIGNOR-195546 panobinostat chemical CHEBI:85990 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257749 NBEAL2 protein Q6ZNJ1 UNIPROT IQGAP1 protein P46940 UNIPROT down-regulates 10090 BTO:0000132 29187380 NO lperfetto We found that the level of Iqgap1, a protein that stabilizes the active forms of Cdc42 and Rac1, was also significantly higher in Nbeal2−/− platelets 0.2 SIGNOR-261890 DEK protein P35659 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 YES miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 0.447 SIGNOR-268823 USP36 protein Q9P275 UNIPROT FBL protein P22087 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000567 19208757 YES lperfetto USP36 deubiquitylated the nucleolar proteins nucleophosmin/B23 and fibrillarin, and stabilized them by counteracting ubiquitylation-mediated proteasomal degradation.  0.361 SIGNOR-272291 CDH2 protein P19022 UNIPROT CDON/SPAG9 complex SIGNOR-C21 SIGNOR up-regulates binding 9606 20160094 YES lperfetto We report here that n-cadherin ligation activates p38alpha/beta in myoblasts in a cdo-, bnip-2-, and jlp-dependent manner 0.547 SIGNOR-217517 JUN protein P05412 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16149046 NO miannu Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2. 0.2 SIGNOR-252225 CSNK2B protein P67870 UNIPROT SORT1 protein Q99523 UNIPROT up-regulates quantity by stabilization phosphorylation Ser825 KSGYHDDsDEDLLE 10090 BTO:0003449 25805502 YES miannu  Phosphorylation of Ser-825 is required for insulin to induce Sort1 in AML12 cells. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome-dependent Sort1 degradation.  0.2 SIGNOR-273636 DAPK1 protein P53355 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 YES gcesareni Dna damage-activated protein kinases like chk1/2 modify the box-i domain of p53 at thr18 and ser20 (46) by an allosteric mechanism (10). 0.559 SIGNOR-153491 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 18793634 YES gcesareni Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow. 0.573 SIGNOR-180895 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1039 HSQLSDLyGKFSFKS -1 11024032 YES Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. 0.767 SIGNOR-251169 MAPKAPK2 protein P49137 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ -1 11844797 YES miannu Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO. 0.545 SIGNOR-250143 ACE2 protein Q9BYF1 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Pro40 GDRVYIHpFHLVIHN -1 11815627 YES miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. 0.758 SIGNOR-256315 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Ser187 REKRRSTsRQFVDGP 9606 BTO:0000567 14744859 YES llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 0.779 SIGNOR-250588 CDK20 protein Q8IZL9 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity phosphorylation 9606 25500144 YES miannu In addition to the transcriptional feedback loop, we also identified a feed-forward loop in which CCRK induces EZH2 phosphorylation, thereby promoting p-EZH2 Ser21 -AR physical interaction for CCRK promoter co-occupancy and transcriptional activation. 0.2 SIGNOR-279017 IRF1 protein P10914 UNIPROT DST protein Q03001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15560761 YES miannu Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes. 0.2 SIGNOR-254492 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 22945643 YES lperfetto Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation. 0.484 SIGNOR-198934 KCNJ16 protein Q9NPI9 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 24561201 YES miannu KCNJ10 encodes Kir4.1, a member of the K+ channel family known as inwardly rectifying K+ (Kir) channels. Kir4.1 channels may comprise either Kir4.1 homomers or Kir4.1/Kir5.1 heteromers 0.8 SIGNOR-269447 FLI1 protein Q01543 UNIPROT ANKRD26 protein Q9UPS8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000843 24430186 YES lperfetto In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs. 0.284 SIGNOR-266070 ADGRG1 protein Q9Y653 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0000142 31515243 YES lperfetto Binding of collagen III to ADGRG1 provides a canonical example of adhesion GPCR interactions with ECM proteins (Luo et al., 2011). Identified by an in vitro biotinylation/proteomics approach, extracellular interactions with collagen III were subsequently proven capable of activating ADGRG1-mediated signaling via Gα12/13 followed by RhoA activation to regulate corticogenesis 0.2 SIGNOR-272345 PRLHR protein P49683 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257198 SP1 protein P08047 UNIPROT ATP2C1 protein P98194 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 15955096 NO miannu when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. 0.2 SIGNOR-255194 ATR protein Q13535 UNIPROT XRCC3 protein O43542 UNIPROT up-regulates activity phosphorylation Ser225 PFRCEFDsQASAPRA 9606 23438602 YES miannu HXRCC3 S225 phosphorylation is mediated by ATR via an ATM-dependent signaling pathway. These data clearly indicate that ATR mediates the late activation of XRCC3 following DSB accumulation. 0.465 SIGNOR-262666 CSNK1A1 protein P48729 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. 0.2 SIGNOR-183667 NDUFS7 protein O75251 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. 0.863 SIGNOR-262181 AKT proteinfamily SIGNOR-PF24 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr39 LKKIRLDtETEGVPS 9606 18354084 YES lperfetto Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity. 0.2 SIGNOR-244176 PPP1CA protein P62136 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity dephosphorylation Ser8 MTTEQRRsLQAFQDY 9606 BTO:0000007 23499489 YES lperfetto We identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.|endogenous RIG-I and MDA5 that interacted with PP1 exhibited markedly decreased phosphorylation levels at S8 and S88, respectively  0.2 SIGNOR-264581 L-isoprenaline chemical CHEBI:6257 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257456 SIRT2 protein Q8IXJ6 UNIPROT PGAM proteinfamily SIGNOR-PF78 SIGNOR up-regulates activity deacetylation 9606 24786789 YES miannu Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. 0.28 SIGNOR-266519 MAPKAPK3 protein Q16644 UNIPROT HSPB1 protein P04792 UNIPROT unknown phosphorylation Ser82 RALSRQLsSGVSEIR -1 8774846 YES miannu MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15) 0.684 SIGNOR-250161 ZMIZ1 protein Q9ULJ6 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 10090 BTO:0001825 26522984 NO miannu Our data suggest that Zmiz1 and Notch1 cooperatively recruit each other to chromatin through direct interaction via the TPR resulting in a slight increase in activating histone marks and decrease of repressive histone marks. 0.7 SIGNOR-263938 TNF protein P01375 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 8530143 NO andrea cerquone perpetuini Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation. 0.677 SIGNOR-255689 nintedanib chemical CHEBI:85164 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 18559524 YES Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. 0.8 SIGNOR-257798 IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation 0.675 SIGNOR-249494 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates activity phosphorylation 9606 15586017 YES Regulation of localization miannu The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane. 0.787 SIGNOR-251949 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR NANOS3 protein P60323 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.35 SIGNOR-269259 MBD2 protein Q9UBB5 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.732 SIGNOR-263835 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 19059439 YES llicata Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. pkc? Kinase assay then indicated that at least two residues, serine 6 and threonine 221, are phosphorylated by pkc? 0.2 SIGNOR-182619 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR GRIK2 protein Q13002 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 17062563 YES miannu Here, we report that actinfilin is able to bind to GluR6, a kainate-type glutamate receptor subunit, and target GluR6 for degradation. Like many members of its protein family, actinfilin acts as a substrate adaptor, binding Cullin 3 (Cul3) and linking GluR6 to the E3 ubiquitin-ligase complex. Together our data demonstrate that actinfilin acts as a scaffold, linking GluR6 to the Cul3 ubiquitin ligase to provide a novel mechanism for kainate receptor degradation. 0.285 SIGNOR-271614 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser694 QTSKRHDsDTFPELK 9606 20085797 YES lperfetto We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation 0.507 SIGNOR-163472 PRKCA protein P17252 UNIPROT ADD3 protein Q9UEY8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser693 KKKFRTPsFLKKNKK -1 11895774 YES lperfetto Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. | Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. | The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin 0.335 SIGNOR-249143 NEK3 protein P51956 UNIPROT NEK3 protein P51956 UNIPROT down-regulates activity phosphorylation Thr165 FACTYVGtPYYVPPE -1 27489110 YES Manara Autophosphorylation at Thr-165 is required for NEK3 kinase activity in vitro. 0.2 SIGNOR-260919 Caspase 3 complex complex SIGNOR-C221 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 NO amattioni Caspase-3 is responsible for apoptosis execution 0.7 SIGNOR-256548 FYN protein P06241 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates activity phosphorylation Tyr436 EWKVVNAyHLRVRRK 10090 BTO:0000944 27626315 YES miannu Here we identified that Fyn phosphorylates the α subunit of AMPK on Y436 and inhibits AMPK enzymatic activity without altering the assembly state of the AMPK heterotrimeric complex.  0.257 SIGNOR-277279 NMDA receptor_2D complex SIGNOR-C350 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 YES miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  0.8 SIGNOR-264221 ITGB1BP1 protein O14713 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.282 SIGNOR-257668 SOX9 protein P48436 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003858 19745029 NO miannu Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2. 0.2 SIGNOR-255188 TNFRSF17 protein Q02223 UNIPROT ELK1 protein P19419 UNIPROT up-regulates 9606 10903733 NO miannu Bcma overexpression activates elk-1 nuclear factor 0.2 SIGNOR-79486 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT up-regulates activity dephosphorylation Tyr118 VGEEEHVySFPNKQK -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.26 SIGNOR-254721 PTGER3 protein P43115 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity relocalization 9606 BTO:0000018 28415726 YES Marta Tosoni These results demonstrate that PGE2 -mediated EGFR nuclear translocation requires the EP3 receptor. 0.332 SIGNOR-278884 DLG4 protein P78352 UNIPROT TANC2 protein Q9HCD6 UNIPROT up-regulates activity binding 10116 BTO:0000142 21068316 YES miannu In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses. 0.312 SIGNOR-266895 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 0.745 SIGNOR-161617 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK8 protein P45983 UNIPROT up-regulates chemical activation 9606 Other YES CellSignaling gcesareni 0.8 SIGNOR-189702 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser483 SMQPDNSsDSDYDLH 9606 9834084 YES lperfetto In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461) 0.343 SIGNOR-62307 heparan sulfate octasaccharide smallmolecule CHEBI:142519 ChEBI ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 27241222 NO miannu Many observations in animal models deficient for HSPGs and recent observations of human genetic mutations for biosynthesis of HSPGs have identified the importance of HSPGs for normal embryonic development and ECM organization. 0.7 SIGNOR-264017 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL 9606 16116087 YES llicata The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms. 0.729 SIGNOR-139906 miR-23a mirna URS00001CC864_9606 RNAcentral GLS protein O94925 UNIPROT down-regulates quantity post transcriptional regulation 10090 20060380 YES These results suggest that miR-27a would suppress adipocyte differentiation through targeting PPARgamma and thereby down-regulation of miR-27a might be associated with adipose tissue dysregulation in obesity. 0.4 SIGNOR-255929 GPER1 protein Q99527 UNIPROT GNB1 protein P62873 UNIPROT up-regulates activity binding 10696571 YES GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNB1 stands for the subunit β, which dissociates from the receptor after the binding of GTP on α-subunit. 0.383 SIGNOR-251103 CBL protein P22681 UNIPROT MYCBPAP protein Q8TBZ2 UNIPROT up-regulates activity monoubiquitination 9606 BTO:0000007 17255943 YES miannu We moreover found that AMAP1 is monoubiquitinated, rather than polyubiquitinated, by virtue of Cbl and provide evidence that the ability of AMAP1 to be monoubiquitinated is important for its involvement in invasion.  0.298 SIGNOR-272627 NBR1 protein Q14596 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 YES gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family 0.756 SIGNOR-184261 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193615 RIPK2 protein O43353 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser446 DSIRLQIsNPDLKDR 9606 22412986 YES lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay 0.305 SIGNOR-196524 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252328 GAST protein P01350 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 BTO:0000142 10368033 YES gcesareni A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin, 0.782 SIGNOR-66987 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JAK2 protein O60674 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 NO miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. 0.2 SIGNOR-260120 PRKAA1 protein Q13131 UNIPROT HNF4A protein P41235 UNIPROT down-regulates activity phosphorylation Ser303 DPDAKGLsDPGKIKR 9606 SIGNOR-C15 12740371 YES lperfetto Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect 0.285 SIGNOR-101101 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity relocalization 9606 19352540 YES lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. 0.87 SIGNOR-168450 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr5 tQTQDQPM 9606 BTO:0000567 2507541 YES lperfetto Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha. 0.428 SIGNOR-248887 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates binding 9606 15767678 YES gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. 0.744 SIGNOR-134555 PPP1CC protein P36873 UNIPROT AHCYL1 protein O43865 UNIPROT unknown dephosphorylation Ser68 RSLSRSIsQSSTDSY 10090 17635105 YES Moreover, IRBIT-associated PP1 specifically dephosphorylated Ser68 of IRBIT. Phosphorylation of Ser68 was required for subsequent phosphorylation of Ser71 and Ser74, but the latter two sites were not targeted by PP1. We found that phosphorylation of Ser71 and Ser74 were sufficient to enable inhibition of IP3 binding to the IP3R|Given the importance of phosphorylation for the function of IRBIT in suppressing IP3R activity [7,10], in the present study, we searched for a protein phosphatase involved in the dephosphorylation and, hence, inactivation of IRBIT. We found that IRBIT contains a specific well-conserved binding site for PP1. 0.2 SIGNOR-248498 PTPN11 protein Q06124 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates activity dephosphorylation -1 19066472 YES miannu Moreover, SHP-2 was strongly activated on G-CSF stimulation and specifically dephosphorylated p27(Kip1) in vitro.|Most importantly, we could illustrate that SHP-2 modulates p27 (Kip1) stability and contributes to p27 (Kip1)-mediated cell cycle progression. 0.281 SIGNOR-277168 DRD5 protein P21918 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.282 SIGNOR-257156 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189966 SLC1A1 protein P43005 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 YES miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). 0.8 SIGNOR-264804 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 YES Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK. 0.2 SIGNOR-252079 BRF2 protein Q9HAW0 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR form complex binding 29378333 YES lperfetto Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1). 0.721 SIGNOR-266191 CACNA1A protein O00555 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 30849329 NO miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). 0.7 SIGNOR-264328 ZFPM1 protein Q8IX07 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21853041 YES miannu GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1. 0.745 SIGNOR-256061 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser173 MLETLSQsPPKGVTI 9606 17475908 YES miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 0.319 SIGNOR-262910 MTHFD1 protein P11586 UNIPROT formate smallmolecule CHEBI:15740 ChEBI up-regulates quantity chemical modification -1 18767138 YES lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate 0.8 SIGNOR-268251 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4520 GGHGSRHsLASTDEK 9606 15272003 YES lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. 0.2 SIGNOR-127207 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR1 protein P21453 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257577 GNA15 protein P30679 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9534 BTO:0000298 1334487 YES This suggests that both Gal4 and Gal6 can activate PLC b1. 0.482 SIGNOR-278120 EP300 protein Q09472 UNIPROT KPNA2 protein P52292 UNIPROT up-regulates acetylation Lys22 HRFKNKGkDSTEMRR 9606 15342649 YES lperfetto Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300 0.357 SIGNOR-128625 Ub:E2 complex SIGNOR-C497 SIGNOR DTX1 protein Q86Y01 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271106 bisphenol F chemical CHEBI:34575 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 31995776 YES miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 0.8 SIGNOR-268731 ITGAL protein P20701 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.915 SIGNOR-253189 INTS2 protein Q9H0H0 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 YES lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  0.755 SIGNOR-261466 MAP4K1 protein Q92918 UNIPROT LCP2 protein Q13094 UNIPROT down-regulates activity phosphorylation Ser376 PRKQLSESSDDDYDD 9606 BTO:0000661 17353368 YES Barakat The serine/threonine kinase HPK-1 phosphorylates serine 376 of SLP-76 and induces the interaction with 14-3-3 proteins 0.777 SIGNOR-274153 AD/b2 integrin complex SIGNOR-C172 SIGNOR VCAM1 protein P19320 UNIPROT up-regulates activity binding 9606 BTO:0000751 10438935 YES lperfetto These results indicate that VCAM-1 can bind to an I domain and that the binding of alpha D beta 2 to VCAM-1 may contribute to the trafficking of a subpopulation of leukocytes that express alpha D beta 2. 0.589 SIGNOR-253375 ABL1 protein P00519 UNIPROT ERCC6 protein Q03468 UNIPROT up-regulates activity phosphorylation Tyr932 GANRVVIyDPDWNPS 9606 17626041 YES Regulation miannu N-terminal region of CSB interacts with the SH3 domain of c-Abl in vitro and in vivo. In addition, c-Abl kinase phosphorylates CSB at Tyr932. our results suggest that c-Abl interacts with and tyrosine phosphorylates CSB. This interaction may play an important role in the response to oxidative stress, resulting in activation of c-Abl, tyrosine phosphorylation of CSB and more efficient BER of oxidative DNA damage. Tyrosine-phosphorylated CSB may serve as a signal for repair proteins to localize to DNA damage and may help maintain active transcription in the nucleolus. 0.271 SIGNOR-251933 HOMER proteinfamily SIGNOR-PF59 SIGNOR SHANK3 protein Q9BYB0 UNIPROT up-regulates activity binding 9606 BTO:0000938 17243894 YES miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD 0.2 SIGNOR-264697 PLK1 protein P53350 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates activity phosphorylation Ser386 HESFLDLsLPVLDDQ -1 26323689 YES done miannu Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D). 0.344 SIGNOR-274015 DNM1 protein Q05193 UNIPROT SYP protein P08247 UNIPROT up-regulates activity binding 9606 10823955 YES miannu The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. 0.333 SIGNOR-264119 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser146 PALEVSDsESDEALV 9606 10618498 YES lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability 0.43 SIGNOR-73887 ASDURF protein L0R819 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 YES miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  0.2 SIGNOR-270922 SRC protein P12931 UNIPROT CDC42 protein P60953 UNIPROT up-regulates phosphorylation Tyr64 DTAGQEDyDRLRPLS 9606 14506284 YES gcesareni Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation. 0.694 SIGNOR-118206 NFATC1 protein O95644 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates activity 10358178 NO The transcription factor NF-ATc that controls gene expression in T lymphocytes and embryonic cardiac cells is expressed in three prominent isoforms. 0.7 SIGNOR-252344 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-252978 STK11 protein Q15831 UNIPROT SIK2 protein Q9H0K1 UNIPROT up-regulates phosphorylation Thr175 KSGELLAtWCGSPPY 9606 14976552 YES llicata A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold. 0.479 SIGNOR-122788 GSK3A protein P49840 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000812 27875297 YES lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation 0.2 SIGNOR-264886 GART protein P22102 UNIPROT 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI down-regulates quantity chemical modification 9606 33179964 YES miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. 0.8 SIGNOR-267314 beta-alanine smallmolecule CHEBI:16958 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 BTO:0000007 9009272 YES inferred from family member miannu For each mutant GlyR we examined the agonist efficacies of taurine and beta-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where beta-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human alpha-1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and beta-alanine act as full agonists of huma nalpha-1 GlyRs when expressed in this system. 0.8 SIGNOR-267795 SOCS1 protein O15524 UNIPROT IFNGR1 protein P15260 UNIPROT down-regulates binding 9606 18708154 YES gcesareni Suppressor of cytokine signaling (socs)-1, the key negative regulator of interferon (ifn)-gamma-dependent signaling, is induced in response to ifngamma. Socs-1 binds to and inhibits the ifngamma receptor-associated kinase janus-activated kinase (jak) 2 and inhibits its function in vitrothe binding of socs-1 to tyr441 also blocks the access of stat1 to tyr419 and that this effect may be the principal mechanism of inhibition of downstream signaling 0.673 SIGNOR-180140 Synaptonemal_complex complex SIGNOR-C351 SIGNOR Meiotic_recombination phenotype SIGNOR-PH162 SIGNOR up-regulates 9606 33262143 NO miannu The synaptonemal complex (SC) is a meiosis-specific structure formed between homologous chromosomes during prophase that promotes DSB formation and biases repair of DSBs to homologs over sister chromatids. 0.7 SIGNOR-264204 STOML2 protein Q9UJZ1 UNIPROT LCK protein P06239 UNIPROT up-regulates activity binding 9606 18641330 YES Giorgia In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. 0.2 SIGNOR-260376 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR PDPK1 protein O15530 UNIPROT down-regulates activity dephosphorylation 9606 21075311 YES gcesareni Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation. 0.283 SIGNOR-243515 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg27 PTGGGRGrGMRSRGR 9606 24726729 YES miannu Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding 0.369 SIGNOR-204962 ACTR8 protein Q9H981 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.632 SIGNOR-270848 MEN1 protein O00255 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15640349 NO irozzo Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. 0.404 SIGNOR-255889 PRKCA protein P17252 UNIPROT CD163 protein Q86VB7 UNIPROT unknown phosphorylation Ser1084 QRQRLAVsSRGENLV 9606 BTO:0000801 11298324 YES lperfetto Furthermore, we demonstrated that the cytoplasmic domains of CD163 variants are phosphorylated by PKC-alpha in vitro. Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines. 0.323 SIGNOR-249082 PPP1CB protein P62140 UNIPROT CASP2 protein P42575 UNIPROT up-regulates activity dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 YES llicata Nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. 0.2 SIGNOR-248576 PRKACA protein P17612 UNIPROT RYR1 protein P21817 UNIPROT up-regulates activity phosphorylation Ser2843 KKKTRKIsQSAQTYD -1 14532276 YES miannu PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure 0.326 SIGNOR-250078 EEF1A1 protein P68104 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269508 UVB radiation stimulus SIGNOR-ST17 SIGNOR IL1B protein P01584 UNIPROT up-regulates 9606 9767234 NO miannu UVB can stimulate the synthesis of IL-1, TNF-a and ET-1, and other cytokines by keratinocytes. 0.7 SIGNOR-252382 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257455 ETV6 protein P41212 UNIPROT BBC3 protein Q96PG8 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002883 16828711 NO miannu Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma. 0.2 SIGNOR-254137 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser702 AVILTVEsEEEEEES 21296876 YES lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. 0.2 SIGNOR-275503 PTPRA protein P18433 UNIPROT KCNB1 protein Q14721 UNIPROT down-regulates dephosphorylation 9606 16870705 YES gcesareni Ptpalpha inhibits kv channels more strongly than ptpepsilon;this correlates with constitutive association of ptpalpha with kv2.1, driven by membranal localization of ptpalpha. 0.2 SIGNOR-148301 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 YES lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. 0.2 SIGNOR-26582 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser439 AGSPFQSsPLSLGSR 9606 16880739 YES lperfetto Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis. 0.277 SIGNOR-216821 KATNAL2 protein Q8IYT4 UNIPROT Acrosome_assembly phenotype SIGNOR-PH156 SIGNOR up-regulates 9606 28347630 NO miannu The majority of elongated spermatids also displayed a detached acrosome (Fig 5B), indicating that KATNAL2, or KATNAL2-regulated structures, have a role in the deposition of ‘adhesive components’ into the acroplaxome. The acroplaxome is an electron dense structure that overlies the anterior pole of the sperm nucleus and is thought to play a pivotal role in acrosome formation and attachment. These data strongly suggest that KATNAL2 is required for multiple aspects of male haploid germ cell development, and depending on the cellular context, KATNAL2 may act in either a KATNB1-dependent (manchette function) and KATNB1-independent manner (acrosome and axoneme development). 0.7 SIGNOR-267179 POLR2F protein P61218 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.873 SIGNOR-266170 SCAF11 protein Q99590 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 YES lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. 0.294 SIGNOR-261742 DDR2 protein Q16832 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 16186108 YES gcesareni Collectively, our findings are consistent with the following mechanism for src-dependent ddr2 activation and signaling: 1) ligand binding promotes phosphorylation of tyr-740 in the ddr2 activation loop by src;2) tyr-740 phosphorylation stimulates intramolecular autophosphorylation of ddr2;3) ddr2 autophosphorylation generates cytosolic domain phosphotyrosines that promote the formation of ddr2 cytosolic domain-shc signaling complexes. 0.394 SIGNOR-140724 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 12686604 YES lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. 0.439 SIGNOR-100165 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR LIN28A protein Q9H9Z2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.53 SIGNOR-269246 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT unknown phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 14551205 YES llicata In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. 0.49 SIGNOR-118588 PRKCA protein P17252 UNIPROT EIF6 protein P56537 UNIPROT unknown phosphorylation Ser235 QPSTIATsMRDSLID 9606 14654845 YES llicata Pkc stimulation led to eif6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eif6 impaired rack1/pkc-mediated translational rescue. 0.316 SIGNOR-119600 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates activity phosphorylation Ser534 KSQHRSSsSAPHHNH 10441130 YES miannu Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation 0.429 SIGNOR-250341 MMP2 protein P08253 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 YES miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. 0.339 SIGNOR-256333 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Ala) smallmolecule CHEBI:29170 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269480 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 22413754 YES miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites 0.2 SIGNOR-248545 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1B protein P47901 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257462 DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 15735151 YES amattioni Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1. 0.806 SIGNOR-134285 Nalorphine chemical CHEBI:7458 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258814 FZR1 protein Q9UM11 UNIPROT DTYMK protein P23919 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 16103219 YES miannu We demonstrate that TMPK is recognized and degraded by APC/C-Cdc20/Cdh1-mediated pathways from mitosis to the early G1 phase, whereas TK1 is targeted for degradation by APC/C-Cdh1 after mitotic exit.  0.226 SIGNOR-272652 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 YES lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. 0.289 SIGNOR-249000 PTPN2 protein P17706 UNIPROT GJA1 protein P17302 UNIPROT up-regulates dephosphorylation Tyr247 VKGKSDPyHATSGAL 9606 BTO:0000671 24849651 YES lperfetto Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43. 0.324 SIGNOR-205097 MAPK8IP3 protein Q9UPT6 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 10523642 YES gcesareni Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct. 0.628 SIGNOR-71468 CHFR protein Q96EP1 UNIPROT SIRT1 protein Q96EB6 UNIPROT down-regulates quantity ubiquitination 9606 27883020 YES miannu CHFR binds to and ubiquitylates SIRT1, leading to its proteasomal degradation.|CHFR ubiquitylates and promotes the proteasomal degradation of SIRT1. 0.373 SIGNOR-278691 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 16461343 YES amattioni T cell signaling is negatively regulated by the activity of protein-tyrosine phosphatases. Native ptpn22 dephosphorylated tcrzeta in vitro and in cells. 0.448 SIGNOR-144337 AGT protein P01019 UNIPROT REN protein P00797 UNIPROT up-regulates activity binding 9606 32201502 YES miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). 0.928 SIGNOR-260224 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.477 SIGNOR-259001 TNF protein P01375 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.2 SIGNOR-253477 DRAM2 protein Q6UX65 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 NO irozzo DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. 0.2 SIGNOR-259147 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr59 SSSAASSySFSDLNS 9606 BTO:0000567 BTO:0000887 19789182 YES llicata Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf 0.452 SIGNOR-188308 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser434 LTLASERsSPQRKSQ -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.286 SIGNOR-262748 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 YES lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2 0.26 SIGNOR-112495 SLC9A3 protein P48764 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265602 TTL protein Q8NG68 UNIPROT TUBA4A protein P68366 UNIPROT down-regulates tyrosination 9606 22020298 YES miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization 0.286 SIGNOR-176927 HIPK2 protein Q9H2X6 UNIPROT PAX6 protein P26367 UNIPROT up-regulates activity phosphorylation Thr373 GRSYDTYtPPHMQTH 9606 BTO:0001938 16407227 YES HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. 0.464 SIGNOR-251271 TNFSF10 protein P50591 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 BTO:0000815 23647548 YES Treatment with TRAIL increased the NF-κB transcriptional activity by approximately twofold in MDA-MB-231 cells compared to the control. 0.302 SIGNOR-277936 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 20086174 YES lperfetto We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. 0.2 SIGNOR-244345 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR2 protein Q9HBW0 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193561 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI down-regulates quantity chemical modification 9606 33179964 YES miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). 0.8 SIGNOR-268110 WWP2 protein O00308 UNIPROT ABI3 protein Q9P2A4 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 15998807 YES miannu The AIP2 E3 ligase acts as a novel negative regulator of ABA signaling by promoting ABI3 degradation. Here, we show that ABI3 is an unstable protein and that an ABI3-interacting protein (AIP2), which contains a RING motif, can polyubiquitinate ABI3 in vitro. 0.2 SIGNOR-272656 PYCARD protein Q9ULZ3 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.685 SIGNOR-256408 HRH2 protein P25021 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257317 EFNA3 protein P52797 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.749 SIGNOR-52387 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 YES lperfetto Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration 0.307 SIGNOR-97938 1-(1-naphthalenyl)piperazine chemical CHEBI:108599 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258683 RUNX3 protein Q13761 UNIPROT CHUK protein O15111 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255090 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000165 19319192 YES miannu We previously showed that the level of MAFbx protein increased in skeletal muscle during aging and/or food deprivation. Immunoprecipitation of the SCFMAFbx complexes from mouse atrophic muscles exhibited ubiquitination activity by using MyoD as substrate. Food deprivation and oxidative stress–induced atrophy increase polyubiquitination by the SCFMAFbx pathway and degradation of MyoD by the proteasome 0.288 SIGNOR-271804 PLK1 protein P53350 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser30 EADSPSDsGQGSYET 9606 16885022 YES gcesareni We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase 0.772 SIGNOR-148447 Ub:E2 complex SIGNOR-C497 SIGNOR HACE1 protein Q8IYU2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271304 FOXO6 protein A8MYZ6 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 YES miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. 0.2 SIGNOR-260092 MPP5 protein Q8N3R9 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR form complex binding 9606 24366813 YES lperfetto To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a), 0.65 SIGNOR-203494 VAC14 protein Q08AM6 UNIPROT PAS complex complex SIGNOR-C190 SIGNOR form complex binding 9606 BTO:0000007 17556371 YES miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. 0.924 SIGNOR-253530 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2NL protein Q5JXB2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271370 HOOK3 protein Q86VS8 UNIPROT MSR1 protein P21757 UNIPROT down-regulates binding 9606 BTO:0000801 17237231 YES miannu We have identified a microtubule-binding protein, hook3, as a novel interacting partner of sr-a. / by transfecting small interfering rna targeting hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of sr-a were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that hook3 may participate in the turnover of the endocytosed scavenger receptor 0.334 SIGNOR-152314 MC1R protein Q01726 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.479 SIGNOR-256813 Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.2 SIGNOR-269159 PRKCG protein P05129 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 BTO:0000887 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.2 SIGNOR-134632 ITGB1BP1 protein O14713 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.269 SIGNOR-257663 TGFB1 protein P01137 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000988 35816922 YES miannu COL1A1 expression is regulated by upstream genes and the binding of regulatory elements at multiple binding sites upstream of its promoter. During cancer progression, CAFs reorganize and cross-link COL1A1, which accumulates and stiffens in the tumor stroma [12], [18]. This process may involve fibrogenic factors, especially transforming growth factor-beta (TGF-β1). Indeed, a TGF-β1 response sequence was identified 174 nucleotides upstream of the COL1A1 transcription start site, and was shown to up-regulate COL1A1 promoter activity 0.485 SIGNOR-277678 HOXA7 protein P31268 UNIPROT KRT10 protein P13645 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11435435 NO miannu Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. 0.2 SIGNOR-254472 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr735 LKGPTCQyRAAQSGP 9606 BTO:0000661 11741929 YES lperfetto Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling. 0.355 SIGNOR-112923 GPAA1 protein O43292 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32432756 NO miannu GPAA1 may contribute to the malignant progression of childhood ALL via activating c-myc. Luciferase reporter gene assay demonstrated that overexpression of c-myc remarkably attenuated the Luciferase activity of the wild-type GPAA1 vector without attenuating that of the mutant vector or empty vector, further demonstrating that GPAA1 can be targeted by c-myc. 0.2 SIGNOR-261240 PRKD1 protein Q15139 UNIPROT PTRH2 protein Q9Y3E5 UNIPROT up-regulates phosphorylation Ser87 GKVAAQCsHAAVSAY 9606 18703509 YES lperfetto Overexpression of constitutively active pkd or pkd activation by treatment with phorbol 12-myristate 13-acetate results in phosphorylation of two serine residues (ser5 and ser87) in a form of bit1 that is confined to the cytoplasm and concomitantly increases the apoptotic activity of cytoplasmic bit1 0.3 SIGNOR-180089 D-thyroxine smallmolecule CHEBI:30659 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 9606 BTO:0003736 6777394 YES inferred from family member miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. 0.8 SIGNOR-270294 hsa-miR-361-5p mirna URS00000CF1D2_9606 RNAcentral CXCR6 protein O00574 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 26872014 YES MiR-361-5p inhibits CXCR6 expression by targeting its 3’-UTR. 0.4 SIGNOR-277952 AHR protein P35869 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 17012224 YES The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 . 0.49 SIGNOR-253642 phenylalanine smallmolecule CHEBI:28044 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264758 ESR1 protein P03372 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000938 22169964 NO miannu In this study, quantitative real-time PCR analysis showed that the gene expression levels of TTX-S (Nav1.1 and Nav1.7) and TTX-R (Nav1.8 and Nav1.9) sodium channel subtypes were elevated in DRGs of αERKO and βERKO mice, whereas Nav1.6 mRNA decreased in αERKOs but showed no changes in βERKO mice 0.2 SIGNOR-253476 PTPRF protein P10586 UNIPROT DAPK1 protein P53355 UNIPROT up-regulates dephosphorylation Tyr491 CAAWHGYySVAKALC 9606 17803936 YES amattioni Lar tyrosine phosphatase dephosphorylates dapk at py491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of dapk 0.2 SIGNOR-157706 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 21695114 YES gcesareni We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins 0.2 SIGNOR-174539 RB1 protein P06400 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 21524151 NO lperfetto Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. 0.7 SIGNOR-267284 OMG protein P23515 UNIPROT LINGO1 protein Q96FE5 UNIPROT up-regulates binding 9606 BTO:0000938 15694321 YES flangone Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1... 0.503 SIGNOR-133640 EGR2 protein P11161 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 NO miannu Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene. 0.31 SIGNOR-256041 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR PGAM5 protein Q96HS1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 17046835 YES miannu Keap1-dependent ubiquitination of PGAM5 results in proteasome-dependent degradation of PGAM5. Keap1 is a Bric-a-Brac (BTB) 2 -Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. 0.409 SIGNOR-272647 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 YES lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  0.34 SIGNOR-249070 STXBP1 protein P61764 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 YES miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. 0.84 SIGNOR-263970 calcium(2+) smallmolecule CHEBI:29108 ChEBI KCNMA1 protein Q12791 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 31152168 YES miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway) 0.8 SIGNOR-269199 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser379 SKILGETsLMRTLCG 9606 BTO:0000007 18644861 YES lperfetto Regulation of chk2 ubiquitination and signaling through autophosphorylation of serine 379.Thus, auto-/transphosphorylation of s379 is required for chk2 ubiquitination and effector function 0.2 SIGNOR-179537 SPRY4 protein Q9C004 UNIPROT CD82 protein P27701 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002058 20501643 NO miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 0.2 SIGNOR-253039 BLK protein P51451 UNIPROT SOCS1 protein O15524 UNIPROT down-regulates activity phosphorylation Tyr80 LLDACGFyWGPLSVH -1 31101761 YES miannu These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors. 0.2 SIGNOR-277889 SOD1 protein P00441 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI down-regulates quantity chemical modification 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272285 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 21502402 YES inferred from 70% family members llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro 0.2 SIGNOR-270209 OPHN1 protein O60890 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000938 12932438 YES miannu OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro 0.59 SIGNOR-268399 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24168260 NO miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis 0.7 SIGNOR-260446 NOD1 protein Q9Y239 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18079694 NO miannu Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase. 0.294 SIGNOR-252411 PKA proteinfamily SIGNOR-PF17 SIGNOR SLC4A4 protein Q9Y6R1 UNIPROT up-regulates activity phosphorylation Ser1026 KKKKKKGsLDSDNDD 10090 11744745 YES miannu Ser(982) in the C-terminus of kNBC1 is a target for PKA phosphorylation. Phosphorylation of Ser(982) in the sodium bicarbonate cotransporter kNBC1 shifts the HCO(3)(-) : Na(+) stoichiometry from 3 : 1 to 2 : 1 in murine proximal tubule cells Replacing Ser(982) at the C-terminus consensus PKA phosphorylation site with alanine resulted in a failure of PKA to phosphorylate the transporter and induce a stoichiometry shift. 0.2 SIGNOR-263158 NCOR1 protein O75376 UNIPROT BCL6 protein P41182 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 YES miannu The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT. 0.571 SIGNOR-252239 ABL1 protein P00519 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr232 FLMTKSGyQPPRLKE 9606 BTO:0000007 11278340 YES C-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. the c-Abl phosphorylation site (YXXP) in HPK1 (Y232QPP; aa 232–235) is localized in HPK1-KD 0.379 SIGNOR-251429 RING1 protein Q06587 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity ubiquitination 10090 BTO:0002572 16359901 YES miannu Polycomb group (PcG) proteins exist in at least two biochemically distinct protein complexes, the EED-EZH2 complex and the PRC1 complex, that respectively possess H3-K27 methyltransferase and H2A-K119 ubiquitin E3 ligase activities. How the enzymatic activities are regulated and what their role is in Hox gene silencing are not clear. Here, we demonstrate that Bmi-1 and Ring1A, two components of the PRC1 complex, play important roles in H2A ubiquitylation and Hox gene silencing. We show that both proteins positively regulate H2A ubiquitylation. 0.2 SIGNOR-271417 ARHGEF4 protein Q9NR80 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.739 SIGNOR-260532 MAPK14 protein Q16539 UNIPROT GATA2 protein P23769 UNIPROT up-regulates phosphorylation 9606 25056917 YES miannu P38_ increases gata_2 activity at endogenous target genes by inducing gata_2 multi_site phosphorylation. 0.27 SIGNOR-205242 (2S)-2-[[2-(2,3-dihydro-1H-inden-5-yloxy)-9-[(4-phenylphenyl)methyl]-6-purinyl]amino]-3-phenyl-1-propanol chemical CHEBI:94469 ChEBI ARFGAP1 protein Q8N6T3 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 17460038 YES Through affinity chromatography and subsequent functional assays, we showed that QS11 binds and inhibits the GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1), suggesting that QS11 modulates Wnt/beta-catenin signaling through an effect on protein trafficking. Consistent with its function as an ARFGAP inhibitor, QS11 inhibits migration of ARFGAP overexpressing breast cancer cells 0.8 SIGNOR-261914 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270981 SRC protein P12931 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates phosphorylation Tyr361 KVMENFIyESMRYQP 9606 BTO:0000150 19556341 YES amattioni Phosphorylation of the 361-tyrosine residue is crucial in the up-regulation of aromatase activity. c-src protein directly phosphorylates aromatase on tyrosine 361. 0.351 SIGNOR-186284 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Thr385 ILTSNQKtLTPEKGQ 9606 BTO:0002181 31843895 YES miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. 0.289 SIGNOR-276765 ADGRG1 protein Q9Y653 UNIPROT ADGRG1 protein Q9Y653 UNIPROT up-regulates activity cleavage 24949629 YES Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); | We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation. 0.2 SIGNOR-253980 CLOCK protein O15516 UNIPROT MAGEL2 protein Q9UJ55 UNIPROT down-regulates activity binding 9606 BTO:0000007 22208286 YES miannu Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. 0.2 SIGNOR-253516 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CIITA protein P33076 UNIPROT down-regulates phosphorylation 9606 18245089 YES inferred from 70% family members gcesareni In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. 0.2 SIGNOR-270067 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser558 GSSQGRNsPAPAVTA 10090 BTO:0000964 34048556 YES lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. 0.258 SIGNOR-268340 TNF protein P01375 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates 9606 10485710 NO gcesareni Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k) 0.265 SIGNOR-70622 Ub:E2 complex SIGNOR-C497 SIGNOR DCST1 protein Q5T197 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271164 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 BTO:0000887 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.275 SIGNOR-163792 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser327 DPEMEEDsYDSFGEP -1 9558331 YES llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. 0.307 SIGNOR-250933 MRPL50 protein Q8N5N7 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.69 SIGNOR-262338 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.34 SIGNOR-273140 MAPKAPK2 protein P49137 UNIPROT HSPA1L protein P34931 UNIPROT up-regulates activity phosphorylation Ser241 DFDNRLVsHFVEEFK -1 31642047 YES done miannu  We demonstrate that MK2 phosphorylates HspA1L solely on Ser241, a residue within the N-terminal nucleotide-binding domain of the enzyme. This phosphorylation event enhances the chaperone activity of HspA1L in vitro and renders male germ cells more resistant to heat stress-induced apoptosis. 0.2 SIGNOR-273674 MMP8 protein P22894 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu442 TSKGDKElRTGKEKV -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-8 20ADSGEGD a-chain | 442LRTGKEKV a-chain 0.2 SIGNOR-263626 SLC4A10 protein Q6U841 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 23056253 YES miannu The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons.  0.8 SIGNOR-264687 PAK6 protein Q9NQU5 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 18465753 YES miannu PAK5 phosphorylates Raf-1 on serine 338 and stimulates Raf-1 activity. 0.2 SIGNOR-278971 MBD2/NuRD complex complex SIGNOR-C337 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 27098840 NO miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. 0.7 SIGNOR-263859 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity precursor of 9606 9367159 YES Gianni The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K 0.8 SIGNOR-268865 NOD2 protein Q9HC29 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates activity binding 9606 BTO:0000567 19898471 YES miannu By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease. 0.755 SIGNOR-252405 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 YES gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase 0.27 SIGNOR-76080 PPP1CA protein P62136 UNIPROT PREX1 protein Q8TCU6 UNIPROT up-regulates activity dephosphorylation Ser1001 IRFGRKPsLIGLDPE 9606 22242915 YES lperfetto MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation. 0.2 SIGNOR-277024 MYC protein P01106 UNIPROT IMPDH1 protein P20839 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 YES miannu Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The mRNA levels of IMPDH1 and IMPDH2, the rate-limiting enzyme in purine de novo synthesis, increased with MYC induction both in vitro and in vivo. 0.243 SIGNOR-267378 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser13 GQDMSQVsGKESPPV 9606 BTO:0001271 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway 0.2 SIGNOR-174844 TLR4 protein O00206 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 BTO:0000801 7635431 NO lperfetto The activation of NF-kB is triggered by different stimuli, eg., lipopolysaccharides (LPSs), muramyl peptides, viruses,e inflammatory cytokines tumor necrosis factor-alpha(TNF-a) and interleukin (IL)-1b, irradiation, and reactive xygen intermediates (H2O2). 0.576 SIGNOR-249517 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT down-regulates activity phosphorylation Thr495 LLSLFEDtLDPT -1 12738781 YES miannu Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site. 0.72 SIGNOR-263097 XPO1 protein O14980 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates relocalization 9606 11074002 YES gcesareni We demonstrate that inhibition of crm1-mediated nuclear export by treatment of cells with leptomycin b results in endogenous smad4 accumulating very rapidly in the nucleus. 0.301 SIGNOR-84247 FZD3 protein Q9NPG1 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 17251915 YES gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. 0.2 SIGNOR-152597 Ggamma proteinfamily SIGNOR-PF3 SIGNOR PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 FSGIESSsPEVKGYW 10090 BTO:0000666 17475908 YES miannu All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells. 0.2 SIGNOR-262670 AKT3 protein Q9Y243 UNIPROT TBX3 protein O15119 UNIPROT up-regulates activity phosphorylation Ser719 AEKEAATsELQSIQR 9606 25595898 YES miannu We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion. 0.355 SIGNOR-223534 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR3 protein P32745 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257583 PRKAA1 protein Q13131 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17609368 NO gcesareni Several in vivo studies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochrome c, uncoupling protein 3 (ucp-3)] and proteins involved in glucose uptake (glut4)are increased at the transcriptional level in skeletal muscle. 0.302 SIGNOR-156786 PRKAA1 protein Q13131 UNIPROT EGLN1 protein Q9GZT9 UNIPROT down-regulates activity phosphorylation Ser61 HKLVCQGsEGALGHG 9606 BTO:0000599 35538889 YES miannu Mechanistically, AMPKα1 directly phosphorylated prolyl hydroxylase domain-containing (PHD)2 at serines 61 and 136, which suppressed PHD2-dependent hydroxylation of hypoxia-inducible factor (HIF)1α and subsequent regulation of hepatic hepcidin-related iron signalling. 0.373 SIGNOR-277592 SMURF1 protein Q9HCE7 UNIPROT UBQLN1 protein Q9UMX0 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.301 SIGNOR-272701 ATR protein Q13535 UNIPROT MCM2 protein P49736 UNIPROT unknown phosphorylation Ser108 DVEELTAsQREAAER 9606 15210935 YES lperfetto Atm phosphorylates mcm3 on s535 in response to ionizing radiation. Second, atr phosphorylates mcm2 on s108 in response to multiple forms of dna damage and stalling of replication forksthe functional consequences of mcm2 s108 and mcm3 s535 phosphorylation are not clear 0.707 SIGNOR-126363 EIF3K protein Q9UBQ5 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.924 SIGNOR-266390 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 10090 BTO:0002572 10988287 YES amattioni The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis. 0.726 SIGNOR-256451 POLR2K protein P53803 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.861 SIGNOR-266150 PF-04691502 chemical CID:25033539 PUBCHEM AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck;inhibitor of phosphorylation of AktT308 and AktS473 gcesareni 0.8 SIGNOR-252631 SKP1 protein P63208 UNIPROT SCF-FBW2 complex SIGNOR-C525 SIGNOR form complex binding 9606 BTO:0000007 15640526 YES miannu FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system 0.847 SIGNOR-271526 DOK1 protein Q99704 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.335 SIGNOR-257687 oligopeptide smallmolecule CHEBI:25676 ChEBI peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity precursor of 9606 31810556 YES scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. 0.8 SIGNOR-267863 PPP2R5B protein Q15173 UNIPROT KIF20A protein O95235 UNIPROT up-regulates activity dephosphorylation Ser878 RILRSRRsPLLKSGP 9606 BTO:0000567 27939310 YES miannu We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878. 0.2 SIGNOR-262660 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT up-regulates activity phosphorylation Tyr447 RLSSFTSyENPT 9606 12121988 YES lperfetto Mutation of a C-terminal tyrosine (Tyr-447) increases enzyme activity and SH2 domain accessibility, consistent with a role for this residue in autoinhibition. | These results suggest that the Y447F and W44A mutations disrupt the normal intramolecular regulation of Brk and increase the catalytic activity of Brk. 0.2 SIGNOR-249152 RNF208 protein Q9H0X6 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization ubiquitination Lys97 DAINTEFkNTRTNEK 9606 BTO:0000815 31862882 YES Gianni Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells 0.2 SIGNOR-269051 ITGA11 protein Q9UKX5 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.706 SIGNOR-253187 TNKS2 protein Q9H2K2 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 21478859 YES lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.2 SIGNOR-263382 C5AR2 protein Q9P296 UNIPROT SELL protein P14151 UNIPROT down-regulates quantity by repression 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.2 SIGNOR-263467 ADAM17 protein P78536 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage -1 9774383 YES lperfetto By the use of gene disruption (knockout), we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulated alpha-cleavage in cultured cells.  0.54 SIGNOR-262829 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 10090 BTO:0002882 16122376 YES Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work 0.2 SIGNOR-235951 PRKAA1 protein Q13131 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Ser801 KLRRRTFsLTEVRGQ -1 28992084 YES miannu We found that the strong direct substrate KIF4A is phosphorylated by AMPK at Ser801.Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis. 0.2 SIGNOR-265991 Ub:E2 complex SIGNOR-C497 SIGNOR NHLRC1 protein Q6VVB1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271135 OXTR protein P30559 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.429 SIGNOR-256793 MLL/SET subcomplex complex SIGNOR-C87 SIGNOR MLL1 complex complex SIGNOR-C89 SIGNOR form complex binding 9606 24680668 YES miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. 0.2 SIGNOR-204819 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser150 PELCGPGsPPVLTPG 9606 15952796 YES lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation 0.298 SIGNOR-138171 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.2 SIGNOR-262998 quinpirole chemical CHEBI:75401 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 YES miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. 0.8 SIGNOR-258440 TNF protein P01375 UNIPROT SCN1A protein P35498 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.258 SIGNOR-253478 IL22RA2 protein Q969J5 UNIPROT IL22 protein Q9GZX6 UNIPROT up-regulates binding 9606 11390453 YES gcesareni Il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4. 0.745 SIGNOR-86113 TP53 protein P04637 UNIPROT HR protein O43593 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15489903 NO miannu P53 may downregulate HR through multiple mechanisms including the reported associations with the Rad51 and Rad54 recombinases, and the BLM and WRN helicases. 0.342 SIGNOR-255436 RYBP protein Q8N488 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8943360 YES gcesareni We identified a novel protein, aap1 (abl-associated protein 1), that associates with these c-abl domains and fails to bind to the sh3 domain in the activated oncoprotein bcrabl. we conclude that aap1 inhibits c-abl tyrosine kinase activity 0.334 SIGNOR-45325 ATP6V1B1 protein P15313 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.79 SIGNOR-277744 OTULIN protein Q96BN8 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.717 SIGNOR-270829 AR protein P10275 UNIPROT SEPTIN7 protein Q16181 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 NO After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. 0.2 SIGNOR-253677 AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C7 17964260 YES lperfetto Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. 0.2 SIGNOR-244239 CDK2 protein P24941 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Thr141 RRDARGLtPLELALQ 9606 22558186 YES lperfetto Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response 0.526 SIGNOR-197274 CTNNBL1 protein Q8WYA6 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR form complex binding 9606 BTO:0000567 20176811 YES miannu In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27. 0.767 SIGNOR-271971 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 YRPKPSSsPVIFAGG 9606 17475908 YES miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 0.323 SIGNOR-262915 FIS1 protein Q9Y3D6 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 NO lperfetto During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2) 0.7 SIGNOR-272976 17beta-estradiol smallmolecule CHEBI:16469 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of -1 8994190 YES Luana Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues.  0.8 SIGNOR-269757 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120004 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR up-regulates activity phosphorylation 9606 9442019 YES ggiuliani In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus. 0.69 SIGNOR-255779 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr668 SYCGKRFtRSDELQR 9606 BTO:0000887;BTO:0001260 18258854 YES llicata Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter. 0.485 SIGNOR-160770 FYN protein P06241 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 11005864 YES lperfetto Study of t cells from a fyn-deficient tcr transgenic mouse also showed that fyn was required for tyrosine phosphorylation and activation of vav induced by both antagonist and agonist peptides. 0.635 SIGNOR-82287 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser347 PVYSPPGsPPPGDPR 9606 BTO:0000567 10806207 YES llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. 0.603 SIGNOR-77212 SLC9A9 protein Q8IVB4 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265599 SCF-betaTRCP complex SIGNOR-C5 SIGNOR RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 24290981 YES miannu Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. 0.2 SIGNOR-276607 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 22493066 NO svumbaca Both binding sites were enriched by more than 5-fold in the ChIP assay with RBP-Jk antibody, suggesting that RBP-Jk occupies these sequences in the Pax7 promoter region. 0.377 SIGNOR-255365 PPM1F protein P49593 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates dephosphorylation Thr286 SCMHRQEtVDCLKKF 9606 BTO:0000938 15140879 YES gcesareni Ppm1f specifically dephosphorylates the phospho-thr-286 in autophosphorylated camkii substrate and thus deactivates the camkii in vitro. 0.332 SIGNOR-124309 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 10567369 YES lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 0.754 SIGNOR-244912 AKT1 protein P31749 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity phosphorylation Ser19 KMAVESPsDSAENGQ 9606 BTO:0000815 33574926 YES miannu Akt interacts with and phosphorylates RSK2 at S19. 0.265 SIGNOR-277548 APAF1 protein O14727 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR form complex binding -1 10206961 YES lperfetto  APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9.  0.873 SIGNOR-256431 P2RY6 protein Q15077 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257189 GPSM3 protein Q9Y4H4 UNIPROT GNAI1 protein P63096 UNIPROT down-regulates activity binding 9606 BTO:0000007 22843681 YES lperfetto GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Galpha(i) subunits|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET. 0.49 SIGNOR-264864 HIPK2 protein Q9H2X6 UNIPROT PDX1 protein P52945 UNIPROT unknown phosphorylation Ser268 LPPGLSAsPQPSSVA 10090 BTO:0000783;BTO:0002284 20637728 YES Our results suggest that HIPK2-mediated phosphorylation of PDX1 at Ser-269 might be a regulatory mechanism connecting signals generated by changes in extracellular glucose concentration to downstream effectors via changes in subnuclear localization of PDX1, thereby influencing islet cell differentiation and function 0.353 SIGNOR-255539 CRYBB2 protein P43320 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 16319073 NO miannu At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency. 0.7 SIGNOR-252151 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT unknown phosphorylation Ser1859 PPRIHRAsDPGLPAE 11986331 YES miannu CAD is down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation. 0.307 SIGNOR-250343 STAG2 protein Q8N3U4 UNIPROT TNF protein P01375 UNIPROT up-regulates 9606 14660624 NO miannu Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner. 0.2 SIGNOR-119988 PRKACA protein P17612 UNIPROT ITGA4 protein P13612 UNIPROT up-regulates activity phosphorylation Ser1021 QEENRRDsWSYINSK 9606 BTO:0000782 11533025 YES lperfetto PKA phosphorylationin vitro blocks the binding of the alpha4 tail to paxillin. A mutation that mimics alpha4 phosphorylation disrupts paxillin binding and promotes cell spreading 0.492 SIGNOR-110119 Sin3B_complex complex SIGNOR-C409 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity binding 9606 21041485 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.2 SIGNOR-266973 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 BTO:0000848 BTO:0001253 20959475 YES lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). 0.2 SIGNOR-168762 Ub:E2 complex SIGNOR-C497 SIGNOR RNF212 protein Q495C1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271160 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RHOA protein P61586 UNIPROT up-regulates activity phosphorylation Thr100 ENIPEKWtPEVKHFC 9534 BTO:0000298 26816343 YES miannu We have recently reported that Rac1 is phosphorylated on threonine 108 (108T) by extracellular signal-regulated kinases (ERK) in response to epidermal growth factor (EGF) stimulation. Here, we provide evidence that RhoA is phosphorylated by ERK on 88S and 100T in response to EGF stimulation. 0.2 SIGNOR-277203 CDK19 protein Q9BWU1 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Thr2511 VPEHPFLtPSPESPD -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.302 SIGNOR-273137 CILK1 protein Q9UPZ9 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Thr908 LPSGRPGtTGPAGAQ 9606 SIGNOR-C3 22356909 YES gcesareni Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division. 0.2 SIGNOR-196198 MPHOSPH10 protein O00566 UNIPROT UTP3 protein Q9NQZ2 UNIPROT up-regulates activity binding -1 28813493 YES miannu Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome. 0.934 SIGNOR-261176 P2RY4 protein P51582 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-256727 ketanserin chemical CHEBI:6123 ChEBI SLC18A2 protein Q05940 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000318 8643547 YES miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. 0.8 SIGNOR-258494 STAT3 protein P40763 UNIPROT HSPA1B protein P0DMV9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 NO miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. 0.2 SIGNOR-255241 RBPJ protein Q06330 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000165 10066785 YES gcesareni ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA 0.598 SIGNOR-243178 GNB1 protein P62873 UNIPROT PLCB2 protein Q00722 UNIPROT up-regulates binding 9606 1465133 YES gcesareni Activation of plc-beta 2 by beta gamma subunits may be an important mechanism by which pertussis toxin-sensitive g proteins stimulate plc. 0.552 SIGNOR-19447 PRKACA protein P17612 UNIPROT ITPKB protein P27987 UNIPROT down-regulates activity phosphorylation -1 9374536 YES miannu Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328 0.352 SIGNOR-249995 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203576 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser358 WPLSRTRsEPLPPSA 9606 18339811 YES Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. 0.2 SIGNOR-248605 EPO protein P01588 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 NO Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. 0.319 SIGNOR-251786 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser43 RNPEAALsPTFRSDS 9606 BTO:0000007 33217317 YES miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.272 SIGNOR-265949 ATM protein Q13315 UNIPROT CDC25C protein P30307 UNIPROT down-regulates 9606 10097108 NO gcesareni Atm also contributes to the cdc25c activity, particularly in ir-damaged cells, by activating chk2. 0.495 SIGNOR-65966 GSK3B protein P49841 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser226 PKPGVTPsKSTSASA 9606 BTO:0000938 32599005 YES lperfetto Our laboratory has also demonstrated that FGF14 is a key accessory protein that binds to the intracellular Nav1.6 C-terminal tail, and that GSK3β can phosphorylate FGF14 both in vitro and in vivo at S226 [20] in an experimental model of Alzheimer's disease 0.259 SIGNOR-275746 PRKCD protein Q05655 UNIPROT TUT1 protein Q9H6E5 UNIPROT up-regulates activity phosphorylation 9606 22244330 YES miannu PKCdelta associates with and directly phosphorylates Star-PAP. 0.2 SIGNOR-279385 MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 YES gcesareni Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. 0.619 SIGNOR-179912 XBP1 protein P17861 UNIPROT NPPB protein P16860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20170659 NO miannu The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. 0.2 SIGNOR-255609 POU5F1 protein Q01860 UNIPROT SOX17/POU5F1 complex SIGNOR-C451 SIGNOR form complex binding 23474895 YES SimoneGraziosi Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm|We show that Sox17 partners with Oct4 and binds to a unique ‘compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical' binding sites. 0.609 SIGNOR-269221 SQSTM1 protein Q13501 UNIPROT WDFY3 protein Q8IZQ1 UNIPROT up-regulates quantity binding 9606 BTO:0000452 20168092 YES miannu  We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions.  0.563 SIGNOR-266792 JAK1 protein P23458 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 YES miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). 0.724 SIGNOR-260149 CDK2 protein P24941 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates phosphorylation Ser244 QPVSAPPsPRDISME 9606 14712216 YES amattioni Serine 244 phosphorylation is required for h4 apoptotic function. 0.2 SIGNOR-121198 NOTCH1 protein P46531 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 16256737 YES lperfetto The notch intracellular domain interacts with hif-1alpha and hif-1alpha is recruited to notch-responsive promoters upon notch activation under hypoxic conditions. 0.648 SIGNOR-141315 SRC protein P12931 UNIPROT AREG protein P15514 UNIPROT up-regulates cleavage 9606 17251915 YES lperfetto Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network. 0.345 SIGNOR-236537 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 BTO:0000007 8702708 YES lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. 0.895 SIGNOR-42984 FOXO1 protein Q12778 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 30519351 YES miannu To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter. 0.625 SIGNOR-277739 DEK protein P35659 UNIPROT PRDX5 protein P30044 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 19229864 NO lperfetto We further demonstrated by ChIP analysis that knock-down of DEK caused hyperacetylation of histones around Prx VI promoter which is upregulated in our profile. 0.2 SIGNOR-254125 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser78 NKDQHSIsYTLSRAQ -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.657 SIGNOR-276126 Galanin smallmolecule CHEBI:80161 ChEBI GALR2 protein O43603 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257495 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization ubiquitination Lys331 ELKETIKkLLASANL 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). 0.3 SIGNOR-272832 SLIT2 protein O94813 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding -1 16226035 YES miannu Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit. 0.94 SIGNOR-268377 FGR protein P09769 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276188 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser357 DGSGDTSsNEEIGST -1 12107178 YES llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. 0.425 SIGNOR-250871 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273068 ABCE1 protein P61221 UNIPROT 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR down-regulates quantity by destabilization binding 9606 28368393 YES miannu The essential ATP-binding cassette protein ABCE1 splits 80S ribosomes into 60S and 40S subunits after canonical termination or quality-control-based mRNA surveillance processes. Compared to the pre-splitting state, we observe repositioning of ABCE1's iron-sulfur cluster domain, which rotates 150° into a binding pocket on the 40S subunit. This repositioning explains a newly observed anti-association activity of ABCE1. Notably, the movement implies a collision with A-site factors, thus explaining the splitting mechanism. 0.2 SIGNOR-270816 NFX1 protein Q12986 UNIPROT TERT protein O14746 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17267499 NO miannu NFX1-123 augments the activation of hTERT expression through interactions with PABPCs 0.519 SIGNOR-226015 Nalorphine chemical CHEBI:7458 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258813 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT up-regulates activity phosphorylation Ser661 QNEFAGFsYTNPEFV 9606 10828076 YES The effect has been demonstrated using P05771-2 llicata We found in preliminary studies that autophosphorylation at ser660 was enhanced in response to angiotensin ii and phorbol esters|However, it was apparent that the return of the mutant GFP-S660A from the membrane to the cytoplasm was impaired, suggesting a specific role for this autophosphorylation site in the regulation of reverse translocation. 0.2 SIGNOR-77583 F2RL2 protein O00254 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257033 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr322 GDGPAVDyENQDVAS 9606 12540842 YES lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src. 0.407 SIGNOR-247337 NAD(1-) smallmolecule CHEBI:57540 ChEBI NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity precursor of 9606 28139779 YES miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 0.8 SIGNOR-268113 KDM4C protein Q9H3R0 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys37 APATGGVkKPHRYRP 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-263866 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser318 CKIFRRPsLPCISRE 10090 BTO:0000011 10454575 YES gcesareni PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B. 0.687 SIGNOR-252554 CSNK1A1 protein P48729 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Ser267 PPTTSSDsEEEQEDE 9606 BTO:0000007 22025562 YES miannu  Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation. 0.282 SIGNOR-276387 SKP2 protein Q13309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 17409098 YES gcesareni Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3). 0.766 SIGNOR-154194 PTPRR protein Q15256 UNIPROT MAPK7 protein Q13164 UNIPROT down-regulates activity dephosphorylation Tyr221 HQYFMTEyVATRWYR 9534 12042304 YES In this study we concentrated on whether and how PTP-SL, a kinase-interacting motif-containing PTP, might be involved in the down-regulation of the ERK5 signal|Whereas inactivation of ERK5 by PTP-SL monitored in vitro is most probably simply due to the dephosphorylation of tyrosine 220 in the activating TEY motif 0.451 SIGNOR-248721 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser227 FGSFPVHsPITQGTP 9606 BTO:0005043 22798426 YES miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. 0.287 SIGNOR-276103 ETS1 protein P14921 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000948 22270366 NO miannu VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. 0.306 SIGNOR-254084 GSK3B protein P49841 UNIPROT BICD1 protein Q96G01 UNIPROT up-regulates activity phosphorylation Thr597 KEPSPTKtPTISPVI 9606 BTO:0000567 17139249 YES miannu Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein. 0.332 SIGNOR-262744 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257951 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 20444238 YES gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.468 SIGNOR-165200 DNAH10 protein Q8IVF4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000667 31836722 NO miannu Epidermal expression of axonemal dynein heavy chain 10 (DNAH10) was increased 20-fold in samples having had regenerating dermis vs control. Our results associate DNAH10 expression with cell proliferation and inflammation as well as with the epidermal memory resulting from the previous regenerative signals of dermis. 0.7 SIGNOR-265550 ESR1 protein P03372 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11000528 NO gcesareni Inhibition of ar-induced transactivation that was er cdna dose-responsive and estradiol dependent 0.416 SIGNOR-82158 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9534 BTO:0000298 10880354 YES miannu Ser(155) is phosphorylated preferentially by PKA in vitro and is the only residue in BAD that becomes phosphorylated when cells are exposed to cAMP-elevating agents. The phosphorylation of BAD at Ser(155) prevents it from binding to Bcl-X(L) and promotes its interaction with 14-3-3 proteins. 0.541 SIGNOR-250338 AKT1 protein P31749 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser143 RTPRRSKsDGEAKPE 9606 21151116 YES gcesareni Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1. 0.528 SIGNOR-170530 DIDO1 protein Q9BTC0 UNIPROT ITGA5 protein P08648 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001673 22469980 YES Luana Dido1 upregulates the expression of Integrin αV, thereby influencing the attachment, apoptosis and migration of melanoma cells. 0.2 SIGNOR-261580 PRKG1 protein Q13976 UNIPROT RGS2 protein P41220 UNIPROT up-regulates activity phosphorylation Ser64 KPKTGKKsKQQAFIK -1 14608379 YES lperfetto Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.  0.679 SIGNOR-249241 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates activity phosphorylation Ser741 TKADKRRsVRIGSYI 9823 BTO:0004007 7539802 YES lperfetto We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling. 0.53 SIGNOR-248898 STK4 protein Q13043 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Thr108 GEASDGGtMENLSRR 9606 24141421 YES miannu These results suggest that Mst1 directly stimulates interaction between Beclin1 and Bcl-2.|We here demonstrate that Mst1-induced phosphorylation of Beclin1 in its BH3 domain at Thr 108 promotes binding of Beclin1 with Bcl-2/Bcl-xL. 0.312 SIGNOR-278502 CDT1 protein Q9H211 UNIPROT CDT1 protein Q9H211 UNIPROT up-regulates activity binding 9606 BTO:0000007 14672932 YES We further show that Cdc6 physically associates with Cdt1 via its N-terminal noncatalytic domain, a region we had previously shown to be essential for Cdc6 function. 0.2 SIGNOR-261682 SYNE4 protein Q8N205 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.451 SIGNOR-263288 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity acetylation 9606 25545885 YES miannu C-terminal acetylation of p53 by p300/CBP and PCAF promotes an open conformation of p53 by preventing the occlusion of the DNA binding domain by the C-terminal tail. This enhances p53 transcriptional activity, leading to growth arrest and/or apoptosis 0.912 SIGNOR-261496 WNT1 protein P04628 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 10090 BTO:0000887 16936075 YES lperfetto Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6) 0.766 SIGNOR-253126 CSK protein P41240 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22479394 YES Leads to Furin-cleavage activity gcesareni We found that the notch-1-furin interaction is regulated by the non-receptor tyrosine kinase, c-src. c-src and notch-1 are physically associated, and this association is responsible for notch-1 processing and activation 0.281 SIGNOR-196824 GRIK3 protein Q13003 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264944 AHCTF1 protein Q8WYP5 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.509 SIGNOR-262086 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 BTO:0000007 BTO:0000671 18270262 YES gcesareni We demonstrate that wnk1 is rapidly activated and phosphorylated at multiple residues after exposure of cells to hyperosmotic conditions and that activation is mediated by the phosphorylation of its t-loop ser382 residue, possibly triggered by a transautophosphorylation reaction. 0.2 SIGNOR-160850 RB1 protein P06400 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21524151 NO miannu Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. 0.7 SIGNOR-262533 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser276 AAQQTKGsYMEVEDN 9615 BTO:0000837 11742978 YES llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. 0.416 SIGNOR-250826 SKP2 protein Q13309 UNIPROT MYBL2 protein P10244 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 10871850 YES miannu P19Skp1 and Cul-1 bind to the F-box protein p45Skp2 to form a complex (SCF) that functions as E3 ubiquitin ligase.We show that B-Myb physically and functionally interacts with components of the Cdc34-SCFp45Skp2 ubiquitin pathway and propose that B-Myb degradation may be required for controlling the correct alternation of events during progression through the cell division cycle. 0.379 SIGNOR-272572 ULK1 protein O75385 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser63 HLYGIAGsTNVTGDQ 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274032 SMARCD3 protein Q6STE5 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding -1 22068056 YES lperfetto We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes. 0.539 SIGNOR-238289 CSNK2A1 protein P68400 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser118 EVVGGDDsDGLRAED 9606 23226345 YES lperfetto More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis 0.286 SIGNOR-200083 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12777400 YES Manara These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386 0.34 SIGNOR-260772 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA10 protein Q9Y5H3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265682 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 11839802 YES gcesareni Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta 0.893 SIGNOR-252616 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Ser104 SQQQFGYsPGQQQTH 9606 17310276 YES lperfetto Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1 0.341 SIGNOR-153300 WNT11 protein O96014 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000887 22309736 NO gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. 0.2 SIGNOR-195963 SCNN1B protein P51168 UNIPROT CACNA1H protein O95180 UNIPROT up-regulates activity binding 9606 BTO:0000142 30736831 YES miannu This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues. 0.2 SIGNOR-269273 BAG5 protein Q9UL15 UNIPROT HSPA1A protein P0DMV8 UNIPROT down-regulates activity binding 9606 BTO:0000142 15603737 YES Monia Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction. 0.753 SIGNOR-261196 alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-267936 HSPA9 protein P38646 UNIPROT iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI up-regulates activity relocalization 27714045 YES lperfetto Cluster transfer from ISCU to recipient apoproteins is assisted by a dedicated chaperone/cochaperone (HSPA9/HSC20) system that facilitates cluster release from the primary scaffold ISCU and transfer to recipient apoproteins or to intermediate carriers 0.8 SIGNOR-262131 CEP68 protein Q76N32 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity relocalization 25503564 YES lperfetto We also found that Cep68 forms a complex with Cep215 (also known as Cdk5Rap2) and PCNT (also known as pericentrin), two PCM (pericentriolar material) proteins involved in centriole engagement. |Retention of Cep68 or PCNT in late mitosis prevents the removal of Cep215 0.453 SIGNOR-275624 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 YES miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. 0.2 SIGNOR-259422 CCKAR protein P32238 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.252 SIGNOR-257148 EEF1A1 protein P68104 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269521 SMARCC2 protein Q8TAQ2 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.835 SIGNOR-270695 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 YES inferred from 70% of family members gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr 0.653 SIGNOR-269880 HEY1 protein Q9Y5J3 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 16682003 YES gcesareni These findings suggest a novel mechanism for negative feedback on notch signaling that requires rbp-jkappa to interact physically with hrt and hes. 0.656 SIGNOR-146687 PYHIN1 protein Q6K0P9 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001570 16479015 YES miannu Here, we show that IFIXalpha1 downregulates HDM2, a principal negative regulator of p53, at the posttranslational level. IFIXalpha1 destabilizes HDM2 protein and promotes its ubiquitination. The E3 ligase activity of HDM2 appears to be required for this IFIXalpha1 effect. Importantly, HDM2 downregulation is required for the IFIXalpha1-mediated increase of p53 protein levels, transcriptional activity, and nuclear localization, suggesting that IFIXalpha1 positively regulates p53 by acting as a negative regulator of HDM2. 0.414 SIGNOR-268493 Core mediator complex complex SIGNOR-C405 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 25693131 YES miannu The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator — a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). Because of its direct and extensive interactions with Pol II, Mediator regulates multiple stages of Pol II transcription (for example, initiation and re-initiation). Mediator interactions with the super elongation complex (SEC) also seem to be important for its regulation of Pol II elongation. 0.335 SIGNOR-266682 SMO protein Q99835 UNIPROT MAL protein P21145 UNIPROT up-regulates quantity transcriptional regulation 10090 35082605 NO Non-canonical pathway (Gli1-indipendent): SMO/AMPK SimoneGraziosi We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. 0.2 SIGNOR-269224 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 NO lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin 0.456 SIGNOR-235346 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI up-regulates quantity precursor of 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272768 ACAN protein P16112 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 16051604 YES lperfetto Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix of the musculoskeletal system.  0.7 SIGNOR-266983 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates phosphorylation Ser49 IEGMILLsELSRRRI 9606 3352609 YES lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b. 0.89 SIGNOR-24539 BDKRB2 protein P30411 UNIPROT Vascular_Permeability phenotype SIGNOR-PH140 SIGNOR up-regulates 9606 28966616 NO lperfetto BK binds receptor B2 (B2R) and triggers inflammation, edema, and symptoms of anaphylaxis. 0.7 SIGNOR-263540 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248375 FGF1 protein P05230 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 22298955 YES gcesareni Reports also show that fgf/fgfr3 signals mediate some of the effects of tgf-beta on embryonic bone formation 0.8 SIGNOR-195585 PRKAA1 protein Q13131 UNIPROT INSIG1 protein O15503 UNIPROT up-regulates quantity by stabilization phosphorylation Thr222 ITIAFLAtLITQFLV 9606 BTO:0000007 30733434 YES miannu Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPKα1 subunit associates with Insig-1 in a dose-dependent manner. 0.256 SIGNOR-277430 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT up-regulates activity phosphorylation Thr389 RVITQREtENNQMTS -1 21423175 YES miannu In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h). 0.2 SIGNOR-276323 PRKCA protein P17252 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY -1 12893243 YES lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚  0.318 SIGNOR-249223 FAS protein P25445 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0000944 7538908 YES lperfetto Fas associates with rip. Rip is a novel form of apoptosis-inducing protein 0.65 SIGNOR-235430 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser615 GEKNERTsVAGTVRK 9606 BTO:0002181 34216621 YES miannu  Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction.  0.574 SIGNOR-277322 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Thr355 EPSTVPGtPPPKKFR 9606 24376897 YES The effect has been demonstrated using Q9UKI8-2 llicata Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue. 0.448 SIGNOR-203503 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Ser898 SECDPTPsHRGQLNK 9606 BTO:0000567 31167143 YES miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  0.2 SIGNOR-276729 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000938 9346240 NO lperfetto Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt 0.816 SIGNOR-236428 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM41 protein Q8WV44 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270954 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR TP73 protein O15350 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001620 19581926 YES miannu The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73.Importantly, SCFFBXO45 ubiquitylates p73 both in vivo and in vitro. Expression of Cul1 dominant negative mutant, but not Cul2, Cul3, Cul4 and Cul5 dominant negative mutants, increased p73 levels (Figure 1c) to an extent similar to that observed in the ts41 cell line at not permissive temperature, suggesting that a Cul1-associated activity is required for p73 protein stability. 0.283 SIGNOR-271877 ABCC8 protein Q09428 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 YES lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. 0.652 SIGNOR-262056 TLN1 protein Q9Y490 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.551 SIGNOR-257635 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 YES Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. 0.569 SIGNOR-248334 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT up-regulates activity phosphorylation Ser209 LQKQPQPsPAEGRAV 9606 BTO:0000567 25097229 YES miannu Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins. 0.2 SIGNOR-277834 MYOD1 protein P15172 UNIPROT FST protein P19883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15130492 NO lperfetto MyoD, CREB, and NFAT Mediate the Transcriptional Activation of the Follistatin Promoter Induced by TSA 0.388 SIGNOR-251727 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 16613856 YES gcesareni Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation 0.459 SIGNOR-145983 FGFR4 protein P22455 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 10918587 YES Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. 0.349 SIGNOR-251141 Ub:E2 complex SIGNOR-C497 SIGNOR VPS8 protein Q8N3P4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271194 FBXO33 protein Q7Z6M2 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 10090 BTO:0000165 18354498 YES miannu Mediation of eIF3-f polyubiquitination by the SCFMAFbx. The association of MAFbx with the essential Skp1, Roc 1 and Cul1 proteins, specific components of an E3 ubiquitin–protein ligase (SCFMAFbx), was previously described. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome. 0.419 SIGNOR-271769 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser183 GLRTRTGsNIDCEKL 9606 15703181 YES lperfetto We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195. 0.2 SIGNOR-133880 KDM3B protein Q7LBC6 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 YES miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. 0.2 SIGNOR-266636 RAD23B protein P54727 UNIPROT RPA1 protein P27694 UNIPROT up-regulates activity binding 24086043 YES lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.574 SIGNOR-275698 SLC12A2 protein P55011 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 YES lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  0.8 SIGNOR-264634 CDK1 protein P06493 UNIPROT EIF4G2 protein P78344 UNIPROT up-regulates activity phosphorylation Thr508 AQPPRTQtPPLGQTP 9606 BTO:0000007 29530922 YES miannu To test whether CDK1 phosphorylates T508, Flag-DAP5 was purified from dox-induced HEK293 cells and incubated with active recombinant JNK2 or CDK1 in the presence of ATP (Fig. 3G). DAP5(T508) was phosphorylated only upon incubation with CDK1 (Fig. 3G). 0.339 SIGNOR-266387 DYRK1A protein Q13627 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation 9606 12138125 YES Dyrk1 acts synergistically with Shh to induce transcription of a Gli-promoter-driven luciferase reporter gene and of endogenous alkaline phosphatase. gcesareni Dyrk1 phosphorylates gli1 on more than one domain. 0.514 SIGNOR-90809 HOXC11 protein O43248 UNIPROT S100B protein P04271 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17488478 YES Luana HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells. 0.252 SIGNOR-261647 quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 19754199 YES Compound 7 (AC220) (quizartinib) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. 0.8 SIGNOR-255666 CDK1 protein P06493 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr78 KTRKTTTtPGRKPRG 9606 1939057 YES lperfetto Phosphorylation of the dna-binding domain of nonhistone high-mobility group i protein by cdc2 kinase: reduction of binding affinity 0.384 SIGNOR-22338 SLC4A8 protein Q2Y0W8 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 26136660 YES miannu Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride 0.8 SIGNOR-264918 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 1303753 YES gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. 0.577 SIGNOR-16235 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser159 KKKKKRFsFKKSFKL -1 1560845 YES gcesareni Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin 0.729 SIGNOR-243192 ZMYND11 protein Q15326 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding methylation:Lys38 PSTGGVKkPHRYRPG 24675531 YES miannu We found that full-length BS69 specifically interacted with H3K36me3 in native nucleosome co-immunoprecipitation (co-IP) experiments. We propose that BS69 specifically associates with H3K36me3-enriched chromatin through the PWWP domain, which facilitates the recruitment of MYND-bound transcription and chromatin remodeling factors including EZH2, HDAC1, Brg1 and E2F6 to target gene loci, thereby repressing target gene transcription. 0.2 SIGNOR-263897 G6PC1 protein P35575 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266582 MTOR protein P42345 UNIPROT DAP protein P51397 UNIPROT down-regulates activity phosphorylation Ser3 DQEWESPsPPKPTVF 9606 20537536 YES miannu A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51. 0.395 SIGNOR-259813 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser834 GSHTSGQsNGRDHQA 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.369 SIGNOR-276509 WT1 protein P19544 UNIPROT REN protein P00797 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18496514 YES Here, we show that a splice variant of the Wilms' tumor protein lacking three amino acids WT1(-KTS) suppresses renin gene transcription 0.422 SIGNOR-252296 NELFB protein Q8WX92 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 YES miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 0.857 SIGNOR-271402 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BU1 protein Q8N257 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRGRkESYSIYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271990 ATM protein Q13315 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 BTO:0000887 18534819 NO gcesareni The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity. 0.448 SIGNOR-161434 GNAL protein P38405 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates activity binding 9606 BTO:0004032 21303898 YES miannu D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum. 0.537 SIGNOR-264992 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr199 VKKSIRDtPAKNAQK 11278991 YES llicata Here, we identified that threonine 199 (Thr(199)) of NPM/B23 is the major phosphorylation target site of CDK2-cyclin E in vitro, and the same site is phosphorylated in vivo.|NPM/B23 binds specifically to unduplicated centrosomes and loses its centrosome binding activity when phosphorylated by CDK2-cyclin E 0.405 SIGNOR-250744 UNC5A protein Q6ZN44 UNIPROT Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 30108487 NO miannu Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion 0.7 SIGNOR-268182 GYS1 protein P13807 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI down-regulates quantity chemical modification 9606 26882899 YES miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. 0.8 SIGNOR-267938 Ub:E2 complex SIGNOR-C497 SIGNOR DTX4 protein Q9Y2E6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271108 trichostatin A chemical CHEBI:46024 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257941 MPHOSPH10 protein O00566 UNIPROT IMP4 protein Q96G21 UNIPROT up-regulates activity binding -1 28813493 YES miannu Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA. 0.818 SIGNOR-261174 PRKD1 protein Q15139 UNIPROT RTKN protein Q9BST9 UNIPROT up-regulates activity phosphorylation Ser448 QALAKQGsLYHEMAI 22228765 YES Phosphosite positions are derived from Figure 2 lperfetto Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane. 0.355 SIGNOR-275511 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 24632615 YES miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. 0.8 SIGNOR-266555 PAMPs stimulus SIGNOR-ST11 SIGNOR ITLN1 protein Q8WWA0 UNIPROT up-regulates activity binding 26148048 YES Human intelectin-1 (hIntL-1) does not bind known human glycan epitopes but does interact with multiple glycan epitopes found exclusively on microbes: β-linked D-galactofuranose (β-Galf), D-phosphoglycerol-modified glycans, heptoses, D-glycero-D-talo-oct-2-ulosonic acid (KO) and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO). | This ligand selectivity suggests that hIntL-1 functions in microbial surveillance. 0.7 SIGNOR-272498 UHRF1 protein Q96T88 UNIPROT RIF1 protein Q5UIP0 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0002181 26727879 YES miannu UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation.  0.2 SIGNOR-277193 DYRK1B protein Q9Y463 UNIPROT HDAC9 protein Q9UKV0 UNIPROT down-regulates phosphorylation Ser240 KVAERRSsPLLRRKD 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 YES lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner 0.2 SIGNOR-235813 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp242 VRQKSEVdIVVSEDL 9606 11741536 YES gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. 0.365 SIGNOR-112788 ULK1 protein O75385 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19211835 YES gcesareni Ulks directly phosphorylate atg13 0.917 SIGNOR-183957 CBLB protein Q13191 UNIPROT NCK1 protein P16333 UNIPROT up-regulates activity binding 9606 BTO:0000782 16503409 YES lperfetto Activated Cbl and Cbl-b interacted with Crk-L, Zap-70, Nck, PLC-gamma 0.524 SIGNOR-236054 MTOR protein P42345 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser2481 TVPESIHsFIGDGLV 10090 BTO:0000944 SIGNOR-C2 SIGNOR-C2 20022946 YES lperfetto We have found that in HEK293 cells and 3T3-L1 adipocytes, insulin promotes both raptor- and rictor-associated mTOR Ser(P)-2481 in a wortmannin-sensitive manner. Thus, insulin signals via PI3K to promote both mTORC1- and mTORC2-associated mTOR Ser-2481 autophosphorylation. 0.2 SIGNOR-235427 PAMPs stimulus SIGNOR-ST11 SIGNOR MEFV protein O15553 UNIPROT up-regulates activity 16037825 NO lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-256426 NSL1 protein Q96IY1 UNIPROT MIS12 complex complex SIGNOR-C362 SIGNOR form complex binding -1 27881301 YES lperfetto Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits 0.913 SIGNOR-265191 MRGPRX2 protein Q96LB1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257385 CDK2 protein P24941 UNIPROT ID3 protein Q02535 UNIPROT down-regulates phosphorylation Ser5 sPVRGCYE 9606 9372912 YES lperfetto We now show that an analogous cell-cycle-regulated phosphorylation of id3 alters the specificity of id3 for abrogating both e-box-dependent bhlh homo- or heterodimer complex formation in vitro and e-box-dependent reporter gene function in vivo._ 0.343 SIGNOR-53306 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser102 EEGISQEsSEEEQ -1 2806554 YES llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. 0.328 SIGNOR-251004 ZFP36 protein P26651 UNIPROT EIF4E2/GIGYF2 complex complex SIGNOR-C257 SIGNOR up-regulates activity relocalization 9606 30917308 YES lperfetto A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs 0.2 SIGNOR-261015 PTGS2 protein P35354 UNIPROT prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI up-regulates chemical modification 9606 11751058 YES gcesareni Cox catalyzes two enzymatic activities;namely, the conversion of aa to the hydroperoxy endoperoxide pgg2, followed by its subsequent reduction to the labile product pgh2. Pgh2_ is the common substrate for a number of different cell-specific synthases, which convert pgh2_ to the individual pgs or tx, including pge2, pgi2_ (prostacyclin), pgd2, pgf2alfa, and txa2. 0.8 SIGNOR-113291 HIF-1 complex complex SIGNOR-C418 SIGNOR PDK1 protein Q15118 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16517405 YES miannu Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. 0.41 SIGNOR-267446 SOHLH1 protein Q5JUK2 UNIPROT ZP3 protein P21754 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16690745 YES Luana Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters. 0.378 SIGNOR-266078 MAPK1 protein P28482 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 YES lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. 0.381 SIGNOR-264439 P2RY6 protein Q15077 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257076 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr194 NMMDILTtPSMAKPR 9606 BTO:0002181 24391510 YES miannu We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194.Gwl phosphorylation by CycA/Cdk2 in vitro. Flag WT and Thr194A Gwl was transiently expressed and purified from asynchronous HEK 293T cells and incubated with recombinant CycA/Cdk2, following treatment with alkaline phosphatase (aPh) in the indicated samples. The proteins were analysed by immuno-blotting with anti-Gwl and Gwl pThr194 antibodies 0.275 SIGNOR-276614 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000891 10929711 YES amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. 0.791 SIGNOR-80209 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser323 HCSAEAGsPAMAVLD 9606 16286470 YES lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain 0.786 SIGNOR-141609 CPSF4 protein O95639 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 BTO:0000007 19224921 YES lperfetto The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30. 0.917 SIGNOR-268334 PRKACA protein P17612 UNIPROT STK24 protein Q9Y6E0 UNIPROT unknown phosphorylation Thr18 ALNKRRAtLPHPGGS 9606 BTO:0000007 BTO:0000142;BTO:0000671 10644707 YES llicata Further experiments demonstrated that mst3b, but not mst3, was effectively phosphorylated by activation of cyclic amp-dependent protein kinase (pka) in both in vivo and in vitro assays. The mutation of thr-18 into ala in mst3b (t18a), a putative pka phosphorylation site that is absent in mst3, abolished its phosphorylation by pka. 0.218 SIGNOR-74284 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 phosphorylation:Thr185 HDHTGFLtEYVATRW 16456541 YES gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk 0.62 SIGNOR-143052 MAPK14 protein Q16539 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 BTO:0000132 8910365 YES lperfetto These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets 0.667 SIGNOR-44673 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB3 protein P79483 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.2 SIGNOR-254001 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 12213813 YES lperfetto In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E 0.67 SIGNOR-262994 MICU1 protein Q9BPX6 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.69 SIGNOR-270876 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 29901072 YES miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. 0.8 SIGNOR-262218 Quadazocine chemical CID:115077 PUBCHEM OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258418 CDK7 protein P50613 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity phosphorylation Thr160 GVPVRTYtHEVVTLW -1 10085115 YES llicata Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP. 0.57 SIGNOR-250768 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 11108261 YES lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. 0.765 SIGNOR-84971 IL1R1 protein P14778 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 9625767 NO lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab) 0.525 SIGNOR-249512 CDK7 protein P50613 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 17901130 YES llicata In conclusion, our results indicate that cdk7, as part of the cak complex and tfiih, phosphorylates sf1 at s203 followed by increased transcriptional activity of sf1 0.367 SIGNOR-157952 PRKD1 protein Q15139 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates phosphorylation Ser1981 ASLGRRAsFHLECLK 9606 22100296 YES gcesareni Both the expression of a dominant-negative mutant of pkd and the mutation of serine 1884 but not serine 1930, putative targets of pkd, strongly reduced l-type calcium currents and single channel activity without affecting the channel's expression at the plasma membrane. Our results suggest that serine 1884 is essential for the regulation of hcav1.2 by pkd. 0.255 SIGNOR-177481 PRKCB protein P05771 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 BTO:0004737 11325528 YES lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. 0.283 SIGNOR-249090 CSNK1A1 protein P48729 UNIPROT TUT1 protein Q9H6E5 UNIPROT up-regulates activity phosphorylation Ser6 sDVESLPR 9606 BTO:0000007 26138484 YES done miannu We identified a phosphorylated residue (serine 6, S6) on Star-PAP in the zinc finger region, the domain required for PIPKIα interaction. We show that S6 is phosphorylated by CKIα within the nucleus which is required for Star-PAP nuclear retention and interaction with PIPKIα.  0.267 SIGNOR-273619 MK-2206 chemical CHEBI:67271 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 BTO:0001286 21841310 YES gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. 0.8 SIGNOR-176043 long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI up-regulates quantity precursor of 9606 24269233 YES ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity 0.8 SIGNOR-267711 GSK3B protein P49841 UNIPROT FCAR protein P24071 UNIPROT down-regulates activity phosphorylation Ser284 LTFARTPsVCK 10090 BTO:0001516 30766540 YES lperfetto GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state. 0.2 SIGNOR-264857 CEP350 protein Q5VT06 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR form complex binding 9606 16314388 YES miannu Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring. 0.2 SIGNOR-142355 DRD5 protein P21918 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.481 SIGNOR-256771 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser828 EHDSAEGsHTSGQSN 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.369 SIGNOR-276512 FGF12 protein P61328 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.235 SIGNOR-253444 Collagen proteinfamily SIGNOR-PF103 SIGNOR ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 35268340 NO miannu The extracellular matrix is a structure composed of many molecules, including fibrillar (types I, II, III, V, XI, XXIV, XXVII) and non-fibrillar collagens (mainly basement membrane collagens: types IV, VIII, X), non-collagenous glycoproteins (elastin, laminin, fibronectin, thrombospondin, tenascin, osteopontin, osteonectin, entactin, periostin) embedded in a gel of negatively charged water-retaining glycosaminoglycans (GAGs) such as non-sulfated hyaluronic acid (HA) and sulfated GAGs which are linked to a core protein to form proteoglycans (PGs). 0.7 SIGNOR-269732 TLR2 protein O60603 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 9606 BTO:0001025 19185596 NO miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection. 0.559 SIGNOR-260973 NEDD4 protein P46934 UNIPROT DCUN1D1 protein Q96GG9 UNIPROT up-regulates quantity monoubiquitination Lys171 FAKNPGQkGLDLEMA 9606 BTO:0000007 21813641 YES miannu Here we revealed a previously unknown mechanism that regulates hDCNL1. In cultured mammalian cells ectopically expressed hDCNL1 was mono-ubiquitinated predominantly at K143, K149, and K171. Using a classical chromatographic purification strategy, we identified Nedd4-1 as an E3 ligase that can catalyze mono-ubiquitination of hDCNL1 in a reconstituted ubiquitination system.Taken together, these results suggest a mono-ubiquitination-mediated mechanism that governs nuclear-cytoplasmic trafficking of hDCNL1, 0.368 SIGNOR-272719 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268591 MYC protein P01106 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity binding 10090 BTO:0000944 8266081 YES miannu Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1. 0.546 SIGNOR-268795 CHUK protein O15111 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Ser1043 CRPEALNsGVEYYWD 9606 BTO:0000567 30217973 YES lperfetto Furthermore, we show that mitophagy function of AMBRA1 is post-translationally controlled, upon HUWE1 activity, by a positive phosphorylation on its serine 1014. This modification is mediated by the IKKα kinase and induces structural changes in AMBRA1, thus promoting its interaction with LC3/GABARAP (mATG8) proteins and its mitophagic activity. 0.2 SIGNOR-272974 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser321 LNSEDDVsDEEGQEL -1 11278496 YES llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. 0.375 SIGNOR-250998 WNT9A protein O14904 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.656 SIGNOR-132073 LSM-1231 chemical CHEBI:91471 ChEBI NTRK3 protein Q16288 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258240 PTPRJ protein Q12913 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates dephosphorylation 9606 18348712 YES gcesareni As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors. 0.262 SIGNOR-178049 CKM complex complex SIGNOR-C406 SIGNOR CCNH protein P51946 UNIPROT down-regulates activity phosphorylation Ser5 sSQKRHWT 9606 10993082 YES gcesareni Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth. 0.44 SIGNOR-273139 FLI1 protein Q01543 UNIPROT KLF1 protein Q13351 UNIPROT down-regulates activity binding 10090 BTO:0004475 12556498 YES irozzo FLI-1 represses the transcriptional activity of EKLF.Our data indicate that the ETS domain of FLI-1 is absolutely required to inhibit EKLF activity. Since the FLI-1 ETS domain interacts with the DNA binding domain of EKLF, one possibility could be that FLI-1 inhibits the binding of EKLF to its DNA targets 0.371 SIGNOR-256044 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr439 VVIPPPDyLECLSMG -1 21840312 YES miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. 0.389 SIGNOR-263042 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203564 IL1B protein P01584 UNIPROT IL1RAP protein Q9NPH3 UNIPROT up-regulates binding 9606 9820540 YES gcesareni The recently described il-1r accessory protein (il-1r acp) interacts with il-1beta and the il-1 type-ir (il-1ri). 0.867 SIGNOR-61744 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser269 PCNKRKYsLNGRQPP 9606 BTO:0001061 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276769 STXBP1 protein P61764 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9534 11036064 YES miannu We propose that all these neurexin complexes can interact with Munc18. Both Mint1 and Mint2 could function as direct adaptors of Munc18 to neurexins, whereas Mint1 in addition could recruit Munc18 to CASK-neurexin (Fig. 5 B). 0.525 SIGNOR-264040 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser299 SQPPGEDsDTDVDDD 9606 18678890 YES gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. 0.347 SIGNOR-179875 Hexocyclium chemical CHEBI:5707 ChEBI CHRM5 protein P08912 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258399 axitinib chemical CHEBI:66910 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258075 DLGAP4 protein Q9Y2H0 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.743 SIGNOR-264596 N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide chemical CHEBI:91360 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates activity chemical inhibition -1 16162000 YES miannu A novel structural class of 4-phenyl-5-pyridyl-1,3-thiazoles was optimized as inhibitors of p38 MAP kinase and the proinflammatory cytokine TNF-α. it only significantly inhibited p38α (IC50 = 7.1 nM) and p38β (IC50 = 200 nM) in a concentration-dependent manner and was approximately 28 times more selective for p38α over p38β. 0.8 SIGNOR-262223 HAUS6 protein Q7Z4H7 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 YES lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) 0.893 SIGNOR-262320 SKIL protein P12757 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 10531062 YES lperfetto Thus, SnoN can interact with Smad4 and Smad2 and inhibit their abilities to activate transcription. 0.8 SIGNOR-227479 BMP7 protein P18075 UNIPROT BMP7 protein P18075 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 YES lperfetto Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interac- tion with receptors 0.2 SIGNOR-236172 imatinib chemical CHEBI:45783 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258226 MAPK3 protein P27361 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates activity phosphorylation Thr699 TELVEPLtPSGTAPN 9606 BTO:0000007 31053301 YES miannu We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation.  0.532 SIGNOR-277448 SYMPK protein Q92797 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 16230528 NO lperfetto Reconstitution experiments reveal that symplekin, previously shown to be necessary for cytoplasmic poly(A) tail elongation and translational activation of mRNAs during Xenopus oocyte maturation, is the essential heat-labile component. 0.7 SIGNOR-268368 Complement C1 complex complex SIGNOR-C309 SIGNOR C2 protein P06681 UNIPROT up-regulates activity cleavage Arg243 KTKESLGrKIQIQRS 31331124 YES lperfetto C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex 0.497 SIGNOR-263418 FGF10 protein O15520 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 9582367 YES gcesareni Rfgf-10 bound the kgfr with high affinity comparable to that of kgf 0.893 SIGNOR-57380 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser398 VDLHISNsHPLSLTS -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.741 SIGNOR-178375 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB5 protein Q30154 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.283 SIGNOR-254003 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr178 LLEDEADyVVPVEDN 9606 BTO:0000776 12456653 YES llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. 0.805 SIGNOR-96040 FCN3 protein O75636 UNIPROT MASP2 protein O00187 UNIPROT up-regulates activity binding 17204478 YES lperfetto In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2) 0.518 SIGNOR-263412 NF1 protein P21359 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity binding 9606 BTO:0000007 32697994 YES miannu Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS. 0.72 SIGNOR-273661 ACTN1 protein P12814 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity binding 9534 16291744 YES lperfetto Consistent with the results obtained with COS-7 cells, coexpression of wild-type Œ±-actinin with PTP 1B in PTP 1B-null cells resulted in Src/Œ±-actinin binding and limited the interaction between FAK and Src 0.573 SIGNOR-261799 PPP2R5C protein Q13362 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates binding 9606 20444422 YES gcesareni The human homolog of pp2a-b', ppp2r5c, also counteracts s6k1 phosphorylation, indicating a conserved mechanism in mammals 0.341 SIGNOR-165224 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 11581251 YES inferred from 70% family members lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. 0.2 SIGNOR-270119 PBRM1 protein Q86U86 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18339845 NO miannu Endogenous wild-type baf180 bound to the p21 promoter and was required for proper p21 expression and g(1) arrest after transforming growth factor-beta and gamma-radiation treatment. 0.263 SIGNOR-178022 Ub:E2 complex SIGNOR-C497 SIGNOR ZNRF1 protein Q8ND25 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270949 Ub:E2 complex SIGNOR-C497 SIGNOR UBE3A protein Q05086 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271284 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12185584 YES gcesareni Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies. 0.622 SIGNOR-91546 MAPK13 protein O15264 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation 9606 9199504 YES miannu Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in the ability of tau to promote microtubule assembly. 0.53 SIGNOR-278313 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267904 NKX2-5 protein P52952 UNIPROT MYL2 protein P10916 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003265 9043061 NO The mammalian homolog of the Drosophila tinman homeobox gene, Nkx2-5, is specifi- cally required for ventricular chamber-specific myosin light chain-2 (MLC-2v) expression and looping morphogenesis during mammalian heart development. 0.619 SIGNOR-253645 MAPK3 protein P27361 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 12169099 YES gcesareni Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. 0.78 SIGNOR-91379 GABRA1 protein P14867 UNIPROT GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.655 SIGNOR-263750 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr982 SLISPAStPSCLSAA 9606 BTO:0000567 21818122 YES miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  0.428 SIGNOR-276241 HIF1A protein Q16665 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.267 SIGNOR-271571 ARPP19 protein P56211 UNIPROT PPP2R2D protein Q66LE6 UNIPROT down-regulates activity binding -1 phosphorylation:Ser62 KGQKYFDsGDYNMAK 21164014 YES gcesareni We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. 0.693 SIGNOR-243731 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 19574738 YES gcesareni Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c 0.858 SIGNOR-186617 PRKCA protein P17252 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity phosphorylation Thr115 ADRRKAAtMRERRRL 9534 1335366 YES lperfetto FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains. 0.364 SIGNOR-248845 WNT3A protein P56704 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 YES gcesareni Here, we report that ryk directly binds wnt-1 and wnt-3a via its wif domain and is required for the tcf. 0.763 SIGNOR-129580 TNFRSF21 protein O75509 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 32454942 NO miannu Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress. 0.7 SIGNOR-263831 RUNX1 protein Q01196 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004850 14594802 NO miannu We find that LEF-1 and CBFalpha co-activate ELA2 expression. 0.318 SIGNOR-254553 CASP6 protein P55212 UNIPROT Caspase 6 complex complex SIGNOR-C228 SIGNOR form complex binding cleavage:Asp193 DTNITEVdAASVYTL 21621544 YES lperfetto It is generally recognized that effector caspases undergo proteolytic cleavage of the inactive zymogen at a specific aspartate residue, resulting in a large N-terminal p20 polypeptide chain and a small C-terminal p10 polypeptide chain, leading to a p202/p102 tetramer. 0.2 SIGNOR-256392 TP73 protein O15350 UNIPROT PMAIP1 protein Q13794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17700533 NO miannu Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. 0.32 SIGNOR-255469 GCG protein P01275 UNIPROT GCGR protein P47871 UNIPROT up-regulates binding 9606 12529935 YES fspada Mutation of a highly conserved d64 residue in the n-terminal portion of the rat glucagon receptor completely eliminates glucagon binding. This residue corresponds to a mutated asp residue at amino acid 60 in the growth hormone releasing hormone receptor that gives rise to the little mouse phenotype (lin et al.1993). Antisera directed against amino acid sequences 126_137 of the n-terminal region, and agai residues 206_219 of the first extracellular loop block [125i]-glucagon binding and interfere with glucagon-induced adenylyl cyclase generation in rat liver membranes. 0.776 SIGNOR-97338 PAX7 protein P23759 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates binding 9606 SIGNOR-C89 22863532 YES miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. 0.2 SIGNOR-198626 PALB2 protein Q86YC2 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates binding 9606 19423707 YES miannu We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage. 0.753 SIGNOR-185656 HDAC4 protein P56524 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 9606 BTO:0000887 10737771 YES gcesareni We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2. 0.712 SIGNOR-76234 clozapine chemical CHEBI:3766 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258516 ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11739736 NO miannu The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing. 0.7 SIGNOR-263946 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. 0.91 SIGNOR-252856 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12226093 YES The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. 0.704 SIGNOR-251600 GTF2I protein P78347 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19097122 NO miannu Transcription factor TFII-I causes transcriptional upregulation of GRP78 synthesis in prostate cancer cells. 0.371 SIGNOR-254221 CUX2 protein O14529 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 10090 26221032 NO miannu Genetic inactivation in mouse embryo fibroblasts or CUX2 knockdown in HCC38 cells delayed DNA repair and increased DNA damage. These results demonstrate that CUX2 functions as an accessory factor that stimulates the repair of oxidative DNA damage 0.7 SIGNOR-263958 KCNJ3 protein P48549 UNIPROT KCNJ5/KCNJ3 complex SIGNOR-C56 SIGNOR form complex binding 9606 BTO:0000562 22362083 YES miannu The muscarinic k(+) channel (i (k,ach)) is a heterotetramer composed of girk1 (kir3.1) andgirk4(kir3.4) subunits of a g protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart. 0.473 SIGNOR-196202 TRIM13 protein O60858 UNIPROT AKT2 protein P31751 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21333377 YES miannu Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. 0.2 SIGNOR-271853 DEAF1 protein O75398 UNIPROT RAC3 protein P60763 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 18826651 YES Gianni Affymetrix gene profiling studies revealed Rac3 as a potential target gene and quantitative RT-PCR analysis confirmed that Rac3 was upregulated by Deaf-1 in immortalized mouse mammary epithelial cells. 0.2 SIGNOR-269059 CUL1 protein Q13616 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR form complex binding 9606 15340381 YES gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. 0.945 SIGNOR-243557 CXCL12 protein P48061 UNIPROT ACKR3 protein P25106 UNIPROT up-regulates binding 9606 BTO:0000782 16107333 YES gcesareni Here we show that cxcl12, the only known natural ligand for cxcr4, binds to and signals through rdc1. 0.719 SIGNOR-139709 HSD17B1 protein P14061 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification -1 8994190 YES Luana Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues.  0.8 SIGNOR-269760 MAP3K7 protein O43318 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 9480845 NO lperfetto Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene...[]...These Results suggest that tak1 induces nf-kappa b activation through a novel nik-independent signaling pathway 0.653 SIGNOR-55710 CTSG protein P08311 UNIPROT C3 protein P01024 UNIPROT up-regulates activity cleavage Arg748 ASHLGLArSNLDEDI 9606 BTO:0001412 1861080 YES miannu Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752. These proteases are, thus, able to generate, on the U937 surface, active fragments of C3, which are likely to be involved in cell-protein and cell-cell interactions. 0.598 SIGNOR-256347 dabrafenib chemical CHEBI:75045 ChEBI LIMK1 protein P53667 UNIPROT down-regulates activity chemical inhibition -1 24720932 YES miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations 0.8 SIGNOR-259216 sabcomeline chemical CHEBI:134846 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10116 9399977 YES miannu SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes 0.8 SIGNOR-258677 INSIG1 protein O15503 UNIPROT SCAP protein Q12770 UNIPROT down-regulates activity binding 10029 BTO:0000246 12202038 YES Using coimmunoprecipitation and tandem mass spectrometry, we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER. 0.766 SIGNOR-267495 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT up-regulates activity phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0002181 24841198 YES miannu When the CaMKI activity is elevated, it phosphorylates PME-1 at Ser15. 0.396 SIGNOR-276636 GRIK3 protein Q13003 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264344 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation 9606 9878069 YES gcesareni Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e. 0.778 SIGNOR-62936 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 YES lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf 0.2 SIGNOR-244152 MAP3K2 protein Q9Y2U5 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11343802 YES lperfetto Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation 0.415 SIGNOR-244888 DTX3L protein Q8TDB6 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity monoubiquitination Lys92 MDVVYALkRQGRTLY 9606 BTO:0000007 19818714 YES miannu Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage.  In response to DNA damage, BBAP expression increases and the E3 ligase selectively monoubiquitylates H4K91. Disruption of BBAP-mediated monoubiquitylation of H4K91 is associated with loss of chromatin-associated PR-Set7/Set8 and mono- and dimethyl H4K20, delayed kinetics of 53BP1 foci formation and increased sensitivity to DNA damage. 0.2 SIGNOR-271897 KAT2B protein Q92831 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates acetylation 9606 BTO:0000782;BTO:0001271 23029358 YES gcesareni In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia. 0.601 SIGNOR-199024 MMP25 protein Q9NPA2 UNIPROT MMP2 protein P08253 UNIPROT up-regulates activity cleavage Asn109 CGNPDVAnYNFFPRK -1 14583471 YES miannu Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr. 0.376 SIGNOR-256345 SORBS1 protein Q9BX66 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000887 11001060 YES gcesareni Cbl is recruited to the insulin receptor by interaction with the adapter protein cap, through one of three adjacent sh3 domains in the carboxy terminus of cap 0.687 SIGNOR-82283 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.675 SIGNOR-263423 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1168 HGHVSDAsISLGESV -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262903 SIL1 protein Q9H173 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates activity binding 9534 BTO:0001538 12356756 YES Simone BAP, a Mammalian BiP-associated Protein, Is a Nucleotide Exchange Factor That Regulates the ATPase Activity of BiP. In addition,BAP was associated with BiP in mammalian cells and inter-acted with BiP functionallyin vitro. BAP stimulated the ATPase activity of BiP when added alone or together with the ER DnaJ protein, ERdj4, by promoting the release of ADP from BiP. Together, these data demonstrate that BAP serves as a nucleotide exchange factor for BiP and provide insights into the mechanisms that control protein folding in the mammalian ER. 0.578 SIGNOR-261045 PPP3CC protein P48454 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 YES When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. 0.263 SIGNOR-248506 ATG13 protein O75143 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates binding 9606 19225151 YES gcesareni Atg13 directly binds fip200. 0.919 SIGNOR-184120 resveratrol chemical CHEBI:27881 ChEBI SIRT1 protein Q96EB6 UNIPROT up-regulates activity chemical activation -1 12939617 YES gcesareni We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53 0.8 SIGNOR-238786 IL1RL1 protein Q01638 UNIPROT IL1RAP protein Q9NPH3 UNIPROT up-regulates activity binding 9606 35238669 YES miannu The initial step in IL-33 signal transduction is ligand-induced conformational changes in IL-33R, which facilitate recruitment of interleukin-1 receptor accessory protein (IL-1RAP). 0.505 SIGNOR-277715 MSI2 protein Q96DH6 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001271 21084860 NO miannu Msi2 was shown to be upregulated in blast crisis cml and to negatively regulate expression ofnumb. 0.419 SIGNOR-169848 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR DOCK6 protein Q96HP0 UNIPROT down-regulates activity phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 YES lperfetto Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching 0.2 SIGNOR-275668 ATM protein Q13315 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser1039 NSNHGSQsPRNVEER 29939287 YES phosphorylation site remapping based on Fig 1 lperfetto To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. 0.2 SIGNOR-273434 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Thr409 GQGEKSAtPSRKILD 9606 SIGNOR-C17 15037602 YES lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. The m-phase kinase cyclin b/cdk1 phosphorylates rangap1 efficiently in vitro, and t409 phosphorylation correlates with nuclear accumulation of cyclin b1 in vivo. 0.493 SIGNOR-123524 RBPJ protein Q06330 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11432830 NO gcesareni The rbp-jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated notch1 through rbp-jkappa-dependent transcription. 0.307 SIGNOR-109042 MITF protein O75030 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004595 14982938 NO miannu These studies define the VMD2 promoter region sufficient to drive RPE-specific expression in the eye, identify positive regulatory regions in vitro, and suggest that MITF as well as other E-box binding factors may act as positive regulators of VMD2 expression. 0.376 SIGNOR-254586 PPM1D protein O15297 UNIPROT RBM38 protein Q9H0Z9 UNIPROT up-regulates activity dephosphorylation Ser195 DQYPYAAsPATAASF 9606 25823026 YES lperfetto Interestingly, we showed that PPM1D directly interacts with and dephosphorylates RBM38 at serine 195. 0.363 SIGNOR-277020 Galanthamine hydrobromide chemical CID:121587 PUBCHEM ACHE protein P22303 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192583 CAMK2A protein Q9UQM7 UNIPROT ANKS1B protein Q7Z6G8 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 27477489 YES miannu CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. The present study indicates that CaMKII activation is necessary for the NMDA-induced movement of AIDA-1 out of the PSD core. 0.257 SIGNOR-264231 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 BTO:0000887 15769444 YES lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. 0.344 SIGNOR-134613 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr263 TTLSLPLtPESPNDP 9606 BTO:0000887 11741533 YES gcesareni Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298 0.584 SIGNOR-112770 ULK1 protein O75385 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates phosphorylation 9606 20921139 YES gcesareni When autophagy is induced, ulk1 phosphorylates ambra1, releasing the autophagy core complex from dynein. Its subsequent relocalization to the endoplasmic reticulum enables autophagosome nucleation. Ambra1-dlc1 dissociates from the dynein complex upon ulk1-dependent ambra1 phosphorylation. 0.694 SIGNOR-168292 IGF1R protein P08069 UNIPROT CRK protein P46108 UNIPROT down-regulates activity phosphorylation Tyr221 GGPEPGPyAQPSVNT 10090 BTO:0000944 9480911 YES On activation of the IGF-I receptor, Crk-II binds to phosphorylated tyrosine residues, especially in the juxtamembrane region. As a result of this binding, the IGF-I receptor kinase phosphorylates Tyr-221 of Crk-II, resulting in a change in intramolecular folding and binding of the SH2 domain to the phosphorylated Tyr-221, which causes rapid disassociation of the Crk-II-IGF-I receptor complex. 0.721 SIGNOR-251273 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser511 DSPFYRDsLPGSQRK 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. 0.641 SIGNOR-183692 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser772 LFKKIFPsLELNITD 9606 BTO:0004553 24614225 YES gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. 0.307 SIGNOR-266441 LRRC4 protein Q9HBW1 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 NO miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. 0.2 SIGNOR-264057 NEDD4L protein Q96PU5 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 YES miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 0.325 SIGNOR-253461 AMPK complex SIGNOR-C15 SIGNOR HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 21892142 YES lperfetto Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) 0.312 SIGNOR-216550 E protein P59637 UNIPROT SDCBP protein O00560 UNIPROT up-regulates activity relocalization 9534 25122212 YES Luana Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation. 0.2 SIGNOR-260752 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr293 PAPSGRAyTSPLIDM -1 21840312 YES miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. 0.389 SIGNOR-263040 CDK1 protein P06493 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser465 MVPGGDRsPSRMLPP 9606 BTO:0000150;BTO:0001130 16407259 YES llicata In vitro kinase assays using recombinant cdc2 kinase showed that runx2 was phosphorylated at ser(451) the cdc2 inhibitor roscovitine dose dependently inhibited in vivo runx2 dna-binding activity during mitosis and the runx2 mutant s451a exhibited lower dna-binding activity and reduced stimulation of anchorage-independent growth relative to wild type runx2. 0.479 SIGNOR-143586 practolol chemical CHEBI:258351 ChEBI ADRB1 protein P08588 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 10079020 YES Luana In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue 0.8 SIGNOR-258336 AGTR1 protein P30556 UNIPROT NPHS1 protein O60500 UNIPROT down-regulates activity 10116 21982880 NO miannu Ang II-receiving rats displayed diminished phosphorylation of nephrin but enhanced glomerular/podocyte injury and proteinuria when compared to control rats. These findings indicate that Ang II induces nephrin dephosphorylation and podocyte injury through a caveolin-1-dependent mechanism. 0.363 SIGNOR-253342 ASNS protein P08243 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 29084849 YES miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. 0.8 SIGNOR-267532 DMPK protein Q09013 UNIPROT PLN protein P26678 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 15598648 YES gcesareni Coimmunoprecipitation studies showed that dmpk and pln can physically associate. Furthermore, purified wild-type dmpk, but not a kinase-deficient mutant (k110a dmpk), phosphorylates pln in vitro 0.539 SIGNOR-131371 ARF1 protein P84077 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 NO lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface 0.7 SIGNOR-272149 HTR4 protein Q13639 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.374 SIGNOR-256912 MAPK11 protein Q15759 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 NO Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). 0.2 SIGNOR-251834 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates transcriptional regulation 9606 BTO:0001103 21576360 YES When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita 0.538 SIGNOR-256249 LRRK2 protein Q5S007 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Thr127 KVLSSLVtLNKVTAD 9606 21048939 YES gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence 0.457 SIGNOR-169221 miR-155 mirna URS000062749E_9606 RNAcentral FOS protein P01100 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 24708856 YES miannu We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2. 0.4 SIGNOR-255766 EEF1A1P5 protein Q5VTE0 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269561 SRP19 protein P09132 UNIPROT SRP54 protein P61011 UNIPROT up-regulates activity binding -1 30649418 YES miannu Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. 0.962 SIGNOR-261168 AKT2 protein P31751 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 YES flangone Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. 0.255 SIGNOR-242097 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 YES Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts 0.827 SIGNOR-201703 RBPJ protein Q06330 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9528780 NO gcesareni Rbp-jkappa is a strong transcriptional repressor of nf-kappab2. Moreover, this repression can be overcome by activated notch-1. 0.267 SIGNOR-56100 CTBP2 protein P56545 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 21315774 YES Luana Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner  0.381 SIGNOR-261578 RAB5B protein P61020 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 0.481 SIGNOR-276874 CRHR1 protein P34998 UNIPROT Beta-endorphin protein P01189-PRO_0000024975 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 23504413 NO lperfetto CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). 0.2 SIGNOR-268614 ATP5F1C protein P36542 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261405 KNDC1 protein Q76NI1 UNIPROT MAP2 protein P11137 UNIPROT up-regulates activity phosphorylation 9606 17984326 YES miannu V-KIND enhances Thr phosphorylation of MAP2. 0.369 SIGNOR-278950 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM36 protein Q9NQ86 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271229 BUB1 protein O43683 UNIPROT BUB3 protein O43684 UNIPROT up-regulates activity relocalization 11402067 YES lperfetto Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity 0.943 SIGNOR-252019 SNAI2 protein O43623 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 21044962 NO miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. 0.458 SIGNOR-255176 MRGPRX1 protein Q96LB2 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.249 SIGNOR-257058 DIO2 protein Q92813 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20978344 NO miannu The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. 0.264 SIGNOR-256203 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser133 GHSQRREsFLYRSDS 9534 BTO:0001538 12023945 YES miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. 0.2 SIGNOR-275986 NUP214 protein P35658 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C9 12917407 YES gcesareni We demonstrate that smad3 and smad4 are capable of interaction with the nucleoporin can/nup214, and this interaction is required for nuclear import 0.559 SIGNOR-117647 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0004419 12840032 YES lperfetto The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase (14), protein-tyrosine phosphatase (ptp) (14, 15), or dual specificity phosphatases 0.664 SIGNOR-103035 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR MYB protein P10242 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0005790 30335887 YES PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms. 0.2 SIGNOR-259939 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 17591690 YES llicata We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active 0.731 SIGNOR-156422 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser283 CASVRRAsSADDIEA 9606 10488078 YES lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) 0.307 SIGNOR-70722 MK-2461 chemical CID:44137946 PUBCHEM MST1R protein Q04912 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194387 SIRT1 protein Q96EB6 UNIPROT ACAN protein P16112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21337390 NO miannu The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5. 0.316 SIGNOR-255142 GLI2 protein P10070 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates NBK6142 NO Whilst shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development.  SimoneGraziosi 0.7 SIGNOR-269214 EEF1A2 protein Q05639 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269532 SPAG9 protein O60271 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 YES Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP lperfetto Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants. 0.56 SIGNOR-149979 MAPK9 protein P45984 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 YES miannu we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391 0.37 SIGNOR-250142 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.2 SIGNOR-275956 GARS1 protein P41250 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI down-regulates quantity chemical modification 9606 24898252 YES miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. 0.8 SIGNOR-270478 CLOCK protein O15516 UNIPROT CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 NO Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. 0.925 SIGNOR-253632 FBLIM1 protein Q8WUP2 UNIPROT FLNB protein O75369 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 YES miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 0.723 SIGNOR-266106 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 YES lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis 0.729 SIGNOR-252817 KRAS protein P01116 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k 0.633 SIGNOR-175210 POMT2 protein Q9UKY4 UNIPROT POMT complex SIGNOR-C372 SIGNOR form complex binding 9606 BTO:0000007 16698797 YES miannu  Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex. 0.603 SIGNOR-265429 PTPN6 protein P29350 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates binding 9606 14551136 YES gcesareni All together, our results indicate that shp-1 inhibits prlr and epor signaling by recruitment and targeting of socs-1 to jak2, highlighting a new mechanism of shp-1 regulation of cytokine-receptor signaling. 0.325 SIGNOR-118572 SETDB2 protein Q96T68 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity methylation Lys 10 RTKQTARkSTGGKAP 9606 BTO:0000007 20404330 YES miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. 0.2 SIGNOR-263895 CDK1 protein P06493 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10766756 YES gcesareni Using synthetic peptides and mutant cell lines, we identified threonine 56, one of two consensus sites for cdc2 within the bcl-2 sequence, as a residue phosphorylated by cdc2. Mutation at threonine 56 abrogated the cell cycle inhibitory effect of bcl-2 without affecting anti-apoptotic function.Taken together, our present findings indicate that phosphorylation of bcl-2 at threonine 56 by cdc2 is required for bcl-2-mediated cell cycle inhibition, which may have some roles during mitosis in the normal cell cycle. 0.346 SIGNOR-76837 panitumumab antibody DB01269 DRUGBANK EGFR protein P00533 UNIPROT down-regulates activity binding 9606 BTO:0000176 11255078 YES miannu ABX-EGF binds EGFr with high affinity (5x10(-11) M), blocks the binding of both EGF and transforming growth factor-alpha (TGF-alpha) to various EGFr-expressing human carcinoma cell lines, and inhibits EGF-dependent tumor cell activation, including EGFr tyrosine phosphorylation, increased extracellular acidification rate, and cell proliferation. Being a fully human antibody, ABX-EGF is anticipated to exhibit a long serum half-life and minimal immunogenicity with repeated administration, even in immunocompetent patients. These results demonstrate the potent anti-tumor activity of ABX-EGF and its therapeutic potential for the treatment of multiple human solid tumors that overexpress EGFr. 0.4 SIGNOR-259898 8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid chemical CHEBI:95064 ChEBI PTPN11 protein Q06124 UNIPROT down-regulates activity chemical inhibition 9606 16717135 YES These results identified NSC-87877 as the first PTP inhibitor capable of inhibiting Shp2 PTP in cell cultures without a detectable off-target effect. 0.8 SIGNOR-261912 KDM4C protein Q9H3R0 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity binding 9606 29207681 YES miannu In hypoxia, HIF-1α dimerizes with HIF-1β to form active HIF-1 complex. JMJD2C interacts with HIF-1α and promotes the transcriptional activation of HIF-1 targeting genes via demethylating di- and trimethylated H3K9. 0.2 SIGNOR-263873 MAFA protein Q8NHW3 UNIPROT PDX1 protein P52945 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 NO miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. 0.746 SIGNOR-254562 IL1R1 protein P14778 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9625767 YES lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab 0.281 SIGNOR-249514 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT up-regulates activity phosphorylation Thr169 EGNNANYtEYVATRW -1 16935860 YES gcesareni Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. 0.2 SIGNOR-262289 CSMD1 protein Q96PZ7 UNIPROT C3 protein P01024 UNIPROT down-regulates quantity binding 9606 28345259 YES miannu CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor 0.2 SIGNOR-265148 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 15526160 NO apalma The SFK family of tyrosine kinases is named after its prototypic family member c-Src. SCF-induced chemotaxis of Mo7 cells was dependent on SFK activity 0.7 SIGNOR-254996 dopamine smallmolecule CHEBI:18243 ChEBI DRD1 protein P21728 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257477 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination 9606 18570872 YES amattioni CIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. In this way RIP1 functions as a prosurvival scaffold molecule instead of a proapoptotic adaptor protein 0.767 SIGNOR-179100 MTOR protein P42345 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 SIGNOR-C2 18925875 YES gcesareni Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422) 0.849 SIGNOR-181531 KAT2B protein Q92831 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269612 ZEB2 protein O60315 UNIPROT VDR protein P11473 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11432806 YES Luisa ZEB, a Krüppel-type transcription factor known to repress the transcription of several genes, binds to two sites within the VDR promoter and activates the transcription of this receptor in a cell-specific manner. Transfection of ZEB into SW620 colon carcinoma cells results in an up-regulation of the expression of endogenous VDR, confirming the role of ZEB in the transcriptional activation of the VDR gene. 0.2 SIGNOR-268954 MMP27 protein Q9H306 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272371 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 12754301 YES llicata The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop 0.391 SIGNOR-248448 ATG10 protein Q9H0Y0 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR up-regulates binding 9606 18704115 YES lperfetto Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein. 0.784 SIGNOR-226699 BRCA1 protein P38398 UNIPROT RNASEL protein Q05823 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15940267 NO miannu We propose that BRCA1 may be an upstream regulator of RNaseL, acting in concert with IFN-gamma to transcriptionally activate 2,5 OAS, leading to the downstream activation of RNaseL and apoptosis. 0.315 SIGNOR-253762 STK4 protein Q13043 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Thr90 CHLAWVNtPKKQGGL -1 23386615 YES miannu Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183. 0.2 SIGNOR-276487 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNJ2 protein P63252 UNIPROT down-regulates activity phosphorylation Ser425 PRPLRREsEI -1 19843922 YES done miannu KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, I(K1). This PKA-simulated catecholaminergic stimulation caused marked reduction of outward I(K1) compared with Kir2.1-WT. PKA-induced reduction in I(K1) was eliminated by mutating the phosphorylation site at serine 425 (S425N). 0.2 SIGNOR-273779 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269358 MAP3K1 protein Q13233 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates phosphorylation Thr211 LVDSVAKtIDAGCKP 9606 9712898 YES gcesareni Both wild type and kinase-inactive mutant rip immunoprecipitates can active mkk6 in vitrohe sapks are activated by at least two meks, sapk/erk kinase-1 (sek1, also called mapk-kinase (mkk)) and mkk7 0.452 SIGNOR-59679 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 YES gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. 0.918 SIGNOR-137236 ABL1 protein P00519 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Tyr1357 HPQAASIyQSSEMKG 9606 18765637 YES lperfetto Tyrosine phosphorylation of the nuclear receptor coactivator aib1/src-3 is enhanced by abl kinase and is required for its activity in cancer cellstyrosine kinase directly phosphorylates aib1/src-3 at y1357 and modulates the association of aib1 with c-abl, eralpha, the transcriptional cofactor p300, 0.349 SIGNOR-180571 MAPK8 protein P45983 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 19279717 NO areggio To date it is not clear whether any genes are transcribed downstream of these two GTPases for non-canonical signaling. The prevailing dogma remains that their primary roles are indeed solely for cytoskeletal modulation 0.7 SIGNOR-258976 NOTCH3 protein Q9UM47 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 11404076 YES gcesareni Both notch 1 and notch 3 ics displace the co-repressor smrt from the dna-binding protein rbp-j kappa on the hes promoter. The latter observation suggests that both notch 3 ic and notch 1 ic can access rbp-j kappa in vivo, and that the difference in activation capacity instead stems from structural differences in the two ics when positioned on rbp-j kappa. 0.856 SIGNOR-86128 POGLUT1 protein Q8NBL1 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates glycosylation 9606 22872643 YES O-glycosilation gcesareni O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus. 0.605 SIGNOR-198713 AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 YES lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta 0.658 SIGNOR-244281 MAML2 protein Q8IZL2 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 12370315 NO gcesareni We recently cloned a mammalian homologue of the mastermind gene of drosophila melanogaster, maml1 (mastermind-like-1 molecule) and determined that it functions as a transcriptional coactivator for notch receptors. 0.863 SIGNOR-254307 AXIN1 protein O15169 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates 9606 16601693 NO gcesareni Axin promotes smad3 phosphorylation;phosphorylated smad3 dissociates from the axin complex and then combines with smad4 to activate transcription in the nucleus. 0.665 SIGNOR-145848 p38 proteinfamily SIGNOR-PF16 SIGNOR HNF4A protein P41235 UNIPROT up-regulates phosphorylation Ser167 VLSRQITsPVSGING 9606 16351573 YES lperfetto Our results indicate that p38 kinase-mediated ser158 phosphorylation is essential for augmentation of the dna binding and transactivation potential of hnf4alpha 0.2 SIGNOR-143046 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1247 AMQSNSPsQEQQQQQ 9606 15173573 YES lperfetto Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp 0.271 SIGNOR-125077 HRH3 protein Q9Y5N1 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-256832 POLR2E protein P19388 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.89 SIGNOR-266138 AKT proteinfamily SIGNOR-PF24 SIGNOR PRKACA protein P17612 UNIPROT up-regulates 9606 BTO:0000938 16537363 NO gcesareni Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation. 0.2 SIGNOR-145113 PRKCB protein P05771 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates activity phosphorylation Ser86 AFFGRTSsGKSSVIN -1 30659190 YES done miannu Here we report that βIIPKC accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Mfn1 phosphorylation results in partial loss of its GTPase activity and in a buildup of fragmented and dysfunctional mitochondria in heart failure. 0.2 SIGNOR-273826 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser39 TTSTRTYsLGSALRP -1 2500966 YES miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. 0.309 SIGNOR-250067 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 22413754 YES miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites 0.2 SIGNOR-248544 MAP3K14 protein Q99558 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Ser40 IFIIMGAsGDLAKKK 9606 BTO:0000007 33398181 YES miannu Mass spectrometry identified four serine residues of G6PD phosphorylated by NIK (Extended Data Fig. 8f). All of these serines, except S278, are conserved between human and mouse G6PD proteins. In transfected cells, NIK stimulated G6PD activity, which was not affected by S8A or S486A mutation but abolished by S40A mutation (Extended Data Fig. 8g). 0.2 SIGNOR-277545 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 YES lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B 0.788 SIGNOR-249368 LEF1 protein Q9UJU2 UNIPROT DSG4 protein Q86SJ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19683850 NO miannu we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle. 0.288 SIGNOR-254183 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser18 EKLQYYYsSSEDEDS 9606 16717095 YES lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. 0.385 SIGNOR-146825 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257961 SOD2 protein P04179 UNIPROT dioxygen smallmolecule CHEBI:15379 ChEBI up-regulates quantity chemical modification 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272282 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser96 TSLSDEDsGKGSQPP 9606 15448698 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-129422 PPM1A protein P35813 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates dephosphorylation 9606 10644691 YES lperfetto Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin. 0.362 SIGNOR-227955 CEP250 protein Q9BV73 UNIPROT CCDC102B protein Q68D86 UNIPROT up-regulates activity relocalization 30404835 YES lperfetto CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis. 0.2 SIGNOR-275625 regorafenib chemical CHEBI:68647 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259206 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Ser30 DAKPDRSsFVPSLFS 9606 BTO:0000150 21555521 YES gcesareni Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. 0.351 SIGNOR-173659 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT up-regulates activity phosphorylation Tyr248 HASDVTDySYPATPN 9606 BTO:0000815 17623672 YES WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. 0.58 SIGNOR-262300 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 15048722 NO We demonstrate that NF-kappa B binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappa B nuclear translocation in living cells blocked binding of NF-kappa B to the IL-4 promoter. The data provide first evidence that NF-kappa B is directly involved in IL-4 transcription 0.424 SIGNOR-254497 RF-C complex complex SIGNOR-C375 SIGNOR PCNA protein P12004 UNIPROT up-regulates activity binding 9534 BTO:0004055 12930972 YES lperfetto Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. 0.818 SIGNOR-265510 TP53 protein P04637 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 28073943 YES miannu KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter. 0.281 SIGNOR-263729 MCRS1 protein Q96EZ8 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. 0.646 SIGNOR-267161 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257452 pimozide chemical CHEBI:8212 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258719 DUSP5 protein Q16690 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 10224087 YES inferred from 70% of family members gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway 0.2 SIGNOR-269912 NF1 protein P21359 UNIPROT ADCY9 protein O60503 UNIPROT up-regulates 9606 BTO:0000938 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.305 SIGNOR-204354 AKT proteinfamily SIGNOR-PF24 SIGNOR SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21777568 YES gcesareni We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner. 0.2 SIGNOR-174017 hydroxyurea chemical CHEBI:44423 ChEBI RRM2 protein P31350 UNIPROT down-regulates activity chemical inhibition 9606 14583450 YES miannu In PC3 cells, hydroxyurea inhibited hRRM2 and resulted in increased sensitivity to UV irradiation. 0.8 SIGNOR-259355 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 10575014 YES lperfetto Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling. 0.741 SIGNOR-217658 RPL13A protein P40429 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.838 SIGNOR-262485 ARHGEF2 protein Q92974 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.806 SIGNOR-260529 RAC1 protein P63000 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR up-regulates activity 9606 27871158 YES lperfetto Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex 0.624 SIGNOR-261877 ADORA2B protein P29275 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.292 SIGNOR-257039 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 YES llicata Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3 0.2 SIGNOR-268152 CACNA2D3 protein Q8IZS8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 31746409 NO miannu The results indicated that the overexpression of CACNA2D3 induced an increase in intracellular Ca2+ and increased the levels of p-p38 MAPK. These data indicated that the p38 MAPK pathway is activated by overexpression of CACNA2D3 and P4 induction. 0.2 SIGNOR-266857 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12370315 NO gcesareni It has been shown that maml1 binds directly to the ankyrin repeat region of notch1 and forms a dna-binding complex with icn and csl 0.923 SIGNOR-94029 ARNT protein P27540 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 21544813 NO lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC 0.282 SIGNOR-253692 FBXL12 protein Q9NXK8 UNIPROT CAMK1 protein Q14012 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0002268 23707388 YES Monia Here, we show that a ubiquitin E3 ligase component, F-box protein Fbxl12, mediates CaMKI degradation via a proteasome-directed pathway leading to disruption of cyclin D1/cdk4 complex. Endogenous Fbxl12 and CaMKI interacted as demonstrated after Fbxl12 immuno-precipitation followed by immunoblot analysis with CaMKI antibodies assembly and resultantG1 arrest in lung epithelia. Fbxl12 targets CaMKI for ubiquitination. 0.476 SIGNOR-261193 PRKACA protein P17612 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation Thr130 GEKSRYEtSLNLTTK 9606 BTO:0000007 33110360 YES miannu We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence. 0.2 SIGNOR-277536 AMPK complex SIGNOR-C15 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 YES lperfetto Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka. 0.298 SIGNOR-216523 RPS20 protein P60866 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.878 SIGNOR-262430 PLK1 protein P53350 UNIPROT RAD21 protein O60216 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser454 EPSRLQEsVMEASRT 9606 BTO:0000567 15737063 YES lperfetto We suspected that the observed enhancement of Scc1's cleavability in the presence of Plk1 might be due to phosphorylation at two sites that are directly adjacent to the cleavage sites, Ser175 and Ser454, which we had found to be phosphorylated in mitosis in vivo (Table 1). We therefore mutated these two residues to alanine, thereby creating mutant Scc1-S175A/S454A (see Figure 1C), and tested the cleavability of this mutant in the absence or presence of Plk1 in vitro. |Scc1 phosphorylation is dispensable for cohesin dissociation from chromosomes in early mitosis but enhances the cleavability of Scc1 by separase. 0.736 SIGNOR-275536 TRIM37 protein O94972 UNIPROT TRIM37 protein O94972 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 14561866 YES miannu In this paper, we present data showing that TRIM37, a member of the TRIM subfamily of RING finger proteins, is autoubiquitinated in a RING domain-dependent manner.  However, we feel tempted to speculate that the most likely mechanism, in which TRIM37-mediated ubiquitination could be involved, is proteasomal degradation of a target protein and, possibly, its own turnover. 0.2 SIGNOR-271503 TCF3 protein P15923 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 26212009 YES lperfetto The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). |In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation 0.31 SIGNOR-275654 PDX1 protein P52945 UNIPROT GCK protein P35557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8866550 NO miannu The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. 0.604 SIGNOR-254911 IKBKG protein Q9Y6K9 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C14 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. 0.791 SIGNOR-217382 PER1 protein O15534 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. 0.717 SIGNOR-267974 MARK2 protein Q7KZI7 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates activity phosphorylation Ser406 TRLRRTEsVPSDINN 9606 22206009 YES miannu In vivo, MARK2 appears to negatively regulate KSR1 in insulin sensitivity.|These data suggest that MARK2 phosphorylates KSR1 on Ser392, which has been shown previously to function as a negative regulatory site xref . 0.315 SIGNOR-279343 zotepine chemical CHEBI:32316 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258552 PRKCD protein Q05655 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity phosphorylation 9606 19363025 YES gcesareni We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation. 0.2 SIGNOR-265368 TRMT10B protein Q6PF06 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 YES lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). 0.205 SIGNOR-267705 CGAS protein Q8N884 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR down-regulates activity 9606 31544964 NO Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death 0.7 SIGNOR-259951 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18593906 YES tpavlidou Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene. 0.393 SIGNOR-259427 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Tyr502 TTANVVYyVGENVVN 9606 BTO:0000567 12637538 YES gcesareni Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity. 0.34 SIGNOR-246215 KDM4C protein Q9H3R0 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-265333 NR3C1 protein P04150 UNIPROT TDO2 protein P48775 UNIPROT down-regulates quantity by repression transcriptional regulation 16272140 YES lperfetto Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development. 0.338 SIGNOR-268995 HAT1 protein O14929 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys13 KGGKGLGkGGAKRHR -1 28143904 YES lperfetto Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4|Lys12 for direct attack of the acetyl group of the cofactor.| It is postulated that histone acetylation, through charge neutralization of the cationic histone tails, weakens nucleosomal electrostatic interactions with anionic DNA, thus destabilizing internucleosomal contacts and nucleosomal structure and facilitating access to the promoter region for RNA polymerase and transcription factors. 0.2 SIGNOR-264790 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9606 BTO:0000007 20048145 YES lperfetto Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha. 0.616 SIGNOR-252785 PRKAA1 protein Q13131 UNIPROT EP300 protein Q09472 UNIPROT down-regulates phosphorylation Ser89 SELLRSGsSPNLNMG 9606 BTO:0000801;BTO:0001271;BTO:0000876 21940946 YES gcesareni The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity. 0.377 SIGNOR-176637 EPX protein P11678 UNIPROT RNASE3 protein P12724 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 YES miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. 0.478 SIGNOR-261705 MMP8 protein P22894 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272375 PPAT protein Q06203 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 8106516 YES Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù 0.8 SIGNOR-267187 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10116 BTO:0000452 11287630 YES lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten 0.766 SIGNOR-106570 PRKCA protein P17252 UNIPROT RGS7 protein P49802 UNIPROT down-regulates activity phosphorylation -1 12077120 YES miannu TNF-α rapidly increases the concentration of functionally active RGS7 protein through two mechanisms. TNF-induced dephosphorylation of serine 434 liberates RGS7 from 14-3-3 binding and inhibition. , PKC α catalyzes the incorporation of phosphate into a truncation of RGS7 fused to maltose-binding protein (MBP.RGS7315–469). 0.365 SIGNOR-263165 STAT1 protein P42224 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR form complex binding 10090 BTO:0000667 15284024 YES lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. 0.614 SIGNOR-235661 Macropinosomes formation phenotype SIGNOR-PH227 SIGNOR Early macropinosomes phenotype SIGNOR-PH228 SIGNOR up-regulates 9606 33722976 YES miannu Completion of macropinosome formation requires membrane fusion and is followed by maturation of the resulting vacuole, which proceeds to merge with endosomes and, ultimately, lysosomes.  0.7 SIGNOR-277775 DAXX protein Q9UER7 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 BTO:0000776;BTO:0000785 11483955 YES gcesareni Tgf-beta-induced apoptosis is mediated by the adapter protein daxx that facilitates jnk activation 0.527 SIGNOR-109542 SOHLH2 protein Q9NX45 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 22328502 YES Luana Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression. 0.326 SIGNOR-266206 PP1 proteinfamily SIGNOR-PF54 SIGNOR IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 21750978 YES lperfetto Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway 0.2 SIGNOR-264663 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr373 VNVIPPHtPVRTVMN 9606 1756735 YES lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. 0.687 SIGNOR-21564 LMO2 protein P25791 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 NO miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. 0.383 SIGNOR-253922 KLHL2 protein O95198 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 23838290 YES miannu We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body. 0.623 SIGNOR-272122 ABT-737 chemical CID:11228183 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 Other YES The effect has been demonstrated using Q07817-1 gcesareni 0.8 SIGNOR-189171 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ 9606 15946941 YES Luana Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. 0.2 SIGNOR-260841 CERK protein Q8TCT0 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI down-regulates quantity chemical modification 9606 34202192 YES miannu Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). 0.8 SIGNOR-268500 GFI1B protein Q5VTD9 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 NO miannu Here, we analyzed the MEF2C 5'-region, thus identifying potential regulatory binding sites for GFI1B, basic helix-loop-helix proteins, STAT5, and HOXA9/HOXA10. Chromatin immunoprecipitation and overexpression analyses demonstrated direct activation by GFI1B and LYL1 and inhibition by STAT5. 0.283 SIGNOR-254206 AMPK complex SIGNOR-C15 SIGNOR INSR protein P06213 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 22207502 YES lperfetto Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway. 0.304 SIGNOR-216619 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2R2 protein Q712K3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.784 SIGNOR-271358 ITGB4 protein P16144 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 9428518 YES gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. 0.2 SIGNOR-54700 NCK1 protein P16333 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity binding 9606 11494134 YES lperfetto We also show that overexpression of nck could repress the phosphorylation of cbl by abl in vivo. Studies with nck mutants suggested that the nck sh2 domain is responsible for inhibiting the activity of abl toward both cbl and nck itself, most likely by competing with the abl sh2 for tyrosine-phosphorylated binding sites 0.401 SIGNOR-109672 SOCS3 protein O14543 UNIPROT SIGLEC7 protein Q9Y286 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001516 17138568 YES miannu SOCS proteins can act as E3 ligases by forming a complex with Elongin B/C and Cul5/Rbx1/2.SOCS3 targets Siglec 7 for degradation 0.373 SIGNOR-272642 Glycine cleavage system complex SIGNOR-C437 SIGNOR (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity chemical modification 9606 16051266 YES lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. 0.8 SIGNOR-268239 MMP19 protein Q99542 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272386 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR RGS18 protein Q9NS28 UNIPROT down-regulates activity binding 9606 BTO:0000132 24244663 YES done miannu Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216.  0.2 SIGNOR-273787 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR THRB protein P10828 UNIPROT down-regulates activity phosphorylation 9606 12809513 YES inferred from 70% family members llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. 0.2 SIGNOR-270143 SOD1 protein P00441 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity binding 10090 BTO:0004488 18519638 YES P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK 0.316 SIGNOR-262786 MAPK3 protein P27361 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser441 SPRRFIGsPRTPVSP 10116 15774499 YES lperfetto Thr 421/Ser 424 have been reported to be targeted by ERK1, 2 (39), JNK or p38 MAPKs (36). Interestingly, with a comparable kinetics, FSH represses ERK1, 2 constitutive phosphorylation in Sertoli cells isolated from 19-d-old rats 0.606 SIGNOR-111515 DVL3 protein Q92997 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates binding 9606 10535959 YES gcesareni Ckiepsilon was in a complex with axin and other downstream components of the wnt pathway, including dishevelled. 0.668 SIGNOR-71759 VKORC1 protein Q9BQB6 UNIPROT vitamin K smallmolecule CHEBI:28384 ChEBI down-regulates quantity chemical modification 9606 31226734 YES lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) 0.8 SIGNOR-265904 APC-c complex SIGNOR-C150 SIGNOR PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization ubiquitination 21596315 YES lperfetto Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B. 0.569 SIGNOR-265049 FLT3 protein P36888 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity 10090 BTO:0001516 23246379 NO miannu Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation. These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K-Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. 0.565 SIGNOR-260081 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser792 DKMRRASsYSSLNSL 10090 BTO:0002572 SIGNOR-C15 SIGNOR-C3 18439900 YES lperfetto The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress. 0.686 SIGNOR-161375 ZNF292 protein O60281 UNIPROT GH1 protein P01241 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 10687855 YES lperfetto Rat Zn-15 is a transcription factor activating GH gene expression by synergistic interactions with Pit-1, named for 15 DNA-binding zinc fingers, including fingers IX, X, and XI that are responsible for GH promoter binding. 0.2 SIGNOR-268969 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KAT5 protein Q92993 UNIPROT up-regulates activity phosphorylation Ser90 LPGSRPGsPEREVPA 9606 BTO:0000567 12468530 YES llicata Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex. 0.419 SIGNOR-250642 CHRM3 protein P20309 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256882 PPP4C protein P60510 UNIPROT NDEL1 protein Q9GZM8 UNIPROT down-regulates activity dephosphorylation Thr219 ASLSLPAtPVGKGTE 9606 18347064 YES Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation|PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome.|We next examined the ability of PP4c to dephosphorylate a Cdk1 phosphorylation site, phospho-T219 0.396 SIGNOR-248550 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser77 YEPEGSAsPTPPYLK 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.333 SIGNOR-248552 LCK protein P06239 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 17998336 YES inferred from 70% of family members gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. 0.586 SIGNOR-269921 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser316 VEEEPLNsEDDVSDE -1 11278496 YES llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. 0.375 SIGNOR-250997 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT up-regulates quantity by stabilization sumoylation Lys454 VPTSQSVkHETALVN 9606 BTO:0000007 23686912 YES miannu Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. 0.453 SIGNOR-263900 GLI3 protein P10071 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity transcriptional regulation 10090 12435361 YES Gianni Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH 0.445 SIGNOR-268949 AZD1480 chemical CID:16659841 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190167 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. 0.895 SIGNOR-267968 CDK1 protein P06493 UNIPROT KDM5B protein Q9UGL1 UNIPROT down-regulates activity phosphorylation Ser1456 FKLERERsYELVRSA 9606 BTO:0000815 31776402 YES lperfetto Phosphorylation of the histone demethylase KDM5B and regulation of the phenotype of triple negative breast cancer|Here, we demonstrate that KDM5B is phosphorylated at Ser1456 by the cyclin-dependent kinase 1 (CDK1). Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. 0.258 SIGNOR-273435 MAOB protein P27338 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI down-regulates quantity chemical modification 9606 31024440 YES brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). 0.8 SIGNOR-264015 ACTB protein P60709 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 28233384 YES lperfetto Here, we report the highest resolution, cryo-EM structures of actin filaments with bound ATP analog β,γ-imidoadenosine 5′-triphosphate (AMPPNP) (3.1 Å) and ADP with inorganic phosphate (ADP-Pi) (3.1 Å) as well as a 3.6-Å resolution structure of the ADP filament. These structures of the three well-characterized nucleotide states of actin monomers and filaments 0.7 SIGNOR-261879 UBR5 protein O95071 UNIPROT PAIP2 protein Q9BPZ3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 16601676 YES miannu We demonstrate a mechanism for this co-regulation that involves an E3 ubiquitin ligase, EDD, which targets Paip2 for degradation. PABP depletion by RNA interference (RNAi) causes co-depletion of Paip2 protein without affecting Paip2 mRNA levels. Upon PABP knockdown, Paip2 interacts with EDD, which leads to Paip2 ubiquitination. 0.446 SIGNOR-272648 NR1H3 protein Q13133 UNIPROT BHLHE40 protein O14503 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19032342 NO lperfetto LXRα and LXRβ are potent positive regulators for hepatic Dec1 0.268 SIGNOR-253691 dacomitinib chemical CHEBI:132268 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates chemical inhibition 9606 23405260 YES gcesareni The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor. 0.8 SIGNOR-200908 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 17567956 YES gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) 0.341 SIGNOR-155987 ARHGAP8 protein P85298 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.428 SIGNOR-260463 ATP6V0D2 protein Q8N8Y2 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.798 SIGNOR-277746 GATA2 protein P23769 UNIPROT TRH protein P20396 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 33201916 YES scontino The rat prepro-TRH gene is activated by GATA2. 0.263 SIGNOR-267258 spiperone chemical CHEBI:9233 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258692 PPP2CA protein P67775 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates dephosphorylation 9606 2826472 YES gcesareni Protein phosphatase 2a inactivates the mitogen-stimulated s6 kinase from swiss mouse 3t3 cells 0.719 SIGNOR-23575 NRL protein P54845 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 NO miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. 0.373 SIGNOR-253818 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 10090 SIGNOR-C16 11278991 YES lperfetto We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. Upon phosphorylation by CDK2-cyclin E, NPM/B23 dissociates from centrosomes, which is a prerequisite step for centrosomes to initiate duplication. 0.562 SIGNOR-235725 CACNA1G protein O43497 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 YES miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). 0.8 SIGNOR-264324 EFNB1 protein P98172 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates binding 9606 11713248 YES tpavlidou We show here that despite its lack of kinase activity, ephb6 undergoes inducible tyrosine phosphorylation upon stimulation with the eph-b receptor subfamily ligand ephrin-b1. Overexpression of a catalytically active member of the eph-b subfamily, ephb1, resulted in increased ephb6 phosphorylation. Ephb1-induced ephb6 phosphorylation was ligand-dependent and required the functional catalytic activity of ephb1. 0.827 SIGNOR-111851 PLK1 protein P53350 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates activity phosphorylation 9606 30202980 YES miannu PLK1 targets CtIP to promote microhomology mediated end joining.|We further showed that the DSB repair factor CtIP is jointly phosphorylated by CDK1 and Aurora A and PLK1. 0.348 SIGNOR-279253 FLT3 protein P36888 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 16266983 NO gcesareni We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. 0.431 SIGNOR-252626 TFG protein Q92734 UNIPROT SEC16A protein O15027 UNIPROT up-regulates binding 9606 21478858 YES miannu We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits. 0.641 SIGNOR-173242 ADP chemical CHEBI:16761 ChEBI PRKAG1 protein P54619 UNIPROT up-regulates chemical activation 9606 SIGNOR-C15 21399626 YES gcesareni Amp binding to the gamma-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation.Adp also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive. 0.8 SIGNOR-172813 CARD8 protein Q9Y2G2 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 16678772 YES amattioni Tucan is a recently identified card-containing protein that can complex with caspase-9 and prevent cytochrome c-induced caspase activation. 0.426 SIGNOR-146663 UCHL3 protein P15374 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity deubiquitination Lys57 EAVAYAPkKELINIK 27941124 YES lperfetto Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. 0.326 SIGNOR-275907 DDOST protein P39656 UNIPROT OST-B complex complex SIGNOR-C536 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.762 SIGNOR-272073 PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT down-regulates activity binding 9606 BTO:0001757;BTO:0001298 12192414 YES lperfetto We show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. 0.785 SIGNOR-91709 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266459 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2M protein P61081 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.725 SIGNOR-271332 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.76 SIGNOR-260583 TWIST1 protein Q15672 UNIPROT mir-10b mirna URS00004CAC40_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 23132946 NO irozzo We then showed that ectopic expression of MLL fusion genes in both human and mouse normal hematopoietic stem/progenitor cells could significantly down-regulate endogenous expression of miR-495 and that the depletion of MLL fusions resulted in the up-regulation of miR-495. Thus, our data suggest that there is an MLL-fusion–mediated negative regulation of the production of miR-495 in hematopoietic cells. 0.4 SIGNOR-255887 LIN28A protein Q9H9Z2 UNIPROT IGF2 protein P01344 UNIPROT up-regulates quantity by expression translation regulation 9606 17473174 YES miannu Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency 0.397 SIGNOR-277339 AKT proteinfamily SIGNOR-PF24 SIGNOR YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 YES lperfetto Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined. 0.2 SIGNOR-244381 dehydroepiandrosterone chemical CHEBI:28689 ChEBI androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 2139411 YES lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. 0.8 SIGNOR-268641 PRKCD protein Q05655 UNIPROT HAX1 protein O00165 UNIPROT down-regulates quantity by destabilization phosphorylation Ser210 QPKSYFKsISVTKIT 10090 BTO:0002572 25419709 YES lperfetto FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells, 0.2 SIGNOR-275562 A1/b1 integrin complex SIGNOR-C159 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269008 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 YES gcesareni The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. 0.374 SIGNOR-184591 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation -1 16326050 YES miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast 0.8 SIGNOR-268751 PRKACA protein P17612 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity phosphorylation 9606 8019002 YES miannu Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L. 0.2 SIGNOR-252401 CREB5 protein Q02930 UNIPROT TGFBR3 protein Q03167 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002818 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253811 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 20887952 NO These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs 0.3 SIGNOR-253603 TFE3 protein P19532 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.338 SIGNOR-276826 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 15856019 YES gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. Lpa2also can couple to the gi/o, g12/13, and gqfamilies. 0.624 SIGNOR-135840 MTHFR protein P42898 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity chemical modification 9606 10720211 YES lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. 0.8 SIGNOR-268229 SGK3 protein Q96BR1 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.436 SIGNOR-249135 PRKCA protein P17252 UNIPROT HLA-A protein P04439 UNIPROT unknown phosphorylation Ser359 SAQGSDVsLTACKV 2941417 YES lperfetto As shown in Fig. 6A, the HLA heavy chain was phosphorylated by kinase C. | The major site of in vivo phosphorylation of the HLA-B7 heavy chain was localized to Ser-335 which is conserved in all specificitie 0.323 SIGNOR-248891 KDM4C protein Q9H3R0 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys37 APATGGVkKPHRYRP 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-263864 PAK5 protein Q9P286 UNIPROT PAK5 protein Q9P286 UNIPROT up-regulates activity phosphorylation His19 SGPSNFEhRVHTGFD -1 12860998 YES miannu Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation. 0.2 SIGNOR-250248 MIB1 protein Q86YT6 UNIPROT RYK protein P34925 UNIPROT down-regulates ubiquitination 9606 21875946 YES gcesareni We discovered that ryk both physically and functionally interacts with the e3 ubiquitin ligase mind bomb 1 (mib1).We Found that overexpressed ryk and mib1 colocalized and that the overexpression of mib1 leads to the loss of surface ryk expression. In addition, biochemical studies revealed that mib1 promotes the ubiquitination and degradation of ryk. Endogenous ryk and mib1 were required for the wnt-dependent activation of wnt/ctnnb1 signaling 0.328 SIGNOR-176282 SLIT2 protein O94813 UNIPROT ROBO3 protein Q96MS0 UNIPROT up-regulates activity binding -1 16226035 YES miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. 0.627 SIGNOR-268381 NFE2L1 protein Q14494 UNIPROT NQO1 protein P15559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8962164 NO irozzo These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2. 0.384 SIGNOR-256280 PPP3CB protein P16298 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18177723 NO lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy 0.2 SIGNOR-251734 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 YES gcesareni Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.697 SIGNOR-163262 TESK1 protein Q15569 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 9606 BTO:0001363 11418599 YES lperfetto Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin 0.529 SIGNOR-246723 NEURL1 protein O76050 UNIPROT PDE9A protein O76083 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31068605 YES miannu Neuralized family member NEURL1 is a ubiquitin ligase for the cGMP-specific phosphodiesterase 9A. We also demonstrate that NEURL1 can promote polyubiquitination of PDE9A that leads to its proteasome-mediated degradation mainly via lysine residue K27 of ubiquitin. 0.2 SIGNOR-272305 PAF1C complex SIGNOR-C471 SIGNOR TCEA1 protein P23193 UNIPROT up-regulates activity binding 9606 BTO:0000567 20178742 YES miannu HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription. 0.633 SIGNOR-269838 HDLBP protein Q00341 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 33941620 NO miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. 0.7 SIGNOR-266694 RHOA protein P61586 UNIPROT FHL2 protein Q14192 UNIPROT up-regulates relocalization 9606 11847121 YES gcesareni Here, we show that stimulation of the rho pathway induces translocation of the transcriptional lim-only coactivator fhl2 to the nucleus and subsequent activation of fhl2- and androgen receptor-dependent genes. 0.348 SIGNOR-114071 EEF1A1P5 protein Q5VTE0 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269558 C3AR1 protein Q16581 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 NO lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. 0.7 SIGNOR-263471 SLC12A5 protein Q9H2X9 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates activity relocalization 9606 26951057 YES miannu As shown in Fig. 2, the intracellular Cl− concentration is regulated mainly by two cation-chloride cotransporters, NKCC1 and KCC2 [32]. NKCC1 imports Cl− whereas KCC2 extrudes intracellular Cl−. 0.8 SIGNOR-264987 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PML protein P29590 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 15093545 YES The effect has been demonstrated using P29590-4 gcesareni Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. 0.2 SIGNOR-270034 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 21808241 YES MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. 0.851 SIGNOR-175837 BICRA protein Q9NZM4 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.2 SIGNOR-269781 MMP20 protein O60882 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage -1 10922468 YES lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function 0.478 SIGNOR-266981 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr772 EDDPEATyTTSGGKI -1 21538645 YES gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates 0.659 SIGNOR-246027 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249347 ERBB2 protein P04626 UNIPROT DOCK7 protein Q96N67 UNIPROT up-regulates phosphorylation Tyr1257 METVPQLyDFTETHN 9606 18426980 YES llicata We show that the nrg1 receptor erbb2 directly binds and activates dock7 by phosphorylating tyr-1118. thus, dock7 functions as an intracellular substrate for erbb2 to promote schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of rho gtpase-gefs of the dock180 family. 0.529 SIGNOR-178348 PALB2 protein Q86YC2 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 YES miannu Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates 0.536 SIGNOR-204541 TRIM7 protein Q9C029 UNIPROT RNF187 protein Q5TA31 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 25851810 YES miannu Taken together, these data suggest that Trim7 directly ubiquitinates RACO-1. 0.269 SIGNOR-278536 TESK1 protein Q15569 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11294912 YES lperfetto These results suggest that TESK1 functions downstream of integrins and plays a key role in integrin-mediated actin reorganization, presumably through phosphorylating and inactivating cofilin. We propose that tesk1 and lim-kinases commonly phosphorylate cofilin but are regulated in different ways and play distinct roles in actin reorganization in living cells. 0.529 SIGNOR-106777 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT unknown phosphorylation Thr17 PSEGEEStVRFARKG -1 2377895 YES lperfetto Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16 0.2 SIGNOR-248868 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 NO lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor 0.7 SIGNOR-228622 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr33 KFKNEDLtDELSLNK -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276204 DPDPE chemical CHEBI:73356 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258792 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation 0.312 SIGNOR-129304 TBX3 protein O15119 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25595898 NO miannu AKT phosphorylation potentiates the ability of TBX3 to repress the transcription of the E-cadherin gene 0.41 SIGNOR-223537 CDK1 protein P06493 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Thr128 RPPQKCStPCGPLRL 9606 BTO:0000567 24413556 YES miannu Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis. 0.2 SIGNOR-275419 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser276 PQRSRSPsPQPSSHV 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248376 CTNNA3 protein Q9UI47 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 YES miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 0.566 SIGNOR-265492 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 BTO:0000667 30029643 YES Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated 0.525 SIGNOR-256221 PKA proteinfamily SIGNOR-PF17 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates activity phosphorylation Ser461 VPAGPRMsGAPGRLP 9606 BTO:0003250 20943948 YES lperfetto On the other hand, our group has shown that protein kinase A (PKA) inhibits Nox1 activity in colon epithelial cells by phosphorylating NoxA1 at two distinct sites, Ser172 and Ser461 0.2 SIGNOR-264713 TBX21 protein Q9UL17 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0003432 10761931 YES Luana T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells 0.476 SIGNOR-266234 TFEB protein P19484 UNIPROT IL6R protein P08887 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 NO lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB 0.2 SIGNOR-276798 FOXA2 protein Q9Y261 UNIPROT OTX2 protein P32243 UNIPROT down-regulates activity binding 9606 BTO:0000567 10623575 YES miannu Here we show that OTX2 directly associates with LIM1 and HNF-3beta. The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3beta represses, OTX2-directed gene expression. 0.549 SIGNOR-221164 AGTR1 protein P30556 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 21289285 YES gcesareni These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction. 0.521 SIGNOR-171760 PRKN protein O60260 UNIPROT GPR37 protein O15354 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 12666095 YES lperfetto Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R). 0.2 SIGNOR-249706 PRPS1 protein P60891 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity chemical modification 9606 16939420 YES miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. 0.8 SIGNOR-267079 EGR3 protein Q06889 UNIPROT NAB2 protein Q15742 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 20506119 NO miannu In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression. 0.486 SIGNOR-253884 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 7545671 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.595 SIGNOR-28800 ACP3 protein P15309 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI down-regulates quantity chemical modification -1 18940592 YES Luana Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. 0.8 SIGNOR-269740 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25520508 NO miannu Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactivated or coopted by many viruses to promote productive infection 0.7 SIGNOR-260747 HDAC1 protein Q13547 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity transcriptional regulation 10090 18762022 NO These data suggest that the GR recruits cellular HDAC activities to the Hes1 promoter, thereby conferring transcriptional repression in response to GC signaling. 0.37 SIGNOR-253054 PLCB2 protein Q00722 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity 23994464 NO apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release 0.8 SIGNOR-255013 MADD protein Q8WXG6 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity guanine nucleotide exchange factor 10116 BTO:0000142 11809763 YES miannu Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). 0.396 SIGNOR-265579 VCPIP1 protein Q96JH7 UNIPROT VCP protein P55072 UNIPROT up-regulates activity binding 23500464 YES lperfetto Golgi biogenesis requires two distinct p97ATPase-mediated membrane fusion, the p97/p47 and p97/p37 pathways. |We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. 0.552 SIGNOR-265039 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser153 NRLKVLYsQKATPGS 9606 BTO:0000567 15525512 YES llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  0.992 SIGNOR-250604 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT unknown phosphorylation Ser16 PPSEGEEsTVRFARK -1 2377895 YES lperfetto Thus four peptides containing six major sites of intrapeptide autophosphorylation of protein kinase C have been identified. | Phosphoamino acid analyses indicated that only the NH2-terminal peptide contained phosphoserine. The modified residue was determined to be Ser16 0.2 SIGNOR-248863 CRX protein O43186 UNIPROT RS1 protein O15537 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18927113 NO miannu Our in vitro and in vivo results indicate that two CRE sites in the minimal RS1 promoter region control retinal RS1 expression and establish CRX as a key factor driving this expression. 0.331 SIGNOR-253822 CACNA1G protein O43497 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 10090 33393208 YES miannu Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG) 0.7 SIGNOR-264033 PELP1 protein Q8IZL8 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18682536 YES gcesareni MNAR functionally interacts with both NH2- and COOH-terminal GR domains to modulate transactivation 0.552 SIGNOR-251681 KDM3A protein Q9Y4C1 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 YES miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  0.2 SIGNOR-276844 MAPK1 protein P28482 UNIPROT GIGYF2 protein Q6Y7W6 UNIPROT unknown phosphorylation Ser30 SITSPPLsPALPKYK 10090 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262775 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000007 25081058 YES lperfetto PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. 0.67 SIGNOR-262597 MTCP1 protein P56278 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES lperfetto Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.477 SIGNOR-244413 MAPKAPK5 protein Q8IW41 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser377 PPLLRPLsENSGDEN -1 12171600 YES miannu Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity. 0.295 SIGNOR-249708 IC-87114 chemical CHEBI:90686 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206184 IDH complex SIGNOR-C396 SIGNOR NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 28139779 YES miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 0.8 SIGNOR-266260 RRAGA protein Q7L523 UNIPROT RAGAD complex SIGNOR-C114 SIGNOR form complex binding 9606 20381137 YES gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant 0.777 SIGNOR-228167 WT1 protein P19544 UNIPROT SLC29A4 protein Q7RTT9 UNIPROT up-regulates quantity by expression transcriptional regulation 18523561 YES lperfetto ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses. 0.274 SIGNOR-268985 BIRC5 protein O15392 UNIPROT XIAP protein P98170 UNIPROT up-regulates binding 9606 15218035 YES gcesareni Formation of a survivin-xiap complex promotes increased xiap stability against ubiquitination/proteasomal destruction and synergistic apoptosis 0.495 SIGNOR-126367 ETS2 protein P15036 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 YES miannu Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin 0.2 SIGNOR-259875 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 YES lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. 0.2 SIGNOR-275959 AMFR protein Q9UKV5 UNIPROT GPI protein P06744 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24810856 YES miannu Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. 0.531 SIGNOR-272177 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates activity phosphorylation Ser29 QRRSARLsAKPAPPK 9606 BTO:0000567 11438671 YES lperfetto We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets. 0.29 SIGNOR-249103 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 15780598 YES lperfetto JAK2 and STAT3 are dephosphorylated by PTP1B in vitro 0.796 SIGNOR-133852 GSK3A protein P49840 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Thr254 RQVAIVFRtPPYADPS 10090 BTO:0000249 22761446 YES Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation 0.2 SIGNOR-255827 HDAC2 protein Q92769 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.8 SIGNOR-263838 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266522 MAPK1 protein P28482 UNIPROT TAGLN2 protein P37802 UNIPROT up-regulates quantity by stabilization phosphorylation Ser145 ARDDGLFsGDPNWFP 9606 BTO:0003491 30041673 YES lperfetto ERK2 interacted with 29-31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC.| We found that the protein stability of transgelin-2 was regulated by KRAS. ERK-mediated phosphorylation resulted in accumulation of transgelin-2 protein. 0.269 SIGNOR-265221 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. 0.8 SIGNOR-267308 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser619 PTPPKRSsSFREMDG 9606 18161990 YES lperfetto The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl. 0.415 SIGNOR-160219 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269337 PLK1 protein P53350 UNIPROT TPT1 protein P13693 UNIPROT down-regulates phosphorylation Ser64 PEGEGTEsTVITGVD 9606 12167714 YES lperfetto Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase 0.715 SIGNOR-91348 messenger RNA smallmolecule CHEBI:33699 ChEBI 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.8 SIGNOR-269164 PAFAH1B1 protein P43034 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 20133715 NO miannu The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. 0.7 SIGNOR-252169 TRIM22 protein Q8IYM9 UNIPROT TRIM22 protein Q8IYM9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18656448 YES miannu  Importantly, TRIM22 was conjugated with poly-ubiquitin chains and stabilized by the proteasome inhibitor in 293T cells, suggesting that TRIM22 targeted itself for proteasomal degradation through the poly-ubiquitylation. We also found that TRIM22 was located in the nucleus, indicating that TRIM22 might function as a nuclear E3 ubiquitin ligase. 0.2 SIGNOR-271780 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI dehydroepiandrosterone chemical CHEBI:28689 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268647 PRKCA protein P17252 UNIPROT ARRB1 protein P49407 UNIPROT up-regulates activity phosphorylation Ser163 EKIHKRNsVRLVIRK 9606 BTO:0000661 24502978 YES miannu  We demonstrate that β-arrestin-1 recruitment to the TCR, and bystander TCR and CXCR4 downregulation, are mechanistically mediated by the TCR-triggered PKC-mediated phosphorylation of β-arrestin-1 at Ser163.  0.2 SIGNOR-276619 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 phosphorylation:Thr187 NAGSVEQtPKKPGLR 10375532 YES miannu Isolated SCF(Skp2) contained an E3 ubiquitin ligase activity towards p27. Our data thus suggest that SCF(Skp2) specifically targets p27 for degradation during cell-cycle progression.Immunodepletion of components of the complex - Cul-1, Skp1, or Skp2 - from the extract abolished p27 degradation, while addition of purified SCF(Skp2) to Skp2- depleted extract restored the capacity to degrade p27.  0.694 SIGNOR-272933 FGF14 protein Q92915 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253425 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA proteinfamily SIGNOR-PF56 SIGNOR up-regulates activity chemical activation 9606 24564659 YES miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.8 SIGNOR-264692 HCRTR1 protein O43613 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257404 NOG protein Q13253 UNIPROT BMP2 protein P12643 UNIPROT down-regulates binding 9606 12700180 YES lperfetto Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides 0.81 SIGNOR-100657 ROS stimulus SIGNOR-ST2 SIGNOR SNCA protein P37840 UNIPROT up-regulates quantity 9606 16000336 NO lperfetto The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions. 0.7 SIGNOR-249699 ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT up-regulates activity phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 YES gcesareni We show here that c-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. Importantly, the very same site of Rad52 is phosphorylated on exposure of cells to ionizing radiation (IR). 0.684 SIGNOR-247661 FBXO8 protein Q9NRD0 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9534 BTO:0000298 18094045 YES miannu Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A). 0.379 SIGNOR-271765 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004958; BTO:0002648 9182762 NO Giulio Giuliani Indeed, we identified Osf2/Cbfa1 binding sites in the promoter of four genes expressed only (the Osteocalcin genes) or highly (Œ±1(I) collagen, Bsp, and Osteopontin) in osteoblasts. Each of these elements was able to bind Osf2/Cbfa1. 0.578 SIGNOR-255408 malonyl-CoA smallmolecule CHEBI:15531 ChEBI long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity precursor of 9606 15507492 YES Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-267210 AKT proteinfamily SIGNOR-PF24 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates -1 14663477 NO Luana Multiple studies supporting the role of Akt in apoptosis suppression have connected Akt to cell death regulation either by demonstrating its downregulation following pro-apoptotic insults, or by using gene-transfer experiments that transduce both activated, anti-apoptotic and inactive, pro-apoptotic mutants of Akt. 0.7 SIGNOR-260215 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR CCL2 protein P13500 UNIPROT up-regulates quantity 10090 32283152 NO miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. 0.7 SIGNOR-260962 SAR1A protein Q9NR31 UNIPROT SEC24C protein P53992 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 YES lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 0.708 SIGNOR-265302 STAT3 protein P40763 UNIPROT CASP3 protein P42574 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25787076 NO miannu We determined that Stat3 activation increases caspase-3 expression in C2C12 cells. 0.462 SIGNOR-255335 MITF protein O75030 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20530484 NO miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. 0.376 SIGNOR-255185 EDNRB protein P24530 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.455 SIGNOR-257254 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 25627476 NO lperfetto Mitochondrial phospholipids are important components of this system. Phospholipids make up the characteristic outer and inner membranes that give mitochondria their shape.  0.7 SIGNOR-267005 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 8119945 YES gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. 0.858 SIGNOR-36267 MACROD2 protein A1Z1Q3 UNIPROT ADP-D-ribose(2-) smallmolecule CHEBI:57967 ChEBI up-regulates quantity chemical modification 9606 32257385 YES miannu MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins 0.8 SIGNOR-269840 DDHD1 protein Q8NEL9 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269650 RPS6K proteinfamily SIGNOR-PF26 SIGNOR METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 YES gcesareni Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro. 0.2 SIGNOR-252800 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b6 integrin complex SIGNOR-C179 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.338 SIGNOR-259008 ADSS2 protein P30520 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 10496970 NO miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.7 SIGNOR-267834 SH3GLB1 protein Q9Y371 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates 9606 BTO:0000567 16227588 NO gcesareni Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change. 0.2 SIGNOR-141163 EIF3E protein P60228 UNIPROT PLAU protein P00749 UNIPROT up-regulates quantity translation regulation 9606 BTO:0000815; BTO:0001938 20453879 NO irozzo Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. 0.2 SIGNOR-259155 MTURN protein Q8N3F0 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 10090 BTO:0002572 28704656 YES miannu Here we report that viral infection induced upregulation of INKIT, an inhibitor for NF-κB and IRF3 that restricted innate antiviral responses by blocking phosphorylation of p65 and IRF3. Viral infection induced IKK-mediated phosphorylation of INKIT at Ser58, resulting in its dissociation from the IKKs. INKIT is associated with IKKα/β and TBK1/IKKɛ and inhibits the recruitment and phosphorylation of p65 and IRF3, respectively. IKKα and TBK1 phosphorylate INKIT at Ser58, which results in disassociation of INKIT from IKKα or TBK1 and thereby allows for the subsequent recruitment and phosphorylation of p65 and IRF3 0.2 SIGNOR-273664 AHR protein P35869 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 NO miannu Human UDP-glucuronosyltransferase (UGT)1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds, such as potentially neurotoxic bilirubin and the anticancer drug irinotecan SN-38, via conjugation with glucuronic acid. A 290-bp distal enhancer module, phenobarbital-responsive enhancer module of UGT1A1 (gtPBREM), fully accounts for constitutive androstane receptor (CAR)-, pregnane X receptor (PXR)-, glucocorticoid receptor (GR)-, and aryl hydrocarbon receptor (AhR)-mediated activation of the UGT1A1 gene. 0.405 SIGNOR-253734 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 YES gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. 0.577 SIGNOR-76005 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 9535909 YES inferred from 70% family members lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. 0.2 SIGNOR-270025 PLK3 protein Q9H4B4 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 YES lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. 0.319 SIGNOR-189053 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203556 WDR5 protein P61964 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. 0.661 SIGNOR-267157 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser172 LCLSPASsGSSASFI 9606 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248366 PGD protein P52209 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI down-regulates quantity chemical modification 9606 34775382 YES miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. 0.8 SIGNOR-267060 KATNAL2 protein Q8IYT4 UNIPROT KATNB1 protein Q9BVA0 UNIPROT up-regulates activity binding 9606 BTO:0000567 10751153 YES miannu Katanin, a heterodimeric microtubule-severing ATPase, is found localized at mitotic spindle poles. In this paper we demonstrate that human p60 katanin and the C-terminal domain of human p80 katanin both bind microtubules in vitro. Association of these two proteins results in an increased microtubule affinity and increased microtubule-severing activity in vitro. Association of these subunits in transfected HeLa cells increases microtubule disassembly activity and targeting to spindle poles.  0.586 SIGNOR-267180 MAPK11 protein Q15759 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 16932740 YES gcesareni P38 map kinase mediates stress-induced internalization of egfrthe underlying mechanism entails phosphorylation of egfr at a short segment (amino acids 1002-1022) containing multiple serines and threonines, as well as phosphorylation of two rab5 effectors, eea1 and gdi. 0.334 SIGNOR-149086 PKA proteinfamily SIGNOR-PF17 SIGNOR ARHGAP17 protein Q68EM7 UNIPROT down-regulates activity phosphorylation Ser702 LSAPRRYsSSLSPIQ 9606 BTO:0000132 26507661 YES lperfetto Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex. 0.2 SIGNOR-272156 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 YES lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. 0.929 SIGNOR-41941 RPS6KA1 protein Q15418 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser409 HGLSLIPsTGLCSPD 9606 10673502 YES The effect has been demonstrated using O75030-9 gcesareni The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73, whereas serine 409 serves as a substrate for p90 rsk-1. An unphosphorylatable double mutant at these two residues is at once profoundly stable and transcriptionally inert. 0.41 SIGNOR-75034 GYPC protein P04921 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 YES lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] 0.363 SIGNOR-266034 KIF3C protein O14782 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272536 SMURF1 protein Q9HCE7 UNIPROT PRR16 protein Q569H4 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272703 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 19864428 YES gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. Phosphorylation and activation of p70s6k by pdk1. 0.727 SIGNOR-188907 CREB5 protein Q02930 UNIPROT RDX protein P35241 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002816 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253809 RNA Polymerase I complex SIGNOR-C390 SIGNOR rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates 22260999 NO lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.7 SIGNOR-266177 MAPK3 protein P27361 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 YES gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. 0.46 SIGNOR-196034 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser215 DRNTFRHsVVVPYEP 9606 15469940 YES llicata Here we show that p53 is phosphorylated by the mitotic kinase aurora-a at serine 215. Unlike most identified phosphorylation sites of p53 that positively associate with p53 function (brooks, c. L., and gu, w. (2003) curr. Opin. Cell biol. 15, 164-171), the phosphorylation of p53 by aurora-a at ser-215 abrogates p53 dna binding and transactivation activity. 0.778 SIGNOR-129809 RRAGC protein Q9HB90 UNIPROT RAGAC complex SIGNOR-C113 SIGNOR form complex binding 9606 20381137 YES gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant 0.781 SIGNOR-228161 PPP4R3A protein Q6IN85 UNIPROT PPP4C protein P60510 UNIPROT up-regulates binding 9606 18715871 YES gcesareni Our data demonstrate that pp4r4 forms a novel cytosolic complex with pp4c, independent from the complexes containing pp4r1, pp4r2.PP4R3, and alpha4, and that the regulatory subunits of pp4c have evolved different modes of interaction with the catalytic subunit. 0.2 SIGNOR-180244 SP1 protein P08047 UNIPROT THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22406829 NO miannu In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells. 0.2 SIGNOR-255216 CYP21A2 protein P08686 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI down-regulates quantity chemical modification 9606 BTO:0000050 25855791 YES lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively 0.8 SIGNOR-268644 IL21R protein Q9HBE5 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000776 12093291 YES gcesareni Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5 0.627 SIGNOR-90266 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Ser518 KTVTPASsAKTSPAK 10116 BTO:0000938 15652488 YES lperfetto Ser-518 is also a potential phosphorylation site of CRMP-2 by GSK-3_. 0.723 SIGNOR-133251 ERN1 protein O75460 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 31226023 YES miannu Upon activation by oligomerization and autophosphorylation, the cytosolic RNase domain of IRE1 mediates an unconventional splicing of the mRNA of X-box-binding protein 1 (XBP1). The spliced and frameshifted transcript encodes XBP1S, a bZIP transcription factor inducing the expression of numerous UPR effector genes that enhance ER folding capacity. 0.646 SIGNOR-260183 PLK1 protein P53350 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Thr39 PVETIETtVVGEEEE 9606 23226345 YES lperfetto More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis 0.392 SIGNOR-200087 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR FBXL2 protein Q9UKC9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25721664 YES miannu F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway. 0.622 SIGNOR-272447 VEGFB protein P49765 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252276 IKZF3 protein Q9UKT9 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 NO miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 0.2 SIGNOR-255405 IL12A protein P29459 UNIPROT IL12RB2 protein Q99665 UNIPROT up-regulates binding 9606 11086056 YES gcesareni Il-12r beta 2 plays an essential role in mediating the biological functions of il-12 in mice. 0.577 SIGNOR-84361 MECOM protein Q03112 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000669 15889140 YES Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  0.319 SIGNOR-266061 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 15735019 YES miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates 0.648 SIGNOR-134212 GRM7 protein Q14831 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. 0.8 SIGNOR-264938 PMS1 protein P54277 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 9500552 NO Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer 0.7 SIGNOR-257597 CREBBP protein Q92793 UNIPROT CREB1 protein P16220 UNIPROT up-regulates binding 9606 9829964 YES gcesareni When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. 0.941 SIGNOR-62260 PTPN11 protein Q06124 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates dephosphorylation Tyr614 KSTGSVDyLALDFQP 9606 15170389 YES gcesareni Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2. 0.741 SIGNOR-124958 PRKACA protein P17612 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1166 SDDFKRDsVSGGGPC 9606 BTO:0000007 24431445 YES miannu Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. 0.412 SIGNOR-276616 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000459 SIGNOR-C13 10469655 YES lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. 0.853 SIGNOR-70469 ATP2A2 protein P16615 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 16402920 YES lperfetto In the present study, we have analysed the expression and functional characteristics of SERCA2c relative to SERCA2a and SERCA2b isoforms upon their stable heterologous expression in HEK-293 cells (human embryonic kidney 293 cells). All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells. 0.8 SIGNOR-262050 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation Thr385 APEKGLPtPQVLQRN 9606 BTO:0000567 9155018 YES lperfetto Mnk1 was phosphorylated and activated in vitro by erk1 and p38 map kinasespreliminary results showed that thr344 at least was one of the major sites phosphorylated by erk1 0.575 SIGNOR-48360 USF1 protein P22415 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 NO miannu We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. 0.2 SIGNOR-254814 CERS5 protein Q8N5B7 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 YES done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  0.8 SIGNOR-273996 PPARGC1A protein Q9UBK2 UNIPROT APOC3 protein P02656 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.276 SIGNOR-255059 MCM10 protein Q7L590 UNIPROT POLA1 protein P09884 UNIPROT up-regulates quantity by stabilization relocalization -1 19608746 YES Federica Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin. 0.861 SIGNOR-261271 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr86 AASASPYtPEHAASV 9606 12676926 YES lperfetto Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. 0.473 SIGNOR-216849 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120064 DAPK1 protein P53355 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 17339337 YES gcesareni A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53. 0.559 SIGNOR-153487 RNF2 protein Q99496 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 YES miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b 0.827 SIGNOR-266811 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNK9 protein Q9NPC2 UNIPROT down-regulates activity phosphorylation Thr341 IEEISPStLKNSLFP 9606 BTO:0004232 17374744 YES miannu PKC acts directly on hTASK3 channels to phosphorylate an identified amino acid in the C terminus region (Thr341), thereby reducing channel current.  0.2 SIGNOR-276059 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275758 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser444 PLSLSAQsVMEELNT 9606 BTO:0000938 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.547 SIGNOR-204740 USP9X protein Q93008 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.648 SIGNOR-270831 PTPRJ protein Q12913 UNIPROT CEACAM3 protein P40198 UNIPROT down-regulates activity dephosphorylation 9606 35850306 YES miannu We also determined that recombinant PTPRJ directly dephosphorylates the cytoplasmic tyrosine residues of purified full-length CEACAM3 and recognizes synthetic CEACAM3-derived phospho-peptides as substrates.|We show depletion of PTPRJ results in a gain-of-function phenotype, while overexpression of a constitutively active PTPRJ phosphatase strongly reduces bacterial uptake via CEACAM3. 0.385 SIGNOR-277091 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 BTO:0000887;BTO:0001103 22944199 YES gcesareni The wnt/ca2+ signaling pathway is defined by the activation of plc (phospholipase c) through wnt/fzd resulting in an increase in intracellular ca2+ levels, which activate pkcs (protein kinase c) and camkii (calcium-calmodulin-dependent kinase ii) or cn (calcineurin), a phosphatase that activates the transcription factor nfat (nuclear factor of activated t cell). 0.8 SIGNOR-198822 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 BTO:0000938 7691597 YES gcesareni Endogenous pp60c-src kinase activity is enhanced in the rptp alpha-transfected cells, which may be due to direct dephosphorylation of the regulatory tyr residue at position 527 in pp60c-src by rptp alpha. 0.742 SIGNOR-32014 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1178 IMSKHLDsPPAIPPR 9534 BTO:0004055 8816480 YES lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 0.713 SIGNOR-235925 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization 0.2 SIGNOR-186796 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9534 BTO:0000298 9482734 YES lperfetto Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin 0.894 SIGNOR-227862 AKAP8L protein Q9ULX6 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 NO miannu These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA. 0.7 SIGNOR-260953 ITGAM protein P11215 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.753 SIGNOR-253191 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0001271 7637391 YES gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. 0.2 SIGNOR-30353 SND1 protein Q7KZF4 UNIPROT STAT6 protein P42226 UNIPROT up-regulates activity binding -1 12234934 YES irozzo STAT6 interacted with p100 in vitro and in vivo. Here, we show that the TAD of STAT6 is interacting with p100. p100 was found to enhance the STAT6-mediated transcription [.]. 0.48 SIGNOR-259134 DLG4 protein P78352 UNIPROT TANC1 protein Q9C0D5 UNIPROT up-regulates activity binding 10116 BTO:0000142 21068316 YES miannu In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses. 0.597 SIGNOR-266894 PCC complex SIGNOR-C414 SIGNOR propionyl-CoA(4-) smallmolecule CHEBI:57392 ChEBI down-regulates quantity chemical modification 9606 15890657 YES miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. 0.8 SIGNOR-267184 CALM1 protein P0DP23 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 YES miannu To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. We show that Ca2+/CaM-dependent modulation on KIF1A allows for binding to vesicular cargo. Our results indicate that at low calcium concentrations, the tail domain of KIF1A does not bind to vesicular cargo, whereas at high calcium concentrations, CaM binds KIF1A, allowing for subsequent DCV motility. 0.275 SIGNOR-266888 BIRC2 protein Q13490 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 12525502 YES miannu  Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac. 0.894 SIGNOR-271392 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 YES lperfetto Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2. 0.731 SIGNOR-59627 PPM1A protein P35813 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 YES Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2Cα dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity 0.325 SIGNOR-248489 PCM1 protein Q15154 UNIPROT CETN1 protein Q12798 UNIPROT up-regulates relocalization 9606 12403812 YES miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome 0.407 SIGNOR-94947 CUL1 protein Q13616 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR form complex binding 9606 10023660 YES gcesareni The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin. 0.888 SIGNOR-64502 bevacizumab antibody DB00112 DRUGBANK VEGFC protein P49767 UNIPROT down-regulates activity binding 9606 BTO:0001615 15961063 YES miannu Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. 0.4 SIGNOR-259886 NFE2L2 protein Q16236 UNIPROT PIR protein O00625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003081 39534872 YES miannu The activation of NFE2L2 is pivotal in protecting cells from ferroptotic death. To achieve this protective function, NFE2L2 regulates a broad spectrum of genes involved in multiple cellular pathways, including those that modulate ROS, detoxify harmful agents, and repair damaged proteins. In human pancreatic cancer cell lines, the expression of PIR is upregulated by NFE2L2 in response to ferroptosis-inducing agents (erastin or RSL3) 0.2 SIGNOR-279850 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 17151142 NO [...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation 0.3 SIGNOR-253601 GATA2 protein P23769 UNIPROT CYBB protein P04839 UNIPROT down-regulates quantity transcriptional regulation 9606 10734088 YES These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils. 0.25 SIGNOR-259948 HMGA1 protein P17096 UNIPROT KITLG protein P21583 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 15378028 NO miannu Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells. 0.328 SIGNOR-254426 OST4 protein P0C6T2 UNIPROT OST-B complex complex SIGNOR-C536 SIGNOR form complex binding 9606 31831667 YES miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  0.54 SIGNOR-272069 Hypoxia stimulus SIGNOR-ST25 SIGNOR EGLN2 protein Q96KS0 UNIPROT down-regulates 9606 24990963 NO lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization 0.7 SIGNOR-262001 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 SIGNOR-C83 17015473 YES The effect has been demonstrated using Q01196-8 gcesareni Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a. 0.2 SIGNOR-149976 TACSTD2 protein P09758 UNIPROT CLDN7 protein O95471 UNIPROT up-regulates quantity binding 9606 BTO:0001109 31177095 YES done miannu In summary, our findings provide evidence that Trop-2 is phosphorylated at Ser-322 by PKCα/δ and that this phosphorylation enhances cell motility and decreases claudin-7 localization to cellular borders. 0.394 SIGNOR-273822 saxagliptin chemical CHEBI:71272 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 19149538 YES Luana Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. 0.8 SIGNOR-257813 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI IDH1 protein O75874 UNIPROT up-regulates activity chemical activation 9606 32943735 YES Wild-type IDH1 and IDH2 catalyze the reaction by converting isocitrate and NADP+ into α-KG and CO2 with the concomitant generation of NADPH in the cytosol and mitochondrial matrix 0.8 SIGNOR-267369 SRC protein P12931 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation 9606 BTO:0002181 26198631 YES miannu YY1 phosphorylation is mediated by Src family kinases. 0.284 SIGNOR-276940 NLRX1 protein Q86UT6 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity relocalization 9606 BTO:0002181 18219313 NO lperfetto NLRX1 synergistically potentiated ROS production induced by tumour necrosis factor alpha, Shigella infection and double-stranded RNA, resulting in amplified NF-kappaB-dependent and JUN amino-terminal kinases-dependent signalling. We observed that NLRX1-positive cells showed increased p65 translocation as early as 15 min after infection, an effect that was maintained over time. 0.271 SIGNOR-260399 mesulergine chemical CHEBI:73378 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258686 PABIR1 protein Q96E09 UNIPROT PPP2R2A protein P63151 UNIPROT down-regulates activity binding 9606 BTO:0000007 27588481 YES miannu We demonstrate that the highly conserved protein in mammals, designated FAM122A, directly interacts with PP2A-Aα and B55α rather than B56α subunits, and inhibits the phosphatase activity of PP2A-Aα/B55α/Cα complex. 0.2 SIGNOR-266379 HDAC4 protein P56524 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005173 17656568 NO miannu We have hypothesized that histone deacetylases (HDACs) are involved with PTH-induced MMP-13 gene expression in the osteoblastic cell line, UMR 106-01. We have shown that PTH profoundly regulates HDAC4 in UMR 106-01 cells through a PKA-dependent pathway, leading to removal of HDAC4 from the MMP-13 promoter and its enhanced transcription. 0.326 SIGNOR-254235 choline smallmolecule CHEBI:15354 ChEBI choline phosphate(1-) smallmolecule CHEBI:295975 ChEBI up-regulates quantity precursor of 27149373 YES lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes 0.8 SIGNOR-275633 KDM6A protein O15550 UNIPROT HOXA7 protein P31268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.275 SIGNOR-260024 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM21 protein P19474 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271063 SQSTM1 protein Q13501 UNIPROT KEAP1 protein Q14145 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 39534872 YES miannu When autophagy is impaired, accumulated SQSTM1 interacts with KEAP1, leading to the proteasomal degradation of KEAP1. This interaction sequesters KEAP1 away from NFE2L2, preventing the ubiquitination and degradation of NFE2L2. Consequently, NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. 0.714 SIGNOR-279849 ARID5B protein Q14865 UNIPROT GATA3 protein P23771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 NO miannu We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). 0.334 SIGNOR-256158 CRYGS protein P22914 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 10521291 NO The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. 0.7 SIGNOR-253625 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 YES flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. 0.622 SIGNOR-75910 ETS2 protein P15036 UNIPROT SPARC protein P09486 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 YES miannu Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin 0.305 SIGNOR-259874 PTK2B protein Q14289 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity phosphorylation Tyr591 KFDKQKLyYHATKAM 9606 BTO:0002181 37989995 YES miannu  Mechanistically, we demonstrate that PTK2B directly phosphorylates residue Tyr591 of TBK1, which increases TBK1 oligomerization and activation. 0.267 SIGNOR-277910 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 12746313 YES scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. 0.8 SIGNOR-266940 NGF protein P01138 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003306 24493753 NO miannu Long-term (more than 24 h) treatment with nerve growth factor (NGF) upregulated Nav1.7 functional expression in the strongly metastatic MAT-LyLu rat PCa cell line; acute application had no effect 0.37 SIGNOR-253495 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 25081058 YES miannu In the present study, we demonstrated that PTPN18 specifically dephosphorylates HER2 pY 1112, pY 1196 and pY 1248 sites among ten HER2 and EGFR C-terminal tyrosine phosphorylation sites (XREF_FIG).|Taken together, these data suggest that PTPN18 promotes the proteasome dependent degradation of HER2 through K48 linked polyubiquitination. 0.67 SIGNOR-277031 FOXO6 protein A8MYZ6 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 NO lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. 0.272 SIGNOR-236567 precursor messenger RNA smallmolecule CHEBI:139356 ChEBI SF3b complex SIGNOR-C442 SIGNOR up-regulates activity relocalization 9606 32140746 YES lperfetto The SF3b complex is an intrinsic component of the functional U2 small nuclear ribonucleoprotein (snRNP). As U2 snRNP enters nuclear pre-mRNA splicing, SF3b plays key roles in recognizing the branch point sequence (BPS) and facilitating spliceosome assembly and activation. 0.8 SIGNOR-268413 H2BC11 protein P06899 UNIPROT Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR form complex binding -1 24311584 YES miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. 0.2 SIGNOR-263716 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 YES lperfetto Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potential, 0.523 SIGNOR-124047 MicroRNA-223 ncrna URS0002321F26_9606 RNAcentral NLRP3 protein Q96P20 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0003575 39252576 YES miannu MicroRNA-223 alleviates inflammatory response in renal ischemia-reperfusion injury by targeting c 0.2 SIGNOR-279980 CREB5 protein Q02930 UNIPROT DGKG protein P49619 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253804 NODAL protein Q96S42 UNIPROT TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003879 20383200 NO Regulation miannu Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway. 0.659 SIGNOR-251942 BCL2 protein P10415 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 1286168 NO lperfetto Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis 0.7 SIGNOR-256637 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120148 veliparib chemical CHEBI:62880 ChEBI PARP2 protein Q9UGN5 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189224 Sin3B_complex complex SIGNOR-C409 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity binding 9606 21041482 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.2 SIGNOR-266970 SP1 protein P08047 UNIPROT POR protein P16435 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0004428 8660656 NO miannu Regulation of the NADPH-cytochrome P-450 oxidoreductase gene is controlled by both positive and negative regulatory elements, and, of the nine Sp1 consensus sites, the two proximal sites are sufficient to support basal transcription. 0.2 SIGNOR-255213 RBBP8 protein Q99708 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity relocalization SIGNOR-C295 24832651 YES lperfetto DNA damage activates ATM and CHK2 kinases, which mediate phosphorylation of CtIP and BRCA1. Phosphorylated CtIP associates with BRCA1 and with the MRN complex leading to the recruitment of the BRCC complex at the site of DNA damage where HR is initiated. 0.841 SIGNOR-263203 FOXA1 protein P55317 UNIPROT LOXL2 protein Q9Y4K0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 20043065 NO miannu These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes. FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells. 0.2 SIGNOR-254166 TEAD1 protein P28347 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21211055 NO gcesareni Tead1 can regulate transcription of the foxo3a gene through the binding to the m-cat element, demonstrated with independent chip-pcr analysis, emsa and luciferase reporter system assay. The over-expression and inhibition analysis suggest that foxo3a was positively regulated by tead1. 0.305 SIGNOR-170976 MAPK1 protein P28482 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 YES esanto We demonstrate that p90 ribosomal s6 kinase (rsk) is recruited to the nfat-dna transcription complex upon activation.Bound Rsk phosphorylates ser(676) and potentiates nfatc4 dna binding. Ser(676) is also targeted by the erk map kinase. 0.283 SIGNOR-133272 SCNN1A protein P37088 UNIPROT CACNA1H protein O95180 UNIPROT up-regulates activity binding 9606 BTO:0000142 30736831 YES miannu This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues. 0.2 SIGNOR-269272 RTF1 protein Q92541 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 YES miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  0.887 SIGNOR-269835 MBTPS1 protein Q14703 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates activity cleavage 10029 BTO:0000246 10644685 YES We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2 0.593 SIGNOR-267496 F2 protein P00734 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Arg1046 HHAPLSPrTFHPLRS -1 10026263 YES lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 0.882 SIGNOR-263631 TFEB protein P19484 UNIPROT GNS protein P15586 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 NO lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) 0.312 SIGNOR-276792 HSPB1 protein P04792 UNIPROT CASP3 protein P42574 UNIPROT down-regulates 9606 10544189 NO gcesareni Hsp27 overexpression delays poly(adp-ribose)polymerase cleavage and procaspase-3 activation. 0.566 SIGNOR-71869 MAPK14 protein Q16539 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser389 ARIQAAAsTPTNATA 9606 BTO:0000142 17726008 YES gcesareni However p38alfa also inactivates gsk3b by direct phosphorilation of the c-terminal residue ser389. this non-canonicl p38 mapk-dependent phosphorilation of gsk3b seems to occur primarily in the brain and thymocytes. 0.291 SIGNOR-157548 SF3B4 protein Q15427 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 YES lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). 0.918 SIGNOR-268406 CTF1 protein Q16619 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 11834704 YES gcesareni We conclude that gp130/lif receptor and et(a) receptor activation are essential for cardiac fibroblast growth by ct-1 0.73 SIGNOR-114758 glutamine smallmolecule CHEBI:28300 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 NO Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 0.8 SIGNOR-268008 DYRK2 protein Q92630 UNIPROT KATNA1 protein O75449 UNIPROT down-regulates quantity by destabilization phosphorylation Thr133 HGNRPSTtVRVHRSS 9606 BTO:0000007 19287380 YES miannu DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d). 0.51 SIGNOR-262849 FYN protein P06241 UNIPROT FYB1 protein O15117 UNIPROT up-regulates activity phosphorylation Tyr595 IEDDQEVyDDVAEQD 9606 10570256 YES  two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription. 0.2 SIGNOR-251163 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates phosphorylation Thr1491 DYHFVNAtEESDALA 9606 BTO:0000938 19824698 YES lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. eduction in the gtp-bound form of lrrk2 caused by t1491d mutation might have lowered the kinase activity, implicating the autophosphorylation of the roc domain in a negative feedback regulation of the kinase activity of lrrk2. 0.2 SIGNOR-188425 SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 15367216 YES The TCR, IL-2R, and TbetaR must all be stimulated to induce Foxp3 + Tregs. Failure to engage any one of these receptors prevents the generation of Foxp3 + Tregs 0.524 SIGNOR-254363 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity precursor of 9606 21876188 YES lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. 0.8 SIGNOR-268233 ROR2 protein Q01974 UNIPROT FLNA protein P21333 UNIPROT up-regulates binding 9606 18667433 YES gcesareni Additionally, the association of ror2 with the actin-binding protein filamin a is required for wnt5a-induced jnk activation and polarized cell migration. 0.438 SIGNOR-179668 CAMK2A protein Q9UQM7 UNIPROT DAGLA protein Q9Y4D2 UNIPROT down-regulates activity phosphorylation Ser808 RSIRGSPsLHAVLER 23502535 YES lperfetto Activated CaMKII interacted with the C-terminal domain of DGLalpha, phosphorylated two serine residues and inhibited DGLalpha activity. |CaMKIIalpha phosphorylates DGLalpha at Ser808 and Ser782 0.2 SIGNOR-275540 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000007 11691836 YES lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 0.658 SIGNOR-249392 AMER1 protein Q5JTC6 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates activity relocalization 9606 21304492 YES lperfetto Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6. 0.648 SIGNOR-227991 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR DBP protein Q10586 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 30100984 YES miannu The albumin D-box binding protein (DBP) is a member of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family and functions as important regulator of circadian core and output gene expression. Gene expression of DBP itself is under the control of E-box-dependent binding by the Bmal1-Clock heterodimer and CRE-dependent binding by the cAMP responsive element binding protein (CREB). 0.711 SIGNOR-268029 IL2RB protein P14784 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 YES milica The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival 0.556 SIGNOR-204975 NQO1 protein P15559 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000849 20226854 NO irozzo More importantly, our results also indicate that NF-kappaB p50 correlates with the expression of NQO1 and mediates its role in the proliferation of melanoma cells. 0.7 SIGNOR-256264 RPGR protein Q92834 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 20631154 YES miannu PGR interacts with the small GTPase RAB8A, which participates in cilia biogenesis and maintenance. We show that RPGR primarily associates with the GDP-bound form of RAB8A and stimulates GDP/GTP nucleotide exchange. RPGR functions as a GEF for RAB8A and RPGR–RAB8A association may facilitate ciliary trafficking. 0.427 SIGNOR-253030 Pyridostigmine chemical CHEBI:8665 ChEBI BCHE protein P06276 UNIPROT down-regulates activity chemical inhibition -1 20627738 YES Luana The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors  0.8 SIGNOR-257880 USP45 protein Q70EL2 UNIPROT SPDL1 protein Q96EA4 UNIPROT up-regulates activity deubiquitination 9606 BTO:0001938 30258100 YES miannu Spindly is mono-ubiquitylated and this ubiquitin can be removed by active USP45. K48 ubiquitylated complex that interacts with Spindly is also de-ubiquitylated by USP45. In the absence of USP45 catalytic activity, interaction is abolished and cell migration is affected similarly to the phenotype described for lack of Spindly. 0.2 SIGNOR-268505 ABCA13 protein Q86UQ4 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity relocalization 9606 33478937 YES miannu ATP-binding cassette subfamily A member 13 (ABCA13) is predicted to be the largest ABC protein, consisting of 5058 amino acids and a long N-terminal region. Mutations in the ABCA13 gene were reported to increase the susceptibility to schizophrenia, bipolar disorder, and major depression.Here, we examined the biochemical activity of ABCA13 using HEK293 cells transfected with mouse ABCA13. The expression of ABCA13 induced the internalization of cholesterol and gangliosides from the plasma membrane to intracellular vesicles. These findings suggest that ABCA13 accelerates cholesterol internalization by endocytic retrograde transport in neurons and that loss of this function is associated with the pathophysiology of psychiatric disorders. 0.8 SIGNOR-265158 ARHGEF12 protein Q9NZN5 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.905 SIGNOR-260539 MED11 protein Q9P086 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.787 SIGNOR-266670 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207941 CyclinC/CDK19 complex SIGNOR-C544 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.39 SIGNOR-273163 NME1 protein P15531 UNIPROT FZD1 protein Q9UP38 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 NO miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 0.2 SIGNOR-255162 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR BIRC5 protein O15392 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys91 CAFLSVKkQFEELTL 10090 BTO:0002268 25778398 YES miannu Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation. 0.331 SIGNOR-272439 RANBP3 protein Q9H6Z4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity relocalization 9606 20704570 YES lperfetto Importantly, PPM1A facilitates the interaction of dephosphorylated Smad2/3 with RanBP3, a nuclear export factor [75]. As a result, PPM1A-mediated dephosphorylation of Smad2/3 promotes nuclear export of Smad2/3 and shuts off TGF-_-induced anti-proliferative and transcriptional responses 0.436 SIGNOR-217625 PTPN2 protein P17706 UNIPROT SHC1 protein P29353 UNIPROT down-regulates activity dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 9488479 YES llicata However, TC45 inhibited the EGF-induced association of p52Shc with Grb2, which was attributed to the ability of the PTP to recognize specifically p52Shc phosphorylated on Y239. These results indicate that TC45 recognizes not only selected substrates in a cellular context but also specific sites within substrates and thus may regulate discrete signaling events. 0.57 SIGNOR-248397 IL18 protein Q14116 UNIPROT IL18R1 protein Q13478 UNIPROT up-regulates binding 9606 9792649 YES gcesareni Acpl was required for il-18 responsiveness in terms of nf?B Induction and jnk activation 0.835 SIGNOR-60991 BCL3 protein P20749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16384933 NO gcesareni One mechanism by which this inhibition occurs is through bcl-3-mediated induction of the p53 inhibitor hdm2. Both stable and transient overexpression of bcl-3 leads to increased hdm2 expression, and small interfering rna (sirna)-mediated knockdown of bcl-3 blocks expression of hdm2. ( articolo-abstract) 0.286 SIGNOR-143403 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 21295084 YES amattioni Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction. 0.726 SIGNOR-256452 SMURF2 protein Q9HAU4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates activity ubiquitination 9606 18448069 YES lperfetto The association of Smurf2 with Smad7 and its ubiquitination were inhibited by AIMP1, thereby protecting its autocatalytic degradation stimulated by Smad7. 0.87 SIGNOR-178501 AKT3 protein Q9Y243 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates activity phosphorylation Thr151 FCNGRGNtSGSHIVN 9606 BTO:0002181 35675814 YES miannu AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity 0.2 SIGNOR-277596 SRGAP2 protein O75044 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.587 SIGNOR-260516 HNRNPH2 protein P55795 UNIPROT TERF2 protein Q15554 UNIPROT down-regulates quantity post transcriptional regulation 10116 BTO:0001009 27117401 YES miannu During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. However, the RNA-binding proteins (RBPs) controlling this splicing event are unknown. Here, using affinity pull-down analysis, we identified heterogeneous nuclear ribonucleoproteins H1 and H2(HNRNPH) as RBPs specifically capable of interacting with the spliced RNA segment (exon 7) of Trf2 pre-mRNA. HNRNPH proteins prevent the production of the short isoform of Trf2 mRNA, as HNRNPH silencing selectively elevates TRF2-S levels. 0.333 SIGNOR-266806 GSK3A protein P49840 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 YES gcesareni GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function. 0.637 SIGNOR-252455 CENPP protein Q6IPU0 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.738 SIGNOR-265208 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000773 11278964 YES lperfetto Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion. 0.8 SIGNOR-106440 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu76 CSFEEAReVFENTER 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263694 SARS1 protein P49591 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 24095058 YES miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis 0.8 SIGNOR-270497 GSK3B protein P49841 UNIPROT DEK protein P35659 UNIPROT down-regulates quantity by destabilization phosphorylation Thr67 KKKVERLtMQVSSLQ 9606 BTO:0002181 21282377 YES miannu  These data suggest that the E3 ligase SCFFbxw7-α degrades p-DEK in a GSK-3β–dependent manner.Therefore, the phosphorylation of DEK by GSK-3β is a crucial step to mediate Tpm RNA splicing. 0.435 SIGNOR-276303 MAP3K1 protein Q13233 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 15001534 YES gcesareni The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells 0.502 SIGNOR-123168 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one chemical CID:56597938 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002181 22025698 YES Luana Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands.  0.8 SIGNOR-258320 TP53 protein P04637 UNIPROT AIFM2 protein Q9BRQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12135761 YES miannu The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identified PRG3 (p53-responsive gene 3), which is induced specifically under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. these results support the hypothesis that the expression of the PRG3 gene in cells undergoing p53‐dependent apoptosis involves direct activation of its promoter by p53. 0.502 SIGNOR-261808 JAK2 protein O60674 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 23898330 YES lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation 0.713 SIGNOR-249490 PRKACA protein P17612 UNIPROT TRIM71 protein Q2Q1W2 UNIPROT up-regulates quantity by stabilization phosphorylation Ser3 sFPETDFQ -1 31160797 YES miannu  These observations suggested that LINK-A expression potentially inhibits PKA phosphorylation/activity and PKA-mediated phosphorylation of TRIM71 at Ser3. 0.2 SIGNOR-277454 IFNG protein P01579 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18647246 NO miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. 0.281 SIGNOR-252410 L-thyroxine smallmolecule CHEBI:18332 ChEBI THRB protein P10828 UNIPROT up-regulates activity chemical activation 10116 BTO:0000759 2158622 YES miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 0.8 SIGNOR-258383 HACD proteinfamily SIGNOR-PF86 SIGNOR ELOVL proteinfamily SIGNOR-PF93 SIGNOR up-regulates activity binding 18554506 YES miannu Very long-chain fatty acids are produced through a four-step cycle. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle. 0.2 SIGNOR-267915 SLRP proteinfamily SIGNOR-PF31 SIGNOR ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Proteoglycans are ubiquitous in connective tissue, and muscle ECM is no exception. A number of PGsare present in muscle ECM, and many belong to the family of small leucine-rich proteoglycans (SLRPs). 0.7 SIGNOR-255345 NR0B1 protein P51843 UNIPROT NR5A1 protein Q13285 UNIPROT down-regulates activity binding 9606 BTO:0002588 19237537 YES miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. 0.704 SIGNOR-271784 pipamperone chemical CHEBI:78549 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258573 IRX1 protein P78414 UNIPROT EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.2 SIGNOR-261661 ESR1 protein P03372 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 16169518 YES gcesareni Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k. 0.544 SIGNOR-140473 SMAD3 protein P84022 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity 9606 BTO:0000599 10890911 NO lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity 0.516 SIGNOR-229308 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser276 VHPATPIsPGRASGM 9606 BTO:0002181 16046550 YES miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 0.2 SIGNOR-268221 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation Ser674 PGRERGEsPTTPPTP 9606 BTO:0000938 12458207 YES lperfetto Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation. 0.2 SIGNOR-96062 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258454 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM38 protein O00635 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271141 CDKN2A protein P42771 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 8891723 YES miannu The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb. 0.87 SIGNOR-44557 RXRG protein P48443 UNIPROT GLI2 protein P10070 UNIPROT up-regulates quantity transcriptional regulation 31390799 NO SimoneGraziosi Despite RXRγ being heavily down-regulated upon silencing (average silencing was about 80%), the reduction in Gli2 expression levels was statistically significant only for Clobetasol-treated but not for Gefitinib-treated cells. 0.259 SIGNOR-269267 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 18682241 YES flangone We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity. 0.438 SIGNOR-242052 SLN protein O00631 UNIPROT ATP2A1 protein O14983 UNIPROT down-regulates activity binding 9606 28487373 YES lperfetto These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity. 0.551 SIGNOR-265929 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr187 CDIQTHMtNNKGSAA -1 20538596 YES lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. 0.2 SIGNOR-227540 SNRPG protein P62308 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.929 SIGNOR-270683 NEDD4L protein Q96PU5 UNIPROT NF2 protein P35240 UNIPROT up-regulates activity ubiquitination Lys396 QITEEEAkLLAQKAA 9606 33058421 YES miannu Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control. 0.262 SIGNOR-263662 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser251 PLSPFPVsPLAGPGS 9606 10330152 YES lperfetto The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a). 0.595 SIGNOR-67528 PAK3 protein O75914 UNIPROT SYN1 protein P17600 UNIPROT up-regulates activity phosphorylation Ser605 AGPTRQAsQAGPVPR 10116 BTO:0001009 12237306 YES miannu Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release 0.334 SIGNOR-250246 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation 9606 BTO:0001103 21798082 YES lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). 0.91 SIGNOR-252841 SNX9 protein Q9Y5X1 UNIPROT DNM1 protein Q05193 UNIPROT up-regulates binding 9606 BTO:0000567 15703209 YES miannu Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes. 0.788 SIGNOR-133892 NFE2L2 protein Q16236 UNIPROT GCLM protein P48507 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy 0.439 SIGNOR-279869 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 10090 BTO:0002572 SIGNOR-C3 20670887 YES lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2), both of which control specific steps in the initiation of cap-dependent translation 0.926 SIGNOR-167180 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGC5 protein Q9Y5F6 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265705 CDH6 protein P55285 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.577 SIGNOR-265868 retinal smallmolecule CHEBI:15035 ChEBI all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity precursor of 9606 21621639 YES lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. 0.8 SIGNOR-265121 SUFU protein Q9UMX1 UNIPROT SAP18 protein O00422 UNIPROT up-regulates binding 9606 11960000 YES gcesareni Here we report that the mouse homolog of su(fu) [msu(fu)] specifically interacts with sap18, a component of the msin3 and histone deacetylase complex. In addition, we demonstrate that msu(fu) functionally cooperates with sap18 to repress transcription by recruiting the sap18-msin3 complex to promoters containing the gli-binding element. 0.672 SIGNOR-117311 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR USP37 protein Q86T82 UNIPROT up-regulates activity phosphorylation Ser628 MVNSCITsPSTPSKK 9606 BTO:0000007;BTO:0000567 21596315 YES lperfetto There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity 0.513 SIGNOR-265046 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 28370702 NO lperfetto A specific subtype of non-small cell lung cancer (NSCLC) characterized with an EML4-ALK fusion gene, which drives constitutive oncogenic activation of ALK kinase. We demonstrated that exogenous introduction of EML4-ALK protein with the substitution of lysine 1610 to an alanine in these two cell lines reduced the phosphorylation levels of AKT, one of downstream oncogenic molecules in the EML4-ALK pathway, and suppressed the growth of the two cell lines. 0.2 SIGNOR-253218 EGR3 protein Q06889 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 20506119 NO miannu In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2. 0.486 SIGNOR-253882 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Thr317 EDATLEEtLVKKKKK 9606 20573420 YES lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. 0.362 SIGNOR-166333 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251593 CDK5 protein Q00535 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation 9606 15471880 YES miannu In addition, we demonstrate that co-expression of cdk5 and its regulatory activator p35 with TH increases the stability of TH.|We show that cdk5 phosphorylates TH at serine 31 and that this phosphorylation is associated with an increase in total TH activity. 0.408 SIGNOR-279022 EGLN3 protein Q9H6Z9 UNIPROT ADRB2 protein P07550 UNIPROT up-regulates quantity by stabilization hydroxylation Pro382 KLLCEDLpGTEDFVG 9606 BTO:0000007 19584355 YES lperfetto We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation. 0.318 SIGNOR-262006 ILK protein Q13418 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 YES lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. 0.889 SIGNOR-265762 PHIP protein Q8WWQ0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000664 30018425 YES miannu One member of the CRL4 complex, the WD-40 containing protein RepID (DCAF14/PHIP), selectively binds and activates a group of replication origins. Here we show that RepID recruits the CRL4 complex to chromatin prior to DNA synthesis, thus playing a crucial architectural role in the proper licensing of chromosomes for replication. In the absence of RepID, cells rely on the alternative ubiquitin ligase, SKP2-containing SCF, to progress through the cell cycle. 0.327 SIGNOR-266963 HIPK2 protein Q9H2X6 UNIPROT PAX6 protein P26367 UNIPROT up-regulates activity phosphorylation Thr281 QRRQASNtPSHIPIS 9606 BTO:0001938 16407227 YES HIPK2 phosphorylates the activation domain of Pax6, which augments Pax6 transactivation by enhancing its interaction with p300. Mass spectrometric analysis identified three Pax6 phosphorylation sites as threonines 281, 304, and 373. 0.464 SIGNOR-251269 MELK protein Q14680 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates quantity by stabilization phosphorylation Ser220 RPPRKFPsDKIFEAI 9606 BTO:0002030 31434700 YES miannu We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination.  0.329 SIGNOR-277480 ELOVL proteinfamily SIGNOR-PF93 SIGNOR 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267902 GSK3B protein P49841 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 SIGNOR-C110 16341017 YES gcesareni Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin. 0.793 SIGNOR-143041 DAB2IP protein Q5VWQ8 UNIPROT NRAS protein P01111 UNIPROT down-regulates activity gtpase-activating protein 9606 27858941 YES miannu The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP. 0.493 SIGNOR-254747 AKT1 protein P31749 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 YES lperfetto  In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis 0.784 SIGNOR-235340 SMARCB1 protein Q12824 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.755 SIGNOR-270725 PPP2R1B protein P30154 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 19114990 YES lperfetto Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity 0.943 SIGNOR-217872 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR HSPA5 protein P11021 UNIPROT down-regulates 9606 31226023 NO miannu In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation. 0.7 SIGNOR-260163 serine smallmolecule CHEBI:17822 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264760 TBK1 protein Q9UHD2 UNIPROT TNIP1 protein Q15025 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 PPSSGTSsEFEVVTP 36574265 YES lperfetto TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1 0.375 SIGNOR-275734 pentazocine chemical CHEBI:7982 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258935 GABRD protein O14764 UNIPROT GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.406 SIGNOR-263773 SIM1 protein P81133 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR down-regulates activity binding -1 9020169 YES 2 miannu SIM1 can inhibit AHR·ARNT binding to the XRE and can inhibit expression from an XRE-driven reporter gene indicates that SIM1 may act as negative regulator of transcription as well as a positive regulator. The above inhibitory effects may result from SIM1 competing with AHR for binding to ARNT, although we cannot exclude the possibility that SIM1 may also have other inhibitory effects of AHR·ARNT activity. In a similar fashion, SIM1 may act as a negative regulator of all ARNT-dependent genes. 0.411 SIGNOR-240811 Ub:E2 complex SIGNOR-C497 SIGNOR RFPL4B protein Q6ZWI9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271178 SPOP protein O43791 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20463034 YES Gianni RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins 0.704 SIGNOR-268861 AMHR2 protein Q16671 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 14746809 YES gcesareni See table2 0.552 SIGNOR-121593 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270406 RNF138 protein Q8WVD3 UNIPROT RAD51D protein O75771 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27161866 YES miannu RNF138 dependent ubiquitination of RAD51D and proteasome mediated degradation. 0.391 SIGNOR-278775 MAP3K11 protein Q16584 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 9003778 NO gcesareni The kinase-inactive mlk-3 failed to activate sapk, demonstraiting that mlk-3 catalytic activity is necessary for the induction of the sapk pathway. 0.625 SIGNOR-45791 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser183 PTQQYAKsLPVSVPV 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 17517883 YES lperfetto The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor-binding protein that is phosphorylated directly by mammalian target of rapamycin (mTOR) complex 1 (mTORC1) but not mTORC2 in vitro, predominantly at PRAS40 (Ser(183)).PRAS40 binding to raptor was also abolished by mutation of the major mTORC1 phosphorylation site, Ser(183), to Asp. 0.904 SIGNOR-154956 FAD smallmolecule CHEBI:16238 ChEBI FADH2 smallmolecule CHEBI:17877 ChEBI up-regulates quantity precursor of 9606 33450351 YES miannu ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a). 0.8 SIGNOR-269456 MAP3K10 protein Q02779 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9182538 YES miannu MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase. 0.446 SIGNOR-278954 AURKA protein O14965 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Thr206 GTSVRRRtSFYLPKD 9606 17563743 YES llicata AuroraT-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest. 0.448 SIGNOR-155819 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120104 RNF111 protein Q6ZNA4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates ubiquitination 9606 14657019 YES gcesareni Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia 0.735 SIGNOR-119666 TDGF1 protein P13385 UNIPROT ACVR2A protein P27037 UNIPROT down-regulates binding 9606 BTO:0000007 12682303 YES acerquone Here we show that cripto can form a complex with activin and actrii/iib cripto inhibited crosslinking of activin to alk4 and the association of alk4 with actrii/iib. 0.641 SIGNOR-100052 HDAC11 protein Q96DB2 UNIPROT BRD2 protein P25440 UNIPROT down-regulates activity binding 9606 BTO:0000007 30089714 YES lperfetto Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein. 0.339 SIGNOR-262058 EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 12297050 YES lperfetto Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase. 0.949 SIGNOR-186159 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser299 SSPTLSSsPPVLCNP 9606 22017875 YES llicata Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome. 0.754 SIGNOR-176853 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity phosphorylation Ser1220 NLHSSHSsGLMDKSS 9606 BTO:0000565 28630147 YES miannu Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C). 0.371 SIGNOR-266418 MAPK1 protein P28482 UNIPROT CITED2 protein Q99967 UNIPROT up-regulates activity phosphorylation Thr175 GGSGGSStPGGSGSS 9606 23082118 YES miannu CITED2 coactivation is enhanced by activation of MAPK1 and requires T166.|CITED2 is phosphorylated by MAPK1 at S85, T166 and T175. 0.455 SIGNOR-278408 diazepam chemical CHEBI:49575 ChEBI GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. 0.8 SIGNOR-263798 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT down-regulates activity phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000007 16023596 YES lperfetto The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance 0.711 SIGNOR-235892 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273073 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 19797085 YES llicata In addition, we show that the beta-trcp-mediated degradation requires phosphorylation of phlpp1 by casein kinase i and glycogen synthase kinase 3beta (gsk-3beta), and activation of the phosphatidylinositol 3-kinase/akt pathway suppresses the degradation of phlpp1 by inhibiting the gsk-3beta activity. 0.354 SIGNOR-188330 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity binding 9606 17761676 YES lperfetto PLpro interacts with IRF-3, and inhibits the phosphorylation and nuclear translocation of IRF-3, thereby disrupting the activation of type I IFN responses through either Toll-like receptor 3 or retinoic acid inducible gene I/melanoma differentiation-associated gene 5 pathways. 0.2 SIGNOR-260276 CREB1 protein P16220 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 NO inferred from family member gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 0.25 SIGNOR-270285 PRKCH protein P24723 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 YES gcesareni Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9 0.322 SIGNOR-115730 NCOA3 protein Q9Y6Q9 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 15808510 NO gcesareni Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1. 0.476 SIGNOR-135056 MAP3K21 protein Q5TCX8 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 9606 23319808 YES Manara These experiments showed that MEK1 is phosphorylated by MLK4 on Ser217/221 0.2 SIGNOR-260768 GRM8 protein O00222 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264351 PAX6 protein P26367 UNIPROT CTNND2 protein Q9UQB3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16973151 NO Indirect:regulation of expression miannu In Pax6 mutant embryos, delta-catenin expression was severely reduced in the optic vesicle neural ectoderm, in the ventricular zone of the neocortex and in the external granule layer of the cerebellum. We identified a Pax6 binding site in delta-catenin promoter that is conserved between mice and humans and which is effectively bound by Pax6 in vitro. Our results suggest that Pax6 regulates delta-catenin expression during CNS development in mice. 0.378 SIGNOR-251878 LYN protein P07948 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Tyr222 MEAPTTAyKKTTPIE -1 10066823 YES HS1 was shown to undergo a process of sequential phosphorylation both in vitro and in vivo, which is synergistically mediated by Syk and Src family protein-tyrosine kinases and essential for B cell antigen receptor-mediated apoptosis. We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn 0.713 SIGNOR-251399 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. 0.2 SIGNOR-255855 ELAVL3 protein Q14576 UNIPROT ANK3 protein Q12955 UNIPROT down-regulates quantity post transcriptional regulation 9606 BTO:0000938 29614249 YES miannu NElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Here, we found that the alternative splicing of AnkyrinG exon 34 was misregulated in the cerebella of Elavl3-/- mice. AnkyrinG is an essential factor for the formation of neuronal polarity and is required for normal neuronal functions. 0.25 SIGNOR-266861 FGF13 protein Q92913 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.358 SIGNOR-253423 MECP2 protein P51608 UNIPROT GAMT protein Q14353 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 BTO:0000614 18511691 YES Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. 0.28 SIGNOR-264678 MAPK1 protein P28482 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000671 19261619 YES gcesareni Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation. 0.359 SIGNOR-184469 methyltestosterone chemical CHEBI:27436 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 17202804 YES miannu GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5 0.8 SIGNOR-259266 RAD51AP1 protein Q96B01 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 17996711 NO miannu Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand-pairing step in HR. RAD51 associated protein 1 (RAD51AP1) is a RAD51-interacting protein whose function has remained elusive. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Purified RAD51AP1 binds both dsDNA and a D loop structure and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D loop reaction. 0.7 SIGNOR-261961 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation 9606 15356145 YES inferred from 70% family members lperfetto Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623. 0.2 SIGNOR-270000 CTSD protein P07339 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Ala92 DHIGFQEaYRRFYGP -1 9076588 YES miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 0.314 SIGNOR-256319 SLX4 protein Q8IY92 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR up-regulates binding 9606 24726326 YES lperfetto Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair. 0.819 SIGNOR-217652 PDPK1 protein O15530 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10480933 YES gcesareni We characterize two monoclonal antibodies raised against phosphorylated forms of the n- and c-terminal domain of rsk2 (p-s227 and p-t577, respectively). Using these two antibodies, we show that stress signals, such as uv light, induce phosphorylation and activation of the three rsks. 0.654 SIGNOR-70612 CDK2 protein P24941 UNIPROT LARP1 protein Q6PKG0 UNIPROT up-regulates activity phosphorylation 9606 34449924 YES miannu CDK2 phosphorylates LARP1 protein, regulates TOP-protein expression and LARP1\u2019s translational activity. 0.2 SIGNOR-279015 BBC3 protein Q9BXH1 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 YES gcesareni Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1. 0.553 SIGNOR-133814 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT down-regulates activity phosphorylation Ser688 KRRRSEDsEEEELAS 9606 15659405 YES llicata CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity. 0.703 SIGNOR-250961 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 YES lperfetto Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. 0.779 SIGNOR-217853 FOXC1 protein Q12948 UNIPROT SOX13 protein Q9UN79 UNIPROT up-regulates quantity by expression transcriptional regulation 31650548 NO lperfetto Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX14 0.2 SIGNOR-275916 PTPN6 protein P29350 UNIPROT VAV1 protein P15498 UNIPROT down-regulates activity dephosphorylation 9606 30567306 YES miannu SHP-1 dephosphorylates and inactivates the guanine exchange factor Vav1. 0.575 SIGNOR-277171 PPP1CA protein P62136 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members fstefani P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases 0.2 SIGNOR-269906 AKT1 protein P31749 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 YES lperfetto We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity 0.696 SIGNOR-148983 CASP3 protein P42574 UNIPROT RAD51 protein Q06609 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0002882 11684015 YES lperfetto The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin 0.467 SIGNOR-271709 TP53 protein P04637 UNIPROT PMAIP1 protein Q13794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14500851 NO gcesareni P53 has the ability to activate transcription of various proapoptotic genes, including those encoding members of the bcl-2 family, such as the bh-3 only proteins bax, noxa, and puma pmaip1 may thus represent a mediator of tp53-dependent apoptosis. 0.7 SIGNOR-118048 FOXO proteinfamily SIGNOR-PF27 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12913110 NO lperfetto FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. 0.2 SIGNOR-252914 ITCH protein Q96J02 UNIPROT BCL10 protein O95999 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000661 15082780 YES miannu The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation.  0.276 SIGNOR-271414 AURKA protein O14965 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser962 SSRSGREsVSTASDQ 9606 BTO:0000938 19812038 YES llicata Aurora a interacts directly with the atypical protein kinase c binding domain of par3 and phosphorylates it at serine 962. The phosphorylation of par3 at serine 962 contributes to its function in the establishment of neuronal polarity. 0.351 SIGNOR-188398 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser462 GSPHNPIsSVS 9606 9335504 YES llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. 0.642 SIGNOR-52662 CDK1 protein P06493 UNIPROT PTHLH protein P12272 UNIPROT down-regulates phosphorylation Thr121 YKEQPLKtPGKKKKG 9606 10373465 YES lperfetto Phosphorylation at the cyclin-dependent kinases site (thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization 0.2 SIGNOR-68544 CDK1 protein P06493 UNIPROT VCPIP1 protein Q96JH7 UNIPROT down-regulates activity phosphorylation Thr761 GPSSAPAtPTKAPYS 23500464 YES lperfetto We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97.  0.536 SIGNOR-265037 BAZ2B protein Q9UIF8 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 YES miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. 0.2 SIGNOR-266621 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 YES miannu Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK.  0.256 SIGNOR-277858 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000887 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.275 SIGNOR-163788 Cullin 7-RBX1-Skp1 complex SIGNOR-C528 SIGNOR NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 0.26 SIGNOR-272837 CREB1 protein P16220 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 17584923 NO Luana These findings, together with studies in Aplysia and Drosophila, strongly suggest that CREB is an evolutionary conserved component of the molecular cascade of events leading to memory consolidation. 0.7 SIGNOR-265773 RPAP3 protein Q9H6T3 UNIPROT R2TP core co-chaperone complex SIGNOR-C515 SIGNOR form complex binding 9606 29662061 YES miannu  Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90.  0.894 SIGNOR-270927 CKM complex complex SIGNOR-C406 SIGNOR STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 29239838 YES lperfetto We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. 0.294 SIGNOR-273182 BIRC5 protein O15392 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 11069302 YES amattioni Survivin (an inhibitor of apoptosis) phosphorylation on thr34 may regulate apoptosis at cell division via an interaction with caspase-9. 0.505 SIGNOR-84065 IL3 protein P08700 UNIPROT IL3RA protein P26951 UNIPROT up-regulates binding 9606 11700046 YES gcesareni The results demonstrate that both the association and dissociation rates for the binding of il-3 to the il-3ralpha are altered by truncation and by amino acid substitution at individual sites. Intracellular signaling studies using k116w and e43n demonstrate that differences in the il-3alpha binding characteristics are reflected in magnitude and kinetics of stat5 phosphorylation. 0.887 SIGNOR-111404 E2F1 protein Q01094 UNIPROT DHFR protein P00374 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.534 SIGNOR-253853 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 YES gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. 0.2 SIGNOR-49367 WNT2B protein Q93097 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors andinitiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.588 SIGNOR-131780 TRIM65 protein Q6PJ69 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity ubiquitination Lys743 QWITENEkFAEVGVK 9606 28031478 YES miannu These results indicate that TRIM65 promotes MDA5 ubiquitination at lysine 743, which is important for MDA5 activation. 0.448 SIGNOR-278535 leukotriene A4(1-) smallmolecule CHEBI:57463 ChEBI leukotriene C4(2-) smallmolecule CHEBI:57973 ChEBI up-regulates quantity precursor of 9606 27365393 YES miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). 0.8 SIGNOR-277260 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9136927 YES lperfetto Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro 0.664 SIGNOR-249648 cyclosporin A chemical CHEBI:4031 ChEBI PPP3CA protein Q08209 UNIPROT down-regulates chemical inhibition 9606 15276472 YES gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. 0.8 SIGNOR-127225 EGFR protein P00533 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates binding 9606 11279155 YES inferred from 70% of family members gcesareni These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity 0.67 SIGNOR-269876 SMAD1 protein Q15797 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0002729 23993924 NO flangone Engagement of BMP4-mediated signaling in adult mouse ovary-derived OSCs cultured in vitro drives differentiation of these cells into IVD oocytes through Smad1/5/8 activation and transcriptional up-regulation of key meiosis-initiating genes. 0.7 SIGNOR-255259 PPM1A protein P35813 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates dephosphorylation 9606 16751101 YES lpetrilli Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. 0.667 SIGNOR-146919 CCK protein P06307 UNIPROT CCKAR protein P32238 UNIPROT up-regulates binding 9606 10368033 YES gcesareni Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b 0.785 SIGNOR-68474 ZBTB46 protein Q86UZ6 UNIPROT PTGS1 protein P23219 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 30312731 YES miannu ZBTB46 acts as a transcriptional coactivator that binds to the promoter of prostaglandin-endoperoxide synthase 1 (PTGS1) and transcriptionally regulated PTGS1 levels. 0.2 SIGNOR-277991 GFI1 protein Q99684 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 BTO:0002181 17213822 YES miannu Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1-mediated transcriptional activation and ETS1 repressed GFI1-mediated transcriptional activation, in a dose-dependent manner. 0.427 SIGNOR-254201 LRIG1 protein Q96JA1 UNIPROT CBLC protein Q9ULV8 UNIPROT up-regulates binding 9606 BTO:0001253 15282549 YES gcesareni Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation 0.2 SIGNOR-127301 EIF2AK2 protein P19525 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser32 LLDDRHDsGLDSMKD 10723127 YES lperfetto As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation. 0.531 SIGNOR-249335 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1060 HGHVSDAsIRVGENV -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262900 MAPK8 protein P45983 UNIPROT AIMP1 protein Q12904 UNIPROT down-regulates phosphorylation Ser140 KKEKKQQsIAGSADS 9606 20510162 YES llicata We further demonstrated that serine-140 residue of aimp1 was phosphorylated by jnk and alanine mutation of serine-140 suppressed lps-induced cell surface altogether, these results suggest that aimp1 is phosphorylated by jnk through tlr-myd88 pathway and lose the regulatory activity for er retention of gp96expression of gp96. 0.474 SIGNOR-165763 MAML1 protein Q92585 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 11101851 YES gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes0 0.874 SIGNOR-84919 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Thr514 SVTPKTVtPASSAKT 9606 phosphorylation:Ser522 PASSAKTsPAKQQAP 25040932 YES lperfetto Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition 0.723 SIGNOR-264840 SL-327 chemical CHEBI:92211 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 BTO:0000938 BTO:0000142 11160424 YES lperfetto The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity 0.8 SIGNOR-244955 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser910 SLLGRSGsYSYLEER 9606 20354225 YES gcesareni Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. 0.507 SIGNOR-22572 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 9606 SIGNOR-C16 12105215 YES gcesareni To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313 0.346 SIGNOR-90434 INSR protein P06213 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 11075717 YES gcesareni The npxy motif around 960-tyr residue of the insulin receptor binds to the n-terminal ptb domain of shc. 0.709 SIGNOR-84251 pazopanib chemical CHEBI:71219 ChEBI CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 YES Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. 0.8 SIGNOR-257740 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser639 DEICIAGsPLTPRRV 9606 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104679 SDC4 protein P31431 UNIPROT FN1/SDC4 complex SIGNOR-C210 SIGNOR form complex binding 23290138 YES apalma We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells 0.71 SIGNOR-255286 RAB38 protein P57729 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR up-regulates activity relocalization 9606 23247405 YES lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. 0.355 SIGNOR-260697 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT up-regulates phosphorylation Tyr465 VPVDPATyGQFYGGD 9606 10210201 YES lperfetto Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently 0.572 SIGNOR-67014 RIT2 protein Q99578 UNIPROT POU4F1 protein Q01851 UNIPROT up-regulates activity binding 9606 BTO:0000934 12934100 YES miannu we describe the evidence for a functional interaction between Brn-3a and Rin and demonstrate the role of Rin in modulating the activation of the Brn-3a regulated egr-1 promoter by the N-terminal domain of Brn-3a. 0.526 SIGNOR-224546 TALDO1 protein P37837 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 19401148 YES miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (‚Äúdihydroxyacetone‚Äù) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. 0.8 SIGNOR-267091 DYRK1A protein Q13627 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity 0.316 SIGNOR-183677 AP3S1 protein Q92572 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 YES lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) 0.886 SIGNOR-260680 GLI1 protein P08151 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 NO gcesareni GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin 0.402 SIGNOR-188872 RNF26 protein Q9BY78 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity ubiquitination 9606 25254379 YES miannu As a result, knockdown of RNF26 promoted degradation of MITA after viral infection and prevented degradation of IRF3.|In addition, RNF26 could not induce polyubiquitination of MITA (K150R) in in vitro ubiquitination assays (XREF_FIG). 0.2 SIGNOR-278573 RNF8 protein O76064 UNIPROT TPP1 protein O14773 UNIPROT up-regulates activity ubiquitination 9606 22101936 YES miannu Our data demonstrate that RNF8 directly ubiquitylates and stabilizes TPP1 at telomeres.|Taken together, these results suggest that RNF8 dependent K63 linked, but not K48 linked ubiquitin chain formation on TPP1 is required to promote TPP1 stability and function at telomeres. 0.302 SIGNOR-278574 PRKACA protein P17612 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Thr686 QQKIRKYtMRRLLQE 9606 18799465 YES lperfetto Pka directly phosphorylated erbb2 on thr-686, a highly conserved intracellular regulatory site that was required for the pka-mediated synergistic enhancement of neuregulin-induced erbb2-erbb3 activation and proliferation in scs. 0.403 SIGNOR-181191 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258087 GHSR protein Q92847 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.372 SIGNOR-257054 CSNK2A1 protein P68400 UNIPROT TTI1 protein O43156 UNIPROT down-regulates phosphorylation Ser828 DVADGNVsDFDNEEE 9606 23263282 YES lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1 0.2 SIGNOR-200240 GATA3 protein P23771 UNIPROT PPARG protein P37231 UNIPROT down-regulates transcriptional regulation 9606 15632071 NO fspada Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity 0.348 SIGNOR-210025 MARCHF9 protein Q86YJ5 UNIPROT FCGR2B protein P31994 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 YES miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  0.2 SIGNOR-271541 ADAMTS5 protein Q9UNA0 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Glu392 PRNITEGeARGSVIL 9606 9202061 YES lperfetto Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374 0.764 SIGNOR-266985 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190708 HES1 protein Q14469 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000759 14614508 YES CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo 0.248 SIGNOR-253584 CHEK2 protein O96017 UNIPROT TRIM32 protein Q13049 UNIPROT up-regulates activity phosphorylation Ser55 LEKLLASsINGVRCP 9606 BTO:0000007 37943659 YES miannu We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.  0.2 SIGNOR-277804 PKA proteinfamily SIGNOR-PF17 SIGNOR GATA4 protein P43694 UNIPROT up-regulates activity phosphorylation Ser262 IKPQRRLsASRRVGL 9606 BTO:0000093 16109788 YES miannu  PKA-mediated phosphorylation increases the interaction between GATA3 and LRH-1 and the requirement for PKA in aromatase PII promoter stimulation involves at least three specific amino acid residues: GATA3 Ser308, GATA4 Ser261, and LRH-1 Ser469.  0.2 SIGNOR-276043 LYN protein P07948 UNIPROT SLAMF1 protein Q13291 UNIPROT unknown phosphorylation Tyr327 ETNSITVyASVTLPE 9606 15315965 YES llicata Cd150-mediated akt phosphorylation required syk and sh2d1a, was negatively regulated by lyn and btk, but was ship independent. Lyn directly phosphorylated y327 in cd150, but the akt pathway did not depend on cd150 tyrosine phosphorylation and cd150-shp-2 association. 0.301 SIGNOR-127997 RACK1 protein P63244 UNIPROT LARP4B protein Q92615 UNIPROT up-regulates activity binding 9606 BTO:0005238 20573744 YES miannu Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex. 0.2 SIGNOR-260941 WNT5A protein P41221 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 18697834 YES Simone Vumbaca Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells 0.833 SIGNOR-255651 aclidinium chemical CHEBI:65346 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 9606 19653626 YES Luana This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. 0.8 SIGNOR-258151 CHKB protein Q9Y259 UNIPROT choline phosphate(1-) smallmolecule CHEBI:295975 ChEBI up-regulates quantity chemical modification 27149373 YES lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes 0.8 SIGNOR-275634 Ub:E2 complex SIGNOR-C497 SIGNOR SH3RF2 protein Q8TEC5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271203 FUS protein P35637 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 NO inferred from family member This conclusion is also supported by the analysis of alternative splicing events inhFUS+/+;Smn+/‚àímice. As shown in Fig.6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected inhFUS+/+mice, is not further modified by SMN decrease 0.282 SIGNOR-270231 PIM1 protein P11309 UNIPROT YWHAZ protein P63104 UNIPROT up-regulates activity phosphorylation Ser64 SSWRVVSsIEQKTEG 9606 BTO:0001321 34697370 YES miannu PIM1 phosphorylates the AR and 14-3-3 ζ and coordinates their interaction. PIM1 phosphorylation of the AR and 14-3-3 ζ enhances their interaction and shifts their occupancy on chromatin, resulting in 14-3-3 ζ co-regulation of AR, likely by recruiting other AR co-regulators such as hnRNPK and TRIM28. 0.31 SIGNOR-277574 CSNK2A1 protein P68400 UNIPROT SSB protein P05455 UNIPROT up-regulates phosphorylation Ser366 GKKTKFAsDDEHDEH 9606 18257391 YES gcesareni Prior studies indicate that hla is activated by phosphorylation of serine-366 by protein kinase ck2, neutralizing a negative effect of a short basic motif (sbm) 0.337 SIGNOR-160761 PTPRG protein P23470 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity dephosphorylation Tyr313 SSEPVGIyQGFEKKT -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.2 SIGNOR-254716 BCOR protein Q6W2J9 UNIPROT BCL6 protein P41182 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 YES miannu In this study we have shown that BCoR interacts with BCL-6 and potentiates transcriptional repression by BCL-6 with striking specificity. 0.885 SIGNOR-252235 IYD protein Q6PHW0 UNIPROT 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI down-regulates quantity chemical modification 9606 28153798 YES scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. 0.8 SIGNOR-267032 MC4R protein P32245 UNIPROT GNAS protein Q5JWF2 UNIPROT up-regulates activity 9606 22215617 YES lperfetto We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus. 0.52 SIGNOR-253067 CDH20 protein Q9HBT6 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.298 SIGNOR-265859 RPL18 protein Q07020 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.854 SIGNOR-262481 PRKAA1 protein Q13131 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by stabilization phosphorylation Ser92 SFLVRKPsDPNRKPN 9606 19923321 YES lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. 0.2 SIGNOR-161779 CHD8 protein Q9HCK8 UNIPROT SOX2 protein P48431 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.318 SIGNOR-268921 ABR protein Q12979 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.502 SIGNOR-260525 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates activity binding 9606 19008118 YES FFerrentino Perhaps through Wnt5a acting via FZD2, might also inhibit adipocyte differentiation. 0.765 SIGNOR-253520 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-249687 MAPK11 protein Q15759 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 BTO:0001255 12839928 NO miannu Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes. 0.447 SIGNOR-263512 lanreotide chemical CHEBI:135901 ChEBI SSTR5 protein P35346 UNIPROT up-regulates activity chemical activation 9606 26416534 YES miannu Lanreotide Autogel (known as lanreotide Depot in the USA) is a synthetic octapeptide analog of somatostatin with a longer half-life than the native molecule and with selectivity for somatostatin receptor (SSTR) 2 and, to a lesser extent, SSTR 5 0.8 SIGNOR-259243 CASP6 protein P55212 UNIPROT N protein P59595 UNIPROT up-regulates activity cleavage Asp400 VTLLPAAdMDDFSRQ 9534 BTO:0001444 18155731 YES Luana Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403 0.2 SIGNOR-260211 MAPK14 protein Q16539 UNIPROT ATF6 protein P18850 UNIPROT up-regulates activity phosphorylation Thr166 NKTENGLtPKKKIQV 10090 BTO:0002572 25135476 YES miannu This observation not only confirms the specific role for IFN-γ-induced p38 MAPK-dependent phosphorylation of ATF6 at the T166 site but also indicates a connection between phosphorylation and proteolytic activation. 0.583 SIGNOR-276841 PP121 chemical CHEBI:50915 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-252655 POU3F4 protein P49335 UNIPROT POU3F3 protein P20264 UNIPROT up-regulates activity binding -1 9105675 YES miannu POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes. 0.314 SIGNOR-220127 SLC38A9 protein Q8NBW4 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000007 29053970 NO Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. 0.483 SIGNOR-255311 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 31422819 YES miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-268058 MEF2D protein Q14814 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.34 SIGNOR-238751 TUT4 protein Q5TAX3 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 NO lperfetto Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. 0.7 SIGNOR-268355 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 10710310 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-75641 FADS1 protein O60427 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267911 olanzapine chemical CHEBI:7735 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258512 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI up-regulates quantity precursor of 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-268131 MCUB protein Q9NWR8 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.2 SIGNOR-270863 THRA protein P10827 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 15650024 YES gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.43 SIGNOR-133240 PFAS protein O15067 UNIPROT 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI up-regulates quantity chemical modification 9606 33179964 YES miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. 0.8 SIGNOR-267311 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 15769897 YES we observed constitutive activation of Erk-1 and Erk-2, Akt, and of Shc by both Flt3-ITD and Flt3-D835Y 0.445 SIGNOR-261540 FBXO8 protein Q9NRD0 UNIPROT ARF6 protein P62330 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0000298 18094045 YES miannu Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A). 0.709 SIGNOR-271764 TBK1 protein Q9UHD2 UNIPROT PBXIP1 protein Q96AQ6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser147 REEGRCSsSDDDTDV 9606 BTO:0000007 24488098 YES miannu Phosphorylation of HPIP on serine 147 by TBK1 promotes E2-mediated GREB1 expression. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. 0.29 SIGNOR-273643 PTPRF protein P10586 UNIPROT LRRC4B protein Q9NT99 UNIPROT up-regulates activity binding 9606 19467332 YES miannu The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. 0.616 SIGNOR-264049 HRAS protein P01112 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 9606 21779497 YES lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. 0.759 SIGNOR-175189 FYN protein P06241 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.633 SIGNOR-268213 EPB41 protein P11171 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates activity relocalization 9615 BTO:0000837 12807908 YES lperfetto Together, our results demonstrate that in addition to the N-terminal targeting domain, the alternatively spliced I3 insertion plays a critical role in recruiting hDlg to the lateral membrane in epithelial cells via its interaction with protein 4.1R. 0.473 SIGNOR-266011 MMP1 protein P03956 UNIPROT COL2A1 protein P02458 UNIPROT down-regulates quantity by destabilization cleavage Gly906 EGPPGPQgLAGQRGI 9606 8609233 YES miannu MMP-1 cleaves type II collagen at the peptide bond Gly906-Leu907 Proteolysis of triple-helical collagen is an important step in the progression toward irreversible tissue damage in osteoarthritis. Earlier work on the expression of enzymes in cartilage suggested that collagenase-1 (MMP-1) contributes to the process. 0.445 SIGNOR-256341 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr759 LYDVSRMyVDPSEIN 9606 BTO:0000776 11606584 YES gcesareni By measuring the ability of human plcgamma2 to restore calcium responses to the b-cell receptor stimulation or oxidative stress in a b-cell line (dt40) deficient in plcgamma2, we have demonstrated that two tyrosine residues, tyr(753) and tyr(759), were important for the plcgamma2 signaling function.Of the two kinases that previously have been proposed to phosphorylate plcgamma2, btk, and syk, purified btk had much greater ability to phosphorylate recombinant plcgamma2 in vitro, whereas syk efficiently phosphorylated adapter protein blnk. 0.777 SIGNOR-111073 C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR C3 protein P01024 UNIPROT up-regulates activity cleavage Arg671 QPAARRRrSVQLTEK 9606 BTO:0000089 26489954 YES lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). 0.906 SIGNOR-263477 SGK1 protein O00141 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser1130 GARDRVRsMSGGHGL -1 27451907 YES miannu SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.  0.58 SIGNOR-277266 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 NO irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. 0.602 SIGNOR-256287 POU5F1 protein Q01860 UNIPROT SOX17 protein Q9H6I2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.609 SIGNOR-253167 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 11085989 NO miannu We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation. 0.866 SIGNOR-263500 ANK3 protein Q12955 UNIPROT DMD protein P11532 UNIPROT up-regulates quantity relocalization 10090 BTO:0001103 19109891 YES miannu We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4. 0.368 SIGNOR-266715 S1PR2 protein O95136 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.588 SIGNOR-257401 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser855 QRVLDTSsLTQSAPA 9606 BTO:0000007 19864431 YES lperfetto Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855)) 0.989 SIGNOR-174882 PTEN protein P60484 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity dephosphorylation Thr926 LDIPTGTtPQRKSYL 9606 27492783 YES lperfetto PTEN significantly reduces EG5 phosphorylation at Thr926 (XREF_FIG), suggesting PTEN may target this EG5 site for dephosphorylation. 0.455 SIGNOR-277000 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys666 IRAGDTTkFDVEVLK 9606 BTO:0000007 28448495 YES miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 0.2 SIGNOR-272803 SNRPD1 protein P62314 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.821 SIGNOR-270635 CDK4 protein P11802 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates phosphorylation Ser632 LVVSRNLsPPNCTEL 9606 BTO:0000150 SIGNOR-C18 17334399 YES lperfetto In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo. 0.664 SIGNOR-153450 pazopanib chemical CHEBI:71219 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 YES Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. 0.8 SIGNOR-257735 OPRL1 protein P41146 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.353 SIGNOR-257209 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser347 RSDIESSsDEEDSEP 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273989 TSC22D3 protein Q99576 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity binding 9606 BTO:0000007 11468175 YES GILZ inhibits NF-kappaB nuclear translocation and DNA binding due to a direct protein-to-protein interaction of GILZ with the NF-kappaB subunits. 0.374 SIGNOR-253297 COPS6 protein Q7L5N1 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.931 SIGNOR-270768 CRP protein P02741 UNIPROT GCH1 protein P30793 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004602 17942113 NO miannu The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. 0.278 SIGNOR-252216 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49D1 protein C9J1S8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271270 HCK protein P08631 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates activity phosphorylation Tyr787 LTPSPKSyENLWFQA -1 9790917 YES Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. the ability of Hck to phosphorylate the G-CSF-R in vitro, both Y728 and Y763 fit the Src consensus phosphorylation site. we investigated the activation of Hck by the G-CSF-R in intact cells as well as in vitro. These studies revealed recruitment of Hck to activated G-CSF-R, mediated by direct binding via its SH2 domain to multiple phosphotyrosines of the receptor. In addition, we show that Hck becomes activated upon G-CSF treatment and is, in turn, able to phosphorylate the G-CSF-R, indicating a clear functional and physical involvement in G-CSF signaling. 0.386 SIGNOR-251264 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr662 PGDSNPIySQIWSIQ -1 12051764 YES miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. 0.2 SIGNOR-274010 SH3BP1 protein Q9Y3L3 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.381 SIGNOR-260514 SATB2 protein Q9UPW6 UNIPROT IGHM protein P01871 UNIPROT up-regulates quantity transcriptional regulation 9606 14701874 YES gianni The SATB2 protein was shown to bind MAR sequences flanking the enhancer of the endogenous immunoglobulin μ heavy chain (IgH) gene in vivo, and this binding was found to correlate with an increase in the expression of a transfected rearranged μ wild-type gene 0.2 SIGNOR-268933 PFK proteinfamily SIGNOR-PF79 SIGNOR β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266470 SH3RF1 protein Q7Z6J0 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 12514131 YES gcesareni We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2. 0.33 SIGNOR-96955 CCL3 protein P10147 UNIPROT CCR1 protein P32246 UNIPROT up-regulates activity binding 9606 20219869 YES areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.  0.71 SIGNOR-255114 NTRK2 protein Q16620 UNIPROT FYN protein P06241 UNIPROT up-regulates binding 9606 BTO:0000938 9648856 YES gcesareni All these data suggest the involvement of fyn in the neurotrophin signal transduction pathways downstream of trkb. We investigated whether fyn is involved in the trk-dependent signal transduction pathways of neurotrophin. The fyn-src homology domain 2 (sh2) was observed to associate in vitro with the intracellular domain of trkb (icd-trkb). 0.382 SIGNOR-58424 PLK1 protein P53350 UNIPROT ATXN10 protein Q9UBB4 UNIPROT down-regulates phosphorylation Ser77 QVENLASsLQLITEC 9606 21857149 YES lperfetto Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis 0.353 SIGNOR-176122 DVL1 protein O14640 UNIPROT JUN protein P05412 UNIPROT up-regulates binding 9606 BTO:0000007 18347071 YES gcesareni In this study, we discovered two novel interactions between dvl and c-jun and between dvl and beta-catenin in the nucleus that mediate the formation of a dvlc-junbeta-catenintcf functional complex. 0.459 SIGNOR-178038 Caspase 3 complex complex SIGNOR-C221 SIGNOR IL18 protein Q14116 UNIPROT up-regulates activity cleavage Asp71 PLFEDMTdSDCRDNA 9606 BTO:0001370 9334240 YES lperfetto We also found two precursor hIL-18 (prohIL-18)-processing activities in the cytosol of THP.1 cells. These activities were blocked separately by the caspase inhibitors Ac-YVAD-CHO and Ac-DEVD-CHO. Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products. 0.484 SIGNOR-256378 NFKB1 protein P19838 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 NO gcesareni Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2 0.41 SIGNOR-59948 RPS6KA1 protein Q15418 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 BTO:0000848 15024089 YES gcesareni We show that the n-terminal kinase domain of rsk phosphorylates flna on ser(2152) in response to mitogens 0.383 SIGNOR-123458 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11486031 YES lperfetto Using this inducible system, we show that Notchic activates transcription of the cyclin D1 gene with rapid kinetics. 0.61 SIGNOR-209753 TPH2 protein Q8IWU9 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI down-regulates quantity chemical modification 9606 31024440 YES brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. 0.8 SIGNOR-264011 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii 0.777 SIGNOR-203520 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.91 SIGNOR-252524 MMP19 protein Q99542 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272363 CHUK protein O15111 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity phosphorylation 9606 26516792 YES miannu Indeed, IKKa and IKKb may directly repress RIPK1 kinase activity by addition of an inhibitory phosphate group on RIPK1.|Mass spectrometry analysis of kinase assays performed with recombinant proteins allowed us to identify Ser166, Ser331, and Ser416 as highly conserved RIPK1 residues phosphorylated by IKKa and IKKb. 0.539 SIGNOR-278927 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates 10090 10564272 NO lperfetto We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 0.642 SIGNOR-235622 H3C1 protein P68431 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 YES miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. 0.2 SIGNOR-263711 REL protein Q04864 UNIPROT CSRP1 protein P21291 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14522018 NO We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter 0.2 SIGNOR-254063 CTNNA3 protein Q9UI47 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 YES miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 0.752 SIGNOR-265493 BCAR1 protein P56945 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 BTO:0000182 27447856 YES lperfetto One such SH2-domain containing protein is the p85 subunit of PI3K, as its docking with tyrosine-phosphorylated p130cas activates the p110alpha subunit| tyrosine-165 and tyrosine-128 on p130cas both are phosphorylated to a greater extent in parental versus paxillin Y88F mutan 0.562 SIGNOR-263980 RNF5 protein Q99942 UNIPROT JKAMP protein Q9P055 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 19269966 YES miannu RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97. 0.51 SIGNOR-271483 CDK1 protein P06493 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity phosphorylation Ser91 EGMGEEPsPFRGRSR 24677263 YES lperfetto CDK1-mediated Bcl-2 serine 70 phosphorylation enhances its pro-apoptotic function, whereas CDK1-mediated Bad serine 128 phosphorylation promotes apoptosis.  0.2 SIGNOR-267921 TSH complex SIGNOR-C412 SIGNOR TSHR protein P16473 UNIPROT up-regulates activity binding 9606 BTO:0001379 25905363 YES scontino The thyroid-stimulating hormone (TSH) receptor (TSHR) is a member of the glycoprotein hormone receptors (GPHRs), a sub-group of class A G protein-coupled receptors (GPCRs). TSHR and its ligand thyrotropin are of essential importance for growth and function of the thyroid gland. 0.577 SIGNOR-267048 imatinib chemical CHEBI:45783 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition 9606 22045730 YES Recently, imatinib, an inhibitor of several tyrosine kinases, including c-abl, c-kit and PDGFRs, was demonstrated to ameliorate dystrophic phenotypes in mdx mice by suppressing the phosphorylation of PDGFRa 0.8 SIGNOR-254378 SMARCA2 protein P51531 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.81 SIGNOR-270742 RIMBP3B protein A6NNM3 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.265 SIGNOR-264374 MTOR protein P42345 UNIPROT TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 22343943 YES Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity. 0.477 SIGNOR-255310 PTPRU protein Q92729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity dephosphorylation 9606 25337216 YES miannu Protein tyrosine phosphatase receptor U (PTPRU) has been shown to be a tumor suppressor in colon cancer by dephosphorylating \u03b2-catenin and reducing the activation of \u03b2-catenin signaling. 0.401 SIGNOR-277095 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 10669763 YES gcesareni The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-Œ± or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. 0.559 SIGNOR-74943 UMPS protein P11172 UNIPROT orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity chemical modification 9606 2912371 YES miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). 0.8 SIGNOR-267438 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Ser160 GVTKAISsPTVSRLT -1 17693641 YES miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. 0.403 SIGNOR-262931 NUP35 protein Q8NFH5 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.625 SIGNOR-262080 PIM proteinfamily SIGNOR-PF34 SIGNOR RPS19 protein P39019 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 16266891 YES gcesareni The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay. 0.2 SIGNOR-259412 EPHB6 protein O15197 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity binding 9606 BTO:0000093 25239188 YES miannu EphB6 is frequently silenced in invasive and metastatic cancers; however, its role in cancer progression is poorly understood. Here we show that EphB6 interacts with EphA2 and suppresses EphA2-mediated promotion of anoikis resistance in MCF7 breast cancer cells.  0.42 SIGNOR-273853 PIM2 protein Q9P1W9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 16146838 NO lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. 0.7 SIGNOR-256575 acetoacetyl-CoA smallmolecule CHEBI:15345 ChEBI (3S)-3-hydroxy-3-methylglutaryl-CoA(5-) smallmolecule CHEBI:43074 ChEBI up-regulates quantity precursor of 29597274 YES lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis 0.8 SIGNOR-267652 Autophagy phenotype SIGNOR-PH31 SIGNOR Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 32218723 NO lperfetto In many neurodegenerative conditions protein aggregation may occurs without specific GOF mutations in genes encoding aggregate-prone proteins. In these conditions protein aggregation is associated to the decline of cellular degradative functions, specifically of the autophagy-lysosomal pathway (ALP) (Figure 1). 0.7 SIGNOR-262269 CDK2 protein P24941 UNIPROT CDK7 protein P50613 UNIPROT up-regulates phosphorylation Thr170 GSPNRAYtHQVVTRW 9606 11113184 YES amattioni Threonine-170 of cdk7 is phosphorylated in vitro by cdk2. Full activation of cdk7 requires phorylation of a conserved threonine residue at position 170 in its own t loop. 0.57 SIGNOR-85013 FOXO proteinfamily SIGNOR-PF27 SIGNOR RBL2 protein Q08999 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000944 11884591 YES gcesareni Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression. 0.2 SIGNOR-252934 FABP5 protein Q01469 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264459 PRKCQ protein Q04759 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser644 NLMFRKFsLERPFRP 9606 BTO:0000782 21157432 YES lperfetto NF-kappaB activation is triggered by PKCteta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCteta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCteta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. 0.774 SIGNOR-249193 barium(2+) chemical CHEBI:37136 ChEBI KCNJ13 protein O60928 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9620703 YES miannu Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations 0.8 SIGNOR-258925 ADP chemical CHEBI:16761 ChEBI AMPK complex SIGNOR-C15 SIGNOR up-regulates chemical activation 9606 21399626 YES lperfetto Amp binding to the gamma-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation.Adp also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive. 0.8 SIGNOR-217475 APC-c complex SIGNOR-C150 SIGNOR PHF8 protein Q9UPP1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23979597 YES miannu  We showed that PHF8 interacts with the CDC20-containing APC (APC(cdc20)) primarily during mitosis. we demonstrate that mutations of the LXPKXLF motif abrogate polyubiquitylation of PHF8 by the APC. APC substrates are typically cell cycle regulators, and consistent with this, the loss of PHF8 leads to prolonged G2 phase and defective mitosis. 0.306 SIGNOR-272881 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 10209155 YES gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 0.722 SIGNOR-67006 SMURF1 protein Q9HCE7 UNIPROT UVRAG protein Q9P2Y5 UNIPROT down-regulates activity ubiquitination Lys559 DTSLDFSkENKKKGE 9606 BTO:0000007 30686098 YES miannu Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux.  0.2 SIGNOR-273653 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr960 GHQKRIAySLLGLKD -1 21538645 YES gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates 0.659 SIGNOR-246023 MDM2 protein Q00987 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000038 26718225 YES miannu  Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase.  0.39 SIGNOR-277191 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1327 CCSPPPDyNSVVLYS 9606 9722576 YES lperfetto Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor. 0.2 SIGNOR-59758 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT up-regulates activity phosphorylation Tyr175 EITTNRFyGPQVNNI -1 16199863 YES Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation. 0.551 SIGNOR-251436 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 YES Luana AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites. 0.484 SIGNOR-21316 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr348 LPMDTEVyESPYADP 9606 BTO:0000776 9820500 YES lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 0.2 SIGNOR-246609 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 10090 18619954 NO We found that directed expression of MRFs in the neural tube of chicken embryos induced ectopic expression of miR-1 and miR-206. Conversely, the lack of Myf5 but not of MyoD resulted in a loss of miR-1 and miR-206 expression. 0.4 SIGNOR-255920 MLNR protein O43193 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256737 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates activity dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 16461343 YES In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22. 0.705 SIGNOR-248838 RPL18A protein Q02543 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.825 SIGNOR-262480 ELOVL2 protein Q9NXB9 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267890 DPF2 protein Q92785 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.586 SIGNOR-270719 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Platelet_morphogenesis phenotype SIGNOR-PH135 SIGNOR up-regulates 9606 BTO:0000132 27871158 NO lperfetto Each step in platelet shape change involves the participation of a variety of actin filament-related proteins that are highly concentrated in platelets (Fig. 1). In resting human platelets, the actin filaments from the core to the membrane skeleton are tightly bound to the plasma membrane by GP1b/IX-filamin A complexes  0.7 SIGNOR-261839 Glycogenin proteinfamily SIGNOR-PF95 SIGNOR α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR form complex binding 9606 22160680 YES miannu Glycogenin initiates the synthesis of a maltosaccharide chain covalently attached to itself on Tyr195 via a stepwise glucosylation reaction, priming glycogen synthesis.  0.2 SIGNOR-267922 SLBP protein Q14493 UNIPROT H2AC12 protein Q96KK5 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265402 MECP2 protein P51608 UNIPROT SGK1 protein O00141 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16002417 YES Luana These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress. 0.292 SIGNOR-264543 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr583 RRPPGLEyCYNPSHN 10116 BTO:0002809;BTO:0001009 8622701 YES lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 0.2 SIGNOR-236183 PIK3CA protein P42336 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 24647478 YES AKT is a serine-threonine protein kinase that plays important roles in cell growth, proliferation and apoptosis. It is activated after binding to phosphatidylinositol phosphates (PIPs) with phosphate s at positions 3, 4 and 3,4,5 on the inositol ring miannu Stimulation of tyrosine kinase receptors initiates a signaling cascade that activates pi3k. Activated pi3k uses pip2 to generate pip3, which recruit akt to the plasma membrane through its pleckstrin homology (ph) domain, permitting its activation by pdks. 0.8 SIGNOR-65409 ARHGEF25 protein Q86VW2 UNIPROT RAC1 protein P63000 UNIPROT up-regulates guanine nucleotide exchange factor 10090 16314529 YES gcesareni Exogenous expression of geft promotes myogenesis ofc2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process. 0.621 SIGNOR-236882 threonine smallmolecule CHEBI:26986 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264761 TCF4 protein P15884 UNIPROT SOX9 protein P48436 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15240568 NO The β-catenin–TCF4 complex activity is required for SOX9 expression. 0.392 SIGNOR-253323 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 YES Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. 0.96 SIGNOR-255839 AKT1 protein P31749 UNIPROT CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 YES llicata Furthermore, ha-tagged akt can phosphorylate gst-cct_ protein in vitro 0.2 SIGNOR-184922 PTPN11 protein Q06124 UNIPROT MPZL1 protein O95297 UNIPROT down-regulates dephosphorylation Tyr263 NKSESVVyADIRKN 9606 10681522 YES gcesareni In vitro, tyrosine-phosphorylated pzr was efficiently dephosphorylated by the full-length form of shp-2 but not by its sh2 domain-truncated form. The coexisting binding and dephosphorylation of pzr by shp-2 may function to terminate signal transduction initiated by pzr and shp-2 and to set a threshold for the signal transduction to be initiated. 0.522 SIGNOR-75220 DDX28 protein Q9NUL7 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 NO miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. 0.7 SIGNOR-261229 MSX1 protein P28360 UNIPROT DLX5 protein P56178 UNIPROT down-regulates activity binding 10090 BTO:0000946 9111364 YES 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. 0.39 SIGNOR-240987 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2C complex SIGNOR-C349 SIGNOR up-regulates activity chemical activation 9606 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate 0.8 SIGNOR-264130 AP3B1 protein O00203 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 YES lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) 0.91 SIGNOR-260681 GHSR protein Q92847 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.372 SIGNOR-257167 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI THBD protein P07204 UNIPROT up-regulates quantity by expression 9606 22406829 NO miannu In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells. 0.8 SIGNOR-255217 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser105 TGAGAAGsPAQQHAH 9606 BTO:0000567 26183396 YES miannu In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. 0.258 SIGNOR-276927 prostaglandin E2 smallmolecule CHEBI:15551 ChEBI GNG12 protein Q9UBI6 UNIPROT up-regulates chemical activation 9606 16293724 YES gcesareni Although pge2 promotes nucleotide exchange on gas and subsequent dissociation of gtp-bound gas from gbg subunits. 0.8 SIGNOR-141820 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Ser990 SRSTSVTsQISNGSH 9606 17396146 YES gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. 0.418 SIGNOR-154167 LAMA4 protein Q16363 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR form complex binding 10809728 YES lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 0.505 SIGNOR-253223 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 12167717 YES lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, 0.816 SIGNOR-244429 MAPK14 protein Q16539 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser567 SLAWLSDsPLFDLIK 9606 20871633 YES llicata P38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates rb on ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not cdks, triggers an interaction between rb and the human homolog of murine double minute 2 (hdm2), leading to degradation of rb, release of e2f1 and cell death. 0.538 SIGNOR-168178 PRKAA1 protein Q13131 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887 SIGNOR-C15 21565617 YES gcesareni We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases. 0.272 SIGNOR-173689 calcium(2+) smallmolecule CHEBI:29108 ChEBI INS protein P01308 UNIPROT up-regulates quantity relocalization 9606 BTO:0000783 24843404 YES miannu The increased Ca2+ concentrations eventually trigger fusion of insulin‐containing granules with the plasma membrane and insulin secretion from the β cells. Increased Ca2+ levels also promote transcription of the proinsulin gene, thereby increasing the insulin content of the β cell. Activation of EPAC2 has been shown to increase the density of insulin‐containing granules near the plasma membrane to potentiate insulin secretion from the β cell. 0.8 SIGNOR-278144 PTPN13 protein Q12923 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity dephosphorylation 9606 17638892 YES miannu Finally, we report that PTPL1 expression is sufficient to block the IRS-1/phosphatidylinositol 3-kinase/Akt signaling pathway, to inhibit the insulin-like growth factor-I effect on cell survival, and to induce apoptosis.|We first show by complementary approaches that PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1) in vitro and in cellulo. 0.467 SIGNOR-277053 LCK protein P06239 UNIPROT CD5 protein P06127 UNIPROT up-regulates activity phosphorylation Tyr487 DNSSDSDyDLHGAQR 9606 BTO:0000782 11298344 YES lperfetto Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck 0.542 SIGNOR-106803 FFAR4 protein Q5NUL3 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257246 CAMK2G protein Q13555 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 8663317 YES llicata Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site. 0.299 SIGNOR-250692 SREBF1 protein P36956 UNIPROT SND1 protein Q7KZF4 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29296233 YES irozzo These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. 0.2 SIGNOR-259137 NRAS protein P01111 UNIPROT RAF1 protein P04049 UNIPROT up-regulates relocalization 9606 21779497 YES Translocation from Cytosol to Membrane gcesareni The raf family of proteins (raf-1, a-raf, and b-raf) bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. 0.87 SIGNOR-175231 MYC protein P01106 UNIPROT HK2 protein P52789 UNIPROT up-regulates quantity transcriptional regulation 9606 17785433 YES Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. 0.37 SIGNOR-259986 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 21079800 YES gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.423 SIGNOR-169686 telmisartan chemical CHEBI:9434 ChEBI AGTR1 protein P30556 UNIPROT down-regulates activity chemical inhibition 9606 9878991 YES miannu Telmisartan is a nonpeptide angiotensin II receptor antagonist which selectively and insurmountably inhibits the angiotensin II AT1 receptor subtype without affecting other receptor systems involved in cardiovascular regulation. 0.8 SIGNOR-259072 MAPK1 protein P28482 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 19723873 YES gcesareni Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction. 0.715 SIGNOR-187798 VEGFD protein O43915 UNIPROT FLT4 protein P35916 UNIPROT up-regulates binding 9606 9435229 YES gcesareni Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors. 0.2 SIGNOR-55065 ESR2 protein Q92731 UNIPROT TGFA protein P01135 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 NO ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression 0.259 SIGNOR-253944 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser189 DEEFREPsTGKTCLP -1 19661060 YES miannu We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.2 SIGNOR-276233 ACOT8 protein O14734 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271809 CDK2 protein P24941 UNIPROT RAD54L protein Q92698 UNIPROT down-regulates activity phosphorylation Ser49 QIQECFLsPFRKPLS -1 29295984 YES miannu Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM. 0.347 SIGNOR-273599 atropine chemical CHEBI:16684 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258391 AKT proteinfamily SIGNOR-PF24 SIGNOR HTT protein P42858 UNIPROT unknown phosphorylation Ser419 GGRSRSGsIVELIAG 9606 BTO:0000938 12062094 YES llicata We demonstrate that huntingtin is a substrate of akt and that phosphorylation of huntingtin by akt is crucial to mediate the neuroprotective effects of igf-1. 0.2 SIGNOR-89696 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 22397367 YES lperfetto Ezrin, a member of the erm family of proteins, is frequently over-expressed in human breast cancers, and is required for motility and invasion of epithelial cells. In particular, ezrin phosphorylation on y477 by src is specific to ezrin within the erm family, and is required for hgf-induced scattering of epithelial cells. 0.647 SIGNOR-196443 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000782 25336630 YES miannu stimulations were performed in the presence or absence of Akt inhibitor VIII, which selectively inhibits Akt1/Akt2 activity. 0.8 SIGNOR-262227 KCNQ3 protein O43525 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 YES miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. 0.8 SIGNOR-265984 873837-23-1 chemical CID:46930994 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190467 IFNB1 protein P01574 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 11278538 YES gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.866 SIGNOR-104663 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN2D protein P55273 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17873901 NO gcesareni Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity 0.2 SIGNOR-252918 SH2B1 protein Q9NRF2 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 27154742 YES lperfetto The SH2B adaptor protein 1 (SH2B1) is a key regulator of leptin, as it enhances leptin signalling by both stimulating Janus kinase 2 (JAK2) activity and assembling a JAK2/IRS1/2 signalling complex 0.691 SIGNOR-253078 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser139 EDLTNVSsLLNMERA 9606 25670858 YES lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 0.587 SIGNOR-265233 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273080 ATF4 protein P18848 UNIPROT WARS2 protein Q9UGM6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.246 SIGNOR-269430 PRKG1 protein Q13976 UNIPROT SEPTIN3 protein Q9UH03 UNIPROT up-regulates activity phosphorylation Ser91 SQVSRKAsSWNREEK -1 15107017 YES miannu Mutation of Ser-91 to Ala in recombinant Sept3 also abolished PKG phosphorylation, confirming that Ser-91 is the major site in vitro. Therefore Sept3 is phosphorylated on Ser-91 in nerve terminals and its phosphorylation may contribute to the regulation of its subcellular localization in neurons. 0.2 SIGNOR-263183 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 27487822 YES miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. 0.8 SIGNOR-266265 MAML2 protein Q8IZL2 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12386158 NO gcesareni Similarly, maml1 and maml2 amplified notch ligand (both jagged2 and delta1)-induced transcription of the hes-1 gene, whereas maml3 displayed little effect. 0.404 SIGNOR-94276 alectinib chemical CHEBI:90936 ChEBI ALK protein Q9UM73 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190961 MAPK1 protein P28482 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 YES llicata We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro. 0.268 SIGNOR-203286 NCOR1 protein O75376 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18588516 NO miannu The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor). 0.354 SIGNOR-254229 AURKB protein Q96GD4 UNIPROT ATM protein Q13315 UNIPROT up-regulates phosphorylation Ser1403 CHKTKLKsILEILSK 9606 22099307 YES lperfetto Aurora-b mediated atm serine 1403 phosphorylation is required for mitotic atm activation and the spindle checkpoint 0.431 SIGNOR-177280 DUSP3 protein P51452 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation Tyr1221 SPAFDNLyYWDQDPP 9606 BTO:0002552 21262974 YES Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2. 0.268 SIGNOR-248534 HEY1 protein Q9Y5J3 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19917614 NO lperfetto Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis. 0.307 SIGNOR-235819 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189150 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192461 SEC24A protein O95486 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.716 SIGNOR-265295 PIM2 protein Q9P1W9 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 YES done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  0.2 SIGNOR-273896 CENPK protein Q9BS16 UNIPROT SOX6 protein P35712 UNIPROT up-regulates activity binding 10029 BTO:0000246 10996314 YES miannu Here we report the cloning of a novel cDNA, termed Solt, from a mouse testis cDNA library. Its gene product, Solt, interacts with the leucine zipper region of SoxLZ/Sox6. In transient transfection assays with SoxLZ/Sox6 containing the transactivation domain of herpes simplex virus VP16, the expression of a luciferase reporter gene under the control of a promoter containing a synthetic cis element that is bound by the HMG box of SoxLZ/Sox6 was poorly enhanced in the presence of Solt. 0.471 SIGNOR-221820 PPP2CB protein P62714 UNIPROT PRKCB protein P05771 UNIPROT down-regulates activity dephosphorylation Thr500 WDGVTTKtFCGTPDY 10116 8749392 YES Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. 0.469 SIGNOR-248585 FYN protein P06241 UNIPROT AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Tyr1038 ESWIRAKyEQLLFLA 9606 16841086 YES llicata We demonstrate that fyn is essential for phosphorylating pike-a and protects it from apoptotic cleavage. Active but not kinase-dead fyn interacts with pike-a and phosphorylates it on both y682 and y774 residues. Tyrosine phosphorylation in pike-a is required for its association with active fyn but not for akt. Mutation of d into a in pike-a protects it from caspase cleavage and promotes cell survival. 0.466 SIGNOR-147932 SH3GL3 protein Q99963 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 NO miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 0.7 SIGNOR-263884 HIC1 protein Q14526 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 19486893 NO miannu HIC1 is also implicated in growth control since it recruits BRG1, one of the two alternative ATPases (BRM or BRG1) of SWI/SNF chromatin-remodeling complexes to repress transcription of E2F1 in quiescent fibroblasts. 0.289 SIGNOR-254239 S1PR3 protein Q99500 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256790 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 12853467 YES 14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling. 0.653 SIGNOR-252575 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A2 protein Q05639 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. 0.703 SIGNOR-269388 WDR18 protein Q9BV38 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 YES miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. 0.871 SIGNOR-265471 SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 19701891 YES TGF-beta1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-beta1-induced-Treg generation from Smad3(-/-) mice is markedly reduced and abolished by inactivating Smad2 0.524 SIGNOR-254362 KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates quantity ubiquitination 9606 31257023 YES Keap1 is a substrate receptor of a Cul3-RING ubiquitin ligase (CRL3) that, in physiological conditions, constitutively binds and targets Nrf2 for degradation 0.813 SIGNOR-259335 ERBB2 protein P04626 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 14967450 YES gcesareni All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor 0.85 SIGNOR-121968 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser59 GDSCPHGsPQGPLAP 10090 12818176 YES miannu JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. 0.689 SIGNOR-250130 GSK3B protein P49841 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by destabilization phosphorylation Ser211 SSVKLRGsSLFMDTE -1 24817118 YES miannu Serine 211 phosphorylation occurred under control conditions in the absence of CK1δ and in the presence of GSK3-β (Fig. 5, D and E). 0.329 SIGNOR-276632 Caspase 9 complex complex SIGNOR-C229 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 YES lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. 0.638 SIGNOR-256448 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR CREB3L1 protein Q96BA8 UNIPROT up-regulates 9606 16417584 NO miannu Oasis (old astrocyte specifically induced substance) is an er stress transducer in astrocytes, a membrane-bound transcription factor that activates genes in the er stress response / when unfolded proteins accumulate in the er, oasis is cleaved at the membrane to release its cytoplasmic domain, which then enters the nucleus and activates target genes. 0.7 SIGNOR-143823 HRH4 protein Q9H3N8 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.515 SIGNOR-256672 SLC6A3 protein Q01959 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 YES miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. 0.8 SIGNOR-269196 2-N,6-N-Bis(2,3-dihydroxy-N-benzoyl)-L-serine amide chemical CHEBI:1219 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 YES miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. 0.8 SIGNOR-258436 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Thr143 RCFTRKYtLPPGVDP 9606 19593530 YES 11383510: to test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization 0.2 SIGNOR-186947 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity methylation 9606 12670868 YES miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. 0.2 SIGNOR-265349 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 YES The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. 0.85 SIGNOR-175809 MAPK3 protein P27361 UNIPROT TCF3 protein P15923 UNIPROT down-regulates quantity by destabilization phosphorylation Thr355 NFSSSPStPVGSPQG 10090 14592976 YES lperfetto Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG) 0.373 SIGNOR-249117 INHBA protein P08476 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates activity binding 9606 8622651 YES gcesareni Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. 0.787 SIGNOR-235142 TNF protein P01375 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.252 SIGNOR-253488 EEF1A1 protein P68104 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269506 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257985 CDK1 protein P06493 UNIPROT PML protein P29590 UNIPROT down-regulates phosphorylation 9606 21840486 YES gcesareni Here, we show that klhl20, a cullin3 (cul3) substrate adaptor induced by hif-1, coordinates with the actions of cdk1/2 and pin1 to mediate hypoxia-induced pml proteasomal degradation. 0.345 SIGNOR-176033 SREBF2 protein Q12772 UNIPROT SND1 protein Q7KZF4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29296233 YES irozzo These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression. 0.342 SIGNOR-259136 SAR1A protein Q9NR31 UNIPROT SEC24A protein O95486 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 YES lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 0.755 SIGNOR-265303 PAK1 protein Q13153 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 19667072 YES gcesareni We identify gef-h1 as a binding target and substrate for p21-activated kinase 1 (pak1), we show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules. 0.353 SIGNOR-187573 PRKCD protein Q05655 UNIPROT MEP1B protein Q16820 UNIPROT down-regulates quantity phosphorylation Ser687 KKYRERMsSNRPNLT 9534 BTO:0001538 12941954 YES miannu These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate. 0.307 SIGNOR-263171 VPS39 protein Q96JC1 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity relocalization 9534 12941698 YES miannu The data demonstrating binding of TLP to TGF-β and activin type II receptors and selective inhibition of Smad3/Smad4 complex formation by deregulated TLP suggest that TLP is involved in localizing these receptors and Smad4 to specific intracellular compartments, where it regulates formation of Smad3/Smad4 but not Smad2/Smad4 complexes. 0.318 SIGNOR-261377 MAPK12 protein P53778 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity phosphorylation Ser201 SGDSDASsPRSNCSD 10090 BTO:0005930 20026657 YES miannu  We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity. Phosphorylation of MyoD by p38-γ directs the assembly of a repressive transcriptional complex at the Myogenin promoter. 0.444 SIGNOR-276273 WWTR1 protein Q9GZV5 UNIPROT TEAD2 protein Q15562 UNIPROT up-regulates binding 9606 23431053 YES YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. 0.808 SIGNOR-201382 EGFR protein P00533 UNIPROT TRIP13 protein Q15645 UNIPROT up-regulates quantity phosphorylation Tyr56 HNIVFGDyTWTEFDE 9606 BTO:0000007 32860853 YES lperfetto Reciprocally, TRIP13 was phosphorylated at tyrosine(Y) 56 by EGFRvIII and EGF-activated EGFR. Abrogating TRIP13 Y56 phosphorylation dramatically attenuated TRIP13 expression-enhanced EGFR signaling and GBM cell growth. 0.2 SIGNOR-265083 NHS protein Q6T4R5 UNIPROT ABI2 protein Q9NYB9 UNIPROT up-regulates activity binding 9606 BTO:0000723 20332100 YES miannu NHS may preferentially bind one or more Abi's in vivo, and it is also likely that specificity is governed by spatiotemporal expression of both proteins. Abi2 is highly expressed in the lens and plays a pivotal role in the development of the anterior and posterior sutures. This suggests that an NHS–Abi2 interaction may be physiologically important for lens development and that null mutations in the NHS gene could cause congenital cataract by disruption of this interaction and the actin cytoskeleton. 0.2 SIGNOR-253579 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT up-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL -1 11171059 YES miannu EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499 0.306 SIGNOR-250354 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 BTO:0000567 19836242 YES We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173 0.491 SIGNOR-248697 HNF1B protein P35680 UNIPROT ALB protein P02768 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 1673926 NO Regulation miannu VHNF1 transactivated the albumin promoter in transfection experiments 0.292 SIGNOR-251930 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 8755651 YES scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3 0.8 SIGNOR-266950 TRIP11 protein Q15643 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 9256431 YES inferred from family member miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. 0.422 SIGNOR-267803 GSK3B protein P49841 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 17726008 YES gcesareni Here we show that similar to the interaction with traf4 and axin, the kinase domain of mekk4 interacts with the multifunctional serine/threonine kinase gsk3beta. Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways 0.291 SIGNOR-157544 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3). 0.8 SIGNOR-257853 bevacizumab antibody DB00112 DRUGBANK VEGFB protein P49765 UNIPROT down-regulates activity binding 9606 BTO:0001615 15961063 YES miannu Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. 0.4 SIGNOR-259885 GPR119 protein Q8TDV5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257153 MCL1 protein Q07820 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17289999 YES gcesareni Which of the multiple pro-survival proteins that can bind Bax (fig. S15A) can functionally restrain it? Mcl-1 must, because neutralizing Mcl-1 by enforced Noxa expression rendered MEFs containing only Bax (Bak KO cells) sensitive to the Bad BH3 mimetic ABT-737 (Fig. 4A), which inactivates Bcl-2, Bcl-xL, and Bcl-w 0.736 SIGNOR-151787 vadimezan chemical CHEBI:75934 ChEBI NQO1 protein P15559 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191397 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser136 ATNNLSRsNSDESNF 9606 BTO:0000007 16818229 YES miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. 0.772 SIGNOR-276290 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser321 SKPSGNDsCELRNLK -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276212 CTSH protein P09668 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 YES miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 0.283 SIGNOR-256324 CoREST-HDAC complex complex SIGNOR-C105 SIGNOR SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 16140033 NO lperfetto This suggests that the HDACs in the LSD1 complex are likely to function upstream of CoREST/LSD1, generating a hypoacetylated histone substrate, which can then be better recognized by CoREST/LSD1. Further supporting this model, we found that inhibition of HDAC activity by TSA resulted in derepression of two LSD1 target genes, the human neuronal-specific sodium channel (SCN) genes, SCNA2 and SCNA3 (Figure 1H). 0.273 SIGNOR-268541 Ub:E2 complex SIGNOR-C497 SIGNOR RNF34 protein Q969K3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271046 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24505269 YES miannu Recurrent gene fusion between the androgen-regulated gene TMPRSS2 and members of the ETS transcription factor family, most commonly ERG, are present in about 50% of prostate cancer cases. Presence of this fusion gene is a critical event in the development of prostate cancer. the more aggressive phenotype that arises with the presence of TMPRSS2-ERG at least in part is caused by changes in the tumor stroma. 0.576 SIGNOR-251545 FLT3 protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15574429 NO Expression of FLT3/ITD induces down-regulation of SHP-1 expression and activity 0.368 SIGNOR-261532 NMBR protein P28336 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 YES gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways. 0.25 SIGNOR-107028 HNF1A protein P20823 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8383844 NO miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators 0.311 SIGNOR-253834 MYT1L protein Q9UL68 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002572 28379941 YES miannu ChIP–seq experiments showed that 80% of Myt1l targets, including the transcription factor Hes1, were co-bound by the repressive Sin3b–HDAC1 complex early during reprogramming 0.2 SIGNOR-266775 USP37 protein Q86T82 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity binding 9606 BTO:0000007 21596315 YES lperfetto Here we show that USP37 binds the APC/C coactivator CDH1|Deubiquitinase USP37 is activated by CDK2 to antagonize APC(CDH1) and promote S phase entry 0.337 SIGNOR-265054 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 YES lperfetto Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. 0.507 SIGNOR-252906 EIF5 protein P55010 UNIPROT EIF5B protein O60841 UNIPROT up-regulates activity relocalization 9606 30211544 YES lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. 0.749 SIGNOR-269122 AKT proteinfamily SIGNOR-PF24 SIGNOR SH2B2 protein O14492 UNIPROT up-regulates activity phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 YES gcesareni This study identifies APS as a novel physiological substrate for PKB and the first serine phosphorylation site on APS 0.2 SIGNOR-248042 RCOR1 protein Q9UKL0 UNIPROT REST protein Q13127 UNIPROT up-regulates activity binding 9606 BTO:0000007 10449787 YES miannu We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity. 0.768 SIGNOR-220618 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Ser1403 AGREEFYsTHPHFMT 9606 BTO:0000938 19824698 YES lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. 0.2 SIGNOR-188429 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDCA5 protein Q96FF9 UNIPROT up-regulates activity phosphorylation Ser79 AVQSPRRsPRISFFL 9606 BTO:0000567 20551060 YES miannu Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy. 0.2 SIGNOR-262969 GTP smallmolecule CHEBI:15996 ChEBI Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 YES lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. 0.8 SIGNOR-269118 ABL1 protein P00519 UNIPROT RAPH1 protein Q70E73 UNIPROT up-regulates activity phosphorylation Tyr513 GKQLYMNyQEALKRT -1 20417104 YES miannu Here we show that phosphorylation of Lpd by c-Abl increases its interaction with Ena/VASP proteins. This analysis revealed that, in vitro, four Lpd peptides harboring tyrosines (Y426, Y456, Y513, Y1226) are highly phosphorylated, and eight additional peptides are phosphorylated to a lesser extent (Figure 1C). 0.285 SIGNOR-262608 ACLY protein P53396 UNIPROT citrate(3-) smallmolecule CHEBI:16947 ChEBI down-regulates quantity by destabilization chemical modification 9606 19286649 YES miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. 0.8 SIGNOR-267101 BCL10 protein O95999 UNIPROT CBM complex SIGNOR-C555 SIGNOR form complex binding 9606 15122200 YES miannu CARMA1, the adaptor protein BCL-10 (B-cell lymphoma 10) and the caspase-like protein MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) form a signalling complex that has a key role in antigen-receptor-mediated activation of the nuclear factor-κB (NF-κB) and JUN N-terminal kinase (JNK) pathways. 0.832 SIGNOR-276294 EXOC4 protein Q96A65 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.923 SIGNOR-270779 HDAC1 protein Q13547 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19417144 NO miannu We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275 but also by exogenous overexpression and small interfering RNA knockdown of specific HDACs. 0.261 SIGNOR-254227 GRPR protein P30550 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257421 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT down-regulates activity dephosphorylation Thr309 SDGATMKtFCGTPEY 10090 BTO:0000944 15367694 YES Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes 0.748 SIGNOR-248633 CDH11 protein P55287 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.653 SIGNOR-265851 SRC protein P12931 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Tyr732 YDRLVDEySLNAGKQ 9606 BTO:0002181 28054552 YES miannu Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation.  0.493 SIGNOR-277335 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 YES inferred from 70% family members gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.2 SIGNOR-270206 MAPK10 protein P53779 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 YES gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.744 SIGNOR-134533 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 18171681 YES llicata Plk1 phosphorylates ser(1337) and ser(1524) of topoiialpha plk1-associated phosphorylation is essential for the functions of topoiialpha in mitosis 0.481 SIGNOR-160237 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 12551925 YES gcesareni For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1. 0.557 SIGNOR-37844 irinotecan chemical CHEBI:80630 ChEBI TOP1MT protein Q969P6 UNIPROT down-regulates activity chemical inhibition 9606 15170677 YES miannu Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I) 0.8 SIGNOR-259315 HLTF protein Q14527 UNIPROT OCA2 protein Q04671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 22234890 NO miannu The SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression. 0.352 SIGNOR-254425 GARS1 protein P41250 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 YES miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. 0.8 SIGNOR-270804 MAPK1 protein P28482 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 YES We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction 0.627 SIGNOR-259920 ATM protein Q13315 UNIPROT UCHL3 protein P15374 UNIPROT up-regulates activity phosphorylation Ser75 EEEEKIKsQGQDVTS 27941124 YES lperfetto The deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. |Mutation of S75 (S75A) abolished the pSQ/TQ signal, suggesting that S75 is a major ATM phosphorylation site following DNA damage 0.331 SIGNOR-275910 MAPK9 protein P45984 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 YES gcesareni Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset. 0.377 SIGNOR-164093 INSR protein P06213 UNIPROT GYS1 protein P13807 UNIPROT up-regulates activity 9606 BTO:0000887;BTO:0001103 10909964 NO lperfetto In skeletal muscle, insulin activates glycogen synthase by reducing phosphorylation at both NH2- and COOH-terminal sites of the enzyme and by elevating the levels of glucose-6-phosphate, an allosteric activator of glycogen synthase. 0.366 SIGNOR-236803 DDX5 protein P17844 UNIPROT mir-10b mirna URS00004CAC40_9606 RNAcentral up-regulates quantity post transcriptional regulation 34936874 YES lperfetto Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. 0.4 SIGNOR-275660 CAMTA1 protein Q9Y6Y1 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0005397 21385898 NO irozzo Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma. 0.7 SIGNOR-259100 MAPK1 protein P28482 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates activity phosphorylation Thr906 SLDNNYStPNERGDH 9615 BTO:0000837 32010791 YES miannu  Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. 0.27 SIGNOR-277505 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr751 SKDESVDyVPMLDMK -1 7545675 YES Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides 0.69 SIGNOR-248414 Ub:E2 complex SIGNOR-C497 SIGNOR ANAPC11 protein Q9NYG5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271110 AKT proteinfamily SIGNOR-PF24 SIGNOR CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 YES lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta 0.2 SIGNOR-244210 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10593990 YES Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. lperfetto Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. 0.957 SIGNOR-217743 VCP protein P55072 UNIPROT UFD1 protein Q92890 UNIPROT up-regulates activity binding 9606 20442859 YES miannu These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes. 0.2 SIGNOR-252424 F2RL2 protein O00254 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257409 GRID1 protein Q9ULK0 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264951 VAV1 protein P15498 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 7809090 YES gcesareni Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation. 0.298 SIGNOR-33840 AT9283 chemical CID:11696609 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190017 Av/b1 integrin complex SIGNOR-C175 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.334 SIGNOR-253272 CD163 protein Q86VB7 UNIPROT hb:hp complex SIGNOR-C149 SIGNOR down-regulates quantity by destabilization binding 9606 11854029 YES miannu CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis. 0.744 SIGNOR-251823 PIAS3 protein Q9Y6X2 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 14691252 YES lperfetto We have further shown that PIAS3, Smad3, and p300 can form a ternary complex, which is significantly increased by TGF-_ treatment. Taken together, these results suggest that PIAS3 stimulates Smad transcriptional activity through formation of a complex with Smad proteins and p300/CBP. 0.596 SIGNOR-217725 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 SIGNOR-C16 12105215 YES gcesareni To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313 0.346 SIGNOR-90438 DPYD protein Q12882 UNIPROT thymine smallmolecule CHEBI:17821 ChEBI down-regulates quantity chemical modification 10499634 YES Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil. 0.8 SIGNOR-253989 SRC protein P12931 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15695828 YES llicata These data indicate that pyk2 activation via phosphorylation at tyr-402 requires ?V?3 Ligation and src activity. 0.623 SIGNOR-133870 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation 9606 12510059 YES inferred from 70% family members gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.2 SIGNOR-270132 NLK protein Q9UBE8 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000150 17563747 YES gcesareni Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna. 0.348 SIGNOR-155828 MMP27 protein Q9H306 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272394 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 BTO:0000938 12367505 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. 0.809 SIGNOR-94021 SKI protein P12755 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 BTO:0000848 12793438 YES lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway 0.727 SIGNOR-236077 CDK5R1 protein Q15078 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity binding 9606 BTO:0000938 10604467 YES Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular location and alters its substrate specificity. 0.943 SIGNOR-268153 RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates binding 9606 11130076 YES gcesareni Here we demonstrate that irsp53, a substrate for insulin receptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex. 0.739 SIGNOR-85302 RPS6KA5 protein O75582 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 BTO:0000975 11145955 YES gcesareni Phosphorylation on ser383 and ser389 of elk-1 by mapk enhances this basal binding but, most importantly, elk-1 exhibits new interactions with p300. 0.2 SIGNOR-85514 Daunorubicin hydrochloride chemical CHEBI:31456 ChEBI TOP2B protein Q02880 UNIPROT down-regulates activity chemical inhibition 9606 1963303 YES miannu DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives. 0.8 SIGNOR-259323 fulvestrant chemical CHEBI:31638 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000150 12113237 YES miannu Fulvestrant (Faslodex, formerly ICI 182,780) is a potent steroidal antiestrogen that mediates its effects by estrogen receptor downregulation. 0.8 SIGNOR-259305 TRPV4 protein Q9HBA0 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000443 23021218 NO lperfetto TRPV4 negatively regulated the expression of PGC1α, UCP1, and cellular respiration. Additionally, it potently controlled the expression of multiple proinflammatory genes involved in the development of insulin resistance. 0.2 SIGNOR-253095 BRCA2 protein P51587 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 YES lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  0.799 SIGNOR-263256 PRKDC protein P78527 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation 9606 25925375 YES miannu DNA-PKcs Promotes Plk1 Activation.|Further analysis revealed that DNA-PKcs could directly phosphorylate the C-terminal PBD domain of Plk1 (lane 8). 0.425 SIGNOR-279562 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.32 SIGNOR-161573 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Thr84 TVGGPAPtPLLPPSA 9606 12478298 YES lperfetto In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites 0.665 SIGNOR-96418 FBXO45 protein P0C2W1 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25460509 YES miannu One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. 0.358 SIGNOR-272181 STX10 protein O60499 UNIPROT LE-TGN SNARE complex SIGNOR-C157 SIGNOR form complex binding 9606 BTO:0000567 18195106 YES lperfetto We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport 0.762 SIGNOR-253080 CHFR protein Q96EP1 UNIPROT PLK1 protein P53350 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 17442268 YES miannu Chfr, a mitotic stress checkpoint, plays an important role in cell cycle progression, tumor suppression and the processes that require the E3 ubiquitin ligase activity mediated by the RING finger domain. Chfr stimulates the formation of polyubiquitin chains by ub-conjugating enzymes, and induces the proteasome-dependent degradation of a number of cellular proteins including Plk1 and Aurora A. 0.469 SIGNOR-271464 UBE2O protein Q9C0C9 UNIPROT SMAD6 protein O43541 UNIPROT down-regulates ubiquitination Lys173 LLLEQELkTVTYSLL 9606 23455153 YES gcesareni We showed that ube2o functions as an e2-e3 hybrid to monoubiquitinate smad6 at lysine 174 0.465 SIGNOR-192255 MEX3B protein Q6ZN04 UNIPROT SNUPN protein O95149 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 24326307 YES miannu HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation. 0.557 SIGNOR-272079 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 BTO:0000007 8565075 YES lperfetto The strong interaction between tradd and fadd occurs via their death domains. 0.78 SIGNOR-39951 IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 15489227 YES lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. 0.819 SIGNOR-216341 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates chemical inhibition 9606 19759537 YES gcesareni Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2. 0.8 SIGNOR-188057 TAOK1 protein Q7L7X3 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 YES gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. 0.369 SIGNOR-201324 ABL1 protein P00519 UNIPROT ATR protein Q13535 UNIPROT up-regulates phosphorylation Tyr291 DTDQLKLyEEPLSKL 9606 20798688 YES lperfetto C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress. 0.598 SIGNOR-167632 F2RL3 protein Q96RI0 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256915 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr833 EQCEYLSyDASQWEF 9606 20431062 YES lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. 0.511 SIGNOR-165051 BCOR protein Q6W2J9 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity binding 9606 10898795 YES miannu BCoR can interact w Because HDACs appear to be involved in repression by an increasing number of transcriptional repressors, we tested whether BCoR can associate with HDACs. BCoR can interact with HDAC1, HDAC3, and HDAC-B/5 more strongly than with HDAC-A/4, HDAC-C, HDAC-D, and HDAC-E. 0.313 SIGNOR-252237 MBD3/NuRD complex complex SIGNOR-C338 SIGNOR NOTCH2 protein Q04721 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000578 31659254 YES miannu Here we report that ZNF774, a novel zinc-finger protein, inhibits the proliferation and invasion of HCC cells. Molecular characterization of this protein indicated that ZNF774 acts as a transcription repressor, and interrogation of ZNF774 interactome by affinity purification-coupled mass spectrometry revealed that ZNF774 is physically associated with the Mi-2/nucleosome remodeling and deacetylase (NuRD) complex in cells. We demonstrated that ZNF774 recruits the NuRD complex to the NOTCH2 promoter and represses NOTCH2 transcription. 0.272 SIGNOR-265561 AGPAT3 protein Q9NRZ7 UNIPROT 1-acyl-sn-glycerol 3-phosphate(2-) smallmolecule CHEBI:57970 ChEBI down-regulates quantity chemical modification 9606 21173190 YES lperfetto The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬† 0.8 SIGNOR-267009 MYLIP protein Q8WY64 UNIPROT MYLIP protein Q8WY64 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0001976 14550572 YES miannu MIR contains, beside the ERM domain, a RING zinc finger region.  The present study shows that the ubiquitin ligase activity of the RING can also be directed towards the protein itself indicating that the degradation of MIR can be regulated by autoubiquitination. 0.2 SIGNOR-271480 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268579 1-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-2-methoxyphenyl)-3-(1-(thiazol-2-yl)ethyl)urea chemical CID:9869779 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258126 CDK1 protein P06493 UNIPROT VIM protein P08670 UNIPROT down-regulates phosphorylation Ser55 TSRSLYAsSPGGVYA 9606 7983050 YES llicata These results strongly suggest that cdc2 kinase is the kinase which phosphorylates vimentin ser55 in the entire cytoplasm during mitosis and that the appearance of immunoreactivities with antibody 4a4 in cell staining indeed reflect the vimentin phosphorylation by cdc2 kinase. immunofluorescent evidence using antibody 4a4 and biochemical analysis using vimentin ser55 peptide showed that the degree of disassembly of vimentin filament of various cell types at early mitotic phase correlated well with the amount of mitotically activated cdc2 kinase. 0.362 SIGNOR-35492 IDH2 protein P48735 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 29090344 YES miannu Two of the most commonly mutated genes in AML encode for two isoforms of isocitrate dehydrogenase (IDH), IDH1 and IDH2. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert √鬱-ketoglutarate (√鬱KG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple √鬱KG-dependent dioxygenases. 0.8 SIGNOR-253134 ALPK1 protein Q96QP1 UNIPROT TIFA protein Q96CG3 UNIPROT up-regulates activity phosphorylation Thr9 TSFEDADtEETVTCL -1 30111836 YES miannu Infection-induced activation of NF-κB and formation of eGFP–TIFA foci required ALPK1-dependent phosphorylation of TIFA at T9 (Extended Data Fig. 3a–e). Upon phosphorylation at T9, TIFA forms foci to activate TRAF6-dependent NF-κB signalling 0.248 SIGNOR-273543 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22469984 YES irozzo The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a 0.338 SIGNOR-256122 ABT-737 chemical CID:11228183 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates chemical inhibition 9606 17200714 YES gcesareni A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells. 0.8 SIGNOR-151790 CSNK1E protein P49674 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1430 LGYVPHPsSLSGSLP 9606 16513652 YES gcesareni We find that ckiepsilon binds to lrp5 and lrp6 in vitro and in vivo and identify three ckiepsilon-specific phosphorylation sites in lrp6. Two of the identified phosphorylation sites, ser1420 and ser1430, influence wnt signaling in vivo, 0.262 SIGNOR-145053 NRXN3 protein Q9HDB5 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626546 YES miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites 0.824 SIGNOR-265456 BMPR2 protein Q13873 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 7791754 YES gcesareni Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. 0.714 SIGNOR-33434 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 16476742 YES lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin 0.477 SIGNOR-144478 VAV1 protein P15498 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0001271 9209406 YES gcesareni Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7. 0.686 SIGNOR-49362 TFDP1 protein Q14186 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.512 SIGNOR-253862 FBN1 protein P35555 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity 9606 17242066 NO Regulation miannu Fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling. 0.365 SIGNOR-251889 PTPRJ protein Q12913 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 11259588 YES miannu Cd148 can dephosphorylate lat and plc?1 In vitro. / plc?1 Undergoes inducible tyrosine phosphorylation following tcr stimulation (46), and this phosphorylation is required to stimulate its catalytic activity 0.369 SIGNOR-105790 NuA4 complex complex SIGNOR-C459 SIGNOR Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity acetylation 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.2 SIGNOR-269287 TAF1B protein Q53T94 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 YES lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. 0.844 SIGNOR-269565 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Thr492 QDVGAFStVKGVAFD -1 1527025 YES The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase. 0.2 SIGNOR-251188 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Cys) smallmolecule CHEBI:29167 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269484 MAPK1 protein P28482 UNIPROT LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser362 PVHPKPLsPDSRASS 9606 BTO:0001033 23188829 YES miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. 0.2 SIGNOR-263054 CDK1 protein P06493 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates phosphorylation Ser728 VVKQEQLsPKKKENN 9606 SIGNOR-C17 22163316 YES gcesareni We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase. 0.368 SIGNOR-195233 IRF9 protein Q00978 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity binding 9606 BTO:0000567 9242679 YES lperfetto Coimmunoprecipitation assays demonstrate p48 association with STAT2 but not STAT1.The studies demonstrate the in vivo existence of a STAT2.p48 complex and a distinct STAT2.STAT1 complex after IFN-alpha stimulation. Data suggest that distinct bipartite complexes STAT2.p48 and STAT2.STAT1 translocate to the nucleus and associate on the DNA target site as ISGF3. 0.921 SIGNOR-217806 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.34 SIGNOR-273152 CDK3 protein Q00526 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser106 PLNSVSPsPLMLLHP 26202215 YES lperfetto CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3 0.259 SIGNOR-273188 PAK3 protein O75914 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser744 GLKVGVSsRINEWLT 9606 BTO:0000887;BTO:0001260 20858431 YES gcesareni We investigated the effects of phosphorylation by p(21)-activated kinase 3 (pak) and calmodulin on the 22 kda c-terminal fragment of caldesmon (cad22). We substituted the major pak sites, ser-672 and ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. Phosphorylation at these sites weakened ca(2+)-calmodulin binding further and reduced the inhibitory activity of cad22 in the absence of ca(2+)-calmodulin. 0.2 SIGNOR-167980 CAMKK1 protein Q8N5S9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10833263 YES llicata Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway. 0.38 SIGNOR-252609 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT up-regulates activity phosphorylation Ser83 QHDDGRVsYPLCFIF -1 9030586 YES miannu Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82. 0.307 SIGNOR-249983 PTK2 protein Q05397 UNIPROT ATP2B4 protein P23634-6 UNIPROT up-regulates activity phosphorylation Tyr1176 LDGEVTPyANTNNNA 9606 12540962 YES miannu Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif. 0.2 SIGNOR-263194 superoxide smallmolecule CHEBI:18421 ChEBI SOD2 protein P04179 UNIPROT up-regulates activity precursor of 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272284 CTLA4 protein P16410 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 26086965 NO Barakat Both PD-1 and CTLA-4 inhibited the activity of Akt, a crucial molecular in regulating glucose metabolism of T cells by elevating glucose transporter 1 expression and glycolysis, suggesting that glucose metabolism may contribute to T-cell exhaustion 0.7 SIGNOR-275415 PTPN1 protein P18031 UNIPROT NTRK2 protein Q16620 UNIPROT down-regulates activity dephosphorylation Tyr707 DVYSTDYyRVGGHTM 9606 26214522 YES Luana Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling 0.381 SIGNOR-264553 TP73 protein O15350 UNIPROT BBC3 protein Q96PG8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17700533 NO miannu Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. 0.472 SIGNOR-255467 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser293 FNTLAFPsMKRKDVV 9606 BTO:0000007 12496252 YES lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation 0.767 SIGNOR-96735 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDK9 protein P50750 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11689688 YES miannu Here we report that CDK9 is ubiquitinated and degraded by the proteasome whereas cyclin T1 is stable. SCF(SKP2) was recruited to CDK9/cyclin T1 via cyclin T1 in an interaction requiring its PEST domain. CDK9 ubiquitination was modulated by cyclin T1 and p45(SKP2).  0.349 SIGNOR-272666 CAMK2G protein Q13555 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1070 DSFLQRYsSDPTGAL BTO:0000017 1309762 YES llicata The mechanism of desensitization of kinase activity can be accounted for, in part, by the EGF-stimulated phosphorylation of the receptor at Ser1046/7, a substrate for the multifunctional calmodulin-dependent protein kinase II in vitro. Mutation of Ser1046/7 by replacement with Ala residues blocks desensitization of the EGF receptor protein-tyrosine kinase activity.  0.363 SIGNOR-250694 MAPK3 protein P27361 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser643 KILIASPsPTHIHKE 9606 BTO:0000567 18519666 YES lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ 0.695 SIGNOR-178735 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR IFITMs proteinfamily SIGNOR-PF49 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 25599080 NO miannu The IFITM (interferon-induced transmembrane) proteins comprise a family of interferon-induced antiviral cell-intrinsic restriction factors with high constitutive expression in many cells, including barrier epithelial cells. As their names imply, the expression of human IFITM1, IFITM2, and IFITM3 is also strongly upregulated by both type I and type II interferons 0.2 SIGNOR-260220 CAPN1 protein P07384 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Phe59 GVTVETVfSVDEFSA -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.298 SIGNOR-263580 ELK1 protein P19419 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001861 19757157 YES lperfetto Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level. 0.2 SIGNOR-254096 SPI1 protein P17947 UNIPROT B-Lymphocyte_diff phenotype SIGNOR-PH113 SIGNOR up-regulates activity 10090 10203717 NO PU.1 regulates the expression of several genes, including those encoding immunoglobulins, receptors and enzymes. The expression of these genes is crucial for macrophage and B-cell differentiation and for the functional activity of neutrophils. 0.7 SIGNOR-259955 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser574 NSNSCRSsTTTCPEQ 9606 BTO:0000007 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249303 DNMT1 protein P26358 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 23242655 NO Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells. 0.399 SIGNOR-254027 DOK1 protein Q99704 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.316 SIGNOR-257669 AURKB protein Q96GD4 UNIPROT HDAC9 protein Q9UKV0 UNIPROT down-regulates phosphorylation Ser239 QKVAERRsSPLLRRK 9606 22865920 YES lperfetto We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions 0.262 SIGNOR-198654 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2N protein P61088 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.855 SIGNOR-271320 GRIN1 protein Q05586 UNIPROT NMDA receptor_2A complex SIGNOR-C347 SIGNOR form complex binding 9606 BTO:0000938 12871085 YES miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits 0.726 SIGNOR-264120 CASP6 protein P55212 UNIPROT Caspase 6 complex complex SIGNOR-C228 SIGNOR form complex binding cleavage:Asp23 EENMTETdAFYKREM 21621544 YES lperfetto It is generally recognized that effector caspases undergo proteolytic cleavage of the inactive zymogen at a specific aspartate residue, resulting in a large N-terminal p20 polypeptide chain and a small C-terminal p10 polypeptide chain, leading to a p202/p102 tetramer. 0.2 SIGNOR-256391 AP-2 complex complex SIGNOR-C245 SIGNOR SYNJ1 protein O43426 UNIPROT up-regulates activity binding 10116 15496985 YES Giorgia Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs 0.519 SIGNOR-260396 SF3B2 protein Q13435 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.783 SIGNOR-270664 PKA proteinfamily SIGNOR-PF17 SIGNOR GNMT protein Q14749 UNIPROT unknown phosphorylation Ser10 DSVYRTRsLGVAAEG -1 12697024 YES miannu Activation of cAMP-dependent protein kinase by dibutyryl-cAMP, reported to cause GNMT phosphorylation under cell-free conditions, also had little effect on hepatocytic AdoMet and AdoHcy levels. Phosphorylation of GNMT would thus seem to play no role in regulation of the intracellular AdoMet/AdoHcy ratio, but could be involved in other GNMT functions, such as the binding of folates or aromatic hydrocarbons. The amino acid sequence surrounding Ser-10 (Val-Tyr-Arg-Thr-Arg-SerLeu-Gly-Val-Ala-Ala) could possibly qualify as a recognition site for AMPK as well as for PKA [32], the latter enzyme being capable of phosphorylating GNMT in intact hepatocytes (present study) as well as under cell-free conditions 0.2 SIGNOR-263151 PTK2B protein Q14289 UNIPROT SNCA protein P37840 UNIPROT unknown phosphorylation Tyr125 VDPDNEAyEMPSEEG 9534 BTO:0000298 12096713 YES lperfetto The present report demonstrates that the protein tyrosine kinase Pyk2/RAFTK is involved in cell stress-induced tyrosine phosphorylation of alpha S. Hyperosmotic stress induced tyrosine phosphorylation of alpha S via Pyk2/RAFTK at tyrosine residue 125. 0.316 SIGNOR-249151 TFEB protein P19484 UNIPROT FABP3 protein P05413 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 NO lperfetto On the contrary, proteins increasing the most included those degraded by autophagy (e.g., SQSTM1/p62 and GABARAPL2 0.2 SIGNOR-276790 TNF protein P01375 UNIPROT SCN3A protein Q9NY46 UNIPROT up-regulates activity 10090 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.2 SIGNOR-253494 MAPK1 protein P28482 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 YES lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.378 SIGNOR-217574 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK 10090 BTO:0000782 10037717 YES the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function 0.618 SIGNOR-251393 N-[3-[[5-bromo-4-[2-(1H-imidazol-5-yl)ethylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91357 ChEBI PDPK1 protein O15530 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190804 PI3K complex SIGNOR-C156 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 12167717 NO lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, 0.791 SIGNOR-252715 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120124 axitinib chemical CHEBI:66910 ChEBI PDGFRB protein P09619 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 YES gcesareni Inhibitors for fgf (azd4547), vegf, or pdgf receptors (axitinib), but not that for tgf receptor (ly364947), significantly decreased the abundance of (pcna) in endothelial cells. 0.8 SIGNOR-171869 THR proteinfamily SIGNOR-PF84 SIGNOR RARB protein P10826 UNIPROT up-regulates activity binding 9606 15650024 YES inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs 0.2 SIGNOR-267780 MAPK9 protein P45984 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 YES gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress. 0.256 SIGNOR-166698 BCL10 protein O95999 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14695475 NO Barakat The adaptor protein Bcl10 promotes activation of NF-κB transcription factors through paracaspase- and UBC13-dependent ubiquitination of NEMO. 0.525 SIGNOR-274145 PF-5274857 chemical CID:56956240 PUBCHEM SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206058 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser543 SLLSTLSsPGPKLDN 9606 BTO:0000093 15383283 YES miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. 0.525 SIGNOR-250104 PDPK1 protein O15530 UNIPROT PRKCE protein Q02156 UNIPROT up-regulates phosphorylation Thr566 LNGVTTTtFCGTPDY 9606 11964154 YES llicata In the present study, we analysed the contribution of the phosphoinositide-dependent kinase 1 (pdk-1) and pkcepsilon kinase activity in controlling the phosphorylation of thr(566) and ser(729). pdk-1 phosphorylation of the activation loop triggers autophosphorylation of the hydrophobic motif 0.572 SIGNOR-117320 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 YES milica Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by Casein Kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ 0.42 SIGNOR-201170 PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 19713933 YES lperfetto In addition, wip1 can dephosphorylate atm, as well as other components of the dna damage checkpoint, such as p38. 0.444 SIGNOR-187770 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RARB protein P10826 UNIPROT up-regulates activity chemical activation 9606 18321241 YES miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). 0.8 SIGNOR-259235 PRKAA1 protein Q13131 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser635 DTHFRSPsSSVGSPP 9606 SIGNOR-C15 19815529 YES llicata We show that ampk down-regulates rrna synthesis under glucose restriction by phosphorylating the rna polymerase i (pol i)-associated transcription factor tif-ia at a single serine residue (ser-635). 0.2 SIGNOR-188403 PAICS protein P22234 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 33179964 YES miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). 0.8 SIGNOR-267321 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser25 PCLIIEDsQPESQVL 9606 12697768 YES llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 0.873 SIGNOR-100641 CDK3 protein Q00526 UNIPROT CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser273 PGQGGSTsAFEQLQR 9534 11733001 YES miannu P70ik3-1 is phosphorylated by either cyclin A/cdk3 or cyclin E/cdk3 reconstituted in COS7 cells. Accordingly, we can conclude that in COS7 cells, Ser274 in p70ik3-1 is phosphorylated by endogenous kinases other than cdk5 (Fig. 4), at least one of which is cdk3 as shown in this work. Currently, however, the question of how ik3-1 function is modified by its cdk3-mediated phosphorylation of Ser274 remains to be adressed. 0.481 SIGNOR-250679 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 YES inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.2 SIGNOR-270213 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR methionine smallmolecule CHEBI:16811 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270397 indometacin chemical CHEBI:49662 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9057869 YES miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). 0.8 SIGNOR-258606 MAPK3 protein P27361 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 YES gcesareni Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation. 0.559 SIGNOR-74716 RUNX2 protein Q13950 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 NO Osteoblast-like cell lines lpetrilli In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast differentiation, including alkaline phosphatase, a1 and a2 collagen, osteopontin and osteoprotegerin ligand. 0.451 SIGNOR-107163 MEN1 protein O00255 UNIPROT MLL-ENL fusion protein SIGNOR-FP7 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 YES irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. 0.2 SIGNOR-255866 TAL1 protein P17542 UNIPROT UBE2H protein P62256 UNIPROT up-regulates quantity by expression transcriptional regulation 20028976 YES lperfetto Tal1 expression activated UBE2H expression, whereas Tal1 knock-down reduced UBE2H expression and ubiquitin transfer activity.|Binding of Tal1 to UBE2H was confirmed by chromatin immunoprecipitation. 0.326 SIGNOR-269000 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser567 DSSRFPMsPRPDSVH 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.632 SIGNOR-249462 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr487 SQKVVVTtPLHRDKT 9606 SIGNOR-C83 9840932 YES lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk2 0.718 SIGNOR-62361 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 12747827 YES lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. 0.755 SIGNOR-236690 STOML2 protein Q9UJZ1 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21746876 NO Giorgia We performed real-time RT-PCR to measure the levels of PGC-1alpha mRNA and found that these were increased in SLP-2hi cells (Fig. 3h), supporting the idea that upregulation of SLP-2 expression is associated with an increase in the expression of mitochondrially targeted genes. 0.2 SIGNOR-260379 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A10/b1 integrin complex SIGNOR-C167 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.446 SIGNOR-259021 CHUK protein O15111 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 10469655 YES lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). 0.797 SIGNOR-217397 WNK3 protein Q9BYP7 UNIPROT SLC12A4 protein Q9UP95 UNIPROT down-regulates activity phosphorylation 21613606 YES lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs 0.464 SIGNOR-264627 FHL1 protein Q13642 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 9418910 YES With differential splicing resulting in deletion of an exon, KyoT2 lacked two LIM domains from the C terminus and had a frameshift in the last exon, creating the RBP-J-binding region in the C terminus gcesareni It was demonstrated by emsa that kyot2 can form a complex with dna-bound rbp-j, but the dna-binding affinity of the kyot2rbp-j complex is greatly weakened and it exists mostly dissociated from dna 0.65 SIGNOR-54277 PPP3CA protein Q08209 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 YES CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). 0.266 SIGNOR-248677 HIPK2 protein Q9H2X6 UNIPROT MECP2 protein P51608 UNIPROT up-regulates activity phosphorylation Ser80 AVPEASAsPKQRRSI 9606 19820693 YES Luana Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo. 0.478 SIGNOR-264549 GNGT1 protein P63211 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 YES gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt 0.424 SIGNOR-252687 YME1L1 protein Q96TA2 UNIPROT OPA1 protein O60313 UNIPROT up-regulates activity cleavage 9606 BTO:0003298 29748581 YES Barakat YME1L cleaves OPA1 at S2 and S3 site to transform into L-OPA1 to induce fusion when cells are faced with increased oxidative phosphorylation, whereas OMA1 cleaves OPA1 at an S1 site to transform into S-OPA1, resulting in the fragmented response to cellular stress, mitochondrial dysfunction, or deletion of YME1L 0.455 SIGNOR-274140 PNCK protein Q6P2M8 UNIPROT EIF4G3 protein O43432 UNIPROT up-regulates phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 22514323 YES lperfetto Here we report that activity-dependent translational initiation in cultured rat hippocampal neurons is enhanced by camki-mediated phosphorylation of ser1156 in eukaryotic initiation factor eif4gii (4gii). 0.2 SIGNOR-197190 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 YES lperfetto Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. 0.405 SIGNOR-24778 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 YES inferred from 70% family members gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity. 0.2 SIGNOR-270115 PJA1 protein Q8NG27 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000165 28067271 YES Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2 0.489 SIGNOR-255664 GRB2 protein P62993 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 YES milica The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival 0.911 SIGNOR-204969 Fibrinolysis phenotype SIGNOR-PH6 SIGNOR Fibrin complex SIGNOR-C317 SIGNOR down-regulates 9606 BTO:0000131 1447176 NO lperfetto The fibrinolytic system is sequentially composed of plasminogen activation and fibrin degradation [1, 2]. Three distinct inhibitors of the fibrinolytic system that differently regulate these two steps are plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin (α2AP) and thrombin activatable fibrinolysis inhibitor (TAFI) [3]. PAI-1 limits the amount of free tissue-type plasminogen activator (tPA) both in plasma and on vascular endothelial cells (VECs), and regulates plasminogen activation potential to dissolve fibrin 0.7 SIGNOR-263532 GATA1 protein P15976 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 NO miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 0.502 SIGNOR-254430 tandutinib chemical CHEBI:90237 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258299 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269334 YAP1 protein P46937 UNIPROT FSTL3 protein O95633 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 NO gcesareni In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression. 0.2 SIGNOR-199072 S1PR1 protein P21453 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates 9606 9488656 NO gcesareni Edg-1 is known to activate the mitogen-activated protein (map) kinase known as extracellular signal-regulated kinase 2 (erk-2) through pertussis toxin (ptx)sensitive giprotein 0.503 SIGNOR-54770 Ub:E2 complex SIGNOR-C497 SIGNOR LONRF2 protein Q1L5Z9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271157 RNF19A protein Q9NV58 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT up-regulates quantity ubiquitination 9606 BTO:0000007 12750386 YES miannu Ubiquitylation of synphilin-1 by Dorfin. A, synphilin-1 is ubiquitylated in HEK293 cells. Several lines of evidence have suggested that derangements in the ubiquitin-proteasome protein degradation pathway may have a prominent role in the pathogenesis of PD (5). Our present study shows that Dorfin, an E3 ubiquityl ligase, is colocalized with ubiquitin in LBs of PD and physically binds to ubiquitylate synphilin-1, which is known to be a major component of LBs 0.453 SIGNOR-271455 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Ser358 EFCIPTSsNIEQQNS 9606 BTO:0000007 12123746 YES gcesareni These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells 0.2 SIGNOR-249661 COX4I1 protein P13073 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.752 SIGNOR-267744 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 YES lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps 0.735 SIGNOR-153420 AKT2 protein P31751 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000150 10576742 YES lperfetto Akt (protein kinase b), a member of a different signaling pathway that also regulates these responses, interacted with raf and phosphorylated this protein at a highly conserved serine residue in its regulatory domain in vivo. This phosphorylation of raf by akt inhibited activation of the raf-mek-erk signaling pathway and shifted the cellular response in a human breast cancer cell line from cell cycle arrest to proliferation. 0.45 SIGNOR-235678 CHFR protein Q96EP1 UNIPROT PARP1 protein P09874 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001109 23268447 YES miannu  Here, we show that checkpoint with Forkhead-associated (FHA) and RING finger domain protein (CHFR), an E3 ubiquitin ligase, is recruited to DSBs by poly(ADP-ribose) (PAR). Moreover, CHFR ubiquitinates PAR polymerase 1 (PARP1) and regulates chromatin-associated PARP1 in vivo.  Moreover, the poly-ubiquitin chain on PARP1 could be recognized by both anti-K48 and K63-linked poly-ubiquitin chain antibodies, suggesting that CHFR mediates a mixed poly-ubiquitin chain linkage on PARP1. With MG132 treatment, ubiquitinated PARP1 was significantly accumulated (Figure 4D), suggesting that the ubiquitination of PARP1 is likely involved in protein degradation. Consistently, we found that following DNA damage, PARP1 quickly dissociated from the chromatin in the wild-type cells (Figure 4F). However, in the Chfr−/− cells, the dissociation of PARP1 from the chromatin was significantly delayed. 0.428 SIGNOR-271470 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser363 LKNKTESsLLAKLEE -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276208 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr485 GGLSDGPySNPYENS 12441334 YES JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 0.811 SIGNOR-251353 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1034 AIETDKEyYTVKDDR 10090 11909529 YES The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP 0.766 SIGNOR-248395 GSK3B protein P49841 UNIPROT CEBPA protein P49715 UNIPROT up-regulates activity phosphorylation Thr230 GHPTPPPtPVPSPHP 10090 BTO:0000944 10567568 YES Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes. 0.38 SIGNOR-251232 UBR2 protein Q8IWV8 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 YES miannu The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells 0.531 SIGNOR-128214 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10085140 YES lperfetto On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38. 0.793 SIGNOR-65593 CSNK2A1 protein P68400 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser423 LNSGDDVsEQDVPDL -1 12107178 YES llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. 0.425 SIGNOR-250873 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 YES gcesareni Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling 0.624 SIGNOR-191673 CPI-0610 carboxylic acid chemical CID:67815062 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0004479 26815195 YES Monia Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610). 0.8 SIGNOR-261101 CSNK2A1 protein P68400 UNIPROT PTGES3 protein Q15185 UNIPROT up-regulates phosphorylation Ser113 WKDWEDDsDEDMSNF 9606 15040786 YES gcesareni Several lines of evidence suggest that a cpges-activating protein kinase is ck-ii (casein kinase ii). Recombinant cpges was phosphorylated directly by and associated with ck-ii in vitro, resulting in marked reduction of the k m for the substrate pgh2. 0.354 SIGNOR-123594 MYCT1 protein Q8N699 UNIPROT CCNE2 protein O96020 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 NO miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 0.2 SIGNOR-261733 TFEB protein P19484 UNIPROT ANKFY1 protein Q9P2R3 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) 0.2 SIGNOR-276782 NKX2-5 protein P52952 UNIPROT GATA4 protein P43694 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19479054 NO Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5. 0.849 SIGNOR-253654 dexamethasone chemical CHEBI:41879 ChEBI PPARG protein P37231 UNIPROT up-regulates quantity by expression 10090 11279134 NO lperfetto The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-235328 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Thr892 KPRYHKRtSSAVWNS 9606 12925766 YES gcesareni Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites. 0.974 SIGNOR-118019 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15143153 YES gcesareni These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling. 0.645 SIGNOR-124737 SRC protein P12931 UNIPROT PANX1 protein Q96RD7 UNIPROT up-regulates activity phosphorylation Tyr199 KYPIVEQyLKTKKNS 9606 BTO:0004578 30814251 YES miannu We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198 0.379 SIGNOR-277803 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Thr221 AGTSFMMtPYVVTRY 9606 15911620 YES lperfetto Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19). 0.58 SIGNOR-137609 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu69 EETCSYEeAFEALES -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263682 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 YES gcesareni Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro. 0.722 SIGNOR-134541 PLK4 protein O00444 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 9606 20531387 YES lperfetto Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap 0.798 SIGNOR-166007 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr589 SHDSEENyVPMNPNL 9606 BTO:0000018 10734310 YES miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. 0.673 SIGNOR-250288 PLK1 protein P53350 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates activity phosphorylation Ser330 ILKAFGNsTEKLDEE -1 26323689 YES done miannu Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D). 0.344 SIGNOR-274016 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide chemical CHEBI:95008 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207459 ERBB3 protein P21860 UNIPROT AR protein P10275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001130 15542423 NO gcesareni Suspected erbb receptor involvement in prostate cancer originates partly from the realization that these proteins are capable of promoting the transcriptional activity of the androgen receptor (ar), her2/her3 effects on ar included effects on protein stability and stimulation of dna binding to ar target genes. 0.506 SIGNOR-130443 SRC protein P12931 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Tyr89 GSLPEFYyRPPRPPK 9606 BTO:0000150 17254967 YES lperfetto Src regulates p27 stability through phosphorylation of p27 at tyrosine 74 and tyrosine 88. Our data indicate that phosphorylation by src impairs the cdk2 inhibitory action of p27 0.497 SIGNOR-152839 F2RL2 protein O00254 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-256761 RBCK1 protein Q9BYM8 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18711448 YES miannu Here we show that the E3 ubiquitin ligase RBCC protein interacting with PKC1 (RBCK1) catalyzes the ubiquitination and degradation of IRF3. We transfected 293 cells with expression plasmids for Flag-IRF3, HA-ubiquitin, and HA-RBCK1. Coimmunoprecipitation and western blot analysis indicated that RBCK1 significantly polyubiquitinated IRF3 (Figure 4D). 0.325 SIGNOR-271737 PIK3CA protein P42336 UNIPROT PI3K complex SIGNOR-C156 SIGNOR form complex binding 9606 19805105 YES miannu Phosphoinositol 3- kinase alpha (PI3Kα) is a heterodimeric enzyme formed by a catalytic subunit (p110α, encoded by PIK3CA) and one of several regulatory subunits (a major one being p85α, encoded by PI3KR1). 0.936 SIGNOR-255299 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr981 DNCSEEMyRLMLQCW 9606 14711813 YES lperfetto Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesthe results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity. 0.2 SIGNOR-121169 GLA protein P06280 UNIPROT 1,3-dichloro-7-hydroxy-9,9-dimethyl-9H-acridin-2-one smallmolecule CHEBI:52012 ChEBI up-regulates quantity by expression chemical modification -1 31996391 YES lperfetto DDAOG is cleaved by -galactosidase ( Lindvall et al., 2009 ) in the Trpv1 cells to produce 7-hydroxy-9H(I,3-dichloro-9,9-dimethylacridin-2-one (DDAO). 0.8 SIGNOR-261334 PPP2R5D protein Q14738 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 16239230 YES gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. 0.448 SIGNOR-243420 SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 9606 BTO:0000007 19212654 YES miannu The human WW45 protein enhances MST1-mediated apoptosis in vivo In this model, hWW45 binds both MST1 and LATS through its coiled-coil domains and WW domains, respectively, and facilitates the phosphorylation of LATS by MST1. This model could explain the enhanced apoptotic efficacy of MST1 with the over-expression of hWW45 and the attenuated MST1-induced apoptosis with the down-regulation of endogenous hWW45. 0.895 SIGNOR-263661 TFE3 protein P19532 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.283 SIGNOR-276816 CENPE protein Q02224 UNIPROT BUB1B protein O60566 UNIPROT up-regulates activity binding -1 12925705 YES miannu CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. 0.845 SIGNOR-266118 SRC protein P12931 UNIPROT CELF2 protein O95319 UNIPROT up-regulates activity phosphorylation Tyr63 LKELFEPyGAVYQIN -1 17855367 YES miannu Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA. 0.322 SIGNOR-263195 FOXO1 protein Q12778 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000165 15125842 YES The IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; 0.248 SIGNOR-256258 POLD4 protein Q9HCU8 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR form complex binding -1 12403614 YES lperfetto Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme. 0.877 SIGNOR-265517 Riluzole chemical CHEBI:8863 ChEBI KCNN1 protein Q92952 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 YES Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  0.8 SIGNOR-258021 phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI GSN protein P06396 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 12788695 YES lperfetto We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations. 0.8 SIGNOR-261841 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT up-regulates activity phosphorylation Tyr327 ETNSITVyASVTLPE 9534 BTO:0000298 11806999 YES All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. 0.657 SIGNOR-251183 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser172 LCLSPASsGSSASFI 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248511 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr607 NENTEDQySLVEDDE 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. 0.616 SIGNOR-252693 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser43 FGYQRRAsDDGKLTD 9534 BTO:0004055 12801936 YES miannu Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259). 0.499 SIGNOR-250039 PPP2CA protein P67775 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates dephosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 YES gcesareni Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. 0.403 SIGNOR-252974 zotepine chemical CHEBI:32316 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258550 MAPK14 protein Q16539 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 20626350 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni The p38 mapk pathway can positevely regulate nf-kb activity by different mechanisms, including chromatin remodelling through ser10 phosphorylation of histone h3 at nf-kb dependent promoters such as il-8 and mcp or by impinging on ikk or the p65 subunit in a direct or indirect manner. 0.2 SIGNOR-166602 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 BTO:0000007 11997495 YES lperfetto We have shown that the interaction of the bims and bimad isoforms with bax leads to a conformational change in this protein analogous to that triggered by the bh3-only protein bid.We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome. 0.832 SIGNOR-87280 CBP/p300 complex SIGNOR-C6 SIGNOR FLI1 protein Q01543 UNIPROT down-regulates acetylation 9606 21321929 YES lperfetto We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter. 0.291 SIGNOR-172109 Pentostatin chemical CID:439693 PUBCHEM ADA protein P00813 UNIPROT down-regulates activity chemical inhibition 9606 2433905 YES miannu 2'-Chloropentostatin is a new inhibitor of adenosine deaminase isolated from the fermentation broth of an unidentified actinomycete, ATCC 39365. It contains the aglycone of coformycin, i.e. 3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-o1, coupled to the unusual carbohydrate, 2'-chloro-2'-deoxyribose. 2'-Chloropentostatin is a slightly weaker inhibitor of rat and human adenosine deaminases than coformycin, and considerably weaker than pentostatin. Unlike pentostatin, which appears to undergo a two-stage interaction with adenosine deaminase, 2'-chloropentostatin forms a single enzyme-inhibitor complex. The enzyme-inhibitor complex between adenosine deaminase and 2'-chloropentostatin was much more rapidly dissociable than the complex with pentostatin. 0.8 SIGNOR-259261 CASP3 protein P42574 UNIPROT KDM4C protein Q9H3R0 UNIPROT down-regulates activity cleavage 9606 29207681 YES miannu JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels. 0.2 SIGNOR-263870 CDC20 protein Q12834 UNIPROT REV1 protein Q9UBZ9 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23287467 YES miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. 0.273 SIGNOR-272892 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.91 SIGNOR-252845 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT unknown phosphorylation Tyr857 DIMRDSNyISKGSTF 9606 2550144 YES llicata We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site. 0.2 SIGNOR-22997 GRIK2 protein Q13002 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264943 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 10394594 YES lperfetto The Ras protein sits at the center of a many-tiered cascade of molecular interactions. Most of the proteins along this cascade are activated by phosphorylation, but Ras uses a bound guanine nucleotide to toggle between its “on” and “off” states. Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off,” and a collection of GTPase-activating proteins (GAPs) speed up the processthe complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved. 0.848 SIGNOR-68990 IRF2BPL protein Q9H1B7 UNIPROT PDYN protein P01213 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 17627301 YES miannu EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function. 0.263 SIGNOR-267156 AKT2 protein P31751 UNIPROT SRSF5 protein Q13243 UNIPROT up-regulates activity phosphorylation Ser86 GRGRGRYsDRFSSRR 10116 15684423 YES miannu Here we show that Akt2 kinase phosphorylated SRp40 in vivo and in vitro. Mutation of Ser86 on SRp40 blocked in vitro phosphorylation. 0.362 SIGNOR-262633 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 YES Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif. gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). 0.743 SIGNOR-83721 SLC34A2 protein O95436 UNIPROT EGF protein P01133 UNIPROT down-regulates 9606 BTO:0000195 BTO:0000763 11171583 NO miannu In vivo and in vitro studies showed that egf treatment decreased intestinal napi-iib mrna abundance by _50%, suggesting possible transcriptional regulation. 0.352 SIGNOR-105161 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 7545671 YES gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase 0.595 SIGNOR-28796 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194919 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 YES gcesareni Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). 0.91 SIGNOR-252843 FGF14 protein Q92915 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.548 SIGNOR-253413 p38 proteinfamily SIGNOR-PF16 SIGNOR FOXC1 protein Q12948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser241 PSPPQPLsPAAALGS 31650548 YES lperfetto P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. 0.2 SIGNOR-275914 HSF2 protein Q03933 UNIPROT HSPA6 protein P17066 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12813038 NO miannu These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells. 0.339 SIGNOR-254478 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Thr274 SNYHQLGtPGTESCF -1 15014043 YES miannu We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of hum an RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. However, when both S2 and S11 were simultaneously mutated to As, the resulting 6His-RCC1S2,11A failed to be phosphorylated, whereas all of the other double mutants were phosphorylated (Fig. 1C). As expected, mutating all four sites to As (the 6His-RCC1S2,11,387A-T274A) also blocked phosphorylation (Fig. 1C). 0.505 SIGNOR-262704 FANCC protein Q00597 UNIPROT STAT1 protein P42224 UNIPROT up-regulates 9606 11520787 NO miannu Fancc is also required for optimal activation of stat1 in response to cytokine and growth factors 0.466 SIGNOR-110043 SH2B2 protein O14492 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 10029 BTO:0000977 10854852 YES lperfetto APS-mediated recruitment of c-Cbl to the insulin receptor led to rapid ubiquitination of the insulin receptor beta-subunit in CHO. T-APS but not in parental CHO.T cells. These results suggest that the function of APS is to facilitate coupling of the insulin receptor to c-Cbl in order to catalyse the ubiquitination of the receptor and initiation of internalisation or degradation. 0.646 SIGNOR-78337 DKC1 protein O60832 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 YES lperfetto Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity 0.814 SIGNOR-263332 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 21423276 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-172911 1-[2-[(diphenylmethylene)amino]oxyethyl]-3,6-dihydro-2H-pyridine-5-carboxylic acid chemical CHEBI:92744 ChEBI SLC6A1 protein P30531 UNIPROT down-regulates activity chemical inhibition -1 7851497 YES miannu Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. 0.8 SIGNOR-258479 CIC protein Q96RK0 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates activity binding 10090 BTO:0000142 32229723 YES miannu Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1-containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. CIC interacts with mSWI/SNF complex during neurogenesis. CIC tethers SIN3-HDAC corepressor complex and mSWI/SNF complex to VGF promoter during neurogenesis. 0.27 SIGNOR-269207 mTORC1 complex SIGNOR-C3 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000944 18372248 YES lperfetto We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competition. We also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1. 0.835 SIGNOR-235518 SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 21779497 YES lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. 0.779 SIGNOR-175259 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 24157836 YES miannu FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. To demonstrate that FBXL5 has a direct activity on Snail1, we carried out polyubiquitination reactions in vitro. For this we purified Snail1 and the SCFFBXL5 complex from Sf9 insect cells infected with different baculoviruses corresponding to Flag-FBXL5, His-Skp1, HA-Cullin1 and Rbx1 (Supplementary Figure S3C). 0.266 SIGNOR-272137 ZNF804A protein Q7Z570 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23434502 YES miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 0.2 SIGNOR-269467 AMPK complex SIGNOR-C15 SIGNOR HNF4A protein P41235 UNIPROT down-regulates phosphorylation Ser303 DPDAKGLsDPGKIKR 9606 12740371 YES lperfetto Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect 0.307 SIGNOR-216511 ATM protein Q13315 UNIPROT USP10 protein Q14694 UNIPROT up-regulates quantity by stabilization phosphorylation Thr42 SGTVLCGtQAVDKLP 9606 BTO:0001109 20096447 YES miannu The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337.  0.252 SIGNOR-276275 FZD6 protein O60353 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 YES amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. 0.677 SIGNOR-198828 HOTAIR ncrna URS000075C808_9606 RNAcentral MET protein P08581 UNIPROT down-regulates 9606 32650779 NO lperfetto LncRNA HOTAIR overexpression induced downregulation of c-Met signaling promotes hybrid epithelial/mesenchymal phenotype in hepatocellular carcinoma cells 0.2 SIGNOR-272090 LYN protein P07948 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.707 SIGNOR-268212 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 YES gcesareni This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses. 0.414 SIGNOR-191664 JUN protein P05412 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 10871633 YES irozzo These results indicate that interaction between Smad3 and c-Jun may repress Smad3 transcriptional activity. 0.75 SIGNOR-256284 KMN network complex SIGNOR-C366 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 18007590 NO lperfetto Based on our results, we propose that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis. 0.7 SIGNOR-265220 Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 YES gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. 0.828 SIGNOR-252323 CSNK2A1 protein P68400 UNIPROT IL16 protein Q14005 UNIPROT up-regulates activity phosphorylation Ser743 MPLQPNAsLNEEEGT -1 12450396 YES llicata We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation. 0.326 SIGNOR-250905 ADCYAP1 protein P18509 UNIPROT VIPR1 protein P32241 UNIPROT up-regulates binding 9606 11897681 YES gcesareni Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip). 0.813 SIGNOR-116066 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 phosphorylation:Thr187 NAGSVEQtPKKPGLR 10559916 YES lperfetto SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27|We conclude that the stable interaction of p27 with SKP2 is highly specific and dependent upon phosphorylation of p27 on T187. 0.694 SIGNOR-267557 MAPK1 protein P28482 UNIPROT UBAP2L protein Q14157 UNIPROT unknown phosphorylation Thr844 IPFPTPTtPLTGRDG 10090 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262774 WNT9B protein O14905 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.595 SIGNOR-132114 PPP6C protein O00743 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates dephosphorylation Thr187 CDIQTHMtNNKGSAA 9606 17079228 YES gcesareni Our results demonstrate that pp6 specifically down-regulates tak1 through dephosphorylation of thr-187 in the activation loop, which is likely important for suppressing inflammatory responses via tak1 signaling pathways. 0.372 SIGNOR-150408 ABL1 protein P00519 UNIPROT SORBS1 protein Q9BX66 UNIPROT up-regulates activity phosphorylation Tyr632 Y-->N 9606 19891780 YES miannu We have here identified Tyr360 in CAP as a major phosphorylation site by c-Abl, although Tyr 632 also might contribute since its substitution in combination with the Y360F mutation reduced the phosphorylation of CAP to a very low level. Y360 in CAP is the major phosphorylation site of c-Abl. Since Tyr326 was not a major c-Abl phosphorylation site, we sought to identify a putative other kinase that might be involved in the phosphorylation of Y326 in CAP. 0.425 SIGNOR-278154 WWTR1 protein Q9GZV5 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22470139 NO miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. 0.2 SIGNOR-255605 Laminin-1 complex SIGNOR-C183 SIGNOR a7/b1 integrin complex SIGNOR-C126 SIGNOR up-regulates activity binding 1839357 YES lperfetto By using specific proteolytically derived fragments of laminin, it was determined that the alpha 7 beta 1 complex binds selectively to the E8 region, which represents part of the long arm of laminin. 0.557 SIGNOR-253257 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Thr183 DTMAKRNtVIGTPFW 9534 BTO:0004055 12223493 YES lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity. 0.2 SIGNOR-247577 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI PTGER4 protein P35408 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257572 ADP chemical CHEBI:16761 ChEBI P2RY13 protein Q9BPV8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257561 PDGFRB protein P09619 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr155 LNDSAAYyLNDLDRI -1 33139573 YES miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. 0.2 SIGNOR-277232 REN protein P00797 UNIPROT ATP6AP2 protein O75787 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000142;BTO:0000671;BTO:0001260 12045255 YES gcesareni We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2 0.786 SIGNOR-88416 TBK1 protein Q9UHD2 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR up-regulates phosphorylation 9606 16888014 YES lperfetto The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel. 0.596 SIGNOR-217667 RBKS protein Q9H477 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 25749547 YES miannu Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds. 0.8 SIGNOR-267073 CBLB protein Q13191 UNIPROT PIK3R2 protein O00459 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000661 11087752 YES miannu Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. it can be postulated that Cbl-b, as an E3 Ub ligase, may play a general role in functional regulation of its target proteins through ubiquitination in a protein degradation-independent manner. 0.498 SIGNOR-271424 GXYLT2 protein A0PJZ3 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 22117070 YES Xylosylation in ER membrane. gcesareni Recently, we have shown (28) that two members of the human glycosyltransferase 8 family (gt8) (29), gxylt1 and gxylt2 (glucoside-xylosyltransferase 1/2), are able to transfer the first alfa1,3-linked xylose to o-glucosylated mammalian notch egf repeats. 0.383 SIGNOR-254314 AKT1 protein P31749 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 YES lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. 0.804 SIGNOR-252499 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 NO irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. 0.2 SIGNOR-255853 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203528 SMAD9 protein O15198 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR form complex binding 9606 20957627 YES lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. 0.684 SIGNOR-255268 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000887;BTO:0001260 14593115 YES gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. 0.652 SIGNOR-248066 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 YES gcesareni Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle 0.341 SIGNOR-237047 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 17535811 YES lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.772 SIGNOR-155242 ING3 protein Q9NXR8 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.678 SIGNOR-269294 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10090 BTO:0000944 11579209 YES lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. 0.788 SIGNOR-235495 CSNK2A1 protein P68400 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser106 DDIDLFGsDDEEESE -1 8547318 YES llicata EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent. 0.344 SIGNOR-250854 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser181 YQPRRRKsVKNGQAE 9606 15889150 YES llicata We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta. 0.464 SIGNOR-137085 CAMTA1 protein Q9Y6Y1 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0005397 21385898 NO irozzo Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma. 0.7 SIGNOR-259099 IKBKE protein Q14164 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 23691078 YES lperfetto Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation. 0.407 SIGNOR-202054 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation 10090 11163214 YES gcesareni Several experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity: c-Abl was hyperphosphorylated in PTP-PEST-deficient cells; disruption of the c-Abl-PSTPIP1-PEST-type PTP ternary complex by overexpression of PSTPIP1 mutants increased c-Abl phosphotyrosine content 0.439 SIGNOR-246222 CHUK protein O15111 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation Ser107 AGMGPHLsPSLSPLG 9606 22196886 YES lperfetto Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression 0.2 SIGNOR-195312 BTK protein Q06187 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr216 SSTSLAQyDSNSKKI 9606 12573241 YES lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. 0.335 SIGNOR-98028 MMP16 protein P51512 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272384 clozapine chemical CHEBI:3766 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 BTO:0000601 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258517 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr3 tSQKHRDF 9606 16495336 YES gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell 0.503 SIGNOR-144803 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Ser96 IEDLSQNsITGEHSQ 9606 24043619 YES Manara WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048.  0.445 SIGNOR-260911 RPS6KA4 protein O75676 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0001253 17429437 YES gcesareni Ser-343 and ser-196 are autophosphorylated by the c-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain. 0.2 SIGNOR-154324 PTPN6 protein P29350 UNIPROT IL2RB protein P14784 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 9520455 YES gcesareni We have found that il-2 induces association of shp-1 with the il-2 receptor complex, and that once shp-1 is recruited to the activated receptor it is able to decrease tyrosine phosphorylation of il-2rbeta and the associated tyrosine kinases jak1 and jak3. 0.53 SIGNOR-55989 IL6ST protein P40189 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 32234467 NO miannu Interleukin-6 (IL-6) is an important member of the cytokine network and plays a central role in acute inflammation. IL-6 binds to its receptor IL-6R to form a complex, and then binds to the membrane protein gp130 to initiate intracellular signal transduction. IL-6 is the terminal helper factor of cytotoxic T lymphocyte (CTL), which can induce CTL activity and make immature thymocytes develop into CTL. In addition, IL-6 is a pro-inflammatory regulator of T cells. 0.7 SIGNOR-261028 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. 0.91 SIGNOR-252852 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr970 GEGYKKKyQQVDEEF -1 19275932 YES miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  0.526 SIGNOR-276143 STAT3 protein P40763 UNIPROT PLK1 protein P53350 UNIPROT up-regulates quantity by expression transcriptional regulation 22108192 YES lperfetto Stat3 directly activated transcription of PLK1 in esophageal cancer cells and mouse embryonic fibroblast cell NIH3T3. 0.306 SIGNOR-271690 PRKCA protein P17252 UNIPROT GFPT1 protein Q06210 UNIPROT down-regulates activity phosphorylation Ser205 AVGTRRGsPLLIGVR -1 10806197 YES lperfetto Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMP-dependent protein kinase at serine 205 blocks the enzyme activity. 0.307 SIGNOR-249040 PRKCA protein P17252 UNIPROT NPHS1 protein O60500 UNIPROT up-regulates activity phosphorylation Thr1120 EYEESQWtGERDTQS 9606 BTO:0000007 21321125 YES llicata Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_. 0.2 SIGNOR-178695 TG101209 chemical CHEBI:90304 ChEBI JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207266 SETD2 protein Q9BYW2 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity trimethylation Lys37 APATGGVkKPHRYRP 9606 16118227 YES Gianni Our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD. 0.2 SIGNOR-269071 SELENOS protein Q9BQE4 UNIPROT VCP protein P55072 UNIPROT up-regulates activity binding 9606 BTO:0000567 15215856 YES miannu VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97. 0.2 SIGNOR-261371 CSNK1A1 protein P48729 UNIPROT CTPS2 protein Q9NRF8 UNIPROT down-regulates phosphorylation Ser568 LSSSDRYsDASDDSF 9606 20739275 YES gcesareni Hctps2 ser(568) was phosphorylated by casein kinase 1 both in vitro and in vivo. Mutation of ser(568) (s568a) significantly increased hctps2 activity, demonstrating that ser(568) is a major inhibitory phosphorylation site. 0.2 SIGNOR-167623 PIK3C3 protein Q8NEB9 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 10698680 NO acerquone Pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1) 0.435 SIGNOR-75376 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0002524 32989218 YES miannu  The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. 0.2 SIGNOR-277822 MAP4K2 protein Q12851 UNIPROT MAP4K2 protein Q12851 UNIPROT up-regulates activity phosphorylation Ser170 ASVAKRRsFIGTPYW 9606 BTO:0002524 37595580 YES miannu MAP4K2 is autophosphorylated at S170 for activation 0.2 SIGNOR-277826 GPRIN1 protein Q7Z2K8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 22956546 NO Luana  GAP-43 and G protein regulated inducer of neurite outgrowth 1 (Gprin1) in differentiating cells. 0.7 SIGNOR-265799 NFIB protein O00712 UNIPROT WNT5A protein P41221 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268883 metformin chemical CHEBI:6801 ChEBI NR0B2 protein Q15466 UNIPROT up-regulates quantity by expression 9606 17909097 NO gcesareni As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells 0.8 SIGNOR-158068 LYL1 protein P12980 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21261500 NO miannu TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C 0.337 SIGNOR-254208 PTPN5 protein P54829 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 BTO:0000938 23932588 YES A study conducted by Zhang et al. showed that STEP is significantly less efficient than PTPSL and HePTP at dephosphorylating p38a. gcesareni First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a. 0.489 SIGNOR-194829 PRKCA protein P17252 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates phosphorylation Ser462 TLFQTKNsVMRKLYG 9606 17463002 YES llicata These data indicated that protein kinase c phosphorylation at ser(462) stimulates human ctp synthetase 1 activity, whereas phosphorylation at thr(455) inhibits activity. 0.2 SIGNOR-154617 PEA15 protein Q15121 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates 9606 11702783 NO inferred from 70% of family members gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. 0.867 SIGNOR-269925 NVP-AEW541 chemical CID:11476171 PUBCHEM INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194895 CIITA protein P33076 UNIPROT HLA-DMB protein P28068 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 NO Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. 0.352 SIGNOR-254010 nafamostat chemical CHEBI:135466 ChEBI TMPRSS2 protein O15393 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002750 27550352 YES Monia Nafamostat also blocked MERS-CoV infection in vitro. This inhibition was most likely a result of inhibition of TMPRSS2 on the plasma membrane. Because MERS-CoV may infect cells via a TMPRSS2-independent endocytotic pathway, we evaluated the effects of nafamostat on MERS-CoV infection using an in vitro virus infection assay 0.8 SIGNOR-261065 PRKCD protein Q05655 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates phosphorylation Ser473 SGVKRSRsGEGEVSG 9606 18590578 YES gcesareni This work demonstrates that tif1beta is phosphorylated on ser473, the alteration of which is dynamically associated with cell cycle progression and functionally linked to transcriptional regulation. Phosphorylation of tif1beta/ser473 is mediated by the pkcdelta pathway and is closely linked to cell proliferation. Phosphorylation of tif1beta/ser473 coincides with the induction of cell cycle gene cyclin a2 at the s-phase. Promoter of cyclin a2 gene is occupied by tif1beta and such occupancy is inversely correlated with ser473 phosphorylation. Non-phosphorylated tif1beta/ser473 allowed greater tif1beta association with the regulatory regions and the consequent repression of these genes. 0.2 SIGNOR-179250 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0001253 15020233 YES lperfetto In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta. 0.2 SIGNOR-244780 MAP4K1 protein Q92918 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Ser281 WHKTTQMsAAGTYAW 9606 11053428 YES gcesareni Hpk1 also phosphorylated mlk-3 activation loop in vitro, and ser281 was found to be the major phosphorylation site, indicating that hpk1 also activates mlk-3 via phosphorylation of the kinase activation loop. 0.573 SIGNOR-83415 TP53 protein P04637 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 19007744 YES Cytosolic p53 lperfetto Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis 0.748 SIGNOR-99712 L-thyroxine smallmolecule CHEBI:18332 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 10116 BTO:0000759 2158622 YES inferred from 70% of family members miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. 0.8 SIGNOR-269881 CD82 protein P27701 UNIPROT Cell_invasion phenotype SIGNOR-PH226 SIGNOR down-regulates 9606 BTO:0002552 16488391 NO This result indicated that the enhanced expression of KAI1/CD82 in the H1299 cells was associated with a reduced invasive ability of the cancer cells. 0.7 SIGNOR-278113 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 11154281 YES lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. 0.794 SIGNOR-252987 ANK2 protein Q01484 UNIPROT DMD protein P11532 UNIPROT up-regulates quantity relocalization 10090 BTO:0001103 19109891 YES miannu We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4. 0.531 SIGNOR-266712 TLR4 protein O00206 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity 10090 16484370 NO Our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells 0.39 SIGNOR-256083 TAL1 protein P17542 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 NO miannu TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C 0.329 SIGNOR-254209 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 18245089 YES gcesareni Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. ... Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. 0.432 SIGNOR-160613 CREB1 protein P16220 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity binding 9606 15126506 YES lperfetto We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity 0.515 SIGNOR-252894 KLHL3 protein Q9UH77 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 23453970 YES miannu Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein. 0.657 SIGNOR-272106 IL21 protein Q9HBE4 UNIPROT IL21R protein Q9HBE5 UNIPROT up-regulates binding 9606 16424177 YES gcesareni Il-21 mediates its biological effects via the il-21r in conjunction with the common receptor gamma-chain that is also shared by members of the il-2 family 0.9 SIGNOR-143849 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 16552184 YES llicata Here, we report for the first time that cyclin dependent kinase 9, whose well-known substrate is rna polymerase ii, can also phosphorylate p53. Specifically, ser33 on the n-terminus and, ser315 and ser392 on the c-terminus of p53 were found to be phosphorylated. The precise biological role of this phosphorylation remains to be elucidated. 0.535 SIGNOR-145315 perfluorodecanoic acid chemical CHEBI:35546 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268770 TIMP3 protein P35625 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates activity 10090 BTO:0005300 28709001 NO Hh signaling through FAP cilia regulated the expression of TIMP3, a secreted metalloproteinase inhibitor, that inhibited MMP14 to block adipogenesis. A pharmacological mimetic of TIMP3 blocked the conversion of FAPs into adipocytes 0.7 SIGNOR-255906 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000132 SIGNOR-C2 21592956 YES lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. 0.929 SIGNOR-217869 RNF8 protein O76064 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 31225475 NO miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. 0.7 SIGNOR-266790 BRIP1 protein Q9BX63 UNIPROT BRCA1-B complex complex SIGNOR-C298 SIGNOR form complex binding 25400280 YES lperfetto Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation 0.674 SIGNOR-263219 RPL36A protein P83881 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.826 SIGNOR-262492 PPP2CA protein P67775 UNIPROT RPS3 protein P23396 UNIPROT down-regulates dephosphorylation Ser6 sKKRKFVA 9606 15950189 YES lperfetto We identified that pp2a interacts with wild-type rps3, but not with mutants (s6a/t221a) (fig. 8), and that it associates with the n-terminal region of rps3 (fig. 2). From our results presented here, we conclude that pp2a is involved in the dephosphorylation of phosphorylated rps3 by pkc, and that serine 6 on the n-terminal region of rps3 appears to mediate the pp2a recruitment. 0.425 SIGNOR-137963 BAX protein Q07812 UNIPROT VDAC1 protein P21796 UNIPROT up-regulates activity binding 10365962 YES lperfetto The recombinant pro-apoptotic proteins Bax and Bak accelerate the opening of VDAC 0.584 SIGNOR-249613 MOB1B protein Q7L9L4 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates binding 9606 21084559 YES Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. 0.921 SIGNOR-269865 CSNK2A1 protein P68400 UNIPROT SIRT1 protein Q96EB6 UNIPROT unknown phosphorylation Ser661 GAEVYSDsEDDVLSS 9606 19236849 YES llicata We demonstrate that sirt1 is a substrate for protein kinase ck2 both in vitro and in vivo. Both, deletion construct analyses and serine-to-alanine mutations identified sirt1 ser-659 and ser-661 as major ck2 phosphorylation sites that are phosphorylated in vivo as well. 0.635 SIGNOR-184155 MAPK14 protein Q16539 UNIPROT DLX5 protein P56178 UNIPROT up-regulates activity phosphorylation Ser34 MHHPSQEsPTLPESS 10090 18056716 YES ggiuliani We show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38 0.291 SIGNOR-255792 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TOB1 protein P50616 UNIPROT down-regulates phosphorylation 9606 12050114 YES inferred from 70% family members gcesareni Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation. 0.2 SIGNOR-270210 SEC61 complex complex SIGNOR-C368 SIGNOR HSPA5 protein P11021 UNIPROT up-regulates activity binding 33925740 YES lperfetto This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game 0.449 SIGNOR-265276 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251293 MSX2 protein P35548 UNIPROT DLX5 protein P56178 UNIPROT down-regulates activity binding 10090 BTO:0000947 9111364 YES 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. 0.57 SIGNOR-240990 TAOK1 protein Q7L7X3 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 YES gcesareni In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. 0.298 SIGNOR-201321 MOB1A protein Q9H8S9 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 YES Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1 0.866 SIGNOR-169755 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates dephosphorylation Thr32 QSRPRSCtWPLQRPE 9606 20110348 YES gcesareni Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. 0.403 SIGNOR-163684 IL1RAP protein Q9NPH3 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 12530978 YES gcesareni Here we report that the soluble form of the il-1 receptor accessory protein (acp) increases the affinity of binding of human il-1alpha and il-1beta to the soluble human type ii il-1 receptor by approximately 100-fold, 0.73 SIGNOR-97396 MAPK14 protein Q16539 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity 9606 BTO:0000887;BTO:0001103 15466486 NO lperfetto Here, we show that p38 activity facilitates myod and mef2 binding at a subset of late-activated promoters, and the binding of mef2d recruits pol ii. 0.483 SIGNOR-129702 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266449 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT unknown phosphorylation Thr417 SLPQATVtPPRKEER 9606 14551205 YES llicata In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. 0.49 SIGNOR-86696 AGRP protein O00253 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.441 SIGNOR-268699 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR NFY complex SIGNOR-C1 SIGNOR up-regulates activity binding 9606 BTO:0000972 18025157 YES We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. 0.2 SIGNOR-255747 ZAP70 protein P43403 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates activity phosphorylation Tyr614 KSTGSVDyLALDFQP 9606 BTO:0000782 11572860 YES lperfetto In the present study, we found that gab2 is phosphorylated by zap-70, associates with the tcr signaling complex, and acts as an inhibitory adaptor molecule via recruitment of shp-2 following tcr ligation. 0.461 SIGNOR-110731 FYN protein P06241 UNIPROT TRIO protein O75962 UNIPROT up-regulates activity phosphorylation Tyr2681 LLNPNYIyDVPPEFV -1 23230270 YES miannu Here, we demonstrate that Trio is phosphorylated by Src family kinases in the embryonic rat cortex in response to netrin-1. In vitro, Trio was predominantly phosphorylated at Tyr(2622) by the Src kinase Fyn. 0.2 SIGNOR-273855 SMC1A protein Q14683 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 YES lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin 0.883 SIGNOR-263313 MAP3K5 protein Q99683 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 YES lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. 0.612 SIGNOR-45353 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1784 TPTSPNYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248790 HMGA1 protein P17096 UNIPROT POU3F1 protein Q03052 UNIPROT up-regulates activity binding 9606 BTO:0002127 7791781 YES 2 miannu Direct contacts were identified between the POU domain of Tst-1/Oct-6 and a short stretch of 10 amino acids in the central portion of HMG-I/Y. In the presence of HMG-I/Y, Tst-1/Oct-6 exhibited an increased affinity for this AT-rich element. 0.307 SIGNOR-240155 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 9892110 YES lperfetto Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3. 0.612 SIGNOR-64085 PRKCA protein P17252 UNIPROT EIF4G1 protein Q04637 UNIPROT up-regulates activity phosphorylation Ser1185 RTPATKRsFSKEVEE 9606 BTO:0000007 21576361 YES miannu Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186.  0.258 SIGNOR-276327 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 14579029 YES gcesareni Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632 0.705 SIGNOR-118881 PTH1R protein Q03431 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 28363951 YES lperfetto This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11. 0.275 SIGNOR-270550 MED17 protein Q9NVC6 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.833 SIGNOR-266669 ARRB1 protein P49407 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates binding 9606 18497258 YES gcesareni Kif3a is essential for shh-mediated signaling in mammalian systems (5), and we identified kif3a as a arr1 binding partner in a proteomics screen (18). To test whether arrs, smo, and kif3a might work in concert. 0.549 SIGNOR-178672 8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid chemical CID:92577 PUBCHEM DUSP26 protein Q9BV47 UNIPROT down-regulates activity chemical inhibition -1 19233143 YES lperfetto Phosphatase activity of dual-specificity protein phosphatase 26 (DUSP26) was decreased by the inhibitor in a dose-dependent manner. Kinetic studies with NSC-87877 and DUSP26 revealed a competitive inhibition. 0.8 SIGNOR-261979 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity deubiquitination 9606 16027725 YES lperfetto Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases 0.378 SIGNOR-217610 RXRB protein P28702 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 1310351 YES inferred from 70% of family members gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.721 SIGNOR-269852 FBXO21 protein O94952 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding -1 26299618 YES miannu Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation.Purified in vitro translated FLAG-tagged P-gp along with E2 (UbcH5c), E3 ligase FBXO21, Cul1, Skp1, Roc1 purified from Sf-9 insect cells were incubated in vitro. 0.61 SIGNOR-272424 SMURF1 protein Q9HCE7 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 17317136 YES gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. 0.659 SIGNOR-153399 LFNG protein Q8NES3 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates glycosylation 9606 BTO:0000975 12486116 YES Fringe is a fucose-specific beta1,3-N-acetylglucosaminyltransferase that modifies O-fucose moieties on the epidermal growth factor-like (EGF) repeats of Notch. gcesareni We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1. 0.756 SIGNOR-96540 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser174 DKENGSVsSSETPPP 9606 BTO:0001938 11861906 YES llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. 0.38 SIGNOR-251068 CFL1 protein P23528 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR down-regulates 9606 16226035 NO miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. 0.7 SIGNOR-268382 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr228 HEGAVTHtFCGTIEY -1 11733037 YES miannu  Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities. 0.608 SIGNOR-250273 WWTR1 protein Q9GZV5 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23075495 NO gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. 0.7 SIGNOR-256668 ATR protein Q13535 UNIPROT KIFC1 protein Q9BW19 UNIPROT up-regulates quantity by stabilization phosphorylation Ser26 RPLIKAPsQLPLSGS 9606 BTO:0000815 33397932 YES miannu  ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro. 0.257 SIGNOR-277296 ZMYND8 protein Q9ULU4 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27477906 YES lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported 0.2 SIGNOR-262038 PHLPP1 protein O60346 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 YES gcesareni Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth. 0.759 SIGNOR-135005 MAPK1 protein P28482 UNIPROT PARVA protein Q9NVD7 UNIPROT up-regulates activity phosphorylation Ser8 MATSPQKsPSVPKSP 9606 BTO:0001938 22955285 YES lperfetto Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7). 0.26 SIGNOR-265759 CDK1 protein P06493 UNIPROT HMGA2 protein P52926 UNIPROT down-regulates phosphorylation Ser44 QEPTGEPsPKRPRGR 9606 10636877 YES lperfetto Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone. 0.375 SIGNOR-74094 FKBP15 protein Q5T1M5 UNIPROT WIPF1 protein O43516 UNIPROT up-regulates activity binding 9606 19121306 YES Giulio However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. 0.2 SIGNOR-260596 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.336 SIGNOR-262752 Aflibercept chemical SID:134445687 PUBCHEM VEGFA protein P15692 UNIPROT down-regulates activity chemical inhibition 9606 22813448 YES miannu Aflibercept, a fusion protein with binding domains from native VEGF receptors, binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity.This soluble decoy receptor is produced by fusing all-human DNA sequences of the second immunoglobulin (Ig) domain of human VEGF receptor (VEGFR) 1 to the third Ig domain of human VEGFR-2, which then is fused to the Fc region of human IgG-1.2 Aflibercept binds to all VEGF-A and VEGF-B isoforms, as well as the highly related placental growth factor. 0.8 SIGNOR-259386 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR tRNA(Phe) smallmolecule CHEBI:29184 ChEBI down-regulates quantity chemical modification 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.8 SIGNOR-270438 DKK1 protein O94907 UNIPROT KREMEN1 protein Q96MU8 UNIPROT up-regulates binding 9606 12050670 YES gcesareni Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/betBeta-catenin. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membrane. 0.838 SIGNOR-88838 MTOR protein P42345 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 YES Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. 0.538 SIGNOR-255841 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258739 CDC42 protein P60953 UNIPROT GSK3B protein P49841 UNIPROT down-regulates binding 9606 14657655 YES gcesareni Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent. 0.377 SIGNOR-119885 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr1128 VEEEMQStIREHRDG 9606 BTO:0000567 21818122 YES miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  0.428 SIGNOR-276244 USP6 protein P35125 UNIPROT MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20418905 NO miannu In this study we show that tre17 is sufficient to induce expression of mmp-9 and mmp-10, in a manner requiring its usp activity, but not its ability to bind arf6. Tre17 induces transcription of mmp-9 through activation of nuclear factor-kappab (nf-kappab), mediated in part by the gtpase rhoa and its effector kinase, rock. 0.327 SIGNOR-164946 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259707 RET protein P07949 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates binding 9606 8631863 YES gcesareni Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell 0.57 SIGNOR-41765 paliperidone chemical CHEBI:82978 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258564 HIF3A protein Q9Y2N7 UNIPROT EPAS1 protein Q99814 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000972 21479871 YES Luana None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2.  0.528 SIGNOR-261616 BTF3 protein P20290 UNIPROT HPSE2 protein Q8WWQ2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17312387 NO miannu BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. 0.2 SIGNOR-253765 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser185 WDSEDFGsPQKSCSP 9606 20864540 YES lperfetto Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability. 0.252 SIGNOR-168045 GPR17 protein Q13304 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256971 lapatinib chemical CHEBI:49603 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258234 AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser215 SGRAREAsGAPTSSK 9606 BTO:0000938 17470458 YES lperfetto The work presented here is the first demonstration that phosphorylation at s215 and s792 by akt regulates ligand binding, and the subcellular distribution of the receptor 0.2 SIGNOR-244140 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser831 SAEGSHTsGQSNGRD 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.369 SIGNOR-276508 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr447 SEELDENyVPMNPNS 9606 BTO:0000527;BTO:0000017 9890893 YES lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). 0.76 SIGNOR-236420 RNF146 protein Q9NTX7 UNIPROT TNKS protein O95271 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 YES We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. 0.722 SIGNOR-260004 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM46 protein Q7Z4K8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271182 JDP2 protein Q8WYK2 UNIPROT ATF2 protein P15336 UNIPROT down-regulates activity binding 9606 18671972 YES miannu JDP2 dimerizes with other AP-1 proteins such as activating transcription factor-2 (ATF2) and Jun to repress transcription from promoters that contain a cyclic AMP-responsive element (CRE). 0.556 SIGNOR-226395 DRD4 protein P21917 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.462 SIGNOR-256703 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0005014 27856324 YES irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. 0.2 SIGNOR-255882 4E2RCat chemical CID:2287236 PUBCHEM EIF4E protein P06730 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000414 21507972 YES miannu Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers. 0.8 SIGNOR-260187 FFAR4 protein Q5NUL3 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257045 MAK protein P20794 UNIPROT MAK protein P20794 UNIPROT up-regulates activity phosphorylation Tyr159 SQPPYTDyVSTRWYR 9606 21986944 YES Manara We conclude that dual phosphorylation on the TDY motif is crucial for MAK activity, and that the autokinase activity is required for this phosphorylation 0.2 SIGNOR-260780 ACVR1B protein P36896 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity phosphorylation Thr92 VDLTNEEtTDSTTSK 9606 BTO:0000007 18039968 YES miannu ALK4 phosphorylated TTRAP in vitro (Fig. 6A). The band migrating at the position of TTRAP was excised and analyzed by LC-MS/MS. One TTRAP peptide was phosphorylated either on T88 and T92, or on T92 only (Fig. 6B).We tested in vivo phosphorylation of Strep-TTRAP by co-expression with mouse Alk4 in HEK293T cells, and affinity-purified TTRAP. In this preparation TTRAP-specific peptides were reproducibly found in both the singly (T92) and doubly phosphorylated form (T88/T92). mutant TTRAPT88A,T92A is not able to rescue the TtrapMO phenotype, suggesting that phosphorylation of Ttrap on Thr88 and Thr92 is essential for Ttrap function. 0.28 SIGNOR-262612 FCER1G protein P30273 UNIPROT FCER1G/FCER1G complex SIGNOR-C199 SIGNOR form complex binding 9606 BTO:0000830 16470226 YES Alessandro Palma FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling. 0.2 SIGNOR-254961 HK1 protein P19367 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266455 BCL3 protein P20749 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates 9606 16713561 NO gcesareni The cyclin d1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of bcl-3-associated nf-kappab p50 and p52 0.572 SIGNOR-146771 CyclinE1/CDK3 complex SIGNOR-C546 SIGNOR LIN9 protein Q5TKA1 UNIPROT up-regulates activity phosphorylation Thr96 KFTATMStPDKKASQ 9606 BTO:0002181 24475316 YES lperfetto In this report, we demonstrate that cyclin e1/cdk3 phosphorylates lin-9 on thr-96. Mutating thr-96 to alanine inhibits activation of cyclins a2 and b1 promoters, whereas a phosphomimetic asp mutant strongly activates their promoters and triggers accelerated entry into g2/m phase in 293t cells. 0.416 SIGNOR-273184 ELL protein P55199 UNIPROT ELL/ICE1 complex SIGNOR-C48 SIGNOR form complex binding 9606 BTO:0001271 22195968 YES miannu The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes. 0.57 SIGNOR-193458 HES1 protein Q14469 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000931 11054669 NO miannu Our data show that functional sympathetic neuronal differentiation of neuroblastoma cells is associated with transient activation of HES-1 and down-regulation of HASH-1 expression. 0.441 SIGNOR-254824 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR PAX7 protein P23759 UNIPROT down-regulates quantity by repression transcriptional regulation 20887952 YES The results presented above demonstrate a signal-dependent interaction between p38a, YY1, and EZH2 on the chromatin of the Pax7 regulatory elements that coincides with p38-mediated repression of Pax7 at early stages of myoblast differentiation. 0.367 SIGNOR-253598 TNFRSF17 protein Q02223 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 10903733 NO miannu Bcma overexpression induces nf-kb activation 0.281 SIGNOR-79510 LRRK2 protein Q5S007 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19576176 YES lperfetto Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD. 0.625 SIGNOR-249690 ASXL3 protein Q9C0F0 UNIPROT NR1H3 protein Q13133 UNIPROT down-regulates activity binding 9606 BTO:0000972 25450400 YES miannu We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRα and TRβ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRα target genes through its recruitment to the LXR-response elements. 0.2 SIGNOR-266765 PHB2 protein Q99623 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 YES lperfetto Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation. 0.311 SIGNOR-235840 VCP protein P55072 UNIPROT NPLOC4 protein Q8TAT6 UNIPROT up-regulates activity binding 9606 20442859 YES miannu These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes. 0.946 SIGNOR-252423 SMURF2 protein Q9HAU4 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity ubiquitination 9606 18671942 YES miannu However, co-transfection of Smurf2, but not Smurf2-C/A, drastically increased the potential of TNF-R2 to induce JNK phosphorylation.|In conclusion, these results indicate that Smurf2 is able to ubiquitinate TNF-R2, which is further enhanced by the TRAF2-mediated targeting of Smurf2 to TNF-R2. 0.327 SIGNOR-278716 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 YES lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. 0.273 SIGNOR-198138 Gbeta proteinfamily SIGNOR-PF4 SIGNOR METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 BTO:0000007 33217317 YES inferred from 70% family members miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.2 SIGNOR-270035 CCND1 protein P24385 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103 20219869 NO apalma Importantly, NF-kB can promote the expression and stability of cyclin D1 in muscle (4, 35, 39, 132), leading to increased cell proliferation and inhibition of differentiation. 0.7 SIGNOR-255351 Terfenadine chemical CHEBI:9453 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition -1 19660947 YES Luana  hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7 0.8 SIGNOR-257826 CAMK1 protein Q14012 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser637 VPVARKLsAREQRDC 31063459 YES lperfetto For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission 0.333 SIGNOR-262552 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 10090 15367694 YES Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes 0.737 SIGNOR-248652 XAF1 protein Q6GPH4 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 17613533 YES gcesareni Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3. 0.559 SIGNOR-155637 ENG protein P17813 UNIPROT GDF2 protein Q9UK05 UNIPROT up-regulates activity binding 9606 BTO:0003767 21737454 YES miannu Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays. 0.749 SIGNOR-276656 AXIN1 protein O15169 UNIPROT RNF111 protein Q6ZNA4 UNIPROT up-regulates binding 9606 14657019 YES gcesareni Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia. 0.641 SIGNOR-119660 HOXA9 protein P31269 UNIPROT MSI2 protein Q96DH6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20805843 NO gcesareni Nup98-hoxa9 oncogene binds the putative element at 5.7 kb upstream of transcription start site to trigger the upregulated expression of musashi2 gene (b). The elevated level of musashi2 leads to the downregulation of numb, by binding to the 3' utr of numb mrna to inhibit translation 0.428 SIGNOR-167725 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates activity phosphorylation 9606 19620713 YES lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.679 SIGNOR-255260 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr763 DMKGDVKyADIESSN 9823 10391677 YES miannu Activation of the beta-receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2. 0.2 SIGNOR-250258 SEPTIN7 protein Q16181 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity binding 9606 BTO:0000567 18460473 YES lperfetto These findings reveal a key role for the SEPT7-CENP-E interaction in the distribution of CENP-E to the kinetochore and achieving chromosome alignment. We propose that SEPT7 forms a link between kinetochore distribution of CENP-E and the mitotic spindle checkpoint. 0.2 SIGNOR-252040 RIPK2 protein O43353 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates activity 9606 SIGNOR-C14 16493424 NO miannu In the case of NOD2, activation of RICK leads to K63 (Lys63)-linked polyubiquitylation of IKKgamma, the scaffold of the inhibitor of NF-kappaB (IkappaB)-kinase complex (the IKK complex), which also consists of IKKalpha and IKKbeta. This is followed by the phosphorylation of IKKbeta, as well as the phosphorylation of IkappaB and the release of nuclear factor-kappaB (NF-kappaB) for translocation to the nucleus. So, in activating the IKK complex, RICK either activates an E3 ubiquitin ligase that promotes K63-linked polyubiquitylation or inhibits an enzyme (such as cylindromatosis protein, CYLD) that de-ubiquitylates proteins that are modified with K63-linked polyubiquitin, so RICK does not require its own kinase activity for this function. 0.676 SIGNOR-252413 MDM2 protein Q00987 UNIPROT RB1 protein P06400 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15577944 YES miannu In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB 0.666 SIGNOR-278530 PLK2 protein Q9NYY3 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 19889641 YES lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. 0.248 SIGNOR-189049 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10116 14512875 YES lperfetto P38 mapk mediates fibrogenic signal through smad3 phosphorylation in rat myofibroblasts. the phosphorylation promoted hetero-complex formation and nuclear translocation of smad3 and smad4. 0.538 SIGNOR-236136 GATA1 protein P15976 UNIPROT GP9 protein P14770 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002581 15466856 NO miannu Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. 0.355 SIGNOR-254161 DUSP3 protein P51452 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation Tyr877 LDIDETEyHADGGKV 9606 BTO:0002552 21262974 YES Expression of VHR inhibited the activation of phospholipase Cγ and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. | We found that VHR decreased ErbB2 phosphorylation in vitro and in a cellular context, and the dephosphorylation of ErbB2 was more evident at Tyr-877 and Tyr-1221 than those at Tyr-1139 and Tyr-1248 (supplemental Fig. S1). Our data indicated that VHR was a cellular PTP against EGFR and ErbB2. 0.268 SIGNOR-248533 TFEB protein P19484 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 YES lperfetto We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α. 0.2 SIGNOR-276789 dothiepin chemical CHEBI:36798 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258697 GTF2A2 protein P52657 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding -1 8626665 YES lperfetto The general transcription factor IIA (TFIIA) binds to the TATA binding protein (TBP) and mediates transcriptional activation by distinct classes of activators. |Our results show that different activators utilize the general factor TFIIA in unique ways and that TFIIA contributes transcription activation functions in addition to the facilitation of TBP-DNA binding. 0.9 SIGNOR-262591 DAB2IP protein Q5VWQ8 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 27858941 NO miannu DAB2IP inactivation promotes tumor growth and survival, development, and proliferation of CSC, and resistance to chemo- and radiotherapy. It induces EMT, increases cell migration and invasion, and counteracts pro-apoptotic signaling. 0.7 SIGNOR-254779 SMARCC2 protein Q8TAQ2 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 YES miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. 0.87 SIGNOR-132936 KCNJ5 protein P48544 UNIPROT KCNJ5/KCNJ3 complex SIGNOR-C56 SIGNOR form complex binding 9606 BTO:0000562 22362083 YES miannu The muscarinic k(+) channel (i (k,ach)) is a heterotetramer composed of girk1 (kir3.1) andgirk4(kir3.4) subunits of a g protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart. 0.473 SIGNOR-196205 EP300 protein Q09472 UNIPROT XBP1 protein P17861-2 UNIPROT up-regulates quantity by stabilization acetylation 9606 BTO:0000007 20955178 YES miannu P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR. 0.285 SIGNOR-260429 UNC5 proteinfamily SIGNOR-PF98 SIGNOR Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 30108487 NO miannu Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion 0.7 SIGNOR-268177 PAX6 protein P26367 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19034419 NO miannu PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin. 0.334 SIGNOR-254900 CAMK1 protein Q14012 UNIPROT EIF4G3 protein O43432 UNIPROT unknown phosphorylation Ser1156 NTFMRGGsSKDLLDN 9606 14507913 YES llicata Endogenous eIF4GII immunoprecipitated from HEK293T cells was phosphorylated by CaMKI, in vitro as was a recombinant fragment of eIF4GII encompassing the central and C-terminal regions. The latter phosphorylation occurred with favorable kinetics (Km = 1 microm; kcat = 1.8 s-1) at a single site, Ser1156, located in a segment of eIF4GII aligning with the phosphoregion of eIF4GI. Phosphopeptide mapping and back phosphorylation experiments revealed [Ca2+]i-dependent, CaMKI site-specific, eIF4GII phosphorylation in vivo. 0.473 SIGNOR-250613 LYN protein P07948 UNIPROT PPP1R8 protein Q12972 UNIPROT down-regulates activity phosphorylation Tyr264 FAFSGGLyGGLPPTH -1 11104670 YES Tyrosine phosphorylation of NIPP1 by Lyn was abolished by the Tyr-264 to Asp mutation. 0.313 SIGNOR-251405 PAX5 protein Q02548 UNIPROT PRDM1 protein O75626 UNIPROT down-regulates quantity transcriptional regulation 10090 9120274 YES Gianni Overexpression of BSAP reduced Blimp-1 expression in CH12.LX.A2 clones but not in MPC11 clones. In addition, overexpression of BSAP in CH12.LX.A2 cells suppressed spontaneous appearance of cells with high Syndecan-1 expression and high amounts of intracytosolic as well as secreted Ig synthesi 0.502 SIGNOR-269085 H4C1 protein P62805 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 YES miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. 0.2 SIGNOR-263726 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270408 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.552 SIGNOR-89170 PITX2 protein Q99697 UNIPROT TBX1 protein O43435 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20129917 NO Regulation miannu Pitx2 activated Tbx4, Tbx15, and Mga and repressed Tbx1, Tbx2, Tbx5, and Tbx6 expression. 0.42 SIGNOR-251870 SF1 protein Q15637 UNIPROT FUS protein P35637 UNIPROT down-regulates binding 9606 9660765 YES miannu We speculate that zfm1 may inhibit transcription driven by the ntds of tls 0.559 SIGNOR-58967 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT down-regulates activity phosphorylation Ser693 LVGQLYKsSLLDDLL -1 23185298 YES miannu After identifying Ser693 as a GSK3beta phosphorylation site, we also determined that K679 is crucial for GSK3beta-binding, which strongly suggests that Drp1 is a novel substrate for GSK3beta. Our results suggest that GSK3beta-mediated phosphorylation at Ser693 does cause a dramatic decrease of GTPase activity; in contrast, GSK3beta-mediated phosphorylation at Ser693 appears not to affect Drp1 inter-/intra-molecular interactions. 0.389 SIGNOR-276430 VEGFA protein P15692 UNIPROT DLL4 protein Q9NR61 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22426001 NO gcesareni Activation triggered by vegf-a (also known as vegf) has been shown to induce expression of thenotchligand dll4 in angiogenic vessels. 0.473 SIGNOR-196736 DKK1 protein O94907 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 19874086 NO Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass. 0.733 SIGNOR-188961 ERG protein P11308 UNIPROT TDRD1 protein Q9BXT4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003215 23319146 NO miannu In the prostate cancer cell line VCaP, downregulation of ERG by shRNA lead to a lower expression level of TDRD1 and resulted in a decreased activity of the TDRD1 promoter. 0.2 SIGNOR-254067 IL3 protein P08700 UNIPROT IL3RA protein P26951 UNIPROT up-regulates binding 9606 1465408 YES fspada These results show the generation of an il-3 analog with increased biological and binding activities and support a model where the c terminus of il-3 interacts with the alpha chain of the il-3 receptor, making this region a useful focus for the development of more potent il-3 agonists or antagonists 0.887 SIGNOR-19538 MAP2K5 protein Q13163 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates phosphorylation 9606 11782488 YES gcesareni Kato et al. reported that mek5 specifically activates bmk1 but not other mammalian map kinasesin vivo. 0.702 SIGNOR-113770 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR TUBB protein P07437 UNIPROT up-regulates quantity by expression transcriptional regulation 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276583 DDX5 protein P17844 UNIPROT Microprocessor complex complex SIGNOR-C356 SIGNOR up-regulates activity binding 34936874 YES lperfetto Both the phosphorylation and sumoylation of DDX5 enhance the formation of a DDX5/Drosha/DGCR8 complex, thus promoting microRNA-10b processing. 0.723 SIGNOR-275659 GAPDHS protein O14556 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity chemical modification 9606 11724794 YES miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion 0.8 SIGNOR-266497 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM26 protein Q12899 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271086 AKT proteinfamily SIGNOR-PF24 SIGNOR STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr120 IIRLRNKtLTEDEIA 9606 19940129 YES llicata Akt interacts with mst1 and phosphorylates a highly conserved residue threonine 120 of mst1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of thr(183). 0.2 SIGNOR-161829 YY1 protein P25490 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates activity binding 9606 BTO:0000664 12913000 YES Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling. 0.622 SIGNOR-254305 LRRK2 protein Q5S007 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Ser75 LSMINTMsKIRGQEK 9606 22998870 YES gcesareni We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75. 0.472 SIGNOR-192072 FTH1 protein P02794 UNIPROT Ferritin complex SIGNOR-C563 SIGNOR form complex 9606 39534872 YES miannu Ferritin is a spherical protein complex composed of 24 subunits, which include two types: the heavy chain (FTH1) and the light chain (FTL). 0.603 SIGNOR-279859 AQP5 protein P55064 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR up-regulates activity binding phosphorylation:Ser156 STDSRRTsPVGSPAL 18583321 YES lperfetto We performed immunoprecipitation and western blotting analysis in transfected cell lines using CDK4 and cyclin D1 antibodies. As expected, cells transfected with AQP5 WT showed an increase of the CDK4/cyclin D1 complex, whereas cells transfected with vector did not|hAQP5 Increases Phosphorylation of Retinoblastoma Protein through Cyclin D1/CDK4 Complex 0.247 SIGNOR-272089 ARHGAP23 protein Q9P227 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.547 SIGNOR-260479 IFNAR complex SIGNOR-C243 SIGNOR JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 15120645 YES miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). 0.736 SIGNOR-260147 AURKB protein Q96GD4 UNIPROT CENPA protein P49450 UNIPROT unknown phosphorylation Ser7 sRKPEAPR 9606 BTO:0000567 11756469 YES llicata CENP-A–GST constructs were prepared in which Ser7 was mutated to alanine or glutamic acid. Phosphorylation of these proteins by Aurora B was reduced by 50%, demonstrating that Ser7 is a kinase substrate | Therefore, under the short term induction conditions used in these experiments, we can conclude that CENP-A Ser7 mutations do not grossly interfere with kinetochore formation, spindle assembly, or cell cycle progression. 0.822 SIGNOR-250585 BCR protein P11274 UNIPROT YWHAQ protein P27348 UNIPROT unknown phosphorylation Ser232 LTLWTSDsAGEECDA -1 16045749 YES llicata We show here that BCR interacts with at least five isoforms of 14-3-3 in vivo and phosphorylates 14-3-3tau on Ser233 and to a lesser extent 14-3-3zeta on Thr233 0.306 SIGNOR-250594 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 BTO:0000007 16582879 YES Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR 0.788 SIGNOR-248408 FOXO3 protein O43524 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR up-regulates quantity by expression transcriptional regulation 20978344 NO inferred from family member Forkhead box O3 (FoxO3) was identified as a key molecule inducing D2 expression and thereby increasing intracellular T3 production. Accordingly, FoxO3-depleted primary myoblasts also had a differentiation deficit that could be rescued by high levels of T3. 0.342 SIGNOR-270245 NGEF protein Q8N5V2 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.674 SIGNOR-260562 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser740 SFTALDWsWLQTEEE 9606 SIGNOR-C14 SIGNOR-C14 10195894 YES lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response 0.2 SIGNOR-236048 PI4K2A protein Q9BTU6 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser984 ALALCSGsFPTDKEE 9606 18082599 YES gcesareni These results indicate that plx1 phosphorylates claspin on s934, which is relatively close to the plx1-docking site at t906. Human claspin also contains a serine at position 984 in a homologous sequence 0.2 SIGNOR-159937 PPP2CA protein P67775 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12840032 YES gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). 0.646 SIGNOR-103162 crizotinib chemical CHEBI:64310 ChEBI ALK protein Q9UM73 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258101 AMPK complex SIGNOR-C15 SIGNOR HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 21892142 YES lperfetto Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) 0.312 SIGNOR-216596 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271812 ATF5 protein Q9Y2D1 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18332083 NO miannu We induced endoplasmic reticulum stress by means of amino acid limitation or selective chemicals, and assessed the time course response of ATF5 and CYP2B6. We found a post-transcriptional up-regulation of ATF5 and a parallel induction of CYP2B6 mRNA. 0.2 SIGNOR-253751 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser19 SHGSSACsQPHGSVT 9606 BTO:0000007 10973490 YES lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir 0.834 SIGNOR-81391 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 YES The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.614 SIGNOR-138965 USP5 protein P45974 UNIPROT UBB protein P0CG47 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.767 SIGNOR-270821 PKC proteinfamily SIGNOR-PF53 SIGNOR GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation -1 15894802 YES inferred from 70% family members lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.2 SIGNOR-269972 Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity binding 9606 BTO:0000427 9511957 YES miannu  Neurophysins I and II (NPI and NPII) serve in the neurosecretory granules of the posterior pituitary as carrier proteins for the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively, until the latter are released into blood.  0.2 SIGNOR-270351 ZRANB1 protein Q9UGI0 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000007 29748601 YES miannu Trabid inhibits Twist1 activity by cleaving RNF8-mediated Twist1 K63-linked ubiquitination 0.331 SIGNOR-273502 E2F1 protein Q01094 UNIPROT SERPINB5 protein P36952 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 20197383 NO lperfetto Importantly, we show that E2F1-mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization. 0.2 SIGNOR-254135 PRKAA1 protein Q13131 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates activity phosphorylation 9606 SIGNOR-C15 21892142 YES lperfetto Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation 0.36 SIGNOR-176497 CSNK1E protein P49674 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity phosphorylation Tyr116 EILALQIyCRNESRG 9606 BTO:0002181 32779804 YES miannu We found that the interaction of CK1ε with TRAF3Y116F, TRAF3Y446F were markedly decreased compared with interactions with WT TRAF3 by Co‐IP (Figure 6C); as expected, TRAF3Y116F and TRAF3Y446F mutants exhibited reduced K63‐linked ubiquitination (Figure 6D). These data suggest that the phosphorylation of TRAF3 at Tyr 116 and Tyr 446 regulate CK1ε‐induced K63‐linked ubiquitination. 0.307 SIGNOR-277525 SIRT7 protein Q9NRC8 UNIPROT DDB1 protein Q16531 UNIPROT down-regulates activity deacetylation 28886238 YES lperfetto Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction. 0.358 SIGNOR-275900 PRKAA1 protein Q13131 UNIPROT NOS2 protein P35228 UNIPROT down-regulates 9606 BTO:0000801 BTO:0000887 14985344 NO gcesareni Ampk by insulin-sensitizing drugs markedly inactivates in- ducible nitric-oxide synthase (inos). 0.32 SIGNOR-120827 HNF1A protein P20823 UNIPROT UGT1A10 protein Q9HAW8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 YES Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. 0.251 SIGNOR-253971 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR BRCA1 protein P38398 UNIPROT down-regulates phosphorylation Ser632 LVVSRNLsPPNCTEL 9606 BTO:0000150 17334399 YES lperfetto In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo. 0.579 SIGNOR-216984 vorinostat chemical CHEBI:45716 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257949 PRKAA2 protein P54646 UNIPROT HAS2 protein Q92819 UNIPROT down-regulates activity phosphorylation Thr110 LQSVKRLtYPGIKVV 9534 BTO:0000298 21228273 YES miannu We found that AMPK phosphorylated Thr-110 of human HAS2, which inhibits its enzymatic activity. 0.2 SIGNOR-276299 SKP2 protein Q13309 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 15314162 YES gcesareni We found that skp2, the f-box component of scfskp2, physically interacted with smad4 at the physiological levels. Several cancer-derived unstable mutants exhibited significantly increased binding to skp2, which led to their increased ubiquitination and accelerated proteolysis. These results suggest an important role for the scfskp2 complex in switching cancer mutants of smad4 to undergo polyubiquitination-dependent degradation. 0.398 SIGNOR-127964 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu47 RANSFLEeMKKGHLE -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263665 LSM-1231 chemical CHEBI:91471 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258237 L-thyroxine smallmolecule CHEBI:18332 ChEBI Thermogenesis phenotype SIGNOR-PH192 SIGNOR up-regulates 9606 24692351 NO scontino TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight. 0.7 SIGNOR-267492 RIMBP3 protein Q9UFD9 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.286 SIGNOR-264370 PARD6A protein Q9NPB6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 23151663 NO gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. 0.623 SIGNOR-199530 PPP1R1B protein Q9UD71 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity binding 9606 BTO:0000938 10604473 YES inferred from 70% of family members miannu DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.√¢‚Ǩ≈°√Ǭ† 0.685 SIGNOR-269869 PTPN12 protein Q05209 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr580 YIEDEDYyKASVTRL 10116 11337490 YES Inhibition of the catalytic activity of cell adhesion kinase beta by protein-tyrosine phosphatase-PEST-mediated dephosphorylation|CAKbeta was found to be a substrate for PTP-PEST. Both the major autophosphorylation site of CAKbeta (Tyr(402)) and activation loop tyrosine residues, Tyr(579) and Tyr(580), were targeted for dephosphorylation by PTP-PEST. Dephosphorylation of CAKbeta by PTP-PEST dramatically inhibited CAKbeta kinase activity. 0.545 SIGNOR-248664 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR MYLPF protein Q96A32 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.334 SIGNOR-136726 ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 14967450 YES miannu All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor 0.2 SIGNOR-256162 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr59 GETRFTDtRKDEQER 9606 2261989 YES gcesareni Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58. 0.787 SIGNOR-22928 CYP11B2 protein P19099 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI down-regulates quantity chemical modification 9606 BTO:0000050 9814482 YES lperfetto Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. 0.8 SIGNOR-268677 AP-3 complex complex SIGNOR-C247 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 NO lperfetto BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton. 0.7 SIGNOR-265942 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser536 SGDEDFSsIADMDFS 9606 SIGNOR-C13 15489227 YES gcesareni Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. 0.439 SIGNOR-129943 4.1 complex complex SIGNOR-C386 SIGNOR SPTB protein P11277 UNIPROT up-regulates activity binding 9606 BTO:0000424 22465511 YES lperfetto The junctional complex is focused around a hub or ‘junction’ arising from lateral connections between protein 4.1, actin and beta spectrin (the first of which stabilises the actin spectrin association via direct binding to both proteins [8]). 0.354 SIGNOR-266041 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 YES irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. 0.2 SIGNOR-255878 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 10090 SIGNOR-C17 11278991 YES lperfetto CDK1-cyclin B phosphorylates NPM/B23 on Thr234. 0.519 SIGNOR-235530 nalbuphine chemical CHEBI:7454 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 19282177 YES Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. 0.8 SIGNOR-258041 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10497236 YES Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. lperfetto Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. 0.957 SIGNOR-217746 RAD23B protein P54727 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 16401726 NO miannu The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome. 0.7 SIGNOR-261062 HECTD3 protein Q5T447 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity polyubiquitination Lys231 KVYQMKSkPRGYCLI 9606 BTO:0000007 24287696 YES miannu HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 ubiquitinates caspase-8 with K63-linked polyubiquitin chains at K215. 0.337 SIGNOR-272077 MAPK8 protein P45983 UNIPROT JUNB protein P17275 UNIPROT up-regulates activity phosphorylation Thr102 SNGVITTtPTPPGQY 10090 9889198 YES miannu JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. 0.719 SIGNOR-250120 PRKAA1 protein Q13131 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser170 PSALNRTsSDSALHT 9606 SIGNOR-C15 21892142 YES gcesareni Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation 0.543 SIGNOR-176426 SMARCD1 protein Q96GM5 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.817 SIGNOR-270604 Ub:E2 complex SIGNOR-C497 SIGNOR RNF135 protein Q8IUD6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271092 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser633 WRRKRKEsSNTDSAG 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.398 SIGNOR-251616 SMO protein Q99835 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates binding 9606 23074268 YES The binding occours if Smo is phosphorylated gcesareni Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2 0.66 SIGNOR-199153 ZAP70 protein P43403 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 YES gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2). 0.676 SIGNOR-59651 RPS8 protein P62241 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.907 SIGNOR-262416 VRK1 protein Q99986 UNIPROT SOX2 protein P48431 UNIPROT up-regulates activity phosphorylation 9606 27334688 YES miannu VRK1, but not kinase-dead VRK1 (K179E), phosphorylated Sox2 (XREF_FIG). 0.469 SIGNOR-279578 LAMB2 protein P55268 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR form complex binding 10809728 YES lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 0.559 SIGNOR-253224 GSK3B protein P49841 UNIPROT MNX1 protein P50219 UNIPROT down-regulates phosphorylation Ser79 RLRAESPsPPRLLAA 9606 24425879 YES miannu Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9). 0.295 SIGNOR-203661 Ub:E2 complex SIGNOR-C497 SIGNOR DTX2 protein Q86UW9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271062 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy 0.47 SIGNOR-279868 CLOCK protein O15516 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR form complex binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. 0.538 SIGNOR-267965 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. 0.8 SIGNOR-266500 HDAC2 protein Q92769 UNIPROT CCND1 protein P24385 UNIPROT up-regulates binding 9606 15713663 YES gcesareni Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5. 0.47 SIGNOR-134062 NTN1 protein O95631 UNIPROT DCC protein P43146 UNIPROT up-regulates activity binding 9606 BTO:0001484 25881791 YES miannu DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes. 0.909 SIGNOR-268162 CDK1 protein P06493 UNIPROT RAP1GAP protein P47736 UNIPROT unknown phosphorylation Ser484 SLIVPGKsPTRKKSG 9606 1406653 YES lperfetto Two of the sites of phosphorylation by cyclic amp (camp)-dependent kinase were localized to serine residues 490 and 499, and one site of phosphorylation by p34cdc2 was localized to serine 484. 0.446 SIGNOR-18735 HNF1A protein P20823 UNIPROT SLCO1B3 protein Q9NPD5 UNIPROT up-regulates quantity by expression transcriptional regulation 16741617 YES lperfetto Farnesoid X receptor, hepatocyte nuclear factors 1alpha and 3beta are essential for transcriptional activation of the liver-specific organic anion transporter-2 gene.|This study demonstrated that the transcription of the LST-2 gene is regulated by three transcription factors, FXR, HNF1alpha, and HNF3beta. 0.251 SIGNOR-268988 LFNG protein Q8NES3 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 11346656 YES Fucosylation gcesareni These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch. It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2. 0.696 SIGNOR-107702 NTN1 protein O95631 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity post transcriptional regulation 443947 BTO:0001036 16980963 YES miannu Netrin-1 induces β-actin translation driven by its 3’UTR. 0.28 SIGNOR-268161 F2RL1 protein P55085 UNIPROT KLF6 protein Q99612 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254841 ZIC3 protein O60481 UNIPROT GLI3 protein P10071 UNIPROT up-regulates binding 9606 17764085 YES lperfetto Zic3 functions as a transcriptional coactivator of gli3 when it physically associates with gli3 0.375 SIGNOR-157637 FFAR4 protein Q5NUL3 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256916 CDK1 protein P06493 UNIPROT KIFC1 protein Q9BW19 UNIPROT up-regulates quantity by stabilization phosphorylation Ser6 sPLLEVKG -1 24510915 YES miannu We confirmed that CDK1 phosphorylates Ser6 (Supplementary Fig S5B) and demonstrated that KIFC1 displays CDK1-mediated resistance to ubiquitination by the APC/C (Fig S5C). 0.459 SIGNOR-277294 SMO protein Q99835 UNIPROT ARRB2 protein P32121 UNIPROT up-regulates binding 9606 15618519 YES The binding occours if Smo is phosphorylated gcesareni Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2 0.66 SIGNOR-132759 ANGPT4 protein Q9Y264 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 BTO:0004980 BTO:0000763 15284220 YES gcesareni In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2. 0.698 SIGNOR-127351 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-138479 ALDH1A3 protein P47895 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity chemical modification 9606 21621639 YES lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. 0.8 SIGNOR-265129 F3 protein P13726 UNIPROT Factor FVIIa:TF complex SIGNOR-C319 SIGNOR form complex binding 9606 BTO:0000131 32665005 YES lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. 0.933 SIGNOR-263556 chlorphenamine chemical CHEBI:52010 ChEBI HRH3 protein Q9Y5N1 UNIPROT down-regulates activity chemical inhibition -1 12781173 YES Luana Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine. 0.8 SIGNOR-257897 SMO protein Q99835 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates binding 9606 BTO:0000785 23074268 YES gcesareni This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1 0.267 SIGNOR-199192 FASN protein P49327 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 15507492 YES miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-268086 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Ser395 PSVNPSIsPAHGVAR 9606 10660621 YES lperfetto Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. 0.365 SIGNOR-74876 SF1 protein Q15637 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates binding 9606 9660765 YES miannu Here we report that zfm1 also interacts withews / overexpression of zfm1 in hepg2 cells represses the transactivation of reporter gene expression driven by gal4-ews-ntd fusion protein and this repression correlates with zfm1 binding to ews. 0.419 SIGNOR-58928 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Ser886 TSSSDTLsEEKNSEC 9606 BTO:0000567 31167143 YES miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  0.2 SIGNOR-276731 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 11481331 YES miannu In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue. 0.2 SIGNOR-250268 Ub:E2 complex SIGNOR-C497 SIGNOR PPCDC protein Q96CD2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271251 DCTN2 protein Q13561 UNIPROT Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR up-regulates activity relocalization 25364732 YES lperfetto ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores 0.2 SIGNOR-265018 Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 9606 27487822 YES miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. 0.8 SIGNOR-266267 UBE2D3 protein P61077 UNIPROT ZSWIM2 protein Q8NEG5 UNIPROT up-regulates activity binding 9606 BTO:0000007 16522193 YES miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  0.331 SIGNOR-271557 ZNF804A protein Q7Z570 UNIPROT MGAM protein O43451 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23434502 YES miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 0.2 SIGNOR-269466 TXNIP protein Q9H3M7 UNIPROT DDIT4 protein Q9NX09 UNIPROT up-regulates quantity by stabilization binding 9606 21460850 YES miannu  In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein.  0.509 SIGNOR-277470 MAPK3 protein P27361 UNIPROT BAG3 protein O95817 UNIPROT down-regulates quantity by destabilization phosphorylation Ser377 PVPCPPPsPGPSAVP 9606 BTO:0002181 34215846 YES miannu We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377. 0.312 SIGNOR-277318 HRAS protein P01112 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity phosphorylation Ser192 PSTTGAAsPASSSAG 9606 25056917 NO Oncogenic Ras enhanced S192-dependent GATA-2 phosphorylation, nuclear foci localization, and transcriptional activation. These studies define a mechanism that controls a key regulator of hematopoiesis and a dual mode of impairing GATA-2-dependent genetic networks: mutational disruption of chromatin occupancy yielding insufficient GATA-2, and oncogenic Ras-mediated amplification of GATA-2 activity 0.356 SIGNOR-259945 SFRP1 protein Q8N474 UNIPROT Wnt proteinfamily SIGNOR-PF40 SIGNOR down-regulates binding 9606 BTO:0000782 10347172 YES gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. 0.793 SIGNOR-262527 CSTF3 protein Q12996 UNIPROT CSTF complex complex SIGNOR-C441 SIGNOR form complex binding 9606 10669729 YES lperfetto We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other.  0.955 SIGNOR-268367 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser276 VHPATPIsPGRASGM 9606 17015473 YES The effect has been demonstrated using Q01196-8. gcesareni Aml1/runx1 phosphorylation by cyclin-dependent kinases regulates the degradation of aml1/runx1 by the anaphase-promoting complex. 0.342 SIGNOR-149972 PRKCA protein P17252 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 YES lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. 0.371 SIGNOR-248973 ERG protein P11308 UNIPROT ADAMTS1 protein Q9UHI8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 19396168 NO miannu ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. 0.2 SIGNOR-253910 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR RRM2 protein P31350 UNIPROT up-regulates quantity by expression transcriptional regulation 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276581 GPR17 protein Q13304 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257087 TRIM62 protein Q9BVG3 UNIPROT CARD9 protein Q9H257 UNIPROT up-regulates activity polyubiquitination Lys125 LLMTEVMkLQKKVQD 9606 BTO:0000007 26488816 YES miannu We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity.  0.51 SIGNOR-272420 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273086 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273087 MAPK14 protein Q16539 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates activity phosphorylation Ser93 ALQRQPPsPKQLEEE -1 10206983 YES miannu The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP. 0.59 SIGNOR-250109 SWI/SNF complex complex SIGNOR-C92 SIGNOR CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18332116 NO irozzo HSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15INK4b and p16INK4a, but not of p14ARF.Reexpression of hSNF5 in MRT cells overcomes epigenetic silencing and mediates transcriptional activation of p15INK4b and p16INK4a 0.351 SIGNOR-256299 TP53BP2 protein Q13625 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates binding 9606 8549741 YES gcesareni The phosphorylase phosphatase activity of pp1 was inhibited by p53bp2 at nanomolar concentrations. 0.2 SIGNOR-39666 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser222 EVEEEADsCFGDDED 9606 BTO:0000567 11546811 YES lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. 0.395 SIGNOR-110395 INS protein P01308 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization 9606 17360977 NO lperfetto Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 0.679 SIGNOR-236737 SLC2A5 protein P22732 UNIPROT D-fructofuranose smallmolecule CHEBI:37721 ChEBI up-regulates quantity relocalization 9606 28083649 YES Although increased dietary fructose consumption is associated with metabolic impairments, the mechanisms and regulation of intestinal fructose absorption are poorly understood. GLUT5 is considered to be the main intestinal fructose transporter. 0.8 SIGNOR-267493 CCT129202 chemical CID:16202152 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190883 AKT1 protein P31749 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser230 LKRNRYLsFHFKSGS 15870194 YES lperfetto Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target. 0.297 SIGNOR-275517 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0001271 7637391 YES gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. 0.2 SIGNOR-30357 DDX3X protein O00571 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 BTO:0001950 17667941 YES miannu DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G. 0.629 SIGNOR-269200 PAN2 protein Q504Q3 UNIPROT PAN2-PAN3 deadenylation complex complex SIGNOR-C553 SIGNOR form complex binding 9606 34280615 YES miannu There are two major deadenylase complexes, Ccr4-Not and Pan2-Pan3, which shorten the 3′ poly(A) tail of mRNA and are conserved from yeast to human.The Ccr4-Not complex has two catalytic subunits including the Ccr4 (Carbon catabolite repressor 4) and Pop2 (PGK promoter directed overproduction). The Pan2-Pan3 complex comprises the catalytic subunit Pan2, a member of the RNase D family, and the regulatory subunit Pan3. Degradation of mRNA begins with either shortening of the poly(A) tail by deadenylases or removal of 5′ cap structure by the decapping enzyme Dcp1-Dcp2. 0.827 SIGNOR-273870 Ub:E2 complex SIGNOR-C497 SIGNOR SYVN1 protein Q86TM6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271126 HIPK2 protein Q9H2X6 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates activity phosphorylation 9606 30609136 YES miannu In conclusion, the phosphorylation of FOXM1 by HIPK2 can promote FOXM1 transcription activity and cell proliferation in RCC, thus, indicating a potential mechanism for the treatment of human RCC in the future. 0.2 SIGNOR-278944 SF3A1 protein Q15459 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.727 SIGNOR-270668 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM8 protein O00222 UNIPROT up-regulates activity chemical activation 9606 25042998 YES miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate 0.8 SIGNOR-264073 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 10660596 YES gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. 0.897 SIGNOR-74856 TWIST1 protein Q15672 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.277 SIGNOR-255527 P2RY10 protein O00398 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257005 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT up-regulates activity dephosphorylation Tyr999 YASSNPEyLSASDVF -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.366 SIGNOR-254703 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by myod and other regulatory proteins. 0.459 SIGNOR-135984 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation -1 11287604 YES inferred from 70% family members lperfetto Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 0.2 SIGNOR-270109 SIRT1 protein Q96EB6 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity transcriptional regulation 9606 19553684 NO gcesareni Collectively, these data indicate that SIRT1 controls PGC-1alpha gene expression in skeletal muscle and that MyoD is a key mediator of this action 0.798 SIGNOR-238790 POT1 protein Q9NUX5 UNIPROT POT1/ACD complex SIGNOR-C64 SIGNOR form complex binding 9606 17237768 YES miannu We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme. 0.884 SIGNOR-152324 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 1756735 YES gcesareni The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. 0.687 SIGNOR-21556 NSMCE3 protein Q96MG7 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 YES miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks 0.2 SIGNOR-265485 CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity binding 10090 BTO:0003346 16847334 YES Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain 0.539 SIGNOR-256072 LPAR2 protein Q9HBW0 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256927 dopamine smallmolecule CHEBI:18243 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258377 TNFRSF10D protein Q9UBN6 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 9382840 YES amattioni One function of trail-r4 may be inhibition of trail cytotoxicy. Dcr2 functions as an inhibitory apo2l receptor. 0.727 SIGNOR-53447 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR up-regulates 25838379 NO lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules. 0.7 SIGNOR-262599 GBE1 protein Q04446 UNIPROT α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR down-regulates quantity chemical modification 9606 26199317 YES miannu Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating α-1,6-glucosidic branches from α-1,4-linked glucose chains, to increase solubility of the glycogen polymer. In eukaryotes, glycogenin (EC 2.4.1.186) initiates the synthesis of the linear glucan chain (2), which is elongated by glycogen synthase (GYS, EC 2.4.1.11) (3), functioning in concert with glycogen branching enzyme (GBE, EC 2.4.1.18) to introduce side chains 0.2 SIGNOR-267941 FNTB protein P49356 UNIPROT MRAS protein O14807 UNIPROT up-regulates activity 9606 24294527 YES lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. 0.273 SIGNOR-242562 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258273 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr177 GVRWAKLySLVIWGC 9606 16226010 YES lperfetto Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway. 0.262 SIGNOR-141103 miR-155 mirna URS000062749E_9606 RNAcentral CEBPB protein P17676 UNIPROT down-regulates quantity post transcriptional regulation 9606 25477897 YES miannu MiR-155 directly inhibits src homology 2 domaincontaining inositol-5-phosphatase (SHIP1) as well as CCAATenhancer-binding protein-beta (CEBP-β) to mediate leukemogenesis 0.4 SIGNOR-255770 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates phosphorylation Ser623 KGEKRASsPFRRVRE 9606 12167624 YES gcesareni Here we demonstrate that protein kinase a (pka)-dependent phosphorylation of nopp140 at ser 627, together with c/ebpbeta, induces agp gene expression synergistically. 0.307 SIGNOR-91186 GSK690693 chemical CHEBI:90677 ChEBI AKT2 protein P31751 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193003 RNF4 protein P78317 UNIPROT NFYC protein Q13952 UNIPROT up-regulates activity binding 9606 15496512 YES miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. 0.2 SIGNOR-252231 ESR1 protein P03372 UNIPROT GREB1 protein Q4ZG55 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 17666587 NO miannu Long-range activation of GREB1 by estrogen receptor via three distal consensus estrogen-responsive elements in breast cancer cells. . GREB1 (gene regulated by estrogen in breast cancer 1) is an ER target gene that regulates estrogen-induced proliferation in breast cancer cells. 0.713 SIGNOR-254074 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser615 VPESSKIsQENEIGK 9606 10839545 YES lperfetto In vivo, nbs was phosphorylated on many serine residues, of which s343, s397 and s615 were phosphorylated by atm in vitro. Reconstituting nbs cells with a mutant form of nbs that cannot be phosphorylated at selected, atm-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. 0.855 SIGNOR-78034 CDK4 protein P11802 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 YES gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.283 SIGNOR-176518 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM73 protein Q86UV7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271187 MAPK1 protein P28482 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 NFDFVTEtPLEGDFA 9606 19364816 YES lperfetto We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation. 0.364 SIGNOR-185219 CSNK1A1 protein P48729 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser79 QRMGSSEsTDSGFCL 9606 20348946 YES lperfetto Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a 0.333 SIGNOR-164734 SRC protein P12931 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr566 RYVLDDQyVSSVGTK 9606 10688651 YES lperfetto Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk. 0.534 SIGNOR-75330 acetyl-CoA smallmolecule CHEBI:15351 ChEBI hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity precursor of 9606 15507492 YES miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-268089 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000567 SIGNOR-C13 10469655 YES lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). 0.746 SIGNOR-70449 PGK2 protein P07205 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. 0.8 SIGNOR-266503 2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine chemical CHEBI:95074 ChEBI EHMT1 protein Q9H9B1 UNIPROT down-regulates activity chemical inhibition -1 26320100 YES miannu Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression. 0.8 SIGNOR-262239 mir-10b mirna URS00004CAC40_9606 RNAcentral CADM2 protein Q8N3J6 UNIPROT down-regulates quantity destabilization 9606 25477897 YES miannu The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT2 0.4 SIGNOR-255794 BTK protein Q06187 UNIPROT ITK protein Q08881 UNIPROT up-regulates phosphorylation Tyr180 ETVVIALyDYQTNDP 9606 12573241 YES lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanismthe major phosphorylation sites were identified as conserved tyrosines, for itk y180 0.496 SIGNOR-98036 AKT2 protein P31751 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 NO gcesareni Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu). 0.275 SIGNOR-157770 CBX3 protein Q13185 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR form complex binding 10090 BTO:0002896 29795351 YES miannu Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP. 0.418 SIGNOR-266753 IFNW1 protein P05000 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 11278538 YES gcesareni Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.728 SIGNOR-105979 PIGS protein Q96S52 UNIPROT PIGK protein Q92643 UNIPROT up-regulates activity binding 10090 BTO:0000095 11483512 YES miannu To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8. 0.943 SIGNOR-261362 PRKCQ protein Q04759 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Ser309 MMKKYGKsFRKLLSL -1 14988727 YES miannu Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. 0.486 SIGNOR-276006 SRPK1 protein Q96SB4 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 10196197 YES gcesareni These results suggest that the formation of complexes between sf2/asf and srpks, which is influenced by the phosphorylation state of sf2/asf, may have regulatory roles in the assembly and localization of this splicing factor. 0.798 SIGNOR-66465 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 22045613 YES svumbaca NICD is translocated to the nucleus where it binds recombining binding protein-Jj (RBP-Jj) 0.95 SIGNOR-255364 MMP9 protein P14780 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage His31 LDHDRAIhIQAENGP -1 7694569 YES miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. 0.342 SIGNOR-256328 PVR protein P15151 UNIPROT TIGIT protein Q495A1 UNIPROT up-regulates activity binding 9606 30591568 YES lperfetto Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12). 0.867 SIGNOR-261425 BCL3 protein P20749 UNIPROT CTCF protein P49711 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004298 21912613 NO miannu In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription. 0.301 SIGNOR-253757 ID2 protein Q02363 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.586 SIGNOR-241140 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 YES lperfetto The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 0.2 SIGNOR-263221 MAP4K4 protein O95819 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Thr322 SNVNRNStIENTRRH 9606 BTO:0002181 21690388 YES miannu Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.  0.2 SIGNOR-276335 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EGFR protein P00533 UNIPROT down-regulates phosphorylation Thr693 RELVEPLtPSGEAPN 9606 10816576 YES lperfetto It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation. 0.2 SIGNOR-244529 CHEK1 protein O14757 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Thr521 MALGKDVtPPPETEV 9606 36991467 YES miannu MAP4 is a novel target of FBXW7 via the phosphorylated threonine T521 modified by CHEK1 in ESCC. The threonine T521 of MAP4, which was phosphorylated by CHEK1, played a key role in the FBXW7-related degradation system. 0.2 SIGNOR-277846 CLCF1 protein Q9UBD9 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 BTO:0000938 10966616 YES gcesareni Striking phenotypic differences between cntf- and cntfr-deficient mice suggest that cntfr serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (clc) and the soluble receptor cytokine-like factor-1 (clf). 0.702 SIGNOR-81376 ABL1 protein P00519 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity phosphorylation Tyr533 VTQMEVHyARPIIIL 9606 20220006 YES miannu Moreover, c-Abl phosphorylates PSD-95 at tyrosine 533.|c-Abl modulates the synaptic contact number and PSD-95 clustering. 0.441 SIGNOR-278391 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Ser126 SVYYKPSsPPTPTTP 9606 BTO:0000938 BTO:0000142 17681692 YES llicata We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter. 0.395 SIGNOR-157167 CCND3 protein P30281 UNIPROT CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR form complex binding -1 12082095 YES lperfetto Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3| 0.393 SIGNOR-273118 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 11019781 YES lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. 0.256 SIGNOR-82760 MAPK3 protein P27361 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser343 KSDCQPNsPTESCSS 9606 BTO:0000782;BTO:0000785 9649500 YES gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. 0.406 SIGNOR-58493 ALDOA protein P04075 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266479 GALP protein Q9UBC7 UNIPROT GALR2 protein O43603 UNIPROT up-regulates binding 9606 10601261 YES gcesareni Galp is therefore an endogenous ligand that preferentially binds the galr2 receptor 0.431 SIGNOR-73143 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR CCND2 protein P30279 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0002268 22323446 YES miannu F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation. Purified SCF complex components were incubated with V5-cyclin D2 and the full complement of ubiquitination reaction components (second lane from left) showing polyubiquitinated cyclin D2. 0.439 SIGNOR-272007 masitinib chemical CHEBI:63450 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258245 TFG protein Q92734 UNIPROT SEC16B protein Q96JE7 UNIPROT up-regulates binding 9606 21478858 YES miannu We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits. 0.498 SIGNOR-173279 hsa-miR-1-3p mirna URS00001DC04F_9606 RNAcentral TNKS2 protein Q9H2K2 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000093 26497855 YES Parnian Our data indicate that miR-1 down-regulates breast CSC stemness, proliferation and migration by targeting the Frizzled 7 and TNKS2 to inhibit the Wnt/β-catenin signaling. 0.4 SIGNOR-277965 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 9419975 YES Epiregulin may be a mediator of localized cell proliferation gcesareni Chemical cross-linking experiments showed that [125i]epiregulin directly bound to each of egfr and erbb-4 but not to erbb-2 and erbb-3. remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. 0.892 SIGNOR-54351 HTR2A protein P28223 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.607 SIGNOR-257137 TKT protein P29401 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity chemical modification 9606 24929114 YES miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. 0.8 SIGNOR-267087 ERBB3 protein P21860 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.325 SIGNOR-146870 ME1 protein P48163 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 33064660 YES miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. 0.8 SIGNOR-267723 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck lperfetto 0.8 SIGNOR-244820 NR5A2 protein O00482 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 NO miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.409 SIGNOR-254872 MAST4 protein O15021 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 29066835 YES miannu MAST4 phosphorylation of FOXO1 regulates RTKN2 expression. 0.335 SIGNOR-279079 ATE1 protein O95260 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000567 29295953 YES miannu We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway. 0.295 SIGNOR-261345 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH12 protein P55289 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265830 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273088 ITGB4 protein P16144 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9428518 YES gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. 0.2 SIGNOR-54703 PRKCA protein P17252 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Thr141 RRDARGLtPLELALQ 9606 22558186 YES lperfetto Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response 0.2 SIGNOR-197289 TFIIH complex SIGNOR-C457 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Thr433 DCDFGDLtPLDF 9606 10428966 YES lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase.  here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. 0.319 SIGNOR-269354 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 9784611 YES gcesareni we conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin.We Found that the binding of beta-trcp to beta-catenin was direct 0.746 SIGNOR-60751 TNFRSF11A protein Q9Y6Q6 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 10075662 NO miannu RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. 0.259 SIGNOR-253047 ITGB1BP1 protein O14713 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.314 SIGNOR-257652 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Thr641 TRHPPVLtPPDQEVI 10116 8749392 YES Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme. 0.469 SIGNOR-248587 NFY complex SIGNOR-C1 SIGNOR CCNB1 protein P14635 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 BTO:0000887;BTO:0001103 10362252 NO lperfetto In conclusion, our data demonstrate that nf-y is required for cyclin b1 promoter activity. 0.356 SIGNOR-235834 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT unknown phosphorylation Ser408 SIKSEPIsPPRDRMT 9606 BTO:0000938 BTO:0000887 12586839 YES lperfetto A p38 mapk-induced phosphopeptide with no mapk consensus the phosphorylation site is identified as ser-408 0.66 SIGNOR-98224 P4HA1 protein P13674 UNIPROT Collagen proteinfamily SIGNOR-PF103 SIGNOR up-regulates quantity chemical modification 9606 BTO:0003081 40332386 YES miannu P4HA1 Mediates Hypoxia-Induced Invasion in Human Pancreatic Cancer Organoids.Collagen prolyl 4-hydroxylase subunit alpha-1 (P4HA1) is the most common isoform of the collagen prolyl 4-hydroxylases and contributes to collagen synthesis and deposition 0.2 SIGNOR-279877 Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR FLNB protein O75369 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000165 19300455 YES miannu Here, we provide the first evidence that a novel ASB2 isoform, ASB2beta, is important for muscle differentiation. ASB2beta is expressed in muscle cells during embryogenesis and in adult tissues. ASB2beta is part of an active E3 ubiquitin ligase complex and targets the actin-binding protein filamin B (FLNb) for proteasomal degradation.  Altogether, our results indicated that ASB2β can assemble with elongin B, elongin C, Cullin 5 and Rbx2 to reconstitute an active E3 ubiquitin ligase complex.ASB2β induces polyubiquitylation of FLNb. 0.266 SIGNOR-271801 SRC protein P12931 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 8629002 YES This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation. 0.528 SIGNOR-251100 spiperone chemical CHEBI:9233 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258859 CAMK1 protein Q14012 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 BTO:0000887 11114197 YES gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation. 0.42 SIGNOR-85018 NANOG protein Q9H9S0 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003298 22795133 YES lperfetto Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation 0.433 SIGNOR-253157 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 YES gcesareni The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex. 0.2 SIGNOR-72669 CDK5 protein Q00535 UNIPROT EPRS1 protein P07814 UNIPROT down-regulates phosphorylation Ser886 LSQSSDSsPTRNSEP 9606 BTO:0000801 21220307 YES lperfetto Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation 0.2 SIGNOR-171138 HDAC1 protein Q13547 UNIPROT VDR protein P11473 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 18485278 NO miannu We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. 0.385 SIGNOR-255179 XRCC6 protein P12956 UNIPROT UBE2S protein Q16763 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 27593939 YES lperfetto As shown in Figure 4, we found that Ku70 (Figure 4b) and Ku80 (Figure 4c) co-immunoprecipitated with UBE2S.>Taken together, these results demonstrate that ETO enhances the UBE2S–Ku70 interaction, and UBE2S can be recruited to the same sites of DSBs with Ku70 upon ETO treatment. 0.347 SIGNOR-265079 hsa-miR-21-5p mirna URS000039ED8D_9606 RNAcentral CCL20 protein P78556 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000038 22099878 YES Parnian As miR-21 regulates the expression of a luciferase construct which contains the 30UTR of CCL20 mRNA, we suggest that miR-21 regulates CCL20 gene expression by a regulatory element present in the 3UTR of CCL20 mRNA. 0.4 SIGNOR-278005 NKX2-1 protein P43699 UNIPROT SFTPB protein P07988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 18003659 NO miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. 0.472 SIGNOR-254172 DCN protein P07585 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000951 17200203 NO Regulation miannu Decorin Induces Fibrillin-1 Protein Expression in NRK Cells via IGF-IR. we report a novel mechanism of action that involves two key molecules: decorin, a small leucine-rich proteoglycan, and the IGF-IR. These two players, together with the downstream signaling pathway evoked by decorin-mediated activation of the receptor, lead to an enhanced translation of fibrillin-1 and its deposition in the extracellular environment both in vitro and in vivo. 0.561 SIGNOR-251893 miR-155 mirna URS000062749E_9606 RNAcentral SPI1 protein P17947 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 22195016 YES Our results elucidate a negative feedback circuit in which IGF-1-stimulated miR-133 in turn represses IGF-1R expression to modulate the IGF-1R signaling pathway during skeletal myogenesis. 0.4 SIGNOR-255915 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001271 BTO:0000671 14551213 YES gcesareni The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1 0.719 SIGNOR-118600 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 11971971 YES lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. 0.75 SIGNOR-235937 TTM complex complex SIGNOR-C305 SIGNOR Shelterin complex complex SIGNOR-C306 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 33015044 YES lperfetto The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1 0.2 SIGNOR-263308 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI TXN protein P10599 UNIPROT up-regulates chemical activation 9606 15556622 YES gcesareni We show that 10 and 50 microm h2o2 and short-term exposure to shear stress significantly increased trx-1 mrna and protein levels in endothelial cells. 0.8 SIGNOR-131049 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser70 RSSHYGGsLPNVNQI 9606 BTO:0000567 16306228 YES lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 0.633 SIGNOR-249171 MYOD1 protein P15172 UNIPROT PJA1 protein Q8NG27 UNIPROT up-regulates quantity transcriptional regulation 10090 28067271 YES ... chromatin immunoprecipitation (ChIP) analysis showed MYOD binds to a site upstream the Pja1 promoter preferentially in C2C12 cells induced to differentiate (Fig. 2c). In addition, over-expression of MyoD in human fibroblasts is sufficient to up-regulate Pja1 expression 0.2 SIGNOR-255718 3-[(2-Bromo-4,5-dimethoxyphenyl)methyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one chemical CID:44436444 PUBCHEM ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001239 17888667 YES Luana AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. 0.8 SIGNOR-257760 GFI1 protein Q99684 UNIPROT BAX protein Q07812 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 17213822 NO miannu Our results suggest that the interaction between ETS1 and GFI1 facilitates their binding to specific sites on the Bax promoter and represses Bax expression in vivo. 0.2 SIGNOR-254203 125-L-serine-2-133-interleukin 2 (human reduced) smallmolecule SID:46508054 PUBCHEM IL2RG protein P31785 UNIPROT up-regulates activity chemical activation 9606 18031103 YES miannu Aldesleukin (recombinant IL-2) has similar pharmacodynamic properties to endogenous IL-2 and, when administered to patients with cancer, stimulates the antitumour immune response. 0.8 SIGNOR-259390 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT unknown phosphorylation Tyr175 EITTNRFyGPQVNNI 10090 16199863 YES gcesareni Mutation of both tyrosines 175 and 256 to phenylalanine was required to abolish Abl-mediated phosphorylation of N-WASP in the presence of Grb2 [€] suggesting that phosphorylation at tyrosine 175 is not critical for comet tail formation by Shigella 0.551 SIGNOR-247666 Hexocyclium chemical CHEBI:5707 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258397 ACOT8 protein O14734 UNIPROT glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI down-regulates quantity chemical modification 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271814 CBS protein P35520 UNIPROT L-serine zwitterion smallmolecule CHEBI:33384 ChEBI down-regulates quantity chemical modification 9606 23981774 YES lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. 0.8 SIGNOR-275829 TANK protein Q92844 UNIPROT DUSP14 protein O95147 UNIPROT up-regulates activity ubiquitination lys103 9606 BTO:0000007 26521044 YES miannu TRAF2-mediated Lys63-linked ubiquitination of DUSP14/MKP6 is essential for its phosphatase activity. Mass spectrometry and mutational analyses identified that DUSP14 was Lys63-linked ubiquitinated at lysine 103 residue.Here we report that DUSP14 was Lys63-linked ubiquitinated at Lys103 residue by the E3 ligase TRAF2 during TCR signaling. Furthermore, ubiquitination of DUSP14 was essential for its phosphatase activity. 0.2 SIGNOR-272811 KIF13A protein Q9H1H9 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR up-regulates relocalization 9606 30404817 YES lperfetto Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. 0.295 SIGNOR-260703 aliskiren chemical CHEBI:601027 ChEBI REN protein P00797 UNIPROT down-regulates activity chemical inhibition 9606 18307734 YES Luana Aliskiren has a low bioavailality (between 2.6 and 5.0%) compensated by its high potency to inhibit renin (IC50: 0.6 nmol/L) and a long plasma half-life (23–36 h) 0.8 SIGNOR-257771 UV stress stimulus SIGNOR-ST7 SIGNOR KRT14 protein P02533 UNIPROT up-regulates 9606 11875647 NO miannu UVB increases keratin 5 and keratin 14 expression through direct activation of the EGF receptor in SVHK. 0.7 SIGNOR-251900 THOC2 protein Q8NI27 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 YES miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. 0.943 SIGNOR-268509 pyruvate smallmolecule CHEBI:15361 ChEBI (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity precursor of 9606 24929216 YES lperfetto Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. 0.8 SIGNOR-267655 RIPK1 protein Q13546 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates activity binding 9606 SIGNOR-C14 16603398 YES lperfetto Interestingly, polyubiquitinated rip1 recruits ikk through the binding between the polyubiquitin chains and nemo, a regulatory subunit of the ikk complex. Mutations of nemo that disrupt its polyubiquitin binding also abolish ikk activation. 0.915 SIGNOR-145858 EGFR protein P00533 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr264 EGLSHTPtVKHLEAL 9606 BTO:0000815 36841821 YES miannu EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase.  0.2 SIGNOR-277874 IRF3 protein Q14653 UNIPROT Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 NO lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. 0.7 SIGNOR-126962 FASN protein P49327 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 15507492 YES Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-267211 JAK2 protein O60674 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 8977526 YES lperfetto JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation. 0.531 SIGNOR-249503 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by stabilization phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 12717439 YES lperfetto We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage 0.487 SIGNOR-100898 CHEK2 protein O96017 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity phosphorylation Ser99 KDGVADVsIEDSVIS 4932 24647101 YES ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes. 0.377 SIGNOR-262795 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 19819937 NO In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. 0.7 SIGNOR-254354 STAT3 protein P40763 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12545153 YES luana Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells.  0.785 SIGNOR-259456 AKT1 protein P31749 UNIPROT RANBP3 protein Q9H6Z4 UNIPROT unknown phosphorylation Ser126 VKRERTSsLTQFPPS 9606 18280241 YES llicata Akt regulates ranbp3 phosphorylation in vitro and in vivo 0.359 SIGNOR-252504 WNT6 protein Q9Y6F9 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 9753670 NO gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. 0.309 SIGNOR-60415 MAPK3 protein P27361 UNIPROT MAGEA11 protein P43364 UNIPROT up-regulates phosphorylation Ser174 ESPSPPQsPQEESFS 9606 BTO:0000848 19828458 YES llicata Mage-11 ser-174 appears to be a post-translational regulatory site phosphorylated by erk1, based on the inhibitory effect of the s174a mutation in the context of shorter ar nh2-terminal fragments (19), and the greater transcriptional activity of gal-mage-11 fusion proteins containing the s174d phosphomimetic. 0.3 SIGNOR-188466 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 7838153 YES gcesareni Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii. 0.2 SIGNOR-252807 PKC proteinfamily SIGNOR-PF53 SIGNOR SLITRK1 protein Q96PX8 UNIPROT up-regulates activity phosphorylation Ser695 DCGSHSLsD -1 19640509 YES miannu In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides. 0.2 SIGNOR-273635 IFNG protein P01579 UNIPROT SLC11A1 protein P49279 UNIPROT up-regulates 9606 BTO:0000801 11909746 NO Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS) 0.348 SIGNOR-254038 hsa-miR-23b-3p mirna URS00004E57E7_9606 RNAcentral FZD7 protein O75084 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001109 22109528 YES Parnian MiR-23b, which is downregulated in human colon cancer samples, potently mediates the multiple steps of metastasis, including tumour growth, invasion and angiogenesis in vivo . | Mutation of the putative miR-23b site(s) in the 3′-UTR of FZD7, MAP3K1 (MEKK1), PAK2, TGFβR2, RRAS2 or uPA resulted in an abrogated responsiveness to miR-23b. 0.4 SIGNOR-277959 CAMK2A protein Q9UQM7 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 16982419 YES gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16. 0.401 SIGNOR-149640 arachidonic acid smallmolecule CHEBI:15843 ChEBI FOS protein P01100 UNIPROT up-regulates 9606 15878913 NO miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. 0.8 SIGNOR-255392 PCDHAC1 protein Q9H158 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-269032 P2RY1 protein P47900 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.425 SIGNOR-257339 UCHL5 protein Q9Y5K5 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates quantity by stabilization binding 9606 17052192 YES gcesareni Smad7 can act as an adaptor able to recruit uch37 to the type i tgf-beta receptor. Consequently, uch37 dramatically up-regulates tgf-beta-dependent gene expression by de-ubiquitinating and stabilizing the type i tgf-beta receptor. 0.503 SIGNOR-150135 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 YES apalma Therefore, these genetic data further support the hypothesis that activation of Notch-1 promotes a less committed myogenic phenotype and that the attenuation of Notch-1 activity by Numb promotes progression along the myogenic lineage toward a myoblast cell fate. 0.797 SIGNOR-255375 spironolactone chemical CHEBI:9241 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18038968 YES Luana Results of the RALES trial (Randomized Aldactone Evaluation Study) demonstrated that the published MR antagonist spironolactone, added to standard therapy, reduced mortality due to all causes by 30% as well as reduced hospitalizations and improved cardiac function in patients with severe heart failure.2 0.8 SIGNOR-257762 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 YES gcesareni Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program 0.752 SIGNOR-121895 AKT2 protein P31751 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE 9606 10377430 YES lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. 0.657 SIGNOR-68656 RASGEF1A protein Q8N9B8 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.425 SIGNOR-183826 KISS1 protein Q15726 UNIPROT KISS1R protein Q969F8 UNIPROT up-regulates binding 9606 11385580 YES gcesareni Here we show that kiss-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan g-protein-coupled receptor (hot7t175) and have named 'metastin' 0.806 SIGNOR-108480 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr179 GGPAQDIyQVPPSAG 10090 12972425 YES lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs 0.802 SIGNOR-246389 WWTR1 protein Q9GZV5 UNIPROT NKX2-1 protein P43699 UNIPROT up-regulates binding 9606 BTO:0000887 16397409 YES gcesareni Taz also binds to the transcription factor ttf-1 that is involved in formation and differentiation of the lungs and respiratory epithelia, and stimulates the production of pulmonary surfactant. 0.425 SIGNOR-143472 TTL protein Q8NG68 UNIPROT TUBAC Family proteinfamily SIGNOR-PF110 SIGNOR down-regulates tyrosination 9606 22020298 YES miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization 0.324 SIGNOR-176921 ZMYND8 protein Q9ULU4 UNIPROT CD44 protein P16070 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 YES lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported 0.2 SIGNOR-262039 CASP1 protein P29466 UNIPROT Pyrin inflammasome complex SIGNOR-C226 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.718 SIGNOR-256412 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser170 GGAFFSPsPGSSSLS 9606 11997522 YES lperfetto Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity. 0.2 SIGNOR-87397 TNFSF10 protein P50591 UNIPROT TNFRSF10A protein O00220 UNIPROT up-regulates binding 9606 14585074 YES amattioni Trail interacts with tril-r1 and trail-r2 and activetes them 0.934 SIGNOR-101082 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser321 NSNASTVsGRLSPIM 9606 20110348 YES lperfetto Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export 0.416 SIGNOR-252900 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates phosphorylation Tyr771 ADIESSNyMAPYDNY 9606 1314164 YES llicata Mutagenesis studies show that tyr740 and 751 are involved in the pdgf-stimulated binding of phosphatidylinositol (pi) 3 kinase, and tyr771 is required for efficient binding of gap, the gtpase activator of ras. 0.2 SIGNOR-16892 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr627 KGDKQVEyLDLDLDS 10090 BTO:0000944 10978177 YES HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin 0.501 SIGNOR-251316 MYCT1 protein Q8N699 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 NO miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. 0.2 SIGNOR-261730 RPS6KA3 protein P51812 UNIPROT NR4A1 protein P22736 UNIPROT unknown phosphorylation Ser351 GRRGRLPsKPKQPPD 9606 BTO:0000007 16223362 YES lperfetto In the present paper, we have re-examined the phosphorylation of Nur77 on Ser354. Using a combination of cell-permeable kinase inhibitors and mouse knockin mutations, we show that Nur77 is phosphorylated by RSK in response to mitogenic stimulation of cells. Phosphorylation of Nur77 on Ser354 did not, however, appear to affect the transcriptional activity of Nur77, or its ability to bind 14-3-3 proteins in vivo. 0.465 SIGNOR-249295 KIF1C protein O43896 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272517 DAMPS stimulus SIGNOR-ST18 SIGNOR AIM2 protein O14862 UNIPROT up-regulates activity 16037825 NO lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-256419 venlafaxine chemical CHEBI:9943 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9615 20378347 YES Luana The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD). 0.8 SIGNOR-257835 PPP1CC protein P36873 UNIPROT CASP2 protein P42575 UNIPROT up-regulates activity dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 YES llicata nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. 0.2 SIGNOR-248503 CSNK1D protein P48730 UNIPROT BACE1 protein P56817 UNIPROT unknown phosphorylation Ser498 DDFADDIsLLK 9606 BTO:0000007 11278841 YES llicata Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. | After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes. 0.368 SIGNOR-250797 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser469 AHEENPEsILDEHVQ 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.27 SIGNOR-248497 CUL1 protein Q13616 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001271 SIGNOR-C5 12835716 YES lperfetto Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2 0.641 SIGNOR-102725 N2,N4-Dibenzylquinazoline-2,4-diamine chemical CID:676352 PUBCHEM VCP protein P55072 UNIPROT down-regulates activity chemical inhibition -1 21383145 YES Monia DBeQ (1) is a reversible and selective inhibitor of p97 0.8 SIGNOR-261100 GABRG2 protein P18507 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.65 SIGNOR-263767 PRKG1 protein Q13976 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 YES lperfetto Studies with human lasp mutants identified serine 146 as a specific phosphorylation site for cgk and cak in vivo. Lasp is an actin-binding protein, and the phospho-lasp-mimicking mutant s146d showed reduced binding affinity for f-actin in cosedimentation experiments. 0.36 SIGNOR-97946 etorphine chemical CHEBI:4912 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258804 NUP155 protein O75694 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.749 SIGNOR-262082 CSNK2A1 protein P68400 UNIPROT ERCC3 protein P19447 UNIPROT down-regulates activity phosphorylation Ser751 FGTMSSMsGADDTVY -1 15549133 YES miannu Phosphorylation of S751 by CKII inhibits 5′ incision. 0.2 SIGNOR-276013 KAT2B protein Q92831 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 BTO:0000887 10944526 YES gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo 0.646 SIGNOR-81059 NT5E protein P21589 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity chemical modification -1 31461341 YES Luana Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine. 0.8 SIGNOR-269742 SGI-1776 chemical CID:24795070 PUBCHEM PIM proteinfamily SIGNOR-PF34 SIGNOR down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-259435 PICK1 protein Q9NRD5 UNIPROT ASIC1 protein P78348 UNIPROT up-regulates activity relocalization 10116 BTO:0000938 11802773 YES miannu we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction 0.538 SIGNOR-223417 PRKACA protein P17612 UNIPROT ITPR1 protein Q14643 UNIPROT down-regulates activity phosphorylation Ser1764 RPSGRREsLTSFGNG -1 12529267 YES miannu IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site. 0.555 SIGNOR-249997 AP1 complex SIGNOR-C154 SIGNOR CD3 complex SIGNOR-C432 SIGNOR up-regulates activity binding 9606 16473826 YES scontino When T cells encounter antigens via the T cell antigen receptor (TCR), information about the quantity and quality of antigen engagement is relayed to the intracellular signal transduction machinery. The TCR itself lacks a significant intracellular domain. Instead, it is associated with CD3 molecules that contain intracellular signaling domains that couple the TCR/CD3 complex to the downstream signaling machinery. 0.337 SIGNOR-267994 MAPK1 protein P28482 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 18204439 YES lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. 0.716 SIGNOR-160407 AT9283 chemical CID:11696609 PUBCHEM JAK3 protein P52333 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190020 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDCA5 protein Q96FF9 UNIPROT up-regulates activity phosphorylation Ser209 DMTLPGIsPPPEKQK 9606 BTO:0000567 20551060 YES miannu Phosphorylation and activation of cell division cycle associated 5 by mitogen-activated protein kinase play a crucial role in human lung carcinogenesis. Our data suggest that transactivation of CDCA5 and its phosphorylation at Ser209 by ERK play an important role in lung cancer proliferation, and that the selective suppression of the ERK-CDCA5 pathway could be a promising strategy for cancer therapy. 0.2 SIGNOR-262968 ARNTL protein O00327 UNIPROT VWF protein P04275 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000394 20658528 YES lperfetto We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype. 0.324 SIGNOR-253704 VEGFA protein P15692 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 16301830 NO VEGF as a key mediator of angiogenesis in cancer. 0.7 SIGNOR-256597 GSK3B protein P49841 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates phosphorylation Ser55 CPTYFPPsPTGSLTQ 9606 16484495 YES llicata We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock. 0.282 SIGNOR-144566 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Ser118 DKSTQTPsPPCQAFN 9606 12591950 YES lperfetto Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58) 0.2 SIGNOR-98388 levomilnacipran chemical CHEBI:136040 ChEBI SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18468895 YES Luana Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors 0.8 SIGNOR-257944 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT up-regulates activity phosphorylation Tyr188 PPVPNPDyEPIRKGQ 9534 BTO:0004055 11855827 YES Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways. 0.691 SIGNOR-251368 CSNK1A1L protein Q8N752 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 YES gcesareni We show that a complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45). 0.507 SIGNOR-87430 p38 proteinfamily SIGNOR-PF16 SIGNOR FOXC1 protein Q12948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser272 SSLSSGSsPPGSLPS 31650548 YES lperfetto P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. 0.2 SIGNOR-275912 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 YES lperfetto Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. 0.727 SIGNOR-40349 GSK3B protein P49841 UNIPROT DZIP1 protein Q86YF9 UNIPROT up-regulates activity phosphorylation 9606 25860027 YES miannu Phosphorylation of Dzip1 by GSK3\u03b2 Promotes the Release of Rab8 GDP from GDI2. 0.391 SIGNOR-278251 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 21133840 YES simone vumbaca TNF alpha and IFN gamma exhibit a cross-talk at the level of TNFR1 to induce activation of macrophages 0.925 SIGNOR-256025 JNK proteinfamily SIGNOR-PF15 SIGNOR CDC25C protein P30307 UNIPROT down-regulates phosphorylation 9606 20220133 YES inferred from 70% family members gcesareni Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset. 0.2 SIGNOR-269983 SLC36A2 protein Q495M3 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI up-regulates quantity relocalization 9606 12748860 YES lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. 0.8 SIGNOR-264740 HDAC1 protein Q13547 UNIPROT SERPINB5 protein P36952 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 18247378 YES miannu We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1. 0.413 SIGNOR-268494 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 27846390 YES lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  0.312 SIGNOR-262982 TRIB3 protein Q96RU7 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity binding 9606 BTO:0000007 BTO:0000759 12791994 YES llicata TRB3 expression is induced in liver under fasting conditions, and TRB3 disrupts insulin signaling by binding directly to Akt and blocking activation of the kinase. 0.618 SIGNOR-237850 DAPK1 protein P53355 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates activity phosphorylation 9606 32500074 YES miannu DAPK1 phosphorylates and activates N-myc downstream-regulated gene 2 (NDRG2), resulting in increased tau phosphorylation via a reduction in Pin1 expression ( xref ; xref ). 0.273 SIGNOR-279983 FYN protein P06241 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates activity phosphorylation 9606 33827252 YES miannu Our studies show that Gab2 is activated by Fyn kinase upon the engagement of ligand to TNFR1, IL-1R, or TLR4.|TNF\u03b1, IL-1\u03b2, and LPS induce Fyn kinase-mediated phosphorylation of Gab2. 0.603 SIGNOR-279984 FYN protein P06241 UNIPROT LCK protein P06239 UNIPROT down-regulates activity phosphorylation Tyr505 FTATEGQyQPQP 9606 22043010 YES miannu In nonactivated T cells, CCR7 triggering induced a Fyn dependent phosphorylation of the inhibitory Tyr505 of Lck.|Inhibiting Fyn in these nonactivated T cells prevented the negative regulation of Lck and facilitated high CCR7 driven T cell chemotaxis. 0.409 SIGNOR-279986 FYN protein P06241 UNIPROT PAG1 protein Q9NWQ8 UNIPROT up-regulates activity phosphorylation 9606 12218089 YES miannu Thus, Fyn mediates Csk-binding protein-Csk interaction and recruits Csk to rafts by phosphorylating Csk-binding protein. 0.702 SIGNOR-279987 FYN protein P06241 UNIPROT PLEKHG1 protein Q9ULL1 UNIPROT up-regulates activity phosphorylation 9606 35031323 YES miannu We also show that this activation of PLEKHG1 by FYN requires interaction between these two proteins and FYN-induced tyrosine phosphorylation of PLEKHG1 .|We also show that this activation of PLEKHG1 by FYN requires interaction between these two proteins and FYN-induced tyrosine phosphorylation of PLEKHG1. 0.2 SIGNOR-279988 DYRK1A protein Q13627 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 9606 22110360 YES miannu Regarding to the functional role of Dyrk1A, active Dyrk1A phosphorylates the transcription factor cAMP response element -binding protein (CREB), which subsequently leads to the stimulation of cAMP response element-mediated gene transcription during neuronal differentiation ( ). 0.487 SIGNOR-279989 DYRK1A protein Q13627 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT up-regulates activity phosphorylation 9606 22876196 YES miannu This Minibrain/Dyrk1a kinase phosphorylates and activates the Silent information regulator 2/Sirtuin1 deacetylase, which in turn deacetylates and activates the FOXO transcription factor. 0.293 SIGNOR-279990 FYN protein P06241 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation 9606 34575985 YES miannu ROS could be detected by Fyn, which is required to activate TRPV4 in a redox-sensitive manner.|The Ca 2+ response to H 2 O 2 required the basal phosphorylation of TRPV4 by the Src kinase Fyn, which may serve as the redox sensor responsible for TRPV4 activation (Figure 2 ) [220] , and was able to increase barrier permeability [219] . 0.35 SIGNOR-279991 DYRK1A protein Q13627 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 31454149 YES miannu DYRK1A overexpression promotes STAT3 activity by phosphorylating STAT3 at Ser727 and contributes to reduced neuronal production and increased astroglial generation in DS. 0.265 SIGNOR-279992 GRK1 protein Q15835 UNIPROT F2RL2 protein O00254 UNIPROT down-regulates activity phosphorylation 9606 20463241 YES miannu For example, RhoK phosphorylates and inhibits TIAM1, STEF, and PAR3; disrupts the polarity complex; and prevents Rac activation ( xref ). 0.2 SIGNOR-279993 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG protein P37231 UNIPROT up-regulates quantity by expression phosphorylation 10090 BTO:0000011 12270934 YES lperfetto Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression. 0.2 SIGNOR-235334 DYRK1A protein Q13627 UNIPROT TOMM70 protein O94826 UNIPROT up-regulates activity phosphorylation Ser91 KTPEGRAsPAPGSGH 9606 34257281 YES miannu Phosphorylation of TOM70 Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. 0.2 SIGNOR-279994 GRK1 protein Q15835 UNIPROT TIAM1 protein Q13009 UNIPROT down-regulates activity phosphorylation 9606 20463241 YES miannu For example, RhoK phosphorylates and inhibits TIAM1, STEF, and PAR3; disrupts the polarity complex; and prevents Rac activation ( xref ). 0.2 SIGNOR-279995 EGFR protein P00533 UNIPROT ACAT1 protein P24752 UNIPROT up-regulates activity phosphorylation 9606 27867011 YES miannu We found that purified EGFR and FGFR1 directly phosphorylate and activate ACAT1 ( xref ).|We found that purified EGFR and FGFR1 directly phosphorylate and activate ACAT1 (XREF_FIG). 0.2 SIGNOR-279996 GRK1 protein Q15835 UNIPROT TIAM2 protein Q8IVF5 UNIPROT down-regulates activity phosphorylation 9606 20463241 YES miannu For example, RhoK phosphorylates and inhibits TIAM1, STEF, and PAR3; disrupts the polarity complex; and prevents Rac activation ( xref ). 0.2 SIGNOR-279997 EGFR protein P00533 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr371 TQEQYELyCEMGSTF 9606 29920512 YES miannu As activated EGFR induces phosphorylation (on tyrosine 371) and activation of Cbl (reaction 19) , which eventually leads to EGFR degradation, EGFR and Cbl are connected via a negative feedback.|As activated EGFR induces phosphorylation (on tyrosine 371) and activation of Cbl (reaction 19) [ xref ], which eventually leads to EGFR degradation, EGFR and Cbl are connected via a negative feedback. 0.886 SIGNOR-279998 GRK2 protein P25098 UNIPROT GPR17 protein Q13304 UNIPROT down-regulates activity phosphorylation 9606 24613411 YES miannu As depicted in Fig. 8 A and B, GRK2 silencing resulted in up-regulation of GPR17 and down-regulation of the mature markers CNPase and MBP, indicating a shift of cells toward a less differentiated stage.Having established that, in primary cultured OPCs, LTD 4 mediated desensitization of GPR17 through the primary recruitment of GRK2, we then asked whether GRK2 pharmacological inhibition had any effects on cysLT promoted cell maturation.|These data demonstrate that LTD 4 -induced GPR17 phosphorylation is preferentially mediated by GRK2 and only partially by GRK5, whereas UDP-glucose-mediated receptor phosphorylation exclusively requires the GRK5 isoform.We examined the involvement of GRK2 and GRK5 in agonist induced desensitization of GPR17. 0.2 SIGNOR-279999 EGFR protein P00533 UNIPROT MST1R protein Q04912 UNIPROT up-regulates activity phosphorylation 9606 23799848 YES miannu This showed that EGFR activation transphosphorylated Ron.|Together, these data suggested that (1) Ron activation transphosphorylated EGFR and vice versa and (2) activated Ron biochemically interacted with EGFR. 0.334 SIGNOR-280000 GRK2 protein P25098 UNIPROT RAPGEF3 protein O95398 UNIPROT down-regulates activity phosphorylation Ser108 S-->L 9606 28580839 YES miannu The observation that GRK2 co-immunoprecipitates with Epac1 suggests a direct association between GRK2 and Epac1 in DRGs. xref A detailed study of the influence of GRK2 on the Epac1 level found that phosphorylation of ser108 in Epac1 by GRK2 can lead to a reduction of Epac1 activation. xref Downstream consequence of a reduction of GRK2 was explored. xref Low GRK2 expression in GRK2(\u00b1) DRGs was found to facilitate CPT-induced Rap1 activation and increase the phosphorylated ERK1/2 level. 0.2 SIGNOR-280001 HOXB4 protein P17483 UNIPROT IGFBP1 protein P08833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12489992 YES Luana These data showed that Hox genes selectively activate the transcription of theIGFBP-1 0.2 SIGNOR-261636 EGFR protein P00533 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates activity phosphorylation 9606 25125655 YES miannu Here, we report that treatment of EGFR mutated lung cancer cell lines with erlotinib, while showing robust cell death, enriches the ALDH+ stem like cells through EGFR dependent activation of Notch3.|We also find a kinase-dependent physical association between the Notch3 and EGFR receptors and tyrosine phosphorylation of Notch3. 0.592 SIGNOR-280002 EIF2AK2 protein P19525 UNIPROT PRKRA protein O75569 UNIPROT up-regulates activity phosphorylation 9606 19580324 YES miannu In stressed cells, this activation occurs when PACT, a PKR-binding protein, is phosphorylated and activates PKR. 0.796 SIGNOR-280003 tRNA(Phe) smallmolecule CHEBI:29184 ChEBI Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates quantity precursor of 9606 20223217 YES miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. 0.8 SIGNOR-270443 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-142147 EIF2AK3 protein Q9NZJ5 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity phosphorylation Thr19 YRYQDEDtPPLEHSP 9606 28522733 YES miannu To elucidate the molecular mechanism, we found that activated PERK phosphorylates CAMP response element binding protein (CREB) and PSD95 directly at the S129 and T19 residues, respectively. 0.268 SIGNOR-280004 EIF2AK4 protein Q9P2K8 UNIPROT EIF2A protein Q9BY44 UNIPROT down-regulates activity phosphorylation 9606 19498172 YES miannu Activated GCN2 phosphorylates and inhibits eukaryotic translation initiation factor 2A (eIF2\u03b1), leading to a transient reduction in protein synthesis, while enhancing the translation of ATF4 ( xref ), a transcription factor that activates stress-induced gene expression ( xref \u2013 xref ). 0.485 SIGNOR-280005 EPHA3 protein P29320 UNIPROT UXS1 protein Q8NBZ7 UNIPROT up-regulates activity phosphorylation 9606 25505462 YES miannu However, it is possible that etk is a principal activator of Ugd.|The phosphorylation of the Ugd protein (a UDP-glucose dehydrogenase) by Etk increases Ugd dehydrogenase activity. 0.2 SIGNOR-280006 EPHA4 protein P54764 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates activity phosphorylation 9606 22040915 YES miannu EphA4 and FGFR1 heterodimer promotes FGFR1 signaling in glioma cell line.|Ligand stimulation of EphA4 stimulates FGFR1 phosphorylation and signaling. 0.403 SIGNOR-280007 EPHB1 protein P54762 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr14 VDSEGHLyTVPIREQ 9606 32238105 YES miannu EphB1-dependent Y-14 phosphorylation of Cav-1 regulates caveolae endocytosis and endothelial permeability. 0.2 SIGNOR-280008 WASHC4 protein Q2M389 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 YES lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. 0.2 SIGNOR-261018 RUNX2 protein Q13950 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 20551513 YES gcesareni Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphory-lated runx2, promoting its association with the coac-tivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs. 0.407 SIGNOR-166170 ERBB2 protein P04626 UNIPROT SHCBP1 protein Q8NEM2 UNIPROT up-regulates activity phosphorylation Ser273 SSLSNCNsDSEQENI 9606 35013128 YES miannu Blocking HER2 activation using trastuzumab effectively abolished EGF-induced nuclear localization of SHCBP1 in gastric cancer cells [7].|In addition, nuclear translocation of SHCBP1 is a downstream consequence of HER2 activation, which is dependent on phosphorylation of SHCBP1 at the Ser273 site. 0.2 SIGNOR-280009 FAM20C protein Q8IXL6 UNIPROT AMBN protein Q9NP70 UNIPROT up-regulates activity phosphorylation 9606 25789606 YES miannu Disruption of Fam20C completely eliminated AMBN phosphorylation, suggesting that Fam20C is the kinase that phosphorylates enamel matrix proteins in vivo (XREF_FIG). 0.663 SIGNOR-280010 FAM20C protein Q8IXL6 UNIPROT DMP1 protein Q13316 UNIPROT up-regulates quantity phosphorylation 9606 25026495 YES miannu Fam20c knockdown decreased Dmp1 mRNA and increased Fgf23 mRNA in UMR-106 cells.|Relative migration distances of OPN and DMP1, which were the ratio of the migration distances of OPN or DMP1 co-expressed with mutant FAM20C to that with WT FAM20C, showed that only WT FAM20C could fully phosphorylate OPN and DMP1. 0.658 SIGNOR-280011 FAM20C protein Q8IXL6 UNIPROT SLC35G1 protein Q2M3R5 UNIPROT up-regulates activity phosphorylation 9606 30520731 YES miannu Notably, phosphorylation of Stim1 by Fam20C enhances Stim1 activation and store-operated Ca 2+ entry.|We feel that the western blot shows an appropriate range of contrast to support the conclusion that Stim1 can be activated by Fam20C under high calcium conditions. 0.2 SIGNOR-280012 FGFR1 protein P11362 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates activity phosphorylation Tyr196 AEEQVHTyVNTTGVQ 9606 25394172 YES miannu As shown in xref , wild type FGFR1c phosphorylated FRS2\u03b1 on tyrosine 196 whereas the V429E mutant did not. 0.867 SIGNOR-280013 dactolisib chemical CHEBI:71952 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0000848 21803746 YES ATP-competitive inhibitor of PI3K and mTOR gcesareni The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific 0.8 SIGNOR-252665 RPS6KB1 protein P23443 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation 9606 24771995 YES miannu P70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro apoptotic BAD by producing a reaction that disrupts BAD 's binding to other pro apoptotic molecules thereby allowing cell survival.|p70S6K, the downstream target of mTORC1, can phosphorylate and inactivate pro-apoptotic BAD by producing a reaction that disrupts BAD\u2019s binding to other pro-apoptotic molecules thereby allowing cell survival. xref , xref On the other hand, in a recent study, Li et al showed that increased expression of anti-apoptotic BCL2 was induced in myeloid progenitor cells upon activation of p76S6K, thereby promoting cell survival. xref Further studies are needed to better understand the effect of rapamycin and its derivatives on apoptosis in various cancer cells. 0.295 SIGNOR-280016 TBK1 protein Q9UHD2 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation 9606 30791439 YES miannu Only TBK1 phosphorylates and activates IKK\u03b2, functioning additionally as an IKK kinase [ xref ]. 0.404 SIGNOR-280017 PDK2 protein Q15119 UNIPROT PARL protein Q9H300 UNIPROT up-regulates activity phosphorylation 9606 28178523 YES miannu As expected, knocking down PDK2 in HEK293 cells that overexpress PARL resulted in a significant increase in beta cleavage in comparison to the control cells.|Furthermore, we show that PDK2, a key regulator in metabolic plasticity, phosphorylates PARL and regulates \u03b2 cleavage. 0.2 SIGNOR-280018 MAP4K4 protein O95819 UNIPROT protein Q6DN90 UNIPROT up-regulates activity phosphorylation 9606 25490267 YES miannu Together, our results provide compelling evidence that MAP4K4 promotes FA dynamics by regulating IQSEC1 and Arf6 pathway and controlling endocytosis of integrin.|Upon targeting to FAs via MTs, MAP4K4 can bind and phosphorylate IQSEC1, which in turn activates Arf6 and endocytosis, leading to turnover of FAs. 0.2 SIGNOR-280020 MAPK1 protein P28482 UNIPROT CPEB4 protein Q17RY0 UNIPROT up-regulates activity phosphorylation 9606 27802129 YES miannu Our results indicate that CPEB4 activation is driven by ERK2- and Cdk1 mediated hyperphosphorylation of at least 12 residues in the intrinsically disordered NTD.|We concluded that, in interphase, unphosphorylated CPEB4 phase separates into liquid like droplets that recruit mRNAs but are inactive for cytoplasmic polyadenylation and translation, whereas in M-phase, CPEB4 is phosphorylated by ERK2 and Cdk1 and recovers its monomeric form, which can drive the cytoplasmic polyadenylation of target mRNAs. 0.325 SIGNOR-280021 MAPK1 protein P28482 UNIPROT SEC16A protein O15027 UNIPROT up-regulates activity phosphorylation 9606 20548102 YES miannu Recombinant active ERK2 also phosphorylated Sec16 (XREF_FIG). 0.352 SIGNOR-280022 MAPK11 protein Q15759 UNIPROT CCND3 protein P30281 UNIPROT down-regulates quantity by destabilization phosphorylation Thr283 QGPSQTStPTDVTAI 9606 15326477 YES miannu P38SAPK2 phosphorylates cyclin D3 at Thr-283 and targets it for proteasomal degradation. 0.2 SIGNOR-280023 PRKCA protein P17252 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser26 TPPSAYGsVKAYTNF 9606 BTO:0000452 2946940 YES lperfetto The protein-tyrosine kinase substrate p36 is also a substrate for protein kinase C in vitro and in vivo. | We present evidence suggesting that protein kinase C mediates phosphorylation of serine 25. 0.357 SIGNOR-248892 hsa-miR-30a-3p mirna URS0000065D58_9606 RNAcentral UBE2E3 protein Q969T4 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000093 39621672 YES miannu MiR-379-5p affects breast cancer cell behavior by targeting UBE2E3 ubiquitin conjugating enzyme 0.4 SIGNOR-279977 miR-139-3p mirna URS000023BE29_9606 RNAcentral WNT5A protein P41221 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000599 36917402 YES miannu Bioinformatics analysis showed that hsa-miR-139-3p may target Wnt5A to regulate the WNT pathway, which was further confirmed by Western-blot and dual-luciferase assays. 0.4 SIGNOR-279978 IL1RAPL2 protein Q9NP60 UNIPROT NCS1 protein P62166 UNIPROT up-regulates activity binding 10116 BTO:0001009 12783849 YES miannu IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction. 0.321 SIGNOR-264476 FUBP1 protein Q96AE4 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30500954 NO irozzo Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. 0.2 SIGNOR-259132 ATG7 protein O95352 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22170151 YES gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe 0.871 SIGNOR-195236 MTHFR protein P42898 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000567 24769206 NO miannu MTHFR promotes heterochromatin maintenance at the centromeric region. 0.7 SIGNOR-263889 AKT proteinfamily SIGNOR-PF24 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 YES flangone Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. 0.2 SIGNOR-242092 MAPKAPK2 protein P49137 UNIPROT ARPC5 protein O15511 UNIPROT unknown phosphorylation Ser77 AVKDRAGsIVLKVLI -1 12829704 YES miannu MAPKAPK2 also phosphorylated p16-Arc in intact Arp2/3 complexes precipitated from neutrophil lysates. Mutation of serine-77 to alanine on the A isoform prevented phosphorylation by MAPKAPK2. 0.352 SIGNOR-250144 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD80 protein P33681 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12860928 NO miannu Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. 0.297 SIGNOR-254783 PPP4C protein P60510 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity dephosphorylation Ser1618 LTKAADIsLDNLVEG -1 24703952 YES lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Depletion of PP4C, or PP4R3beta, causes persistence of phospho-T1609 and phospho-S1618 0.358 SIGNOR-264451 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Asp) smallmolecule CHEBI:29186 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269483 AKT1 protein P31749 UNIPROT PHF20 protein Q9BVI0 UNIPROT down-regulates phosphorylation Ser291 ELRRRKIsKGCEVPL 9606 22334668 YES llicata Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function. 0.551 SIGNOR-252529 NXPH1 protein P58417 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 YES gcesareni We show that neurexophilins 1 and 3 but not 4 (neurexophilin 2 is not expressed in rodents) bind to a single individual lns domain, the second overall lns domain in all three alpha-neurexins. 0.375 SIGNOR-60643 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr577 SCRSSTTtCPEQDFF 9606 BTO:0000007 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249301 AP-2 complex complex SIGNOR-C245 SIGNOR ITSN1 protein Q15811 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 YES Giorgia Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples 0.659 SIGNOR-260397 C2 protein P06681 UNIPROT C3 convertase complex complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg243 KTKESLGrKIQIQRS 17204478 YES complement C2a fragment: PRO_0000027612 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex 0.64 SIGNOR-263399 SPSB2 protein Q99619 UNIPROT Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR up-regulates activity binding -1 20603330 YES miannu We have identified SPRY domain-containing SOCS (suppressor of cytokine signaling) box protein 2 (SPSB2) as a novel negative regulator that recruits an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in its proteasomal degradation. A cell-free ubiquitination assay was established to demonstrate SPSB2-dependent ubiquitination of iNOS. LPS/IFN-γ–stimulated macrophage lysates from Spsb2−/− mice were used as a source of iNOS and incubated with ubiquitin and a trimeric SPSB2/elongin BC complex in the presence of E1 and E2 (UbcH5a) enzymes, Rbx2, and Cullin5 for various times. 0.57 SIGNOR-271899 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser574 EEVSDKGsDSEEEET 9606 BTO:0000599 23287549 YES lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. 0.2 SIGNOR-265270 CHUK protein O15111 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT up-regulates activity phosphorylation Ser666 RPPVRVPsWGLEDNV 10090 BTO:0002572 21765415 YES The effect has been demonstrated using Q86VP1-2 lperfetto Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, but not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1). 0.383 SIGNOR-175062 MAPK11 protein Q15759 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates activity phosphorylation 9606 10330143 YES miannu In this study, we demonstrate that among the different Mitogen-activated protein kinases, the MADS-box transcription factors MEF2A and MEF2C are preferentially phosphorylated and activated by the p38 subfamily members p38alpha and p38beta2. 0.532 SIGNOR-280024 MAPK12 protein P53778 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser33 LPENNVLsPLPSQAM 9606 19251701 YES miannu Furthermore, upon activation by oncogenic ras, p38gamma stimulated the transcriptional activity of p53 by phosphorylating p53 at Ser(33), suggesting that the ability of p38gamma to mediate senescence is at least partly achieved through p53. 0.473 SIGNOR-280026 MAPK3 protein P27361 UNIPROT MAFG protein O15525 UNIPROT up-regulates quantity phosphorylation Ser124 FARTVARsPVAPARG 9606 25219500 YES miannu By contrast, MAFG-S124A was not phosphorylated, indicating that ERK1 phosphorylates MAFG at S124.|Notably, cotransfection of ERK1 increased total levels of wild-type MAFG and MAFG-T3A but not MAFG-S124A, indicating that phosphorylation increased MAFG stability. 0.368 SIGNOR-280027 MAPK7 protein Q13164 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity phosphorylation 9606 30804322 YES miannu Moreover, we demonstrate that ERK5 facilitates Chk1 phosphorylation induced by IR.|Since we have found that ERK5 was able to accelerate the phosphorylation and activation of IR-induced Chk1, therapeutic targeting of Chk1 in NSCLC cells with high ERK5 expression might be an effective strategy for overcoming radioresistance. 0.276 SIGNOR-280028 MAPK8 protein P45983 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser574 SAKHQQQsPVSQSMQ 9606 27669435 YES miannu As JNK1 phosphorylates FOXO3 at S574, 12 allowing formation of the proapoptotic species, we tested whether FOXO3 acetylation is required for the JNK1-FOXO3 interaction. 0.65 SIGNOR-280030 hsa-mir-17-3p-1 mirna URS00004636A3_9606 RNAcentral SOX6 protein P35712 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 10090 BTO:0004473 32946669 YES miannu MiR-17-3p inhibits osteoblast differentiation by downregulating Sox6 expression 0.4 SIGNOR-279933 miRNA-214-5p mirna URS00004DAA89_9606 RNAcentral SOX4 protein Q06945 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 34863188 YES miannu MiRNA-214-5p inhibits prostate cancer cell proliferation by targeting SOX4 0.4 SIGNOR-279934 Mir-615-5p mirna URS00004D8280_9606 RNAcentral TMIGD2 protein Q96BF3 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000567 39789663 YES miannu Mir-615-5p inhibits cervical cancer progression by targeting TMIGD2 0.4 SIGNOR-279935 miR-642a-3p mirna URS00000E7139_9606 RNAcentral SERPINE1 protein P05121 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 39544420 YES miannu CAF-derived miR-642a-3p supports migration, invasion, and EMT of hepatocellular carcinoma cells by targeting SERPINE1 0.4 SIGNOR-279936 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation 9606 19237534 YES inferred from 70% family members lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. 0.2 SIGNOR-270110 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser203 DLEFSSGsPGKETNE 9606 23650397 YES gcesareni SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|Having demonstrated that SGK1 mediates the cortisol-induced increase in GR phosphorylation at the S203 and S211 phospho-sites, which enhance GR nuclear translocation, but not at the S226 site, which inhibits nuclear translocation 0.461 SIGNOR-251669 CTNNB1 protein P35222 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23645839 NO apalma For example, prostaglandin E2 (PGE2), 1 of the major metabolites downstream of both COX-1 and COX-2, has been shown to activate β-catenin–dependent signaling in hematopoietic stem cells (HSCs) and promote HSC expansion 0.7 SIGNOR-255695 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT up-regulates activity phosphorylation Ser122 RIQEQESsGEEDSDL -1 8288648 YES llicata Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action. 0.307 SIGNOR-251021 hsa-miR-361-5p mirna URS00000CF1D2_9606 RNAcentral CXCR6 protein O00574 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000599 26872014 YES miannu MicroRNA-361-5p Inhibits Cancer Cell Growth by Targeting CXCR6 in Hepatocellular Carcinoma 0.4 SIGNOR-279937 hsa-miR-133b mirna URS000032BD73_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 24330809 YES miannu CXCR4 was shown to be a direct target of miR-133b by luciferase reporter assays, and transfection of miR-133b mimics inhibited invasion and stimulated apoptosis of SW-480 and SW-620 CRC cells. 0.4 SIGNOR-279940 miR‑137 mirna URS00001E3523_9606 RNAcentral SPHK2 protein Q9NRA0 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002126 37533491 YES miannu MiR‑137 is a diagnostic tumor‑suppressive miRNA that targets SPHK2 to promote M1‑type tumor‑associated macrophage polarization 0.4 SIGNOR-279941 miR‑137 mirna URS00001E3523_9606 RNAcentral USP30 protein Q70CQ3 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 38111333 YES miannu MiRNA-137-5p improves spatial memory and cognition in Alzheimer's mice by targeting ubiquitin-specific peptidase 30 0.4 SIGNOR-279942 hsa-miR-138-5p mirna URS000040780F_9606 RNAcentral LCN2 protein P80188 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 10116 BTO:0001009 39794698 YES miannu Rat hippocampal tissues were collected and analyzed for inflammatory factor concentration and miR-138-5p expression using ELISA and qRT-PCR, respectively, and the targeting link between miR-138-5p and LCN2 was verified by dual luciferase reporter. 0.4 SIGNOR-279943 miRNA-142-3p mirna URS00002620A7_9606 RNAcentral SIRT1 protein Q96EB6 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0004980 38663003 YES miannu MiRNA-142-3p aggravates hydrogen peroxide-induced human umbilical vein endothelial cell premature senescence by targeting SIRT1 0.4 SIGNOR-279944 hsa-mir-152-3p mirna URS00003AFD9B_9606 RNAcentral FGFR3 protein P22607 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0004980 40075158 YES miannu Further investigation using dual-luciferase reporter assays, qRT-PCR, and Western blot revealed that miR-152-3p inhibits the expression of FGFR3 by binding to its 3' UTR.  0.4 SIGNOR-279945 hsa-miR-182-5p mirna URS00001CC379_9606 RNAcentral FOXF2 protein Q12947 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0001345 35068163 YES miannu These findings suggested that FOXF2 directly binds to miR-182-5p and that miR-182-5p acts as a tumor promoter in BC genesis and metastasis by targeting FOXF2. In addition, miR-182-5p plays a pro-cancer role by downregulating FOXF2 and activating the SHH pathway. 0.4 SIGNOR-279946 hsa-miR-183-5p mirna URS0000528CBC_9606 RNAcentral TET1 protein Q8NFU7 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000007 37584255 YES miannu MiR-183-5p promotes renal cell carcinoma metastasis by targeting TET1 0.4 SIGNOR-279947 MiRNA-188-5p mirna URS0000083D87_9606 RNAcentral CCNT2 protein O60583 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0001596 31957815 YES miannu MiRNA-188-5p alleviates the progression of osteosarcoma via target degrading CCNT2 0.4 SIGNOR-279948 hsa-miR-21-5p mirna URS000039ED8D_9606 RNAcentral NTF3 protein P20783 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0003109 39828780 YES miannu The dual luciferase reporter assay confirmed that NTF3 is a direct target of miR-21. 0.4 SIGNOR-279949 miR-223-5p mirna URS0000485CBB_9606 RNAcentral CHAC2 protein Q8WUX2 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000007 39854306 YES miannu Overexpression of miR-223-5p in BMSCs inhibited hypoxia-induced apoptosis and activated the Wnt/β-catenin pathway by directly targeting CHAC2. 0.4 SIGNOR-279950 MAPK8 protein P45983 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates activity phosphorylation 9606 11406366 YES miannu It has been previously shown that NF-ATc1 accumulates in the nucleus of activated CD4 + T cells from Jnk1 \n \u2212/\u2212 mice 35\u2022 and that JNK1 phosphorylates and inactivates NFATc1 in Jurkat T cells 47 , indicating that JNK1 is an inhibitor of NFAT. 0.62 SIGNOR-280031 MAPK8 protein P45983 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates activity phosphorylation Ser213 ASRFGLGsPLPSPRA 9606 17875713 YES miannu Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose dependent manner by JNK1 or JNK2. 0.468 SIGNOR-280032 MAPK8 protein P45983 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates activity phosphorylation Ser217 GLGSPLPsPRASPRP 9606 17875713 YES miannu Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose dependent manner by JNK1 or JNK2. 0.468 SIGNOR-280033 MAPK8 protein P45983 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation 9606 32787872 YES miannu Ethanol induced JNK1 phosphorylation activated the NLRP3 inflammasome that induced caspase-1 dependent mitophagy inhibition, thereby exacerbating ROS accumulation and causing cell death.|However, recent studies suggested that Ser 194 phosphorylation of NLRP3 was essential for the control of inflammasome activation and that JNK1 directly phosphorylates NLRP3, which stimulates the self-association and oligomerization of NLRP3 [ xref , xref ]. 0.369 SIGNOR-280034 MAPK9 protein P45984 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates activity phosphorylation Ser213 ASRFGLGsPLPSPRA 9606 17875713 YES miannu Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose-dependent manner by JNK1 or JNK2. 0.42 SIGNOR-280035 MAPK9 protein P45984 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates activity phosphorylation Ser217 GLGSPLPsPRASPRP 9606 17875713 YES miannu Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose-dependent manner by JNK1 or JNK2. 0.42 SIGNOR-280036 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 YES gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. 0.2 SIGNOR-150140 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 24556163 YES miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 0.8 SIGNOR-262237 INSR protein P06213 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates activity phosphorylation 9606 10650943 YES miannu We found that insulin receptor can directly phosphorylate FRS2. 0.372 SIGNOR-278945 miRNA-30a-5p mirna URS000043D1A9_9606 RNAcentral VCAN protein P13611 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000018 37032373 YES miannu  Besides, dual-luciferase assay validated the targeting relationship between miRNA-30a-5p and VCAN. MiRNA-30a-5p, by negatively regulating VCAN, was capable of hindering LUAD cell proliferation, migration, invasion, adhesion, viability and EMT. 0.4 SIGNOR-279952 MAPKAPK5 protein Q8IW41 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity phosphorylation 9606 23878308 YES miannu The kinase MK5 phosphorylates and activates Foxo1 at serine 215, and this modification is required for Foxo1 to induce Rag transcription. 0.42 SIGNOR-280037 MARK2 protein Q7KZI7 UNIPROT MAPT protein P10636 UNIPROT down-regulates quantity phosphorylation 9606 36048712 YES miannu Notably, phosphorylation of Tau by microtubule affinity regulating kinase 2 (MARK2), dramatically enhances the binding affinity of Hsp27 to Tau. 0.706 SIGNOR-280038 MELK protein Q14680 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation 9606 24185907 YES miannu MELK, as an upstream kinase of ASK1, phosphorylates threonine 838 in an activation loop of human ASK1, thereby stimulating ASK1 kinase activity. 0.271 SIGNOR-280039 MET protein P08581 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates activity phosphorylation 9606 22188814 YES miannu In this study, using a protein array approach, we found that c-Met phosphorylates FAK and Pyk2 in medulloblastoma cells.|Our study shows for the first time that c-Met activates FAK and Pyk2 and that FAK and Pyk2 mediate the effects of c-Met in medulloblastoma. 0.28 SIGNOR-280040 MET protein P08581 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 30143645 YES miannu It has been reported that c-Met can activate STAT3 at the endosome and phosphorylated STAT3 induced by c-Met is colocalized with EEA1, an early endosome marker. 0.705 SIGNOR-280041 MINK1 protein Q8N4C8 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation 9606 34480147 YES miannu MINK1-mediated NLRP3 phosphorylation at Ser725 is critical for inflammasome activation.|These results suggest that MINK1 promotes NLRP3 inflammasome activation via direct interaction with NLRP3.|To determine whether MINK1 phosphorylated NLRP3 directly, we used Phos-tag SDS\u2013PAGE to detect the phosphorylation of NLRP3. 0.2 SIGNOR-280042 ATM protein Q13315 UNIPROT USP24 protein Q9UPU5 UNIPROT up-regulates activity phosphorylation 9606 25578727 YES miannu Taken together, these data suggest that the ATM kinase mediated phosphorylation of USP24 is involved in USP24 stabilization/up regulation following UV irradiation.|Taken together, these data suggest that the ATM kinase-mediated phosphorylation of USP24 is involved in USP24 stabilization/up-regulation following UV irradiation. 0.25 SIGNOR-280043 MTOR protein P42345 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation 9606 26584640 YES miannu Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively.|Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR/InsR. 0.494 SIGNOR-280044 MTOR protein P42345 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation 9606 26584640 YES miannu Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively.|Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF-IR and InsR. 0.391 SIGNOR-280045 MTOR protein P42345 UNIPROT IGF2BP2 protein Q9Y6M1 UNIPROT up-regulates activity phosphorylation 9606 29736175 YES miannu IGF2BP2 can be activated by mTOR and promotes its binding to IGF2 mRNA of IGF2 thereby leading to diabetes mellitus [ xref , xref ].|In addition, phosphorylation of IGF2BP2 in the linker region between RRM2 and KH1 by mTOR promotes its binding to the IGF leader 3 mRNA 5\u2032-UTR, enhancing the initiation of IGF2 translation through eIF-4E- and 5\u2032 cap-independent internal ribosomal entry [ xref ]. 0.2 SIGNOR-280046 MTOR protein P42345 UNIPROT SIRT1 protein Q96EB6 UNIPROT down-regulates activity phosphorylation Ser47 DGPGLERsPGEPGGA 9606 21471201 YES miannu These results demonstrate that the inhibition of SIRT1 by mTOR fosters survival of DNA damage-induced prematurely senescent squamous cell carcinoma cells via Bfl-1/A1 in the absence of functional p53.|This process involved the mTOR-dependent phosphorylation of SIRT1 at serine 47, resulting in the inhibition of the deacetylase activity of SIRT1. 0.552 SIGNOR-280047 NLK protein Q9UBE8 UNIPROT MYB protein P10242 UNIPROT down-regulates activity phosphorylation 9606 23935942 YES miannu Furthermore, the downregulation of c-Myb by NLK overexpression could be inhibited in cells that had been treated with the 26S proteasome inhibitor MG132 but not in those treated with DMSO ( ).|HIPK2 and NLK directly bind to c-Myb, and NLK phosphorylates c-Myb at multiple sites, resulting in its ubiquitination and proteasome-dependent degradation [32]. 0.713 SIGNOR-280049 NTRK2 protein Q16620 UNIPROT VAV2 protein P52735 UNIPROT up-regulates activity phosphorylation 9606 21880903 YES miannu Finally, the TrkB kinase dependent increase in P-Y172 Vav2 was largely independent of the Vav2 SH2 domain (XREF_FIG, right), which was previously shown to be important for activation by Eph receptors.|These findings reveal a strong kinase independent binding mechanism between Vav and TrkB in cells, and suggest that activation of TrkB kinase activity stimulates Vav2 tyrosine phosphorylation and GEF activity. 0.303 SIGNOR-280050 NUAK2 protein Q9H093 UNIPROT LAT protein O43561 UNIPROT down-regulates activity phosphorylation 9606 30158528 YES miannu Analysis by an in vitro kinase assay revealed that NUAK2 could phosphorylate immunoprecipitated LATS and that this phosphorylation was lost in the LATS double mutant (DM), T246A/S613A (Fig.\u00a0 xref ).|We showed that phosphorylation of Ser613, located upstream of the KD, adjacent to the MOB binding site and to a lesser extent the N-terminal localized T246, are required for NUAK2 to inhibit LATS. 0.2 SIGNOR-280052 PAK1 protein Q13153 UNIPROT MYL12B protein O14950 UNIPROT up-regulates activity phosphorylation 9606 25860930 YES miannu It has been shown that PAK1 phosphorylates and activates MLC2, leading to cell motility [ xref ]. 0.483 SIGNOR-280053 PAK1 protein Q13153 UNIPROT SLC6A2 protein P23975 UNIPROT down-regulates activity phosphorylation 9606 15684429 YES miannu PAK1 negatively regulates the activity of the Rho exchange factor NET1.|Specifically, PAK1 phosphorylates NET1 on three sites in vitro : serines 152, 153, and 538. 0.2 SIGNOR-280054 PAK4 protein O96013 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Thr235 SSSSPPGtPSPADAK 9606 30808546 YES miannu Importantly, we found that PAK4 enhanced CEBPB phosphorylation on Thr 235.|In summary, we showed that PAK4 mediated CEBPB activation upregulated CLDN4 expression to promote breast cancer cell migration and invasion. 0.2 SIGNOR-280055 SYK protein P43405 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Tyr18 MEDHAGTyGLGDRKD 9606 BTO:0000938 18070606 YES lperfetto We established that tyrosine 18 was the primary residue in tau phosphorylated by sykphosphorylation of tau by syk could be involved in neurite outgrowth. 0.467 SIGNOR-159648 PAK4 protein O96013 UNIPROT ITGB1BP1 protein O14713 UNIPROT down-regulates activity phosphorylation Ser10 RKGKKRHsSSSSQSS 9606 32005669 YES miannu We further demonstrate that p21 activated kinase 4 (PAK4) can phosphorylate ICAP1 at Ser 10 both in vitro and in cultured cells, and that active PAK4 inhibits ICAP1 nuclear accumulation in a Ser-10-dependent manner.|We further demonstrate that p21-activated kinase 4 (PAK4) can phosphorylate ICAP1 at Ser-10 both in vitro and in cultured cells, and that active PAK4 inhibits ICAP1 nuclear accumulation in a Ser-10-dependent manner. 0.2 SIGNOR-280056 PAK4 protein O96013 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 30685413 YES miannu P21 activated kinase 4 (PAK4) directly phosphorylates Slug, resulting in pro malignant Slug stabilization. 0.2 SIGNOR-280057 PAK4 protein O96013 UNIPROT STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation Ser16 KELEKRAsGQAFELI 9606 20805321 YES miannu Indeed, we show here that inactivating phosphorylation of the endogenous stathmin on serine-16 is also induced by the active PAK4 in mitotic egg extract and is likely to participate in the observed stabilization of the MT asters ( xref , right). 0.284 SIGNOR-280058 PAK6 protein Q9NQU5 UNIPROT RHOC protein P08134 UNIPROT down-regulates activity phosphorylation 9606 28486133 YES miannu It is possible that Pak6 may directly phosphorylate RhoC to regulate its activity.|Nevertheless, our results clearly show that the kinase activity of Pak6 is required to inhibit RhoC induced cell contraction. 0.2 SIGNOR-280059 PAK6 protein Q9NQU5 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity phosphorylation 9606 32721391 YES miannu PAK5 promotes the cell stemness ability by phosphorylating SOX2 in lung squamous cell carcinomas.|The absence of PAK5 abolishes self-renewal ability of LUSC cells by decreasing the expression and phosphorylation of SOX2 in vitro and in vivo. 0.2 SIGNOR-280060 PBK protein Q96KB5 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation 9606 17545598 YES miannu Taken together, these findings showed that TOPK positively modulated UVB-induced JNK1 activity and played a pivotal role in JNK1-mediated cell transformation induced by H-Ras.|We showed that TOPK associated with and phosphorylated JNK1 following UVB irradiation in vitro or in vivo. 0.304 SIGNOR-280061 PDPK1 protein O15530 UNIPROT PRKCH protein P24723 UNIPROT up-regulates activity phosphorylation 9606 12223477 YES miannu Protein kinase C(eta) is phosphorylated by PDK1 in vitro, leading to kinase activation as similarly reported for protein kinase C(epsilon) activation by PDK1. 0.317 SIGNOR-280062 CD3G protein P09693 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates 9606 BTO:0000782 17668895 NO gcesareni Tcr stimulation also activates the mitogen- and stress-activated kinases (msk) downstream of erk1/2. 0.2 SIGNOR-157148 PDPK1 protein O15530 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation 9606 29575487 YES miannu PDK1, but not PKCs, phosphorylate and activate Raf1 in MAPK pathway when platelets are stimulated with 2MeSADP. 0.311 SIGNOR-280063 glutamine smallmolecule CHEBI:28300 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 YES lperfetto All extant life employs the same 20 amino acids for protein biosynthesis 0.7 SIGNOR-264751 PKN1 protein Q16512 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates activity phosphorylation 9606 31564129 YES miannu Although RHOA mediated actin polymerization accelerated MRTFA induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with G-actin by phosphorylating MRTFA, causing increased serum response factor (SRF)-mediated expression of cardiac hypertrophy- and fibrosis associated genes.|Further, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK in vitro . 0.2 SIGNOR-280067 PLK1 protein P53350 UNIPROT EME1 protein Q96AY2 UNIPROT up-regulates activity phosphorylation 9606 24528857 YES miannu In human cells, EME1 is phosphorylated by both cyclin-dependent kinases (CDKs) and PLK1, and this modification is directly correlated with increased MUS81 cleavage activity in\u00a0vitro. 0.447 SIGNOR-280068 PLK1 protein P53350 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation 9606 27330107 YES miannu Subsequently, Plk1 phosphorylation of PTEN was shown to be responsible for its inactivation. 0.535 SIGNOR-280070 PLK1 protein P53350 UNIPROT STK3 protein Q13188 UNIPROT up-regulates activity phosphorylation 9606 29250521 YES miannu How this destabilizes the interaction of Nek2 with PP1 remains unclear, although one possibility is that Plk1 phosphorylation activates Mst2; this in turn would cause increased phosphorylation of Nek2, potentially decreasing its affinity for PP1.|Meanwhile, phosphorylation of Mst2 by Plk1 prevents association of PP1 with Nek2 leading to increased phosphorylation of Nek2 substrates, such as C-Nap1. 0.332 SIGNOR-280071 PLK1 protein P53350 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 36520312 YES miannu The Hsp90 client Plk1 phosphorylates Sgt1, which had a positive impact on Sgt1 function, whereas phosphorylation of Tsc1 by Plk1 led to its ubiquitination and degradation. 0.468 SIGNOR-280072 PLK3 protein Q9H4B4 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity phosphorylation 9606 25202016 YES miannu Phosphorylation of H2AX at serine 139 was catalyzed by hyperosmotic stress-induced activation of Plk3.|Osmotic stress induced phosphorylation of H2AX by polo like kinase 3 affects cell cycle progression in human corneal epithelial cells.|Our results for the first time reveal that hyperosmotic stress-activated Plk3 elicited \u03b3H2AX. 0.2 SIGNOR-280073 hsa-mir-379-5p  mirna URS000060A1F4_9606 RNAcentral UBE2E3 protein Q969T4 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000815 39621672 YES miannu The luciferase assay showed that the miR-379-5p mimic suppressed luciferase activity for the WT binding sequence reporter, but not for the scrambled reporter, showing that the effect of miR-379-5p on UBE2E3 expression is likely to be direct. 0.4 SIGNOR-279954 CDC14A protein Q9UNH5 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity dephosphorylation 9606 20956543 YES lperfetto Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).|Together, these data indicate that Cdc14A dephosphorylates Cdc25B, inhibiting its catalytic activity. 0.561 SIGNOR-276968 PLK4 protein O00444 UNIPROT CDC25C protein P30307 UNIPROT up-regulates quantity phosphorylation 9606 35912011 YES miannu Conclusion: PLK4 contributes to the formation of PGCCs by regulating the expression of CDC25C and is associated with the expression and subcellular location of CDC25C, pCDC25C-ser216 and pCDC25C-ser198.|PLK4 could interact with CDC25C and promote CDC25C phosphorylation which was associated with the formation of PGCCs. 0.461 SIGNOR-280074 PLK4 protein O00444 UNIPROT CEP131 protein Q9UPN4 UNIPROT up-regulates activity phosphorylation Ser78 NNLRRSNsTTQVSQP 9606 30804208 YES miannu We conclude that PLK4 phosphorylates CEP131 at Ser 78 to maintains centriolar satellite integrity. 0.533 SIGNOR-280075 PRKAA1 protein Q13131 UNIPROT SIRT1 protein Q96EB6 UNIPROT down-regulates activity phosphorylation 9606 26363315 YES miannu Previous studies have reported that AMP-activated protein kinase phosphorylates and inactivates SIRT1, resulting in increased p53 acetylation in liver cancer [ xref , xref ]. 0.395 SIGNOR-280076 DCAF1 protein Q9Y4B6 UNIPROT H2AC14 protein Q99878 UNIPROT up-regulates activity phosphorylation Thr121 AVLLPKKtESHHKTK 9606 BTO:0001332 24140421 YES miannu Here we report that VprBP possesses an intrinsic protein kinase activity and is capable of phosphorylating histone H2A on threonine 120 (H2AT120p) in a nucleosomal context. Functional studies reveal that H2AT120p by VprBP is sufficient to repress chromatin transcription. 0.2 SIGNOR-279884 hsa-miR-410-3p mirna URS000047E765_9606 RNAcentral AGTR1 protein P30556 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000794 25646808 YES miannu MicroRNA-410 functions as a tumor suppressor by targeting angiotensin II type 1 receptor in pancreatic cancer 0.4 SIGNOR-279955 hsa-miR-424-5p mirna URS00000F0F49_9606 RNAcentral SMURF1 protein Q9HCE7 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 39850720 YES miannu Mechanistically, it was found that miR-424-5p downregulated the expression of SMURF1 to regulate the expression of ING2 and p53, thereby modulating CDDP resistance in GC.  0.4 SIGNOR-279956 PRKACA protein P17612 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation Ser321 KCQRLFRsPSMPCSV 9606 27038604 YES miannu Overall, PRKACA may directly phosphorylate CDC25B on Ser321 to control cell cycle progression in mouse-fertilized eggs [ xref ].|PRKACA phosphorylates and activates CDC25B in fertilized eggs of mice [ xref ]. 0.2 SIGNOR-280077 miR-455-5p mirna URS00000AD002_9606 RNAcentral TNFAIP8 protein O95379 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000249 40170451 YES miannu TNFAIP8 was targeted by miR-455-5p and negatively regulated by miR-455-5p.  0.4 SIGNOR-279957 PRKCA protein P17252 UNIPROT ARPC5 protein O15511 UNIPROT up-regulates activity phosphorylation 9606 21281821 YES miannu PKC\u03b1 phosphorylates and activates ARPC5, which organizes the actin net dorsolateral of nucleus. 0.2 SIGNOR-280078 PRKCA protein P17252 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 24909179 YES miannu Phosphorylation of BAD at ser112 and ser136 in the setting of lapatinib treatment was fully restored by PRKACA expression in BT474, SKBr3, and ZR-75-30 cells (XREF_FIG).|We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro apoptotic protein BAD, thereby permitting survival signaling through BCL-XL. 0.2 SIGNOR-280079 PRKCB protein P05771 UNIPROT RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser780 STRPPTLsPIPHIPR 9606 29088742 YES miannu The exact mechanism by which PKCbeta degrades RB is unknown.|To attribute increased RB phosphorylation specifically to PKC\u03b2, we transiently transfected PKC\u03b2 -/- hepatocytes, and reintroduction of PKC\u03b2 specifically resulted in increased in phospho-RB (Ser780) levels, further supporting that PKC\u03b2 phosphorylates RB specifically at Ser780 without affecting phosphorylation at other residues (Ser807 and Ser811) (Figure xref ). 0.353 SIGNOR-280083 PRKCD protein Q05655 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation 9606 29903018 YES miannu In the TFEB activation pathway, activated PKC\u03b4 phosphorylates and inactivates GSK3\u03b2, leading to the reduced phosphorylation of TFEB at Ser134 and Ser138 residues; this reduced phosphorylation is critical for the cytoplasmic sequestration of TFEB.|In the TFEB activation pathway, activated PKCdelta phosphorylates and inactivates GSK3beta, leading to the reduced phosphorylation of TFEB at Ser134 and Ser138 residues; this reduced phosphorylation is critical for the cytoplasmic sequestration of TFEB. 0.271 SIGNOR-280084 PRKCD protein Q05655 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation 9606 27198223 YES miannu Interestingly, comparable experiments with the Ca 2+ -independent PKC\u03b4 isoform revealed that PKC\u03b4 phosphorylates ARTD1 at the N-terminus (amino acids 1\u2013214) and phosphorylation of ARTD1 by PKC\u03b4 inhibited DNA-induced PAR formation by ARTD1 in vitro (Supplementary Figure S6A and S6B), suggesting that the observed stimulatory effect of the PKCi on PAR formation might be due to inhibition of ARTD1 by PKC\u03b4. 0.2 SIGNOR-280085 PRKCD protein Q05655 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity phosphorylation Ser349 SSKEVDPsTGELQSL 9606 28846113 YES miannu Data presented here suggested that Vps34 stimulates tumor development mainly through PKC-\u03b4- activation of p62.|In conclusion, elevation of Vps34 results in tumor progression via the PKC-\u03b4-phosphorylation of p62 at S349 and PKC-\u03b4 involved phosphorylation of Raf 1 at Y340/341.|Vps34 induces PKC-\u03b4-dependent phosphorylation of p62. 0.368 SIGNOR-280086 PRKCE protein Q02156 UNIPROT DLG4 protein P78352 UNIPROT up-regulates quantity phosphorylation 9606 27330081 YES miannu PKCepsilon directly phosphorylated PSD-95 and JNK1 in vitro Inhibiting PKCepsilon, JNK, or calcium/calmodulin dependent kinase II activity prevented the effects of PKCepsilon activators on PSD-95 phosphorylation.|These results indicate that PKCepsilon promotes synaptogenesis by activating PSD-95 phosphorylation directly through JNK1 and calcium/calmodulin dependent kinase II and also by inducing expression of PSD-95 and synaptophysin. 0.286 SIGNOR-280087 PRKCI protein P41743 UNIPROT CDK7 protein P50613 UNIPROT up-regulates activity phosphorylation Thr170 GSPNRAYtHQVVTRW 9606 31784510 YES miannu PKC\u03b9 activates CDK7 to promote glucose consumption.|PKC\u03b9 phosphorylates Thr170 on CDK7 in vitro, can associate with CDK7 in cells, and is activated downstream of PI3K signaling xref , xref \u2013 xref . 0.344 SIGNOR-280088 Adalimumab (Imraldi) antibody DB00051 DRUGBANK TNF protein P01375 UNIPROT down-regulates activity binding 9606 33125196 YES Adalimumab is a recombinant human immunoglobulin monoclonal antibody that specifically binds to tumor necrosis factor α (TNF-α) 0.4 SIGNOR-272493 PRKCZ protein Q05513 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity phosphorylation 9606 17389234 YES miannu Hence, it may be reasonable to deduce that N-formyl-methionyl-leucyl-phenylalanine binds its receptors to activate protein kinase C\u03b6 to generate superoxide, which in turn stimulates the motility in an autocrine manner via the protein kinase C\u03b6-RhoGDI-1-RhoGTPase pathway.|In these cells, protein kinase C zeta was activated to phosphorylate RhoGDI-1, which liberated RhoGTPases, leading to their activation. 0.246 SIGNOR-280089 PRKDC protein P78527 UNIPROT KAT2B protein Q92831 UNIPROT up-regulates activity phosphorylation 9606 28854354 YES miannu In response to UV-induced DNA damage, DNA-PK phosphorylates and activates PCAF, and activated PCAF is transferred to photo lesion sites and further acetylates RPA1 at K163. 0.417 SIGNOR-280092 PRKDC protein P78527 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation 9606 22504299 YES miannu Therefore, through its interaction with Ku70/80 in the presence of dsDNA , DNA-PK phosphorylated PARP-1 at its catalytic CTD. 0.526 SIGNOR-280093 PRKG1 protein Q13976 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation 9606 22131966 YES miannu Moreover, PrkG1 inhibits GSK3\u03b2 by binding and directly phosphorylating GSK3\u03b2 at its serine-9 residue (Zhao et al., xref ).|Moreover, PrkG1 inhibits GSK3beta by binding and directly phosphorylating GSK3beta at its serine 9 residue. 0.26 SIGNOR-280094 PRKG2 protein Q13237 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation 9606 18551195 YES miannu These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII. 0.258 SIGNOR-280095 PRKG2 protein Q13237 UNIPROT SLC9A3 protein P48764 UNIPROT down-regulates activity phosphorylation 9606 25480791 YES miannu CGMP and cGKII increased NHE3 phosphorylation at three sites (rabbit Ser (554), Ser (607), and Ser (663), equivalent to mouse Ser (552), Ser (605), and Ser (659)), all of which had to be present at the same time for cGMP to inhibit NHE3.|cGMP and cGKII rapidly inhibited NHE3, which was associated with reduced surface NHE3. 0.377 SIGNOR-280096 PTK2 protein Q05397 UNIPROT ARHGAP42 protein A6NI28 UNIPROT up-regulates activity phosphorylation Tyr376 MDGKEPIyTLPAIIS 9606 32331391 YES miannu FAK and Src Mediated Phosphorylation of GRAF3 at Y376 Promotes Allosteric Activation. 0.309 SIGNOR-280097 PTK2 protein Q05397 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation 9606 32452639 YES miannu It indicates that FAK positively regulates the phosphorylation of MLC2. 0.286 SIGNOR-280098 miR-508-5p mirna URS000021202F_9606 RNAcentral SOX11 protein P35716 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 39873049 YES miannu MiR-508-5p downregulation significantly increased SOX11; a dual luciferase reporter assay provided evidence for their direct targeting. 0.4 SIGNOR-279958 miR-542-5p mirna URS000050C722_9606 RNAcentral GREM1 protein O60565 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0003575 39180371 YES miannu MiR-542-5p targets GREM1 to affect the progression of renal fibrosis 0.4 SIGNOR-279959 PTK6 protein Q13882 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation 9606 33391524 YES miannu It was also observed that the attenuation of BRK phosphorylation in turn inhibits BRK mediated activation of its direct targets, STAT3, SAM68, and Paxillin.|The EGF pathway also stimulates BRK 's phosphorylation of paxillin to promote migratory and invasive characteristics in breast cancer cells. 0.629 SIGNOR-280102 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates activity phosphorylation 9606 25795775 YES miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. 0.2 SIGNOR-280103 RIPK1 protein Q13546 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 34654937 YES miannu RIPK1 also activates DRP1 by phosphorylating DRP1 at Ser616 in a RIPK3-dependent fashion independent of MLKL. 0.509 SIGNOR-280104 RIPK2 protein O43353 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 35115556 YES miannu Collectively, the results suggest that RIPK2 binds to and activates MKK7.|Radioactive in vitro kinase assay showed that RIPK2 can directly phosphorylate kinase-dead (K149A) MKK7 (Fig.\u00a0 xref ). 0.438 SIGNOR-280105 RIPK3 protein Q9Y572 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation 9606 24535827 YES miannu Collectively, TAK1 activates RIPK3, RIPK3 activates TAK1, and RIPK1 activates RIPK3 and facilitates interaction between TAK1 and RIPK3.|RIPK1 kinase activity is required for RIPK3 phosphorylation, and reciprocally RIPK3 phosphorylates RIPK1. 0.753 SIGNOR-280106 ROCK1 protein Q13464 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates activity phosphorylation 9606 34285210 YES miannu The results showed that SMAD5 was directly phosphorylated at Ser463/465 by ROCK1 (Fig.\u00a04g).|These data indicated that the activation of SMAD5 induced by TEM8 was mediated directly by the RhoC/ROCK1 pathway.To evaluate the effect of SMAD5 on the cellular functions of TEM8, SMAD5 was knockdown in TEM8-overexpressing cells. 0.306 SIGNOR-280107 ROCK1 protein Q13464 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 33297931 YES miannu Besides, ROCK1 phosphorylated p53 at ser15 to up-regulate its protein level. 0.409 SIGNOR-280108 ROCK2 protein O75116 UNIPROT APP protein P05067 UNIPROT up-regulates quantity phosphorylation Thr729 MLKKKQYtSIHHGVV 9606 24305806 YES miannu Moreover, SR3677 blocked ROCK2 phosphorylation of APP at threonine 654 (T654); in neurons, T654 was critical for APP processing to Abeta.|These observations suggest that ROCK2 inhibition reduces Abeta levels through independent mechanisms. 0.386 SIGNOR-280109 ROCK2 protein O75116 UNIPROT LHX3 protein Q9UBR4 UNIPROT up-regulates activity phosphorylation 9606 24071938 YES miannu Rok-\u03b1 phosphorylates and activates LIM kinase, which in turn phosphorylates and inactivates cofilin. 0.2 SIGNOR-280110 RPS6KA1 protein Q15418 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation 9606 22068162 YES miannu 13 The data presented support previous findings that C/EBPbeta can be a molecular target of RSK1, 16 but provide the first indication that RSK1 can phosphorylate and activate C/EBPbeta to mediate the IL-6 signalling events in cholangiocarcinoma.|As mentioned above, RSK1 has been shown to activate C/EBPbeta in hepatic stellate cells in an experimental model of liver fibrosis. 0.682 SIGNOR-280112 RPS6KA1 protein Q15418 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates activity phosphorylation Ser897 RVSIRLPsTSGSEGV 9606 32574556 YES miannu These comprehensive analyses indicate that high matrix stiffness activates ERK/RSK1-mediated EPHA2 non-canonical signalling to induce LYN activation, TWIST1 nuclear localization, and cell invasion (Fig. 6M).|We next knocked down the most abundant RSK family members and found that loss of RSK1, but not RSK2 or RSK3, drastically inhibited EPHA2 S897 phosphorylation, prevented ECM stiffness-induced LYN activation and recruitment to EPHA2, and inhibited cell EMT and invasion induced by increasing rigidities (Fig. 6F\u2013I and S6H\u2013L). 0.292 SIGNOR-280113 miRNA-576-5p mirna URS000035E9A9_9606 RNAcentral ZBTB4 protein Q9P1Z0 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 36538280 YES miannu MiRNA-576-5p promotes endometrial cancer cell growth and metastasis by targeting ZBTB4 0.4 SIGNOR-279960 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser469 AHEENPEsILDEHVQ 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.333 SIGNOR-248554 RPS6KA1 protein Q15418 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates quantity by destabilization phosphorylation Ser19 DADEWCDsGLGSLGP 9606 16822942 YES miannu By using recombinant wild-type and mutant IkappaBbeta proteins, both active ERK2 and RSK1 were found to directly phosphorylate IkappaBbeta, but only active RSK1 phosphorylated IkappaBbeta on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation. 0.37 SIGNOR-280114 RPS6KA1 protein Q15418 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates quantity by destabilization phosphorylation Ser23 WCDSGLGsLGPDAAA 9606 16822942 YES miannu By using recombinant wild-type and mutant IkappaBbeta proteins, both active ERK2 and RSK1 were found to directly phosphorylate IkappaBbeta, but only active RSK1 phosphorylated IkappaBbeta on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation. 0.37 SIGNOR-280115 MiR-744-5p mirna URS00002ED61F_9606 RNAcentral NFIX protein Q14938 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 10116 BTO:0001879 39617504 YES miannu Bone Marrow Mesenchymal Stem Cell-Derived Exosomal MiR-744-5p Alleviates Obstructive Sleep Apnea-Induced Myocardial Injury by Targeting NFIX 0.4 SIGNOR-279962 RPS6KA2 protein Q15349 UNIPROT MRE11 protein P49959 UNIPROT down-regulates activity phosphorylation Ser676 TSSSKIMsQSQVSKG 9606 24297933 YES miannu Rsk can phosphorylate the Mre11 protein directly at S676 both in vitro and in intact cells and thereby can inhibit the binding of Mre11 to DNA with DSBs.|ribosomal s6 kinase can phosphorylate the Mre11 protein directly at S676 both in vitro and in intact cells and thereby can inhibit the binding of Mre11 to DNA with double-stranded breaks. 0.2 SIGNOR-280116 RPS6KA3 protein P51812 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation 9606 10723128 YES miannu ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinase. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.|ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases. 0.318 SIGNOR-280117 hsa-mir-204-5p mirna URS000029D9F1_9606 RNAcentral BDNF protein P23560 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 39520743 YES miannu Additionally, our findings confirmed that miR-204 has the ability to directly target BDNF through a luciferase assay. Downregulation of miR-204 abrogated the BPA exposure-mediated effects on proliferation and autophagy.  0.4 SIGNOR-279963 miRNA-30a-5p mirna URS000043D1A9_9606 RNAcentral EDNRA protein P25101 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0003792 26675258 YES miannu MiR-30a was found to specifically bind to the 3'UTR of ETAR mRNA, indicating that ETAR is a direct target of miR-30a.  0.4 SIGNOR-279964 MicroRNA-877-5p mirna URS00005240FD_9606 RNAcentral EIF4G2 protein P78344 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 10090 BTO:0000944 38342889 YES miannu MicroRNA-877-5p promotes osteoblast differentiation by targeting EIF4G2 expression 0.4 SIGNOR-279965 hsa-mir-152-3p mirna URS00003AFD9B_9606 RNAcentral FGFR3 protein P22607 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 40075158 YES miannu  Further investigation using dual-luciferase reporter assays, qRT-PCR, and Western blot revealed that miR-152-3p inhibits the expression of FGFR3 by binding to its 3' UTR. 0.4 SIGNOR-279966 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 YES Phosphorylation is the signal for ubiquitination lperfetto We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. 0.842 SIGNOR-106808 RPS6KA3 protein P51812 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 24086335 YES miannu Furthermore, using RSK2 knockout mouse fibroblasts and RSK2 deficient cells from CLS patients, we demonstrate that ablation of RSK2 impairs the phosphorylation of Atm at Ser1981 and the phosphorylation of p53 at Ser18 (mouse) or Ser15 (human) in response to genotoxic stress.|We postulate that the phosphorylation of RSK2 is required to fully activate Atm at Ser1981 and p53 at Ser18 (mouse) or Ser15 (human) in response to genotoxic stress. 0.389 SIGNOR-280118 RPS6KA3 protein P51812 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates activity phosphorylation Ser703 MSRARIGsDPLAYEP 9606 30377223 YES miannu In pressured arteries, RSK2 dependent activation of NHE-1 was associated with increased intracellular Ca 2+ transients, which would be expected to increase MLCK activity, thereby contributing to basal tone and myogenic responses.|Together, these data indicate that Ser 703 in NHE-1 is phosphorylated by RSK2, that RSK2 is associated with NHE-1, and that the time course of NHE-1 phosphorylation in response to intraluminal pressure is fast enough for this phosphorylation event to contribute to myogenic vasoconstriction. 0.415 SIGNOR-280119 RPS6KB1 protein P23443 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity phosphorylation 9606 33240877 YES miannu Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation.|Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element-binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation ( xref ). 0.425 SIGNOR-280120 SGK1 protein O00141 UNIPROT NCSTN protein Q92542 UNIPROT down-regulates quantity phosphorylation Ser437 FLRARNIsGVVLADH 9606 22590650 YES miannu Furthermore, SGK1 directly bound to and phosphorylated Nicastrin on Ser437, thereby promoting protein degradation.|We showed that SGK1 downregulates Nicastrin protein levels. 0.338 SIGNOR-280122 SGK1 protein O00141 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates activity phosphorylation Ser703 MSRARIGsDPLAYEP 9606 25270604 YES miannu Phosphorylation of NHE1 Ser 703 by SGK1 is essential for the binding of 14-3-3 protein to NHE1 , ] which, in turn, is critical in the activation of this Na + / H + exchanger , ].|These data suggest that endothelial SGK1 activates NHE1 in response to MG treatment. 0.304 SIGNOR-280123 SGK3 protein Q96BR1 UNIPROT ARL6IP4 protein Q66PJ3 UNIPROT down-regulates activity phosphorylation 9606 23201781 YES miannu AIP4 is phosphorylated by CISK in vitro on WW domain residues, which may impact its ability to interact with and ubiquitinate substrate proteins.|Expression of a constitutively active CISK inhibits CXCR4 degradation, possibly by attenuating CXCR4 binding to and ubiquitination by AIP4 and/or modulating the action of AIP4 on a protein involved in CXCR4 endosomal sorting . 0.2 SIGNOR-280124 SGK3 protein Q96BR1 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates activity phosphorylation 9606 15496163 YES miannu Moreover, S422DSGK1, SGK1, and SGK3 also phosphorylated Nedd4-2 and thereby inhibited Nedd4-2 binding to its target. 0.446 SIGNOR-280125 miRNA‑22‑3p mirna URS0000096022_9606 RNAcentral FOXP1 protein Q9H334 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 39697977 YES miannu MiRNA‑22‑3p inhibits cell viability and metastasis of nasopharyngeal carcinoma by targeting FOXP1 0.4 SIGNOR-279967 SLK protein Q9H2G2 UNIPROT ETV5 protein P41161 UNIPROT up-regulates activity phosphorylation 9606 24958772 YES miannu Here, we report that the direct activation of the three mammalian ERMs by the Ste20-like kinase (SLK) is crucial for guiding the mitotic spindle toward the expected orientation in two mammalian models of oriented cell division: micropatterned cells and apical progenitors of the mouse neocortex.|SLK directly phosphorylates mammalian ERMs and controls their cortical activation in mitosis. 0.2 SIGNOR-280126 SRC protein P12931 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates activity phosphorylation 9606 31406243 YES miannu Our findings reveal a novel mechanism by which reversible tyrosine phosphorylation of DAAM1 by Src and PTPN3 regulates actin dynamics and lung cancer invasiveness.|PTPN3 suppresses lung cancer cell invasiveness by counteracting Src mediated DAAM1 activation and actin polymerization. 0.326 SIGNOR-280128 SRC protein P12931 UNIPROT NPHS1 protein O60500 UNIPROT up-regulates activity phosphorylation 9606 22718751 YES miannu Inhibition of Src kinase dependent Nephrin phosphorylation achieved by incubation of WT-Nephrin-overexpressing cells with 1 mum PP2 abolished the positive effect of Nephrin on GSIR (XREF_FIG D).|We were able to demonstrate a complete prevention of Nephrin phosphorylation, confirming that Nephrin phosphorylation is mediated by Src. 0.481 SIGNOR-280129 profenamine chemical CHEBI:313639 ChEBI MAPK10 protein P53779 UNIPROT down-regulates chemical inhibition 9606 BTO:0000142 19261605 YES Inhibitor of p38;ATP binding pocket gcesareni Indazole-based inhibitors exemplified by sr-3737 were potent inhibitors of both jnk3 (ic50 12 nm). 0.8 SIGNOR-184443 BRAF protein P15056 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 21900390 NO miannu RAF, a cytoplasmic serine-threonine protein kinase, is a member of the RAS-RAF-MEK-ERK cell-signaling pathway [also known as the MAP kinase (MAPK) pathway], and it plays an essential role in mediating cellular differentiation, proliferation, senescence, and survival in response to extracellular cues. Raf phosphorylates and activates MAP-ERK kinase (MEK), which phosphorylates and activates extracellular signal-regulated kinase (ERK). 0.659 SIGNOR-260082 PTPN6 protein P29350 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 YES Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B 0.528 SIGNOR-248472 miR-618 mirna URS0000450F92_9606 RNAcentral JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 39716199 YES miannu For further exploration of this interaction, we conducted a dual-luciferase reporter assay. The findings indicated that after co-transfection of miR-618 mimics with JAK2 wild-type, the luciferase activity was significantly reduced, while co-transformation with the JAK2 mutant sequence had no effect (Fig. 3C).  0.4 SIGNOR-279968 miR-325 mirna URS000075C2FC_9606 RNAcentral LIG1 protein P18858 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000018 39231317 YES miannu MiR-325 Supresses Cell Proliferation and Migration in Non-Small Cell Lung Cancer via Targeting DNA Ligase 1 (LIG1) 0.4 SIGNOR-279969 miR-129-5p mirna URS00004E1410_9606 RNAcentral NUSAP1 protein Q9BXS6 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002181 39212774 YES miannu NUSAP1 was confirmed as a target of miR-129-5p and negatively regulated by it. 0.4 SIGNOR-279970 SRC protein P12931 UNIPROT PANX1 protein Q96RD7 UNIPROT up-regulates activity phosphorylation Tyr199 KYPIVEQyLKTKKNS 9606 30814251 YES miannu This work implicates SRC mediated PANX1 function in normal vascular hemodynamics and suggests that Tyr-198-phosphorylated PANX1 is involved in hypertensive vascular pathology.|Using a PANX1 Tyr-198-specific antibody, SFK inhibitors, SRC knockdown, temperature-dependent SRC cells, and kinase assays, we found that PANX1-mediated ATP release and vasoconstriction involves constitutive phosphorylation of PANX1 Tyr-198 by SRC. 0.379 SIGNOR-280131 SRC protein P12931 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity phosphorylation Tyr64 DTAGQEDyDRLRPLS 9606 30544910 YES miannu In addition, Rac1 is phosphorylated at Y64 by FAK and Src kinases ( xref ); Y64 phosphorylation targets Rac1 to focal adhesions. 0.613 SIGNOR-280132 SRC protein P12931 UNIPROT RASGRF1 protein Q13972 UNIPROT down-regulates activity phosphorylation 9606 24597981 YES miannu These proximal Src kinases could potentially directly or indirectly phosphorylate Rasgrf-1 upon BCR activation and thereby further increase its GEF activity. 0.471 SIGNOR-280133 SRC protein P12931 UNIPROT SH3PXD2A protein Q5TCZ1 UNIPROT up-regulates activity phosphorylation Tyr558 LKYEEPEyDIPAFGF 9606 24174371 YES miannu First, we observed that the co-expression of both activated Src and wild-type Tks5 stimulated gelatin degradation beyond that of Tks5 overexpression alone ( ).|In melanoma cells Src dependent phosphorylation of Tks5 at tyrosine 557 is important for binding to Nck, for Nck recruitment to invadopodia, and for invadopodia associated matrix degradation activity . 0.64 SIGNOR-280134 SRC protein P12931 UNIPROT TEC protein P42680 UNIPROT up-regulates activity phosphorylation 9606 19482777 YES miannu The proximal event following T cell-APC synapse formation is immediate activation of several signaling molecules: The Src kinase phosphorylates and activates Tec tyrosine kinases, which then activate PLC-\u03b3 that is required for IP 3 generation to sustain intracellular calcium flux. 0.321 SIGNOR-280135 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser22 QASSTPLsPTRITRL 9606 18815303 YES gcesareni Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm 0.537 SIGNOR-181310 SRC protein P12931 UNIPROT TPI1 protein P60174 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 23266470 YES miannu As shown in xref , Tim was phosphorylated by both Hck and c-Src, and to a lesser extent by Fyn and c-Yes.|In the case of Hck and Fyn, co-expression led to enhanced Tim turnover, while c-Src and c-Yes promoted Tim stability. 0.2 SIGNOR-280136 SRC protein P12931 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates activity phosphorylation 9606 23645696 YES miannu Among SFKs, Src strongly induces tyrosine phosphorylation of KAP1.|Immunostaining and chromatin fractionation show that Src and Lyn decrease the association of KAP1 with heterochromatin in a kinase activity-dependent manner. 0.2 SIGNOR-280137 SRC protein P12931 UNIPROT VAV2 protein P52735 UNIPROT up-regulates activity phosphorylation 9606 11448999 YES miannu Since we find that Vav2 is necessary for cell spreading and Src activity is necessary for Vav2 activation of Rac and lamellipodia formation, our data suggest a model of Rac activation by integrins that depends on Src phosphorylation of Vav2.|We did not detect increased Rac activation when Vav2 was cotransfected with activated Src, although Vav2 tyrosine phosphorylation was increased (data not shown), indicating that endogenous Src activity is sufficient to fully activate Vav2. 0.525 SIGNOR-280138 STK11 protein Q15831 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation 9606 23027127 YES miannu LKB1 induces phosphorylation of Yap, leading to Yap nuclear exclusion and ultimately its degradation.|These data indicated that LKB1 expression inhibits Yes-associated protein transcriptional function. 0.305 SIGNOR-280139 STK24 protein Q9Y6E0 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates activity phosphorylation 9606 25456499 YES miannu Thus, MST3 phosphorylates TAO1 and TAO2, enabling their association with Myosin Va. 0.2 SIGNOR-280140 STK26 protein Q9P289 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr40 SGIHSGAtTTAPSLS 9606 34240584 YES miannu In response to Wnt3a stimulation, the kinase MST4 directly phosphorylates \u03b2-catenin at Thr40 to block its Ser33 phosphorylation by GSK3\u03b2. 0.2 SIGNOR-280141 STK38 protein Q15208 UNIPROT MYC protein P01106 UNIPROT down-regulates activity phosphorylation 9606 23178486 YES miannu Previously, we demonstrated that STK38 kinase mediates MYC phosphorylation.|STK38-WT overexpression dramatically reduced MYC half-life (4-fold), compared to control un induced cells (XREF_FIG), while STK38-KD overexpression led to increased MYC half-life (1.7 fold), illustrating an involvement in MYC protein turnover regulation (XREF_FIG). 0.282 SIGNOR-280142 STK4 protein Q13043 UNIPROT AR protein P10275 UNIPROT down-regulates activity phosphorylation 9606 21512132 YES miannu Here we showed that MST1 is an androgen receptor kinase and phosphorylates androgen receptor at Ser-650 ( ).|Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter. 0.2 SIGNOR-280143 STK4 protein Q13043 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Thr75 RDKPDLPtWKRNFRS 9606 32174922 YES miannu Beyond that, another investigation demonstrated that MST1 directly phosphorylated IRF3 at T75 and T253, which disrupted the dimerization of IRF3 and restrained RLRs and cGAS-mediated innate antiviral response. 0.2 SIGNOR-280145 STK4 protein Q13043 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Thr228 PQWNESFtFKLKPSD 9606 26414765 YES miannu Mst1 and Mst2 activate PKC\u03b1 to disrupt the LyGDI-Rac complex.|Thus, the phosphorylation of PKC\u03b1 at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKC\u03b1. 0.2 SIGNOR-280147 STK11 protein Q15831 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation 9606 21272562 YES miannu In this regard, it was shown that LKB1 physically associates with PKC-zeta, which is known to inhibit GSK3beta kinase activity by promoting its phosphorylation.|Thus, inhibitory phosphorylation of GSK3beta by LKB1 and/or AKT may be a cardinal event leading to constitutive activation of Wnt and beta-catenin signaling (XREF_FIG). 0.379 SIGNOR-280148 STRADA protein Q7RTN6 UNIPROT STK11 protein Q15831 UNIPROT up-regulates quantity phosphorylation Ser428 SSKIRRLsACKQQ 9606 17482549 YES miannu Furthermore, interaction of STRAD with LKB1 promoted LKB1 phosphorylation at a PKA site S431 and elevated the LKB1 level, and overexpressing LKB1 with a serine-to-alanine mutation at S431 (LKB1 (S431A)) prevented axon differentiation. 0.939 SIGNOR-280149 TBK1 protein Q9UHD2 UNIPROT CALCOCO2 protein Q13137 UNIPROT up-regulates activity phosphorylation 9606 32034138 YES miannu Furthermore, we found that TBC1D9-regulated TBK1 activation and recruitment of NDP52 and ULK1 complex to damaged mitochondria (Fig.\u00a0 xref ).|TBK1 can phosphorylate p62, OPTN, and NDP52 to promote selective autophagy by facilitating their interaction with LC3, ubiquitin, and RAB35, respectively xref , xref , xref . 0.794 SIGNOR-280151 TBK1 protein Q9UHD2 UNIPROT SIKE1 protein Q9BRV8 UNIPROT down-regulates quantity phosphorylation 9606 23649622 YES miannu Mechanism of endogenous regulation of the type I interferon response by suppressor of I\u03baB kinase epsilon (SIKE), a novel substrate of TANK-binding kinase 1 (TBK1).|TBK1 phosphorylation of IRF3 and SIKE displayed negative cooperativity. 0.717 SIGNOR-280152 TBK1 protein Q9UHD2 UNIPROT TNIP1 protein Q15025 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 36574265 YES miannu Under inflammatory conditions, here TLR3-activation by poly(I:C) treatment, the inflammation repressor TNIP1 (TNFAIP3 interacting protein 1) is phosphorylated by Tank-binding kinase 1 (TBK1) activating an LIR motif that leads to the selective autophagy-dependent degradation of TNIP1, supporting the expression of pro-inflammatory genes and proteins. 0.375 SIGNOR-280153 NUP188 protein Q5SRE5 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.612 SIGNOR-262084 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 12213813 YES lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. 0.2 SIGNOR-252769 TNIK protein Q9UKE5 UNIPROT GSN protein P06396 UNIPROT up-regulates activity phosphorylation 9606 18701680 YES miannu In vitro , TNIK can phosphorylate and activate the F-actin-fragmenting enzyme gelsolin, and in cultured cells, TNIK induces actin fiber disassembly ( xref ).|In vitro, TNIK can phosphorylate and activate the F-actin-fragmenting enzyme gelsolin, and in cultured cells, TNIK induces actin fiber disassembly. 0.5 SIGNOR-280154 PTPN6 protein P29350 UNIPROT TRPV1 protein Q8NER1 UNIPROT down-regulates activity dephosphorylation 10116 25790452 YES miannu Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.|These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia. 0.2 SIGNOR-277129 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15964798 NO gcesareni Reduction in p53 expression also blocks p65 binding to the intronic region of the dr5 gene, indicating cooperation between p53 and p65 in dr5 expression. (articolo-abstract) 0.646 SIGNOR-138293 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. 0.8 SIGNOR-267313 YAP1 protein P46937 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21233212 NO miannu We also found that KIBRA mRNA is induced by YAP overexpression in both murine and human cells, suggesting the evolutionary conservation of KIBRA as a transcriptional target of the Hippo signaling pathway. Thus, our study revealed a new connection between KIBRA and mammalian Hippo signaling. 0.366 SIGNOR-263660 TNK2 protein Q07912 UNIPROT WASL protein O00401 UNIPROT up-regulates activity phosphorylation 9606 31769754 YES miannu Because TNK2 phosphorylation of WASL increases its actin nucleation activity ( xref ), we reasoned that it might be possible to complement the TNK2 deficiency by overexpression of WASL.|For NCK1, based on its reported binding to WASL and TNK2, we hypothesized that its function is to recruit WASL to TNK2, which could then activate WASL via phosphorylation ( xref ; xref ). 0.308 SIGNOR-280155 TTK protein P33981 UNIPROT BLM protein P54132 UNIPROT up-regulates activity phosphorylation 9606 23700430 YES miannu Moreover, in mitosis, TTK promotes phosphorylation of Bloom syndrome protein (BLM) and subsequent interaction of BLM with PLK1, ensuring accurate chromosome segregation xref .|Moreover, in mitosis, TTK promotes phosphorylation of Bloom syndrome protein and subsequent interaction of Bloom syndrome protein with PLK1, ensuring accurate chromosome segregation . 0.315 SIGNOR-280156 MiR-210 mirna URS000075D16F_9606 RNAcentral SIN3A protein Q96ST3 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0002035 25481483 YES miannu MiR-210 up-regulation inhibits proliferation and induces apoptosis in glioma cells by targeting SIN3A 0.4 SIGNOR-279973 miR-582-5p mirna URS00000B0E50_9606 RNAcentral SKP1 protein P63208 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 10090 BTO:0003292 36592647 YES miannu MiR-582-5p targets Skp1 and regulates NF-κB signaling-mediated inflammation 0.4 SIGNOR-279974 miR-342-3p mirna URS0000148B91_9606 RNAcentral SOX12 protein O15370 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000670 36120594 YES miannu MiR-342-3p Inhibits Acute Myeloid Leukemia Progression by Targeting SOX12 0.4 SIGNOR-279975 PI-103 chemical CHEBI:90524 ChEBI PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206175 TTK protein P33981 UNIPROT NT5E protein P21589 UNIPROT up-regulates activity phosphorylation 9606 29502948 YES miannu Intermolecular NTE phosphorylation by Mps1 requires a topology in which sites proximal to the NTE interact with the active Mps1 in order to promote phosphorylation. 0.2 SIGNOR-280157 hsa-mir-24-3p mirna URS000059273E_9606 RNAcentral S100A8 protein P05109 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003936 22139384 YES Tiberia S100A8 protein level was significantly downregulated when Hep2 cells were co-transfected with miR-24. 0.4 SIGNOR-279932 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000007 14761950 YES The effect has been demonstrated using P10636-8 lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. 0.374 SIGNOR-121705 SMO protein Q99835 UNIPROT GNAT1 protein P11488 UNIPROT up-regulates binding 9606 23074268 YES gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. 0.262 SIGNOR-199168 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 23729744 YES apalma The NECD undergoes O-linked glycosylation during Notch synthesis and secretion, which is crucial for proper folding of the Notch receptor and the interaction with its ligand DSL (Delta, Serrate, Lag-2)(Rana and Haltiwanger, 2011). The Notch receptor on the signal-receiving cell binds directly to ligands located on the apposing signal-sending cell 0.64 SIGNOR-255369 ULK1 protein O75385 UNIPROT CDC37 protein Q16543 UNIPROT down-regulates activity phosphorylation Ser339 HMQRCIDsGLWVPNS 9606 28073914 YES miannu Serine/Threonine Kinase Unc-51-like Kinase-1 (Ulk1) Phosphorylates the Co-chaperone Cell Division Cycle Protein 37 (Cdc37) and Thereby Disrupts the Stability of Cdc37 Client Proteins.|Ulk1-mediated phosphorylation of Ser-339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90) but only modestly affected Cdc37 binding to Hsp90. 0.2 SIGNOR-280158 VRK1 protein Q99986 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates activity phosphorylation 9606 29340707 YES miannu In the VRK1 overexpression of experiment, VRK1 caused a significant stabilization of AURKB, with no change in level after 24h, which is consistent with protection of AURKB against its known degradation by ubiquitylation .|The phosphorylation of AURKB by VRK1 and VRK1 by AURKB was tested using a kinase-dead form as substrate. 0.429 SIGNOR-280160 VRK2 protein Q86Y07 UNIPROT FBXW2 protein Q9UKT8 UNIPROT down-regulates activity phosphorylation 9606 28090088 YES miannu Collectively, CK1 and VRK2, but not GRK2 kinase, appears to mediate FBXW2 phosphorylation at the beta-TrCP binding motif.|We followed this lead, and inactivated VRK2 and GRK2 by siRNA silencing, or CK1 and VRK2 by small molecule inhibitor IC-261, and found that GRK2 knockdown had no effect, whereas CK1 and VRK2 inhibition or VRK2 silencing largely blocked the degradation of exogenously expressed FBXW2 (XREF_FIG and XREF_SUPPLEMENTARY). 0.296 SIGNOR-280161 VRK2 protein Q86Y07 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 16704422 YES miannu Endogenous p53 is also phosphorylated in Thr18 by VRK2B, promoting its stabilization and transcriptional activation in A549 cells.|Only overexpression of the nuclear VRK2B isoform induces p53 stabilization by post-translational modification, largely due to Thr18 phosphorylation. 0.384 SIGNOR-280162 WNK1 protein Q9H4A3 UNIPROT SLC12A5 protein Q9H2X9 UNIPROT down-regulates activity phosphorylation 9606 23300475 YES miannu The activity of the neuronal specific KCC2 had recently been shown to be regulated by the WNK1 kinase, where phosphorylation decreased KCC2 activation .|WNK1 phosphorylation of KCC2 occurs in immature neurons but is absent in adult neurons , , emphasizing a developmental role. 0.462 SIGNOR-280163 WNK1 protein Q9H4A3 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates quantity phosphorylation 9606 28236964 YES miannu In addition, WNK1 and WNK4 can phosphorylate Smad2, and silencing of WNK1 reduces Smad2 protein levels in HeLa cells, suggesting that WNKs have complex effects on TGFbeta signaling, which itself can promote cancer or act in a tumor suppressing manner. 0.2 SIGNOR-280164 ZAP70 protein P43403 UNIPROT SLC39A6 protein Q13433 UNIPROT up-regulates activity phosphorylation 9606 34394081 YES miannu To summarize, upon TCR triggering Zap70 activates Zip6, which is localized to the IS, through phosphorylation of tyrosine residues likely located in the long cytoplasmic loop.|Zip6 Is Phosphorylated by Zap70 in Response to TCR Stimulation. 0.2 SIGNOR-280165 INPP5D protein Q92835 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity binding 9606 BTO:0000007 24817116 YES lperfetto Of note, SHIP1 was associated with TRAF6 in co-transfected HEK293T cells (Fig. 6A). Moreover, SHIP1 overexpression suppressed TRAF6 autoubiquitination in a dose-dependent manner 0.33 SIGNOR-261429 OPTN protein Q96CV9 UNIPROT NTF3 protein P20783 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 NO same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. 0.248 SIGNOR-259879 ABL1 protein P00519 UNIPROT CLASRP protein Q8N2M8 UNIPROT up-regulates activity phosphorylation 9606 24520051 YES miannu In biochemical assays and in Xenopus growth cones we find that Abl kinase activity enhances the association or co-localization of CLASP2 and F-actin, consistent with previous reports of CLASP binding to actin [Tsvetkov et al., ].|In vitro, Abl phosphorylates CLASP with a Km of 1.89 \u00b5M, indicating that CLASP is a bona fide substrate. 0.2 SIGNOR-280166 ABL1 protein P00519 UNIPROT FUS protein P35637 UNIPROT down-regulates activity phosphorylation Tyr526 QDRRERPy 9606 37071594 YES miannu Abl kinase-mediated FUS Tyr526 phosphorylation alters nucleocytoplasmic FUS localization in FTLD-FUS. 0.325 SIGNOR-280168 ABL1 protein P00519 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity phosphorylation 9606 25561363 YES miannu Despite the fact that HDAC1 was phosphorylated by co-expression with c-Abl, stabilization of HDAC1 by c-Abl was not affected by mutations in its sites phosphorylated by c-Abl.|c-Abl induces stabilization of histone deacetylase 1 (HDAC1) in a kinase activity dependent manner. 0.505 SIGNOR-280169 ABL1 protein P00519 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates activity phosphorylation 9606 32792487 YES miannu As shown in Fig. xref and c, c-Abl-phosphorylated NOX5 was mostly inhibited when c-Abl plasmid co-transfected with NOX5 Y476/Y478F mutant, then the NOX5 Y487F mutant, but not with NOX5 Y519F mutant.|Collectively, these results indicate that Pyk2 may act as a scaffolding protein for c-Abl stimulation of NOX5 activity in Pyk2 and NOX5 complex, and c-Abl-enhanced NOX5 activity is mainly dependent on phosphorylation of NOX5 Tyr 476/478 sites. 0.303 SIGNOR-280170 ABL1 protein P00519 UNIPROT PITX1 protein P78337 UNIPROT up-regulates activity phosphorylation 9606 20563669 YES miannu Notably, c-Abl controls augmentation of Pitx1 at the post-transcriptional level.|Overexpression of c-Abl induces tyrosine phosphorylation of Pitx1, either directly or indirectly. 0.2 SIGNOR-280171 ABL1 protein P00519 UNIPROT SORBS3 protein O60504 UNIPROT up-regulates activity phosphorylation 9606 16831423 YES miannu Abl kinase interacts with and phosphorylates vinexin. 0.412 SIGNOR-280172 AKT1 protein P31749 UNIPROT CELF1 protein Q92879 UNIPROT up-regulates activity phosphorylation Ser28 GQVPRTWsEKDLREL 9606 18570922 YES miannu In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA. 0.411 SIGNOR-280173 AKT1 protein P31749 UNIPROT GAPDH protein P04406 UNIPROT down-regulates activity phosphorylation Thr237 GMAFRVPtANVSVVD 9606 23332158 YES miannu GAPDH is phosphorylated by protein kinase B (AKT) on T237, which prevents GAPDH nuclear translocation and suppresses GAPDH mediated apoptosis.|GAPDH is phosphorylated by protein kinase B (AKT) on T237, which prevents GAPDH nuclear translocation and suppresses GAPDH-mediated apoptosis ( ). 0.583 SIGNOR-280174 HDAC1 protein Q13547 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005192 20037778 NO miannu we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter. 0.288 SIGNOR-254223 RXRB protein P28702 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates binding 9606 BTO:0000938 9636132 YES lperfetto The recent discovery that the nuclear transcription factor, nurr1, in heterodimeric tandem with rxr, is unequivocally necessary for the expression of dopaminergic neurons 0.418 SIGNOR-58309 AKT1 protein P31749 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation 9606 25247763 YES miannu Of note, the amino acid sequence adjacent to Ser204 phosphorylation site matches the minimal AKT substrate motif (RxxpS) suggesting that AKT1 could potentially directly regulate PRKCD through phosphorylation.|This integrative analysis allowed us to confirm that the enrichment of PRKCD centered network is likely the result of elevated phosphorylation of PRKCD by AKT1. 0.26 SIGNOR-280175 PTPN11 protein Q06124 UNIPROT SPRY1 protein O43609 UNIPROT down-regulates dephosphorylation 9606 16481357 YES gcesareni These results identify sprouty proteins as in vivo targets of corkscrew/shp-2 tyrosine phosphatases and show how corkscrew/shp-2 proteins can promote rtk signaling by inactivating a feedback inhibitor. 0.409 SIGNOR-144547 AKT1 protein P31749 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity phosphorylation 9606 23389849 YES miannu Here we show that Akt kinase directly phosphorylates Runx2 to regulate invasive properties of breast cancer cells. 0.446 SIGNOR-280176 AKT2 protein P31751 UNIPROT ARNTL protein O00327 UNIPROT down-regulates activity phosphorylation 9606 27576939 YES miannu Consistent with mass spectrometry results, constitutive active Akt2 (Akt2-CA) induced wild-type (WT) Bmal1 protein phosphorylation, which was abolished by a serine to alanine mutation at Ser42 residue (S42A) but not a S422A/S513A double mutation, as shown by immunoblot assay with phospho-Akt substrate antiserum ( xref ).|In line with the in vivo results, overexpression of Akt2-CA strikingly lowered Bmal1 protein abundance in the nucleus in primary hepatocytes (XREF_FIG and XREF_SUPPLEMENTARY). 0.358 SIGNOR-280177 AKT2 protein P31751 UNIPROT ATF2 protein P15336 UNIPROT up-regulates activity phosphorylation 9606 25890336 YES miannu Taken together, these data suggest that AMPK regulates EC migration through phosphorylation of AKT2, which promotes ATF2 transactivation of MMP-2 during EC migration.|Within this subgroup, we chose AKT2 for analysis because AKT2 phosphorylates activating transcription factor 2 (ATF2) [ xref , xref ]. 0.425 SIGNOR-280178 AKT2 protein P31751 UNIPROT TBC1D4 protein O60343 UNIPROT down-regulates activity phosphorylation 9606 33810522 YES miannu AKT2 phosphorylation blocks AS160 function enhancing GLUT4 intracellular vesicular transport, and as such promotes glucose uptake following insulin release .|Notable mechanisms promoting this involves AKT2 mediated phosphorylation of the Rab-GTPase-activating protein TBC1D4, also known as AS160. 0.64 SIGNOR-280179 ALK protein Q9UM73 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation 9606 33479180 YES miannu It has been reported that Alk phosphorylates and activates Gsk3beta in mouse neural crest explants and neuroblastoma cell lines.|Therefore, we tested whether Alk indeed phosphorylates Y279-GSK3\u03b2 in stomach epithelial cells. 0.248 SIGNOR-280180 ATM protein Q13315 UNIPROT NPM1 protein P06748 UNIPROT up-regulates activity phosphorylation 9606 21499441 YES miannu In addition to Serine 125, ATM may also phosphorylate other sites on NPM. 0.352 SIGNOR-280182 THR proteinfamily SIGNOR-PF84 SIGNOR RARG protein P13631 UNIPROT up-regulates binding 9606 15650024 YES inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. 0.2 SIGNOR-270315 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser161 ENLTQVGsILGNLKD 9606 12930825 YES lperfetto Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion. 0.33 SIGNOR-249227 ATR protein Q13535 UNIPROT CDC25A protein P30304 UNIPROT down-regulates activity phosphorylation 9606 29054375 YES miannu ATR and CHK1 mediated loss of CDC25A activity suspends CDKs, such as CDK2, in an inactive phosphorylated state, blocking initiation of DNA replication origins.|In the presence of replication stalling, activated CHK1 and ATR phosphorylates CDC25A and promotes its degradation. 0.642 SIGNOR-280183 AURKA protein O14965 UNIPROT CBX3 protein Q13185 UNIPROT up-regulates activity phosphorylation 9606 23829974 YES miannu We report for the first time that during mitotic cell division, heterochromatin protein 1\u03b3 colocalizes and is phosphorylated at serine 83 in G2/M phase by Aurora A. 0.364 SIGNOR-280185 AURKA protein O14965 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity phosphorylation 9606 30250494 YES miannu A second wave of Cyclin B1-CDK1 phosphorylation by AurA occurs in late prophase.|Simultaneously, AurA activates and targets the Cyclin B1-CDK1 complex at centrosomes [ xref ]. 0.577 SIGNOR-280186 AURKA protein O14965 UNIPROT CENPE protein Q02224 UNIPROT down-regulates activity phosphorylation 9606 31881080 YES miannu Aurora A also phosphorylates and inhibits the centromere-associated kinesin CENP-E involved in efficient chromosome congression ( xref ; xref ). 0.48 SIGNOR-280187 AURKA protein O14965 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation 9606 25501815 YES miannu A schematic of regulation between these three kinases is shown in XREF_FIG, suggesting that Src was the upstream kinase regulating both FAK and AURA, whereas FAK might be downstream of AURA (as AURA phosphorylation of FAK yielded more incorporation of [32 P] gammaATP compared to FAK phosphorylation of AURA).|The effect of AURA on cell migration is augmented in the presence of Src and, in return, AURA also activates FAK. 0.255 SIGNOR-280188 AURKB protein Q96GD4 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation 9606 28434146 YES miannu When SAC is active, Aurora kinase B (AurkB) phosphorylates and inactivates CDC20, to prevent the activation of anaphase promoting complex and cyclosome (APC/C).|When SAC is active, Aurora kinase B (AurkB) phosphorylates and inactivates CDC20, to prevent the activation of anaphase-promoting complex/cyclosome (APC/C) (Hagting et al., xref ; Nasmyth, xref ; Ruchaud et al., xref ). 0.766 SIGNOR-280190 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 21159646 YES gcesareni In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases with ic50 values well below 1 ?mol/l 0.8 SIGNOR-170614 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 2808370 YES gcesareni Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway. 0.765 SIGNOR-23441 Av/b1 integrin complex SIGNOR-C175 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression 10090 18757303 NO lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. 0.321 SIGNOR-253276 AURKB protein Q96GD4 UNIPROT CDCA2 protein Q69YH5 UNIPROT down-regulates activity phosphorylation Ser893 SETKVRRsTRLQKDL 9606 23746640 YES miannu Aurora B defines its own chromosomal targeting by opposing the recruitment of the phosphatase scaffold Repo-Man.|Here, we show that Aurora B phosphorylates Repo-Man at S893, preventing its recruitment by histones. 0.447 SIGNOR-280191 AURKB protein Q96GD4 UNIPROT KIF23 protein Q02241 UNIPROT down-regulates quantity phosphorylation 9606 25512391 YES miannu Furthermore, reduced turnover of regulatory phosphorylation on another Aurora B substrate MKlp1 was observed, suggesting that PP2A-B56\u03b3 and -\u03b5 play a general role opposing Aurora B at the central spindle.|In anaphase, the KIF4A-targeted pool of B56\u03b3 and -\u03b5 is ideally placed to counteract Aurora B phosphorylations on other central spindle proteins such as MKlp1. 0.726 SIGNOR-280192 PRKACA protein P17612 UNIPROT CSK protein P41240 UNIPROT up-regulates activity phosphorylation Ser364 ALREKKFsTKSDVWS 9606 BTO:0000782 11181701 YES lperfetto Activation of the cooh-terminal src kinase (csk) by camp-dependent protein kinase inhibits signaling through the t cell receptor.Pka phosphorylates csk at s364 in vitro and in vivo leading to a two- to fourfold increase in csk activity that is necessary for camp-mediated inhibition of tcr-induced interleukin 2 secretion. 0.338 SIGNOR-105229 AXL protein P30530 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity phosphorylation 9606 20818175 YES miannu Blockade of Axl function abrogated phosphorylation of ERBB2 (Her-2 and neu) at the Tyr877 residue, indicative of receptor crosstalk.|We have demonstrated that either pharmacological or genetic inhibition of Axl function abrogates phosphorylation of ERBB2 at the critical Tyr877 residue and sensitizes OE33 cells to lapatinib in vitro. 0.316 SIGNOR-280193 BLK protein P51451 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation 9606 29545808 YES miannu Lyn, Syk, Btk, and Blk can also phosphorylate and enhance the activation of phospholipase C gamma 2 (PLCgamma2), which hydrolyzes PI (4,5) P2 to create inositol 3,4,5-trisphosphate (IP3) and diacylglycerol (DAG), stimulating Ca 2+ mobilization and protein kinase C (PKC), respectively. 0.555 SIGNOR-280195 TERB1 protein Q8NA31 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C305 SIGNOR-C306 33015044 YES lperfetto The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1 0.2 SIGNOR-263315 BTK protein Q06187 UNIPROT CNN3 protein Q15417 UNIPROT up-regulates quantity phosphorylation 9606 26046660 YES miannu Co-expression of calponin-3 with various kinases in S2 Schneider cells promoted a phosphorylation of calponin-3 by Syk, but also by the Tec family kinase Btk. 0.2 SIGNOR-280196 BTK protein Q06187 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation 9606 26018652 YES miannu Btk induces the phosphorylation of NF-\u03baB p65 which can be induced by the expression of inflammation cytokines [ ].|Btk induces the phosphorylation of NF-\u03baB p65 which can be induced by the expression of inflammation cytokines [ xref ]. 0.404 SIGNOR-280197 BUB1 protein O43683 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 34852826 YES miannu This study showed that the BUB1 kinase drives the progression and proliferation of BCa by regulating the transcriptional activation of STAT3 signaling and may be an attractive candidate for therapeutic targeting in BCa.|We further identified through a series of molecular and cell biological approaches that BUB1 interacted directly with STAT3 and mediated the phosphorylation of STAT3 at Ser727. 0.252 SIGNOR-280198 BUB1 protein O43683 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 22852086 YES miannu In addition, purified Bub1 directly phosphorylates p53 on Ser-37 in vitro , possibly inducing cellular senescence [ xref ].|Studies have shown that depletion and inhibition of Aurora A, Aurora B, Plk1, or Bub1 induces cellular senescence or cell death in a p53 dependent or -independent but p73 dependent manner in many different cell types , - ]. 0.484 SIGNOR-280199 CAMK2G protein Q13555 UNIPROT FBXO43 protein Q4G163 UNIPROT down-regulates activity phosphorylation 9606 25546390 YES miannu Activated CaMKII and polo-like kinase simultaneously phosphorylate and inactivate Emi2 [ xref , xref , xref , xref , xref ]). 0.2 SIGNOR-280200 CAMK4 protein Q16566 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 19696021 YES miannu An active form of CaMKIV but not CaMKI enhanced Thr 508 phosphorylation of LIMK1 and increased the kinase activity of LIMK1.|Taken together, our results suggest that LIMK1 mediated cofilin phosphorylation is critical for ionomycin induced neurite outgrowth and that CaMKIV mediates ionomycin induced LIMK1 activation. 0.256 SIGNOR-280201 CAMKK1 protein Q8N5S9 UNIPROT BRSK1 protein Q8TDC3 UNIPROT up-regulates activity phosphorylation 9606 18324781 YES miannu In transfected COS-7 cells, kinase activity and Thr (189) phosphorylation of overexpressed SAD-B were significantly enhanced by coexpression of constitutively active CaMKKalpha (residues 1-434) in a manner similar to that observed with coexpression of LKB1, STRAD, and MO25.|Taken together, these results indicate that CaMKKalpha is capable of activating SAD-B through phosphorylation of Thr (189) both in vitro and in vivo and demonstrate for the first time that CaMKK may be an alternative activating kinase for SAD-B. 0.307 SIGNOR-280202 CDC7 protein O00311 UNIPROT CDC5L protein Q99459 UNIPROT down-regulates activity phosphorylation 9606 32099015 YES miannu During SPOC, Dbf4 binds to Cdc5 and promotes Cdc7-mediated phosphorylation of Cdc5, which then presumably prevents Cdc5 from recognizing its substrates in the MEN pathway . 0.344 SIGNOR-280203 CDK1 protein P06493 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation 9606 18500339 YES miannu We show that adequate accumulation of Cin8 and Kip1 requires inactivation of the anaphase promoting complex-activator Cdh1 through sequential phosphorylation by Cdk1 and polo kinase.|We show that adequate accumulation of Cin8 and Kip1 requires inactivation of the anaphase-promoting complex-activator Cdh1 through sequential phosphorylation by Cdk1 and polo kinase. 0.368 SIGNOR-280204 CDK1 protein P06493 UNIPROT TREH protein O43280 UNIPROT up-regulates activity phosphorylation 9606 31468142 YES miannu Ewald et al. reported that at the G1/S transition, cyclin-dependent kinase 1 (CDK1) phosphorylates and activates the neutral trehalase (NTH1) to funnel trehalose into glycolysis (Ewald et al. xref ). 0.269 SIGNOR-280206 CDK1 protein P06493 UNIPROT VHL protein P40337 UNIPROT up-regulates activity phosphorylation Ser80 QVIFCNRsPRVVLPV 9606 36813923 YES miannu Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1.|PIN1 and CDK1 cooperatively modulate the protein turnover of pVHL, thereby conferring tumor growth, chemotherapeutic resistance and metastasis both in vitro and in vivo. 0.2 SIGNOR-280207 DVL1 protein O14640 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity binding 9534 SIGNOR-C110 10196136 YES lperfetto We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly. 0.818 SIGNOR-219356 ESCRT-III complex SIGNOR-C379 SIGNOR Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates 9606 26775243 NO miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. 0.7 SIGNOR-265534 CDK11B protein P21127 UNIPROT PRPF4 protein O43172 UNIPROT up-regulates activity phosphorylation 9606 11418604 YES miannu Furthermore, hPRP4 interacted directly with Clk1 on its COOH terminus, and the arginine and serine rich domain of hPRP4 was phosphorylated by Clk1 in vitro.|Overexpression of Clk1 caused redistribution of hPRP4, from the speckled to the diffuse pattern in nucleoplasm, whereas inactive mutant of Clk1 caused no change of hPRP4 localization. 0.2 SIGNOR-280208 CDK11B protein P21127 UNIPROT THRAP3 protein Q9Y2W1 UNIPROT up-regulates activity phosphorylation Ser243 ASAVSELsPRERSPA 9606 34526909 YES miannu In addition, genetic knockout of CLK1 or chemical inhibition in mice ameliorated diet-induced obesity and insulin resistance at 22\u00b0C. Through proteomics, we uncovered thyroid hormone receptor-associated protein 3 (THRAP3) as an interacting partner of CLK1, further confirmed by co-immunoprecipitation assays.|We further demonstrated that CLK1 phosphorylates THRAP3 at Ser243, which is required for its regulatory interaction with phosphorylated peroxisome proliferator-activated receptor gamma (PPAR\u03b3), resulting in impaired adipose tissue browning and insulin sensitivity. 0.206 SIGNOR-280209 CDK2 protein P24941 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization phosphorylation Thr743 VEVDAAVtPEERHLS 9606 30881282 YES miannu These include a significant increase in APP phosphorylation at Thr 668 by cdk2, cdk4, and cdk5, which increases its beta-amyloid production and APP proteolysis by the activated caspases during cell cycle ( xref ; xref ; xref ; xref ). 0.267 SIGNOR-280210 CDK2 protein P24941 UNIPROT BARD1 protein Q99728 UNIPROT down-regulates activity phosphorylation 9606 15665273 YES miannu CDK2-cyclin A1/E1 and CDK1-cyclin B1 phosphorylate BARD1 on its NH(2) terminus in vivo and in vitro. 44999999="E1" 45999998="terminus"}|Here we show that the ubiquitin ligase activity of BRCA1-BARD1 is down-regulated by CDK2. 0.608 SIGNOR-280211 CDK4 protein P11802 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization phosphorylation Thr743 VEVDAAVtPEERHLS 9606 30881282 YES miannu These include a significant increase in APP phosphorylation at Thr 668 by cdk2, cdk4, and cdk5, which increases its beta-amyloid production and APP proteolysis by the activated caspases during cell cycle ( xref ; xref ; xref ; xref ). 0.258 SIGNOR-280214 CDK5 protein Q00535 UNIPROT CASK protein O14936 UNIPROT up-regulates activity phosphorylation 9606 18054859 YES miannu Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK.|We found that Cdk5 phosphorylates and regulates CASK distribution to membranes. 0.288 SIGNOR-280216 CDK5 protein Q00535 UNIPROT MIB1 protein Q86YT6 UNIPROT up-regulates activity phosphorylation 9606 21763614 YES miannu Similar to the mechanism of PAR-1 regulation of Mib in neurogenesis, CDK5 phosphorylation is proposed to enhance Mib1 ligase activity leading to destabilization.|The cyclin dependent kinase 5 (CDK5) enriched in neurons phosphorylates Mib1 and suppresses the inhibitory effects of Mib1 on neurite morphology. 0.325 SIGNOR-280217 CDK5 protein Q00535 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates activity phosphorylation 9606 31786229 YES miannu In vitro, the results show that murine wild-type AMPK-alpha2 was phosphorylated by Cdk5 at a (S/T) PX (K/H/R) phosphorylation consensus sequence, which was associated with decreased AMPK-alpha2 activity.|Inactivated AMPK-alpha2 promotes the progression of diabetic brain damage by Cdk5 phosphorylation at Thr485 site. 0.216 SIGNOR-280218 CDK5 protein Q00535 UNIPROT SPAAR protein A0A1B0GVQ0 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 28502042 YES miannu Cdk5 also phosphorylates PSD-95-interacting protein Spine Associated RapGAP (SPAR), resulting in its degradation ([98], Table 2). 0.2 SIGNOR-280219 CDK5 protein Q00535 UNIPROT TRIO protein O75962 UNIPROT up-regulates activity phosphorylation 9606 15331630 YES miannu Roscovitine inhibits the ability of Trio to activate Rac, and peptides corresponding to the Cdk5 consensus sites in Trio are phosphorylated by Cdk5.|Together, these data suggest that control of the cortical actin cytoskeleton, long known to modulate hormone exocytosis and subsequent endocytosis, involves Cdk5 mediated activation of Trio. 0.2 SIGNOR-280220 CDK5 protein Q00535 UNIPROT XDH protein P47989 UNIPROT up-regulates activity phosphorylation 9606 25831123 YES miannu Finally, threonine 222 of XOR is the critical target site for CDK5 dependent activation of XOR.|Once we determined CDK5 was necessary for hypoxia induced hyperactivation of XOR, we tested whether CDK5 was sufficient to phosphorylate XOR and induce increased enzymatic activity in a cell free system. 0.2 SIGNOR-280221 SKP1 protein P63208 UNIPROT SCF(TBL1) complex SIGNOR-C533 SIGNOR form complex binding 9606 BTO:0000007 20181957 YES miannu Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC).  0.518 SIGNOR-271950 EEF2 protein P13639 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 14709557 NO lperfetto In mammalian cells, peptide chain elongation requires two main elongation factors, eEF1A and eEF2. 0.7 SIGNOR-269396 RPS6KA4 protein O75676 UNIPROT HMGN1 protein P05114 UNIPROT unknown phosphorylation Ser7 sSAEGAAK 10090 BTO:0000452 12773393 YES lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin. 0.336 SIGNOR-249216 5-(1,1-Dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol chemical CID:104895 PUBCHEM CNR1 protein P21554 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257473 CDK6 protein Q00534 UNIPROT JUN protein P05412 UNIPROT up-regulates quantity phosphorylation 9606 17454300 YES miannu CDK6 additionally induced c-Jun phosphorylation, but did not activate JNK, as determined by examining JNK phosphorylation at various time-points.|CDK6 upregulates c-Jun expression. 0.424 SIGNOR-280222 CHEK1 protein O14757 UNIPROT BUB1B protein O60566 UNIPROT up-regulates activity phosphorylation 9606 19778378 YES miannu Nonetheless, in our experimental system a Chk1-dependent BubR1 phosphorylation was also observed after Noc treatment.|Possible requirement of Chk1 in U2OS cells to activate the mitotic spindle checkpoint proteins Mad2 and BubR1. 0.447 SIGNOR-280223 CHEK1 protein O14757 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates activity phosphorylation 9606 23706767 YES miannu In addition, upon treatment with genotoxic agents, the checkpoint kinases Chk1 and Chk2 also phosphorylate and activate FOXM1. 0.371 SIGNOR-280224 CHEK1 protein O14757 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Thr505 EAITRLVtGAQRPPD 9606 15775976 YES miannu Here we demonstrate that ARF induces the ATR- and Chk1-dependent phosphorylation of the RelA transactivation domain at threonine 505, a site required for ARF-dependent repression of RelA transcriptional activity. 0.454 SIGNOR-280225 CHEK1 protein O14757 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity phosphorylation Ser473 SGVKRSRsGEGEVSG 9606 21851590 YES miannu These data suggested that KAP1 Ser473 phosphorylation by Chk1 and Chk2 does not take place predominantly at sites of DNA damage, and are consistent with previous work indicating that, following their DNA-damage-localized phosphorylation and activation by ATR and ATM, Chk1 and Chk2 dissociate from chromatin to phosphorylate their substrates , ].|These results therefore indicated that both Chk1 and Chk2 can target KAP1 Ser473, and are in agreement with IR triggering both the ATM and Chk2 and ATR and Chk1 pathways . 0.282 SIGNOR-280226 CHEK2 protein O96017 UNIPROT TBPL1 protein P62380 UNIPROT down-regulates activity phosphorylation 9606 19375317 YES miannu In vitro, TRF2 was phosphorylated by recombinant Chk2 ( Figure\u00a04 C) on residues located in the first 350 aa ( Figure\u00a0S11 ).|To evaluate whether Chk2 activity affected the binding of TRF2 for telomeric TTAGGG repeats in duplex DNA, electrophoretic mobility shift assays (EMSA) were performed in the presence of ATP to allow phosphorylation and found that in contrast to Chk2 KD, Chk2 WT decreased the binding of TRF2 to DNA. 0.291 SIGNOR-280227 ATM protein Q13315 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity phosphorylation Ser384 KILRQELsQQQPQAG 10090 BTO:0002572 33097595 YES miannu Using biochemical approaches and MS analysis, we show that upon the onset of the DNA-damage response, SMURF2 becomes phosphorylated at Ser384 by ataxia telangiectasia mutated (ATM) serine/threonine kinase, and this phosphorylation is required for its interaction with RNF20. 0.2 SIGNOR-277534 CSNK1D protein P48730 UNIPROT DCK protein P27707 UNIPROT up-regulates activity phosphorylation 9606 20637175 YES miannu Site-directed mutagenesis demonstrated that only Ser-74 phosphorylation was involved in Deoxycytidine kinase activation by CKI delta, strengthening the key role of this residue in the control of Deoxycytidine kinase activity.|We showed that recombinant CKI delta phosphorylated several residues of bacterially overexpressed Deoxycytidine kinase: Ser-74, but also Ser-11, Ser-15, and Thr-72. 0.339 SIGNOR-280233 CSNK1D protein P48730 UNIPROT ERG protein P11308 UNIPROT down-regulates activity phosphorylation 9606 26344095 YES miannu Interestingly, only CKId, but not other CKI isoforms or CKII could promote ERG degradation under ectopic expression conditions (XREF_FIG).|These results indicate that phosphorylation of ERG by CKIdelta within the SPOP-recognition degron triggers its interaction with SPOP to promote ERG destruction . 0.2 SIGNOR-280234 CSNK1D protein P48730 UNIPROT KDR protein P35968 UNIPROT down-regulates activity phosphorylation 9606 22711876 YES miannu CKIdelta phosphorylates VEGFR2 at both DSG and DDTD phosphodegrons to promote its interaction with beta-TRCP1.|In a reciprocal set of experiments, we found that overexpression of CKIdelta markedly decreased the half-life of VEGFR2 (XREF_FIG). 0.328 SIGNOR-280235 CSNK1G2 protein P78368 UNIPROT MTA1 protein Q13330 UNIPROT up-regulates activity phosphorylation 9606 15077195 YES miannu CKI-gamma2 could further potentiate the ER corepressive function of metastasis-associated protein-1 short form.|These findings identified metastasis-associated protein-1 short form as a target of CKI-gamma2, and provided new evidence to suggest that CKI-gamma2 phosphorylates and modulates the functions of metastasis-associated protein-1 short form, and that these extranuclear effects of estrogen might have important implications in regulating the functions of metastasis-associated protein-1 short form in human mammary epithelial and cancer cells. 0.345 SIGNOR-280236 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT down-regulates activity dephosphorylation Tyr796 GGTGGSVyTEDNDDD 9606 BTO:0000007 10364224 YES Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs. 0.479 SIGNOR-248460 VRK1 protein Q99986 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10951572 YES gcesareni Vrk1 phosphorylates murine p53 in threonine 18. This threonine is within the p53 hydrophobic loop (residues 13-23) required for the interaction of p53 with the cleft of its inhibitor mdm-2. 0.524 SIGNOR-81222 HPS4 protein Q9NQG7 UNIPROT BLOC-3 complex SIGNOR-C253 SIGNOR form complex binding 9606 20048159 YES lperfetto Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer. 0.752 SIGNOR-260692 STAT5A protein P42229 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001096 14530308 NO apalma Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells 0.7 SIGNOR-256583 PRKAA2 protein P54646 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates activity phosphorylation Thr119 HNLMRRStVSLLDTY 23871434 YES Phosphosite positions are derived from Figure S5 lperfetto AMPKalpha2-mediated inhibition of WIP1 phosphorylation by HIPK2|Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKalpha2 in vitro 0.2 SIGNOR-275485 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.267 SIGNOR-269241 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation Thr200 EHQVLMKtVCGTPGY 9606 15143065 YES lperfetto In response to an increase in intracellular Ca2+, CaMKIV binds Ca2+/CaM and becomes phosphorylated on T200 by CaMKK. 0.619 SIGNOR-124732 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Ser87 VRPSDEDsSSLESAA -1 12852856 YES lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction 0.699 SIGNOR-103352 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates chemical activation 9606 16014605 YES gcesareni Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors. 0.8 SIGNOR-138582 PRKDC protein P78527 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 15668230 YES gcesareni We have found that dna-pk is the major constituent of an activity present in extracts of mammalian cells that phosphorylates chk2. Our results suggest that hypophosphorylated chk2 can be phosphorylated at thr68 by dna-pk in vitro. 0.591 SIGNOR-133384 DDX17 protein Q92841 UNIPROT Microprocessor complex complex SIGNOR-C356 SIGNOR up-regulates activity binding 9606 26045258 YES miannu In addition, nuclear YAP has also been found to regulate miRNA processing. Nuclear YAP/TAZ bind and sequester DEAD box helicase 17 (DDX17) (also known as p72) to repress its association with Microprocessor, a complex that regulates miRNA processing (Figure 3B). 0.555 SIGNOR-277660 UMPS protein P11172 UNIPROT Pyrimidine_nucleotide_metabolic_process phenotype SIGNOR-PH85 SIGNOR up-regulates 26059768 NO miannu The bifunctional enzyme UMP synthase leads to the synthesis of uridine 5′-monophosphate (UMP). UMP could be considered one of the hub molecules in pyrimidine metabolism because it is the precursor of other pyrimidine nucleotides. 0.7 SIGNOR-253582 PP1 proteinfamily SIGNOR-PF54 SIGNOR CFTR protein P13569 UNIPROT up-regulates activity dephosphorylation 10090 BTO:0000988 21317537 YES lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, 0.2 SIGNOR-264646 MARK4 protein Q96L34 UNIPROT MAPT protein P10636-5 UNIPROT down-regulates activity phosphorylation Ser262 NVKSKIGsTENLKHQ -1 21204788 YES miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.42 SIGNOR-273933 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000887 11940578 YES gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. 0.616 SIGNOR-116485 ATP5F1A protein P25705 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261396 CYP11B2 protein P19099 UNIPROT 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 YES lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone 0.8 SIGNOR-268684 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10606744 YES gcesareni Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. 0.577 SIGNOR-73270 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0002181 SIGNOR-C3 10942774 YES lperfetto PHAS-I in adipocytes and HEK293 cells is phosphorylated in the following five sites, all of which conform to a (S/T)P motif (9, 10): Thr-36, Thr-45, Ser-64, Thr-69, and Ser-82. Thr-45 and Ser-64 flank the eIF4E-binding motif (7, 8), and phosphorylation of either site blocks eIF4E binding in vitro (10, 11). Insulin stimulates the phosphorylation of Thr-36, Thr-45, Ser-64, and Thr-69 in both fat cells and HEK293 cells, and incubating cells with rapamycin decreases the phosphorylation of these sites.Immunoprecipitated epitope-tagged mammalian target of rapamycin (mTOR) phosphorylated Thr-36/45. mTOR also phosphorylated Thr-69 and Ser-64 but only when purified immune complexes were incubated with the activating antibody, mTAb1. 0.926 SIGNOR-226710 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 YES Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. 0.2 SIGNOR-269958 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 YES gcesareni Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase. 0.601 SIGNOR-58259 SIRT2 protein Q8IXJ6 UNIPROT PGAM1 protein P18669 UNIPROT up-regulates activity deacetylation Lys100 GGLTGLNkAETAAKH 9606 24786789 YES miannu Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. 0.28 SIGNOR-266517 MMP7 protein P09237 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272374 CCND1 protein P24385 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates activity 9606 15713663 NO areggio Collectively, these studies suggest an important role of cyclin D1 in regulation of PPARgamma-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARgamma function. 0.7 SIGNOR-258981 OGT protein O15294 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity glycosylation Ser84 VADIRKQsEPFFKAT 9606 BTO:0000007 26399441 YES lperfetto O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth|O-GlcNAcylation of G6PD activates enzyme activity|G6PD is dynamically modified by O-GlcNAc at serine 84|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 0.264 SIGNOR-267582 CSF2 protein P04141 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 BTO:0000130 7691413 YES gcesareni A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants these results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells. 0.591 SIGNOR-31963 FGF11 protein Q92914 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.252 SIGNOR-253430 SREBF1 protein P36956 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 YES inferred from family member gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) 0.333 SIGNOR-267799 MAPK8 protein P45983 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr278 SVSAATLtPSSQAVT 9606 19245816 YES gcesareni In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed. 0.705 SIGNOR-184190 PAK2 protein Q13177 UNIPROT SORT1 protein Q99523 UNIPROT down-regulates activity phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 YES miannu PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. 0.2 SIGNOR-273717 MIB1 protein Q86YT6 UNIPROT DLL1 protein O00548 UNIPROT up-regulates activity ubiquitination 9606 16140393 YES lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. 0.742 SIGNOR-209750 TGFB1 protein P01137 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8142649 NO Regulation miannu Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. 0.262 SIGNOR-251797 NOTCH1 protein P46531 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates 9606 22298955 NO gcesareni Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro. 0.354 SIGNOR-114592 ROCK1 protein Q13464 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9534 BTO:0000298 9856983 YES lperfetto Rho-associated kinase (Rho-kinase), which is activated by the small GTPase Rho, phosphorylates moesin at Thr558 in vitro. Here, using a site- and phosphorylation state-specific antibody, we found that the expression of dominant active RhoA in COS7 cells induced moesin phosphorylation and the formation of microvilli-like structures at apical membranes where the Thr558-phosphorylated moesin accumulated, whereas the expression of dominant negative Rho-kinase inhibited both of these processes. 0.687 SIGNOR-249014 CDK2 protein P24941 UNIPROT TTK protein P33981 UNIPROT up-regulates quantity by stabilization phosphorylation Thr468 DYMSCFRtPVVKNDF 9606 20861309 YES miannu Cdk2 phosphorylates Mps1 at T468, attenuating the function of a degradation signal found in amino acids 420\u2013507 (encoded by exons 12 and 13) and allowing the accumulation of a centrosomal pool of Mps1 that represents no more than 10% of total cellular Mps1 ( xref ). 0.411 SIGNOR-279398 ARRB2 protein P32121 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity binding -1 2163110 YES The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors 0.723 SIGNOR-256501 FBXW7 protein Q969H0 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by destabilization ubiquitination 9606 15546612 YES lperfetto Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. 0.614 SIGNOR-254310 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9606 16116087 YES llicata The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms. 0.729 SIGNOR-139910 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17643073 YES gcesareni In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function. 0.738 SIGNOR-156941 SLX4 protein Q8IY92 UNIPROT ERCC4 protein Q92889 UNIPROT up-regulates binding 9606 SIGNOR-C50 24726326 YES miannu Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair. 0.754 SIGNOR-204890 SPAG1 protein Q07617 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 YES miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. 0.384 SIGNOR-270938 UBE2J1 protein Q9Y385 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys237 VCIVQRQkIAYLGGK 9606 BTO:0001379 29892818 YES scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. 0.379 SIGNOR-267481 KCNE3 protein Q9Y6H6 UNIPROT KCNQ1 protein P51787 UNIPROT up-regulates activity binding 21911611 YES lperfetto Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K⁺ channels|The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation 0.659 SIGNOR-275923 CDK1 protein P06493 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Thr706 TTEGGSLtPVRDSPC 9606 20169205 YES llicata Cdc2 is the raptor ser696, thr706 kinase 0.386 SIGNOR-163853 S100A9 protein P06702 UNIPROT Calprotectin complex complex SIGNOR-C293 SIGNOR form complex binding 9867828 YES Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse. 0.73 SIGNOR-262828 CLTCL1 protein P53675 UNIPROT AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.73 SIGNOR-260679 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 SIGNOR-C15 22137581 YES lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction 0.2 SIGNOR-195102 HBEGF protein Q99075 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 10209155 YES gcesareni It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response. 0.749 SIGNOR-67009 pyruvate smallmolecule CHEBI:15361 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24363178 YES miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) 0.8 SIGNOR-266553 GSK3B protein P49841 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0000007 14570592 YES lperfetto However, in the present study, we clearly demonstrate that GSK3_ is capable of catalysing the autophosphorylation of Tyr216 in vitro. 0.2 SIGNOR-236564 CDK1 protein P06493 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Thr355 EPSTVPGtPPPKKFR 9606 12734188 YES lperfetto Here we present evidence that thr292 of hrad9 is subject to cdc2-dependent phosphorylation in mitosis. Furthermore, our data are also consistent with four other hrad9 phosphorylation sites (ser277, ser328, ser336, and thr355) being regulated in part by cdc2. We also identify ser387 as a novel site of hrad9 constitutive phosphorylation and show that phosphorylation at ser387 is a prerequisite for one form of dna damage-induced hyperphosphorylation of hrad9. 0.362 SIGNOR-101059 SNX5 protein Q9Y5X3 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 YES miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. 0.269 SIGNOR-269444 POFUT1 protein Q9H488 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 12909620 YES Fucosylation gcesareni Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling. 0.744 SIGNOR-254326 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 7538655 NO lperfetto We demonstrate that il4r triggering induced the tyrosine phosphorylation of jak3 0.715 SIGNOR-34756 SYK protein P43405 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates activity phosphorylation Tyr289 SSCGSSGyFSSSPTL 9606 BTO:0002181 34634301 YES miannu We found that tyrosine (Tyr) 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (spleen tyrosine kinase) as a kinase involved in DEPTOR Tyr 289 phosphorylation in an ephrin (erythropoietin-producing hepatocellular carcinoma) receptor-dependent manner. 0.2 SIGNOR-277572 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Ser978 VVSASLIsPASTPSC 9606 BTO:0000567 21818122 YES miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  0.428 SIGNOR-276242 CRK protein P46108 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000007 11314030 YES llicata Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression | Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II. 0.732 SIGNOR-250777 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 17535811 YES lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.772 SIGNOR-155246 PRKCI protein P41743 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000195 18270268 YES llicata Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation. 0.343 SIGNOR-160855 NCOR2 protein Q9Y618 UNIPROT BCL6 protein P41182 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 YES miannu The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT. 0.633 SIGNOR-252240 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT down-regulates phosphorylation Tyr522 YTATESQyQQQP 9606 10934191 YES gcesareni We demonstrate that autophosphorylation of the recombinant src family kinase hck leads to a 20-fold increase in its specific enzymatic activity. 0.2 SIGNOR-76996 DYRK2 protein Q92630 UNIPROT TERT protein O14746 UNIPROT down-regulates activity phosphorylation 9606 23362280 YES miannu Dyrk2 phosphorylates TERT protein, a catalytic subunit of telomerase.|In this study, we found that dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (Dyrk2) negatively regulates telomerase activity. 0.445 SIGNOR-279611 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 16446360 YES gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. 0.962 SIGNOR-143992 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 YES lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.2 SIGNOR-174878 CHEK2 protein O96017 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser90 IPPARMMsTESANSF 9606 BTO:0002552 32187724 YES lperfetto We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration 0.299 SIGNOR-264557 PRKACA protein P17612 UNIPROT CCND1 protein P24385 UNIPROT unknown phosphorylation Ser90 NYLDRFLsLEPVKKS -1 8058338 YES miannu PKA phosphorylates three distinct serine residues in cyclin D1 at positions 90, 197 and 234. 0.334 SIGNOR-250347 NRAS protein P01111 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 YES gcesareni The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. 0.835 SIGNOR-175216 ELOVL4 protein Q9GZR5 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267892 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 9914500 YES lperfetto In nonstimulated cells, nf-kappab is present in the cytosol where it is complexed to its inhibitor ikappab however, we found that only one of the activities, namely the ikk1/2 complex, exists as a pre-assembled kinase-substrate complex in which the ikks are directly or indirectly associated with several nf-kappab-related and ikappab-related proteins: rela, relb, crel, p100, p105, ikappa balpha, ikappa bbeta and ikappa bepsilon. 0.815 SIGNOR-64092 PP2B proteinfamily SIGNOR-PF18 SIGNOR PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation 10116 11278334 YES inferred from 70% family members In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. 0.2 SIGNOR-269991 glutamic acid smallmolecule CHEBI:18237 ChEBI GRID2 protein O43424 UNIPROT up-regulates activity chemical activation 9606 27586965 YES miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors 0.8 SIGNOR-264469 MIF protein P14174 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by destabilization relocalization 10090 BTO:0004488 29371591 YES P00441:p.Gly94Ala (mutation causing interaction) Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells|SOD1WT is evenly distributed between the cytoplasm and the nucleus while mutant SOD1G93A shows predominantly cytoplasmic distribution (Fig. 1a, b). Expression of MIF in cells expressing SOD1WT had no effect on the distribution of the SOD1WT–EGFP protein. However, expression of MIF together with the mutant SOD1G93A–EGFP, inhibited the nuclear clearance of misfolded SOD1 resulting in a more wild-type-like distribution of the mutant SOD1 protein 0.307 SIGNOR-262797 NR0B1 protein P51843 UNIPROT NCOR2 protein Q9Y618 UNIPROT up-regulates activity binding 9606 BTO:0002588 19237537 YES miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. 0.393 SIGNOR-271785 ADNP protein Q9H2P0 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates activity binding 10116 BTO:0000601 24365867 YES miannu Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes. 0.369 SIGNOR-266759 Ub:E2 complex SIGNOR-C497 SIGNOR RNF19B protein Q6ZMZ0 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271173 GDF5 protein P43026 UNIPROT Ossification phenotype SIGNOR-PH74 SIGNOR up-regulates 9606 21976273 NO miannu Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. 0.7 SIGNOR-252419 Integrator complex complex SIGNOR-C265 SIGNOR SDC4 protein P31431 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 25675981 NO lperfetto The Integrator complex controls the termination of transcription at diverse classes of gene targets.|Following INTS3 or INTS9 knockdown, the levels of SDC4, JUNB, FOSL1, and GADD45B increased, suggesting that the Integrator complex negatively regulates the transcription of these genes. 0.2 SIGNOR-261480 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR FOS protein P01100 UNIPROT down-regulates activity sumoylation Lys265 SISSMELkTEPFDDF 9606 SIGNOR-C154 16055711 YES lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 0.2 SIGNOR-263014 IFNB1 protein P01574 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity binding 9534 BTO:0004055 11278538 YES lperfetto Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. 0.674 SIGNOR-219304 MAPK1 protein P28482 UNIPROT CITED2 protein Q99967 UNIPROT up-regulates activity phosphorylation Thr166 KHSGGSStPGGSGGS 9606 23082118 YES miannu CITED2 coactivation is enhanced by activation of MAPK1 and requires T166.|CITED2 is phosphorylated by MAPK1 at S85, T166 and T175. 0.455 SIGNOR-278410 TSPOAP1 protein O95153 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.2 SIGNOR-264368 embelin chemical CHEBI:4778 ChEBI XIAP protein P98170 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001271 28704451 YES lperfetto Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells. 0.8 SIGNOR-262013 RIMS2 protein Q9UQ26 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 YES miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle 0.762 SIGNOR-264377 N-[3-[[5-Cyclopropyl-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide chemical CID:44465558 PUBCHEM TBK1 protein Q9UHD2 UNIPROT down-regulates activity chemical activation 10090 BTO:0001413 23099093 YES Federica We herein describe the development of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines as potent inhibitors of TBK1/IKKɛ, with improved kinase selectivity and drug-like properties. 0.8 SIGNOR-261109 ABL1 protein P00519 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity phosphorylation 9606 19914245 YES miannu A phosphotyrosine specific antibody indicated that MAVS was phosphorylated by c-Abl. 0.453 SIGNOR-279673 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192811 MAP3K12 protein Q12852 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 11781833 YES gcesareni Zip kinase (hzipk) phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. In this study, we demonstrate that hzipk also induces the diphosphorylation of mrlc in nonmuscle cells. 0.2 SIGNOR-113664 IKBKB protein O14920 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 19188143 YES gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway 0.691 SIGNOR-183684 RHOA protein P61586 UNIPROT RDX protein P35241 UNIPROT up-regulates activity phosphorylation Thr564 AGRDKYKtLRQIRQG 9606 BTO:0000132 35267019 YES miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. 0.471 SIGNOR-268430 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 7549116 NO miannu HNF-1 beta was found to be more potent than HNF-1 alpha in activating the AFP promoter in the HepG2 cells. 0.329 SIGNOR-254637 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates sumoylation Lys490 QCPRKVIkMESEEGK 9534 9756909 YES lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation. 0.779 SIGNOR-261787 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI PTGER3 protein P43115 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257571 torkinib chemical CHEBI:90679 ChEBI PIK3CA protein P42336 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258269 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser40 RRTDALTsSPGRDLP 9606 19647517 YES lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry 0.962 SIGNOR-187392 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268594 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F7 protein P08709 UNIPROT up-regulates activity cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 YES lperfetto The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa. 0.933 SIGNOR-263521 NAB2 protein Q15742 UNIPROT EGR3 protein Q06889 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000414 20506119 NO miannu Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. 0.486 SIGNOR-253887 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser133 GHSQRREsFLYRSDS 9534 BTO:0001538 12023945 YES done miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. 0.2 SIGNOR-273940 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.499 SIGNOR-248303 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PTTG1 protein O95997 UNIPROT up-regulates phosphorylation 9606 10906323 YES inferred from 70% family members gcesareni Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function. 0.2 SIGNOR-270038 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR LNPK protein Q9C0E8 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 32433973 YES miannu   Lunapark Is Ubiquitylated by the CRL3KLHL12 Ubiquitin Ligase Complex. Taken together, these results demonstrate that Lunapark is ubiquitylated by the CRL3KLHL12 ubiquitin ligase, and the CRL3KLHL12-dependent ubiquitylation of Lunapark does not lead to its proteasomal degradation. Inhibition of Lunapark Ubiquitylation Affects Lysosomal Recruitment of mTORC3 0.2 SIGNOR-272199 STK39 protein Q9UEW8 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 21317537 YES miannu SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. 0.348 SIGNOR-263133 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates binding 9606 12055200 YES fspada Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6 0.663 SIGNOR-89134 MAPK11 protein Q15759 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 YES gcesareni Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site. 0.618 SIGNOR-58131 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 YES lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 0.607 SIGNOR-161601 miR-183 ncrna URS000232E153_9606 RNAcentral PPP2CA protein P67775 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000007 31694919 YES miannu We also found that the miR-183 cluster activates the IFN pathway and inhibits vesicular stomatitis virus infection by directly targeting several negative regulators of IRF3 and STAT1 activities, including protein phosphatase 2A (PPP2CA) and tripartite motif-containing 27 (TRIM27). 0.2 SIGNOR-279981 miR-183 ncrna URS000232E153_9606 RNAcentral TRIM27 protein P14373 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000007 31694919 YES miannu We also found that the miR-183 cluster activates the IFN pathway and inhibits vesicular stomatitis virus infection by directly targeting several negative regulators of IRF3 and STAT1 activities, including protein phosphatase 2A (PPP2CA) and tripartite motif-containing 27 (TRIM27). 0.2 SIGNOR-279982 PRKCA protein P17252 UNIPROT CDC42EP4 protein Q9H3Q1 UNIPROT down-regulates activity phosphorylation Ser18 SVHSKRRsRADLTAE 9606 BTO:0001939 25086031 YES miannu Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes). 0.2 SIGNOR-263160 GRK2 protein P25098 UNIPROT RPLP2 protein P05387 UNIPROT up-regulates phosphorylation Ser105 KKEESEEsDDDMGFG 9606 12379128 YES gcesareni The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity. 0.2 SIGNOR-94258 HSF1 protein Q00613 UNIPROT HSPA6 protein P17066 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12813038 NO miannu These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells. 0.43 SIGNOR-254477 Exosome_Complex complex SIGNOR-C255 SIGNOR FUS protein P35637 UNIPROT up-regulates activity relocalization 9606 BTO:0000793 27460707 YES P35637:p.Arg495_Tyr526del (mutation increasing interaction) We hypothesized that FUS could be secreted via the exosome pathway. We tested and confirmed that FUS was indeed present in exosomes in both SH-SY5Y and N2A cells (Fig. 6 and Supplemental Fig. 2). It is also noted that the level of the R495X mutant in exosomes was significantly higher than that of WT or the R521G mutant. |It raises the possibility that the exosome-mediated secretion of FUS may contribute to the cell-to-cell propagation of FUS pathology. 0.232 SIGNOR-262812 HPX protein P02790 UNIPROT HBB protein P68871 UNIPROT down-regulates activity 9606 20617898 NO Regulation miannu The endogenous molecule hemoglobin and its derivative heme are often released into tissue compartments where there is infection in the presence of degrading blood. We found that hemoglobin synergizes with multiple TLR agonists to induce high levels of tumor necrosis factor and interleukin-6 from macrophages and that this synergy is independent of TLR4 and MyD88. In contrast, heme synergized with some but not all TLR agonists studied. Furthermore, the synergy of both hemoglobin and heme with lipopolysaccharide was suppressed by hemopexin, a plasma heme-binding protein. 0.503 SIGNOR-251811 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser1056 FLTQRRPsASSPNNN 9606 BTO:0000007 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h). 0.2 SIGNOR-264513 MAPK1 protein P28482 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Tyr187 HTGFLTEyVATRWYR 1712480 YES lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| 0.2 SIGNOR-249415 CHRM3 protein P20309 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.409 SIGNOR-257134 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Thr709 PKRLGAHtP 9606 14697653 YES lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.268 SIGNOR-120483 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr740 TGESDGGyMDMSKDE -1 8195171 YES miannu Synthetic peptide analysis revealed that certain autophosphorylation sites in the PDGF beta-receptor (Tyr-579, Tyr-740, Tyr-751, and Tyr-771) were able to mediate the specific binding of the Shc SH2 domain as well as intact Shc proteins. 0.2 SIGNOR-250257 PTPN5 protein P54829 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates activity dephosphorylation Tyr108 QPTAENAyEYFTKIA 9606 20959805 YES In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation. 0.2 SIGNOR-248542 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates quantity by destabilization phosphorylation Ser280 YKKVKKNsSPPLSLY 9606 19833968 YES miannu We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1 0.364 SIGNOR-268047 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 11062067 YES lperfetto In the present study, we found that mkk7 phosphorylates sapk2a/p38 exclusively at tyr-182, albeit at a low rate. Therefore one possibility is that the interaction of mkk7 and/or sapk1/jnk with another cellular protein alters the conformation of one of these enzymes in such a way as to facilitate phosphorylation of tyr-185 by mkk7 in vivo. 0.636 SIGNOR-83748 haloperidol chemical CHEBI:5613 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258838 hsa-miR-329-5p mirna URS000075BD0A_9606 RNAcentral WNT7B protein P56706 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003964 25351956 YES Parnian Downregulated miR329 and miR410 Promote the Proliferation and Invasion of Oral Squamous Cell Carcinoma by Targeting Wnt-7b.| miR329 and miR410 directly target Wnt-7b. 0.4 SIGNOR-278857 KLHL3 protein Q9UH77 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000567 23387299 YES miannu CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms. 0.657 SIGNOR-272101 FGF8 protein P55075 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002314 BTO:0000887;BTO:0001103 24209627 NO gcesareni Loss of fgf signaling in fgf24 and fgf8 double-deficient zebrafish 0.339 SIGNOR-203148 GDP smallmolecule CHEBI:17552 ChEBI GNAS protein P63092 UNIPROT down-regulates chemical inhibition 9606 17095603 YES gcesareni Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis. 0.8 SIGNOR-150549 clobetasol chemical CHEBI:205919 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 YES gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. 0.8 SIGNOR-248212 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr589 TGSSDNEyFYVDFRE 9606 BTO:0001271 11971190 YES lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation 0.2 SIGNOR-117571 ELF4 protein Q99607 UNIPROT LYZ protein P61626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 14976184 NO miannu Myeloid elf-1-like factor (mef) or elf4, which is a member of the ets transcription factor family, up-regulates the basal expression of lysozyme gene in epithelial cells and is constitutively localized in the nucleus 0.258 SIGNOR-122236 miR-495 mirna URS000075C517_9606 RNAcentral Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 26344767 YES Luana To further determine whether MeCP2 regulates the expression of miR-199a, we also re-expressed MeCP2 in MeCP2-KO neurons. As expected, this restored the level of mature-miR-199a expression to that in WT neurons 0.4 SIGNOR-264545 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates activity phosphorylation 9606 21078677 YES miannu PLK1 phosphorylates mitotic centromere-associated kinesin and promotes its depolymerase activity. 0.811 SIGNOR-278908 RPS6KA3 protein P51812 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser33 DGKKRKRsRKESYSI 9606 21646345 YES lperfetto Here, we studied the histone h2b core domain and found that phosphorylation of h2b serine 32 occurs in normal cycling and mitogen-stimulated cells. Notably, this phosphorylation is elevated in skin cancer cell lines and tissues compared with normal counterparts. We identified ribosomal s6 kinase 2 (rsk2) as the kinase responsible for h2bs32 phosphorylation. 0.2 SIGNOR-174026 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral PIK3R2 protein O00459 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 25240815 YES Parnian We demonstrated that miR-126-3p was shown to directly bind to the 3′UTR of PIK3R2 by both up-regulation and inhibition of miR-126-3p in Hep-G2 and BEL-7402 cells.| These data suggests that miR-126-3p suppresses angiogenesis in HCC through PIK3R2/P-AKT pathway. 0.4 SIGNOR-278837 DRD5 protein P21918 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.264 SIGNOR-257418 maraviroc chemical CHEBI:63608 ChEBI CCL5 protein P13501 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194127 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.551 SIGNOR-273176 CDK5 protein Q00535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation Ser786 RGGSDDSsKDPIDVN -1 21922195 YES miannu These results would suggest that the phosphorylation of PARP-1 via Cdk5's kinase activity is necessary for its persistence at damage sites.Based on these results and the recruitment data, we hypothesize that the phosphorylation of the PARP-1 protein by Cdk5 on one or more of the serines 782, 785, and 786 results in an attenuation of its ribosylating activity facilitating its persistence at the sites of DNA damage. 0.258 SIGNOR-276359 RAP1GDS1 protein P52306 UNIPROT CDC42 protein P60953 UNIPROT up-regulates binding 9606 21242305 YES miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob 0.288 SIGNOR-171412 SRF protein P11831 UNIPROT PLAU protein P00749 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000161 15514113 NO miannu We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. 0.257 SIGNOR-255227 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser204 SGAEGDVsSEREP -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.321 SIGNOR-273965 A-966492 chemical CID:16666333 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-205698 AKT proteinfamily SIGNOR-PF24 SIGNOR PEA15 protein Q15121 UNIPROT up-regulates activity phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 BTO:0000007 12808093 YES lperfetto Protein kinase b/akt binds and phosphorylates ped/pea-15, stabilizing its antiapoptotic action. 0.2 SIGNOR-244326 TFEB protein P19484 UNIPROT GLA protein P06280 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.285 SIGNOR-276539 STAT2 protein P52630 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR form complex binding -1 8943351 YES 2 miannu The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3 0.737 SIGNOR-240603 ATR protein Q13535 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR 9606 19843584 YES llicata Atr phosphorylates s33 in response to replication stress 0.755 SIGNOR-188666 CDC14B protein O60729 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser64 SNLGHPEsPPRKRLK 9606 18239684 YES The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1). 0.358 SIGNOR-248333 MTOR protein P42345 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C3 21659604 YES gcesareni The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase. 0.413 SIGNOR-174071 PRKACA protein P17612 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation 10090 BTO:0000944 23644383 YES milica Here, we show that cyclic amp (camp)-dependent protein kinase (pka) phosphorylates lats and thereby enhances its activity sufficiently to phosphorylate yap on ser381. 0.2 SIGNOR-236994 PPM1D protein O15297 UNIPROT UNG protein P13051 UNIPROT down-regulates activity dephosphorylation 9606 15327777 YES miannu PPM1D dephosphorylation of UNG2 is correlated with reduced UNG2 activity on uracil-containing templates.|This result suggests that PPM1D specifically inhibits UNG2 and not other uracil DNA glycosylases. 0.377 SIGNOR-277156 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273090 SEC23IP protein Q9Y6Y8 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269654 VEPH1 protein Q14D04 UNIPROT LATS1 protein O95835 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 NO In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r8 0.2 SIGNOR-177074 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258795 DRD5 protein P21918 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.289 SIGNOR-257043 SCF-betaTRCP complex SIGNOR-C5 SIGNOR GBF1 protein Q92538 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 29898406 YES miannu We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation. 0.251 SIGNOR-277399 HECT E3 ligase proteinfamily SIGNOR-PF104 SIGNOR Ub:HECT_E3 complex SIGNOR-C518 SIGNOR form complex binding 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 0.2 SIGNOR-271376 PLK1 protein P53350 UNIPROT TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr27 SSLEPDStYFDLPQS 9606 18418051 YES llicata P73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. tap73 is phosphorylated by this kinase on threonine-27 (thr-27) within the ta domain. 0.508 SIGNOR-178253 SRC protein P12931 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 16619028 YES lperfetto Src kinase phosphorylates caspase-8 on tyr380: a novel mechanism of apoptosis suppressionwe identified caspase-8 as a new substrate for src kinase. Phosphorylation occurs on tyr380, situated in the linker region between the large and the small subunits of human procaspase-8, and results in downregulation of caspase-8 proapoptotic function 0.454 SIGNOR-146127 NR0B2 protein Q15466 UNIPROT ESR1 protein P03372 UNIPROT down-regulates binding 9606 BTO:0000975 11861507 YES gcesareni Our results identify shp as an inhibitor of 4-oht agonist activity in rl95-2 human endometrial carcinoma cells that express endogenous er?. We conclude that shp does not decrease er expression, but rather it is the direct interaction of shp with er that inhibits er transcriptional activity. 0.648 SIGNOR-115033 PAK1 protein Q13153 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser192 VNSVRRKsCLVKEVE 9606 23055517 YES lperfetto Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes 0.385 SIGNOR-199084 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8422248 YES lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. 0.729 SIGNOR-248931 ATP2A1 protein O14983 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9986 28487373 YES lperfetto SERCA1, the sarco(endo)plasmic reticulum Ca2+-ATPase of skeletal muscle, is essential for muscle relaxation and maintenance of low resting Ca2+ levels in the myoplasm. 0.8 SIGNOR-265928 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser702 AVILTVEsEEEEEES -1 21296876 YES miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis 0.2 SIGNOR-276253 PPM1F protein P49593 UNIPROT PAK2 protein Q13177 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 YES gcesareni Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity. 0.261 SIGNOR-162149 MARK3 protein P27448 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity phosphorylation Ser151 LSLAKSVsTTNIAGH 9606 BTO:0002181 29089450 YES miannu Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules. 0.382 SIGNOR-277368 HSPH1 protein Q92598 UNIPROT HSPA1B protein P0DMV9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 NO miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. 0.476 SIGNOR-255243 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser116 PQKLLGCsPALKRSH 9606 12411508 YES lperfetto Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover. 0.848 SIGNOR-216761 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity binding 9606 29407449 YES scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. 0.8 SIGNOR-267276 PRKD2 protein Q9BZL6 UNIPROT HDAC5 protein Q9UQL6 UNIPROT up-regulates activity phosphorylation Ser498 RPLSRTQsSPLPQSP 18692497 YES lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. 0.295 SIGNOR-275929 KDM4B protein O94953 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 30759871 YES miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways. 0.2 SIGNOR-265359 NEDD4 protein P46934 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26363003 YES SARA We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels. 0.268 SIGNOR-260998 TNK1 protein Q13470 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates quantity binding 9606 10873601 YES miannu  GST-protein precipitations from cell lysates confirmed that GST-PLC-gamma1(SH3) associated with endogenously expressed Tnk1. 0.34 SIGNOR-273864 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation Tyr221 GGPEPGPyAQPSVNT 10090 15886098 YES gcesareni Rin1 binds to the abl sh3 and sh2 domains, and these interactions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl, inhibiting these cytoskeletal regulators by promoting intramolecular over intermolecular associations. the ability of crk to function as an adaptor protein is negatively regulated and terminated by phosphorylation on y221, which results in an intramolecular sh2-ptyr clamp, thereby resulting in the disassembly of crk-mediated signaling complexes 0.694 SIGNOR-136955 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR form complex binding 9606 24816100 YES miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. 0.765 SIGNOR-270834 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr100 TNTYYLQtFGHNTMD 9606 BTO:0000007 21321328 YES miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). 0.578 SIGNOR-276307 Caspase 3 complex complex SIGNOR-C221 SIGNOR SPTAN1 protein Q13813 UNIPROT down-regulates cleavage 9606 BTO:0000150;BTO:0000567 9624143 YES amattioni Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. 0.674 SIGNOR-256450 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.67 SIGNOR-156852 EPHB2 protein P29323 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 9233798 YES gcesareni We have localized an in vitro rasgap-binding site to conserved tyrosine residues y604 and y610 in the juxtamembrane region of ephb2, and demonstrated that substitution of these amino acids abolishes ephrin-b1-induced signalling events in ephb2-expressing ng108-15 cells. 0.575 SIGNOR-50100 PROX1 protein Q92786 UNIPROT RORC protein P51449 UNIPROT down-regulates 23723244 NO azuccotti In this study, we identify Prospero-related homeobox 1 (Prox1) as a novel co-repressor of the retinoic acid-related orphan receptors, RORgamma and RORalpha. Prox1 interacts directly with RORgamma and RORalpha and negatively regulates their transcriptional activity. 0.27 SIGNOR-254507 ADIPOQ protein Q15848 UNIPROT ADIPOR2 protein Q86V24 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 12802337 YES acerquone Expression of adipor1/r2 or suppression of adipor1/r2 expression by small-interfering rna supports our conclusion that they serve as receptors for globular and full-length adiponectin, 0.772 SIGNOR-101809 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.497 SIGNOR-248311 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000782 14679297 YES lperfetto We show that purified recombinant ikk-epsilon and tbk1 directly phosphorylate the critical serine residues in irf3 allowing its translocation into the nucleus and production of interferon type i. 0.822 SIGNOR-120355 MAPK3 protein P27361 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Ser387 PATVEPAsPTPAHSL 9606 BTO:0000150 17311928 YES llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 0.52 SIGNOR-153387 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263784 MAPK14 protein Q16539 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 YES Translocation from Nucleus to Cytoplasm esanto We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats. 0.621 SIGNOR-74560 Ub:E2 complex SIGNOR-C497 SIGNOR LNX1 protein Q8TBB1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271094 HIPK2 protein Q9H2X6 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Ser882 IVIPDTPsPTVSVIT 9606 BTO:0002181 24145406 YES miannu  Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. 0.2 SIGNOR-276600 COPS6 protein Q7L5N1 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.927 SIGNOR-270767 PPP2CA protein P67775 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity dephosphorylation Ser129 NEAYEMPsEEGYQDY 9606 21562258 YES α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129 0.333 SIGNOR-248635 AKT proteinfamily SIGNOR-PF24 SIGNOR PLN protein P26678 UNIPROT down-regulates activity phosphorylation Thr17 SAIRRAStIEMPQQA 10090 BTO:0003265 19696029 YES Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17). 0.2 SIGNOR-252035 ITGB1BP1 protein O14713 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.288 SIGNOR-257654 WNT6 protein Q9Y6F9 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 22944199 NO gcesareni In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. 0.323 SIGNOR-198916 morphine chemical CHEBI:17303 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258932 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 10090 BTO:0004831 11896587 YES lperfetto Serine 20 phosphorylation of p53 has been shown to be required for the activation of p53 following UV radiation. we determined the role of map kinases in uvb-induced phosphorylation and found that jnks are directly involved in the phosphorylation of p53 at serine 20 0.796 SIGNOR-106538 MYT1L protein Q9UL68 UNIPROT SIN3B protein O75182 UNIPROT up-regulates activity binding 10090 BTO:0002572 28379941 YES miannu We found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. 0.451 SIGNOR-266774 PPARG protein P37231 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 20553736 NO lperfetto Pigment epithelium-derived factor induces interleukin-10 expression in human macrophages by induction of PPAR gamma. 0.37 SIGNOR-271688 UBA52 protein P62987 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding 10090 BTO:0002572 phosphorylation: ser65 DYNIQKEsTLHLVLR 24784582 YES The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. 0.2 SIGNOR-270344 FGF9 protein P31371 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 NO FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1 gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts 0.307 SIGNOR-195594 mTORC1 complex SIGNOR-C3 SIGNOR PIP4K2C protein Q8TBX8 UNIPROT up-regulates quantity phosphorylation Ser324 GPPALVGsYGTSPEG 9606 BTO:0000567 25372051 YES miannu  PIP4kγ was phosphorylated by mTORC1 and associated with the complex. Phosphorylated PIP4kγ was enriched in light microsomal vesicles, whereas the unphosphorylated form was enriched in heavy microsomal vesicles associated with the Golgi.  0.284 SIGNOR-273680 CHKB protein Q9Y259 UNIPROT ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI down-regulates quantity chemical modification 29928787 YES lperfetto In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells. 0.8 SIGNOR-275640 PTPN13 protein Q12923 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation Tyr226 KRNKPTVyGVSPNYD 9606 28924170 YES lperfetto We also found that PTPN13 dephosphorylates and inhibits c-Abl.|While the above results indicated that calpain-2 could cleave PTPN13 and that PTPN13 could dephosphorylate c-Abl at tyrosine 245, they did not determine whether calpain-2-mediated cleavage of PTPN13 resulted in its inactivation and increased tyrosine phosphorylation of c-Abl at tyrosine 245. 0.39 SIGNOR-277012 MFF protein Q9GZY8 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 NO lperfetto These proteins include the classical mitochondrial fusion (MFN1, MFN2, and OPA1) and fission proteins (DRP1, MFF, FIS1, etc.) as well as several other proteins that are directly or indirectly involved in these processes (e.g. YME1L, OMA1, INF2, GDAP1, MIC13, etc. 0.7 SIGNOR-272983 FGR protein P09769 UNIPROT SDHA protein P31040 UNIPROT unknown phosphorylation Tyr543 CGKISKLyGDLKHLK -1 17997986 YES miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. 0.2 SIGNOR-262872 PSMC6 protein P62333 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.858 SIGNOR-263370 NR4A1 protein P22736 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0005761 15666793 NO miannu Herein we discuss the evidence that suggests a role for NURR1 (NR4A2) in the expression of CYP11B2 in the glomerulosa as well as in the dysregulation of CYP11B2 gene expression as is seen in aldosterone-producing adenoma (APA), a major cause of endocrine hypertension. NURR1 appears to be important for CYP11B2 transcription and is found at higher levels in glomerulosa and in APA. 0.364 SIGNOR-254866 NCOA6 protein Q14686 UNIPROT GREB1 protein Q4ZG55 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003041 31744881 YES miannu Herein, using growth-regulating estrogen receptor binding 1 (GREB1) as an ERα target gene in Ishikawa cells, we demonstrate that nuclear receptor co-activator 6 (NCOA6) is essential for estradiol (E2)/ERα-activated GREB1 transcription. We found that NCOA6 associates with the GREB1 promoter and enhancer in an E2-independent manner and that NCOA6 knockout reduces chromatin looping, enhancer-promoter interactions, and basal GREB1 expression in the absence of E2. 0.2 SIGNOR-265883 NFATC1 protein O95644 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 17111365 NO Regulation miannu Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. 0.274 SIGNOR-251956 TNFAIP3 protein P21580 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity ubiquitination 9606 15258597 YES A20The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. 0.654 SIGNOR-259977 ID2 protein Q02363 UNIPROT TCF12 protein Q99081 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C128 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.552 SIGNOR-241131 FZD8 protein Q9H461 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000971 21078818 YES amattioni Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate Wnt–Beta-catenin signaling. 0.754 SIGNOR-169638 MAPK3 protein P27361 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3. 0.622 SIGNOR-66781 Class II MHC:Antigen complex SIGNOR-C429 SIGNOR TCR complex SIGNOR-C153 SIGNOR up-regulates activity binding 9606 31001252 YES scontino The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes. 0.2 SIGNOR-267992 GFAP protein P14136 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity binding 9606 BTO:0000099 31626364 YES miannu GFAP is the major cytoskeletal element and scaffold of astrocytes In astrocytes, GFAP has close interaction with F-actin molecularly and functionally. 0.375 SIGNOR-269271 PKA proteinfamily SIGNOR-PF17 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser525 TSMKPRSsRGSIFTF 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.2 SIGNOR-275766 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RRAS protein P10301 UNIPROT up-regulates activity phosphorylation Ser201 QEQELPPsPPSAPRK 9606 BTO:0002181 27086924 YES miannu  In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo.  0.2 SIGNOR-277219 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 15718470 YES lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 0.642 SIGNOR-252600 DMTF1 protein Q9Y222 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 YES Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  0.2 SIGNOR-261587 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Gln711 PTYKFFEqMQN -1 8943232 YES lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261790 NAD(1-) smallmolecule CHEBI:57540 ChEBI SIRT1 protein Q96EB6 UNIPROT up-regulates activity binding 9606 10693811 YES gcesareni Here we show that yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases 0.8 SIGNOR-238539 FBP2 protein O00757 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 30616754 YES lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle 0.8 SIGNOR-267612 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 YES lperfetto The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. 0.746 SIGNOR-235438 TUT1 protein Q9H6E5 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 21102410 NO miannu Star-PAP is a poly (A) polymerase (PAP) that is putatively required for 3'-end cleavage and polyadenylation of a select set of pre-messenger RNAs (mRNAs) 0.7 SIGNOR-272322 MERTK protein Q12866 UNIPROT MERTK protein Q12866 UNIPROT up-regulates phosphorylation Tyr753 KKIYSGDyYRQGRIA 9606 8702477 YES gcesareni By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain. 0.2 SIGNOR-42918 ARFGEF1 protein Q9Y6D6 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000599 14973189 YES lperfetto Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) is an approximately 200-kDa brefeldin A-inhibited guanine nucleotide-exchange protein that preferentially activates ADP-ribosylation factor 1 (ARF1) and ARF3.  0.599 SIGNOR-272147 CDK1 protein P06493 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR form complex binding 9606 25603287 YES lperfetto The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase. 1 SIGNOR-205593 ITK protein Q08881 UNIPROT BMX protein P51813 UNIPROT up-regulates activity phosphorylation Tyr216 SSTSLAQyDSNSKKI -1 12573241 YES Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. 0.334 SIGNOR-251331 CTSB protein P07858 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg95 GFQEAYRrFYGPV -1 9076588 YES miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. 0.33 SIGNOR-256320 WNT1 protein P04628 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 18697834 YES Simone Vumbaca Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells 0.766 SIGNOR-255649 ATP5IF1 protein Q9UII2 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261400 ADRA2B protein P18089 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.372 SIGNOR-257201 YY1 protein P25490 UNIPROT HOXB13 protein Q92826 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001130 19013255 NO miannu Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers. 0.273 SIGNOR-254233 PLK1 protein P53350 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 20890306 YES gcesareni Fas-associated death domain-containing protein (FADD) was first identified as an adapter molecule involved in formation of a death-inducing signaling complex upon Fas stimulation| Plk1 phosphorylates fadd at ser-194 in response to treatment with taxol Phosphorylation by polo-like kinase 1 induces the tumor-suppressing activity of FADD 0.46 SIGNOR-168204 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu79 EDSDKTNeFWNKYKD -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263674 mTORC1 complex SIGNOR-C3 SIGNOR NRBF2 protein Q96F24 UNIPROT up-regulates activity phosphorylation Ser120 SPLSQKYsPSTEKCL 9606 28059666 YES miannu Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished. Phosphorylated NRBF2 preferentially interacts with PIK3C3/PIK3R4. Suppression of NRBF2 phosphorylation by MTORC1 inhibition alters its binding preference from PIK3C3/PIK3R4 to ATG14/BECN1, leading to increased autophagic PtdIns3K complex assembly, as well as enhancement of ULK1 protein complex association. 0.2 SIGNOR-265877 metaproterenol chemical CHEBI:6792 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation -1 19168263 YES Luana Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, a compound designed to act as a β2 adrenoceptor agonist | After that, in vitro assays were carried out and the Kd value obtained for BR-AEA was compared with reported in vitro data for salbutamol and other well-known ligands. 0.8 SIGNOR-257814 PKN3 protein Q6P5Z2 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Ser428 PAEGKRLsASSTGST -1 30422386 YES lperfetto These results verified the presence of a PKN3 phosphorylation motif in the sequence surrounding Ser432 and indicated that PKN3 phosphorylates p130Cas on Ser432 in vitro.|Human Ser428 of p130Cas corresponds to mouse p130Cas Ser432| 0.2 SIGNOR-264574 CDK5 protein Q00535 UNIPROT BACE1 protein P56817 UNIPROT up-regulates activity phosphorylation Thr252 YTGSLWYtPIRREWY 9606 26317805 YES miannu BACE1 is phosphorylated by p25 and Cdk5 at Thr252.|Our finding that p25/Cdk5 stimulates BACE1 activity supports that p25/Cdk5 may represent a promising target for the development of drugs to treat Alzheimer's disease. 0.44 SIGNOR-278249 CEBPD protein P49716 UNIPROT IL23A protein Q9NPF7 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 NO CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. 0.2 SIGNOR-254061 A5/b1 integrin complex SIGNOR-C163 SIGNOR Activated PSC phenotype SIGNOR-PH224 SIGNOR up-regulates 9606 32928643 YES miannu CTGF is highly expressed in PDAC tissues, especially in tumor stroma (as shown by immunohistochemistry, CTGF: brown stain). The tumor cell-secreted CTGF promotes pancreatic stellate cell (PSC) proliferation, adhesion, and migration via integrin α5β1, leading to extracellular matrix (ECM) deposition.Pancreatic cancer cells secrete high levels of CTGF that binds to integrin α5β1, promoting PSC proliferation, adhesion, and migration 0.7 SIGNOR-277688 KDM4C protein Q9H3R0 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates activity demethylation 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-265315 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg1220 LSPELIQrNLSPALG -1 10026263 YES lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 0.499 SIGNOR-263648 EAPP protein Q56P03 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23542036 NO miannu We show here that EAPP stimulates the MDR1 promoter resulting in higher PGP levels. Independently of EAPP, E2F1 also increases the activity of the MDR1 promoter. 0.2 SIGNOR-253842 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249350 RHEB protein Q15382 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 10090 BTO:0000011 19299511 YES lperfetto These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation. 0.798 SIGNOR-235355 P4HA1 protein P13674 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 31239153 NO miannu Subsequent functional experiments confirmed our conclusions that P4HA1 is a crucial regulator of PDAC glycolysis. Therefore, our findings uncovered a previous unprecedented role of P4HA1 in cancers. Increased glycolysis provides cancer cells with abundant cellular buildings and reducing substrate, which are needed for rapid cell proliferation 0.7 SIGNOR-279876 PAK3 protein O75914 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser150 TLRRVRIsADAMMQA 9606 BTO:0000887 12242269 YES llicata Importantly, cardiac troponin i was found to be phosphorylated at serine 149 of human cardiac troponin i, representing a novel phosphorylation site. These findings suggest a novel mechanism of modulating the calcium sensitivity of cardiac muscle contraction. 0.2 SIGNOR-92990 PSMC3 protein P17980 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.878 SIGNOR-263369 PKN1 protein Q16512 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser118 QVKIWRRsYDVPPPP 9606 BTO:0000130 12189148 YES llicata Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. 0.254 SIGNOR-91602 AKT2 protein P31751 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 17277771 YES lperfetto Furthermore, pras40 phosphorylation by akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mtor. These findings identify pras40 as an important regulator of insulin sensitivity of the akt-mtor pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes. 0.584 SIGNOR-235967 UBA1 protein P22314 UNIPROT Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR form complex binding 9606 24816100 YES miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. 0.2 SIGNOR-270833 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22521266 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-197197 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 21079800 YES gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.468 SIGNOR-169674 Ub:E2 complex SIGNOR-C497 SIGNOR RNF2 protein Q99496 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271025 NAALAD2 protein Q9Y3Q0 UNIPROT Ac-Asp-Glu(3-) smallmolecule CHEBI:76931 ChEBI down-regulates quantity chemical modification 9606 10085079 YES miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. 0.8 SIGNOR-267541 RPS6KA3 protein P51812 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8688081 YES lperfetto MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression 0.725 SIGNOR-248951 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser175 EEEEDLSsPPGLPEP 9606 14697653 YES lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.259 SIGNOR-120451 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263776 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1367 LVQGSPSsQEQQVTL 9606 15173573 YES lperfetto Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp 0.271 SIGNOR-125081 SYVN1 protein Q86TM6 UNIPROT CLU protein P10909 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 17451556 YES miannu We also report that the ER-associated ubiquitin ligase Hrd1/synoviolin can interact with, and ubiquitinate clusterin. The fact that cleaved endogenous clusterin appears, under certain conditions, to be subject to polyubiquitination (Figure 2C) and proteasomal degradation (1, 2) strongly suggests that it passed through the secretory pathway before reaching the cytosol. 0.321 SIGNOR-272629 Wnt proteinfamily SIGNOR-PF40 SIGNOR LPR5/6 complex SIGNOR-C219 SIGNOR up-regulates activity binding 9606 23209147 YES miannu FZD and LRP5/6 transduce Wnt signal via engaging downstream cytoplasmic components, among which two scaffolding proteins, Dishevelled and Axin, have prominent roles. 0.808 SIGNOR-256174 SATB2 protein Q9UPW6 UNIPROT BCL11B protein Q9C0K0 UNIPROT down-regulates quantity transcriptional regulation 9606 31666685 YES gianni Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development 0.495 SIGNOR-268931 OGA protein O60502 UNIPROT PFKM protein P08237 UNIPROT up-regulates activity deglycosylation Ser530 VVIPATVsNNVPGSD 9606 26399441 YES lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. 0.2 SIGNOR-267607 SF3B3 protein Q15393 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.806 SIGNOR-270665 MYOD1 protein P15172 UNIPROT MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR form complex binding 9606 BTO:0001103 17194702 YES miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes 0.41 SIGNOR-151682 POLR2K protein P53803 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.806 SIGNOR-266141 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 YES lperfetto Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2. 0.731 SIGNOR-59623 SMAD2 protein Q15796 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9606 11389444 YES lperfetto We show that in the presence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases.Thus, stimulation by TGF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation. 0.778 SIGNOR-108490 regorafenib chemical CHEBI:68647 ChEBI DDR2 protein Q16832 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259208 azelastine chemical CHEBI:2950 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257790 RFC2 protein P35250 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 YES lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned 0.771 SIGNOR-265506 PRKCA protein P17252 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 YES lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. 0.522 SIGNOR-96692 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser13 KRTADSSsSEDEEEY 9606 21245376 YES gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. 0.367 SIGNOR-171703 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 YES lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  0.357 SIGNOR-249075 CTNND1 protein O60716 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0003564 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.735 SIGNOR-252125 DDIT3 protein P35638 UNIPROT ANKRD1 protein Q15327 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0003324 19299913 NO lperfetto Promoter deletion and reporter analysis revealed that hypoxia transcriptionally activates a GADD153 promoter through the AP-1 element in neonatal cardiomyocytes. Ectopic overexpression of GADD153 resulted in the downregulation of CARP expression. 0.274 SIGNOR-254122 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser110 SDKKEKKsFSLEEKS 9606 20573420 YES lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. 0.362 SIGNOR-166317 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 YES miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors 0.8 SIGNOR-258848 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 10197981 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 0.713 SIGNOR-236242 GRK2 protein P25098 UNIPROT OPRD1 protein P41143 UNIPROT down-regulates activity phosphorylation Ser363 RVTACTPsDGPGGGA 9606 BTO:0000007 11040053 YES gcesareni Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus. 0.2 SIGNOR-249660 vandetanib chemical CHEBI:49960 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207624 TFEB protein P19484 UNIPROT NDUFB10 protein O96000 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). 0.2 SIGNOR-276704 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT up-regulates activity phosphorylation Ser44 AMKFLRAsEEHLKQH 9606 BTO:0000093 8245015 YES miannu An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells. 0.2 SIGNOR-250201 EPGN protein Q6UW88 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 YES EPGN may stimulate the phosphorylation of EGFR and mitogen-activated protein kinases gcesareni Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. 0.62 SIGNOR-165779 RAF1 protein P04049 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation 9606 22225925 YES miannu In hESC, Raf-1 directly phosphorylates and inactivates MYPT1, and this process requires kinase active Raf-1 protein. 0.275 SIGNOR-278979 RELA protein Q04206 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 SIGNOR-C6 10207072 YES gcesareni Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo. 0.879 SIGNOR-66953 TSC22D3 protein Q99576 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity relocalization 9606 BTO:0000738 20018851 YES inferred from 70% of family members GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. 0.398 SIGNOR-269854 MAPK8 protein P45983 UNIPROT NEIL1 protein Q96FI4 UNIPROT up-regulates activity phosphorylation Ser61 KELRLILsPLPGAQP 9606 27518429 YES miannu These data confirm that NEIL1 can be phosphorylated by JNK1 in vitro at S207, S306, and S61. 0.2 SIGNOR-278317 ATM protein Q13315 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1083 ESERGSGsQSSVPSV 9606 18442975 YES llicata Ser-1083 phosphorylation is ir-inducible, depends on atm and nijmegen breakage syndrome 1 (nbs1), and is required for intra-s phase checkpoint. 0.74 SIGNOR-178479 MAPK3 protein P27361 UNIPROT SPIB protein Q01892 UNIPROT unknown phosphorylation Thr56 VAPPVPAtPYEAFDP 9606 BTO:0000776 8632909 YES lperfetto The threonine 56 was defined as the erk1 phosphorylation site by using phosphoamino-acid analyses and a spi-b mutant version 0.312 SIGNOR-41800 SRC protein P12931 UNIPROT CHKA protein P35790 UNIPROT up-regulates activity phosphorylation Tyr197 RSLGPKLyGIFPQGR 9606 BTO:0000093 21822308 YES miannu We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. 0.337 SIGNOR-266351 BVES protein Q8NE79 UNIPROT VAMP3 protein Q15836 UNIPROT up-regulates activity binding -1 20057356 YES llicata Taken together, these data demonstrate that Bves interacts with VAMP3 and facilitates receptor recycling both in vitro and during early development. 0.42 SIGNOR-237771 DNM1L protein O00429 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 10090 BTO:0002295 31063459 YES lperfetto Importantly, we found that crosstalk between phosphorylated Drp1S600 (p-Drp1S600) and the actin-binding protein com- plex Arp2/3 is a required step in mitochondrial Drp1 recruitment and mitochondrial fission under HG conditions. 0.283 SIGNOR-262550 KCNN4 protein O15554 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10116 BTO:0000078 25274816 YES miannu KCa3.1 activation is expected to maintain a negative membrane potential, which will increase Ca2+ influx through nonvoltage gated Ca2+-release-activated Ca2+ (CRAC) channels that are prevalent in rat microglia 0.8 SIGNOR-276856 TFAP2C protein Q92754 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 NO SimoneGraziosi SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation. 0.7 SIGNOR-269262 ACE2 protein Q9BYF1 UNIPROT APLN protein Q9ULZ1 UNIPROT up-regulates activity cleavage -1 11815627 YES miannu ACE2 hydrolyzes the hormone apelin-13 with high catalytic efficiency and cleaves apelin-36, whose C-terminal 13 amino acids are identical to those of apelin-13. 0.423 SIGNOR-256316 SWI/SNF complex complex SIGNOR-C92 SIGNOR Myog/SWI/SNF complex complex SIGNOR-C94 SIGNOR form complex binding 9606 BTO:0001103 17194702 YES miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle 0.395 SIGNOR-151706 LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 BTO:0000782 16938345 YES gcesareni Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation. 0.757 SIGNOR-149186 STAT1 protein P42224 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 16628196 NO miannu The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection. 0.483 SIGNOR-255231 TCF4 protein P15884 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20459685 NO miannu Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. 0.249 SIGNOR-255389 CBX1 protein P83916 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-264492 PLK1 protein P53350 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates activity phosphorylation Ser486 SEYEAEMsLQGEVNI -1 26323689 YES done miannu Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D). 0.344 SIGNOR-274017 tRNA(Val) smallmolecule CHEBI:29183 ChEBI Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates quantity precursor of 9606 30755602 YES miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 0.8 SIGNOR-270531 CTNNB1 protein P35222 UNIPROT CCN4 protein O95388 UNIPROT up-regulates quantity transcriptional regulation 10116 BTO:0002409 10716946 YES This study identifies WISP-1 as a beta-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and beta-catenin expression. 0.2 SIGNOR-256270 PPP1CB protein P62140 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 21750978 YES miannu Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway 0.265 SIGNOR-174862 MAP4K2 protein Q12851 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 9712898 YES gcesareni The mekk1 associated with the gck carboxyl terminus is catalytically active. 0.564 SIGNOR-59682 CDH22 protein Q9UJ99 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.333 SIGNOR-265860 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 YES miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). 0.578 SIGNOR-276308 AR protein P10275 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 11916967 NO lperfetto Transcription assays demonstrated that liganded ar repressed beta-catenin/t cell factor-responsive reporter gene activity 0.728 SIGNOR-116260 RAPH1 protein Q70E73 UNIPROT EVL protein Q9UI08 UNIPROT up-regulates activity binding 9606 20417104 YES miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. 0.346 SIGNOR-268427 SCF-FBW7 complex SIGNOR-C135 SIGNOR MED13L protein Q71F56 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23322298 YES miannu The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association. 0.359 SIGNOR-266689 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser358 WPLSRTRsEPLPPSA 9606 18339811 YES Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. 0.318 SIGNOR-248648 BIRC2 protein Q13490 UNIPROT EIF4E protein P06730 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28852129 YES miannu We found that endogenous eIF4E was ubiquitinated by cIAP1, and ubiquitinated eIF4E accumulated upon MG132 treatment. 0.401 SIGNOR-278741 KMT2A protein Q03164 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0002884 22012064 YES irozzo Furthermore, we show that both MLL and AML1/CBFβ are required for maintaining the H3K4-me3 mark at the PU.1 upstream regulatory element (URE) and promoter region, and for full PU.1 gene expression. 0.44 SIGNOR-255874 MYC protein P01106 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18677108 YES miannu Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. 0.294 SIGNOR-267375 PAK4 protein O96013 UNIPROT PAK4 protein O96013 UNIPROT up-regulates phosphorylation Ser474 KEVPRRKsLVGTPYW 9606 20926745 YES gcesareni Intracellular localization;enzymatic activity, induced;cell growth, altered; 0.2 SIGNOR-168301 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one chemical CID:56593482 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 22025698 YES Luana Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands.  0.8 SIGNOR-258321 PTGS2 protein P35354 UNIPROT prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI up-regulates chemical modification 9606 20219869 YES apalma NSAIDs are strong inhibitors of cycloxygenases (COX), and thereby impair the metabolism of arachidonic acid that is necessary for the synthesis of prostaglandins 0.8 SIGNOR-255359 CDK2 protein P24941 UNIPROT PTPN2 protein P17706 UNIPROT unknown phosphorylation Ser304 LSPAFDHsPNKIMTE 9606 15030318 YES llicata Our studies identify ser-304 as a major phosphorylation site in human tcptp, and the tc45 variant as a novel mitotic cdk substrate. 0.36 SIGNOR-123471 VDR protein P11473 UNIPROT HLA-DRB1 protein P01911 UNIPROT up-regulates quantity by expression transcriptional regulation -1 19956544 NO The promoter sequence analysis of HLA-DRB1 0301 showed presence of VDRE involved in higher expression of HLA-DRB1 030, which was confirmed by flow cytometry and real time PCR analysis| The data shows an average of 1.79±0.28 (mean±S.D. of three independent experiments) fold increase in the HLA-DRB1 transcripts from B-LCL treated with calcitriol as compared to the vehicle control. 0.305 SIGNOR-253978 SMAD3 protein P84022 UNIPROT PAX8 protein Q06710 UNIPROT down-regulates activity binding 9606 14623893 YES miannu DNA Binding Activity of Pax8 to the NIS Promoter Is Reduced by Smad3. TGF-β decreases Pax8 DNA binding to the NIS promoter and also found a physical interaction between Pax8 and Smad3. 0.367 SIGNOR-251992 mianserin chemical CHEBI:51137 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258689 ZBTB14 protein O43829 UNIPROT ZBTB14 protein O43829 UNIPROT up-regulates activity binding 9606 10080939 YES miannu ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter, has the POZ domain at the amino-terminus and the Kruppel-type zinc finger domain at the carboxy-terminus. We demonstrated that the POZ domain has a function mediating homomeric protein-protein interaction and this interaction requires the zinc finger domain. 0.2 SIGNOR-220534 RELA protein Q04206 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 17350185 YES Luana Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells  0.2 SIGNOR-266087 PASK protein Q96RG2 UNIPROT WDR5 protein P61964 UNIPROT up-regulates activity phosphorylation Ser49 AGHTKAVsSVKFSPN 9606 27661449 YES miannu Pask directly interacts with and phosphorylates Wdr5 at Ser49.|We therefore believe that differentiation cues act, at least in part, to drive the myogenic transcriptional program via Pask activation and phosphorylation of Wdr5. 0.307 SIGNOR-278266 SOSTDC1 protein Q6X4U4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates activity 9606 BTO:0000815 21113658 NO lperfetto In this context, SOSTDC1 leads to decreased cellular proliferation and inhibition of Wnt3a- and BMP-7-induced signaling 0.297 SIGNOR-242714 CDK14 protein O94921 UNIPROT CCNY protein Q8ND76 UNIPROT down-regulates quantity by destabilization phosphorylation Ser71 RASTIFLsKSQTDVR 9606 BTO:0000599 24794231 YES lperfetto Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation|Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex 0.829 SIGNOR-273008 GDF11 protein O95390 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 BTO:0000671 16845371 YES acerquone The identity of the receptors that mediate gdf11 signalling during embryogenesis remains unclear. gdf11 could only bind directly to acvr2b but not to any type i receptor 0.626 SIGNOR-147940 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT down-regulates quantity by destabilization phosphorylation Ser37 KHSSYPDsEGAPDSL 9606 BTO:0000567 10618498 YES llicata Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo 0.307 SIGNOR-251042 KDM5B protein Q9UGL1 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264304 PPP3CC protein P48454 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 NO gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. 0.455 SIGNOR-83740 RPS6KA4 protein O75676 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser29 ATKVARKsAPATGGV 10090 12773393 YES lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 0.2 SIGNOR-249212 NF1 protein P21359 UNIPROT ADCY5 protein O95622 UNIPROT up-regulates 9606 BTO:0000938 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.27 SIGNOR-204140 GABARAP protein O95166 UNIPROT GPHN protein Q9NQX3 UNIPROT up-regulates activity binding 9606 BTO:0000938 25882190 YES miannu The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms. 0.562 SIGNOR-264971 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15498859 YES Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. 0.376 SIGNOR-261517 PYG proteinfamily SIGNOR-PF96 SIGNOR alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 YES miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. 0.8 SIGNOR-267954 phosphatidic acid smallmolecule CHEBI:16337 ChEBI CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates quantity precursor of 9606 25375833 YES lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). 0.8 SIGNOR-267019 PLK1 protein P53350 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser730 VLDTMNDsLSKILLD 9606 19737929 YES lperfetto It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression 0.704 SIGNOR-187888 KRAS protein P01116 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 9727023 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner. 0.777 SIGNOR-59819 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -1 2413024 YES miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-162 0.347 SIGNOR-250012 VRK2 protein Q86Y07 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates phosphorylation Ser31 PQDELDFsILFDYEY 9606 23105117 YES gcesareni We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain. 0.369 SIGNOR-199263 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates quantity by destabilization phosphorylation Ser268 SSNASSVsTRLSPLR 9606 BTO:0001109 28945225 YES miannu Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268.  0.2 SIGNOR-277326 FBXO7 protein Q9Y3I1 UNIPROT CRBN protein Q96SW2 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0005490 30026574 YES miannu We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase.  0.257 SIGNOR-272311 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser379 AGAPGALsPSYDGGL 9606 19801649 YES llicata Mlk2 inhibits e47 transactivation activity on the trkb promote 0.2 SIGNOR-161540 TGFBR1 protein P36897 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 9435577 YES lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. 0.343 SIGNOR-227531 PAR-1 (Protease-Activated Receptor) Selective Activating Peptide smallmolecule CID:71312048 PUBCHEM F2RL1 protein P55085 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257485 PRKCA protein P17252 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates activity phosphorylation Ser240 TKSGDKKsGRNFFRK 9606 32881857 YES miannu We showed that the first and second phase of RhoA activity are dependent on p63 and Ca2+/PKC, respectively, and further identified phosphorylation of serine 240 on p115 RhoGEF by PKC to be the mechanistic link between PKC and RhoA. 0.44 SIGNOR-277530 MAPK1 protein P28482 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 20231899 NO gcesareni An erk pharmacological inhibitor, pd98059, and the pld inhibitor, 1-btoh, both attenuate (14)c-glucose uptake in muscle cells. Finally, the extracellular stresses caused by glucose deprivation or aminoimidazole carboxamide ribonucleotide (aicar;ampk activator) regulate (14)c-glucose uptake and cell surface glucose transport (glut) 4 through erk stimulation by ampk-mediated pld1 activation. 0.334 SIGNOR-164286 CyclinY/CDK16 complex SIGNOR-C540 SIGNOR PRKAR1A protein P10644 UNIPROT up-regulates activity phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000567 25605337 YES lperfetto PCTK1 regulates spindle orientation in a kinase-dependent manner. Phosphoproteomic analysis together with an RNA interference screen revealed that PCTK1 regulates spindle orientation through phosphorylation of Ser83 on KAP0, a regulatory subunit of protein kinase A (PKA) 0.272 SIGNOR-273014 CDK1 protein P06493 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9606 26259146 YES miannu Moreover, CDK1 phosphorylates RSF1 at Ser1375, and this phosphorylation is necessary for PLK1 recruitment. Subsequently, PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition. 0.61 SIGNOR-273589 hsa-mir-126-5p mirna URS00001D69F6_9606 RNAcentral ADGRE5 protein P48960 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000815 24274104 YES Parnian This approach led us to the discovery that CD97, a pro-metastatic adhesion G-protein coupled receptor (GPCR), is a direct target of miR-126.| These results confirm the binding site for miR-126 in the 3’-UTR OF CD97 0.4 SIGNOR-277994 SRC protein P12931 UNIPROT YAP1 protein P46937-3 UNIPROT up-regulates activity phosphorylation Tyr341 PFLNSGTyHSRDEST 10090 27013234 YES done miannu We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation. 0.63 SIGNOR-274024 TIMM21 protein Q9BVV7 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.62 SIGNOR-267698 RAD23B protein P54727 UNIPROT ERCC5 protein P28715 UNIPROT up-regulates activity binding 24086043 YES lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.638 SIGNOR-275702 PPP1R9B protein Q96SB3 UNIPROT SPATA13 protein Q96N96 UNIPROT up-regulates activity binding 9606 BTO:0000007 19151759 YES miannu Here we show that Asef2, but not Asef, interacts with Neurabin2/Spinophilin, a scaffold protein that binds to Filamentous actin (F-actin). Neurabin2 is required for Asef2-induced filopodia formation. RNA interference experiments showed that Asef2, Neurabin2 and APC are involved in HGF-induced cell migration. Furthermore, knockdown of Neurabin2 resulted in the suppression of Asef2-induced filopodia formation. 0.481 SIGNOR-269174 TGFBI protein Q15582 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 10090 BTO:0001175 10906123 YES lperfetto In addition, we demonstrated the functional receptor for betaig-h3 is alpha(3)beta(1) integrin. These results, therefore, establish the essential motifs within the 2nd and the 4th domains of betaig-h3, which interact with alpha(3)beta(1) integrin to mediate HCE cell adhesion to betaig-h3 and suggest that other proteins containing Asp-Ile in their fas-1 domains could possibly function as cell adhesion molecules. 0.452 SIGNOR-253211 MEFV protein O15553 UNIPROT Pyrin inflammasome complex SIGNOR-C226 SIGNOR form complex binding 30288079 YES lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. 0.597 SIGNOR-256413 TLE5 protein Q08117 UNIPROT ZNF503 protein Q96F45 UNIPROT down-regulates activity binding 9534 19056829 YES miannu these results show that Grg5 can specifically interact with the C-terminus of Nolz1. these data suggest that Nolz1 functions as a repressor molecule, and that Grg5 interactions with Nolz1 serve to modulate Nolz1 repressor function. Mechanistically, Grg5 is known to modulate Grg co-repressor activity, raising the possibility that classical Grg proteins mediate Nolz1-dependent transcriptional repression. GalNolz1ΔC22 showed increased repressor activity compared with GalNolz1, consistent with the ability of Grg5 to modulate Nolz1 repressor function. 0.2 SIGNOR-261192 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr171 AIPSNTDyPGPHSFD 9606 19783996 YES Manara In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. 0.541 SIGNOR-260932 VEGFA protein P15692 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252275 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25096180 NO Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy 0.7 SIGNOR-252072 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser295 LSDTPYDsSASYEKE 9606 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo 0.29 SIGNOR-174828 BMS-754807 chemical CHEBI:88339 ChEBI INSR protein P06213 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001802 19996272 YES lperfetto BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR 0.8 SIGNOR-262026 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 YES lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity 0.2 SIGNOR-244509 Gbeta proteinfamily SIGNOR-PF4 SIGNOR EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 1651322 YES inferred from 70% family members lperfetto It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation. 0.2 SIGNOR-270017 DRD5 protein P21918 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.356 SIGNOR-257244 PIP3 smallmolecule CHEBI:16618 ChEBI PLEKHG1 protein Q9ULL1 UNIPROT up-regulates chemical activation 9606 21041639 YES gcesareni Phosphatidylinositol-3,4,5-trisphosphate (pip3), the product of pi3k activity and a key signaling molecule, acts by recruiting pleckstrin-homology (ph) domain-containing proteins to cell membranes 0.8 SIGNOR-169179 PRKCA protein P17252 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 15730925 NO irozzo PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC. 0.7 SIGNOR-256660 WT1 protein P19544 UNIPROT RBM4 protein Q9BWF3 UNIPROT down-regulates binding 9606 16934801 YES miannu Wilm's tumor protein 1 (wt1), a protein implicated in various cancers and developmental disorders, consists of two major isoforms: wt1(-kts), a transcription factor, and wt1(+kts), a post-transcriptional regulator that binds to rna and can interact with splicing components. Here we show that wt1 interacts with the novel splicing regulator rbm4. / we conclude that the (+kts) form of wt1 is able to inhibit the effect of rbm4 on alternative splicing. 0.365 SIGNOR-149166 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 YES miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. 0.8 SIGNOR-262247 GSK3B protein P49841 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity phosphorylation Ser404 SMRPDVSsPPSSSST 9606 18838540 YES gcesareni We found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta [ ]Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB 0.539 SIGNOR-181541 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9534 BTO:0000298 16757346 YES miannu We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ 0.29 SIGNOR-261717 RBR E3 ligase proteinfamily SIGNOR-PF107 SIGNOR Ub:RBR_E3 complex SIGNOR-C520 SIGNOR form complex binding 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. 0.2 SIGNOR-271378 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Ser243 RWLVVKDsFLLYMCL 9606 15979581 YES miannu The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity 0.691 SIGNOR-138351 FN1 protein P02751 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR up-regulates binding 9606 1532572 YES gcesareni Integrin alpha v beta 6 binds to fibronectin, but not to vitronectin or collagen i. cell adhesion assays show that fg-2 cell attachment to fibronectin is only partially inhibited by anti-beta 1 integrin antibodies, implying that other fibronectin receptors may be involved. 0.735 SIGNOR-19793 CSNK2A2 protein P19784 UNIPROT RGS19 protein P49795 UNIPROT unknown phosphorylation Ser24 ADRPPSMsSHDTASP -1 10760275 YES llicata Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles. 0.329 SIGNOR-251033 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.246 SIGNOR-268604 BTK protein Q06187 UNIPROT BTK protein Q06187 UNIPROT up-regulates phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 BTO:0000776 8630736 YES lperfetto Overexpression of btk with a src family kinase increases tyrosine phosphorylation and catalytic activity of btk. This occurs by transphosphorylation at y551 in the btk catalytic domain and the enhancement of btk autophosphorylation at a second site. We mapped the major btk autophosphorylation site to y223 within the sh3 domain 0.2 SIGNOR-41480 SOCS3 protein O14543 UNIPROT Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR up-regulates quantity binding 10090 BTO:0001516 17138568 YES miannu SOCS proteins can act as E3 ligases by forming a complex with Elongin B/C and Cul5/Rbx1/2.SOCS3 targets Siglec 7 for degradation 0.652 SIGNOR-272643 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 20937773 YES lperfetto In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387 0.372 SIGNOR-216737 APOB protein P04114 UNIPROT VLDL_assembly phenotype SIGNOR-PH62 SIGNOR up-regulates 9606 23721961 NO miannu Apolipoprotein B is a structural protein that is an integral component of chylomicrons, as well as very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles. In man, VLDL contains only ApoB100, the full length protein 0.7 SIGNOR-252115 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD 9606 19661060 YES Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. 0.379 SIGNOR-260882 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr224 MSRFSSStEQSSASR 9606 22609948 YES lperfetto We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle 0.692 SIGNOR-197555 PRKCA protein P17252 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates activity phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 9341188 YES miannu Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation. 0.332 SIGNOR-52850 NEK6 protein Q9HC98 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser53 EGGQLNEsMDHGGVG -1 12023960 YES miannu Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation. 0.368 SIGNOR-262952 FAM83C protein Q9BQN1 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273760 CDC34 protein P49427 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR up-regulates activity binding 9606 25425648 YES miannu The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. 0.803 SIGNOR-277333 SRC protein P12931 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates activity phosphorylation 9606 15039213 YES miannu 26 In particular, Sam68 was shown to play a scaffold role in Src kinase activated pathways, 16,27 and tyrosine phosphorylation of Sam68 by Src kinases triggers the release of bound RNA and might allow translational activation. 0.825 SIGNOR-279121 Vincristine sulfate chemical CHEBI:79401 ChEBI MMP10 protein P09238 UNIPROT down-regulates activity chemical inhibition 9606 30599272 YES miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 0.8 SIGNOR-259253 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser94 SLLSRSSsGYFSFDT 9606 BTO:0002181 23912711 YES miannu  We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.  0.377 SIGNOR-276248 CCN2 protein P29279 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 9606 32928643 YES miannu CTGF is highly expressed in PDAC tissues, especially in tumor stroma (as shown by immunohistochemistry, CTGF: brown stain). The tumor cell-secreted CTGF promotes pancreatic stellate cell (PSC) proliferation, adhesion, and migration via integrin α5β1, leading to extracellular matrix (ECM) deposition.Pancreatic cancer cells secrete high levels of CTGF that binds to integrin α5β1, promoting PSC proliferation, adhesion, and migration 0.2 SIGNOR-277687 EEF1A1 protein P68104 UNIPROT Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269505 HIC1 protein Q14526 UNIPROT SIRT1 protein Q96EB6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21277938 NO miannu HIC1, via its BTB/POZ domain, forms a transcriptional repressor complex with Sirt1 [8] that binds directly to Sirt1 promoter itself, repressing its transcription. 0.589 SIGNOR-254419 abarelix chemical CHEBI:337298 ChEBI GNRHR protein P30968 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001033 22416801 YES miannu Two GnRH antagonists are currently available: abarelix and degarelix. 0.8 SIGNOR-259159 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR form complex binding 9606 24816100 YES miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. 0.739 SIGNOR-270836 DLGAP4 protein Q9Y2H0 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.695 SIGNOR-264595 HAUS4 protein Q9H6D7 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 YES lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) 0.822 SIGNOR-262324 BDKRB1 protein P46663 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257237 LPAR3 protein Q9UBY5 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256747 CSNK2A1 protein P68400 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 YES gcesareni CK2 hyperactivates AKT by phosphorylation at Ser129 0.372 SIGNOR-174691 HNRNPU protein Q00839 UNIPROT HOXA2 protein O43364 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 NO lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. 0.2 SIGNOR-262284 LRRC4C protein Q9HCJ2 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 YES miannu A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles 0.365 SIGNOR-264050 GRB2 protein P62993 UNIPROT CBL protein P22681 UNIPROT up-regulates relocalization 9606 11823423 YES GRB2 is an adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. gcesareni The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization. 0.904 SIGNOR-114704 PRKAA2 protein P54646 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates quantity by destabilization phosphorylation Ser334 AVLDRGTsTTTVFNF 9606 BTO:0000007 25799226 YES miannu Taken together, these results imply that nicotine acts via AMPKα2 to phosphorylate MKP1 at Ser334, instigating MKP1 ubiquitination and proteasome-mediated degradation. 0.273 SIGNOR-276890 SMARCC2 protein Q8TAQ2 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.84 SIGNOR-269823 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 YES miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. 0.2 SIGNOR-268219 CDK3 protein Q00526 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15084261 YES gcesareni The active form of prb is underphosphorylated. Cdk3/cyclin-c-mediated phosphorylation at ser-807 and ser-811 is required for g0-g1 transition. 0.444 SIGNOR-124212 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates phosphorylation Ser196 RSLEVWGsQEALEEA 9606 23178497 YES lperfetto Atr phosphorylates xpa. at serine 196. Atr-mediated xpa phosphorylation enhances xpa stability by inhibiting herc2-mediated ubiquitination and subsequent degradation. 0.493 SIGNOR-199802 PCDH15 protein Q96QU1 UNIPROT TMC2 protein Q8TDI7 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000630 25114259 YES lperfetto Although several studies show that the tip links, composed of PCDH15 and CDH23, are required for normal mechanotransduction, it is unclear how they are coupled to the transduction machinery. Likewise, it has been demonstrated that the transmembrane channel-like proteins TMC1 and TMC2 are required for mechanosensitive responses in hair cells, but how they interact with other components of the mechanotransduction complex is not known. Here, we show that TMC1 and TMC2 can interact with PCDH15, thereby establishing a critical connection between the tip link and these putative components of the mechanotransduction channel in hair cells. 0.436 SIGNOR-262583 NFASC protein O94856 UNIPROT ANK1 protein P16157 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 YES miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. 0.684 SIGNOR-266718 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT up-regulates activity phosphorylation Ser1121 AHSERPLsAPASHLN 9606 BTO:0000599 21189263 YES lperfetto ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking. 0.296 SIGNOR-272295 iodide smallmolecule CHEBI:16382 ChEBI TPO protein P07202 UNIPROT up-regulates activity chemical activation 9606 BTO:0004708 23349248 YES miannu After transport through the apical membrane, Iodide is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO). 0.8 SIGNOR-268139 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser272 RSRLTPVsPESSSTE 9606 BTO:0000551 20974803 YES lperfetto Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. 0.349 SIGNOR-216932 AURKA protein O14965 UNIPROT POU6F1 protein Q14863 UNIPROT down-regulates activity phosphorylation Ser197 KLDITPKsAQKLKPV -1 31665313 YES miannu  Here, we report that Aurora kinase A phosphorylates mPOU at Ser197 and inhibit its DNA-binding ability.  0.2 SIGNOR-273546 STK3 protein Q13188 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity phosphorylation Thr1061 KMDWIFHtIKQHALN -1 38060450 YES miannu MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061  0.2 SIGNOR-277922 TNFRSF6B protein O95407 UNIPROT FASLG protein P48023 UNIPROT down-regulates binding 9606 BTO:0001271;BTO:0000661 BTO:0000763 10318773 YES amattioni Tr6 specifically binds fas ligand. Tr6 may play a regulatory role for suppressing in fasl- mediated cell death. 0.652 SIGNOR-67434 RIMS2 protein Q9UQ26 UNIPROT RAB3C protein Q96E17 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 YES miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle 0.559 SIGNOR-264378 SLC6A8 protein P48029 UNIPROT creatine smallmolecule CHEBI:16919 ChEBI up-regulates quantity relocalization 9606 18652074 YES miannu CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour. 0.8 SIGNOR-265808 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr936 SESTNHIySNLANCS 9606 10377264 YES miannu Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr 0.2 SIGNOR-68647 TGFB1 protein P01137 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity 9606 10611320 NO lperfetto Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2. 0.276 SIGNOR-217502 phosphatidic acid smallmolecule CHEBI:16337 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates chemical activation 9606 12401205 YES gcesareni The pkc isoform pkc-zeta appear to be activated by direct interactions with pa 0.8 SIGNOR-94867 GP1BB protein P13224 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 BTO:0000132 16293600 YES lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. 0.654 SIGNOR-261850 HDAC1 protein Q13547 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR form complex binding 9606 23213415 YES gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes 0.655 SIGNOR-199958 GNAO1 protein P09471 UNIPROT TAOK2 protein Q9UL54 UNIPROT up-regulates 9606 BTO:0000007 12665513 NO lperfetto These results suggest that go alpha q205l activates p38 through taos and mek3/6. 0.2 SIGNOR-235542 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001412 8021507 YES In these studies, we show that NF-kappa B induces transcription from the human pro-IL-1 beta (IL-1 beta) gene. 0.584 SIGNOR-255938 FOXF2 protein Q12947 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding -1 9722567 YES miannu The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. 0.408 SIGNOR-220373 STXBP4 protein Q6ZWJ1 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity binding -1 31782549 YES WW domain‐containing protein STXBP4 inhibits YAP activity via LATS1‐mediated phosphorylation. 0.2 SIGNOR-260013 nefazodone chemical CHEBI:7494 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 9871604 YES miannu Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2. Nefazodone has similar affinities at hSERT, hNET, and hDAT, but has low potency 0.8 SIGNOR-259068 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18621737 YES amattioni In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein. 0.746 SIGNOR-179443 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17446862 YES gcesareni In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function. 0.738 SIGNOR-154477 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT up-regulates phosphorylation Ser106 DNQLTIKsPSKRELA 9606 SIGNOR-C83 10339564 YES lperfetto Based on these results, we propose that phosphorylation of hscdc6 by cdks regulates dna replication of at least two steps: first, by promoting initiation of dna replication and, second, through nuclear exclusion preventing dna rereplication. hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106) 0.942 SIGNOR-67540 Ub:E2 complex SIGNOR-C497 SIGNOR HUWE1 protein Q7Z6Z7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271305 TNKS2 protein Q9H2K2 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19759537 YES gcesareni Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. 0.704 SIGNOR-188033 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation Thr255 ITTPELTtPCGSAEY 9606 BTO:0000093 17130135 YES We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation 0.2 SIGNOR-253015 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI HR protein O43593 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273463 HSPA1A protein P0DMV8 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity post transcriptional regulation 9606 19083193 YES miannu We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. 0.2 SIGNOR-252197 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 11691836 YES lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding 0.658 SIGNOR-249393 TLRs proteinfamily SIGNOR-PF20 SIGNOR TIRAP protein P58753 UNIPROT up-regulates activity binding 9606 20404851 YES lperfetto These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways 0.2 SIGNOR-216298 Erlin complex SIGNOR-C532 SIGNOR RNF170 protein Q96K19 UNIPROT up-regulates activity binding 9606 BTO:0000567 21610068 YES miannu In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound. 0.493 SIGNOR-271918 DVL1P1 protein P54792 UNIPROT PRKCA protein P17252 UNIPROT up-regulates binding 9606 23151663 YES gcesareni Our findings suggest a molecular interaction between pka, hdpr1, and dvl and a possible contribution of this interaction to tumorigenesis. 0.2 SIGNOR-199454 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser72 QPRFIVYsYKYQHDD -1 9030586 YES lperfetto Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively. 0.323 SIGNOR-248959 CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 YES lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. 0.638 SIGNOR-133264 KANSL3 protein Q9P2N6 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 26243146 NO miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. 0.7 SIGNOR-267171 BIRC5 protein O15392 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 9850056 YES amattioni Survivin binds specifically to caspase-3. Survivin protected from apoptosis induced by overexpression of procaspase-3 and inhibited the processing of these zymogens into active caspases. Survivin, which is commonly expressed in human tumor cell lines, can bind the effector cell death proteases caspase-3 in vitro and inhibits caspase activity 0.49 SIGNOR-62484 CSNK1D protein P48730 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser314 SREQSTDsGLGLGCY 9606 24715453 YES lperfetto LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) 0.364 SIGNOR-234438 MPO protein P05164 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR up-regulates activity binding 9606 BTO:0000133 15972951 YES lperfetto Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis are associated with myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (ANCAs). 0.2 SIGNOR-270585 SRSF1 protein Q07955 UNIPROT Alternative_Splicing_Regulation phenotype SIGNOR-PH204 SIGNOR up-regulates 9606 26273603 NO miannu In particular, SRSF1 recognizes SREs in its own transcripts, leading to alternative splicing, with some transcript forms being degraded by nonsense-mediated mRNA decay (NMD). 0.7 SIGNOR-273861 afatinib chemical CHEBI:61390 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 22418700 YES gcesareni Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members. 0.8 SIGNOR-196621 NAT8L protein Q8N9F0 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 19524112 YES miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. 0.8 SIGNOR-267521 VHL protein P40337 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity binding 9606 BTO:0000567 17936701 YES We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. 0.394 SIGNOR-257603 Laminin-5 complex SIGNOR-C184 SIGNOR A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 9790905 YES lperfetto We propose that these alpha6 beta4/Ln-5 complexes may provide links between plasma membrane and basement membrane that resist mechanical stress and support epithelial integrity. 0.597 SIGNOR-253238 YY1 protein P25490 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.554 SIGNOR-270849 PRKCD protein Q05655 UNIPROT CYTH1 protein Q15438 UNIPROT unknown phosphorylation Ser394 ARKKKVSsTKRH 9606 BTO:0001948 11438522 YES lperfetto We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1.  0.324 SIGNOR-249098 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 YES lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 0.2 SIGNOR-244573 PTPN11 protein Q06124 UNIPROT NEDD9 protein Q14511 UNIPROT down-regulates activity dephosphorylation 9606 19275884 YES miannu In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity. 0.489 SIGNOR-277083 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser413 VRYIKENsPCVTPVS 9606 11157749 YES llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. 0.849 SIGNOR-104675 PAK1 protein Q13153 UNIPROT STIM1 protein Q13586 UNIPROT up-regulates activity phosphorylation 9606 29780159 YES miannu Taken together, our data demonstrate that PAK1 interacts with STIM1 and phosphorylates specific STIM1 cytosolic domains. 0.354 SIGNOR-279244 PTP4A1 protein Q93096 UNIPROT CDK2 protein P24941 UNIPROT up-regulates 9606 14643450 NO gcesareni Cells overexpressing either prl-1 or prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity and significantly lower p21cip1/waf1 protein levels 0.2 SIGNOR-119418 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 DGSCSSSsPPLPVLG 9606 15632084 YES gcesareni In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. 0.904 SIGNOR-132967 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR TRiC complex SIGNOR-C539 SIGNOR down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24298020 YES miannu Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme 0.2 SIGNOR-272873 SMARCD2 protein Q92925 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.779 SIGNOR-270745 AANAT protein Q16613 UNIPROT N-acetylserotonin smallmolecule CHEBI:17697 ChEBI up-regulates quantity chemical modification -1 22775292 YES miannu Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS. 0.8 SIGNOR-265478 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR MLLT3 protein P42568 UNIPROT down-regulates quantity relocalization 9606 BTO:0000567 14603337 YES irozzo The AF4–AF9 interaction is maintained by the MLL–AF4 fusion protein, and expression of the MLL–AF4 fusion can alter the subnuclear localization of AF9. This fusion does, however, contain the AF9 interaction domain we have identified. These findings imply that the interaction that we have characterized plays an important role in MLL leukemogenesis. Furthermore, we show that MLL–AF4 does interact with AF9 and has the ability to misdirect AF9 expression from the AF4 body to alternative foci within the nucleolus. 0.2 SIGNOR-255857 SELPLG protein Q14242 UNIPROT SELE protein P16581 UNIPROT up-regulates binding 9606 BTO:0000130 9024699 YES gcesareni PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro. 0.77 SIGNOR-46330 p38 proteinfamily SIGNOR-PF16 SIGNOR Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 11591790 NO The p21 G protein Rho and its targets, Rho-associated coiled-coil forming protein kinases (p160ROCK/ROCK I/ROKβ and Rho kinase/ROCK II/ROKα), play a crucial role in actin cytoskeleton reorganization 0.7 SIGNOR-254360 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249325 GTF3C2 protein Q8WUA4 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 YES lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains 0.873 SIGNOR-266187 NFYC protein Q13952 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15496512 NO miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. 0.2 SIGNOR-252234 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR CCNA2 protein P20248 UNIPROT up-regulates quantity by expression transcriptional regulation 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276575 PIM1 protein P11309 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates quantity phosphorylation Ser339 GKRGGHSsVSTESES 9606 26075720 YES miannu Pim-1 and Pim-3 enhance phosphorylation and cell surface expression of CXCR4.|When the in vitro phosphorylated fragments were detected with the anti-phospho (Ser339)-CXCR4 antibody, it became evident that both Pim-1 and Pim-3, but not Pim-2 can phosphorylate CXCR4 on Ser339 (XREF_FIG). 0.366 SIGNOR-278450 PRKCH protein P24723 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 10197446 YES llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. 0.356 SIGNOR-66734 IGF2BP1 protein Q9NZI8 UNIPROT ACTB protein P60709 UNIPROT up-regulates quantity post transcriptional regulation 10116 BTO:0004102 21734271 YES miannu We found that ZBP1 is necessary for netrin-1 stimulated local translation of β-actin mRNA in axonal growth cones. ZBP1 binds to β-actin mRNA in the soma and transports it to the growth cone on microtubules. 0.34 SIGNOR-268160 PAMPs stimulus SIGNOR-ST11 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR up-regulates 9606 25720354 NO scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. 0.7 SIGNOR-267859 KLHL21 protein Q9UJP4 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates activity binding 9606 BTO:0000567 19995937 YES miannu KLHL21 directly binds to Aurora B and mediates ubiquitination of Aurora B in vitro. In contrast to KLHL9 and KLHL13, KLHL21 localizes to midzone microtubules in anaphase and recruits Aurora B and Cul3 to this region. Together, our results suggest that different Cul3 adaptors nonredundantly regulate Aurora B during mitosis, possibly by ubiquitinating different pools of Aurora B at distinct subcellular localizations. 0.508 SIGNOR-271848 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 15735019 YES miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates 0.648 SIGNOR-150476 ACTB protein P60709 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.499 SIGNOR-270711 IL1B protein P01584 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 NO inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. 0.2 SIGNOR-270241 PAK proteinfamily SIGNOR-PF13 SIGNOR MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation -1 10748018 YES inferred from 70% family members miannu PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991. 0.2 SIGNOR-269973 PRKCZ protein Q05513 UNIPROT ADARB1 protein P78563 UNIPROT up-regulates activity phosphorylation Ser216 SASPVPAsLAQPPLP 9606 BTO:0001615 29694894 YES miannu  Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.  0.2 SIGNOR-277391 BMP2 protein P12643 UNIPROT BMP2 protein P12643 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 YES lperfetto Bmps are dimeric proteins with a single interchain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interaction with receptors 0.2 SIGNOR-236166 HSD17B11 protein Q8NBQ5 UNIPROT estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 YES lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. 0.8 SIGNOR-268663 PRKCD protein Q05655 UNIPROT DNM1L protein O00429 UNIPROT up-regulates phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 17301055 YES gcesareni Drp1 was specifically phosphorylated in mitosis by cdk1/cyclin b on ser-585. Exogenous expression of unphosphorylated mutant drp1s585a led to reduced mitotic mitochondrial fragmentation. 0.2 SIGNOR-153148 JNK proteinfamily SIGNOR-PF15 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 BTO:0005493 10601313 YES lperfetto JNK-mediated phosphorylation of Smad3 outside the -SSXS motif enhances Smad3 nuclear translocation and potentiates transcriptional activation independent of Smad3 phosphorylation by T_RI. 0.2 SIGNOR-236113 Exon junction complex complex SIGNOR-C369 SIGNOR Upf-EJC complex SIGNOR-C367 SIGNOR up-regulates activity binding -1 18066079 YES miannu Nonsense-mediated mRNA decay (NMD) eliminates mRNAs containing a premature translation termination codon through the recruitment of the conserved NMD factors UPF1, UPF2 and UPF3. In humans, a dynamic assembly pathway allows UPF1 to join UPF2 and UPF3 recruited to the mRNA by the exon-junction complex (EJC).  0.863 SIGNOR-265244 PGM1 protein P36871 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 32898648 YES miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). 0.8 SIGNOR-267932 EIF2B2 protein P49770 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.749 SIGNOR-269140 PRKG1 protein Q13976 UNIPROT GKAP1 protein Q5VSY0 UNIPROT unknown phosphorylation Ser106 SNPVQKDsREENWQE 9534 10671526 YES lperfetto Although both cGK-Ialpha and -Ibeta, but not cAMP-dependent protein kinase, phosphorylated GKAP42 in vitro, GKAP42 was a good substrate only for cGK-Ialpha in intact cells, suggesting that the association with kinase protein is required for the phosphorylation in vivo. 0.625 SIGNOR-249037 GNAS protein P63092 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates activity binding 9606 17652154 YES gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR 0.741 SIGNOR-267848 (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI orotate smallmolecule CHEBI:30839 ChEBI up-regulates quantity precursor of 9606 30449682 YES miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway 0.8 SIGNOR-267428 CDK1 protein P06493 UNIPROT RPA2 protein P15927 UNIPROT up-regulates activity phosphorylation Ser29 QSPGGFGsPAPSQAE 9606 1318195 YES llicata Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell 0.508 SIGNOR-16975 FUS protein P35637 UNIPROT CSDE1 protein O75534 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0000551 32808651 YES lperfetto These findings demonstrated that LINC00205 facilitates malignant phenotypes in LC by recruiting FUS to stabilize CSDE1, suggesting LINC00205 as a potential target for LC therapy.|Subsequent RIP assay con- firmed such prediction, as CSDE1 mRNA was evidently precipitated by anti-FUS (Figure 3A). 0.2 SIGNOR-262110 YY1 protein P25490 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 9606 BTO:0000664 12913000 YES Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling. 0.622 SIGNOR-251654 OTUD7B protein Q6GQQ9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity deubiquitination 9606 BTO:0000007 18178551 YES lperfetto NF-kappaB Suppression by the Deubiquitinating Enzyme Cezanne|Our study provides several lines of evidence to suggest that Cezanne suppresses TNFR signaling to NF-κB by targeting RIP1 for deubiquitination. 0.537 SIGNOR-268411 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu75 EEAFEALeSSTATDV -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263684 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser214 LVRSREVsVDEGRAC -1 9677319 YES llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. 0.313 SIGNOR-250944 DMXL2 protein Q8TDJ6 UNIPROT MADD protein Q8WXG6 UNIPROT up-regulates quantity binding 10116 BTO:0000142 11809763 YES miannu We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles. 0.448 SIGNOR-265581 SRC protein P12931 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr754 DTRDNVYyYDEEGGG 9606 27203386 YES miannu In addition, the phosphorylation of E-cadherin Tyr753 and Tyr754 by Src recruits the binding of Hakai, a Cbl like E3 ubiquitin ligase, leading to ubiquitination and endocytosis of the E, cadherin, beta, and catenin complex . 0.754 SIGNOR-278497 17beta-estradiol smallmolecule CHEBI:16469 ChEBI AKT2 protein P31751 UNIPROT up-regulates 9606 BTO:0000150 12554767 NO gcesareni Treatment of cells with estradiol resulted in phosphorylation of akt and a 9-fold increase in akt activity in 10 min. 0.8 SIGNOR-97798 TAF1A protein Q15573 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 YES lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. 0.824 SIGNOR-269566 CACNA1A protein O00555 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 20655485 YES miannu The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release. 0.8 SIGNOR-266708 SRC protein P12931 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr219 DGSDHPYyNSIPSKM -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.575 SIGNOR-273921 CAMK2B protein Q13554 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 YES gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). 0.404 SIGNOR-154771 CSNK2A1 protein P68400 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates phosphorylation Ser421 IACEEEFsDSEEEGE 9606 11602581 YES gcesareni Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1. 0.62 SIGNOR-111011 DCST1 protein Q5T197 UNIPROT STAT2 protein P52630 UNIPROT down-regulates activity ubiquitination 9606 27782195 YES miannu DCST1 promotes ubiquitination of STAT2.|The ability of DCST1 to degrade STAT2 levels was visible both in the presence and absence of IFNbetastimulation.|In our study, DCST1 was found to interact with and promote ubiquitination of STAT2, leading to reduced STAT2 expression and attenuated activation of the ISG induction pathway. 0.448 SIGNOR-278747 FGFR2 protein P21802 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 10090 BTO:0000011 12270934 NO lperfetto Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors 0.302 SIGNOR-244868 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 17190791 YES gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1). 0.447 SIGNOR-151667 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 YES gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. 0.333 SIGNOR-40497 AURKB protein Q96GD4 UNIPROT KNL1 protein Q8NG31 UNIPROT down-regulates phosphorylation Ser60 KKNSRRVsFADTIKV 9606 20471944 YES lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). 0.2 SIGNOR-165506 RPL11 protein P62913 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.876 SIGNOR-262488 PRKCD protein Q05655 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity phosphorylation Ser418 KTQTPPVsPAPQPTE 10029 26490115 YES Manara Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration. In addition, the MCP1-induced cortactin phosp 0.246 SIGNOR-260890 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr66 LHQEDNDyINASLIK -1 11506178 YES lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B 0.788 SIGNOR-249370 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17873901 NO gcesareni Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity 0.2 SIGNOR-252917 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 16293107 YES gcesareni Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2. the raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade. 0.846 SIGNOR-141641 NCOA1 protein Q15788 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO inferred from family member miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.2 SIGNOR-270223 IGF1R protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 YES gcesareni Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively) 0.696 SIGNOR-252690 EPAS1 protein Q99814 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20534544 NO Regulation miannu We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. 0.284 SIGNOR-251791 HYDIN protein Q4G0P3 UNIPROT GATA4 protein P43694 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 32376282 YES miannu HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs 0.2 SIGNOR-265479 HNF4A protein P41235 UNIPROT AKR1C4 protein P17516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003846 2044952 NO 2 miannu Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene. HNF-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C. 0.256 SIGNOR-240016 NEDD4L protein Q96PU5 UNIPROT TTYH2 protein Q9BSA4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18577513 YES miannu Our data indicate that Nedd4-2 binds to two family members, TTYH2 and TTYH3, which contain consensus PY ((L/P)PXY) binding sites for HECT type E3 ubiquitin ligases, but not to TTYH1, which lacks this motif. Consistently, Nedd4-2 ubiquitinates both TTYH2 and TTYH3. Importantly, we have shown that endogenous TTYH2 and Nedd4-2 are binding partners and demonstrated that the TTYH2 PY motif is essential for these interactions. We have also shown that Nedd4-2-mediated ubiquitination of TTYH2 is a critical regulator of cell surface and total cellular levels of this protein.  0.286 SIGNOR-272632 FABP1 protein P07148 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264455 CTNNB1 protein P35222 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.925 SIGNOR-265813 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser491 SSTPQRSCsAAGLHRPR 10116 BTO:0002135 17023420 YES These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine. 0.422 SIGNOR-256112 ERRFI1 protein Q9UJM3 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0001867 20421427 YES We report here an additional mechanism of EGFR suppression mediated by RALT, demonstrating that RALT-bound EGF receptors undergo endocytosis and eventual degradation into lysosomes 0.643 SIGNOR-252073 SHH protein Q15465 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0002314 18662193 NO gcesareni In addition, shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors myf-5 and myod, decreases the up-regulation of insulin-like growth factor (igf)-1 and reduces the number of myogenic satellite cells at injured site. 0.428 SIGNOR-179632 EPN1 protein Q9Y6I3 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19054389 YES gcesareni Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr. 0.595 SIGNOR-182562 ITGAD protein Q13349 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.74 SIGNOR-253195 CALM1 protein P0DP23 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 YES gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.66 SIGNOR-114104 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 9465032 YES lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.755 SIGNOR-217090 RPS6KA1 protein Q15418 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Ser947 CRLNRSDsDSSTLSK 9606 BTO:0000149 24269383 YES llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. erk_rsk phosphorylation of kibra is required for proper cell proliferation and rsk-mediated phosphorylation also positively modulates kibra's migratory activity. 0.335 SIGNOR-203294 ITGAV protein P06756 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.771 SIGNOR-253207 PKA proteinfamily SIGNOR-PF17 SIGNOR GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity phosphorylation 9606 BTO:0000938 25600368 YES miannu The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface. 0.2 SIGNOR-264991 MIPOL1 protein Q8TD10 UNIPROT RHOB protein P62745 UNIPROT up-regulates activity binding 9606 31609475 YES miannu MIPOL1 protein interacts with tumor suppressor RhoB and enhances its cellular activity 0.2 SIGNOR-261134 TOR1AIP1 protein Q5JTV8 UNIPROT VIM protein P08670 UNIPROT up-regulates activity binding 9606 BTO:0000452 16361107 YES Sara Co-immune precipitation studies revealed association between vimentin and torsinA in a complex. these studies suggest that mutant torsinA interferes with cytoskeletal events involving vimentin, possibly by restricting movement of these particles/filaments, and hence may affect development of neuronal pathways in the brain. 0.2 SIGNOR-261313 EEF1A1 protein P68104 UNIPROT Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269514 Av/b5 integrin complex SIGNOR-C178 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269027 TNFRSF17 protein Q02223 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates 9606 10903733 NO inferred from 70% of family members miannu Overexpression of bcma activates jnk 0.291 SIGNOR-269887 ATR protein Q13535 UNIPROT SMARCAL1 protein Q9NZC9 UNIPROT down-regulates activity phosphorylation Ser652 RLKSDVLsQLPAKQR 9606 BTO:0000007 23873943 YES miannu ATR phosphorylates SMARCAL1 on S652, thereby limiting its fork regression activities and preventing aberrant fork processing. Thus, phosphorylation of SMARCAL1 is one mechanism by which ATR prevents fork collapse, promotes the completion of DNA replication, and maintains genome integrity. 0.537 SIGNOR-273516 CDK4 protein P11802 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser991 PALPPPEsPPKVQPE 9606 BTO:0000150 20807815 YES llicata Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function. 0.352 SIGNOR-167774 GSK3B protein P49841 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates activity phosphorylation Ser212 KLDTFCGsPPYAAPE 9606 16257959 YES miannu GSK-3beta directly phosphorylates and activates MARK2/PAR-1.|Our further findings led us to conclude that GSK-3beta phosphorylates MARK2 on Ser-212, one of the two reported phosphorylation sites (Thr-208 and Ser-212) found in the activation loop of MARK2. 0.349 SIGNOR-279413 IL1A protein P01583 UNIPROT FBN1 protein P35555 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 9036927 NO Regulation miannu UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. Addition to the cultured fibroblasts of several cytokines upregulated by UVB showed that IL-1alpha had no effect on fibrillin mRNA in unirradiated cells, but in irradiated cells, this cytokine enhanced the suppression of fibrillin mRNA. 0.2 SIGNOR-251890 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 18794113 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. 0.541 SIGNOR-180902 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation Ser422 LSTPVVLsPGPQKP 10090 BTO:0000944 7889942 YES lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency. 0.562 SIGNOR-235463 ERG protein P11308 UNIPROT VWF protein P04275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 9444957 NO miannu Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells. 0.248 SIGNOR-253914 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1787 SPNYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248779 XXYLT1 protein Q8NBI6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22117070 YES Xylosylation in ER membrane gcesareni Xxylt1 acts on the xyl1,3glc-o-linked glycan of notch egf domains. 0.313 SIGNOR-177745 FBXO3 protein Q9UK99 UNIPROT EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0004573 18809579 YES miannu O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.  0.341 SIGNOR-271742 AAK1 protein Q2M2I8 UNIPROT AP1M1 protein Q9BXS5 UNIPROT up-regulates phosphorylation Thr144 QEGHKLEtGAPRPPA 9606 BTO:0000938 11877461 YES lperfetto Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis. 0.2 SIGNOR-115589 ANKRD11 protein Q6UB99 UNIPROT BDNF protein P23560 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 YES miannu Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.  0.2 SIGNOR-266732 FAM20C protein Q8IXL6 UNIPROT SPP1 protein P10451 UNIPROT down-regulates quantity phosphorylation 9606 34433585 YES miannu OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C-deficiency-induced osteoclast differentiation and bone metastasis. 0.682 SIGNOR-278936 AKT proteinfamily SIGNOR-PF24 SIGNOR SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 YES miannu We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh. 0.2 SIGNOR-155229 CASP9 protein P55211 UNIPROT Caspase 9 complex complex SIGNOR-C229 SIGNOR form complex binding 29500231 YES lperfetto The caspase-9 CARD has been thought to be principally involved in recruitment to the apoptosome, but its roles outside this interaction have yet to be uncovered. In this work, we show that the CARD is involved in physical interactions with the catalytic core of caspase-9 in the absence of the apoptosome; this interaction requires a properly formed caspase-9 active site.  0.2 SIGNOR-256397 TAL1 protein P17542 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 NO miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. 0.2 SIGNOR-198279 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. 0.8 SIGNOR-267323 OXTR protein P30559 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 30739093 YES miannu OT binds to its cognate G protein–coupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). 0.551 SIGNOR-270332 SAM complex complex SIGNOR-C422 SIGNOR Insertion into mitochondrial membrane phenotype SIGNOR-PH193 SIGNOR up-regulates 33408415 NO lperfetto The mitochondrial outer membrane contains so-called β-barrel proteins, which allow communication between the cytosol and the mitochondrial interior1-3. Insertion of β-barrel proteins into the outer membrane is mediated by the multisubunit mitochondrial sorting and assembly machinery (SAM, also known as TOB) 0.7 SIGNOR-267687 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates quantity binding 9606 BTO:0000567 14960576 YES amattioni Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells. 0.894 SIGNOR-121883 Vps34 Complex II complex SIGNOR-C241 SIGNOR Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 30397185 NO lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.7 SIGNOR-260324 phosphatidic acid smallmolecule CHEBI:16337 ChEBI CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates quantity precursor of 9606 25375833 YES lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). 0.8 SIGNOR-267022 MDH1 protein P40925 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI down-regulates quantity chemical modification 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-266283 PRKCZ protein Q05513 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.268 SIGNOR-275447 ixabepilone chemical CHEBI:63605 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 18945860 YES miannu Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy. 0.8 SIGNOR-259450 ABL1 protein P00519 UNIPROT SORBS1 protein Q9BX66 UNIPROT up-regulates activity phosphorylation Tyr326 Y-->S 9606 19891780 YES miannu We have here identified Tyr360 in CAP as a major phosphorylation site by c-Abl, although Tyr 632 also might contribute since its substitution in combination with the Y360F mutation reduced the phosphorylation of CAP to a very low level. Y360 in CAP is the major phosphorylation site of c-Abl. Since Tyr326 was not a major c-Abl phosphorylation site, we sought to identify a putative other kinase that might be involved in the phosphorylation of Y326 in CAP. 0.425 SIGNOR-278153 MRPS11 protein P82912 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.771 SIGNOR-261458 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22703233 NO lperfetto Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products. 0.7 SIGNOR-249550 LYN protein P07948 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity phosphorylation Tyr254 SPPDYSEyMTGKKLP 9606 BTO:0002181 26198631 YES miannu In the case of Lyn overexpression, single mutations at either tyrosine 8, 254, or 383 severely reduced Lyn-mediated YY1 phosphorylation, suggesting that these three sites may be targets of Lyn in vivo (Fig. 3, A and B). 0.2 SIGNOR-276929 NUMA1 protein Q14980 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates binding 9606 11956313 YES Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.2 SIGNOR-256541 PHT-427 chemical CID:44240850 PUBCHEM PDPK1 protein O15530 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21715304 YES gcesareni Consistent with the results described in figures 3c and and4a,4a, treatment of 32d/bcr-abl cells with the bcr-abl inhibitor imatinib, the pi3k inhibitor ly294002 or the akt/pdpk1 inhibitor pht-427 substantially reduced atf5 promoter-directed luciferase activity 0.8 SIGNOR-174612 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3'-diiodothyronine smallmolecule CHEBI:35430 ChEBI up-regulates quantity small molecule catalysis 9606 BTO:0004055 12746313 YES inferred from family member scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. 0.8 SIGNOR-270307 ERG protein P11308 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25277175 NO miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. 0.345 SIGNOR-251555 KDM5C protein P41229 UNIPROT SYN1 protein P17600 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 31691806 NO miannu The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. 0.345 SIGNOR-264314 AMPK complex SIGNOR-C15 SIGNOR CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 YES Luana AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions 0.417 SIGNOR-250350 TRAPPC9 protein Q96Q05 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity binding 9606 BTO:0000007 15951441 YES miannu We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates. 0.49 SIGNOR-269673 F2RL1 protein P55085 UNIPROT MSC protein O60682 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254861 CDK2 protein P24941 UNIPROT POLL protein Q9UGP5 UNIPROT up-regulates quantity by stabilization phosphorylation Thr553 GPGRVLPtPTEKDVF 9606 BTO:0002181 18688254 YES miannu Phosphorylation of DNA polymerase λ is required to maintain its stability.  Recently, we identified Pol lambda as an interaction partner of cyclin-dependent kinase 2 (CDK2) that is central to the cell cycle G1/S transition and S-phase progression. Experiments with phosphorylation-defective mutants suggest that phosphorylation of Thr 553 is important for maintaining Pol lambda stability, as it is targeted to the proteasomal degradation pathway through ubiquitination unless this residue is phosphorylated. 0.336 SIGNOR-276169 CFI protein P05156 UNIPROT C3 protein P01024 UNIPROT down-regulates activity cleavage 9606 BTO:0000089 26806831 YES lperfetto FH also serves as cofactor for the serine protease factor I (FI) that cleaves C3b into iC3b, unable to form C3 convertase (Fig 1B). 0.878 SIGNOR-263489 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 9335504 YES llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 0.607 SIGNOR-52674 PTPRR protein Q15256 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 11493009 YES Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.|PTP-SL dephosphorylates the regulatory phosphotyrosine on the active loop of ERK1/2. Tyrosine dephosphorylation of ERK1/2 causes the inactivation of ERK1/2 and its retention in the cytoplasm 0.823 SIGNOR-248840 SOCS1 protein O15524 UNIPROT STAT1 protein P42224 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16628196 NO miannu SOCS1, which is another inducible gene, not only blocks STAT1 activation but also inhibits STAT1-dependent TLR3, IRF-7, and MIP-1α. 0.625 SIGNOR-255229 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser55 KPRHKIIsIFSGTEK -1 10075701 YES miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. 0.2 SIGNOR-250229 TAF5L protein O75529 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.685 SIGNOR-269586 GABA-A proteinfamily SIGNOR-PF61 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.7 SIGNOR-264970 IL1R1 protein P14778 UNIPROT IL1RAP protein Q9NPH3 UNIPROT up-regulates activity binding 9606 BTO:0000007 10854325 YES lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) 0.73 SIGNOR-251981 FYN protein P06241 UNIPROT ITCH protein Q96J02 UNIPROT down-regulates activity phosphorylation Tyr420 QFNQRFIyGNQDLFA 10090 BTO:0002417 16387660 YES gcesareni Tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation 0.367 SIGNOR-245332 SLC27A1 protein Q6PCB7 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264463 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000975 10359597 YES lperfetto Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 ras activation leads to raf and subsequently mek activation. Phospholipide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. 0.748 SIGNOR-235991 PPARA protein Q07869 UNIPROT ACSL1 protein P33121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003204 17150915 NO miannu To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA. 0.55 SIGNOR-255044 CYBB protein P04839 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.7 SIGNOR-264716 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 YES Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. 0.5 SIGNOR-248388 HOXA7 protein P31268 UNIPROT TGM1 protein P22735 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 11435435 NO miannu Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. 0.2 SIGNOR-254474 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 YES miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. 0.463 SIGNOR-163458 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates activity phosphorylation Tyr321 LGQRIYQyIQSRFYR 9606 BTO:0000298 11672423 YES lperfetto Direct identification of phosphorylated residues by tandem ms confirmed that tyr-321, but not tyr-319, was phosphorylated. When expressed in cos-7 cells, dyrk1a was found to be fully phosphorylated on tyr-321. A catalytically inactive mutant of dyrk1a contained no detectable phosphotyrosine, indicating that tyr-321 is autophosphorylated by dyrk1a. 0.2 SIGNOR-111145 tadalafil chemical CHEBI:71940 ChEBI PDE5A protein O76074 UNIPROT down-regulates activity chemical inhibition 9606 21189023 YES Luana All of the final compounds and intermediates synthesized were screened for in vitro tumor cell growth inhibition activity using the human MDA-MB-231 breast tumor cell line and for inhibition of recombinant human PDE5 at a single concentration of 10 μM. For compounds showing >60% inhibition, the IC50 was determined by testing a range of eight concentrations with quadruple replicates per concentration, tadalafil used as a positive control.| Conversely, tadalafil possessed a selectivity index of just 16.6 for PDE5 versus PDE11 0.8 SIGNOR-257887 ZNF804A protein Q7Z570 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 YES miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 0.2 SIGNOR-269464 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT down-regulates activity phosphorylation Ser436 TCSPLRHsFQKQQRE -1 8810272 YES miannu Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin. 0.311 SIGNOR-250330 PRKCA protein P17252 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates phosphorylation Ser234 QRAIPPRsIRGDQIA 9606 18710826 YES tpavlidou Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity. 0.363 SIGNOR-180203 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1A protein P54750 UNIPROT down-regulates activity chemical inhibition 9606 22014080 YES Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. 0.8 SIGNOR-256274 PRKCQ protein Q04759 UNIPROT CARD11 protein Q9BXL7 UNIPROT down-regulates activity phosphorylation Ser893 SPRLSRAsFLFGQLL -1 35230873 YES miannu PKCθ-catalyzed CARD11 Ser893 phosphorylation impairs CBM complex formation 0.774 SIGNOR-276298 GSK3B protein P49841 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates quantity phosphorylation 9606 21554241 YES miannu GSK-3beta phosphorylates PTP1B at serine residues, and activation of GSK-3beta reduces the mRNA level of PTP1B. 0.47 SIGNOR-279724 TAF12 protein Q16514 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.754 SIGNOR-269580 OR5B21 protein A6NL26 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 9606 34917897 NO Since NF-κB activation is an important characteristic of EMT and cancer metastasis, we evaluated the effect of OR5B21 on this pathway as well as two transcription factors known to co-operate with NF-κB as synergistic initiators and master regulators of EMT, the signal transducer and activator of transcription 3 (STAT3) and the CCAAT/enhancer binding protein b (C/EBPβ) | Of importance, OR5B21 knockdown inhibited phosphorylation of STAT3 and reversed the expression of MMP2, MMP9, and Snail, which coincided with a decrease in both C/EBPβ levels and activation of NF-κB, whereas overexpression of OR5B21 had the opposite effect, endorsing the role of C/EBPβ/STAT3 in OR5B21-induced metastasis | Together, these data suggest that OR5B21 promotes breast cancer metastasis to different tissues by activating EMT through the STAT3/NF-κB/C/EBPβ signaling axis, revealing OR5B21 as a potential target for breast cancer therapy 0.2 SIGNOR-272503 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Ser518 GEDPYAGsTDENTDS 9606 BTO:0000567 15367657 YES lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 0.396 SIGNOR-128893 FOXO proteinfamily SIGNOR-PF27 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity transcriptional regulation 10090 BTO:0002314 24749067 NO gcesareni We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration. 0.2 SIGNOR-252940 S1RA chemical CID:44247568 PUBCHEM SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000195 22784008 YES Simone Vumbaca The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862) emerged as the most interesting candidate. Compound 28 is a highly selective σ1R antagonist and has successfully completed phase I safety and pharmacokinetic evaluation in humans. 0.8 SIGNOR-261122 GSK3B protein P49841 UNIPROT DDIT4 protein Q9NX09 UNIPROT down-regulates quantity by destabilization phosphorylation Thr23 SPSSLPRtPTPDRPP 9606 23717519 YES miannu It has been reported that GSK3beta phosphorylates REDD1 at residues Thr23 and Thr25, resulting in REDD1 recruitment to the Cullin 4a-beta-Trcp E3 ligase complex. 0.34 SIGNOR-279525 ECT2 protein Q9H8V3 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.711 SIGNOR-260550 FOXO proteinfamily SIGNOR-PF27 SIGNOR GK protein P32189 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18805788 NO gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription foxo1 localizes to the nucleus, where it represses hnf-4-dependent activity of the gk promoter as a corepressor. 0.2 SIGNOR-252919 NFATC2 protein Q13469 UNIPROT MYOF protein Q9NZM1 UNIPROT up-regulates transcriptional regulation 9606 23612709 NO Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin 0.2 SIGNOR-255461 WICH complex SIGNOR-C449 SIGNOR RNA Polymerase I complex SIGNOR-C390 SIGNOR up-regulates activity binding 9606 16514417 YES miannu Here, we show by biochemical fractionation of nuclear extracts, protein-protein interaction studies and chromatin immunoprecipitation assays that NM1 is part of a multiprotein complex that contains WICH, a chromatin remodelling complex containing WSTF (Williams syndrome transcription factor) and SNF2h. NM1, WSTF and SNF2h were found to be associated with RNA polymerase I (Pol I) and ribosomal RNA genes (rDNA). RNA interference-mediated knockdown of NM1 and WSTF reduced pre-rRNA synthesis in vivo, and antibodies to WSTF inhibited Pol I transcription on pre-assembled chromatin templates but not on naked DNA. The results indicate that NM1 cooperates with WICH to facilitate transcription on chromatin. 0.463 SIGNOR-268830 SPI1 protein P17947 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0004730 12130514 NO lperfetto The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. 0.7 SIGNOR-249633 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 20626350 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. 0.809 SIGNOR-166637 PKN1 protein Q16512 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser246 QACARTFsRMSLLHK 9606 BTO:0000150 15833848 YES lperfetto Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functionswe found for the first time that pak1 promotes transcription repression activity of snail from e-cadherin, occludin, and aromatase promoters. Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions. 0.2 SIGNOR-135609 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Ser438 TPTLTNQsPTLTLQS 9606 BTO:0000801 14592977 YES lperfetto Tab1, a subunit of the kinase tak1, was phosphorylated by sapk2a/p38alpha at ser423, thr431 and ser438 in vitro. the results presented here also show that sapk2a/p38? Suppresses the activity of tak1 in cells, because the activation of tak1 by proinflammatory cytokines and lps is enhanced if cells are first pre?incubated With sb 203580 or in cells that do not express sapk2a/p38?. 0.823 SIGNOR-118922 TRIM27 protein P14373 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000671 12807881 NO miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. 0.271 SIGNOR-102031 axitinib chemical CHEBI:66910 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258073 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259809 CARS1 protein P49589 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 11347887 YES miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. 0.8 SIGNOR-270472 ZBTB47 protein Q9UFB7 UNIPROT CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR form complex binding 9606 BTO:0000007 20116376 YES Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. 0.455 SIGNOR-253957 PAX8 protein Q06710 UNIPROT TPO protein P07202 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 27347897 YES scontino TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8. 0.399 SIGNOR-267277 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr86 TYSEELCyTLINHRV -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.245 SIGNOR-273560 tyrphostin B42 chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition 9606 11368440 YES gcesareni The Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel 0.8 SIGNOR-238542 CSNK2A1 protein P68400 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates activity phosphorylation Ser236 LQRALALsRQEIDME 9606 BTO:0000007 19542537 YES miannu Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs. 0.2 SIGNOR-276225 TACR3 protein P29371 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257066 SRC protein P12931 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 YES lperfetto In our work we show that, in contrast to BCR-ABL and prolactin, NPM-ALK phosphorylates Grb2 mainly in Tyr160)Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation. 0.642 SIGNOR-247138 MECP2 protein P51608 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000614 18511691 YES Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. 0.347 SIGNOR-264680 irinotecan chemical CHEBI:80630 ChEBI TOP1 protein P11387 UNIPROT down-regulates activity chemical inhibition 9606 15170677 YES miannu Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I) 0.8 SIGNOR-259316 AKT1 protein P31749 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 18394876 YES lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity 0.647 SIGNOR-252582 PRKCD protein Q05655 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Ser360 ELKALLQsSASRKTQ 9606 BTO:0000938 21145366 YES gcesareni Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb 0.507 SIGNOR-170348 ACAT1 protein P24752 UNIPROT ME1 protein P48163 UNIPROT up-regulates activity acetylation Lys337 KIWLVDSkGLIVKGR 31735643 YES lperfetto PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. 0.249 SIGNOR-275571 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 8242752 YES lperfetto The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. 0.876 SIGNOR-37145 SRC protein P12931 UNIPROT FERMT2 protein Q96AC1 UNIPROT up-regulates activity phosphorylation Tyr193 SKTMTPTyDAHDGSP 9606 BTO:0000007 26037143 YES miannu Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. 0.37 SIGNOR-266100 nitric oxide smallmolecule CHEBI:16480 ChEBI Vascular_Permeability phenotype SIGNOR-PH140 SIGNOR up-regulates 9606 BTO:0001176 24078390 NO VEGF pathway Gianni After a period of controversial reports, evidence based on eNOS knockout mice and on eNOS-depleted EC established that microvascular hyperpermeability in response to an inflammatory challenge is regulated mainly by endothelial cells through eNOS-derived NO 0.7 SIGNOR-261947 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000938 17591690 YES gcesareni Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro, 0.731 SIGNOR-156418 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 15367694 YES Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes 0.893 SIGNOR-248629 BMX protein P51813 UNIPROT F2R protein P25116 UNIPROT down-regulates activity phosphorylation Tyr381 ASSECQRyVYSILCC 9606 31910739 YES miannu As shown in xref \u2013 xref , BMX overexpression increased PAR1-WT phosphorylation but had no effect on PAR1 Y 381 FY 383 F mutant, indicating that BMX phosphorylated PAR1 at Y 381 and Y 383 .|Mechanically , BMX represses PAR1 signaling in ECs by promoting PAR1 phosphorylation and internalization . 0.2 SIGNOR-279593 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193630 PRKN protein O60260 UNIPROT ZNF746 protein Q6NUN9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000793 28122242 YES miannu PINK1 is required for Parkin ubiquitination and degradation of PARIS. PINK1 interacts with and phosphorylates serines 322 and 613 of PARIS to control its ubiquitination and clearance by parkin. 0.2 SIGNOR-273726 CDK2 protein P24941 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates phosphorylation Ser154 PMDGSFEsPHTMDMS 9606 10652300 YES lperfetto Here we present evidence from in vitro and in vivo assay systems that the degradation of human cyclin a can be inhibited by kinase-inactive mutants of cdk2 and cdc2cdk2 can phosphorylate cyclin a on ser-154 0.977 SIGNOR-74466 ABL1 protein P00519 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Tyr88 KGSLPEFyYRPPRPP -1 17254966 YES Lyn and Abl phosphorylate Y88 of p27 in vitro. phosphorylation of Y88 in p27 impaired its ability to inhibit the bound kinase complex 0.594 SIGNOR-251426 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). 0.8 SIGNOR-268109 CELF4 protein Q9BZC1 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 23209433 NO miannu CELF4 (CUGBP, ELAV-like family member 4) is one of six mammalian CELF proteins that function in mRNA metabolism. CELF4 is expressed predominantly in excitatory neurons, with highest expression in pyramidal neurons of the hippocampus and the cerebral cortex. we suggest that CELF4 deficiency leads to abnormal neuronal function by combining a specific effect on neuronal excitation with a general impairment of synaptic transmission. 0.7 SIGNOR-264257 GDNF protein P39905 UNIPROT RHOQ protein P17081 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.2 SIGNOR-252185 dexmedetomidine chemical CHEBI:4466 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258907 IL23R protein Q5VWK5 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 YES gcesareni Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12. 0.581 SIGNOR-87841 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates activity binding 9606 BTO:0001593 BTO:0000140 22298955 YES lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptorsNoggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285) 0.61 SIGNOR-192799 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser463 SPHNPISsVS 9606 BTO:0000416 9136927 YES lperfetto Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro 0.664 SIGNOR-217985 KDR protein P35968 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity relocalization 9825 BTO:0004007 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 9405464 YES VEGF pathway Gianni In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function. 0.71 SIGNOR-261949 CSNK2A2 protein P19784 UNIPROT SUZ12 protein Q15022 UNIPROT up-regulates activity phosphorylation Ser583 PQEMEVDsEDEKDPE 9606 BTO:0002181 36351927 YES miannu CK2 is the kinase for the phosphorylation of S583 of SUZ12. 0.2 SIGNOR-277811 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation 9606 15632084 YES inferred from 70% family members amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 0.2 SIGNOR-270205 AKT proteinfamily SIGNOR-PF24 SIGNOR SLC2A4 protein P14672 UNIPROT up-regulates 9606 8940145 NO Translocation from intracellular compartment to cell surface in muscle and adipose tissue gcesareni The constitutively active Akt induced glucose uptake into adipocytes in the absence of insulin by stimulating translocation of the insulin-responsive glucose transporter 4 to the plasma membrane. 0.2 SIGNOR-45117 EGFR protein P00533 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19882665 NO miannu We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression. 0.48 SIGNOR-189033 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.402 SIGNOR-259028 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr74 SVLTGKLtTVFLPIV -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.374 SIGNOR-263596 pirenzepine chemical CHEBI:8247 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258396 CDK1 protein P06493 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr194 NMMDILTtPSMAKPR 8355 22354989 YES gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop 0.511 SIGNOR-243414 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT up-regulates phosphorylation His118 QVGRNIIhGSDSVES 9606 BTO:0000763 22869372 YES llicata Ndpk catalytic function requires autophosphorylation at the catalytic his-118 residue. the simplest interpretation of these data is that ampk does not directly phosphorylate ndpk-a at ser-120 or ser-122 (or at any other site) but rather enhances ndpk-a autophosphorylation at his-118. 0.2 SIGNOR-198667 Phagocytosis phenotype SIGNOR-PH97 SIGNOR IL1B protein P01584 UNIPROT down-regulates quantity BTO:0000801 22933625 NO apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype 0.7 SIGNOR-255445 PRKD1 protein Q15139 UNIPROT KAT7 protein O95251 UNIPROT up-regulates quantity by stabilization phosphorylation Thr97 KKYPLRQtRSSGSET 9606 BTO:0002181 33014433 YES miannu We show that PKD1 directly interacts and phosphorylates KAT7 at Thr97 and Thr331 in vitro and in vivo. PKD1-mediated phosphorylation of KAT7 enhances its expression levels and stability by reducing its ubiquitination-mediated degradation.  0.2 SIGNOR-277829 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Thr138 GGFIRRVtNDARENE 9606 12459461 YES lperfetto This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C 0.353 SIGNOR-249179 HES6 protein Q96HZ4 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000938 19891787 NO gcesareni Expression of hes-6 resulted in induction of e2f-1, a crucial target gene for the transcriptional repressor hes-1 0.2 SIGNOR-189101 CDK2 protein P24941 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 S-->E 9606 35039060 YES miannu Cdk2 phosphorylates c-Myc at Ser62 to suppress its ubiquitination modification/degradation, resulting in enhanced stability of c-Myc [ xref ]. 0.748 SIGNOR-279808 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258304 DAMPS stimulus SIGNOR-ST18 SIGNOR NLRP1 protein Q9C000 UNIPROT up-regulates activity 16037825 NO lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage 0.7 SIGNOR-256421 hsa-miR-493-5p mirna URS0000077AED_9606 RNAcentral FZD4 protein Q9ULV1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001345 22057916 YES MiR-493 is a new tumor suppressor microRNA in bladder cancer and inhibits cell motility through down-regulation of RhoC and FZD4. 0.4 SIGNOR-277955 FLT4 protein P35916 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates phosphorylation Tyr707 KGAMAATySALNRNQ 9606 12601080 YES llicata Upon truncation of this c-terminal stretch, or mutation of the tyr-707 residue alone, autoinhibition is attenuated, and the kinase becomes constitutively active. Based on these findings we propose that phosphorylation of the tyr-707 represents a novel alternative regulatory mechanism for p90rsk activation. 0.2 SIGNOR-98708 N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide chemical CHEBI:91408 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258301 CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser243 TDSEVDSsCSGQPIH 9606 BTO:0000007 26885618 YES lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| 0.356 SIGNOR-273123 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser65 PCSSVPSsPSFCAPS 9606 BTO:0000567 11416124 YES lperfetto These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription. 0.335 SIGNOR-108564 ATM protein Q13315 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity phosphorylation Ser391 ERAELNQsEEPEAGE 9606 28977635 YES miannu RAGE is phosphorylated at Serine 376 and Serine 389 by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response. 0.2 SIGNOR-278907 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr241 SHQGPVIyAQLDHSG 9606 11751924 YES lperfetto Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr 0.469 SIGNOR-113406 AR protein P10275 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 15861399 NO miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation 0.7 SIGNOR-251540 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser123 EEGFGSSsPVKSPAA 9606 BTO:0000007 23051732 YES lperfetto In particular, we found that Cdc14A inhibits Wee1 degradation through the dephosphorylation of Ser-123 and Ser-139 residues.  0.545 SIGNOR-267469 COMMD5 protein Q9GZQ3 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity relocalization 9606 30021164 NO miannu Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. COMMD5 participates in long-range endosome transport, including epidermal growth factor receptor (EGFR) recycling, and provides the strength to deform and assist the scission of vesicles into sorting endosomes. This study establishes the molecular mechanism by which COMMD5 acts as an adaptor protein to coordinate endosomal trafficking and reveals its important role for EGFR transport and activity. 0.2 SIGNOR-261692 MAP3K7 protein O43318 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates phosphorylation 9606 9480845 YES gcesareni Overexpression oftak1together with its activator protein,tak1binding protein 1 (tab1), induced thenucleartranslocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene. 0.513 SIGNOR-55719 RFX complex complex SIGNOR-C104 SIGNOR HLA-DPB1 protein P04440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 NO Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. 0.287 SIGNOR-254007 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation 9606 11266449 YES lperfetto Overexpression of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation. We propose that shp-1 is an important downstream regulator of ros signaling. 0.368 SIGNOR-105922 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser349 STGEQEIsVGL 9534 BTO:0000298 10085131 YES gcesareni Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. 0.2 SIGNOR-249679 PKC proteinfamily SIGNOR-PF53 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity phosphorylation Ser165 CSMAALTsHLQNQSN 23195996 YES lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] 0.2 SIGNOR-275675 CTDSP1 protein Q9GZU7 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR form complex binding 9606 BTO:0000007 9452425 YES lperfetto Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas. 0.2 SIGNOR-236839 CSNK2A2 protein P19784 UNIPROT ARRB2 protein P32121 UNIPROT unknown phosphorylation Thr382 EFDTNYAtDDDIVFE -1 11877451 YES llicata We found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. | However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex. 0.31 SIGNOR-250977 Cy3-bifunctional dye zwitterion chemical CHEBI:37990 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257858 RBBP4 protein Q09028 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 YES lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). 0.89 SIGNOR-241906 CHEK1 protein O14757 UNIPROT E2F7 protein Q96AV8 UNIPROT down-regulates activity phosphorylation 9606 29363506 YES miannu Chk1 inhibits the transcriptional repressor function of E2F7 and E2F8 to promote cell cycle progression and prevent apoptosis.|Here, we demonstrate that Chk1 phosphorylates both E2F7 and E2F8 in response to DNA damage. 0.388 SIGNOR-279692 GRB14 protein Q14449 UNIPROT INSR protein P06213 UNIPROT down-regulates activity binding 24535599 YES lperfetto Growth factor receptor-bound protein 14 (Grb14) interacts with insulin receptor (IR) through the between PH and SH2 (BPS) domain. Grb14-IR complex formation is initiated by insulin stimulation, and the binding event results in the inhibition of insulin signalling. 0.76 SIGNOR-264873 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser172 LCLSPASsGSSASFI 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248680 Anacetrapib chemical CID:11556427 PUBCHEM CETP protein P11597 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189605 MYF6 protein P23409 UNIPROT DES protein P17661 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8382796 YES lperfetto Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression 0.242 SIGNOR-241497 PSMD13 protein Q9UNM6 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.886 SIGNOR-263348 CHUK protein O15111 UNIPROT TP73 protein O15350 UNIPROT up-regulates activity phosphorylation 9606 22084676 YES miannu IKK-alpha had an ability to stabilize p73 by inhibiting its polyubiquitination, and enhanced p73 mediated transcriptional activation as well as proapoptotic activity.|In addition, IKK-alpha phosphorylated the NH 2 -terminal portion of p73 and a kinase deficient mutant form of IKK-alpha had undetectable effect on p73. 0.337 SIGNOR-279697 EFNA2 protein O43921 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.923 SIGNOR-52203 IRF9 protein Q00978 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity binding 9606 BTO:0000007 17923090 YES lperfetto By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2. 0.727 SIGNOR-217779 ELOVL2 protein Q9NXB9 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267897 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding 10090 9442088 YES gcesareni Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s). 0.876 SIGNOR-55300 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr1029 TPSDSLIyDDGLSEE 9534 BTO:0004055 8621380 YES lperfetto Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map  0.2 SIGNOR-248940 CHD8 protein Q9HCK8 UNIPROT DCX protein O43602 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.2 SIGNOR-268915 SPDEF protein O95238 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003160 22761428 NO miannu Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. 0.2 SIGNOR-255219 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Thr219 ASLSLPAtPVGKGTE 10090 BTO:0000142 12796778 YES llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. 0.636 SIGNOR-250678 CDC14A protein Q9UNH5 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT unknown dephosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 YES Here, we demonstrate that SIRT2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1, and dephosphorylated by the phosphatases CDC14A and CDC14B. Overexpression of SIRT2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation|Additionally, we found that SIRT2, like other Cdk1 targets, can be dephosphorylated by the phosphatases CDC14A and CDC14B. In contrast to a published report (8), we did not observe any degradation of SIRT2 by the 26 S proteasome in response to CDC14B overexpression|However, we cannot exclude the possibility that phosphorylation of serine 368 might affect the activity of SIRT2 on other unidentified acetylated substrates. 0.422 SIGNOR-248834 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2D3 protein P61077 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.838 SIGNOR-271314 PPARGC1A protein Q9UBK2 UNIPROT OTC protein P00480 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 NO miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. 0.2 SIGNOR-255056 DOK1 protein Q99704 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.297 SIGNOR-257682 PTGER4 protein P35408 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256903 NDUFB8 protein O95169 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 0.823 SIGNOR-262171 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 BTO:0000887 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.275 SIGNOR-163764 PRKACA protein P17612 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 YES gcesareni Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase aon serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. 0.398 SIGNOR-112371 PIK3CG protein P48736 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser70 LFGGFNSsDTVTSPQ 9606 BTO:0000007 27169346 YES miannu PI3Kγ mediated phosphorylation of Src enhances Src activity protein kinase activity of PI3K phosphorylates serine residue 70 on Src to enhance its activity and induce EGFR transactivation following βAR stimulation.  0.365 SIGNOR-277225 CHEK1 protein O14757 UNIPROT CLSPN protein Q9HAW4 UNIPROT up-regulates phosphorylation Thr916 DELLDLCtGKFTSQA 9606 16963448 YES gcesareni We found that thr-916 on claspin is phosphorylated by chk1, suggesting that chk1 regulates claspin during checkpoint response. 0.793 SIGNOR-149411 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD40 protein P25942 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 NO miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. 0.571 SIGNOR-254785 CALM3 protein P0DP25 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 YES miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.578 SIGNOR-266338 CCR4-NOT complex complex SIGNOR-C439 SIGNOR NANOS1 protein Q8WY41 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 YES lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins 0.349 SIGNOR-268346 SMC5 protein Q8IY18 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 YES miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks 0.895 SIGNOR-265481 COLGALT2 protein Q8IYK4 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates activity glycosylation -1 19075007 YES Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. 0.441 SIGNOR-261156 TFE3 protein P19532 UNIPROT CTSS protein P25774 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). 0.27 SIGNOR-276818 NPC complex SIGNOR-C263 SIGNOR Nuclear_pore_function phenotype SIGNOR-PH130 SIGNOR up-regulates 9606 BTO:0000007 9660920 NO miannu Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus. 0.7 SIGNOR-261395 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR proline smallmolecule CHEBI:26271 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270429 TNFRSF17 protein Q02223 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 10903733 NO miannu Overexpression of bcma activates the p38 mapk 0.265 SIGNOR-79504 hsa-miR-1-5p mirna URS000075C105_9606 RNAcentral CCND2 protein P30279 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000196 21752897 YES This result indicates that miR-1 affects CCND2 protein synthesis by facilitating the specific degradation of CCND2 mRNA. 0.4 SIGNOR-277929 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.384 SIGNOR-129264 PRPS1 protein P60891 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI down-regulates quantity chemical modification 9606 16939420 YES miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. 0.8 SIGNOR-267078 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser197 KEDRSASsGAEGDVS -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.285 SIGNOR-273972 2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide chemical CHEBI:125569 ChEBI PPARG protein P37231 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001950 27489280 YES lperfetto We performed reporter assays to examine the effect of NeoB on the transcriptional activity of specific nuclear hormone receptors, including PPARs, retinoic acid receptor (RAR), ER, and LXR, in uninfected Huh7-25 cells (Fig. 3A). NeoB did not have a significant effect [...] in contrast to the transcriptional repression by known antagonists as positive controls (GW6471, GSK0660, FH535, Ro41-5253, and 4-hydroxytamoxifen) (Fig. 3A) 0.8 SIGNOR-262015 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 25750431 YES svumbaca The results of this study show that the absence of HIFs in MPs has no impact on the resolution of inflammation in two sterile models of skeletal muscle regeneration 0.336 SIGNOR-256236 HACE1 protein Q8IYU2 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17694067 YES miannu Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. 0.307 SIGNOR-271405 PRKACA protein P17612 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 18768928 YES llicata The results indicate that phosphorylation of gdi_ at ser174 by pka suppresses rhoa activity, providing a potential protective signaling mechanism for inflammatory injury. 0.385 SIGNOR-180576 DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 29479476 YES miannu The initial step of signaling inside the cell after netrin-1/DCC ligation is the binding of DCC cytoplasmic P3 motif to focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK). Here we report the crystal structure of P3/FAT complex. The helical P3 peptide interacts with a helix-swapped FAT dimer in a 2:2 ratio. Dimeric FAT binding is P3-specific and stabilized by a calcium ion. We propose that netrin-1/DCC engagement creates a small cluster of P3/FAT for FAK recruitment close to the cell membrane, which exerts a concerted effect with PIP2 for FAK signaling. Axon guidance assays confirm that this DCC/FAK complex is physiologically essential for netrin-1-induced chemoattraction. 0.719 SIGNOR-268370 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LCK protein P06239 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 8618896 YES inferred from 70% family members lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. 0.2 SIGNOR-270074 RRN3 protein Q9NYV6 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 11250903 YES lperfetto HRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters|We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription. 0.661 SIGNOR-269647 ARHGAP44 protein Q17R89 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.588 SIGNOR-260498 PPP2CA protein P67775 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR form complex binding 9606 23454242 YES gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. 0.936 SIGNOR-243424 PKA proteinfamily SIGNOR-PF17 SIGNOR HDAC4 protein P56524 UNIPROT up-regulates activity phosphorylation Ser584 EPGQRQPsEQELLFR -1 30661366 YES miannu  In vitro kinase assays have established that Ser584 and Ser265/266 are phosphorylated by protein kinase A (PKA). Overexpression of site-specific HDAC4 mutants (S584A, S265/266A) in HEK 293T cells, followed by HDAC activity assays, revealed the mutants to be less active than the wild-type protein. 0.2 SIGNOR-277423 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251598 S100A8 protein P05109 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 9606 28137827 YES miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33 0.317 SIGNOR-261919 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21041712 YES gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. 0.8 SIGNOR-169194 NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys17 GLGKGGAkRHRKVLR 9606 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8. 0.2 SIGNOR-267166 UBE4B protein O95155 UNIPROT MAPT protein P10636 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 34078905 YES miannu Ubiquitination and degradation of Tau by UBE4B and STUB1 in mammalian neuroblastoma cells. 0.2 SIGNOR-278682 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.545 SIGNOR-270896 FBXO2 protein Q9UK22 UNIPROT BACE1 protein P56817 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000938 20854419 YES miannu SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production. 0.524 SIGNOR-271904 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr39 TDPTPQHyPSFGVTS -1 9425276 YES Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. 0.2 SIGNOR-251166 CD19 protein P15391 UNIPROT VAV1 protein P15498 UNIPROT up-regulates activity binding 10090 25673924 YES lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. 0.723 SIGNOR-242897 ITGB2 protein P05107 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.915 SIGNOR-253190 SRC protein P12931 UNIPROT ARHGAP5 protein Q13017 UNIPROT up-regulates activity phosphorylation 9606 24858043 YES miannu Knockdown of MCT-1 abolished the Src-p190B activation and suppressed the interaction of active Src and p190B, suggesting that the MCT-1-enhanced interaction facilitated Src activation of p190B. The role of p190B in multinucleation was next assessed by the interference of p190B gene expression (p190B siRNA nos.|The Src activity-independent p190B/MCT-1 interaction (Figure 3d) and a direct involvement of MCT-1 in the signaling activation of Src/p190B (Figures 3b and 4a) imply the proximity complex of MCT-1/p190B/Src facilitating Src phosphorylation and activation of p190B. 0.606 SIGNOR-278904 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258539 TTK protein P33981 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 19332559 YES llicata Ttk/hmps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at thr18. phosphorylation at thr18 enhances p53-dependent activation of not only p21 but also lats2, two mediators of the postmitotic checkpoint. 0.5 SIGNOR-184931 GNAS protein P63092 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity 9606 12145344 NO lperfetto HETEROTRIMERIC G PROTEINS are essential for cell signaling throughout the body. The stimulatory G protein, Gs, couples activation of a host of different transmembrane receptors to adenylyl cyclase stimulation, leading to intracellular generation of cAMP 0.8 SIGNOR-268692 TOP2B protein Q02880 UNIPROT PBX3 protein P40426 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 NO lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development 0.2 SIGNOR-242308 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194925 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity phosphorylation Ser13 FESYGSSsYGGAGGY -1 9295339 YES lperfetto We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13 0.58 SIGNOR-248982 CHUK protein O15111 UNIPROT BCL3 protein P20749 UNIPROT up-regulates activity phosphorylation Ser122 CPMEHPLsADIAMAT -1 28689659 YES miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  0.429 SIGNOR-277362 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L3 protein P68036 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.568 SIGNOR-271326 HTR6 protein P50406 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.253 SIGNOR-257186 PSMA7 protein O14818 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.829 SIGNOR-263365 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 12242151 YES gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma 0.824 SIGNOR-92945 CSNK1A1 protein P48729 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity phosphorylation Ser349 SSKEVDPsTGELQSL 10090 37723657 YES miannu Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation. 0.392 SIGNOR-273769 DUSP6 protein Q16828 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates activity dephosphorylation 9606 24861519 YES miannu Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK.|The main findings of our studies are (1) MKP-3 preferentially reduces p-JNK over p-ERK and p-p38 in primary astrocytes; (2) This MAPK modulation pattern in primary astrocytes significantly reduced NO and completely abolished IL-6 and TNF accumulation; and (3) These effects are specifically induced by MKP-3 since block-age of MKP-3 mRNA expression reversed its action on MAPKs and pro-inflammatory mediators in BV-2 microglia cells. 0.631 SIGNOR-277150 MAFA protein Q8NHW3 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 NO miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. 0.287 SIGNOR-254566 RUNX3 protein Q13761 UNIPROT TIAL1 protein Q01085 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255088 AKT proteinfamily SIGNOR-PF24 SIGNOR ADARB1 protein P78563 UNIPROT down-regulates activity phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 YES miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. 0.2 SIGNOR-266358 CD300LB protein A8K4G0 UNIPROT TYROBP protein O43914 UNIPROT up-regulates activity binding 9534 20959446 YES lperfetto The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2. 0.702 SIGNOR-264834 CSNK2A2 protein P19784 UNIPROT UBE2R2 protein Q712K3 UNIPROT up-regulates activity phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 YES llicata UBC3B is specifically phosphorylated by CK2 in vitro and in vivo. We mapped by deletions and site directed mutagenesis the phosphorylation site to a serine residue within the C-terminal domain in position 233 of UBC3B and in the corresponding serine residue of UBC3. | Following CK2-dependent phosphorylation both UBC3B and UBC3 bind to the F-box protein beta-TrCP, the substrate recognition subunit of an SCF (Skp1, Cul1, F-box) ubiquitin ligase. Furthermore, we observed that co-transfection of CK2alpha' together with UBC3B, but not with UBC3DeltaC, enhances the degradation of beta-catenin. 0.45 SIGNOR-251047 GSK3B protein P49841 UNIPROT CABYR protein O75952 UNIPROT unknown phosphorylation Ser155 KTTTPPSsPPPTAVS -1 15752768 YES GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated. 0.401 SIGNOR-251223 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1337 LDSDEDFsDFDEKTD 9606 18171681 YES llicata Plk1 phosphorylates ser(1337) and ser(1524) of topoiialpha plk1-associated phosphorylation is essential for the functions of topoiialpha in mitosis 0.481 SIGNOR-160233 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser400 PINACELsPKGKEQA -1 12361598 YES miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) 0.516 SIGNOR-265956 DDC protein P20711 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI down-regulates quantity chemical modification 9606 31024440 YES brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT 0.8 SIGNOR-264013 PRKCB protein P05771 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276023 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 YES llicata Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291. 0.2 SIGNOR-176875 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268581 NR0B2 protein Q15466 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 17909097 NO inferred from family member gcesareni As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells 0.2 SIGNOR-270256 FYN protein P06241 UNIPROT CD300LF protein Q8TDQ1 UNIPROT up-regulates activity phosphorylation Tyr263 AEDQEPTyCNMGHLS 17202342 YES lperfetto Y236 (YVTM) and Y263 (YCNM) fit with the consensus motif reported to bind the p85α regulatory subunit of PI3K (16). |The association between IREM-1 and p85α was only perceived in the presence of c-Fyn, suggesting that tyrosine phosphorylation of IREM-1 cytoplasmic tail of IREM-1 was required for the interaction. 0.343 SIGNOR-275620 ATP6V1G2 protein O95670 UNIPROT V-ATPase complex SIGNOR-C560 SIGNOR form complex binding 9606 33065002 YES miannu Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. 0.737 SIGNOR-277745 MAPK14 protein Q16539 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser7 sPAPLSPL 9606 BTO:0000150 22128155 YES gcesareni Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin 0.52 SIGNOR-252960 Ub:E2 complex SIGNOR-C497 SIGNOR CNOT4 protein O95628 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271004 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2Q2 protein Q8WVN8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.424 SIGNOR-271363 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 BTO:0000142 12486117 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.286 SIGNOR-96632 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 SIGNOR-C3 12747827 YES lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. 0.926 SIGNOR-101127 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636-5 UNIPROT down-regulates activity phosphorylation Ser262 NVKSKIGsTENLKHQ -1 21204788 YES miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.255 SIGNOR-273928 MAPK1 protein P28482 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 9606 BTO:0000938 20444238 YES gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. 0.468 SIGNOR-165204 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NUP153 protein P49790 UNIPROT unknown phosphorylation 9606 19767751 YES inferred from 70% family members llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. 0.2 SIGNOR-270044 REN protein P00797 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage 9606 16816138 YES Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I 0.928 SIGNOR-252297 PRKDC protein P78527 UNIPROT XRCC4 protein Q13426 UNIPROT up-regulates activity phosphorylation Ser328 LETLRNSsPEDLFDE 9606 BTO:0002137 26774286 YES miannu In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.  0.907 SIGNOR-277199 D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 34775382 YES miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. 0.8 SIGNOR-267064 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser641 KVTSKCGsLGNIHHK -1 10090741 YES miannu We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs. 0.43 SIGNOR-250174 UBE2D2 protein P62837 UNIPROT KPC complex SIGNOR-C523 SIGNOR up-regulates activity binding 10090 BTO:0000944 15531880 YES miannu  We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation.  Polyubiquitination activity of KPC was apparent with only Ubc4 or UbcH5A. 0.435 SIGNOR-271515 PRKD2 protein Q9BZL6 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity phosphorylation Ser358 WPLSRTRsEPLPPSA 18692497 YES Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7 lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. 0.438 SIGNOR-275935 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr266 TDLDAVRtPEPLEEF BTO:0000007 10593981 YES llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 0.718 SIGNOR-250736 PRIM2 protein P49643 UNIPROT DNA primase complex complex SIGNOR-C261 SIGNOR form complex binding -1 24043831 YES lperfetto Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit. 0.99 SIGNOR-261340 ERBB2 protein P04626 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 YES gcesareni Erbb3 is characterized by a large number of binding sites for phosphatidylinositol-3-kinase (pi3k), while erbb2 has only few interaction partners with shc as the most frequent one. 0.548 SIGNOR-146855 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK7 protein P50613 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206136 PPP2R2A protein P63151 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 16239230 YES gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. 0.462 SIGNOR-243417 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-138467 TOP2B protein Q02880 UNIPROT CDH13 protein P55290 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 NO lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development 0.2 SIGNOR-242302 HHIP protein Q96QV1 UNIPROT IHH protein Q14623 UNIPROT down-regulates activity binding 10090 10050855 YES lperfetto Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal. 0.712 SIGNOR-65075 GSK3B protein P49841 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by stabilization phosphorylation Ser907 QAHSLPLsPASTRQQ 10090 BTO:0000452 12871932 YES GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α. 0.389 SIGNOR-251252 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 15141161 YES gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus 0.879 SIGNOR-124727 COX5B protein P10606 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR down-regulates 10090 BTO:0000165 18701479 NO lperfetto Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.|R-cadherin expression inhibits myoblast cell cycle exit 0.7 SIGNOR-253105 MARK1 protein Q9P0L2 UNIPROT TNK1 protein Q13470 UNIPROT down-regulates activity phosphorylation Ser502 RMKGISRsLESVLSL 9606 BTO:0000018 34504101 YES miannu We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.Phosphorylation of TNK1 at S502 within the proline rich domain is required for TNK1 binding to 14-3-3.MARKs mediate phosphorylation at S502 and 14-3-3 binding to TNK1, which restrains the movement of TNK1 into heavy membrane-associated clusters. 0.2 SIGNOR-273866 MYC protein P01106 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664;BTO:0004465 26179066 YES lperfetto In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer. 0.2 SIGNOR-272143 RPS29 protein P62273 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.884 SIGNOR-262422 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 24710148 YES lperfetto The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). 0.799 SIGNOR-236369 MORF4L2 protein Q15014 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.674 SIGNOR-269300 TSC2 protein P49815 UNIPROT RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000142 15340059 YES lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. 0.922 SIGNOR-128432 SMAD2 protein Q15796 UNIPROT CREB1 protein P16220 UNIPROT up-regulates binding 9606 SIGNOR-C8 9689110 YES gcesareni We demonstrate that human smad2 and smad4, two essential smad proteins involved in mediating tgf-beta transcriptional responses in endothelial and other cell types, can functionally interact with the transcriptional coactivator creb binding protein (cbp). This interaction is specific in that it requires ligand (tgf-beta) activation and is mediated by the transcriptional activation domains of the smad proteins. 0.326 SIGNOR-59462 P2RY4 protein P51582 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-256870 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 11113114 YES gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. 0.417 SIGNOR-85009 ERAP1 protein Q9NZ08 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 31810556 YES scontino While peptides loaded onto MHC class I molecules are 8‚Äì11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1. 0.8 SIGNOR-267772 MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 16280346 NO These data support a role for myoferlin in the maturation of myotubes and the formation of large myotubes that arise from the fusion of myoblasts to multinucleate myotubes 0.7 SIGNOR-255973 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258376 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 YES esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. 0.448 SIGNOR-89217 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser356 VDGSGDTsSNEEIGS -1 12107178 YES llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. 0.415 SIGNOR-250991 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.387 SIGNOR-263607 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding -1 2467839 YES irozzo The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation. 0.952 SIGNOR-256362 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr368 SEHAQDTyLVLDKWL 12441334 YES JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 0.811 SIGNOR-251348 Frizzled proteinfamily SIGNOR-PF11 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates BTO:0001103 23209147 NO apalma The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization. 0.2 SIGNOR-255687 GNAO1 protein P09471 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates 9606 12665513 NO lperfetto These results suggest that go alpha q205l activates p38 through taos and mek3/6. 0.2 SIGNOR-235539 MAPK1 protein P28482 UNIPROT DYNC1I2 protein Q13409 UNIPROT unknown phosphorylation Ser87 YWVPPPMsPSSKSVS 10090 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262772 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser10 LNRTLSMsSLPGLED -1 2117608 YES llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. | From analysis of 32P release during Edman degradation, no radioactively labeled phosphate was associated with Thr3 or Ser7, but could be accounted for by phosphorylation at Ser10 0.33 SIGNOR-250878 KDM4C protein Q9H3R0 UNIPROT H2AC4 protein P04908 UNIPROT down-regulates activity demethylation Lys 10 GRGKQGGkARAKAKT 9606 29207681 YES miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation 0.2 SIGNOR-263863 PLK1 protein P53350 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates quantity by destabilization phosphorylation Ser170 KTCRYIPsLPDRILD -1 23643811 YES miannu Plk1 directly bound to Cdc20 and phosphorylates it on serine-170 located in CRY-box. Whereas wild-type Cdc20 was degraded according to progress cell cycle beyond mitosis, the phosphorylation-defective mutant, which serine-170 was changed into alanine, was not destroyed in early G1 phase.  0.977 SIGNOR-276493 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000590 10090741 YES lperfetto We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. 0.595 SIGNOR-249314 DPF2 protein Q92785 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 24332853 NO miannu Here, DPF2 appears to be another important regulator of myeloid differentiation that can cooperate with PRMT4 to maintain the “stemness” of HSPCs. 0.7 SIGNOR-261969 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203536 DRD5 protein P21918 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.5 SIGNOR-257369 MAP2K4 protein P45985 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation 9606 10527909 YES miannu SEK1 phosphorylates and activates both p38 and c-Jun NH(2)-terminal kinase (JNK), whereas MKK3 and MKK6 selectively phosphorylate and activate p38. 0.538 SIGNOR-279063 EXOC3 protein O60645 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.959 SIGNOR-270786 CDK1 protein P06493 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Thr88 QQQPTPVtPKKYPLR 9606 18250300 YES lperfetto Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate. 0.355 SIGNOR-160747 AKT proteinfamily SIGNOR-PF24 SIGNOR GRIN2C protein Q14957 UNIPROT up-regulates activity phosphorylation Ser1081 GSRPRHAsLPSSVAE 10090 BTO:0004278 19477150 YES miannu Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells. 0.2 SIGNOR-262620 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Arg41-Ser42 activation site 0.582 SIGNOR-263561 CDK2 protein P24941 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Thr40 DAESYTFtVPRRHLE 23972993 YES For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP 0.43 SIGNOR-274050 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120232 PLK1 protein P53350 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser286 KFIMGDSsVQDQWKE 9606 BTO:0000567 phosphorylation:Ser386 LRGAQAAsPAKGEPS 23348582 YES lperfetto Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. 0.354 SIGNOR-272990 ELAVL2 protein Q12926 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 YES miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure 0.2 SIGNOR-266863 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4D protein Q08499 UNIPROT up-regulates activity phosphorylation Ser125 CRAMDRTsYAVETGH 9534 12023945 YES miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. 0.2 SIGNOR-275988 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 YES gcesareni In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain (band 4.1 and ezrin/radixin/moesin homology domain). 0.496 SIGNOR-167654 serotonin smallmolecule CHEBI:28790 ChEBI HTR3A protein P46098 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264282 RXRA protein P19793 UNIPROT THRB protein P10828 UNIPROT up-regulates binding 9606 10976919 YES gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr 0.721 SIGNOR-81449 LIMS3 protein P0CW19 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 YES lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. 0.563 SIGNOR-265765 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFKP protein Q01813 UNIPROT up-regulates activity binding 9606 19454274 YES The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux 0.8 SIGNOR-267268 CHM protein P24386 UNIPROT RABGGTB protein P53611 UNIPROT down-regulates activity binding 9606 18532927 YES miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. 0.767 SIGNOR-265571 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI up-regulates quantity precursor of 9606 33179964 YES miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. 0.8 SIGNOR-267324 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 YES lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. 0.678 SIGNOR-109559 SPRY4 protein Q9C004 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity 9606 BTO:0002058 20501643 NO miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. 0.267 SIGNOR-253037 SPI1 protein P17947 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 25092144 NO miannu We showed a strong induction of miR-155 promoter activity by p65. We demonstrate that NF-κB (p65) directly binds to the miR-155 promoter in FLT3-ITD-associated MV4;11 cells. 0.4 SIGNOR-255816 CHEK1 protein O14757 UNIPROT RASSF1 protein Q9NS23 UNIPROT unknown phosphorylation Ser188 PSSKKPPsLQDARRG 9606 24197116 YES llicata This study reveals that chk1-mediated phosphorylation of rassf1a, at serine 184, plays an important role in cell-cycle regulation 0.352 SIGNOR-203144 RAP1GAP protein P47736 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity binding 9606 BTO:0001949 22173489 YES Marta Tosoni Overexpression of Rap1GAP significantly inhibited Rap1 activation, ERK and Akt phosphorylation of HUVECs compared with pcDNA transfection controls 0.329 SIGNOR-278055 PCDH19 protein Q8TAB3 UNIPROT GABRA1 protein P14867 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C330 29360992 YES miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  0.364 SIGNOR-267217 PTPRJ protein Q12913 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates dephosphorylation 9606 18348712 YES gcesareni As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors. 0.262 SIGNOR-252727 BRMS1 protein Q9HCU9 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding 9606 BTO:0000093 30416854 YES miannu Our results have showed that BRMS1 together with LSD1 are required for inhibition of breast cancer cell migration and invasion. Collectively, these findings demonstrate that BRMS1 executes transcriptional suppression of breast cancer metastasis by associating with the LSD1 and thus can be targeted for breast cancer therapy. 0.257 SIGNOR-266409 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257966 EGFR protein P00533 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 YES llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. 0.594 SIGNOR-167646 GSK3A protein P49840 UNIPROT GSK3A protein P49840 UNIPROT up-regulates phosphorylation Tyr279 RGEPNVSyICSRYYR 9606 BTO:0000527 18701488 YES gcesareni Gsk3a is activated by phosphorylation at tyr-279. 0.2 SIGNOR-180035 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR AURKA protein O14965 UNIPROT up-regulates activity monoubiquitination 9606 BTO:0001938 23213400 YES miannu We identify Aurora-A as a KLHL18-interacting partner. Overexpression of KLHL18 and CUL3 promotes Aurora-A ubiquitylation in vivo, and the CUL3-KLHL18-ROC1 ligase ubiquitylates Aurora-A in vitro. Our study reveals that the CUL3-KLHL18 ligase is required for timely entry into mitosis, as well as for the activation of Aurora-A at centrosomes. 0.431 SIGNOR-272023 PRKAA1 protein Q13131 UNIPROT TGFB1 protein P01137 UNIPROT down-regulates 9606 BTO:0000887 23324179 NO gcesareni Amp-activated protein kinase inhibits tgf-__-, angiotensin ii-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition. 0.2 SIGNOR-200404 NR3C1 protein P04150 UNIPROT RXRA protein P19793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12573484 NO gcesareni Physiological concentrations of glucocorticoids increase cellular cyp2c9 (and cyp3a5) but also car, rxr and pxr levels via a gr-mediated mechanism 0.462 SIGNOR-98102 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT up-regulates activity binding 9606 BTO:0000459 18621737 YES lperfetto Through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2. 0.872 SIGNOR-179449 ADORA1 protein P30542 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.46 SIGNOR-256840 PRKG1 protein Q13976 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates activity phosphorylation Ser101 RRRRGAIsAEVYTEE 9606 BTO:0002181 29378851 YES miannu  In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells.These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells. 0.234 SIGNOR-277383 INSR protein P06213 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr576 RYMEDSTyYKASKGK -1 9507031 YES P125(Fak) sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor. p125(Fak) phosphorylation by the receptor results in its activation. 0.354 SIGNOR-251323 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 10191262 YES miannu The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp 0.649 SIGNOR-250274 FLNA protein P21333 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity by stabilization binding 9606 11706047 YES lperfetto We conclude that FLNa is essential in cells that express it for stabilizing orthogonal actin networks suitable for locomotion.  0.7 SIGNOR-261851 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10949026 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. 0.427 SIGNOR-81145 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates activity dephosphorylation Ser671 RKRSTRRsVRGSQAQ 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.2 SIGNOR-272507 LIMK2 protein P53671 UNIPROT SPOP protein O43791 UNIPROT down-regulates activity phosphorylation Ser226 AARSPVFsAMFEHEM 9606 33311589 YES miannu LIMK2 phosphorylates SPOP at S59, S171 and S226.|Together, these results depict that LIMK2-mediated SPOP degradation is a key mechanism that regulates AR stability. 0.2 SIGNOR-278338 MAPK14 protein Q16539 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates quantity by destabilization phosphorylation Thr367 NNSSRPStPTINVLE 10090 BTO:0000165 28067271 YES Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372 0.372 SIGNOR-255663 lenalidomide chemical CHEBI:63791 ChEBI IKZF1 protein Q13422 UNIPROT down-regulates quantity by destabilization chemical inhibition 9606 24328678 YES gcesareni Members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3 respectively), are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment. 0.8 SIGNOR-236910 HLX protein Q14774 UNIPROT ELK1 protein P19419 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003980 20008130 YES Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. 0.2 SIGNOR-261622 CDK2 protein P24941 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 YES gcesareni Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity 0.378 SIGNOR-92265 TRIM26 protein Q12899 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25763818 YES miannu TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.  0.671 SIGNOR-272440 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9973379 YES CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.¬† Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. 0.77 SIGNOR-251161 MSC protein O60682 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 9606 BTO:0000776 9584154 YES 2 miannu ABF-1 contains a transcriptional repression domain and is capable of inhibiting the transactivation capability of E47 in mammalian cells. 0.464 SIGNOR-241315 CBL protein P22681 UNIPROT LCK protein P06239 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11904433 YES miannu Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain. 0.71 SIGNOR-272614 DOK7 protein Q18PE1 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 23467009 YES gcesareni In addition, dok7, a cytoplasmic adaptor protein, is also required for musk activation in vivo. This review focuses on the physical interplay between these proteins and musk for activation and downstream signaling, which culminates in nmj formation. 0.723 SIGNOR-192264 CALM3 protein P0DP25 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates binding 9606 11796223 YES miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. 0.489 SIGNOR-266347 PPP3CA protein Q08209 UNIPROT FLNA protein P21333 UNIPROT down-regulates dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 YES gcesareni We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells 0.26 SIGNOR-143979 NHLRC1 protein Q6VVB1 UNIPROT EPM2A protein O95278 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 15930137 YES miannu Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation.  0.786 SIGNOR-271547 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Ser229 VKIYSSNsGPTRRED 9606 BTO:0000672 15793569 YES llicata In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues. 0.655 SIGNOR-134851 NME1 protein P15531 UNIPROT SMO protein Q99835 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 NO miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 0.2 SIGNOR-255168 MAP3K7 protein O43318 UNIPROT NLK protein Q9UBE8 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12482967 YES gcesareni The tak1-nlk-mapk-related pathway antagonizes signalling between beta-catenin and transcription factor tcf. 0.65 SIGNOR-96425 RHEB protein Q15382 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity binding 9606 BTO:0000007 20006481 YES lperfetto Rheb stimulates the phosphorylation of mtor and plays an essential role in regulation of s6k and 4ebp1 in response to nutrients and cellular energy status. 0.95 SIGNOR-162006 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR SMYD2 protein Q9NRG4 UNIPROT up-regulates activity methylation 9606 BTO:0001911 28370702 YES irozzo In the present study, we have shown that SMYD2‐mediated methylation of lysine 1610 on the EML4‐ALK fusion protein is likely to be critically important for autophosphorylation of some tyrosine residues and the oncogenic activity of the fused proteins. 0.2 SIGNOR-259175 MUSK protein O15146 UNIPROT MUSK protein O15146 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000887 23458718 YES miannu AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer. 0.2 SIGNOR-273851 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser1073 PPLQRGKsQQLTVSA -1 14970204 YES miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII 0.43 SIGNOR-262687 F2R protein P25116 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.437 SIGNOR-257293 GRK6 protein P43250 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity phosphorylation 9606 15650023 YES miannu Overexpression of GRK6 Inhibits Agonist-Induced cAMP Production in HBL Human Melanoma Cells, without Affecting MC1R Gene Expression 0.314 SIGNOR-252389 STAT6 protein P42226 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22025054 NO lperfetto IL-4R signals through a JAKSTAT6 pathway, and many of the genes associated with mouse M2 macrophages are regulated by STAT6, including arginase 1 (Arg1), macrophage mannose receptor 1 (Mrc1; also known as Cd206), resistin-like-? (Retnla; also known as Fizz1) and chitinase 3-like 3 (Chi3l3; also known as Ym1). 0.7 SIGNOR-249541 PKA proteinfamily SIGNOR-PF17 SIGNOR TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 31057087 YES inferred from 70% family members miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 0.2 SIGNOR-270130 Ub:E2 complex SIGNOR-C497 SIGNOR RNF157 protein Q96PX1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270959 VPS39 protein Q96JC1 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR down-regulates quantity binding 9534 12941698 YES miannu Overexpression of TLP blocks TGF-β-induced formation of Smad3/4 complexes while it does not alter Smad2/4 complex levels. 0.315 SIGNOR-261378 PTEN protein P60484 UNIPROT CFL1 protein P23528 UNIPROT up-regulates activity dephosphorylation 9606 22317922 YES lperfetto Unexpectedly, cofilin-1 activation by PGE 2 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated.|Unexpectedly, cofilin-1 dephosphorylation and activation in our model was mediated by the protein phosphatase activity of PTEN. 0.442 SIGNOR-276980 LEO1 protein Q8WVC0 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 YES miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  0.939 SIGNOR-269832 SOSTDC1 protein Q6X4U4 UNIPROT WNT11 protein O96014 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.276 SIGNOR-242721 TRIM33 protein Q9UPN9 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 BTO:0000574;BTO:0002625;BTO:0000414 16751102 YES lperfetto The ubiquitious nuclear protein transcriptional intermediary factor 1gamma (tif1gamma) selectively binds receptor-phosphorylated smad2/3 in competition with smad4. Rapid and robust binding of tif1gamma to smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to tgfbeta. Tif1gamma mediates the differentiation response while smad4 mediates the antiproliferative response with smad2/3 participating in both responses. 0.584 SIGNOR-236060 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser262 TFRPRSSsNASSVST 10090 10217147 YES Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. 0.91 SIGNOR-252862 EIF2AK1 protein Q9BQI3 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19946423 NO Regulation of expression miannu Translation of α- and β-globin is tightly controlled by eIF2 and downregulated by HRI. 0.2 SIGNOR-251780 ERO1B protein Q86YB8 UNIPROT ERP44 protein Q9BS26 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 11847130 YES Simone Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits. 0.2 SIGNOR-261048 ERG protein P11308 UNIPROT WNT3A protein P56704 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001321 23913826 YES Luana Interestingly, our data showed that ERG drastically induced Wnt ligand gene expression. 0.2 SIGNOR-261598 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273106 SRCAP protein Q6ZRS2 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 20432434 YES miannu The SNF2-related CBP activator protein (SRCAP) serves as a coactivator for several nuclear receptors including the androgen receptor (AR). SRCAP is an ATPase that is the core subunit of a large multiprotein complex and was shown to incorporate the histone variant H2A.Z into nucleosomes. In this report, we demonstrate that SRCAP is expressed in the epithelium of normal prostate and in prostate carcinoma cells, and is associated with AR in the nucleus 0.411 SIGNOR-255221 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257974 CFAP53 protein Q96M91 UNIPROT DNAH5 protein Q8TE73 UNIPROT up-regulates activity binding 10090 BTO:0000379 33347437 YES miannu CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). 0.2 SIGNOR-265544 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu54 YNSGKLEeFVQGNLE 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263687 KLHL15 protein Q96M94 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 23135275 YES miannu Here, we report that KLHL15-Cul3 specifically targets B'β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B'β. 0.46 SIGNOR-272018 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 9606 BTO:0000150 BTO:0001129 20606012 YES gcesareni Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. 0.474 SIGNOR-166510 MAPK1 protein P28482 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 YES gcesareni In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e. 0.496 SIGNOR-94003 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 20978344 YES inferred from family member miannu The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4) 0.8 SIGNOR-267809 XIAP protein P98170 UNIPROT OGT protein O15294 UNIPROT down-regulates quantity ubiquitination 9606 32994395 YES miannu These results demonstrate that XIAP acts as an E3 ubiquitin ligase and ubiquitinates OGT in HCT116 colon cancer cells.|XIAP promotes the ubiquitin-dependent proteasomal degradation of OGT. 0.2 SIGNOR-278800 CAMK2G protein Q13555 UNIPROT FLNA protein P21333 UNIPROT unknown phosphorylation Ser2523 VTGPRLVsNHSLHET BTO:0001141 11290523 YES llicata Our TER experiments using a CaM peptide, which functions as a specific competitive inhibitor of nonmuscle filamin phosphorylation by CaM kinase II, strongly suggest that filamin phosphorylation is involved in endothelial cell barrier regulation, although the exact mechanism is not clear and consequent signaling events are not well understood.  0.429 SIGNOR-250696 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT up-regulates activity phosphorylation Thr134 KKVRKPRtIYSSYQL -1 11343707 YES lperfetto Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3. 0.307 SIGNOR-249097 MAPK3 protein P27361 UNIPROT ASB2 protein Q96Q27 UNIPROT up-regulates activity phosphorylation Ser371 RIRRSGVsPLHLAAE 24044920 YES lperfetto Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. |Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation. 0.265 SIGNOR-272241 PRKACA protein P17612 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation Ser173 DGEFLRTsCGSPNYA 9606 19942859 YES gcesareni Pka associates with and phosphorylates ampk?1 At ser-173 to impede threonine thr-172 phosphorylation and thus activation of ampk1 by lkb1 in response to lipolytic signals 0.419 SIGNOR-161860 C3AR1 protein Q16581 UNIPROT Vascular_Permeability phenotype SIGNOR-PH140 SIGNOR up-regulates 10984054 NO lperfetto The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability 0.7 SIGNOR-263458 STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 18177723 NO andrea cerquone perpetuini We identified cyclin D1 as a STAT3 target gene product downregulated in satellite cells from IL-6-deficient muscle in vitro and in vivo. 0.787 SIGNOR-255411 ATF4 protein P18848 UNIPROT FGF19 protein O95750 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 23205607 YES lperfetto Reporter gene analyses using the 5'-promoter region of FGF19 revealed that a functional AARE (amino-acid-response element) was localized in this region, and this site was responsible for inducing its transcription through ATF4 (activating transcription factor 4), which is activated in response to ER stress 0.2 SIGNOR-253727 PTPRG protein P23470 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity dephosphorylation Tyr783 DTGENPIyKSAVTTV -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.265 SIGNOR-254706 HMGB2 protein P26583 UNIPROT POU3F1 protein Q03052 UNIPROT up-regulates activity binding 10090 BTO:0002910 7720710 YES 2 miannu HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins 0.307 SIGNOR-240148 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT up-regulates ubiquitination 9606 BTO:0000938 BTO:0000142 16862145 YES gcesareni Treatment of cells with egf stimulates parkin binding to both eps15 and the egfr and promotes parkin-mediated ubiquitination of eps15 0.2 SIGNOR-148218 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.473 SIGNOR-270891 CSNK2A2 protein P19784 UNIPROT KIF1C protein O43896 UNIPROT unknown phosphorylation Ser1092 PRMRRQRsAPDLKES -1 10559254 YES llicata Serine 1092 was a substrate for the protein kinase casein kinase II in vitro, and inhibition of casein kinase II in cells diminished the association of KIF1C with 14-3-3gamma. Our data thus suggest that KIF1C can form dimers and is associated with proteins of the 14-3-3 family. 0.31 SIGNOR-251010 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 20708156 YES gcesareni Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination 0.346 SIGNOR-167513 KAT2A protein Q92830 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 BTO:0000150 SIGNOR-C7 15009097 YES gcesareni Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo. 0.525 SIGNOR-123318 TRIM32 protein Q13049 UNIPROT PBRM1 protein Q86U86 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26057645 YES miannu TRIM32 ubiquitination of PB1 leads to its protein degradation. 0.2 SIGNOR-278735 CSNK2A2 protein P19784 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Ser484 RSRAIHSsDEGEDQA 9606 BTO:0001412 12769847 YES llicata We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.  0.348 SIGNOR-251049 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe635 HHQKLVFfAEDVGSN 9606 10931940 YES lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Aβ is produced from the Aβ precursor protein (APP) by two proteolytic events. A β-secretase activity cleaves APP at the N terminus of Aβ (β site) between amino acids Met-671 and Asp-672 |We show here that BACE2 cleaves APP at its β site and more efficiently at sites within the Aβ region of APP, after Phe-19 and Phe-20 of Aβ. 0.545 SIGNOR-261775 POGLUT1 protein Q8NBL1 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 22872643 YES gcesareni O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. O-glucose can be elongated by xylose to the trisaccharide, xylalfa1-3xylalfa1-3glcbeta1-o-ser, whose synthesis is catalyzed by the consecutive action of three glycosyltransferases. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus. 0.574 SIGNOR-198716 NEDD4 protein P46934 UNIPROT SYK protein P43405 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 11046148 YES miannu The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is implicated in the maintenance of viral latency and appears to function in part by inhibiting B-cell receptor (BCR) signaling. LMP2A enhances Lyn and Syk ubiquitination in vivo in a fashion that depends on the activity of Nedd4 family members and correlates with destabilization of the Lyn tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin ligases.  0.291 SIGNOR-272581 MBOAT7 protein Q96N66 UNIPROT 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 ChEBI up-regulates quantity chemical modification -1 18772128 YES miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. 0.8 SIGNOR-267248 CBLB protein Q13191 UNIPROT SYK protein P43405 UNIPROT down-regulates quantity ubiquitination 9606 12771181 YES miannu In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling. 0.695 SIGNOR-278754 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000007 23287467 YES miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. 0.852 SIGNOR-272897 RPS6KB2 protein Q9UBS0 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 YES lperfetto In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway 0.2 SIGNOR-178594 CCNC protein P24863 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 YES miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. 0.922 SIGNOR-266685 TRIO protein O75962 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.691 SIGNOR-260579 TLK1 protein Q9UKI8 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Ser160 NLLFKDNsLDAPVKL 9606 BTO:0000007 35064619 YES miannu We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. 0.2 SIGNOR-276745 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 20305697 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-164629 BCL9 protein O00512 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 15208637 YES amattioni The transcriptional activity of beta-catenin depends on bcl-9. Bcl-9 functions in targeting beta-catenin to the nucleus and thus increases the transcriptional activity of beta-catenin 0.938 SIGNOR-126059 MAPK3 protein P27361 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 YES lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity 0.716 SIGNOR-203480 CUL1 protein Q13616 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 SIGNOR-C5 10023660 YES lperfetto These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin. 0.597 SIGNOR-64499 LCK protein P06239 UNIPROT EZR protein P15311 UNIPROT unknown phosphorylation Tyr146 KEVHKSGyLSSERLI -1 12560083 YES Lck phosphorylated ezrin in vitro, and the major phosphotyrosine was identified as Y145. Whether tyrosine phosphorylation of ezrin is an alternative mechanism to regulate dynamic changes of the actin cytoskeleton, as has been suggested in EGF-, PDGF- or HGF-treated epithelial cells, is still unclear. Alternatively, Lck-induced tyrosine phosphorylation of ezrin may be linked to its other functions, including participation in signaling pathways that control proliferation and apoptosis 0.506 SIGNOR-251374 PDX1 protein P52945 UNIPROT SLC2A2 protein P11168 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11309388 YES In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. 0.523 SIGNOR-255540 UBE2I protein P63279 UNIPROT JUN protein P05412 UNIPROT down-regulates activity sumoylation Lys254 MESQERIkAERKRMR 9606 SIGNOR-C154 16055711 YES lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 0.421 SIGNOR-263001 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity binding 9534 BTO:0000298 11278251 YES miannu Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.  0.882 SIGNOR-272942 ACE protein P12821 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage 9606 11076943 YES gcesareni Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide. 0.782 SIGNOR-253326 CSNK2A1 protein P68400 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1126 TEEFSSEsDMEESKE 9606 BTO:0000938 19064667 YES lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. 0.2 SIGNOR-275761 AKT3 protein Q9Y243 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 23603119 YES lperfetto Phosphorylation of argonaute 2 at serine-387 facilitates its localization to processing bodies. , akt3-mediated phosphorylation of ago2 is a molecular switch between target mrna cleavage and translational repression activities of ago2 0.423 SIGNOR-201918 CDC14B protein O60729 UNIPROT CDCA3 protein Q99618 UNIPROT up-regulates dephosphorylation 9606 18662541 YES gcesareni The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1 0.282 SIGNOR-179664 BMP15 protein O95972 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 BTO:0000975 SIGNOR-C29 16446785 YES gcesareni Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle. 0.537 SIGNOR-144098 IRF2BP1 protein Q8IU81 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 BTO:0000567 12799427 YES miannu We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation. 0.693 SIGNOR-224045 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Gly) smallmolecule CHEBI:29176 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269487 COPS2 protein P61201 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.924 SIGNOR-270766 RPS6KA3 protein P51812 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 15867353 YES miannu Here we show that ribosomal S6 kinase 2 (RSK2) activates and phosphorylates p53 (Ser15) in vitro and in vivo and colocalizes with p53 in the nucleus. 0.336 SIGNOR-279567 2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide chemical CHEBI:91331 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191103 PTGDR protein Q13258 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256898 OXGR1 protein Q96P68 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257243 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 YES inferred from 70% family members gcesareni Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells. 0.2 SIGNOR-270037 APC2 protein O95996 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 9601641 YES lperfetto Human axin (haxin) binds directly to beta-catenin, gsk3 beta, and apc in vitro, and the endogenous proteins are found in a complex in cells. 0.589 SIGNOR-227945 FBXL2 protein Q9UKC9 UNIPROT AURKB protein Q96GD4 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002268 23370391 YES miannu The SCF complex contains a catalytic core consisting of Skp1, Cullin1, and the E2 ubiquitin-conjugating (Ubc) enzyme and a F box component that acts as a receptor targeting numerous substrates via phosphodegron elicited interactions. our screening studies suggested that FBXL2 also targets Aurora B protein for ubiquitination and degradation. 0.484 SIGNOR-272097 CAMK2G protein Q13555 UNIPROT GRIA1 protein P42261 UNIPROT up-regulates activity phosphorylation Ser849 FCLIPQQsINEAIRT 12609872 YES llicata Direct phosphorylation of the GluR1 subunit of postsynaptic AMPA receptors by Ca(2+)/calmodulin-dependent protein kinase II (CaM-KII) is believed to be one of the major contributors to the enhanced strength of glutamatergic synapses in CA1 area of hippocampus during long-term potentiation. | Validity of the approach was confirmed by modeling, and silence analysis was applied then to the GluR1 AMPA receptor mutated at S831, the site phosphorylated by CaM-KII during long-term potentiation. Silence analysis indicates that a negative charge at S831 is a critical determinant for the enhanced channel function as a charge carrier. Silence and variance analyses, when applied to the same sets of data, were in agreement on the receptor regulation upon mutations. 0.629 SIGNOR-250698 A9/b1 integrin complex SIGNOR-C166 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression 9606 24241034 NO lperfetto Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages. 0.356 SIGNOR-253313 MARK2 protein Q7KZI7 UNIPROT PINK1 protein Q9BXM7 UNIPROT up-regulates activity phosphorylation 9606 22238344 YES miannu MARK2 phosphorylated and activated the cleaved form of PINK1 (DeltaN-PINK1 0.367 SIGNOR-278975 SRC protein P12931 UNIPROT MMP14 protein P50281 UNIPROT unknown phosphorylation Tyr573 GTPRRLLyCQRSLLD 9606 17389600 YES llicata We show that mt1-mmp is phosphorylated on the unique tyrosine residue located within this cytoplasmic sequence (tyr(573)) and that this phosphorylation requires the kinase src. accordingly, overexpression of a nonphosphorylable mt1-mmp mutant (y573f) blocked sphingosine-1-phosphate-induced migration of human umbilical vein endothelial cells and ht-1080 (human fibrosarcoma) cells and failed to stimulate migration of cells lacking the enzyme (bovine aortic endothelial cells). 0.436 SIGNOR-154006 PKA proteinfamily SIGNOR-PF17 SIGNOR SLC2A2 protein P11168 UNIPROT down-regulates activity phosphorylation Ser491 VPETKGKsFEEIAAE 9534 8626492 YES miannu GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity. 0.2 SIGNOR-250049 RPS6KB1 protein P23443 UNIPROT PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 YES gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. 0.612 SIGNOR-160989 ETS1 protein P14921 UNIPROT TBXAS1 protein P24557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14586398 NO miannu We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. 0.2 SIGNOR-254088 HMGB1 protein P09429 UNIPROT HOXD10 protein P28358 UNIPROT up-regulates activity binding -1 8890171 YES 2 miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. 0.293 SIGNOR-240556 TNF protein P01375 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 9606 16813528 NO lperfetto These observations suggest that tnf-alpha activates p38 map kinase during the inflammatory response at the injured growth plate, and tnf-alpha-p38 signaling seems to be required for marrow mesenchymal cell proliferation and migration at the growth plate injury site and in cell culture. 0.642 SIGNOR-147369 ADIPOR2 protein Q86V24 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 16622416 YES milica Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin. 0.74 SIGNOR-146215 ANXA3 protein P12429 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9606 26095609 NO miannu ANXA3 Induces a Feed-Forward Loop that Is Mediated by the MKK4/JNK Signaling Cascade. To substantiate the importance of the JNK/AP-1 pathway in ANXA3-driven HCC, we performed rescue experiments using the JNK-specific inhibitor (JNKi) SP600125. JNKi suppressed the oncogenic properties conferred by ANXA3 overexpression, as evidenced by the diminished abilities of HCC cells to form colonies, migrate, invade, induce angiogenesis, form hepatospheres, and resist apoptosis and chemotherapy (Figures 6F–6J). Interestingly, treatment of parental HCC cells or HCC cells overexpressing ANXA3 with JNKi resulted in not only a reduction in JNK activity and modulation of downstream target genes (c-MYC and p21) but also a marked decrease in ANXA3 expression, suggesting that ANXA3 induces a feed-forward loop that is mediated by MKK4/JNK signaling (Figures 6K–6L). 0.277 SIGNOR-262214 SUPT20H protein Q8NEM7 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.748 SIGNOR-269575 GSK3B protein P49841 UNIPROT ROR2 protein Q01974 UNIPROT down-regulates activity phosphorylation Ser864 PKPSSHHsGSGSTST 9606 SIGNOR-C110 21078818 YES gcesareni We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a. 0.313 SIGNOR-169642 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.91 SIGNOR-252850 PK proteinfamily SIGNOR-PF80 SIGNOR HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates activity binding 9606 BTO:0000567 21620138 YES PKM2 interacts directly with the HIF-1Œ± subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, 0.389 SIGNOR-268150 BMPR1A protein P36894 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 10090 10712517 YES gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors 0.63 SIGNOR-75652 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 YES lperfetto AMPK inhibits mTORC1 through two means: first, through phosphorylation of TSC2 to activate its GAP (GTPase-activating protein) activity that converts Rheb into an inactive GDP-bound state, thus switching off mitogenic stimulation of mTORC1 [31], and, secondly, through phosphorylation of raptor at Ser722 and Ser792, which leads to 14-3-3 protein binding and mTORC1 inhibition 0.467 SIGNOR-209862 SLC36A1 protein Q7Z2H8 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity relocalization 9606 12748860 YES lperfetto Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut. 0.8 SIGNOR-264741 ACACA protein Q13085 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 20952656 YES miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA 0.8 SIGNOR-267105 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 14699505 YES gcesareni Pias1 inhibits binding of stat1 dimers to the response elements in the promoters of target genes 0.794 SIGNOR-120548 MACC1 protein Q6ZN28 UNIPROT MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000038 19098908 YES Luana Human colon carcinoma SW480 cells express virtually no MACC1. MACC1 cDNA transfection led not only to strong increases in MACC1 mRNA expression (Fig. 3a), but also to a 40-fold upregulation of the HGF receptor MET mRNA expression (Fig. 3b). This was confirmed on the protein level 0.394 SIGNOR-266058 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr806 NQMAKGTtEEMKYVL 9606 18680479 YES miannu We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / t806d mps1 was significantly less active than t806a, demonstrating a potential negative correlation between phosphorylation and activity at this site. 0.2 SIGNOR-179908 RNF185 protein Q96GF1 UNIPROT BNIP1 protein Q12981 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931693 YES miannu RNF185 functions as a ubiquitin E3 ligase, enabling BNIP1-p62 interaction. Here we show that human RNF185 is a mitochondrial ubiquitin E3 ligase that regulates selective mitochondrial autophagy in cultured cells.  Human BNIP1 colocalizes with RNF185 at mitochondria and is polyubiquitinated by RNF185 through K63-based ubiquitin linkage in vivo. The polyubiquitinated BNIP1 is capable of recruiting autophagy receptor p62, which simultaneously binds both ubiquitin and LC3 to link ubiquitination and autophagy. RNF185 interacts with BNIP1 and ATG5 0.534 SIGNOR-271931 CREB1 protein P16220 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000158 15955695 NO miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. 0.418 SIGNOR-253798 IL13 protein P35225 UNIPROT IL13RA1 protein P78552 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 YES milica It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1. 0.852 SIGNOR-100750 PTPN12 protein Q05209 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 19350555 YES miannu PTP-PEST increases dephosphorylation of Src at Y527 and activates it.|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src). 0.541 SIGNOR-277086 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263774 MAPK3 protein P27361 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation Ser189; Ser283 SGILGITsPSADTNK;DMKANLAsPTPADIG 9606 BTO:0003079 22593617 YES Gianni In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5. 0.247 SIGNOR-269086 PRKACA protein P17612 UNIPROT APOBEC3G protein Q9HC16 UNIPROT up-regulates phosphorylation Thr32 PILSRRNtVWLCYEV 9606 18836454 YES llicata Here we show that pka binds and specifically phosphorylates a3g at thr32 in vitro and in vivo. This phosphorylation event reduces the binding of a3g to vif and its subsequent ubiquitination and degradation, and thus promotes a3g antiviral activity. 0.325 SIGNOR-181526 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000527 21419810 YES lperfetto In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer 0.32 SIGNOR-172890 FRK protein P42685 UNIPROT PTEN protein P60484 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr336 NKDKANRyFSPNFKV 9606 BTO:0000093 19345329 YES miannu Rak phosphorylates PTEN on Tyr 336 to prevent its protein degradation. In this study, we demonstrate that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr336. Knockdown of Rak enhanced the binding of PTEN to its E3 ligase NEDD4-1 and promoted PTEN polyubiquitination, leading to PTEN protein degradation.  0.597 SIGNOR-275458 NR3C1 protein P04150 UNIPROT KLF9 protein Q13886 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 YES We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα 0.322 SIGNOR-256119 SPOP protein O43791 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates binding 9606 BTO:0000007 28448495 YES miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 0.661 SIGNOR-272799 TFEB protein P19484 UNIPROT GALNS protein P34059 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.289 SIGNOR-276538 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 YES miannu Taken together, these data show that of the NRs studied, PPARα is the most likely target of PFOA and PFOS, although PPARγ is also activated to some extent. 0.8 SIGNOR-268787 C5AR1 protein P21730 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 NO lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. 0.7 SIGNOR-263460 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM ITK protein Q08881 UNIPROT down-regulates activity chemical inhibition -1 24556163 YES miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine 0.8 SIGNOR-262236 RORB protein Q92753 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18418469 YES miannu RORβ and RORγ are also able to induce Bmal1 activity; however, RORα4 appears the most effective in inducing this activity. The ROREs in the Bmal1 promoter also bind ROR receptors. Overexpression of RORα1 and RORα4 induces Bmal1-promoter activity by interacting with these ROREs 0.478 SIGNOR-266852 CSNK2A1 protein P68400 UNIPROT PKD2 protein Q13563 UNIPROT up-regulates phosphorylation Ser812 FPRSLDDsEEDDDED 9606 14742446 YES gcesareni Ser(812) can be phosphorylated by ck2 in vitro and substitution s812a results in failure to incorporate phosphate in cultured epithelial cells. 0.421 SIGNOR-121572 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser126 EESESEDsEDSGGEE 9606 16308564 YES lperfetto Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. 0.2 SIGNOR-142351 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified. 0.8 SIGNOR-266463 NOG protein Q13253 UNIPROT BMP4 protein P12644 UNIPROT down-regulates binding 9606 12700180 YES lperfetto Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides 0.814 SIGNOR-100660 NFE2L3 protein Q9Y4A8 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by repression transcriptional regulation 15385560 NO lperfetto Nrf3 negatively regulates antioxidant-response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. 0.338 SIGNOR-268975 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.493 SIGNOR-248610 KDM6A protein O15550 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.324 SIGNOR-260025 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 YES lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. 0.819 SIGNOR-133820 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser713 GAEIVYKsPVVSGDT 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.738 SIGNOR-249345 GEMIN6 protein Q8WXD5 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 YES lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. 0.833 SIGNOR-253120 PRKCA protein P17252 UNIPROT TBXA2R protein P21731-2 UNIPROT down-regulates activity phosphorylation Ser145 FSRPAVAsQRRAWAT 9606 16956790 YES done miannu  These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization. 0.52 SIGNOR-274092 FERMT1 protein Q9BQL6 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 YES miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 0.449 SIGNOR-266103 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1437 RYPDSYEsMSEPPIA -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262907 Ub:E2 complex SIGNOR-C497 SIGNOR RFPL1 protein O75677 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271147 JAK1 protein P23458 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR form complex binding 10090 15284024 YES lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. 0.2 SIGNOR-235608 GDNF protein P39905 UNIPROT CLU protein P10909 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.261 SIGNOR-252187 H3-3A protein P84243 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 YES miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. 0.2 SIGNOR-263876 NCS1 protein P62166 UNIPROT GRK2 protein P25098 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000938 12351722 YES miannu Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization. 0.2 SIGNOR-263965 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Ser2093 GPNRSFLsLKHTPMG 9606 BTO:0000007 12794074 YES Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes. 0.482 SIGNOR-251253 AP 23573 chemical CHEBI:79700 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 BTO:0000887 20554235 YES gcesareni Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mtor inhibitors. 0.8 SIGNOR-166186 VRK2 protein Q86Y07 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR up-regulates activity binding 9606 BTO:0000007 24298020 YES miannu Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme 0.326 SIGNOR-272874 MDH2 protein P40926 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI down-regulates quantity chemical modification 9606 24068518 YES miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle 0.8 SIGNOR-266284 6-(3,4-Dimethoxyphenyl)-3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole chemical CID:661498 PUBCHEM DCTPP1 protein Q9H773 UNIPROT down-regulates activity chemical inhibition 9606 28145708 YES Federica Here we report on thediscovery of a series of 3,6-disubstituted triazolothiadiazolesas potent dCTPase inhibitors. 0.8 SIGNOR-261113 CBX1 protein P83916 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-264493 PRKACA protein P17612 UNIPROT CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser39 TPKRRRAsSLSRDAE 27149373 YES lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. 0.253 SIGNOR-275630 STK3 protein Q13188 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity phosphorylation Thr622 KEGGVTFtWVEKDIS -1 35722967 YES miannu Hippo pathway component MST2 kinase phosphorylates STAT3 at T622, which is located in the SH2 domain of STAT3. This phosphorylation blocks the SH2 domain in one STAT3 molecule to bind with the phosphorylated Y705 site in another STAT3 molecule, which further counteracts IL6-induced STAT3 dimerization and activation. 0.2 SIGNOR-277599 HECTD3 protein Q5T447 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000007 23358872 YES miannu HECTD3 promotes MALT1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it.  0.367 SIGNOR-272096 AGTR1 protein P30556 UNIPROT GNA11 protein P29992 UNIPROT up-regulates activity binding 9606 BTO:0000007 20181817 YES The angiotensin II type 1 receptor (AT1 R) is a G q/11-coupled G protein-coupled receptor that is widely expressed in multiple tissues, including vascular smooth muscle cells, brain, and kidney. 0.51 SIGNOR-278125 tamoxifen citrate chemical CHEBI:9397 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000150 20512796 YES miannu Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. 0.8 SIGNOR-259301 FBXL5 protein Q9UKA1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding -1 24157836 YES miannu FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. To demonstrate that FBXL5 has a direct activity on Snail1, we carried out polyubiquitination reactions in vitro. For this we purified Snail1 and the SCFFBXL5 complex from Sf9 insect cells infected with different baculoviruses corresponding to Flag-FBXL5, His-Skp1, HA-Cullin1 and Rbx1 (Supplementary Figure S3C). 0.657 SIGNOR-272136 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser739 GSIDMVDsPQLATLA 9606 BTO:0000938 16923168 YES The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. 0.451 SIGNOR-148978 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr741 NLYSGDYyRIQGRAV 9606 16186108 YES gcesareni Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues. 0.381 SIGNOR-140767 Ub:E2 complex SIGNOR-C497 SIGNOR CBLC protein Q9ULV8 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271060 BIX-02188 chemical CID:66524294 PUBCHEM MAP2K5 protein Q13163 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190365 CUL4A protein Q13619 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 YES miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. 0.281 SIGNOR-268847 CASP12 protein Q6UXS9 UNIPROT CASP9 protein P55211 UNIPROT up-regulates cleavage 9606 BTO:0000222 12097332 YES gcesareni Caspase-12 specifically cleaves and activates procaspase-9 in cytosolic extracts. Results suggest that caspase-12 can activate caspase-9 without involvement of cytochromec. 0.2 SIGNOR-90318 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization binding 10090 BTO:0001103 24003218 YES lperfetto SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 0.911 SIGNOR-252996 PRKCQ protein Q04759 UNIPROT MSN protein P26038 UNIPROT unknown phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 BTO:0001545 9856983 YES lperfetto By using mass spectroscopy and direct microsequencing of CNBr fragments of phospho-moesin, the phosphorylation site was identified as KYKT*LRQIR (where * indicates the phosphorylation site) (Thr558), which is conserved in the ERM family | Thus, PKC-theta is identified as a major kinase within cells with specificity for moesin and with activation under non-classical PKC conditions. It appears likely that this activity corresponds to a specific intracellular pathway controlling the function of moesin as well as other ERM proteins. 0.449 SIGNOR-249013 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270841 CKM complex complex SIGNOR-C406 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 15546612 YES gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. 0.383 SIGNOR-273153 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258305 MYBBP1A protein Q9BQG0 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 YES miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 0.483 SIGNOR-268821 CAMK2D protein Q13557 UNIPROT ANKRD28 protein O15084 UNIPROT down-regulates activity phosphorylation Ser1011 TNTSKTVsFEALPIM -1 17023142 YES lperfetto We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K 0.2 SIGNOR-264793 GABA-B receptor complex SIGNOR-C336 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 9872316 NO brain lperfetto GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. 0.7 SIGNOR-263794 BMP4 protein P12644 UNIPROT MRTFA protein Q969V6 UNIPROT up-regulates 9606 21673106 NO gcesareni These results demonstrate that mrtf-a is essential for the bmp4-mediated induction of pri-mir-143/145 and mature mir-143/145, whereas tgf- -mediated induction of mir-143/145 requires myocd. Mrtf-a is primarily localized in the cytoplasm in unstimulated cells;upon stimulation with bmp4, mrtf-a translocates into the nucleus to promote changes in gene expression. 0.2 SIGNOR-174124 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys709 QTLESFFkPLTH 9606 21791603 YES miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). 0.58 SIGNOR-272733 NR3C1 protein P04150 UNIPROT NR4A2 protein P43354 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 NO gcesareni We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors. 0.306 SIGNOR-132254 GCC1 protein Q96CN9 UNIPROT ITSN1 protein Q15811 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 30540523 YES Giulio GFP-GCC88 was immunoprecipitated by both the short and long form of ITSN-1 but not with FLAG-Rheb (Figure 4A). These data demonstrate that both GCC88 and ITSN-1 are part of a complex. We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A). 0.2 SIGNOR-260600 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser197 TKSIYTRsVIDPVPA -1 10075701 YES miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites 0.2 SIGNOR-250226 NR3C1 protein P04150 UNIPROT IRAK3 protein Q9Y616 UNIPROT up-regulates quantity transcriptional regulation 9606 25585690 YES We show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter 0.361 SIGNOR-259287 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Ser742 GEKSFRRsVVGTPAY 18692497 YES lperfetto The results presented in this study indicate that during mitosis, PKD3 and PKD are phosphorylated at Ser(731) and Ser(744) within their activation loop by a mechanism that requires protein kinase C. Mitosis-associated PKD3 Ser(731) and PKD Ser(744) phosphorylation is related to the catalytic activation of these kinases as evidenced by in vivo phosphorylation of histone deacetylase 5, a substrate of PKD and PKD3. 0.2 SIGNOR-275925 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr111 PIPQISStPKTSEEA 9606 18055457 YES lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta 0.272 SIGNOR-159578 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser7 sSSSYRRM -1 2500966 YES lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. 0.285 SIGNOR-248886 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Thr194 FPKTSSAtPQETLIS -1 12361598 YES miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) 0.516 SIGNOR-265961 PAK2 protein Q13177 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Ser19 KRPQRATsNVFAMFD -1 10047984 YES miannu In this study we report that gamma-PAK, which is activated by the GTP-binding proteins Cdc42 and Rac, catalyses phosphorylation of intact non-muscle myosin II and isolated recombinant RLC. Phosphopeptide maps and phosphoamino acid analysis revealed that gamma-PAK phosphorylates Ser-19 but does not phosphorylate Thr-18.Taken together, these data suggest that myosin II activation by the p21-activated family of kinases may be physiologically important in regulating cytoskeletal organization. 0.493 SIGNOR-263020 CENPO protein Q9BU64 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.826 SIGNOR-265209 17beta-estradiol smallmolecule CHEBI:16469 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258591 WNT7A protein O00755 UNIPROT FZD7 protein O75084 UNIPROT up-regulates activity binding 9606 BTO:0002314 BTO:0001103 23290138 YES apalma Our previous work has demonstrated that ligation of Wnt7a to Fzd7 activates the planar cell polarity (PCP) pathway […] Therefore, we conclude that the Fzd7/Sdc4 co-receptor complex binds both Wnt7a and FN. 0.677 SIGNOR-255845 CDK5 protein Q00535 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 18003833 YES lperfetto These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness. 0.621 SIGNOR-159318 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser44 KPTFGKLsINKPTSE 9606 20471944 YES lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). 0.847 SIGNOR-165558 PRKD1 protein Q15139 UNIPROT PKD2 protein Q13563 UNIPROT up-regulates activity phosphorylation Ser801 SSLPRPMsSRSFPRS 9606 BTO:0000007 20881056 YES miannu Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. Phosphorylation at this site was significantly increased in response to serum and epidermal growth factor stimulation.We confirmed previous studies showing that PC2 mediated Ca2+ release from the ER can be stimulated by ATP.Phosphorylation at Ser801 seems to be permissive for this activity without altering the subcellular localization nor homophilic and heterophilic (with PC1) interactions of wild-type PC2. 0.458 SIGNOR-259829 FAM83C protein Q9BQN1 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273752 TICAM1 protein Q8IUC6 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 20404851 YES lperfetto TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation. 0.733 SIGNOR-216313 RNF139 protein Q8WU17 UNIPROT INSIG2 protein Q9Y5U4 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 YES miannu Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner  0.437 SIGNOR-271956 blinatumomab antibody DB09052 DRUGBANK CD19 protein P15391 UNIPROT down-regulates activity binding 9606 BTO:0000731 25883042 YES miannu Blinatumomab, a bispecific antibody construct targeting CD19, is the most advanced member of bispecific T-cell engager (BiTE®) molecules.Blinatumomab recently gained approval in the United States by the U.S. Food and Drug Administration for treatment of Philadelphia chromosome-negative B-precursor relapsed/refractory acute lymphoblastic leukemia. 0.4 SIGNOR-259888 NR3C1 protein P04150 UNIPROT SGK1 protein O00141 UNIPROT up-regulates quantity transcriptional regulation 10116 15793248 NO We show here that dexamethasone upregulates transcription and expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in insulin-secreting cells, an effect reversed by mifepristone (RU486), an antagonist of the nuclear glucocorticoid receptor. 0.461 SIGNOR-255926 PFKFB2 protein O60825 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 20640476 NO lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. 0.7 SIGNOR-209950 NOTCH1 protein P46531 UNIPROT HEYL protein Q9NQ87 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887;BTO:0001260 11044625 NO gcesareni These data confirm heyl as a notch1 target gene that is likely involved in somite formation and patterning. 0.608 SIGNOR-83399 CLASP1 protein Q7Z460 UNIPROT CLIP2 protein Q9UDT6 UNIPROT up-regulates activity binding 9606 BTO:0000567 15631994 YES lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. 0.595 SIGNOR-265092 PPP2CA protein P67775 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). 0.2 SIGNOR-269896 lofexidine chemical CHEBI:51368 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 22341244 YES Luana Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism.  0.8 SIGNOR-258332 PRKCI protein P41743 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates quantity by stabilization phosphorylation Ser345 RGDGSGFsL 9606 BTO:0002181 23249950 YES miannu APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation. 0.865 SIGNOR-276432 MIS12 complex complex SIGNOR-C362 SIGNOR KMN network complex SIGNOR-C366 SIGNOR form complex binding 18007590 YES lperfetto The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, 0.2 SIGNOR-265216 GPR119 protein Q8TDV5 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256911 triptorelin chemical CHEBI:63633 ChEBI GNRH1 protein P01148 UNIPROT up-regulates activity chemical activation 9606 22416801 YES miannu The comparative effects of degarelix and GnRH agonists were assessed in two studies in a rat model of prostate cancer.14 In a 2‐month study, rats receiving the GnRH agonist, triptorelin (0.5 mg/kg daily), experienced an initial testosterone surge, followed by suppression to castration levels by day 28, which was maintained for the remainder of the study. 0.8 SIGNOR-259158 TP53 protein P04637 UNIPROT LRBA protein P50851 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15064745 NO miannu We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA. 0.274 SIGNOR-253847 AKT proteinfamily SIGNOR-PF24 SIGNOR PRPH protein P41219 UNIPROT up-regulates activity phosphorylation Ser59 SSSVRLGsFRSPRAG 9606 BTO:0000007 17569669 YES miannu Here we demonstrate that peripherin, which is a peripheral nervous system neuron-specific intermediate filament protein, is a novel Akt substrate, and that Ser66 of peripherin is the phosphorylation site. Peripherin phosphorylation is apparently induced in motor neurons after nerve injury, suggesting that the Akt-mediated peripherin phosphorylation may play a role in motor nerve regeneration. 0.2 SIGNOR-262627 SIN3B protein O75182 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR form complex binding 9606 BTO:0000007 21041482 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.758 SIGNOR-266967 WNT16 protein Q9UBV4 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000887 22309736 NO gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. 0.2 SIGNOR-195969 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 BTO:0001253 9811851 YES lperfetto Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH. 0.942 SIGNOR-61552 PRKACA protein P17612 UNIPROT GJA5 protein P36382 UNIPROT up-regulates activity phosphorylation Ser120 RAKEVRGsGSYEYPV 9606 BTO:0003477 10728420 YES miannu Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345 0.307 SIGNOR-250357 RACK1 protein P63244 UNIPROT TRPM6 protein Q9BX84 UNIPROT down-regulates activity binding 9606 BTO:0000007 18258429 YES Manara We identified RACK1 as the first TRPM6-associated protein and demonstrated that RACK1 inhibits TRPM6 channel activity depending on the phosphorylation state T1851 in the α-kinase domain. 0.2 SIGNOR-260921 glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). 0.8 SIGNOR-268136 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1466 KSSEYPIsQNPEGLS 9606 BTO:0000150 10550055 YES lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks 0.819 SIGNOR-72060 PGR protein P06401 UNIPROT KLK4 protein Q9Y5K2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 19147544 NO miannu we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. 0.258 SIGNOR-254913 MAPK10 protein P53779 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 20395206 YES gcesareni With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation. 0.886 SIGNOR-164804 DZIP3 protein Q86Y13 UNIPROT H2AC7 protein P20671 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 YES miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. 0.2 SIGNOR-271753 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA4 protein Q9Y5G9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265697 AP1 complex SIGNOR-C154 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 NO lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. 0.7 SIGNOR-252356 RARA protein P10276 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins 0.725 SIGNOR-16433 EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 16179259 YES lperfetto The antiviral protein kinase pkr inhibits protein synthesis by phosphorylating the translation initiation factor eif2alpha on ser51the protein kinases pkr, hri, perk, and gcn2 specifically phosphorylate ser51 on the _ subunit of the translation initiation factor eif2, a gtp binding protein that delivers the initiator methionyl-trna to the small ribosomal subunit in the first step of translation initiation. Phosphorylation of eif2_ converts eif2 from a substrate to an inhibitor of its gdp-gtp exchange factor eif2b, thereby blocking protein synthesis 0.727 SIGNOR-140656 HES1 protein Q14469 UNIPROT ATOH1 protein Q92858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 NO lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 0.472 SIGNOR-265144 MAPK13 protein O15264 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser68 GQNGEEKsPPNASHP -1 15850461 YES miannu CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. 0.419 SIGNOR-263084 LSM7 protein Q9UK45 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.805 SIGNOR-270647 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 YES gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). 0.8 SIGNOR-141786 MET protein P08581 UNIPROT MET protein P08581 UNIPROT up-regulates phosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 8302603 YES lperfetto Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation 0.2 SIGNOR-37727 ERBB3 protein P21860 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16729043 YES gcesareni All erbb ligands and receptors couple to activation of the ras-mapk pathway, either directly through sh2 domain-mediated recruitment of grb-2 or indirectly through ptb domain-mediated binding of the shc adaptor. In this study, we identify grb2 as a specific binding partner to tyrosines y1199 and y1268 of erbb3. 0.838 SIGNOR-146858 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser899 RSKKRKGsDDAPYSP 9606 BTO:0000007 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h). 0.2 SIGNOR-264511 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.718 SIGNOR-219349 SRF protein P11831 UNIPROT SERPINE1 protein P05121 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000161 15514113 NO miannu We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. 0.264 SIGNOR-255228 RPL10 protein P27635 UNIPROT JUN protein P05412 UNIPROT down-regulates binding 9606 12138090 YES miannu The qm gene encodes a 24.5 kda ribosomal protein l10 known to be highly homologous to a jun-binding protein (jif-1), which inhibits the formation of jun-jun dimers. 0.387 SIGNOR-90750 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser38 QVSSLSEsEESQDSS 9606 20730097 YES lperfetto These data suggested that atf1 is always hyperphosphorylated on the ck sites in vivo. Also, the antibody reactivity suggested that in addition to ser-36 and ser-41, ser-38 and ser-44 were phosphorylated in vivo. To accommodate these findings, we propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. 0.297 SIGNOR-167548 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16882717 YES lpetrilli In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes. 0.499 SIGNOR-148434 TFDP1 protein Q14186 UNIPROT PCNA protein P12004 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.482 SIGNOR-253858 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.8 SIGNOR-106481 CDK5 protein Q00535 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates quantity phosphorylation Ser274 TLELGGKsPCIVLAD 9606 29948941 YES miannu Cdk5 Phosphorylates ALDH1A1 at S75 and S274.|These results demonstrate that Cdk5 increases ALDH1A1 levels in neurotoxin exposed neuronal cells both at transcriptional level and by direct phosphorylation at S75 and S274 sites. 0.2 SIGNOR-279399 arecoline chemical CHEBI:2814 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258641 SOSTDC1 protein Q6X4U4 UNIPROT WNT16 protein Q9UBV4 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.265 SIGNOR-242718 MAP4K3 protein Q8IVH8 UNIPROT MAP4K3 protein Q8IVH8 UNIPROT up-regulates phosphorylation Ser170 ATIAKRKsFIGTPYW 9606 20227368 YES gcesareni We identify a transautophosphorylation site in the map4k3 kinase activation segment (ser170) that is required for map4k3 activity and its activation of mtorc1 signaling. 0.2 SIGNOR-164103 IL21R protein Q9HBE5 UNIPROT JAK3 protein P52333 UNIPROT up-regulates binding 9606 BTO:0000776 12093291 YES gcesareni Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5 0.557 SIGNOR-90269 CDK4 protein P11802 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 YES gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.28 SIGNOR-176524 Ac-Asp-Glu(3-) smallmolecule CHEBI:76931 ChEBI N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity precursor of 9606 10085079 YES miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. 0.8 SIGNOR-268124 IRF1 protein P10914 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22291912 NO miannu SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. 0.31 SIGNOR-254494 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr531 NTTGSDNtDTEGS 9606 BTO:0000567 17936701 YES PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2 0.346 SIGNOR-262290 MAPK11 protein Q15759 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation Ser139 LNSPGPLsPSGMKGT 9606 BTO:0000887 15719023 YES p38 MAPK in particular phosphorylates Ser140 of E47. Its been observed that phosphorylation of E47 improves its ability to form heterodimers with Myod transcription factor gcesareni Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription, while the nonphosphorylatable e47 mutant ser140ala fails to heterodimerize with myod and displays impaired myogenic potentia 0.434 SIGNOR-134190 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 10090 SIGNOR-C3 18439900 YES lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK 0.692 SIGNOR-263045 EXOSC4 protein Q9NPD3 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.92 SIGNOR-261383 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Ser231 LSTSSSSsPPGTPSP 9606 phosphorylation:Thr235 IFGATDYtSSIDVWS 17601773 YES fspada Mass spectrometric analysis revealed that cdk2/cyclinA phosphorylates C/EBPbeta on Thr(188) and is required for phosphorylation (on Ser(184) or Thr(179)) of C/EBPbeta by GSK3beta and maintenance of DNA binding activity. However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs. 0.458 SIGNOR-156514 GNA12 protein Q03113 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity binding 10090 12024019 YES P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation. 0.765 SIGNOR-256522 FANCD2 protein Q9BXW9 UNIPROT Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR form complex binding 9606 BTO:0000007 17412408 YES lperfetto Immunoprecipitation of HA-FLAG-tagged FANCI expressed in 293T cells with antibodies against either HA or FLAG, but not MYC, resulted in coimmunoprecipitation of endogenous FANCD2|The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage. 0.956 SIGNOR-263268 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates quantity by destabilization cleavage Asp317 VSGISLLdNSNASVW 9606 BTO:0000567 11815631 YES Giulio Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage 0.396 SIGNOR-260602 PRKG2 protein Q13237 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates activity phosphorylation Ser26 VETLRRGsKFIKWDE 10116 BTO:0004576 11278298 YES lperfetto PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG. 0.524 SIGNOR-249080 PDPK1 protein O15530 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 YES gcesareni The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma) 0.651 SIGNOR-55937 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation./Phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.274 SIGNOR-163780 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 1377674 YES lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function 0.507 SIGNOR-18237 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22378047 YES lperfetto STAT6 coordinates and synergizes with both PPAR? and KrŸppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function. 0.346 SIGNOR-249568 MAPKAPK2 protein P49137 UNIPROT TRIM29 protein Q14134 UNIPROT up-regulates activity phosphorylation Ser550 GYPSLMRsQSPKAQP 9606 BTO:0000007 24469230 YES done miannu ATDC was phosphorylated directly by MAPKAP kinase 2 (MK2) at Ser550 in an ATM-dependent manner. Phosphorylation at Ser-550 by MK2 was required for the radioprotective function of ATDC.  0.307 SIGNOR-273675 ERLIN2 protein O94905 UNIPROT Erlin complex SIGNOR-C532 SIGNOR form complex binding 10119 BTO:0003293 19240031 YES miannu Here we report that the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex that binds to IP(3)R tetramers immediately after their activation and is required for their processing. The complex is ring-shaped (diameter approximately 250A(),) and RNA interference-mediated depletion of SPFH1 and SPFH2 blocks IP(3)R polyubiquitination and degradation. 0.65 SIGNOR-275393 JAK2 protein O60674 UNIPROT LEPR protein P48357 UNIPROT up-regulates activity phosphorylation Tyr1141 SKKTFASyMPQFQTC 9606 BTO:0000007 11018044 YES miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. 0.773 SIGNOR-263494 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates activity chemical activation 9606 17132853 YES miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 0.8 SIGNOR-256197 ITCH protein Q96J02 UNIPROT BCL10 protein O95999 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000661 15082780 YES miannu The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation.  0.276 SIGNOR-271413 HES1 protein Q14469 UNIPROT FLT3 protein P36888 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25234168 YES We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. 0.2 SIGNOR-261563 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273046 PKC proteinfamily SIGNOR-PF53 SIGNOR NOXO1 protein Q8NFA2 UNIPROT up-regulates activity phosphorylation Ser159 SRAAGRLsIHSLEAQ 9606 28336130 YES lperfetto Importantly, the constitutive activity of NoxO1 can be modulated. NoxO1 phosphorylation by PKC at Ser154 doubles its binding ability to NoxA1, which in turn acts as a molecular switch, allowing optimal interaction of NoxO1 with p22phox 0.2 SIGNOR-264728 TP53 protein P04637 UNIPROT OGG1 protein O15527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16293709 YES miannu Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1. 0.429 SIGNOR-255440 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 22575959 YES gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane. 0.655 SIGNOR-197420 ATF4 protein P18848 UNIPROT DDIT4 protein Q9NX09 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19439225 NO lperfetto We additionally identified Redd1 as a downstream effector of C/EBP-beta stimulated by ATF4 activated under the stress conditions examined. RNA interference studies provided further evidence of the requirement of C/EBP-beta for Redd1 expression. We conclude that the Redd1 gene is transactivated by the ATF4 and C/EBP family of transcription factors, leading to mTOR inhibition in response to oxidative and ER stress. 0.414 SIGNOR-253726 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14565864 YES miannu Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner. 0.246 SIGNOR-253907 CAMK2A protein Q9UQM7 UNIPROT PEA15 protein Q15121 UNIPROT up-regulates phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 15916534 YES gcesareni Pea-15 is a phosphoprotein containing a ser-104 phosphorylated by protein kinase c and a ser-116 phosphorylated by camkii (calcium/calmodulin-dependent protein kinase ii) or akt. Phosphorylation of ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at ser-116 is required for pea-15 recruitment to the disc (death-initiation signalling complex) 0.2 SIGNOR-137614 PKC proteinfamily SIGNOR-PF53 SIGNOR ABCB1 protein P08183 UNIPROT up-regulates activity dephosphorylation Ser661 SSNDSRSsLIRKRST 9606 BTO:0000007 24333728 YES Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp 0.2 SIGNOR-272512 AUTS2 protein Q8WXX7 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR down-regulates activity binding 9606 BTO:0000007 25519132 YES miannu We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation. 0.362 SIGNOR-266814 LPAR3 protein Q9UBY5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257141 P4HA2 protein O15460 UNIPROT Collagen proteinfamily SIGNOR-PF103 SIGNOR up-regulates quantity by stabilization hydroxylation 9606 9211872 YES miannu Prolyl 4-hydroxylase (proline hydroxylase, EC 1.14.11.2) catalyzes the hydroxylation of proline in -Xaa-Pro-Gly- triplets in collagens and other proteins with collagen-like sequences. The enzyme plays a central role in the synthesis of all collagens, as the 4-hydroxyproline residues formed in the reaction are essential for the folding of the newly synthesized collagen polypeptide chains into triple helical molecules.  0.2 SIGNOR-269733 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser568 SSRRRRSsSTAPPTS 9606 16513649 YES llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization 0.2 SIGNOR-145040 NOSIP protein Q9Y314 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity ubiquitination 9534 BTO:0000298 12746455 YES miannu Erythropoietin receptors associate with a ubiquitin ligase, p33RUL, and require its activity for erythropoietin-induced proliferation. This receptor-associated ubiquitin ligase, RUL, co-precipitated with EpoR from mammalian cells and mediated ubiquitination of EpoR. RUL mediates EpoR ubiquitination in COS7 cells and is inducibly ubiquitinated after Epo treatment. This observation is consistent with the lack of effects on EpoR stability by RUL-mediated ubiquitination in COS7 cells (Fig. 4). 0.331 SIGNOR-271477 DLGAP5 protein Q15398 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.449 SIGNOR-264598 PCGF2 protein P35227 UNIPROT HSF2 protein Q03933 UNIPROT down-regulates activity sumoylation 9606 BTO:0000007 18211895 YES miannu MEL-18, in contrast to the polycomb protein PC2/CBX4, in which SUMO E3 activity stimulates sumoylation of certain proteins, actually functions like an anti-SUMO E3 protein, interacting with both HSF2 and the SUMO E2 UBC9 but acting to inhibit UBC9 activity and thereby decreasing sumoylation of a target protein, in this case that of HSF2. sumoylation of HSF2 is up-regulated during mitosis and is important for the interaction of this factor with a subunit of the condensin complex during the bookmarking process 0.325 SIGNOR-226245 HCFC1 protein P51610 UNIPROT CREB3 protein O43889 UNIPROT up-regulates activity binding -1 9658067 YES 2 miannu We also show that while interaction with HCF is not required for the ability of Luman to activate transcription when tethered to the GAL4 promoter, it appears to be essential for Luman to activate transcription through CRE sites. 0.567 SIGNOR-241372 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 YES lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity 0.2 SIGNOR-236294 PLK1 protein P53350 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser30 EADSPSDsGQGSYET 9606 16885021 YES gcesareni We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase 0.772 SIGNOR-148442 GNAI1 protein P63096 UNIPROT TNFAIP8 protein O95379 UNIPROT up-regulates activity binding 9606 20607800 YES TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation 0.2 SIGNOR-256491 MAPK3 protein P27361 UNIPROT CREM protein Q03060 UNIPROT down-regulates quantity by destabilization phosphorylation Ser277 ASPGSLHsPQQLAEE 10090 BTO:0001077 11466319 YES miannu  The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.  0.41 SIGNOR-275978 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1A protein P35348 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190604 MYC protein P01106 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12835716 YES gcesareni C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation 0.496 SIGNOR-102731 carfilzomib chemical CHEBI:65347 ChEBI PSMB2 protein P49721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 YES miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. 0.8 SIGNOR-259310 AGTR1 protein P30556 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 21289285 YES gcesareni These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction. 0.432 SIGNOR-171763 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser488 YSDSEDDsSEFDEDD 9606 19012317 YES gcesareni Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo. 0.2 SIGNOR-182358 ECM stimulus SIGNOR-ST20 SIGNOR Av/b8 integrin complex SIGNOR-C185 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259042 ADORA2A protein P29274 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.3 SIGNOR-256766 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2K protein P61086 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.844 SIGNOR-271333 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 24697349 YES Adaptor protein Grb2 binds phosphotyrosines in the epidermal growth factor (EGF) receptor (EGFR) and thereby links receptor activation to intracellular signaling cascades. 0.923 SIGNOR-267725 PCNA protein P12004 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR up-regulates activity binding 9534 BTO:0004055 12930972 YES lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). 0.575 SIGNOR-265512 HECW2 protein Q9P2P5 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity binding 9606 BTO:0000093 27119228 YES miannu NEDL2 acts as a scaffold protein to promote GDNF-stimulated Akt activation. biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. NEDL2 binds p85, p110 and Akt with different domains 0.2 SIGNOR-269459 AURKA protein O14965 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity phosphorylation Ser675 QDYKKRLsVELTSSL 9606 25217103 YES miannu In addition, Aurora-A overexpression is significantly correlated with increased cytoplasmic \u03b2-catenin expression in esophageal squamous cell carcinoma tissues.|We also demonstrate for the first time that Aurora-A directly interacts with \u03b2-catenin and phosphorylates \u03b2-catenin at Ser552 and Ser675. 0.346 SIGNOR-278469 CEBPA protein P49715 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17671233 NO irozzo C/EBPα binds and activates the PU.1 distal enhancer to induce monocyte lineage commitment.Transcriptional induction of PU.1 by C/EBPα may play a role in myeloid lineage specification. 0.529 SIGNOR-256055 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273044 AKT1 protein P31749 UNIPROT DOCK6 protein Q96HP0 UNIPROT up-regulates activity phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 YES lperfetto Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching 0.373 SIGNOR-275666 MED30 protein Q96HR3 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.755 SIGNOR-266673 ACLY protein P53396 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI up-regulates quantity chemical modification 9606 19286649 YES miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. 0.8 SIGNOR-267103 PAK1 protein Q13153 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12151336 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Histone h3 is a substrate of pak1 both in vitro and in vivo, and it specifically interacted with pak1 but not pak2 or pak3. Site-directed mutagenesis indicated that pak1 phosphorylates histone h3 on ser10. 0.2 SIGNOR-91050 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.499 SIGNOR-248300 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr325 GQLRGSAtRALPPGP 9606 BTO:0000007 10542239 YES llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T 0.2 SIGNOR-250811 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 YES lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.564 SIGNOR-161646 AHCYL1 protein O43865 UNIPROT PAPOLA protein P51003 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 YES lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. 0.246 SIGNOR-268329 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 YES milica Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ 0.42 SIGNOR-201143 ERBB4 protein Q15303 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 16729043 YES gcesareni We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5. 0.811 SIGNOR-146894 OSM protein P13725 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0001271 1536831 YES gcesareni Oncostatin m binds the high-affinity leukemia inhibitory factor receptor 0.725 SIGNOR-19873 risperidone chemical CHEBI:8871 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258530 OMA1 protein Q96E52 UNIPROT OPA1 protein O60313 UNIPROT up-regulates activity cleavage 9606 BTO:0003298 29748581 YES Barakat YME1L cleaves OPA1 at S2 and S3 site to transform into L-OPA1 to induce fusion when cells are faced with increased oxidative phosphorylation, whereas OMA1 cleaves OPA1 at an S1 site to transform into S-OPA1, resulting in the fragmented response to cellular stress, mitochondrial dysfunction, or deletion of YME1L 0.603 SIGNOR-274139 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 10029 BTO:0000246 7651388 YES lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). 0.914 SIGNOR-236745 AKT1 protein P31749 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Thr527 PPKAKDPtVS 9606 35080342 YES miannu AKT1 and AKT2 phosphorylate HSF1 at S326 but only AKT1 activates HSF1.|Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. 0.405 SIGNOR-278371 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT down-regulates activity phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0000007 24841198 YES lperfetto CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15|Our results also demonstrated that the phosphorylated levels of PME-1/Ser15 and CaMKI/Thr177 are inversely correlated with the phosphatase activity of SIK2·PP2A complex, further implying that the demethylase activity of phosphorylated PME-1/Ser15 may be higher than that of its unphosphorylated state. 0.396 SIGNOR-265747 WWP1 protein Q9H0M0 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates ubiquitination 9606 15221015 YES gcesareni Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7 0.532 SIGNOR-126581 Calprotectin complex complex SIGNOR-C293 SIGNOR AGER protein Q15109 UNIPROT up-regulates activity binding 9606 28137827 YES miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33 0.332 SIGNOR-262825 ITGB1BP1 protein O14713 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257638 BABAM2 protein Q9NXR7 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 YES lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  0.2 SIGNOR-263212 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Thr17 RVSSYRRtFGGAPGF -1 12686604 YES lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro. 0.545 SIGNOR-100115 PDE3A protein Q14432 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity binding 9606 BTO:0000199 25593322 YES lperfetto Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2.|PDE3A co-localized with PLB, SERCA2, and an AKAP18 variant|our studies show that PDE3-selective inhibition (but not PDE4 inhibition) potentiates the phosphorylation of PLB by endogenous PKA and stimulation of SERCA2 activity and Ca2+ uptake in SR-enriched vesicles prepared from human myocardium. 0.34 SIGNOR-262051 ARF6 protein P62330 UNIPROT PIP4K2A protein P48426 UNIPROT up-regulates activity 10116 BTO:0003102 14565977 YES miannu Effects of ARF6 upon Axonogenesis Are Mediated by Phosphatidyl-inositol-4-phosphate 5-Kinase α. activated ARF6 stimulates the lipid-modifying enzyme PI(4)P 5-Kinase, leading to local increases in plasma membrane PIP2 and changes in actin dynamics. Alternatively, activation of Rac1 by upstream Rac1 activators or indirectly by ARF6-GTP results in stimulation of actin polymerization.  0.338 SIGNOR-264911 CEBPA protein P49715 UNIPROT SOX4 protein Q06945 UNIPROT down-regulates transcriptional regulation 9606 24183681 YES apalma In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding. 0.382 SIGNOR-255675 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation 9606 15657420 YES inferred from 70% family members lperfetto The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity. 0.2 SIGNOR-270160 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 YES miannu AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase 0.491 SIGNOR-250314 (2s)-1-{[5-(3-Methyl-1h-Indazol-5-Yl)pyridin-3-Yl]oxy}-3-Phenylpropan-2-Amine chemical CID:11314340 PUBCHEM AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258064 MAPK14 protein Q16539 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser113 STSVTPHsPSSPVGS 9606 BTO:0000007 16713578 YES miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles 0.317 SIGNOR-262948 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 15659650 YES lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 0.779 SIGNOR-217803 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21697284 YES gcesareni Exel-2880 (xl880, gsk1363089) is a small-molecule kinase inhibitor that targets members of the hgf and vegf receptor tyrosine kinase families, with additional inhibitory activity toward kit, flt-3, platelet-derived growth factor receptor _, and tie-2. 0.8 SIGNOR-174552 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates activity binding 9606 29958106 YES miannu The genes encoding CBFβ and RUNX1 are frequent targets of mutations in hematologic malignancies. The chromosome inversion inv(16)(p13;q22), found in 8% of acute myeloid leukemia (AML) cases, fuses the CBFB and MYH11 genes to produce the leukemic oncoprotein CBFβ-SMMHC. This fusion protein has higher affinity and altered stoichiometry for RUNX1 relative to the native CBFβ (Cao et al., 1997; Lukasik et al., 2002). During development, CBFβ-SMMHC expression blocks definitive hematopoiesis and embryos die at mid-gestation (Castilla et al., 1996), a similar phenotype to that of Runx1- and Cbfb-knock out embryos (Wang et al., 1996a; Wang et al., 1996b), indicating that CBFβ-SMMHC has a dominant negative effect on RUNX function. 0.2 SIGNOR-255743 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD4 protein Q13485 UNIPROT down-regulates activity ubiquitination 9606 BTO:0002181 15817471 YES In the presence of smad6 or smad7 acting as adaptors lperfetto Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes. 0.2 SIGNOR-253259 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 12056906 YES lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. 0.394 SIGNOR-89268 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Ser408 GPLPRAPsISTVEPK 9606 26190112 YES Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. 0.334 SIGNOR-259863 LAMC1 protein P11047 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR form complex binding 7496033 YES lperfetto Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1. 0.617 SIGNOR-253234 CSNK1G2 protein P78368 UNIPROT CERT1 protein Q9Y5P4 UNIPROT down-regulates phosphorylation Ser132 SSLRRHGsMVSLVSG 9606 BTO:0000567 BTO:0000975 19005213 YES lperfetto These results indicate that ckigamma2 hyperphosphorylates the serine-repeat motif of cert, thereby inactivating cert and down-regulating the synthesis of sphingomyelin. 0.2 SIGNOR-182160 PTPN11 protein Q06124 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 11085989 YES miannu SHP-2 is thus a positive regulator of ERK by leptin receptors, and both the adaptor function and the phosphatase activity of SHP-2 are critical for this regulation. Based on these data, we conclude that tyrosinephosphorylation of SHP-2 is a mediator of ERK activation viaTyr-985. This is likely to occur via Grb-2 binding to SHP-2 atthe C terminus followed by activation of the Ras-Raf pathwayas suggested for other signaling systems (55, 56) and morerecently for the leptin receptor (33). 0.736 SIGNOR-263498 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL 9606 23650397 YES gcesareni SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|Having demonstrated that SGK1 mediates the cortisol-induced increase in GR phosphorylation at the S203 and S211 phospho-sites, which enhance GR nuclear translocation, but not at the S226 site, which inhibits nuclear translocation 0.461 SIGNOR-251670 ESR1 protein P03372 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000150 16169518 YES gcesareni Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k. 0.627 SIGNOR-140470 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258292 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.397 SIGNOR-275770 tolazoline chemical CHEBI:28502 ChEBI ADRA2A protein P08913 UNIPROT down-regulates activity chemical inhibition 9606 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258912 HNF1B protein P35680 UNIPROT FXYD2 protein P54710 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19389850 NO Regulation miannu We analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. 0.293 SIGNOR-251927 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr118 AGPLIVPyNLPLPGG 9606 20600357 YES llicata In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility. 0.355 SIGNOR-166497 SAICAR(4-) smallmolecule CHEBI:58443 ChEBI 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI up-regulates quantity precursor of 9606 22812634 YES miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case 0.8 SIGNOR-266609 testolactone chemical CHEBI:9460 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates activity chemical inhibition -1 7083195 YES miannu Recently, it was discovered that 4-hydroxy-4-androstene-3,17-dione, 4-androstene-3,6,17-trione, and 1,4,6-androstatriene-3,17-dione, compounds previously reported to be competitive inhibitors of aromatase, cause a time-dependent loss of aromatase activity in human placental microsomes.We report here that 1,4-androstadiene 3,17-dione (Ki 0.32 microM; kinact 0.91 X 10(-3)/sec) and testolactone (Ki 35 microM; kinact 0.36 X 10(-3)/sec) also cause a similar loss of aromatase activity. 0.8 SIGNOR-258406 A5/b1 integrin complex SIGNOR-C163 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.61 SIGNOR-257705 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.613 SIGNOR-248371 NFIA protein Q12857 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268896 NEDD4 protein P46934 UNIPROT NANOS2 protein P60321 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28585553 YES miannu We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation.|To examine whether complex formation of NEDD4 and NDFIP2 promotes NANOS2 ubiquitination in vivo, FLAG tagged NANOS2 was expressed in HEK293 cells with or without MYC-NEDD4 and MYC-NDFIP2. 0.2 SIGNOR-278770 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI up-regulates quantity precursor of 9606 19524112 YES miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. 0.8 SIGNOR-267519 PTPN1 protein P18031 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates dephosphorylation 9606 phosphorylation:Tyr177 9566916 YES gcesareni We have observed association and dephosphorylation of p210 bcr-abl, but not v-abl, by ptp1b in vivo. 0.2 SIGNOR-56822 RPS6KA3 protein P51812 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates quantity by destabilization phosphorylation Thr263 SIRDRNGtHLDAGAL 21183680 YES lperfetto The ribosomal S6 kinase 2 (RSK2) is a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins and plays a critical role in proliferation, cell cycle, and cell transformation. Here, we report that RSK2 phosphorylates caspase-8, and Thr-263 was identified as a novel caspase-8 phosphorylation site. In addition, we showed that EGF induces caspase-8 ubiquitination and degradation through the proteasome pathway, and phosphorylation of Thr-263 is associated with caspase-8 stability. 0.369 SIGNOR-272997 TRPM7 protein Q96QT4 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser5 sEFLKQAW 9606 24103589 YES lperfetto Trpm7 was responsible for phosphorylation of the serine 5 (ser5) residue [29]. In 2009, the study focused on an association between anxa1 and trpm7 confirmed the presence of a trpm7/annexin a1/mg2_+ complex, suggesting a novel pathway in bradykinin signaling, dependent on pkc and c-src [30]. Even though that pathway is not fully characterized, the same team that discovered the ser5 phosphorylation of anxa1 also reported crucial relevance of this modification for anxa1 membrane binding and especially for the interaction between annexin a1 and its known partner, the calcium binding protein s100a11 0.545 SIGNOR-202804 IL1RAP protein Q9NPH3 UNIPROT TOLLIP protein Q9H0E2 UNIPROT down-regulates activity binding 9606 BTO:0000007 10854325 YES lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) 0.637 SIGNOR-251979 GSK3B protein P49841 UNIPROT SOX10 protein P56693 UNIPROT down-regulates quantity phosphorylation 9606 26461473 YES miannu Besides, GSK3\u03b2 phosphorylates SOX10 at CPD domain and facilitates Fbxw7\u03b1-mediated SOX10 degradation.|Besides, GSK3beta phosphorylates SOX10 at CPD domain and facilitates Fbxw7alpha mediated SOX10 degradation. 0.407 SIGNOR-279617 SRC protein P12931 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000876 25624455 YES miannu PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role. 0.448 SIGNOR-254740 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1742 KAQAKVGsLDNAHHV 9606 BTO:0000567 11029056 YES miannu CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA 0.359 SIGNOR-250003 SP1 protein P08047 UNIPROT CD34 protein P28906 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 10989198 YES lperfetto Activation of the CD34 promoter by Sp1 requires the presence of a binding domain at -48 bp as well as the 5' untranslated region, which also binds Sp1 0.263 SIGNOR-241481 EGFR protein P00533 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 11602604 YES lperfetto Rgs16 contains two conserved tyrosine residues in the rgs box, tyr(168) and tyr(177), which are predicted sites of phosphorylation. Rgs16 underwent phosphorylation in response to m2 muscarinic receptor or egfr stimulation in hek 293t or cos-7 cells, which required egfr kinase activity. Mutational analysis suggested that rgs16 was phosphorylated on both tyrosine residues (tyr(168) tyr(177)) after egf stimulation.Phosphorylated rgs16 demonstrated enhanced gtpase accelerating (gap) activity on galpha(i). Mutation of tyr(168) to phenylalanine resulted in a 30% diminution in rgs16 gap activity mutation of tyr(177) to phenylalanine had no effect on rgs16 gap activity but also abolished its regulation of g(i)-mediated signal transduction in these cells. 0.416 SIGNOR-111024 RNF115 protein Q9Y4L5 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 23418353 YES miannu RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded. 0.376 SIGNOR-272104 APC-c complex SIGNOR-C150 SIGNOR CCNF protein P41002 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27653696 YES miannu We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. 0.458 SIGNOR-266362 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr791 TPMYGSQtPLQDGSR 9606 16427012 YES lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif 0.776 SIGNOR-143931 CDK11B protein P21127 UNIPROT EIF3F protein O00303 UNIPROT up-regulates activity phosphorylation Ser46 PAAAPASsSDPAAAA 19245811 YES lperfetto EIF3f is phosphorylated by CDK11p46 at Ser46 during apoptosis.|Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis.  0.516 SIGNOR-273133 hsa-miR-26a-5p mirna URS000019B0F7_9606 RNAcentral WNT5A protein P41221 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002181 24972966 YES Parnian Altogether, the findings suggested that miR-26a may function as a tumor suppressor in prostate cancer by targeting Wnt5a. 0.4 SIGNOR-279809 Elongator complex complex SIGNOR-C466 SIGNOR TUBA1B protein P68363 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 YES miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 0.254 SIGNOR-269719 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 NO miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. 0.7 SIGNOR-268384 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257516 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 20577053 YES gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 0.488 SIGNOR-166365 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 21154127 YES irozzo Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. 0.8 SIGNOR-255819 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D7 protein Q9P0N9 UNIPROT up-regulates quantity by stabilization phosphorylation Ser124 GKLPRSPsFPLEPDD 9606 BTO:0000007 30143532 YES miannu  Sequence analysis identified a putative site for both Akt-mediated phosphorylation and 14-3-3 binding at Ser-124, and we found that Akt phosphorylates TBC1D7 at Ser-124. However, this phosphorylation had no effect on the binding of TBC1D7 to TSC1, but stabilized TBC1D7. 0.2 SIGNOR-273541 TLR2 protein O60603 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 YES miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.673 SIGNOR-266740 C9orf72 protein Q96LT7 UNIPROT RAB1A protein P62820 UNIPROT up-regulates activity binding 9606 BTO:0000007 27334615 YES miannu C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation 0.475 SIGNOR-261297 cabozantinib chemical CHEBI:72317 ChEBI MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207845 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 21157483 YES lperfetto Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism 0.642 SIGNOR-251982 TRIM27 protein P14373 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates activity ubiquitination Lys73 RRSQHARkETEFLRL 10090 35670107 YES K6 corresponds to the 6th Lysine, which is in position 73 in the full length sequence lperfetto TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1 0.2 SIGNOR-270346 HTR4 protein Q13639 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257154 docetaxel anhydrous chemical CHEBI:4672 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 23337758 YES miannu Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called "dynamic instability," which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer. 0.8 SIGNOR-259342 PELI1 protein Q96FA3 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0002552 27248820 YES miannu Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity. 0.455 SIGNOR-259395 CHUK protein O15111 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG -1 10022904 YES llicata Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays. 0.669 SIGNOR-250771 BMPR2 protein Q13873 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR form complex binding 9606 7791754 YES lperfetto Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. 0.714 SIGNOR-33437 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL -1 7493944 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.581 SIGNOR-246268 CDH1 protein P12830 UNIPROT CTNNA1 protein P35221 UNIPROT up-regulates binding 9606 24336504 YES milica Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm. 0.685 SIGNOR-203468 NMBR protein P28336 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.25 SIGNOR-256775 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT down-regulates phosphorylation Thr1471 IAALKEEtEEEVQDT 9606 21930781 YES lperfetto Cftr possesses two ck2 phosphorylation sites (s422 and t1471) the t1471 residue, previously described as a site for cftr phosphorylation by ck2 (25), seems to be critical for cftr turnover and processing. 0.278 SIGNOR-176627 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR BIRC6 protein Q9NR09 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.381 SIGNOR-271318 FZD1 protein Q9UP38 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 YES amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. 0.687 SIGNOR-253512 L-cysteine zwitterion smallmolecule CHEBI:35235 ChEBI hydrosulfide smallmolecule CHEBI:29919 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275814 NTRK2 protein Q16620 UNIPROT FRS3 protein O43559 UNIPROT up-regulates activity phosphorylation Tyr417 EPPRQLNyIQVELKG 9606 11432792 YES miannu The tyrosine phosphoryla tion of FRS2/SNT2 was stimulated dependently on the TrkB activation. to explore the possibility that tyrosine residues 417 and 455 on FRS2/SNT2 function as the binding sites for Shp2, we coexpressed Y417F or Y455F phenylalanine mutants and the Y417/455F double phenylalanine mutant of Myc/Histagged FRS2/SNT2 with TrkB. The active TrkB induced somewhat reduced tyrosine phosphorylation of all of the phenylalanine mutants of FRS2/SNT2 in comparison with tyrosine phosphorylation of the wild type 0.601 SIGNOR-250202 HAUS8 protein Q9BT25 UNIPROT HAUS complex complex SIGNOR-C281 SIGNOR form complex binding 9606 BTO:0000567 19369198 YES lperfetto Here, by using mass spectrometry, we identified the full human augmin complex of 8 subunits and show that it interacts with the gamma-tubulin ring complex (gamma-TuRC) 0.753 SIGNOR-262321 ACSL5 protein Q9ULC5 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI down-regulates quantity chemical modification 9606 24269233 YES ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity 0.8 SIGNOR-267713 CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 18316399 YES Simone Vumbaca Together, these results suggest that B-Cat increases MyoD binding to E box elements 0.406 SIGNOR-255653 TCAP protein O15273 UNIPROT TTN protein Q8WZ42 UNIPROT up-regulates activity binding 9606 BTO:0001103 32937135 YES lperfetto TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc 0.908 SIGNOR-264854 CDK2 protein P24941 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates activity phosphorylation Ser251 EVSIRVGsPQPSSSG 9606 BTO:0002181 29229926 YES miannu  During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs. 0.329 SIGNOR-277374 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000007 20554525 YES lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. 0.2 SIGNOR-246281 AKT1 protein P31749 UNIPROT GATA1 protein P15976 UNIPROT up-regulates phosphorylation Ser310 QTRNRKAsGKGKKKR 9606 16107690 YES llicata We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter. 0.515 SIGNOR-139782 BUB1 protein O43683 UNIPROT BUB1 protein O43683 UNIPROT up-regulates activity phosphorylation Ser969 FTAKCETsGFQCVEM -1 26658523 YES miannu  Conversely, Bub1 is an active kinase regulated by intra-molecular phosphorylation at the P+1 loop. 0.2 SIGNOR-277186 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 BTO:0000801;BTO:0000776 10347215 YES miannu Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5. 0.809 SIGNOR-68010 C9 protein P02748 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 YES lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer 0.488 SIGNOR-263441 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM6 protein Q9C030 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271217 GRK2 protein P25098 UNIPROT RPLP2 protein P05387 UNIPROT up-regulates phosphorylation Ser102 KDEKKEEsEESDDDM 9606 12379128 YES gcesareni The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity. 0.2 SIGNOR-94254 R2TP core co-chaperone complex SIGNOR-C515 SIGNOR PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 YES miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  0.568 SIGNOR-270925 CyclinY/CDK16 complex SIGNOR-C540 SIGNOR PRC1 protein O43663 UNIPROT up-regulates activity phosphorylation Thr481 RRGLAPNtPGKARKL 9606 BTO:0000815 35449080 YES lperfetto Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis.|Indeed, immunoblot analysis showed that PRC1 phosphorylation at the T481 site (CDK-dependent major phosphorylation site) fluctuated with the abundance of CDK16 protein in the cell cycle process 0.345 SIGNOR-273013 VPS11 protein Q9H270 UNIPROT RDX protein P35241 UNIPROT up-regulates activity binding 9606 BTO:0000567 21148287 YES Sara Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation. 0.348 SIGNOR-261312 NPFFR1 protein Q9GZQ6 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256851 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RXRB protein P28702 UNIPROT up-regulates activity chemical activation 9606 17132853 YES miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. 0.8 SIGNOR-256191 IFNAR complex SIGNOR-C243 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 21631354 YES miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity 0.2 SIGNOR-260436 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT down-regulates activity monoubiquitination Lys682 SAVSHQGkRNPKSPL 9606 21791603 YES miannu Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709). 0.58 SIGNOR-272730 PRPS1 protein P60891 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 BTO:0006038 29074724 NO lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. 0.7 SIGNOR-265733 IL2 protein P60568 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 22128144 NO miannu We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. 0.358 SIGNOR-253895 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr2229 QAEEREHtLRRCQQE 9606 22820163 YES lperfetto Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1 0.335 SIGNOR-198353 ATG4B protein Q9Y4P1 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR down-regulates activity 9606 BTO:0000586 29165041 NO lperfetto In this study, we identified a novel phosphorylation site at Ser34 of ATG4B induced by AKT in HCC cells.| In brief, our results demonstrate for the first time that the phosphorylation of ATG4B at Ser34 participates in the metabolic reprogramming of HCC cells via repressing mitochondrial function, which possibly results from the Ser34 phosphorylation-induced mitochondrial enrichment of ATG4B and the subsequent inhibition of F1Fo-ATP synthase activity. 0.2 SIGNOR-275837 GPHN protein Q9NQX3 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000938 25882190 YES miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. 0.473 SIGNOR-264974 SKP2 protein Q13309 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR form complex binding 9606 15340381 YES gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. 0.927 SIGNOR-243560 MMP26 protein Q9NRE1 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272393 RAD52 protein P43351 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27649245 NO lperfetto Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans| in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. |These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals. 0.7 SIGNOR-251507 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser397 SMVGGERsPPRILPP 9606 21059642 YES The effect has been demonstrated using Q01196-8 lperfetto Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.342 SIGNOR-216912 APH1B protein Q8WW43 UNIPROT NCSTN protein Q92542 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 YES gcesareni By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.These data indicate that maph-1 is probably a functional component of the gamma-secretase complex 0.94 SIGNOR-93307 UCK2 protein Q9BZX2 UNIPROT uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity chemical modification 11306702 YES lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 0.8 SIGNOR-275860 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser412 GIPFRRPsTYGIPRL 9606 BTO:0000671 12082086 YES lperfetto G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells 0.568 SIGNOR-89849 Ub:E2 complex SIGNOR-C497 SIGNOR SIAH1 protein Q8IUQ4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271033 ROCK2 protein O75116 UNIPROT MYL12B protein O14950 UNIPROT up-regulates activity phosphorylation 9606 25412762 YES miannu In addition, an in vitro kinase assay with mixed recombinant GST-ROCK2 and MLC2 revealed that ROCK2 phosphorylated WT MLC2, but not MLC2 S15A mutant, indicating that it phosphorylates MLC2 at S15 in vitro (XREF_FIG). 0.596 SIGNOR-279103 PTPRG protein P23470 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKAR -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.298 SIGNOR-254695 CSNK2A1 protein P68400 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser737 PEEIIVLsDSD 9606 21474068 YES lperfetto Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors. 0.327 SIGNOR-173105 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 YES gcesareni DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. 0.86 SIGNOR-184789 GLUL protein P15104 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 30158707 YES miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. 0.8 SIGNOR-267824 CTNNB1 protein P35222 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165 19000719 YES Through Armadillo repeat domain gcesareni Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential. 0.774 SIGNOR-236858 SPRY2 protein O43597 UNIPROT CBLB protein Q13191 UNIPROT down-regulates binding 9606 11053437 YES gcesareni One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis. 0.488 SIGNOR-83507 TRPC4AP protein Q8TEL6 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000007 20551172 YES miannu We characterize a new Myc-interacting factor, TRPC4AP (transient receptor potential cation channel, subfamily C, member 4-associated protein)/TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein), which is the receptor for a DDB1 (damage-specific DNA-binding protein 1)-CUL4 (Cullin 4) E3 ligase complex for selective Myc degradation through the proteasome. TRPC4AP/TRUSS binds specifically to the Myc C terminus and promotes its ubiquitination and destruction through the recognition of evolutionarily conserved domains in the Myc N terminus.  0.507 SIGNOR-271964 CDK5 protein Q00535 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates activity phosphorylation Ser408 SIKSEPIsPPRDRMT 9606 BTO:0004102 12691662 YES lperfetto Cdk5-mediated inhibition of the protective effects of transcription factor mef2 in neurotoxicity-induced apoptosis.We have identified the prosurvival transcription factor mef2 as a direct nuclear target of cdk5. Cdk5 phosphorylates mef2 at a distinct serine in its transactivation domain to inhibit mef2 activity. 0.507 SIGNOR-100574 PRKD1 protein Q15139 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 YES lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. 0.2 SIGNOR-249260 PKN3 protein Q6P5Z2 UNIPROT ARHGAP18 protein Q8N392 UNIPROT up-regulates activity phosphorylation Ser156 QKRVETVsQTLRKKN -1 33092266 YES lperfetto We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158. 0.2 SIGNOR-264571 CEBPB protein P17676 UNIPROT GFER protein P55789 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 20690902 NO miannu In the present study, we investigated transcription of hHSS triggered by EGF (epidermal growth factor) and the role of C/EBPβ (CCAAT/enhancer-binding protein β) as a potential core factor responsible for hHSS transcription in HepG2 cells. The results show that EGF suppresses hHSS mRNA expression at early time points. Using a promoter deletion assay, we identified a proximal region (-358/-212) that is required for EGF suppression. Overexpression of C/EBPβ enhances EGF suppression of hHSS, and mutation of the C/EBPβ-binding site at -292/-279 or siRNA (short interfering RNA) interference abolishes EGF suppression. 0.2 SIGNOR-253772 Thrombin smallmolecule CHEBI:9574 ChEBI F2RL2 protein O00254 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257486 PHKG1 protein Q16816 UNIPROT PYG proteinfamily SIGNOR-PF96 SIGNOR up-regulates activity phosphorylation 9606 BTO:0002049 22225877 YES It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 0.683 SIGNOR-267960 FLT3 protein P36888 UNIPROT PTPRJ protein Q12913 UNIPROT down-regulates activity 10090 22438257 NO Taken together, the described findings supported the notion that FLT3 ITD causes reduced DEP-1 activity compared with cells expressing WT FLT3 rather than alterations in mRNA or protein levels. 0.491 SIGNOR-261553 RNF146 protein Q9NTX7 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 YES By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. 0.516 SIGNOR-259998 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK3 protein Q13003 UNIPROT up-regulates activity chemical activation 9606 27586965 YES miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors 0.8 SIGNOR-264472 MTA1 protein Q13330 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000812 18719363 NO miannu Screening for the expression of angiogenic cytokines expressed by ovarian cancer cells revealed MTA1-mediated upregulation of the oncogenic and angiogenic cytokine GRO (growth-regulated oncogene, CXCL1). 0.2 SIGNOR-254598 NFE2L2 protein Q16236 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 NO lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC 0.25 SIGNOR-268996 Neuregulin proteinfamily SIGNOR-PF37 SIGNOR ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates activity binding 9606 18415007 YES miannu The neuregulin family consists of four genes, NRG1-4 which can each encode products containing a domain related to the epidermal growth factor family of ligands. they may be released by regulated proteolysis to act as soluble proteins which can interact and activate members of the EGF receptor family of receptor tyrosine kinases 0.908 SIGNOR-256161 PRKCD protein Q05655 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser939 SFRARSTsLNERPKS 9606 BTO:0002181 30684133 YES miannu In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC. 0.2 SIGNOR-277427 LRRK2 protein Q5S007 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Thr164 LGSQSLHtRTSKLFQ 9606 21048939 YES gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence 0.457 SIGNOR-169225 RRM2B protein Q7LG56 UNIPROT RRM1 protein P23921 UNIPROT up-regulates activity binding 9606 BTO:0001061 14583450 YES miannu Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3. 0.935 SIGNOR-259366 PAK5 protein Q9P286 UNIPROT TCF3 protein P15923 UNIPROT up-regulates activity phosphorylation Ser39 NGKGRPAsLAGAQFG 9606 BTO:0000150 26212009 YES lperfetto The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). |In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation 0.2 SIGNOR-275653 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Leu) smallmolecule CHEBI:29169 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269489 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNI2 protein P48788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.345 SIGNOR-136786 MKRN1 protein Q9UHC7 UNIPROT TERT protein O14746 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 15805468 YES miannu MKRN1 functions as an E3 ubiquitin-ligase for hTERT in vitro and in vivo. Furthermore, we have used the yeast two-hybrid method to identify a novel RING finger gene (MKRN1) encoding an E3 ligase that mediates ubiquitination of hTERT. Overexpression of MKRN1 in telomerase-positive cells promotes the degradation of hTERT and decreases telomerase activity and subsequently telomere length.  0.476 SIGNOR-271529 PLCG2 protein P16885 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification 9606 23000145 YES scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). 0.8 SIGNOR-268454 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser295 FPFRNLGsPTQVISK 9606 23977114 YES lperfetto Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined 0.344 SIGNOR-202532 SATB2 protein Q9UPW6 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates activity binding 9606 21965674 YES miannu SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding. 0.372 SIGNOR-255149 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.54 SIGNOR-270903 JAK3 protein P52333 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 19088846 YES gcesareni For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated. 0.854 SIGNOR-182817 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser649 PVLYMQPsPL 9606 12620228 YES llicata Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth. 0.2 SIGNOR-98984 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR CDKN2A protein Q8N726 UNIPROT down-regulates transcriptional regulation 9606 12091906 YES apalma We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. 0.2 SIGNOR-255677 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser243 SLKPGALsNSESIPT 9534 BTO:0000298 11483516 YES llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. 0.291 SIGNOR-250597 JAK2 protein O60674 UNIPROT SLC6A8 protein P48029 UNIPROT down-regulates activity relocalization 443947 BTO:0000964 22407360 YES miannu Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane. 0.2 SIGNOR-265781 MARCHF7 protein Q9H992 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity ubiquitination 9606 24905733 YES miannu We have identified and characterized axotrophin, a protein that binds and preferentially mono-ubiquitinates tau protein. 0.2 SIGNOR-278655 BTRC protein Q9Y297 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 10835356 YES miannu Here we demonstrate that following IkappaB kinase (IkappaK)-mediated phosphorylation, the C-terminal domain of p105 (residues 918-934) serves as a recognition motif for the SCF(beta)(-TrCP) ubiquitin ligase.In vitro, SCF(beta)(-TrCP) specifically conjugates and promotes processing of phosphorylated p105. 0.588 SIGNOR-272570 RIPK3 protein Q9Y572 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates activity phosphorylation Ser473 SGVKRSRsGEGEVSG 9606 34419074 YES miannu These results indicate that TRIM28 phosphorylation at S473 is RIPK3-dependent and suggest that RIPK1/RIPK3 activation induces TRIM28 phosphorylation at S473, which may play an important role in the regulation of transcriptional activity. 0.2 SIGNOR-279107 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 YES Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  0.8 SIGNOR-258030 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR TP73 protein O15350 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277663 SMDT1 protein Q9H4I9 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.627 SIGNOR-270870 CDK2 protein P24941 UNIPROT MCM3 protein P25205 UNIPROT up-regulates phosphorylation Thr722 EEMPQVHtPKTADSQ 9606 SIGNOR-C16 21965652 YES gcesareni In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722. 0.796 SIGNOR-176656 FBXW11 protein Q9UKB1 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 YES tpavlidou We found that in vitro-translated 35s- labeled slimb indeed specifically bound to su(fu) in the gst pull-down assay. In our functional gli reporter assay, slimb alone did not alter gli-induced reporter expression;however, when cotransfected with hsu(fu), slimb significantly potentiated the inhibitory effect of su(fu) on gli activity. 0.292 SIGNOR-72240 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Thr404 NSHPLSLtSDQYKAY -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.741 SIGNOR-178387 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 11242052 YES lperfetto A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis 0.922 SIGNOR-105702 SRC protein P12931 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 14551213 YES lperfetto In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants. 0.788 SIGNOR-247341 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser99 AGEKEAKsD 9606 10739259 YES lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. 0.2 SIGNOR-76278 ULK1 protein O75385 UNIPROT FUNDC1 protein Q8IVP5 UNIPROT up-regulates activity phosphorylation Ser17 DYESDDDsYEVLDLT 9606 BTO:0000567 24671035 YES done miannu Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3.  0.594 SIGNOR-273606 S100A9 protein P06702 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000876 16690079 YES miannu Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner 0.2 SIGNOR-261936 CDC7 protein O00311 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser205 GAEGDVSsEREP -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.321 SIGNOR-273969 NEK2 protein P51955 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization phosphorylation Thr210 TNEIFYCtFRRLDPE 10090 BTO:0000584 34315872 YES miannu NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen.  0.2 SIGNOR-277314 MDM2 protein Q00987 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates quantity by destabilization ubiquitination Lys74 YHSDDYIkFLRSIRP 9606 26832969 YES miannu MDM2 induces ubiquitination of HDAC1 in VSMCs.|Under calcification inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. 0.468 SIGNOR-278761 GSK3B protein P49841 UNIPROT KLF5 protein Q13887 UNIPROT down-regulates phosphorylation Ser303 QATYFPPsPPSSEPG 9606 24398687 YES lperfetto Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5 0.369 SIGNOR-203627 TRAC protein P01848 UNIPROT TCR complex SIGNOR-C153 SIGNOR form complex binding 9606 12507424 YES miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ 0.2 SIGNOR-255297 AURKA protein O14965 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 YES miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. 0.332 SIGNOR-276061 GATA4 protein P43694 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001086 32376282 NO miannu HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs 0.7 SIGNOR-265480 IKBKB protein O14920 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 11815618 YES lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. The phosphorylation of I_Balpha on Ser32 and Ser36 is initiated by an IkapapB kinase (IKK) complex that includes a catalytic heterodimer composed of I_B kinase 1 (IKK-1) and IkapapB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator. 0.922 SIGNOR-249366 PTPN1 protein P18031 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity dephosphorylation 9606 22169477 YES miannu Finally, we demonstrated that wild-type PTP1B directly dephosphorylated myc-tagged PERK that had been isolated from tunicamycin-treated HEK293T cells by immunoprecipitation ( xref ).|The ability of PTP1B to dephosphorylate Tyr619 and inactivate PERK is fine tuned by the production of H 2 S by CSE in response to ER stress. 0.267 SIGNOR-277051 MAP3K7 protein O43318 UNIPROT TNFAIP8L2 protein Q6P589 UNIPROT down-regulates quantity by destabilization phosphorylation Ser3 sFSSKSLA 9606 BTO:0000007 32188758 YES done miannu  TAK1 phosphorylated the Ser3 in the noncanonical degron motif of TIPE2 to trigger its interaction with β-TrCP for subsequent ubiquitination and degradation. 0.2 SIGNOR-273668 FOXO3 protein O43524 UNIPROT TSC1 protein Q92574 UNIPROT up-regulates quantity transcriptional regulation 10090 20371605 YES FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1 0.449 SIGNOR-259382 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 BTO:0000007 SIGNOR-C3 12747827 YES lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. 0.926 SIGNOR-101119 PRKACA protein P17612 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 YES miannu Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII). Incubation of Rad with PKA decreases GTP binding by 60-70%, but this effect seems to be independent of phosphorylation, as it is observed with the Ser273-->Ala mutant of Rad containing a mutation at the site of PKA phosphorylation. 0.341 SIGNOR-250048 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR HIPK2 protein Q9H2X6 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0004573 18809579 YES miannu O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.  0.309 SIGNOR-271745 RNF123 protein Q5XPI4 UNIPROT KPC complex SIGNOR-C523 SIGNOR form complex binding 10090 BTO:0000944 15531880 YES miannu  We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation.  0.881 SIGNOR-271511 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB1 protein Q9Y5G3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265681 P2RY12 protein Q9H244 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.402 SIGNOR-256712 MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Ser257 ISGQLVDsIAKTRDA -1 9162092 YES Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4. 0.2 SIGNOR-251420 VEGFA protein P15692 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000876 17658244 YES gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. 0.82 SIGNOR-157100 POU5F1 protein Q01860 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 NO flangone Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes. 0.7 SIGNOR-242070 FAM83A protein Q86UY5 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273756 TP53 protein P04637 UNIPROT ZNF365 protein Q70YC5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23776040 YES Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability| Our study identified ZNF365 as a necessary target whose activation by p53 in the presence of critically short telomeres contributes to genomic stability. We provide evidence that loss of ZNF365 leads to increased expression of CFS and dysfunctional telomeres, aberrant sister telomere recombination, and increased aneuploidy 0.29 SIGNOR-272476 NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys9 SGRGKGGkGLGKGGA 9606 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8. 0.2 SIGNOR-267168 ATM protein Q13315 UNIPROT AVEN protein Q9NQS1 UNIPROT up-regulates activity phosphorylation Ser135 VNNESGEsQRGTDFS -1 18571408 YES miannu Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site). 0.382 SIGNOR-262636 STAT3 protein P40763 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27141364 YES irozzo STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia.The protein-DNA binding assay revealed that pSTAT3 was bound to the PD-L1 promoter region in H23 cells transfected with EML4-ALK. 0.465 SIGNOR-259188 sorafenib tosylate chemical CHEBI:50928 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 0.8 SIGNOR-259229 VDR protein P11473 UNIPROT CYP3A4 protein P08684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12147248 NO miannu Expression of cytochrome P450 3A4 (CYP3A4) is induced by 1,25-dihydroxyvitamin D(3)(1,25(OH)(2)D(3)) in Caco-2 cells. However, since a typical vitamin D responsive element has not been found in the 5(')-flanking region of the CYP3A4 gene, the mechanism of 1,25(OH)(2)D(3)-induced CYP3A4 mRNA expression is poorly understood. In the present study, we demonstrated that vitamin D receptor (VDR) is a critical factor for the induction using the antisense oligonucleotide technique. 0.403 SIGNOR-255600 LRFN5 protein Q96NI6 UNIPROT PTPRD protein P23468 UNIPROT up-regulates activity binding 9606 BTO:0000938 27225731 YES miannu SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). 0.277 SIGNOR-264086 PTPN5 protein P54829 UNIPROT GRIA2 protein P42262 UNIPROT down-regulates activity dephosphorylation 9606 21883219 YES miannu One study showed that stimulation of the metabotrophic glutamate receptor mGluR5 leads to a STEP mediated tyrosine dephosphorylation of GluA2 and internalization of GluA1 and GluA2, although the tyrosine residue on GluA2 that is dephosphorylated by STEP remains unidentified. 0.413 SIGNOR-277040 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK5 protein Q16478 UNIPROT up-regulates activity chemical activation 9606 27586965 YES miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors 0.8 SIGNOR-264474 CTDP1 protein Q9Y5B0 UNIPROT WEE1 protein P30291 UNIPROT up-regulates activity dephosphorylation 9606 27670139 YES miannu At mitosis exit, Fcp1 promoted inhibitory Cdk1 phosphorylation by dephosphorylating Wee1, and ubiquitin dependent cyclin B degradation by dephosphorylating Cdc20 and USP44.|This lead us to hypothesize that, during prolonged mitosis in AMCDs treated cancer cells, progressive Fcp1 induced Wee1 reactivation might lead to progressive loss of Cdk1 activity that weakens the SAC to a point in which the mitotic state could not be sustained . 0.382 SIGNOR-277142 PPM1G protein O15355 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation 9606 22361354 YES miannu After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. |ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.|DNA Damage Leads to ATM Dependent USP7S Dephosphorylation by PPM1G. 0.303 SIGNOR-277158 EGLN3 protein Q9H6Z9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates activity hydroxylation 9606 BTO:0000567 21620138 YES inferred from family member Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1Œ± and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. 0.436 SIGNOR-270290 PHF21A protein Q96BD5 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity binding -1 16140033 YES miannu BHC80 Inhibits LSD1 Demethylase Activity In Vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity. 0.715 SIGNOR-264505 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.59 SIGNOR-270911 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser439 EPGTATGsGIKSHNS 9606 15574499 YES amattioni Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility. 0.253 SIGNOR-131447 E2F1 protein Q01094 UNIPROT PCNA protein P12004 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 NO miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. 0.494 SIGNOR-253856 MAPK1 protein P28482 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 YES miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. 0.2 SIGNOR-277857 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR PSEN1 protein P49768 UNIPROT down-regulates activity phosphorylation Ser357 PHRSTPEsRAAVQEL 9606 BTO:0000007 17360711 YES gcesareni We demonstrate that phosphorylation of serines 353 and 357 by glycogen synthase kinase-3beta (gsk3beta) induces a structural change of the hydrophilic loop of ps1the structural change of ps1 reduces the interaction with beta-catenin leading to decreased phosphorylation and ubiquitination of beta-catenin. 0.395 SIGNOR-228022 ritanserin chemical CHEBI:64195 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 YES miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- 0.8 SIGNOR-258691 SYK protein P43405 UNIPROT LCK protein P06239 UNIPROT down-regulates activity phosphorylation Tyr192 NLDNGGFyISPRITF 9606 BTO:0000782 8798764 YES lperfetto Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling 0.591 SIGNOR-246562 PLK1 protein P53350 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Thr466 REAWRIFtPLLHQIE 9606 BTO:0000007 29138396 YES lperfetto We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD 0.346 SIGNOR-267581 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 YES miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. 0.2 SIGNOR-159394 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr775 TPMYGSQtPMYGSGS 9606 16427012 YES lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif 0.776 SIGNOR-143923 CDC42BPA protein Q5VT25 UNIPROT PPP1R12C protein Q9BZL4 UNIPROT down-regulates activity phosphorylation Thr560 MRQSRRStQGVTLTD BTO:0000298 11399775 YES llicata Identification of the Phosphorylation Site of p85 on Threonine 560 by MRCKα-CAT | Wild-type p85 but not the mutant p85AA, when phosphorylated in vitro with MRCKα-CAT, showed significant reduction in the rate of MLC2 dephosphorylation. These results confirm a similar observation with MBS130 where phosphorylation of a conserved threonine 695 within a highly conserved motif was essential for the inhibition of phosphatase catalytic activity 0.559 SIGNOR-250724 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120136 EN2 protein P19622 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. 0.417 SIGNOR-265775 MAPK3 protein P27361 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10906323 YES gcesareni Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function. 0.304 SIGNOR-79519 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.2 SIGNOR-263009 ITCH protein Q96J02 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys420 GLGSELSkPGVLASQ 9606 BTO:0002181 19881509 YES Giorgia These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation 0.645 SIGNOR-260363 CDC7 protein O00311 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates activity phosphorylation Ser409 GSSMDSKsSGWGM 9606 23424178 YES miannu Among these, CDC7 directly phosphorylates TDP-43 on serines 409 and 410 both in vitro and in vivo . 0.2 SIGNOR-278256 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 11108261 YES lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. 0.765 SIGNOR-84967 PCDH19 protein Q8TAB3 UNIPROT GABRA6 protein Q16445 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C334,SIGNOR-C328,SIGNOR-C329 29360992 YES miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  0.2 SIGNOR-267221 GPS1 protein Q13098 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.924 SIGNOR-270774 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser205 GVRRRRLsNVSLTGV 9606 10867018 YES llicata Activation of the serine/threonine kinase, protein kinase d (pkd/pkc mu) via a phorbol ester/pkc-dependent pathway involves phosphorylation events. the second autophosphorylation site (ser(203)) lies in that region of the regulatory domain 0.2 SIGNOR-78676 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248742 EIF3I protein Q13347 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.935 SIGNOR-266392 Calcineurin complex SIGNOR-C155 SIGNOR CACNA1H protein O95180 UNIPROT up-regulates activity dephosphorylation Ser2137 RDLRRLYsVDAQGFL 10090 BTO:0003695 38001892 YES miannu  we also discovered that a novel CaMKII-phosphorylated site, S2137, underwent dephosphorylation by calcineurin.  0.27 SIGNOR-277872 PTH1R protein Q03431 UNIPROT DKK1 protein O94907 UNIPROT down-regulates quantity 28363951 NO lperfetto Furthermore, PTH acts on osteocytes to suppress the expression of sclerostin, an inhibitor of canonical Wnt signaling (Li, et al. 2005; Semenov, et al. 2005)). PTH action on sclerostin is primarily through cAMP signaling (Keller and Kneissel 2005) and mediated by Myocyte enhancer factor-2 (MEF2) transcriptional regulators (Leupin, et al. 2007). Using the cAMP signaling pathway in osteoblasts, PTH also inhibits the expression of Dickkopf 1 (Dkk1) (Guo et al. 2010a), which is another Wnt pathway inhibitor  0.311 SIGNOR-270553 STK11 protein Q15831 UNIPROT MARK1 protein Q9P0L2 UNIPROT up-regulates phosphorylation Thr215 TVGNKLDtFCGSPPY 9606 14976552 YES lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold 0.411 SIGNOR-122545 tertatolol chemical CHEBI:135244 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258862 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR LEF1 protein Q9UJU2 UNIPROT up-regulates transcriptional regulation 9606 10890911 NO lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity 0.6 SIGNOR-217169 MAPKAPK2 protein P49137 UNIPROT KRT20 protein P35900 UNIPROT up-regulates activity phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 YES miannu P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13. 0.2 SIGNOR-263071 PRKDC protein P78527 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser33 ASGDYKYsGRDSLIF 9606 BTO:0001546 26337656 YES done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. 0.94 SIGNOR-274023 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 YES lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. 0.44 SIGNOR-144465 TNPO1 protein Q92973 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates activity relocalization 29970603 YES lperfetto TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import 0.574 SIGNOR-262099 DNA_damage stimulus SIGNOR-ST1 SIGNOR KDM4B protein O94953 UNIPROT up-regulates 9606 30759871 NO miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia. 0.7 SIGNOR-263736 SP1 protein P08047 UNIPROT IFITM5 protein A6NNB3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23530031 NO miannu Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation. 0.2 SIGNOR-254218 SOCS1 protein O15524 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates binding 9606 12433373 YES flangone Coimmunoprecipitation analyses demonstrated association of socs-1 with irak...This Finding suggests that socs-1 might suppress myd88-dependent signal pathways at least by binding to irak 0.401 SIGNOR-95528 NVP-BVU972 chemical CID:44206063 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194943 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates relocalization 10116 8645147 YES Activated hyperphosphorylated Akt-1 bound to Ptd Ins(3,4,5)P3 -containing vesicles in a similar manner to the inactive dephosphorylated enzyme 0.8 SIGNOR-254982 MMP13 protein P45452 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu442 TSKGDKElRTGKEKV -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain 0.2 SIGNOR-263613 AMPK complex SIGNOR-C15 SIGNOR YBX2 protein Q9Y2T7 UNIPROT up-regulates quantity by stabilization phosphorylation Thr115 GFINRNDtKEDVFVH 10090 BTO:0006430 37860762 YES miannu In this context, YBX2 is a dual substrate for both AMPK and Akt2. The phosphorylation at Thr115 by AMPK or at Ser137 by Akt2 facilitates YBX2 accumulation in brown adipocytes by decreasing ubiquitination-mediated degradation.  0.2 SIGNOR-277868 STUB1 protein Q9UNE7 UNIPROT DDIAS protein Q8IXT1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28079882 YES miannu HSP70 recruits DDIAS to the CHIP E3 ligase, whereas CHIP promotes the ubiquitination of DDIAS.|However, the findings clearly demonstrated that HSP70 was solely involved in CHIP mediated proteasomal degradation of DDIAS. 0.323 SIGNOR-278784 MAPK14 protein Q16539 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser982 VVGANRAsHRAAAPP 9606 BTO:0002181 38307877 YES miannu Here, we show that SHH inactivates p38α (MAPK14) in a smoothened-dependent manner, conversely, p38α directly phosphorylates GLI1 on Ser937/Ser941 (human/mouse) to induce GLI1's proteasomal degradation and negates the transcription of SHH signaling.  0.271 SIGNOR-277917  SAR1A protein Q9NR31 UNIPROT SEC24B protein O95487 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 YES lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 0.746 SIGNOR-265300 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRNA7 protein P36544 UNIPROT up-regulates activity chemical activation 27167578 YES Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth. 0.8 SIGNOR-253984 hsa-miR-338-3p mirna URS00000254A6_9606 RNAcentral SMO protein Q99835 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000675 23599646 YES Parnian MiR-338-3p, acts as a local regulator of SMO by binding to the 3’-UTR of its mRNA, thereby modulating CRC development. 0.4 SIGNOR-277977 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 17804415 YES gcesareni Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun. 0.37 SIGNOR-157721 PASK protein Q96RG2 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation -1 16275910 YES gcesareni Recombinant human PASK (hPASK) phosphorylates purified muscle glycogen synthase, causing robust inactivation. Furthermore, hPASK interacts directly with glycogen synthase when expressed in cultured cells and this interaction and the phosphorylation of glycogen synthase by human PASK (hPASK) are inhibited by glycogen. 0.509 SIGNOR-245866 CAMK2G protein Q13555 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates phosphorylation 9606 12482967 YES gcesareni Camkii interacts with and phosphorylates tak1. 0.2 SIGNOR-96422 LPAR2 protein Q9HBW0 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257324 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser64 EPDLKKEsEEDKFPV 9606 15889150 YES llicata We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta. 0.464 SIGNOR-137089 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr589 TGSSDNEyFYVDFRE 10090 BTO:0001516 16627759 YES lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.|This finding suggests that the combination of tyrosine residues 589 and 591 is required for activation of STAT-5 signaling pathways. 0.2 SIGNOR-271926 MAPK1 protein P28482 UNIPROT ZFP36 protein P26651 UNIPROT unknown phosphorylation Ser228 PPGDLPLsPSAFSAA 10090 BTO:0000944 7768935 YES lperfetto By a combination of protease digestion experiments and site-directed mutagenesis strategies, we found that serine 220 was phosphorylated by p42 MAP kinase in vitro. Expression of mutant TTP in fibroblasts confirmed that serine 220 was one of the major, mitogen-stimulated phosphorylation sites on the protein in intact cells. |It is not obvious how phosphorylation of TTP at serine 220 would alter DNA binding, since this residue lies well outside of the putative zinc finger region, which is between amino acids 95 to 159 in the mouse protein 0.457 SIGNOR-249456 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Arg707 ESTVMATrKMHDRLE -1 7989361 YES lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. 0.6 SIGNOR-263630 CDK1 protein P06493 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 YES gcesareni We show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of beta-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2) 0.858 SIGNOR-139465 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 11606584 YES gcesareni By measuring the ability of human plcgamma2 to restore calcium responses to the b-cell receptor stimulation or oxidative stress in a b-cell line (dt40) deficient in plcgamma2, we have demonstrated that two tyrosine residues, tyr(753) and tyr(759), were important for the plcgamma2 signaling function.Of the two kinases that previously have been proposed to phosphorylate plcgamma2, btk, and syk, purified btk had much greater ability to phosphorylate recombinant plcgamma2 in vitro, whereas syk efficiently phosphorylated adapter protein blnk. 0.777 SIGNOR-111069 CREBBP protein Q92793 UNIPROT POU1F1 protein P28069 UNIPROT up-regulates activity binding 9606 BTO:0001379 10931853 YES scontino  We and others have recently shown that CBP can constitutively bind to Pit-1 and synergistically activate transcription of promoters containing Pit-1 DNA-binding sites. 0.381 SIGNOR-267204 MAPK1 protein P28482 UNIPROT ESPL1 protein Q14674 UNIPROT down-regulates phosphorylation Ser1126 IAPSTNSsPVLKTKP 9606 11747808 YES lperfetto Both cdc2/cyclinb1 and mapk (erk2) efficiently phosphorylate separase at its major inhibitory site in vitro 0.277 SIGNOR-113130 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 16166196 YES lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. 0.8 SIGNOR-268661 USF2 protein Q15853 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 NO miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. 0.2 SIGNOR-222608 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1644 SPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248817 GSK3B protein P49841 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity phosphorylation Ser663 EFDELNPsAQRDACL 9606 BTO:0000562 37291092 YES miannu GSK3β-dependent phosphorylation of SERCA2 at serine 663 in human and mouse hearts. Phosphorylation of SERCA2 at serine 663 regulates SERCA2 activity.  0.283 SIGNOR-277886 FADS3 protein Q9Y5Q0 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267913 POMT complex SIGNOR-C372 SIGNOR DGC complex SIGNOR-C217 SIGNOR up-regulates activity glycosylation 9606 BTO:0000007 14699049 YES miannu we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O-mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O-mannosylation is complex. Further, protein O-mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain. 0.407 SIGNOR-265431 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 9219684 YES gcesareni The three-dimensional structure of the complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms. 0.848 SIGNOR-49477 EIF4H protein Q15056 UNIPROT EIF4A1 protein P60842 UNIPROT up-regulates activity binding -1 11418588 YES Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability 0.802 SIGNOR-261294 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 10910062 YES AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬† 0.2 SIGNOR-251482 IMPDH1 protein P20839 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 19480389 YES miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). 0.8 SIGNOR-267331 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Thr714 EESDSSEtEKEDDEG 21296876 YES lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. 0.2 SIGNOR-275502 MECP2 protein P51608 UNIPROT IGFBP3 protein P17936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 17278996 NO miannu We found that MeCP2 directly regulates expression of insulin-like growth factor binding protein 3 (IGFBP3) gene in human and mouse brains. IGFBP3 overexpression was observed in the brains of mecp2-null mice and human RTT patients using real-time quantitative polymerase chain reaction and Western blot analyses. 0.251 SIGNOR-254580 inosine smallmolecule CHEBI:17596 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity precursor of -1 15926889 YES Luana Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates 0.8 SIGNOR-269734 STK3 protein Q13188 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 YES lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 0.2 SIGNOR-181056 Elongator complex complex SIGNOR-C466 SIGNOR TUBA3E protein Q6PEY2 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 YES miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. 0.252 SIGNOR-269718 CSF1 protein P09603 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 33505964 NO miannu  Exosomes from tumor cells package assorted proteins and chemokines with immunomodulatory capability, including CSF-1, CCL2, and TGF-β, to promote M2-like characterization of TAMs 0.7 SIGNOR-277708 Ub:E2 complex SIGNOR-C497 SIGNOR SH3RF3 protein Q8TEJ3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271039 MTSS1 protein O43312 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 YES miannu We found that in vitro translated gli1 and sufu bind to gst-mim, but not gst-mim?N399 Or gst columns (fig. 4f). Indicative of the importance of the mim/gli complex interactions, the mim?N399 Mutant that fails to interact with gli and sufu showed a markedly reduced capacity to potentiate gli-dependent transcription (fig. 4g). Although these results indicate that a mim/gli/sufu complex is important for mim-mediated transcriptional potentiation 0.438 SIGNOR-130545 PTMS protein P20962 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 16150697 YES miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner 0.329 SIGNOR-268460 AP1 complex SIGNOR-C154 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 NO Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. 0.7 SIGNOR-260765 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR TOP2A protein P11388 UNIPROT up-regulates quantity by expression transcriptional regulation 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276582 CEBPB protein P17676 UNIPROT SLC19A1 protein P41440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15652157 YES Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation. 0.2 SIGNOR-254053 PHF1 protein O43189 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 YES miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. 0.287 SIGNOR-260069 Ub:E2 complex SIGNOR-C497 SIGNOR SMURF2 protein Q9HAU4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271298 STK11 protein Q15831 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr167 NKDYHLQtCCGSLAY 9606 16216881 YES fstefani Site-directed mutagenesis indicated that thr167 and ser171, located between the dfg and ape motifs in the activation loop or t-loop, need to be autophosphorylated for melk to be active as a protein kinase (fig. 5). These sites are conserved in all other ampk-related protein kinases (fig. 4a), and the site corresponding to thr167 has been shown to be phosphorylated by protein kinase lkb1 (5). 0.2 SIGNOR-141038 PRKCD protein Q05655 UNIPROT ITGB7 protein P26010 UNIPROT unknown phosphorylation Thr783 PLYKSAItTTINPRF 10090 BTO:0001825 12682249 YES lperfetto Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784). 0.306 SIGNOR-249205 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr199 VKKSIRDtPAKNAQK 9606 12058066 YES lperfetto However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation. 0.408 SIGNOR-216845 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001109 27517626 YES Our findings suggested that miR-126 acts as a tumor suppressor by inactivating the RhoA signaling pathway via CXCR4 in colon cancer. And miR-126 may serve as a prognostic marker for monitoring and treating colon cancer. 0.4 SIGNOR-277930 DRD1 protein P21728 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.494 SIGNOR-257335 PLK1 protein P53350 UNIPROT RAD21 protein O60216 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser175 REIMREGsAFEDDDM 9606 BTO:0000567 15737063 YES lperfetto We suspected that the observed enhancement of Scc1's cleavability in the presence of Plk1 might be due to phosphorylation at two sites that are directly adjacent to the cleavage sites, Ser175 and Ser454, which we had found to be phosphorylated in mitosis in vivo (Table 1). We therefore mutated these two residues to alanine, thereby creating mutant Scc1-S175A/S454A (see Figure 1C), and tested the cleavability of this mutant in the absence or presence of Plk1 in vitro. |Scc1 phosphorylation is dispensable for cohesin dissociation from chromosomes in early mitosis but enhances the cleavability of Scc1 by separase. 0.736 SIGNOR-275535 RPIA protein P49247 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI down-regulates quantity chemical modification 9606 34775382 YES miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. 0.8 SIGNOR-267067 TRIM41 protein Q8WV44 UNIPROT PRKCE protein Q02156 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 17893151 YES miannu RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear. 0.2 SIGNOR-271668 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.91 SIGNOR-252844 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.8 SIGNOR-260675 IL34 protein Q6ZMJ4 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000801 39416792 YES miannu CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK 0.912 SIGNOR-277714 GNE protein Q9Y223 UNIPROT UDP-N-acetyl-alpha-D-glucosamine smallmolecule CHEBI:16264 ChEBI down-regulates quantity chemical modification 10745088 YES lperfetto UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate. 0.8 SIGNOR-266073 PCDHAC2 protein Q9Y5I4 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-269033 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271808 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 19623618 YES gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. 0.303 SIGNOR-187209 TANK protein Q92844 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity binding 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.734 SIGNOR-262714 Ub:E2 complex SIGNOR-C497 SIGNOR RNF165 protein Q6ZSG1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271176 RPS6KA3 protein P51812 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19112174 YES gcesareni S6k1 regulates estrogen receptor alpha (eralpha) by phosphorylating it on serine 167, leading to transcriptional activation of eralpha. 0.403 SIGNOR-182958 PIK3CA protein P42336 UNIPROT MTOR protein P42345 UNIPROT up-regulates 9606 18721898 NO lperfetto Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3. 0.547 SIGNOR-180453 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21524151 NO miannu In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F 0.7 SIGNOR-262532 WWP1 protein Q9H0M0 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT up-regulates activity ubiquitination Lys408 ANRRLASkTQEAQAG 9606 BTO:0000007 34404733 YES lperfetto AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation|Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408. 0.29 SIGNOR-271874 PRKCE protein Q02156 UNIPROT NSF protein P46459 UNIPROT up-regulates activity phosphorylation Ser460 MNRHIKAsTKVEVDM 9606 20962217 YES miannu PKCepsilon phosphorylation enhances the ATPase activity of NSF.|These results indicate that PKCepsilon phosphorylates NSF at both S460 and T461 in vitro. 0.234 SIGNOR-278300 RHOQ protein P17081 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates binding 9606 12687004 YES gcesareni Here we show that tc10 interacts with one of the components of the exocyst complex, exo70. 0.635 SIGNOR-100486 CRH protein P06850 UNIPROT CRHR1 protein P34998 UNIPROT up-regulates binding 9606 11416224 YES gcesareni Crf and ucn bind and activate crf-r1 with similarly high affinities. 0.958 SIGNOR-108713 AKT1 protein P31749 UNIPROT MAPKAP1 protein Q9BPZ7 UNIPROT up-regulates activity phosphorylation Thr86 GIRRRSNtAQRLERL 10090 BTO:0002572 26235620 YES miannu Akt phosphorylates SIN1 at T86, enhancing mTORC2 kinase activity, which leads to phosphorylation of Akt S473 by mTORC2, thereby catalyzing full activation of Akt. 0.702 SIGNOR-276932 DYRK1B protein Q9Y463 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL 9534 BTO:0000298 14593110 YES miannu DYRK Family Protein Kinases Phosphorylate and Inactivate Glycogen Synthase. both protein kinases phosphorylate site 3a but no other sites that affect glycogen synthase activity. 0.258 SIGNOR-260633 HCRTR2 protein O43614 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257290 TSPO2 protein Q5TGU0 UNIPROT VDAC1 protein P21796 UNIPROT up-regulates activity binding 9606 BTO:0000424 30061676 YES miannu Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT. 0.309 SIGNOR-261826 SLC9A6 protein Q92581 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 YES miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  0.8 SIGNOR-265596 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser803 QREIQMDsPMLLADL 9606 BTO:0000567 20667468 YES miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. 0.2 SIGNOR-259826 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11486000 YES lperfetto Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes. 0.871 SIGNOR-109647 PPME1 protein Q9Y570 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates activity demethylation Leu309 RRTPDYFl -1 18394995 YES lperfetto Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. 0.715 SIGNOR-265750 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 YES miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. 0.8 SIGNOR-256239 USF1 protein P22415 UNIPROT GATA5 protein Q9BWX5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22625849 NO miannu The present study provides the first evidence that USF1 activates GATA5 gene expression through the E-box motif and suggests a potential mechanism (disruption of the E-box) by which GATA5 promoter methylation reduces GATA5 expression in cancer. 0.335 SIGNOR-255596 PRKCA protein P17252 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Thr276 GFRKRWFtMDDRRLM -1 12893243 YES lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5). 0.318 SIGNOR-249225 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr969 VSECPHTyQNRRPFS 10090 BTO:0001516 16627759 YES lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. 0.2 SIGNOR-271920 Ub:E2 complex SIGNOR-C497 SIGNOR VPS41 protein P49754 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271153 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL6 protein P41182 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0000785 9649500 YES inferred from 70% family members gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. 0.2 SIGNOR-270140 HDAC4 protein P56524 UNIPROT HOXB13 protein Q92826 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19013255 NO miannu Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers. 0.261 SIGNOR-254232 ATM protein Q13315 UNIPROT PIDD1 protein Q9HB75 UNIPROT up-regulates activity phosphorylation Thr788 DAETGFLtQSNLLSV 9606 BTO:0000567 22854598 YES miannu ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury. 0.635 SIGNOR-262640 LPAR3 protein Q9UBY5 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 15856019 YES gcesareni Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. 0.465 SIGNOR-135843 PRKCA protein P17252 UNIPROT HMGN2 protein P05204 UNIPROT down-regulates phosphorylation Ser29 QRRSARLsAKPAPPK 9606 10739259 YES lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. 0.29 SIGNOR-76324 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser247 GALSNSEsIPTIDGL 9534 BTO:0000298 11483516 YES llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. 0.291 SIGNOR-250599 MCHR2 protein Q969V1 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257439 CSNK1E protein P49674 UNIPROT APC protein P25054 UNIPROT up-regulates activity phosphorylation Ser1279 SRCSSLSsLSSAEDE 9606 BTO:0000038 11487578 YES lperfetto Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin. 0.613 SIGNOR-109660 Av/b8 integrin complex SIGNOR-C185 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 NO miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. 0.7 SIGNOR-269029 PPP2CA protein P67775 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser87 PLKQKQPsFSAKKMT 9606 BTO:0000567 24781523 YES miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase 0.295 SIGNOR-276378 PTK2B protein Q14289 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15105428 YES llicata Overexpression of pyk2 alone led to its spontaneous activation and tyrosine phosphorylation, resulting in activation of stat5b, indicated by the reporter gfp-stat5b. These effects were completely dependent upon tyr(402), the autophosphorylation site of pyk2, which allows recruitment of src family members for further activating phosphorylations at other sites on pyk2. 0.2 SIGNOR-124339 CDK1 protein P06493 UNIPROT USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2047 QRVSDQNsPVLPKKS 9606 BTO:0000018 27991932 YES lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. 0.2 SIGNOR-275604 IKBKE protein Q14164 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 24622840 YES miannu STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3. 0.645 SIGNOR-260155 APOB protein P04114 UNIPROT LDLR protein P01130 UNIPROT up-regulates binding 9606 11986215 YES gcesareni In the case of ldl, binding of apolipoprotein b (apob) to the ldl-r18-20 and proteoglycans17 21 initiates plasma clearance and lipoprotein degradation 0.804 SIGNOR-87035 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates activity phosphorylation Thr267 KSNLKRVtLELGGKS -1 28193222 YES miannu AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.  0.372 SIGNOR-276750 CBLB protein Q13191 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity 9606 BTO:0004175 27773928 NO miannu We have also shown that the E3 ubiquitin ligase Cbl-b is crucial for activation of the p53 pathway through ubiquitinating and promoting degradation of Siva1, the E3 ubiquitin ligase targeting ARF, a positive regulator of p53. On the basis of our data presented in the study, we propose the model (Figure 2i) that Cbl-b negatively regulates Siva1 by ubiquitination and subsequent degradation of Siva1, which is followed by stabilization of ARF. This in turn downregulates MDM2, thereby promoting the induction of p53 and activation of its downstream targets. 0.2 SIGNOR-261320 PRKACA protein P17612 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Ser189 GGGERFDsLTDLVEH 9606 BTO:0002181 25802336 YES miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  0.45 SIGNOR-276892 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR PLK1 protein P53350 UNIPROT down-regulates activity monoubiquitination Lys492 YMSEHLLkAGANITP -1 23455478 YES miannu Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors.  0.418 SIGNOR-272110 LPAR3 protein Q9UBY5 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.498 SIGNOR-257357 PRKAA2 protein P54646 UNIPROT ACACB protein O00763 UNIPROT down-regulates activity phosphorylation Ser222 PTMRPSMsGLHLVKR 9606 9148944 YES miannu The results suggest that the decrease in ACC activity during muscle contraction is caused by an increase in its phosphorylation, most probably due, at least in part, to activation of the alpha2 isoform of AMPK. 0.648 SIGNOR-250318 MECOM protein Q03112 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates activity binding 21695170 YES lperfetto The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA|Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. 0.294 SIGNOR-273432 TP53 protein P04637 UNIPROT TBXAS1 protein P24557 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14586398 NO miannu We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription. 0.2 SIGNOR-254086 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 NO lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth 0.816 SIGNOR-236436 INS protein P01308 UNIPROT RHOQ protein P17081 UNIPROT up-regulates 9606 12687004 NO gcesareni Exo70 translocates to the plasma membrane in response to insulin through the activation of tc10, where it assembles a multiprotein complex that includes sec6 and sec8 0.287 SIGNOR-100483 XRCC4 protein Q13426 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 10854421 NO miannu The DNA-dependent protein kinase (DNA-PK), consisting of Ku and the DNA-PK catalytic subunit (DNA-PKcs), and the DNA ligase IV-XRCC4 complex function together in the repair of DNA double-strand breaks by non-homologous end joining. 0.7 SIGNOR-264530 ACE2 protein Q9BYF1 UNIPROT Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT up-regulates quantity cleavage 9606 32201502 YES miannu At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function. 0.2 SIGNOR-260227 EGFR protein P00533 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr168 TLMEKDSyPRFLKSP 9606 12588871 YES gcesareni Phosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). We show here that endogenous rgs16 is phosphorylated after epidermal growth factor stimulation of mcf-7 cells. 0.416 SIGNOR-98267 AKAP13 protein Q12802 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.744 SIGNOR-260527 ATP5ME protein P56385 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 YES miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. 0.2 SIGNOR-261407 YAP1 protein P46937 UNIPROT TEAD proteinfamily SIGNOR-PF22 SIGNOR up-regulates activity binding 9606 23431053 YES miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death 0.942 SIGNOR-230719 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser411 RNCSTNDsLL -1 8662852 YES we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). 0.693 SIGNOR-251198 NRCAM protein Q92823 UNIPROT ANK3 protein Q12955 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 YES miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. 0.72 SIGNOR-266720 GSK3B protein P49841 UNIPROT MUC1 protein P15941 UNIPROT down-regulates activity phosphorylation Ser1227 PPSSTDRsPYEKVSA BTO:0000567 9819408 YES lperfetto GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo. 0.457 SIGNOR-249356 RBBP7 protein Q16576 UNIPROT HAT1 protein O14929 UNIPROT up-regulates activity binding -1 28143904 YES lperfetto AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity 0.898 SIGNOR-264786 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 YES gcesareni Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase. 0.685 SIGNOR-33201 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition 9606 20570526 YES Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], 0.8 SIGNOR-257849 SL-327 chemical CHEBI:92211 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 11160424 YES gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity 0.8 SIGNOR-104930 CEP63 protein Q96MT8 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 YES lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. 0.373 SIGNOR-271725 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 16420481 YES The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. 0.407 SIGNOR-143841 tiotropium chemical CHEBI:90960 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition -1 8441333 YES miannu A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors. 0.8 SIGNOR-258485 CAMKK1 protein Q8N5S9 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 YES gcesareni Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli. 0.464 SIGNOR-176598 DNM1 protein Q05193 UNIPROT MYO1E protein Q12965 UNIPROT up-regulates activity binding 10116 BTO:0000142 17257598 YES miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. 0.333 SIGNOR-265424 MBD3/NuRD complex complex SIGNOR-C338 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 27098840 NO miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. 0.7 SIGNOR-263860 MAPK1 protein P28482 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 1939237 YES lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. 0.554 SIGNOR-22420 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity phosphorylation Tyr795 FPNTEPFyAAFGNRP 9606 BTO:0002181 33203880 YES miannu Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. 0.2 SIGNOR-277291 SUZ12 protein Q15022 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 YES lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). 0.926 SIGNOR-241900 C1D protein Q13901 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates activity binding 9606 BTO:0000567 9405624 YES 2 miannu SUN-CoR is a protein involved in transcriptional repression by nuclear hormone receptors. The C terminus of SUN-CoR interacts with TR and RevErb in vitro and associates with RevErb in cells, SUN-CoR potentiates repression by both receptors in cells, and the N terminus of SUN-CoR contains an intrinsic repression domain. 0.314 SIGNOR-241272 CDK1 protein P06493 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity phosphorylation 9606 BTO:0003918 19917720 YES lperfetto Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis. 0.538 SIGNOR-267986 SMARCC1 protein Q92922 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.836 SIGNOR-269824 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFV1 protein P49821 UNIPROT up-regulates activity phosphorylation Thr383 HESCGQCtPCREGVD 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275602 PLK1 protein P53350 UNIPROT GTSE1 protein Q9NYZ3 UNIPROT up-regulates phosphorylation Ser435 RSIRRRDsCLNSKTK 9606 20577264 YES lperfetto In this study, we show that g2 and s-phase-expressed 1 (gtse1) protein, a negative regulator of p53, is required for g2 checkpoint recovery and that plk1 phosphorylation of gtse1 at ser 435 promotes its nuclear localization, and thus shuttles p53 out of the nucleus to lead to its degradation during the recovery. 0.735 SIGNOR-166417 OPRK1 protein P41145 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.314 SIGNOR-257105 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile chemical CHEBI:95341 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition 9606 20363976 YES Luana INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). 0.8 SIGNOR-257832 NDFIP2 protein Q9NV92 UNIPROT NEDD4 protein P46934 UNIPROT down-regulates activity relocalization 9606 BTO:0002181 26363003 YES SARA Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. 0.57 SIGNOR-260995 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 YES amattioni Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation. 0.34 SIGNOR-85175 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C15 17900900 YES gcesareni The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation 0.517 SIGNOR-252981 DYRK1A protein Q13627 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates phosphorylation 9606 BTO:0000142 19383720 YES gcesareni Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch . 0.396 SIGNOR-254313 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr531 HEEDADSyENMDNPD 10090 BTO:0000776 10933394 YES lperfetto Experiments with purified proteins demonstrated that CD19-Y513 was Lyn's initial phosphorylation and binding site. This led to processive phosphorylation of CD19-Y482, which recruited a second Lyn molecule, allowing for transphosphorylation and amplification of Lyn activation|Tyrosine phosphorylation of CD19 following BCR and/or CD19 ligation provides Src homology 2 (SH2) recognition motifs that recruit regulatory molecules to the cell surface. CD19 dually phosphorylated at CD19€“Y482 and CD19€“Y513 binds the tandem SH2 domains of phosphatidylinositol 3-kinase (PI 3-kinase) p85 subuni 0.772 SIGNOR-249377 JAK2 protein O60674 UNIPROT LEPR protein P48357 UNIPROT up-regulates activity phosphorylation Tyr986 QRQPFVKyATLISNS 9606 BTO:0000007 11018044 YES miannu LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2. 0.773 SIGNOR-263493 CTTN protein Q14247 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 NO miannu Cortactin is an F-actin binding protein and activator of the Arp2/3 actin nucleation machinery that also interacts with the postsynaptic density (PSD) protein Shank. Cortactin is concentrated in dendritic spines of cultured hippocampal neurons, and the N-terminal half of the protein containing the Arp2/3 and F-actin binding domains is necessary and sufficient for spine targeting. 0.7 SIGNOR-266595 CLOCK protein O15516 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21164265 YES lperfetto We recently reported that the basic helix-loop- helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the 'lysine cluster' located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a target tissue counter-regulatory mechanism to the diurnally fluctuating circulating glucocorticoids. 0.411 SIGNOR-253699 SOD1 protein P00441 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity binding 10090 BTO:0004488 18519638 YES P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK 0.274 SIGNOR-262787 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 YES Epiregulin may be a mediator of localized cell proliferation gcesareni Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. 0.892 SIGNOR-165782 SLC27A3 protein Q5K4L6 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264464 dothiepin chemical CHEBI:36798 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 YES miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. 0.8 SIGNOR-258698 NFIB protein O00712 UNIPROT ANOS1 protein P23352 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268878 PPP2R2A protein P63151 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity binding 10090 BTO:0000944 18042541 YES gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). 0.483 SIGNOR-243526 NBEA protein Q8NFP9 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 9606 BTO:0000007 BTO:0000227 26999814 YES lperfetto Yeast two-hybrid identified the Notch1 intracellular domain as a physical interactor of the PBW domain and a role for NBEA as a negative regulator in Notch-mediated transcription was demonstrated.|Defining novel interaction partners of conserved NBEA domain modules identified a role for NBEA as transcriptional regulator in the nucleus. The physical interaction of NBEA with NOTCH1 is most relevant for ASD pathogenesis because NOTCH signaling is essential for neural development. 0.305 SIGNOR-266010 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser397 GKNQDFSsFDDTGKS 9606 BTO:0000567 19509060 YES lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. 0.617 SIGNOR-272994 TGFBRAP1 protein Q8WUH2 UNIPROT CORVET tethering complex complex SIGNOR-C550 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.748 SIGNOR-273695 FLI1 protein Q01543 UNIPROT IL10 protein P22301 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20879862 NO In terms of cytokine expression, increased FLI-1 levels specifically enhanced IL-10 expression 0.2 SIGNOR-254516 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 21310273 YES miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans 0.8 SIGNOR-267814 RNF43 protein Q68DV7 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates relocalization 9606 23151663 YES gcesareni Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation61 (see above), and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane 0.308 SIGNOR-199585 LATS2 protein Q9NRM7 UNIPROT YWHAG protein P61981 UNIPROT up-regulates phosphorylation Ser59 VVGARRSsWRVISSI 9606 25086053 YES lperfetto Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions, 0.331 SIGNOR-205247 CHUK protein O15111 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Thr205 EGPSEYQtIPLNKIE -1 31950832 YES lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. 0.325 SIGNOR-275508 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 21454478 YES gcesareni In addition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r/co-smad complex and further promoting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner 0.344 SIGNOR-172996 SNU13 protein P55769 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.2 SIGNOR-270629 VRK1 protein Q99986 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr2 tTSQKHRD 9606 16495336 YES lperfetto Herein, we demonstrate that b1, vrk1, and vrk2 efficiently phosphorylate the extreme n' terminus of the baf protein. We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain 0.876 SIGNOR-144787 WNT6 protein Q9Y6F9 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 NO gcesareni In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. 0.323 SIGNOR-60418 AP2M1 protein Q96CW1 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19351721 YES gcesareni The removal of the epidermal growth factor receptor (egfr) from the cell surface by endocytosis is triggered by receptor activation, but many facets of egfr trafficking remain unresolvedthe ap-2 complex is involved in the internalization of activated egfr. 0.523 SIGNOR-185124 PKA proteinfamily SIGNOR-PF17 SIGNOR SLC8B1 protein Q6J4K2 UNIPROT up-regulates activity phosphorylation Ser258 YQRQRRGsLFCPMPV 36476859 YES Phosphosite is derived from the graphical abstract lperfetto However, the PDE2-inhibitory effect is eliminated when the mitochondrial S258A NCLX mutant that mimics a non-PKA phosphorylated state of NCLX is expressed. Altogether, our findings indicate that NCLX is regulated by the mitochondrial PDE2A2 form.|We show that caffeine, by inhibiting PDE2, enhances PKA phosphorylation leading to mitochondrial NCLX activation, thereby reducing neuronal excitotoxicity and enhancing learning in mice. |Moreover, PDE2 acts by diminishing mitochondrial cAMP, thus promoting NCLX phosphorylation at its PKA site. 0.2 SIGNOR-275728 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser165 RESSLSPsPASSISS 9606 BTO:0000782 9374467 YES lperfetto Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation 0.711 SIGNOR-53368 FLNA protein P21333 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 20156194 YES miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself 0.522 SIGNOR-260629 FBXL5 protein Q9UKA1 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 19762596 YES miannu  We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus.  0.657 SIGNOR-271884 TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 11847341 YES lperfetto Here, we report an unexpected activation mechanism for p38alpha MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38alpha with TAB1 [transforming growth factor-beta-activated protein kinase 1 (TAK1)-binding protein 1] leading to autophosphorylation and activation of p38alpha. 0.823 SIGNOR-114843 RPS6K proteinfamily SIGNOR-PF26 SIGNOR WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 YES llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. 0.2 SIGNOR-252810 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 YES gcesareni We have identified ptp1b and tcptp as negative regulators of the hepatocyte growth factor receptor, the met receptor-tyrosine kinase. In vivo, loss of ptp1b or tcptp enhances hepatocyte growth factor-mediated phosphorylation of met. 0.5 SIGNOR-181335 SMARCB1 protein Q12824 UNIPROT CCNA2 protein P20248 UNIPROT down-regulates 9606 12226744 NO miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. 0.345 SIGNOR-92782 CUL2 protein Q13617 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 YES miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. 0.31 SIGNOR-268845 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC5R protein P33032 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.2 SIGNOR-268716 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 BTO:0000567 10702313 YES gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. 0.8 SIGNOR-75389 DVL2 protein O14641 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity 9606 19279717 YES areggio Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin 0.268 SIGNOR-258979 SMARCD1 protein Q96GM5 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.67 SIGNOR-269785 GNG12 protein Q9UBI6 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000586 16293724 YES gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. 0.411 SIGNOR-141792 PRSS1 protein P07477 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 YES lperfetto Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. 0.387 SIGNOR-263602 ROCK1 protein Q13464 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 12686604 YES lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. 0.312 SIGNOR-100181 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 23431053 YES milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity 0.816 SIGNOR-201290 metoprolol chemical CHEBI:6904 ChEBI ADRB1 protein P08588 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 10079020 YES Luana In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue 0.8 SIGNOR-258337 PIK3R4 protein Q99570 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 YES lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.884 SIGNOR-260321 SRC protein P12931 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 YES lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. 0.635 SIGNOR-247316 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 19008118 YES FFerrentino In mesenchymal precursor cells, Wnt10b (and Wnt10a) binding to frizzled (FZD1) 0.663 SIGNOR-253511 MAP3K7 protein O43318 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser463 SPHNPISsVS 9606 19536134 YES miannu This analysis showed that phosphorylation of Smad1 at the C-terminal serines S463 and S465 was increased by co-expression of constitutively active TAK1. 0.374 SIGNOR-279419 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 15568999 YES lperfetto Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites 0.61 SIGNOR-131375 RPS6KB1 protein P23443 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates 10090 BTO:0002572 20670887 NO lperfetto We find that srebp1 and 2 promote proliferation downstream of mtorc1, and the activation of these transcription factors is mediated by s6k1. 0.425 SIGNOR-167190 GART protein P22102 UNIPROT N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI down-regulates quantity chemical modification 9606 34283828 YES miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 0.8 SIGNOR-268101 FHIT protein P49789 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates 9606 BTO:0000551 15313915 NO miannu We found that this synergistic inhibition of tumor cell growth corresponded with the fhit-mediated inactivation of mdm2, which thereby blocked the association of mdm2 with p53, thus stabilizing the p53 protein. 0.429 SIGNOR-127610 hsa-miR-133b mirna URS000032BD73_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000038 24330809 YES CXCR4 was shown to be a direct target of miR-133b by luciferase reporter assays, and transfection of miR-133b mimics inhibited invasion and stimulated apoptosis of SW-480 and SW-620 CRC cells. 0.4 SIGNOR-277931 MYC protein P01106 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates activity binding 9606 19786833 YES irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. 0.711 SIGNOR-255806 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507-3 UNIPROT down-regulates phosphorylation Thr11 SPSLRRMtVMREKGR 9606 BTO:0000007 16331690 YES The effect has been demonstrated using Q13507-3 llicata The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263. 0.408 SIGNOR-142957 PRKACA protein P17612 UNIPROT KCNK9 protein Q9NPC2 UNIPROT up-regulates phosphorylation Ser373 RLMKRRKsV 9606 BTO:0000007 21357689 YES llicata Patch clamp analysis, flow cytometry, and immunocytochemistry studies of hek293 transfected with wt hk2p3.1 and cultured in the presence of pka activators or inhibitors all confirm that activation of pka resulted in an increase in hk2p3.1 current expression (figs. 4_4?6) and demonstrate the dynamic regulatory effect of pka activity on k2p3.1 channel expression. 0.2 SIGNOR-172466 PRKG1 protein Q13976 UNIPROT RGS18 protein Q9NS28 UNIPROT up-regulates activity phosphorylation Ser216 PTNLRRRsRSFTCNE 9606 BTO:0000132 24244663 YES done miannu Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216. S216 phosphorylation might activate PP1 leading to dephosphorylation of both 14-3-3 binding sites, S49 and S218, and detachment of 14-3-3. Removal of 14-3-3 activates RGS18 to turn off Gq signaling thus contributing to platelet inhibition. 0.332 SIGNOR-273785 EGFR protein P00533 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000356 12354693 YES llicata Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. | In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation. 0.613 SIGNOR-251094 belinostat chemical CHEBI:61076 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257747 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-138475 STOML2 protein Q9UJZ1 UNIPROT OPA1 protein O60313 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 NO Giorgia Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion. 0.312 SIGNOR-260381 AMPK complex SIGNOR-C15 SIGNOR FH protein P07954 UNIPROT up-regulates activity phosphorylation Ser75 YGAQTVRsTMNFKIG -1 28628081 YES miannu Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes. 0.2 SIGNOR-266313 MAPKAPK2 protein P49137 UNIPROT PARN protein O95453 UNIPROT down-regulates phosphorylation Ser557 NHYYRNNsFTAPSTV 9606 20932473 YES lperfetto Mk2 phosphorylates parn, blocking gadd45_ mrna degradation. Parn can serve as a direct substrate for mk2, and demonstrating that ser-557 is the dominant mk2 phosphorylation site. 0.376 SIGNOR-168377 CPT1B protein Q92523 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 ChEBI down-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267121 TCL1B protein O95988 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES gcesareni In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation. 0.559 SIGNOR-81716 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser474 HFPQFSYsASGRE 9606 18160256 YES Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. 0.493 SIGNOR-248609 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20044479 YES lperfetto We have described that upon ligand binding, igf-1r directly interacts with and phosphorylates pdk1 at tyr373/376 0.341 SIGNOR-236544 FBXO27 protein Q8NI29 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 28743755 YES miannu Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment.We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy. 0.674 SIGNOR-272325 TFAP2A protein P05549 UNIPROT ECM1 protein Q16610 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17187826 NO miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. 0.2 SIGNOR-255401 SH2B3 protein Q9UQQ2 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22101255 NO miannu Our results indicated that lnk/sh2b3 constrains expression of bcl-xl and participates in the regulation of hsc homeostasis by maintaining proper responses against various proapoptotic stimuli. 0.2 SIGNOR-177485 PBX3 protein P40426 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.2 SIGNOR-265779 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR BORA protein Q6PGQ7 UNIPROT up-regulates activity phosphorylation 9606 18521620 YES gcesareni Our data additionally identify the cdk1 site s252 as critical for the recruitment of plk1 to hbora. collectively, our findings lead us to propose that hbora contributes to integrate the functions of three major mitotic kinases, cdk1, plk1, and aurora a. 0.573 SIGNOR-178799 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser281 DGTGDTSsEEDEDEE 9606 11278496 YES lperfetto TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels 0.677 SIGNOR-246634 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser296 KQRRSIIsPNFSFMG 9606 16286470 YES lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain 0.786 SIGNOR-141605 STK38 protein Q15208 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates activity phosphorylation Ser277 RTHQRSKsDATASIS 10090 BTO:0000142 22445341 YES miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. 0.267 SIGNOR-263033 pazopanib hydrochloride chemical CHEBI:71217 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition -1 17620431 YES miannu The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. 0.8 SIGNOR-259451 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser402 ISNSHPLsLTSDQYK -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.741 SIGNOR-178379 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 9606 10828059 YES The effect has been demonstrated using Q08499-5 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. 0.353 SIGNOR-77571 NUP54 protein Q7Z3B4 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR form complex binding 10116 BTO:0000154 2050741 YES Simone Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. 0.94 SIGNOR-261259 DPM complex complex SIGNOR-C289 SIGNOR dolichyl beta-D-mannosyl phosphate smallmolecule CHEBI:17624 ChEBI up-regulates quantity chemical modification 9606 10835346 YES lperfetto Dolichol-phosphate-mannose (DPM) synthase generates mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation. 0.8 SIGNOR-262566 DLX5 protein P56178 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17335796 NO gcesareni Dlx5 can drive runx2 expression and osteogenic differentiation in developing cranial suture mesenchyme. 0.484 SIGNOR-153454 HCRTR2 protein O43614 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.265 SIGNOR-256872 MUL1 protein Q969V5 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by destabilization ubiquitination Lys284 LENLMLDkDGHIKIT 9606 22410793 YES gcesareni The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability. 0.476 SIGNOR-252460 RNF128 protein Q8TEB7 UNIPROT CD83 protein Q01151 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys192 LPVTSPNkHLGLVTP 9606 BTO:0000007 19542455 YES miannu In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83. 0.353 SIGNOR-271849 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr740 RNLYSGDyYRIQGRA 9606 16186108 YES gcesareni Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues. 0.381 SIGNOR-140763 oxaprozin chemical CHEBI:7822 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132;BTO:0003652 9650852 YES miannu We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively. 0.8 SIGNOR-258929 PRKCG protein P05129 UNIPROT STK17B protein O94768 UNIPROT down-regulates activity phosphorylation Ser351 PEDSSMVsKRFRFDD 10090 BTO:0000944 18084041 YES miannu These results suggest that phosphorylation of Ser350 plays an essential role in regulating translocation of DRAK2 to the nucleus from the cytoplasm, possibly by affecting the activity of the NLS. Ectopic expression of PKC-gamma induced cytoplasmic localization of DRAK2 and PKC-gamma phosphorylated Ser350 flanking the NLS. 0.2 SIGNOR-263178 BUD13 protein Q9BRD0 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.522 SIGNOR-270672 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15923619 YES flangone These studies point to an important interaction between wnt7b, lrp5, and fzd1 and fzd10. 0.672 SIGNOR-137937 PLCE1 protein Q9P212 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 17251915 YES gcesareni Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. 0.8 SIGNOR-152771 TSPOAP1 protein O95153 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 YES miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. 0.2 SIGNOR-264373 GABRB1 protein P18505 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR form complex binding 9606 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.616 SIGNOR-263763 phosphatidylethanolamine chemical CHEBI:16038 ChEBI Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR form complex binding 9606 25627476 YES lperfetto The lipid composition of the IMM varies from that of the OMM. PC and PE are still the most abundant phospholipids in the IMM, comprising about 75 % of total lipids.|One of the biggest differences between OMM and IMM lipid composition is the greater concentration of CL that is found in the IMM. Here, CL makes up about 15–20 % of the total phospholipid mass 0.8 SIGNOR-267002 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Ser676 LSPIIEDsREATHSS 9606 17785528 YES lperfetto We identify s676 as a plk1-specific phosphorylation site on bubr1. These findings describe the first in vivo verified phosphorylation site for human bubr1, identify plk1 as the kinase responsible for causing the characteristic mitotic bubr1 upshift, and attribute a kt-specific function to the hyperphosphorylated form of bubr1 in the stabilization of kt-mt interactions. 0.84 SIGNOR-157646 regorafenib chemical CHEBI:68647 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 26254357 YES miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF 0.8 SIGNOR-259177 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 YES llicata These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells. 0.796 SIGNOR-115831 ROCK2 protein O75116 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 YES lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. 0.413 SIGNOR-90832 ABL1 protein P00519 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 16943190 YES lperfetto we show that activated Abl phosphorylates the EGFR primarily on tyrosine 1173Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability. These findings reveal a novel role for Abl in promoting increased cell-surface expression of the EGFR and suggest that Abl/EGFR signaling may cooperate in human 0.42 SIGNOR-149277 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000671 15694384 YES llicata Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925. 0.2 SIGNOR-133849 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates phosphorylation Ser1382 MKSRFVDsGEMSESF 9606 BTO:0000551 17434128 YES lperfetto Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities 0.519 SIGNOR-154329 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266476 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 YES Uninhibited YAP/TAZ localize to the nucleus where they serve as coactivators for the TEA-domain family member (TEAD) of DNA-binding transcription factors. milica In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. 0.82 SIGNOR-197655 VARLITINIB chemical CID:42642648 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189900 EEF1A1 protein P68104 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269519 CREBBP protein Q92793 UNIPROT DDX21 protein Q9NR30 UNIPROT down-regulates activity acetylation Lys18 LESDTAMkKGETLRK 28790157 YES lperfetto Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21. 0.245 SIGNOR-275902 TTK protein P33981 UNIPROT USP16 protein Q9Y5T5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser415 VEDEDQDsEEEKDND 9606 BTO:0002181 28380042 YES miannu  Usp16 is a TTK phosphorylation substrate.  0.371 SIGNOR-277350 WNK4 protein Q96J92 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Thr231 TRNKVRKtFVGTPCW 16990453 YES lperfetto Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1 0.508 SIGNOR-264640 UBR2 protein Q8IWV8 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates quantity ubiquitination 9606 23408894 YES miannu Mub1 and Ubr2 mediate Dsn1 ubiquitylation and degradation.|The levels of WT Dsn1 were also increased in the mub1Delta and ubr2Delta strains, suggesting that Mub1 and Ubr2 mediate the degradation of WT Dsn1 protein. 0.2 SIGNOR-278795 OPRK1 protein P41145 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.458 SIGNOR-256853 GNA12 protein Q03113 UNIPROT ARHGEF11 protein O15085 UNIPROT up-regulates activity binding 9606 11799111 YES This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho 0.63 SIGNOR-256516 WWTR1 protein Q9GZV5 UNIPROT LTBR protein P36941 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22470139 NO miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. 0.2 SIGNOR-255604 PRKACA protein P17612 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 10116 11297520 YES miannu Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth. 0.501 SIGNOR-250055 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268578 FADS6 protein Q8N9I5 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267910 TBKBP1 protein A7MCY6 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity relocalization 9606 31792381 YES TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation 0.604 SIGNOR-272469 CBLB protein Q13191 UNIPROT STAT6 protein P42226 UNIPROT down-regulates quantity ubiquitination Lys108 QILQGEKkAVMEQFR 9606 24508458 YES miannu Having shown that Cbl-b negatively regulates Stat6, we further investigated the mechanism of this regulation by determining whether Cbl-b associates with Stat6.|Our data demonstrate that Stat6 is ubiquitinated at K108 and K398 by Cbl-b, and that Stat6 ubiquitination is a critical post-translational regulatory mechanism for Stat6. 0.2 SIGNOR-278805 zotepine chemical CHEBI:32316 ChEBI ADRA2B protein P18089 UNIPROT down-regulates activity chemical inhibition 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258559 BAMBI protein Q13145 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 BTO:0000763 2662247 YES gcesareni These data together suggest that bambi may form a ternary coreceptor complex with fzd5 and lrp6 0.583 SIGNOR-23040 LFNG protein Q8NES3 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000975 12486116 YES gcesareni We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1. 0.756 SIGNOR-96537 BIRC3 protein Q13489 UNIPROT BIRC3 protein Q13489 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000567 14960576 YES amattioni Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria. 0.2 SIGNOR-121880 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates activity phosphorylation Tyr223 TSFMMTPyVVTRYYR -1 10715136 YES Activation of JNK3 alpha 1 requires both MKK4 and MKK7. both MKK4 and MKK7 were required for bisphosphorylation and maximal enzyme activity. a processive mechanism for JNK3R1 activation that requires phosphorylation of Thr 221 by MKK7 prior to phosphorylation of Tyr 223 by MKK4 0.743 SIGNOR-251423 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu54 EMKKGHLeRECMEET -1 9538022 YES lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). 0.613 SIGNOR-263666 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269377 MAPK1 protein P28482 UNIPROT RGS19 protein P49795 UNIPROT up-regulates phosphorylation Ser151 EDYVSILsPKEVSLD 9606 10993892 YES gcesareni Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation. 0.475 SIGNOR-82083 BRDT protein Q58F21 UNIPROT EIF4EBP1 protein Q13541 UNIPROT up-regulates quantity binding 9606 33125143 YES lperfetto It was revealed that eIF4EBP1 interacted with BRDT, a novel interacting protein. In addition, the present study further demonstrated that BRDT inhibitors PLX51107 and INCB054329 blocked the progression of RCC cells, along with suppressing eIF4EBP1 and c‑myc expression. 0.2 SIGNOR-262049 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 12746313 YES scontino Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144. 0.8 SIGNOR-266946 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT up-regulates activity phosphorylation Tyr99 RGRYRSPySGPKFNS 9606 BTO:0000007 27018250 YES miannu In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner. 0.322 SIGNOR-262610 DLG1 protein Q12959 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 34960191 YES Barakat Immunoblot analysis showed that phosphorylation of the activating ZAP70 kinase domain residue Tyr 493 was decreased in the DLG1 KD cells. Similarly, the Tyr 319 residue of ZAP70 and Tyr 83 residue of TCR- ζ also showed reduced phosphorylation. 0.528 SIGNOR-274142 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 20626350 YES gcesareni In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a . p38 mapks activity stimulates the physical association between pp2a and erk complex, leading to mkk1/2 dephosphorylation by pp2a. 0.62 SIGNOR-166655 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC4R protein P32245 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257538 LATS2 protein Q9NRM7 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 23886938 YES miannu Phosphorylation by Lats2 induces degradation of p21 and promotes apoptosis.|Subsequently, Lats2 phosphorylates p21 at S146. 0.418 SIGNOR-279530 MMP20 protein O60882 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE -1 10922468 YES lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development. 0.478 SIGNOR-266979 AR protein P10275 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16697957 YES miannu Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events. 0.502 SIGNOR-251546 FGR protein P09769 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity phosphorylation Tyr354 SSNQELIyEGRRLVL 9606 BTO:0002181 28618271 YES miannu The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.  0.2 SIGNOR-276725 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr580 LRKTRDQyLMWLTQK 9534 BTO:0000298 8385099 YES The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. 0.616 SIGNOR-252691 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity 9606 19777070 YES NF1 negatively regulates Ras as an exchangefactor converting Ras-GTP to Ras-GDP by its GTPase-activating (Ras-GAP) domain. 0.813 SIGNOR-256067 AMPK complex SIGNOR-C15 SIGNOR MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 10116 21892142 YES lperfetto AMPK has also been suggested to phosphorylate the glucose-sensitive transcription factor ChREBP89 which dictates expression of an overlapping lipogenic gene signature with Srebp1 0.429 SIGNOR-216561 MDM2 protein Q00987 UNIPROT RPL26 protein P61254 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 18951086 YES miannu In addition, Mdm2 ubiquitylates L26, leading to its proteasome-mediated degradation.|We now report that Mdm2 regulates p53 levels also by targeting ribosomal protein L26. 0.499 SIGNOR-278828 CSTF complex complex SIGNOR-C441 SIGNOR mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 10669729 NO lperfetto Polyadenylation of mRNA precursors is a two-step reaction requiring multiple protein factors. Cleavage stimulation factor (CstF) is a heterotrimer necessary for the first step, endonucleolytic cleavage, and it plays an important role in determining the efficiency of polyadenylation. 0.7 SIGNOR-268369 SCN1A protein P35498 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 YES miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. 0.8 SIGNOR-253402 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity relocalization 9606 12897152 YES amattioni The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism. 0.834 SIGNOR-104493 FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 YES gcesareni in vitro kinase assays revealed that STAT5 is a direct target of Flt3 0.604 SIGNOR-245069 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270404 CDK1 protein P06493 UNIPROT CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR form complex binding 9606 29870721 YES lperfetto Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. 0.922 SIGNOR-267570 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273079 PTEN protein P60484 UNIPROT PTK6 protein Q13882 UNIPROT down-regulates activity dephosphorylation Tyr342 RLIKEDVyLSHDHNI -1 29142193 YES lperfetto PTEN inhibits PTK6 activity and downstream signaling in prostate cancer cells.|Using an in vitro phosphatase assay, we observed that PTEN was able to dephosphorylate PTK6 at tyrosine residue 342 in a dose dependent manner. 0.417 SIGNOR-276975 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation -1 14614828 YES lperfetto We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli 0.61 SIGNOR-217469 UBXN1 protein Q04323 UNIPROT NGLY1 protein Q96IV0 UNIPROT up-regulates activity binding 9606 15362974 YES miannu PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome. 0.486 SIGNOR-261060 PTGER3 protein P43115 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 BTO:0000938 12038972 YES gcesareni Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i) 0.449 SIGNOR-88195 RBBP4 protein Q09028 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.832 SIGNOR-263849 FBXO25 protein Q8TCJ0 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 23940030 YES miannu The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1 protein. FBXO25 is one of the 69 known human F-box proteins that serve as specificity factors for a family of ubiquitin ligases composed of SKP1, Rbx1, Cullin1, and F-box protein (SCF1) that are involved in targeting proteins for degradation across the ubiquitin proteasome system. FBXO25 interacted with and mediated the ubiquitination and proteasomal degradation of ELK-1 in HEK293T cells. 0.599 SIGNOR-272128 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser187 LNSAAYSsPKLRGTL 9606 25726523 YES miannu In addition, we defined GATA1 Ser161, Ser187 were the main phosphorylation sites by PAK5. 0.2 SIGNOR-278297 ATM protein Q13315 UNIPROT RBBP8 protein Q99708 UNIPROT down-regulates phosphorylation Ser664 IDPGADLsQYKMDVT 9606 BTO:0000150 10910365 YES llicata Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45 0.828 SIGNOR-79872 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 10085140 YES gcesareni On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38. 0.793 SIGNOR-65601 MBOAT7 protein Q96N66 UNIPROT 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI down-regulates quantity chemical modification -1 18772128 YES miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. 0.8 SIGNOR-267246 SMAD5 protein Q99717 UNIPROT SMAD6 protein O43541 UNIPROT up-regulates quantity transcriptional regulation 10090 22219353 YES Gianni Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation 0.598 SIGNOR-268940 ARG1 protein P05089 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI up-regulates quantity chemical modification 9606 14617280 YES miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) 0.8 SIGNOR-255545 PRKD1 protein Q15139 UNIPROT OSBP protein P22059 UNIPROT down-regulates phosphorylation Ser240 TALQRSLsELESLKL 9606 21285358 YES gcesareni Pkd attenuates the function of both cert and osbp by phosphorylation at their respective ser(132) and ser(240) residues (phosphorylation inhibition) 0.444 SIGNOR-171756 AMG 458 chemical CID:24764449 PUBCHEM MET protein P08581 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189516 PAK1 protein Q13153 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity binding 9606 BTO:0000007 11804587 YES lperfetto We show that pak1 forms homodimers in vivo and that its dimerization is regulated by the intracellular level of gtp-cdc42 or gtp-rac1. The dimerized pak1 adopts a trans-inhibited conformation. 0.2 SIGNOR-236338 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 10339564 YES lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. 0.942 SIGNOR-67548 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser330 MEEDSYDsFGEPSYP -1 9558331 YES llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. 0.307 SIGNOR-250934 ABL1 protein P00519 UNIPROT PDP1 protein Q9P0J1 UNIPROT down-regulates activity phosphorylation Tyr94 SILKANEySFKVPEF 10090 BTO:0000944 24962578 YES miannu Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.  0.268 SIGNOR-276641 Exon junction complex complex SIGNOR-C369 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 11532962 YES lperfetto The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay 0.8 SIGNOR-268315 PRKCQ protein Q04759 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS 9606 BTO:0000782 16479000 YES miannu PKC θ is required for HePTP translocation to the immune synapse. PKC θ phosphorylates HePTP at S225 in primary T cells. 0.2 SIGNOR-276045 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser536 GRGSKRLsRSVTMRK 9606 24505490 YES llicata A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498. 0.2 SIGNOR-204546 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser1138 PSITKQHsQTPSTLN -1 14970204 YES miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. We identify four major sites of phosphorylation, serines 1123, 1058, 750/751/756, and 764/765. 0.43 SIGNOR-262688 TEC protein P42680 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr224 DSNSKKIyGSQPNFN 9606 12573241 YES lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180 0.333 SIGNOR-98094 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser641 GKVYGKTsHLRAHLR 9606 19464346 YES gcesareni The hdac inhibitor tsa-induced cell-specific phosphatase release from the promoter, which serves as an 'on' mechanism for sp1 phosphorylation by phosphatidylinositol 3-kinase/protein kinase czeta (pi3k/pkczeta) at ser641, leading to p107 repressor derecruitment and lhr transcriptional activation. 0.485 SIGNOR-185741 HSP90AA1 protein P07900 UNIPROT LGMN protein Q99538 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000815 24610907 YES miannu We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. We now present evidence that AEP is a substrate for TRAF6 ubiquitination, resulting in AEP/TRAF6/HSP90α complex formation. 0.2 SIGNOR-272855 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-B receptor complex SIGNOR-C336 SIGNOR up-regulates activity chemical activation 9606 18790874 YES miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-264962 AKT1 protein P31749 UNIPROT NIBAN1 protein Q9BZQ8 UNIPROT unknown phosphorylation Ser602 ASPARRAsAILPGVL 9606 22510990 YES llicata We demonstrate here that ultraviolet irradiation induces phosphorylation of niban at s602 by akt, which increases the association of niban with nucleophosmin and disassociation of nucleophosmin from the mdm2 complex. 0.2 SIGNOR-252530 Ub:E2 complex SIGNOR-C497 SIGNOR MECOM protein Q03112 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271024 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates activity phosphorylation Ser166 EPRSRHLsVSSQNPG 9534 BTO:0001538 12392720 YES miannu It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3. 0.2 SIGNOR-250004 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser363 LKNKTESsLLAKLEE -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.2 SIGNOR-276209 CEBPA protein P49715 UNIPROT HAMP protein P81172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001950 18671304 NO miannu HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter. 0.297 SIGNOR-253770 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser348 EAVTSKTsNIRANFE 9606 BTO:0000150 19038333 YES lperfetto Here we have investigated the possible role of pkd as a cortactin kinase. Using a mass spectrometric approach, we found that pkd phosphorylates cortactin on ser 298 examination of cortactin phosphorylation kinetics revealed that ser 298 serves as a priming site for subsequent phosphorylation of ser 348 0.421 SIGNOR-182502 PRSS2 protein P07478 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 YES lperfetto Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. 0.2 SIGNOR-263603 GTF3C1 protein Q12789 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR form complex binding 9606 29378333 YES lperfetto Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains 0.881 SIGNOR-266188 NTRK2 protein Q16620 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates activity phosphorylation Tyr817 LAKASPVyLDILG 10090 BTO:0000944 10533983 YES miannu TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. the Y785F mutation abolish the BDNF-inducible tyrosine phosphorylation of PLCy, but receptors containing this mutation are also defective in the ability to induce the tyrosine phosphorylation of the c-cbl proto-oncogene product. 0.2 SIGNOR-250312 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000142 20308788 YES The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. 0.2 SIGNOR-164675 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser360 RKTQTSMsLGTTREK -1 24012422 YES gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays 0.753 SIGNOR-266440 KRAS protein P01116 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k. 0.713 SIGNOR-175207 PCDH19 protein Q8TAB3 UNIPROT GABRA4 protein P48169 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C327,SIGNOR-C326,SIGNOR-C333 29360992 YES miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  0.2 SIGNOR-267220 PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 9388184 YES lperfetto PIAS3 blocked the DNA- binding activity of Stat3 and inhibited Stat3-mediated gene activation. Although Stat1 is also phosphorylated in response to IL-6, PIAS3 did not interact with Stat1 or affect its DNA-binding or transcriptional activity. The results indicate that PIAS3 is a specific inhibitor of Stat3. 0.73 SIGNOR-238648 PAK4 protein O96013 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity by destabilization phosphorylation Ser465 SPSVRCSsMS 9606 23934187 YES miannu In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. 0.339 SIGNOR-279084 TRIM26 protein Q12899 UNIPROT NTHL1 protein P78549 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 29610152 YES miannu We also demonstrated that TRIM26 directly polyubiquitylates NTH1 in cells and that TRIM26 targets newly synthesized NTH1 protein for ubiquitylation dependent degradation. 0.263 SIGNOR-278733 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr74 TRGDADMyDLPKKED 9606 BTO:0000567 BTO:0000887 19789182 YES llicata Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf 0.452 SIGNOR-188312 SUN1 protein O94901 UNIPROT MAJIN protein Q3KP22 UNIPROT up-regulates activity binding 9606 BTO:0000007 SIGNOR-C303 SIGNOR-C305 33015044 YES lperfetto In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex. 0.2 SIGNOR-263300 CTNND1 protein O60716 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000414 14610055 YES miannu P120 regulates E-cadherin turnover at the cell membrane. Because direct binding of p120 to E-cadherin is required, it is possible that p120 binding blocks the interaction of an unknown binding partner (or event) that targets E-cadherin for degradation 0.947 SIGNOR-252123 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR VWF protein P04275 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000394 20658528 YES lperfetto We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype. 0.324 SIGNOR-253703 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Ser270 SVRMLSGsKEKDRNL 9606 BTO:0000671 10908300 YES gcesareni The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization. 0.2 SIGNOR-79682 TGFB1 protein P01137 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity 10090 BTO:0000944 17673906 NO lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. 0.452 SIGNOR-242631 TNKS2 protein Q9H2K2 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization 9606 BTO:0000007 19759537 YES Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. 0.451 SIGNOR-261248 ZMYM2 protein Q9UBW7 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity binding 9606 BTO:0000599 32439918 YES miannu Here we have identified the zinc-finger proteins ZMYM2 and ZMYM4 as novel B-MYB binding proteins. B-MYB has been implicated in cell cycle progression at two steps, namely at the G1/S- and the G2/M-transition. ZMYM2 is required for the G1/S-transition in HepG2 cells. 0.2 SIGNOR-269801 HTR6 protein P50406 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257274 MSH6 protein P52701 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR form complex binding 9606 15064730 YES miannu The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors. 0.813 SIGNOR-123708 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser63 NVKVETQsDEENGRA 9606 BTO:0001271 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo 0.29 SIGNOR-174832 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 15574335 YES gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma 0.824 SIGNOR-131442 YWHAB protein P31946 UNIPROT SRPK2 protein P78362 UNIPROT down-regulates binding 9606 phosphorylation:Thr492 PSHDRSRtVSASSTG 19592491 YES lperfetto 14-3-3 interacts with akt-phosphorylated srpk2 and blocks its nuclear translocation. kt phosphorylates SRPK2 on Thr-492 and promotes its nuclear translocation leading to cyclin D1 up-regulation, cell cycle reentry, and neuronal apoptosis. In addition, SRPK2 phosphorylates SC35 and, thus, inactivates p53, resulting in cyclin D1 up-regulation. 14-3-3 binding to SRPK2, regulated by Akt phosphorylation, inhibits these events. 0.331 SIGNOR-186767 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser29 ATKAARKsAPATGGV 9606 21282660 YES Ser 27 (29) phosphorylation of H3 isinhibitory as induces transcription. gcesareni Histone code pathway involving h3 s28 phosphorylation and k27 acetylation activates transcription and antagonizes polycomb silencingaurora-b phosphorylates histone h3 at serine28 with regard to the mitotic chromosome condensation 0.2 SIGNOR-171717 PRKACG protein P22612 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 BTO:0000007 31057087 YES miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. 0.2 SIGNOR-259404 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0001538 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.73 SIGNOR-252761 WDR83 protein Q9BRX9 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates binding 9606 15118098 YES gcesareni Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. 0.524 SIGNOR-124470 KIT protein P10721 UNIPROT PHB protein P35232 UNIPROT up-regulates activity phosphorylation Tyr259 SRSRNITyLPAGQSV 9606 32169072 YES miannu In this study, we showed that c-Kit associates with PHB to upregulate phospho-PHB in the lipid raft of the plasma membrane.|c-Kit phosphorylates PHB at the Tyr259 residue. 0.2 SIGNOR-278362 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 9606 21317289 YES gcesareni We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation 0.466 SIGNOR-200496 RPL10 protein P27635 UNIPROT YES1 protein P07947 UNIPROT down-regulates binding 9606 12138090 YES miannu Several c-yes kinase activity assays indicated that the qm protein reduced c-yes kinase activity by 70% 0.389 SIGNOR-90805 AURKA protein O14965 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-98289 tRNA(Ile) smallmolecule CHEBI:29174 ChEBI Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates quantity precursor of 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270425 SPI1 protein P17947 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12433372 NO irozzo Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene.The above experiments suggested that PU.1 may physiologically downregulate the expression of the GATA-2 gene during the differentiation of myeloid progenitors into macrophages. 0.578 SIGNOR-256069 AKAP11 protein Q9UKA4 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates quantity binding 9606 21776420 YES miannu We show that IQGAP2 is regulated by an interaction with the A-kinase anchoring protein AKAP220. Phosphorylation of IQGAP2 via AKAP220-anchored PKA leads to enhanced Rac binding. Since AKAPs function to direct PKA toward specific substrates, we proposed that the formation of an IQGAP2/AKAP220/PKA ternary complex sharpens the response to cAMP. 0.426 SIGNOR-273741 UBE2N protein P61088 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000785 14713952 YES lperfetto Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38. 0.429 SIGNOR-121274 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Thr285 QMRQRKGtLSVNFVD -1 27292631 YES miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. 0.304 SIGNOR-274061 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 11970898 YES Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner 0.796 SIGNOR-248405 GSK3B protein P49841 UNIPROT ETS1 protein P14921 UNIPROT up-regulates quantity by stabilization phosphorylation Thr265 YDSCDRLtQSWSSQS 9606 BTO:0000007 34023818 YES miannu Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration. 0.2 SIGNOR-277560 SRC protein P12931 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr142 MELALGQyHRNGCIS 10116 BTO:0000132 21992875 YES miannu We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.  0.259 SIGNOR-276386 JNJ-28312141 free base chemical CID:11676971 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258125 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr313 HGSGWAEtPRTDRGG 9606 SIGNOR-C16 12105215 YES llicata We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1 0.346 SIGNOR-90442 TGFB1 protein P01137 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252282 NR1D1 protein P20393 UNIPROT NPAS2 protein Q99743 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 20817722 YES miannu In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. 0.63 SIGNOR-267981 FOXO1 protein Q12778 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 NO inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.32 SIGNOR-270251 DOCK6 protein Q96HP0 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 23462102 YES lperfetto Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. 0.527 SIGNOR-275670 ABL1 protein P00519 UNIPROT SORBS1 protein Q9BX66 UNIPROT up-regulates activity phosphorylation Tyr360 Y-->K 9606 19891780 YES miannu We have here identified Tyr360 in CAP as a major phosphorylation site by c-Abl, although Tyr 632 also might contribute since its substitution in combination with the Y360F mutation reduced the phosphorylation of CAP to a very low level. Y360 in CAP is the major phosphorylation site of c-Abl. Since Tyr326 was not a major c-Abl phosphorylation site, we sought to identify a putative other kinase that might be involved in the phosphorylation of Y326 in CAP. 0.425 SIGNOR-278152 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr226 GSSGSLStSSSSSPP 9606 phosphorylation:Ser237 SSPPGTPsPADAKAP 22369944 YES fspada However, the acquisition of dna binding and transactivation capacity of c/ebpbeta is delayed until further phosphorylation (on ser(184) or thr(179)) by gsk3beta occurs. 0.458 SIGNOR-210129 CDK5 protein Q00535 UNIPROT DLG4 protein P78352 UNIPROT down-regulates activity phosphorylation Ser25 DTPPLEHsPAHLPNQ 9606 28502042 YES miannu Cdk5 was shown to phosphorylate PSD-95 at three sites, Thr19, Ser25, and Ser35, in PSD fractions, which reduces the ability of PSD-95 to multimerize, resulting in decreased NMDAR clustering (Table 2). 0.654 SIGNOR-279150 EDNRB protein P24530 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257321 LEPR protein P48357 UNIPROT AGRP protein O00253 UNIPROT down-regulates quantity 27154742 NO lperfetto Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production 0.451 SIGNOR-253076 C1QBP protein Q07021 UNIPROT KRT1 protein P04264 UNIPROT up-regulates activity binding 9606 14691569 YES Regulation of binding miannu Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored. 0.373 SIGNOR-251881 Nitrendipine chemical CID:4507 PUBCHEM NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18250364 YES Luana Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression.  0.8 SIGNOR-257767 DYRK1A protein Q13627 UNIPROT DNM1 protein Q05193 UNIPROT down-regulates phosphorylation Ser857 ASPSRPEsPRPPFDL 9606 BTO:0000142 15287745 YES lperfetto Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation. 0.417 SIGNOR-127444 CENPA protein P49450 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR form complex binding -1 23324462 YES miannu In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro. 0.2 SIGNOR-263702 TRIM25 protein Q14258 UNIPROT FBXW7 protein Q969H0 UNIPROT down-regulates activity ubiquitination Lys412 VWSAVTGkCLRTLVG 9606 BTO:0002181 31186535 YES miannu This newly stabilized TRIM25 then directly ubiquitinates Lys412 of FBXW7α, a core subunit of the SKP1-Cullin-F-box (SCF) ubiquitin ligase complex involved in Myc ubiquitination, thereby stabilizing Myc.  0.265 SIGNOR-277457 CDK5 protein Q00535 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity phosphorylation Ser273 TGKTTDKsPFVIYDM 9606 25827822 YES miannu CDK5 in turn phosphorylates PPARgamma at Ser273 and prevents the transcription of specific PPARgamma target genes that have anti-diabetic effects . 0.575 SIGNOR-278189 SOX6 protein P35712 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity binding 10090 BTO:0000011 26893351 YES SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis. 0.653 SIGNOR-256073 CBL protein P22681 UNIPROT LCK protein P06239 UNIPROT down-regulates quantity ubiquitination 9606 18535581 YES miannu One study indicated that loss of CBL expression increases the constitutive level of LCK 80, but other studies have not shown this - .|The ubiquitylation of LCK by CBL (Casitas B-lineage lymphoma) is known to be a negative mechanism that regulates the signalling function of LCK xref . 0.71 SIGNOR-278804 BRAF protein P15056 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000797 27340238 NO These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein. 0.7 SIGNOR-259373 NANOG protein Q9H9S0 UNIPROT LAMB1 protein P07942 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 NO miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. 0.266 SIGNOR-254628 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr219 DGSDHPYyNSIPSKM -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.755 SIGNOR-273918 CHMP4B protein Q9H444 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.73 SIGNOR-265533 MED6 protein O75586 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.849 SIGNOR-266677 trichostatin A chemical CHEBI:46024 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257939 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.791 SIGNOR-263011 EZH2 protein Q15910 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 SIGNOR form complex binding 9606 16712789 YES miannu Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2. 0.961 SIGNOR-146758 CDK2 protein P24941 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates activity phosphorylation Ser73 NGATGHSsSLDAREV 9606 27239332 YES miannu Our findings show that Cdk2 phosphorylation of Bcl-xL at Ser73, but not the Bcl-xL cleavage products, is necessary and sufficient to induce cell death. 0.496 SIGNOR-278242 JUN protein P05412 UNIPROT RCAN1 protein P53805 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18641051 NO lperfetto Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death. 0.276 SIGNOR-253148 FOXO3 protein O43524 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 NO gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. 0.387 SIGNOR-181618 GRID2IP protein A4D2P6 UNIPROT GRID2 protein O43424 UNIPROT up-regulates quantity binding 9606 11826110 YES miannu We identified a novel GluRdelta2-interacting protein, named Delphilin, that contains a single PDZ domain and formin homology (FH) domains FH1 and FH2 plus coiled-coil structure. Delphilin is selectively localized at the postsynaptic junction site of the parallel fiber-Purkinje cell synapse and colocalized with GluRdelta2. Thus, Delphilin is a postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GluRdelta2 with actin cytoskeleton and various signaling molecules. 0.61 SIGNOR-264475 SIRT1 protein Q96EB6 UNIPROT EP300 protein Q09472 UNIPROT down-regulates deacetylation Lys1024 TELKTEIkEEEDQPS 9606 BTO:0000150 19047049 YES gcesareni Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024 0.835 SIGNOR-182511 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser477 ELIERKTsSLDPNDQ 9606 BTO:0001109 17157788 YES lperfetto Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability. 0.359 SIGNOR-264417 THRA protein P10827 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 NO lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. 0.2 SIGNOR-268550 hsa-miR-31-5p mirna URS00005416E3_9606 RNAcentral GNA13 protein Q14344 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000815 25889182 YES Parnian This data provide compelling evidence that miR-31 directly binds to the GNA13-3′-UTR and inhibits its activity. | our data indicates that loss of miR-31 in breast cancers leads to increased GNA13 expression and cancer cell invasion. 0.4 SIGNOR-278023 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser558 AEQMANDsDDSISAA -1 28436950 YES miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. 0.2 SIGNOR-265896 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273083 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1387 EDCSGLSsQSDILTT 9606 BTO:0000150 12183412 YES gcesareni Phosphorylation of serine 1387 in brca1 is specifically required for the atm-mediated s-phase checkpoint after ionizing irradiation.We recently reported that brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the s-phase and the g2 phase of the cell cycle. We also found that mutation of serine 1423 in brca1, a target of atm phosphorylation, abrogates the g2-m checkpoint but not the ionizing irradiation-induced s-phase checkpoint. Here we demonstrate that mutation of serine 1387 in brca1, another target of atm phosphorylation, conversely abrogates the radiation-induced s-phase arrest but does not affect the g2-m checkpoint. 0.819 SIGNOR-91482 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PCYT1A protein P49585 UNIPROT down-regulates phosphorylation 9606 BTO:0000763 15788406 YES inferred from 70% family members gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. 0.2 SIGNOR-270028 FBXO22 protein Q8NEZ5 UNIPROT BAG3 protein O95817 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 34215846 YES miannu We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCFFBXO22. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377. 0.2 SIGNOR-277319 NDUFS1 protein P28331 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.858 SIGNOR-262175 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 YES gcesareni Mechanism of protein tyrosine phosphatase 1b-mediated inhibition of leptin signalling. Ptp1b plays a critical role in the down-regulation of activated-stat3 by dephosphorylating tyr705, that is the phosphorylation site of activation of stat3. 0.553 SIGNOR-135211 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity binding 9606 11350724 YES lperfetto Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein– protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptor’s repertoire of activated intracellular pathways. 0.913 SIGNOR-107712 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269365 ATF4 protein P18848 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 YES miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. 0.815 SIGNOR-260170 EGFR protein P00533 UNIPROT RASA1 protein P20936 UNIPROT unknown phosphorylation Tyr460 TVDGKEIyNTIRRKT 9606 1850098 YES llicata We conclude that tyr-460 is a site of gap tyrosine phosphorylation by the egf receptor in vitro and likely in vivo. Gap tyr-460 is located immediately c terminal to the second gap sh2 domain, suggesting that its phosphorylation might have a role in regulating protein-protein interactions. 0.654 SIGNOR-21875 PRKACA protein P17612 UNIPROT CIITA protein P33076 UNIPROT down-regulates activity phosphorylation Ser1050 AASLLRLsLYNNCIC 9606 BTO:0000984 11416140 YES lperfetto Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription. 0.31 SIGNOR-108569 PLK1 protein P53350 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Ser57 SQSSQDSsPVRNLQS 9606 18250300 YES lperfetto Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate. 0.504 SIGNOR-160751 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Thr1074 QRGSSGHtPPPSGPP 9606 26190112 YES Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. 0.334 SIGNOR-259862 metyrapone chemical CHEBI:44241 ChEBI CYP11B2 protein P19099 UNIPROT down-regulates activity chemical inhibition -1 21129965 YES Luana In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades. 0.8 SIGNOR-257885 MUTYH protein Q9UIF7 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates 9606 21615992 NO miannu Hmyh is involved in the activation mechanism of chk1 upon dna damage, but not in stability or inactivation. 0.342 SIGNOR-173969 KAT8 protein Q9H7Z6 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. 0.651 SIGNOR-267160 TCF4 protein P15884 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR form complex binding 9606 16847330 YES 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. 0.702 SIGNOR-241382 RFX complex complex SIGNOR-C104 SIGNOR HLA-DQB2 protein P05538 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 NO The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex 0.2 SIGNOR-253997 ESR1 protein P03372 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 NO ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression 0.478 SIGNOR-253940 PRKCA protein P17252 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Thr475 TPLSSSNtIRRPRNY -1 1322130 YES lperfetto The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme. 0.44 SIGNOR-248844 PRKCG protein P05129 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.293 SIGNOR-249249 MLKL protein Q8NB16 UNIPROT Necroptosis phenotype SIGNOR-PH174 SIGNOR up-regulates activity 9606 24316671 YES gianni Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. 0.7 SIGNOR-266431 FGF2 protein P09038 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 NO lperfetto Furthermore, FGF-2 and FGF-9 increased expression of other osteogenic factors BMP-2 and TGFbeta-1. Meanwhile, blocking endogenous FGF signaling, using a virally transduced dominant-negative FGF receptor (FgfR), resulted in drastically reduced expression of the BMP-2 gene, demonstrating for the first time that endogenous FGF/FgfR signaling is a positive upstream regulator of the BMP-2 gene in calvarial osteoblasts 0.472 SIGNOR-134785 Palomid 529 chemical CID:11998575 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-199120 BMI1 protein P35226 UNIPROT H2AX protein P16104 UNIPROT up-regulates activity ubiquitination 9606 26633535 YES miannu In this process, BMI1 ubiquitinates histone H2A and \u03b3H2AX, thereby facilitating the repair of double-stranded DNA breaks through stimulating homologous recombination and non-homologous end joining. 0.2 SIGNOR-278744 TNKS protein O95271 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19759537 YES lperfetto Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. 0.772 SIGNOR-187975 BIRC2 protein Q13490 UNIPROT UBE2J1 protein Q9Y385 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 28321712 YES miannu We also found that ubiquitin-ligase (E3), c-IAP1 preferentially interacts with phosphorylated Ube2j1. Moreover, we noticed that phosphorylated Ube2j1 is rapidly degraded by the proteasome during ER stress cell recovery. Taken together, these data suggest that Ube2j1 and its phosphorylation is important for transient ER stress cell recovery and the phosphorylated Ube2j1 is degraded by the proteasome. 0.37 SIGNOR-263092 PRKACA protein P17612 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates activity phosphorylation Ser1897 LLRKANPsRCHSRES 10090 28119464 YES These findings reveal an essential role for _1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes 0.497 SIGNOR-251709 TIMELESS protein Q9UNS1 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates activity binding 9534 23418588 YES miannu We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization. 0.675 SIGNOR-268053 CSNK2A1 protein P68400 UNIPROT EXOSC9 protein Q06265 UNIPROT up-regulates phosphorylation Ser392 QDAPIILsDSEEEEM 9606 19217413 YES lperfetto Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay 0.2 SIGNOR-184031 cyproterone acetate chemical CHEBI:50743 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-191235 CUL9 protein Q8IWT3 UNIPROT FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 35469017 YES miannu M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2. 0.2 SIGNOR-276718 MORC2 protein Q9Y6X9 UNIPROT NAT10 protein Q9H0A0 UNIPROT up-regulates activity binding 9606 BTO:0000007 31616951 YES done miannu MORC2 directly interacts with PARP1. MORC2 mediates the interaction between PARP1 and NAT10 and thereby promotes NAT10-mediated PARP1 acetylation at K949, which blocks CHFR-mediated ubiquitination and degradation of PARP1. 0.2 SIGNOR-273716 MKRN1 protein Q9UHC7 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 19536131 YES miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21.  0.314 SIGNOR-271845 NEDD4 protein P46934 UNIPROT LYN protein P07948 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001931 10683340 YES miannu These findings suggest that LMP2A recruits Nedd4-like ubiquitin-protein ligases and B-cell signal transduction molecules, resulting in the degradation of LMP2A and Lyn by a ubiquitin-dependent mechanism.  0.457 SIGNOR-272558 SELP protein P16109 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 YES lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. 0.409 SIGNOR-261860 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269372 cholesterol smallmolecule CHEBI:16113 ChEBI SOAT1 protein P35610 UNIPROT up-regulates activity chemical activation 9606 BTO:0000759 31848472 YES miannu Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters 0.8 SIGNOR-265159 LRP6 protein O75581 UNIPROT LPR5/6 complex SIGNOR-C219 SIGNOR form complex binding 9606 27821587 YES miannu Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands. 0.405 SIGNOR-256175 TNK2 protein Q07912 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Tyr365 AYQSRDYyNFPLALA 9606 25950519 YES miannu Ack1 phosphorylates AR at Tyr-267 and possibly Tyr-363, both in the N-terminal transactivation domain.|Mutation of these two sites in AR inhibited Ack1 induced AR transactivation and DNA binding as well as tumor growth. 0.546 SIGNOR-278195 RAB23 protein Q9ULC3 UNIPROT GLI3 protein P10071 UNIPROT down-regulates 9606 16364285 NO gcesareni Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization. 0.577 SIGNOR-143160 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UBTF protein P17480 UNIPROT up-regulates activity phosphorylation Ser484 ERGKLPEsPKRAEEI 10090 BTO:0000944 10202152 YES llicata We have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro.  0.34 SIGNOR-250754 CASP5 protein P51878 UNIPROT GSDMD protein P57764 UNIPROT up-regulates activity cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 YES lperfetto Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence | 0.619 SIGNOR-256418 NMDA proteinfamily SIGNOR-PF56 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264691 DOCK6 protein Q96HP0 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 23462102 YES lperfetto Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. 0.676 SIGNOR-275671 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 17158707 YES lperfetto The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity 0.2 SIGNOR-36466 PPP1R2 protein P41236 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates binding 9606 18250156 YES lperfetto Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1. 0.802 SIGNOR-264672 CTNND1 protein O60716 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 22946057 YES gcesareni We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn 0.584 SIGNOR-198938 LCK protein P06239 UNIPROT SSBP3 protein Q9BWW4 UNIPROT up-regulates activity phosphorylation Tyr23 AREKLALyVYEYLLH 9606 BTO:0000007 18080319 YES miannu  The Src tyrosine kinase inhibitor PP2 blocked the nuclear translocation of Ssdp1. Western blot analysis showed that co-expression of Ssdp1 and Lck in 293T cells induces Ssdp1 phosphorylation. Mutation of the Ssdp1 N terminal tyrosine residues 23 and 25 markedly reduced both the phosphorylation and the nuclear localization of Ssdp1.  Lck enhanced the transcriptional activity of Ssdp1 in the context of known components of a LIM-homeodomain (LIM-HD)/cofactor complex. 0.2 SIGNOR-273649 COL4A1 protein P02462 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.5 SIGNOR-253242 CMA1 protein P23946 UNIPROT EDN1 protein P05305 UNIPROT up-regulates activity cleavage Tyr83 TPEHVVPyGLGSPRS 9606 BTO:0000830 9257865 YES miannu Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products. 0.473 SIGNOR-256356 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr261 GLVTTLHyPAPKCNK -1 15735735 YES miannu The results show that Arg is stabilized in response to 0.1 mM H2O2 by autophosphorylation of Y-261, consistent with involvement of the Arg kinase function in regulating Arg levels. The results further demonstrate that c-Abl-mediated phosphorylation of Arg on Y-261 similarly confers Arg stabilization.. These findings indicate that abrogation of the Arg kinase function by the Y261F mutation is dependent on phosphorylation of the Y-439 site. 0.2 SIGNOR-276033 TTC3 protein P53804 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 20059950 YES gcesareni TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus 0.396 SIGNOR-252436 NEK6 protein Q9HC98 UNIPROT EML4 protein Q9HC35 UNIPROT up-regulates activity phosphorylation Ser144 QSPQIRAsPSPQPSS -1 31409757 YES done miannu The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression. 0.253 SIGNOR-273883 WNT16 protein Q9UBV4 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.541 SIGNOR-131677 SUFU protein Q9UMX1 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity binding 15367681 YES lperfetto Here we characterize structural and functional determinants of Su(fu) required for Gli regulation and show that Su(fu) contains at least two distinct domains: a highly conserved carboxy-terminal region required for binding to the amino-terminal ends of the Gli proteins and a unique amino-terminal domain that binds the carboxy-terminal tail of Gli1. While each domain is capable of binding to different Gli1 regions independently, interactions between Su(fu) and Gli1 at both sites are required for cytoplasmic tethering and repression of Gli1 0.949 SIGNOR-249591 RAPGEF6 protein Q8TEU7 UNIPROT NRAS protein P01111 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 YES gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. 0.332 SIGNOR-183799 CADPS protein Q9ULU8 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 YES miannu CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1 0.403 SIGNOR-264336 GART protein P22102 UNIPROT 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI up-regulates quantity chemical modification 9606 33179964 YES miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. 0.8 SIGNOR-267315 GSK3B protein P49841 UNIPROT CLASP2 protein O75122 UNIPROT down-regulates activity phosphorylation Ser537 REASRESsRDTSPVR 9534 BTO:0004055 19638411 YES lperfetto GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells 0.516 SIGNOR-264826 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27141364 NO irozzo EML4-ALK enhanced HIF-1α expression through increasing transcription and decreasing ubiquitination of HIF-1α. 0.2 SIGNOR-259172 tyrosine smallmolecule CHEBI:18186 ChEBI tyramine smallmolecule CHEBI:15760 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬¨‚Ć 0.8 SIGNOR-264175 PLAAT3 protein P53816 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates 9606 17374643 NO miannu The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity. 0.2 SIGNOR-153775 CALM3 protein P0DP25 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 BTO:0001853 24379783 YES miannu Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer 0.567 SIGNOR-266339 NPY protein P01303 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 YES gcesareni Npy expression significantly increases whereas the gene expression of its receptors npy1r, npy2r, and npy5r initially decreases. 0.74 SIGNOR-114746 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258627 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 YES lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | 0.341 SIGNOR-249121 PRKACA protein P17612 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 10464286 YES gcesareni Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation. 0.2 SIGNOR-265344 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser373 RASSRASsRPRPDDL 9606 16474210 YES lperfetto We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity. 0.44 SIGNOR-144473 ibuprofen chemical CHEBI:5855 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 22091869 YES Luana  Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2.  0.8 SIGNOR-258325 TTK protein P33981 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity phosphorylation 18541701 YES lperfetto Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2. 0.715 SIGNOR-252036 STAT5A protein P42229 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15003515 NO Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. 0.323 SIGNOR-261518 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.2 SIGNOR-250558 JMJD6 protein Q6NYC1 UNIPROT MEPCE protein Q7L2J0 UNIPROT down-regulates activity cleavage Arg171 HPAFKRRrRVNSDCD 10090 BTO:0002572 32048991 YES miannu JMJD6 cleaves MePCE. we propose that JMJD6 is the cognate protease of MePCE and cleaves at the R171 site within MePCE. Experiments using purified JMJD6 showed that it could make a cut in an enzyme called MePCE, which belongs to the group of proteins that hold P-TEFb in its inactive form. The levels of activated Pol II were lower in cells without JMJD6 and higher in those without MePCE. Together, the results suggest that JMJD6 cuts MePCE to release P-TEFb, which then activates Pol II. 0.269 SIGNOR-261037 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269345 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000891 10929712 YES amattioni Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria. 0.894 SIGNOR-80222 SCAF11 protein Q99590 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 YES lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. 0.294 SIGNOR-261758 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 YES inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. 0.2 SIGNOR-270061 EEF1A2 protein Q05639 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269524 FURIN protein P09958 UNIPROT VWF protein P04275 UNIPROT up-regulates activity cleavage BTO:0001538 8218226 YES Giorgia Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine 0.482 SIGNOR-260368 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 11013247 YES gcesareni Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer. 0.593 SIGNOR-82501 TFEB protein P19484 UNIPROT PIP4P1 protein Q86T03 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.2 SIGNOR-276547 CREBBP protein Q92793 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 NO lperfetto In A549 cells activation of 15-LOX by IL-4 required the coactivation of histone acetyltransferases CREB-binding protein/p300 and led to a sizable production of 15(S)-HETE 0.2 SIGNOR-254093 NADP(3-) smallmolecule CHEBI:58349 ChEBI NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity precursor of 9606 33064660 YES miannu Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. 0.8 SIGNOR-268078 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000165 12063245 YES inferred from 70% family members lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. 0.2 SIGNOR-270026 PPM1D protein O15297 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 9606 11101524 YES lperfetto Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue 0.444 SIGNOR-84793 CASP2 protein P42575 UNIPROT Caspase 2 complex complex SIGNOR-C227 SIGNOR form complex binding cleavage:Asp347 SPGCEESdAGKEKLP 21828056 YES lperfetto Like other caspases, caspase-2 is synthesized as an inactive zymogen. The zymogen sequence includes a long prodomain containing a CARD followed by a large domain, a linker, and a small domain. Caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit (p19) and the small subunit (p12). This p19/p12 dimer self-associates to form the active caspase-2 0.2 SIGNOR-256389 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12471034 YES gcesareni We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch). 0.967 SIGNOR-96250 SRC protein P12931 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr220 RHSVVVPyEPPEVGS 9606 BTO:0002181 25071020 YES miannu We recently found that ISGylation of the p53 tumor suppressor is an important novel mechanism to control its stability. Here we identified that Isg15-dependent regulation of p53 can be enhanced by different oncogenes. We further show that the Src-mediated phosphorylation of p53 on Tyr126 and Tyr220 has a positive effect on p53 ISGylation by enhancing Herc5 binding. 0.525 SIGNOR-276669 CDK13 protein Q14004 UNIPROT EIF4B protein P23588 UNIPROT up-regulates activity phosphorylation Ser422 RERSRTGsESSQTGT 9606 BTO:0001109 36882522 YES lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. 0.252 SIGNOR-273115 CEBPA protein P49715 UNIPROT Mast-Cell_diff phenotype SIGNOR-PH117 SIGNOR down-regulates activity 10090 BTO:0000725 23990620 NO Notably, enforced overexpression of C/EBP-α in BMCPs results in exclusive differentiation into basophils, whereas conditional deletion of C/EBP-α in these same cells promotes mast cell differentiation,1 suggesting that C/EBP-α is an essential “switch factor” for basophil lineage choice 0.7 SIGNOR-259967 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120072 CD226 protein Q15762 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates 9606 BTO:0000914 15039383 NO lperfetto CD226 and LFA-1 cooperate in cytotoxicity and cytokine secretion mediated by T and NK cells|These results were consistent with our observation that cross-linking CD226 with anti- CD226 mAb did not induce re-directed cytotoxicity against P815 by LFA-1-deficient LAD NK clones (Fig. 4D), suggesting a requirement for LFA-1 for CD226-mediated cytotoxicity. 0.541 SIGNOR-261427 MAT2B protein Q9NZL9 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity binding 9606 BTO:0000599 23325601 YES miannu We found both MAT2B variants interact with GIT1. MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. MAT2B and GIT1 require each other to activate MEK1/ERK and increase growth. 0.398 SIGNOR-261244 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 17311928 YES inferred from 70% family members llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 0.2 SIGNOR-270036 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR BSG protein P35613 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007;BTO:0003227;BTO:0005816 28117675 YES lperfetto F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells 0.2 SIGNOR-273453 MAPK1 protein P28482 UNIPROT RAI14 protein Q9P0K7 UNIPROT unknown phosphorylation Thr249 SQDADLKtPTKPKQH 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.267 SIGNOR-262760 NCKIPSD protein Q9NZQ3 UNIPROT NCK1 protein P16333 UNIPROT unknown binding 9606 14559906 YES gcesareni Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck 0.665 SIGNOR-118750 POU5F1 protein Q01860 UNIPROT ZFP42 protein Q96MM3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.465 SIGNOR-254944 PLK1 protein P53350 UNIPROT STARD9 protein Q9P2P6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser312 SVSNGGDsGILSSPS 9606 25501367 YES miannu NI indicates the noninduced control. (B) Plk1 phosphorylates STARD9-motor domain at serine 312. 0.31 SIGNOR-279804 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 YES gcesareni Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. 0.748 SIGNOR-243203 FBXO45 protein P0C2W1 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001620 19581926 YES miannu The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73.Importantly, SCFFBXO45 ubiquitylates p73 both in vivo and in vitro. Expression of Cul1 dominant negative mutant, but not Cul2, Cul3, Cul4 and Cul5 dominant negative mutants, increased p73 levels (Figure 1c) to an extent similar to that observed in the ts41 cell line at not permissive temperature, suggesting that a Cul1-associated activity is required for p73 protein stability. 0.596 SIGNOR-271876 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT up-regulates activity dephosphorylation Tyr505 FTATEGQyQPQP 10090 BTO:0000782 17719247 YES CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56(lck) pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity. 0.796 SIGNOR-259933 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser853 LPLLPPEsPGPLRQR 9606 BTO:0000007 20622900 YES miannu HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further. 0.2 SIGNOR-263065 GATA3 protein P23771 UNIPROT FOXC2 protein Q99958 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22120723 NO miannu We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. 0.331 SIGNOR-254089 NHS protein Q6T4R5 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity relocalization 9606 20332100 YES miannu NHS knockdown also resulted in the mislocalization of the Arp2/3 complex and disruption of the actin cytoskeleton. in the absence of NHS, Arp2/3 localization and F-actin distribution are disrupted, suggesting that Arp2/3 actin-nucleation activity is mediated, in part, by NHS providing an additional functional link between NHS and actin. 0.2 SIGNOR-253566 olaparib chemical CHEBI:83766 ChEBI PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-195016 FOXS1 protein O43638 UNIPROT FASLG protein P48023 UNIPROT down-regulates quantity by repression transcriptional regulation 9913 BTO:0004577 18288644 YES Luana As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells 0.2 SIGNOR-261612 MYC protein P01106 UNIPROT HLA-A protein P04439 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8206526 NO miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. 0.269 SIGNOR-254603 TRIM9 protein Q9C026 UNIPROT VASP protein P50552 UNIPROT down-regulates quantity ubiquitination 9606 26702829 YES miannu TRIM9 ubiquitinates VASP but not Mena or EVL.|Thus TRIM9 negatively regulates VASP localization to filopodia tips, whereas netrin promotes VASP tip localization. 0.345 SIGNOR-278580 CSNK2A1 protein P68400 UNIPROT TCOF1 protein Q13428 UNIPROT up-regulates activity phosphorylation Thr210 TSSSSDEtDVEGKPS 9606 BTO:0000567 25064736 YES lperfetto Phosphorylated Thr 210 in Treacle is the major interaction site for NBS1|A purified GST fragment of this region was efficiently phosphorylated by CK2 in vitro (Supplementary Fig. 4; T-2) and this fragment pulled down the MRN complex from Hela nuclear extracts only when previously phosphorylated by CK2 0.305 SIGNOR-265086 CREB1 protein P16220 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9600 BTO:0000567 26652733 YES inferred from family member Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB 0.2 SIGNOR-270250 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17937911 YES lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. 0.2 SIGNOR-158427 ULK1 protein O75385 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser282 QLADLYKsFIKDYPV 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274029 POLR2F protein P61218 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.901 SIGNOR-266148 PRKCA protein P17252 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR unknown phosphorylation -1 10366608 YES inferred from 70% of family members lperfetto In addition, we identified threonine 830 as a potential PKC phosphorylation site. 0.714 SIGNOR-269853 MC5R protein P33032 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.292 SIGNOR-256941 SIK2 protein Q9H0K1 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 BTO:0006293 35277657 YES miannu Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation. 0.2 SIGNOR-275404 NF1 protein P21359 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000938 24431436 YES miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.813 SIGNOR-204357 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser15 SSYRGRKsGNKPPSK 9606 9649584 YES gcesareni This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation. 0.2 SIGNOR-58498 SLBP protein Q14493 UNIPROT Histone H2B proteinfamily SIGNOR-PF68 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265375 GRK2 protein P25098 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10852916 YES llicata We found that grk-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and pld2. These findings suggest that gpcrs may be able to indirectly stimulate pld2 activity via their ability to regulate grk-promoted phosphorylation of synuclein. 0.2 SIGNOR-78333 MAPK6 protein Q16659 UNIPROT KALRN protein O60229 UNIPROT up-regulates activity phosphorylation -1 22508986 YES miannu The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements. 0.404 SIGNOR-263094 trichostatin A chemical CHEBI:46024 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258012 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 25910399 NO Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged. 0.7 SIGNOR-257599 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 13760840 YES gcesareni 0.8 SIGNOR-251700 A11/b1 integrin complex SIGNOR-C168 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.568 SIGNOR-257710 MAPK3 protein P27361 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser641 DIKILIAsPSPTHIH 9606 BTO:0000567 18519666 YES lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ 0.695 SIGNOR-178731 SYK protein P43405 UNIPROT BTK protein Q06187 UNIPROT up-regulates activity phosphorylation Tyr551 RYVLDDEyTSSVGSK 9606 11226282 YES lperfetto We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity. 0.588 SIGNOR-247586 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 2846551 YES gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. 0.2 SIGNOR-23753 BDKRB2 protein P30411 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257399 NLRX1 protein Q86UT6 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity binding 9606 21703539 YES Giorgia Immunoprecipitation experiments showed that NLRX1 interacted with TRAF6 and TRAF3, but not with TRAF2 or TRAF5. These results further suggest that NLRX1 specifically inhibits TLR-induced TRAF6-dependent NF-kB signaling through targeting TRAF6. 0.472 SIGNOR-260364 AP-2 complex complex SIGNOR-C245 SIGNOR EPN1 protein Q9Y6I3 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 YES Giorgia Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs 0.567 SIGNOR-260395 STRN protein O43815 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 YES miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms 0.596 SIGNOR-261700 MBOAT7 protein Q96N66 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification -1 18772128 YES miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. 0.8 SIGNOR-267247 LCK protein P06239 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates activity phosphorylation 9606 10799545 YES Phosphorylation of p56 dok and p62 dok is increased following CD2 stimulation and requires Lck. Phosphorylation of Dok proteins by Lck might provide a mechanism by which SH2-containing proteins can be recruited and co-localized with their substrates. 0.599 SIGNOR-251373 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 YES flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. 0.622 SIGNOR-75922 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JAK2 protein O60674 UNIPROT down-regulates phosphorylation 9606 16705159 YES 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner 0.2 SIGNOR-270046 CD38 protein P28907 UNIPROT NAD(+) smallmolecule CHEBI:15846 ChEBI down-regulates quantity chemical modification 9606 18626062 YES miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. 0.8 SIGNOR-264246 AKT1 protein P31749 UNIPROT PLN protein P26678 UNIPROT down-regulates activity phosphorylation Thr17 SAIRRAStIEMPQQA 10090 BTO:0003265 19696029 YES Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17). 0.289 SIGNOR-252578 PRKCZ protein Q05513 UNIPROT PIAS4 protein Q8N2W9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser18 MVMSFRVsDLQMLLG 27162139 YES lperfetto In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFbeta signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCzeta and GSK3beta. Specifically, PKCzeta phosphorylation of PIAS4 and GSK3beta phosphorylation of FIEL1 are both essential for the degradation of PIAS4.|These experiments suggested that PKCzeta is an authentic regulator of PIAS4 protein stability; Q21 and phosphorylated S18 of PIAS4 are both required for FIEL1 interaction. 0.518 SIGNOR-275513 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.41 SIGNOR-249688 SEC24D protein O94855 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.69 SIGNOR-265291 ATR protein Q13535 UNIPROT USP28 protein Q96RU2 UNIPROT up-regulates activity phosphorylation Ser67 DERVKEPsQDTVATE 31938050 YES lperfetto Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity.|Representative immunoblots of n = 3. C Immunoblotting of total and phosphorylated USP28 at serine 67 and 714 in A431 cells exposed to indicated concentrations of CPPD for 6 h. 0.2 SIGNOR-275850 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 23119004 YES lperfetto Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1. 0.8 SIGNOR-236509 PRKCH protein P24723 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 YES llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. 0.356 SIGNOR-66730 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR S100A6 protein P06703 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12859951 NO miannu NF-kappaB transcription factor contributes to the activation of S100A6 gene expression in response to TNFalpha in HepG2 cells. 0.2 SIGNOR-254803 Dihydromorphine chemical CHEBI:4575 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258788 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr308 KDGATMKtFCGTPEY 10116 BTO:0000142 10226025 YES lperfetto Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. 0.748 SIGNOR-244421 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser459 TSSSPPIsPASSDLS 9606 BTO:0000007 16141410 YES In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity 0.398 SIGNOR-251243 PPP2CA protein P67775 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates dephosphorylation 9606 19061640 YES gcesareni In the absence of the wt apc protein, phosphorylated beta-catenin is rapidly dephosphorylated by serine/threonine protein phosphatase 2a (pp2a). phosphorylated beta-catenin associated with the wild-type apc protein is recruited to the scf(beta-trcp) complex, ubiquitin conjugated, and degraded. 0.461 SIGNOR-182637 PKN1 protein Q16512 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr678 RHIVRKRtLRRLLQE 9606 21749319 YES lperfetto This identified thr654 in egfr as the pkn1 phosphorylation siteit has been shown that the phosphorylation of egfr at thr654 by pkc reduces the tyrosine kinase activity of the receptor 0.2 SIGNOR-174755 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 16362042 YES gcesareni Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. 0.905 SIGNOR-143109 diazepam chemical CHEBI:49575 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The traditional BZ site agonists (GABA-enhancing CNS depressants such as diazepam) are active on the GABAA-Rs containing a gamma2 subunit (Pritchett et al., 1989), a beta subunit, and one of the alpha subunits, alpha1, 2, 3, or 5. 0.8 SIGNOR-263796 PRKACA protein P17612 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Thr369 DLINKKItPPFNPNV -1 11096081 YES miannu In this publication, we demonstrate that cAMP can activate Sgk and that this effect is mediated by PKA, which directly phosphorylates Thr369 in Sgk.  0.297 SIGNOR-275972 SRC protein P12931 UNIPROT HK1 protein P19367 UNIPROT down-regulates activity phosphorylation Tyr732 YDRLVDEySLNAGKQ 9606 28054552 YES miannu Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its K m and increases its V max by disrupting its dimer formation.|Mechanistically, c-Src-mediated Y732 phosphorylation disrupts HK1 dimer formation, alters its enzyme kinetics and eventually enhances enzymatic activity ( ). 0.493 SIGNOR-278209 CASP6 protein P55212 UNIPROT LMNA protein P02545 UNIPROT down-regulates cleavage 9606 11058599 YES amattioni Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis. 0.661 SIGNOR-83611 TBX21 protein Q9UL17 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000782 20154735 NO azuccotti Similarly, an increase in IL-10 expression was observed in mice deficient for the TH1 cell-specific transcription factor T-bet (also known as TBX21) that were infected with M.tuberculosis, suggesting that T-bet might have a role in the negative regulation of IL-10 expression by TH1 cells 0.447 SIGNOR-254524 MMP3 protein P08254 UNIPROT SPP1 protein P10451 UNIPROT up-regulates activity cleavage 25545242 YES lperfetto In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA. 0.669 SIGNOR-253320 GSK3B protein P49841 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity phosphorylation Ser166 GAEDTASsQLGFGVL 9606 29328365 YES miannu Based on these observations, we hypothesized that the IR induced GSK3beta nuclear translocation may activate 53BP1 via phosphorylation at the S/T-Q motif.|Importantly, our in vivo and in vitro data clearly indicated that GSK3\u03b2 induced the phosphorylation of 53BP1 at the Ser166 site. 0.283 SIGNOR-278226 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11090075 NO Overexpression of cyclin A1 observed in APL cells is caused by the expression of the aberrant fusion proteins, PML-RARα and PLZF-RARα. PML-RARα itself can lead to activation of the cyclin A1 promoter.Since both fusion proteins disrupt the normal RARα function, our results strongly suggested that the RARα pathway negatively regulates the expression of cyclin A1 and that this negative regulation is disrupted by the aberrant fusion proteins. 0.2 SIGNOR-255725 PRKCB protein P05771 UNIPROT STXBP1 protein P61764 UNIPROT down-regulates activity phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 YES lperfetto Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation. 0.398 SIGNOR-249186 NOX3 protein Q9HBY0 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity chemical modification 9606 17237347 YES lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). 0.8 SIGNOR-264722 CASP3 protein P42574 UNIPROT MYL3 protein P08590 UNIPROT down-regulates quantity by destabilization cleavage Glu135 GTYEDFVeGLRVFDK 9986 BTO:0003324 12186978 YES lperfetto By sequencing and site-directed mutagenesis, a noncanonical cleavage site for caspase-3 was mapped to the C-terminal DFVE(135)G motif. We demonstrated that vMLC1 cleavage in failing myocardium in vivo is associated with a morphological disruption of the organized vMLC1 staining of sarcomeres, and with a reduction in myocyte contractile performance. 0.378 SIGNOR-270593 PRKCA protein P17252 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by stabilization phosphorylation Ser144 TLPSDKLsKIQTLKL 9606 BTO:0002181 30733340 YES miannu Because most of these sites were predicted to be phosphorylated by protein kinase C (PKC), we overexpressed PKCα in several cell lines and found that it phosphorylates Twist1 on Ser-144. we observed that PKCα-mediated Twist1 phosphorylation at Ser-144 inhibits Twist1 ubiquitination and consequently stabilizes it. 0.2 SIGNOR-277429 PPP1CA protein P62136 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR down-regulates activity dephosphorylation 9606 14751588 YES miannu Dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa (DARPP-32) is a key element of dopamine/D1/DARPP-32/protein phosphatase-1 (PP-1) signaling cascades of mammalian brain. Phosphorylation of AMPA receptors due to DARPP-32/PP1 signaling cascade increases AMPA channel activity and currents 0.513 SIGNOR-265060 IL1B protein P01584 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000766 10435048 NO miannu IL-1 beta induces expression of GTP cyclohydrolase-1 which leads to increased generation of BH4 and activation of eNOS. 0.343 SIGNOR-252224 DTX4 protein Q9Y2E6 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates ubiquitination 9606 BTO:0000938 10531053 YES gcesareni Nlrp4 negatively regulates type i interferon signaling by targeting the kinase tbk1 for degradation via the ubiquitin ligase dtx4 0.583 SIGNOR-71565 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR ALDH3A2 protein P51648 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001078 26124079 YES miannu We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members. 0.263 SIGNOR-272818 LPAR2 protein Q9HBW0 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.467 SIGNOR-257169 AMER1 protein Q5JTC6 UNIPROT CSNK1G1 protein Q9HCP0 UNIPROT up-regulates binding 9606 21304492 YES gcesareni Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6. 0.2 SIGNOR-171889 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 22198508 YES lperfetto Our results demonstrate that human atrial I(to) and cloned hKv4.3 channels are modulated by EGFR kinase via phosphorylation of the Y136 residue and by Src-family kinases via phosphorylation of the Y108 residue|We found that human atrial I(to) was inhibited by the broad-spectrum PTK inhibitor genistein, the selective epidermal growth factor receptor (EGFR) kinase inhibitor AG556, and the Src-family kinases inhibitor PP2. 0.2 SIGNOR-275566 EGFR protein P00533 UNIPROT FUS protein P35637 UNIPROT up-regulates activity phosphorylation 9606 32678881 YES miannu Thus, EGFR appears to mediate FUS nuclear translocation by phosphorylating Y6 and Y296 in FUS. 0.259 SIGNOR-279168 EGFR protein P00533 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation 9606 30573522 YES miannu EGFR and MET heterodimer interacts with and phosphorylates PARP1. 0.395 SIGNOR-279169 MMP2 protein P08253 UNIPROT PZP protein P20742 UNIPROT down-regulates quantity by destabilization cleavage Thr718 PYVPQLGtYNVIPLN -1 9344465 YES lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.33 SIGNOR-261796 SNAI1 protein O95863 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000599 27239445 NO Marta Tosoni We also observed that SNAI1 expression was correlated with distal metastasis, incomplete tumor capsule formation, and histological differentiation in hepatocellular carcinoma (HCC). 0.7 SIGNOR-278098 ruxolitinib chemical CHEBI:66919 ChEBI JAK3 protein P52333 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258278 AMP smallmolecule CHEBI:456215 ChEBI ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 YES miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. 0.8 SIGNOR-269468 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C3 17510057 YES gcesareni In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.834 SIGNOR-154821 MYCN protein P04198 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000661 21261500 NO miannu HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. 0.3 SIGNOR-254214 FBXO22 protein Q8NEZ5 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000356 31138683 YES lperfetto SCFFBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis|we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCFFBXO22) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. 0.2 SIGNOR-273440 IRF3 protein Q14653 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 27337441 YES lperfetto Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation 0.407 SIGNOR-251721 HDAC1 protein Q13547 UNIPROT UBE2D3 protein P61077 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 21044962 NO miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. 0.264 SIGNOR-255175 CREB1 protein P16220 UNIPROT PLAT protein P00750 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001282 8647095 NO lperfetto We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells. 0.264 SIGNOR-253732 MAPK3 protein P27361 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 BTO:0000150;BTO:0000551 22139079 YES Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. 0.2 SIGNOR-195157 SOX4 protein Q06945 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 24183681 NO miannu These data demonstrate an HSC cell intrinsic role for Sox4 on proliferation induced by loss of C/EBPα. 0.7 SIGNOR-260133 pazopanib hydrochloride chemical CHEBI:71217 ChEBI CSF1R protein P07333 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-199527 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273057 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT down-regulates activity phosphorylation Ser714 ESSTNSSsQDYSTSQ 31938050 YES lperfetto Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization. 0.312 SIGNOR-275853 BIRC2 protein Q13490 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys51 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. 0.355 SIGNOR-272706 GSK3B protein P49841 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser62 EPDSGSHsRQSSTDS 9606 BTO:0002181 22692215 YES miannu GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3  phosphorylation, whereas the Ser-66 is not (Fig. 4D). 0.2 SIGNOR-277647 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT down-regulates activity phosphorylation Thr239 VPEMPGEtPPLSPID 9606 BTO:0000007 16023596 YES lperfetto The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance 0.711 SIGNOR-236717 COPS3 protein Q9UNS2 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.918 SIGNOR-270769 AKT proteinfamily SIGNOR-PF24 SIGNOR ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 15538381 YES lperfetto Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity. 0.2 SIGNOR-244385 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser9 EEPQSDPsVEPPLSQ 9606 11875057 YES gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. 0.843 SIGNOR-115348 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 11875057 YES gcesareni In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization. 0.843 SIGNOR-115344 C5 protein P01031 UNIPROT C5AR1 protein P21730 UNIPROT up-regulates activity binding 9606 cleavage:Arg751;Arg677 HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE 1847994 YES complement C5a (anaphylatoxin) fragment: PRO_0000005988 lperfetto The chemotactic receptor for human C5a anaphylatoxin|The human C5a receptor was cloned from U937 and HL-60 cells and identified by high affinity binding when expressed in COS-7 cells. 0.756 SIGNOR-263457 TTC8 protein Q8TAM2 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 YES lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome 0.76 SIGNOR-262554 DEPDC5 protein O75140 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR form complex binding 9606 23723238 YES miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 0.95 SIGNOR-255280 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser186 YSSPGLYsKTMTPTY 9606 BTO:0000567 35469017 YES miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. 0.2 SIGNOR-276714 CDC45 protein O75419 UNIPROT MCM complex SIGNOR-C268 SIGNOR up-regulates activity binding 9606 19614620 YES done miannu The Cdc (cell division cycle) 45 protein has a central role in the regulation of the initiation and elongation stages of eukaryotic chromosomal DNA replication. Cdc45 interacts physically and functionally with the putative eukaryotic replicative DNA helicase, the MCM (mini-chromosome maintenance) complex, and forms a helicase active 'supercomplex', the CMG [Cdc45-MCM2-7-GINS (go-ichi-ni-san)] complex. These known protein-protein interactions, as well as unknown interactions and post-translational modifications, may be important for the regulation of Cdc45 and the initiation of DNA replication following DNA damage. 0.954 SIGNOR-273974 FANCG protein O15287 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 YES lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  0.736 SIGNOR-263254 MT-ND4L protein P03901 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 0.692 SIGNOR-262147 SEMA3B protein Q13214 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 YES miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  0.652 SIGNOR-261812 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 16046550 YES The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. 0.614 SIGNOR-138953 NF1 protein P21359 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates 9606 BTO:0000938 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.399 SIGNOR-267847 Protocadherin_beta proteinfamily SIGNOR-PF102 SIGNOR ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-269039 TNF protein P01375 UNIPROT REL protein Q04864 UNIPROT up-regulates 9606 BTO:0000782 10823840 NO miannu C-rel emerges as the main nf-kb family member stimulated by tnf_ in the context of physiologic activation of resting t cells. 0.413 SIGNOR-77547 FZD5 protein Q13467 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 23151663 YES areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  0.703 SIGNOR-258960 SP1 protein P08047 UNIPROT CD151 protein P48509 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20149781 NO miannu SP1 is required for basal activation and chromatin accessibility of CD151 promoter in liver cancer cells. 0.2 SIGNOR-255195 CPC complex SIGNOR-C554 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 37292983 NO miannu Here, we focus on the chromosome passenger complex (CPC), that forms a chromatin body that regulates chromosome segregation in mitosis. 0.7 SIGNOR-275427 CASP9 protein P55211 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR form complex binding -1 10206961 YES lperfetto  APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9.  0.916 SIGNOR-256429 C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg677 KEILRPRrTLQKKIE 9606 BTO:0000089 26489954 YES lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). 0.557 SIGNOR-263481 ATF2 protein P15336 UNIPROT POLB protein P06746 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001025 10518804 NO miannu We identified the heterodimeric transcription factor ATF2/CREB as constitutively binding to the essential cAMP response element (CRE) site within the Ca2+-regulated DNA polymerase beta promoter and contributing to the activation of this promoter. 0.2 SIGNOR-253744 HEXIM1 protein O94992 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR down-regulates activity binding 9606 18371977 YES miannu Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. The mislocalization of HEXIM1 and the increased P-TEFb-dependent transcription caused by NPMc+ suggests that the misregulated activity of PTEFb may contribute to the tumorigenesis of NPMc+ AML. 0.72 SIGNOR-260135 ANKRD11 protein Q6UB99 UNIPROT GAP43 protein P17677 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 YES miannu Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.  0.2 SIGNOR-266736 TNF protein P01375 UNIPROT JAG2 protein Q9Y219 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004914 14586405 NO We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. 0.318 SIGNOR-253608 HRAS protein P01112 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization. 0.821 SIGNOR-175195 SRC protein P12931 UNIPROT ANXA2 protein P07355 UNIPROT up-regulates phosphorylation Tyr24 HSTPPSAyGSVKAYT 9606 15302870 YES lperfetto Translocation requires the presence of the annexin 2 binding partner p11 (s100a10) and the phosphorylation of annexin 2 at tyr23 through a src-like tyrosine kinase-dependent mechanism both in vitro and in vivo. 0.548 SIGNOR-127872 BRCA1 protein P38398 UNIPROT TOP1 protein P11387 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002201 28415827 YES miannu Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. Taken together, we conclude that BRCA1 is the E3 ligase for topoI, and the rate of topoI proteasomal degradation determines CPT response. 0.464 SIGNOR-277353 MECP2 protein P51608 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000093 15870696 NO miannu Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters 0.39 SIGNOR-254573 NUCKS1 protein Q9H1E3 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 26323318 NO miannu From these results, we can conclude that NUCKS1 plays a role in HR DNA repair, as does its paralog RAD51AP1. we have tested and uncovered a role for NUCKS1 in HR and in maintaining DNA replication integrity and genome stability. 0.7 SIGNOR-261960 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000552 9736735 YES lperfetto Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21CIP1/WAF1 and cyclin D proteins|These data suggest that the human p19(SKP1)/p45(SKP2)/CUL-1 complex is likely to function as an E3 ligase to selectively target cyclin D and p21 for the ubiquitin-dependent protein degradation. 0.68 SIGNOR-267556 BTF3 protein P20290 UNIPROT RRAS2 protein P62070 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17312387 NO miannu BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. 0.259 SIGNOR-253766 ULK2 protein Q8IYT8 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser115 ANAILGVsLAVCKAG 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274038 RAF1 protein P04049 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Ser621 PKINRSAsEPSLHRA 9534 19595761 YES lperfetto We show that phosphorylation of s621 turns over rapidly and is enriched in the activated pool of endogenous raf-1. The phosphorylation on this site can be mediated by raf-1 itself but also by other kinase(s) 0.2 SIGNOR-235770 MTNR1A protein P48039 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.475 SIGNOR-256706 P2RY14 protein Q15391 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.401 SIGNOR-256866 BAIAP2 protein Q9UQB8 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 11130076 YES gcesareni Here we demonstrate that irsp53, a substrate forinsulinreceptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex. 0.627 SIGNOR-85299 EIF2B3 protein Q9NR50 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 YES lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. 0.805 SIGNOR-269141 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser664 QLPYYYLsPDRIPNS 9606 BTO:0000567 12670876 YES lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. 0.2 SIGNOR-264442 NDUFC2 protein O95298 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 0.81 SIGNOR-262174 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1A protein P37288 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257461 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR EIF4EBP1 protein Q13541 UNIPROT up-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0001109 36882522 YES lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. 0.2 SIGNOR-273114 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser217 AHYSPRTsPIMSPRT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248686 CYFIP1 protein Q7L576 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 YES lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  0.906 SIGNOR-261873 HSPA1B protein P0DMV9 UNIPROT GSTA4 protein O15217 UNIPROT up-regulates activity relocalization phosphorylation:Thr193;Ser189 VKLSNIPtIKRFLEP;QEYTVKLsNIPTIKR 21929724 YES lperfetto Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation 0.2 SIGNOR-264800 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT down-regulates quantity by destabilization cleavage Ile105 ESSKPNMiDAATLKS -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain 0.2 SIGNOR-263618 paliperidone chemical CHEBI:82978 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258563 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 4344326 YES Bell's palsy gcesareni 0.8 SIGNOR-251704 BLOC1S5 protein Q8TDH9 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 YES lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. 0.691 SIGNOR-265938 NARS2 protein Q96I59 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270463 SDHC protein Q99643 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 30030361 YES lperfetto Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites 0.955 SIGNOR-262186 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT up-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ 8355 BTO:0001175 18803695 YES miannu Recently, we have defined sites of phosphorylation by cAMP-dependent protein kinase (PKA) in the amino termini of both GRK1 and GRK7 in vitro. To determine the conditions under which GRK7 is phosphorylated in vivo, we have generated an antibody that recognizes GRK7 phosphorylated on Ser36, the PKA phosphorylation site. Using this phospho-specific antibody, we have shown that GRK7 is phosphorylated in vivo and is located in the cone inner and outer segments of mammalian, amphibian and fish retinas. The conservation of phosphorylation at Ser36 in GRK7 in these different species (which span a 400 million-year evolutionary period), and its light-dependent regulation, indicates that phosphorylation plays an important role in the function of GRK7 0.2 SIGNOR-263152 F2RL3 protein Q96RI0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257044 p38 proteinfamily SIGNOR-PF16 SIGNOR DROSHA protein Q9NRR4 UNIPROT down-regulates activity phosphorylation Ser300 RHRDNRRsPSLERSY 9606 BTO:0000007 25699712 YES lperfetto Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.  0.2 SIGNOR-264847 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 YES PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3. 0.553 SIGNOR-248427 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR2 protein P30518 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257463 pemetrexed disodium chemical CHEBI:63722 ChEBI GART protein P22102 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 YES miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). 0.8 SIGNOR-259291 NR5A2 protein O00482 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 NO miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.363 SIGNOR-254873 DNAAF10 protein Q96MX6 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 YES miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  0.2 SIGNOR-270921 CAMK2A protein Q9UQM7 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Thr107 ELTHNWGtEDDETQS -1 32966793 YES miannu This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax). 0.2 SIGNOR-273553 CALM2 protein P0DP24 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 YES miannu The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases 0.489 SIGNOR-266328 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser455 HFGSTSSsPPISPAS 9606 BTO:0000007 16141410 YES In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity 0.398 SIGNOR-251244 masitinib chemical CHEBI:63450 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258244 NARS1 protein O43776 UNIPROT asparagine smallmolecule CHEBI:22653 ChEBI down-regulates quantity chemical modification 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270454 NDN protein Q99608 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates 9606 24392140 NO lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, 0.278 SIGNOR-253383 NDUFB7 protein P17568 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 0.822 SIGNOR-262170 ABL1 protein P00519 UNIPROT DDX5 protein P17844 UNIPROT up-regulates phosphorylation Tyr593 NGMNQQAyAYPATAA 9606 17018282 YES llicata These results suggested that p68 was phosphorylated by c-abl in ht-29 cells under stimulation of pdgf. we demonstrated that tyrosine phosphorylation of p68 at y593 mediated pdgf-stimulated epithelial-mesenchymal transition (emt). We showed that pdgf treatment led to phosphorylation of p68 at y593 in the cell nucleus. The y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a wnt-independent pathway. 0.358 SIGNOR-149988 PLK1 protein P53350 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates activity phosphorylation Ser486 SEYEAEMsLQGEVNI 9606 26323689 YES miannu In this study, we show that ubiquitin-specific peptidase 16 (Usp16) is a novel substrate for Plk1, and sequential phosphorylation by CDK1 and Plk1 activates Usp16, which, in turn, deubiquitinates Plk1 and promotes the recruitment of Plk1 to, and its retention on, the kinetochores for proper chromosome alignment.|In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. 0.344 SIGNOR-278270 PRKCB protein P05771 UNIPROT NOX1 protein Q9Y5S8 UNIPROT up-regulates activity phosphorylation Thr430 CADHNLKtKKIYFYW -1 25228390 YES lperfetto Site-directed mutagenesis and isothermal titration calorimetry indicated that protein kinase C-beta1 phosphorylates Nox1 at threonine 429. Moreover, Nox1 threonine 429 phosphorylation facilitated the association of Nox1 with the NoxA1 activation domain and was necessary for NADPH oxidase complex assembly 0.2 SIGNOR-264729 RPS6KA4 protein O75676 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates activity phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0002181 19933278 YES miannu Here we report that the CK2 protein kinase, which contributes to NF-kappaB activation following UV radiation in a p38-dependent manner, physically interacts with MSK2 but not MSK1 and that CK2 inhibition specifically impairs UV-induced MSK2 kinase activation. A putative site of CK2 phosphorylation was mapped to MSK2 residue Ser(324) and when substituted to alanine (S324A) also compromised MSK2 activity.Serine 324 is required for UV-induced MSK2 activation and for autophosphorylation at MSK2-Ser196. 0.2 SIGNOR-276269 SRC protein P12931 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates activity phosphorylation Tyr721 FDLSEQTyDFLGEMR 9606 21357692 YES miannu Src-induced tyrosine phosphorylation could be prevented by mutating the tyrosine residue at position 721 to phenylalanine ( C, lane 12) suggesting that Src kinase phosphorylates NPHP1 at tyrosine 721. 0.297 SIGNOR-279122 PCDHA2 protein Q9Y5H9 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265661 STK38 protein Q15208 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 BTO:0000007 21262772 YES no lperfetto More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. | 0.2 SIGNOR-272961 NOD2 protein Q9HC29 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity binding 9606 17355968 YES miannu The function of NOD2 could be to recruit RICK at the plasma membrane to form an active complex able to activate part of the NF-κB pathway. NOD2 induces a membrane recruitment of RICK that is dependent on a CARD-CARD interaction. 0.764 SIGNOR-252402 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 19162178 YES gcesareni The hgf-induced wave2 transport, lamellipodia formation, stathmin/op18 phosphorylation at ser38 and binding to kinesin-wave2 complex, but not stathmin/op18 phosphorylation at ser25 and microtubule growth, were abrogated by pak1 inhibitor ipa-3 0.375 SIGNOR-183503 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity phosphorylation Tyr567 IRVDTPHyPRWITKE -1 11812791 YES Src, Fyn, or Lyn are the essential kinases that tyrosine phosphorylate and inactivate PKC δ. Lyn phosphorylates tyrosine residue 565 in vitro 0.556 SIGNOR-251407 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser14 PFSFGTLsSWELEAW 9606 BTO:0000567 12876286 YES llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites 0.345 SIGNOR-250850 CUDC-101 chemical CID:24756910 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262257 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr387 LMRTLCGtPTYLAPE 9606 BTO:0000007 11901158 YES gcesareni Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387 0.2 SIGNOR-116131 ROCK2 protein O75116 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 YES lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. 0.413 SIGNOR-96696 OGT protein O15294 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 YES miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. 0.556 SIGNOR-267158 DOCK10 protein Q96BY6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.521 SIGNOR-260549 PPP2R1A protein P30153 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR form complex binding 9606 23454242 YES gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. 0.924 SIGNOR-243427 PRKACA protein P17612 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 YES gcesareni Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a. 0.372 SIGNOR-83221 SNTG2 protein Q9NY99 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.528 SIGNOR-255995 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263812 CDK5 protein Q00535 UNIPROT EPRS1 protein P07814 UNIPROT down-regulates phosphorylation Ser886 LSQSSDSsPTRNSEP 9606 19647514 YES lperfetto Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation 0.2 SIGNOR-187383 NR3C1 protein P04150 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 10090 BTO:0000944 11742987 NO inferred from 70% of family members gcesareni Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. 0.633 SIGNOR-269920 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Gln) smallmolecule CHEBI:29168 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270387 DMTF1 protein Q9Y222 UNIPROT DSPP protein Q9NZW4 UNIPROT up-regulates quantity by expression transcriptional regulation 23349460 YES lperfetto In addition, our in vitro analyses showed that DMP1 and its 57-kDa C-terminal fragment significantly up-regulated the Dspp promoter activities in a mesenchymal cell line. 0.2 SIGNOR-271685 PRKCG protein P05129 UNIPROT TOP2A protein P11388 UNIPROT up-regulates activity phosphorylation Ser29 EDAKKRLsVERIYQK 9606 BTO:0000567 12569090 YES lperfetto Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides. 0.359 SIGNOR-249196 NFIX protein Q14938 UNIPROT ETV5 protein P41161 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268886 PTPN11 protein Q06124 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr906 CQLPPEGyVVVVKNV 9606 10880513 YES miannu We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. |We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. Moreover, overexpression of dominant negative SHP2 blocked the protective effect of IL-6 against Dex-induced apoptosis. These findings demonstrate that SHP2 mediates the anti-apoptotic effect of IL-6 and suggest SHP2 as a novel therapeutic target in MM..... 1) RAFTK is a substrate of SHP2 in vitro and 2) dephosphorylation of RAFTK by SHP2 inhibits its kinase activity. 0.724 SIGNOR-277084 TRIB3 protein Q96RU7 UNIPROT ACACB protein O00763 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 16794074 YES miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). 0.258 SIGNOR-271601 TSC22D3 protein Q99576 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity relocalization 9606 BTO:0000738 20018851 YES GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. 0.301 SIGNOR-256146 CIITA protein P33076 UNIPROT HLA-DQB1 protein P01920 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11332992 NO The class II transactivator (CIITA) regulates expression of the classical and non-classical MHC class II genes, HLA-DR, -DP, -DQ and -DM, 0.515 SIGNOR-254017 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19254573 NO fspada Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression. 0.392 SIGNOR-184277 CFAP53 protein Q96M91 UNIPROT ODAD4 protein Q96NG3 UNIPROT up-regulates activity binding 10090 BTO:0000379 33347437 YES miannu CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). 0.2 SIGNOR-265543 BRAF protein P15056 UNIPROT SLC5A5 protein Q92911 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19861538 YES miannu The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression. 0.2 SIGNOR-251989 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation 0.312 SIGNOR-129300 PRPF19 protein Q9UMS4 UNIPROT RPA2 protein P15927 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000567 24332808 YES miannu PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment. 0.479 SIGNOR-272075 trichostatin A chemical CHEBI:46024 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257938 GNAS protein Q5JWF2 UNIPROT RACK1 protein P63244 UNIPROT down-regulates activity binding 9606 BTO:0000972 34657150 YES Marta Tosoni The results showed that RACK1 severed as an oncogene to enhance the proliferation capacity of liver cancer cell lines, meanwhile, downregulated GNA14 expression in Huh7 cell lines reversed the effects of RACK1 on cell proliferation 0.2 SIGNOR-278048 MAPK1 protein P28482 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 YES miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. 0.2 SIGNOR-277856 EEF1A1P5 protein Q5VTE0 UNIPROT Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269545 Infliximab (Remicade) antibody DB00065 DRUGBANK TNF protein P01375 UNIPROT down-regulates activity binding 9606 26092578 YES Infliximab [IFX] is a monoclonal antibody designed to intercept and neutralise tumour necrosis factor alpha [TNFα], a key inflammatory cytokine 0.4 SIGNOR-272489 GPSM3 protein Q9Y4H4 UNIPROT GNB1 protein P62873 UNIPROT down-regulates quantity by destabilization binding 22843681 YES lperfetto GPSM3 was found not only to modulate heterotrimeric G-protein subunit signaling through its two active GoLoco motifs, but also to affect monomeric Gbeta subunit biosynthesis and stability|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET. 0.383 SIGNOR-264865 Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 BTO:0000143 25195934 NO miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.7 SIGNOR-270759 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 YES llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. 0.365 SIGNOR-250802 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr410 GVVDSGVyAVPPPAE 9606 12601080 YES lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. 0.256 SIGNOR-98569 3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol hydrochloride chemical CHEBI:64057 ChEBI HTR1D protein P28221 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190774 sirolimus chemical CHEBI:9168 ChEBI AKT1 protein P31749 UNIPROT up-regulates 9606 16452206 NO gcesareni We now show that mtor inhibition induces insulin receptor substrate-1 expression and abrogates feedback the pathway, resulting in akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, rad001. 0.8 SIGNOR-252643 RNF7 protein Q9UBF6 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates activity ubiquitination 9606 23136067 YES miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. 0.39 SIGNOR-271446 CSNK2B protein P67870 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 YES lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. 0.27 SIGNOR-275744 DCAF1 protein Q9Y4B6 UNIPROT MCM10 protein Q7L590 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 22570418 YES miannu By screening the known DDB1 interacting proteins, we discovered that VprBP is the substrate recognition subunit that targets Mcm10 for degradation. Hence, these results establish that Cul4-DDB1-VprBP ubiquitin ligase mediates the stress-induced proteolysis of replication factor, Mcm10. 0.2 SIGNOR-272046 ALDOA protein P04075 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266487 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser642 NACTLTTsPRLPVF 10090 BTO:0000944 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.631 SIGNOR-249444 KAT2B protein Q92831 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269621 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD83 protein Q01151 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 NO miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. 0.259 SIGNOR-254781 GSK3B protein P49841 UNIPROT DROSHA protein Q9NRR4 UNIPROT up-regulates activity phosphorylation Ser300 RHRDNRRsPSLERSY -1 25699712 YES lperfetto Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.  0.278 SIGNOR-264845 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 ChEBI ADP-D-ribose(2-) smallmolecule CHEBI:57967 ChEBI up-regulates quantity precursor of 9606 32257385 YES miannu MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins 0.8 SIGNOR-269841 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD7 protein O15105 UNIPROT down-regulates activity ubiquitination 9606 12519765 YES lperfetto Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm 0.2 SIGNOR-253260 MAPK13 protein O15264 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 YES lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK 0.2 SIGNOR-264449 STUB1 protein Q9UNE7 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. 0.422 SIGNOR-272752 CCNF protein P41002 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27653696 YES miannu We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. 0.537 SIGNOR-266363 CAMK4 protein Q16566 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 32531122 YES miannu CAMK4 phosphorylates GSK3\u03b2 at serine 9, which leads to its inactivation. xref Accordingly, we examined the levels of phosphorylated GSK3\u03b2 at serine 9 (pGSK3\u03b2-ser9) in podocytes exposed to IgG from TG patients and calculated the ratio of pGSK3\u03b2-ser9 to total GSK3\u03b2. 0.264 SIGNOR-279142 PGK1 protein P00558 UNIPROT PGK1 protein P00558 UNIPROT up-regulates activity phosphorylation Tyr324 GPESSKKyAEAVTRA -1 31492635 YES miannu PGK1 functions not only as a glycolytic enzyme but also as a protein kinase intermolecularly autophosphorylating itself at Y324 for activation.  0.2 SIGNOR-277482 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 16495336 YES gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell 0.503 SIGNOR-144795 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM5C protein P41229 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273468 PRKCA protein P17252 UNIPROT RAB37 protein Q96AX2 UNIPROT down-regulates activity phosphorylation Thr172 YGVPFLEtSAKTGMN 9606 29312551 YES miannu PKCalpha phosphorylates Rab37 on threonine 172.|These data therefore supported a mechanism by which PKCalpha blocks Rab37 mediated cargos secretion by facilitating the dissociation of phosphorylated Rab37 from its targeting vesicles. 0.2 SIGNOR-278322 PP1 proteinfamily SIGNOR-PF54 SIGNOR TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 YES lperfetto Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. 0.2 SIGNOR-264670 SPTAN1 protein Q13813 UNIPROT Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR form complex binding 9606 24302288 YES lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell 0.574 SIGNOR-266026 hsa-miR-381-5p mirna URS00004A35E2_9606 RNAcentral GPR34 protein Q9UPC5 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003109 33086148 YES Parnian In sum, the results reveal that GPR34 is targeted by miRNA-381 in cervical cancer to exercise its regulator control and relieving of post-transcriptional silencing of GPR34 might be acting as one of the crucial clues for the development of human cervical cancer. 0.4 SIGNOR-279811 hsa-miR-1225-5p mirna URS000075D0F5_9606 RNAcentral GPR15 protein P49685 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001109 33708462 YES Parnian The results reveal that miR-1225 is down-regulated in colorectal cancer alleviating the post-transcriptional suppression of GPR15 resulting in higher GPR15 expression. The latter enhances the colorectal cancer cell proliferation, migration, and invasion. 0.4 SIGNOR-279812 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr366 ASSSTSVtPDVSDNE -1 12297295 YES llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  0.704 SIGNOR-251026 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr153 SEDIKSYyTVRQLEL -1 11506178 YES Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. 0.2 SIGNOR-248425 SLC46A1 protein Q96NT5 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity relocalization 9606 BTO:0000575 17129779 YES lperfetto However, the current study establishes that a major function of this gene product is proton-coupled folate transport required for folate homeostasis in man, and we have thus amended the name to PCFT/HCP1. 0.8 SIGNOR-268264 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 YES Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. 0.318 SIGNOR-248500 RQC complex complex SIGNOR-C559 SIGNOR 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates quantity by destabilization ubiquitination 30940912 YES lperfetto The stalling of ribosomes during protein synthesis results in the production of truncated polypeptides that can have deleterious effects on cells, and therefore must be eliminated. In eukaryotes, this function is carried out by a dedicated surveillance mechanism known as ribosome-associated protein quality control (RQC). 0.2 SIGNOR-277699 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 YES gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation 0.726 SIGNOR-67630 CSNK2A1 protein P68400 UNIPROT USP7 protein Q93009 UNIPROT up-regulates quantity by stabilization phosphorylation Ser18 KAGEQQLsEPEDMEM 22361354 YES lperfetto We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53. 0.373 SIGNOR-276530 superoxide smallmolecule CHEBI:18421 ChEBI Oxidative_stress phenotype SIGNOR-PH215 SIGNOR up-regulates 9606 29301787 NO lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.7 SIGNOR-272276 FGR protein P09769 UNIPROT ACO2 protein Q99798 UNIPROT unknown phosphorylation Tyr665 VVIGDENyGEGSSRE -1 17997986 YES miannu Here, we provide evidence that the flavoprotein of succinate dehydrogenase and aconitase are "in vitro" substrates of Fgr tyrosine kinase. Fgr phosphorylates flavoprotein of succinate dehydrogenase at Y535 and Y596 and aconitase at Y71, Y544 and Y665. Further experiments will be necessary to verify if Fgr is the tyrosine kinase responsible for the tyrosine phosphorylation of these proteins in vivo and to elucidate the role of these phosphorylations. 0.2 SIGNOR-262870 PRKN protein O60260 UNIPROT DNM1L protein O00429 UNIPROT down-regulates quantity ubiquitination 9606 27597885 YES miannu Parkin interacts with and subsequently ubiquitinates Drp1, thus promoting its proteasome dependent degradation .|We have demonstrated that parkin promotes Drp1 degradation after OGDR insult. 0.2 SIGNOR-278589 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Leu649 NKGAIIGlMVGGVVI -1 10605825 YES lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. 0.489 SIGNOR-261783 DSCAM protein O60469 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 YES miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. 0.2 SIGNOR-264279 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr279 TDGEDADyTHFTNQQ 9606 BTO:0000567 19059208 YES miannu We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. 0.416 SIGNOR-262851 ACTL6A protein O96019 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.835 SIGNOR-269827 SMARCA4 protein P51532 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates binding 9606 20418909 YES miannu Zeb1 represses e-cadherin transcription / we reported that brg1 binds to the ntr of zeb1 acting as its co-repressor in the regulation of the e-cadherin promoter. 0.405 SIGNOR-165017 MAPK1 protein P28482 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates phosphorylation 9606 12359725 YES lperfetto In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e. 0.396 SIGNOR-217499 Condensin II complex SIGNOR-C342 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 32445620 NO miannu Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.7 SIGNOR-263913 MMP7 protein P09237 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Glu273 ANTPHLReLHLDNNK -1 9148753 YES miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. 0.609 SIGNOR-256352 MAPK1 protein P28482 UNIPROT AEBP1 protein Q8IUX7 UNIPROT up-regulates activity phosphorylation Thr621 GEPEFRYtAGIHGNE 10090 BTO:0000944 15654748 YES miannu We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1. 0.2 SIGNOR-262897 CAMK2D protein Q13557 UNIPROT ITPR2 protein Q14571 UNIPROT down-regulates activity phosphorylation Ser150 EKNAMRVsLDAAGNE 9534 BTO:0001538 23019322 YES miannu Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability. 0.308 SIGNOR-262692 hsa-mir-106b-5p mirna URS00004449AE_9606 RNAcentral CYBB protein P04839 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0003292 28235791 YES Tiberia MiR-106b is able to regulate the expression of CYBB and its downstream products in human and murine macrophages. In vitro and in vivo studies in mice have confirmed that miRNA PK3 particles can inhibit the expression and activity of CYBB and significantly improve infarct size and acute cardiac function after myocardial infarction. 0.4 SIGNOR-279898 Ub:E2 complex SIGNOR-C497 SIGNOR RNF112 protein Q9ULX5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271235 DDC protein P20711 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬¨‚Ć 0.8 SIGNOR-263993 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser469 AHEENPEsILDEHVQ 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.2 SIGNOR-248570 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F8 protein P00451 UNIPROT down-regulates activity cleavage Arg355 CPEEPQLrMKNNEEA -1 10350471 YES lperfetto N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin. 0.455 SIGNOR-263643 PTPN12 protein Q05209 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11432829 YES gcesareni Ptp-pest is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway. 0.547 SIGNOR-109032 prazosin chemical CHEBI:8364 ChEBI ADRA1B protein P35368 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258469 LAT protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000661 10811803 YES Our results showed that three distal tyrosines, Tyr(171), Tyr(191), and Tyr(226), are responsible for Grb2-binding; 0.804 SIGNOR-251521 PAX8 protein Q06710 UNIPROT SLC3A1 protein Q07837 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000671 15673291 NO miannu Expression of SLC3A1 mRNA was found to be tenfold higher in postnatal vs. fetal kidney; SLC3A1 expression is doubled by the proximal tubule transcription factor, PAX8. rBAT is expressed in the proximal convoluted and straight tubules in both fetal and adult kidney. 0.251 SIGNOR-254907 PAK4 protein O96013 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 22173096 YES lperfetto Pak4 interacts with and phosphorylates _-catenin on ser675, which promotes the tcf/lef transcriptional activity and stabilizes _-catenin through inhibition of its degradation. 0.287 SIGNOR-191557 SRC protein P12931 UNIPROT DAG1 protein Q14118 UNIPROT down-regulates phosphorylation Tyr892 PYRSPPPyVPP 9606 BTO:0000887;BTO:0001103 12795607 YES lperfetto Tyrosine 892 is now thought to be the principal site for recognition by the c-src tyrosine kinase;. We show that upon tyrosine phosphorylation, beta-dystroglycan undergoes a profound change in its sub-cellular localization (e.g., from the plasma membrane to an internal membrane compartment). One possibility is that the net negative charge at position 892 causes the redistribution of beta-dystroglycan to this intracellular vesicular location 0.549 SIGNOR-101655 RINT1 protein Q6NUQ1 UNIPROT NRZ complex complex SIGNOR-C358 SIGNOR form complex binding 25364732 YES lperfetto NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay. 0.872 SIGNOR-265025 MAPK1 protein P28482 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser46 SASGSAFsPYPGSAA -1 15133517 YES miannu We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation. 0.2 SIGNOR-263052 SLN protein O00631 UNIPROT ATP2A2 protein P16615 UNIPROT down-regulates activity binding -1 23455424 YES lperfetto The structure suggests a mechanism for selective Ca2+ loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca2+. 0.505 SIGNOR-264779 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 93934 BTO:0000475 17431006 YES lperfetto One such gene was identified, encoding steroidogenic acute regulatory protein (StAR), which showed 24-h changes in expression in the F1 follicle coinciding with those of Per2. Evidence that StAR gene expression is clock driven was obtained by showing that its 5' flanking region contains E-box enhancers that bind to CLOCK/BMAL1 heterodimers to activate gene transcription 0.285 SIGNOR-253700 MCU_MICUB_variant complex SIGNOR-C499 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.8 SIGNOR-270864 PDGFRA protein P16234 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 24743741 NO To further investigate the signaling pathway through which PDGFRα promotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα 0.346 SIGNOR-254376 FOXO1 protein Q12778 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 BTO:0000007 25510553 YES miannu FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription. 0.595 SIGNOR-263496 miR-29a mirna URS00004E9304_9606 RNAcentral TET2 protein Q6N021 UNIPROT down-regulates quantity by repression post transcriptional regulation 10116 17994015 YES Luana Here, we show that MeCP2 levels are repressed by miR132, a brain-enriched microRNA (miRNA). We propose that the interaction of miR132 with its miRNA recognition element (MRE) in the MeCP2 3′ UTR prevents MeCP2 levels from becoming deleteriously high during neuronal maturation. 0.4 SIGNOR-264703 TP53 protein P04637 UNIPROT FASLG protein P48023 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9841917 NO Nuclear p53 amattioni Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53 0.404 SIGNOR-62379 Gbeta proteinfamily SIGNOR-PF4 SIGNOR DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation 9606 15632084 YES inferred from 70% family members amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 0.2 SIGNOR-270116 AKT1 protein P31749 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000007 11154276 YES lperfetto Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1. 0.728 SIGNOR-252465 STX17 protein P56962 UNIPROT STX17-VAMP8 SNARE complex complex SIGNOR-C551 SIGNOR form complex binding 9606 BTO:0000007 23217709 YES miannu Here, we identify syntaxin 17 (Stx17) as the autophagosomal SNARE required for fusion with the endosome/lysosome. Stx17 localizes to the outer membrane of completed autophagosomes but not to the isolation membrane (unclosed intermediate structures); for this reason, the lysosome does not fuse with the isolation membrane. Stx17 interacts with SNAP-29 and the endosomal/lysosomal SNARE VAMP8. 0.923 SIGNOR-273709 DAPK1 protein P53355 UNIPROT SNCA protein P37840 UNIPROT up-regulates quantity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 32624505 YES miannu We demonstrated that DAPK1 directly phosphorylates \u03b1-synuclein at Ser129, and induces the formation of insoluble \u03b1-synuclein aggregates. 0.27 SIGNOR-278440 CDKL5 protein O76039 UNIPROT MECP2 protein P51608 UNIPROT unknown phosphorylation -1 16935860 YES Luana Phosphorylation assays performed with the wild-type protein confirm its capability to mediate the modification of MeCP2 in vitro, whereas Rett missense mutations within the conserved catalytic domain abrogate or significantly impair the enzymatic activity 0.602 SIGNOR-264702 FOXE1 protein O00358 UNIPROT MSX1 protein P28360 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21177256 NO miannu The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets. 0.385 SIGNOR-254173 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser748 RFARRSVsDNDIRKY 9606 BTO:0000150 16551632 YES llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I 0.2 SIGNOR-145292 PTPN9 protein P43378 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 20335174 YES miannu Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. 0.309 SIGNOR-277130 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity precursor of 9606 34283828 YES miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 0.8 SIGNOR-267296 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser540 KVMARSLsPPPELEE 10090 BTO:0000944 15851026 YES lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. 0.2 SIGNOR-249455 POLR3A protein O14802 UNIPROT Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 19631370 YES miannu Here we show that the cytosolic poly(dA-dT) DNA is converted into 5′-ppp RNA to induce IFN-β through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5′-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-β induction by transfection of DNA or infection with DNA viruses. 0.7 SIGNOR-265563 EXOSC5 protein Q9NQT4 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.928 SIGNOR-261385 CyclinC/CDK3 complex SIGNOR-C545 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser811 IYISPLKsPYKISEG 9606 15084261 YES gcesareni The active form of prb is underphosphorylated. Cdk3/cyclin-c-mediated phosphorylation at ser-807 and ser-811 is required for g0-g1 transition. 0.416 SIGNOR-273181 CDK1 protein P06493 UNIPROT SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr62 RRPESFTtPEGPKPR 9606 18490441 YES lperfetto Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase 0.42 SIGNOR-265258 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser9 LTFMASDsEEEVCDE -1 8972483 YES llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  0.365 SIGNOR-250804 GTF2IRD1 protein Q9UHL9 UNIPROT GTF2I protein P78347 UNIPROT down-regulates 9534 BTO:0004055 11438732 NO lperfetto Here we describe a repressor (MusTRD1/BEN) that appears to specifically regulate the nucleocytoplasmic shuttling of TFII-I. Nuclear exclusion of TFII-I results in a repression of its target reporter gene, and such repression can be alleviated when MusTRD1/BEN is retained in the cytoplasm through targeted mutation. 0.444 SIGNOR-268534 diethylstilbestrol chemical CHEBI:41922 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258597 RAVER1 protein Q8IY67 UNIPROT PTBP1 protein P26599 UNIPROT up-regulates activity binding 9606 14633994 YES Raver1 was identified in two-hybrid screens by its interactions with the cytoskeletal proteins actinin and vinculin, and was also found to interact with PTB || Here we show that raver1 is able to promote the smooth muscle-specific alternative splicing of TM by enhancing PTB-mediated repression of exon 3. This suggests a novel mechanism for PTB-mediated splicing repression involving recruitment of raver1 as a potent splicing co-repressor. 0.494 SIGNOR-272475 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr171 ETSKSFVtPPQSHFV 9606 BTO:0002181 26028025 YES miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. 0.429 SIGNOR-276907 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser134 DGATNNLsRSNSDES 9606 BTO:0000007 16818229 YES miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. 0.772 SIGNOR-276291 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 BTO:0000567 BTO:0000887;BTO:0001103 8454633 YES gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. 0.378 SIGNOR-39147 hsa-miR-138-5p mirna URS000040780F_9606 RNAcentral GNAI2 protein P04899 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003775 21079996 YES Parnian Our data suggests that miR-138 directly targets the 3′-UTR of the GNAI2 mRNA. The down-regulation of miR-138 in TSCC resulted in increased expression of GNAI2 which led to enhanced cell proliferation and suppressed apoptosis in TSCC. 0.4 SIGNOR-278029 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT up-regulates activity phosphorylation -1 18029386 YES miannu Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro. 0.351 SIGNOR-271730 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1333 DYNSVVLySTPPI 9606 9722576 YES lperfetto Receptor tyrosine phosphorylation is crucial for signal transduction by creating high affinity binding sites for src homology 2 domain-containing molecules. By expressing the intracellular domain of flt-1/vascular endothelial growth factor receptor-1 in the baculosystem, we identified two major tyrosine phosphorylation sites at tyr-1213 and tyr-1242 and two minor tyrosine phosphorylation sites at tyr-1327 and tyr-1333 in this receptor. 0.2 SIGNOR-59762 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 17510057 YES lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.755 SIGNOR-217071 SUN3 protein Q8TAQ9 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 YES lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. 0.413 SIGNOR-263291 Class I MHC complex SIGNOR-C425 SIGNOR Class I MHC:Antigen complex SIGNOR-C426 SIGNOR form complex binding 9606 33374673 YES scontino The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). 0.2 SIGNOR-267774 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser440 RSSPQRKsQRSSYVS -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.336 SIGNOR-262753 MAPK1 protein P28482 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Ser1185 GTPPASTsPFSQLAA 9606 10660621 YES lperfetto Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. 0.365 SIGNOR-74872 MAPK1 protein P28482 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser455 SIDSEPGsPLLDDAK 9606 14988395 YES lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. 0.359 SIGNOR-123045 Riluzole chemical CHEBI:8863 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 21030469 YES Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. 0.8 SIGNOR-258053 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 9753670 NO gcesareni Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5 0.337 SIGNOR-60285 BUB1 protein O43683 UNIPROT PLK1 protein P53350 UNIPROT up-regulates binding 9606 BTO:0000567 phosphorylation:Thr609 SAAQLAStPFHKLPV 16760428 YES gcesareni The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609 0.864 SIGNOR-147061 TFE3 protein P19532 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 NO miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. 0.2 SIGNOR-222504 CUDC-101 chemical CID:24756910 PUBCHEM HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262261 MAPKAPK5 protein Q8IW41 UNIPROT KALRN protein O60229 UNIPROT up-regulates activity phosphorylation Ser487 DVLQRPLsPGNSESL -1 22508986 YES miannu The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements. The fragment SR3-6, but not the mutated fragment SR3-6-S487A, is phosphorylated by MK5. 0.383 SIGNOR-263093 KIT protein P10721 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates activity binding 9606 BTO:0000567 phosphorylation:Tyr936 SESTNHIySNLANCS 10377264 YES gcesareni We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936. 0.583 SIGNOR-248291 CDK7 protein P50613 UNIPROT RARG protein P13631 UNIPROT up-regulates activity phosphorylation Ser77 SEEMVPSsPSPPPPP 9534 10748061 YES Luana RARg Is Phosphorylated by cdk7 in Its B and F Regions | Mutation into alanine of Ser-77 and Ser-79 located in the A/B region reduced the transcriptional activity of hRARg1 (Fig. 9A), confirming that these phosphorylation sites are required for optimal transcription. 0.417 SIGNOR-259853 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Ser327 SEEDEMDsGTMVRAV 9534 12223493 YES lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues 0.2 SIGNOR-247569 domperidone chemical CHEBI:31515 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 YES miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. 0.8 SIGNOR-258721 CDH1 protein P12830 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.96 SIGNOR-265863 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr319 TSVYESPySDPEELK -1 10202147 YES done miannu  In this report, we identify Tyr319 as a functionally important phosphorylation site in the ZAP-70 interdomain B region. Phosphorylation of Tyr319 promoted the association of ZAP-70 with the SH2 domains of two key signaling molecules, Lck and PLC-gamma1. These studies suggest that Tyr319 phosphorylation is required for the assembly of a ZAP-70-containing signaling complex that leads to the activation of the PLC-gamma1- and Ras-dependent signaling cascades in antigen-stimulated T cells. 0.618 SIGNOR-273948 RNF146 protein Q9NTX7 UNIPROT RNF146 protein Q9NTX7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 YES We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. 0.2 SIGNOR-260006 FZD5 protein Q13467 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 25902418 YES areggio Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. 0.669 SIGNOR-258969 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr27 SHHSGLEyADPEKFA 9606 15504032 YES lperfetto Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1. 0.675 SIGNOR-129961 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.34 SIGNOR-273143 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr774 SENEDDGyDVPKPPV 10090 BTO:0000944 11997497 YES Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation. 0.526 SIGNOR-251306 methiothepin chemical CHEBI:64203 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 YES miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. 0.8 SIGNOR-258853 SMO protein Q99835 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 28709001 NO We identified that ciliary Hh signaling in FAPs regulates expression of Timp3. Future experiments will determine whether Timp3 is a direct or indirect target of Hh signaling. 0.2 SIGNOR-255907 STAT5A protein P42229 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 NO Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. 0.244 SIGNOR-251784 CSNK2A1 protein P68400 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity phosphorylation Ser137 LSEDEYYsEEERNAK 9606 BTO:0002181 25999347 YES miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. 0.318 SIGNOR-276903 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 YES miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. 0.8 SIGNOR-264980 RNF146 protein Q9NTX7 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity ubiquitination 9606 21799911 YES By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. 0.644 SIGNOR-259996 BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity relocalization 9606 BTO:0000007 15694340 YES lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. 0.801 SIGNOR-133756 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr285 TEADGELyVFNTPSG 9606 BTO:0000018 10734310 YES miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. 0.673 SIGNOR-250552 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 10090 10448861 YES lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. 0.8 SIGNOR-235590 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr302 DYGMMSDyGTARRTG -1 11382764 YES lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 0.922 SIGNOR-246504 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 YES milica IL-4Rα, γc, and IL-13Rα1 all contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectively. Il-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells. 0.715 SIGNOR-100774 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 18550549 YES gcesareni Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144. 0.272 SIGNOR-178880 SAR1A protein Q9NR31 UNIPROT SEC23A protein Q15436 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 YES lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. 0.823 SIGNOR-265299 vorinostat chemical CHEBI:45716 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257950 FERMT3 protein Q86UX7 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 YES miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 0.489 SIGNOR-266104 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 YES milica In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. 0.2 SIGNOR-230710 edrophonium chemical CHEBI:251408 ChEBI ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition -1 9301662 YES miannu With the aim of performing a rigorous test of the anti-AChE properties of our compounds, the kinetics of enzyme inhibition were studied in purified enzyme preparations. The inhibition data are shown in Table 1. Additionally, known competitive inhibitors of AChE (procainamide and edrophonium) were included in the study for comparative purposes. 0.8 SIGNOR-258667 STK25 protein O00506 UNIPROT SAV1 protein Q9H4B6 UNIPROT down-regulates activity phosphorylation Thr26 GKYVKKEtSPLLRNL 9606 32292165 YES miannu STK25 inhibits the ability of SAV1 to counteract STRIPAK.|Using this antibody, we confirmed that SAV1 WT was indeed phosphorylated by STK25 at T26 in human cells (XREF_FIG). 0.28 SIGNOR-278369 AKAP8L protein Q9ULX6 UNIPROT DHX9 protein Q08211 UNIPROT up-regulates activity binding 9606 11402034 YES miannu We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA. 0.545 SIGNOR-260950 MAPK14 protein Q16539 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation 9606 20626350 YES gcesareni Jnk and p38 mapk activation have antagonistic effects in many cases. From a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab2 0.305 SIGNOR-166605 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000887 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.274 SIGNOR-163772 PLK3 protein Q9H4B4 UNIPROT VRK1 protein Q99986 UNIPROT up-regulates phosphorylation Ser342 DDGKLDLsVVENGGL 9606 19103756 YES llicata Vrk1 does not phosphorylate plk3, but plk3 phosphorylates the c-terminal region of vrk1 in ser342. Vrk1 with substitutions in s342 is catalytically active but blocks golgi fragmentation, indicating that its specific phosphorylation is necessary for this process. 0.475 SIGNOR-182858 4'-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile chemical CID:9843116 PUBCHEM ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001239 17888667 YES Luana AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. 0.8 SIGNOR-257759 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2E1 protein P51965 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.598 SIGNOR-271359 ATM protein Q13315 UNIPROT MCM3 protein P25205 UNIPROT unknown phosphorylation Ser535 ATDDPNFsQEDQQDT 9606 15210935 YES lperfetto Atm phosphorylates mcm3 on s535 in response to ionizing radiation. Second, atr phosphorylates mcm2 on s108 in response to multiple forms of dna damage and stalling of replication forksthe functional consequences of mcm2 s108 and mcm3 s535 phosphorylation are not clear 0.446 SIGNOR-126308 IL10 protein P22301 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 23357618 NO miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. 0.2 SIGNOR-253502 PPM1L protein Q5SGD2 UNIPROT CERT1 protein Q9Y5P4 UNIPROT up-regulates activity dephosphorylation 9606 18165232 YES miannu The expression of PP2Cepsilon also enhanced the association between CERT and VAPA.|These results suggest that CERT is a physiological substrate of PP2Cepsilon and that dephosphorylation of CERT by PP2Cepsilon may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus. 0.2 SIGNOR-277113 BAG1 protein Q99933 UNIPROT STUB1 protein Q9UNE7 UNIPROT up-regulates activity binding 9534 BTO:0001538 11676916 YES miannu BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association 0.541 SIGNOR-272587 ATR protein Q13535 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 17526493 YES gcesareni We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint. 0.785 SIGNOR-155214 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 YES lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. 0.716 SIGNOR-118031 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 18303014 YES lperfetto The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner 0.263 SIGNOR-216627 CSNK2A2 protein P19784 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity phosphorylation Ser423 CEEEFSDsEEEGEGG 9606 BTO:0000661 11602581 YES llicata Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1. 0.399 SIGNOR-251000 MARK2 protein Q7KZI7 UNIPROT KIF13B protein Q9NQT8 UNIPROT down-regulates activity phosphorylation Ser1410 SNKGRWEsQQDVSQT 9534 BTO:0000298 20194617 YES miannu We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410. 0.416 SIGNOR-262956 SNRPD2 protein P62316 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.936 SIGNOR-270685 LSM6 protein P62312 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.804 SIGNOR-270634 ACP1 protein P24666 UNIPROT PKM protein P14618 UNIPROT up-regulates activity dephosphorylation 9606 30251652 YES miannu Indeed, it is evident that LMW-PTP, hydrolyzing phosphotyrosine residues, contributes to maintain PKM2 in its active form.|We speculate that this effect is in large part due to LMW-PTP inhibition, which leads a fast PKM2 phosphorylation and inactivation.|we demonstrate that in melanoma cells the overexpression of LMW-PTP is functional to maintain PKM2 in its dephosphorylate status – the tetrameric, “full active” form - which is retained in the cytoplasm 0.279 SIGNOR-277134 L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI up-regulates quantity precursor of 9606 16098474 YES scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 0.8 SIGNOR-266955 UNC13A protein Q9UPW8 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 YES miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. 0.456 SIGNOR-263971 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates gtpase-activating protein 9606 9641915 YES gcesareni The guanine nucleotide exchange factor (gef) for rho, p115 rhogef, has an amino-terminal region with similarity to rgs proteins. Recombinant p115 rhogef and a fusion protein containing the amino terminus of p115 had specific activity as gtpase activating proteins toward the alpha subunits of the g proteins g12 and g13, but not toward members of the gs, gi, or gq subfamilies of galpha proteins. This gef may act as an intermediary in the regulation of rho proteins by g13 and g12. 0.607 SIGNOR-58413 EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 YES lperfetto P85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation. 0.781 SIGNOR-252671 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252325 KRAS protein P01116 UNIPROT MAP4K5 protein Q9Y4K4 UNIPROT up-regulates 9606 BTO:0001271 9949177 NO fstefani Bcr-abl_mediated ras activation is crucial for the ability of bcr-abl to activate gckr and is consistent with the previously known requirement for ras in bcr-abl_induced sapk activation how ras activates gckr remains enigmatic. 0.2 SIGNOR-64262 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1252 CKKAGNLyDISEDNS 9606 BTO:0000007 11024032 YES Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed. 0.767 SIGNOR-251172 KSR1 protein Q8IVT5 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 YES miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. 0.653 SIGNOR-273880 CASP1 protein P29466 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp387 QPPSLVVdSRDAGIC 9606 BTO:0005111 32122970 YES miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. 0.2 SIGNOR-272193 MAPK3 protein P27361 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser267 RVQSKIGsLDNITHV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.499 SIGNOR-275434 AXIN2 protein Q9Y2T1 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 SIGNOR-C110 10911903 YES gcesareni It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. 0.832 SIGNOR-79950 IFNG protein P01579 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003355 18647246 NO miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. 0.387 SIGNOR-252408 SNAI2 protein O43623 UNIPROT MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 22074556 NO miannu We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression. 0.452 SIGNOR-255170 GDNF protein P39905 UNIPROT NRG1 protein Q02297 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.364 SIGNOR-252182 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 YES Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs 0.744 SIGNOR-258996 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 YES lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain 0.2 SIGNOR-137255 CID 122201421 chemical CID:122201421 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 26035625 YES Monia Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4; These data confirmed that BRD4 is removed from the cell nuclei in a time dependent manner due to the presence of MZ1 0.8 SIGNOR-261097 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr79 GAPAPGVyPGPPSGP 9606 20600357 YES llicata In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility. 0.355 SIGNOR-166501 LAG3 protein P18627 UNIPROT T cell exhaustion phenotype SIGNOR-PH221 SIGNOR up-regulates 9606 BTO:0000782 27192565 NO Barakat Lag-3, Tim-3, and TIGIT are highly expressed on dysfunctional or exhausted T cells in chronic diseases such as chronic viral infection and cancer. 0.7 SIGNOR-275414 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 YES lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. 0.2 SIGNOR-244505 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11242034 YES Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif. gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) and p38 subs of map kinases, respectively. Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). 0.743 SIGNOR-105692 RAB5A protein P20339 UNIPROT OCRL protein Q01968 UNIPROT up-regulates activity binding 9606 33722976 YES miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis 0.695 SIGNOR-277771 ZNF143 protein P52747 UNIPROT TCP1 protein P17987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10893243 YES Luana The transcription from the minimalCcta promoter was up-regulated 3-fold by ZNF143 and 6-fold by ZNF76 when full-length proteins were co-expressed, indicating that both ZNF143 and ZNF76 can enhance Ccta transcription. 0.279 SIGNOR-266220 PBX4 protein Q9BYU1 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.2 SIGNOR-265780 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000007 12600984 YES lperfetto We also showed that phosphorylation of Tyr-315 in Akt induced by Src or EGF is dependent on the integrity of this proline-rich motif. Furthermore, the Akt mutant lacking this proline motif fails to block the transcription activity of Forkhead in 293 cells and poorly stimulates the proliferation of Madin-Darby canine kidney cells. Taken together, our data suggest that the interaction between the SH3 domain of Src family kinases and the proline-rich motif in the C-terminal regulatory region of Akt is required for tyrosine phosphorylation of Akt and its subsequent activation. 0.676 SIGNOR-246373 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation 10090 8387505 YES lperfetto The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases 0.718 SIGNOR-38999 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr226 KRNKPTVyGVSPNYD 9606 11847100 YES lperfetto c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. 0.537 SIGNOR-246307 DUSP4 protein Q13115 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity dephosphorylation 10116 7535768 YES inferred from 70% of family members Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK 0.761 SIGNOR-269933 SND1 protein Q7KZF4 UNIPROT MGLL protein Q99685 UNIPROT down-regulates quantity by destabilization binding 9606 26997225 YES irozzo Interaction of SND1 with MGLL resulted in ubiquitination and proteosomal degradation of MGLL. We demonstrate that interaction of SND1 with MGLL results in increased ubiquitination and subsequent proteosomal degradation of MGLL. This down-regulation of MGLL is required for SND1 to exert its pro-tumorigenic activity because forced overexpression of MGLL markedly abrogates cell proliferation. 0.2 SIGNOR-259138 NUMB protein P49757 UNIPROT GLI1 protein P08151 UNIPROT down-regulates binding 9606 20818436 YES gcesareni The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. 0.621 SIGNOR-167841 TRIP11 protein Q15643 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 9256431 YES inferred from family member miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. 0.422 SIGNOR-270295 MAPK8 protein P45983 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 YES gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. 0.779 SIGNOR-32425 WNT2B protein Q93097 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.629 SIGNOR-131777 FYN protein P06241 UNIPROT KIRREL1 protein Q96J84 UNIPROT up-regulates activity phosphorylation Tyr605 MKDPTNGyYNVRAHE 9606 BTO:0000007 18258597 YES miannu Here we have characterized Neph1, another SD component, as a novel substrate of SFK. Fyn interacts with and phosphorylates the cytoplasmic domain of Neph1 in vitro and in intact cells. Both tyrosine 637 and 638 of Neph1 are crucial for Neph1-Grb2 binding. 0.2 SIGNOR-262745 MN1 protein Q10571 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 17494859 NO irozzo MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment. 0.7 SIGNOR-256015 PAK6 protein Q9NQU5 UNIPROT SYNJ1 protein O43426 UNIPROT up-regulates activity phosphorylation -1 22371566 YES miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. 0.2 SIGNOR-263022 FADS2 protein O95864 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267908 ACTL6B protein O94805 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.709 SIGNOR-270740 AKT proteinfamily SIGNOR-PF24 SIGNOR HK2 protein P52789 UNIPROT up-regulates activity phosphorylation Thr473 QHRARQKtLEHLQLS 9606 BTO:0003324 25323588 YES miannu Hexokinase II is phosphorylated by Akt leading to increased mitochondrial binding and mitochondrial protection.We found that Akt, activated by receptor agonists, translocates to mitochondria and phosphorylates HK-II at Thr473, a critical step in Akt-mediated mitoHK-II increase and protection in cardiomyocytes 0.2 SIGNOR-267576 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser121 PTEEEEEsESEDSED 9606 16308564 YES lperfetto Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. 0.2 SIGNOR-142343 SLC2A2 protein P11168 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity relocalization 9606 25421524 YES The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. 0.8 SIGNOR-267385 SCAP protein Q12770 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity binding 10029 12242332 YES miannu Insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. 0.694 SIGNOR-256210 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0001939 15520018 YES miannu Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways. 0.538 SIGNOR-250112 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 YES lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. 0.273 SIGNOR-198134 RDH10 protein Q8IZV5 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI down-regulates quantity chemical modification 9606 21621639 YES lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS10 0.8 SIGNOR-265119 AKAP11 protein Q9UKA4 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR down-regulates activity binding 26088133 YES lperfetto A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). 0.426 SIGNOR-264818 SRC protein P12931 UNIPROT PTPRA protein P18433 UNIPROT up-regulates activity phosphorylation Tyr798 YIDAFSDyANFK 9606 7518772 YES The effect has been demonstrated using P18433-2 lperfetto Transient overexpression of c-src together with rptp alpha in human embryonic kidney 293 cells increased phosphorylation of tyr789, suggesting that c-src may phosphorylate rptp alpha in vivo. 0.742 SIGNOR-111306 MYOD1 protein P15172 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates binding 9606 BTO:0001103 17194702 YES lperfetto Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes 0.335 SIGNOR-217737 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser321 LNSEDDVsDEEGQEL -1 11278496 YES llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. 0.38 SIGNOR-250877 PRKACA protein P17612 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation Ser320 ASPGRPSsVDTLLSP 9606 21085490 YES lperfetto Protein kinase a binds and activates heat shock factor 1hsf1 binds avidly to the catalytic subunit of pka, (pkac_) and becomes phosphorylated on a novel serine phosphorylation site within its central regulatory domain (serine 320 or s320), both in vitro and in vivo. Intracellular pkac_ levels and phosphorylation of hsf1 at s320 were both required for hsf1 to be localized to the nucleus, bind to response elements in the promoter of an hsf1 target gene 0.315 SIGNOR-169853 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.2 SIGNOR-250554 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Thr19 GSRRGRAtPAQTPRS 9606 BTO:0000567 12714602 YES lperfetto We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex. 0.766 SIGNOR-100893 GSK3B protein P49841 UNIPROT CAP1 protein Q01518 UNIPROT up-regulates activity phosphorylation Ser308 SAPKPQTsPSPKRAT 9606 BTO:0000763 30123351 YES lperfetto We found that GSK3 phosphorylates S307 and S309 by using inhibitors LiCl. Inhibition of GSK3beta can cause loss of cell polarity as well as accumulation of stress fibers. We propose that GSK3 regulates CAP1 through at least two mechanisms. First, GSK3 (and potentially other kinases) phosphorylate CAP1 at S309 and promote CAP1 localization to the cytosol. Second, phosphorylation at S309 affects protein-protein interactions with actin and cofilin. The loss of this phospho-regulation by GSK3 inhibition is expected to disrupt CAP1 function and actin dynamics. 0.254 SIGNOR-264822 BRAF protein P15056 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates quantity phosphorylation Tyr221 HQYFMTEyVATRWYR 9606 29483645 YES miannu Our data indicate that oncogenic BRAF increases ERK5 protein level, phosphorylation at several residues and kinase activity.|Overexpression of oncogenic BRAF induced ERK5 phosphorylation at Thr218 and Tyr220, although to a lower level than that induced by MEK5DD. 0.292 SIGNOR-278353 JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 19041276 YES lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. 0.702 SIGNOR-249488 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 BTO:0002572 18498745 YES lperfetto In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8 0.787 SIGNOR-236599 PPM1D protein O15297 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 15870257 YES Here we show that the oncogenic p53-induced serine/threonine phosphatase, PPM1D (or Wip1), dephosphorylates two ATM/ATR targets, Chk1 and p53. PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. 0.473 SIGNOR-248317 CDH16 protein O75309 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.366 SIGNOR-265855 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation Thr250 NSCTPITtPELTTPC 9606 BTO:0000093 17130135 YES We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation 0.2 SIGNOR-253014 CSNK2A1 protein P68400 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Ser215 IKEEDTPsDNDSGIC 9606 BTO:0000567 23123191 YES miannu By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.  0.2 SIGNOR-276425 EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 YES miannu Besides PERK, eIF2α can also be phosphorylated by three other kinases: heme-regulated inhibitor kinase (HRI), general control nonderepressible 2 (GCN2), and PKR. PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. Together, these four eIF2α kinases and their convergent downstream signaling pathways are known as the integrated stress response (ISR) 0.727 SIGNOR-260168 CSNK2A1 protein P68400 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser59 SETNQNSsSDSEAER -1 11711551 YES llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. 0.359 SIGNOR-250963 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16106106 NO Regulation miannu TNF-α and IL-6 inhibit lipoprotein lipase 0.391 SIGNOR-251855 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser245 KPGALSNsESIPTID 9534 BTO:0000298 11483516 YES llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. 0.291 SIGNOR-250598 ACTB protein P60709 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.515 SIGNOR-270739 ALDH1A1 protein P00352 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI up-regulates quantity chemical modification 9606 21621639 YES lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. 0.8 SIGNOR-265123 CDK1 protein P06493 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 12791267 YES miannu We find that both Emi1 phosphorylation by cyclin and Cdc2 and phosphorylation on a consensus site (DSGxxS) direct recruitment of betaTrCP and subsequent Emi1 ubiquitination and destruction. 0.752 SIGNOR-279143 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 NO miannu Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. 0.7 SIGNOR-268383 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 16582879 YES Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR 0.788 SIGNOR-248409 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SHC4 protein Q6S5L8 UNIPROT down-regulates activity phosphorylation Thr159 GHRATALtPDSCPLP -1 31121283 YES done miannu The luminescence obtained in the kinase assay with FLAG-ShcD as substrate was significantly different to that with FLAG peptide suggesting that ShcD is a direct substrate of ERK (Fig. 2C).Furthermore, Thr159 was mutated to either alanine (A) or glutamic acid (E) to study whether the threonine phosphorylation state influences the ShcD/ERK interaction. Introducing the T159E mutation obliterated the ShcD/ERK interaction. 0.2 SIGNOR-273669 ILK protein Q13418 UNIPROT NACA protein Q13765 UNIPROT up-regulates phosphorylation Ser43 PELEEQDsTQATTQQ 9606 15299025 YES lperfetto Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase. 0.425 SIGNOR-127694 hsa-mir-126-5p mirna URS00001D69F6_9606 RNAcentral CXCL12 protein P48061 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004465 25015105 YES Parnian In this study, we show that miR-126 transferred to endothelial cells via LAMA84 exosomes directly targets the 3’ UTR of CXCL12 and VCAM1 mRNA, significantly down-regulating the expression and function of both proteins. 0.4 SIGNOR-278009 SRC protein P12931 UNIPROT PDCD6IP protein Q8WUM4 UNIPROT down-regulates activity phosphorylation Tyr319 KKDNDFIyHDRVPDL 9606 15557335 YES miannu Src phosphorylation of Alix/AIP1 modulates its interaction with binding partners and antagonizes its activities. Phosphorylation of Alix by Src caused it to translocate from the membrane and cytoskeleton to the cytoplasm and reduced its interaction with binding partners SETA/CIN85, epidermal growth factor receptor, and Pyk2. 0.394 SIGNOR-263201 MT-ND1 protein P03886 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. 0.813 SIGNOR-262143 KRN-633 chemical CID:9549295 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193582 estramustine chemical CHEBI:4868 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation 9606 14755680 YES miannu A variety of new estrogenic/anti‐estrogenic/selective estrogen receptor modulator (SERM)‐like compounds, including 2‐methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. 0.8 SIGNOR-259296 PRKACA protein P17612 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 YES llicata The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl. 0.2 SIGNOR-17901 BCAR1 protein P56945 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22431919 NO miannu In MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression. 0.2 SIGNOR-253891 ABL1 protein P00519 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity phosphorylation Tyr30 FATTDDFyDDPCFDSP 9606 BTO:0000007 12415271 YES We have found that c-Abl can phosphorylate MyoD at a conserved N-terminal tyrosine (Tyr30) that is located within the transactivation domain. Mutation of Tyr30 to Phe does not interfere with the function of MyoD, but theTyr30Phe mutant becomes resistant to the inhibitory effect of DNA damage. 0.286 SIGNOR-253055 UNC80 protein Q8N2C7 UNIPROT NALCN protein Q8IZF0 UNIPROT up-regulates activity binding 9606 BTO:0000142 22196327 YES miannu The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80. 0.809 SIGNOR-265184 DYNLT1 protein P63172 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity binding 9606 BTO:0002181 29089450 YES miannu Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules. 0.288 SIGNOR-277369 GPR55 protein Q9Y2T6 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256670 REST protein Q13127 UNIPROT BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21832040 NO miannu HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). 0.421 SIGNOR-255075 ACP1 protein P24666 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10090 19088431 YES LMWPTP dephosphorylated pY(527)-Src and pY(416)-Src in vitro, with greater specificity for pY(527)Src. Activation of LMWPTP produced strong activation of Src mediated by fast dephosphorylation of pY(527)-Src, followed by slower deactivation of this kinase via dephosphorylation of pY(416)Src. 0.438 SIGNOR-248454 CDK19 protein Q9BWU1 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2516 FLTPSPEsPDQWSSS -1 25344755 YES lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues 0.302 SIGNOR-273135 JNK proteinfamily SIGNOR-PF15 SIGNOR SFN protein P31947 UNIPROT down-regulates phosphorylation 9606 15071501 YES Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191 0.2 SIGNOR-269979 CRTC2 protein Q53ET0 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 YES These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK. 0.386 SIGNOR-256106 BCL6 protein P41182 UNIPROT SUMO1 protein P63165 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000182 22723377 NO QPCR analysis of the resulting gene expression levels identified three genes that were affected in opposite sense by the downregulation of either BCL-6 or STAT5, namely cyclin D2 (CCND2), cyclin-dependent kinase inhibitor p15INK4B (CDKN2B), and SUMO1 0.306 SIGNOR-253929 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity phosphorylation Thr607 IPTPPVTtPEGDDRP 10116 BTO:0000601 11080179 YES miannu We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP. 0.367 SIGNOR-262936 MEN1 protein O00255 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 16415155 NO irozzo We also found that menin is important for the proliferation of MLL oncoprotein-transformed myeloid cells, pointing to a paradoxically oncogenic role for the tumor suppressor menin in proliferation of transformed myeloid cells. 0.7 SIGNOR-255895 miR-155 mirna URS000062749E_9606 RNAcentral MEIS1 protein O00470 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 19219026 YES Luana Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.  0.4 SIGNOR-268040 TNFAIP3 protein P21580 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity ubiquitination 9606 15258597 YES The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. 0.654 SIGNOR-259978 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR POLM protein Q9NP87 UNIPROT down-regulates activity phosphorylation Ser372 HQHSCCEsPTRLAQQ -1 23933132 YES miannu  In vitro kinase assays showed that the S phase-associated Cdk2/cyclin A complex was able to phosphorylate Polμ. We identified Ser12, Thr21 (located in the BRCT domain) and Ser372 (located in loop1) as the target residues. Mutation of these residues to alanine indicated that Ser372 is the main phosphorylation site.Our evidences suggest that Polμ could be regulated in vivo by phosphorylation of the BRCT domain (Ser12/Thr21) and of Ser372, affecting the function of loop1. 0.27 SIGNOR-273596 CREBBP protein Q92793 UNIPROT INSM1 protein Q01101 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000944 17300785 NO miannu The ngn3/E47 heterodimer selectively binds and activates the E-box3 of the INSM1 promoter. The endogenous ngn3 and CREB-binding protein (CBP) co-activator occupy the INSM1 promoter, resulting in hyper-acetylation of histone H3/H4 chromatin in a human neuroblastoma cell line, IMR-32. 0.2 SIGNOR-253813 dothiepin chemical CHEBI:36798 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  0.8 SIGNOR-258878 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 10090 7791789 NO lperfetto The upregulation of p21 occurred at the levels of mrna and protein, 0.401 SIGNOR-235831 COL6A1 protein P12109 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. 0.7 SIGNOR-254673 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity precursor of 9606 16939420 YES miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. 0.8 SIGNOR-267077 IRX1 protein P78414 UNIPROT PTGER1 protein P34995 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.2 SIGNOR-261656 CASP3 protein P42574 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000142 10200555 NO amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation 0.7 SIGNOR-66866 AURKB protein Q96GD4 UNIPROT CKAP2 protein Q8WWK9 UNIPROT up-regulates phosphorylation Ser628 FLTPVRRsRRLQEKT 9606 20458174 YES lperfetto Here, we report that tmap is a novel substrate of the aurora b kinase. Ser627 of tmap was specifically phosphorylated by aurora b both in vitro and in vivo. Nearly all mutations at the phosphorylation motif had dramatic effects on the subcellular localization of tmap. 0.296 SIGNOR-165410 AKT proteinfamily SIGNOR-PF24 SIGNOR ATXN1 protein P54253 UNIPROT up-regulates quantity by stabilization phosphorylation Ser775 ATRKRRWsAPESRKL 9606 BTO:0000567 12757707 YES Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation. 0.2 SIGNOR-251468 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192901 GABRG2 protein P18507 UNIPROT GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR form complex binding 9606 BTO:0000227 18790874 YES brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. 0.657 SIGNOR-263752 FGF13 protein Q92913 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253439 Ub:E2 complex SIGNOR-C497 SIGNOR RMND5A protein Q9H871 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271255 MRPL15 protein Q9P015 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.701 SIGNOR-262378 Goserelin chemical CHEBI:5523 ChEBI LHCGR protein P22888 UNIPROT up-regulates activity chemical activation 9606 BTO:0001033 11900209 YES miannu LHRH analogues, such as goserelin, reduce circulating concentrations of oestrogen in premenopausal women via an inhibitory effect on the hypothalamic–pituitary–ovarian axis. At the cellular level, LHRH analogues bind to LHRH receptors on pituitary gland cells, an action which causes an initial surge in the secretion of luteinizing hormone (LH). Once bound to ligand, these LHRH receptors form clusters, which are then sequestered within the cell, thereby reducing the number of unoccupied LHRH receptors. 0.8 SIGNOR-259162 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR INF2 protein Q27J81 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys345 VERLLSVkGRPRPSP 9606 BTO:0000007 28448495 YES miannu SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. It revealed that INF2 was ubiquitinated at least at 7 lysine residues (Fig 2I). Interestingly, 5 of 7 ubiquitin attachment sites are localized in a short stretch of sequence (amino acids 612–682) within the FH2 domain of INF2 (Fig 2J). 0.2 SIGNOR-272800 G3BP2 protein Q9UN86 UNIPROT G3BP1 protein Q13283 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 YES miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. 0.46 SIGNOR-260863 NMDA receptor_2C complex SIGNOR-C349 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 YES miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor 0.748 SIGNOR-264224 TADA3 protein O75528 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.758 SIGNOR-269584 GSK3B protein P49841 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 20466847 YES miannu HG activates GSK3beta, which phosphorylates IRS1 at serine 332, leading to the ubiquitination and proteasome mediated degradation of IRS1. 0.455 SIGNOR-279183 Stress_granules phenotype SIGNOR-PH124 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 27920254 NO miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. 0.7 SIGNOR-260866 SPRY4 protein Q9C004 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity binding 9606 12717443 YES miannu Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4. 0.434 SIGNOR-253033 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser47 DGPGLERsPGEPGGA 9606 20027304 YES This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. 0.602 SIGNOR-162318 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 11108261 YES lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. 0.765 SIGNOR-84975 CDK1 protein P06493 UNIPROT RRM2 protein P31350 UNIPROT down-regulates phosphorylation Thr33 SLVDKENtPPALSGT 9606 22632967 YES gcesareni We found that, during g2, following cdk-mediated phosphorylation of thr33, rrm2 is degraded via scf(cyclin f) to maintain balanced dntp pools and genome stability. 0.505 SIGNOR-197630 AKT1 protein P31749 UNIPROT FBXO31 protein Q5XUX0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser33 AETAAADsEPDTDPE 9606 BTO:0002181 29343641 YES miannu Here we show that the low levels of FBXO31 are maintained through proteasomal degradation by anaphase-promoting complex/cyclosome (APC/C). We find that the APC/C coactivators CDH1 and CDC20 bind to a destruction-box (D-box) motif present in FBXO31 to promote its polyubiquitination and degradation in a cell-cycle-regulated manner, which requires phosphorylation of FBXO31 on serine-33 by the prosurvival kinase AKT. 0.2 SIGNOR-277376 CHEK1 protein O14757 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation 9606 32345958 YES miannu Phosphorylation of Cdh1 by Chk1 promotes recognition of Cdh1 by SCF betaTRCP1.|These data suggest that Chk1 negatively regulates APC/C Cdh1 activity by both promoting Cdh1 destruction and by destabilizing its association with the APC/C. 0.301 SIGNOR-278396 WIPI1 protein Q5MNZ9 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates quantity binding 9606 BTO:0001938 28561066 YES miannu WIPI1 assists WIPI2 in recruiting ATG16L for LC3 lipidation. WIPI1-WIPI2 heterodimer may function more efficiently in ATG16L complex recruitment. 0.605 SIGNOR-268477 PPARG protein P37231 UNIPROT UCP1 protein P25874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 32991581 YES brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, 0.534 SIGNOR-263985 HIF1A protein Q16665 UNIPROT KDM2A protein Q9Y2K7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.2 SIGNOR-271566 EPHA2 protein P29317 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates 9606 BTO:0000782 7982920 NO gcesareni In keeping with the above observations, activation of eck by its ligand, b61, increased phosphatidylinositol 3-kinase activity 0.364 SIGNOR-35418 3-(4-{[5-Fluoro-2-(4-methylphenyl)phenyl]methoxy}phenyl)propanoic acid chemical CID:57522038 PUBCHEM FFAR4 protein Q5NUL3 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257491 IKBKE protein Q14164 UNIPROT IRF1 protein P10914 UNIPROT down-regulates activity phosphorylation Ser219 FQVSPMPsTSEATTD 9606 BTO:0000007 24396068 YES miannu We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.  0.35 SIGNOR-276478 NRAS protein P01111 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity binding 9606 21779497 YES lperfetto Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k 0.843 SIGNOR-175222 WWTR1 protein Q9GZV5 UNIPROT ASNS protein P08243 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001615 22470139 NO miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. 0.2 SIGNOR-255608 FANCA protein O15360 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 YES lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  0.951 SIGNOR-263240 GSK3B protein P49841 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser298 ACSSAPGsGPSSPNN 9606 21118993 YES lperfetto The double mutation of serines 298/302 into alanines, but also the sole mutation of serine 302, abolishes hdac4 phosphorylation by gsk3_we have shown that cells lacking gsk3_ are unable to degrade hdac4 after serum starvation 0.364 SIGNOR-170144 PPP2R2A protein P63151 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 BTO:0000018 33108758 YES miannu Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. 0.385 SIGNOR-266381 RAD51AP1 protein Q96B01 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding 9606 17996711 YES miannu Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand-pairing step in HR. RAD51 associated protein 1 (RAD51AP1) is a RAD51-interacting protein whose function has remained elusive. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Purified RAD51AP1 binds both dsDNA and a D loop structure and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D loop reaction. 0.77 SIGNOR-261962 PRKCE protein Q02156 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 YES llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. 0.469 SIGNOR-97291 SMURF1 protein Q9HCE7 UNIPROT ELOF1 protein P60002 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272685 SKIL protein P12757 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates binding 9606 SIGNOR-C85 12419246 YES gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad8. 0.448 SIGNOR-95474 ZAP70 protein P43403 UNIPROT VAV1 protein P15498 UNIPROT up-regulates activity phosphorylation 9606 23620790 YES miannu These results suggest that CBAP may serve as an adaptor or scaffold in the integrin \u03b21/CBAP/ZAP70-containing complex that, upon chemokine treatment, would allow Vav1 or ZAP70 (or both) to adopt an optimal conformation(s) for ZAP70 to phosphorylate Vav1.|Together, these results suggested that CBAP is an important component in ZAP70 dependent activation of the Vav1 and Rac1 signaling axis. 0.837 SIGNOR-278390 LFNG protein Q8NES3 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates binding 9606 11346656 YES gcesareni Although both manic fringe (mfng) and lunatic fringe (lfng) decreased the binding of jagged1 to notch2 and not that of delta1, the decrease by mfng was greater in degree than that by lfng. We also found that both fringe proteins reduced jagged1-triggered notch2 signaling, whereas neither affected delta1-triggered notch2 signaling. 0.696 SIGNOR-107705 MAPKAPK5 protein Q8IW41 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Ser727 RQNPSRCsVSLSNVE 9606 BTO:0000007;BTO:0000567 10978317 YES miannu The p38-activated protein kinases MNK1, MSK1, and PRAK1 phosphorylate cPLA2 in vitro uniquely on Ser-727. By using Chinese hamster ovary, HeLa, and HEK293 cells stably transfected with wild type and phosphorylation site mutant forms of cPLA2, we show that phosphorylation of cPLA2 at both Ser-505 and Ser-727 and elevation of Ca(2+) leads to its activation in agonist-stimulated cells. 0.334 SIGNOR-250162 clenbuterol chemical CHEBI:174690 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257862 LAMB1 protein P07942 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 YES lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. 0.722 SIGNOR-253230 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 20305697 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-164617 L-thyroxine smallmolecule CHEBI:18332 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 BTO:0000759 24692351 NO scontino TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis. 0.7 SIGNOR-267489 ITCH protein Q96J02 UNIPROT GLI1 protein P08151 UNIPROT down-regulates ubiquitination 9606 BTO:0001573 17115028 YES gcesareni The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation 0.577 SIGNOR-150847 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP -1 12468540 YES gcesareni Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect 0.414 SIGNOR-246236 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys377 HLHTDILkRGSEMDN 31476572 YES lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. 0.2 SIGNOR-275681 regorafenib chemical CHEBI:68647 ChEBI NTRK1 protein P04629 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259212 RRAGD protein Q9NQL2 UNIPROT RAGAD complex SIGNOR-C114 SIGNOR form complex binding 9606 20381137 YES gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant 0.777 SIGNOR-228170 PNPLA6 protein Q8IY17 UNIPROT Lysophosphatidylcholine smallmolecule CID:5311264 PUBCHEM down-regulates quantity chemical modification 9606 25033069 YES PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus 0.8 SIGNOR-253610 SFRP1 protein Q8N474 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000782 10347172 YES gcesareni Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling. 0.783 SIGNOR-67806 PPM1D protein O15297 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity dephosphorylation Ser137 LSEDEYYsEEERNAK 9606 BTO:0002181 25999347 YES miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. 0.466 SIGNOR-276905 MRPS25 protein P82663 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.706 SIGNOR-261448 AARS1 protein P49588 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 32314272 YES miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). 0.8 SIGNOR-270450 ECM stimulus SIGNOR-ST20 SIGNOR AE/b7 integrin complex SIGNOR-C186 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259040 NOP10 protein Q9NPE3 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 YES lperfetto Dyskerin was recently found to be associated with active human telomerase (34), and mutations in dyskerin or NOP10 or deletion of the H/ACA motif of hTERC result in diminished telomerase activity 0.619 SIGNOR-263331 FBXW11 protein Q9UKB1 UNIPROT CHUK protein O15111 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10321728 YES miannu We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.  0.439 SIGNOR-272545 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR miR-495 mirna URS000075C517_9606 RNAcentral down-regulates quantity by repression transcriptional regulation 9606 17996649 NO miannu MiR-223 Expression Is Downregulated in AML1/ETO-Positive Primary Blasts and Cell Lines Here, we show that miR-223 is a direct transcriptional target of AML1/ETO. By recruiting chromatin remodeling enzymes at an AML1-binding site on the pre-miR-223 gene, AML1/ETO induces heterochromatic silencing of miR-223. Ectopic miR-223 expression, RNAi against AML1/ETO, or demethylating treatment enhances miR-223 levels and restores cell differentiation. Here, we identify an additional action for a leukemia fusion protein linking the epigenetic silencing of a microRNA locus to the differentiation block of leukemia. 0.4 SIGNOR-261972 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257520 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr142 SVGDEDIySGLSDQI -1 10669745 YES Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function. 0.783 SIGNOR-251389 PRKACA protein P17612 UNIPROT ETV5 protein P41161 UNIPROT up-regulates activity phosphorylation Ser367 PPYQRRGsLQLWQFL 9606 BTO:0002909 11682477 YES lperfetto We further show that the increase in erm transcriptional activity after pka phosphorylation is closely correlated with a drastic reduction in the dna binding of the transcription factor. These results indicate that the phosphorylation of erm by pka is involved in erm-mediated transcription and suggest that the activation of erm is probably related to conformational changes. 0.2 SIGNOR-111239 SRC protein P12931 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 11152665 YES lperfetto The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin 0.445 SIGNOR-85938 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr682 SRTTDGVyEGVAIGG 9606 BTO:0000007 32420483 YES done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. 0.2 SIGNOR-274103 GRK2 protein P25098 UNIPROT NTSR1 protein P30989 UNIPROT up-regulates activity phosphorylation 9606 26120872 YES miannu Here we report the unique phosphorylation\nof NTSR1 by GRK2 and GRK5, which belong to the GRK2 and GRK4 subfamilies,\nrespectively. 0.2 SIGNOR-278280 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12556363 YES flangone Inhibition of c-src with herbimycin a significantly decreased the tyrosine phosphorylation level of romk1... tyrosine dephosphorylation enhances the exocytosis of romk1 0.313 SIGNOR-97803 DUSP2 protein Q05923 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 8626452 YES fstefani Pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively. 0.744 SIGNOR-40915 SYBU protein Q9NX95 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 15459722 YES miannu Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes. 0.421 SIGNOR-264812 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser144 DSPALEVsDSESDEA 9606 10618498 YES lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability 0.43 SIGNOR-73883 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Thr449 DDIRQNFtQLPLHKN 9606 22123827 YES lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. 0.376 SIGNOR-177801 NBN protein O60934 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR form complex binding 17713585 YES lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. 0.914 SIGNOR-251505 CSNK1A1L protein Q8N752 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates activity phosphorylation Ser158 LLDNSRMsCQDEGCG 9606 BTO:0000567 18411282 YES done miannu However, the siRNA knockdown of CK1α1L significantly reduced the nuclear export of OREBP/TonEBP under hypotonic conditions (Fig. 5F). Taken together, these data suggest that CK1α1L is the kinase that phosphorylates Ser-158 in the regulation of OREBP/TonEBP export. 0.2 SIGNOR-274111 CSNK1A1L protein Q8N752 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 19293931 YES gcesareni Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms 0.254 SIGNOR-184699 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity phosphorylation Tyr413 DPEVAALyFPKNGDP 9606 BTO:0002181 33203880 YES miannu Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. 0.2 SIGNOR-277293 SRC protein P12931 UNIPROT CHRNA7 protein P36544 UNIPROT down-regulates phosphorylation Tyr386 ASNGNLLyIGFRGLD 9606 16251431 YES gcesareni ?7 Neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and src-family kinases 0.2 SIGNOR-141307 Laminin-1 complex SIGNOR-C183 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.554 SIGNOR-253221 PBX4 protein Q9BYU1 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.2 SIGNOR-265806 RAB9A protein P51151 UNIPROT PLIN3 protein O60664 UNIPROT up-regulates activity 18195106 YES lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector 0.59 SIGNOR-253089 ARHGEF11 protein O15085 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.902 SIGNOR-260538 ARF5 protein P84085 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 NO lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface 0.7 SIGNOR-272152 SGK3 protein Q96BR1 UNIPROT FLII protein Q13045 UNIPROT up-regulates phosphorylation Thr818 LHRPRHAtVSRSLEG 9606 19293151 YES lperfetto Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator. 0.356 SIGNOR-184692 CNOT2 protein Q9NZN8 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 YES lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. 0.829 SIGNOR-268306 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI KDM4E protein B2RXH2 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273459 TEC protein P42680 UNIPROT BMX protein P51813 UNIPROT up-regulates activity phosphorylation Tyr216 SSTSLAQyDSNSKKI 9606 BTO:0000873 12573241 YES lperfetto Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk 0.333 SIGNOR-246647 AR protein P10275 UNIPROT CLK3 protein P49761 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 NO After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. 0.2 SIGNOR-253672 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248753 RXRA protein P19793 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 YES inferred from 70% of family members gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr). 0.723 SIGNOR-269877 RPS15A protein P62244 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.856 SIGNOR-262436 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 8702756 YES miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. 0.646 SIGNOR-261708 PRKCA protein P17252 UNIPROT NPHS1 protein O60500 UNIPROT up-regulates activity phosphorylation Thr1125 QWTGERDtQSSTVST 9606 BTO:0000007 21321125 YES llicata Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_. 0.2 SIGNOR-172056 PRKCD protein Q05655 UNIPROT CYTH1 protein Q15438 UNIPROT unknown phosphorylation Thr395 RKKKVSStKRH 9606 BTO:0001948 11438522 YES lperfetto We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1.  0.324 SIGNOR-249099 Caspase 3 complex complex SIGNOR-C221 SIGNOR PARP1 protein P09874 UNIPROT down-regulates activity cleavage 10090 BTO:0000331 11907276 YES amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process 0.775 SIGNOR-256465 KAT2B protein Q92831 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269619 YWHAE protein P62258 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding 10449590 YES lperfetto The in vitro binding with general transcription factors TBP and TFIIB together with its nuclear location provide evidence supporting a role for 14-3-3 proteins as transcriptional activators or coactivators when part of a DNA binding complex. 0.348 SIGNOR-262834 POM121 protein Q96HA1 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.481 SIGNOR-262071 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 BTO:0000149;BTO:0001129 22730327 YES gcesareni Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1) 0.728 SIGNOR-197998 TWIST2 protein Q8WVJ9 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255500 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 24385927 YES lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself 0.777 SIGNOR-203560 FGF11 protein Q92914 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253438 SRC protein P12931 UNIPROT SH3PXD2B protein A1X283 UNIPROT up-regulates activity phosphorylation Tyr508 DMSASAGyEEISDPD 9606 20943948 YES lperfetto C-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells|Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation. 0.521 SIGNOR-264705 Histone H2A proteinfamily SIGNOR-PF70 SIGNOR Nucleosome complex SIGNOR-C371 SIGNOR form complex binding -1 21812398 YES lperfetto The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.2 SIGNOR-265309 BZW2 protein Q9Y6E2 UNIPROT EIF3A protein Q14152 UNIPROT up-regulates activity binding 9606 31643092 YES miannu BZW2, as an evolutionary highly conserved protein, interacts with eIF2 and eIF3 and promotes ternary complex formation in vitro 0.324 SIGNOR-261221 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257478 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 12874243 YES gcesareni Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity. 0.728 SIGNOR-103983 CDC42BPA protein Q5VT25 UNIPROT CDC42BPA protein Q5VT25 UNIPROT up-regulates activity phosphorylation Thr240 QSSVAVGtPDYISPE 9534 BTO:0000298 11283256 YES miannu N terminus-mediated dimerization and transautophosphorylation are essential for MRCKα catalytic activity. Three mutations, S234A, T240A, and T403A, strongly affected the in vitro autophosphorylation activity of FLAG-MRCKα-CAT1–473 (Fig. ​(Fig.5D).5D). 0.2 SIGNOR-275975 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267906 RAGAC complex SIGNOR-C113 SIGNOR MTOR protein P42345 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 YES lperfetto The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb 0.811 SIGNOR-228657 ETV6 protein P41212 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000960;BTO:0002062 15958056 NO irozzo We thus conclude that TEL is also an accelerator for erythroid differentiation upon cytokine stimulation in human hematopoietic cells. We demonstrated in the present study that TEL accelerates erythroid differentiation induced by a physiological cytokine EPO in human leukemia cell line UT-7/GM. 0.7 SIGNOR-256017 EDNRB protein P24530 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.435 SIGNOR-257166 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser505 SPVAGVHsPMASSGN 9606 BTO:0000093 15383283 YES miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. 0.525 SIGNOR-250103 MAPK7 protein Q13164 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity binding 9606 BTO:0001176 16835228 YES In endothelial cells, flow-mediated activation of ERK5 has been shown to lead to activation of PPAR gamma by direct binding to the hinge-helix region of PPAR gamma 0.377 SIGNOR-278108 TMIGD2 protein Q96BF3 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 32978258 YES miannu  Upon activation by autophagy stimuli, IGPR-1 is phosphorylated at Ser220 via IKKβ. IGPR-1 acts as a pro-autophagy signaling receptor leading to activation of AMPK.  0.2 SIGNOR-273665 IL7 protein P13232 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 YES gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, il-15, il-2, il21 0.709 SIGNOR-108864 PRKD1 protein Q15139 UNIPROT PAK4 protein O96013 UNIPROT up-regulates activity phosphorylation Ser474 KEVPRRKsLVGTPYW 24840177 YES lperfetto When PKD3 was knocked-down using isoform-specific shRNA (PKD3-shRNA), PAK4 activity (judged by its phosphorylation status at the activation loop using the pS474-PAK4 antibody) was decreased 0.252 SIGNOR-275930 KCTD13 protein Q8WZ19 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity binding 9606 19782033 YES miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. 0.378 SIGNOR-264236 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 12408818 YES gcesareni Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300 0.464 SIGNOR-95165 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser68 LRDAIRQsNQILRER 9606 SIGNOR-C14 SIGNOR-C14 17977820 YES lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I 0.962 SIGNOR-158659 9-HODE chemical CHEBI:72651 ChEBI GPR132 protein Q9UNW8 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257501 PHACTR1 protein Q9C0D0 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates activity binding 9606 BTO:0001949 21939755 YES lperfetto Phactr-1 was previously identified as protein phosphatase 1 (PP1) Œ±-interacting protein that possesses actin-binding domains. We showed that Phactr-1 depletion decreased PP1 activity, disrupted the fine-tuning of actin polymerization and impaired lamellipodial dynamics. Taken together our results strongly suggest that Phactr-1 is a key component in the angiogenic process. 0.537 SIGNOR-264656 ABCC4 protein O15439 UNIPROT sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI up-regulates quantity relocalization 9606 29304533 YES lperfetto Release of Platelet-Derived Sphingosine-1-Phosphate Involves Multidrug Resistance Protein 4 (MRP4/ABCC4) and Is Inhibited by Statins 0.8 SIGNOR-265912 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19188143 YES gcesareni Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.708 SIGNOR-183648 ACOT4 protein Q8N9L9 UNIPROT glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity chemical modification 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271817 NEK2 protein P51955 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates activity phosphorylation 9606 27297360 YES miannu Intriguingly, Nek2A is found to stabilize SuFu at least partly depending on its kinase activity, thereby triggering phosphorylation of the SuFu protein.|Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism. 0.2 SIGNOR-279235 PPP2CA protein P67775 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates dephosphorylation Thr250 NSCTPITtPELTTPC 9606 20927323 YES gcesareni Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e. 0.513 SIGNOR-168310 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression 0.2 SIGNOR-244602 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 YES lperfetto Dapk phosphorylates camkk. S511 was identified as the phosphorylation site . a potential mechanism of action was identified on the basis of the location of s511 near the cam recognition domain of camkk and demonstrated by attenuation of cam-stimulated camkk autophosphorylation after dapk phosphorylation. 0.283 SIGNOR-126241 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu105 NNKDSHSlTTNIMEI -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain 0.2 SIGNOR-263619 PRKAG1 protein P54619 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 YES lperfetto Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. 0.765 SIGNOR-139170 SMAD1 protein Q15797 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates binding 9606 SIGNOR-C85 21454478 YES lperfetto Upon ligand binding, the specific heteromeric transmembrane serine/threonine kinase receptor complexes undergo phosphorylation/activation and subsequently phosphorylate the two ser residues in the c-terminal sxs motif of specific r-smads, smad1/5/8 for bmp pathway and smad2/3 for tgf-_/activin signaling. The activated r-smads then associate with co-smad, smad4. The heteromeric complexes translocate into the nucleus, where they bind to dna directly or indirectly to regulate the transcription of specific genes. 0.67 SIGNOR-172990 MAPK8IP1 protein Q9UQF2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10490659 YES gcesareni Both jip1 and jip2 selectively bind the mapkk isoform mkk7. 0.722 SIGNOR-70848 AMPK complex SIGNOR-C15 SIGNOR DNMT1 protein P26358 UNIPROT down-regulates activity phosphorylation Ser714 DNIPEMPsPKKMHQG -1 28143904 YES lperfetto Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity 0.288 SIGNOR-264788 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12226093 YES The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. 0.704 SIGNOR-251599 CDK1 protein P06493 UNIPROT NUCKS1 protein Q9H1E3 UNIPROT down-regulates activity phosphorylation Ser181 LKATVTPsPVKGKGK -1 12413487 YES miannu putative phosphorylation site for Cdk1 is present in the DNA-binding domain peptide. This site, corresponding to Ser 181 in the NUCKS primary structure, is phosphorylated in vitro by Cdk1 with a Km of approximately 35 μM [7]. Phosphorylation of Ser 181 in the synthetic, DNA-binding domain peptide reduces its affinity for DNA-by 100%. 0.475 SIGNOR-261959 PRKCD protein Q05655 UNIPROT DBI protein P07108 UNIPROT up-regulates phosphorylation Thr42 ATVGDINtERPGMLD 9606 18194441 YES gcesareni Acyl coenzyme a-binding protein (acbp) is phosphorylated following protein kinase c activation. 0.2 SIGNOR-160393 DUSP19 protein Q8WTR2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 11959861 YES gcesareni Skrp1 was highly specific for c-jun n-terminal kinase (jnk) in vitro and effectively suppressed the jnk activation in response to tumor necrosis factor alpha or thapsigargin skrp1 does not bind directly to its target jnk, but co-precipitation of skrp1 with the mapk kinase mkk7, a jnk activator, was found in vitro and in vivo. 0.422 SIGNOR-117260 AKT2 protein P31751 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates activity phosphorylation Ser571 RMRSRSRsFSRHRSC 10090 17554339 YES miannu Here we describe a mechanism by which insulin, through the intermediary protein kinase Akt2/protein kinase B (PKB)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (PGC-1alpha), a global regulator of hepatic metabolism during fasting.  Akt phosphorylates PGC-1α at Ser 570. 0.349 SIGNOR-262626 LCK protein P06239 UNIPROT CD3D protein P04234 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000782 2470098 YES Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. 0.569 SIGNOR-259929 MAPK1 protein P28482 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 15116093 YES miannu In summary, our results suggest that phosphorylation of p53Thr55 by ERK2 is important for doxorubicin-induced p53 activation and cell death. 0.777 SIGNOR-279068 RHOBTB1 protein O94844 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 30896450 YES miannu RhoBTB1 augmented the cGMP response to nitric oxide by restraining the activity of phosphodiesterase 5 (PDE5) by acting as a substrate adaptor delivering PDE5 to the Cullin-3 E3 Ring ubiquitin ligase complex for ubiquitination inhibiting PDE5. 0.481 SIGNOR-272313 ACAN protein P16112 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 BTO:0003858 16051604 YES lperfetto Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation. 0.264 SIGNOR-266987 SP1 protein P08047 UNIPROT NDUFV2 protein P19404 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000931 17786189 NO miannu Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin. 0.344 SIGNOR-255207 IRX1 protein P78414 UNIPROT CELF2 protein O95319 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.2 SIGNOR-261657 serotonin smallmolecule CHEBI:28790 ChEBI HTR5A protein P47898 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264298 NFYA protein P23511 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 NO miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. 0.2 SIGNOR-254434 SMURF1 protein Q9HCE7 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates activity ubiquitination 9606 12519765 YES lperfetto Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ubiquitin ligase, interacts with inhibitory Smad7 and induces translocation of Smad7 to the cytoplasm 0.882 SIGNOR-97064 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9534 16757346 YES miannu We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ 0.29 SIGNOR-261707 CDK5 protein Q00535 UNIPROT TPX2 protein Q9ULW0 UNIPROT up-regulates quantity by stabilization phosphorylation Ser486 LPITVPKsPAFALKN 9606 BTO:0003897 31272499 YES lperfetto CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular tumorigenesis 0.273 SIGNOR-265100 SRC protein P12931 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Tyr151 IEFVNQYyGSFKEAK 9606 19875457 YES llicata We identify human inos residue tyr(1055) as a target for src-mediated phosphorylation. src kinase-mediated phosphorylation stabilizes inducible nitric-oxide synthase in normal cells and cancer cells. 0.68 SIGNOR-188974 SMARCC2 protein Q8TAQ2 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.836 SIGNOR-270605 SLC16A4 protein O15374 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 26384349 NO lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. 0.7 SIGNOR-256582 TLRs proteinfamily SIGNOR-PF20 SIGNOR Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20404851 NO lperfetto TLR signaling pathways can be largely classified as either MyD88-dependent pathways, which drive the induction of inflammatory cytokines, or TRIF-dependent pathways, which are responsible for the induction of type I interferon as well as inflammatory cytokines3. 0.7 SIGNOR-216310 CDK5 protein Q00535 UNIPROT PEBP1 protein P30086 UNIPROT down-regulates quantity by destabilization phosphorylation Thr42 DELGKVLtPTQVKNR 9606 BTO:0000007 25104559 YES miannu  Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif "KLYEQ" in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA).  0.337 SIGNOR-276672 AVPR1B protein P47901 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256934 FZD4 protein Q9ULV1 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 27096005 YES areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. 0.597 SIGNOR-258955 AZD1480 chemical CID:16659841 PUBCHEM JAK1 protein P23458 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190164 MFGE8 protein Q08431 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 10116 BTO:0000801 19020771 NO Giorgia In our current study, we have shown that after LPS-stimulation, MFG-E8-mediated apoptotic cell phagocytosis suppresses various ERK1/2, p38, JNK, and NFκB activation, resulting in a lower TNF-α release. We also explored whether MFG-E8 helps to suppress the proinflammatory pathway within RPMs. We hence incubated the macrophages with apoptotic cells and stimulated them with LPS and examined the activation of MAP kinase and NFkB pathways after the exogenous addition of recombinant MFG-E8 (rMFG-E8). While apoptotic cells alone had no effect on these pathways, the addition of rMFG-E8 to apoptotic cells prior to phagocytosis and LPS stimulation had a marked suppressive effect on all of the investigated pathways, particularly on the p38 and NFκB pathways that play a key role in the cytokine response of macrophages 0.2 SIGNOR-260652 MAPK3 protein P27361 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD -1 9199329 YES lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. 0.54 SIGNOR-154409 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 YES gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation 0.416 SIGNOR-252453 EGFR protein P00533 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 11887937 YES gcesareni Activation of estrogen receptor-alpha (eralpha) by growth factors in the absence of estrogen is a well-documented phenomenon.Egfr tyrosine kinase in vitro stimulated the phosphorylation of recombinant er 0.591 SIGNOR-115734 CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887 18316399 YES gcesareni We showed that beta-catenin interacts directly with myod, a basic helix-loop-helix transcription factor essential for muscle differentiation and enhances its binding to e box elements and transcriptional activity. 0.406 SIGNOR-161113 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 21576360 YES When IFN-γ binds to its receptor, the receptor-associated protein tyrosine kinases Janus kinase I (JAK1) and JAK2 are activated (37). This leads to the phosphorylation of STAT1, which then dimerizes, translocates to the nucleus, and activates its target promoters, including the pIV promoter of Ciita 0.805 SIGNOR-256248 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN1 protein Q92952 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 YES Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  0.8 SIGNOR-258026 R547 chemical CID:6918852 PUBCHEM CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258274 APOB protein P04114 UNIPROT LDL_assembly phenotype SIGNOR-PH63 SIGNOR up-regulates 9606 23721961 NO miannu Apolipoprotein B is a structural protein that is an integral component of chylomicrons, as well as very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) particles. 0.7 SIGNOR-252116 GLI2 protein P10070 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates NBK6142 NO Whilst shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development.  SimoneGraziosi 0.7 SIGNOR-269215 MRPL57 protein Q9BQC6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.635 SIGNOR-262341 CTTNBP2 protein Q8WZ74 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity binding 9606 BTO:0000938 35562389 YES miannu Synaptopathy, a key feature of autism spectrum disorders (ASD), is likely relevant to the impaired phase separation and/or transition of ASD-linked synaptic proteins. Here, we report that LLPS and zinc-induced liquid-to-gel phase transition regulate the synaptic distribution and protein-protein interaction of cortactin-binding protein 2 (CTTNBP2), an ASD-linked protein. CTTNBP2 forms self-assembled condensates through its C-terminal intrinsically disordered region and facilitates SHANK3 co-condensation at dendritic spines. 0.2 SIGNOR-269702 DAGLB protein Q8NCG7 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI down-regulates quantity chemical modification 9606 26787883 YES miannu Diacylglycerol lipases (DAGL√鬱 and DAGL√é¬≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. 0.8 SIGNOR-264263 3-(2-Carboxyethyl)-4,6-dichloro-1H-indole-2-carboxylic acid chemical CID:446916 PUBCHEM GPR17 protein Q13304 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257502 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.75 SIGNOR-249640 TNKS2 protein Q9H2K2 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0000142 32409565 YES lperfetto Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. 0.2 SIGNOR-262116 PIM3 protein Q86V86 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 YES lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. 0.347 SIGNOR-249605 PDHB protein P11177 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 YES miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. 0.937 SIGNOR-266547 PEX12 protein O00623 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity ubiquitination -1 19687296 YES miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. 0.654 SIGNOR-253020 1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one chemical CHEBI:93578 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258891 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16611981 YES gcesareni Gli2 can also be phosphorylated directly by ck-1 at the non-optimal sites 0.567 SIGNOR-146112 hsa-miR-29c-5p mirna URS0000497496_9606 RNAcentral GNA13 protein Q14344 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000675 25193986 YES Parnian These data provide evidence that PTP4A1 and GNA13 are direct targets of miR-29c, and that their expression is negatively regulated by miR-29c in CRC cells. | miR-29c directly targets PTP4A1 and GNA13 3'-UTR. 0.4 SIGNOR-278024 MAPK12 protein P53778 UNIPROT CARM1 protein Q86X55 UNIPROT down-regulates activity phosphorylation Ser595 GPAISMAsPMSIPTN 10090 29681515 YES apalma Here, we identify a role for the mitogen-activated protein kinase (MAPK) p38g/MAPK12 as a critical regulator of satellite stem cell fate through phosphorylation of Carm1. 0.362 SIGNOR-255897 TRIM28 protein Q13263 UNIPROT ALDOA protein P04075 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17900823 NO miannu We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. 0.2 SIGNOR-255628 CBLL1 protein Q75N03 UNIPROT ANXA2 protein P07355 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 31952268 YES miannu By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. 0.2 SIGNOR-271473 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser1219 DDTESLHsQGEEEFD 9606 22621922 YES gcesareni Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm. 0.873 SIGNOR-197611 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 18621737 YES gcesareni A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution. 0.892 SIGNOR-179452 DNAJC3 protein Q13217 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity binding 9606 BTO:0000567 25329545 YES gcesareni The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK 0.615 SIGNOR-246201 NCOA1 protein Q15788 UNIPROT PGR protein P06401 UNIPROT up-regulates 9606 10449719 NO miannu Progesterone receptor (pr) functions as a transcription factor that modulates the transcription of target genes in response to progesterone and other signals. The transcriptional activity of pr requires the involvement of coactivators such as steroid receptor coactivator-1 (src-1). 0.683 SIGNOR-70149 PPP4C protein P60510 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates activity dephosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 YES lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Depletion of PP4C, or PP4R3beta, causes persistence of phospho-T1609 and phospho-S1618 0.358 SIGNOR-264450 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 YES Luana Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity. 0.2 SIGNOR-260755 UHRF2 protein Q96PU4 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization ubiquitination 9534 BTO:0000298 21952639 YES miannu We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1. 0.294 SIGNOR-271885 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr451 TDPEALHyDYIDVEM 9534 BTO:0004055 9655255 YES lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. 0.573 SIGNOR-246351 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 20570526 YES Luana Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors], 0.8 SIGNOR-257851 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251595 DRAP1 protein Q14919 UNIPROT BTAF1 protein O14981 UNIPROT up-regulates activity binding 9986 15509807 YES miannu We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP. 0.504 SIGNOR-263918 RNMT protein O43148 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity chemical modification 9606 27422871 YES lperfetto Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. 0.8 SIGNOR-268316 AURKA protein O14965 UNIPROT FAF1 protein Q9UNN5 UNIPROT down-regulates activity phosphorylation Ser289 ITDVHMVsDSDGDDF 9606 18790738 YES llicata This study reports that aurora-a (aur-a) phosphorylates fas-associated factor-1 (faf1) at ser-289 and ser-29 our findings support the negative feedback regulation of aur-a via phosphorylation of the death-promoting protein, faf1 0.2 SIGNOR-180887 APOBEC3C protein Q9NRW3 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 NO lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). 0.7 SIGNOR-261326 RNF146 protein Q9NTX7 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21478859 YES lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.644 SIGNOR-263335 PTK6 protein Q13882 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr250 PFLLDEDyEKVLGYV 9606 19393627 YES lperfetto Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates the signaling pathways downstream of them. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by Brk, using a series of STAP-2 YF mutants and anti-phospho-STAP-2 Tyr250 antibody. Furthermore, overexpression of the STAP-2 Y250F mutant protein affected Brk-mediated STAT3 activation. 0.723 SIGNOR-247067 BDKRB2 protein P30411 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.456 SIGNOR-257090 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 YES lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.2 SIGNOR-244651 TCF12 protein Q99081 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 NO miannu Hebalt positively regulates t-cell genes, such as pt_ and notch3 0.257 SIGNOR-197517 MPO-ANCA complex SIGNOR-C474 SIGNOR Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000133 2161532 NO lperfetto ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. 0.7 SIGNOR-270583 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr168 TLMEKDSyPRFLKSP 9606 12588871 YES miannu Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. / this result suggests src phosphorylates native rgs16 at residue tyr177 in vitro. 0.347 SIGNOR-98271 UBR5 protein O95071 UNIPROT MOAP1 protein Q96BY2 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27721409 YES miannu We demonstrate that UBR5 interacts physically with MOAP-1, ubiquitylates MOAP-1 in vitro and inhibits MOAP-1 stability in cultured cells. 0.346 SIGNOR-278581 ADAM17 protein P78536 UNIPROT HBEGF protein Q99075 UNIPROT up-regulates activity cleavage 9606 26284334 YES miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF 0.589 SIGNOR-259844 pindolol chemical CHEBI:8214 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 YES miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. 0.8 SIGNOR-258884 SLC34A2 protein O95436 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 BTO:0000671 11009570 YES lperfetto Three families of NPCs have been reported to date. The type I family consists of a single species (NaPi-1), which has thus far been found only in rabbit kidney.28 The type II family consists of six species homologues, NaPi 2 to 7, that are expressed predominantly in renal epithelial tissues.The type III family is the most recently identified and consists of two members, Pit-1 (also called Glvr-1) and Pit-2 (also called Ram-1).34 0.8 SIGNOR-270578 RNF41 protein Q9H4P4 UNIPROT PRKN protein O60260 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 18541373 YES miannu Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate. 0.2 SIGNOR-272639 GATA2 protein P23769 UNIPROT GATA2 protein P23769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27545880 NO irozzo GATA-2 phosphorylation facilitates GATA-2 chromatin occupancy at GATA-2 target genes. GATA-2 stimulates GATA2 transcription through positive autoregulation 0.2 SIGNOR-256090 SNRPA protein P09012 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.679 SIGNOR-270627 FAM83E protein Q2M2I3 UNIPROT CSNK1A1 protein P48729 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273750 WNT7B protein P56706 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 22944199 NO gcesareni In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod. 0.295 SIGNOR-198925 DDC protein P20711 UNIPROT tyramine smallmolecule CHEBI:15760 ChEBI up-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† 0.8 SIGNOR-263994 eplerenone chemical CHEBI:31547 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18038968 YES Luana Indeed, eplerenone, 1, also acts as a mineralocorticoid receptor antagonist and is used to treat numerous patients for hypertension and congestive heart failure. 0.8 SIGNOR-257763 DVL1 protein O14640 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates activity binding 9606 19365405 YES gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. 0.734 SIGNOR-185271 MAP1LC3A protein Q9H492 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 BTO:0001623 20921139 NO lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation 0.7 SIGNOR-219406 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Met) smallmolecule CHEBI:29173 ChEBI up-regulates quantity chemical modification 9606 27911719 YES lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) 0.8 SIGNOR-269491 ID1 protein P41134 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.531 SIGNOR-241110 TBL1XR1 protein Q9BZK7 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 24243687 YES miannu We showed that tblr1 physically interacts with ar and directly occupies the androgen-response elements of the affected ar target genes in an androgen-dependent manner. / we characterized tblr1 as a coactivator of ar 0.393 SIGNOR-203235 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 21808241 YES The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. 0.85 SIGNOR-175805 MYH9 protein P35579 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 BTO:0004953 32685004 YES miannu Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo. 0.255 SIGNOR-269285 CDK2 protein P24941 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 YES lperfetto Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1. 0.651 SIGNOR-150028 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 YES milica Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna. 0.794 SIGNOR-202039 RPS6KA1 protein Q15418 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates activity phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 10398585 YES miannu Mitogen activated ribosomal S6 kinase (p90 rsk1) phosphorylates IkappaBalpha at S32, binds IkappaBalpha in vivo, and overexpression of dominant negative p90 rsk1 inhibits degradation of IkappaBalpha in response to TPA. 0.386 SIGNOR-279311 CPSF1 protein Q10570 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 14749727 YES miannu Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. 0.941 SIGNOR-121646 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257986 NFATC3 protein Q12968 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001260 17079331 YES lperfetto The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. 0.284 SIGNOR-251732 FBXW11 protein Q9UKB1 UNIPROT EEF2K protein O00418 UNIPROT down-regulates ubiquitination 9606 phosphorylation:Ser441;Ser445 ESENSGDsGYPSEKR;SGDSGYPsEKRGELD 22669845 YES gcesareni Eef2k was degraded by the ubiquitin-proteasome system through the ubiquitin ligase scf(__trcp) (skp1-cul1-f-box protein, __-transducin repeat-containing protein) to enable rapid resumption of translation elongation. This event required autophosphorylation of eef2k on a canonical __trcp-binding domain 0.437 SIGNOR-197730 perfluorodecanoic acid chemical CHEBI:35546 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 YES miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. 0.8 SIGNOR-268758 GRB2 protein P62993 UNIPROT SOS2 protein Q07890 UNIPROT up-regulates binding 9606 21779497 YES gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. 0.88 SIGNOR-175180 MEN1 protein O00255 UNIPROT MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 YES irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. 0.2 SIGNOR-255867 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 9606 18239683 YES lperfetto Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres. 0.309 SIGNOR-160544 CASP3 protein P42574 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates cleavage Asp1405 CPGYPETdHGLFEDP 9606 23074268 YES gcesareni Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain. 0.321 SIGNOR-199111 MAPK7 protein Q13164 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates phosphorylation Ser180 LTDPRLLsPQQPALQ 9606 BTO:0000567 10849446 YES lperfetto Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b. the sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. 0.704 SIGNOR-236041 PRKCB protein P05771 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 11700305 YES lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | 0.353 SIGNOR-249119 DIO proteinfamily SIGNOR-PF83 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20978344 NO inferred from family member miannu The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. 0.2 SIGNOR-270306 PKA proteinfamily SIGNOR-PF17 SIGNOR PIK3CG protein P48736 UNIPROT down-regulates activity phosphorylation Thr1024 YLALRHHtNLLIILF 9606 BTO:0002181 21474070 YES miannu Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP(3) production.  0.2 SIGNOR-276321 IRX1 protein P78414 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. 0.2 SIGNOR-261662 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT down-regulates activity phosphorylation Ser792 CVRMRHLsQEFGWLQ 9534 BTO:0001538 11404460 YES lperfetto Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790 0.587 SIGNOR-108508 F2RL1 protein P55085 UNIPROT SERPINB2 protein P05120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 NO miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). 0.2 SIGNOR-254856 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2049 DAAVVLLkNGANKDM 9606 17636029 YES gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. 0.415 SIGNOR-156915 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser214 ARRSRAAsSQRAEEE 9606 22724069 YES lperfetto Moreover, we find that the cpc's catalytic subunit, aurora b kinase, phosphorylates one of the three human snf7 paralogues-chmp4c-in its c-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for chmp4c function because their mutation leads to cytokinesis defects. The introduction of the s214a and s215a mutations together with s210a almost completely abolished aurora b phosphorylation 0.47 SIGNOR-197971 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 9606 10318826 YES miannu AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor. 0.774 SIGNOR-252379 PRKCA protein P17252 UNIPROT KCNQ2 protein O43526 UNIPROT up-regulates quantity phosphorylation Ser558 SKRKFKEsLRPYDVM 10029 BTO:0000246 12754513 YES lperfetto Phosphorylation of KCNQ2 channels was increased by muscarinic stimulation; this was prevented either by coexpression with AKAP(DeltaA) or pretreatment with PKC inhibitors that compete with diacylglycerol. These inhibitors also reduced muscarinic inhibition of M-current. | These results suggest that Ser534 and 541 are key sites for PKC phosphorylation, although we have not ruled out the possibility that other PKC sites are involved in this process. 0.325 SIGNOR-249210 GRK5 protein P34947 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation 9606 23658733 YES miannu GRK5 phosphorylates and promotes the nuclear export of the histone deacetylase, HDAC5. 0.357 SIGNOR-279045 HTR4 protein Q13639 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.496 SIGNOR-256769 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser251 KNDYRKLsMQCKDFV 9606 16331690 YES gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. 0.408 SIGNOR-142953 PBK protein Q96KB5 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser469 IRRSGSTsPLGFARA 9606 BTO:0002181 31378785 YES miannu We found that TOPK could directly bind with and phosphorylate ULK1 at Ser469, Ser495, and Ser533. The phosphorylation of ULK1 at Ser469, Ser495, and Ser533 by TOPK decreased the activity and stability of ULK1.  0.2 SIGNOR-277474 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259708 SUN1 protein O94901 UNIPROT NUP153 protein P49790 UNIPROT up-regulates activity binding 9606 BTO:0000567 SIGNOR-C303 SIGNOR-C263 28831067 YES lperfetto The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export. 0.43 SIGNOR-263294 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 17827393 YES gcesareni Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K). 0.868 SIGNOR-157746 GABARAP protein O95166 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 11146101 YES lperfetto N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions 0.328 SIGNOR-219391 PPARA protein Q07869 UNIPROT SLC25A20 protein O43772 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19577614 NO miannu CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting. 0.489 SIGNOR-255049 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 21059642 YES The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.614 SIGNOR-169326 estriol smallmolecule CHEBI:27974 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258585 CIB2 protein O75838 UNIPROT TMC2 protein Q8TDI7 UNIPROT up-regulates activity binding 10090 BTO:0004744 28663585 YES miannu  Furthermore, we report that calcium and integrin-binding protein 2 binds to the components of the hair cell mechanotransduction complex, TMC1 and TMC2, and these interactions are disrupted by deafness-causing Cib2 mutations. We conclude that calcium and integrin-binding protein 2 is required for normal operation of the mechanotransducer channels and is involved in limiting the growth of transducing stereocilia. 0.352 SIGNOR-269665 NDN protein Q99608 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by stabilization binding 9606 26971449 YES lperfetto Necdin binds and stabilizes PGC-1α|Necdin strongly stabilizes PGC-1α by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration. 0.327 SIGNOR-253390 denileukin diftitox smallmolecule SID:125240988 PUBCHEM IL2RG protein P31785 UNIPROT up-regulates activity chemical activation 9606 15757436 YES miannu Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells.  0.8 SIGNOR-259394 PDK1 protein Q15118 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 YES gcesareni Human pdh1 and rat pdh2 were expressed previously and were shown to have different specific activities and the ability to be phosphorylated by pdk1 and pdk2 0.503 SIGNOR-143966 C3 protein P01024 UNIPROT C3AR1 protein Q16581 UNIPROT up-regulates activity binding 9606 cleavage:Arg671;Arg748 QPAARRRrSVQLTEK;ASHLGLArSNLDEDI 8765043 YES complement C3a fragment: PRO_0000005910 lperfetto A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells|The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a. 0.733 SIGNOR-263451 PTK2 protein Q05397 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9566877 YES Luana  In vitro, FAK directly phosphorylated Shc Tyr-317 to promote Grb2 binding. FAK can associate and directly phosphorylate Shc at Tyr-317 to promote Grb2 binding and low-level signaling to ERK2. 0.673 SIGNOR-259854 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity precursor of 9606 30158707 YES miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. 0.8 SIGNOR-267822 RPS6KA3 protein P51812 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Thr1326 VNGADEDtISRFLAE 9606 BTO:0002181 23608533 YES miannu We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. 0.2 SIGNOR-276462 HTR4 protein Q13639 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257309 NUF2 protein Q9BZD4 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR form complex binding 27881301 YES lperfetto Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits 0.974 SIGNOR-265187 PDHX protein O00330 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 YES miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. 0.817 SIGNOR-266543 BRCA1-A complex complex SIGNOR-C296 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR down-regulates 25400280 NO lperfetto Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks. 0.7 SIGNOR-263226 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr227 KVDATADyICKVKWG 9606 BTO:0000007 32420483 YES done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. 0.2 SIGNOR-274104 NCK1 protein P16333 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9534 8824201 YES lperfetto We describe here a specific interaction of the Nck adapter molecule with PAK1 both in vitro and in vivo. Association of Nck with PAK1 may serve to link this important regulatory kinase to cell activation by growth factor receptors. 0.708 SIGNOR-236324 FNTA protein P49354 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity 9606 24294527 YES lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. 0.383 SIGNOR-242559 KDM6A protein O15550 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.267 SIGNOR-260020 NFE2L2 protein Q16236 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 NO lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC 0.25 SIGNOR-268998 CDK5RAP2 protein Q96SN8 UNIPROT WDR62 protein O43379 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 YES lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. 0.545 SIGNOR-271723 HSF4 protein Q9ULV5 UNIPROT DNASE2B protein Q8WZ79 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23507146 NO miannu We found that HSF4 promoted the expression and DNase activity of DLAD by directly binding to the DLAD promoter. 0.368 SIGNOR-254479 H2AZ2 protein Q71UI9 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 YES miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. 0.2 SIGNOR-263709 NDEL1 protein Q9GZM8 UNIPROT DYNC1H1 protein Q14204 UNIPROT up-regulates activity binding 10090 BTO:0000938 11163259 YES miannu LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex 0.719 SIGNOR-252159 RAB7A protein P51149 UNIPROT PSMA7 protein O14818 UNIPROT up-regulates activity binding 10036 14998988 YES Sara Rab7 Forms a Complex with the Proteasome -Subunit XAPC. In this study the proteasome alpha-subunit XAPC7 (also known as PSMA7, RC6-1, and HSPC in mammals) was identified to interact specifically with Rab7 and was recruited to multivesicular late endosomes through this interaction. 0.343 SIGNOR-261303 FYCO1 protein Q9BQS8 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates activity binding 9606 BTO:0000007 26468287 YES Giulio The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures. 0.562 SIGNOR-260598 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 8702790 YES llicata These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1. 0.525 SIGNOR-43080 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates phosphorylation Tyr686 IITEYCRyGDLVDYL 9606 BTO:0000150;BTO:0000527 19275932 YES gcesareni These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis. 0.526 SIGNOR-184552 TBP protein P20226 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR form complex binding 29378333 YES lperfetto Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1). 0.834 SIGNOR-266192 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser35 SQGSSSQsQGISSSS 9606 BTO:0000007 10973490 YES lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir 0.834 SIGNOR-81403 CDK5 protein Q00535 UNIPROT VRK3 protein Q8IV63 UNIPROT up-regulates activity phosphorylation Ser108 RPPTPKSsPQKTRKS 27346674 YES lperfetto Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation| 0.356 SIGNOR-275544 PTPN7 protein P35236 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 BTO:0000776 19047375 YES gcesareni Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation 0.59 SIGNOR-182525 NTN1 protein O95631 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 BTO:0001484 25881791 YES miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. 0.853 SIGNOR-268183 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr463 MLAGVSEyELPEDPR 10116 BTO:0003293 19224897 YES lperfetto This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region 0.2 SIGNOR-235762 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Ser474 RTHFPQFsYSASIRE 9606 15743829 YES lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation. 0.731 SIGNOR-134481 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser341 KVSKDDRsDIESSSD 9606 BTO:0000007 26887952 YES miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  0.2 SIGNOR-273990 AKT2 protein P31751 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 17554339 YES miannu Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1? At ser?570 Is required for akt to inhibit recruitment of pgc-1? To chromatin. 0.349 SIGNOR-155536 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Ser213 TRKLMEFsEHCAIIL 9606 BTO:0002181 9155023 YES lperfetto Here we show that TbetaRII kinase is regulated intricately by autophosphorylation on at least three serine residues. Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. 0.2 SIGNOR-236087 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 YES lperfetto We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites. 0.374 SIGNOR-249044 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 YES gcesareni Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs. 0.2 SIGNOR-89423 PLEKHG5 protein O94827 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.771 SIGNOR-260566 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser175 SPASSGSsASFISDT 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.407 SIGNOR-248513 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr941 EETGTEEyMKMDLGP 10116 BTO:0000443 7651388 YES lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). 0.914 SIGNOR-235975 PLK1 protein P53350 UNIPROT ERCC6L protein Q2NKX8 UNIPROT up-regulates relocalization 9606 17218258 YES lperfetto Human pich was identified as an interaction partner and substrate of plk1. Our data indicate that plk1 prevents the association of pich with chromosome arms and restricts its localization to the kt/centromere region 0.88 SIGNOR-152136 NSMCE2 protein Q96MF7 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 YES miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks 0.883 SIGNOR-265484 MAPK1 protein P28482 UNIPROT TNKS1BP1 protein Q9C0C2 UNIPROT unknown phosphorylation Thr1032 GGLFSPStAHVPDGA 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262781 MAPK8 protein P45983 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 NO JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax. gcesareni We demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein. 0.558 SIGNOR-124012 FYN protein P06241 UNIPROT JUP protein P14923 UNIPROT down-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 14517306 YES Phosphorylation of plakoglobin by Fer and Fyn kinases decreases plakoglobin-desmoplakin interaction and increases plakoglobin-α-catenin association. Fyn mainly phosphorylated Tyr549 0.56 SIGNOR-251177 TEK protein Q02763 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9534 14665640 YES lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival 0.537 SIGNOR-242634 arecoline chemical CHEBI:2814 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258639 GSK3B protein P49841 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates phosphorylation Ser59 FPPSPTGsLTQDPAR 9606 16484495 YES llicata We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock. 0.282 SIGNOR-144570 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 8381049 YES inferred from 70% family members gcesareni Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane. 0.2 SIGNOR-270192 TIMP2 protein P16035 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 NO lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 0.7 SIGNOR-252273 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr215 ATGSVPStPIAHRGP 9606 BTO:0000007 16682949 YES done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 0.543 SIGNOR-274082 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 YES lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376 (11, 12, 14, 17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 0.341 SIGNOR-166710 EGR1 protein P18146 UNIPROT PDGFC protein Q9NRA1 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001685 15247255 NO The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter 0.251 SIGNOR-254268 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr45 PGGTLFStTPGGTRI 9606 11777913 YES gcesareni Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126. 0.658 SIGNOR-113563 SRC protein P12931 UNIPROT PTP4A3 protein O75365 UNIPROT down-regulates activity phosphorylation Tyr53 VRVCEVTyDKTPLEK 9606 23691193 YES miannu Our results show that Src kinase activity leads to the tyrosine phosphorylation of PRL-3, primarily on Y53.|Collectively these results support a model in which Src causes phosphorylation of PRL-3 on Y53 to promote its pro-invasion functions, and suggest for the first time that the metastasis-associated tyrosine phosphatase PRL-3 may itself be regulated by post-translational modification. 0.359 SIGNOR-278262 BAX protein Q07812 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates 9606 21210296 NO gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c,(diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. 0.543 SIGNOR-170969 hsa-mir-132-3p mirna URS00006054DA_9606 RNAcentral SPRED1 protein Q7Z699 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001949 25945589 YES Tiberia We found that miR-132 can significantly suppress the luciferase activity of Spred1 -3'UTR at 25 nmol/l, compared with scramble control miRNAs. 0.4 SIGNOR-279921 MAPK1 protein P28482 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 YES gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily. 0.45 SIGNOR-166686 EREG protein O14944 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 YES gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4. 0.705 SIGNOR-147859 ATM protein Q13315 UNIPROT WRN protein Q14191 UNIPROT unknown phosphorylation Ser1141 PEKAYSSsQPVISAQ -1 10608806 YES llicata We determined a general phosphorylation consensus sequence for ATM and identified putative in vitro targets by using glutathione S-transferase peptides as substrates. Putative ATM in vitro targets include p95/nibrin, Mre11, Brca1, Rad17, PTS, WRN, and ATM (S440) itself. 0.826 SIGNOR-250577 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 YES gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. 0.2 SIGNOR-252812 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity phosphorylation Tyr280 PKPSNPIyNEPDEPI 9606 BTO:0000782 18541536 YES miannu Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition. 0.579 SIGNOR-262888 P2RY13 protein Q9BPV8 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256892 MAP2K4 protein P45985 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Tyr249 VEPKTETyVEANMGL 9606 10938283 YES miannu Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1. 0.2 SIGNOR-80619 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2A protein Q02078 UNIPROT down-regulates binding 9606 21902831 YES lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.268 SIGNOR-216960 CSNK2A1 protein P68400 UNIPROT PIP4K2A protein P48426 UNIPROT up-regulates phosphorylation Ser304 DGEEEGEsDGTHPVG 9606 BTO:0000567 10508590 YES lperfetto Here, we demonstrate the partial purification of a protein kinase that phosphorylates the type iialpha pip kinase at a single site unique to that isoform - ser304. This kinase was identified as protein kinase ck2 (formerly casein kinase 2). Mutation of ser304 to aspartate to mimic its phosphorylation had no effect on pip kinase activity, but promoted both redistribution of the green fluorescent protein (gfp)-tagged enzyme in hela cells from the cytosol to the plasma membrane, and membrane ruffling. 0.422 SIGNOR-71014 CREB5 protein Q02930 UNIPROT LGALS3BP protein Q08380 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002812 21132541 NO miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), 0.2 SIGNOR-253805 MAPK1 protein P28482 UNIPROT ASB2 protein Q96Q27 UNIPROT up-regulates activity phosphorylation Ser371 RIRRSGVsPLHLAAE 24044920 YES lperfetto Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. |Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation. 0.265 SIGNOR-272240 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr452 GLEKTQTtPNGSLQA 9606 BTO:0000007 16862148 YES lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). 0.434 SIGNOR-249310 phentolamine chemical CHEBI:8081 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258444 BCL3 protein P20749 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16713561 YES gcesareni The cyclin d1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of bcl-3-associated nf-kappab p50 and p52. 0.572 SIGNOR-146768 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT up-regulates activity phosphorylation Tyr256 LKAALKLyHVSDSEG 9606 15342783 YES lperfetto These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton 0.364 SIGNOR-247433 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser396 DDKKAKTsTRSSAKT -1 21204788 YES done miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.255 SIGNOR-273930 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000007 17197020 YES llicata In HEK293 cells, transfected with the Ca2+ channel protein TRPV6, Ca2+ influx is increased and TRPV6 is tyrosine phosphorylated following addition of the tyrosine phosphatase inhibitor|PTP1B interacts with the N-terminal domain of TRPV6 within a region of amino acids 1-191 as shown by co-immunoprecipitation, bimolecular fluorescence complementation and the yeast 2-hybrid system. Point mutation of both tyrosines 161 and 162 in the TRPV6 protein abolishes the DMHV-effect on Ca2+ influx and tyrosine phosphorylation by Src. Single mutations of Y161 or Y162 shows that each of both tyrosines alone is sufficient for the DMHV-effect. We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of Ca2+ influx through TRPV6 Ca2+ channels in HEK293 cells. 0.63 SIGNOR-248433 ELAVL4 protein P26378 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 YES miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure 0.2 SIGNOR-266865 AXL protein P30530 UNIPROT NEDD9 protein Q14511 UNIPROT up-regulates activity phosphorylation 9606 32681075 YES miannu Mechanistically, AXL phosphorylates NEDD9, leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1.|These results reveal NEDD9 as a specific AXL substrate.We next validated whether AXL promotes canonical NEDD9 signaling. 0.2 SIGNOR-278905 pipamperone chemical CHEBI:78549 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258575 EFNB1 protein P98172 UNIPROT EPHB4 protein P54760 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.753 SIGNOR-52580 DUSP3 protein P51452 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9606 32475380 YES miannu DUSP3 interacted with the C-terminal domain of STAT3 and dephosphorylated p-Y705 of STAT3.|In summary, DUSP3 downregulated the transcriptional activity of STAT3 via dephosphorylation at Y705 and also suppressed the migratory activity of cancer cells. 0.2 SIGNOR-277070 TBK1 protein Q9UHD2 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser158 QRMLPSLsLTEDVKW 9606 22412986 YES lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated 0.542 SIGNOR-196528 NEDD4L protein Q96PU5 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates ubiquitination 9606 19917253 YES gcesareni Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation 0.78 SIGNOR-161710 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 11504915 YES lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. 0.81 SIGNOR-116270 AURKB protein Q96GD4 UNIPROT KNL1 protein Q8NG31 UNIPROT down-regulates phosphorylation Ser24 RPVRRRHsSILKPPR 9606 20471944 YES lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). 0.2 SIGNOR-165502 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser448 QGYRERLsLLRSEVE 9606 20864540 YES lperfetto Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability. 0.252 SIGNOR-168049 NEFL protein P07196 UNIPROT Neurofilament bundle assembly phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 8376466 NO miannu Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons. 0.7 SIGNOR-252392 LTC4S protein Q16873 UNIPROT glutathionate(1-) smallmolecule CHEBI:57925 ChEBI down-regulates quantity chemical modification 9606 27365393 YES miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). 0.8 SIGNOR-277259 CREBBP protein Q92793 UNIPROT FBL protein P22087 UNIPROT down-regulates activity acetylation Lys121 GESVYGEkRVSISEG 30540930 YES lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) 0.27 SIGNOR-275899 PRKDC protein P78527 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 YES gcesareni DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform 0.753 SIGNOR-252431 SKP1 protein P63208 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 YES miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. 0.442 SIGNOR-255278 RPS6KA3 protein P51812 UNIPROT VGLL1 protein Q99990 UNIPROT down-regulates activity phosphorylation Ser84 PNQWRYSsPWTKPQP 9606 BTO:0002597 33069758 YES done miannu Site-directed mutagenesis and immunoprecipitation experiments revealed that RSK2 phosphorylated VGLL1 at S84 in the presence of TGF-β. Mutation of VGLL1 at S84 suppressed VGLL1-TEAD4 binding and the subsequent transcriptional activation of matrix metalloprotease 9 (MMP9). 0.2 SIGNOR-273842 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 16076840 YES gcesareni The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex. 0.34 SIGNOR-139316 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC12 protein O60814 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 YES miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. 0.2 SIGNOR-271979 ACE2 protein Q9BYF1 UNIPROT Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 18554741 NO miannu Endocytosis of the Receptor-Binding Domain of SARS-CoV Spike Protein Together With Virus Receptor ACE2. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells. 0.7 SIGNOR-260235 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 YES lperfetto In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e. 0.2 SIGNOR-244614 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 YES milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) 0.42 SIGNOR-230743 AURKA protein O14965 UNIPROT KNSTRN protein Q9Y448 UNIPROT down-regulates activity phosphorylation 9606 BTO:0001938 22535524 YES lperfetto The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation. 0.261 SIGNOR-252052 ARHGAP29 protein Q52LW3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.55 SIGNOR-260484 DLG4 protein P78352 UNIPROT Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 17243894 NO miannu PSD-95 (the best-studied scaffold protein of the PSD, which binds to NR2 subunits of NMDA receptors) was found to be highly abundant in the adult forebrain PSD 0.7 SIGNOR-264230 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser270 EFRPRSKsQSSSNCS -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251289 NFE2 protein Q16621 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 NO Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. 0.528 SIGNOR-251840 a7/b1 integrin complex SIGNOR-C126 SIGNOR A5/b1 integrin complex SIGNOR-C163 SIGNOR down-regulates activity 9925758 NO lperfetto These data indicate that alpha7 expression leads to the functional down regulation of alpha5beta1 integrin by decreasing ligand binding affinity and surface expression. In conclusion, the data reported establish the existence of a negative cooperativity between alpha7 and alpha5 integrins that may be important in determining functional regulation of integrins during myogenic differentiation. 0.751 SIGNOR-253251 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation -1 9155018 YES These results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways 0.2 SIGNOR-253013 IL21 protein Q9HBE4 UNIPROT PAX5 protein Q02548 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782;BTO:0000785 22486304 NO miannu Interleukin-21 inhibits humoral response to an hiv dna vaccine by enhancing bcl-6 andpax-5expression. 0.252 SIGNOR-196921 CHRM1 protein P11229 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.401 SIGNOR-257130 AKT1 protein P31749 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 15048128 YES gcesareni Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis. 0.623 SIGNOR-123606 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser246 RGGPEPLsPFPVSPL 9606 10330152 YES lperfetto The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a). 0.595 SIGNOR-67524 MAPK1 protein P28482 UNIPROT PDXDC1 protein Q6P996 UNIPROT unknown phosphorylation Thr691 AGVTLPPtPSGSRTK 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.2 SIGNOR-262759 UBQLN2 protein Q9UHD9 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates quantity by stabilization binding 25616961 YES lperfetto Confirmation of binding of recombinant full-length hnRNPA1 and hnRNPU proteins with ubiquilin-2 by GST-pull-down assays|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein 0.459 SIGNOR-262270 MAP2K6 protein P52564 UNIPROT HSF4 protein Q9ULV5 UNIPROT up-regulates activity phosphorylation Thr471 LGLPGALtIYSTPES 24361130 YES lperfetto Regulation of Hsf4b nuclear translocation and transcription activity by phosphorylation at threonine 472| At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI 0.2 SIGNOR-275493 NUP85 protein Q9BW27 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.731 SIGNOR-262093 RNF146 protein Q9NTX7 UNIPROT BLZF1 protein Q9H2G9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21478859 YES lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.41 SIGNOR-263340 GSK3A protein P49840 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000812 phosphorylation:Ser64 EPGTPPSsPLSAEQL 27875297 YES lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation 0.2 SIGNOR-264887 FBLIM1 protein Q8WUP2 UNIPROT FLNC protein Q14315 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 YES miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. 0.789 SIGNOR-266107 MAPK3 protein P27361 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 22802261 YES gcesareni Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1 0.292 SIGNOR-198292 KLHL15 protein Q96M94 UNIPROT RBBP8 protein Q99708 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001938 27561354 YES miannu  Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. 0.475 SIGNOR-272410 Gbeta proteinfamily SIGNOR-PF4 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21071439 YES inferred from 70% family members lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.2 SIGNOR-270027 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19819937 NO In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils. 0.7 SIGNOR-254355 ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates -1 10542278 NO miannu HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay. 0.7 SIGNOR-259064 KDM2B protein Q8NHM5 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR up-regulates activity binding 10090 BTO:0000011 25533466 YES miannu We show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. 0.656 SIGNOR-252247 ARHGEF25 protein Q86VW2 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.835 SIGNOR-260544 CSNK2A1 protein P68400 UNIPROT EIF3J protein O75822 UNIPROT up-regulates activity phosphorylation Ser127 LKKLQEEsDLELAKE 9606 BTO:0000007 25887626 YES miannu CK2 phosphorylates the eIF3j subunit at Ser127. CK2-phosphorylation of eIF3j triggers its association with the eIF3 complex. 0.327 SIGNOR-266402 PASK protein Q96RG2 UNIPROT EEF1A1 protein P68104 UNIPROT unknown phosphorylation 9606 BTO:0000567 17595531 YES gcesareni Kinase assays, mass spectrometry and site-directed mutagenesis revealed PASKIN auto-phosphorylation as well as eEF1A1 target phosphorylation mainly but not exclusively at Thr432. 0.374 SIGNOR-245862 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249319 TG101209 chemical CHEBI:90304 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207260 FGF1 protein P05230 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 YES gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. 0.827 SIGNOR-18454 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 SIGNOR-C110 10318824 YES lperfetto From the binding experiments, we defined the domains of Axin that bind glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin. We also examined the ability of each Axin mutant to inhibit lymphoid enhancer factor-1 (Lef-1) reporter activity in a cell line expressing high levels of beta-catenin. 0.92 SIGNOR-67438 BGJ-398 chemical CHEBI:63451 ChEBI FGFR3 protein P22607 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190269 1124329-14-1 chemical CID:56973724 PUBCHEM TTK protein P33981 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-190137 EID1 protein Q9Y6B2 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates 11073990 NO lperfetto Thus, EID-1 binds both Rb and p300 and is a novel repressor of MyoD function. 0.343 SIGNOR-253378 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 15356634 YES gcesareni Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. 0.548 SIGNOR-128735 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 18423396 NO fspada Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation. 0.7 SIGNOR-178281 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 YES Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37. 0.589 SIGNOR-248619 LUBAC complex SIGNOR-C527 SIGNOR GLYR1 protein Q49A26 UNIPROT down-regulates quantity by destabilization ubiquitination Lys535 NEVYKRAkALDQSDN 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 0.2 SIGNOR-272840 LTBR protein P36941 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 12571250 YES lperfetto Endogenous association of traf2, traf3, ciap1, and smac with lymphotoxin beta receptor reveals a novel mechanism of apoptosis. 0.585 SIGNOR-97950 NLGN3 protein Q9NZ94 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.839 SIGNOR-264147 CSNK2A2 protein P19784 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser106 DDIDLFGsDDEEESE -1 8547318 YES llicata EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent. 0.337 SIGNOR-250987 DLGAP3 protein O95886 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 YES miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. 0.757 SIGNOR-264211 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24321385 YES miannu We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells 0.283 SIGNOR-259973 DAMPS stimulus SIGNOR-ST18 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR up-regulates activity binding 9606 25644504 YES The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) 0.7 SIGNOR-252096 MAPK3 protein P27361 UNIPROT PTPRR protein Q15256 UNIPROT up-regulates activity phosphorylation Thr361 EPFVSIPtPREKVAM 11493009 YES lperfetto Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. 0.67 SIGNOR-249477 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT down-regulates quantity by destabilization cleavage Asp372 EFEVSFLdSPGAQAQ 9606 BTO:0000567 11815631 YES Giulio Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage 0.396 SIGNOR-260603 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 17713585 NO lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB. 0.7 SIGNOR-251502 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-268073 PRKCD protein Q05655 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates activity phosphorylation Ser78 PAYSRALsRQLSSGV 9606 22974980 YES miannu Radioactive kinase assays confirmed that PKC\u03b4 phosphorylated Hsp27 at Ser78 and Ser82 ( Fig. 3 B). 0.515 SIGNOR-278424 PTK6 protein Q13882 UNIPROT ARAP1 protein Q96P48 UNIPROT up-regulates activity phosphorylation Tyr231 PEFDDSDyDEVPEEG 9606 BTO:0000007 20554524 YES miannu ARAP1 associated with PTK6 in an EGF/EGF receptor (EGFR)-dependent manner. In addition, the SH2 domain of PTK6, particularly the Arg(105) residue that contacts the phosphate group of the tyrosine residue, was essential for the association. Moreover, PTK6 phosphorylated residue Tyr(231) in the N-terminal domain of ARAP1. Expression of ARAP1, but not of the Y231F mutant, inhibited the down-regulation of EGFR in HEK293 cells expressing PTK6. These results demonstrate that PTK6 enhances EGFR signaling by inhibition of EGFR down-regulation through phosphorylation of ARAP1 in breast cancer cells. 0.483 SIGNOR-263188 ITGB2 protein P05107 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.83 SIGNOR-253194 EPHA8 protein P29322 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates activity phosphorylation Tyr839 LAYGERPyWNMTNRD 9606 BTO:0000007 10498895 YES Tyr-615 and Tyr-838 are major autophosphorylation sites of the EphA8 receptor. phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for efficient phosphorylation at Tyr-615 as well as other major sites. 0.2 SIGNOR-251121 ARHGAP11B protein Q3KRB8 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.489 SIGNOR-260468 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 9606 16733250 YES lperfetto Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins. 0.396 SIGNOR-146902 POU4F2 protein Q12837 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity binding 9606 BTO:0000093 9448000 YES 2 miannu the POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect. 0.57 SIGNOR-241208 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR WBP2 protein Q969T9 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277665 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates activity binding 9606 15829516 YES irozzo Two classes of models can describe how AML1-ETO could interfere with normal AML1 activity. First, because AML1-ETO has the potential to interact with AML1 co-factors (such as CBFβ) through its RD, it could act as a dominant-negative molecule by competing with AML1 for these co-factors. Although AML1-ETO has been shown to interact with CBFβ and repress the expression of AML1-regulated genes in vitro and in cell culture, the available data do not distinguish between these two models. 0.2 SIGNOR-256100 YAP1 protein P46937 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates activity binding 9606 33358571 YES miannu The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter 0.927 SIGNOR-277685 YWHAG protein P61981 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 YES miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. 0.294 SIGNOR-252400 regorafenib chemical CHEBI:68647 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259214 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 YES Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop. 0.337 SIGNOR-248491 NXF1 protein Q9UBU9 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 28831067 NO lperfetto SUN1, a component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, functions in mammalian mRNA export through the NXF1-dependent pathway. It associates with mRNP complexes by direct interaction with NXF1. 0.7 SIGNOR-263298 PINK1 protein Q9BXM7 UNIPROT RHOT1 protein Q8IXI2 UNIPROT down-regulates quantity by destabilization phosphorylation Ser156 AKNLKNIsELFYYAQ 9606 BTO:0000007 22078885 YES miannu PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner.  0.774 SIGNOR-273723 WEE1 protein P30291 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr183 FQRLTPSyNADILLS 9606 BTO:0001033 32871104 YES miannu Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively. 0.2 SIGNOR-277529 glucose chemical CHEBI:17234 ChEBI HK2 protein P52789 UNIPROT up-regulates quantity by stabilization 9606 BTO:0004424 26323688 YES Consistently, treatment of cells with 2-deoxy-d-glucose (2DG), which completely inhibits glucose metabolism, leads to HK2 degradation and cell death in combination with C43 0.8 SIGNOR-261323 PRKACA protein P17612 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser7 sSAEGAAK 9606 11438671 YES miannu PKA preferentially phosphorylates serine 6 in human HMGN1. specific phosphorylation of the NBD of HMGN proteins serves to prevent the interaction of these proteins with their chromatin targets during mitosis. 0.307 SIGNOR-249993 SMARCD1 protein Q96GM5 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. 0.795 SIGNOR-270734 Av/b1 integrin complex SIGNOR-C175 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.705 SIGNOR-277737 AKT2 protein P31751 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 11579209 YES lperfetto We conclude that ptp1b is a novel substrate for akt and that phosphorylation of ptp1b by akt at ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism forinsulin signaling 0.372 SIGNOR-235491 RAI1 protein Q7Z5J4 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR up-regulates quantity by expression transcriptional regulation 10090 BTO:0000614 22578325 NO miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 0.397 SIGNOR-266844 ethanol chemical CHEBI:16236 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 8355 BTO:0000964 8700149 YES inferred from family member miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. 0.8 SIGNOR-270260 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.2 SIGNOR-250553 GOT1 protein P17174 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √É≈Ω√Ǭ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-268061 DLGAP4 protein Q9Y2H0 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 YES miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). 0.2 SIGNOR-264597 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 9606 BTO:0000782 15735648 YES lperfetto Thus, phosphorylation of tyr323 dependent on the tyrosine kinase lck and mediated by zap70 serves as an important mechanism for tcr activation of p38 in t cells. 0.474 SIGNOR-134329 progesterone smallmolecule CHEBI:17026 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258705 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 9927207 YES llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. 0.591 SIGNOR-64186 DISC1 protein Q9NRI5 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity binding 9606 BTO:0000938 17202468 YES miannu Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3ε. 14-3-3ε is involved in the proper localization of NUDEL and LIS1 in axons. the association with NUDEL and LIS1 supports the notion that DISC1 contributes to the neuronal development and morphology  0.581 SIGNOR-252162 P2RY6 protein Q15077 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256947 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2Z protein Q9H832 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.699 SIGNOR-271313 RNF185 protein Q96GF1 UNIPROT DVL2 protein O14641 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001957 24727453 YES miannu The E3 ligase RNF185 negatively regulates osteogenic differentiation by targeting Dvl2 for degradation. Overexpression of RNF185 decreases the exogenous and endogenous level of Dvl2, promotes the ubiquitination and degradation of Dvl2 0.467 SIGNOR-272173 SIRT7 protein Q9NRC8 UNIPROT H3C15 protein Q71DI3 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 YES lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. 0.2 SIGNOR-275887 4-oxobutanoate smallmolecule CHEBI:57706 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 19300440 YES miannu Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. 0.8 SIGNOR-266615 PFKP protein Q01813 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. 0.8 SIGNOR-266473 MBTPS1 protein Q14703 UNIPROT CREB3L1 protein Q96BA8 UNIPROT up-regulates cleavage 9606 16417584 YES miannu Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes 0.569 SIGNOR-143785 diarsenic trioxide chemical CHEBI:30621 ChEBI PIN1 protein Q13526 UNIPROT down-regulates activity chemical inhibition 9606 30093655 YES Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site 0.8 SIGNOR-259923 NF90-NF45 complex SIGNOR-C443 SIGNOR DNA-PK complex SIGNOR-C107 SIGNOR up-regulates activity binding -1 9442054 YES miannu These proteins are NF90 and NF45, which are the 90- and 45-kDa subunits of a protein known to bind specifically to the antigen receptor response element of the interleukin 2 promoter, and the alpha, beta, and gamma subunits of eukaryotic translation initiation factor eIF-2. We also show that NF90, NF45, and eIF-2 beta are substrates for DNA-PK in vitro. In addition, recombinant NF90 promotes formation of a complex between DNA-PKcs, Ku, and DNA, and antibodies to recombinant NF90 or recombinant NF45 immunoprecipitate DNA-PKcs in vitro. Together, our data suggest that NF90, in complex with NF45, interacts with DNA-PKcs and Ku on DNA and that NF90 and NF45 may be important for the function of DNA-PK. 0.405 SIGNOR-268489 SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 9606 21084559 YES miannu Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. 0.895 SIGNOR-256183 GDNF protein P39905 UNIPROT BIN1 protein O00499 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.2 SIGNOR-252178 AKT3 protein Q9Y243 UNIPROT ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 YES miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively 0.2 SIGNOR-276191 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser362 TLKNKTEsSLLAKLE -1 26119734 YES miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro 0.381 SIGNOR-276200 ABL1 protein P00519 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Tyr292 RLGHCHTyWAVSEEL 9606 BTO:0000007 30842273 YES miannu The data in this study show that IRF3 is physically associated with c-Abl in vivo and directly binds to c-Abl in vitro. IRF3 is phosphorylated by c-Abl and c-Abl-related kinase, Arg, mainly at Y292. 0.2 SIGNOR-277440 CASP8 protein Q14790 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp387 QPPSLVVdSRDAGIC 9606 BTO:0005111 32122970 YES miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. 0.315 SIGNOR-272195 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity 10116 BTO:0000452;BTO:0000099 BTO:0001279 31623154 NO P00441:p.Gly94Ala (mutation increasing interaction) We found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis 0.2 SIGNOR-262783 PKA proteinfamily SIGNOR-PF17 SIGNOR PPM1B protein O75688 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 MIQRVNGsLAVSRAL 9606 BTO:0000007 23756813 YES miannu Collectively, these data suggest that PKA destabilizes PP2Cβ upon inflammatory stimuli via phosphorylation of Ser-195 in PP2Cβ. 0.2 SIGNOR-277825 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Thr62 VVGIDLGtTNSCVAV 9606 17573779 YES lperfetto Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin 0.2 SIGNOR-156185 NEK9 protein Q8TD19 UNIPROT NEK7 protein Q8TDX7 UNIPROT up-regulates activity phosphorylation Ser195 SKTTAAHsLVGTPYY 9606 BTO:0000007 12840024 YES lperfetto Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity 0.714 SIGNOR-103030 CSNK2A1 protein P68400 UNIPROT VTN protein P04004 UNIPROT up-regulates activity phosphorylation Thr69 VTRGDVFtMPEDEYT 10090 BTO:0000944 9733784 YES llicata  Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant 0.328 SIGNOR-250970 PRKCA protein P17252 UNIPROT NCF4 protein Q15080 UNIPROT up-regulates activity phosphorylation Thr154 LRRLRPRtRKVKSVS 9606 BTO:0000776 34264265 YES miannu In murine and guinea pig neutrophils, PKCδ is required for the phosphorylation of p40phox, a subunit of the NADPH oxidase complex (Li et al., 2016; Someya et al., 1999). In particular, it mediates phosphorylation of the threonine 154 (T154) residue of p40phox, a key regulatory step in the activation of the NADPH oxidase complex in peripheral neutrophils and B cells, in both mice and humans. In conclusion, the EBV-B cells of patients with PKCδ deficiency have impaired ROS production, associated with lower levels of phosphorylation of the cytosolic NADPH oxidase subunit p40phox by PKCδ. 0.2 SIGNOR-277628 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Thr246 LPRPRLNtSDFQKLK 9606 BTO:0000007 12524439 YES gcesareni 1) PRAS40 was phosphorylated in vitro by purified Akt on the same site that was phosphorylated in insulin-treated cells; 2) activation of an inducible Akt was alone sufficient to stimulate the phosphorylation of PRAS40; and 3) cells lacking Akt1 and Akt2 exhibit a diminished ability to phosphorylate this protein 0.673 SIGNOR-248046 Skp1-Pam E3 complex SIGNOR-C537 SIGNOR PAWR protein Q96IZ0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24992930 YES miannu Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis.Fbxo45 forms an atypical ubiquitin ligase complex that contains Skp1 and the Ring-finger protein PAM (protein-associated with myc) also known as MYCBP2 (myc-binding protein 2). 0.2 SIGNOR-272224 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr153 YGPRPEEyEFLTPVE 9606 19321744 YES llicata Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes. 0.395 SIGNOR-184908 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT down-regulates dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 BTO:0000007 16461343 YES gcesareni Native ptpn22 dephosphorylated lck at its activating tyrosine residues tyr-394. 0.75 SIGNOR-144341 panobinostat chemical CHEBI:85990 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257750 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser80 PPNPEDRsPSPEPIY 9606 16420481 YES The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. 0.407 SIGNOR-143837 UBE2G2 protein P60604 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys237 VCIVQRQkIAYLGGK 9606 BTO:0001379 29892818 YES scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. 0.2 SIGNOR-267483 TFIIH complex SIGNOR-C457 SIGNOR NR5A1 protein Q13285 UNIPROT up-regulates phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 17901130 YES llicata In conclusion, our results indicate that cdk7, as part of the cak complex and tfiih, phosphorylates sf1 at s203 followed by increased transcriptional activity of sf1 0.2 SIGNOR-269355 XAV939 chemical CHEBI:62878 ChEBI CTNNB1 protein P35222 UNIPROT down-regulates 9606 19759537 NO amattioni Xav939 selectively inhibits beta-catenin-mediated transcription. Xav939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. 0.8 SIGNOR-188051 H2BC11 protein P06899 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR form complex binding -1 23324462 YES miannu In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro. 0.2 SIGNOR-263699 SMAD1 protein Q15797 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004058 12589053 NO lperfetto Overexpression of smad6, a natural antagonist for smad1, blocked ppargamma expression and adipocytic differentiation induced by bmp2 0.262 SIGNOR-236227 PRKACA protein P17612 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by stabilization phosphorylation Ser937 ETSFRKLsFTESLTS 19531803 YES lperfetto Ser940 of p105 was phosphorylated by PKA to a similar extent, whereas no phosphorylation of the same sequence occurred when Ser940 was substituted by Ala|Mechanistically, phosphorylation of p105 at Ser940 by PKA appeared to attenuate the extent of IKK-dependent phosphorylation of p105 at Ser935, which could in turn influence the rate of activation of NF-kappaB 0.508 SIGNOR-260327 Ub:E2 complex SIGNOR-C497 SIGNOR RNF180 protein Q86T96 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271028 PPARG protein P37231 UNIPROT FABP4 protein P15090 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000975 8943212 NO fspada We report that insulin and a ppargamma ligand (thiazolidinedione (tzd)) stimulate in a synergistic manner the expression of an adipocyte-specific gene (ap2) in rat adipocytes and 3t3-l1 cells 0.683 SIGNOR-45294 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT down-regulates activity binding 9606 22037168 YES gcesareni Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality 0.846 SIGNOR-235134 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity phosphorylation Ser12 GFESYGSsSYGGAGG -1 9295339 YES lperfetto We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13 0.58 SIGNOR-248981 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9606 BTO:0000567 10669763 YES lperfetto Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo. 0.551 SIGNOR-74919 TSC2 protein P49815 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 9606 12172553 NO gcesareni Here, we show that tsc1-tsc2 inhibits the p70 ribosomal protein s6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4e binding protein 1 (4e-bp1, an inhibitor of translational initiation). 0.527 SIGNOR-91395 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 phosphorylation:Ser473 RPHFPQFsYSASGTA 12167717 YES gcesareni Together, these results suggest a mechanism in which 3' phosphoinositide lipid-dependent translocation of pkb to the plasma membrane promotes serine 473 phosphorylation, which is, in turn, necessary for pdk1-mediated phosphorylation of threonine 308 and, consequentially, full pkb activation. 0.748 SIGNOR-91354 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 BTO:0000887 11114197 YES gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. 0.509 SIGNOR-85106 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 17010989 YES lperfetto Pkc-betaii sensitizes cardiac myofilaments to ca2+ by phosphorylating troponin i on threonine-144. 0.2 SIGNOR-149957 RAD50 protein Q92878 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR form complex binding 17713585 YES lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. 0.914 SIGNOR-251506 PTPRZ1 protein P23471 UNIPROT ALK protein Q9UM73 UNIPROT down-regulates dephosphorylation 9606 BTO:0000785 17681947 YES gcesareni Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation. 0.546 SIGNOR-157227 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 YES miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 0.2 SIGNOR-265818 GSK3A protein P49840 UNIPROT FCAR protein P24071 UNIPROT down-regulates activity phosphorylation Ser284 LTFARTPsVCK 10090 BTO:0001516 30766540 YES lperfetto GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state. 0.2 SIGNOR-264856 IDH complex SIGNOR-C396 SIGNOR NADH smallmolecule CHEBI:16908 ChEBI down-regulates quantity chemical modification 9606 28139779 YES miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. 0.8 SIGNOR-268114 SLC35A2 protein P78381 UNIPROT UDP-D-galactose smallmolecule CHEBI:18307 ChEBI up-regulates quantity relocalization 9606 34384782 YES miannu The CMP-sialic acid transporter SLC35A1 and UDP-galactose transporter SLC35A2 are two well-characterized nucleotide sugar transporters with distinctive substrate specificities. Nucleotide sugar transporters (NSTs) transport nucleotide sugars from the cytosol into the lumen of the endoplasmic reticulum or the Golgi apparatus, where the nucleotide sugars serve as substrates for protein glycosylation and glycosphingolipid synthesis. 0.8 SIGNOR-268465 VPS11 protein Q9H270 UNIPROT CORVET tethering complex complex SIGNOR-C550 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.832 SIGNOR-273694 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Ser314 MLATRNFsGGKSGGN 9606 1324926 YES lperfetto After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314 0.2 SIGNOR-17308 ARHGAP22 protein Q7Z5H3 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.541 SIGNOR-260478 sorafenib tosylate chemical CHEBI:50928 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 0.8 SIGNOR-259226 RFFL protein Q8WZ73 UNIPROT PRR5L protein Q6MZQ0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22609986 YES miannu RFFL is an E3 ligase for PRR5L. 0.261 SIGNOR-271495 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr283 RQGSSDIySTPEGKL -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.755 SIGNOR-273917 DSCAM protein O60469 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000938 30745319 NO miannu Nuclear DSCAM and DSCAML1 impair neurite outgrowth. this demonstrates that enhanced nuclear translocation of the DSCAM and DSCAML1 ICDs profoundly impairs neurite outgrowth and development of primary cortical neurons. 0.7 SIGNOR-264276 MAX protein P61244 UNIPROT MXI1 protein P50539 UNIPROT up-regulates activity binding 9606 7954804 YES 2 miannu The role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. 0.559 SIGNOR-240314 NRG2 protein O14511 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 YES gcesareni Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4 0.82 SIGNOR-26881 PRKCD protein Q05655 UNIPROT CARD9 protein Q9H257 UNIPROT up-regulates activity phosphorylation Thr231 CKVERKHtLKLRHAM 9606 22265677 YES miannu Here we demonstrated that protein kinase C-delta (PKCdelta) was activated upon Dectin-1-Syk signaling, mediated phosphorylation of Card9 at Thr231, and was responsible for Card9 and Bcl10 complex assembly and canonical NF-kappaB control. 0.431 SIGNOR-278383 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr112 PGQIVETyTEEDPEG -1 11382764 YES lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 0.922 SIGNOR-246480 PPP2CA protein P67775 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates dephosphorylation Ser298 ACSSAPGsGPSSPNN 9606 18045992 YES lperfetto Different signal-regulated serine/threonine kinases phosphorylate class ii histone deacetylases (hdacs) to promote nuclear export, cytosolic accumulation, and activation of gene transcriptionhere we show that hdac4 forms a complex with the pp2a holoenzyme c alpha, a alpha, b/pr55 alpha. In vitro and in vivo binding studies demonstrate that the n-terminus of hdac4 interacts with the catalytic subunit of pp2a. Hdac4 is dephosphorylated by pp2a 0.351 SIGNOR-159492 CCT4 protein P50991 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.751 SIGNOR-272866 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000938 16923168 YES The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. 0.451 SIGNOR-148970 ESR1 protein P03372 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 NO lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. 0.427 SIGNOR-268546 PTPRR protein Q15256 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001616 17360477 YES Here, we report identification of signal transducer and activator of transcription 3 (STAT3) as a substrate of PTPRT. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. 0.2 SIGNOR-248719 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 YES lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression 0.91 SIGNOR-252829 ATP(4-) smallmolecule CHEBI:30616 ChEBI P2RY11 protein Q96G91 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257559 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120248 PRKCD protein Q05655 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 YES lperfetto In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. 0.301 SIGNOR-249108 Av/b2 integrin complex SIGNOR-C176 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.629 SIGNOR-257715 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b2 integrin complex SIGNOR-C176 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.359 SIGNOR-259027 CDK1 protein P06493 UNIPROT CCNY protein Q8ND76 UNIPROT down-regulates activity phosphorylation 9606 30154440 YES miannu Therefore, CDK1 may trigger CFP1 degradation through some indirect mechanisms rather than CFP1 phosphorylation.|This result suggests that, although CDK1 triggers both phosphorylation and degradation of CFP1 protein, phosphorylation of CFP1 by CDK1 is not a prerequisite for its degradation during cell division. 0.594 SIGNOR-279012 GSK3B protein P49841 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser40 TQSSGKSsVLESLVG 9606 25192600 YES miannu The schematic for GSK3beta phosphorylating Drp1 at Ser 40 and Ser 44 was shown. 0.389 SIGNOR-278480 CYSLTR2 protein Q9NS75 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256746 CDH4 protein P55283 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 10090 18701479 YES lperfetto Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS. 0.274 SIGNOR-253103 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273096 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser752 PSADRDSsPTTNSKL 9606 22966201 YES llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. 0.322 SIGNOR-199004 RANBP2 protein P49792 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.626 SIGNOR-262088 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser972 KEFGVERsVRPTDSN -1 10487978 YES miannu Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation) 0.2 SIGNOR-250281 SRC protein P12931 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates phosphorylation Tyr284 KIFPYEEyASWKTEK 9606 19114990 YES gcesareni Tbetarii can also be phosphorylated by src, a non-rtk, on y284, which can serve as a docking site for the recruitment of grb2 and shc, thereby bridging tbetarii to mapk activation. 0.281 SIGNOR-182963 FNIP2 protein Q9P278 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 YES miannu FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. 0.263 SIGNOR-261416 Factor Va-Xa complex SIGNOR-C318 SIGNOR F2 protein P00734 UNIPROT up-regulates activity cleavage 11983337 YES lperfetto This activation is accomplished at a physiologically relevant rate by the prothrombinase complex, a macromolecular association of the serine protease factor Xa (fXa) with its cognate cofactor, factor Va (fVa), and substrate, prothrombin|Factor Va Increases the Affinity of Factor Xa for Prothrombin 0.67 SIGNOR-263546 AURKA protein O14965 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates activity phosphorylation Ser115 ISSTPKTsEEAVDPL 9606 BTO:0002181 25009111 YES miannu We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.  0.512 SIGNOR-276648 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268650 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR IL18 protein Q14116 UNIPROT up-regulates quantity 9606 BTO:0000801 10653850 NO miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement. 0.7 SIGNOR-260964 POLE protein Q07864 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR form complex binding 9606 BTO:0000567 10801849 YES lperfetto Identification and cloning of two histone fold motif-containing subunits of HeLa DNA polymerase epsilon. 0.923 SIGNOR-265520 RABGGTB protein P53611 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity lipidation 9606 BTO:0000007 18532927 YES miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional 0.655 SIGNOR-265575 ITGB1BP1 protein O14713 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.28 SIGNOR-257657 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120196 CDK1 protein P06493 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity phosphorylation 9606 12202491 YES lperfetto Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. 0.575 SIGNOR-264648 CDKL5 protein O76039 UNIPROT SOX9 protein P48436 UNIPROT down-regulates activity phosphorylation Ser199 ATEQTHIsPNAIFKA 9606 32317630 YES miannu Based on these studies, we hypothesized that Cdkl5 dependent phosphorylation at Ser 199 suppresses Sox9 function during AKI.|We also found that Cdkl5 phosphorylates Sox9 at Ser 199 residue during kidney injury in vivo. 0.2 SIGNOR-279457 PDGFRB protein P09619 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr542 SKRKGHEyTNIKYSL 10090 BTO:0000944 8041791 YES miannu Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw. 0.749 SIGNOR-250260 eribulin mesylate chemical CHEBI:70710 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 16940412 YES miannu The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. 0.8 SIGNOR-259344 CDK1 protein P06493 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser386 LRGAQAAsPAKGEPS 9606 BTO:0000567 23348582 YES phosphorylation site remapping based on mass spec table lperfetto Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. 0.503 SIGNOR-272970 PRKCA protein P17252 UNIPROT NOS1 protein P29475 UNIPROT unknown -1 1375933 YES lperfetto We now report that NOS is stoichiometrically phosphorylated by cAMP dependent protein kinase, protein kinase C, and calcium/calmodulin-dependent protein kinase, with each kinase phosphorylating a different serine site on NOS. 0.511 SIGNOR-248848 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser4 sPRRPLIL 9606 22094256 YES lperfetto We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627) 0.623 SIGNOR-177251 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 10090 18278053 NO lperfetto Activated alphaIIbbeta3 integrins bind fibrinogen, vWF and fibronectin, thus allowing firm platelet adhesion and platelet aggregation. 0.7 SIGNOR-266067 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser436 TNGSIGHsPLSLSAQ 9606 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.547 SIGNOR-204728 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates activity binding 10029 BTO:0000246 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.667 SIGNOR-258411 fumarate(2-) smallmolecule CHEBI:29806 ChEBI (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI up-regulates quantity precursor of 9606 30761759 YES miannu Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. 0.8 SIGNOR-266278 SLBP protein Q14493 UNIPROT H2AC14 protein Q99878 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265404 RPS2 protein P15880 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.907 SIGNOR-262431 ITGB1 protein P05556 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.819 SIGNOR-253182 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258541 belinostat chemical CHEBI:61076 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257745 PIM1 protein P11309 UNIPROT UHRF1 protein Q96T88 UNIPROT down-regulates quantity by destabilization phosphorylation Ser311 S-->R 9606 28394343 YES miannu Here we report that UHRF1 is a novel substrate of PIM1 kinase, which could be phosphorylated at Ser311 and therefore promoted to degradation.  0.2 SIGNOR-277349 HSPA1A protein P0DMV8 UNIPROT GSTA4 protein O15217 UNIPROT up-regulates activity relocalization phosphorylation:Thr193;Ser189 VKLSNIPtIKRFLEP;QEYTVKLsNIPTIKR 21929724 YES lperfetto Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation 0.2 SIGNOR-264799 TWIST2 protein Q8WVJ9 UNIPROT F2R protein P25116 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255502 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 NO inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. 0.2 SIGNOR-270252 MLNR protein O43193 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257222 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser907 TDASRRSsEASQSDG 9606 10693759 YES lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. 0.467 SIGNOR-75355 TYRO3 protein Q06418 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr376 DRVKSTAyLSPQELE 9606 BTO:0000007 31230815 YES done miannu TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6). 0.2 SIGNOR-274120 Ub:E2 complex SIGNOR-C497 SIGNOR BIRC2 protein Q13490 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271051 Ub:E2 complex SIGNOR-C497 SIGNOR RNF8 protein O76064 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270987 RUVBL1 protein Q9Y265 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 YES miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. 0.515 SIGNOR-270939 PRKACA protein P17612 UNIPROT MORC2 protein Q9Y6X9 UNIPROT up-regulates quantity by stabilization phosphorylation Thr582 LEALQKTtPIRSQAD 9606 BTO:0000007 32401166 YES done miannu Mechanistically, GPER1 activates PRKACA (protein kinase cAMP-activated catalytic subunit alpha), which in turn phosphorylates MORC2 at threonine 582 (T582). Phosphorylated MORC2 decreases its interaction with HSPA8 (heat shock protein family A [Hsp70] member 8) and LAMP2A (lysosomal associated membrane protein 2A), two core components of the chaperone-mediated autophagy (CMA) machinery, thus protecting MORC2 from lysosomal degradation by CMA. 0.2 SIGNOR-273781 CHUK protein O15111 UNIPROT NPM1 protein P06748 UNIPROT up-regulates activity phosphorylation Ser125 AVEEDAEsEDEEEED 9606 24290756 YES miannu S125A and a delta form lacking the aa 119-195 region completely abolished NPM phosphorylation by IKKalpha (XREF_FIG), suggesting that IKKalpha phosphorylates S125 of NPM.|We found that TNFalpha treatment induced IKKalpha phosphorylation and increased NPM hexamers, which were correlated with increased NPM phosphorylation (XREF_FIG). 0.2 SIGNOR-279405 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 9922370 YES gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus 0.879 SIGNOR-64175 CDK18 protein Q07002 UNIPROT AQP2 protein P41181 UNIPROT down-regulates quantity by destabilization phosphorylation Ser261 RQSVELHsPQSLPRG 9606 BTO:0000007 32164329 YES lperfetto CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. |We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance 0.26 SIGNOR-264562 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser50 SPTFRSDsPVPTAPT 9606 BTO:0000007 33217317 YES miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.2 SIGNOR-265951 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4A protein P27815 UNIPROT up-regulates activity phosphorylation Ser89 TRMSWPSsFHGTGTG 9534 BTO:0001538 12023945 YES done miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. 0.2 SIGNOR-273937 FYN protein P06241 UNIPROT PTPRJ protein Q12913 UNIPROT up-regulates activity phosphorylation Tyr1311 DSKVDLIyQNTTAMT 9606 BTO:0000007 22898603 YES miannu  We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin. 0.366 SIGNOR-276372 ULK1 protein O75385 UNIPROT ATG4B protein Q9Y4P1 UNIPROT down-regulates activity phosphorylation Ser316 SIAELDPsIAVGFFC 9606 28821708 YES miannu Here we find that ULK1, a protein kinase activated at the autophagosome formation site, phosphorylates human ATG4B on serine 316.|Thus ULK1 is able to inhibit LC3 processing by a direct effect on ATG4B, possibly by phosphorylation of a serine residue of ATG4B.Fig. 1ULK1 inhibits ATG4B-mediated LC3 cleavage. a Average ATG4B activity in Actin-LC3-DelN Luciferase HEK293T obtained by measuring the secreted luciferase activity 48 h after transfection with the indicated constructs (n = 3, average \u00b1 s.d.) and representative immunoblot from one experiment showing expression of the different constructs. b GST-LC3 assay to measure in vitro activity of recombinant ATG4B after incubation with active recombinant ULK1. 0.616 SIGNOR-279434 MAPK3 protein P27361 UNIPROT KLC1 protein Q07866 UNIPROT down-regulates phosphorylation Ser460 YKACKVDsPTVTTTL 9606 21385839 YES gcesareni Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro. 0.264 SIGNOR-172642 TRIM28 protein Q13263 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity binding 9606 BTO:0000007 16107876 YES 2 miannu we present evidence that MDM2 interacts with the nuclear corepressor KAP1. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. 0.597 SIGNOR-240405 ARNT protein P27540 UNIPROT AHR-ARNT complex SIGNOR-C125 SIGNOR form complex binding -1 9020169 YES 2 miannu SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix·PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. SIM1 inhibits binding of the AHR·ARNT dimer to the xenobiotic response element in vitro Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR·ARNT dimer. 0.754 SIGNOR-240814 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 YES lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. 0.789 SIGNOR-244831 PRKACA protein P17612 UNIPROT GJA5 protein P36382 UNIPROT up-regulates activity phosphorylation Ser345 HSDKRRLsKASSKAR 9606 BTO:0003477 10728420 YES miannu Gap junction channels formed of Cx40 are modulated by protein-kinase-A-mediated phosphorylation. Macroscopic conductance and permeability of Cx40 gap junctions is strongly increased by cAMP. two serine residues that can be phosphorylated by PKA, S120 and S345 0.307 SIGNOR-249982 RAF1 protein P04049 UNIPROT STK3 protein Q13188 UNIPROT down-regulates binding 9606 15618521 YES gcesareni Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2) 0.36 SIGNOR-132824 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr200 LPLLVQRtIARTIVL 452646 7774578 YES lperfetto The tgf-beta type ii receptor (t beta r-ii) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, t beta r-i, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. 0.722 SIGNOR-32744 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 21620960 YES gcesareni Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. 0.2 SIGNOR-174021 FGF13 protein Q92913 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253443 Ub:E2 complex SIGNOR-C497 SIGNOR RNF144A protein P50876 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271154 POLA1 protein P09884 UNIPROT DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 19608746 NO lperfetto Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin. 0.7 SIGNOR-261275 Hypoxia stimulus SIGNOR-ST25 SIGNOR EGLN1 protein Q9GZT9 UNIPROT down-regulates 9606 32755251 NO lperfetto Under hypoxic conditions, PHD2 activity is limited, and therefore HIF-1α protein is stabilized, leading to an increase in the transcription of erythropoietin as well as hundreds of target genes that coordinate diverse processes 0.7 SIGNOR-261995 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one chemical CHEBI:91348 ChEBI SYK protein P43405 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258295 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 YES gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase 0.27 SIGNOR-76084 TRIO protein O75962 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity binding 10116 BTO:0004102 23230270 YES miannu TrioY2622 is required for both netrin-1-induced activation of Rac1 and enhanced association with DCC. Phosphorylation of Trio at Tyr2622 participates in maintaining the level of surface DCC at the growth cone plasma membrane leading to axon outgrowth. Therefore, we propose that TrioY2622 is essential for the proper assembly and stability of the DCC/Trio signaling complex at the cell surface of growth cones in order to mediate netrin-1-induced cortical axon outgrowth. 0.605 SIGNOR-273856 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15907471 YES lperfetto Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome. 0.791 SIGNOR-137295 TLK1 protein Q9UKI8 UNIPROT NEK1 protein Q96PY6 UNIPROT up-regulates activity phosphorylation Thr141 IFLTKDGtVQLGDFG 9606 31914854 YES miannu We now show that the activating phosphorylation of Nek1-T141 by TLK1 contributes to the phosphorylation and stability of VDAC1 and thereby to mitochondrial permeability and integrity. 0.291 SIGNOR-279301 TNK2 protein Q07912 UNIPROT WWP2 protein O00308 UNIPROT up-regulates activity phosphorylation 9606 36773333 YES miannu ACK1 phosphorylates WWP2 at the 2, 3-linker and partially activates the ubiquitination ligase activity.|Activation of E3 ubiquitin ligase WWP2 by non-receptor tyrosine kinase ACK1. 0.342 SIGNOR-279302 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 21098032 YES gcesareni Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro. 0.2 SIGNOR-170004 CDK2 protein P24941 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity 0.517 SIGNOR-183655 DLG1 protein Q12959 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.543 SIGNOR-270913 Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 27487822 YES miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. 0.8 SIGNOR-266270 diallyl disulfide chemical CHEBI:4488 ChEBI hsa-miR-22-5p mirna URS0000142DC3_9606 RNAcentral up-regulates quantity by expression post transcriptional regulation 9606 BTO:0004953 23851184 YES Parnian The results indicated that DADS can suppress gastric cell proliferation and induce apoptosis through up-regulation of miR-22 and miR-200b expression. 0.4 SIGNOR-278846 FFAR1 protein O14842 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256942 TP53 protein P04637 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10029407 NO miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. 0.615 SIGNOR-255435 PIK3CA protein P42336 UNIPROT TPM1 protein P09493 UNIPROT up-regulates activity phosphorylation Ser61 EDELDKYsEALKDAQ -1 16094730 YES miannu Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization. 0.2 SIGNOR-263027 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr676 NQMQPDTtSVVKDSQ 9606 19120698 YES llicata Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity 0.2 SIGNOR-183026 KCNC3 protein Q14003 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 YES miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height 0.8 SIGNOR-265587 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 16733250 YES lperfetto Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins. 0.396 SIGNOR-146906 MMP10 protein P09238 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage His31 LDHDRAIhIQAENGP -1 7694569 YES miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. 0.324 SIGNOR-256331 PRKD2 protein Q9BZL6 UNIPROT PKD2 protein Q13563 UNIPROT up-regulates activity phosphorylation Ser801 SSLPRPMsSRSFPRS 9615 BTO:0000837 20881056 YES miannu Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. These results suggest that growth factor-stimulated, protein kinase D-mediated phosphorylation of polycystin-2 is essential for its ER channel function and links extracellular stimuli to its effects on cell growth and intracellular calcium regulation. 0.2 SIGNOR-276284 PRKACA protein P17612 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 16537363 YES lperfetto Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity 0.283 SIGNOR-145131 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-202807 Calcineurin complex SIGNOR-C155 SIGNOR NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 14722106 YES gcesareni Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes 0.828 SIGNOR-252313 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 YES SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.514 SIGNOR-248797 PRKACA protein P17612 UNIPROT SYN2 protein Q92777 UNIPROT down-regulates activity phosphorylation Ser10 NFLRRRLsDSSFIAN -1 10571231 YES miannu Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I 0.327 SIGNOR-250059 PRKACA protein P17612 UNIPROT TPPP protein O94811 UNIPROT unknown phosphorylation Ser32 DRAAKRLsLESEGAG -1 17693641 YES miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. Thus our data suggest that ERK2 or Cdk5 can perturb the interaction of TPPP with tubulin, in contrast to PKA that is ineffective in this respect. 0.2 SIGNOR-262930 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys64 RAGCCLGkAVRGAKG 9606 17098745 YES gcesareni Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells. 0.442 SIGNOR-150595 SLIT2 protein O94813 UNIPROT ROBO2 protein Q9HCK4 UNIPROT up-regulates activity binding -1 16226035 YES miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. 0.862 SIGNOR-268380 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11390662 YES gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.Maml1 functions as a transcriptional co-activator for notch signalling. 0.923 SIGNOR-86117 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser101 ASESSLSsESSESSD 9606 BTO:0000567 21807946 YES miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). 0.2 SIGNOR-276350 PSMD7 protein P51665 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 YES lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line 0.907 SIGNOR-263349 TFEB protein P19484 UNIPROT PPM1D protein O15297 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; 0.2 SIGNOR-276557 KLHL12 protein Q53G59 UNIPROT LNPK protein Q9C0E8 UNIPROT up-regulates activity binding 9606 BTO:0000007 32433973 YES miannu   Lunapark Is Ubiquitylated by the CRL3KLHL12 Ubiquitin Ligase Complex. Taken together, these results demonstrate that Lunapark is ubiquitylated by the CRL3KLHL12 ubiquitin ligase, and the CRL3KLHL12-dependent ubiquitylation of Lunapark does not lead to its proteasomal degradation. Inhibition of Lunapark Ubiquitylation Affects Lysosomal Recruitment of mTORC1 0.2 SIGNOR-272197 MAPK3 protein P27361 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser294 DPRQAQSsPPWSYDQ 9606 19801668 YES llicata In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation. 0.563 SIGNOR-188343 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR TEAD proteinfamily SIGNOR-PF22 SIGNOR up-regulates activity binding 9606 23431053 YES miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death 0.942 SIGNOR-277635 TFEB protein P19484 UNIPROT IL24 protein Q13007 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 NO lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) 0.2 SIGNOR-276797 FGF2 protein P09038 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 20974802 NO gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription 0.612 SIGNOR-168989 PPM1F protein P49593 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 31944151 YES lperfetto As a result, inactivation of Chk1 by POPX2 leads to impaired G1S checkpoint activation and cells are able to proceed from G1 to S phase despite DNA damage.|We also determined that POPX2 can dephosphorylate Chk1Ser317 and -Ser345 and is a potential regulator of Chk1 function in the cell. 0.2 SIGNOR-276987 TNF protein P01375 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252285 HES1 protein Q14469 UNIPROT NEUROG1 protein Q92886 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 NO lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 0.346 SIGNOR-265140 PRKCQ protein Q04759 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates activity phosphorylation Thr219 SAINSREtMFHKERF 9606 16252004 YES lperfetto Critical role of novel Thr-219 autophosphorylation for the cellular function of PKCtheta in T lymphocytes. 0.2 SIGNOR-249298 SETD2 protein Q9BYW2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18158893 NO gcesareni In response to hypoxia, foxo3a transcript levels accumulate in an hif1-dependent way, resulting in enhanced foxo3a activity. 0.2 SIGNOR-252986 EFNA1 protein P20827 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9576626 YES tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity 0.81 SIGNOR-56910 SNRPD1 protein P62314 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.909 SIGNOR-270684 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2C protein P28335 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257523 JARID2 protein Q92833 UNIPROT NPPA protein P01160 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0003324 15542826 NO miannu JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4. 0.2 SIGNOR-224790 ELOVL6 protein Q9H5J4 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267894 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 18796614 YES gcesareni We previously showed that nucleoside diphosphate kinase beta (ndpk-b), a mammalian histidine kinase, is required for kca3.1 channel activation in human cd4 t lymphocytes. 0.42 SIGNOR-181083 GRB2 protein P62993 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 YES scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. 0.582 SIGNOR-268449 RXRG protein P48443 UNIPROT MBP protein P02686 UNIPROT up-regulates quantity transcriptional regulation 31390799 NO SimoneGraziosi RXRγ gene silencing reduces the ability of the drugs to promote MBP expression. 0.2 SIGNOR-269266 SEC62 protein Q99442 UNIPROT Protein_translocation phenotype SIGNOR-PH176 SIGNOR up-regulates 22375059 NO lperfetto Silencing the SEC62 gene inhibits post-translational transport of small presecretory proteins into the human ER 0.7 SIGNOR-265280 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT down-regulates activity phosphorylation Ser23 YLQARKPsDCDSKEL 9606 15946941 YES Luana Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. 0.2 SIGNOR-260839 FGF2 protein P09038 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates 9606 20974802 NO gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. 0.601 SIGNOR-168995 PTK2 protein Q05397 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity phosphorylation 9606 19273616 YES miannu These results suggest that LARG is phosphorylated on tyrosine by FAK after stimulation with RGMa. 0.304 SIGNOR-279310 NUMA1 protein Q14980 UNIPROT TUBB4B protein P68371 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.403 SIGNOR-117078 NFRKB protein Q6P4R8 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.626 SIGNOR-270856 FOS protein P01100 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 YES miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. 0.2 SIGNOR-254877 PRKCD protein Q05655 UNIPROT LIMK2 protein P53671 UNIPROT down-regulates phosphorylation Ser283 EGTLRRRsLRRSNSI 9606 16820362 YES Translocation from Cytosol to Nucleus gcesareni Recently we have shown that limk2 shuttles between cytoplasm and nucleus in endothelial cells and that nuclear import is inhibited by protein kinase c-mediated phosphorylation of ser-283. 0.256 SIGNOR-147716 sapitinib chemical CHEBI:132986 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 20145185 YES AZD8931 has a unique pharmacologic profile providing equipotent EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. 0.8 SIGNOR-163727 PPP2CA protein P67775 UNIPROT EIF4E protein P06730 UNIPROT down-regulates dephosphorylation Ser209 DTATKSGsTTKNRFV 9606 20927323 YES tpavlidou A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function. 0.348 SIGNOR-168306 CDK5RAP2 protein Q96SN8 UNIPROT CEP152 protein O94986 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 YES lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. 0.754 SIGNOR-271721 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Thr409 GQGEKSAtPSRKILD 9606 15037602 YES lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. The m-phase kinase cyclin b/cdk1 phosphorylates rangap1 efficiently in vitro, and t409 phosphorylation correlates with nuclear accumulation of cyclin b1 in vivo. 0.468 SIGNOR-216789 NLGN4X protein Q8N0W4 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.767 SIGNOR-264155 H4C1 protein P62805 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 YES miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.2 SIGNOR-263722 EIF3E protein P60228 UNIPROT MCM7 protein P33993 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0002181 17310990 YES irozzo Our data show that INT6 interacts with a C-terminal domain of MCM7. Collectively, our observations suggest that INT6 restrains the increased degradation of MCM7 occurring during DNA replication by protecting its polyubiquitylated derivatives from the proteasome activity. 0.336 SIGNOR-259154 LCK protein P06239 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 BTO:0000782 8114715 YES llicata The two sites (y-536 and y-564) which are directly phosphorylated by lck in vitro are also phosphorylated in vivo in lstra cells. One of these sites (y-564) is phosphorylated in t cells in response to lck activation. 0.612 SIGNOR-36121 PRKAA1 protein Q13131 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser214 GGKERPGsKEEVDED -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.2 SIGNOR-275439 UNC5A protein Q6ZN44 UNIPROT PICK1 protein Q9NRD5 UNIPROT up-regulates activity binding 10116 BTO:0003036 16554470 YES miannu Recently, our laboratory showed that UNC5A is coimmunoprecipitated with PICK1 and PKCα. Moreover, we demonstrated that the association of PKCα with UNC5A depends on the activation of PKCα and the ability of UNC5A to bind PICK1 0.288 SIGNOR-268181 PAK4 protein O96013 UNIPROT FH protein P07954 UNIPROT down-regulates quantity phosphorylation Ser46 PNAARMAsQNSFRIE 9606 BTO:0002058 30683654 YES miannu  FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation.  0.2 SIGNOR-266315 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.765 SIGNOR-252745 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr72 IKALRTDyNASVSVP 9606 12052863 YES lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). 0.603 SIGNOR-88919 2-deoxy-alpha-D-ribose 1-phosphate smallmolecule CHEBI:11563 ChEBI 2-deoxy-D-ribose 5-phosphate smallmolecule CHEBI:16132 ChEBI up-regulates quantity precursor of 9606 17804405 YES miannu Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. 0.8 SIGNOR-267093 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR up-regulates relocalization 9606 25627476 YES lperfetto One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP.  0.2 SIGNOR-267008 PPP3CA protein Q08209 UNIPROT PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 YES In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. 0.412 SIGNOR-248693 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser951 GFHPRRSsQGATQMP 10090 BTO:0000944 11581251 YES lperfetto HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme 0.601 SIGNOR-249204 CRTC2 protein Q53ET0 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity binding 9606 26652733 YES The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting 0.912 SIGNOR-256102 HIF1A protein Q16665 UNIPROT ALAS2 protein P22557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 21207956 NO miannu Hypoxia-induced expression of erythroid-specific ALAS2 is mediated by HIF1 in erythroid cells. 0.2 SIGNOR-254421 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr518 SMDNTPHtPTPFKNA 10593981 YES llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. 0.718 SIGNOR-250740 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Thr5 tPDEKLRL 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.249 SIGNOR-275597 ACSL1 protein P33121 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI up-regulates quantity chemical modification 9606 21242590 YES miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). 0.8 SIGNOR-267877 PRKCD protein Q05655 UNIPROT EEF1A1 protein P68104 UNIPROT unknown phosphorylation Thr432 AVRDMRQtVAVGVIK 7890750 YES lperfetto PKC delta phosphorylates eEF-1 alpha at Thr-431 0.335 SIGNOR-248902 PRKCE protein Q02156 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276021 CDK5 protein Q00535 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 YES gcesareni We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5 0.358 SIGNOR-173685 26S Proteasome complex SIGNOR-C307 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity cleavage 9606 15571818 YES scontino The proteasome system is the central proteolytic system of the eukaryotic cell [1] and plays an important role in the generation of MHC-class I peptides. The enzyme complex responsible for the selectivity of intracellular protein degradation is the 26S proteasome that degrades poly-ubiquitinated substrates. 0.8 SIGNOR-267768 FNIP1 protein Q8TF40 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 YES miannu FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. 0.2 SIGNOR-261415 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 BTO:0000150 15009097 YES lperfetto Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo. 0.632 SIGNOR-217230 THRSP protein Q92748 UNIPROT MID1IP1 protein Q9NPA3 UNIPROT down-regulates activity binding 10029 BTO:0000457 20952657 YES miannu In the current study, we have determined the crystal structure of mouse S14 to 2.65-Å resolution. The structure of S14 reveals a helical protein arranged as a symmetric dimer. Cultured cell experiments indicate that S14 can form heterodimers with MIG12, suggesting a mechanism through which S14 could modulate ACC activity and subsequently rates of fatty acid synthesis via heterodimer formation with MIG12.In the current study, we have shown that regulating the levels of S14∶MIG12 heterodimers regulates the ability of MIG12 to activate ACC. Increasing S14∶MIG12 heterodimers by the overexpression of S14 resulted in decreased ACC activity and polymerization, whereas decreasing S14∶MIG12 heterodimers by knockdown of S14 increased ACC activity and polymerization. 0.511 SIGNOR-267113 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr373 ASDTDSSyCIPTAGM 10090 10978177 YES HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin 0.501 SIGNOR-251312 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 YES brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.8 SIGNOR-263813 hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral GNA12 protein Q03113 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 25965999 NO Parnian Our data indicates that Gα12 overexpressed in liver cancer mostly greatly dysregulates the expression of miR-122. 0.4 SIGNOR-279815 nociceptin smallmolecule CHEBI:80266 ChEBI OPRL1 protein P41146 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257553 AP3B2 protein Q13367 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 YES miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) 0.657 SIGNOR-268521 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr86 TYSEELCyTLINHRV -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.356 SIGNOR-273574 STK38 protein Q15208 UNIPROT RAB3IP protein Q96QF0 UNIPROT up-regulates activity phosphorylation Ser288 KGHTRNKsTSSAMSG 10090 BTO:0000142 22445341 YES miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. 0.366 SIGNOR-263036 SRC protein P12931 UNIPROT CNKSR1 protein Q969H4 UNIPROT up-regulates activity phosphorylation Tyr519 PPREEDCySETEAED 26319181 YES lperfetto We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. 0.505 SIGNOR-275918 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity precursor of 9606 16051738 YES miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. 0.8 SIGNOR-266501 PRKCB protein P05771 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 YES lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. 0.2 SIGNOR-202784 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MYB protein P10242 UNIPROT down-regulates phosphorylation 9606 8798443 YES inferred from 70% family members llicata Here we describe that human c-myb can be phosphorylated by mitogen-activated protein kinases (mapk's) at serine 532 of the carboxy (c-) terminal regulatory domain in vitro. expression of a constitutively active form of ras together with c-myb in transient transfection experiments had no effect on the transcriptional activity of c-myb, while expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. 0.2 SIGNOR-270089 BCOR protein Q6W2J9 UNIPROT HOXA5 protein P20719 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 26847029 NO irozzo Importantly, our results showed that BCOR is a repressor of HoxA cluster of genes (HoxA5, HoxA7 and HoxA9) in myeloid cells. Knock-down of HoxA5, HoxA7 and HoxA9 significantly decreased the clonogenic growth of Bcor mutant and wild type cells, demonstrating the Hox genes, as targets of BCOR, played an important role in mediating BCOR’s function in regulating myeloid cell proliferation. 0.2 SIGNOR-256012 PRKAA1 protein Q13131 UNIPROT PRKAB1 protein Q9Y478 UNIPROT up-regulates phosphorylation Ser108 SKLPLTRsHNNFVAI 9606 SIGNOR-C15 SIGNOR-C15 17728241 YES gcesareni Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by amp 0.925 SIGNOR-157553 RAP1A protein P62834 UNIPROT CAMK1 protein Q14012 UNIPROT up-regulates activity 9606 21791615 NO miannu The present study indicates that Epac1 and Rap1 are involved in activation of CaMKI for Ser47 phosphorylation in GCM1. We found here that cAMP-dependent activation of Epac1 and Rap1 but not PKA is able to activate CaMKI to mediate Ser47 (S47) phosphorylation in GCM1. 0.292 SIGNOR-262683 TP53 protein P04637 UNIPROT PERP protein Q96FX8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10733530 NO gcesareni Perp induction is linked to p53-dependent apoptosis, including in response to e2f-1-driven hyperproliferation. Furthermore, analysis of the perp promoter suggests that perp is directly activated by p53. 0.639 SIGNOR-75877 GSK3B protein P49841 UNIPROT MAP1B protein P46821 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000938 25040932 YES lperfetto GSK-3beta phosphorylates MAP1B and the adenomatous polyposis coil gene product (APC; Grimes and Jope 2001; Frame and Cohen 2001). The phosphorylation of MAP1B by GSK-3beta suppresses detyrosination of microtubules and decreases the numbers of stable microtubules 0.528 SIGNOR-264843 PKN1 protein Q16512 UNIPROT PGAM proteinfamily SIGNOR-PF78 SIGNOR down-regulates phosphorylation 9606 BTO:0000130 12189148 YES inferred from family member llicata Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. 0.324 SIGNOR-270282 CSNK2A2 protein P19784 UNIPROT EEF1B2 protein P24534 UNIPROT unknown phosphorylation Ser112 GSDDEEEsEEAKRLR -1 8547318 YES llicata EF-1 beta was highly phosphorylated by casein kinase II, with up to 1.3 mol of phosphate incorporated per mol protein. From microsequence analysis and manual Edman degradation, the majority of the phosphate was shown to be present in serine 106 in the peptide DLFGS106DDEEES112EEA. Serine 112 was also phosphorylated by casein kinase II, but to a lesser extent. 0.337 SIGNOR-250988 MRPL32 protein Q9BYC8 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.711 SIGNOR-262339 NEK6 protein Q9HC98 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000007 20595392 YES done miannu Our data also show that NEK6 interacts with STAT3, an oncogenic transcription factor, and phosphorylates STAT3 on Ser(727), which is important for transcriptional activation. These results demonstrate that NEK6 interacts with and phosphorylates STAT3, an event that could play an important role in oncogenesis. For the maximal activation of STAT3 signaling, phosphorylation of both Tyr705 and Ser727 is required. Phosphorylation of Tyr705 induces dimerization, nuclear translocation, and DNA binding of the STAT3 protein, whereas phosphorylation of Ser727 is important for transcriptional activation. 0.332 SIGNOR-273902 MAPK1 protein P28482 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser12 ESPLCPLsPLEAGDL 9606 BTO:0000599 10187842 YES lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. 0.576 SIGNOR-249433 EGFR protein P00533 UNIPROT USP8 protein P40818 UNIPROT up-regulates activity phosphorylation Tyr810 DYFNRNCyQDDINRS 9606 29472535 YES miannu EGFR activates USP8 by phosphorylating Tyr-717 and Tyr-810.|Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr 717 and Tyr 810 in RPE1 cells. 0.71 SIGNOR-279038 EGFR protein P00533 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr13 AVLADVSyLMAMEKS 9606 23904266 YES miannu Previous studies showed that EGFR activation results in association of GRK2 with the EGFR and subsequent phosphorylation of GRK2 at three tyrosine residues (Tyr 13, -86, and -92), resulting in activation of GRK2.|We propose that GRK2 activation by EGFR leads to GRK2 phosphorylation of Mst2 at these sites, which, in turn, regulates the Mst2-Nek2A-PP1\u03b3 complex ( xref ). 0.2 SIGNOR-279368 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 15486195 YES inferred from 70% family members lperfetto In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel 0.2 SIGNOR-270152 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 YES milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity 0.816 SIGNOR-201294 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding -1 3142692 YES irozzo The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun. 0.952 SIGNOR-256366 YARS1 protein P54577 UNIPROT tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI down-regulates quantity chemical modification 9606 16429158 YES miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr 0.8 SIGNOR-270517 DNMT3B protein Q9UBC3 UNIPROT IL32 protein P24001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 20889550 NO lperfetto A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-κB and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells.|Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection. 0.2 SIGNOR-254127 DLG2 protein Q15700 UNIPROT Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.501 SIGNOR-270909 ABL1 protein P00519 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 33644712 YES miannu Our study unexpectedly found that c-Abl, another kinase other than JAKs, also contributes to STAT1 Y701 phosphorylation independently (XREF_FIG).|reported that c-Abl, but not Arg, could induce neuronal loss by prompting STAT1 activation and interferon production. 0.344 SIGNOR-279491 SOX2 protein P48431 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 NO flangone Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency.  0.7 SIGNOR-242002 Endothelin-1 smallmolecule CHEBI:80240 ChEBI EDNRB protein P24530 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257483 PKN1 protein Q16512 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation 9606 17251915 YES gcesareni Rho can sensitize the ar to low levels of circulating androgens by promoting the nuclear translocation of a transcriptional co-activator, fhl2 (four and a half lim domains 2), which binds ar, and by stimulating protein kinase n (pkn), which phosphorylates ar directly. 0.585 SIGNOR-152762 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 12747827 YES lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. 0.755 SIGNOR-236694 RNA helicases DDX5/DDX17 complex SIGNOR-C34 SIGNOR NFAT5 protein O94916 UNIPROT up-regulates activity binding 9606 BTO:0000815 22266867 YES done miannu In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration.  0.353 SIGNOR-274112 CDK2 protein P24941 UNIPROT NBN protein O60934 UNIPROT up-regulates activity phosphorylation Ser432 RIPNYQLsPTKLPSI 9606 22927831 YES miannu Nbs1 is phosphorylated by Cdk2 on Ser432 in human whole-cell extracts. 0.505 SIGNOR-279500 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE11A protein Q9HCR9 UNIPROT up-regulates activity phosphorylation Ser117 GNLQRRAsQKELRKS -1 18312413 YES miannu The N-terminus has two phosphorylation sites for cyclic nucleotide monophosphate-dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP-dependent protein kinase decreased the EC50 value for cGMP from 72 to 23 μm. Effect of phosphorylations at Ser117 and Ser162. Here, serine phosphorylation by the catalytic subunit of cAK, albeit not known whether at position 117, 162 or both, increased cGMP affinity about threefold. 0.2 SIGNOR-276153 DYRK1B protein Q9Y463 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr288 VDLACTPtDVRDVDI 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 YES lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner 0.411 SIGNOR-235801 haloperidol chemical CHEBI:5613 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258521 SLBP protein Q14493 UNIPROT H3-2 protein Q5TEC6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265415 BUB1B protein O60566 UNIPROT CDC20 protein Q12834 UNIPROT up-regulates activity phosphorylation 9606 11030144 YES miannu Furthermore, BUBR1 phosphorylates p55CDC in vitro, and the phosphorylation of p55CDC by BUBR1 appears to be correlated with spindle checkpoint activation. 0.993 SIGNOR-279507 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2D protein Q13557 UNIPROT up-regulates activity chemical activation 9606 19725819 YES areggio Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels. 0.8 SIGNOR-255953 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258799 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr288 QCPVGFNtLAFPSMK 9606 BTO:0000007 12496252 YES lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation 0.767 SIGNOR-96751 AURKC protein Q9UQB9 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14583461 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. 0.2 SIGNOR-118898 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser428 IPKRLRRsLPPGLLR 9606 19261611 YES llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. 0.2 SIGNOR-184452 LRRK1 protein Q38SD2 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates activity phosphorylation Thr1430 EMFGHWAtNCNDDET 25413345 YES Phosphosite positions are derived from Figure 1 lperfetto LRRK1 phosphorylates CLIP-170 at Thr1384, located in its C-terminal zinc knuckle motif, and this promotes the association of CLIP-170 with dynein-dynactin complexes. 0.399 SIGNOR-275469 ACVR1 protein Q04771 UNIPROT VPS39 protein Q96JC1 UNIPROT up-regulates activity binding 9534 12941698 YES miannu TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling. 0.2 SIGNOR-261376 SLC25A1 protein P53007 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity relocalization 9606 29651165 YES SLC25A1, a mitochondrial carrier that promotes the flux of citrate/isocitrate across the mitochondria, in exchange for the entry of cytosolic malate 0.8 SIGNOR-267290 SDHA protein P31040 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 9606 16143825 YES miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. 0.952 SIGNOR-266271 SOX8 protein P57073 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000410 32550913 YES miannu We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance.. Our results showed that SOX8 targets FOXK1, thereby regulating its transcription, which has significant impacts on senescence, glycolysis and chemoresistance in ovarian cancer. 0.289 SIGNOR-273613 RBBP7 protein Q16576 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.834 SIGNOR-263836 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser705 TPSAMKSsPQIPHQT 9606 20236090 YES Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. 0.64 SIGNOR-248833 FADS1 protein O60427 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267907 PLAT protein P00750 UNIPROT PLG protein P00747 UNIPROT up-regulates activity binding 9606 BTO:0000131 1447176 YES lperfetto The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme 0.572 SIGNOR-263533 ATF4 protein P18848 UNIPROT SARS2 protein Q9NP81 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269425 Ub:E2 complex SIGNOR-C497 SIGNOR BMI1 protein P35226 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271050 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser211 LVGVTSSsCPADLTQ -1 29945972 YES miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. 0.2 SIGNOR-277879 Ub:E2 complex SIGNOR-C497 SIGNOR MNAT1 protein P51948 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271124 GAD2 protein Q05329 UNIPROT gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity chemical modification 9606 32041144 YES miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. 0.8 SIGNOR-267555 EGFR protein P00533 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr218 GDGSDHPyYNSIPSK -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.617 SIGNOR-273910 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18593906 YES gcesareni We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro. 0.2 SIGNOR-259426 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr798 VSRNAAEyLLSSGIN 9606 16912036 YES Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. 0.2 SIGNOR-260812 Immunoglobulin lambda-1 light chain protein P0DOX8 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323265 YES scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. 0.2 SIGNOR-268190 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr860 DSLLVFDyEGSGSTA 9606 BTO:0000848 16371504 YES lperfetto Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated. 0.398 SIGNOR-143238 CSNK1G2 protein P78368 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser418 LTQMGSPsIRCSSVS 9606 18794808 YES lpetrilli Cki?2 Directly phosphorylates smad3 at ser418, leading to the increased ubiquitination and proteasomal degradation of activated smad3 following tgf-? Treatment. 0.337 SIGNOR-181069 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Ser371 VRRVPGSsGHLHKTE 9606 16083423 YES gcesareni Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1) 0.447 SIGNOR-253553 NFIB protein O00712 UNIPROT RBFOX3 protein A6NFN3 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268912 CSNK2A2 protein P19784 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 YES lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. 0.307 SIGNOR-275741 ITCH protein Q96J02 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates ubiquitination 9606 15946939 YES gcesareni We identified atrophin 1-interacting protein 4 (aip4) as an e3 ubiquitin ligase that specifically targets smad7 for ubiquitin-dependent degradation without affecting the turnover of the activated tbetari. Surprisingly, we found that despite the ability to degrade smad7, aip4 can inhibit tgf-beta signaling, presumably by enhancing the association of smad7 with the activated tbetari. 0.508 SIGNOR-137951 NEK9 protein Q8TD19 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates phosphorylation Ser944 GQQVGMHsKGTQTAK 9606 21454704 YES lperfetto We find that the interaction of lc8 with nek9 depends on a (k/r)xtqt motif adjacent to the nek9 c-terminal coiled coil motif, results in nek9 multimerization, and increases the rate of nek9 autoactivation. Lc8 binding to nek9 is regulated by nek9 activity through the autophosphorylation of ser(944), a residue immediately n-terminal to the (k/r)xtqt motif. 0.2 SIGNOR-173026 AKT1 protein P31749 UNIPROT PARK7 protein Q99497 UNIPROT up-regulates activity phosphorylation Thr125 GFGSKVTtHPLAKDK 32858971 YES lperfetto Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. |Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation. 0.466 SIGNOR-275582 MAPK8 protein P45983 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 19153595 YES lperfetto In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant 0.534 SIGNOR-183489 KIF4A protein O95239 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 9606 15297875 NO miannu These results suggest that KIF4 and its binding partner PRC1 play essential roles in the organization of central spindles and midzone formation. KIF4 deficiency leads to mislocalization of PRC1, MKLP1, CENP-E and chromosomal passenger proteins 0.7 SIGNOR-265986 CDK7 protein P50613 UNIPROT CDK12 protein Q9NYV4 UNIPROT up-regulates activity phosphorylation Thr893 SEESRPYtNKVITLW 24662513 YES lperfetto Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b). 0.509 SIGNOR-275509 PPP3CA protein Q08209 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 YES Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 0.47 SIGNOR-248694 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2604 HLQQGSEsPMMIGEL 9606 BTO:0000018 27991932 YES lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. 0.258 SIGNOR-275609 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 12466266 YES gcesareni Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity;ser118 is phosphorylated by mitogen-activated protein kinase (mapk) in vitro and in cells treated with epidermal growth factor (egf) and insulin-like growth factor (igf) in vivo. 0.67 SIGNOR-96072 EPHA3 protein P29320 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Tyr552 DHVLPIDyYFPPQKT 9606 20570899 YES miannu These data suggest that Etk may be able to phosphorylate AR at Y534 and Y551/552, and the interaction between the Etk SH2 domain and phosphorylated ARY551/552 may promote their association.|This is supported by our observations that the association between Etk and AR is increased after castration and Etk induces tyrosine phosphorylation of AR, leading an increase in AR stability and transcriptional activity under androgen depleted conditions. 0.273 SIGNOR-279371 Histone H3 proteinfamily SIGNOR-PF69 SIGNOR Nucleosome complex SIGNOR-C371 SIGNOR form complex binding -1 21812398 YES lperfetto The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.2 SIGNOR-265308 APC-c complex SIGNOR-C150 SIGNOR APC-c complex SIGNOR-C150 SIGNOR down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22086178 YES miannu Cdc20 is a co-activator of the anaphase-promoting complex/cyclosome (APC/C complex), which recruits substrates at particular phases of the cell cycle and mediates their degradation. Overexpression of Cdc20 resulted in decreased levels of both endogenous Sp100 protein and overexpressed Sp100 mRNA in HEK 293 cells. Our results suggested that sp100 is a novel substrate of Cdc20 and it is degraded by the ubiquitination pathway. The intact D-box of Sp100 was necessary for this process. 0.885 SIGNOR-272725 GPR161 protein Q8N6U8 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 23332756 YES Shh signaling directs Gpr161 to be internalized from cilia, preventing its activity. 0.375 SIGNOR-259936 MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 YES lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. 0.929 SIGNOR-244417 PTPRM protein P28827 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 31900385 YES lperfetto Thus PTPRM suppresses STAT3 signaling in DDIAS-knockdown cells, suggesting that DDIAS promotes the IL-6\u2013mediated STAT3 signaling in malignant cancer cells by inhibiting the PTPRM function.|We report that PTPRM is a novel STAT3 tyrosine phosphatase and that it negatively regulates STAT3 activation by dephosphorylating Y705 of STAT3 in the presence of IL-6. 0.262 SIGNOR-277016 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser96 TSLSDEDsGKGSQPP 9606 20305697 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-164637 HIF1A protein Q16665 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003123 12067980 NO miannu Examination of the MDR1 gene identified a binding site for hypoxia inducible factor-1 (HIF-1), and inhibition of HIF-1 expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible MDR1 expression and a nearly complete loss of basal MDR1 expression. 0.302 SIGNOR-254420 RNF126 protein Q9BV68 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23026136 YES miannu E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation.We showed that RNF126 interacts with p21 and RNF126 overexpression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner. 0.331 SIGNOR-272033 TAB1 protein Q15750 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. 0.827 SIGNOR-205440 GSK3B protein P49841 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr1938 HREKKEStPSTASLP 10116 BTO:0000938 29642012 YES lperfetto In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity. 0.2 SIGNOR-275763 PRKCQ protein Q04759 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 26431586 NO lperfetto It is known that the teta isoform of the PKC family promotes the fusion of myoblasts and regulates the expression of caveolin-3 and beta1D integrin [15]. Of note, it has also been demonstrated that PKCepsilon expression increases during insulin-induced myogenic differentiation of the C2C12 cells. 0.2 SIGNOR-241525 Met-tRNA(Met) chemical CHEBI:16635 ChEBI Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 YES lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. 0.8 SIGNOR-269117 PCBD1 protein P61457 UNIPROT FXYD2 protein P54710 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000482 24204001 NO miannu Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT. 0.347 SIGNOR-254908 MRPL49 protein Q13405 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.701 SIGNOR-262347 CSNK1A1 protein P48729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates activity binding 9606 19293931 YES lperfetto In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] 0.67 SIGNOR-227964 BTC protein P35070 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 YES gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4 0.722 SIGNOR-147823 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr107 GNSAEEYyENVPCKA -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.356 SIGNOR-273571 CTNNB1 protein P35222 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates activity binding 9606 23151663 YES gcesareni Upon wnt activation, cytoplasmic beta-catenin is stabilized and enters the nucleus, where it associates with transcription factors, notably tcf (t cell factor) and lef (lymphoid enhancer-binding factor), to regulate the transcription of target genes. Thus beta-catenin regulates gene expression by direct interaction with transcription factors such as lef-1, providing a molecular mechanism for the transmission of signals, from cell-adhesion components or wnt protein to the nucleus. 0.917 SIGNOR-199378 Ub:E2 complex SIGNOR-C497 SIGNOR RNF217 protein Q8TC41 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270951 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MYOG protein P15173 UNIPROT down-regulates binding 9606 21902831 YES lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. 0.338 SIGNOR-216972 PRKCB protein P05771 UNIPROT protein Q5T7P8 UNIPROT up-regulates activity phosphorylation Thr418 RLKKKKTtIKKNTLN 9606 BTO:0001277 16111671 YES miannu We found by site-directed mutagenesis that Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain--a key region for the function of synaptotagmins--are the PKC target that regulates its inhibitory effect on acrosomal exocytosis. Similarly, we showed that Thr284 in the polybasic region of C2A (KCKLQTR) is the target for PKC-mediated phosphorylation in this domain. 0.2 SIGNOR-273566 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by stabilization 9606 14623893 NO miannu Uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane 0.38 SIGNOR-251994 GTF2I protein P78347 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity binding 9606 21282467 YES lperfetto TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription 0.49 SIGNOR-268538 MLL/SET subcomplex complex SIGNOR-C87 SIGNOR MLL2 complex complex SIGNOR-C88 SIGNOR form complex binding 9606 24680668 YES miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. 0.2 SIGNOR-204822 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 YES Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.422 SIGNOR-248306 GGCX protein P38435 UNIPROT Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI down-regulates quantity chemical modification 9606 31226734 YES lperfetto GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. 0.8 SIGNOR-265908 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser166 LASFKMWsKLNNEEH -1 18408713 YES miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) 0.2 SIGNOR-276159 PPP2CA protein P67775 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates dephosphorylation 9606 23431053 YES inferred from 70% of family members gcesareni Rassf1a apparently protects mst1/2 against inactivation by pp2a, the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively. 0.742 SIGNOR-269940 F2RL2 protein O00254 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257234 DYDC1 protein Q8WWB3 UNIPROT SH3GL3 protein Q99963 UNIPROT up-regulates activity binding 10029 BTO:0000246 19545932 YES miannu DYDC1 and SH3P13 interact in vitro and in vivo. We recently demonstrated that SH3P13, a BAR domain-containing protein, assists in regulatingclathrin-coated vesicle traffic that is crucial for acrosome biogenesis during spermatogenesis 0.308 SIGNOR-263882 TLR9 protein Q9NR96 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 YES miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.679 SIGNOR-266742 PRKCA protein P17252 UNIPROT DGKZ protein Q13574 UNIPROT unknown phosphorylation Ser265 SKKKKRAsFKRKSSK 9716136 YES lperfetto Two isoforms of protein kinase C, but not others, regulate the localization of DGK-zeta. |The PSD in MARCKS is phosphorylated by PKC, which suggested that DGK-zeta may also be a substrate for PKC, and that this couldregulate its intracellular location. 0.504 SIGNOR-249010 USF1 protein P22415 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 9677331 NO inferred from family member miannu Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element 0.289 SIGNOR-270263 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR CDCA5 protein Q96FF9 UNIPROT up-regulates quantity by expression transcriptional regulation 30224758 NO lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. 0.2 SIGNOR-276577 SMURF proteinfamily SIGNOR-PF29 SIGNOR TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 17317136 YES lperfetto Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation 0.2 SIGNOR-253264 KIF1A protein Q12756 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 10116 30021165 NO miannu To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines 0.7 SIGNOR-266893 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 10998357 YES gcesareni We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain. 0.604 SIGNOR-82150 BAD protein Q92934 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 YES gcesareni Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2. 0.539 SIGNOR-133805 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr492 ALGADDSyYTARSAG 9606 BTO:0000782 7642520 YES lperfetto When expressed in COS cells, Y493F-mutated ZAP-70 demonstrated normal basal kinase activity, but, unlike wild type ZAP-70, could not be activated by tyrosine phosphorylation induced by incubation with pervanadate or by co-expression of constitutively activated Lck 0.618 SIGNOR-30429 CSNK2A2 protein P19784 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser285 MEVEDNRsQVETDDL 9615 BTO:0000837 11742978 YES llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4‐Cter proteins in which only one out of the three C‐terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. 0.338 SIGNOR-250975 RBBP7 protein Q16576 UNIPROT DNMT1 protein P26358 UNIPROT down-regulates activity binding -1 28143904 YES lperfetto AMPK inhibited DNMT1 through phosphorylation of Ser730 in DNMT1 and Ser314 in RBBP7|association with RBBP7 could inhibit DNMT1 0.57 SIGNOR-264785 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Thr348 GNRSRSRtLSQSSES 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 YES llicata Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344 0.395 SIGNOR-129680 GPI protein P06744 UNIPROT AMFR protein Q9UKV5 UNIPROT up-regulates binding 9606 12527360 YES gcesareni Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r) 0.531 SIGNOR-97270 MITF protein O75030 UNIPROT OCA2 protein Q04671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 22234890 NO miannu the SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species.In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression. 0.354 SIGNOR-254556 IQSEC2 protein Q5JU85 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates quantity relocalization 9606 BTO:0000142 27009485 YES miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. 0.2 SIGNOR-264916 INS protein P01308 UNIPROT CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 NO fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.435 SIGNOR-250570 INSR protein P06213 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates activity phosphorylation Tyr398 ARVKEEGyELPYNPA 10029 BTO:0000246 11551902 YES Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway. 0.561 SIGNOR-251308 ID3 protein Q02535 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR down-regulates activity binding 10090 9242638 YES 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.451 SIGNOR-241137 CDK1 protein P06493 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10656688 YES llicata Hpttg is phosphorylated by cdc2 at ser165 these results suggest that hpttg is induced by, and may have a role in, regulatory pathways involved in the control of cell proliferation. 0.599 SIGNOR-74619 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000938 BTO:0000142 SIGNOR-C110 19303846 YES gcesareni DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. 0.86 SIGNOR-184781 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 YES gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. 0.825 SIGNOR-176370 USP7 protein Q93009 UNIPROT RPS27A protein P62979 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.653 SIGNOR-270824 CDK1 protein P06493 UNIPROT EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1038 STSATQSsPAPGQSK 9606 BTO:0000551 24530506 YES miannu In this study, we found that p300 was highly phosphorylated and its level was decreased during mitosis and tumorigenesis. In vitro and in vivo experiments aimed showed that cyclin-dependent kinase 1 (CDK1) and ERK1/2 phosphorylated p300 on Ser1038 and Ser2039. Mutations of Ser1038 and Ser2039 increased p300 protein stability and levels.  0.404 SIGNOR-276457 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 11904305 YES gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1. 0.643 SIGNOR-116162 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT up-regulates activity phosphorylation Ser64 SNLGHPEsPPRKRLK 9606 BTO:0000567 20663873 YES miannu We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. 0.341 SIGNOR-259818 CRK protein P46108 UNIPROT MAP4K5 protein Q9Y4K4 UNIPROT up-regulates activity binding -1 9788432 YES lperfetto Two novel candidates for signalling partners of Crk family adapter proteins, the hematopoietic progenitor kinase 1 (HPK1) and the kinase homologous to SPS1/STE20 (KHS), were found to bind with great selectivity to the first SH3 domains of c-Crk and CRKL.|These results make it likely that HPK1 and KHS participate in the signal transduction of Crk family adapter proteins in certain cell types. 0.364 SIGNOR-262830 SEC61 complex complex SIGNOR-C368 SIGNOR SEC63 protein Q9UGP8 UNIPROT up-regulates activity binding 33925740 YES lperfetto This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game 0.891 SIGNOR-265274 Ub:E2 complex SIGNOR-C497 SIGNOR SMURF1 protein Q9HCE7 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271290 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257975 TNFSF13 protein O75888 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 10956646 YES gcesareni Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys. 0.709 SIGNOR-81308 beta-alanine smallmolecule CHEBI:16958 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9009272 YES miannu For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system. 0.8 SIGNOR-258581 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.718 SIGNOR-219345 DOT1L protein Q8TEK3 UNIPROT HECTD4 protein Q9Y4D8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 YES miannu Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly. 0.2 SIGNOR-267150 HBB protein P68871 UNIPROT APOB protein P04114 UNIPROT up-regulates quantity by stabilization 9606 8611031 NO Regulation of binding miannu Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Crosslinked apo B was shown to resist lysosomal degradation, thereby causing accumulation of oxidized LDL in macrophages 0.275 SIGNOR-251754 CEBPA protein P49715 UNIPROT GFI1 protein Q99684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20924107 NO irozzo We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1. 0.375 SIGNOR-256068 G6PC1 protein P35575 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266564 PRKCA protein P17252 UNIPROT OCLN protein Q16625 UNIPROT up-regulates activity phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 11502742 YES lperfetto Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. 0.364 SIGNOR-249105 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg41 TNATLDPrSFLLRNP -1 10978167 YES lperfetto Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site. 0.624 SIGNOR-263571 GATA3 protein P23771 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 NO fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. 0.7 SIGNOR-78830 RNF25 protein Q96BH1 UNIPROT NKD2 protein Q969F2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18757723 YES miannu Here, we show that Naked2 is a short-lived protein with a half-life of 60 min caused by its rapid ubiquitin-mediated proteasomal degradation. Overexpression of TGF-alpha stabilizes Naked2 protein in an EGF receptor (EGFR)-independent manner; a physical interaction between the cytoplasmic tail of TGF-alpha and Naked2 is necessary and sufficient for this protection. We have identified a RING finger protein, AO7/RNF25, as a ubiquitin ligase for Naked2, and we have shown that overexpression of TGF-alpha reduces binding of AO7 to Naked2. 0.451 SIGNOR-271738 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr696 ARQSRRStQGVTLTD -1 12030846 YES miannu MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition 0.583 SIGNOR-262886 DAPK1 protein P53355 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity phosphorylation Ser8 MTTEQRRsLQAFQDY 9606 30985869 YES miannu DAPK1 also phosphorylates the N-terminal serine at position 8 (S8) of RIG-I, which is also reported to undergo phosphorylation by PKC-\u03b1/\u03b2 to suppress TRIM25-mediated RIG-I ubiquitination, thereby negatively regulating RIG-I activity (84). 0.33 SIGNOR-279519 CHD3 protein Q12873 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.809 SIGNOR-263843 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Thr105 LQTFGHNtMDAVPKI 9606 BTO:0000007 21321328 YES miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). 0.578 SIGNOR-276306 WT1 protein P19544 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9867871 YES miannu The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments. 0.265 SIGNOR-253898 ELOVL1 protein Q9BW60 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267889 PRKACA protein P17612 UNIPROT PARP1 protein P09874 UNIPROT up-regulates activity phosphorylation Ser782 YSLLRGGsDDSSKDP 9606 BTO:0001412 25069723 YES miannu  In the presence of cAMP, recombinant PKA directly phosphorylated recombinant PARP1 on serines 465 (in the automodification domain) and 782 and 785 (both in the catalytic domain).  0.2 SIGNOR-276652 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT unknown phosphorylation Ser83 EEGTFRSsIRRLSTR 9606 21220422 YES llicata We conclude that phosphorylation of plm increases its oligomerization into tetramers, decreases its binding to nka, and alters the structures of both the tetramer and nka regulatory complex. 0.449 SIGNOR-171184 MAPKAPK2 protein P49137 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser522 DTSYINTsLIQDYRH 9606 BTO:0001253 23202365 YES llicata T he mitogen-activated protein kinase (mapk)-activated protein kinase-2 is a proinflammatory kinase and phosphorylates pias1 at the ser522 residue. Activation of mapk-activated protein kinase-2 enhances p53-sumoylation, but a pias1 phosphorylation mutant, pias1-s522a, abolished this p53-sumoylation, suggesting a critical role for pias1-s522 phosphorylation in its sumo ligase activity. 0.2 SIGNOR-199944 PRKCA protein P17252 UNIPROT ICOSLG protein O75144 UNIPROT up-regulates activity phosphorylation Ser285 RDRCLQHsYAGAWAV 9606 BTO:0000567 24837102 YES done miannu PKCα and PKCβ are required for phosphorylation of ICOSL and ICOSL-mediated cytokine induction. Therefore, S285 is required for PKC substrate (serine) phosphorylation of ICOSL, and each of the upstream arginines is similarly required for this phosphorylation. 0.2 SIGNOR-273798 MBTPS1 protein Q14703 UNIPROT CREB3L2 protein Q70SY1 UNIPROT up-regulates cleavage 9606 BTO:0000938 BTO:0000142 17178827 YES miannu Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei 0.559 SIGNOR-151309 CDK1 protein P06493 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates activity phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 BTO:0000567 21642957 YES done miannu We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1. 0.481 SIGNOR-273889 NFE2L2 protein Q16236 UNIPROT SLC40A1 protein Q9NP59 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. SLC40A1 is a target gene of NFE2L2, with a putative ARE identified approximately -7 kb upstream of the SLC40A1 core promoter. 0.257 SIGNOR-279863 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10090 BTO:0000944 11579209 YES lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. 0.788 SIGNOR-235503 JNJ-28312141 free base chemical CID:11676971 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259748 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFS2 protein O75306 UNIPROT up-regulates activity phosphorylation Ser364 KVDDAKVsPPKRAEM 24746669 YES lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation 0.2 SIGNOR-275600 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 BTO:0000007 9890973 YES phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif gcesareni Here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway. 0.636 SIGNOR-63976 EGR1 protein P18146 UNIPROT COL11A1 protein P12107 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 NO Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) 0.2 SIGNOR-251919 FBXO22 protein Q8NEZ5 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0003031 26868148 YES methylated tp53 lperfetto We demonstrate here that SCFFbxo22-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCFFbxo22 ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. |SCFFbxo22 forms a ternary complex with p53 and KDM4A that targets methylated p53 for degradation. 0.338 SIGNOR-273448 CSNK2A1 protein P68400 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates activity phosphorylation Ser324 PFRPQIRsELDVGNF 9606 BTO:0002181 19933278 YES miannu Here we report that the CK2 protein kinase, which contributes to NF-kappaB activation following UV radiation in a p38-dependent manner, physically interacts with MSK2 but not MSK1 and that CK2 inhibition specifically impairs UV-induced MSK2 kinase activation. A putative site of CK2 phosphorylation was mapped to MSK2 residue Ser(324) and when substituted to alanine (S324A) also compromised MSK2 activity.Serine 324 is required for UV-induced MSK2 activation and for autophosphorylation at MSK2-Ser196. 0.281 SIGNOR-276268 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT down-regulates activity dephosphorylation 9606 12857726 YES Using a pharmacological inhibitor, we provide evidence that PTP1B activation and LAT dephosphorylation processes were required for irreversible platelet aggregation.|In collagen-stimulated platelets, the signaling complexes recruited by tyrosine-phosphorylated LAT are essential for PLCgamma2 activation 0.503 SIGNOR-248403 PTPN1 protein P18031 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates dephosphorylation 9606 11350745 YES gcesareni Dephosphorylation of tyrosine residues by ptp1b, a protein tyrosine phosphatase, reduced the enhanced pkcdelta activity. 0.2 SIGNOR-107754 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 12093740 YES lperfetto Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability 0.368 SIGNOR-90274 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 9155018 YES inferred from 70% family members lperfetto Mnk1 was phosphorylated and activated in vitro by erk1 and p38 map kinasespreliminary results showed that thr344 at least was one of the major sites phosphorylated by erk1 0.2 SIGNOR-270022 GPT2 protein Q8TD30 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9606 11863375 YES Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2 0.8 SIGNOR-266925 MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 19920149 YES lperfetto Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7 0.598 SIGNOR-161763 BRMS1 protein Q9HCU9 UNIPROT EP300 protein Q09472 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23269275 YES miannu BRMS1 suppresses lung cancer metastases through an E3 ligase function on histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation. 0.364 SIGNOR-266408 ARHGEF26 protein Q96DR7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.584 SIGNOR-260545 YWHAZ protein P63104 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 14701738 YES miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase 0.303 SIGNOR-261715 ZNF804A protein Q7Z570 UNIPROT PIK3AP1 protein Q6ZUJ8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 YES miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). 0.2 SIGNOR-269463 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1221 SPAFDNLyYWDQDPP 9606 BTO:0000149 1706616 YES gcesareni However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2. 0.2 SIGNOR-21199 ELF3 protein P78545 UNIPROT KRT4 protein P19013 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 10773884 NO Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter. 0.285 SIGNOR-254291 FCGR1A protein P12314 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 24445665 NO lperfetto Although crosslinking of activating FcgammaRs on monocytes and macrophages induces the production of several pro-inflammatory cytokines and chemokines, immune complex-mediated signalling via activating FcgammaRs together with Toll-like receptor (TLR) triggering induces a specific M2 activation state in macrophages macrophages in this state were termed M2b or regulatory macrophages. 0.7 SIGNOR-249524 NF1 protein P21359 UNIPROT ADCY3 protein O60266 UNIPROT up-regulates 9606 24431436 NO miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation 0.265 SIGNOR-204034 UBE3A protein Q05086 UNIPROT ALDH1A2 protein O94788 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 29076503 YES lperfetto Hyperactivity of E3 ubiquitin (Ub) ligase UBE3A, stemming from 15q11-q13 copy number variations, accounts for 1%-3% of ASD cases worldwide, but the underlying mechanisms remain incompletely characterized. Here we report that the functionality of ALDH1A2, the rate-limiting enzyme of retinoic acid (RA) synthesis, is negatively regulated by UBE3A in a ubiquitylation-dependent manner. 0.2 SIGNOR-265135 PTPRT protein O14522 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0001109;BTO:0000182 17360477 YES brain lperfetto Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. 0.517 SIGNOR-263981 Caspase 3 complex complex SIGNOR-C221 SIGNOR KDM4C protein Q9H3R0 UNIPROT down-regulates activity cleavage 9606 29207681 YES miannu JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels. 0.2 SIGNOR-263871 RUNX2 protein Q13950 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 NO gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast 0.44 SIGNOR-107169 CDC20 protein Q12834 UNIPROT PHF8 protein Q9UPP1 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23979597 YES miannu  We showed that PHF8 interacts with the CDC20-containing APC (APC(cdc20)) primarily during mitosis. we demonstrate that mutations of the LXPKXLF motif abrogate polyubiquitylation of PHF8 by the APC. APC substrates are typically cell cycle regulators, and consistent with this, the loss of PHF8 leads to prolonged G2 phase and defective mitosis. 0.339 SIGNOR-272879 LIMS2 protein Q7Z4I7 UNIPROT IPP complex complex SIGNOR-C380 SIGNOR form complex binding 16493410 YES lperfetto Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton. 0.662 SIGNOR-265764 SPI1 protein P17947 UNIPROT miR-34 mirna URS000033F823_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 10090 21986534 NO We revealed that TNFα treatment results in the up-regulation of miR-155 through the NFκB pathway in 3T3-L1 cells. 0.4 SIGNOR-255935 LAT protein O43561 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 11368773 YES lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. 0.41 SIGNOR-252734 SPOP protein O43791 UNIPROT BRMS1 protein Q9HCU9 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22085717 YES Gianni Intriguingly, BRMS1 turns out to be a potent substrate that is ubiquitinated by the Cul3-SPOP complex. Knockdown of SPOP increases the level of BRMS1 protein and represses the expression of BRMS1 repressive target genes such as OPN and uPA in breast cancer cells. 0.403 SIGNOR-268857 CDK1 protein P06493 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C17 7588608 YES lperfetto Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf 0.2 SIGNOR-29501 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Thr767 ESFKRLVtPRKKSKS 9606 BTO:0000007 23063527 YES lperfetto Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis. 0.285 SIGNOR-271840 CDK1 protein P06493 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 BTO:0000567 12435275 YES gcesareni Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase. 0.508 SIGNOR-95574 SIRT5 protein Q9NXA8 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31608237 NO Monia In SIRT5 silenced Mero-14 cells, beclin-1 protein levels were downregulated upon rotenone and resveratrol treatment. In summary, in most cases, where significant effects were detected, SIRT1, SIRT3, and SIRT5 had positive effects on beclin1 and LC3II/LC3I ratio 0.316 SIGNOR-261206 PRKG1 protein Q13976 UNIPROT PPP1R17 protein O96001 UNIPROT up-regulates phosphorylation Thr68 KKPRRKDtPALHIPP 9606 BTO:0001011 10051666 YES miannu Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1. 0.655 SIGNOR-263148 FZD8 protein Q9H461 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 BTO:0000971 21078818 YES amattioni Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate Wnt–Beta-catenin signaling. 0.727 SIGNOR-169635 G6P proteinfamily SIGNOR-PF81 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI up-regulates quantity chemical modification 9606 12093795 YES miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis 0.8 SIGNOR-266567 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser527 RFRKRTHsAGTSPTI -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251296 CALM2 protein P0DP24 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 11807557 YES miannu Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. 0.451 SIGNOR-266330 17beta-estradiol smallmolecule CHEBI:16469 ChEBI Corticotropin protein P01189-PRO_0000024969 UNIPROT up-regulates 24631756 NO lperfetto ACTH and corticosterone responses to the same acute stress stimulus are higher in the pro-estrus phase of the cycle, when the serum concentrations of estrogen are the highest |Moreover, Kirschbaum et al. conducted a double blind study of 32 men, showing that 100 mcg of estradiol/day for two days was sufficient to produce statistically significant increases in ACTH 0.8 SIGNOR-268726 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Thr7 tSAARRSY -1 2155236 YES miannu GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments. 0.283 SIGNOR-249712 FUS protein P35637 UNIPROT DDX3X protein O00571 UNIPROT down-regulates activity relocalization 9606 27460707 YES P35637:p.Pro525Leu (mutation causing interaction) We found that ALS mutants of FUS co-localized with Caprin-1, DDX3X, and DHX9 in cytoplasmic inclusions that could lead to the mis-regulation of their respective pathways, providing further clues to the mechanism of ALS pathogenesis.|FUS interacting proteins were sequestered into the cytoplasmic mutant FUS inclusions that could lead to their mis-regulation or loss of function, contributing to ALS pathogenesis. | We also demonstrated the co-localization of DHX9, DDX3X and Caprin-1 with cytoplasmic EGFP-P525L mutant FUS inclusions in primary cortical neurons 0.256 SIGNOR-262811 UHMK1 protein Q8TAS1 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Ser299 GRDSRSGsPMARR 9606 10880969 YES lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1. 0.2 SIGNOR-78895 MTOR protein P42345 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates activity phosphorylation Ser52 KRVELPDsPRSTFLL 23524951 YES lperfetto We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.|mTOR phosphorylates AMBRA1 at Ser 52, inhibiting its role in ULK1 modification 0.472 SIGNOR-272986 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization ubiquitination Lys349 TMKQICKkVYENYPT 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). 0.3 SIGNOR-272834 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.272 SIGNOR-276092 SP1 protein P08047 UNIPROT UGT1A4 protein P22310 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 19546240 NO miannu our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy. 0.2 SIGNOR-254076 TBXA2R protein P21731 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.653 SIGNOR-256887 LPAR5 protein Q9H1C0 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257113 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT unknown phosphorylation Tyr488 DVYDDGKyVYVVTEL 9606 BTO:0000007 18156174 YES llicata The results showed that tyr-488 is a major site of src but mutations at tyr-529 or tyr-707 did not significantly decrease src-dependent tyrosine phosphorylation of rsk2 (fig. 4c). However, we have previously characterized the tyr-488 site that is also phosphorylated by fgfr3 (14), and substitution of tyr-488 did not affect rsk2 activation. 0.356 SIGNOR-160056 MAPKAPK3 protein Q16644 UNIPROT EEF2K protein O00418 UNIPROT unknown phosphorylation Ser377 PPLLRPLsENSGDEN -1 12171600 YES miannu Identification of Ser-377 as the site on eEF2 kinase phosphorylated in vitro by MAPKAP-K2, MAPKAP-K3 and MAPKAP-K5. Maximal phosphorylation of eEF2 kinase by MAPKAP-K2 (Figure 5) or MAPKAP-K5 (results not shown) had no effect on its activity. 0.324 SIGNOR-249709 RPS6KB2 protein Q9UBS0 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates activity phosphorylation Ser6 sPKEPEQL 9606 25324306 YES miannu Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export. 0.417 SIGNOR-279569 CSNK2A1 protein P68400 UNIPROT CAST protein P20810 UNIPROT up-regulates activity phosphorylation Ser655 QDPIDALsGDLDSCP 9606 BTO:0002036 29581866 YES miannu  We also showed that casein kinase 2, a pro-survival kinase overexpressed in many cancer types, phosphorylated calpastatin at Ser-633. Our results indicate that calpastatin phosphorylation promotes radiation resistance in GBM cells by increasing the activity of calpain proteases, which are known to promote survival and invasion in cancer. 0.2 SIGNOR-277388 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 20179209 YES lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated 0.34 SIGNOR-163916 HSPA1B protein P0DMV9 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by stabilization binding 9606 24790089 YES miannu The molecular chaperone HSP70 binds to and stabilizes NOD2, an important protein involved in Crohn disease. 0.2 SIGNOR-252417 RPS6KA1 protein Q15418 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9606 BTO:0000007 20048145 YES lperfetto Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha. 0.2 SIGNOR-162681 CSK protein P41240 UNIPROT ITCH protein Q96J02 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 16888620 YES gcesareni CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro. 0.2 SIGNOR-245327 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates activity chemical inhibition -1 29901072 YES miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. 0.8 SIGNOR-262220 Ub:E2 complex SIGNOR-C497 SIGNOR ANKIB1 protein Q9P2G1 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271232 Nalmefene chemical CHEBI:7457 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258810 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT up-regulates activity phosphorylation Ser45 LGIRSSKsAGALEEG 9606 30631047 YES miannu We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Moreover, ARMC10 overexpression was sufficient to promote mitochondrial fission, whereas ARMC10 knockout prevented AMPK-mediated mitochondrial fission. These results demonstrate that ARMC10 is an effector of AMPK that participates in dynamic regulation of mitochondrial fission and fusion. 0.2 SIGNOR-266413 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser397 TYHSRDEsTDSGLSM 9606 BTO:0000007 20048001 YES miannu We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition 0.2 SIGNOR-277636 zaleplon chemical CHEBI:10102 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 YES brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). 0.8 SIGNOR-263804 PTEN protein P60484 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates activity dephosphorylation 9606 33348808 YES miannu GluN2B Y1472 site is dephosphorylated by PTEN . 0.296 SIGNOR-277165 CD2AP protein Q9Y5K6 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000007;BTO:0001938 29175910 YES lperfetto One such regulator is the adaptor protein CD2AP, which delivers capping proteins to the barbed ends of polymerizing F-actin. Capping growing filaments can promote the formation of actin branches by increasing the G-actin pool available to form branches 0.2 SIGNOR-264770 MCHR1 protein Q99705 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.274 SIGNOR-257235 TM9SF4 protein Q92544 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity binding 9606 BTO:0000007 29125601 YES miannu TM9SF4 inhibited mTOR activity in HEK293 cells. Under nutrient starvation, TM9SF4 functions to facilitate mTOR inactivation, resulting in an enhanced autophagic flux, which serves to protect cells from apoptotic cell death. 0.2 SIGNOR-266703 NDUFB5 protein O43674 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 0.83 SIGNOR-262168 PRKCD protein Q05655 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.29 SIGNOR-249254 TYRO3 protein Q06418 UNIPROT CBLB protein Q13191 UNIPROT up-regulates activity phosphorylation Tyr363 TQEQYELyCEMGSTF 9606 31531847 YES miannu To test whether phosphorylation of Cbl-b at Tyr133 and/or Tyr363 by Tyro3 is important for its ubiquitin ligase function, we examined the ubiquitination of the Cbl-b mutants and Tyro3. 0.351 SIGNOR-279577 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val48 KVDGTSHvTGKGVTV -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.395 SIGNOR-263589 MMP2 protein P08253 UNIPROT LRP2 protein P98164 UNIPROT up-regulates quantity binding 10116 28659595 YES miannu We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex. We found that RAP, an antagonist of the LDL receptor family18, competed with binding of proMMP-2:TIMP-2 complex onto rat BN16 epithelial cells. 0.342 SIGNOR-265255 CLK1 protein P49759 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation -1 8617202 YES miannu In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors. 0.675 SIGNOR-273857 IRX1 protein P78414 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.2 SIGNOR-261660 GNA12 protein Q03113 UNIPROT RFFL protein Q8WZ73 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 22609986 NO miannu LPA and Gα12 may upregulate the expression of an E3 ubiquitin ligase that catalyzes the polyubiquitination of PRR5L. 0.2 SIGNOR-271496 26S Proteasome complex SIGNOR-C307 SIGNOR Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 29636472 NO lperfetto The proteasome is a sophisticated ATP-dependent molecular machine responsible for protein degradation in all known eukaryotic cells.  0.7 SIGNOR-263375 enzalutamide chemical CHEBI:68534 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194325 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 14967450 YES lperfetto Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr. 0.2 SIGNOR-244333 alvocidib chemical CHEBI:47344 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192104 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 21808241 YES gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. 0.608 SIGNOR-175801 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 34674502 YES scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† 0.8 SIGNOR-267042 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273100 POLR2J2 protein Q9GZM3 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.2 SIGNOR-266174 IGF1R protein P08069 UNIPROT PCNA protein P12004 UNIPROT up-regulates activity phosphorylation Tyr60 RSEGFDTyRCDRNLA -1 28924044 YES miannu In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination. 0.2 SIGNOR-277253 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 18265945 YES lperfetto Dephosphorylation of p53 at serine 15 by Wip1 also contributes to p53 degradation, as does dephosphorylation of Mdm2, which stabilizes Mdm2, an E3 ubiquitin ligase specific for p53 [ xref ]. 0.559 SIGNOR-276943 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function 0.91 SIGNOR-252827 TTC3 protein P53804 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 20059950 YES gcesareni TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus 0.396 SIGNOR-252459 PDZD8 protein Q8NEN9 UNIPROT MSN/PDZD8 complex SIGNOR-C61 SIGNOR form complex binding 9606 21549406 YES miannu These results demonstrated that both human moesin and its newly identified binding partner, pdzd8 had similar effects on host mt networks, suggesting that they are likely to function as part of a stable mt regulatory complex. 0.318 SIGNOR-173650 PCDH15 protein Q96QU1 UNIPROT TMC1 protein Q8TDI8 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000630 25114259 YES lperfetto Although several studies show that the tip links, composed of PCDH15 and CDH23, are required for normal mechanotransduction, it is unclear how they are coupled to the transduction machinery. Likewise, it has been demonstrated that the transmembrane channel-like proteins TMC1 and TMC2 are required for mechanosensitive responses in hair cells, but how they interact with other components of the mechanotransduction complex is not known. Here, we show that TMC1 and TMC2 can interact with PCDH15, thereby establishing a critical connection between the tip link and these putative components of the mechanotransduction channel in hair cells. 0.45 SIGNOR-262582 Activated PSC phenotype SIGNOR-PH224 SIGNOR TGFB2 protein P61812 UNIPROT up-regulates quantity 9606 BTO:0000988 38540204 YES miannu Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction 0.7 SIGNOR-277674 UCK1 protein Q9HA47 UNIPROT cytidine 5'-monophosphate(2-) smallmolecule CHEBI:60377 ChEBI up-regulates quantity chemical modification 11306702 YES lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 0.8 SIGNOR-275859 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Thr213 SASFPHTtPSMCLNP 9606 BTO:0000664 17475908 YES miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). 0.323 SIGNOR-262917 NEK2 protein P51955 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 24695856 YES lperfetto C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro. 0.773 SIGNOR-204837 CTNND2 protein Q9UQB3 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.465 SIGNOR-252131 TBK1 protein Q9UHD2 UNIPROT STAT6 protein P42226 UNIPROT up-regulates phosphorylation Ser407 PIQLQALsLPLVVIV 9606 22000020 YES gcesareni We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing. 0.673 SIGNOR-176771 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 BTO:0000801;BTO:0000876 17658244 YES gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. 0.2 SIGNOR-157089 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18676376 NO gcesareni € provide a novel transcriptional paradigm for the first steps of myogenesis, where a calcineurin/NFATc3 pathway regulates myogenin induction in cooperation with MyoD during myogenesis. 0.459 SIGNOR-235009 GPR17 protein Q13304 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.409 SIGNOR-256692 PRKCD protein Q05655 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Ser171 EKVSRRLsRSKNEPR 9606 20335173 YES lperfetto A novel cross-talk in diacylglycerol signaling: the rac-gap beta2-chimaerin is negatively regulated by protein kinase cdelta-mediated phosphorylation. phosphorylation of beta2-chimaerin on ser(169) located in the sh2-c1 domain linker region via protein kinase cdelta, which retained beta2-chimaerin in the cytosol and prevented its c1 domain-mediated translocation to membranes 0.27 SIGNOR-164687 ATG10 protein Q9H0Y0 UNIPROT ATG12 protein O94817 UNIPROT up-regulates binding 9606 18704115 YES gcesareni Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein. 0.878 SIGNOR-180129 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr285 TEADGELyVFNTPSG 10090 10978177 YES HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin 0.501 SIGNOR-251311 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 YES gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. 0.427 SIGNOR-81141 CREB1 protein P16220 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 21902831 NO gcesareni Chen et al. showed that phosphorylated creb is present at high levels in cells of the dermomyotome that express pax3, myod and myf5 and that this phosphorylation is critical for the induction of these genes. 0.288 SIGNOR-176533 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 YES gcesareni Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks. 0.503 SIGNOR-97006 RFPL4A protein A6NLU0 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates quantity by destabilization ubiquitination 10029 BTO:0000246 12525704 YES miannu We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis. 0.32 SIGNOR-271476 PRKCE protein Q02156 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.271 SIGNOR-275444 RNF4 protein P78317 UNIPROT SP1 protein P08047 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 21983342 YES miannu Here, we identified RNF4 as the ubiquitin E3 ligase of Sp1. From in vitro and in vivo experiments, we found that sumoylated Sp1 can recruit RNF4 as a ubiquitin E3 ligase that subjects sumoylated Sp1 to proteasomal degradation.  0.39 SIGNOR-272720 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR PPME1 protein Q9Y570 UNIPROT up-regulates activity dephosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0000007 24841198 YES lperfetto The results subsequently revealed that phosphorylated PME-1/Ser15 is dephosphorylated by SIK2·PP2A (Fig. 5G). |Our results also demonstrated that the phosphorylated levels of PME-1/Ser15 and CaMKI/Thr177 are inversely correlated with the phosphatase activity of SIK2·PP2A complex, further implying that the demethylase activity of phosphorylated PME-1/Ser15 may be higher than that of its unphosphorylated state. 0.822 SIGNOR-265752 PIK3C2A protein O00443 UNIPROT PIPP smallmolecule CID:24755493 PUBCHEM up-regulates chemical modification 9606 23119004 YES D3 position gcesareni Pi3ks phosphorylate the d3 position of membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (pip3); 0.8 SIGNOR-199364 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21357467 NO gcesareni The nfkb p65/p50 heterodimer increases sod2, and p50/p50 suppresses it nf-kb p65/p50 binds to the enhancer and is important for cytokine-induced sod2 0.496 SIGNOR-172392 (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol chemical CHEBI:94701 ChEBI RRM1 protein P23921 UNIPROT down-regulates activity chemical inhibition -1 7048062 YES miannu In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase 0.8 SIGNOR-258404 CBP/p300 complex SIGNOR-C6 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates binding 9606 BTO:0000887 10944526 YES gcesareni Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo. 0.647 SIGNOR-81047 KLHL20 protein Q9Y2M5 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 26687681 YES miannu Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1 0.555 SIGNOR-272416 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine chemical CID:11617559 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259743 PLK4 protein O00444 UNIPROT FBXW5 protein Q969U6 UNIPROT down-regulates activity phosphorylation Ser151 SQFNKDDsLLLASGV 21725316 YES lperfetto The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. 0.544 SIGNOR-275476 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity precursor of 9606 6698284 YES miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). 0.8 SIGNOR-267336 FOXF2 protein Q12947 UNIPROT IRF2BPL protein Q9H1B7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000498 29374064 YES miannu FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation. 0.253 SIGNOR-267152 STK38 protein Q15208 UNIPROT XPO1 protein O14980 UNIPROT up-regulates activity phosphorylation Ser1055 EKHKRQMsVPGIFNP 9606 BTO:0000567 31544310 YES miannu We further uncover that STK38 modulates XPO1 export activity by phosphorylating XPO1 on serine 1055, thus regulating its own nuclear exit.  0.2 SIGNOR-277483 EGR2 protein P11161 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 11494141 NO miannu Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. 0.7 SIGNOR-260048 RPS6K proteinfamily SIGNOR-PF26 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 YES lperfetto S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity. 0.2 SIGNOR-252788 PKI-402 chemical CID:44187953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206250 ERCC8 protein Q13216 UNIPROT ERCC6 protein Q03468 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 16751180 YES miannu We have previously shown that CSA is a subunit of an E3 ubiquitin ligase complex. Here we demonstrate that CSB is a substrate of this ligase: Following UV irradiation, CSB is degraded at a late stage of the repair process in a proteasome- and CSA-dependent manner. 0.583 SIGNOR-271406 ITGA6 protein P23229 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.77 SIGNOR-253199 PER1 protein O15534 UNIPROT SLC5A1 protein P13866 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000195 22526585 NO miannu Our findings suggest that PER1 exerts an indirect suppressive effect on SGLT1, possibly acting via other clock-controlled genes binding to non-E-box sites on the SGLT1 promoter. 0.336 SIGNOR-254912 SMURF1 protein Q9HCE7 UNIPROT PADI4 protein Q9UM07 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272689 CyclinY/CDK14 complex SIGNOR-C541 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Ser1490 AILNPPPsPATERSH 9606 BTO:0000599 24794231 YES lperfetto Compared with the wild-type CDK14, CDK14D256A mutant showed 2-fold reduced phosphorylation of LRP6 at Ser-1490, a known substrate of the CDK14/CCNY complex| It is also reported to be required for maximal phosphorylation of LRP6 on Ser 1490 and activation of Wnt signaling  0.342 SIGNOR-273015 HOXD13 protein P35453 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16314414 NO miannu We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation. 0.271 SIGNOR-142453 PRKACA protein P17612 UNIPROT CAST protein P20810 UNIPROT up-regulates activity phosphorylation Ser133 DKKKEKKsLTPAVPV -1 36984009 YES miannu  The results showed that PKA promoted the phosphorylation of calpastatin, and a high phosphorylation level was maintained during incubation. Phosphorylation at serine 133 of calpastatin enhanced its inhibition on calpain activity by maintaining its structural stability, thus inhibiting the tenderization of meat. 0.2 SIGNOR-277839 1-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-2-methoxyphenyl)-3-(1-(thiazol-2-yl)ethyl)urea chemical CID:9869779 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259750 PRKCD protein Q05655 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.348 SIGNOR-249287 PPARG protein P37231 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002042 16785230 NO miannu these results uncovered a mechanism by which up-regulation of functional ABCG2 expression can be achieved via exogenous or endogenous activation of the lipid-activated transcription factor, PPARgamma. 0.396 SIGNOR-255054 linifanib chemical CHEBI:91435 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 16648571 YES Gianni ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families 0.8 SIGNOR-262207 CDK5 protein Q00535 UNIPROT CLOCK protein O15516 UNIPROT up-regulates phosphorylation Thr461 KIPTDTStPPRQHLP 9606 24235147 YES lperfetto Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock. 0.328 SIGNOR-203231 IKBKB protein O14920 UNIPROT REL protein Q04864 UNIPROT up-regulates activity phosphorylation 9606 19110719 YES miannu We are the first to identify Ser484 and Ser494 as the major sites of in vitro phosphorylation of REL by IKKalpha and IKKbeta. 0.619 SIGNOR-279620 GREB1 protein Q4ZG55 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity binding 9606 BTO:0000599 31462641 YES miannu GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription 0.2 SIGNOR-265885 EGLN1 protein Q9GZT9 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization hydroxylation 9606 BTO:0000567 32755251 YES lperfetto Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.|Oxygen-dependent hydroxylation by the prolyl hydroxylase domain-2 (PHD2) protein marks HIF-1alpha for ubiquitination by the von Hippel Lindau (VHL) tumor suppressor protein, leading to proteasomal degradation 0.918 SIGNOR-261994 Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 NO miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.7 SIGNOR-270898 LYN protein P07948 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT BTO:0000776 10880360 YES lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. 0.624 SIGNOR-249378 PRKAA1 protein Q13131 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 SIGNOR-C15 18303014 YES gcesareni The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner 0.284 SIGNOR-160838 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 YES llicata Erk phosphorylates threonine 42 residue of ribosomal protein s3. 0.2 SIGNOR-136075 ALOX5 protein P09917 UNIPROT leukotriene A4 smallmolecule CHEBI:15651 ChEBI up-regulates chemical modification 9606 11751058 YES gcesareni 5-lipoxygenase catalyzes the production of leukotriene (lt) a4, from 5- hydroperoxyeicosatetraenoic acid (5-hpete) as well as the nitial oxidation of arachidonic acid to this hydroperoxy in-termediate 0.8 SIGNOR-113198 CLTC protein Q00610 UNIPROT AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 YES lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors 0.745 SIGNOR-260676 MMP28 protein Q9H239 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272372 SAV1 protein Q9H4B6 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 21084559 YES Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2. gcesareni Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. 0.886 SIGNOR-169832 LPCAT1 protein Q8NF37 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272761 BRD9 protein Q9H8M2 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.475 SIGNOR-269787 EMSY protein Q7Z589 UNIPROT ZMYND11 protein Q15326 UNIPROT up-regulates activity binding 9606 BTO:0000567 14651845 YES miannu The binding sites for HP1β and BS69 with EMSY abut each other, and are found directly adjacent to the ENT domain of EMSY. This demonstrates that EMSY has the capacity to contact directly at least two proteins which contain a Royal Family domain. Since this domain is found in proteins with a chromatin connection, we assume that EMSY functions, at least partly, in the regulation of chromatin. 0.2 SIGNOR-263916 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI carnitine smallmolecule CHEBI:17126 ChEBI up-regulates quantity precursor of 9606 11802770 YES miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. 0.8 SIGNOR-269701 1-phospho-alpha-D-glucuronic acid smallmolecule CHEBI:681 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 YES miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1). 0.8 SIGNOR-258434 NHS protein Q6T4R5 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 20332100 NO miannu We demonstrate that NHS is essential for maintaining cell morphology through the regulation of actin cytoskeletal dynamics and suggest that an important mechanism of remodelling of the actin cytoskeleton during development would therefore be lost in patients with NHS. 0.7 SIGNOR-253565 HDAC2 protein Q92769 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 YES miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. 0.704 SIGNOR-222127 NLGN1 protein Q8N2Q7 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 YES brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. 0.775 SIGNOR-264191 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 YES lperfetto The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-α or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro. 0.2 SIGNOR-244494 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 9606 12493777 YES lperfetto We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo 0.2 SIGNOR-96683 BMI1 protein P35226 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20551323 NO gcesareni One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf 0.456 SIGNOR-166163 PIGS protein Q96S52 UNIPROT GPAA1 protein O43292 UNIPROT up-regulates activity binding 10090 11483512 YES miannu To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8. 0.895 SIGNOR-261361 CDK2 protein P24941 UNIPROT SOX2 protein P48431 UNIPROT up-regulates activity phosphorylation Ser37 AGGNQKNsPDRVKRP 9606 26139602 YES miannu Cdk2 physically interacts with Sox2 and phosphorylates Sox2 at Ser 39 and Ser 253 in vitro. 0.394 SIGNOR-279448 CDK2 protein P24941 UNIPROT SOX2 protein P48431 UNIPROT up-regulates activity phosphorylation Ser251 VKSEASSsPPVVTSS -1 26139602 YES miannu Cdk2 physically interacts with Sox2 and phosphorylates Sox2 at Ser 39 and Ser 253 in vitro.|Cyclin-dependent kinase-mediated Sox2 phosphorylation enhances the ability of Sox2 to establish the pluripotent state 0.394 SIGNOR-279449 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT up-regulates phosphorylation Thr286 SCMHRQEtVDCLKKF 9606 BTO:0000975 1849884 YES lperfetto Role of threonine-286 as autophosphorylation site for appearance of ca2(+)-independent activity of calmodulin-dependent protein kinase ii alpha subunit 0.2 SIGNOR-21797 MAP3K3 protein Q99759 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser181 DQGSLCTsFVGTLQY 9606 14636585 YES miannu Genetic analysis showed that MEKK3, which is thought to activate IKK2 through phosphorylation (Yang et al., 2001), is necessary for TNF-alpha-induced NF-kappaB activation.|Our results also suggest that IKK2 is phosphorylated on S177 and S181 on its activation loop by MEKK3. 0.568 SIGNOR-279468 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI PTGER1 protein P34995 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257569 CDK5 protein Q00535 UNIPROT PLD2 protein O14939 UNIPROT down-regulates activity phosphorylation Ser134 ARFAVAYsPARDAGN 9606 BTO:0000007 18625302 YES miannu In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion. We determined that the phosphorylation site of PLD2 was located at Ser(134). 0.368 SIGNOR-276168 DDHD1 protein Q8NEL9 UNIPROT 1-acyl-sn-glycerol 3-phosphate smallmolecule CHEBI:16975 ChEBI up-regulates quantity chemical modification 9606 22922100 YES miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. 0.8 SIGNOR-269656 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 BTO:0000938 12367505 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. 0.809 SIGNOR-94025 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 YES esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. 0.448 SIGNOR-89237 KAT2B protein Q92831 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269618 S protein P59594 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity 9606 16940539 NO miannu SARS-CoV S protein specifically activated PERK but did not significantly affect IRE1/XBP1 or ATF6. 0.2 SIGNOR-260439 CHMP1B protein Q7LBR1 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.712 SIGNOR-265524 LTK protein P29376 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9223670 YES gcesareni Recently, we demonstrated that ltk utilizes shc and irs-1 as two major substrates and while both equally activate the ras pathway, only irs-1 suppresses apoptosis of hematopoietic cells. 0.425 SIGNOR-49625 GSK3B protein P49841 UNIPROT CAP1 protein Q01518 UNIPROT up-regulates activity phosphorylation Ser310 PKPQTSPsPKRATKK 9606 BTO:0000763 30123351 YES lperfetto We found that GSK3 phosphorylates S307 and S309 by using inhibitors LiCl. Inhibition of GSK3beta can cause loss of cell polarity as well as accumulation of stress fibers. We propose that GSK3 regulates CAP1 through at least two mechanisms. First, GSK3 (and potentially other kinases) phosphorylate CAP1 at S309 and promote CAP1 localization to the cytosol. Second, phosphorylation at S309 affects protein-protein interactions with actin and cofilin. The loss of this phospho-regulation by GSK3 inhibition is expected to disrupt CAP1 function and actin dynamics. 0.254 SIGNOR-264823 SDF2L1 protein Q9HCN8 UNIPROT LRP4 protein O75096 UNIPROT up-regulates activity binding 9606 BTO:0000007 24140340 YES llicata Here, we show that the chaperon Mesdc2 binds to the intracellular form of Lrp4 and promotes its glycosylation and cell-surface expression. These results suggest that Mesdc2 plays an essential role in NMJ formation by promoting Lrp4 maturation. 0.2 SIGNOR-237942 PZP protein P20742 UNIPROT MMP2 protein P08253 UNIPROT down-regulates activity binding -1 9344465 YES lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.33 SIGNOR-261804 CREB1 protein P16220 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 NO gcesareni In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1 0.25 SIGNOR-166346 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 23486913 YES lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation 0.755 SIGNOR-217141 LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 21658387 YES lperfetto A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2. 0.38 SIGNOR-174044 HIF1A protein Q16665 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.271 SIGNOR-271563 SPI1 protein P17947 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15767686 NO irozzo These data suggest that a potential positive autoregulatory loop mediated through an upstream regulatory element is essential for proper PU.1 gene expression.These data demonstrate that PU.1 protein is in a complex binding to a site within the kb −14 URE, suggesting that autoregulation through this region might be important for expression of PU.1. 0.2 SIGNOR-256070 ATP1A3 protein P13637 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 22797008 YES miannu The sodium/potassium transporting ATPase subunit alpha-3 (AT1A3; syn.: sodium pump subunit alpha-3; E.C. 3.6.3.9; UniProtKB ID: Q6PIC6) belongs to the cation transport ATPase (P-type) 3.A.3 family catalyzing hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action generates the electrochemical gradient of sodium and potassium ions thus providing energy for active transport of various nutrients. Three sodium/potassium transporting ATPase isoforms are expressed in the brain but AT1A3 is detectable in neurons exclusively. 0.8 SIGNOR-265793 FRK protein P42685 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 BTO:0002035 35723276 YES miannu Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.  0.275 SIGNOR-275456 PTPRJ protein Q12913 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1092 TFLPVPEyINQSVPK 9606 BTO:0000567 19836242 YES We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173 0.491 SIGNOR-248698 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 YES lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 0.584 SIGNOR-249479 Dynorphin B chemical CHEBI:80347 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258798 PRKCB protein P05771 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 YES miannu Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress 0.417 SIGNOR-91830 SMARCE1 protein Q969G3 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.844 SIGNOR-269819 GCG protein P01275 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates 9606 23075495 NO gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. 0.2 SIGNOR-199205 TWIST2 protein Q8WVJ9 UNIPROT NF1 protein P21359 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255505 Ub:E2 complex SIGNOR-C497 SIGNOR RNF32 protein Q9H0A6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271221 AP1 complex SIGNOR-C154 SIGNOR IL6 protein P05231 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 20086235 NO JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes 0.64 SIGNOR-254513 PTPRG protein P23470 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1003 VSNESVDyRATFPED -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.317 SIGNOR-254712 perfluorooctanoic acid chemical CHEBI:35549 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268765 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 21079800 YES gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. 0.706 SIGNOR-169690 SRC protein P12931 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr652 KPELVISyLPPGMAS 9534 11934902 YES lperfetto C-Src-dependent transcriptional activation of TFII-ITFII-I is a multifunctional transcription factor that is also involved in signal transduction. Here we show that TFII-I undergoes a c-Src-dependent tyrosine phosphorylation on tyrosine residues 248 and 611 and translocates to the nucleus in response to growth factor signaling 0.454 SIGNOR-247189 PRKACA protein P17612 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser63 AAEERRKsHEAEVLK 9606 8376365 YES gcesareni Phosphorylation at either ser(16) or ser(63) strongly reduced or abolished the ability of stathmin to bind to and sequester soluble tubulin and its ability to act as a catastrophe factor by directly binding to the microtubules. The known in vivo phosphorylation sites of stathmin are ser-16 and ser-63 for cyclic amp-dependent protein kinase (pka). 0.31 SIGNOR-38322 NEU1 protein Q99519 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0003554 32164705 NO Giorgia Taken together, these findings indicate that NEU1 overexpression reduces cell proliferation and enhances cell apoptosis through by downregulation of FN-integrin β1-mediated Akt signaling pathway. 0.2 SIGNOR-260659 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249318 ULK1 protein O75385 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Ser364 TRLGVEPsDDDCVSV 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.257 SIGNOR-274033 clozapine chemical CHEBI:3766 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258369 WDR62 protein O43379 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity relocalization 10090 30566428 YES lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis 0.557 SIGNOR-271718 paliperidone chemical CHEBI:82978 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258565 DUSP3 protein P51452 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity dephosphorylation 9534 BTO:0004055 10224087 YES inferred from 70% of family members Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2 0.671 SIGNOR-269928 TARDBP protein Q13148 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates post transcriptional regulation 9606 33163270 YES in ALS TDP-43 induces alternative splicing of HNTNPA1 which increases its pathogenic aggregation. TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis 0.406 SIGNOR-262824 CDK1 protein P06493 UNIPROT RNF138 protein Q8WVD3 UNIPROT up-regulates activity phosphorylation Thr27 VCQEVLKtPVRTTAC 9606 BTO:0000007 38309501 YES miannu Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner.Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner. 0.2 SIGNOR-277832 GTF2F1 protein P35269 UNIPROT GTF2F1 protein P35269 UNIPROT down-regulates phosphorylation Ser385 GGSSRGNsRPGTPSA 9606 10428810 YES gcesareni We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process. 0.2 SIGNOR-69767 SB-705498 chemical CID:9910486 PUBCHEM TRPV1 protein Q8NER1 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206826 ATP13A1 protein Q9HD20 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0004093 29650961 NO doi.org/10.1101/185272 francesca Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions 0.7 SIGNOR-261217 PTPRJ protein Q12913 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr868 GSVEMCRyDPLQDNT 9606 28912580 YES miannu These results support PTPRJ preferentially dephosphorylating Y813 and Y868 in JAK2.|We revealed that PTPRJ negatively regulates leptin signaling by dephosphorylating specific tyrosine residues (Y813 and Y868) in JAK2, the simultaneous phosphorylation of which plays a pivotal role in JAK2 activation. 0.324 SIGNOR-277094 CTBP1 protein Q13363 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21681822 YES irozzo Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. 0.602 SIGNOR-259196 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 YES lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. 0.392 SIGNOR-249604 MAPK14 protein Q16539 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000887 18026121 YES lperfetto Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d. 0.611 SIGNOR-159331 ADCY1 protein Q08828 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity 9606 27065076 NO Gianni Adenylate cyclases (AC) produce cAMP from adenosin-tri-phosphate (ATP). High levels of cytosolic cAMP lead to activation of protein kinase A (PKA) 0.511 SIGNOR-262528 HNF4G protein Q14541 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 9792724 NO miannu AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP. 0.2 SIGNOR-254442 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 9606 18769144 YES lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively 0.2 SIGNOR-180771 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 16076840 YES gcesareni The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex. 0.34 SIGNOR-139324 MICU3 protein Q86XE3 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.645 SIGNOR-270872 PARP1 protein P09874 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 22223884 YES alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin 0.483 SIGNOR-254528 arachidonic acid smallmolecule CHEBI:15843 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates 9606 15878913 NO miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. 0.8 SIGNOR-255393 HCRTR1 protein O43613 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257294 HOTAIR ncrna URS000075C808_9606 RNAcentral MEX3B protein Q6ZN04 UNIPROT up-regulates activity binding 9606 BTO:0000567 24326307 YES miannu HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation. 0.2 SIGNOR-272092 IRX1 protein P78414 UNIPROT FGF7 protein P21781 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 NO Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. 0.2 SIGNOR-261654 TLRs proteinfamily SIGNOR-PF20 SIGNOR NLRP3 protein Q96P20 UNIPROT up-regulates quantity by expression 28531279 NO lperfetto The activation of NLRP3 inflammasomes in macrophages requires two stimuli. The first signal, called priming, is provided by an inflammatory stimulus such as TLRs and TNF-α receptor (TNFR) that leads to NF-κB-mediated NLRP3 expression and post-translational modifications of NLRP3 0.2 SIGNOR-256428 MYC protein P01106 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000724 7882978 NO irozzo These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation. 0.7 SIGNOR-259110 SDHB protein P21912 UNIPROT Succinate dehydrogenase-Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR form complex binding 30030361 YES lperfetto Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites 0.966 SIGNOR-262189 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 22303254 NO Polycomb group (PcG) and Trithorax group (TrxG) proteins are epigenetic regulators that control gene expression through modulating chromatin structure and addition of posttranslational modifications (PTMs) on histones 0.7 SIGNOR-268625 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 16266983 NO gcesareni We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. 0.431 SIGNOR-245064 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 NFDFVTEtPLEGDFA 9606 19364816 YES lperfetto We have shown that erk2 interacts with and phosphorylates p21cip1, promoting p21cip1_ubiquitination. We identified two erk2 phosphorylation sites, thr57 and ser130, in p21cip1_and showed that phosphorylation of these residues increases p21cip1_cytoplasmic distribution and proteasome-dependent degradation. 0.2 SIGNOR-244513 MAP2K7 protein O14733 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity phosphorylation 9606 11062067 YES lperfetto Here we report that MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183) in three SAPK1/JNK1 isoforms tested (JNK1 alpha 1, JNK2 alpha 2 and JNK3 alpha 1). 0.698 SIGNOR-83725 CARM1 protein Q86X55 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR form complex binding BTO:0001103 29681515 YES apalma Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated 0.362 SIGNOR-255980 ARHGAP9 protein Q9BRR9 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.605 SIGNOR-260464 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 17277771 YES gcesareni Furthermore, pras40 phosphorylation by akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mtor. These findings identify pras40 as an important regulator of insulin sensitivity of the akt-mtor pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes. 0.673 SIGNOR-152936 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOCS3 protein O14543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19643666 YES lperfetto Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways. 0.391 SIGNOR-249566 HUWE1 protein Q7Z6Z7 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 31905981 YES miannu HUWE1 directly binds and ubiquitinates p53 to target it for proteasomal degradation, independently of MDM2 [ xref ]. 0.496 SIGNOR-278547 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Thr135 PKKMEDLtNVSSLLN 9606 BTO:0000567 25670858 YES lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 0.587 SIGNOR-265234 KLF2 protein Q9Y5W3 UNIPROT PPARG protein P37231 UNIPROT down-regulates transcriptional regulation 9606 12426306 NO fspada Constitutive overexpression of klf2 but not klf15 potently inhibits peroxisome proliferator-activated receptor-gamma (ppargamma) expression with no effect on the upstream regulators c/ebpbeta and c/ebpdelta. 0.418 SIGNOR-210019 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates activity phosphorylation Thr221 AGTSFMMtPYVVTRY -1 10715136 YES Activation of JNK3 alpha 1 requires both MKK4 and MKK7. both MKK4 and MKK7 were required for bisphosphorylation and maximal enzyme activity. a processive mechanism for JNK3R1 activation that requires phosphorylation of Thr 221 by MKK7 prior to phosphorylation of Tyr 223 by MKK4 0.58 SIGNOR-251422 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates activity dephosphorylation Tyr291 AETSKLIyDFIEDQG 10090 14707117 YES Mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities|WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST 0.445 SIGNOR-248660 AVPR1B protein P47901 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257264 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 YES gcesareni This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses. 0.416 SIGNOR-191667 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr951 RFRQGKDyVGAIPVD 9606 BTO:0000801;BTO:0000876 17658244 YES gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. 0.2 SIGNOR-157097 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 YES gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. 0.755 SIGNOR-94268 SPI1 protein P17947 UNIPROT FCRL6 protein Q6DN72 UNIPROT up-regulates quantity by expression transcriptional regulation 12695521 NO lperfetto Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. 0.208 SIGNOR-268966 HIF-1 complex complex SIGNOR-C418 SIGNOR LDHA protein P00338 UNIPROT up-regulates quantity transcriptional regulation 9606 7673128 YES Deletional and mutational analysis of the function of mouse LDH-reporter fusion gene constructs in transient transfection assays defined three domains, between -41 and -84 base pairs upstream of the transcription initiation site, which were crucial for oxygen-regulated expression. The most important of these, although not capable of driving hypoxic induction in isolation, had the consensus of a hypoxia-inducible factor 1 (HIF-1) site, and cross-competed for the binding of HIF-1 with functionally active Epo and phosphoglycerate kinase-1 sequences 0.656 SIGNOR-267479 PPARD protein Q03181 UNIPROT HSD11B2 protein P80365 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001975 15591138 NO miannu Peroxisome proliferator-activated receptor delta suppresses 11beta-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells. 0.314 SIGNOR-255050 CD19 protein P15391 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity 9606 10706702 NO lperfetto CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor. 0.39 SIGNOR-249609 TIMP2 protein P16035 UNIPROT LRP2 protein P98164 UNIPROT up-regulates quantity binding 10116 BTO:0001860 28659595 YES miannu We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex. We found that RAP, an antagonist of the LDL receptor family18, competed with binding of proMMP-2:TIMP-2 complex onto rat BN16 epithelial cells. 0.2 SIGNOR-265254 PRKCD protein Q05655 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity phosphorylation Ser40 SREVFDFsQRRKEYE -1 12198130 YES lperfetto Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. 0.371 SIGNOR-249161 ZBTB46 protein Q86UZ6 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 30962287 YES miannu We identified LIF/ZBTB46 signalling as a key promoter of metabolic reprogramming and NE differentiation of PCa cells through interactions with PCK1. We showed that ZBTB46 directly upregulates the expression of PCK1 and NE marker gene through activation of LIF signalling. 0.2 SIGNOR-277987 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser412 DSLDDSGsCLSGSQR 9534 BTO:0000298 9353340 YES lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  0.391 SIGNOR-248989 MECP2 protein P51608 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 BTO:0004102 22262897 YES inferred from family member Luana Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A. 0.325 SIGNOR-270237 PRKCA protein P17252 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 YES llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. 0.44 SIGNOR-66666 WWP2 protein O00308 UNIPROT POLR2A protein P24928 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0001938 31048545 YES lperfetto WWP2 ubiquitylates RNA polymerase II for DNA-PK-dependent transcription arrest and repair at DNA breaks|In response to DSBs, WWP2 targets the RNAPII subunit RPB1 for K48-linked ubiquitylation, thereby driving DNA-PK- and proteasome-dependent eviction of RNAPII. 0.388 SIGNOR-268851 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277664 TWIST2 protein Q8WVJ9 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 NO miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion 0.2 SIGNOR-255509 AMPK complex SIGNOR-C15 SIGNOR RBBP7 protein Q16576 UNIPROT up-regulates activity phosphorylation Ser314 LKLHTFEsHKDEIFQ -1 28143904 YES lperfetto AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity 0.259 SIGNOR-264789 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 18350175 NO inferred from family member miannu The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase. 0.7 SIGNOR-267782 SWI/SNF complex complex SIGNOR-C92 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002586 12226744 NO irozzo The hSNF5/INI1 gene encodes a member of the SWI/SNF chromatin remodelling complexes.Here, we show that the ectopic expression of wild-type hSNF5/INI1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into S phase of MRT cells. 0.7 SIGNOR-256298 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258646 CHUK protein O15111 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation 9606 27992555 YES miannuccelli In addition, IKK\u03b1 also phosphorylated STAT1 in a type I IFN-independent manner [Fig 8, a dashed line (B)]. 0.332 SIGNOR-279732 dasatinib (anhydrous) chemical CHEBI:49375 ChEBI SRC protein P12931 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258103 SLBP protein Q14493 UNIPROT H2BC4 protein P62807 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265377 CBFA2T3 protein O75081 UNIPROT CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR form complex binding 9606 BTO:0000007 20116376 YES Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. 0.455 SIGNOR-253956 RAD21L1 protein Q9H4I0 UNIPROT RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR form complex binding 10090 BTO:0000534 21242291 YES miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. 0.782 SIGNOR-264535 HES1 protein Q14469 UNIPROT NOC3L protein Q8WTT2 UNIPROT down-regulates quantity transcriptional regulation 9823 BTO:0003298 23611667 YES The expression level of FAD24 is inversely associated with that of HES1 in porcine MSCs after adipogenic induction. Enforced overexpression of HES1 in MSCs during the early stage of adipogenesis significantly repressed the transcription of FAD24 (P < 0.01) and the other pro-adipogenic genes 0.2 SIGNOR-253059 serotonin smallmolecule CHEBI:28790 ChEBI HTR2C protein P28335 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264283 CUL2 protein Q13617 UNIPROT APOBEC3A protein P31941 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 29367246 YES lperfetto Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation|Here, we report that the HPV oncoprotein E7 stabilizes the APOBEC3A (A3A) protein in human keratinocytes by inhibiting ubiquitin-dependent protein degradation in a cullin-dependent manner. 0.251 SIGNOR-261325 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity phosphorylation Ser416 SVDDLANsGQVGTAR 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 YES lperfetto Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function. 0.2 SIGNOR-246737 CAPRIN2 protein Q6IMN6 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0000007 35051932 YES lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|Altogether, the data indicate that CAPRIN2 binds Oxt mRNA |Therefore, we propose that CAPRIN2 facilitates post-transcriptional modifications that increase Oxt transcript stability. 0.2 SIGNOR-268556 PPP2CB protein P62714 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 8650155 YES gcesareni These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity 0.507 SIGNOR-42050 FBXO2 protein Q9UK22 UNIPROT PIK3R2 protein O00459 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 23604317 YES miannu  FBXL2 interacts with the pool of p85β that is free of p110 PI(3)K catalytic subunits and targets this pool for ubiquitylation and subsequent proteasomal degradation. 0.2 SIGNOR-271936 TBR1 protein Q16650 UNIPROT FEZF2 protein Q8TBJ5 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0000938 21228164 YES lperfetto We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2.|(3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene. 0.486 SIGNOR-268967 AMPK complex SIGNOR-C15 SIGNOR KLC2 protein Q9H0B6 UNIPROT up-regulates phosphorylation Ser582 PRMKRASsLNFLNKS 9606 21725060 YES lperfetto Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582 0.288 SIGNOR-216468 ACSL1 protein P33121 UNIPROT hexadecanoic acid smallmolecule CHEBI:15756 ChEBI down-regulates quantity chemical modification 9606 21242590 YES miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). 0.8 SIGNOR-267878 STRN4 protein Q9NRL3 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 YES miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms 0.589 SIGNOR-261699 PIAS3 protein Q9Y6X2 UNIPROT STAT3 protein P40763 UNIPROT down-regulates sumoylation 9606 15138572 YES gcesareni Stat3 mediated signaling pathways can be inhibited by pias3 (protein inhibitor of activated stat3), which was recently found to regulate protein stability and function by its sumo (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins. 0.73 SIGNOR-124723 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser236 DDSGTEEs 9606 11546811 YES lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. 0.395 SIGNOR-110403 ASPG protein Q86U10 UNIPROT ammonia smallmolecule CHEBI:16134 ChEBI up-regulates quantity chemical modification 9606 24657844 YES miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. 0.8 SIGNOR-267539 NLGN1 protein Q8N2Q7 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.828 SIGNOR-264159 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.762 SIGNOR-252750 prostaglandin F2alpha smallmolecule CHEBI:15553 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 NO apalma Prostaglandins are able to affect muscle cell proliferation (142), differentiation (96) and fusion (141), and can also modulate muscle fiber growth and the synthesis and degradation of proteins in muscle 0.7 SIGNOR-255360 PTEN protein P60484 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 NO miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). 0.2 SIGNOR-260051 LSM-1231 chemical CHEBI:91471 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258236 LUBAC complex SIGNOR-C527 SIGNOR PRKCB protein P05771 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 17069764 YES miannu In this report, we demonstrated that LUBAC, a ubiquitin ligase complex, is an E3 of activated cPKCs. LUBAC preferentially bound PMA-activated PKCa and PKCbII and their constitutively active mutants (Fig. 2). degradation of PMA-activated PKCa was delayed in HOIL-1L/-MEF (Fig. 3F). These results indicate that LUBAC is the ubiquitin ligase that induces ubiquitination and degradation of activated cPKCs. 0.332 SIGNOR-271617 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 YES gcesareni Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation. 0.2 SIGNOR-151015 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GORASP1 protein Q9BQQ3 UNIPROT down-regulates activity phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 18762583 YES Giulio Supporting the conclusion that phosphorylation of GRASP65 at Ser277 by ERK is critical for Golgi polarization. We have demonstrated a closely integrated mechanism in which Golgi remodeling by phosphorylation of GRASP65 acts as a negative regulator of Golgi and, surprisingly, centrosome orientation. Our data indicate that ERK phosphorylates GRASP65 in interphase cells, resulting in the loss of GRASP65 oligomerization and causing subsequent Golgi cisternal unstacking. 0.2 SIGNOR-260605 ATR protein Q13535 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 YES lperfetto Atm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.Substitution of thr68 with ala reduced the extent of phosphorylation and activation of chk2 in response to ir 0.859 SIGNOR-81442 TMLHE protein Q9NVH6 UNIPROT 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI up-regulates quantity chemical modification 9606 11431483 YES miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 0.8 SIGNOR-269684 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.2 SIGNOR-253491 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 SIGNOR-C17 21059642 YES The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). 0.342 SIGNOR-169318 FOXO1 protein Q12778 UNIPROT NPY protein P01303 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000614 28270795 NO miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. 0.4 SIGNOR-263502 Food intake phenotype SIGNOR-PH152 SIGNOR vitamin K smallmolecule CHEBI:28384 ChEBI up-regulates quantity 31226734 NO lperfetto Vitamin K obtained from the diet is considered to reach the target tissues via lipid absorption and the transport system  0.7 SIGNOR-265899 SBF1 protein O95248 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 10090 20937701 NO miannu Reduced sciatic nerve axons and normal myelination in the absence of Mtmr5. However, Mtmr5−/− mice had significantly fewer total myelinated axons in sciatic nerves than wild-type controls (Fig. 5G). 0.7 SIGNOR-269812 ATF1 protein P18846 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10540320 NO miannu Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter 0.249 SIGNOR-254521 PTPRT protein O14522 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9606 17360477 YES miannu Here, we report identification of signal transducer and activator of transcription 3 (STAT3) as a substrate of PTPRT. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. Accordingly, overexpression of normal PTPRT in colorectal cancer cells reduced the expression of STAT3 target genes.|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position. 0.517 SIGNOR-277043 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser457 RGRKRFVsEGDGGRL 9606 16357133 YES gcesareni Our results show that akt specifically phosphorylates ser(67) and ser(457) residues of pdcd4 in vitro and in vivo. We further show that phosphorylation of pdcd4 by akt causes nuclear translocation of pdcd4. 0.2 SIGNOR-143098 FNTB protein P49356 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity 9606 24294527 YES lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. 0.419 SIGNOR-242556 CHMP2A protein O43633 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 YES miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. 0.769 SIGNOR-265532 ALDOB protein P05062 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266480 GNAS protein P63092 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding -1 11007482 YES Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src 0.506 SIGNOR-256527 P2RY4 protein P51582 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257006 FOXO1 protein Q12778 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 YES miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. 0.258 SIGNOR-260090 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11593427 YES irozzo In this report, we show that Bcr–Abl forms a complex with Jak2, and induces tyrosine phosphorylation of Jak2; full phosphorylation requires the SH2 domain of Bcr–Abl. We found that Y1007 of Jak2 was phosphorylated in Bcr–Abl positive cells; phosphorylation of Jak2 Y1007 is known to be required for Jak2 kinase activation. 0.2 SIGNOR-255812 MARK4 protein Q96L34 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser396 DDKKAKTsTRSSAKT -1 21204788 YES done miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). 0.42 SIGNOR-273935 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 24449215 NO miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. 0.2 SIGNOR-255971 ATM protein Q13315 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Ser140 GKKATQAsQEY 9606 21690091 YES gcesareni Upon dna damage, h2ax is phosphorylated by ataxia telangiectasia mutated (atm) and atm-related kinases at serine 139, known as ?_?_?_-H2ax, which serves as a docking site to recruit the mediator of dna damage checkpoint protein 1 (mdc1) to sites of dna damage, named dna damage foci 0.2 SIGNOR-174442 PPP1CA protein P62136 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity dephosphorylation Ser88 EALRRTGsPLAARYM 9606 BTO:0000007 23499489 YES lperfetto Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation. 0.2 SIGNOR-264577 AKT proteinfamily SIGNOR-PF24 SIGNOR GATA1 protein P15976 UNIPROT up-regulates phosphorylation Ser310 QTRNRKAsGKGKKKR 9606 16107690 YES lperfetto We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter. 0.2 SIGNOR-244267 CEBPB protein P17676 UNIPROT TNFAIP6 protein P98066 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7876106 YES In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells. 0.302 SIGNOR-254055 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Thr455 TTERDSDtDVEEEEL 9606 18678890 YES gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. 0.347 SIGNOR-179891 FGB protein P02675 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR form complex binding -1 25427968 YES lperfetto Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively). 0.765 SIGNOR-263391 CDK2 protein P24941 UNIPROT POLL protein Q9UGP5 UNIPROT up-regulates activity phosphorylation 9606 16174846 YES miannu Additional observations of Cdk2 localization at the telomeric ends of chromosome from leptotene to diplotene stage of meiosis could support a role of Pol lambda by its terminal transferase activity in germ cells.|DNA polymerase lambda is phosphorylated by the Cdk2 and cyclin E, Cdk2 and cyclin A and Cdk1 and cyclin A complexes in vitro. 0.336 SIGNOR-278919 CDK5 protein Q00535 UNIPROT PRNP protein F7VJQ1 UNIPROT up-regulates quantity phosphorylation 9606 19587281 YES miannu Cdk5 phosphorylated PrP induces the aggregation of non phosphorylated PrP.|Together, these results indicate that S43 is a major Cdk5 phosphorylation site in PrP. 0.332 SIGNOR-278920 POLR2L protein P62875 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.861 SIGNOR-266171 CEBPB protein P17676 UNIPROT ADM protein P35318 UNIPROT up-regulates quantity by expression transcriptional regulation 9480831 YES These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells. 0.245 SIGNOR-254047 CDK1 protein P06493 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation Ser1026 PQQGFFSsPSTSRTP 9606 BTO:0000017 8360196 YES gcesareni Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity. 0.426 SIGNOR-38313 dabrafenib chemical CHEBI:75045 ChEBI NEK11 protein Q8NG66 UNIPROT down-regulates activity chemical inhibition -1 24720932 YES miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations 0.8 SIGNOR-259217 calcium(2+) smallmolecule CHEBI:29108 ChEBI SLC25A13 protein Q9UJS0 UNIPROT up-regulates activity chemical activation 9606 12084073 YES miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. 0.8 SIGNOR-265153 HDAC3 protein O15379 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 SIGNOR-C12 23213415 YES gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes. 0.532 SIGNOR-199964 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser32 LLDDRHDsGLDSMKD 9606 9346241 YES lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation 0.889 SIGNOR-216385 BTK protein Q06187 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity binding 9031 BTO:0004814 9305846 NO Marta Tosoni Our results indicate that Gq-mediated activation of Btk is necessary for stimulation of p38 kinase by Gq-coupled receptors in DT40 lymphoma cells. Hence, stimulation of Btk kinase by Gaq may be essential in vivo for activation of p38 kinase. 0.299 SIGNOR-278085 BRSK1 protein Q8TDC3 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates phosphorylation Ser131 READGSDsLEGFVLC 9606 19648910 YES The effect has been demonstrated using Q8TDC3-2 llicata Sadb kinases associate and phosphorylate gamma-tubulin on ser 131 s131d gamma-tubulin expression amplifies centrosome duplication 0.248 SIGNOR-187405 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Ser102 LQTVIRTsPSSLVAF 9606 26190112 YES Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. 0.334 SIGNOR-259861 AKT1 protein P31749 UNIPROT SRPK2 protein P78362 UNIPROT up-regulates phosphorylation Thr492 PSHDRSRtVSASSTG 9606 BTO:0000938 BTO:0000142 19592491 YES lperfetto Here we show that srpk2, a protein kinase specific for the serine/arginine (sr) family of splicing factors, triggers cell cycle progression in neurons and induces apoptosis through regulation of nuclear cyclin d1. Akt phosphorylates srpk2 on thr-492 and promotes its nuclear translocation leading to cyclin d1 up-regulation, cell cycle reentry, and neuronal apoptosis. 0.466 SIGNOR-186760 MTSS1 protein O43312 UNIPROT GLI1 protein P08151 UNIPROT up-regulates binding 9606 17845852 YES gcesareni Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex 0.542 SIGNOR-157650 HOXB7 protein P09629 UNIPROT FGF2 protein P09038 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 8756643 YES Luana Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter. 0.396 SIGNOR-261639 CXCR4 protein P61073 UNIPROT GNAI2 protein P04899 UNIPROT up-regulates activity binding 9606 BTO:0000007 33073183 YES Marta Tosoni Using this model, we have reported that CXCL12 activates Gi1, Gi2, or Gi3 heterotrimeric G proteins in a concentration-dependent manner 0.482 SIGNOR-278103 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 12601080 YES lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. 0.256 SIGNOR-98488 SRC protein P12931 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 YES miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  0.417 SIGNOR-276370 NBEAL2 protein Q6ZNJ1 UNIPROT VAC14 protein Q08AM6 UNIPROT unknown binding 10090 BTO:0000132 29187380 YES lperfetto In summary, from 129 binding partners of Nbeal2 identified by mass spectrometry, we have confirmed the interaction of 3, Dock7, Sec16a, and Vac14, by different biochemical and cellular approaches|Given the significant reduction of Dock7 levels and its altered localization in Nbeal2−/− platelets, we postulated that this canonical signaling pathway may be disrupted and set out to test this using control and Nbeal2−/− platelets. 0.299 SIGNOR-261892 CASK protein O14936 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 16842202 NO miannu The CASK-Mint1-Veli complex acts as an adaptor protein complex interacting with -neurexin, the current model proposes that the CASK- Mint1-Veli complex functions as a nucleation site for the assembly of proteins involved in synaptic junctions and synaptic vesicle exocytosis (Fig. 3a). 0.7 SIGNOR-278901 Neuronal AP-3 complex SIGNOR-C445 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 NO miannu BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton. 0.7 SIGNOR-268523 PPFIA1 protein Q13136 UNIPROT PTPRF protein P10586 UNIPROT up-regulates activity relocalization 9606 BTO:0000093 7796809 YES brain lperfetto We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions. 0.799 SIGNOR-264141 CHEK2 protein O96017 UNIPROT EXO1 protein Q9UQ84 UNIPROT down-regulates activity phosphorylation 9606 20690856 YES miannu Inhibition of Exo1 activity by the DDR kinase Rad53.|Unlike Sae2/CtIP activation by CDK, Exo1 phosphorylation by Rad53 limits extended resection of ssDNA at uncapped telomeres and consequently minimizes further activation of the DDR. 0.566 SIGNOR-279028 CRYAB protein P02511 UNIPROT CRYGC protein P07315 UNIPROT up-regulates activity binding -1 20621668 YES miannu Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age. 0.532 SIGNOR-253622 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation 9606 23486913 YES mTORC1 phosphorylation of EIF4EBP1 causes dissociation of the complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of translation. gcesareni These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. 0.834 SIGNOR-201541 PRKCG protein P05129 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.416 SIGNOR-249289 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr523 AGSTDENtDSEEHQE 9606 20471329 YES lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 0.396 SIGNOR-165435 TSPO2 protein Q5TGU0 UNIPROT SLC25A4 protein P12235 UNIPROT up-regulates activity binding 9606 BTO:0000424 30061676 YES miannu Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT. 0.277 SIGNOR-261825 Sin3B_complex complex SIGNOR-C409 SIGNOR H3Y1 protein P0DPK2 UNIPROT down-regulates activity binding 9606 21041487 YES miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. 0.2 SIGNOR-266975 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 14640983 YES lperfetto We used non-radioactive electrophoretic mobility shift assays to show that c-terminal phosphorylation of p53 protein by cdk2/cyclin a on ser315 or by pkc on ser378 can efficiently stimulate p53 binding to dna in vitro. 0.809 SIGNOR-217300 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 21592956 YES lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. 0.642 SIGNOR-251983 monoisononyl phthalate chemical CHEBI:132593 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268782 HIF-1 complex complex SIGNOR-C418 SIGNOR HK2 protein P52789 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 YES miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. 0.307 SIGNOR-267453 ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9168117 YES acerquone Our results demonstrate that the sh3 domain of c-abl interacts with a dpapnpphfp motif (residues 1,373-1,382) of atm.These findings indicate that atm is involved in the activation of c-abl by dna damag 0.743 SIGNOR-48822 TARS1 protein P26639 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 25824639 YES miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 0.8 SIGNOR-270505 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser482 RRIAVEYsDSEDDSS 9606 19012317 YES gcesareni Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo. 0.2 SIGNOR-182350 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser191 EDQAEEIsDELMEFS 9606 14968113 YES lperfetto Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation 0.73 SIGNOR-122090 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 BTO:0000007 11024032 YES Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed. 0.767 SIGNOR-251175 SALL4 protein Q9UJQ4 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 23954296 NO miannu Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1. 0.304 SIGNOR-255124 PPP1CB protein P62140 UNIPROT NF2 protein P35240 UNIPROT up-regulates dephosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 YES lperfetto When serine 518 is dephosphorylated by the myosin phosphatase mypt-1-pp1?, The tumor suppressor function of merlin is activated, inhibiting the ras signaling pathway and leading to growth arrest 0.379 SIGNOR-159836 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 10197981 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 0.747 SIGNOR-66778 diallyl disulfide chemical CHEBI:4488 ChEBI hsa-miR-200b-5p mirna URS000012A1DD_9606 RNAcentral up-regulates quantity by expression post transcriptional regulation 9606 BTO:0004953 23851184 YES Parnian The results indicated that DADS can suppress gastric cell proliferation and induce apoptosis through up-regulation of miR-22 and miR-200b expression. 0.4 SIGNOR-278847 NR5A1 protein Q13285 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19237537 YES miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. 0.472 SIGNOR-271788 HCK protein P08631 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9534 12235133 YES Src family kinase Hck induces phosphorylation of WASp-Tyr(291). Phosphorylation of tyrosine 291 enhances the ability of WASp to stimulate actin polymerization and filopodium formation. 0.556 SIGNOR-251268 MMP8 protein P22894 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 YES lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-8 20ADSGEGD a-chain | 442LRTGKEKV a-chain 0.2 SIGNOR-263625 UNC5D protein Q6UXZ4 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 YES miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. 0.583 SIGNOR-268167 RELA protein Q04206 UNIPROT BCL2A1 protein Q16548 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 10049356 NO gcesareni Here we show thata1,abcl-2homolog up-regulated in primary lymphocytes by different mitogens, represents a novel class of rel/nf-kb-regulated prosurvival genes. 0.518 SIGNOR-65020 EEF1A2 protein Q05639 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269530 PDYN protein P01213 UNIPROT OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.673 SIGNOR-258414 S1PR1 protein P21453 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-256992 ROS stimulus SIGNOR-ST2 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates 10090 18074631 NO lperfetto In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat. 0.7 SIGNOR-253397 VCP protein P55072 UNIPROT DDX58 protein O95786 UNIPROT down-regulates quantity by destabilization ubiquitination Lys181 ALEKERNkFSELWIV 9606 26471729 YES lperfetto Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. 0.2 SIGNOR-261000 MK-2461 chemical CID:44137946 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194378 WWP2 protein O00308 UNIPROT PAIP1 protein Q9H074 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 25266661 YES miannu Here, we show that the E6AP carboxyl terminus (HECT)-type ubiquitin ligase WW domain-containing protein 2 (WWP2), a homolog of the HECT-type ubiquitin ligase WWP1, interacts with and targets Paip1 for ubiquitination and proteasomal degradation. 0.333 SIGNOR-272842 NRP2 protein O60462 UNIPROT VEGFC protein P49767 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 YES gcesareni By in vitro binding studies we found that both vegf-c and vegf-d interact with np2, vegf-c in a heparin-independent and vegf-d in a heparin-dependent manner. 0.747 SIGNOR-147530 SRC protein P12931 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr301 PTGEAPTyVNTQQIP -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.575 SIGNOR-273925 PRKDC protein P78527 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser232 LTQLPQQsQANLLQS 9606 9368058 YES lperfetto Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites 0.33 SIGNOR-53258 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates activity phosphorylation Thr493 YTEVKTVtVKISQKN -1 28193222 YES miannu AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.  0.372 SIGNOR-276749 PPP1CC protein P36873 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity dephosphorylation Ser88 EALRRTGsPLAARYM 9606 BTO:0000007 25865883 YES lperfetto A recent study has revealed that PP1alpha and PP1gamma phosphatases are responsible for dephosphorylating MDA5 and are essential for its activation. |PP1gamma mediates dephosphorylation of MDA5 not only at Ser-88 but also at other Ser/Thr residues. 0.247 SIGNOR-264578 PRKCD protein Q05655 UNIPROT PEBP1 protein P30086 UNIPROT up-regulates phosphorylation Ser153 RGKFKVAsFRKKYEL 9606 14654844 YES miannu Here we show that the raf kinase inhibitor protein (rkip) is a physiological inhibitor of grk-2. After stimulation of gpcr, rkip dissociates from its known target, raf-1 (refs 6-8), to associate with grk-2 and block its activity. This switch is triggered by protein kinase c (pkc)-dependent phosphorylation of the rkip on serine 153. 0.301 SIGNOR-119551 IL1RL1 protein Q01638 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 YES miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  0.602 SIGNOR-277706 PLK4 protein O00444 UNIPROT PCM1 protein Q15154 UNIPROT up-regulates activity phosphorylation Ser372 RRQAESLsLTREVSQ 9606 26755742 YES miannu Plk4‚Äêmediated phosphorylation of PCM1 at S372 is critical for the proper localisation of centriolar satellites, its dimer formation and interaction with other satellite components|Therefore, Plk4 is responsible for PCM1 phosphorylation at S372. 0.572 SIGNOR-279556 PRKD1 protein Q15139 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 20179209 YES lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated 0.307 SIGNOR-163928 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 10339564 YES lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. 0.942 SIGNOR-217280 SMURF2 protein Q9HAU4 UNIPROT STAMBP protein O95630 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14755250 YES miannu RNF11 recruits AMSH to Smurf2 E3 ligase. Smurf2 promotes ubiquitination of AMSH in the presence of wt RNF11. Previously, we have shown that RNF11 interacts with the HECT-type E3 ligases AIP4 and Smurf2. Here, we show that RNF11 binds to AMSH in mammalian cells and that this interaction is independent of the RNF11 RING-finger domain and the PY motif. Our results also demonstrate that AMSH is ubiquitinated by Smurf2 E3 ligase in the presence of RNF11 and that a consequent reduction in its steady-state level requires both RNF11 and Smurf2. RNF11 therefore recruits AMSH to Smurf2 for ubiquitination, leading to its degradation by the 26S proteasome. 0.53 SIGNOR-272951 NLRX1 protein Q86UT6 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates activity binding 9606 28956771 YES Giorgia Moreover, poly(rC) binding protein 2 (PCBP2) interacts with NLRX1 to participate in the NLRX1-induced degradation of MAVS and the inhibition of antiviral responses during HCV infection. 0.4 SIGNOR-260359 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.822 SIGNOR-178395 BLVRA protein P53004 UNIPROT bilirubin(2-) smallmolecule CHEBI:57977 ChEBI down-regulates quantity chemical modification 9606 BTO:0000759 7929092 YES lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. 0.8 SIGNOR-275520 AGTR1 protein P30556 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256881 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI CYP26A1 protein O43174 UNIPROT up-regulates activity chemical activation 9606 31963453 YES lperfetto Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development 0.8 SIGNOR-265138 PJA2 protein O43164 UNIPROT PRKAR2A protein P13861 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 YES miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits 0.328 SIGNOR-271856 mTORC2 complex SIGNOR-C2 SIGNOR PRKCE protein Q02156 UNIPROT up-regulates activity phosphorylation Thr710 TREEPVLtLVDEAIV 9606 21806543 YES miannu In the present study, we have identified the mTORC2 subunit Sin1 as a direct binding partner of the PKC (protein kinase C) ε kinase domain and map the interaction to the central highly conserved region of Sin1. Exploiting the conformational dependence for PKC phosphorylation, we demonstrate that mTORC2 is essential for acute priming of PKC.  0.319 SIGNOR-276347 cortisol smallmolecule CHEBI:17650 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 YES miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). 0.8 SIGNOR-258707 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser141 MASQKRPsQRHGSKY -1 2413024 YES miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 0.347 SIGNOR-250010 STAT1 protein P42224 UNIPROT MUC4 protein Q99102 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001861 19757157 YES lperfetto Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level. 0.394 SIGNOR-254099 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 YES lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 0.291 SIGNOR-275780 CDKN2B protein P42772 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 BTO:0000763 9042862 YES gcesareni We present evidence that the different subcellular location of p15 and p27 ensures the prior access of p15 to cdk4. In the cell, p15 is localized mostly in the cytoplasm, whereas p27 is nuclear. p15 prevails over p27 or a p27 construct consisting of the cdk inhibitory domain tagged with a nuclear localization signal. However, when p15 and p27 are forced to reside in the same subcellular location, either the cytoplasm or the nucleus, p15 no longer prevents p27 from binding to cdk4. These properties allow p15 and p27 to coordinately inhibit cdk4 and cdk2. 0.878 SIGNOR-46758 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270380 ABL1 protein P00519 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Tyr268 AKMLDHEyTTKEIFR 9606 15448168 YES Manara This study demonstrates that ABL1-dependent phosphorylation up-regulates topo I activity. The ABL1 SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that ABL1 phosphorylated topo I at Tyr268 in core subdomain II. 0.4 SIGNOR-260775 MAST3 protein O60307 UNIPROT PTEN protein P60484 UNIPROT up-regulates binding 9606 15951562 YES miannu Pten binds to and is phosphorylated by mast kinases./ Pdz domain-mediated binding to pten facilitates its phosphorylation by mast kinases / pdz domain binding increases pten protein stability. 0.57 SIGNOR-138077 FYN protein P06241 UNIPROT TRPC6 protein Q9Y210 UNIPROT up-regulates activity phosphorylation 9606 21471003 YES miannu Fyn phosphorylates TRPC6 and increases its diacylglycerol stimulated single channel activity. 0.506 SIGNOR-279717 lysophosphatidic acid smallmolecule CHEBI:132742 ChEBI LPAR2 protein Q9HBW0 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257529 QSOX2 protein Q6ZRP7 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18034316 NO miannu a pro-apoptotic member of the QSOX superfamily, QSOXN, was described (Wittke et al. 2003). QSOXN was shown to sensitize neuroblastoma cells to INFγ-induced apoptosis, by still unknown mechanisms. In this context, absence of QSOX in fetal epithelia may prevent apoptosis. 0.7 SIGNOR-261365 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates quantity binding -1 10929711 YES amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAPs, and removing their inhibitory activity. Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis. 0.894 SIGNOR-80206 STUB1 protein Q9UNE7 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 30927556 YES miannu These results indicate that CHIP can ubiquitylate and degrade Snail in a GSK\u20103\u03b2\u2010independent manner.|These results suggest that CHIP negatively regulates the stability of Snail through inducing its proteasomal degradation. 0.289 SIGNOR-278545 serotonin smallmolecule CHEBI:28790 ChEBI HTR3C protein Q8WXA8 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 YES miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel 0.8 SIGNOR-264296 MAPKAPK2 protein P49137 UNIPROT RTN4 protein Q9NQC3 UNIPROT unknown phosphorylation Ser107 VAPERQPsWDPSPVS 9606 BTO:0000567;BTO:0000801 16095439 YES llicata Nogo-b is phosphorylated at ser107 in vitro by mapkap-k2 0.2 SIGNOR-139486 PAK6 protein Q9NQU5 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates activity phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 25714010 YES miannu PAK6 bound to LIMK1 and activated it via phosphorylation at Thr-508.|These data indicated that PAK6 directly phosphorylated LIMK1 at Thr-508. 0.2 SIGNOR-278970 MARCHF2 protein Q9P0N8 UNIPROT CFTR protein P13569 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23818989 YES miannu A catalytically dead MARCH2 RING mutant was unable to promote CFTR degradation.|In vivo ubiquitination assays demonstrated the ubiquitination of CFTR by MARCH2, and overexpression of MARCH2, like that of CAL and STX6, led to a dose dependent degradation of mature CFTR that was blocked by bafilomycin A1 treatment. 0.2 SIGNOR-278584 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT3 protein Q9NTG7 UNIPROT up-regulates activity phosphorylation Thr150 MVGAGIStPSGIPDF 9606 BTO:0001109 26141949 YES miannu  Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3.  0.291 SIGNOR-276922 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser296 KQRRSIIsPNFSFMG 9606 16286470 YES lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain 0.805 SIGNOR-141593 STAT1 protein P42224 UNIPROT TLR3 protein O15455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16628196 NO miannu The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection. 0.447 SIGNOR-255230 RPS6KB1 protein P23443 UNIPROT PIP5K1C protein O60331 UNIPROT down-regulates quantity by destabilization phosphorylation Ser555 RYRRRTQsSGQDGRP 27780861 YES miannu Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation. 0.2 SIGNOR-277283 CDK1 protein P06493 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 YES gcesareni At first, the data show that cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins although ar was reported as substrates for cdk9 (5) as well as cdk1 0.531 SIGNOR-175692 FMNL2 protein Q96PY5 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9606 BTO:0000567 19386263 YES miannu Phosphorylation of hCenexin1 at S796 is critical for the hCenexin1-Plk1 interaction.Here we show that a splice variant of hODF2 called hCenexin1, but not hODF2 itself, efficiently localizes to somatic centrosomes via a variant-specific C-terminal extension and recruits Plk1 through a Cdc2-dependent phospho-S796 motif within the extension. This interaction and Plk1 activity were important for proper recruitment of pericentrin and gamma-tubulin, and, ultimately, for formation of normal bipolar spindles. 0.2 SIGNOR-273614 (2s)-1-{[5-(3-Methyl-1h-Indazol-5-Yl)pyridin-3-Yl]oxy}-3-Phenylpropan-2-Amine chemical CID:11314340 PUBCHEM AKT1 protein P31749 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259688 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser320 HQSLSLAsSPKGTIE 9606 BTO:0002181 34363019 YES miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  0.2 SIGNOR-276734 citrate(3-) smallmolecule CHEBI:16947 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity precursor of 9606 24068518 YES miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. 0.8 SIGNOR-266243 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr319 TPVVSVTtPSLPPQG 9606 BTO:0000567 10849446 YES lperfetto We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. 0.71 SIGNOR-236579 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 9162089 YES gcesareni However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2. 0.521 SIGNOR-48561 D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR RAD51 protein Q06609 UNIPROT up-regulates activity relocalization 9606 23438602 YES lperfetto We examined the effect of XRCC3 depletion on redistribution of RAD51 upon IR damage|Interestingly, cells expressing the XRCC3 S225A phosphomutant showed compromised chromatin loading of RAD51 upon IR damage (Fig. 4G) while the nuclear and cytosolic fractions of RAD51 were largely unchanged|It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation. 0.677 SIGNOR-263259 NEK1 protein Q96PY6 UNIPROT ATR protein Q13535 UNIPROT up-regulates activity binding 28426283 YES lperfetto It was reported that NEK1 associates with ATR/ATRIP and primes it for activation in response to a variety of genotoxic agents 0.2 SIGNOR-275841 PLK1 protein P53350 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr206 MTSELEStSLGDSDE 9606 20823832 YES lperfetto Dvl2 bound to and was phosphorylated at thr206 by a mitotic kinase, polo-like kinase 1 (plk1), and this phosphorylation was required for spindle orientation and stable microtubule (mt)-kt attachment 0.466 SIGNOR-167858 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16899510 YES gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. 0.962 SIGNOR-148717 HOOK1 protein Q9UJC3 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity binding 9606 BTO:0000018 25331952 YES miannu The protein-tyrosine phosphatase domain and N-terminal SH2 domain of SHP2 directly interacted with Hook1. Down-regulation of Hook1 increased SHP2 activity. These results suggested that Hook1 was an endogenous negative regulator of SHP2 phosphatase activity. 0.353 SIGNOR-260642 SLBP protein Q14493 UNIPROT H2BC21 protein Q16778 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265386 PIK3CB protein P42338 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 21779497 YES lperfetto The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) 0.8 SIGNOR-175241 SHMT1 protein P34896 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity chemical modification 9606 32439610 YES lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. 0.8 SIGNOR-268226 P2RY10 protein O00398 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257213 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB7 protein Q9Y5F8 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265689 CYP17A1 protein P05093 UNIPROT pregnenolone smallmolecule CHEBI:16581 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268656 PDK4 protein Q16654 UNIPROT PC protein P11498 UNIPROT down-regulates activity phosphorylation 9606 20638986 YES miannu PDK4 phosphorylates and inhibits the pyruvate dehydrogenase complex (PDC) which catalyzes the conversion of pyruvate to acetyl-CoA in the glucose oxidation pathway. 0.374 SIGNOR-278974 PIM1 protein P11309 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation 9606 16684349 YES miannu Furthermore, catalytically active Pim-1 kinase was able to phosphorylate Runx1 and Runx3 proteins and enhance the transactivation activity of Runx1 in a dose-dependent fashion.|Pim-1 potentiates transcriptional activity of the RUNX1 transcription factor. 0.269 SIGNOR-278976 CDK3 protein Q00526 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 19118012 YES gcesareni Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation. 0.444 SIGNOR-183009 SRC protein P12931 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Tyr54 YLKERRVyVTLTCAF 9606 17456551 YES lperfetto Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors. 0.683 SIGNOR-154564 NFYB protein P25208 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15496512 NO miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. 0.2 SIGNOR-252233 SF3A1 protein Q15459 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 YES miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. 0.973 SIGNOR-263948 CHEK1 protein O14757 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity phosphorylation Ser529 ILHLSNGsVQINFFQ 9606 BTO:0000567 37596441 YES miannu  Chk1 directly phosphorylates Plk1 to disturb its interaction with Sgo1.  0.314 SIGNOR-277913 FN1 protein P02751 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates 9606 20457810 NO fspada We conclude that, by interacting with fibronectin, pref-1 activates integrin downstream signaling to activate mek/erk and to inhibit adipocyte differentiation. 0.603 SIGNOR-165350 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 ASAAGGLsPVTNLTV 9606 BTO:0000017 28192398 YES miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  0.627 SIGNOR-277343 CSNK2A1 protein P68400 UNIPROT SP1 protein P08047 UNIPROT down-regulates activity phosphorylation Thr579 GDGIHDDtAGGEEGE 9606 9153193 YES llicata Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA binding activity. | Mutation of a consensus CKII site at amino acid 579, within the second zinc finger, eliminates phosphorylation of this site and the CKII-mediated inhibition of Sp1 binding. 0.341 SIGNOR-250954 ULK2 protein Q8IYT8 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser88 LVMNMLKsSFATCVL 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274039 GYS2 protein P54840 UNIPROT α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR up-regulates quantity chemical modification 9606 26882899 YES miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. 0.2 SIGNOR-267939 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser505 SPERRCRsVELDLNQ 9606 16216881 YES lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. 0.2 SIGNOR-141014 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 16148943 YES gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 0.488 SIGNOR-140238 PRKDC protein P78527 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Thr226 LQAQNLLtQLPQQSQ 9606 9368058 YES lperfetto Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites 0.33 SIGNOR-53262 WDR45 protein Q9Y484 UNIPROT ATG2A protein Q2TAZ0 UNIPROT up-regulates activity binding 9606 BTO:0001938 28561066 YES miannu WIPI4 interacts with ATG2, AMPK and ULK1. Upon starvation and AMPK activation, WIPI4-ATG2 dissociates from AMPK and ULK1 and localizes at nascent autophagosomes, potentially supporting further autophagosome maturation. 0.523 SIGNOR-268483 Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity binding 9606 BTO:0000007 32979938 YES miannu We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F). 0.2 SIGNOR-262512 PTEN protein P60484 UNIPROT ABI1 protein Q8IZP0 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr213 PPTVPNDyMTSPARL 9606 32673396 YES lperfetto After dephosphorylation by PTEN, Abi1 is degraded by calpains.|We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway. 0.241 SIGNOR-276948 RUNX1 protein Q01196 UNIPROT hsa-mir-223 mirna URS000037EC34_9606 RNAcentral up-regulates quantity by expression transcriptional regulation 9606 25092144 NO miannu We could show that STAT5 is involved in miR-155 induction. STAT5 knockdown in FLT3-ITD model systems reduced miR-155 expression in vitro and in vivo. In silico analyses predicted an STAT binding site in the miR-155 promoter. 0.4 SIGNOR-255817 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates quantity phosphorylation 9606 BTO:0000007 16714285 YES miannu NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome. 0.771 SIGNOR-271597 MCU_MICU1_variant complex SIGNOR-C500 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.8 SIGNOR-270868 CAMK2A protein Q9UQM7 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser19 KGFRRAVsELDAKQA 9606 BTO:0000142 1680128 YES llicata This increase in ser19 phosphorylation was associated with enhanced th activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase ii (camkii) activation. 0.256 SIGNOR-20912 EDNRB protein P24530 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.576 SIGNOR-257379 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser222 EVEEEADsCFGDDED 9606 BTO:0000567 11546811 YES llicata CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | Mutation of CDC34 at CK2-targeted residues, Ser-203, Ser-222, Ser-231, Thr-233, and Ser-236, abolishes the phosphorylation of CDC34 observed in vivo and markedly shifts nuclearly localized CDC34 to the cytoplasm.  0.352 SIGNOR-251058 R547 chemical CID:6918852 PUBCHEM CCNE1 protein P24864 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206355 AP3D1 protein O14617 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 YES miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) 0.812 SIGNOR-268519 UBASH3B protein Q8TF42 UNIPROT CBL protein P22681 UNIPROT down-regulates binding 9606 15159412 YES gcesareni Sts-1 and sts-2 contain sh3 domains that interacted with cbl, ub-associated domains, which bound directly to mono-ub or to the egfr/ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of sts-1/2. Ligand-induced recruitment of sts-1/sts-2 into activated egfr complexes led to inhibition of receptor internalization, reduction in the number of egfr-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways. 0.443 SIGNOR-124897 PRKN protein O60260 UNIPROT PARK7 protein Q99497 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 17846173 YES miannu Together, these results demonstrate that parkin selectively recognizes and ubiquitinates misfolded DJ-1 in vivo. 0.2 SIGNOR-278526 LCK protein P06239 UNIPROT CD3G protein P09693 UNIPROT up-regulates activity phosphorylation 10090 2470098 YES Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. 0.559 SIGNOR-259928 APBA3 protein O96018 UNIPROT STXBP1 protein P61764 UNIPROT up-regulates activity binding 10116 9395480 YES miannu Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. 0.499 SIGNOR-264036 FGF2 protein P09038 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 10116 BTO:0001130 7687739 YES lperfetto The FGF-R2(IIIb) isoform displays high affinity for stromal cell-derived FGF-7, whereas the FGF-R2(IIIc) isoform does not recognize FGF-7 but has high affinity for the FGF-2 member of the FGF ligand family 0.897 SIGNOR-236033 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLPRPE 10090 BTO:0000944 11313479 YES Phosphorylation of AFX by PKB occurs in the nucleus. Phosphorylation of S193 reduces the rate of nuclear import. PKB-mediated phosphorylation of AFX, therefore, attenuates the import of the transcription factor, which shifts the localization of the protein from the nucleus to the cytoplasm and results in the inhibition of AFX transcriptional activity. 0.605 SIGNOR-251491 FBXL15 protein Q9H469 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0000007 21572392 YES miannu Here, we report that F-box and LRR domain-containing protein 15 (FBXL15), an F-box protein of the FBXL family, forms an Skp1-Cullin1-F-box protein-Roc1 (SCF)(FBXL15) ubiquitin ligase complex and targets Smurf1 for ubiquitination and proteasomal degradation.  FBXL15, through its leucine-rich repeat domain, specifically recognizes the large subdomain within the N-lobe of the Smurf1 HECT domain and promotes the ubiquitination of Smurf1 on K355 and K357 within the WW-HECT linker region. In this way, FBXL15 positively regulates BMP signalling in mammalian cells. 0.623 SIGNOR-271910 S100A9 protein P06702 UNIPROT TLR4 protein O00206 UNIPROT up-regulates activity binding 9606 28137827 YES miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells. S100A9 binds to TLR4 and induces signaling pathways,promoting leukemic cell differentiation and proliferation arrest. Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-kB. 0.544 SIGNOR-261918 NRG1 protein Q02297 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 YES gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3. 0.872 SIGNOR-26878 GNAQ protein P50148 UNIPROT ARHGEF28 protein Q8N1W1 UNIPROT up-regulates activity binding 9606 BTO:0000007 25922072 YES Marta Tosoni Taken together, the results suggest that active G13 and Gq form a complex with Rgnef and that G13 and Gq are upstream activators of Rgnef. 0.292 SIGNOR-278065 MAPK1 protein P28482 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates activity phosphorylation Ser421 YEPAARIsPLGALQH -1 26346493 YES miannu S421 resides within a Ser-Pro phosphoacceptor motif that is typical for ERK1/2 and recombinant ERK2 phosphorylated DYRK1B at S421 in vitro.  0.369 SIGNOR-276937 FOXJ1 protein Q92949 UNIPROT TUBA1A protein Q71U36 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.298 SIGNOR-266938 MAGEC2 protein Q9UBF1 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity binding 9606 BTO:0000594 28394358 YES lperfetto In this study, we demonstrated that the tripartite motif-containing protein 28 (TRIM28) binds directly to and promotes FBP1 for ubiquitination and degradation. MAGE-A3 and MAGE-C2, which are known to be overexpressed in HCC, can enhance TRIM28-dependent degradation of FBP1 by forming ubiquitin ligase complexes with TRIM28. 0.506 SIGNOR-267593 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr206 PNAILKLtDFGFAKE -1 7592979 YES miannu In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction 0.769 SIGNOR-250101 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR ERBB4 protein Q15303 UNIPROT up-regulates activity binding 9606 25287865 YES miannu The WW domains are essential for YAP-induced cell proliferation (261) and mediate binding of YAP/TAZ to PPxY motif-containing transcription factors such as RUNX, p73, and the cytoplasmic domain of ERBB4 or with the transcriptional cofactor WBP2 0.2 SIGNOR-277666 PRKX protein P51817 UNIPROT PKD1 protein P98161 UNIPROT up-regulates phosphorylation Ser4166 EPLPSRSsRGSKVSP 9606 17980165 YES lperfetto The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd. 0.257 SIGNOR-158852 F10 protein P00742 UNIPROT F7 protein P08709 UNIPROT up-regulates activity cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 YES lperfetto The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa. 0.54 SIGNOR-263523 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257903 MAP3K1 protein Q13233 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation 9606 9630230 YES miannu These results suggested that IKK\u03b2 was a likely substrate for MEKK1 and that MEKK1 phosphorylation of IKK\u03b2 increased its kinase activity. 0.594 SIGNOR-279339 KLF11 protein O14901 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10207080 NO Regulation miannu Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. 0.277 SIGNOR-251829 MACF1 protein Q9UPN3 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization 9606 BTO:0000938 16815997 NO lperfetto In the absence of wnt, macf1 associated with a complex that contained axin, betBeta-catenin, gsk3beta, and apc. Upon wnt stimulation, macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. Macf1 is involved in the translocation of the complex containing axin, Beta-catenin, and gsk3_ but not apc from the cytosol to the cell membrane, where axin and macf1 bind to lrp-5/6. Subsequently, gsk3_ is inactivated by phosphorylation, axin is degraded, and Beta-catenin is released and enters the nucleus, where it can activate the wnt-responsive genes. 0.402 SIGNOR-227997 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Ser239 LIRGVKSsGKVVYFT 9823 21864610 YES miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. 0.2 SIGNOR-262922 HDAC2 protein Q92769 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 28793257 NO Among histone-modifying enzymes, HDAC2 is a crit- ical negative regulator of structural and functional plasticity in the mammalian nervous system (Guan et al., 2009; Hanson et al., 2013). HDAC2 localizes to the promoters of numerous synap- tic-plasticity-associated genes, where it deacetylates histone substrates (Gra ̈ ff et al., 2012; Guan et al., 2009). Consistently, loss of HDAC2 or HDAC inhibitor treatments promotes synaptic gene expression, long-term synaptic plasticity, and memory pro- cesses, while HDAC2 overexpression has opposing effects 0.7 SIGNOR-268624 NRXN1 protein P58400 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 YES miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 0.424 SIGNOR-265459 RAB6B protein Q9NRW1 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 NO miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons 0.7 SIGNOR-266874 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207833 TAB3 protein Q8N5C8 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 YES lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. 0.365 SIGNOR-205449 PRKCA protein P17252 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates activity phosphorylation Thr193 KKRAKTItFSKNAVI -1 22139477 YES miannu The giant patch clamp together with site direct mutagenesis revealed that Thr-193 is the phosphorylation site on PKC that regulates the pH(i) sensitivity of ROMK1 channels. Mutation of PKC-induced phosphorylation sites (T193A) decreases the pH(i) sensitivity and increases the interaction of channel-PIP(2).  0.2 SIGNOR-276389 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser442 STFLAFPsPEKLLRL 9606 SIGNOR-C17 15037602 YES lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain. 0.493 SIGNOR-123520 PTK7 protein Q13308 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 23151663 YES gcesareni Ptk7 has been strongly implicated in pcp and, like many pcp activators, is a negative regulator of beta-catenin-dependent wnt. 0.403 SIGNOR-199536 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000815 18570872 YES miannu  In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. 0.746 SIGNOR-272637 CADPS2 protein Q86UW7 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 YES miannu CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly. 0.255 SIGNOR-264341 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 7889942 YES gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. 0.2 SIGNOR-252086 HBB protein P68871 UNIPROT AHSP protein Q9NZD4 UNIPROT down-regulates activity 9606 2545495 NO Regulation miannu EDRF is rapidly inactivated by hemoglobin and superoxide. 0.556 SIGNOR-251750 AKT proteinfamily SIGNOR-PF24 SIGNOR NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.2 SIGNOR-251628 PIM2 protein Q9P1W9 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 22506047 YES miannuccelli The proteasome-dependent degradation of CDC25A, seen in this study upon PIM-2 over-expression, suggests that PIM-2 promotes CDC25A phosphorylation that triggers its ubiquitylation. 0.361 SIGNOR-279750 MC4R protein P32245 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.27 SIGNOR-256940 MEN1 protein O00255 UNIPROT MLL Fusion fusion protein SIGNOR-FP14 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 YES miannu We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity. 0.2 SIGNOR-260130 MMP1 protein P03956 UNIPROT HBEGF protein Q99075 UNIPROT up-regulates activity cleavage 9606 BTO:0000811 20946474 YES Marta Tosoni We have recently reported that HB-EGF is a substrate of MT1-MMP and that removal of the N-terminal fragment of HB-EGFby MT1-MMP converts the former into a hyperactive growthfactor that does not require heparin as a co-factor. 0.33 SIGNOR-278096 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 YES lperfetto In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1. 0.368 SIGNOR-45330 CNOT9 protein Q92600 UNIPROT GIGYF2 protein Q6Y7W6 UNIPROT up-regulates activity binding 9606 BTO:0000007 20878056 YES miannu Through interaction analysis of RQCD1 with full-length or partial proteins of GIGYF1 and GIGYF2, segments corresponding to 620-665th and 667-712th amino acids were identified as potential interacting regions on GIGYF1 and GIGYF2, respectively, with RQCD1. we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2 0.2 SIGNOR-260058 MAPK13 protein O15264 UNIPROT PRKD1 protein Q15139 UNIPROT down-regulates phosphorylation 9606 19135240 YES gcesareni P38delta catalyzes an inhibitory phosphorylation of pkd1, thereby attenuating stimulated insulin secretion. 0.2 SIGNOR-183280 B4GALT1 protein P15291 UNIPROT UDP(3-) smallmolecule CHEBI:58223 ChEBI up-regulates quantity chemical modification 9606 16157350 YES miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. 0.8 SIGNOR-268470 BIRC3 protein Q13489 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. 0.646 SIGNOR-272714 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT unknown phosphorylation Tyr751 SKDESVDyVPMLDMK 9606 2550144 YES llicata We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site. 0.2 SIGNOR-22993 SCF-FBW7 complex SIGNOR-C135 SIGNOR NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000093 17574025 YES miannu We identified SCFFbw7α as an E3 ligase that binds to SRC-3 in an S505 phosphorylation-dependent manner (Figure 4Ci) and that is responsible for the further ubiquitination of SRC-3 (Figure 4A).  0.296 SIGNOR-276066 MRPL16 protein Q9NX20 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.732 SIGNOR-262377 Selinexor chemical CID:71481097 PUBCHEM XPO1 protein O14980 UNIPROT down-regulates activity chemical inhibition 9606 30510142 YES miannu Selinexor (KPT-330) is a first-in-class selective inhibitor of nuclear export (C17H11F6N7O; see ref. 4; for its chemical structure). The drug binds and inhibits exportin XPO-1 that mediates nuclear export of proteins and mRNAs. 0.8 SIGNOR-262537 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 YES lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. 0.764 SIGNOR-252867 PRKAA1 protein Q13131 UNIPROT KPNA2 protein P52292 UNIPROT up-regulates phosphorylation Ser105 QAARKLLsREKQPPI 9606 SIGNOR-C15 15342649 YES lperfetto Ampk phosphorylated importin alpha1 on ser(105). Accordingly, expression of importin alpha1 proteins bearing k22r or s105a mutations failed to mediate the nuclear import of hur in intact cells. Our results point to importin alpha1 as a critical downstream target of ampk and key mediator of ampk-triggered hur nuclear import. 0.2 SIGNOR-128629 ETNK2 protein Q9NVF9 UNIPROT O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI up-regulates quantity chemical modification 36866238 YES lperfetto Ethanolamine kinase 2 (ETNK2) is a protein-coding gene. Spondylometaphyseal dysplasia with cone-rod dystrophy is one of the diseases linked to the ETNKT2 gene. Glycerophospholipid biosynthesis and nuclear receptor meta-pathways are two of the ETNK2-related pathways. 0.8 SIGNOR-275643 MYOD1 protein P15172 UNIPROT RB1 protein P06400 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 10373569 YES gcesareni Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator. 0.395 SIGNOR-238532 POU2AF1 protein Q16633 UNIPROT POU2F2 protein P09086 UNIPROT up-regulates binding 9606 BTO:0000776 8654375 YES miannu We have shown previously that both octamer binding transcription factors, namely the ubiquitous oct-1 and the b cell-specific oct-2a protein, can be enhanced in transcriptional activity by their association with the b cell-specific coactivator protein bob1, also calledobf-1or oca-b. 0.563 SIGNOR-42278 BUB1 protein O43683 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 19015261 YES miannu Bub1 phosphorylates Sgo1 in the vicinity of its APC/C degrons in vitro.|On the other hand, Bub1 targets PP2A to centromeres, which in turn maintains Sgo1 at centromeres by counteracting Plk1 mediated chromosome removal of Sgo1. 0.2 SIGNOR-278915 Norzotepine chemical CID:10041551 PUBCHEM SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 20223878 YES Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. 0.8 SIGNOR-257830 NTSR1 protein P30989 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 10030 BTO:0000457 28341345 YES Marta Tosoni Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways 0.25 SIGNOR-278060 COL6A3 protein P12111 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 YES Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. 0.7 SIGNOR-254675 MDM4 protein O15151 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization 9606 15735705 NO lperfetto Mdm2 and mdmx function as cellular regulators of the p53 tumor suppressor protein. Intriguingly, the activities of these proteins are interdependent;mdmx stabilizes mdm2, enabling its activities towards p53 0.732 SIGNOR-134391 pertuzumab antibody DB06366 DRUGBANK ERBB2 protein P04626 UNIPROT down-regulates activity binding 9606 BTO:0000176 15093539 YES miannu Pertuzumab binds to ErbB2 near the center of domain II, sterically blocking a binding pocket necessary for receptor dimerization and signaling. 0.4 SIGNOR-259900 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu82 REVFENTeRTTEFWK 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263695 GSK3B protein P49841 UNIPROT MNX1 protein P50219 UNIPROT down-regulates phosphorylation Ser77 ADRLRAEsPSPPRLL 9606 24425879 YES miannu Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9). 0.295 SIGNOR-203657 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 YES lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. 0.846 SIGNOR-196022 IL1B protein P01584 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 NO miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. 0.7 SIGNOR-261026 AMPK complex SIGNOR-C15 SIGNOR PRPS1 protein P60891 UNIPROT down-regulates activity phosphorylation Ser180 GGAKRVTsIADRLNV 9606 BTO:0006038 29074724 YES lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. 0.243 SIGNOR-265730 panobinostat chemical CHEBI:85990 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257751 ATM protein Q13315 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity phosphorylation Ser141 DYNETDWsQEFISEV 9606 BTO:0000007 26344566 YES Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.  0.497 SIGNOR-262792 MMP14 protein P50281 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 YES lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. 0.331 SIGNOR-263610 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 28646232 YES Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels 0.352 SIGNOR-262519 HTR1F protein P30939 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-256816 MT-CO1 protein P00395 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.673 SIGNOR-267746 NTRK1 protein P04629 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 YES esanto Autophosphorylated trka binds directly to plc?, Abl, and shc. 0.843 SIGNOR-75408 DAB2IP protein Q5VWQ8 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR down-regulates 9606 27858941 NO miannu DAB2IP inactivation promotes tumor growth and survival, development, and proliferation of CSC, and resistance to chemo- and radiotherapy. It induces EMT, increases cell migration and invasion, and counteracts pro-apoptotic signaling. 0.7 SIGNOR-254778 RARS1 protein P54136 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.2 SIGNOR-270357 SMURF1 protein Q9HCE7 UNIPROT ANKRD13D protein Q6ZTN6 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272677 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 YES lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. 0.569 SIGNOR-164475 ACTL6A protein O96019 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.593 SIGNOR-269789 SRC protein P12931 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr900 EHAPAEMyDIMKTCW 9606 12878163 YES lperfetto C-src phosphorylates tyr900 in the second part of the kinase domain of c-kit. 0.387 SIGNOR-103999 XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT down-regulates quantity by destabilization binding -1 11583623 YES lperfetto Xiap is an endogenous inhibitor of caspase-7 0.859 SIGNOR-110840 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1165 RDIYETDyYRKGGKG 9606 8940173 YES lperfetto Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor 0.581 SIGNOR-45126 SGK1 protein O00141 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation 9606 28358001 YES miannu In fact, SGK1 activates and phosphorylates SP1 on serine 59, a regulator of nucleocytoplasmic trafficking related genes .|In fact, SGK1 activates and phosphorylates SP1 on serine 59, a regulator of nucleocytoplasmic trafficking-related genes xref . 0.266 SIGNOR-279246 NOTCH4 protein Q99466 UNIPROT HEY2 protein Q9UBP5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12548545 NO gcesareni Herp1 appears to be important particularly in the development of vascular tissue, and herp1might be regulated by vascular-specific isoforms of ligands and receptors such as dll4 and notch4 0.614 SIGNOR-97630 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates sumoylation Lys160 EAHQWFLkHEARPLA 9534 9756909 YES lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation. 0.779 SIGNOR-261786 NMBR protein P28336 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257160 SRC protein P12931 UNIPROT CIT protein O14578 UNIPROT up-regulates activity phosphorylation 9606 27551053 YES miannu CitK is tyrosine phosphorylated by Src in response to EphB2 signaling. 0.274 SIGNOR-279484 PTK2 protein Q05397 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Tyr664 EGGWMEDyDYVHLQG 11604500 YES lperfetto FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD. 0.81 SIGNOR-249111 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 YES gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation 0.642 SIGNOR-252444 MEN1 protein O00255 UNIPROT CDKN2C protein P42773 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15640349 NO irozzo Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. 0.489 SIGNOR-255888 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 7529876 YES llicata We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex. 0.2 SIGNOR-27879 GUCY1A2-B2 complex SIGNOR-C137 SIGNOR IDH2 protein P48735 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Thr197 GTFKMVFtPKDGSGV 34929314 YES lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome 0.2 SIGNOR-267624 TNF protein P01375 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 11287630 NO gcesareni Irs-1 tyrosine phosphorylation by tnf was blocked by rapamycin, an inhibitor of the mammalian target of rapamycin (mtor), a downstream target of akt. these results suggest that tnf impairs insulin signaling through irs-1 0.395 SIGNOR-106599 AGK protein Q53H12 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 YES lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). 0.376 SIGNOR-267708 INO80 protein Q9ULG1 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 YES miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. 0.746 SIGNOR-270853 RNF170 protein Q96K19 UNIPROT ITPR2 protein Q14571 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0000567 21610068 YES miannu In summary, here we present evidence that RNF170 is an E3 ligase that mediates IP3 receptor ubiquitination and processing by the UPP and that it is recruited to activated IP3 receptors by the erlin1/2 complex to which it is constitutively bound. 0.332 SIGNOR-271914 FCHO1 protein O14526 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 YES lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth 0.52 SIGNOR-260715 EP300 protein Q09472 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR form complex binding 9606 10506141 YES lperfetto In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300. 0.464 SIGNOR-70960 ZEB2 protein O60315 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11430829 YES Luisa SIP 1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadh promoter.SIP1 induction resulted in the loss of cell-cell adhesion, in activation of invasion and in at random, multidirectional migration instead of unidirectional coherent migration (required in neurulation). 0.488 SIGNOR-268950 CDK7 protein P50613 UNIPROT CDK11B protein P21127 UNIPROT up-regulates activity phosphorylation Thr595 GSPLKAYtPVVVTLW 9606 BTO:0000567 16327805 YES gcesareni We conclude that CDK7 phsphorylates Cdk11, dependent on the conserved Thr219 residue in the CDK11 T loop, and it is therefore likely to be a genuine Cdk11 activating kinase 0.335 SIGNOR-245871 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser39 TTSTRTYsLGSALRP -1 11895474 YES miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.¬† 0.307 SIGNOR-250239 ROS stimulus SIGNOR-ST2 SIGNOR ATM protein Q13315 UNIPROT up-regulates 9606 BTO:0000007 26344566 NO We report that the PEX5 peroxisome import receptor binds ataxia-telangiectasia mutated (ATM) and localizes this kinase to the peroxisome. In response to ROS, ATM signalling activates ULK1 and inhibits mTORC1 to induce autophagy. 0.7 SIGNOR-262791 MAPK8 protein P45983 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates quantity by stabilization phosphorylation Ser115 SQFSDCSsAKARGDL 9606 BTO:0002932 34048060 YES miannu Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. 0.272 SIGNOR-277562 RBM10 protein P98175 UNIPROT CASP3 protein P42574 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30403180 NO irozzo In this study, we report that RBM10 acts as a tumor suppressor in osteosarcoma via the inhibition of cell growth, cell migration and invasion and the induction of cell apoptosis by inhibiting Bcl-2, activating caspase-3, and producing TNF-α. We also found that RBM10 overexpression significantly inhibited the expression of Bcl-2 and induced the expression of caspase-3 0.2 SIGNOR-259152 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation 9606 31226734 YES lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. 0.668 SIGNOR-265918 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH18 protein Q13634 UNIPROT up-regulates activity chemical activation 9606 22535893 YES miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. 0.8 SIGNOR-265835 CDKN2A protein Q8N726 UNIPROT ATR protein Q13535 UNIPROT up-regulates activity phosphorylation 9606 15775976 YES gcesareni Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressorInduction of ATR activity in Hs68 E2F1ER cells by endogenous ARF. 0.392 SIGNOR-134781 TRIP12 protein Q14669 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20208519 YES miannu ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. 0.583 SIGNOR-266781 CENPI protein Q92674 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 YES lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). 0.764 SIGNOR-265213 DLG4 protein P78352 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.471 SIGNOR-270889 STAT3 protein P40763 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000801 22378047 NO IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype 0.626 SIGNOR-254517 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 YES gcesareni Serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo.cAMP increased Raf-1 serine 259 phosphorylation in a PKA-dependent manner with kinetics that correlated with ERK deactivation. 0.499 SIGNOR-86141 MAVS protein Q7Z434 UNIPROT IFNB1 protein P01574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22588174 NO Giorgia ECSIT enhances IPS-1-mediated IFN-Beta promoter activation 0.488 SIGNOR-260372 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser171 VTHDLRVsLEEIYSG 9606 24309468 YES lperfetto Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1. 0.461 SIGNOR-203464 FOXH1 protein O75593 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 BTO:0001538 9858566 YES lperfetto FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1. 0.777 SIGNOR-108333 RBPJ protein Q06330 UNIPROT PAX7 protein P23759 UNIPROT up-regulates binding 9606 22493066 YES gcesareni Nicd regulates pax7 through interaction with rbp-j, which binds to two consensus sites upstream of the pax7 gene. 0.363 SIGNOR-196948 ADORA2B protein P29275 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.297 SIGNOR-257240 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser390 EEERLRLsPSPTSQR 9606 18815303 YES gcesareni Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm 0.537 SIGNOR-181314 PRKAA1 protein Q13131 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Thr1114 APAALGStGTVAHLV -1 23871434 YES miannu These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J). 0.2 SIGNOR-276469 CAMK2D protein Q13557 UNIPROT VIM protein P08670 UNIPROT unknown phosphorylation Ser83 GVRLLQDsVDFSLAD BTO:0001444 16140754 YES llicata Interestingly, viral DNA replication also resulted in the activation of calcium calmodulin-dependent protein kinase II (CaM kinase II) and phosphorylation of the N-terminal domain of vimentin on serine 82. Immunostaining showed that vimentin within the cage was phosphorylated on serine 82. 0.328 SIGNOR-250690 GUCY1A2-B3 complex SIGNOR-C138 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 YES gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types 0.8 SIGNOR-244093 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1393 GSVPLSSsPPATHFP 9606 7635160 YES llicata We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. phosphopeptide 1 was eliminated by replacement of ser1392 0.526 SIGNOR-30256 GXYLT1 protein Q4G148 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates glycosylation 9606 22117070 YES Xylosylation in endoplasmic reticulum membrane gcesareni Activity on notch egf repeats was proven by in vitro xylosylation of a mouse notch1 fragment recombinantly produced in sf9 insect cells, a bacterially expressed egf repeat from mouse notch2 modified in vitro by rumi and gxylt2 and in vivo by co-expression of the enzyme with the notch1 fragment. 0.383 SIGNOR-177691 FBN1 protein P35555 UNIPROT FBLN5 protein Q9UBX5 UNIPROT down-regulates activity binding 9606 19570982 YES miannu Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. We have determined how they interact with tropoelastin, lysyl oxidase, and fibrillin-1, thereby revealing how they differentially regulate assembly. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin. 0.39 SIGNOR-252138 CFD protein P00746 UNIPROT CFB protein P00751 UNIPROT up-regulates activity cleavage Arg259 GPGEQQKrKIVLDPS 9606 BTO:0000089 26489954 YES lperfetto The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb 0.804 SIGNOR-263487 FBXO30 protein Q8TB52 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0000887 24076600 NO gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1) 0.7 SIGNOR-256489 SRC protein P12931 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity phosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 34725361 YES miannu Src phosphorylation promotes the intrinsic exchange rate of KRAS Q61H.|Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells. 0.657 SIGNOR-278990 BRAF protein P15056 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser465 TVGQRIGsGSFGTVY 9606 31929109 YES miannu We previously identified that BRAFWT can autophosphorylate its P-loop (Ser-465/Ser-467) to inactivate itself in the absence of native substrate MEK 0.2 SIGNOR-277498 DDB2 protein Q92466 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 BTO:0000567 9418871 YES miannu We show that ddb, a putative dna repair protein, associates with the activation domain of e2f1 / expression of ddb specifically stimulated e2f1-activated transcription 0.367 SIGNOR-54102 PPP2R5C protein Q13362 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates binding 9606 16456541 YES inferred from 70% of family members gcesareni B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk 0.519 SIGNOR-269922 SALL4 protein Q9UJQ4 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16840789 YES Luana We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog.  0.791 SIGNOR-266079 STXBP2 protein Q15833 UNIPROT STX11 protein O75558 UNIPROT up-regulates activity binding 9606 BTO:0000782 28265073 YES lperfetto Strikingly, addition of Munc18-2 substantially and selectively facilitates complete fusion mediated by lipid-anchored STX11 by promoting and stabilizing the assembly of SNARE complexes. 0.63 SIGNOR-261898 MUTYH protein Q9UIF7 UNIPROT ATR protein Q13535 UNIPROT up-regulates binding 9606 BTO:0000007 21615992 YES miannu Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis. 0.25 SIGNOR-173966 ATOH1 protein Q92858 UNIPROT MUC2 protein Q02817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17000673 NO miannu This study confirms the importance of HATH1 for the development of intestinal secretory cells. The results further suggest that HATH1 is an important factor in the up-regulation of MUC2 expression that occurs in mucinous cancers and signet ring carcinomas. 0.2 SIGNOR-253755 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 9606 21084559 YES gcesareni Phosphorylation of yap ser127 and of the corresponding sites in yki and taz generates a protein-binding motif for the 14-3-3 family proteins, which, upon binding by a 14-3-3 protein, leads to their cytoplasmic retention. 0.2 SIGNOR-169716 CDK2 protein P24941 UNIPROT RNF4 protein P78317 UNIPROT up-regulates activity phosphorylation Thr26 RTREATStPEISLEA 9606 BTO:0002181 25948581 YES miannu Here we reported that CDK2 could phosphorylate RNF4 on T26 and T112 and enhance RNF4 E3 ligase activity, which is important for MDC1 degradation and proper HR repair during S phase.  0.2 SIGNOR-276900 PI3K complex SIGNOR-C156 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 19436055 NO apalma Low pM concentrations of GM-CSF mediate βc Ser585 phosphorylation, leading to 14-3-3 binding, PI-3 kinase activation, and hemopoietic cell survival, whereas at concentrations of 10 pM or more, GM-CSF mediates βc Tyr577 phosphorylation, Shc recruitment, and PI-3 kinase activation, thereby promoting both survival and proliferation. 0.7 SIGNOR-255576 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000762 12509763 YES lperfetto Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers. 0.2 SIGNOR-253214 MSL2 protein Q9HCI7 UNIPROT MSL acetyltransferase complex SIGNOR-C344 SIGNOR form complex binding 9606 BTO:0000567 16227571 YES miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 0.897 SIGNOR-263941 MMP20 protein O60882 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272365 SRC protein P12931 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 YES miannu Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. 0.42 SIGNOR-277520 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr514 PATPKYAtPAPSAKS 9606 BTO:0000938 16611631 YES lperfetto Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5 0.469 SIGNOR-145999 TBK1 protein Q9UHD2 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 YES lperfetto Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling. 0.408 SIGNOR-252608 LAMTOR4 protein Q0VGL1 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 YES lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant 0.926 SIGNOR-164778 RNF183 protein Q96D59 UNIPROT TNFRSF10B protein O14763 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31889078 YES miannu RNF183 mediated K63-linked ubiquitination and lysosomal degradation of DR5. 0.2 SIGNOR-272212 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates activity phosphorylation Ser866 TAEVKEDsAYGSQSV 9606 BTO:0000007 11239468 YES lperfetto NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870 0.676 SIGNOR-105553 dopamine smallmolecule CHEBI:18243 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 NBK536726 YES brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. 0.8 SIGNOR-264181 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP9X protein Q93008 UNIPROT up-regulates activity phosphorylation Ser2547 YEGSEEVsPPQTKDQ 32152317 YES Phosphosites were derived from Figure S1 lperfetto Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis. 0.27 SIGNOR-275612 PRKG1 protein Q13976 UNIPROT SF1 protein Q15637 UNIPROT down-regulates activity phosphorylation Ser20 PSKKRKRsRWNQDTM 10116 BTO:0000947 10449420 YES lperfetto PKG phosphorylates SF1 at Ser20, which inhibits the SF1-U2AF65 interaction leading to a block of pre-spliceosome assembly. Mutation of Ser20 to Ala or Thr also inhibits the interaction with U2AF65, indicating that Ser20 is essential for binding. 0.439 SIGNOR-249018 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15498859 YES lperfetto Pim-1 is know to be up regulated by signal transducer and activator of transcription 5 (stat5) 0.376 SIGNOR-249606 SMARCB1 protein Q12824 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.855 SIGNOR-270697 IL1R1 protein P14778 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity 9606 BTO:0000007 14625308 NO lperfetto Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1. 0.915 SIGNOR-119208 MAPK3 protein P27361 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 YES Translocation from Nucleus to Cytoplasm esanto We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats. 0.53 SIGNOR-74564 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 19789335 YES gcesareni Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha. 0.841 SIGNOR-188325 APBA1 protein Q02410 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9534 BTO:0000298 11036064 YES miannu Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa. 0.666 SIGNOR-264038 SOD2 protein P04179 UNIPROT hydrogen peroxide smallmolecule CHEBI:16240 ChEBI up-regulates quantity chemical modification 9606 29301787 YES lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). 0.8 SIGNOR-272283 PRKG2 protein Q13237 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity phosphorylation Ser254 WTYPRKEsGRLVEPV 9606 BTO:0001007 35066967 YES miannu Secretory PKG II inhibited PDGF‐BB ‐induced PDGFRβ activation via phosphorylating its Ser254. 0.272 SIGNOR-277577 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser5 sVSSGGAG 9606 20471944 YES lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). 0.847 SIGNOR-165562 CAMK2B protein Q13554 UNIPROT PLCB3 protein Q01970 UNIPROT unknown phosphorylation Ser537 PSLEPQKsLGDEGLN 11325525 YES llicata CaMK II phosphorylated PLCbeta3 but not PLCbeta1 in vitro. Phosphorylation occurred exclusively on 537Ser in the X-Y linker region of PLCbeta3. 537Ser was also phosphorylated in the basal state in cells and phosphorylation was enhanced by ionomycin treatment 0.518 SIGNOR-250689 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 YES lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex 0.416 SIGNOR-216949 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 SIGNOR-C3 12747827 YES lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. 0.926 SIGNOR-101123 AKAP12 protein Q02952 UNIPROT PKC proteinfamily SIGNOR-PF53 SIGNOR up-regulates activity relocalization 14657015 YES lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. 0.46 SIGNOR-271838 TP53 protein P04637 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 19007744 NO Translocation from Mitochondria to Cytosol lperfetto P53 translocation precedes changes of mitochondrial membrane potential, cytochrome c release and caspase activation 0.456 SIGNOR-140251 ADRA1B protein P35368 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.613 SIGNOR-257079 USP5 protein P45974 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.847 SIGNOR-270830 SIRT1 protein Q96EB6 UNIPROT XBP1 protein P17861-2 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 20955178 YES miannu P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR. 0.379 SIGNOR-260430 NDUFA8 protein P51970 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added 0.825 SIGNOR-262159 ANXA3 protein P12429 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates activity 9606 BTO:0000018 27995049 NO miannu We also investigated the potential regulation of cancer-associated signaling pathways by Anxa3 through screening for the altered expression of some common signaling molecules after Anxa3 downregulation. Decreased phosphorylation of MEK1/2, ERK1/2, Akt, and IκBα was detected after downregulating Anxa3 expression in A549 cells. 0.2 SIGNOR-262213 NRBF2 protein Q96F24 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR down-regulates activity binding 9606 BTO:0001938 phosphorylation:Ser113;Ser120 AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL 24785657 YES miannu We have now identified NRBF2 (nuclear receptor-binding factor 2) as a new member of Vps34 Complex I. NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L, but not the Vps34 Complex II component UVRAG (UV radiation resistance-associated gene). NRBF2 directly interacts with Vps15 via the Vps15 WD40 domain as well as other regions of Vps15. Thus NRBF2 plays a critical role in the induction of starvation-induced autophagy as a specific member of Vps34 Complex I. 0.712 SIGNOR-265880 FAM83A protein Q86UY5 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 YES miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. 0.2 SIGNOR-273765 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.2 SIGNOR-269170 MAPK1 protein P28482 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 22139079 YES Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. 0.2 SIGNOR-195153 DVL1 protein O14640 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity binding 9606 SIGNOR-C110 20837657 YES gcesareni In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. 0.62 SIGNOR-167957 IFNLR1 protein Q8IU57 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 15120645 YES gcesareni Despite signaling through distinct receptor complexes, type i ifns and ifn-_s activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (fig. 6). In both cases, receptor engagement leads via the activation of the jak kinases jak1 and tyk2 0.558 SIGNOR-124483 CDC14A protein Q9UNH5 UNIPROT SPAG5 protein Q96R06 UNIPROT down-regulates activity dephosphorylation 9606 27325694 YES miannu We also demonstrate that Cdc14A dephosphorylates Astrin, and therefore the overexpression of Cdc14A sequesters Astrin in the centrosome and results in aberrant chromosome alignment. 0.2 SIGNOR-277066 DUSP22 protein Q9NRW4 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation 9606 27557500 YES miannu Because JKAP dephosphorylates and inactivates Lck in T cells [ xref ], we studied whether JKAP downregulation results in Lck activation in SLE T cells. 0.274 SIGNOR-277148 AKT proteinfamily SIGNOR-PF24 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 YES lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. 0.2 SIGNOR-244222 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser257 DSFESIEsYDSCDRL BTO:0003637 12475968 YES llicata Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1  0.31 SIGNOR-250685 LAMTOR5 protein O43504 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 YES lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant 0.898 SIGNOR-164781 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 18177723 NO miannu Altogether, these data demonstrate that IL-6 loss results in deficient STAT3 signaling in activated satellite cells, leading to their reduced proliferation and myogenic progression, and highlight the major role played by the IL-6/STAT3 axis in controlling these processes during compensatory hypertrophy. 0.7 SIGNOR-255632 HNRNPU protein Q00839 UNIPROT IER3 protein P46695 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 NO lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. 0.2 SIGNOR-262285 NR3C1 protein P04150 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates activity 10090 BTO:0000944 11742987 NO inferred from 70% of family members gcesareni Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. 0.2 SIGNOR-269898 NCBP1 protein Q09161 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 26382858 YES lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. 0.8 SIGNOR-268363 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS -1 8943232 YES lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261770 NR0B2 protein Q15466 UNIPROT ESR2 protein Q92731 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10648597 NO gcesareni These novel insights provide a mechanistic explanation for the inhibitory role of shp in nuclear receptor signaling, and they may explain how shp functions as a negative coregulator or corepressor for ligand-activated receptors, a novel and unique function for an orphan nuclear receptor. 0.624 SIGNOR-74291 NCF1 protein P14598 UNIPROT CYBA protein P13498 UNIPROT up-regulates activity binding 9606 12672956 YES miannu Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase. 0.789 SIGNOR-276625 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14670075 YES lperfetto Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages 0.936 SIGNOR-120268 FFAR2 protein O15552 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.49 SIGNOR-257188 PTPN11 protein Q06124 UNIPROT GRB7 protein Q14451 UNIPROT up-regulates activity dephosphorylation 9606 20142421 YES miannu Dephosphorylation of Grb7 was blocked by the SHP inhibitor NSC-87877 (Zhan et al., 2009), supporting the specificity of SHP-2 in dephosphorylating Grb7.|Nuclear SHP-2 mediates the formation of an EGF induced complex of Grb7, HuR, and CRM1.|Using the \u03ba\u2013opioid receptor (OR [KOR]) as a model, we demonstrate that EGF activates nuclear SHP-2 (Src homology region 2\u2013containing tyrosine phosphatase), which dephosphorylates Grb7 in the nucleus. 0.436 SIGNOR-277169 NUMA1 protein Q14980 UNIPROT TUBB6 protein Q9BUF5 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.2 SIGNOR-117109 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser9 LTFMASDsEEEVCDE -1 8972483 YES llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  0.307 SIGNOR-250937 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity precursor of 9606 6698284 YES miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). 0.8 SIGNOR-268096 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 19833129 YES gcesareni Polo-like kinase-1 phosphorylates mdm2 at ser260 and stimulates mdm2-mediated p53 turnover. 0.466 SIGNOR-188471 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser339 GKRGGHSsVSTESES 9606 10521508 YES Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. 0.2 SIGNOR-260901 POMC protein P01189 UNIPROT MC4R protein P32245 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.777 SIGNOR-268710 COPS5 protein Q92905 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.942 SIGNOR-270775 FOXO3 protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 14981546 NO Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim 0.746 SIGNOR-261527 LATS2 protein Q9NRM7 UNIPROT AMOT protein Q4VCS5 UNIPROT up-regulates quantity by stabilization phosphorylation Ser175 QGHVRSLsERLMQMS 24101513 YES lperfetto Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130 0.517 SIGNOR-275846 AKT1 protein P31749 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 YES lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. 0.87 SIGNOR-236159 PRKCD protein Q05655 UNIPROT TP73 protein O15350 UNIPROT up-regulates phosphorylation Ser289 GQVLGRRsFEGRICA 9606 12097319 YES llicata The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation. 0.307 SIGNOR-90279 BAP1 protein Q92560 UNIPROT KEAP1 protein Q14145 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 35052618 YES miannu BAP1 directly binds to and deubiquitinates KEAP1. BAP1 stabilizes KEAP1 by binding to the BTB domain. 0.2 SIGNOR-268924 FLT3 protein P36888 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates activity 9606 BTO:0002144 28194038 NO Here, we report that FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity 0.7 SIGNOR-259982 IL26 protein Q9NPH9 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 17208301 YES gcesareni See table 2 0.599 SIGNOR-151917 UBE2G2 protein P60604 UNIPROT SYVN1 protein Q86TM6 UNIPROT up-regulates activity ubiquitination 10090 BTO:0000944 14593114 YES miannu We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain. In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation. 0.661 SIGNOR-272593 AKT1 protein P31749 UNIPROT RAB3IP protein Q96QF0 UNIPROT up-regulates activity phosphorylation Ser165 LSRLRSPsVLEVREK 9606 BTO:0001950 36797475 YES miannu Rabin8 is phosphorylated and activated by Akt in cells grown on stiff ECM. 0.2 SIGNOR-277802 CAPN1 protein P07384 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 BTO:0000590 25969760 YES lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain 0.575 SIGNOR-251581 AKT1 protein P31749 UNIPROT LARP6 protein Q9BRS8 UNIPROT up-regulates activity phosphorylation Ser451 QEKSPGTsPLLSRKM 9606 BTO:0000007 26932461 YES miannu Akt dependent phosphorylation of LARP6. We provide the first description that LARP6 is phosphorylated at multiple sites and that phosphorylation of S451 is critical to activate the protein in type I collagen biosynthesis. 0.354 SIGNOR-277213 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1361 SYEEHIPyTHMNGGK -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 0.2 SIGNOR-233560 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser336 QEAPERAsSVYTRST 9534 BTO:0000298 10085131 YES Serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. CCR5 phosphorylation and desensitization through a GRK-mediated mechanism 0.2 SIGNOR-251463 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 20151718 YES miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). 0.275 SIGNOR-163756 Glutaminolysis phenotype SIGNOR-PH119 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 NO Luana Glutaminolysis Is Required for the Activation of mTORC1 by Leucine and Glutamine 0.7 SIGNOR-268007 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1055 VPEGHEYyRVREDGD 9606 8702790 YES llicata These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1. 0.525 SIGNOR-43084 AKT3 protein Q9Y243 UNIPROT IWS1 protein Q96ST2 UNIPROT up-regulates activity phosphorylation Ser720 PQRRRMNsTGGQTPR 9606 BTO:0003536 24462114 YES miannu The data presented in this report confirmed the differential phosphorylation of IWS1 at Ser720/Thr721 by Akt3 and Akt1 and showed that its phosphorylation at this site is required for the recruitment of SetD2 to the Spt6-IWS1-Aly/REF complex. 0.381 SIGNOR-273496 SRC protein P12931 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 11279024 YES lperfetto Beta-catenin is a good substrate of pp60c- src tyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654,although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation. 0.76 SIGNOR-106454 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269379 CSNK1A1 protein P48729 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates activity phosphorylation Ser207 AARFTLGsPLTSPGG 9606 BTO:0001131 9630228 YES lperfetto Dominant-negative cki? Induces nuclear import of nf-at4these results demonstrated that the cki? Phosphorylation sites identified in vitro were also specifically phosphorylated by cki? In vivo, and that these residues were crucial for the masking of the nls of nf-at4. 0.589 SIGNOR-109800 TRIM27 protein P14373 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates activity ubiquitination Lys119 TGHIYAMkILRKSDM 10090 35670107 YES K11 corresponds to the 11th Lysine, which is in position 119 in the full length sequence lperfetto TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1 0.2 SIGNOR-270347 CDK2 protein P24941 UNIPROT TOB2 protein Q14106 UNIPROT up-regulates activity phosphorylation Ser254 PAPQSQLsPNAKEFV -1 32404348 YES miannu Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. 0.246 SIGNOR-273601 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates 9606 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268580 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 26003525 YES miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. 0.8 SIGNOR-267508 DAB2IP protein Q5VWQ8 UNIPROT KIT protein P10721 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 27858941 NO miannu DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene 0.275 SIGNOR-254769 Riluzole chemical CHEBI:8863 ChEBI KCNN3 protein Q9UGI6 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 18955585 YES Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  0.8 SIGNOR-258019 NDUFA7 protein O95182 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. 0.825 SIGNOR-262158 CSNK1A1L protein Q8N752 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 21606194 YES gcesareni Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms 0.254 SIGNOR-173853 p38 proteinfamily SIGNOR-PF16 SIGNOR FH protein P07954 UNIPROT up-regulates activity phosphorylation Thr90 GVTERMPtPVIKAFG 9606 BTO:0002058 30683654 YES miannu In this study, we found that TGFβ induces FH Thr 90 phosphorylation by p38. Upon Notch activation, nuclear NICD promotes the interaction between CSL and p38-phosphorylated FH and thus FH/CSL/p53/Smad complex formation; this facilitates FH recruitment to p53-targed p21 promoter, where FH inhibits KDM2A-mediated demethylation of H3K36me2 through local production of fumarate 0.2 SIGNOR-266316 MAPK1 protein P28482 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 12792650 YES lperfetto Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK 0.534 SIGNOR-101544 sertindole chemical CHEBI:9122 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 9534 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258547 CDK1 protein P06493 UNIPROT DES protein P17661 UNIPROT down-regulates quantity by destabilization phosphorylation Ser31 FPLGSPLsSPVFPRA 9606 32042098 YES miannu In line with this, we found that in Drp/MC mice desmin was hyperphosphorylated in Ser-31 by a hyperactivated Cdk-1. 0.2 SIGNOR-278331 ESR1 protein P03372 UNIPROT MYC protein P01106 UNIPROT unknown transcriptional regulation 9606 BTO:0000356 11517191 NO ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression 0.728 SIGNOR-253941 CDK5R1 protein Q15078 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR form complex binding 9606 11331872 YES lperfetto Induced p35 forms a complex with Cdk5 and activates its kinase activity 0.943 SIGNOR-250682 Caspase 8 complex complex SIGNOR-C231 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 NO amattioni Downstream of caspase-8 activation, apoptosis induction takes place 0.7 SIGNOR-256641 NECTIN2 protein Q92692 UNIPROT CD226 protein Q15762 UNIPROT up-regulates activity binding 9606 BTO:0000914 15039383 YES lperfetto CD226 (DNAM-1) is an adhesion molecule involved in NK and T cell-mediated cytotoxicity against certain tumors. Here, we have identified the human poliovirus receptor-related (PRR) family members CD155 [poliovirus receptor (PVR)] and CD112 (nectin-2/PRR-2) as the ligands for human CD226. 0.2 SIGNOR-261426 PRDM1 protein O75626 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12052884 NO miannu Blimp-1-dependent repression of pax-5 is required for differentiation of b cells to immunoglobulin m-secreting plasma cells 0.502 SIGNOR-89032 PCSK7 protein Q16549 UNIPROT DDB2 protein Q92466 UNIPROT down-regulates 9606 18806262 NO The phosphorylation of DDB2 by p38 promotes its ubiquitination gcesareni The data suggest that p38 mapk is involved in serine phosphorylation of ddb2, which may influence its ubiquitylation following irradiation. 0.2 SIGNOR-181278 YES1 protein P07947 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr80 LLDACGFyWGPLSVH 9606 BTO:0000104 31101761 YES miannu  Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization.  0.2 SIGNOR-277453 TTK protein P33981 UNIPROT MAPT protein P10636 UNIPROT up-regulates activity phosphorylation 9606 11257498 YES miannu Fig. 6C-1 shows that the GST-TTK fusion protein phosphorylated both tau and tubulin, but the phosphorylating activity on tau was much higher than that on tubulin. 0.2 SIGNOR-279132 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Thr481 HVQRVLRtPGRQSPG 9606 10581160 YES Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP 0.92 SIGNOR-251222 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Ile536 RSLDRRGiQRAADIE -1 9242537 YES lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity. 0.367 SIGNOR-263636 ACAT1 protein P24752 UNIPROT IDH2 protein P48735 UNIPROT down-regulates activity acetylation Lys413 VESGAMTkDLAGCIH 9606 BTO:0001545 34289383 YES lperfetto Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers 0.287 SIGNOR-267627 NFKB1 protein P19838 UNIPROT hsa-miR-146a mirna URS00005E1F00_9606 RNAcentral up-regulates quantity by expression post transcriptional regulation 9606 BTO:0000815 23647548 YES These data suggest that TRAIL induces miR-146a expression in an NF-κB-dependent manner in MDA-MB-231 breast cancer cells. 0.4 SIGNOR-277937 FNIP1 protein Q8TF40 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 YES miannu FNIP1 and FNIP2 facilitate FLCN binding to Hsp90 chaperone. Our results suggest that FNIP1 is a potent inhibitor of Hsp90 ATPase activity, as 200 nM of FNIP1 inhibits Hsp90 ATPase activity by 50-fold. FNIP2 also has shown inhibitory activity towards Hsp90; however, it required 1.6 μM of FNIP2 to inhibit the ATPase activity by eightfold. Although we use the term ‘inhibition' here, FNIPs seem only to be slowing the chaperone cycle. 0.548 SIGNOR-261413 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 YES lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation 0.889 SIGNOR-216396 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM6 protein O15303 UNIPROT up-regulates activity chemical activation 9606 25042998 YES miannu Glutamate is the major excitatory neurotransmitter in the central nervous system. Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. 0.8 SIGNOR-264076 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AMPH protein P49418 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 15262992 YES inferred from 70% family members lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. 0.2 SIGNOR-270197 CYP17A1 protein P05093 UNIPROT dehydroepiandrosterone chemical CHEBI:28689 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 YES lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. 0.8 SIGNOR-268651 ATM protein Q13315 UNIPROT PVR protein P15151 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000914 21406724 NO The up-regulation of PVR expression involves DNA-damage response (DDR)-dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker γH2AX. 0.25 SIGNOR-253927 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser70 RSSHYGGsLPNVNQI 9606 BTO:0000567 16306228 YES lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression 0.643 SIGNOR-249169 Carebastine chemical CID:65820 PUBCHEM HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 YES Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells 0.8 SIGNOR-257783 UBE2D1 protein P51668 UNIPROT TRIM65 protein Q6PJ69 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 24778252 YES miannu Ubiquitination assays demonstrate that TRIM65 is an ubiquitin E3 ligase for TNRC6 proteins. The combination of overexpression and knockdown studies establishes that TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6. TRIM65 regulates ubiquitination and stability of TNRC6. (A) In vitro ubiquitination of TNRC6A by TRIM65 plus E1, E2 (UBCH5A, also known as UBE2D1), ATP, and HA-Ub. GST-tagged TRIM65 and mutant TRIM65 were purified from bacteria. TRIM65 regulates ubiquitination and stability of TNRC6. (A) In vitro ubiquitination of TNRC6A by TRIM65 plus E1, E2 (UBCH5A, also known as UBE2D1), ATP, and HA-Ub. GST-tagged TRIM65 and mutant TRIM65 were purified from bacteria. 0.298 SIGNOR-272175 MAPK3 protein P27361 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 18245089 YES gcesareni In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. 0.342 SIGNOR-160617 BCL11A protein Q9H165 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 NO Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. 0.446 SIGNOR-251802 TWIST1 protein Q15672 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 NO miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. 0.483 SIGNOR-255157 SAGA complex complex SIGNOR-C465 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 34811519 YES lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269627 GNB/GNG complex SIGNOR-C202 SIGNOR ADCY5 protein O95622 UNIPROT down-regulates activity binding 9534 BTO:0000298 9707174 YES Marta Tosoni These results demonstrate that adenylyl cyclase types V and Vi are inhibited by Gbetagamma dimers. 0.458 SIGNOR-278046 GP1BA protein P07359 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 BTO:0000132 16293600 YES lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. 0.707 SIGNOR-261847 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI KEAP1 protein Q14145 UNIPROT up-regulates activity chemical modification CYS622 KQIDQQNcTC 9606 32284348 YES miannu In response to oxidative stress, the direct binding of stressors to reactive cysteine residues results in a conformation change in KEAP1, which inhibits the ubiquitination of NRF2. the sensor for H2O2 consists of four residues within KEAP1: Cys226, Cys613, Cys622, and Cys624.KEAP1 uses multiple sensing mechanisms to coordinate the NRF2-dependent oxidative stress response. 0.8 SIGNOR-279847 Immunoglobulin mu heavy chain protein P0DOX6 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323265 YES scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. 0.2 SIGNOR-268191 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser272 EEPSPLPsPTASPNH -1 11113134 YES llicata Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells.  0.522 SIGNOR-250648 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI KEAP1 protein Q14145 UNIPROT up-regulates activity chemical modification CYS624 IDQQNCTc 9606 32284348 YES miannu In response to oxidative stress, the direct binding of stressors to reactive cysteine residues results in a conformation change in KEAP1, which inhibits the ubiquitination of NRF2. the sensor for H2O2 consists of four residues within KEAP1: Cys226, Cys613, Cys622, and Cys624.KEAP1 uses multiple sensing mechanisms to coordinate the NRF2-dependent oxidative stress response. 0.8 SIGNOR-279848 RPS6KA1 protein Q15418 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 23708659 YES lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. 0.253 SIGNOR-202121 FKBP5 protein Q13451 UNIPROT YY1 protein P25490 UNIPROT up-regulates activity 9606 BTO:0000848 34589486 NO miannu FKBP51 Affects the Binding of YY1 Repressor to DR5 Gene. These results suggest that reduced YY1 DNA-binding activity in FKBP51-silenced cells corresponds to reduced YY1 acetylation. 0.2 SIGNOR-268792 SRC protein P12931 UNIPROT PLSCR1 protein O15162 UNIPROT up-regulates activity phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 12871937 YES lperfetto Plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77.|The EGF-mediated Interaction between PLSCR1 and Shc Requires Phosphorylation of Tyr69 and Tyr74 in PLSCR1 0.476 SIGNOR-103769 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 24746699 YES lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH 0.726 SIGNOR-269381 HIP1 protein O00291 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001130 16027218 NO miannu Hip1 as a transcriptional regulator of the ar / silencing hip1 expression reduces the transcriptional activity and protein levels of the ar 0.2 SIGNOR-138820 CSNK2A1 protein P68400 UNIPROT WAS protein P42768 UNIPROT up-regulates phosphorylation Ser484 RSRAIHSsDEGEDQA 9606 12769847 YES gcesareni Here we identify two phosphorylation sites in the vca domain of wasp at serines 483 and 484. S483 and s484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the vca domain for the arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length wasp molecule. 0.354 SIGNOR-101268 PRKCB protein P05771 UNIPROT MSX2 protein P35548 UNIPROT up-regulates quantity phosphorylation Thr135 HMSPTTCtLRKHKTN 9606 22633971 YES miannu PKCbeta increased the level of overexpressed Msx2, but PKC alpha, delta and zeta did not have any significant effects.|Thr135 and Thr141 in Msx2 can be phosphorylated by PKC\u03b2, and Thr135 is important for regulating the protein stability of Msx2 by PKCs. 0.322 SIGNOR-278982 CBX3 protein Q13185 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 YES miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. 0.2 SIGNOR-264496 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL 9606 21364637 YES miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells 0.2 SIGNOR-277644 LYN protein P07948 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates activity phosphorylation Tyr380 TDSEEQPyLEMDLSS 18086677 YES lperfetto The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. 0.311 SIGNOR-272979 NFE2L2 protein Q16236 UNIPROT GSR protein P00390 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy 0.406 SIGNOR-279871 NFE2L2 protein Q16236 UNIPROT GPX4 protein P36969 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.GPX4 stands out within the GPX family due to its unique ability to reduce lipid hydroperoxides directly within cell membranes, thereby safeguarding cells from lipid peroxidation and ferroptosis. 0.384 SIGNOR-279872 JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 YES lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities 0.2 SIGNOR-137631 acetyl-CoA smallmolecule CHEBI:15351 ChEBI (3S)-3-hydroxy-3-methylglutaryl-CoA(5-) smallmolecule CHEBI:43074 ChEBI up-regulates quantity precursor of 29597274 YES lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis 0.8 SIGNOR-267651 CSNK2A1 protein P68400 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Ser204 KNSRVTFsEDDEIIN -1 9407077 YES llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. 0.472 SIGNOR-250930 NFE2L2 protein Q16236 UNIPROT GSR protein P00390 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Importantly, GCLC, GCLM, GSS, and GSR are transcriptional targets of NFE2L2. Their upregulation is implicated in conferring resistance to ferroptosis across various contexts, including chemotherapy and radiation therapy 0.406 SIGNOR-279873 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2M protein P61081 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.7 SIGNOR-271366 NFE2L2 protein Q16236 UNIPROT GPX4 protein P36969 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.GPX4 stands out within the GPX family due to its unique ability to reduce lipid hydroperoxides directly within cell membranes, thereby safeguarding cells from lipid peroxidation and ferroptosis. 0.384 SIGNOR-279874 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257468 SNRPB protein P14678 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.721 SIGNOR-270656 SLC27A4 protein Q6P1M0 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264465 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser306 GPMRRSKsPADSGND 9606 14741103 YES llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. 0.405 SIGNOR-250658 Hypoxia stimulus SIGNOR-ST25 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates activity 9606 11248550 YES miannu The HIF-1α subunit is subjected to oxygen-dependent ubiquitination and proteasomal degradation that is mediated by the von Hippel-Lindau protein. Interaction of HIF-1α transactivation domains with coactivators is induced by hypoxia.  0.7 SIGNOR-279878 EGFR protein P00533 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates phosphorylation Tyr1289 CPASEQGyEEMRAFQ 9606 BTO:0000150 7929151 YES lperfetto The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism. 0.67 SIGNOR-34752 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.936 SIGNOR-51939 MAP2K2 protein P36507 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 YES Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs 0.746 SIGNOR-258995 Calcineurin complex SIGNOR-C155 SIGNOR FLNA protein P21333 UNIPROT down-regulates dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 YES gcesareni We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells 0.267 SIGNOR-252339 TERB2 protein Q8NHR7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates activity relocalization SIGNOR-C305 27025256 YES lperfetto Terb1 and Sun1 are two key proteins linking the meiotic telomeres to the NE. Terb1 participates in telomere fortification by recruiting cohesins to the site 0.2 SIGNOR-263306 SUFU protein Q9UMX1 UNIPROT GLI2 protein P10070 UNIPROT down-regulates activity relocalization 10090 16316410 YES lperfetto We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms 0.909 SIGNOR-129065 MAPK7 protein Q13164 UNIPROT NEUROG1 protein Q92886 UNIPROT up-regulates activity phosphorylation 9606 19365559 YES miannu Activation of ERK5 potentiates while inhibition of ERK5 attenuates Neurog1 stimulated neurogenesis.|ERK5 directly phosphorylated Neurog1 in vitro and modulated the transcriptional and pro-neural activity of Neurog1 in cortical progenitors. 0.35 SIGNOR-278364 miR-3173-5p mirna URS00004216E6_9606 RNAcentral ACSL4 protein O60488 UNIPROT down-regulates quantity by repression translation regulation 9606 BTO:0003081 37003125 YES miannu CAFs promoted chemoresistance in PDAC cells following GEM treatment by secreting exosomes, and maintaining signaling communication with cancer cells. Mechanistically, miR-3173-5p derived from CAF exosomes sponged ACSL4 and inhibited ferroptosis after uptake by cancer cells. 0.4 SIGNOR-279879 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 YES gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. 0.577 SIGNOR-76013 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Ile) smallmolecule CHEBI:29174 ChEBI down-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270419 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR down-regulates quantity by destabilization chemical inhibition 9606 19029980 YES Retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. 0.8 SIGNOR-259926 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT up-regulates activity phosphorylation Ser325 NRMGQAGsTISNSHA 10116 BTO:0000067 12270943 YES lperfetto We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation). 0.6 SIGNOR-249329 RUNX1 protein Q01196 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 NO lperfetto AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability. 0.7 SIGNOR-249631 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser406 CQAVFPPsITSRGDF 9534 BTO:0000298 10759890 YES miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex 0.742 SIGNOR-262720 AR protein P10275 UNIPROT NRAS protein P01111 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 NO After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. 0.283 SIGNOR-253676 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT up-regulates activity phosphorylation Thr336 KDRWRSMtVVPYLED 9606 BTO:0000007;BTO:0000567 12805220 YES lperfetto It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity. 0.2 SIGNOR-101844 progesterone smallmolecule CHEBI:17026 ChEBI CACNA2D3 protein Q8IZS8 UNIPROT up-regulates quantity 9606 31746409 NO miannu In vivo and in vitro, the addition of P4 upregulated the expression of CACNA2D3 and silencing of CACNA2D3 impaired the function of P4 on cell apoptosis and proliferation. 0.8 SIGNOR-266856 CHEK2 protein O96017 UNIPROT TRIM32 protein Q13049 UNIPROT up-regulates activity phosphorylation Ser55 LEKLLASsINGVRCP 9606 BTO:0000007 37943659 YES miannu We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.  0.2 SIGNOR-277790 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17210579 YES Manara These results suggested that ASK2 activates ASK1 by direct phosphorylation of Thr838 of ASK1. 0.55 SIGNOR-260773 ID2 protein Q02363 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000222 8380166 YES 2 miannu Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. 0.541 SIGNOR-240268 ROS stimulus SIGNOR-ST2 SIGNOR Lipid peroxidation phenotype SIGNOR-PH235 SIGNOR up-regulates 9606 BTO:0003081 37834426 YES miannu  ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell’s antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC. 0.7 SIGNOR-279881 UTS2R protein Q9UKP6 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.265 SIGNOR-257051 SYK protein P43405 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 YES miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation 0.2 SIGNOR-262675 ROS stimulus SIGNOR-ST2 SIGNOR ATF4 protein P18848 UNIPROT up-regulates 9606 19439225 NO lperfetto Oxidative and ER stress conditions induce rapid and significant activation of ATF4 downstream of eIF2alpha phosphorylation, which is responsible for Redd1 expression 0.7 SIGNOR-253729 Caspase 9 complex complex SIGNOR-C229 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 YES lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. 0.638 SIGNOR-256462 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 YES lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. 0.2 SIGNOR-170339 SYK protein P43405 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation 9606 25955968 YES miannu Syk in turn phosphorylates and activates the B cell linker protein (BLNK), phosphoinositide 3-kinase (PI3K) and phospholipase C\u03b32 (PLC\u03b32).|Syk in turn phosphorylates and activates the B cell linker protein (BLNK), phosphoinositide 3-kinase (PI3K) and phospholipase Cgamma2 (PLCgamma2). 0.753 SIGNOR-278995 GPC6 protein Q9Y625 UNIPROT SHH protein Q15465 UNIPROT up-regulates activity binding 9606 31756413 YES miannu Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction. 0.452 SIGNOR-264029 NRG1 protein Q02297 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 YES gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3. 0.872 SIGNOR-26061 MAPK14 protein Q16539 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates activity phosphorylation Ser82 STSQSPHsPDSSQSS -1 8650547 YES miannu CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen-activated protein kinase (MAP kinase). 0.609 SIGNOR-250096 VARS1 protein P26640 UNIPROT tRNA(Val) smallmolecule CHEBI:29183 ChEBI down-regulates quantity chemical modification 9606 30755602 YES miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. 0.8 SIGNOR-270525 UNC13B protein O14795 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 31679900 NO miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle. MUNC13 is proposed to tether synaptic vesicles by bridging between vesicle and plasma membrane via its C2C-domain and C1/C2B-domains 0.7 SIGNOR-264386 iron(3+) smallmolecule CHEBI:29034 ChEBI iron(2+) smallmolecule CHEBI:29033 ChEBI up-regulates quantity precursor of 9606 39534872 YES miannu Fe3+ is taken up by TFRC and exported by SLC40A1. Inside the cell, Fe3+ is reduced to Fe2+, with excess iron stored in ferritin (composed of FTH1 and FTL) or sequestered by MT1G. 0.8 SIGNOR-279883 STAT6 protein P42226 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 12947222 YES GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6 0.66 SIGNOR-254299 FOXA1 protein P55317 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 19127412 NO miannu Overexpression of foxa1 promoted apoptosis 0.7 SIGNOR-256642 TBK1 protein Q9UHD2 UNIPROT CDH1 protein P12830 UNIPROT down-regulates activity phosphorylation 9606 33310066 YES miannu Inhibition of TBK1 increases association of Cdh1 with APC1.|It was found that TBK1 phosphorylates both Cdc20 as well as Cdh1 (Figure 2F). 0.273 SIGNOR-278996 CERT1 protein Q9Y5P4 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity relocalization 9606 18184806 YES miannu In mammalian cells, ceramide is synthesized in the endoplasmic reticulum and transferred to the Golgi apparatus for conversion to sphingomyelin. Ceramide transport occurs in a nonvesicular manner and is mediated by CERT, a cytosolic 68-kDa protein with a C-terminal steroidogenic acute regulatory protein-related lipid transfer (START) domain. The CERT START domain efficiently transfers natural D-erythro-C16-ceramide, but not lipids with longer (C20) amide-acyl chains. 0.8 SIGNOR-268496 FYN protein P06241 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.633 SIGNOR-268207 PTK2 protein Q05397 UNIPROT SH3GL1 protein Q99961 UNIPROT unknown phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 YES llicata These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. 0.433 SIGNOR-139146 GSK3B protein P49841 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 18045539 YES gcesareni Phosphorylation at the gsk3 sites represses the transcriptional activity of smad1 by enhancing proteasomal degradation of psmad1cter 0.504 SIGNOR-159484 CPT1A protein P50416 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 ChEBI down-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267120 TBK1 protein Q9UHD2 UNIPROT DDX3X protein O00571 UNIPROT up-regulates activity phosphorylation 9606 18583960 YES miannu Coexpression of TBK1 strongly increased the activity of DDX3X.|This suggests that DDX3X is rather specifically phosphorylated by TBK1 and IKK-i. 0.72 SIGNOR-278997 GSK3B protein P49841 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr269 HNSTTTWtGSRTAPY 10090 BTO:0000944 25373906 YES miannu In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.  0.398 SIGNOR-276441 MYO1E protein Q12965 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 BTO:0000848 28348210 YES miannu Myosin-1E (MYO1E), an actin-dependent molecular motor protein, directly interacts with FAK to induce Y397 autophosphorylation, which, in turn, causes changes in gene expression commonly observed in aggressive cancer. 0.2 SIGNOR-265427 SPC24 protein Q8NBT2 UNIPROT Ndc80 complex complex SIGNOR-C361 SIGNOR form complex binding 27881301 YES lperfetto Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits 0.94 SIGNOR-265185 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr799 PLQDGSRtPHYGSQT 9606 16427012 YES lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif 0.776 SIGNOR-143935 RABGGTB protein P53611 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity lipidation 9606 BTO:0000007 18532927 YES miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional 0.489 SIGNOR-265573 CAMK2A protein Q9UQM7 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 9686569 YES gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16. 0.401 SIGNOR-59354 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM8 protein Q9BZR9 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271091 RUNX2 protein Q13950 UNIPROT MMP2 protein P08253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 NO miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. 0.328 SIGNOR-255082 KAT8 protein Q9H7Z6 UNIPROT MSL acetyltransferase complex SIGNOR-C344 SIGNOR form complex binding 9606 BTO:0000567 16227571 YES miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. 0.81 SIGNOR-263943 RBKS protein Q9H477 UNIPROT D-ribofuranose smallmolecule CHEBI:47013 ChEBI down-regulates quantity chemical modification 9606 25749547 YES miannu Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds. 0.8 SIGNOR-267072 N protein P59595 UNIPROT AP1 complex SIGNOR-C154 SIGNOR up-regulates activity 9606 14623261 YES Luana Taken together, we have shown that the coronavirus N protein can activate AP-1 signal transduction pathway. 0.2 SIGNOR-260725 GRM1 protein Q13255 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 YES miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. 0.406 SIGNOR-264077 FMR1 protein Q06787 UNIPROT DLG4 protein P78352 UNIPROT up-regulates quantity post transcriptional regulation 10090 BTO:0000142 32118033 YES lperfetto These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets. 0.474 SIGNOR-262108 GSK3B protein P49841 UNIPROT CEBPD protein P49716 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 23575666 YES miannu Phosphorylation of C/EBPdelta by GSK-3beta is required for its degradation by FBXW7alpha. 0.384 SIGNOR-279180 SCNN1G protein P51170 UNIPROT CACNA1H protein O95180 UNIPROT up-regulates activity binding 9606 BTO:0000142 30736831 YES miannu This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues. 0.2 SIGNOR-269274 F2R protein P25116 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.423 SIGNOR-257011 ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 20068082 YES gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. 0.844 SIGNOR-163110 CSNK2A1 protein P68400 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates phosphorylation Ser67 DTRKKDAsDDLDDLN 9606 BTO:0000567 16225457 YES lperfetto The n-terminal domain of the human eif2beta subunit and the ck2 phosphorylation sites are required for its function. These results suggest that ser2 and ser67 contribute to the important role of the n-terminal region of eif2beta for its function in mammals. 0.35 SIGNOR-141051 FIZ1 protein Q96SL8 UNIPROT CRX protein O43186 UNIPROT down-regulates activity binding 9913 12566383 YES miannu Interaction of Fiz1 and NRL-leucine zipper was validated by GST pulldown assays and co-immunoprecipitation from bovine retinal nuclear extracts. Fiz1 suppressed NRL- but not CRX-mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells. 0.456 SIGNOR-223799 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr174 EAEGDEIyEDLMRSE -1 10669745 YES Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function. 0.783 SIGNOR-251391 CDK1 protein P06493 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser428 FAQSAPGsPLSSQPV 9606 20810654 YES gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. 0.373 SIGNOR-167826 PRKACA protein P17612 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates activity phosphorylation Ser730 MKMRKKIsNAQLQTE 9534 BTO:0000298 10898738 YES miannu Elimination of the S730 but not the T325 PKA phosphorylation site of VACM-1 resulted in a complete inhibition of the VACM-1 activity, thus suggesting a direct effect of PKA on the VACM-1 receptor. 0.323 SIGNOR-250352 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 16197368 YES llicata We show that, in human platelets, vasp is phosphorylated by pkc on ser157, but not ser239, in response to phorbol ester stimulation, in a manner blocked by the pkc inhibitor bim i (bisindolylmaleimide i). 0.504 SIGNOR-140841 C5 convertase complex complex SIGNOR-C312 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg751 HKDMQLGrLHMKTLL 31331124 YES lperfetto Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b 0.557 SIGNOR-263453 NPFFR2 protein Q9Y5X5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.273 SIGNOR-256988 PPP1R14A protein Q96A00 UNIPROT PPP1CB protein P62140 UNIPROT down-regulates activity binding -1 12144526 YES lperfetto We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin 0.504 SIGNOR-265742 PRKCD protein Q05655 UNIPROT FMNL1 protein O95466 UNIPROT up-regulates activity phosphorylation 9606 32939232 YES miannu PKC\u03b4 induces FMNL1 phosphorylation. 0.27 SIGNOR-279261 ATM protein Q13315 UNIPROT DYRK2 protein Q92630 UNIPROT up-regulates quantity by stabilization phosphorylation Ser442 IELLGMPsQKLLDAS 19965871 YES Phosphosites were derived from Figure 3 lperfetto ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. 0.556 SIGNOR-275577 PRKD1 protein Q15139 UNIPROT DYNLL1 protein P63167 UNIPROT down-regulates activity phosphorylation 9606 21087603 YES miannu We now provide evidence that PKD phosphorylates an additional site in DLC1, namely serine 807 within the GAP domain, adding another layer of complexity to PKD-mediated negative regulation of the DLC1 tumor suppressor protein.|We previously reported that PKD inhibits DLC1 cellular function through phosphorylation of serines 327 and 431 [10]. 0.2 SIGNOR-279265 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 31422819 YES miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). 0.8 SIGNOR-267515 NEK6 protein Q9HC98 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates activity phosphorylation Thr66 VALNPQNtVFDAKRL -1 30108182 YES done miannu Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.  0.425 SIGNOR-273885 pictrelisib chemical CHEBI:65326 ChEBI PIK3CA protein P42336 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258113 ABL2 protein P42684 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Tyr292 RLGHCHTyWAVSEEL 9606 BTO:0000007 30842273 YES miannu The data in this study show that IRF3 is physically associated with c-Abl in vivo and directly binds to c-Abl in vitro. IRF3 is phosphorylated by c-Abl and c-Abl-related kinase, Arg, mainly at Y292. 0.2 SIGNOR-277441 MAPK3 protein P27361 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser282 TAPLSPMsPPGYKLV 9606 BTO:0000567 9535909 YES lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. 0.636 SIGNOR-249467 SRC protein P12931 UNIPROT MEGF10 protein Q96KG7 UNIPROT up-regulates activity phosphorylation 9606 23954233 YES miannu Our data suggest that c-Src augments the phosphorylation of MEGF10 and helps form a signaling complex.|These results indicate that overexpressed MEGF10 is phosphorylated by c-Src. 0.378 SIGNOR-279290 TSC22D3 protein Q99576 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity relocalization 9606 20018851 YES GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells. 0.396 SIGNOR-256147 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser43 FGYQRRAsDDGKLTD 9606 11971957 YES gcesareni Serine 43 phosphorylation decreased the binding to ras in serum-starved but not in mitogen-stimulated cells. However, the kinase activity of a rafs43a mutant was fully inhibited by pka. 0.499 SIGNOR-86145 fenoterol chemical CHEBI:149226 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 YES Luana Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1).  0.8 SIGNOR-257867 EEF1A1 protein P68104 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269515 VEGFD protein O43915 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 9435229 YES gcesareni Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors. 0.2 SIGNOR-55163 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CAD protein P27708 UNIPROT up-regulates activity phosphorylation Thr456 KVYFLPItPHYVTQV -1 17485345 YES miannu The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation.  0.2 SIGNOR-267441 STXBP2 protein Q15833 UNIPROT STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR form complex binding 9606 BTO:0000132 22767500 YES lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.¬† 0.544 SIGNOR-267727 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser24 APIRRRSsNYRAYAT -1 11121119 YES lperfetto In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation. 0.344 SIGNOR-249067 IMPDH1 protein P20839 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity chemical modification 9606 19480389 YES miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). 0.8 SIGNOR-267332 CNTRL protein Q7Z7A1 UNIPROT CEP290 protein O15078 UNIPROT down-regulates activity binding 9606 18694559 YES miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110. CP110 in this complex is to keep CEP290 inactive in growing cells until cells are ready to undergo ciliogenesis as they transit into the quiescent state 0.468 SIGNOR-252149 PLK1 protein P53350 UNIPROT ATXN10 protein Q9UBB4 UNIPROT down-regulates phosphorylation Thr82 ASSLQLItECFRCLR 9606 21857149 YES lperfetto Phosphorylation of ataxin-10 by polo-like kinase 1 is required for cytokinesis. Plk1 phosphorylates ataxin-10 at s77 and t82 in vitro. we found that ataxin-10 is ubiquitinated, and is subject to proteasome-dependent degradation, which is delayed in the 2a mutant. We propose a model in which plk1 phosphorylation of ataxin-10 influences its degradation and cytokinesis 0.353 SIGNOR-176126 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser152 PTPAKRRsSALWSEM -1 15684429 YES miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. 0.249 SIGNOR-263019 RAD1 protein O60671 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 YES gcesareni The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner 0.617 SIGNOR-179379 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2V1 protein Q13404 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.463 SIGNOR-271355 IRF2 protein P14316 UNIPROT TAP1 protein Q03518 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15778351 NO miannu We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. 0.2 SIGNOR-254530 hsa-miR-1-3p mirna URS00001DC04F_9606 RNAcentral FZD7 protein O75084 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000093 26497855 YES Parnian Our data indicate that miR-1 down-regulates breast CSC stemness, proliferation and migration by targeting the Frizzled 7 and TNKS2 to inhibit the Wnt/β-catenin signaling. 0.4 SIGNOR-277964 ERG protein P11308 UNIPROT VIM protein P08670 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093;BTO:0000815 8895512 NO miannu Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3. 0.2 SIGNOR-254069 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates phosphorylation Tyr319 CQLGQRIyQYIQSRF 9606 10910078 YES lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site 0.2 SIGNOR-79760 PRKCD protein Q05655 UNIPROT SRF protein P11831 UNIPROT down-regulates activity phosphorylation Thr160 NKLRRYTtFSKRKTG 9606 15282327 YES miannu Protein kinase C delta blocks immediate-early gene expression in senescent cells by inactivating serum response factor.|The phosphorylation of T160 of SRF by PKC delta in vitro and in vivo led to loss of SRF DNA binding activity. 0.2 SIGNOR-279347 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 YES esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. 0.448 SIGNOR-89233 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273036 STAT5A protein P42229 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0004408 15353555 NO miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. 0.7 SIGNOR-256074 etoposide chemical CHEBI:4911 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 16101488 YES miannu Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II. 0.8 SIGNOR-259325 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258899 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser675 PVSGSPDsMNASRLS 9606 BTO:0000007 10195894 YES Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. 0.2 SIGNOR-251276 TRPM6 protein Q9BX84 UNIPROT H2AC11 protein P0C0S8 UNIPROT down-regulates activity phosphorylation Ser2 sGRGKQGG -1 15010469 YES miannu We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1.  0.2 SIGNOR-276008 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser143 SKKSRSHsAKTPGFS 9606 BTO:0001109 17157788 YES lperfetto Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability. 0.359 SIGNOR-264416 STAT5A protein P42229 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 NO Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. 0.2 SIGNOR-251787 BTRC protein Q9Y297 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 14988407 YES gcesareni Here we show that beta-trcp1, a f-box protein in the scf e3 ligase complex, interacts with smad4 and induces the degradation of smad4 0.388 SIGNOR-123057 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 YES llicata Pka activated src both in vitro and in vivo by phosphorylating src on serine 17 0.361 SIGNOR-114277 STK11 protein Q15831 UNIPROT SIK3 protein Q9Y2K2 UNIPROT up-regulates phosphorylation Thr221 TPGQLLKtWCGSPPY 9606 14976552 YES lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold 0.487 SIGNOR-122835 ZNF304 protein Q9HCX3 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000391 24623306 YES Luana Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells. 0.302 SIGNOR-266098 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 YES lperfetto Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes. 0.778 SIGNOR-157533 CSNK2A1 protein P68400 UNIPROT VAMP4 protein O75379 UNIPROT up-regulates phosphorylation Ser30 RNLLEDDsDEEEDFF 9606 14608369 YES gcesareni The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway. 0.446 SIGNOR-119090 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 9606 12050114 YES gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk 0.352 SIGNOR-88728 PRKACA protein P17612 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates phosphorylation 9606 12536214 YES inferred from family member gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. 0.504 SIGNOR-270232 ARHGAP11B protein Q3KRB8 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.501 SIGNOR-260467 BMP2 protein P12643 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates 9606 21793042 NO gcesareni Upon bmp binding to the bmpr-ii, bmpr-i is recruited to form an activated quaternary complex, which then phosphorylates and activates intracellular smad proteins. Receptor smads bind to a co-smad and translocate to the nucleus to serve as transcription factors. 0.474 SIGNOR-175273 ECM stimulus SIGNOR-ST20 SIGNOR AM/b2 integrin complex SIGNOR-C170 SIGNOR up-regulates 9606 30889378 YES miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions 0.7 SIGNOR-259052 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr199 ELLEQQKyTVTVDYW 9606 SIGNOR-C14 12645577 YES gcesareni These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. 0.363 SIGNOR-99318 NMDA receptor_2C complex SIGNOR-C349 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 NO miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. 0.7 SIGNOR-264134 TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 YES lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. 0.893 SIGNOR-236071 ARAF protein P10398 UNIPROT SLC9A3R2 protein Q15599 UNIPROT up-regulates activity phosphorylation Ser303 QESGLHLsPTAAEAK 9606 BTO:0002269 26310448 YES miannu We also identify A-Raf as a kinase necessary for E3KARP phosphorylation at the G2/M stage of the cell cycle. Phosphorylation of Ser-303 regulates the localization, function, and dynamics of E3KARP 0.376 SIGNOR-273503 RB1 protein P06400 UNIPROT TRIP11 protein Q15643 UNIPROT down-regulates binding 9606 9256431 YES miannu The wild-type rb is able to interact with the rb-binding domain of trip230 / rb represses trip230-mediated activation of tr-regulated transcription. 0.325 SIGNOR-50266 CNOT4 protein O95628 UNIPROT KDM5C protein P41229 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19346402 YES miannu  In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome.  Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression. 0.545 SIGNOR-271468 SCF-FBW7 complex SIGNOR-C135 SIGNOR XRCC4 protein Q13426 UNIPROT up-regulates activity ubiquitination Lys296 QENQLQEkENSRPDS 9606 BTO:0002137 26774286 YES miannu In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.  0.301 SIGNOR-277200 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1070 ISTHTVTyGNIEGNA -1 11024032 YES Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. 0.767 SIGNOR-251170 LIMK1 protein P53667 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity phosphorylation -1 22214762 YES miannu Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology.  0.262 SIGNOR-276400 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Thr7 tSAARRSY -1 12686604 YES lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. 0.439 SIGNOR-100173 SOX6 protein P35712 UNIPROT MEST protein Q5EB52 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003298 26893351 NO We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST. 0.2 SIGNOR-255823 EGFR protein P00533 UNIPROT GPRC5A protein Q8NFJ5 UNIPROT down-regulates activity phosphorylation Tyr350 WPSPYKDyEVKKEGS 9606 25311788 YES miannu EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells. 0.387 SIGNOR-278336 DCAF4 protein Q8WV16 UNIPROT ST7 protein Q9NRC1 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0004297 30945288 YES miannu We found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). 0.2 SIGNOR-272303 PDPK1 protein O15530 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates phosphorylation Thr774 GYGDRTStFCGTPEF 9606 10753910 YES miannu It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively) 0.566 SIGNOR-76640 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 YES lperfetto These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf 0.2 SIGNOR-252814 WASH complex complex SIGNOR-C258 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 YES lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. 0.2 SIGNOR-261006 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Lys76 YRLVSINkSSPLQKQ -1 10978167 YES lperfetto Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site. 0.624 SIGNOR-263574 DUSP26 protein Q9BV47 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation 9606 28701747 YES miannu NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells 0.371 SIGNOR-277105 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 YES miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. 0.8 SIGNOR-262249 STK38 protein Q15208 UNIPROT PANX2 protein Q96RD6 UNIPROT up-regulates activity phosphorylation Ser514 KKHARHFsLDVHPYI 10090 BTO:0000142 22445341 YES miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. 0.2 SIGNOR-263032 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 SIGNOR-C17 12058066 YES gcesareni Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. 0.519 SIGNOR-89597 FGF13 protein Q92913 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates activity binding 9606 BTO:0000199 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.41 SIGNOR-253415 FBXO5 protein Q9UKT4 UNIPROT ANAPC7 protein Q9UJX3 UNIPROT down-regulates binding 9606 11751633 YES gcesareni Emi1 can inhibit apc already activated by cdc20 or cdh1. 0.459 SIGNOR-113382 ATM protein Q13315 UNIPROT ZNF420 protein Q8TAQ5 UNIPROT down-regulates activity phosphorylation Ser68 NTYETELsQWEMSDR 9606 BTO:0001109 19377469 YES done miannu These results indicate that Apak is a genuine substrate of ATM kinase. Apak phosphorylation on Ser 68 is critical for p53-mediated apoptosis. in response to DNA damage, ATM is rapidly activated by autophosphorylation and mediates p53 activation through disruption of the Apak–p53 complex by phosphorylating Apak on Ser 68. 0.457 SIGNOR-273513 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP3K8 protein P41279 UNIPROT up-regulates activity phosphorylation Ser400 EDQPRCQsLDSALLE 9606 BTO:0000007 12138205 YES Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator. 0.2 SIGNOR-251480 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity binding 9606 BTO:0000801 26260587 YES lperfetto IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects. 0.914 SIGNOR-249544 ARHGDIA protein P52565 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity guanine nucleotide exchange factor 10116 BTO:0000526 20696765 YES miannu Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma. 0.811 SIGNOR-268436 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 YES Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. 0.842 SIGNOR-99729 MAP3K7 protein O43318 UNIPROT RASSF9 protein O75901 UNIPROT up-regulates activity phosphorylation Ser284 RILIDKLsAEIEKEV 9606 33717835 YES miannu As expected, increased expression of TAK1 induced by LV-TAK1 stimulated p-RASSF9, whereas p-MEK and p-ERK were reduced.|We further identified RASSF9 as a downstream target of TAK1 which phosphorylates RASSF9 at S284. 0.2 SIGNOR-279534 PPM1F protein P49593 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 YES inferred from 70% of family members gcesareni Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity. 0.391 SIGNOR-269882 Anthra[2,1-d]thiazol-2-ylamine chemical CID:90872293 PUBCHEM KCNN1 protein Q92952 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 18955585 YES Luana Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM.  0.8 SIGNOR-258023 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12589056 NO gcesareni The resulting accumulation of beta-catenin leads to its nuclear translocation and binding to tcf/lef transcription factors to induce target genes including cyclin d1. 0.8 SIGNOR-98379 GATA4 protein P43694 UNIPROT TDO2 protein P48775 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0000575 19003156 YES lperfetto GATA4 inhibits expression of the tryptophan oxygenase gene by binding to the TATA box in fetal hepatocytes. 0.252 SIGNOR-268994 nitric oxide smallmolecule CHEBI:16480 ChEBI DNM1L protein O00429 UNIPROT up-regulates activity 33850055 NO lperfetto Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of dynamin-related protein 1 (Drp1) 0.8 SIGNOR-275650 RUNX1 protein Q01196 UNIPROT CCL3 protein P10147 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 12771199 YES lperfetto We show that RUNX1 can specifically bind to both RUNX sites but that only the proximal RUNX site is essential for PMA/ PHA stimulation of the MIP-1a promoter in Jurkat T-cells. We also show that the endogenous MIP-1a promoter is constitutively bound by RUNX1. 0.2 SIGNOR-251738 sertindole chemical CHEBI:9122 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258549 SRC protein P12931 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Tyr68 GQTVDDPyATFVKML 9606 19802004 YES lperfetto Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway 0.554 SIGNOR-188352 BLK protein P51451 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr310 TDDDKNIyLTLPPND -1 8756631 YES miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation 0.2 SIGNOR-262673 MRPS21 protein P82921 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.672 SIGNOR-261486 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA10 protein Q9Y5H3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265704 ATR protein Q13535 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser72 TLASQALsQCPAAAR 9606 15451423 YES lperfetto When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro. 0.878 SIGNOR-129473 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI 2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-) smallmolecule CHEBI:58725 ChEBI up-regulates quantity precursor of 9606 21310273 YES miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans 0.8 SIGNOR-268097 NRBF2 protein Q96F24 UNIPROT PIK3R4 protein Q99570 UNIPROT down-regulates activity binding 9606 BTO:0001938 phosphorylation:Ser113;Ser120 AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL 28059666 YES miannu NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. 0.65 SIGNOR-265878 BAK1 protein Q16611 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates relocalization 9606 14585074 YES Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi 0.52 SIGNOR-118905 GSK3B protein P49841 UNIPROT DNMT1 protein P26358 UNIPROT down-regulates quantity phosphorylation 9606 20093774 YES miannu We determined that in a human lung cell line, glycogen synthase kinase 3beta (GSK3beta) phosphorylated DNMT1 to recruit beta-transducin repeat-containing protein (betaTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3beta function and thereby attenuating DNMT1 degradation. 0.272 SIGNOR-279181 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity phosphorylation Ser1150 LERGRKVsIVSKPVL 9534 BTO:0000298 19103606 YES miannu these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells 0.414 SIGNOR-276177 PPP2R1A protein P30153 UNIPROT SGO1 protein Q5FBB7 UNIPROT up-regulates binding 9606 BTO:0000567 16580887 YES miannu Identification of subunits of protein phosphatase 2a (pp2a) as sgo1 binding proteins / pp2a is required for proper chromosome segregation and centromeric localization of sgo1 in hela cells 0.2 SIGNOR-145486 NEDD4 protein P46934 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 29251248 YES miannu BECN1 stability was increased by NEDD4 via K6 and K27 ubiquitination during autophagy induction, thereby promoting autophagy activation.|Further, NEDD4 mediated K6- and K27- linkage ubiquitination of BECN1, leading to elevated stability of BECN1 and increased autophagy. 0.461 SIGNOR-278558 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0000938 12040039 YES lperfetto Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun. 0.2 SIGNOR-236130 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Thr185 HDHTGFLtEYVATRW 9606 11971971 YES gcesareni Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. 0.744 SIGNOR-86709 CDK8 protein P49336 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 YES miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. 0.901 SIGNOR-266686 INSR protein P06213 UNIPROT CALM3 protein P0DP25 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 YES miannu The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. 0.376 SIGNOR-266336 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Thr162 SRFHNHTtHMSLVGT 9606 15342622 YES gcesareni Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation. 0.2 SIGNOR-128581 PRSS1 protein P07477 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.387 SIGNOR-263605 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 8702662 YES lperfetto A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function 0.804 SIGNOR-42956 ABL1 protein P00519 UNIPROT TERT protein O14746 UNIPROT down-regulates activity phosphorylation 9606 10837221 YES miannu These findings indicate that phosphorylation of hTERT by c-Abl is associated with inhibition of telomerase activity.|We also found that c-Abl phosphorylates hTERT and inhibits hTERT activity. 0.659 SIGNOR-279354 WNT10A protein Q9GZT5 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.56 SIGNOR-131622 SCF-FBW7 complex SIGNOR-C135 SIGNOR STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 31843895 YES miannu  These results demonstrate that the interaction between STAT2 and FBXW7 is involved in the SCF complex containing cullin 1 and RBX1. 0.286 SIGNOR-276766 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Ser426 CSLLLDSsLSSNWDD 9606 BTO:0000567 12738781 YES lperfetto These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site.  0.72 SIGNOR-249207 KLF8 protein O95600 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 10756197 YES Luana These results establish KLF8 as a CACCC-box binding protein that associates with CtBP and represses transcription. 0.2 SIGNOR-266052 IRF2BPL protein Q9H1B7 UNIPROT PENK protein P01210 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 17627301 YES miannu EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function. 0.308 SIGNOR-267155 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 YES lperfetto Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3) 0.383 SIGNOR-93539 bis(2-ethylhexyl) phthalate chemical CHEBI:17747 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). 0.8 SIGNOR-268774 NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 NO miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. 0.7 SIGNOR-260356 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR SPDEF protein O95238 UNIPROT down-regulates quantity by destabilization phosphorylation Ser242 WTDSEVDsSCSGQPI 9606 BTO:0000007 26885618 YES lperfetto In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.| 0.356 SIGNOR-273127 GADD45A protein P24522 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 BTO:0000782 15735649 YES gcesareni Both phosphorylation of p38 ty323 and the activity of this phosphorylated species are inhibited by binding gadd45alpha, thus preventing these low-treshold signals from activating p38 0.462 SIGNOR-134333 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IFNG protein P01579 UNIPROT up-regulates quantity 9606 10653850 NO miannu IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement. 0.7 SIGNOR-260967 EIF2AK2 protein P19525 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 15229216 YES miannu Consistent with this observation, PKR was capable of activating MKK6 as assessed in a coupled kinase assay containing the components of the p38 MAPK pathway.|In vitro kinase assays revealed that MKK6 was efficiently phosphorylated by PKR, and this could be inhibited by 2-aminopurine. 0.2 SIGNOR-279707 FER protein P16591 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 9606 10878010 YES miannu Replacing the unique 43-amino acid-long N-terminal tail of p51 (ferT) with a parallel segment from the N-terminal tail of p94 (fer) did not change the subcellular localization of p51 (ferT) but enabled it to activate Stat3.|When combined with immunoprecipitation analysis, this assay showed that p94 (fer) can lead to the tyrosine phosphorylation and activation of Stat3 but not of Stat1 or Stat2. 0.402 SIGNOR-279713 PLEKHG2 protein Q9H7P9 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates activity binding 9606 BTO:0000007 24378532 YES done miannu Through deletion and base substitution mutagenesis we have identified Tyr489 of PLEKHG2 as the site phosphorylated by cSrc.The interaction between PLEKHG2 and the full-length of PIK3R3, but not ABL1, occurs in a tyrosine-phosphorylation-dependent manner. 0.249 SIGNOR-273809 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser698 PEWPRRAsCTSSTSG -1 196939 YES The results presented in this paper show that the phosphorylation of glycogen synthetase a by cyclic AMP-dependent protein kinase results in the phosphorylation of two distinct serines termed site-l and site-2, which account for 90% of the total phosphorylation 0.507 SIGNOR-253009 SGTA protein O43765 UNIPROT BAG6 protein P46379 UNIPROT up-regulates activity binding 9606 BTO:0000007 24424410 YES miannu USP13 and gp78 control ubiquitination of Ubl4A.These data suggest that USP13 and gp78 play antagonizing roles in regulation of Ubl4A ubiquitination: While gp78 assembles ubiquitin chains on Ubl4A, USP13 antagonizes this activity to limit Ubl4A ubiquitination.Ubiquitination of Ubl4A preferentially occurs on Lys48. We identify the Bag6 cofactor Ubl4A as a shared substrate of gp78 and USP13. USP13 depletion is associated with hyper-ubiquitination of Ubl4A and altered interaction between the Bag6 complex and its co-chaperone SGTA. Because the interaction of Ubl4A with SGTA is mediated by positively-charged residues in Ubl4A including Lys48 (Chartron et al., 2012; Xu et al., 2012), which happens to be the major ubiquitination site, the simplest model to explain reduced Bag6-SGTA interaction in USP13 knockdown cells is that ubiquitin conjugates on Ubl4A sterically hinder SGTA binding. 0.468 SIGNOR-272859 RBL2 protein Q08999 UNIPROT RAD50 protein Q92878 UNIPROT up-regulates activity binding 9606 BTO:0004784 16600870 YES lperfetto We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.  0.305 SIGNOR-265029 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 20068082 YES gcesareni Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm). 0.8 SIGNOR-163231 ATF4 protein P18848 UNIPROT YARS1 protein P54577 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 YES miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. 0.2 SIGNOR-269431 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 20233713 YES gcesareni The identification of maf1 as an mtor-regulated phosphoprotein implicates mtor in the broader regulatory mechanisms governing pol iii activity in cancer cells. 0.711 SIGNOR-164348 KCNMA1 protein Q12791 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31152168 YES miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. 0.8 SIGNOR-269191 TLRs proteinfamily SIGNOR-PF20 SIGNOR MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 YES miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group 0.2 SIGNOR-260151 ALK protein Q9UM73 UNIPROT CDK9 protein P50750 UNIPROT up-regulates activity phosphorylation Tyr19 FCDEVSKyEKLAKIG -1 36253486 YES miannu We report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. 0.296 SIGNOR-277607 NRXN1 protein Q9ULB1 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 YES miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. 0.424 SIGNOR-265458 MMP9 protein P14780 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Arg719 VMGRGHArLVHVEEP -1 9344465 YES lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.491 SIGNOR-261740 CASP3 protein P42574 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization cleavage -1 9367996 YES lperfetto The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues. 0.422 SIGNOR-51936 Ub:E2 complex SIGNOR-C497 SIGNOR RAG1 protein P15918 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271067 PKA proteinfamily SIGNOR-PF17 SIGNOR PHKA1 protein P46020 UNIPROT down-regulates activity phosphorylation 9606 10487978 YES Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. 0.2 SIGNOR-267409 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser291 PVSSLQAsVPGSVPG -1 16027724 YES GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) 0.381 SIGNOR-251229 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 YES lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling 0.2 SIGNOR-112479 AKT1 protein P31749 UNIPROT CFLAR protein O15519 UNIPROT down-regulates quantity phosphorylation Ser273 LLRDTFTsLGYEVQK 9606 19339247 YES gcesareni TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling. 0.467 SIGNOR-252548 SREBF1 protein P36956 UNIPROT FASN protein P49327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 YES gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) 0.495 SIGNOR-142294 FOXO1 protein Q12778 UNIPROT IGFBP1 protein P08833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10358076 NO miannu Reporter gene studies in hepg2 hepatoma cells show that fkhr stimulates insulin-like growth factor-binding protein-1 promoter activity through an irs 0.377 SIGNOR-68152 KDM1A protein O60341 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000567 15620353 YES miannu Here, we provide evidence that LSD1 (KIAA0601), a nuclear homolog of amine oxidases, functions as a histone demethylase and transcriptional corepressor. LSD1 specifically demethylates histone H3 lysine 4, which is linked to active transcription. 0.2 SIGNOR-264507 ROCK1 protein Q13464 UNIPROT LIMK2 protein P53671 UNIPROT up-regulates phosphorylation Thr505 NDRKKRYtVVGNPYW 9606 11018042 YES lperfetto Specific activation of lim kinase 2 via phosphorylation of threonine 505 by rock, a rho-dependent protein kinase 0.631 SIGNOR-82755 GABARAPL2 protein P60520 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000567 17580304 YES lperfetto P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha 0.862 SIGNOR-156307 ALDH1A2 protein O94788 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI down-regulates quantity chemical modification 9606 21621639 YES lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. 0.8 SIGNOR-265125 CUL1 protein Q13616 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 YES miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. 0.356 SIGNOR-268844 ABCA7 protein Q8IZY2 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 10090 14570867 NO miannu Transfected ABCA7-GFP induced apolipoprotein-mediated assembly of cholesterol-containing HDL also in L929 cells, which otherwise generate only cholesterol-deficient HDL with their endogenous ABCA1. 0.7 SIGNOR-265177 SMO protein Q99835 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation 9606 18455992 YES gcesareni Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion. 0.435 SIGNOR-178610 CDK10 protein Q15131 UNIPROT ETS2 protein P15036 UNIPROT down-regulates quantity by destabilization phosphorylation Ser225 LDSMCPAsTPSVLSS 9606 24218572 YES Manara Altogether, these results suggest that CDK10/cyclin M directly controls ETS2 degradation through the phosphorylation of these two serines. 0.529 SIGNOR-260914 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271816 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr12 FGSRSSKtFKPKKNI 9606 23431053 YES milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity 0.851 SIGNOR-201314 OPRD1 protein P41143 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.459 SIGNOR-256826 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15864272 YES gcesareni The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2 0.713 SIGNOR-135955 L-homocysteine zwitterion smallmolecule CHEBI:58199 ChEBI hydrosulfide smallmolecule CHEBI:29919 ChEBI up-regulates quantity precursor of 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 YES lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. 0.8 SIGNOR-275816 bromocriptine chemical CHEBI:3181 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258367 RXRA protein P19793 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15356291 NO miannu Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential. 0.2 SIGNOR-254582 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR TTI1 protein O43156 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23263282 YES miannu Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. The interaction between Tel2/Tti1 and Fbxo9 identified by mass spectrometry suggests that SCFFbxo9 is probably the ubiquitin ligase that mediates degradation of both proteins. 0.252 SIGNOR-271999 P2RY11 protein Q96G91 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257435 Ub:E2 complex SIGNOR-C497 SIGNOR MKRN4P protein Q13434 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271250 NCOA1 protein Q15788 UNIPROT ASXL1 protein Q8IXJ9 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 YES irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation.Therefore, both the ability to bind SRC-1 and the autonomous activation of ASXL1 are required for its coactivator function. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. 0.283 SIGNOR-255924 CCNF protein P41002 UNIPROT CCP110 protein O43303 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20596027 YES miannu Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation. 0.54 SIGNOR-266364 CD36 protein P16671 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 YES miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). 0.7 SIGNOR-264453 ATXN2 protein Q99700 UNIPROT DDX6 protein P26196 UNIPROT unknown binding 9606 17392519 YES miannu Ataxin-2 interacts with the dead/h-box rna helicase ddx6 / ddx6 is an essential component for the assembly of p-bodies/ 0.57 SIGNOR-154158 EEF1A2 protein Q05639 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269526 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser245 PSTSPRAsVTEESWL 9606 12351631 YES lperfetto Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3) 0.383 SIGNOR-93531 AR protein P10275 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 15861399 NO miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation 0.7 SIGNOR-251538 (R)-carnitine smallmolecule CHEBI:16347 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267119 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Thr234 IVHKRVHtGEKPYKC 9606 BTO:0002552 31399647 YES miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. 0.2 SIGNOR-276752 RPL30 protein P62888 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.88 SIGNOR-262470 PBX1 protein P40424 UNIPROT MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR form complex binding 9606 BTO:0001103 17194702 YES miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes 0.41 SIGNOR-151700 AHI1 protein Q8N157 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 BTO:0000452 23532844 NO miannu Mutations in AHI1 cause Joubert syndrome (JBTS), a neurodevelopmental ciliopathy, characterized by midbrain-hindbrain malformations and motor/cognitive deficits. Here, we show that primary cilia (PC) formation is decreased in fibroblasts from individuals with JBTS and AHI1 mutations. 0.7 SIGNOR-269080 CBX3 protein Q13185 UNIPROT NIPBL protein Q6KC79 UNIPROT up-regulates activity binding 9606 28167679 YES miannu The heterochromatin protein HP1γ (also known as CBX3) recruits NIPBL to DNA double-strand breaks (DSBs) through the corresponding HP1-binding motif within the N-terminus. 0.437 SIGNOR-264524 histamine smallmolecule CHEBI:18295 ChEBI HRH1 protein P35367 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257512 AKT1 protein P31749 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates activity phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 YES miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively 0.2 SIGNOR-276194 INS protein P01308 UNIPROT CEBPB protein P17676 UNIPROT up-regulates 10090 BTO:0000011 11279134 NO lperfetto The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin 0.427 SIGNOR-250565 piroxicam chemical CHEBI:8249 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9083488 YES miannu Meloxicam (5),an NSAID in the enol−carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. This favorable therapeutic index has been confirmed in clinical trials. In subsequent studies we and others discovered that it possessed a selectivity profile for COX-2 superior to several other marketed NSAIDs.1 A comparison of 5 with piroxicam (6) revealed different inhibitory profiles for the two enzymes 0.8 SIGNOR-258608 NUAK2 protein Q9H093 UNIPROT WDR45 protein Q9Y484 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 28561066 YES miannu WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes. 0.262 SIGNOR-268481 ENO1 protein P06733 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI down-regulates quantity chemical modification 9606 29767008 YES miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. 0.8 SIGNOR-266528 TNF protein P01375 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 26112872 NO miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. 0.258 SIGNOR-253480 MVD protein P53602 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity lipidation 10090 25378391 YES miannu Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation. 0.2 SIGNOR-265892 AMPK complex SIGNOR-C15 SIGNOR MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation Ser556 LLRSPGsPQETVPE 10116 11724780 YES lperfetto These results strongly suggested that the fatty acid inhibition of glucose-induced l-PK transcription resulted from AMPK phosphorylation of ChREBP at Ser568, which inactivated the DNA binding activity. 0.429 SIGNOR-216526 SNUPN protein O95149 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR up-regulates quantity relocalization 9606 BTO:0000567 9670026 YES miannu Here, we describe the isolation and cDNA cloning of a 45 kDa protein, termed snurportin1, which interacts specifically with m3G-cap but not m7G-cap structures. Snurportin1 enhances the m3G-capdependent nuclear import of U snRNPs in both Xenopus laevis oocytes and digitonin-permeabilized HeLa cells, demonstrating that it functions as an snRNP-specific nuclear import receptor. 0.406 SIGNOR-272082 JAKMIP1 protein Q96N16 UNIPROT GABBR1 protein Q9UBS5 UNIPROT up-regulates quantity 9534 BTO:0004055 14718537 NO SARA Reduction in the Marlin-1 protein levels interferes with the translation, assembly, or stability of GABAB receptors during the maturation of cortical neurons. 0.522 SIGNOR-260988 HLA-G protein P17693 UNIPROT KLRC1 protein P26715 UNIPROT up-regulates binding 9606 9560253 YES gcesareni Current models of nk cell function have supposed that the cd94/nkg2a heterodimer is interacting with an epitope common to classical hla class i 0.63 SIGNOR-56714 DCK protein P27707 UNIPROT G2/M_transition-checkpoint phenotype SIGNOR-PH146 SIGNOR up-regulates phosphorylation Ser74 27879648 NO lperfetto Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. 0.7 SIGNOR-275806 hsa-miR-222-5p mirna URS0000153377_9606 RNAcentral GNAI3 protein P08754 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003227 25444921 YES Parnian MiR-222 directly binds to the 3′UTR of GNAI3 and post-transcriptionally regulates GNAI3 expression. 0.4 SIGNOR-278031 RET/PTC2 protein Q15300 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 12637586 YES Manara In addition, RET/PTC-mediated cellular transformation and proliferation of transformed cells require tyrosine 705 phosphorylation of STAT3 in NIH3T3 cells. We conclude that STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes, such as cyclin D1, vascular endothelial growth factor, and intercellular adhesion molecule 1, and for cellular transformation. 0.2 SIGNOR-260917 GPR34 protein Q9UPC5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256688 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000018 10734310 YES miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. 0.673 SIGNOR-250289 mTORC1 complex SIGNOR-C3 SIGNOR TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000567 SIGNOR-C3 22692423 YES gcesareni Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB. 0.363 SIGNOR-248274 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 YES lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. 0.269 SIGNOR-198126 CDKN2A protein Q8N726 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization 9606 12091906 NO apalma P14/p19 ARF functions by antagonizing MDM2 and thereby stabilizing p53 (refs. 17,18). Thus, loss of p14/p19ARF impairs p53-mediated growth arrest and/or apoptosis in response to activated oncogenes 0.787 SIGNOR-255694 STK38 protein Q15208 UNIPROT AAK1 protein Q2M2I8 UNIPROT up-regulates activity phosphorylation Ser637 AGHRRILsDVTHSAV 10090 BTO:0000142 22445341 YES miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. AAK1 phosphorylation regulates dendrite branching and length 0.271 SIGNOR-263034 PRKCB protein P05771 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.354 SIGNOR-249286 NKX6-3 protein A6NJ46 UNIPROT GKN1 protein Q9NS71 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007 26314965 YES Luana  In particular, NKX6.3 transcriptional factor was found to bind specifically to the upstream sequences of GKN1, a gastric-specific tumor suppressor, and dramatically increase expression of the latter.  0.371 SIGNOR-266096 EEF1A1P5 protein Q5VTE0 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269560 NFIB protein O00712 UNIPROT GAS6 protein Q14393 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268882 GSK3B protein P49841 UNIPROT IL17RA protein Q96F46 UNIPROT down-regulates quantity phosphorylation 9606 26871944 YES miannu GSK3beta constitutively binds to and phosphorylates IL-17RA.|Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation. 0.2 SIGNOR-279049 SIRT7 protein Q9NRC8 UNIPROT TP53 protein P04637 UNIPROT down-regulates deacetylation 9606 18239138 YES gcesareni We found that sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo. 0.499 SIGNOR-160539 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000007 25658205 YES Barakat Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer. 0.2 SIGNOR-275407 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 20516213 YES lperfetto The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. 0.479 SIGNOR-217145 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR WNK3 protein Q9BYP7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23838290 YES miannu We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body. 0.335 SIGNOR-272126 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROG1 protein Q92886 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19028584 NO miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. 0.249 SIGNOR-254632 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Thr127 RRRRRSRtFSRSSSQ 9606 BTO:0000567 20682768 YES lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva 0.391 SIGNOR-167340 ADRB1 protein P08588 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.526 SIGNOR-256758 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001573 17671177 YES gcesareni Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin. 0.489 SIGNOR-157162 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser502 YFLQRRPsMKTLFVD 9534 BTO:0000298 14523239 YES lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. 0.2 SIGNOR-249230 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys300 PRGPGLVkAPVWWPM 9606 17509614 YES gcesareni Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1 0.256 SIGNOR-154805 RUNX3 protein Q13761 UNIPROT ING4 protein Q9UNL4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255096 afimoxifene chemical CHEBI:44616 ChEBI ESR2 protein Q92731 UNIPROT down-regulates activity chemical inhibition -1 9048584 YES miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. 0.8 SIGNOR-258596 IL22 protein Q9GZX6 UNIPROT IL22RA2 protein Q969J5 UNIPROT down-regulates binding 9606 BTO:0000763;BTO:0000149 11390453 YES gcesareni We identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the il-22 receptor and of the il-20r/cytokine receptor family 2-8,the recombinant protein was found to bind il-10-related t cell-derived inducible factor/il-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist il-22bp for il-22 binding protein. respectively, but lacking the transmembrane and cytoplasmic domains 0.745 SIGNOR-86110 CDK2 protein P24941 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser203 DLEFSSGsPGKETNE -1 9199329 YES lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. 0.291 SIGNOR-249426 TGFBI protein Q15582 UNIPROT A6/b4 integrin complex SIGNOR-C174 SIGNOR up-regulates activity binding 26387839 YES lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers 0.281 SIGNOR-253268 ODAD4 protein Q96NG3 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR up-regulates activity binding 10090 BTO:0000379 33347437 YES miannu CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B). It also interacts with ODA proteins including dynein heavy chains such as DNAH11 and possibly DNAH5/9. CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. 0.2 SIGNOR-265546 TLX1 protein P31314 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates activity binding 9606 BTO:0000661 15897879 YES 2 miannu HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade. 0.309 SIGNOR-240719 KDM3B protein Q7LBC6 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 YES miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. 0.2 SIGNOR-266634 PDGFRA protein P16234 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24743741 NO To further investigate the signaling pathway through which PDGFRαpromotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα. Thus, both PI3K-Akt and MEK2-MAPK pathways are necessary for PDGFRα-driven proliferation. 0.325 SIGNOR-254377 NOTCH1 protein P46531 UNIPROT TCF12 protein Q99081 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22577461 NO miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. 0.366 SIGNOR-197514 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 BTO:0000782 12151396 YES gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk 0.352 SIGNOR-91063 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 YES lperfetto Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo. 0.551 SIGNOR-74923 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.322 SIGNOR-129328 PRKAA1 protein Q13131 UNIPROT RBBP7 protein Q16576 UNIPROT up-regulates activity phosphorylation Ser314 LKLHTFEsHKDEIFQ -1 28143904 YES lperfetto AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity 0.2 SIGNOR-264784 CAMK2D protein Q13557 UNIPROT CEACAM1 protein P13688 UNIPROT up-regulates phosphorylation Thr457 CFLHFGKtGRASDQR 9606 BTO:0000149 24302721 YES lperfetto Camkiid specifically phosphorylates thr-457 on ceacam1-sf, which in turn regulates the process of lumen formation via apoptosis of the central acinar cells. 0.2 SIGNOR-203402 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid chemical CHEBI:76223 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 22091869 YES Luana  Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2.  0.8 SIGNOR-258324 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 12058066 YES lperfetto Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. 0.408 SIGNOR-216745 SP1 protein P08047 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000608 37973952 YES Marta Tosoni The elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription. 0.2 SIGNOR-278106 CXCL1 protein P09341 UNIPROT GLI3 protein P10071 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16885213 NO gcesareni The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i). 0.2 SIGNOR-148460 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 9465032 YES lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.755 SIGNOR-217086 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser261 TGHGLRRsSKFCLKE -1 1848190 YES lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. 0.352 SIGNOR-248854 AKT proteinfamily SIGNOR-PF24 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 12588998 YES lperfetto Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro 0.2 SIGNOR-265319 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192480 ACTB protein P60709 UNIPROT Brain-specific SWI/SNF SMARCA4 variant complex SIGNOR-C486 SIGNOR form complex binding 9606 BTO:0000142 11790558 YES miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. 0.526 SIGNOR-270757 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273084 AKT proteinfamily SIGNOR-PF24 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 10559253 YES esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. 0.2 SIGNOR-72137 PRKAA1 protein Q13131 UNIPROT KLC2 protein Q9H0B6 UNIPROT up-regulates phosphorylation Ser582 PRMKRASsLNFLNKS 9606 SIGNOR-C15 21725060 YES gcesareni Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582 0.2 SIGNOR-174681 LCK protein P06239 UNIPROT CD247 protein P20963 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 8626561 YES amattioni During tcr signaling, lck interacts with numerous molecules, including tcr-zeta. The binding of lck to the tyrosine-phosphorylated zeta chain of the tcr would serve to strengthen the interaction of the associated cd4 and the tcr complex, leading to increased avidity for the antigen-major histocompatibility protein complex. 0.763 SIGNOR-41361 N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 22812634 YES miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case 0.8 SIGNOR-266610 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr360 VSPSPTTyRMFRDKS 9606 BTO:0001271 8622703 YES lperfetto We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr. 0.2 SIGNOR-40619 RUNX2 protein Q13950 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 NO miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. 0.449 SIGNOR-255085 RXRA protein P19793 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 YES gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology 0.742 SIGNOR-105445 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258254 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 9677429 YES MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. lperfetto The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. 0.2 SIGNOR-244806 ARHGEF10 protein O15013 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.498 SIGNOR-260537 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 YES gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. 0.517 SIGNOR-252979 PRLHR protein P49683 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.278 SIGNOR-256694 PAS complex complex SIGNOR-C190 SIGNOR Multivesicular_body_assembly phenotype SIGNOR-PH83 SIGNOR up-regulates 9606 17556371 NO miannu Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. We further demonstrate a key function for each of the three proteins in the biogenesis of ECV/MVB transport intermediates from early endosomes. 0.7 SIGNOR-253532 P2RY1 protein P47900 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257072 PRKACA protein P17612 UNIPROT PPP1R9B protein Q96SB3 UNIPROT down-regulates activity phosphorylation Ser94 SERGVRLsLPRASSL 9606 BTO:0000007 12417592 YES miannu Spinophilin is phosphorylated in vitro by protein kinase A (PKA). two major sites of phosphorylation, Ser-94 and Ser-177, that are located within the actin-binding domain of spinophilin. Phosphorylation of spinophilin by PKA modulated the association between spinophilin and the actin cytoskeleton. phosphorylation of spinophilin reduced the stoichiometry of the spinophilin-actin interaction. In contrast, the ability of spinophilin to bind to PP1 remained unchanged. 0.311 SIGNOR-250035 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB5 protein Q9Y5G0 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265714 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 YES gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. 0.2 SIGNOR-128718 TP53 protein P04637 UNIPROT DRAM2 protein Q6UX65 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 NO irozzo DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. 0.306 SIGNOR-259148 TNKS2 protein Q9H2K2 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 19759537 YES lperfetto Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin. 0.696 SIGNOR-263380 UBE2I protein P63279 UNIPROT JUN protein P05412 UNIPROT down-regulates activity sumoylation Lys226 HPRLQALkEEPQTVP 9606 SIGNOR-C154 16055711 YES lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. 0.421 SIGNOR-263002 AKT1 protein P31749 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates binding 10090 15173318 YES lperfetto Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation 0.486 SIGNOR-252541 NME1 protein P15531 UNIPROT MMP2 protein P08253 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 NO miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 0.331 SIGNOR-255165 STK11 protein Q15831 UNIPROT PRMT5 protein O14744 UNIPROT up-regulates activity phosphorylation Thr144 VLTNHIHtGHHSSMF -1 30289978 YES miannu We found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1.  0.2 SIGNOR-277412 GSK3B protein P49841 UNIPROT ZNF322 protein Q6U7Q0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser391 SEKGLELsPPHASEA 9606 BTO:0002552 28581525 YES lperfetto CK1delta and GSK3beta kinases sequentially phosphorylate ZNF322A at serine-396 and then serine-391. Moreover, the doubly phosphorylated ZNF322A protein creates a destruction motif for the ubiquitin ligase FBXW7alpha leading to ZNF322A protein destruction. 0.2 SIGNOR-264891 ABL1 protein P00519 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates phosphorylation Tyr28 SRIGDELyLEPLEDG 9606 11971963 YES gcesareni C-abl phosphorylates the rad9 bcl-2 homology 3 domain (tyr-28) in vitro and in cells exposed to dna-damaging agents. The results also demonstrate that c-abl-mediated phosphorylation of rad9 induces binding of rad9 to the antiapototic bcl-x(l) protein 0.478 SIGNOR-86186 KCNIP3 protein Q9Y2W7 UNIPROT PDYN protein P01213 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12667101 NO miannu As a transcriptional repressor, DREAM may control the expression of the endogenous opioid gene prodynorphin amongst others, and itself is exquisitely regulated by second messenger molecules, protein kinases and other transcription factors. 0.355 SIGNOR-254540 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR PAK1 protein Q13153 UNIPROT up-regulates activity phosphorylation Ser174 TPAVPPVsEDEDDDD 19520772 YES lperfetto CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression|We show that PAK1 is a substrate of CDK11p58 and can be strongly activated upon phosphorylation. 0.388 SIGNOR-273129 PKM protein P14618 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 YES miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). 0.8 SIGNOR-266534 UTS2R protein Q9UKP6 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.433 SIGNOR-257426 AKT proteinfamily SIGNOR-PF24 SIGNOR PDAC-associated neural remodeling (PANR) phenotype SIGNOR-PH233 SIGNOR up-regulates 9606 BTO:0000584 29269518 NO miannu Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell–promoting factor LIF supports PDAC-associated neural remodeling (PANR).Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. 0.7 SIGNOR-278039 PTPRJ protein Q12913 UNIPROT CBL protein P22681 UNIPROT down-regulates activity 9606 19836242 NO Because c-CBL’s activation is achieved via tyrosine phosphorylation, we tested the effect of DEP-1 on modification of a major site of phosphorylation, namely tyro- sine 731. Upon DEP-1 overexpression, c-CBL displayed reduced phosphorylation on this site compared to control cells (Figure 7B). This result offers a mechanism by which DEP-1 affects EGFR trafficking: by dephosphorylating EGFR, and possibly also SRC family kinases involved in phosphoryla- tion of c-CBL [31, 32], DEP-1 reduces activation of c-CBL and its recruitment to the activated EGFR, hence inhibiting subsequent receptor internalization and degradation. 0.324 SIGNOR-248839 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser390 KEAEEESsGGEEEDE 9606 18649047 YES gcesareni We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2. 0.395 SIGNOR-179546 KDM6A protein O15550 UNIPROT HOXC4 protein P09017 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.466 SIGNOR-260030 AURKA protein O14965 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 16082213 YES lperfetto We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353 0.721 SIGNOR-139396 COPS5 protein Q92905 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.935 SIGNOR-270761 HTR7 protein P34969 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.297 SIGNOR-257256 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr455 ALGTPVLtPPTEAAS 9606 BTO:0000848 BTO:0001253 20959475 YES lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). 0.713 SIGNOR-252956 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser516 ASSQCIAsPNFGTVS -1 12361598 YES miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) 0.516 SIGNOR-265963 SUZ12/EZH2 complex SIGNOR-C77 SIGNOR SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR form complex binding 10090 BTO:0000165;BTO:0002314 20887952 YES lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. 0.733 SIGNOR-235577 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Tyr432 KEGWMVHyTSKDTLR 9606 BTO:0000567 12637538 YES gcesareni Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity. 0.34 SIGNOR-246211 FBXL18 protein Q96ME1 UNIPROT FBXL7 protein Q9UJT9 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002268 25654763 YES miannu F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18. 0.65 SIGNOR-272448 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763;BTO:0000149 10197981 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.2 SIGNOR-244727 PPP2CA protein P67775 UNIPROT TFCP2 protein Q12800 UNIPROT up-regulates dephosphorylation Ser291 TYVNNSPsPGFNSSH 9606 20682773 YES lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a 0.2 SIGNOR-167385 SRC protein P12931 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr753 DDTRDNVyYYDEEGG 9606 27203386 YES miannu In addition, the phosphorylation of E-cadherin Tyr753 and Tyr754 by Src recruits the binding of Hakai, a Cbl like E3 ubiquitin ligase, leading to ubiquitination and endocytosis of the E, cadherin, beta, and catenin complex . 0.754 SIGNOR-278498 AUTS2 protein Q8WXX7 UNIPROT ELMO2 protein Q96JJ3 UNIPROT up-regulates activity binding 10090 BTO:0001909 25533347 YES miannu Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells. 0.269 SIGNOR-266819 HES5 protein Q5TA89 UNIPROT NEUROG2 protein Q9H2A3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 NO lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production 0.41 SIGNOR-265143 MRPL54 protein Q6P161 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.659 SIGNOR-262336 PRKCH protein P24723 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 19836308 YES lperfetto Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka). 0.2 SIGNOR-188585 UBE3A protein Q05086 UNIPROT NOL3 protein O60936 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20211139 YES miannu Incubation of transfected HEK293T cells with the proteasome inhibitor, MG132 blocked Ube3A mediated degradation of Arc suggesting that Ube3A degrades Arc via the ubiquitin proteasome system .|The ubiquitination of Arc by Ube3A was confirmed by mass spectrometry which revealed that Ube3A catalyzed the polyubiquitination of Arc on Lysine 268 and 269 ( xref ). 0.2 SIGNOR-278522 CSNK2A1 protein P68400 UNIPROT TOP1 protein P11387 UNIPROT up-regulates activity phosphorylation Ser10 GDHLHNDsQIEADFR -1 18408216 YES miannu In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells. 0.384 SIGNOR-276155 ZNF322 protein Q6U7Q0 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24550733 YES lperfetto Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays revealed that Zfp322a binds to Pou5f1 and Nanog promoters and regulates their transcription. 0.2 SIGNOR-264899 PTK2B protein Q14289 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates activity phosphorylation Tyr46 PNKRQHIyQRCIQLK 9606 21357692 YES miannu Pyk2 Induces Tyrosine Phosphorylation of NPHP1 at Tyr 46, Tyr 349, and Tyr 721.|The expression of wild-type Pyk2 enhances the amount of co-precipitating PACS-1 with wild-type NPHP1 compared with the presence of the kinase-dead variant of Pyk2. 0.462 SIGNOR-278272 CSNK2A1 protein P68400 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10617630 YES lperfetto In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes. 0.513 SIGNOR-73803 MID1 protein O15344 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates quantity ubiquitination 9606 34434118 YES miannu Proteasome inhibitor treatment diminished the decrease of PTP1B (Figure 5F) caused by TRIM18 overexpression.|TRIM18 Interacts With PTP1B and Promotes PTP1B Ubiquitination. 0.2 SIGNOR-278703 GALR2 protein O43603 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257296 PPP1R1B protein Q9UD71 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR down-regulates activity binding 9606 BTO:0000938 10604473 YES miannu We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. 0.505 SIGNOR-265087 APOA1 protein P02647 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 23077142 NO miannu Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL). 0.7 SIGNOR-252110 RAPGEF4 protein Q8WZA2 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 YES miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. 0.794 SIGNOR-263954 SAGA complex complex SIGNOR-C465 SIGNOR H3-2 protein Q5TEC6 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269641 PRKACA protein P17612 UNIPROT TFAP2A protein P05549 UNIPROT up-regulates phosphorylation Ser239 AEVQRRLsPPECLNA 9606 10037142 YES llicata Recombinant ap-2 was phosphorylated in vitro by protein kinase a (pka) at ser239. Mutation of ser239 to ala abolished in vitro phosphorylation of ap-2 by pka, but not the dna binding activity of ap-2. Cotransfection studies showed that pka stimulated the effect of ap-2 on the apoe promoter, but not that of the s239a mutant. 0.2 SIGNOR-64955 CAD protein P27708 UNIPROT N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI down-regulates quantity chemical modification 9606 28552578 YES miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. 0.8 SIGNOR-267427 JQ1 chemical CHEBI:137113 ChEBI BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition -1 20871596 YES lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. 0.8 SIGNOR-261989 SETDB2 protein Q96T68 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity methylation 9606 20404330 YES miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. 0.2 SIGNOR-265351 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR down-regulates activity binding 9606 BTO:0002552 33188728 YES miannu Our structure of the SARS-CoV-2 Nsp1 protein bound to the 40S ribosomal subunit establishes a mechanistic basis of the cellular effects of Nsp1, revealing a multifaceted mechanism of inhibition of the host protein synthesis at the initiation stage by the virusThis shows that Nsp1 not only plugs the mRNA entry channel but also keeps the 40S subunit in a conformation that is incompatible with mRNA loading. 0.2 SIGNOR-262518 ROS stimulus SIGNOR-ST2 SIGNOR Oxidative_stress phenotype SIGNOR-PH215 SIGNOR up-regulates 9606 22301329 NO lperfetto Oxidative stress is defined by an imbalance between increased levels of reactive oxygen species (ROS) and a low activity of antioxidant mechanisms. An increased oxidative stress can induce damage to the cellular structure and potentially destroy tissues. 0.7 SIGNOR-272275 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 8626512 YES lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. 0.389 SIGNOR-216908 PRKN protein O60260 UNIPROT SEPTIN4 protein O43236 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 22792159 YES miannu Thus, Parkin degrades ARTS in a proteasome dependent manner.|Together, these results suggest that Parkin specifically ubiquitinates and degrades ARTS, and that this degradation may be linked to the pro-apoptotic function of ARTS. 0.2 SIGNOR-278642 Histone H2B proteinfamily SIGNOR-PF68 SIGNOR Nucleosome complex SIGNOR-C371 SIGNOR form complex binding -1 21812398 YES lperfetto The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. 0.2 SIGNOR-265310 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Ser891 TLSEEKNsECDPTPS 9606 BTO:0000567 31167143 YES miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  0.2 SIGNOR-276728 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT down-regulates activity phosphorylation Tyr632 YHPYPEDyGDIEIGS -1 9195949 YES Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor. 0.757 SIGNOR-251319 CDK2 protein P24941 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 HPGFDAEsYTFTVPR 23972993 YES For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP 0.43 SIGNOR-274049 INSR protein P06213 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Tyr228 PGLKRNRyLSFHFKS 15870194 YES lperfetto Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK 0.479 SIGNOR-275515 HNRNPU protein Q00839 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 YES lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. 0.2 SIGNOR-262281 IHH protein Q14623 UNIPROT BMP2 protein P12643 UNIPROT up-regulates 9606 22298955 NO gcesareni Ihh is found to be required for bmp-induced os-teogenesis of a limb-bud cell line in culture. Ihh sig-naling is directly required for the osteoblast lineage in developing long bones. Ihh functions in conjunction with other factors such as bmps to induce osteoblast differentiation. In vivo, ihh acts on potential progeni-tor cells to promote osteoblast differentiation and prevent chondrocyte differentiation. 0.517 SIGNOR-195609 KRAS protein P01116 UNIPROT MINK1 protein Q8N4C8 UNIPROT up-regulates 9606 16337592 NO gcesareni Mink is activated after ras induction via a mechanism involving reactive oxygen species and mediates stimulation of the stress-activated protein kinase p38 mapk downstream of the raf/erk pathway. 0.2 SIGNOR-142985 PC protein P11498 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24363178 YES miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) 0.8 SIGNOR-266552 ABRAXAS1 protein Q6UWZ7 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 17525340 YES gcesareni Full length abraxas binds the brct-repeats of brca1the rap80-abraxas complex may help recruit brca1 to dna damage sites in part through recognition of ubiquitinated proteins 0.2 SIGNOR-155144 WWTR1 protein Q9GZV5 UNIPROT TEAD1 protein P28347 UNIPROT up-regulates binding 9606 23431053 YES YAP/TAZ mainly bind to the transcription factors TEAD1?????_?4 to regulate genes involved in cell proliferation and cell death. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead1?_?_?4. 0.867 SIGNOR-192768 PPP1CA protein P62136 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity dephosphorylation 9606 32585168 YES miannu The current study assessed whether PP1\u03b1 can stimulate GR function and tested two different hypotheses: First, that PP1\u03b1 regulates GR activity through suppression of MDM2 activity by dephosphorylating it at Ser166, thereby reducing the MDM2-mediated ubiquitination of GR and the subsequent proteasomal degradation of the receptor, as shown for the MR and AR ( xref ; xref ); and second, that PP1\u03b1 directly dephosphorylates the GR at a particular site to relieve functional repression as demonstrated for PP2A and PP5 ( xref ; xref ; xref ).|The involvement of GR-Ser211 phosphorylation supports the assumption that altered subcellular trafficking is a mechanism less likely contributing to the PP1\u03b1-dependent GR activation. 0.291 SIGNOR-277161 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.675 SIGNOR-263429 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 8342904 YES ashma gcesareni 0.8 SIGNOR-251698 CSF2 protein P04141 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 BTO:0000130 16492764 YES gcesareni A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants. These results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells 0.591 SIGNOR-144740 PDK1 protein Q15118 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation 9606 15068796 YES miannu Since both AKT-1, AKT-2, and SGK-1 are phosphorylated by PDK-1 and are themselves capable of phosphorylating DAF-16, their direct contact may reflect a temporary, regulatory interaction.|This demonstrates that functional PDK-1 is required to activate AKT-1, AKT-2, and SGK-1 in vivo. 0.602 SIGNOR-278973 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.32 SIGNOR-161666 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr772 EDDPEATyTTSGGKI 9606 18387945 YES lperfetto The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells. 0.2 SIGNOR-178181 EGR1 protein P18146 UNIPROT FAS protein P25445 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9300687 NO Thus, Egr-1 seems to control the expression of downstream target genes not only as a transcriptional activator, but also as a repressor molecule. In B cells, Egr-1 therefore plays a critical role in integrating the short-lived signal delivered by triggering of the Ag receptor into phenotypic changes, including repression of CD95 and CD23 transcription. 0.274 SIGNOR-254278 IKZF4 protein Q9H2S9 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 NO miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. 0.2 SIGNOR-255406 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TOB1 protein P50616 UNIPROT down-regulates phosphorylation 9606 12050114 YES inferred from 70% family members gcesareni Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation. 0.2 SIGNOR-270123 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 20179209 YES lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated 0.34 SIGNOR-163908 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS 9606 10931940 YES lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Aβ is produced from the Aβ precursor protein (APP) by two proteolytic events. A β-secretase activity cleaves APP at the N terminus of Aβ (β site) between amino acids Met-671 and Asp-672 |We show here that BACE2 cleaves APP at its β site and more efficiently at sites within the Aβ region of APP, after Phe-19 and Phe-20 of Aβ. 0.545 SIGNOR-261772 CHD8 protein Q9HCK8 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.2 SIGNOR-268914 CSMD1 protein Q96PZ7 UNIPROT C4B protein P0C0L5 UNIPROT down-regulates quantity binding 9606 28345259 YES miannu CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor 0.2 SIGNOR-265149 VCB-Cul2 complex SIGNOR-C524 SIGNOR VAV1 protein P15498 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 10747851 YES miannu Recent evidence indicates that SOCS1 interacts with elongins B and C, which are components of a ubiquitin ligase complex, VCB (VHL/elonginC/B), based on the VHL (von Hippel Lindau) tumor suppressor protein. 0.246 SIGNOR-272563 CIB1 protein Q99828 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity binding 9606 BTO:0000132 16418530 YES lperfetto In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation. 0.407 SIGNOR-253357 AGRP protein O00253 UNIPROT MC2R protein Q01718 UNIPROT down-regulates activity binding 9606 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.441 SIGNOR-268696 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Val72 GLTEYRLvSINKSSP -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.42 SIGNOR-263579 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity relocalization 9606 21791611 YES lperfetto One of the major mechanisms underlying the inhibitory effect of Smad7 on TGF-_ signaling operates through accelerating T_RI turnover by recruiting ubiquitin E3 ligases such as Smurf1 and Smurf2 0.87 SIGNOR-227556 AKT2 protein P31751 UNIPROT MYO5A protein Q9Y4I1 UNIPROT up-regulates activity phosphorylation Thr1650 PTGLRKRtSSIADEG 10090 BTO:0000944 17515613 YES miannu Here we identify an Akt consensus phosphorylation motif in the actin-based motor protein myosin 5a and show that insulin stimulation leads to phosphorylation of myosin 5a at serine 1650. This Akt-mediated phosphorylation event enhances the ability of myosin 5a to interact with the actin cytoskeleton.Taken together, these data indicate that myosin 5a is a newly identified direct substrate of Akt2 and, upon insulin stimulation, phosphorylated myosin 5a facilitates anterograde movement of GLUT4 vesicles along actin to the cell surface. 0.457 SIGNOR-262632 GEMIN4 protein P57678 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 YES lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. 0.808 SIGNOR-253118 perfluorooctanoic acid chemical CHEBI:35549 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 23764977 YES miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  0.8 SIGNOR-268762 PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 29203338 NO miannu The PAQosome, an R2TP-Based Chaperone for Quaternary Structure Formation. The Rvb1-Rvb2-Tah1-Pih1/prefoldin-like (R2TP/PFDL) complex is a unique chaperone that provides a platform for the assembly and maturation of many key multiprotein complexes in mammalian cells. Here, we propose to rename R2TP/PFDL as PAQosome (particle for arrangement of quaternary structure) to more accurately represent its unique function. 0.7 SIGNOR-270920 PDPK1 protein O15530 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 15175348 YES gcesareni The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. 0.256 SIGNOR-125176 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH4 protein Q99466 UNIPROT up-regulates activity cleavage 9606 25610395 YES lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins. 0.534 SIGNOR-209729 UBTF protein P17480 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0002882 15169904 NO miannu Pescadillo (PES1) and the upstream binding factor (UBF1) play a role in ribosome biogenesis, which regulates cell size, an important component of cell proliferation. We have investigated the effects of PES1 and UBF1 on the growth and differentiation of cell lines derived from 32D cells, an interleukin-3 (IL-3)-dependent murine myeloid cell line. Parental 32D cells and 32D IGF-IR cells (expressing increased levels of the type 1 insulin-like growth factor I [IGF-I] receptor [IGF-IR]) do not express insulin receptor substrate 1 (IRS-1) or IRS-2. 32D IGF-IR cells differentiate when the cells are shifted from IL-3 to IGF-I. Ectopic expression of IRS-1 inhibits differentiation and transforms 32D IGF-IR cells into a tumor-forming cell line. We found that PES1 and UBF1 increased cell size and/or altered the cell cycle distribution of 32D-derived cells but failed to make them IL-3 independent. PES1 and UBF1 also failed to inhibit the differentiation program initiated by the activation of the IGF-IR, which is blocked by IRS-1. 32D IGF-IR cells expressing PES1 or UBF1 differentiate into granulocytes like their parental cells. In contrast, PES1 and UBF1 can transform mouse embryo fibroblasts that have high levels of endogenous IRS-1 and are not prone to differentiation. Our results provide a model for one of the theories of myeloid leukemia, in which both a stimulus of proliferation and a block of differentiation are required for leukemia development. 0.7 SIGNOR-260077 ADRB2 protein P07550 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.659 SIGNOR-256809 nintedanib chemical CHEBI:85164 ChEBI FGFR4 protein P22455 UNIPROT down-regulates activity chemical inhibition -1 18559524 YES Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. 0.8 SIGNOR-257803 PIP3 smallmolecule CHEBI:16618 ChEBI RPS6KC1 protein Q96S38 UNIPROT up-regulates quantity binding 9534 BTO:0000298 12077123 YES In vitro protein kinase assay showing that RPK118 has no protein kinase activity. miannu We have shown here that a newly identified protein, RPK118, can bind to and co-localize with SPHK1 in COS7-cells. As shown in Fig.8, RPK118 exhibited specific binding to PtdIns (3)P compared with other phosphoinositides. RPK118 Interacts Specifically with Phosphatidylinositol 3-Phosphate (PtdIns (3)P) through Its PX Domain. In vitro protein kinase assay showing that RPK118 has no protein kinase activity. 0.8 SIGNOR-273743 PTPN6 protein P29350 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 11294838 YES lperfetto We demonstrate that shp-1 dephosphorylates the lymphoid-specific src family kinase lck at tyr-394. Because phosphorylation of tyr-394 activates lck, the fact that shp-1 specifically dephosphorylates this site suggests that shp-1 is a negative regulator of lck. 0.612 SIGNOR-106604 AKT1 protein P31749 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 YES lperfetto Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity 0.775 SIGNOR-252581 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys74 DTGRILSkLHTVQPK -1 19240029 YES miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). 0.404 SIGNOR-272738 BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 18498746 YES lperfetto Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly. 0.956 SIGNOR-178679 CDK1 protein P06493 UNIPROT EEF1D protein P29692 UNIPROT unknown phosphorylation Ser133 APQTQHVsPMRQVEP 9606 12551973 YES gcesareni The sequence flanking ser-133 of ef-1delta completely matches the consensus phosphorylation site for a cellular protein kinase, cdc2, and in vitro kinase assays revealed that purified cdc2 phosphorylates ser-133 of ef-1delta. 0.362 SIGNOR-97733 SP1 protein P08047 UNIPROT TINF2 protein Q9BSI4 UNIPROT up-regulates quantity by expression transcriptional regulation 21731707 YES lperfetto Transfection of a plasmid carrying the Sp1 transcription factor into Sp-deficient SL2 cells strongly activated TIN2 promoter-driven luciferase reporter expression. 0.2 SIGNOR-271698 GNAS protein P63092 UNIPROT ADCY1 protein Q08828 UNIPROT up-regulates activity binding 9606 17652154 YES gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR 0.626 SIGNOR-156958 PKA proteinfamily SIGNOR-PF17 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8386317 YES miannu CREB is phosphorylated on Ser133 by PKA (protein kinase A), promoting the recruitment of the co-activator proteins CBP (CREB-binding protein) and p300; this has been proposed to increase the transcription of CREB-dependent genes. 0.2 SIGNOR-263653 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR BIRC6 protein Q9NR09 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.408 SIGNOR-271352 FASN protein P49327 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI up-regulates quantity chemical modification 9606 15507492 YES miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-268087 LHX3 protein Q9UBR4 UNIPROT ISL1 protein P61371 UNIPROT up-regulates activity binding 9606 9452425 YES miannu The Lhx3-Isl1 C terminus interaction was dependent on the LIM domains of Lhx3. The combinatorial expression of the LIM homeodomain proteins Isl1, Isl2, Lhx1, and Lhx3 in subsets of developing motor neurons correlates with the future organization of these neurons into motor columns with distinct innervation targets, implying a functional role for LIM homeodomain protein combinations in the specification of neuronal identity 0.623 SIGNOR-220169 CSNK2A1 protein P68400 UNIPROT CASP2 protein P42575 UNIPROT down-regulates phosphorylation Ser157 LYKKLRLsTDTVEHS 9606 16193064 YES gcesareni Here we show that protein kinase (pk) ck2 phosphorylates procaspase-2 directly at serine-157. When intracellular pkck2 activity is low or downregulated by specific inhibitors, procaspase-2 is dephosphorylated, dimerized, and activated in a piddosome-independent manner. 0.31 SIGNOR-140836 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Thr372 STRIRQNtRDHPSTA 9606 BTO:0000671 10908300 YES gcesareni The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization. 0.2 SIGNOR-79686 CALM1 protein P0DP23 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 9822657 YES gcesareni The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk. 0.83 SIGNOR-61922 hsa-miR-424-5p mirna URS00000F0F49_9606 RNAcentral GPER1 protein Q99527 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003041 26638889 YES Parnian The results showed that co-transfection of miR-424 mimic with GPER wt in Ishikawa cells significantly suppressed luciferase activity, but not in GPER mut transfection groups. 0.4 SIGNOR-278002 LRIG1 protein Q96JA1 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0001253 15282549 YES gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. 0.588 SIGNOR-127298 STK11 protein Q15831 UNIPROT STRADA protein Q7RTN6 UNIPROT up-regulates activity phosphorylation Thr329 GLSDSLTtSTPRPSN 9606 BTO:0000007 12805220 YES lperfetto Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners.LKB1 phosphorylates STRAD at Thr329 and Thr419 0.939 SIGNOR-261950 benazepril chemical CHEBI:3011 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition 9606 16407508 YES Angiotensin-converting-enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg per deciliter or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency. 0.8 SIGNOR-253343 UBE2D1 protein P51668 UNIPROT Elongin E3-Cul-5 complex SIGNOR-C531 SIGNOR up-regulates activity binding -1 20603330 YES miannu We have identified SPRY domain-containing SOCS (suppressor of cytokine signaling) box protein 2 (SPSB2) as a novel negative regulator that recruits an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in its proteasomal degradation. A cell-free ubiquitination assay was established to demonstrate SPSB2-dependent ubiquitination of iNOS. LPS/IFN-γ–stimulated macrophage lysates from Spsb2−/− mice were used as a source of iNOS and incubated with ubiquitin and a trimeric SPSB2/elongin BC complex in the presence of E1 and E2 (UbcH5a) enzymes, Rbx2, and Cullin5 for various times. 0.611 SIGNOR-271898 SNRPB protein P14678 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.921 SIGNOR-270680 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 9873633 YES gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. 0.8 SIGNOR-62892 PTPN11 protein Q06124 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 BTO:0001963 19287004 YES miannu In this study, we identified JAK2 and SHP2 as a Tyr-718-specific kinase and phosphatase, respectively. 0.368 SIGNOR-276144 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000007 14761950 YES The effect has been demonstrated using P10636-8 lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. 0.374 SIGNOR-121713 PRKCG protein P05129 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 YES miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently 0.2 SIGNOR-276018 SSU72 protein Q9NP77 UNIPROT STAG2 protein Q8N3U4 UNIPROT up-regulates activity dephosphorylation Ser1224 PASIMDEsVLGVSMF 20818333 YES lperfetto Additional experiments revealed that Ssu72 directly interacts with Rad21 and SA2 in vitro and in vivo, and associates with sister chromatids in human cells. Interestingly, depletion or mutational inactivation of Ssu72 phosphatase activity caused the premature resolution of sister chromatid arm cohesion, whereas the overexpression of Ssu72 yielded high resistance to this resolution.|anti‐phospho SA2 serine 1224 0.299 SIGNOR-275531 HTR1A protein P08908 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.446 SIGNOR-256972 miR-4784 mirna URS000021E7E5_9606 RNAcentral AHDC1 protein Q5TGY3 UNIPROT up-regulates quantity by expression 10090 19933931 YES The activation state of the IGF-1 signal transduction cascade reciprocally regulates miR-1 expression through the Foxo3a transcription factor; 0.4 SIGNOR-255720 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser295 LQASVPGsVPGVLGP 9606 16027724 YES miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation 0.415 SIGNOR-250095 TACR1 protein P25103 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257161 RIPK1 protein Q13546 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 21525013 YES amattioni Degradation of ciaps triggers the release of receptor interacting protein kinase (ripk1) from tnf receptor i (tnfr1) to form a caspase-8 activating complex 0.909 SIGNOR-173432 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR KLF4 protein O43474 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000594 26087183 YES lperfetto F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression 0.374 SIGNOR-273445 RIPK3 protein Q9Y572 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity phosphorylation Thr182 GSGEPGGtLGYLAPE -1 29883609 YES miannu This suggests that Thr182 is a likely auto-phosphorylation target and may be involved in RIP3 activity. 0.2 SIGNOR-277396 PRKCG protein P05129 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates phosphorylation 9606 12536214 YES inferred from family member gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. 0.704 SIGNOR-270233 SRC protein P12931 UNIPROT FHL1 protein Q13642 UNIPROT up-regulates activity phosphorylation Tyr149 FPKGEDFyCVTCHET 9606 29434030 YES miannu However, overexpression of Src promoted most of the Flag-FHL1-WT to translocate to the nucleus, whereas the Flag-FHL1-Y149-272F mutant (phosphorylation deficient mutant) remained in the cytoplasm (XREF_FIG).|We found that Src phosphorylates FHL1 at Y149 and Y272, demonstrating that FHL1 is a bona fide novel substrate of Src. 0.26 SIGNOR-278213 GH1 protein P01241 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 15665309 YES Luana Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells 0.2 SIGNOR-261629 GNA13 protein Q14344 UNIPROT ARHGEF11 protein O15085 UNIPROT up-regulates activity binding 9606 11799111 YES This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho 0.634 SIGNOR-256517 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser592 KCNVKAKsNVDLRRS 9606 BTO:0000007 30279167 YES miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser560 0.2 SIGNOR-277814 TLN1 protein Q9Y490 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.583 SIGNOR-257632 GSK3B protein P49841 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by destabilization phosphorylation Ser94 EDFWRPPsPSASPAS 9606 BTO:0000498 31289136 YES miannu GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. 0.2 SIGNOR-277466 PIEZO2 protein Q9H5I5 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 YES lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). 0.397 SIGNOR-262572 TRAF6 protein Q9Y4K3 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates activity ubiquitination 9606 29729098 YES miannu In contrast to NEDD4L, overexpression of TRAF6 increases the stability of PIK3CA protein and promotes PI3K activation.|TRAF6 ubiquitinates PIK3CA in vivo. 0.456 SIGNOR-278727 MAPK1 protein P28482 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity phosphorylation Ser274 LAPNPSFsPTPGFTP -1 11606045 YES lperfetto Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a 0.501 SIGNOR-249452 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258303 CCDC102B protein Q68D86 UNIPROT CROCC protein Q5TZA2 UNIPROT up-regulates activity binding 30404835 YES lperfetto CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis. 0.2 SIGNOR-275628 RNF126 protein Q9BV68 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 23418353 YES miannu RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded. 0.329 SIGNOR-272103 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR miR-155 mirna URS000062749E_9606 RNAcentral up-regulates quantity transcriptional regulation 9606 26055960 NO miannu Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation. 0.4 SIGNOR-255802 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG5-LLGL1_variant complex SIGNOR-C508 SIGNOR form complex binding 9606 23397623 YES miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. 0.448 SIGNOR-270900 CSNK2A3 protein Q8NEV1 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 YES lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. 0.269 SIGNOR-275742 PEX2 protein P28328 UNIPROT ABCD3 protein P28288 UNIPROT up-regulates activity ubiquitination 9606 27597759 YES miannu PEX5 and PMP70 are ubiquitinated by PEX2 during amino acid starvation. 0.401 SIGNOR-278708 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.788 SIGNOR-120000 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser335 GDGVPVKsRKTTLEQ -1 31730483 YES miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. 0.642 SIGNOR-276776 Ub:E2 complex SIGNOR-C497 SIGNOR COP1 protein Q8NHY2 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271101 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser29 FDGSSCIsPTIVQQF 10090 BTO:0000944 15664191 YES lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 0.631 SIGNOR-249441 PLK1 protein P53350 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates phosphorylation Ser65 SHLLVKHsQSRRPSS 9606 BTO:0000567 16118204 YES llicata Here we demonstrate that ser-65 in pin1 is the major site for plk1-specific phosphorylation, and the polo-box domain of plk1 is required for this phosphorylation. Interestingly, the phosphorylation of pin1 by plk1 does not affect its isomerase activity but rather is linked to its protein stability. pin1 is ubiquitinated in hela s3 cells, and substitution of glu for ser-65 reduces the ubiquitination of pin1. 0.425 SIGNOR-139919 RUVBL1 protein Q9Y265 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.741 SIGNOR-269292 MPO-ANCA complex SIGNOR-C474 SIGNOR thiocyanate smallmolecule CHEBI:18022 ChEBI up-regulates quantity by expression oxidation 9606 BTO:0000133 9922160 YES lperfetto Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids.| Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity. 0.8 SIGNOR-270591 HSPA1A protein P0DMV8 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 16172114 NO gcesareni Hsp70 inhibited stress-induced jnk activation and jnk with sp600125 or by expression of a dominant negative mutant of jnk-blocked bax translocation as effectively as hsp70 overexpression 0.502 SIGNOR-140553 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr621 LQADSAEyAQPLVGG -1 23770091 YES done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. 0.351 SIGNOR-273941 AR protein P10275 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 15861399 YES miannu The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes. 0.2 SIGNOR-251537 PTPN6 protein P29350 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation 9606 31130074 YES miannu Mechanistically, the association of EHEC Tir with SHP-1 facilitated the recruitment of SHP-1 to TAK1 and inhibited TAK1 phosphorylation, which then negatively regulated K63-linked polyubiquitination of TAK1 and downstream signal transduction.|SHP-1 inhibits TAK1 activity to down-regulate signal transduction and subsequent cytokine production.Innate immune responses are achieved by the activation of several pathogen-recognition receptors (PRPs), including TLRs, retinoic acid inducible gene I (RIG-I)-like receptors (RLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). 0.296 SIGNOR-277128 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser54 GGFPRRHsVTLPSSK 9606 18326031 YES lperfetto Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation. 0.619 SIGNOR-161274 STUB1 protein Q9UNE7 UNIPROT TAL1 protein P17542 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 17962192 YES miannu Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively. 0.356 SIGNOR-271393 4'-epidoxorubicin chemical CHEBI:47898 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 17639997 YES miannu The combinatory use of low concentrations of SM with low-toxic topoisomerase II inhibitor epirubicin accelerated apoptotic cell death. 0.8 SIGNOR-259282 CSNK2A1 protein P68400 UNIPROT PDCD5 protein O14737 UNIPROT up-regulates phosphorylation Ser119 NRRKVMDsDEDDDY 9606 19616514 YES lperfetto Programmed cell death 5 (pdcd5), a protein involved in cell death and down-regulated in different forms of human tumors. Pdcd5 is phosphorylated in vitro by both ck2alpha subunit and by the ck2 holoenzyme at a residue, s118, which is found phosphorylated in vivo. Transfection of the non-phosphorylatable mutant (s118a) impairs the pdcd5 acceleration of either doxorubimicin- or uv-induced apoptosis in u2os cells 0.2 SIGNOR-187106 FKBP8 protein Q14318 UNIPROT MTOR protein P42345 UNIPROT down-regulates binding 9606 17991864 YES gcesareni Fkbp38 binds to mtor and inhibits its activity in a manner similar to that of the fkbp12-rapamycin complex. 0.566 SIGNOR-159013 ZNF423 protein Q2M1K9 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates activity 10090 BTO:0000011 20200519 NO Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate. 0.7 SIGNOR-255928 CYBB protein P04839 UNIPROT Phagocyte NADPH oxidase complex complex SIGNOR-C557 SIGNOR form complex binding 9606 37263099 YES miannu NADPH oxidase is composed of essential protein components in its active state: membranous subunits, including p22-phox and gp91-phox, and cytoplasmic subunits, including p47-phox, p67-phox, p40-phox, and RAC2 (in neutrophils), among which NCF4 encodes the cytoplasmic subunit p40-phox 0.736 SIGNOR-277633 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 NO Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 0.8 SIGNOR-268015 MARS1 protein P56192 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 YES miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). 0.2 SIGNOR-270352 GSK3B protein P49841 UNIPROT CD274 protein Q9NZQ7 UNIPROT down-regulates quantity phosphorylation 9606 27572267 YES miannu Together, the results suggest that GSK3\u03b2 binds and phosphorylates the non-glycosylated PD-L1.|We show that glycogen synthase kinase 3\u03b2 (GSK3\u03b2) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by \u03b2-TrCP. 0.307 SIGNOR-279047 LIF protein P15018 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 9143707 YES gcesareni Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors.Some Of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2 0.79 SIGNOR-48108 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19254573 NO fspada Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation 0.326 SIGNOR-184280 TRIM59 protein Q8IWR1 UNIPROT MACROH2A1 protein O75367 UNIPROT down-regulates ubiquitination 9606 31488827 YES miannu Nuclear TRIM59 promotes mH2A1 ubiquitination and degradation.|TRIM59-mediated mH2A1 degradation enhances STAT3 signaling. 0.2 SIGNOR-278677 Ternatin chemical CID:5459184 PUBCHEM EEF1A1 protein P68104 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001109 26651998 YES Simone Vumbaca Ternatins inhibit protein synthesis with potencies that correlate with their ability to block cell proliferation, and photo-ternatin 5 identified eEF1A as aplausible target. 0.8 SIGNOR-261126 EGR1 protein P18146 UNIPROT LHB protein P01229 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19106114 NO miannu EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity. 0.396 SIGNOR-254919 VCAM1 protein P19320 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates activity binding 9606 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.674 SIGNOR-253241 P2RY4 protein P51582 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257122 ADAM10 protein O14672 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity cleavage 9606 28624438 YES miannu One of the most important and best characterized ADAM10 substrates is the Notch receptor [16]. After ligand binding to the Notch receptor, ADAM10 liberates the ectodomain and the membrane remaining part is processed by the γ-secretase complex, which releases a Notch Intracellular Domain (NICD). 0.781 SIGNOR-259836 FOXL2 protein P58012 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000975 16153597 NO miannu We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2 0.7 SIGNOR-256643 SOCS3 protein O14543 UNIPROT JAK3 protein P52333 UNIPROT down-regulates activity binding 9606 21508344 YES lperfetto SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR). 0.698 SIGNOR-238645 GSK3B protein P49841 UNIPROT SIGIRR protein Q6IA17 UNIPROT down-regulates quantity by destabilization phosphorylation Thr372 EPSAPPHtSGVSLGE 9606 33400290 YES miannu Activation of GSK3beta promotes Sigirr degradation in the proteasome .|Taken together, IL-37-induced Sigirr internalization is dependent on phosphorylation of Sigirr in T372 residue by GSK3\u03b2. 0.2 SIGNOR-279053 SHC1 protein P29353 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 BTO:0000944 17673906 NO lperfetto We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases. 0.719 SIGNOR-242628 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 YES MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. 0.851 SIGNOR-175841 PRKD1 protein Q15139 UNIPROT CERT1 protein Q9Y5P4 UNIPROT down-regulates phosphorylation Ser132 SSLRRHGsMVSLVSG 9606 17591919 YES lperfetto In this study, we identify cert as a novel in vivo pkd substrate. Phosphorylation on serine 132 by pkd decreases the affinity of cert toward its lipid target phosphatidylinositol 4-phosphate at golgi membranes and reduces ceramide transfer activity 0.2 SIGNOR-156500 LCK protein P06239 UNIPROT STAT5B protein P51692 UNIPROT up-regulates activity phosphorylation 9606 16446405 YES miannu A constitutively active Lck kinase promotes cell proliferation and resistance to apoptosis through signal transducer and activator of transcription 5b activation.|Expression of the active Lck kinase induces both tyrosine phosphorylation and DNA binding activity of signal transducer and activator of transcription 5b (STAT5b), a STAT family member activated in a variety of tumor cells. 0.642 SIGNOR-279056 PLK4 protein O00444 UNIPROT PLK4 protein O00444 UNIPROT up-regulates phosphorylation Ser305 SSTSISGsLFDKRRL 9606 20032307 YES llicata Autophosphorylation probably plays a role in the process of centriole duplication, because mimicking s305 phosphorylation enhances the ability of overexpressed plk4 to induce centriole amplification. Importantly, we show that s305-phosphorylated plk4 is specifically sequestered at the centrosome contrary to the nonphosphorylated form. 0.2 SIGNOR-162559 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 20590599 YES Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  0.8 SIGNOR-257865 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr339 SDTATNStLPSAEVE -1 7836371 YES Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation. 0.2 SIGNOR-251452 UHRF2 protein Q96PU4 UNIPROT PCNP protein Q8WW12 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31487123 YES miannu Ubiquitination of PEST containing nuclear protein (PEST) by NIRF (Np95/ICBP90‐like RING finger protein) in the nuclear core of the cell: Ubiquitin‐like domain in the N‐terminus and a RING finger motif in the C‐terminus of NIRF confirm the ubiquitin ligase function of NIRF. PCNP acts as a substrate for NIRF mediated proteasome activity. 0.452 SIGNOR-271501 PTPA protein Q15257 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 YES gcesareni Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473) 0.2 SIGNOR-170699 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 BTO:0000782;BTO:0001271 8992971 YES lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor 0.689 SIGNOR-45512 HERC2 protein O95714 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20631078 YES miannu HERC2 ubiquitinates BRCA1; this reaction depends on Cys(4762) of HERC2, the catalytic ubiquitin binding site, and the degron of BRCA1.|Significantly, HERC2 depletion antagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G(2)-M checkpoint activity. 0.56 SIGNOR-278813 PKA proteinfamily SIGNOR-PF17 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates activity phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 BTO:0003250 20943948 YES lperfetto On the other hand, our group has shown that protein kinase A (PKA) inhibits Nox1 activity in colon epithelial cells by phosphorylating NoxA1 at two distinct sites, Ser172 and Ser461 0.2 SIGNOR-264712 CSNK2A1 protein P68400 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates phosphorylation Ser394 EDAVHEDsGDEDGED 9606 12082111 YES gcesareni Protein kinase ck2-mediated phosphorylation of hdac2 regulates co-repressor formation, deacetylase activity and acetylation of hdac2 by cigarette smoke and aldehydesstudies using unfractionated cell extracts with ck2 inhibitors suggest that protein kinase ck2 is the major source of hdac2 kinase. Finally, and perhaps most interesting, hdac2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many hdacs, hdac2 is regulated by post-translational modification, particularly phosphorylation. 0.619 SIGNOR-89937 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser853 IAEPMRRsVSEAALA 10090 BTO:0000944 11581251 YES lperfetto HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme 0.601 SIGNOR-249202 MAPK8 protein P45983 UNIPROT CDC25B protein P30305 UNIPROT down-regulates quantity by destabilization phosphorylation Ser103 ESSLSSEsSESSDAG 9606 BTO:0000567 21807946 YES miannu  Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104). 0.284 SIGNOR-276351 PRKCG protein P05129 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 YES lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. 0.353 SIGNOR-248978 PIM1 protein P11309 UNIPROT HBP1 protein O60381 UNIPROT up-regulates activity phosphorylation Ser380 MARQRRAsLSCGGPG 9606 BTO:0002181 28348080 YES miannu  Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it. 0.2 SIGNOR-277347 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 BTO:0000671 15694384 YES llicata Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925. 0.2 SIGNOR-133837 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT up-regulates activity phosphorylation Ser416 SSAFLGFsYAPEDDD 10548550 YES miannu SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. 0.595 SIGNOR-250376 COX7C protein P15954 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.778 SIGNOR-267754 POLR2I protein P36954 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 YES lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II 0.847 SIGNOR-266166 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 SIGNOR-C3 21071439 YES inferred from 70% family members lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. 0.2 SIGNOR-270032 FZD1 protein Q9UP38 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 NO fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) 0.277 SIGNOR-80598 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr2031 CCRMGIKtSEGTPGF 9606 BTO:0000938 20595391 YES lperfetto Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2. 0.2 SIGNOR-166470 RELA protein Q04206 UNIPROT CITED1 protein Q99966 UNIPROT up-regulates binding 9606 SIGNOR-C13 9660950 YES gcesareni The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276. 0.2 SIGNOR-59054 CMTM4 protein Q8IZR5 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization stabilization 9606 BTO:0002806 28813410 YES Barakat Furthermore, the observations that (i) CMTM6 affects PD-L1 protein stability at late time points after biosynthesis; (ii) CMTM6, CMTM4 and PD-L1 interact, as shown by co-immunoprecipitation; and that (iii) CMTM6 is largely located at the cell surface, collectively suggest a model in which CMTM6 interacts with PD-L1 at the tumour cell surface and thereby protects it from degradation 0.353 SIGNOR-274981 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1784 TPTSPNYsPTSPSYS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248757 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity phosphorylation Ser87 AAAGPALsPVPPVVH 9606 10567572 YES gcesareni Jnk1-mediated phosphorylation of bcl-2 regulates starvation-induced autophagy. 0.581 SIGNOR-48038 NR1I2 protein O75469 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11706036 YES gcesareni The constitutive androstane receptor (car, nr1i4), like fxr and pxr, binds dna as a heterodimer with rxr? 0.534 SIGNOR-111624 SUFU protein Q9UMX1 UNIPROT GLIS3 protein Q8NEA6 UNIPROT down-regulates binding 9606 21543335 YES fspada These data indicate that the inhibition of glis3-mediated transactivation by sufu appears to rely on the interaction with glis3 through the ygh motif and is not related to an effect on the general transcriptional machinery 0.381 SIGNOR-173573 BLK protein P51451 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.647 SIGNOR-268208 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 YES lperfetto Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation 0.308 SIGNOR-181659 LY2784544 chemical CID:46213929 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193796 NPTX1 protein Q15818 UNIPROT BAD protein Q92934 UNIPROT up-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 NO lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control 0.2 SIGNOR-260410 LRRK2 protein Q5S007 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 17447891 YES lperfetto This led to the discovery that moesin, a protein which anchors the actin cytoskeleton to the plasma membrane, is efficiently phosphorylated by lrrk2, at thr558. Moesin phosphorylation could be essential to support the cytoskeletal changes accompanying this process. 0.552 SIGNOR-154498 MAPK3 protein P27361 UNIPROT HNF4A protein P41235 UNIPROT down-regulates activity phosphorylation 9606 28196117 YES miannu Activation of the ERK1/2 signalling pathway, inducing proliferation and survival, inhibits the expression of HNF4\u03b1.|Here we have demonstrated that ERK1 is able to phosphorylate HNF4\u03b1 at several serine and threonine residues. 0.495 SIGNOR-279070 KCNB1 protein Q14721 UNIPROT VAPA protein Q9P0L0 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 YES lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. 0.2 SIGNOR-262122 GTF2I protein P78347 UNIPROT PRRX1 protein P54821 UNIPROT up-regulates binding 9606 9334314 YES miannu Spin binds specifically to multiple sequences in the c-fos promoter and interacts cooperatively withphox1to promote serum-inducible transcription of a reporter gene driven by the c-fos serum response element (sre). 0.345 SIGNOR-52654 IL1B protein P01584 UNIPROT MC1R protein Q01726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 9767234 NO miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. 0.261 SIGNOR-252385 IGF1R protein P08069 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 18595745 YES gcesareni Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively) 0.717 SIGNOR-179386 MGluR proteinfamily SIGNOR-PF55 SIGNOR GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 YES miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. 0.2 SIGNOR-264689 RPS14 protein P62263 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.916 SIGNOR-262438 PRKCZ protein Q05513 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 YES miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. 0.261 SIGNOR-276047 MNAT1 protein P51948 UNIPROT CAK complex complex SIGNOR-C456 SIGNOR form complex binding 9606 30860024 YES lperfetto CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits 0.948 SIGNOR-269320 ADL-5859 chemical CID:46931003 PUBCHEM OPRD1 protein P41143 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189278 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr999 YASSNPEyLSASDVF -1 3166375 YES lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 0.2 SIGNOR-106526 Tifluadom chemical CHEBI:9591 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9262330 YES miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. 0.8 SIGNOR-258665 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Ser258 TSCASLDsPGRIKRK 9606 11931757 YES lperfetto Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. 0.636 SIGNOR-116321 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT down-regulates activity phosphorylation Thr332 KSLAEHRtPDVLKKC 10090 BTO:0000944 14754904 YES miannu Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. A lower level of phosphorylation was observed for the double mutant, suggesting that T332 might also be phosphorylated by cdc2 kinase. 0.265 SIGNOR-262728 KDM5D protein Q9BY66 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-264308 NMUR2 protein Q9GZQ4 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.268 SIGNOR-257126 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT up-regulates activity phosphorylation Tyr80 QDNVDQTySEELCYT -1 31362927 YES miannu Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation. 0.356 SIGNOR-273572 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT down-regulates activity phosphorylation Ser104 GSSLRYYsEGESGGG -1 11328814 YES miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity 0.2 SIGNOR-262974 NUAK2 protein Q9H093 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation 9606 30622137 YES miannu NUAK2 phosphorylates and inhibits MYPT1, the regulatory subunit of MLC phosphatase, stabilizing actin filaments and mediating contraction of smooth muscle cells ( xref ). 0.467 SIGNOR-279081 SH3GL1 protein Q99961 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 NO miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. 0.7 SIGNOR-263885 DNA primase complex complex SIGNOR-C261 SIGNOR DNA polymerase alpha:primase complex complex SIGNOR-C262 SIGNOR form complex binding -1 24043831 YES lperfetto At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation  0.986 SIGNOR-261341 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000938 16923168 YES The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. 0.451 SIGNOR-148966 PRKCD protein Q05655 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr71 VAFSVDNtIKRPNPA 29383184 YES lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. 0.2 SIGNOR-275564 TSHZ3 protein Q63HK5 UNIPROT CASP4 protein P49662 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 19343227 YES miannu Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD. 0.27 SIGNOR-264815 TFIID complex SIGNOR-C343 SIGNOR GTF2B protein Q00403 UNIPROT up-regulates activity relocalization 9606 8990153 YES lperfetto Early in PIC assembly, TFIIA can associate with and stabilize the TFIID–DNA or the TFIIB–TFIID–DNA complexes, allowing them to ward off the deleterious effects of inhibitory negative cofactors and enhance the stimulatory effects of transcriptional activators 0.651 SIGNOR-269308 RAB7A protein P51149 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity guanine nucleotide exchange factor BTO:0001131 14617358 YES Sara The p150 adapter protein is in a complex with rab7. The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7 0.485 SIGNOR-261302 RAD23B protein P54727 UNIPROT XPA protein P23025 UNIPROT up-regulates activity binding 24086043 YES lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.768 SIGNOR-275697 SCNN1A protein P37088 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 26772908 YES miannu The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. 0.8 SIGNOR-269275 SOSTDC1 protein Q6X4U4 UNIPROT WNT9B protein O14905 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.276 SIGNOR-242739 BIRC2 protein Q13490 UNIPROT PACS2 protein Q86VP3 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24633224 YES miannu The principal findings indicate that (i) PACS-2 is constitutively polyubiquitinated and degraded via the proteasome pathway in liver cells; (ii) Cellular Inhibitor of Apoptoses bind to and directly ubiquitinate PACS-2; (iii) pharmacological depletion (by SMAC mimetics) or genetic deletion of both cIAP-1 and cIAP-2 impairs PACS-2 ubiquitination and results in its intracellular accumulation; and (iv) PACS-2 accumulation facilitates its translocation to the lysosomes following TRAIL treatment, promoting TRAIL-induced lysosomal membrane permeabilization and apoptosis.|The principal findings indicate that (i) PACS-2 is constitutively polyubiquitinated and degraded via the proteasome pathway in liver cells; (ii) cIAPs bind to and directly ubiquitinate PACS-2; (iii) pharmacological depletion (by SMAC mimetics) or genetic deletion of both cIAP-1 and cIAP-2 impairs PACS-2 ubiquitination and results in its intracellular accumulation; and (iv) PACS-2 accumulation facilitates its translocation to the lysosomes following TRAIL treatment, promoting TRAIL induced LMP and apoptosis. 0.304 SIGNOR-278743 ATM protein Q13315 UNIPROT UBQLN4 protein Q9NRR5 UNIPROT up-regulates activity phosphorylation Ser318 GNSDSSSsQPLRTEN 9606 BTO:0001938 30612738 YES lperfetto These results suggest that UBQLN4 phosphorylation on S318 is functionally important for its role in the DSB response.>Particularly HRR is dependent on ATM activity (Dietlein et al., 2014). Here, we showed that UBQLN4 is an ATM substrate and that DSB sealing is markedly impaired in UBQLN4-depleted cells. HRR depends on a 5′-3′ DSB end resection, which is initiated by the MRE11 nuclease 0.2 SIGNOR-265076 CSNK2A1 protein P68400 UNIPROT APEX1 protein P27695 UNIPROT up-regulates activity phosphorylation Ser123 HQYWSAPsDKEGYSG 9534 BTO:0004055 10023679 YES llicata Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1. 0.486 SIGNOR-250825 PRKCZ protein Q05513 UNIPROT PARD3 protein Q8TEW0 UNIPROT up-regulates phosphorylation Ser827 REGFGRQsMSEKRTK 9606 12390250 YES gcesareni These results imply that serine 827 in the apkc binding site of par-3 is a target of apkc and that the regulated interaction between a protein kinase, apkc, and its substrate, par-3, plays an essential role in the establishment of cell polarity 0.71 SIGNOR-94523 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9834241 NO miannu CBFbeta-SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-damaging Agents Reduced p53 induction may be caused in part by direct inhibition of p53 gene transcription, because p53 mRNA levels were reduced by CBFβ-SMMHC. Attenuated p53 induction and slowed apoptosis may contribute to leukemogenesis by CBFβ-SMMHC. 0.2 SIGNOR-256132 FLT3 protein P36888 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates quantity transcriptional regulation 9606 BTO:0004760 15574429 NO Furthermore, a small but reproducible growth/survival advantage was observed in both TF-1 and TF-1/ITD cells when SHP-1 expression was knocked down by RNAi. Taken together, these data provide the first evidence that suppression of SHP-1 by FLT3/ITD signaling may be another mechanism contributing to the transformation by FLT3/ITD mutations 0.368 SIGNOR-259950 CHAF1A protein Q13111 UNIPROT MGMT protein P16455 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 15657354 NO miannu Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT. 0.2 SIGNOR-254569 Ub:E2 complex SIGNOR-C497 SIGNOR RNF41 protein Q9H4P4 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271090 POU5F1 protein Q01860 UNIPROT THY1 protein P04216 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.421 SIGNOR-254931 CTNND1 protein O60716 UNIPROT VAV2 protein P52735 UNIPROT up-regulates binding 9606 22946057 YES gcesareni We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn 0.608 SIGNOR-198941 BBsome complex complex SIGNOR-C288 SIGNOR RAB8A protein P61006 UNIPROT up-regulates activity binding 9606 17574030 YES lperfetto Interestingly, the BBSome is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. 0.443 SIGNOR-262562 TP53 protein P04637 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 24212651 NO miannu P53 is a nuclear transcription factor with a pro-apoptotic function 0.7 SIGNOR-256664 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM2 protein Q9C040 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271019 UTS2R protein Q9UKP6 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257319 INPPL1 protein O15357 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI down-regulates chemical modification 9606 9111325 YES gcesareni Sip specifically and markedly reduced the level of phosphatidylinositol (3,4,5) triphosphate [ptdins(3,4,5)p3] generated in oocytes in response to insulin 0.8 SIGNOR-47537 CSK protein P41240 UNIPROT SRC protein P12931 UNIPROT down-regulates phosphorylation Tyr530 FTSTEPQyQPGENL 9606 18614016 YES gcesareni The catalytic activity of the src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the c terminus (tyr 527 in c-src), which is catalyzed by c-terminal src kinase (csk). 0.568 SIGNOR-179417 MAPK3 protein P27361 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation Ser1185 GTPPASTsPFSQLAA 9606 BTO:0001130 12163482 YES lperfetto Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein 0.268 SIGNOR-91139 RIOK1 protein Q9BRS2 UNIPROT MYH9 protein P35579 UNIPROT up-regulates activity phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000950 39488790 YES miannu This study demonstrates that SPC25 acts as a molecular scaffold, mediating SPC25/RIOK1/MYH9 complex formation and triggering the RIOK1‐mediated phosphorylation of MYH9 at Ser1943.Taken together, these results suggested that SPC25 increases MYH9 phosphorylation at Ser1943, enhancing the nuclear accumulation of MYH9 and consequently modulating the transcription of CTNNB1. 0.2 SIGNOR-278895 SLC12A7 protein Q9Y666 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 21613606 YES lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  0.8 SIGNOR-264639 MAP1LC3A protein Q9H492 UNIPROT O-phosphoethanolamine smallmolecule CHEBI:17553 ChEBI up-regulates binding 9606 22170151 YES gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe 0.8 SIGNOR-191546 APOBEC3H protein Q6NTF7 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 NO lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). 0.7 SIGNOR-261330 STAT6 protein P42226 UNIPROT SOCS1 protein O15524 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17093501 YES lperfetto We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent. 0.636 SIGNOR-249570 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr730 SNCTNELyMMMRDCW 10116 19224897 YES lperfetto Furthermore, under conditions in which wild-type or mutant FGFR1 are overexpressed, Y463, Y583, Y585, and Y730 are dispensable for tyrosine phosphorylation of Shc, the mitogen-activated protein kinase (MAPK) response, and stimulation of FGFR1-mediated cell proliferation and differentiation 0.2 SIGNOR-236191 ATP smallmolecule CHEBI:15422 ChEBI 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity precursor of 9606 11376933 YES miannu To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis. 0.8 SIGNOR-267842 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000567 17615152 YES gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity 0.703 SIGNOR-156864 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr334 ALPPGPPtGATANRL 9606 BTO:0000007 10542239 YES llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T 0.2 SIGNOR-250812 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Thr185 HDHTGFLtEYVATRW 9606 BTO:0003807 11971971 YES lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. 0.75 SIGNOR-236447 NANOG protein Q9H9S0 UNIPROT SOX17 protein Q9H6I2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 NO lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) 0.472 SIGNOR-253168 PRKN protein O60260 UNIPROT HIF3A protein Q9Y2N7 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000793 27551449 YES Parkinson miannu Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. 0.2 SIGNOR-263089 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT down-regulates quantity by destabilization phosphorylation Ser129 PYPSPVLsEEEDLPL 9606 BTO:0000567 10618498 YES llicata Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | Serine residues 37 in the transactivation domain and 129, 144 and 146 in the PEST domain of Spi-B are phosphorylated by CKII in vitro | The CKII phosphorylation sites mapped in vitro are phosphorylated in vivo 0.307 SIGNOR-251039 MYCBP2 protein O75592 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates ubiquitination 10116 BTO:0001009 14559897 YES Monia Pam Interacts with the Tuberin-Hamartin Complex—To examine the in vivo association of tuberin and Pam, we performed co-immunoprecipitation experiments in PC12 cells and rat embryonic brain. Immunoprecipitation of tuberin using an anti-tuberin antibody followed by immunoblot analysis showed that endogenous Pam co-immunoprecipitates with tuberin in PC12 cells and embryonic rat brain. Pam Homolog HIW Modulates Tsc1Tsc2 Activity in Drosophila. The enhancement of Tsc1Tsc2 phenotype by the removal of the hiw gene indicates that hiw negatively regulates Tsc1Tsc2 activity in Drosophila eye. Taken together, it is probable that Pam may function as an E3 ligase for tuberin and regulate the ubiquitination and proteasomal degradation of the tuberinhamartin complex particularly in the CNS 0.315 SIGNOR-261202 SPP1 protein P10451 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 9606 24241034 YES lperfetto Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C. 0.622 SIGNOR-253311 EEF1A1P5 protein Q5VTE0 UNIPROT Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269554 KLKB1 protein P03952 UNIPROT HGF protein P14210 UNIPROT up-regulates activity cleavage Arg424 KNMEDLHrHIFWEPD -1 12372819 YES miannu the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain. 0.324 SIGNOR-256513 SGK1 protein O00141 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Ser29 GPRYTNLsYIGEGAY 9606 BTO:0000599 19447520 YES miannu SGK1 was found to physically interact with ERK1/2 as well as MEK1/2. Furthermore, SGK1 mediated the phosphorylation of ERK2 on Ser(29) in a serum-dependent manner. Replacement of Ser(29) to aspartic acid, which mimics the phosphorylation of Ser(29), enhanced the ERK2 activity as well as the MEK/ERK complexes formation. 0.309 SIGNOR-276223 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI aldosterone smallmolecule CHEBI:27584 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 YES lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone 0.8 SIGNOR-268686 CHN2 protein P52757 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.639 SIGNOR-260500 SRC protein P12931 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates phosphorylation Tyr125 PIPLQETyDVCEQPP 9606 16317717 YES lperfetto The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex 0.407 SIGNOR-142724 PTPN9 protein P43378 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation 9606 20335174 YES miannu Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. 0.304 SIGNOR-277170 NEDD4L protein Q96PU5 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21463633 YES miannu As quantified in Fig. 5 B, only Nedd4-2 significantly increased the basal ubiquitylation of hERG1, while Nedd4-2-C801S and the other ubiquitin ligases had no effect.|The major findings of this study are as follows : 1) hERG1 interacts via its PY motif with the ubiquitin ligase Nedd4-2, 2) this interaction promotes the down-regulation of the functional form of the channel at the plasma membrane through Nedd4-2 ubiquitylation of the channel, and 3) I hERG1 is strongly decreased by Nedd4-2 catalytic dependent activity.The hERG1 PY motif is a highly conserved sequence across animal species lines, highlighting its crucial role in the regulation of the hERG1 channel at the cell surface. 0.399 SIGNOR-278771 RAB32 protein Q13637 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR up-regulates activity relocalization 9606 23247405 YES lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. 0.286 SIGNOR-260698 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1034 AIETDKEyYTVKDDR 10090 11201744 YES CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells 0.455 SIGNOR-248355 chloroquine chemical CHEBI:3638 ChEBI IL6 protein P05231 UNIPROT down-regulates quantity 9606 32283152 NO miannu Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19. 0.8 SIGNOR-260854 CHRM5 protein P08912 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256730 CPT1C protein Q8TCG5 UNIPROT O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity chemical modification 9606 14517221 YES miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). 0.8 SIGNOR-267131 C5AR1 protein P21730 UNIPROT ITGAM protein P11215 UNIPROT up-regulates quantity by expression 1847994 NO lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. 0.371 SIGNOR-263464 PIK3AP1 protein Q6ZUJ8 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000801 22187458 YES gcesareni Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling 0.519 SIGNOR-252701 RPS27 protein P42677 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.87 SIGNOR-262444 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1738 SPSYSPTsPSYSPTS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248777 ATRX protein P46100 UNIPROT ZBED1 protein O96006 UNIPROT up-regulates activity binding 7227 BTO:0001138 22021382 YES 1 miannu XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression. 0.413 SIGNOR-239729 SOSTDC1 protein Q6X4U4 UNIPROT WNT10A protein Q9GZT5 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.331 SIGNOR-242695 SGK3 protein Q96BR1 UNIPROT PIKFYVE protein Q9Y2I7 UNIPROT up-regulates activity phosphorylation Ser318 LSLDRSGsPMVPSYE 9606 22470488 YES miannu The Western blot in XREF_FIG demonstrates that SGK3 as well as PKB phosphorylate PIKfyve at position S318, thereby indicating that PIKfyve could be a physiological target of SGK3.|We here identify a novel mechanism involving NMDA receptor triggered, SGK3 dependent stimulation of PIKfyve with subsequent formation of PI (3,5) P 2, which modulates RAB11A facilitated vesicle transport to the plasma membrane, leading to an increased abundance of GluA1 receptor subunits in the plasma membrane. 0.462 SIGNOR-279113 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser97 TIAESEDsQESVDSV 9606 9931297 YES lperfetto Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement. 0.312 SIGNOR-64254 TPI1 protein P60174 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). 0.8 SIGNOR-266492 Caspase 3 complex complex SIGNOR-C221 SIGNOR GSN protein P06396 UNIPROT down-regulates activity cleavage Asp403 WRDPDQTdGLGLSYL 9606 9671712 YES miannu We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death. 0.638 SIGNOR-256433 NEK2 protein P51955 UNIPROT YAP1 protein P46937 UNIPROT up-regulates quantity by stabilization phosphorylation Thr143 AVSPGTLtPTGVVSG 35705994 YES lperfetto NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143 0.2 SIGNOR-276586 TLRs proteinfamily SIGNOR-PF20 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR up-regulates activity binding 9606 24352680 YES lperfetto Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain 0.2 SIGNOR-216301 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.27 SIGNOR-248494 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273108 NDUFC1 protein O43677 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. 0.791 SIGNOR-262173 S3I-201 chemical CHEBI:91224 ChEBI STAT3 protein P40763 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194847 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT down-regulates activity phosphorylation Ser92 SDENYDFsSAESGSS -1 11328814 YES miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity 0.2 SIGNOR-262973 M1_polarization phenotype SIGNOR-PH54 SIGNOR IL1B protein P01584 UNIPROT up-regulates 9606 BTO:0000801 32454942 NO miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ 0.7 SIGNOR-263825 SRC protein P12931 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser386 ARVGGASsLENTVDL 9606 35468896 YES miannu In these experiments, SRC also caused phosphorylation of S386 in wild-type IRF3 but not IRF3Y107F (Fig. 5d), indicating that SRC-mediated tyrosine phosphorylation of IRF3Y107 is required for its activation.|Taken together, these results suggest that P4 induces PGR-dependent activation of SRC, which promotes virus-triggered activation of IRF3 as well as induction of downstream antiviral genes.In the above experiments, we noticed that SeV-induced phosphorylation of IRF3S386 but not phosphorylation of TBK1S172 (p-TBK1S172, a hallmark for TBK1 activation) was increased by P4 treatment (Fig. 4g) or decreased by knockout of PGR (Fig. 4h). 0.314 SIGNOR-279119 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser441 GHSPLSLsAQSVMEE 9606 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.547 SIGNOR-204736 ATR protein Q13535 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 22735644 YES lperfetto  Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.  0.437 SIGNOR-267662 ATM protein Q13315 UNIPROT ZFHX3 protein Q15911 UNIPROT up-regulates activity phosphorylation Ser1180 QEGGASSsQAEKELT 9606 21729327 YES miannu Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation [ xref ].|We also found in this study that ATBF1 mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death. 0.347 SIGNOR-279138 PEBP1 protein P30086 UNIPROT RAF1 protein P04049 UNIPROT down-regulates binding 9606 10490027 YES gcesareni Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras. 0.761 SIGNOR-70838 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 9677319 YES llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. 0.313 SIGNOR-250945 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val61 TVETVFSvDEFSASV -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.374 SIGNOR-263600 CLCN4 protein P51793 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 9606 28972156 YES miannu ClC-3 and ClC-4 are two closely related intracellular chloride/proton exchangers that co-exist in neurons, glia, muscle, heart, and epithelial cells. ClC-4 is an intracellular Cl-/H+ exchanger that is highly expressed in the brain and whose dysfunction has been linked to intellectual disability and epilepsy. ClC-4 is retained in the endoplasmic reticulum (ER) upon overexpression in HEK293T cells. 0.8 SIGNOR-265421 FBXO8 protein Q9NRD0 UNIPROT GSTP1 protein P09211 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000675 31024008 YES miannu Here, we show that loss of FBX8 accelerates chemical-induced colon tumorigenesis. FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC. 0.2 SIGNOR-272304 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1167 ESAPAESsPSKIMSK 9534 BTO:0004055 8816480 YES lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 0.2 SIGNOR-244584 CDK5 protein Q00535 UNIPROT DYNLL1 protein P63167 UNIPROT up-regulates activity phosphorylation 9606 25452387 YES miannu CDK5 activates the tumor suppressor DLC1 by phosphorylating and diminishing the binding of an autoinhibitory region of DLC1 to its Rho-GAP domain and allows it to localize to focal adhesions.|Here, we report that CDK5 coordinately activates multiple DLC1 functions, elucidate the mechanism underlying this activation, and identify a role for DLC1 inactivation in the pro oncogenic activity CDK5. 0.2 SIGNOR-279154 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.4 SIGNOR-259018 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 10037602 YES gcesareni Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity. 0.858 SIGNOR-64960 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM3 protein Q14832 UNIPROT up-regulates activity chemical activation 9606 25042998 YES miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate 0.8 SIGNOR-264075 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BHMT protein Q93088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16953798 NO miannu SAM and MTA down-regulate BHMT expression in HepG2 cells in part by inducing NF-kappaB, which acts as a repressor for the human BHMT gene. While SAM's mechanism is NF-kappaB-dependent, MTA has both NF-kappaB-dependent and -independent mechanisms. 0.2 SIGNOR-254659 MAPK1 protein P28482 UNIPROT THRB protein P10828 UNIPROT down-regulates activity phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 YES llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. 0.41 SIGNOR-102216 EIF2AK2 protein P19525 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates activity phosphorylation 9606 16631606 YES miannu Ebp1 itself is phosphorylated by the PKR protein kinase, suggesting that the effects of Ebp1 overexpression evidenced in vivo on eIF2alpha phosphorylation could be achieved by competition between Ebp1 and eIF2alpha for PKR kinase activity. 0.243 SIGNOR-279170 PPM1F protein P49593 UNIPROT CAMK1 protein Q14012 UNIPROT down-regulates activity dephosphorylation 9606 11726284 YES miannu Calmodulin-dependent protein kinase phosphatase (CaMKP) dephosphorylates and concomitantly deactivates multifunctional Ca(2+)/calmodulin-dependent protein kinases , such as CaMKI, CaMKII, and CaMKIV. 0.462 SIGNOR-277111 LYST protein Q99698 UNIPROT RAB5A protein P20339 UNIPROT down-regulates activity binding 7227 33725482 YES lperfetto Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment 0.266 SIGNOR-266001 JAK2 protein O60674 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation 9606 10938266 YES miannu Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. 0.622 SIGNOR-279197 JAK2 protein O60674 UNIPROT GHR protein P10912 UNIPROT up-regulates activity phosphorylation 9606 23071812 YES miannu Jak2 is then phosphorylated and, in turn, phosphorylates the GHR and the signal transducers and activators of transcription (STAT) protein. 0.765 SIGNOR-279198 WNT5A protein P41221 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity 9606 21078818 NO gcesareni Common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3). 0.715 SIGNOR-169666 RELA protein Q04206 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9733516 NO gcesareni Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2. 0.548 SIGNOR-59957 OXTR protein P30559 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 30739093 YES miannu OT binds to its cognate G protein‚Äìcoupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). 0.429 SIGNOR-270331 MAP2K1 protein Q02750 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser363 DTEGRPPsPPPTSTP 9606 35080342 YES miannu This study indicates that mTORC1, MEK1, p38 and DYRK2 induce HSF1 activity to a similar level but phosphorylate HSF1 primarily at S326 as well as S363, a known inhibitory site [71,72], S221, also thought to be an inhibitory site [70], or at S241 and S344, which are two novel phosphorylation sites with unknown function.|While AKT1, mTORC1, MEK1, p38 and DYRK2 can all activate HSF1, the current study indicates that activity of only AKT1 and mTORC1 maintains a strong association with HSF1 activity in tumours (Fig. 4). 0.287 SIGNOR-279211 arachidonic acid smallmolecule CHEBI:15843 ChEBI prostaglandin E2 smallmolecule CHEBI:15551 ChEBI up-regulates quantity precursor of 9031 BTO:0000369 36571200 YES Marta Tosoni Among the variety of regulatory factors regulating cardiac tube looping and cardiac patterning, a key molecule is COX-2, an inducible isoform of cyclooxygenase that catalyzes the formation of PGE2 from arachidonic acid 0.8 SIGNOR-278093 HOXD12 protein P35452 UNIPROT MAFK protein O60675 UNIPROT down-regulates activity binding -1 11036080 YES miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. 0.377 SIGNOR-221929 CTNND2 protein Q9UQB3 UNIPROT ERBIN protein Q96RT1 UNIPROT up-regulates activity binding 9606 BTO:0000938 11821434 YES miannu We characterized the interactions between the Erbin PDZ domain and both ARVCF and δ-catenin in vitro and in vivo. endogenous δ-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that δ-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex. 0.2 SIGNOR-252120 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 SIGNOR-C301 23438602 YES lperfetto We examined the effect of XRCC3 depletion on redistribution of RAD51 upon IR damage|Interestingly, cells expressing the XRCC3 S225A phosphomutant showed compromised chromatin loading of RAD51 upon IR damage (Fig. 4G) while the nuclear and cytosolic fractions of RAD51 were largely unchanged|It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation. 0.748 SIGNOR-263258 LCK protein P06239 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 10571988 YES gcesareni On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation. 0.383 SIGNOR-72373 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR GKAP1 protein Q5VSY0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 20389280 YES miannu Here, we identify the BTB-Kelch protein KLHL20 as a negative regulator of DAPK. KLHL20 binds DAPK and Cullin 3 (Cul3) via its Kelch-repeat domain and BTB domain, respectively. The KLHL20-Cul3-ROC1 E3 ligase complex promotes DAPK polyubiquitination, thereby inducing the proteasomal degradation of DAPK. 0.2 SIGNOR-271962 ibritumomab tiuxetan antibody DB00078 DRUGBANK MS4A1 protein P11836 UNIPROT down-regulates activity binding 9606 27497027 YES miannu Zevalin® (ibritumomab tiuxetan) is a radioactive drug product, which is the combination of a β-emitting isotope, 90Y, linked to the anti-CD20 monoclonal antibody (mAb), rituximab. It has demonstrated therapeutic efficacy with durable responses and allows delivery of ionizing radiation directly to the tumor site, while minimizing toxicity to normal tissue. Ibritumomab tiuxetan is indicated for treatment of patients with relapsed or refractory low-grade, follicular NHL 0.4 SIGNOR-259893 MCL1 protein Q07820 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 YES gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax 0.624 SIGNOR-149774 SCF-betaTRCP complex SIGNOR-C5 SIGNOR IKBKB protein O14920 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 20068069 YES miannu CLU-2 is a ubiquitin binding protein (UBP) that enhances proteasome activity. sCLU promotes degradation of COMMD1. sCLU interacts with the SCF-βTrCP E3 ligase complex, serving as a scaffolding chaperone to form a multimeric protein complex that facilitates COMMD1 and I-κB ubiquitination and proteasomal degradation. 0.577 SIGNOR-271431 PTCD3 protein Q96EY7 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding Q9Y2Q9 9606 25838379 YES miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. 0.731 SIGNOR-261437 CUL3 protein Q13618 UNIPROT LZTR1 protein Q8N653 UNIPROT up-regulates activity binding 9606 BTO:0000007 31337872 YES Gianni Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. 0.273 SIGNOR-269070 ERBB2 protein P04626 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates activity phosphorylation 9606 23912457 YES miannu HER2 forms heterodimers with HER3 and thereby phosphorylates and activates HER3. 0.587 SIGNOR-278200 AKT2 protein P31751 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity phosphorylation Tyr47 KTGQAPGySYTAANK -1 32781572 YES miannu Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. 0.293 SIGNOR-277236 SGCD protein Q92629 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.511 SIGNOR-255988 PRKCG protein P05129 UNIPROT VTN protein P04004 UNIPROT up-regulates quantity by stabilization phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 YES lperfetto Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin. 0.285 SIGNOR-248964 MC3R protein P41968 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.289 SIGNOR-256748 CYP2D6 protein P10635 UNIPROT tyramine smallmolecule CHEBI:15760 ChEBI down-regulates quantity chemical modification 9606 NBK536726 YES brain lperfetto Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬† 0.8 SIGNOR-263995 AMPK complex SIGNOR-C15 SIGNOR CTH protein P32929 UNIPROT up-regulates activity phosphorylation Ser346 ESLGGFEsLAELPAI 9606 BTO:0000007 37922764 YES miannu  Here we define an important mechanism of increased persulfide and polysulfide production involving cystathionine gamma lyase (CSE) phosphorylation at serine 346 and threonine 355 in a substrate specific manner, under acute hypoxic conditions. Hypoxic phosphorylation of CSE occurs in an AMP kinase dependent manner increasing enzyme activity involving unique inter- and intramolecular interactions within the tetramer.  0.25 SIGNOR-277808 AKT1 protein P31749 UNIPROT CABLES1 protein Q8TDN4 UNIPROT down-regulates activity phosphorylation Thr309 APLRRCRtLSGSPRP -1 25361894 YES miannu Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex.Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. 0.34 SIGNOR-276756 ERBB2 protein P04626 UNIPROT BBC3 protein Q9BXH1 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr172 PSPWRVLyNLIMGLL 9606 BTO:0000093 24236056 YES miannu HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. 0.281 SIGNOR-276474 PPARGC1A protein Q9UBK2 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 NO Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. 0.404 SIGNOR-254262 CDK2 protein P24941 UNIPROT ELK4 protein P28324 UNIPROT up-regulates activity phosphorylation Thr194 SVIKFVTtPSKKPPV 9606 26028036 YES miannu Interestingly, CDK2 directly phosphorylates ELK4 at Thr194 and Ser387 and regulates ELK4 transcriptional activity, which serves as a mechanism to regulate c-fos expression. 0.363 SIGNOR-278211 DHODH protein Q02127 UNIPROT orotate smallmolecule CHEBI:30839 ChEBI up-regulates quantity chemical modification 9606 30449682 YES miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway 0.8 SIGNOR-267433 cetirizine chemical CHEBI:3561 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 YES miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. 0.8 SIGNOR-258868 BRD4 protein O60885 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0000150;BTO:0001271;BTO:0000785 22509028 YES llicata We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality 0.449 SIGNOR-197012 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Phe708 YENPTYKfFEQMQN -1 8943232 YES lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. 0.489 SIGNOR-261776 NEK7 protein Q8TDX7 UNIPROT EML4 protein Q9HC35 UNIPROT down-regulates activity phosphorylation Ser144 QSPQIRAsPSPQPSS 9606 31409757 YES miannu In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules.|The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser 144 and Ser 146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. 0.274 SIGNOR-279237 NTRK1 protein P04629 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Tyr142 AVVNLINyQDDAELA 9606 22558232 YES miannu EGFR and TRKA effect on WNT3a mediated Topflash induction was abolished by U0126 or expression of dominant negative LRP6-5A mutant (XREF_FIG), demonstrating that both EGFR and TRKA signal via ERK and LRP6 pathway to upregulate WNT and beta-catenin signaling.|FGFR2, FGFR3, EGFR and TRKA Phosphorylate \u03b2-catenin at Tyr142. 0.415 SIGNOR-279240 NTRK2 protein Q16620 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation 9606 20445044 YES miannu Both Shc and PLCgamma1 are phosphorylated by TrkB, thereby initiating Shc/Ras/MAP kinase and PLCgamma1 signaling respectively.|We conclude that activation of pY783 PLCgamma1 is due mainly to TrkB activation in these models and that TrkB induced PLCgamma1 signaling promotes limbic epileptogenesis. 0.646 SIGNOR-279241 PAK1 protein Q13153 UNIPROT RUFY3 protein Q7L099 UNIPROT up-regulates quantity phosphorylation 9606 25766321 YES miannu (a) PAK1 phosphorylates RUFY3 in vitro.|Taken together, these results indicate that PAK1 can upregulate RUFY3 protein expression. 0.277 SIGNOR-279243 CSNK2A1 protein P68400 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser101 GSHRDQGsSALSGVG 9606 21750978 YES miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo 0.29 SIGNOR-174820 RHOXF1 protein Q8NHV9 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 23317270 NO lperfetto ShRNA knock down of RHOXF1 resulted in significantly decreased BCL2 expression in both cell lines but no change in CASP8 expression. 0.2 SIGNOR-268957 CDO1 protein Q16878 UNIPROT SHH protein Q15465 UNIPROT up-regulates binding 9606 BTO:0000887 16647304 YES gcesareni Cdo and boc bind shh through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. We propose a model where cdo and boc enhance shh signaling within its target field. 0.2 SIGNOR-146461 PAK6 protein Q9NQU5 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by destabilization phosphorylation Ser579 YGALTCGsCKVFFKR 9606 23132866 YES miannu Furthermore, AR phosphorylation at Ser-578 by PAK6 promotes AR-E3 ligase murine double minute-2 (Mdm2) association, causing AR degradation upon androgen stimuli. 0.2 SIGNOR-279247 PDK1 protein Q15118 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation 9606 15068796 YES miannu Since both AKT-1, AKT-2, and SGK-1 are phosphorylated by PDK-1 and are themselves capable of phosphorylating DAF-16, their direct contact may reflect a temporary, regulatory interaction.|This demonstrates that functional PDK-1 is required to activate AKT-1, AKT-2, and SGK-1 in vivo. 0.376 SIGNOR-279248 CCND3 protein P30281 UNIPROT CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR form complex binding 8114739 YES lperfetto Here, we show that the human PLSTIRE gene product is a novel cyclin-dependent kinase, cdk6. The cdk6 kinase is associated with cyclins D1, D2, and D3 in lysates of human cells and is activated by coexpression with D-type cyclins in Sf9 insect cells. 0.935 SIGNOR-273027 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 YES gcesareni Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. 0.699 SIGNOR-147963 NFKBIA protein P25963 UNIPROT S100A6 protein P06703 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 12859951 NO miannu Transient expression of NF-kappaB (p65) increased S100A6 promoter activity and expression of inhibitor of NF-kappaB (IkappaBalpha) decreased TNFalpha-induced S100A6 promoter activity.  0.2 SIGNOR-254804 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Thr28 PTMPPPEtPSEGRQP 9606 BTO:0001271 15093545 YES The effect has been demonstrated using P29590-4 gcesareni We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3). 0.36 SIGNOR-124313 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10116 11416002 YES lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells 0.914 SIGNOR-235971 RUNX3 protein Q13761 UNIPROT FADD protein Q13158 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002384 17956589 NO miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. 0.2 SIGNOR-255095 F2 protein P00734 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR up-regulates activity cleavage 9606 BTO:0000131 29880919 YES lperfetto Thrombin is a key enzyme in the pathway and cleaves fibrinogen to fibrin, which spontaneously forms the insoluble polymer that is the basis for the haemostatic plug. 0.854 SIGNOR-263525 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1203 LHSVSSKsFRDFLLE 9606 BTO:0000776 21482705 YES llicata We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane. 0.329 SIGNOR-173387 G3BP1 protein Q13283 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity binding 9606 BTO:0002181 30804210 YES SARA G3BP1 binds RIG-I and that this interaction involves the C-terminal RGG domain of G3BP1, G3BP1 significantly enhances RIG-I-induced ifn-b mRNA synthesis. 0.338 SIGNOR-260980 PRKCI protein P41743 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity phosphorylation 9606 26343727 YES miannu Although functioning downstream of SMO, aPKC-\u03b9/\u03bb phosphorylates and activates GLI1, resulting in maximal DNA binding and transcriptional activation [ xref ]. 0.403 SIGNOR-279262 CDKN1A protein P38936 UNIPROT CDK6 protein Q00534 UNIPROT down-regulates binding 9606 7626805 YES gcesareni P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases 0.864 SIGNOR-30030 IL2 protein P60568 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22128144 NO miannu We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. 0.35 SIGNOR-253894 DYRK1A protein Q13627 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser409 LSPTSYMsPTLPALD 9606 28235034 YES miannu DYRK1A phosphorylation of NFATc1 and alphaA at S261, S278, S403 and S409 interfered with NFATc1 ubiquitination and ubiquitin-proteasome degradation.|Here, we demonstrated that DYRK1A increased NFATc1 (NFATc1 and alphaA isoform) protein stability, in contrast to the decrease of NFATc2 protein stability by DYRK1A. 0.429 SIGNOR-278276 MKRN1 protein Q9UHC7 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 26183061 YES miannu EGFR/PI3K/AKT-mediated ubiquitination and degradation of PTEN are dependent on the MKRN1 E3 ligase.|In fact, epidermal growth factor-stimulated pAKT phosphorylates and subsequently stabilizes MKRN1, which then ubiquitinates and induces the degradation of PTEN. 0.428 SIGNOR-278830 RPS6KA1 protein Q15418 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates activity phosphorylation 9606 25106868 YES miannu These results indicate that RSK1 directly phosphorylates the C-terminus of ZFP36L1 downstream of ERK, and inhibits the Messenger RNA destabilization activity of ZFP36L1.|These results indicate that RSK1 directly phosphorylates the C-terminus of ZFP36L1 downstream of ERK, and inhibits the mRNA destabilization activity of ZFP36L1. 0.2 SIGNOR-279280 SGK3 protein Q96BR1 UNIPROT NDRG1 protein Q92597 UNIPROT down-regulates activity phosphorylation 9606 25458846 YES miannu It has been shown that SGK3 phosphorylation of NDRG1 primes for subsequent phosphorylation by GSK-3beta.|Since NDRG1 is a direct SGK substrate, this correlation suggests that SGK3 activation and signaling may modulate NDRG1 degradation. 0.402 SIGNOR-279282 L-arginine chemical CHEBI:16467 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 NO Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. 0.8 SIGNOR-268018 CNR1 protein P21554 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.462 SIGNOR-257003 ULK2 protein Q8IYT8 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity phosphorylation Ser762 YEIDLDTsDHAHLEH 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.2 SIGNOR-274044 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 BTO:0002181 34363019 YES miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  0.2 SIGNOR-276737 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 YES Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) 0.497 SIGNOR-248313 STK4 protein Q13043 UNIPROT GAPDH protein P04406 UNIPROT up-regulates activity phosphorylation 9606 23527007 YES miannu Interestingly, GAPDH is phosphorylated by Mst1 to a comparable extent as its known substrate MBP, suggesting that GAPDH is a good substrate of Mst1 at least in vitro.|Moreover, interaction of Mst1 with GAPDH caused a robust phosphorylation of GAPDH and markedly increased the Mst1 activity in cells. 0.28 SIGNOR-279295 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2J1 protein Q9Y385 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.599 SIGNOR-271308 MAPK14 protein Q16539 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates activity phosphorylation Thr293 TLNSDGYtPEPARIT 9606 BTO:0000782 29440413 YES miannu We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex. 0.474 SIGNOR-277384 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.762 SIGNOR-249322 MAP2K6 protein P52564 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 8974401 YES gcesareni A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subgroups of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) 0.463 SIGNOR-45363 SYK protein P43405 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 25506060 YES miannu SYK Phosphorylates CDC25C on Serine 216.|We now provide new genetic and biochemical evidence that SYK is an inhibitor of CDC25C in B-lineage lymphoid cells as well as non lymphohematopoietic cells, that prevents premature entry into mitosis by phosphorylating CDC25C at S216 when G 2 checkpoint responses are activated. 0.361 SIGNOR-278328 POLR1D protein P0DPB6 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 12391170 YES lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. 0.864 SIGNOR-266137 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK4 protein P11802 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-192464 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBE1 protein Q9UJT0 UNIPROT down-regulates activity chemical inhibition 9606 15579115 YES miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. 0.8 SIGNOR-259258 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR PDGFA protein P04085 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 YES miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. 0.2 SIGNOR-251571 PAX7 protein P23759 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 18066051 YES Simone Vumbaca Together, these experiments indicate that Pax7 enforces satellite cell commitment by recruiting a HMT complex to Myf5, resulting in transcriptional activation. 0.492 SIGNOR-255641 PDPK1 protein O15530 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0000298 10480933 YES miannu Full-length RSK1, RSK2, and RSK3 Are Activated when Coexpressed with PDK1 in COS7 Cells. Ser221 phosphorylation is increased 2–3-fold during ERK-mediated activation of RSK1 in COS1 cells 0.629 SIGNOR-250270 PTK2B protein Q14289 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity phosphorylation Tyr421 RLPSSPVyEDAASFK 9606 29133485 YES miannu In conclusion, these data suggest that Pyk2 phosphorylates cortactin on tyrosine residues Y421, Y466, and Y482.|To confirm the direct and indirect effects of Pyk2 on cortactin phosphorylation, we used cells overexpressing Arg YFP and treated with Pyk2 siRNA or a nonsilencing siRNA. 0.366 SIGNOR-278343 TTK protein P33981 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity phosphorylation Thr306 LADYWKCtSCNEMNP 9606 26531827 YES miannu (D and E) MDM2 was phosphorylated by hMps1 at Thr4, Thr306 and Ser307 in vitro.|In support, the MDM2 Ser307 to Ala mutant was less stable than the wild-type protein when coexpressed with hMps1 (Supplementary Figure S2B and C). hMps1 promotes MDM2-mediated H2B ubiquitination. (A) wild-type but not kinase-dead mutant hMps1 promotes MDM2-mediated H2B ubiquitination. 293T cells were transfected with the indicated plasmids and lysates were prepared for the Ni-NTA bead pulldown assay. 46999999="S307A"} 0.264 SIGNOR-279315 GRB10 protein Q13322 UNIPROT INSR protein P06213 UNIPROT down-regulates binding 9606 21659604 YES gcesareni Grb10 negatively regulates growth factor signaling. It binds the insulin and insulin-like growth factor 1 (igf-1) receptors;mice without grb10 are larger and exhibit enhanced insulin sensitivity. 0.659 SIGNOR-174065 IRF2 protein P14316 UNIPROT DST protein Q03001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15560761 NO miannu Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes. 0.2 SIGNOR-254493 CDK1 protein P06493 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates activity phosphorylation Ser548 GQAWGRQsPRRLEDS -1 35843311 YES miannu Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases. 0.2 SIGNOR-277603 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.2 SIGNOR-269963 SLBP protein Q14493 UNIPROT H2BC3 protein P33778 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265385 prazosin chemical CHEBI:8364 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 YES miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. 0.8 SIGNOR-258468 MAPK11 protein Q15759 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 17254968 YES gcesareni We show that prak activates p53 by direct phosphorylation. 0.609 SIGNOR-152843 MAPKAPK3 protein Q16644 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser90 IPPARMMsTESANSF 9606 25693418 YES miannu Taken together, these data indicate that MK2 and MK3 directly phosphorylate Beclin 1 S90 in vitro, and that MK2 like kinase activity also mediates starvation induced Beclin 1 S90 phosphorylation in cultured cells. 0.425 SIGNOR-279342 SMURF1 protein Q9HCE7 UNIPROT ANKRD13A protein Q8IZ07 UNIPROT unknown ubiquitination -1 20804422 YES miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. 0.2 SIGNOR-272680 AURKB protein Q96GD4 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity phosphorylation Thr210 YDGERKKtLCGTPNY 9606 26206521 YES miannu Aurora B phosphorylates PLK1 on Thr210 to activate its kinase activity at the kinetochores during mitosis.|Thus, we conclude that Aurora B indirectly promotes the phosphorylation of MCAK on Ser715 at the kinetochores through phosphorylation of PLK1 at Thr210 and its ensuing activation. 0.598 SIGNOR-279358 TNK2 protein Q07912 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr176 EKATGRYyAMKILKK 10090 20333297 YES gcesareni Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. 0.427 SIGNOR-252446 PDP2 protein Q9P2J9 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16510868 YES lpetrilli We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1. 0.243 SIGNOR-144909 CDK5 protein Q00535 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Thr733 LPPVFSGtPKGSGAG 9606 27735944 YES miannu CDK5 directly phosphorylated ERK5 at Thr732 and modulated the ERK5\u2013AP-1 signaling axis. 0.2 SIGNOR-279364 ARHGEF10 protein O15013 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.524 SIGNOR-260535 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr934 AHASDEIyEIMQKCW -1 19275932 YES miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  0.526 SIGNOR-276141 MST1R protein Q04912 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 21423209 YES miannu Ron and beta-catenin associate and Ron kinase activity leads to tyrosine phosphorylation of beta-catenin.|We also show that tyrosine residues 654 and 670 of beta-catenin are important in mediating Ron induced beta-catenin transcriptional activation and cell growth. 0.327 SIGNOR-279376 PAK1 protein Q13153 UNIPROT ATF2 protein P15336 UNIPROT down-regulates activity phosphorylation Ser62 FGPARNDsVIVADQT 9606 28918037 YES miannu Overall, our results unequivocally confirmed that Pak1 physically interacts with ATF2 and phosphorylates ATF2 on the Ser62 residue, and this process secludes ATF2 in the cytoplasm. 0.2 SIGNOR-279377 CHEK1 protein O14757 UNIPROT SNCB protein Q16143 UNIPROT unknown phosphorylation Tyr127 EDPPQEEyQEYEPEA 9606 21699177 YES llicata Chk preferentially phosphorylates recombinant _-synuclein at tyrosine-127 0.2 SIGNOR-174590 GSK3B protein P49841 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation 9606 21289184 YES miannu Given that pharmacological inhibition of GSK3beta inhibits HDAC3 neurotoxicity, we explored the possibility that HDAC3 was directly phosphorylated by GSK3beta.|HDAC3 is directly phosphorylated by GSK3\u03b2, suggesting that the neuronal death-promoting action of GSK3\u03b2 could be mediated through HDAC3 phosphorylation. 0.285 SIGNOR-278400 PAK1 protein Q13153 UNIPROT RPA1 protein P27694 UNIPROT up-regulates activity phosphorylation Ser135 APPAPAAsPAASSRP 9606 33704464 YES miannu In this article, we found that Ser-135 and Thr-180 of RPA1 are directly phosphorylated by PAK1 in a DOCK7-Rac1/Cdc42-dependent manner.|We further explored the biological role of PAK1 in replication stress and found that depletion of PAK1 resulted in decreased RPA1 and RPA2 chromatin loading and RPA2 foci formation ( Figure 4I-K ) . 0.2 SIGNOR-279378 CDK10 protein Q15131 UNIPROT ETS2 protein P15036 UNIPROT down-regulates quantity by destabilization phosphorylation Ser220 PKGGLLDsMCPASTP 9606 24218572 YES Manara Altogether, these results suggest that CDK10/cyclin M directly controls ETS2 degradation through the phosphorylation of these two serines. 0.529 SIGNOR-260913 WNT16 protein Q9UBV4 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.616 SIGNOR-131674 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity phosphorylation Thr1226 LRSLRRNtKKPKPKP 9534 BTO:0000298 19103606 YES miannu these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells 0.414 SIGNOR-276178 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1721 SPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248787 pralatrexate chemical CHEBI:71223 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002207 19221750 YES Luana This study reports a head-to-head comparison of in vitro and in vivo activities of three antifolates: pralatrexate, methotrexate, and pemetrexed. A clear difference was demonstrated among the antifolates in regulation of enzymatic activity. Pralatrexate demonstrated a unique activity profile relative to methotrexate and pemetrexed 0.8 SIGNOR-257815 CDK5 protein Q00535 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity phosphorylation 9606 33960694 YES miannu An in vitro kinase reaction demonstrated that T2132, S2136, and S2141 were CDK5\u2010phosphorylated sites in the Notch1 peptide (Figure\u00a02B, C, and D).|In conclusion, CDK5 positively regulates Notch1 function via phosphorylation, which in turn promotes cell proliferation and migration. 0.32 SIGNOR-279401 CDK5 protein Q00535 UNIPROT NR1I2 protein O75469 UNIPROT down-regulates activity phosphorylation -1 20553580 YES miannu In vitro kinase assays showed that Cdk5 directly phosphorylates PXR.|Taken together, these data indicate that Cdk5 negatively regulates PXR activity, and that inhibition of Cdk5 is at least partially responsible for flavonoids induced activation of PXR. 0.345 SIGNOR-279402 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 12832467 YES lperfetto Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk 0.762 SIGNOR-252749 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser82 HSISYTLsRAQTVVV -1 19264966 YES miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. 0.767 SIGNOR-276139 EPHB3 protein P54753 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 10389236 YES miannu In accord with this concept are the findings of Vlach et al. , who have studied point mutants of p27 deficient in their interactions with EK2, and have found that T187 phosphorylation of p27 by EK2 requires an interaction of p27 with the cyclin E subunit, while inhibition of the kinase activity requires an additional interaction with the CDK2 subunit.|The question considered here is the theoretical question whether deactivation of p27 by EK2 can produce binary EK2 release, and if so what biochemical kinetic features are required for this behavior. 0.2 SIGNOR-279406 GLP1R protein P43220 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000783 35065096 YES miannu The GPCRs are allocated in five families where the GLP-1R and GIPR are found within the secretin family, also classified as class B [31,32]. Upon stimulation by an extracellular stimuli (ligand), GPCRs undergo conformational changes, and triggers downstream intracellular signals by coupling with G proteins (or other intracellular proteins such as arrestins), causing a wide range of both physiological and pathological processes.To stimulate insulin secretion, and in the presence of elevated blood glucose concentrations, GLP-1R activation in pancreatic beta cells promote recruitment and activation of Gαs protein leading to adenylate cyclase-mediated cAMP production, elevation of Ca2+, and ERK1/2 phosphorylation (Fig. 3) 0.48 SIGNOR-278137 androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI testosterone smallmolecule CHEBI:17347 ChEBI up-regulates quantity precursor of 10116 BTO:0000534;BTO:0000056 1537836 YES lperfetto We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids. 0.8 SIGNOR-268640 PRDM16 protein Q9HAZ2 UNIPROT SKI protein P12755 UNIPROT up-regulates binding 9606 19049980 YES miannu Biochemical analysis demonstrated that mel1 interacts with ski and inhibits tgf-_ signaling by stabilizing the inactive smad3-ski complex on the promoter of tgf-_ target genes. 0.326 SIGNOR-182529 GSK3B protein P49841 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates activity phosphorylation 9606 23851495 YES miannu GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP mediated degradation of Slug.|Phosphorylation of Slug by GSK3beta promotes CHIP binding and ubiquitin mediated proteolysis. 0.424 SIGNOR-279414 MKNK1 protein Q9BUB5 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Ser112 APLSRSIsTVSSGSR 9606 19864419 YES llicata The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability. 0.529 SIGNOR-188889 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F9 protein P00740 UNIPROT up-regulates activity binding 9606 BTO:0000131 32665005 YES lperfetto During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury. 0.598 SIGNOR-263542 PINK1 protein Q9BXM7 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000793 20871098 NO Barakat Ubiquitination of MFN-1 or MFN-2 was induced in untransfected cells and cells transfected with control siRNA. However, ubiquitination of MFN-1 and MFN-2 was significantly reduced when treated with either PINK1 siRNA combination. These results suggest that PINK1 is required for the ubiquitination of MFN-1 and MFN-2. 0.809 SIGNOR-274136 BRAF protein P15056 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation 9606 28368422 YES miannu BRAF V600E activates Abl and Arg.|Rather, BRAF V600E, a serine threonine kinase, induced Abl threonine phosphorylation (XREF_FIG), and tyrosine phosphorylation of kinase-inactive Abl or Arg, which lack the ability to autophosphorylate (XREF_FIG). 0.275 SIGNOR-278914 RLIM protein Q9NVW2 UNIPROT LDB1 protein Q86U70 UNIPROT down-regulates quantity by destabilization polyubiquitination 10029 BTO:0000246 11882901 YES miannu Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway.  0.567 SIGNOR-272617 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 10454565 YES Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro 0.842 SIGNOR-248480 MAPK8IP3 protein Q9UPT6 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10629060 YES gcesareni These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3 0.7 SIGNOR-73906 APC-c complex SIGNOR-C150 SIGNOR MOAP1 protein Q96BY2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 22529100 YES miannu MOAP-1 is an APC/CCdh1 substrate. Here, we identify MOAP-1 as a novel APC/CCdh1 substrate. MOAP-1 is degraded during G1 by APC/CCdh1, and this degradation is inhibited by Trim39 acting on the APC/C. 0.247 SIGNOR-272912 KAT2A protein Q92830 UNIPROT H3Y2 protein P0DPK5 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 YES Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. 0.2 SIGNOR-269598 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.765 SIGNOR-252744 Tomivosertib chemical CID:118598754 PUBCHEM MKNK1 protein Q9BUB5 UNIPROT down-regulates activity chemical inhibition 9606 29526098 YES Simone Vumbaca Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. 0.8 SIGNOR-261116 CXCL11 protein O14625 UNIPROT ACKR3 protein P25106 UNIPROT up-regulates activity binding 9606 BTO:0000093 16940167 YES Luana This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell alpha chemoattractant (I-TAC; also known as CXCL11) 0.636 SIGNOR-268415 POLR1C protein O15160 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.913 SIGNOR-266145 ABL1 protein P00519 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr155 IKQAKIHyIKNHEFI 9606 28637715 YES miannu Specifically, we have shown that nuclear targeting of PKCdelta is necessary and sufficient for epithelial cell apoptosis, and that nuclear translocation requires phosphorylation of PKCdelta at Y155 and Y64 by c-Abl and c-Src, respectively. 0.384 SIGNOR-279436 MINK1 protein Q8N4C8 UNIPROT PRICKLE1 protein Q96MT3 UNIPROT up-regulates activity phosphorylation Thr370 LSGNADDtLSRKLDD -1 22037766 YES miannu We show that Mink1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, a process required for the localized plasma membrane accumulation and function of Prickle. 0.293 SIGNOR-263095 EFNA3 protein P52797 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.817 SIGNOR-52381 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 23431053 YES milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity 0.9 SIGNOR-201306 BTK protein Q06187 UNIPROT IKZF1 protein Q13422 UNIPROT up-regulates activity phosphorylation Ser214 GRSYKQRsSLEEHKE 9606 23977012 YES miannu We demonstrate that BTK phosphorylates Ikaros at unique phosphorylation sites S214 and S215 in the close vicinity of its zinc finger 4 (ZF4) within the DNA binding domain, thereby augmenting its nuclear localization and sequence-specific DNA binding activity. 0.432 SIGNOR-279443 BTK protein Q06187 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation 9606 31431692 YES miannu Then, BTK and ITK are activated by Src kinases and proceed to phosphorylate the lipase PLCgamma2 / PLCgamma1, which cleaves PIP2 in the plasma membrane and generates the secondary messengers IP3 and DAG. 0.58 SIGNOR-279444 RB1 protein P06400 UNIPROT UBTF protein P17480 UNIPROT down-regulates activity binding -1 7877691 YES lperfetto Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product 0.377 SIGNOR-262589 CDK9 protein P50750 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 28062857 YES miannu AR S81 phosphorylation by CDK9 is tightly linked to chromatin binding and transcriptional activation. 0.538 SIGNOR-279456 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UBTF protein P17480 UNIPROT up-regulates activity phosphorylation Ser484 ERGKLPEsPKRAEEI 10090 BTO:0000944 10202152 YES llicata We have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro.  0.372 SIGNOR-250755 RUNX1 protein Q01196 UNIPROT HHEX protein Q03014 UNIPROT up-regulates quantity transcriptional regulation 9606 28213513 YES We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. 0.271 SIGNOR-256305 RNF111 protein Q6ZNA4 UNIPROT SKI protein P12755 UNIPROT down-regulates ubiquitination 9606 BTO:0000150;BTO:0000551 18451154 YES gcesareni On tgf-beta treatment, the e3 ubiquitin ligase arkadia mediates degradation of ski in a smad-dependent manner 0.594 SIGNOR-178598 MAPK1 protein P28482 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Ser387 PATVEPAsPTPAHSL 9606 17311928 YES llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 0.45 SIGNOR-153379 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 YES Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. 0.2 SIGNOR-251445 CAMK4 protein Q16566 UNIPROT HMGB1 protein P09429 UNIPROT up-regulates activity phosphorylation 9606 18802105 YES miannu Collectively, our results demonstrate that CaMKIV promotes the nucleocytoplasmic shuttling of HMGB1 and suggest that the process may be mediated through CaMKIV-dependent serine phosphorylation of HMGB1. 0.286 SIGNOR-278510 MLL/SET subcomplex complex SIGNOR-C87 SIGNOR MLL3 complex complex SIGNOR-C446 SIGNOR form complex binding 9606 34156443 YES miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 0.2 SIGNOR-268808 regorafenib chemical CHEBI:68647 ChEBI FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition 9606 26254357 YES miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF 0.8 SIGNOR-259178 LRRK2 protein Q5S007 UNIPROT RAB29 protein O14966 UNIPROT up-regulates activity phosphorylation Ser72 AGQERFTsMTRLYYR 9606 29212815 YES miannu In an attempt to mimic phosphorylation of Rab29 by LRRK2, we mutated the phosphorylation sites to Glu and observed that the Rab29[T71E,S72E] mutant failed to activate LRRK2 (Fig\u00a0 xref B).|To test whether phosphorylation of Rab29 at Thr71 and Ser72 by LRRK2 was required for activation of LRRK2, we mutated these sites both to Ala. 0.582 SIGNOR-279474 PRKAA1 protein Q13131 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser30 EDLQEVLsSDENGGT 10090 27650555 YES Luana Here, we report that phosphorylation of CHOP at Ser30 by AMPKα1 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo. 0.265 SIGNOR-259864 CTDSPL2 protein Q05D32 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 20932329 NO Indirect:regulation of transcription miannu CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood. 0.2 SIGNOR-251777 FLT3 protein P36888 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates activity 10090 BTO:0002181 14982881 NO We report here that the Flt3-ITD interferes with the transcriptional and biologic action of the PLZF transcriptional repressor. In the presence of Flt3-ITD, PLZF-SMRT interaction was reduced, transcriptional repression by PLZF was inhibited, and PLZF-mediated growth suppression of leukemia cells was partially blocked. Furthermore, overexpression of Flt3-ITD led to a partial relocalization of SMRT protein from the nucleus to the cytoplasm. 0.314 SIGNOR-261537 RPS6KB1 protein P23443 UNIPROT EPRS1 protein P07814 UNIPROT up-regulates activity phosphorylation Ser999 NQGGGLSsSGAGEGQ 9606 28178239 YES miannu Our studies reveal an unexpected adipogenic pathway resulting from mTORC1-S6K1 activation of EPRS ( xref ).|These results establish the requirement for mTORC1-activated S6K1 to phosphorylate EPRS at Ser 999 ( xref ). 0.2 SIGNOR-279483 TAL1 protein P17542 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0004911 23319051 NO Analysis of SclΔ40/Δ40 embryonic stem (ES) cells revealed impaired erythroid differentiation, which was accompanied by a failure to upregulate Scl when erythropoiesis was initiated. 0.7 SIGNOR-259971 STK38 protein Q15208 UNIPROT HEY1 protein Q9Y5J3 UNIPROT up-regulates activity phosphorylation Ser68 RRDRINNsLSELRRL 9606 27129302 YES miannu We have identified two related kinases, STK38 (serine/threonine kinase 38) and STK38L (serine/threonine kinase 38 like), which interact with and phosphorylate HEY1 at Ser-68. 0.358 SIGNOR-279489 PRKDC protein P78527 UNIPROT H1-2 protein P16403 UNIPROT down-regulates activity phosphorylation Thr146 KKAAGGAtPKKSAKK 9606 BTO:0001938 22249259 YES done miannu Similarly, DNA-PK-mediated phosphorylation of H1.2 at T146 enhances p53 transcriptional activity by impeding H1.2 binding to p53 and thereby attenuating its suppressive effects on p53 transactivation.  0.2 SIGNOR-273834 FYN protein P06241 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Tyr453 ASHVDNEySQPPRNS -1 11298344 YES Tyrosine-mutated CD5 molecules have been used to show that residues Y429 and Y463 are targeted in vivo by protein tyrosine kinases following cell stimulation with anti-CD3 mAb or pervanadate. This is in agreement with data from direct in vitro kinase assays using purified recombinant Lck and Fyn protein tyrosine kinases. 0.492 SIGNOR-251151 CDK1 protein P06493 UNIPROT ZYX protein Q15942 UNIPROT up-regulates activity phosphorylation 9606 10831611 YES miannu As predicted by our hypothesis, the Cdc2 dependent phosphorylation has been shown to allow the full-length zyxin to interact with h-warts and LATS1 (XREF_FIG A).|Phosphorylation of Zyxin by Cdc2 Regulates Binding to h-warts and LATS1. 0.309 SIGNOR-279498 CDK11B protein P21127 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation 9606 25529026 YES miannu In comparison, CLK1 expression leads to speckle dissolution and diffuse GFP-SRSF1 localization in the nucleus.|We showed that CLK1 phosphorylates SRSF1 at approximately 18 sites inducing a gel shift from 35 to about 38 kDa on SDS-PAGE (XREF_FIG, upper panel). 0.283 SIGNOR-279499 PRKAB1 protein Q9Y478 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 SIGNOR-C3 21460634 YES gcesareni Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2. 0.464 SIGNOR-173041 ATM protein Q13315 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation 9606 22976441 YES miannu These results elucidated the specificity of this in vivo degradation assay, and further implicated that CKI\u03b4-dependent phosphorylation events is the major signaling route through which DNA damage-dependent activation of ATM might control timely turnover of Mdm2 during genotoxic stress. (A) ATM-mediated phosphorylation of CK1\u03b4 promotes CK1\u03b4 nuclear localization.|We further demonstrated that DNA damage-induced activation of ATM directly phosphorylated CKI\u03b4 at two well-conserved S/TQ sites, which promotes CKI\u03b4 nuclear localization to increase CKI\u03b4-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCF\u03b2-TRCP. 0.341 SIGNOR-279504 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity transcriptional regulation 10116 11069927 NO In the liver, glucocorticoids induce a 10-15-fold increase in the rate of transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene, which encodes a key gluconeogenic enzyme 0.36 SIGNOR-253056 PDGFRB protein P09619 UNIPROT TNK2 protein Q07912 UNIPROT up-regulates activity phosphorylation Tyr635 PLPPPPAyDDVAQDE 9606 BTO:0002036 25257795 YES miannu  Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT.  0.359 SIGNOR-276854 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8962164 NO irozzo These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2. 0.487 SIGNOR-256279 STUB1 protein Q9UNE7 UNIPROT HSPA8 protein P11142 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11676916 YES miannu BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association 0.728 SIGNOR-272588 OXGR1 protein Q96P68 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-256913 DAPK1 protein P53355 UNIPROT APP protein P05067 UNIPROT up-regulates quantity phosphorylation Thr743 VEVDAAVtPEERHLS 9606 27094130 YES miannu DAPK1, but not its kinase deficient mutant (K42A), significantly increased human AŒ≤ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased AŒ≤ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of AŒ≤.|Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Abeta. 0.287 SIGNOR-279518 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2 protein P10415 UNIPROT up-regulates activity phosphorylation Ser70 RDPVARTsPLQTPAA -1 11323415 YES Luana JNK1 directly phosphorylates Bcl2 at Ser70 in vitro and co-localizes with Bcl2 in mitochondrial membranes in vivo. 0.2 SIGNOR-261133 NFIX protein Q14938 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268909 GRK2 protein P25098 UNIPROT CD36 protein P16671 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 30171848 YES miannu We, therefore, propose a pathway by which inhibition of GRK2 in the failing heart prevents CD36 phosphorylation, ubiquitination, and, in turn, induces its proteasomal degradation.|Our data reveal direct phosphorylation of CD36 by GRK2. 0.2 SIGNOR-279524 GSK3B protein P49841 UNIPROT DDIT4 protein Q9NX09 UNIPROT down-regulates quantity by destabilization phosphorylation Thr25 SSLPRTPtPDRPPRS 9606 23717519 YES miannu It has been reported that GSK3beta phosphorylates REDD1 at residues Thr23 and Thr25, resulting in REDD1 recruitment to the Cullin 4a-beta-Trcp E3 ligase complex. 0.34 SIGNOR-279526 EFNA2 protein O43921 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9330863 YES gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. 0.805 SIGNOR-52206 GSK3B protein P49841 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates quantity phosphorylation 9606 27929056 YES miannu For analysis of phosphorylation of NEMO on Ser8 and Ser17 by GSK-3, we generated phospho-specific antibodies (anti-phospho-NEMO-Ser8 and anti-phospho-NEMO-Ser17) while anti-phospho-NEMO-Ser31 and anti-phospho-NEMO-Ser43 were commercially available. Indeed, GSK-3\u03b2 was able to phosphorylate all four serines of rhNEMO in a time-dependent manner in an in vitro kinase assay (Fig. 3a).|In this study, we identified NEMO as a GSK-3\u03b2 substrate that is phosphorylated at several serine residues located within the N-terminal domain.|The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3Œ≤ binding and subsequent phosphorylation of NEMO resulting in its destabilization 0.432 SIGNOR-279527 MUC12 protein Q9UKN1 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 9606 BTO:0000037 32596961 YES miannu MUC12 promoted the recruitment of c-Jun on the promoter of TGF-β1, leading to its transcription. 0.256 SIGNOR-265474 LRRK2 protein Q5S007 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity phosphorylation Thr56 FSSQPGHtPHPAASR 9606 25446991 YES miannu Thus, we propose that Thr56 phosphorylation of Bcl-2 by LRRK2 G2019S might be a crucial step of mitochondrial disorder, which initiates the subsequent cellular damage in the context of PD relevant to G2019S.|We found that LRRK2 G2019S induced loss of the MMP was recovered in both GFP-Bcl-2 and GFP-M-Bcl-2 stable cells (XREF_FIG -lower panel). 0.329 SIGNOR-279531 9-(1-anilinoethyl)-7-methyl-2-(4-morpholinyl)-4-pyrido[1,2-a]pyrimidinone chemical CHEBI:91428 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207278 GAP43 protein P17677 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10116 26865625 NO miannu Growth-associated protein 43 (GAP43), a protein kinase C (PKC)-activated phosphoprotein, is often implicated in axonal plasticity and regeneration.  0.7 SIGNOR-266771 ABL1 protein P00519 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity phosphorylation Tyr1003 KGKKFLQyNRLQLSR 9606 BTO:0002181 12652307 YES miannu C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity. 0.589 SIGNOR-276002 PLK1 protein P53350 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates activity phosphorylation 9606 17488623 YES miannu Phosphorylation of Ect2 by Plk1 during anaphase might alleviate this intramolecular inhibition by dissociating the Ect2 amino from the carboxyl terminus.|Together with the presence of a prominent microtubule array at the midzone, these data suggest that Plk1 is not essential for the formation of the central spindle at anaphase.The specific failure of Ect2 to localize to the midzone raised the interesting possibility that Plk1 might trigger the initiation of cytokinesis by promoting the interaction of Ect2 with centralspindlin and, thereby, Ect2 activation and recruitment to the central spindle. 0.749 SIGNOR-279553 PRKG1 protein Q13976 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 19593530 YES 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization 0.274 SIGNOR-186784 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser431 ENVYTPKsAVKNEEY 9606 16216881 YES lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. 0.2 SIGNOR-141010 CHD8 protein Q9HCK8 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 15367660 YES gcesareni Duplin (axis duplication inhibitor) interacts with beta-catenin and prevents its binding to tcf, thereby inhibiting downstream wnt signaling 0.643 SIGNOR-128976 A8/b1 integrin complex SIGNOR-C165 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 NO miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. 0.551 SIGNOR-257707 PTH protein P01270 UNIPROT PTH1R protein Q03431 UNIPROT up-regulates binding 9606 18981475 YES gcesareni Here we show that binding of pth to its receptor pth1r induced association of lrp6, a coreceptor of wnt, with pth1r. The formation of the ternary complex containing pth, pth1r, and lrp6 promoted rapid phosphorylation of lrp6, which resulted in the recruitment of axin to lrp6, and stabilization of beta-catenin. 0.771 SIGNOR-182039 ROCK1 protein Q13464 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Thr119 LSRRLKVtGDLFDIM 9606 23877263 YES miannu Beclin1 is phosphorylated by ROCK1 at T119. 0.415 SIGNOR-278198 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr536 LPLNTDAyLSLQELQ -1 10214954 YES Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. 0.643 SIGNOR-251379 MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 YES lperfetto Recently, two MAP kinase kinases (MKK3 and MKK4) that activate p38 MAP kinase have been identified. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182 0.59 SIGNOR-27973 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI TAL2 protein Q16559 UNIPROT up-regulates quantity by expression 10090 24816818 NO irozzo These results demonstrate for the first time that atRA induces Tal2 expression in P19 cells, and suggest that TAL2 commits to the acquisition of neural fate in brain development. 0.8 SIGNOR-259087 TBK1 protein Q9UHD2 UNIPROT OPTN protein Q96CV9 UNIPROT up-regulates activity phosphorylation Ser513 FEDGGRQsLMEMQSR 9606 26365381 YES miannu Given that TBK1 can phosphorylate OPTN on S177, S473 and S513 in response to mitochondrial depolarization, we explored the function of these events in vivo.|Phosphorylation of OPTN on S473 and S513 promotes TBK1 activation and recruitment of OPTN to depolarized mitochondria. 0.788 SIGNOR-278171 CENPE protein Q02224 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity 10090 12925705 NO lperfetto CENP-E is required for efficient recruitment of BubR1, Mad1, and Mad2 to attached and newly unattached kinetochores 0.794 SIGNOR-252045 PDGFA protein P04085 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252286 NLGN4Y protein Q8NFZ3 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.2 SIGNOR-264143 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 19115199 YES gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-182988 AURKB protein Q96GD4 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates activity phosphorylation 9606 26880562 YES miannu Aurkb phosphorylates Oct4(S229) during G2/M phase, leading to the dissociation of Oct4 from chromatin, whereas PP1 binds Oct4 and dephosphorylates Oct4(S229) during M/G1 transition, which resets Oct4-driven transcription for pluripotency and the cell cycle. 0.38 SIGNOR-279592 NMS protein Q5H8A3 UNIPROT NMUR2 protein Q9GZQ4 UNIPROT up-regulates binding 9606 BTO:0000142 15635449 YES gcesareni Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus. 0.63 SIGNOR-133131 PPP4C protein P60510 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates activity dephosphorylation 9606 22732494 YES miannu PP4 dephosphorylated pKAP1 in vitro. 0.359 SIGNOR-277163 PLAAT3 protein P53816 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates 9606 17374643 NO miannu The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity. 0.2 SIGNOR-153772 EGFR protein P00533 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 24212772 YES GRB2 recruit indirectly through PTB domain-mediated binding of the Shc adaptor gcesareni Several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of erbb1 such as the adaptor proteins growth-factor-receptor bound-2 (grb2) and src-homology-2-containing (shc). 0.617 SIGNOR-55861 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser249 LDILHNSsQMKSMST 9606 BTO:0000567 25670858 YES lperfetto Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites. 0.587 SIGNOR-265230 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 YES lperfetto The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 0.845 SIGNOR-263222 BMX protein P51813 UNIPROT F2R protein P25116 UNIPROT down-regulates activity phosphorylation Tyr383 SECQRYVySILCCKE 9606 31910739 YES miannu As shown in xref \u2013 xref , BMX overexpression increased PAR1-WT phosphorylation but had no effect on PAR1 Y 381 FY 383 F mutant, indicating that BMX phosphorylated PAR1 at Y 381 and Y 383 .|Mechanically , BMX represses PAR1 signaling in ECs by promoting PAR1 phosphorylation and internalization . 0.2 SIGNOR-279594 TARS1 protein P26639 UNIPROT tRNA(Thr) smallmolecule CHEBI:29180 ChEBI down-regulates quantity chemical modification 9606 25824639 YES miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. 0.8 SIGNOR-270501 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 12220227 YES lperfetto Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions. 0.914 SIGNOR-236725 PAX3-FOXO1 fusion protein SIGNOR-FP12 SIGNOR IGF1R protein P08069 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 YES miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. 0.2 SIGNOR-251568 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT up-regulates activity phosphorylation Tyr337 LPAQIIEyYNPSGPP 9606 BTO:0000815 17623672 YES WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3. 0.58 SIGNOR-262301 GSK3B protein P49841 UNIPROT ZBTB16 protein Q05516 UNIPROT up-regulates activity phosphorylation Thr282 RGKEGPGtPTRSSVI 9606 25821988 YES miannu Taken together, we conclude that S184 and T282 of ZBTB16 may be phosphorylated by GSK3beta in cells under serum starvation condition. 0.2 SIGNOR-279618 GSK3B protein P49841 UNIPROT ZBTB16 protein Q05516 UNIPROT up-regulates activity phosphorylation Ser184 PGPMVDQsPSVSTSF 9606 25821988 YES miannu Taken together, we conclude that S184 and T282 of ZBTB16 may be phosphorylated by GSK3beta in cells under serum starvation condition. 0.2 SIGNOR-279619 LATS1 protein O95835 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates activity phosphorylation 9606 20407010 YES miannu LATS1 phosphorylates forkhead L2 and regulates its transcriptional activity.|Last, we demonstrated that coexpression with LATS1 enhances FOXL2 's activity as a repressor of the StAR promoter, and this results from the kinase activity of LATS1. 0.453 SIGNOR-279624 EFNA3 protein P52797 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9330863 YES gcesareni The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion 0.802 SIGNOR-52384 SEPTIN6 protein Q14141 UNIPROT SEPT6/SEPT2 complex SIGNOR-C71 SIGNOR form complex binding 9606 16914550 YES miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. 0.2 SIGNOR-148892 FGF3 protein P11487 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 YES gcesareni Using fgf 1 as an internal standard we have determined the relative activity of all the other members of the fgf family. These data should serve as a biochemical foundation for determining developmental, physiological, and pathophysiological processes that involve fgf signaling pathways 0.766 SIGNOR-42374 PRKCD protein Q05655 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser498 RHRPLSRtQSSPLPQ 9606 18332134 YES Manara In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation. 0.353 SIGNOR-260876 MAPK3 protein P27361 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 YES Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels 0.294 SIGNOR-262523 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser289 PALSRRGsLGEEGSE 10090 17213202 YES lperfetto The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo. 0.385 SIGNOR-234473 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 YES lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos 0.791 SIGNOR-263007 WDFY3 protein Q8IZQ1 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates quantity by destabilization relocalization 9606 BTO:0000793 27008544 YES miannu Our data taken together with the known role of ALFY in autophagy, demonstrate specific targeting and autophagy-mediated removal of DVL3 by hALFY. 0.251 SIGNOR-266793 CDK3 protein Q00526 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 YES lperfetto In vitro, lsf is phosphorylated by cyclin e/cyclin-dependent kinase 2 (cdk2), cyclin c/cdk2, and cyclin c/cdk3, predominantly on s309. Phosphorylation by cyclin c/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of lsf during g1 progression 0.264 SIGNOR-184164 HMGB2 protein P26583 UNIPROT POU2F1 protein P14859 UNIPROT up-regulates activity binding 10090 BTO:0002910 7720710 YES 2 miannu HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins 0.307 SIGNOR-240151 PIK3IP1 protein Q96FE7 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity binding 9606 24316979 YES miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. 0.277 SIGNOR-260073 SRC protein P12931 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity phosphorylation Tyr58 AEEMDFEyLEIRQLE 9606 35003083 YES miannu Because MyD88 was phosphorylated at the tyrosine 58 residue in hemi-ITAM by LPS ( xref ), whether Src phosphorylates MyD88 at the tyrosine 58 residue was examined further, and MyD88 was phosphorylated by Src at Y58 ( xref ).|Src activates MyD88 by phosphorylation at Y58 via the Src kinase domain. 0.446 SIGNOR-279655 MAPK8IP1 protein Q9UQF2 UNIPROT MAP3K10 protein Q02779 UNIPROT up-regulates binding 9606 15767678 YES gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. 0.504 SIGNOR-134552 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257969 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 YES lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 0.8 SIGNOR-265115 TBK1 protein Q9UHD2 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation 9606 32772249 YES miannu The feedback of activation of HDAC3 by TBK1 was able to further enhance IFN production and IFN-STAT activation.|We found that HDAC3 could be phosphorylated by TBK1. 0.2 SIGNOR-279662 MYOD1 protein P15172 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001103 12694204 YES Simone Vumbaca We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation. 0.459 SIGNOR-255640 DMTF1 protein Q9Y222 UNIPROT ADM protein P35318 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 NO Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  0.2 SIGNOR-261581 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000830 15526160 NO Numerous studies have implicated the critical importance of the Ras/Erk pathway in cell division and survival 0.7 SIGNOR-254948 CDK5 protein Q00535 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 9606 29742423 YES miannu CDK5 Activates the Self-Renewal Regulator CREB1 in GSCs.|Our data indicate that CDK5, which has previously been shown to activate CREB1 through cAMP and PKA in dopamine neurons present in the ventral tegmental area, can directly bind with and phosphorylate CREB1 in a PKA and cAMP independent manner, at least in GSCs. 0.374 SIGNOR-279682 CDK5 protein Q00535 UNIPROT NEFM protein P07197 UNIPROT down-regulates quantity phosphorylation 9606 28634551 YES miannu Converse to the effect of PKA overexpression, overexpression of CDK5 and its activator, p35, decreased the association between spinophilin and NF-M as well as the expression of NF-M.|Moreover, CDK5 phosphorylates NF-M [ xref ], and this was also apparent in our data, given a dramatic molecular weight shift in the NF-M band following CDK5 overexpression. 0.421 SIGNOR-279683 LYN protein P07948 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 YES scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. 0.707 SIGNOR-268215 CDK5 protein Q00535 UNIPROT SYNJ1 protein O43426 UNIPROT down-regulates activity phosphorylation Ser1147 S-->A 9606 14704270 YES miannu Cdk5 phosphorylation inhibited the inositol 5-phosphatase activity of synaptojanin 1, whereas dephosphorylation by calcineurin stimulated such activity.|The activity of synaptojanin 1 was also stimulated by its interaction with endophilin 1, its major binding partner at the synapse. Notably, Cdk5 phosphorylated serine 1144, which is adjacent to the endophilin binding site. 0.506 SIGNOR-279685 TRIM21 protein P19474 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20668674 YES miannu Furthermore, this Ro52 mediated degradation of IRF7 was inhibited in the presence of MG132, a proteasome inhibitor, indicating that IRF7 is targeted to the proteasome for degradation (XREF_FIG).|Ro52 ubiquitinates IRF7 in a dose dependent manner. 0.676 SIGNOR-278619 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR down-regulates quantity by destabilization ubiquitination 9606 23431053 YES miannu Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ 0.393 SIGNOR-277637 CDK9 protein P50750 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity phosphorylation 9606 35745840 YES miannu As Cdk9 phosphorylates both RNA polymerase II and p300 and increases p300-HAT activity , the effects of CUR and PyrC on the kinase activity of Cdk9 were examined .|As Cdk9 phosphorylates both RNA polymerase II and p300 and increases p300-HAT activity, the effects of CUR and PyrC on the kinase activity of Cdk9 were examined. 0.376 SIGNOR-279690 CDK9 protein P50750 UNIPROT H1-4 protein P10412 UNIPROT down-regulates activity phosphorylation Ser187 KPKKAPKsPAKAKAV 9606 28539972 YES miannu These data provide further evidence that CDK9 phosphorylates H1.4-S187, and that the level of pS187-H1.4 at genes is directly related to the extent of co-enrichment of CDK9.|that enrichment of pS187-H1.4 at genes is positively related to their transcription. 0.2 SIGNOR-279691 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001271 BTO:0000671 14551213 YES gcesareni The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1 0.719 SIGNOR-118596 Obatoclax chemical CID:16681698 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 23336025 YES gcesareni Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol. 0.8 SIGNOR-200478 TRIM25 protein Q14258 UNIPROT AMFR protein Q9UKV5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24810856 YES miannu We further demonstrate that TRIM25 ubiquitylates gp78 and that overexpression of TRIM25 accelerates the degradation of gp78. Our data suggest that TRIM25 not only cooperates with gp78 in polyubiquitylation of AMF but also gauges the steady-state level of gp78.  0.364 SIGNOR-272176 UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI α-D-glucosyl-glycogenin complex SIGNOR-C430 SIGNOR up-regulates quantity precursor of 9606 26882899 YES miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. 0.8 SIGNOR-268129 NPM1 protein P06748 UNIPROT HEXIM1 protein O94992 UNIPROT down-regulates activity binding 9606 BTO:0001545 18371977 YES miannu We identified NPM as a novel HEXIM1-binding protein. NPM functioned as a negative regulator of HEXIM1. cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction. 0.385 SIGNOR-260134 ATM protein Q13315 UNIPROT PPP1R2 protein P41236 UNIPROT down-regulates phosphorylation Ser44 DEELSKKsQKWDEMN 9606 18250156 YES gcesareni Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1. 0.2 SIGNOR-160648 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258002 PRKG1 protein Q13976 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 9606 BTO:0000887;BTO:0001260 21106951 YES lperfetto Pkgi also directly phosphorylates fhod1, and studies with wild-type and mutant fhod1-derived peptides identify ser-1131 in the fhod1 c terminus as the unique pkgi phosphorylation site in fhod1. phosphorylation of three conserved residues within the dad domain activates fhod1 while binding to rac regulates fhod1 subcellular localization 0.355 SIGNOR-170094 TMLHE protein Q9NVH6 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 11431483 YES miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 0.8 SIGNOR-269683 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 YES gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. 0.793 SIGNOR-90521 Shelterin complex complex SIGNOR-C306 SIGNOR Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR up-regulates 33015044 NO lperfetto The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1 0.7 SIGNOR-263309 GSK3B protein P49841 UNIPROT SOX9 protein P48436 UNIPROT down-regulates activity phosphorylation Thr236 GQSQGPPtPPTTPKT 9606 27566146 YES miannu (E) The SOX9 K2 domain is phosphorylated by GSK3\u03b2 at T236.|Based on our findings that inhibition of GSK3\u03b2 prevents DNA damage-induced SOX9 degradation, and that FBW7 targets SOX9 for degradation after DNA damage, we reasoned that phosphorylation of SOX9 by GSK3\u03b2 is required for FBW7-mediated SOX9 degradation. 0.445 SIGNOR-279725 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25934862 NO miannu IL-4-induced macrophage polarization involves induction of STAT6 and KLF4 that induce each other and promote M2 polarization. 0.346 SIGNOR-254519 TFEB protein P19484 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 NO lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) 0.2 SIGNOR-276787 dolichyl beta-D-mannosyl phosphate smallmolecule CHEBI:17624 ChEBI Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 21384228 NO lperfetto Dolichol has a well defined role as a lipid carrier for the glycan precursor in the early stages of N‐linked protein glycosylation, which is assembled in the endoplasmic reticulum of all eukaryotic cells. 0.7 SIGNOR-262568 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 YES Amphiregulin is an autocrine growth factor lperfetto Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. 0.771 SIGNOR-236356 PCDHA9 protein Q9Y5H5 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. 0.2 SIGNOR-265662 PPM1F protein P49593 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates activity dephosphorylation Ser345 LVQGISFsQPTCPDH 9606 31944151 YES lperfetto As a result, inactivation of Chk1 by POPX2 leads to impaired G1S checkpoint activation and cells are able to proceed from G1 to S phase despite DNA damage.|We also determined that POPX2 can dephosphorylate Chk1Ser317 and -Ser345 and is a potential regulator of Chk1 function in the cell. 0.2 SIGNOR-276988 vorinostat chemical CHEBI:45716 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257921 ADAM10 protein O14672 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity cleavage 9606 26284334 YES miannu The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin. 0.546 SIGNOR-259846 SPEG protein Q15772 UNIPROT JPH2 protein Q9BR39 UNIPROT up-regulates activity phosphorylation 9606 27729468 YES miannuccelli Studies in HEK293 cells confirmed that SPEG overexpression increases JPH2 phosphorylation . 0.361 SIGNOR-279759 SMAD1/4 complex SIGNOR-C85 SIGNOR DLX5 protein P56178 UNIPROT up-regulates transcriptional regulation 10090 BTO:0000165 12815054 NO ggiuliani Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining 0.302 SIGNOR-255789 CSNK2A1 protein P68400 UNIPROT SERINC3 protein Q13530 UNIPROT up-regulates activity phosphorylation Ser383 DTTTSGAsDEEDGQP -1 30135209 YES miannu The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro. 0.2 SIGNOR-273632 SRC protein P12931 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates quantity phosphorylation Tyr216 IPTSPTPyTYNKSCD 9606 26042227 YES miannuccelli These data strongly suggest that PRAK phosphorylation by Src on Y188 and Y216 drives the relocalization of PRAK to focal adhesion structures during cell adhesion. 0.373 SIGNOR-279762 fluticasone chemical CHEBI:5134 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 YES gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. 0.8 SIGNOR-248206 ERBB4 protein Q15303 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 16729043 YES gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. 0.484 SIGNOR-146882 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation 28712664 YES AKT phosphorylates and inhibits GSK3 in addition to many other substrates including TSC2, FOXO proteins, TBC1D4. 0.2 SIGNOR-255488 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 BTO:0000759 24692351 NO scontino It has been previously established that T3 stimulates gluconeogenesis, especially in the hyperthyroid state, and that hypothyroidism is associated with reduced gluconeogenesis. 0.7 SIGNOR-267490 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 9130707 YES gcesareni We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase. 0.525 SIGNOR-47630 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr51 SRKLQLKtLLLQIAK 9606 BTO:0000671 18986304 YES llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). 0.2 SIGNOR-182061 RAI1 protein Q7Z5J4 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22578325 NO miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. 0.317 SIGNOR-266843 SCN2A protein Q99250 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 NO miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. 0.7 SIGNOR-253450 FZD3 protein Q9NPG1 UNIPROT NLK protein Q9UBE8 UNIPROT up-regulates binding 9606 20828404 YES gcesareni Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades. 0.353 SIGNOR-167862 KIFC1 protein Q9BW19 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity binding 9606 BTO:0000948 33361741 YES miannu We found that KIFC1 could directly bind to CENPE in SKOV3 cells (Figure 4C, 4D). 0.572 SIGNOR-266116 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT up-regulates activity binding -1 8683730 YES lperfetto Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production. 0.422 SIGNOR-270548 ATR protein Q13535 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser732 TDGILAGsQEHDPGQ 9606 27683220 YES miannu The expression of either ATR-KD or the addition of the ATR kinase inhibitor VE-821 to ATR-WT expressing cells caused AKAP12 to be retained within the cytoplasm.|With UV damage, ATR phosphorylates AKAP12 at S732 which stimulates nuclear translocation of an AKAP12\u2013ATR-pS435 complex that results in enhanced 5\u2032 strand incision of NER. 0.2 SIGNOR-278292 PDPK2P protein Q6A1A2 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation 9606 15505410 YES gcesareni Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2. 0.2 SIGNOR-252628 TFE3 protein P19532 UNIPROT FLCN protein Q8NFG4 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 NO lperfetto We found a TFE3-dependent increase in the amount of FLCN in ARPE-19 cells starved of nutrients for 24 hours (Fig. 3E). Accordingly, we found that overexpression of TFE3 in ARPE-19 cells resulted in an increase in FLCN protein abundance (Fig. 3F), as well as the mRNA abundance of FLCN and two FLCN-interacting proteins, FNIP1 and FNIP2 (Fig. 3G) (32). 0.445 SIGNOR-276819 ROCK1 protein Q13464 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Ser19 KRPQRATsNVFAMFD 9606 BTO:0000567 12185584 YES miannu Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies. we showed that the inhibition of Rho-kinase reduced diphosphorylated MRLC in the center of cells even in the presence of phosphatase inhibitor, suggesting that Rho-kinase directly diphosphorylates MRLC (red arrow in Figure 6). Taken together, we propose a model of diphosphorylation of MRLC through dual pathways of both the direct phosphorylation and the inhibition of myosin phosphatase by Rho-kinase (Figure 6). 0.56 SIGNOR-263073 EFNB2 protein P52799 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 8559144 YES gcesareni Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation 0.883 SIGNOR-39862 ALK protein Q9UM73 UNIPROT STAT3 protein P40763 UNIPROT up-regulates binding 9606 BTO:0000785 14968112 YES gcesareni Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1. 0.44 SIGNOR-122085 AKT1 protein P31749 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Ser517 FLQVRKYsLDLASLI 9606 31138602 YES miannuccelli In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis . 0.431 SIGNOR-279774 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity precursor of 33148467 YES lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). 0.8 SIGNOR-271815 WNT10B protein O00744 UNIPROT FZD2 protein Q14332 UNIPROT up-regulates binding 9606 12055200 YES fspada Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 7 0.639 SIGNOR-89137 AKT1 protein P31749 UNIPROT PFKP protein Q01813 UNIPROT up-regulates quantity phosphorylation 9606 29038421 YES lperfetto A reduction in AKT expression as a result of AKT1 shRNA expression or MK-2206 treatment decreased the half-life of endogenous PFKP, while the expression of active Myr-AKT1 prolonged the half-life of PFKP.|In addition, depletion of endogenous PFKP and reconstitution of RNAi resistant WT Flag-rPFKP or Flag-rPFKP S386A expression in U251 or U87 and EGFRvIII cells revealed that the S386A mutation abolished PFKP phosphorylation induced by EGF, constitutively active Myr-AKT1, and EGFRvIII. 0.563 SIGNOR-279788 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248736 DGC complex SIGNOR-C217 SIGNOR GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 YES miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. 0.2 SIGNOR-265437 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates binding 9606 9390557 YES gcesareni During apoptosis, apaf-1 binds to cytochrome c and in the presence of atp/datp forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 .in particular, caspase-9 is recruited and activated by apaf-1 .casp9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cycs and datp, an event that leads to casp9 activation. 0.954 SIGNOR-53579 IKBKE protein Q14164 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser419 TPDDFLNsVDEMDTG 9606 28481329 YES miannu Virus-activated kinase IKKɛ phosphorylated YAP at Ser403 and thereby triggered degradation of YAP in lysosomes and, consequently, relief of YAP-mediated inhibition of the cellular antiviral response.  0.44 SIGNOR-277355 SIK3 protein Q9Y2K2 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates activity phosphorylation 9606 21565608 YES miannu They find that SIK3 phosphorylates and inhibits HDAC4 during feeding states.|They find that SIK3 phosphorylates and inhibits HDAC4 during feeding\nstates. 0.412 SIGNOR-279430 TANC2 protein Q9HCD6 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 YES miannu Kinesin-3 Family Member KIF1A Interacts with Liprin-α and TANC2. TANC2 and Liprin-α Recruit KIF1A-Driven DCVs in Dendritic Spines. Upon Ca2+/CaM binding, KIF1A is activated, allowing for DCV loading and motility. KIF1A-driven DCVs are recruited in dendritic spines by liprin-α and TANC2, which ensure a precise mechanism of synaptic tagging for the vesicles. 0.248 SIGNOR-266891 FBP1 protein P09467 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 30616754 YES lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle 0.8 SIGNOR-267610 TCF4 protein P15884 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22777675 NO miannu we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays. 0.274 SIGNOR-255391 NDUFB3 protein O43676 UNIPROT NADH-ubiquinone oxidoreductase-Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 YES lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 0.809 SIGNOR-262166 COPS4 protein Q9BT78 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.938 SIGNOR-270762 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 YES gcesareni The mitotic phosphorylation sites on the alpha subunit of casein kinase ii can be phosphorylated in vitro by p34cdc2. 0.355 SIGNOR-161839 MRPL18 protein Q9H0U6 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.643 SIGNOR-262376 PRKCB protein P05771 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Ser180 GSLKPGSsHRKTKKP 9606 BTO:0003076 11598012 YES lperfetto We provide direct evidence that PKCbeta acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCbeta results in a dramatic increase in B-cell receptor (BCR)-mediated Ca2+ signaling. We identified a highly conserved PKCbeta serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and FcepsilonRI-mediated signaling in B and mast cells, respectively. | This deductive analysis indicated that PKCbeta phosphorylates S180 in the region bisecting the Btk motif (BM) and the PRR of the TH domain. 0.383 SIGNOR-249110 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 YES giulio giuliani In Tgfbr2fl/fl control MEPM cells, radioactive TGF-β2 ligands (12.5 kDa) bind to TβRI (53 kDa), TβRII (70 kDa), and TβRIII (100–200 kDa, highly glycosylated molecule) and form the ligand-receptor complexes of TβRI::TGF-β2 (65.5 kDa), TβRII::TGF-β2 (82.5 kDa), and TβRIII::TGF-β2 (112.5–212.5 kDa) 0.846 SIGNOR-255960 haloperidol chemical CHEBI:5613 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 YES miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. 0.8 SIGNOR-258373 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 YES lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal 0.601 SIGNOR-249400 GSK3B protein P49841 UNIPROT FBXL21P protein Q9UKT6 UNIPROT up-regulates activity phosphorylation Thr33 FYSSLNQtHTHTVLL 9606 BTO:0000007 32937135 YES lperfetto GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites. 0.2 SIGNOR-264851 TEAD1 protein P28347 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 21211055 NO gcesareni Tead1 can regulate transcription of the foxo3a gene through the binding to the m-cat element, demonstrated with independent chip-pcr analysis, emsa and luciferase reporter system assay. The over-expression and inhibition analysis suggest that foxo3a was positively regulated by tead1. 0.305 SIGNOR-253003 USP28 protein Q96RU2 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization deubiquitination 18662541 YES lperfetto Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage 0.2 SIGNOR-274057 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Ser394 TRQTPVDsPDDSTLS 9823 BTO:0004712 23486913 YES lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway 0.96 SIGNOR-201530 PRKACB protein P22694 UNIPROT PHKA2 protein P46019 UNIPROT down-regulates activity phosphorylation 9606 10487978 YES Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. 0.324 SIGNOR-267412 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007 SIGNOR-C3 9465032 YES lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.926 SIGNOR-55701 Oxytocin protein P01178-PRO_0000020495 UNIPROT OXTR protein P30559 UNIPROT up-regulates binding 9606 1313946 YES gcesareni The oxytocin receptor, expressed in xenopus oocytes, specifically responds to oxytocin and induces an inward membrane current 0.2 SIGNOR-16758 PI4KB protein Q9UBF8 UNIPROT Receptor_mediated_ endocytosis phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 BTO:0001444 22253445 NO lperfetto PI4KB knockdown inhibits SARS-CoV S-mediated entry, whereas PI3KR1 knockdown increases SARS-CoV S-mediated entry 0.7 SIGNOR-260734 FOXO3 protein O43524 UNIPROT DIO2 protein Q92813 UNIPROT up-regulates quantity by expression transcriptional regulation 20978344 NO Forkhead box O3 (FoxO3) was identified as a key molecule inducing D2 expression and thereby increasing intracellular T3 production. Accordingly, FoxO3-depleted primary myoblasts also had a differentiation deficit that could be rescued by high levels of T3. 0.342 SIGNOR-256204 ABL1 protein P00519 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Tyr81 MQQCDSPyVVKYYGS 9606 BTO:0000938 22590567 YES llicata We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death. 0.2 SIGNOR-197538 A9/b1 integrin complex SIGNOR-C166 SIGNOR TNF protein P01375 UNIPROT up-regulates quantity by expression 9606 24241034 NO lperfetto Importantly, autocrine and paracrine interactions of alpha9beta1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-alpha± and IL-1beta in synovial macrophages. 0.311 SIGNOR-253315 EPAS1 protein Q99814 UNIPROT KDM5A protein P29375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.265 SIGNOR-271580 ALDOC protein P09972 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266481 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr675 ANQMQPDtTSVVKDS 9606 18680479 YES miannu We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / mutation of thr675 to alanine increased mps1 catalytic domain activity, and this was reduced to wt levels by mutation to aspartate 0.2 SIGNOR-179904 RNF31 protein Q96EP0 UNIPROT LUBAC complex SIGNOR-C527 SIGNOR form complex binding 9606 BTO:0000567 17006537 YES miannu Here, we report that a protein complex consisting of two RING finger proteins, HOIL-1L and HOIP, exhibits ubiquitin polymerization activity by recognizing ubiquitin moieties of proteins. The polyubiquitin chain generated by the complex is not formed by Lys linkages, but by linkages between the C- and N-termini of ubiquitin, indicating that the ligase complex possesses a unique feature to assemble a novel head-to-tail linear polyubiquitin chain. 0.946 SIGNOR-271616 PFKFB4 protein Q16877 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000007 29615789 YES PFKFB4, a regulatory enzyme that synthesizes an allosteric stimulator of glycolysis2, was found to be a robust stimulator of SRC-3 that co-activates estrogen receptor (ER). PFKFB4 phosphorylates SRC-3 at serine 857 (S857) enhancing its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient SRC-3 mutant S857A (SRC-3S857A) significantly abolishes SRC-3-mediated transcriptional output 0.326 SIGNOR-267269 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269348 ITGA6 protein P23229 UNIPROT PMP22 protein Q01453 UNIPROT up-regulates activity binding 10090 16436605 YES Regulation miannu PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types. 0.383 SIGNOR-251895 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser789 VSAGPRPsPLPSPQP 9606 BTO:0000007 17711861 YES miannu  The activation of MLK3 by GSK-3beta occurred via phosphorylation of MLK3 on two amino acid residues, Ser(789) and Ser(793), that are located within the C-terminal regulatory domain of MLK3.  0.336 SIGNOR-276071 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8422248 YES lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. 0.675 SIGNOR-248929 RAF1 protein P04049 UNIPROT KLF10 protein Q13118 UNIPROT down-regulates quantity by destabilization phosphorylation Thr93 TIPAFCLtPPYSPSD 9606 BTO:0000018 23994618 YES miannu RAF1 phosphorylates the Thr93 site of KLF10 in vivo. Since the phosphorylation of Thr93 enables KLF10 and PIN1 to bind, it seems likely that RAF-1 will have an effect on KLF10 stability that is similar to that of PIN1.PIN1 facilitates KLF10 protein degradation. ( 0.2 SIGNOR-276502 PTEN protein P60484 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 31374292 YES miannu PTEN targets the protein phosphatase activity of BCR-ABL. PTEN has the same function as PTP1B, which can regulate BCR-ABL dephosphorylation [13]. However, whether PTEN can mediate BCR-ABL dephosphorylation remains unknown. We found that under-expression of PTEN significantly upregulated phosphorylation level of BCR-ABL. In order to verify the mechanisms, co-IP assays were applied, demonstrating the ways in which PTEN and BCR-ABL interact with each other. 0.2 SIGNOR-260080 MAPK3 protein P27361 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates activity phosphorylation Ser244 QPVSAPPsPRDISME 9606 BTO:0000007 14712216 YES miannu We have characterized the H4(D10S170) gene product, showing that it is a ubiquitously expressed 55 KDa nuclear and cytosolic protein that is phosphorylated following serum stimulation. This phosphorylation was found to depend on mitogen-activated protein kinase (MAPK) Erk1/2 activity and to be associated to the relocation of H4(D10S170) from the nucleus to the cytosol. S244 is the major target residue of ERK1 0.367 SIGNOR-276003 TP53INP1 protein Q96A56 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 22421968 YES gcesareni In this work, we show that tp53inp1 is also able to interact with atg8-family proteins and to induce autophagy-dependent cell death. mammalian cells contain multiple atg8 orthologs belonging to three subfamilies: microtubule-associated protein 1 light chain 3, -aminobutyric acid receptor-associated protein (gabarap) and -aminobutyric acid receptor-associated protein like 2 (gabarapl2). 0.38 SIGNOR-196667 BRCA1 protein P38398 UNIPROT TFF1 protein P04155 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356;BTO:0001033 11244506 NO In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. 0.299 SIGNOR-253937 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 21798082 YES lperfetto Positive feedback involves mtorc2, which phosphorylates akt at serine 473, a phosphorylation required for maximum activation of akt in addition to phosphorylation at threonine 308 by pdk1. 0.748 SIGNOR-244396 TGFB2 protein P61812 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 1310899 YES gcesareni A cdna encoding the tgf-beta type ii receptor protein has been isolated by an expression cloning strategy. The cloned cdna, when transfected into cos cells, leads to overexpression of an approximately 80 kd protein that specifically binds radioiodinated tgf-beta 1. Excess tgf-beta 1 competes for binding of radioiodinated tgf-beta 1 in a dose-dependent manner and is more effective than tgf-beta 2. 0.753 SIGNOR-16690 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser177 ASSGSSAsFISDTFS 9606 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.628 SIGNOR-248683 TELO2 protein Q9Y4R8 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 YES miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. 0.536 SIGNOR-272001 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000567 SIGNOR-C13 10469655 YES lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). 0.746 SIGNOR-70453 CEP41 protein Q9BYV8 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity binding 9606 BTO:0000007 31885126 YES miannu We performed these assays in HEK 293T cells and observed CEP41 binds HIF1α under both normoxic and hypoxic conditions. Of note, we found hypoxia induces more expression of HIF1α and increases its binding to CEP41 (Fig 8B and C). Hence, these results suggest CEP41 modulates the activation of HIF1α via a physical interaction 0.2 SIGNOR-269662 ERBB2 protein P04626 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 10085134 YES gcesareni Shc interacts with and is an excellent substrate for erbb2 and appears to play an important role in mitogenic signaling through this receptor tyrosine kinase 0.807 SIGNOR-65579 BARD1 protein Q99728 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 20029420 YES gcesareni Brac1 dimerizes with brca1?associated Ring domain protein 1 (bard1) to yield a functional e3 ligase. 0.795 SIGNOR-162499 MAPK8 protein P45983 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates activity phosphorylation Ser363 DTEGRPPsPPPTSTP 9606 BTO:0000567 10747973 YES miannu JNK is activated by heat shock and phosphorylates HSF-1 on serine 363. JNK Phosphorylation of HSF-1 Leads to Reduction in Its Transcriptional Activity 0.498 SIGNOR-250119 KDM5B protein Q9UGL1 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 YES miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. 0.2 SIGNOR-265335 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 9606 BTO:0000007 BTO:0000671 16083423 YES gcesareni Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1) 0.447 SIGNOR-160846 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu49 RRANTFLeEVRKGNL -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263675 FGF10 protein O15520 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 YES gcesareni Fgf3, fgf7, fgf10 and fgf22 are ligands that activate fgfr2b. 0.893 SIGNOR-42362 FOXJ1 protein Q92949 UNIPROT DNALI1 protein O14645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23822649 YES miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). 0.394 SIGNOR-266933 NFIB protein O00712 UNIPROT ID3 protein Q02535 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.25 SIGNOR-268879 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr884 SSGGEQDyDYLNDWG 9606 BTO:0000848 16371504 YES lperfetto Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated. 0.398 SIGNOR-143242 SP1 protein P08047 UNIPROT ITGA11 protein Q9UKX5 UNIPROT up-regulates quantity by expression 9606 BTO:0001282 16300938 YES lperfetto We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors. 0.2 SIGNOR-253350 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 YES inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr 0.653 SIGNOR-270297 MAP2K4 protein P45985 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity phosphorylation 9534 BTO:0000298 7839144 YES Luana Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. 0.59 SIGNOR-260722 KDM6A protein O15550 UNIPROT HOXA13 protein P31271 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.285 SIGNOR-260022 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-189984 CSNK2A1 protein P68400 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation Ser187 AGSGAASsSGEDKEN -1 12527891 YES llicata Mass spectrometry analysis demonstrates that at least two serine residues, Ser-186 and Ser-187, are phosphorylated in vivo. | Finally, we demonstrate that phosphorylation of CDC25B by protein kinase CK2 increases the catalytic activity of the phosphatase in vitro as well as in vivo. 0.338 SIGNOR-250837 (S)-verapamil chemical CHEBI:77736 ChEBI ABCC1 protein P33527 UNIPROT up-regulates activity chemical activation 10036 17646169 YES Federica (S)-Verapamil acts as a “killer” by activation of MRP1-mediated GSH efflux, leading to the death of potentially resistant tumor cells. 0.8 SIGNOR-261081 PRKCA protein P17252 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 8810272 YES gcesareni These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc. 0.2 SIGNOR-43744 TIP-LINK complex complex SIGNOR-C291 SIGNOR LHFPL5 protein Q8TAF8 UNIPROT up-regulates activity binding 10090 BTO:0000630 23217710 YES lperfetto We conclude that the transmembrane and membrane proximal CR domain of PCDH15 mediate interaction with TMHS.|Based on the interdependence of PCDH15 and TMHS for their efficient localization to stereocilia, we reasoned that interaction between the two proteins might regulate their effective cell surface transport. 0.407 SIGNOR-262580 JAK1 protein P23458 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002882 9305869 YES Janus kinase-dependent activation of insulin receptor substrate 1 0.708 SIGNOR-251343 SIX1 protein Q15475 UNIPROT Six1/Dach complex SIGNOR-C122 SIGNOR form complex binding 10090 14628042 YES llicata The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, 0.596 SIGNOR-238029 PLCE1 protein Q9P212 UNIPROT HRAS protein P01112 UNIPROT up-regulates guanine nucleotide exchange factor 9606 11022047 YES gcesareni The presence of a rasgef motif in the n terminus of plcepsilon suggests that plcepsilon can activate ras by acting as an exchange factor by promoting the exchange of gtp for bound gdp. 0.577 SIGNOR-82859 MYLK protein Q15746 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 YES lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. 0.837 SIGNOR-188801 tRNA(Asn) smallmolecule CHEBI:29172 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 YES miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. 0.8 SIGNOR-270459 Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR BRCA1 protein P38398 UNIPROT up-regulates 18985065 NO lperfetto Once monoubiquitinated, the ID complex becomes associated with chromatin and is redistributed to DNA-damage sites, forming foci that are visible by immunofluorescence and colocalizing with other DNA-repair molecules, notably BRCA1, BRCA2 and γH2AX. 0.832 SIGNOR-263271 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2H protein P62256 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.51 SIGNOR-271362 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser295 TKRRKSMsGASPKES 9606 23708659 YES lperfetto Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b. 0.366 SIGNOR-202117 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation Ser207 ISGYLVDsVAKTIDA 9606 BTO:0000007 11279118 YES lperfetto Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells 0.648 SIGNOR-106465 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT down-regulates activity phosphorylation Tyr628 PKVAYHPyPEDYGDI -1 9195949 YES Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor. 0.757 SIGNOR-251318 PTGFR protein P43088 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-257082 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser38 LGPGTRLsLARMPPP -1 7822264 YES llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. 0.428 SIGNOR-250628 ROCK1 protein Q13464 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Thr18 KKRPQRAtSNVFAMF 9606 12185584 YES miannu Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies. 0.56 SIGNOR-263074 CSNK2A1 protein P68400 UNIPROT CAV1 protein Q03135 UNIPROT unknown phosphorylation Ser88 FDGIWKAsFTTFTVT -1 8058322 YES llicata Here, we have identified this serine kinase activity as a casein kinase II-like enzyme, since the phosphorylation of caveolin-rich membrane domains is stimulated and inhibited by known effectors of casein kinase II (poly-L-lysine, endogenous polyamines, and a casein kinase II inhibitor peptide), but is unaffected by modulators of other known kinases. In support of these observations, caveolin contains a consensus sequence for casein kinase II phosphorylation in its cytoplasmic N-terminal domain (Ser-88) 0.354 SIGNOR-250835 SMURF1 protein Q9HCE7 UNIPROT UVRAG protein Q9P2Y5 UNIPROT down-regulates activity ubiquitination Lys517 ENERLQYkTPPPSYN 9606 BTO:0000007 30686098 YES miannu Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux.  0.2 SIGNOR-273652 SRC protein P12931 UNIPROT WWOX protein Q9NZC7 UNIPROT up-regulates phosphorylation Tyr33 TTKDGWVyYANHTEE 9606 15070730 YES llicata The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73. 0.481 SIGNOR-123819 CYTH2 protein Q99418 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity guanine nucleotide exchange factor 10116 BTO:0003102 14565977 YES miannu Effects of ARNO upon Axonogenesis Are Mediated by Downstream Activation of ARF6. ARNO/ARF6 signaling pathways that could modulate actin reorganization in the axonal growth cone. ARNO stimulates GTP exchange on ARF6, thereby increasing the amount of active ARF6. 0.886 SIGNOR-264910 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression 9606 BTO:0001103;BTO:0002314 22493066 NO gcesareni We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk. 0.2 SIGNOR-254343 MTR protein Q99707 UNIPROT homocysteine smallmolecule CHEBI:17230 ChEBI down-regulates quantity chemical modification 9606 10520212 YES lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. 0.8 SIGNOR-253142 NPFFR2 protein Q9Y5X5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-256852 PRKDC protein P78527 UNIPROT PRKAG1 protein P54619 UNIPROT up-regulates activity phosphorylation Ser192 KPEFMSKsLEELQIG -1 31983282 YES miannu PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity.  0.2 SIGNOR-277503 PTPRB protein P23467 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 YES gcesareni Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. 0.344 SIGNOR-75993 SKP1 protein P63208 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0000007 16547521 YES miannu  KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation. 0.903 SIGNOR-271619 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr96 EENADDSyEPPPVEQ 9606 12456653 YES llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. 0.805 SIGNOR-96052 CD36 protein P16671 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 NO lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 0.7 SIGNOR-252270 PPP1R9A protein Q9ULJ8 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 10090 BTO:0001976 15996550 NO miannu Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc 0.7 SIGNOR-269180 DUSP4 protein Q13115 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 10116 7535768 YES Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK 0.708 SIGNOR-248716 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr90 AIKIIDKtQLNPTSL 9606 15319445 YES gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. 0.419 SIGNOR-128264 CHKA protein P35790 UNIPROT PLIN3 protein O60664 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr251 ERLRQHAyEHSLGKL 9606 BTO:0000527 34929314 YES lperfetto In addition, as a protein kinase, CHKα2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth  0.2 SIGNOR-267650 SUZ12 protein Q15022 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 NO miannu We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. 0.278 SIGNOR-254155 SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR PAX7 protein P23759 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165;BTO:0002314 20887952 YES lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. 0.325 SIGNOR-235583 PRKCZ protein Q05513 UNIPROT TRAF2 protein Q12933 UNIPROT unknown phosphorylation Ser55 QCGHRYCsFCLASIL 9606 BTO:0000785 19336568 YES llicata Here, we report that protein kinase czeta phosphorylates traf2 at ser(55), within the ring domain of the protein, after tnfalpha stimulation 0.434 SIGNOR-184941 SMURF2 protein Q9HAU4 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity ubiquitination 9606 22298955 YES lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. 0.594 SIGNOR-195681 AREL1 protein O15033 UNIPROT PIAS4 protein Q8N2W9 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Ser18;Thr783 MVMSFRVsDLQMLLG;T>782 27162139 YES lperfetto In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4. 0.403 SIGNOR-275575 HIF1A protein Q16665 UNIPROT EPO protein P01588 UNIPROT up-regulates quantity transcriptional regulation 9606 8756616 YES We demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells 0.642 SIGNOR-256593 ABL1 protein P00519 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Tyr74 Y-->P 9606 23318434 YES miannu Altogether, our data demonstrate that Pin1 and Abl cooperate to enhance the interaction of Myc with p300 and its resulting acetylation.|These experiments confirmed that Myc Y74 is phosphorylated by Abl, and provided us with a reagent to detect this form of Myc in cells (see below). 0.469 SIGNOR-278196 HMOX1 protein P09601 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26722274 NO irozzo The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells. 0.25 SIGNOR-256303 OFD1 protein O75665 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR down-regulates quantity by destabilization binding 9606 34027042 YES miannu We showed for the first time that the centrosomal protein OFD1, which is mutated in Oral-Facial-Digital type I syndrome, inhibits early phases of the LC3-mediated autop hagic cascade by acting as a receptor for unc-51-like kinase (ULK1) complex turnover. we demon strated that OFD1 is a novel autophagy receptor which selectively promotes the autophagic degradation of ATG13 via direct interaction with the C3/GABARAP family of proteins (Figure 1). 0.2 SIGNOR-269106 SRC protein P12931 UNIPROT RUNX3 protein Q13761 UNIPROT down-regulates activity phosphorylation 9606 20100835 YES miannu In this study, we provide evidence that Src phosphorylates RUNX3 at multiple tyrosine residues.|Our finding that Src inactivates RUNX3 by cytoplasmic sequestration in gastric cancer and breast cancer suggests that the inactivation of RUNX3 may be a key function of oncogenic kinases. 0.578 SIGNOR-278199 PFKP protein Q01813 UNIPROT ATG4B protein Q9Y4P1 UNIPROT up-regulates activity phosphorylation Ser34 WILGRKYsIFTEKDE 9606 BTO:0000007 33607258 YES lperfetto In vitro kinase assay validated that PFKP functioning as a protein kinase phosphorylated ATG4B at S34. This phosphorylation could enhance ATG4B activity and p62 degradation. In addition, PFKP S386 phosphorylation was important to ATG4B S34 phosphorylation and autophagy in HEK293T cells. 0.2 SIGNOR-275832 HOXD13 protein P35453 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 YES 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. 0.5 SIGNOR-241235 CSNK2A1 protein P68400 UNIPROT CASQ2 protein O14958 UNIPROT unknown phosphorylation Ser385 DDDDDDNsDEEDNDD -1 1985907 YES llicata Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH). 0.337 SIGNOR-250834 NTN3 protein O00634 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR up-regulates activity binding 9606 BTO:0001484 25881791 YES miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. 0.467 SIGNOR-268185 CALM3 protein P0DP25 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 11807557 YES miannu Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. 0.451 SIGNOR-266346 DVL1 protein O14640 UNIPROT APC protein P25054 UNIPROT down-regulates activity binding 9606 10330181 YES amattioni Dvl-1 inhibits Axin-promoted GSK-3_-dependent phosphorylation of _-catenin and APC, leading to beta-catenin stabilization. 0.695 SIGNOR-167951 LAMA1 protein P25391 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR form complex binding 7496033 YES lperfetto Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1. 0.567 SIGNOR-253232 SNTA1 protein Q13424 UNIPROT NOS1 protein P29475 UNIPROT up-regulates relocalization 9606 BTO:0001103 12456711 YES gcesareni biochemical studies showed that the N-terminal PDZ domain of nNOS binds to a similar PDZ domain of syntrophin (Fig. 1), a dystrophin-associated protein 0.559 SIGNOR-236916 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT up-regulates activity phosphorylation Tyr536 LPLNTDAyLSLQELQ 9534 BTO:0000298 8700888 YES In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. 0.63 SIGNOR-251341 FOXO1 protein Q12778 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12913110 NO lperfetto FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. 0.539 SIGNOR-209654 PTGS1 protein P23219 UNIPROT prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity chemical modification -1 7592599 YES Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, 0.8 SIGNOR-269778 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser726 IDPASPQsPESVDLV 9606 11604491 YES llicata Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728. 0.57 SIGNOR-111043 G6PD protein P11413 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI down-regulates quantity chemical modification 9606 24769394 YES miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress 0.8 SIGNOR-268125 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 YES lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. 0.2 SIGNOR-251522 YY1 protein P25490 UNIPROT ACTC1 protein P68032 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9171244 NO miannu Expression of YY1 inhibited cardiac alpha-actin promoter activity, whereas coexpression of Nkx-2.5 and SRF was able to partially reverse YY1 repression. 0.2 SIGNOR-255616 MIB1 protein Q86YT6 UNIPROT SMN1 protein Q16637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23615451 YES lperfetto The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein 0.324 SIGNOR-253112 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization phosphorylation Ser181 QQVQAQLsPLQNISP 9606 BTO:0001109 23277279 YES miannu Phosphorylation of XBP-1u by ERK is critical for the increased interaction of XBP-1u and FoxO1. 0.2 SIGNOR-276439 PRKD2 protein Q9BZL6 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity phosphorylation Ser155 FPLRKTVsEPNLKLR 18692497 YES Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7 lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. 0.438 SIGNOR-275933 PRKCQ protein Q04759 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation 9606 23352416 YES gcesareni At the same time, ea causes pkc?-Mediated phosphorylation and activation of the transcription factor heat shock factor 1, an inducer of glucose dependence. 0.35 SIGNOR-200576 VPS18 protein Q9P253 UNIPROT GGA3 protein Q9NZ52 UNIPROT down-regulates activity monoubiquitination Lys258 LFDQCENkRRTLFKL -1 16996030 YES miannu Monoubiquitylation of GGA3 by hVPS18 regulates its ubiquitin-binding ability. By in vitro ubiquitylation assays, we have identified lysine 258 in the GAT domain as a major ubiquitylation site that resides adjacent to the ubiquitin-binding site. Furthermore, the GAT domain ubiquitylated by hVPS18 no longer binds to ubiquitin, indicating that ubiquitylation negatively regulates the ubiquitin-binding ability of the GAT domain. These results suggest that the ubiquitin binding and ubiquitylation of GGA3-GAT domain are mutually inseparable through a ubiquitin ligase activity of hVPS18. 0.506 SIGNOR-271610 RPL3L protein Q92901 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.764 SIGNOR-262494 PPP2R5C protein Q13362 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization dephosphorylation Thr55 DDIEQWFtEDPGPDE 9606 BTO:0001938 17245430 YES Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation. 0.61 SIGNOR-268154 ZC3H12A protein Q5D1E8 UNIPROT TAL1 protein P17542 UNIPROT up-regulates quantity post transcriptional regulation 9606 BTO:0000007 30842549 YES Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA 0.2 SIGNOR-259944 GSK3B protein P49841 UNIPROT PAX3 protein P23760 UNIPROT up-regulates quantity phosphorylation Ser205 APQSDEGsDIDSEPD 9606 22679108 YES miannu The ubiquitously expressed CK2 often provides the priming phosphorylation for GSK-3, however, we found that GSK-3beta alone was sufficient to phosphorylate PAX3 at both Ser205 and Ser197 and Ser201 in-vitro. 0.334 SIGNOR-278483 GNAL protein P38405 UNIPROT ADCY5 protein O95622 UNIPROT up-regulates activity binding 9606 BTO:0004032 21303898 YES miannu D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum. 0.613 SIGNOR-264997 PTPRG protein P23470 UNIPROT LIMK1 protein P53667 UNIPROT down-regulates activity dephosphorylation Tyr507 KPDRKKRyTVVGNPY -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.261 SIGNOR-254711 OTX2 protein P32243 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation -1 18849347 NO miannu Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. 0.351 SIGNOR-254888 DNMT1 protein P26358 UNIPROT BAG3 protein O95817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 NO lperfetto In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+) 0.2 SIGNOR-254110 PRL protein P01236 UNIPROT KRT15 protein P19012 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 20103718 NO Regulation miannu PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes. 0.2 SIGNOR-251904 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR RAD51 protein Q06609 UNIPROT up-regulates activity ubiquitination Lys58 AVAYAPKkELINIKG -1 25585578 YES miannu The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64. 0.271 SIGNOR-272453 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 15611135 YES gcesareni We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. 0.261 SIGNOR-132559 SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 NO miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.7 SIGNOR-270609 PRKCE protein Q02156 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG 9606 23123196 YES miannu Monoubiquitylated PKC\u03b5 interacts with a ubiquitin-binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKC\u03b5 phosphorylates IKK\u03b2 at Ser177 and activates IKK\u03b2.|These results indicate that PKCepsilon phosphorylates IKKbeta at S177 and activates IKKbeta, which in turn induces PKM2 upregulation. 0.546 SIGNOR-278323 COPS2 protein P61201 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.923 SIGNOR-270772 PPM1D protein O15297 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity dephosphorylation Thr543 IDEDGENtQIEDTEP 9606 31619012 YES miannu In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. 0.393 SIGNOR-277046 PPP1CC protein P36873 UNIPROT CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 21533037 YES amattioni Pp1 is an activator of cdk9. Pp1 dephosphorylates cdk9 thr186. 0.2 SIGNOR-173454 BCL7C protein Q8WUZ0 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.505 SIGNOR-269780 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr45 LIGKVDGtSHVTGKG -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.298 SIGNOR-263582 ORC3 protein Q9UBD5 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 YES lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA 0.955 SIGNOR-267565 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-257976 COPS7A protein Q9UBW8 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 YES miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. 0.917 SIGNOR-270771 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation -1 9525907 YES inferred from 70% family members miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. 0.2 SIGNOR-270058 MFN1 protein Q8IWA4 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 NO lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria 0.7 SIGNOR-272984 NEK7 protein Q8TDX7 UNIPROT TERF1 protein P54274 UNIPROT up-regulates quantity phosphorylation Ser114 AIIHGLSsLTACQLR 9606 28216227 YES miannu Furthermore, we found that Nek7 overexpression could enhance TRF1 protein expression (XREF_FIG), suggesting that Nek7 may regulate TRF1 expression either at the transcription or posttranscriptional levels.|We show that Nek7 phosphorylates TRF1 at Ser114 and in turn maintains stability of the shelterin complex at telomeres. 0.343 SIGNOR-278448 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates quantity by stabilization 9606 27141364 NO irozzo EML4-ALK enhanced HIF-1Œ± expression through increasing transcription and decreasing ubiquitination of HIF-1Œ±. 0.2 SIGNOR-259173 NUMA1 protein Q14980 UNIPROT TUBB4A protein P04350 UNIPROT up-regulates binding 9606 11956313 YES miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. 0.4 SIGNOR-117025 CACNA2D3 protein Q8IZS8 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31746409 NO miannu Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells. 0.7 SIGNOR-266855 PRKCD protein Q05655 UNIPROT CYBA protein P13498 UNIPROT up-regulates phosphorylation Thr147 ERPQIGGtIKQPPSN -1 19948736 YES Manara Phosphorylation of p22phox on threonine 147 enhances NADPH oxidase activity by promoting p47phox binding. | Threonine 147 of p22phox Is Phosphorylated by PKC-α and PKC-δ in Vitro 0.2 SIGNOR-260892 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine smallmolecule CHEBI:44811 ChEBI PTAFR protein P25105 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257567 Isradipine chemical CHEBI:6073 ChEBI CACNA1C protein Q13936 UNIPROT down-regulates activity chemical inhibition 9606 10072735 YES miannu The protein expression as measured by3H-(+)-PN 200-110-binding (Bmax) and Western Blot analysis withcalsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both werereduced in atrial compared to ventricular tissue in failing and non-failing hearts. The KDremained unchanged. 0.8 SIGNOR-259076 Sumanirole maleate chemical CID:9818478 PUBCHEM DRD2 protein P14416 UNIPROT up-regulates chemical activation 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207594 WWC1 protein Q8IX03 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity 9606 BTO:0000007 20159598 NO Hippo pathway Gianni These results shed light on the mechanism of Ex and Mer function and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis. 0.443 SIGNOR-269951 BRIP1 protein Q9BX63 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity binding 9606 BTO:0000093;BTO:0003323 11301010 YES irozzo BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. Moreover, BACH1 likely contributes to the DNA repair function of BRCA1 []. 0.795 SIGNOR-259185 PLK1 protein P53350 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity phosphorylation 9606 31597699 YES miannu As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1.|These results demonstrate that NOTCH1 protects cells from DNA damage\u2013induced arrest and that PLK1-mediated degradation of NOTCH1 may be essential for recovery from a DNA damage-induced arrest. 0.402 SIGNOR-279096 CAMK2A protein Q9UQM7 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT down-regulates activity phosphorylation Thr591 LKQGYNKtLLRLRLR -1 37193065 YES miannu CaM inhibits the function of TRPP3 through promoting CaMK2's phosphorylation towards T591 on TRPP3. 0.2 SIGNOR-277812 NFY complex SIGNOR-C1 SIGNOR CCNB2 protein O95067 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10086339 NO gcesareni In this study, we analysed the mechanisms leading to activation of the cyclin b2 ccaat boxes: a combination of (i) genomic footprinting, (ii) transfections with single, double and triple mutants, (iii) emsas with nuclear extracts, antibodies and nf-y recombinant proteins and (iv) transfections with an nf-ya dominant negative mutant established the positive role of the three ccaat sequences and proved that nf-y plays a crucial role in their activation. 0.361 SIGNOR-65638 PRKCQ protein Q04759 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 YES lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. 0.291 SIGNOR-249290 MDM2 protein Q00987 UNIPROT NUB1 protein Q9Y5A7 UNIPROT up-regulates activity ubiquitination Lys159 KAMVLELkQSEEDAR 9606 28099510 YES miannu Our results rather suggest that Mdm2 specifically ubiquitinates NUB1 on lysine 159 and that this modification is required for NUB1 functions.|We conclude that Mdm2 acts as a positive regulator of NUB1 function, by modulating NUB1 ubiquitination on lysine 159. 0.276 SIGNOR-278556 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation Ser768 LQARRRQsVLNLMTH 9606 19095655 YES Luana AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as "inhibitory" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions 0.492 SIGNOR-259867 TCL1A protein P56279 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 10983986 YES miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation 0.502 SIGNOR-81434 CHD8 protein Q9HCK8 UNIPROT TYMS protein P04818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 19255092 YES miannu In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes. 0.283 SIGNOR-268805 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10558990 YES lperfetto The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. 0.396 SIGNOR-180910 EEF1A2 protein Q05639 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269538 MED16 protein Q9Y2X0 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.79 SIGNOR-266671 NR3C1 protein P04150 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 NO gcesareni Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b. 0.324 SIGNOR-132251 GOLGB1 protein Q14789 UNIPROT GOLGA2 protein Q08379 UNIPROT up-regulates activity binding 9606 23555793 YES miannu The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane. 0.768 SIGNOR-261238 MARCHF7 protein Q9H992 UNIPROT IQCB1 protein Q15051 UNIPROT down-regulates quantity by destabilization ubiquitination Lys48 LGSSELKkIKQDIYC 9606 28498859 YES miannu MARCH7 induces K48 ubiquitination of NPHP5 and protein degradation, while BBS11 triggers K63 ubiquitination and protein delocalization.|Unlike the catalytically inactive mutant , wild type MARCH7 was able to trigger NPHP5 ubiquitination (XREF_FIG). 0.2 SIGNOR-278585 CBL protein P22681 UNIPROT NCK1 protein P16333 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 24287595 YES miannu Taken together, these results show that lysine 178 in Nck1 is the acceptor site for ubiquitin transferred by c-Cbl, and that the ubiquitination of Nck1 by c-Cbl is blocked in the presence of synaptopodin. 0.643 SIGNOR-278606 TACR3 protein P29371 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.45 SIGNOR-257267 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA5 protein Q9Y5G8 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265695 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser266 FGYGGRAsDYKSAHK -1 2413024 YES lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. 0.49 SIGNOR-248873 sorafenib tosylate chemical CHEBI:50928 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 16757355 YES miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. 0.8 SIGNOR-259223 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCGR2B protein P31994 UNIPROT up-regulates activity 9606 BTO:0000801 25475856 NO lperfetto Low affinity-activating Fcgamma receptors (FcgammaRs) that bind immune complexes are controlled by a single inhibitory receptor, FcgammaRIIb (CD32b). 0.7 SIGNOR-249522 ACTA2 protein P62736 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 11988769 NO miannu It has subsequently been shown that most myofibroblasts express α-SM actin (the actin isoform typically found in vascular SM cells)13,14 and that the expression of α-SM actin and collagen type I in these cells is coordinately regulated by transforming growth factor β1 (TGF-β1)15. All these observations indicate that the myofibroblast has a role in the synthesis of ECM and in force generation, which results in ECM reorganization and wound contraction 0.7 SIGNOR-277682 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 YES miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. 0.817 SIGNOR-252355 RPL7 protein P18124 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.864 SIGNOR-262455 KCNQ2 protein O43526 UNIPROT KCNQ3 protein O43525 UNIPROT up-regulates activity binding 10116 BTO:0000938 9836639 YES The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current. 0.514 SIGNOR-268833 TPI1 protein P60174 UNIPROT glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI down-regulates quantity chemical modification 9606 16051738 YES miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). 0.8 SIGNOR-266491 VAV1 protein P15498 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates 9606 BTO:0000782 10725744 NO lperfetto Vav synergizes with protein kinase c theta to mediate il-4 gene expression in response to cd28 costimulation in t cells 0.62 SIGNOR-75827 BRCA1 protein P38398 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 15549093 NO lperfetto The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination 0.7 SIGNOR-251499 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 11971971 YES lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. 0.758 SIGNOR-244776 RXRA protein P19793 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11237216 YES gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology 0.596 SIGNOR-105345 masitinib chemical CHEBI:63450 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258246 WSB1 protein Q9Y6I7 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates ubiquitination 9606 18093972 YES lperfetto Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by wd40 repeat/socs box protein wsb-1 0.569 SIGNOR-160032 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. 0.75 SIGNOR-267969 DOK1 protein Q99704 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.2 SIGNOR-257699 CDKN2A protein P42771 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 10022885 YES gcesareni However, induction of p16(ink4a) also causes marked inhibition of cdk2 activity. 0.48 SIGNOR-64431 MRTFA protein Q969V6 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 YES gcesareni Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf. 0.2 SIGNOR-174264 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000725 21389315 NO irozzo Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair. 0.7 SIGNOR-255873 RPS6KB1 protein P23443 UNIPROT RPS6 protein P62753 UNIPROT up-regulates activity phosphorylation Ser235 IAKRRRLsSLRASTS 10090 15809305 YES lperfetto A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size. 0.937 SIGNOR-135172 hsa-miR-9-5p mirna URS00004208C5_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005855 24141785 YES We demonstrated for the first time that miR-9 functions as a tumor-suppressive miRNA in OSCC via targeting CXCR4 and inhibiting the Wnt/β-catenin signaling pathway 0.4 SIGNOR-277950 CTNNB1 protein P35222 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity 9606 16510874 NO Luana Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. 0.2 SIGNOR-260448 Ub:E2 complex SIGNOR-C497 SIGNOR PEX10 protein O60683 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271040 MCOLN1 protein Q9GZU1 UNIPROT Lysosome fusion phenotype SIGNOR-PH231 SIGNOR up-regulates 9606 39000072 NO miannu The fusion of matured macropinosomes with lysosomes is promoted by TRPML1, and degradation of macropinosomes is inhibited by mTORC1. 0.7 SIGNOR-277788 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264925 JAK2 protein O60674 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Tyr158 Y-->S 9606 BTO:0000938 32599005 YES lperfetto JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation|Patch-clamp electrophysiology revealed that through Y158, JAK2 controls FGF14-dependent modulation of Nav1.6 channels. In hippocampal CA1 pyramidal neurons, the JAK2 inhibitor Fedratinib reduced firing by a mechanism that is dependent upon expression of FGF14. 0.2 SIGNOR-275747 TCL1B protein O95988 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES lperfetto In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation. 0.671 SIGNOR-244452 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val76 LTGKLTTvFLPIVYT -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 0.374 SIGNOR-263601 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr285 AVNPPTMtPDMRSIT 9606 BTO:0000567 26183396 YES miannu In this study, we found that Cdk1 (Cyclin-dependent kinase 1) directly phosphorylated TAZ on six novel sites independent of the Hippo pathway, which further resulted in TAZ degradation through proteasome system. 0.258 SIGNOR-276925 PIP4K2A protein P48426 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity chemical modification 9606 9367159 YES Gianni The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K 0.8 SIGNOR-268864 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid chemical CHEBI:125628 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194527 F2RL1 protein P55085 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.454 SIGNOR-257408 IFNL3 protein Q8IZI9 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 12469119 YES gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. 0.847 SIGNOR-96246 Ub:E2 complex SIGNOR-C497 SIGNOR HECW1 protein Q76N89 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271302 INS protein P01308 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates 9606 15209375 NO gcesareni The interaction ofinsulin and growth factors with their receptors on the outside surface of a cell, leads to the activation of phosphatidylinositol 3-kinase (pi 3-kinase) and generation of the phosphatidylinositol 3,4,5-trisphosphate (ptdins(3,4,5)p3) second messenger at the inner surface of the cell membrane. 0.335 SIGNOR-126063 PPP2CB protein P62714 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation 9606 8650155 YES gcesareni These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity 0.507 SIGNOR-252636 AURKB protein Q96GD4 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Ser894 RYHKRTSsAVWNSPP 9606 12925766 YES gcesareni Human incenp was a substrate of aurora b and mass spectrometry identified three consecutive residues (threonine 893, serine 894, and serine 895) containing at least two phosphorylation sites. 0.974 SIGNOR-118015 GRM7 protein Q14831 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 YES miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. 0.356 SIGNOR-264080 TLN1 protein Q9Y490 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.753 SIGNOR-257612 NFIA protein Q12857 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 32991581 YES brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, 0.246 SIGNOR-263982 PRPF4B protein Q13523 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates phosphorylation 9606 17513757 YES flangone Using yeast two-hybrid screening of a human thymus cdna library, prp4, a serine/threonine protein kinase, was identified as a klf13-binding protein...coexpression of prp4 and klf13 increases nuclear localization of klf13 and ccl5 transcription. 0.343 SIGNOR-154951 BTK protein Q06187 UNIPROT WIPF1 protein O43516 UNIPROT up-regulates activity phosphorylation Tyr468 DLPPPEPyVQTTKSY 9606 25413351 YES lperfetto Based on previous reports and the present data we suggest that Btk can induce WASP activation and also facilitates its subsequent inactivation through WIP phosphorylation.|We confirmed that Btk can indeed phosphorylate Y468 of baculovirus-generated human His-tagged WIP ( xref ), but that this is more difficult to show in cell extracts where WIP would be purified along with cellular WASP (). 0.54 SIGNOR-279801 PLK1 protein P53350 UNIPROT SUGT1 protein Q9Y2Z0 UNIPROT up-regulates activity phosphorylation Ser331 VKRAMNKsFMESGGT 9606 22869522 YES lperfetto Plk1 phosphorylates Sgt1 at the kinetochores to promote timely kinetochore-microtubule attachment|Plk1 is required for the kinetochore localization of Sgt1 and phosphorylates serine 331 of Sgt1 at the kinetochores. This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone 0.438 SIGNOR-265222 KCTD10 protein Q9H3F6 UNIPROT CEP97 protein Q8IW35 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0004790 30404837 YES miannu Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation. we identified the cullin-3-RBX1-KCTD10 complex as the E3 ligase that mediates CEP97 degradation and removal from the mother centriole. 0.2 SIGNOR-272923 G3BP1 protein Q13283 UNIPROT DDX58 protein O95786 UNIPROT up-regulates quantity 9606 31827077 NO miannu We further identified that G3BP1 is able to interact with RIG-I and boost its expression. RIG-I expression could be stabilized by G3BP1 via antagonizing RNF125-mediated RIG-I degradation. Secondly, we demonstrated that G3BP1 potentiates the self-association and auto-ubiquitination of RNF125. Hence, it is more likely that G3BP1 first promotes RNF125 degradation by enhancing self-association and auto-ubiquitination of RNF125, and then RIG-I degradation mediated by RNF125 is alleviated 0.338 SIGNOR-261319 EN2 protein P19622 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. 0.417 SIGNOR-265801 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000007 17035229 YES SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity 0.514 SIGNOR-248794 FERMT2 protein Q96AC1 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 9606 BTO:0000007 26037143 YES miannu Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. 0.782 SIGNOR-266108 COL4A6 protein Q14031 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 YES Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) 0.7 SIGNOR-254670 ATM protein Q13315 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser33 ASGDYKYsGRDSLIF 9606 BTO:0001546 26337656 YES done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. 0.712 SIGNOR-274021 CAMK2A protein Q9UQM7 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates activity phosphorylation Ser230 PKYSRQFsLEHVHGS BTO:0000664 11447121 YES llicata Ser230 is located in the regulatory domain of HSF1, and promotes the magnitude of the inducible transcriptional activity. Ser230 lies within a consensus site for calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII overexpression enhances both the level of in vivo Ser230 phosphorylation and transactivation of HSF1. The importance of Ser230 was further established by the S230A HSF1 mutant showing markedly reduced activity relative to wild-type HSF1 when expressed in hsf1(-/-) cells. 0.511 SIGNOR-250631 GDNF protein P39905 UNIPROT ALCAM protein Q13740 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 NO miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. 0.2 SIGNOR-252177 PHF3 protein Q92576 UNIPROT POLR2A protein P24928 UNIPROT down-regulates activity binding 9606 BTO:0000007 phosphorylation:Ser1594 GAMSPSYsPTSPAYE 34667177 YES miannu PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2 0.461 SIGNOR-266965 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273074 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding -1 3142692 YES irozzo The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun. 0.952 SIGNOR-256365 STOML2 protein Q9UJZ1 UNIPROT ATP smallmolecule CHEBI:15422 ChEBI up-regulates quantity 9606 20359165 NO Giorgia In addition, mitochondrial and whole-cell ATP levels in resting SLP-2hi T cells were significantly higher than those in SLP-2lo T cells (P < 0.05) (Fig. 7d). Such an increase in ATP levels in SLP-2hi T cells correlated with increased resistance to depletion of mitochondrial ATP with oligomycin 0.8 SIGNOR-260384 tacedinaline chemical CHEBI:90195 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 YES Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). 0.8 SIGNOR-258009 CGP-42112A chemical CHEBI:147302 ChEBI AGTR2 protein P50052 UNIPROT down-regulates activity chemical inhibition -1 32278693 YES Luana CGP42112A is an angiotensin AT2 (Angiotensin receptor 2) receptor agonist that may alleviate the virus-induced lung injury 0.8 SIGNOR-262311 TFEB protein P19484 UNIPROT SGSH protein P51688 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.314 SIGNOR-276546 PAK1 protein Q13153 UNIPROT TBCB protein Q99426 UNIPROT up-regulates phosphorylation Ser128 VRSFLKRsKLGRYNE 9606 BTO:0000150 15831477 YES lperfetto P21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor b. Pak1 directly phosphorylated tcob in vitro and in vivo on serines 65 and 128 and colocalized with tcob on newly polymerized microtubules and on centrosomes. Pak1 phosphorylation is necessary for normal tcob function 0.449 SIGNOR-135460 levomethadone chemical CHEBI:136003 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258808 SOCS3 protein O14543 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity binding 9606 24600449 YES miannu The ability of SOCS3 to simultaneously bind to JAK and to the cytokine receptor explains the specificity of the suppression. SOCS3 binds JAK and gp130 receptor simultaneously, using two opposing surfaces: while the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by the gp130 receptor, a subdomain in the SH2 domain of SOCS3 is also required for inhibition of JAK, binding in a phospho-independent manner to a non-canonical surface of JAK2 (58, 59). The KIR of SOCS3 occludes the substrate-binding groove on JAK2. 0.795 SIGNOR-255329 NPR1 protein P16066 UNIPROT ORM1 protein P02763 UNIPROT up-regulates activity phosphorylation 9606 23363605 YES miannu On TORC1 inhibition by rapamycin treatment or nutrient limitation, Npr1 phosphorylates and activates Orm1 and Orm2, which in turn promotes synthesis of complex sphingolipids downstream of SPT.|Thus Npr1 directly phosphorylates Orm1 and Orm2 downstream of TORC1. 0.2 SIGNOR-278966 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI PHF2 protein O75151 UNIPROT up-regulates activity chemical activation 29981745 YES lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. 0.8 SIGNOR-273464 TFEB protein P19484 UNIPROT ATP6V1H protein Q9UI12 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 NO Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. 0.304 SIGNOR-276535 MAOA protein P21397 UNIPROT (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 YES Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. 0.8 SIGNOR-269745 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT down-regulates activity binding 9606 15618519 YES lperfetto Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. .Ptch Exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms. 0.942 SIGNOR-132675 MAPK1 protein P28482 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser664 QLPYYYLsPDRIPNS 9606 BTO:0000567 12670876 YES lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. 0.381 SIGNOR-264409 PPEF1 protein O14829 UNIPROT PDCD5 protein O14737 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser119 NRRKVMDsDEDDDY 9606 28051100 YES lperfetto Here, we report that the serine/threonine phosphatase PPEF-1 interacts with and dephosphorylates PDCD5 at Ser 119, which leads to PDCD5 destabilization.|These results demonstrate that PPEF-1 reduces PDCD5 stability via PDCD5 dephosphorylation. 0.349 SIGNOR-277008 GNAO1 protein P09471 UNIPROT HES1 protein Q14469 UNIPROT down-regulates 9606 BTO:0006001 39580518 YES Marta Tosoni GNAO1 overexpression enhances GSC differentiation by downregulating neural progenitor gene HES1 0.2 SIGNOR-278092 CEBPA protein P49715 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates 9606 11283671 NO apalma We previously reported that the transcription factor C/EBPα is sufficient to induce granulocytic differentiation in multipotential precursor cells, and that Cebpa -knockout mice have a selective block in granulocyte maturation 0.7 SIGNOR-255674 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR EB1/MLL protein Q5UEC6 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 27641145 YES miannu Indeed, KLHL21 localizes to FA structures preferentially at the leading edge, and in complex with Cul3, ubiquitylates EB1 within its microtubule-interacting CH-domain. Cells lacking CRL3(KLHL21) activity or expressing a non-ubiquitylatable EB1 mutant protein are unable to migrate and exhibit strong defects in FA dynamics, lamellipodia formation and cortical plasticity. Our study thus reveals an important mechanism to regulate cortical dynamics during cell migration that involves ubiquitylation of EB1 at focal adhesions. 0.2 SIGNOR-272409 NR0B2 protein Q15466 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17909097 NO gcesareni As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells 0.2 SIGNOR-158065 PTPN12 protein Q05209 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity dephosphorylation 9606 25666508 YES miannu Integrin-bound PTP-PEST dephosphorylates RhoGDI1.|Translocation of Src phosphorylated RhoGDI1 to the cell 's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1 and Cdc42 in the cytoplasm.|Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. 0.2 SIGNOR-277175 BAK1 protein Q16611 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 18097445 NO gcesareni This process of mitochondrial outer membrane permeabilization (momp) results in the release of cycs. It is commonly thought that bax and bak form pores in membranes 0.564 SIGNOR-160036 APC-c complex SIGNOR-C150 SIGNOR CCNA2 protein P20248 UNIPROT down-regulates quantity by destabilization ubiquitination 21596315 YES lperfetto Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B. 0.557 SIGNOR-265050 FBXL6 protein Q8N531 UNIPROT TKT protein P29401 UNIPROT up-regulates activity ubiquitination 9606 BTO:0001950 37653031 YES miannu Mechanistically, VRK2 promoted Thr287 phosphorylation of TKT and then recruited FBXL6 to promote TKT ubiquitination and activation.  0.2 SIGNOR-277843 NELFE protein P18615 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 YES miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. 0.904 SIGNOR-271400 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu66 NLERECMeEKCSFEE 10090 BTO:0001103 11133752 YES lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. 0.682 SIGNOR-263690 MAP3K7 protein O43318 UNIPROT RAB1A protein P62820 UNIPROT up-regulates activity phosphorylation Thr75 AGQERFRtITSSYYR -1 27482120 YES miannu TAK1 preferentially phosphorylates the inactive (GDP-bound) state of Rab1. Phosphorylation of Rab1 disrupts interaction with GDP dissociation inhibitor 1 (GDI1), but not guanine exchange factor (GEF) or GTPase-activating protein (GAP) enzymes, and is exclusive to membrane-localized Rab1, suggesting phosphorylation may stimulate Rab1 membrane association. Furthermore, we found phosphorylation of Rab1 at T75 to be essential for Rab1 function. 0.2 SIGNOR-277270 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 23584478 YES lperfetto Glycogen synthase kinase-3_ positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1We found that GSK-3_ phosphorylates and inactivates 4E-BP1, thereby increasing eIF4E-dependent protein synthesis. 0.364 SIGNOR-201699 Ub:E2 complex SIGNOR-C497 SIGNOR BRAP protein Q7Z569 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271112 TFIIH complex SIGNOR-C457 SIGNOR RARA protein P10276 UNIPROT unknown phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 11955452 YES llicata Thus, we demonstrate that the cdk7 kinase of tfiih phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes. 0.269 SIGNOR-269332 FOXO1 protein Q12778 UNIPROT AGRP protein O00253 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28270795 NO miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. 0.439 SIGNOR-263501 NEK10 protein Q6ZWH5 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Tyr327 KKPLDGEyFTLQIRG 9606 32561851 YES miannu  Here, we describe a function for NEK10 in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10 loss increases cellular proliferation by modulating the p53-dependent transcriptional output. NEK10 directly phosphorylates p53 on Y327, revealing NEK10's unexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response. 0.256 SIGNOR-273881 STX17-VAMP8 SNARE complex complex SIGNOR-C551 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates activity 9606 BTO:0000007 23217709 NO miannu Here, we identify syntaxin 17 (Stx17) as the autophagosomal SNARE required for fusion with the endosome/lysosome. Stx17 localizes to the outer membrane of completed autophagosomes but not to the isolation membrane (unclosed intermediate structures); for this reason, the lysosome does not fuse with the isolation membrane. Stx17 interacts with SNAP-29 and the endosomal/lysosomal SNARE VAMP8. 0.7 SIGNOR-273712 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 17589504 YES lperfetto Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy 0.786 SIGNOR-156409 LPAR4 protein Q99677 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257057 CBM complex SIGNOR-C555 SIGNOR T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 35230873 NO miannu The CBM complex not only induces a productive immune response in activated effector T cells but also controls peripheral tolerance by promoting the development and function of regulatory T (Treg) cells  0.7 SIGNOR-276297 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258793 EXOC2 protein Q96KP1 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.927 SIGNOR-270777 PAK6 protein Q9NQU5 UNIPROT AIFM1 protein O95831 UNIPROT down-regulates activity phosphorylation Thr281 GAEVKSRtTLFRKIG 9606 33867848 YES miannu Furthermore, PAK5 phosphorylates AIF at Thr281 site to inhibit the formation of AIF/importin \u03b13 complex, leading to decrease AIF nuclear translocation.|These results suggested that PAK5 can inhibit AIF from entering the nucleus and prevent caspase- independent apoptosis. 0.2 SIGNOR-278969 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser178 EENVSDGsPNAGSVE 9606 10831586 YES lperfetto Indeed, p27kip1 was phosphorylated by p42 mapk (erk2) in vitrothese results suggest that ser(10) is the major site of phosphorylation of p27(kip1) and that phosphorylation at this site, like that at thr(187), contributes to regulation of p27(kip1) stability. 0.2 SIGNOR-244517 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 7535770 YES gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. 0.333 SIGNOR-28059 SF3B1 protein O75533 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 YES miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription 0.432 SIGNOR-268819 D-fructofuranose 6-phosphate(2-) smallmolecule CHEBI:61527 ChEBI 2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-) smallmolecule CHEBI:58725 ChEBI up-regulates quantity precursor of 9606 21310273 YES miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans 0.8 SIGNOR-268098 RAD21 protein O60216 UNIPROT GATA2 protein P23769 UNIPROT down-regulates activity relocalization 9606 BTO:0001545 26607380 YES miannu Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity. 0.326 SIGNOR-261513 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT down-regulates activity phosphorylation Ser696 TTVGRSFsLSWRSHP 10090 SIGNOR-C469 21148297 YES miannu RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase 0.452 SIGNOR-269798 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser436 TNGSIGHsPLSLSAQ 9606 BTO:0000938 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.542 SIGNOR-204700 FBXO32 protein Q969P5 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 20871233 NO Atrogin-1, but not MuRF-1, was induced at both the gene and protein level as ApcMin/+ mice aged from 3 to 6 months of age, going from a pre-cachectic to a cachectic state. Atrogin-1 mRNA and protein levels were also elevated in ApcMin/+ mice when we over-expressed IL-6 in the circulation. 0.7 SIGNOR-255341 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization ubiquitination Lys57 KSLIVEGkREKKKVE 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. This result aligns well with the observation that multiple ubiquitylated DEK lysine residues were detected in the initial proteome analysis (fig. S2E). 0.3 SIGNOR-272828 HRH2 protein P25021 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.453 SIGNOR-256777 DCAF1 protein Q9Y4B6 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates activity binding 9606 BTO:0000007 18332868 YES miannu VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation. 0.2 SIGNOR-271675 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK -1 25624455 YES miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. 0.307 SIGNOR-254725 CHD8 protein Q9HCK8 UNIPROT SOX3 protein P41225 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 YES Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells 0.2 SIGNOR-268920 IKBKB protein O14920 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity phosphorylation 9606 19488402 YES miannu We present evidence for a signaling network that involves phosphorylation and reduction of Bcl-xL by IKKbeta, and subsequent activation of caspases, which can cleave Htt.|We propose that IKKbeta reduces Bcl-xL levels by phosphorylation (XREF_FIG), a modification known to promote Bcl-xL degradation . 0.339 SIGNOR-279529 NEIL1 protein Q96FI4 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 NO lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). 0.7 SIGNOR-275718 PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 22724072 YES llicata We show that human pink1 is specifically activated by mitochondrial membrane potential (??m) depolarization, enabling it to phosphorylate parkin at ser(65). We further show that phosphorylation of parkin at ser(65) leads to marked activation of its e3 ligase activity that is prevented by mutation of ser(65) or inactivation of pink1. 0.2 SIGNOR-197976 CCL7 protein P80098 UNIPROT Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 NO miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. 0.7 SIGNOR-260850 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM23 protein P36406 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271002 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT up-regulates quantity by stabilization phosphorylation Ser627 VKLFSGLsVSSEGPS 9606 15987997 YES miannu Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life. 0.75 SIGNOR-262649 KDM2B protein Q8NHM5 UNIPROT CDK1 protein P06493 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000011 25533466 NO miannu We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis. 0.28 SIGNOR-252244 CSNK2A2 protein P19784 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Thr89 AAPEEAEtLAETEPE 9606 BTO:0001130 16581776 YES llicata In vitro kinase assays followed by mass spectrometric analyses demonstrated that ck2 phosphorylated recombinant nkx3.1 on thr89 and thr93. We have also determined that nkx3.1 is degraded primarily through a proteasomal pathway, suggesting that phosphorylation by ck2 protects nkx3.1 from degradation. 0.315 SIGNOR-145501 FOXO proteinfamily SIGNOR-PF27 SIGNOR CITED2 protein Q99967 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18158893 NO gcesareni Foxo3a induces expression of cited2 0.2 SIGNOR-252933 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL20 protein P78556 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 31561620 YES miannu CCL20 is a NF-κB target gene in PDAC cells. 0.302 SIGNOR-278041 GSK3B protein P49841 UNIPROT BICD1 protein Q96G01 UNIPROT up-regulates activity phosphorylation Ser585 SEPVAKEsTEASKEP 9606 BTO:0000567 17139249 YES miannu Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein. 0.332 SIGNOR-262743 RBBP8 protein Q99708 UNIPROT SPEN protein Q96T58 UNIPROT down-regulates binding 9606 16287852 YES gcesareni We identify the ctip and ctbp corepressors as novel components of the human rbp-jk/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. 0.541 SIGNOR-141616 IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity binding 9606 BTO:0001271 15895091 YES miannu A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes. 0.869 SIGNOR-48041 BECN1 protein Q14457 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 YES lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. 0.906 SIGNOR-260319 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2H protein P62256 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.756 SIGNOR-271328 KLF9 protein Q13886 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 YES miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. 0.446 SIGNOR-222434 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 10581258 YES lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. 0.772 SIGNOR-72699 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 11460167 YES lperfetto Tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a 0.729 SIGNOR-217445 arformoterol chemical CHEBI:408174 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation -1 20655218 YES Luana Table 1. Human β2- and β1-adrenoceptor binding and calculated log D7.4 values for formoterol, indacaterol, salmeterol, S1319 and the representative library members 11–41 0.8 SIGNOR-257882 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 10090 BTO:0004052 14500898 YES irozzo This up-regulation required BCR-ABL tyrosine kinase activity and led to IL-3Rbetac/beta chain tyrosine phosphorylation in the absence of detectable IL-3 production. These results suggested that cytokine-independent IL-3 receptor activation could be a dominant signaling component in BCR-ABL-induced leukemogenesis. However, the IL-3Rβc/β chain could act as a cofactor in BCR-ABL-induced leukemogenesis by activation of its many known oncogenic signaling pathways. 0.2 SIGNOR-256123 DOK1 protein Q99704 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.2 SIGNOR-257694 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser50 TSTMPNSsQSSHSSS 9606 BTO:0000007 10973490 YES lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to iratm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro. 0.834 SIGNOR-81407 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr116 LASELAKtPQKSVSF 9606 11931757 YES lperfetto We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. 0.711 SIGNOR-217296 MMP8 protein P22894 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272398 Ub:E2 complex SIGNOR-C497 SIGNOR RFPL4AL1 protein F8VTS6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271254 NAA30 protein Q147X3 UNIPROT NatC complex SIGNOR-C417 SIGNOR form complex binding 9606 19398576 YES miannu We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation. 0.755 SIGNOR-267233 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 11904294 YES lperfetto We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation. 0.2 SIGNOR-244975 SMARCD3 protein Q6STE5 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 YES miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. 0.759 SIGNOR-270692 A5/b1 integrin complex SIGNOR-C163 SIGNOR JAG1 protein P78504 UNIPROT up-regulates quantity by expression 10090 25786978 NO lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. 0.305 SIGNOR-253288 NR3C1 protein P04150 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 9162033 YES gcesareni Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity. 0.545 SIGNOR-48516 Ub:E2 complex SIGNOR-C497 SIGNOR NEURL1B protein A8MQ27 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271252 ASH1L protein Q9NR48 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity trimethylation Lys37 APATGGVkKPHRYRP -1 21239497 YES Gianni We show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases 0.2 SIGNOR-269055 Calcineurin complex SIGNOR-C155 SIGNOR BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 YES Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. 0.434 SIGNOR-252324 SMAD6 protein O43541 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates 10090 BTO:0000165 10564272 NO gcesareni We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 0.736 SIGNOR-236861 EN1 protein Q05925 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 YES miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription 0.452 SIGNOR-265802 YES1 protein P07947 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Tyr391 PFLNSGTyHSRDEST 9606 BTO:0000578 35041461 YES miannu Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). 0.72 SIGNOR-277652 CD28 protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7737275 YES fspada In this study, we demonstrate that the co-stimulatory antigen cd28 binds to grb-2 by means of a cytoplasmic pymnm motif, which is the same motif bound by pi 3-kinase. 0.701 SIGNOR-32509 FBXL2 protein Q9UKC9 UNIPROT CCND2 protein P30279 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002268 22323446 YES miannu F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation. Purified SCF complex components were incubated with V5-cyclin D2 and the full complement of ubiquitination reaction components (second lane from left) showing polyubiquitinated cyclin D2. 0.422 SIGNOR-272006 PRKACA protein P17612 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Ser27 TSPTGRGsMAAPSLH 9606 11162439 YES llicata Serine 27, a human retinoid x receptor alpha residue, phosphorylated by protein kinase a is essential for cyclicamp-mediated downregulation of rxralpha function. 0.2 SIGNOR-104954 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 YES lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity 0.757 SIGNOR-182983 valproic acid chemical CHEBI:39867 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 11742974 YES Federica Here we show that VPA inhibits corepressor-associated HDACs at therapeutically employed concentrations and acts as a potent inducer of differentiation in several types of transformed cells. 0.8 SIGNOR-261078 MAX protein P61244 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity binding 9606 7954804 YES 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. 0.301 SIGNOR-240357 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr715 LVMLGASyWYRARLH 9606 11741929 YES lperfetto Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling. 0.355 SIGNOR-112919 ETV2 protein O00321 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24727028 NO miannu We have identified a novel positive feed-forward regulatory loop in which etv2 activates expression of genes involved in vasculogenesis, including fli1. 0.2 SIGNOR-203272 CDK8 protein P49336 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 23562092 YES miannu Biochemical analyses reveal that SREBP-1c can be directly phosphorylated by CDK8 at the conserved Threonine-402 residue (T402) in vitro and in cultured mammalian cells ( xref ).|Therefore, the mechanism of CDK8 regulating SREBP functions is primarily through the phosphorylation initiated control of nuclear SREBP-1 protein stability. 0.475 SIGNOR-279688 BLOC-3 complex SIGNOR-C253 SIGNOR RAB38 protein P57729 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23174301 YES lperfetto HPS1/HPS4 was active exclusively for RAB32 and RAB38. Moreover, when overexpressed with HPS1 in HeLa cells, a mitochondrially restricted form of HPS4 preferentially recruited GFP-tagged RAB32 or RAB38 – but not the related RAB7 or RAB9 – to mitochondria. Activity in both assays required both HPS1 and HPS4. Finally, depletion of HPS1 or HPS4 by siRNA in a pigmented human melanoma cell line, MNT-1, resulted in the mislocalization of RAB32. These data provide strong evidence that BLOC-3 is a selective GEF for RAB32 and RAB38  0.566 SIGNOR-260694 DNAJC15 protein Q9Y5T4 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 YES lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. 0.434 SIGNOR-267692 IFNG protein P01579 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 NO inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells grown in TSH-containing medium. These include TNF-a, IL-lb and INF-g but not TGF-b. 0.2 SIGNOR-267810 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr1102 MLEERKTyVNTTLYE 10090 BTO:0000944 12082108 YES lperfetto Recently, insights into Tie2 activation were provided by a solution of the Tie2 crystal structure (12). This structural analysis revealed several novel features, including two potential autoinhibitory mechanismsIn the unphosphorylated state, the hydroxyl groups of two important tyrosine residues, Tyr1101 and Tyr1112 (murine residue numbers), are hydrogen-bonded to surrounding residues, which may stabilize the C tail in this inhibitory conformationDeletion of the Tie2 C Tail Enhances Autophosphorylation and Kinase Activity in VitroDeletion of the C tail dramatically enhanced Tie2 autophosphorylation, despite the removal of Tyr1112, which was previously shown to be an important autophosphorylation site 0.2 SIGNOR-246657 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 YES lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikkepsilon And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. 0.741 SIGNOR-178363 CHUK protein O15111 UNIPROT ELAVL1 protein Q15717 UNIPROT down-regulates quantity by destabilization phosphorylation Ser304 EAAMAIAsLNGYRLG 9606 BTO:0001321 23115237 YES miannu Furthermore, mutational analysis indicates that IKKα-dependent phosphorylation at Ser-304 is crucial to the binding of HuR to β-TrCP1. Mechanistically, this HuR degradation pathway differs from that reported for heat shock and hypoxia, which underlies the complexity in the regulation of HuR turnover under different stress stimuli.  0.323 SIGNOR-276422 LAMC1 protein P11047 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR form complex binding 10809728 YES lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. 0.586 SIGNOR-253228 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 9606 10318826 YES miannu AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor. 0.593 SIGNOR-252380 HIPK2 protein Q9H2X6 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity phosphorylation 9606 20573984 YES miannu Furthermore, HIPK2 forms a complex with the coactivator p300 and AML1, phosphorylates p300 at multiple Serine/Threonine sites and activates p300 HAT activity and coactivator function. 0.61 SIGNOR-278943 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Ser231 GTENTFPsPKAIPNG 10090 12796778 YES llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. 0.771 SIGNOR-250676 LYN protein P07948 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity phosphorylation Tyr335 QLQGQDLyAIRLCQC 9606 BTO:0002181 27521268 YES miannu Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity. 0.329 SIGNOR-277248 PAK1 protein Q13153 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser23 WNLENRFsGWYDADL 9606 BTO:0000130 12189148 YES Activated pak1 gcesareni Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. 0.2 SIGNOR-91598 Activated PSC phenotype SIGNOR-PH224 SIGNOR IL6 protein P05231 UNIPROT up-regulates 9606 BTO:0000584 30996350 YES miannu IL6 has been implicated in PDAC, and all its family members, like LIF, bind to receptor complexes containing GP130 to activate similar signal cascades, such as the STAT3 pathway. In our initial screens, IL6 and IL11 were also found to be produced by PSCs 0.7 SIGNOR-278036 RBCK1 protein Q9BYM8 UNIPROT LUBAC complex SIGNOR-C527 SIGNOR form complex binding 9606 BTO:0000567 17006537 YES miannu Here, we report that a protein complex consisting of two RING finger proteins, HOIL-1L and HOIP, exhibits ubiquitin polymerization activity by recognizing ubiquitin moieties of proteins. The polyubiquitin chain generated by the complex is not formed by Lys linkages, but by linkages between the C- and N-termini of ubiquitin, indicating that the ligase complex possesses a unique feature to assemble a novel head-to-tail linear polyubiquitin chain. 0.946 SIGNOR-271615 EGFR protein P00533 UNIPROT CALM3 protein P0DP25 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 YES miannu Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. 0.382 SIGNOR-266335 NUP98 protein P52948 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.687 SIGNOR-262074 CAMK2A protein Q9UQM7 UNIPROT SYNGAP1 protein Q96PV0 UNIPROT up-regulates activity phosphorylation Ser779 FMARGLNsSMDMARL -1 14970204 YES miannu Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95%. The Major Phosphorylation Sites, Serines 764/765, 1058, and 1123, All Contribute to Regulation of GAP Activity of synGAP by CaMKII 0.43 SIGNOR-262689 MAPK3 protein P27361 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation Thr693 RELVEPLtPSGEAPN 9606 1651322 YES lperfetto It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation. 0.556 SIGNOR-20549 MYBL2 protein P10244 UNIPROT CLU protein P10909 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0000298 10770937 YES miannu Here we show that the human ApoJ/Clusterin gene contains a Myb binding site in its 5' flanking region, which interacts with bacterially synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the ApoJ/Clusterin promoter in transient transfection assays. Endogenous ApoJ/Clusterin expression is induced in mammalian cell lines following transient transfection of a B-MYB cDNA. 0.274 SIGNOR-269800 CHRM4 protein P08173 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.452 SIGNOR-256686 ACVR2B protein Q13705 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 10090 21966641 YES areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains 0.689 SIGNOR-254985 TAF12 protein Q16514 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 YES miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. 0.889 SIGNOR-263924 dobutamine chemical CHEBI:4670 ChEBI YAP1 protein P46937 UNIPROT down-regulates 9606 23431053 NO These results suggest that the activity of YAP/TAZ can be either up-regulated or down-regulated by GPCR signaling,depending on which Galfa protein is activated gcesareni Dobutamine is an agonist for the beta1 adrenergic receptor, which likely inhibits yap by activating gaalfas. 0.8 SIGNOR-201259 SPRY2 protein O43597 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates 9606 12234920 NO gcesareni Hspry2 prevents c-cbl-mediated ubiquitylation of egfrs. hspry2 interacts specifically with the c-cbl ring finger domain and displaces ubch7 from its binding site on the e3 ligase. 0.452 SIGNOR-92926 MAPK3 protein P27361 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser664 QLPYYYLsPDRIPNS 9606 BTO:0000567 12670876 YES lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. 0.328 SIGNOR-264440 KIT protein P10721 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 9606 BTO:0000830 15526160 NO miannu A number of studies have demonstrated the ability of SCF to activate the Ras-Erk pathway. The adapter protein Grb2 can directly associate with phosphorylated Y703 and Y936 in c-Kit 0.305 SIGNOR-254947 F2RL3 protein Q96RI0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 YES gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13) 0.406 SIGNOR-196015 SMAD1/4 complex SIGNOR-C85 SIGNOR BMP7 protein P18075 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 19896409 NO lperfetto BMPs first bind to and activate their transmembrane serine/threonine kinase receptors, which in turn phosphorylate the transcription factors Smad1/5/8 at its two C-terminal serines (SVS). Phosphorylated Smad1Cter binds to Smad4 (co-Smad) and translocates and accumulates in the nucleus, activating BMP-responsive genes (Fig. 2) [21] and [22], such as BMP4/7 and others. 0.561 SIGNOR-248843 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10116 26556953 YES lperfetto Expression of Dep1 in transformed rat thyroid PCMPSV cells increased Src activity via Y527 dephosphorylation (corresponding to Y530 in human Src) without affecting the level of phosphorylated Y416 (Y419 in human Src).|Reciprocally, Dep1 can be phosphorylated by Src and Fyn on Y1311 and Y1320, leading to the dephosphorylation of Y530 Src by Dep1 . 0.635 SIGNOR-276977 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT down-regulates phosphorylation Tyr561 ESYEGNSyTFIDPTQ 9606 BTO:0001271 15297464 YES lperfetto Csf-1-mediated wild-type (wt)-csf-1r phosphorylation was not markedly affected by sfk inhibition, indicating that lack of sfk binding is not responsible for diminished y559f phosphorylation. Unexpectedly, cells expressing y559f were hyperproliferative in response to csf-1. Hyperproliferation correlated with prolonged activation of akt, erk, and stat5 in the y559f mutant. Consistent with a defect in receptor negative regulation, c-cbl tyrosine phosphorylation and csf-1r/c-cbl co-association were almost undetectable in the y559f mutant. Furthermore, y559f underwent reduced multiubiquitination and delayed receptor internalization and degradation. In conclusion, we propose that tyr559 is a switch residue that functions in kinase regulation, signal transduction and, indirectly, receptor down-regulation. 0.2 SIGNOR-127622 YWHAQ protein P27348 UNIPROT CDC25C protein P30307 UNIPROT down-regulates relocalization 9606 20068082 YES gcesareni Cdc25c: nuclear exclusion/cytoplasmic sequestration via binding to 14-3-3 proteins. 0.574 SIGNOR-163237 LCK protein P06239 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity phosphorylation Tyr688 FAEPYNLySSLKELV 9534 BTO:0004055 9461588 YES The regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85. 0.601 SIGNOR-252699 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12777400 YES Manara These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386 0.404 SIGNOR-260770 CCKAR protein P32238 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 10088 BTO:0000944 12853286 YES Marta Tosoni Our studies indicate that CCK-A receptors inserted into NIH3T3 cells also activate RhoA through G12/13 0.25 SIGNOR-278062 CDC14A protein Q9UNH5 UNIPROT IREB2 protein P48200 UNIPROT up-regulates activity dephosphorylation Ser157 LQKAGKLsPVKVQPK 9606 18574241 YES IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis. 0.348 SIGNOR-248829 PTPN6 protein P29350 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity dephosphorylation Tyr421 RLPSSPVyEDAASFK 9606 34088320 YES lperfetto Shp1 interacts with cortactin and reduces cortactin phosphorylation at tyrosine 421; 3.|induction of Shp1-cortactin complex formation impairs cortactin scaffolding-activity and negatively affects invadopodia behaviour; 4. 0.2 SIGNOR-277003 beta-alanine smallmolecule CHEBI:16958 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 BTO:0000007 9009272 YES inferred from family member miannu For each mutant GlyR we examined the agonist efficacies of taurine and Œ≤-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where Œ≤-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human Œ±1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and Œ≤-alanine act as full agonists of human Œ±1 GlyRs when expressed in this system. 0.8 SIGNOR-270261 SRF protein P11831 UNIPROT PLG protein P00747 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15514113 NO miannu We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. 0.247 SIGNOR-255226 SHPRH protein Q149N8 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination 9606 19706603 YES gcesareni We provide evidence that similar to rad5, shprh physically interacts with the human rad6rad18 and mms2ubc13 protein complexes, and importantly, we show that it exhibits an ubiquitin ligase activity and mediates mms2ubc13-dependent polyubiquitylation of pcna. Thus, shprh is a functional homolog of rad5. 0.552 SIGNOR-187757 SHMT1 protein P34896 UNIPROT glycine zwitterion smallmolecule CHEBI:57305 ChEBI up-regulates quantity chemical modification 9606 11802770 YES miannu HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. 0.8 SIGNOR-269689 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Thr714 EESDSSEtEKEDDEG -1 21296876 YES miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis 0.2 SIGNOR-276250 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser60 PHVLEALsPPQTSGL 9606 SIGNOR-C3 20516213 YES fstefani The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. 0.711 SIGNOR-165791 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr463 MLAGVSEyELPEDPR 10116 BTO:0002809;BTO:0001009 8622701 YES lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 0.2 SIGNOR-236179 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM62 protein Q9BVG3 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270964 MED4 protein Q9NPJ6 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 YES miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. 0.818 SIGNOR-266675 NEK2 protein P51955 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 30266789 YES miannu NEK2 Phosphorylates p53 at Ser315 and Reduces Its Stability.|These results are consistent with NEK2 inhibiting p53 transcriptional activation functions. 0.319 SIGNOR-278488 BCL11A protein Q9H165 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20712774 NO Regulation miannu BCL11A maintains silencing of gamma-globin expression in adult erythroid cells and functions as a direct transcriptional regulator of the fetal to adult hemoglobin switch in humans. we found that BCL11A plays a central role in the evolutionarily divergent globin gene switches of mammals. As a factor critical for gamma-globin gene silencing, BCL11A should be considered as a therapeutic target to increase HbF in a directed manner in beta-thalassemia patients. 0.446 SIGNOR-251774 COL4A4 protein P53420 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 YES lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. 0.454 SIGNOR-253245 ceramide 1-phosphate(2-) smallmolecule CHEBI:84404 ChEBI PRKCA protein P17252 UNIPROT up-regulates activity chemical activation 9606 19948174 YES miannu Here we demonstrate that C1P induces translocation of protein kinase C-alpha (PKC-alpha) from the soluble to the membrane fraction of bone marrow-derived macrophages. 0.8 SIGNOR-268502 RAB4A protein P20338 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 YES lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 0.452 SIGNOR-260617 GNAQ protein P50148 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates binding 9606 8245028 YES gcesareni The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits. 0.767 SIGNOR-37149 POU5F1 protein Q01860 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22795133 YES lperfetto Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation 0.437 SIGNOR-253158 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 10579915 YES lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response toinsulinand nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. 0.755 SIGNOR-217060 Platelet_alpha_granule_formation phenotype SIGNOR-PH136 SIGNOR VWF protein P04275 UNIPROT up-regulates 9606 NBK559062 NO lperfetto Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VW|VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain. 0.7 SIGNOR-261863 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 BTO:0000142 10226025 YES acerquone Protein kinase b (pkb) is activated by phosphorylation of thr308 and of ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (pdk1) but the identity of the kinase that phosphorylates ser473 (provisionally termed pdk2) is unknown. 0.748 SIGNOR-67363 FZD3 protein Q9NPG1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 20828404 YES gcesareni Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades. 0.344 SIGNOR-167865 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 BTO:0000590 10090741 YES lperfetto We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. 0.595 SIGNOR-249316 RPS6KA3 protein P51812 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 9606 BTO:0000848 21087211 YES gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3) 0.2 SIGNOR-169887 STK11 protein Q15831 UNIPROT F2R protein P25116 UNIPROT up-regulates activity phosphorylation 9606 23271647 YES miannu LKB1 phosphorylates PAR-1 at the T408 site xref .|LKB1 thus positively regulates PAR-1 at the postsynapse. 0.2 SIGNOR-278992 NPC2 protein P61916 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity 9606 21084287 NO Giorgia Here we show that NPC2 deficiency in human fibroblasts confers their activation. The activation phenomenon was not limited to fibroblasts as it was also observed in aortic smooth muscle cells upon silencing NPC2 gene by siRNA. The molecular mechanism responsible for activation of NPC2-null cells was shown to be a sustained phosphorylation of ERK 1/2 mitogen-activated protein kinase (MAPK), which fulfills both the sufficient and necessary fibroblast activation criteria. All of these findings highlight a novel mechanism where NPC2 by negatively regulating ERK 1/2 MAPK phosphorylation may efficiently suppress development of maladaptive tissue remodeling and inflammation. 0.383 SIGNOR-260660 MAPK14 protein Q16539 UNIPROT USF1 protein P22415 UNIPROT up-regulates activity phosphorylation Thr153 EALLGQAtPPGTGQF 9606 19389701 YES lperfetto Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes 0.55 SIGNOR-185572 WNT5A protein P41221 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity 10090 BTO:0000887;BTO:0001103 9753670 NO gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. 0.292 SIGNOR-60376 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 YES gcesareni Evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 0.792 SIGNOR-252546 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 YES miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559 0.2 SIGNOR-277813 CCL5 protein P13501 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 10734056 YES In addition to the CCR1 receptor, RANTES activates several members of the CC subfamily of chemokine receptors including CCR3, CCR4, and CCR5 0.767 SIGNOR-254370 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr488 GAEDSGDtEDELRRV 9606 20471329 YES lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair 0.396 SIGNOR-165427 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 YES lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity 0.747 SIGNOR-236067 KDM4B protein O94953 UNIPROT AR protein P10275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23435229 NO miannu KDM4B enzymatic activity is required to enhance AR transcriptional activity 0.33 SIGNOR-254541 FGFR4 protein P22455 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates activity phosphorylation 10116 9182757 YES lperfetto In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. 0.684 SIGNOR-242661 NFIA protein Q12857 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 YES Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) 0.2 SIGNOR-268895 GNA13 protein Q14344 UNIPROT LATS1 protein O95835 UNIPROT down-regulates activity phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0002181 31569999 YES Marta Tosoni These findings suggest that Galpha13 induced phosphorilation of LATS1 at S909 recruits ITCH to trigger LATS1 degradation, leading to EMT-related phenotypes 0.2 SIGNOR-278051 QOCYWLABLBUJOR-UHFFFAOYSA-N chemical CID:53299324 PUBCHEM SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18487050 YES Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  0.8 SIGNOR-257796 MAPK1 protein P28482 UNIPROT KLC1 protein Q07866 UNIPROT down-regulates phosphorylation Ser460 YKACKVDsPTVTTTL 9606 21385839 YES gcesareni Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro. 0.271 SIGNOR-172638 MDM2 protein Q00987 UNIPROT GNAS protein P63092 UNIPROT down-regulates activity binding 9606 BTO:0000007 18948082 YES Marta Tosoni Western blotting showed that increased MDM2 expression decreased Gαs protein content in HEK293 cells (Fig. 4B). Taken together, these data indicate that MDM2 binds to Gαs and has a direct impact on Gαs protein content. 0.395 SIGNOR-278070 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr160 VEEDEDLyDCVENEE -1 10669745 YES Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function. 0.783 SIGNOR-251390 FGF12 protein P61328 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.264 SIGNOR-253436 SRC protein P12931 UNIPROT ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Tyr8 MAQFDTEyQRLEASY 9606 27934868 YES miannu Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. 0.342 SIGNOR-266367 STAT3 protein P40763 UNIPROT GAP43 protein P17677 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000099 26865625 YES miannu  In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-κB and signal transducer and activator of transcription 3-mediated transcriptional activation. 0.301 SIGNOR-266772 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0001950 21561061 YES Luana 3b Induces Phosphorylation of c-Jun (Ser-63) throughActivation of the JNK Pathway.| An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP 0.2 SIGNOR-260758 CSNK2A1 protein P68400 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates activity phosphorylation Ser347 LQAAVTMsLETVRND 9606 BTO:0000007 19542537 YES miannu Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs. 0.2 SIGNOR-276224 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 30017632 YES miannu Smad7 inhibits both transforming growth factor β (TGF-β)- and BMP-induced Smad signaling. Smad7 can use both surfaces in its interaction with the ALK-2, -3, and -4 receptors, but only the basic groove is used in the interaction between Smad7 and the TGF-β type I receptor (TβRI, also known as ALK-5). 0.788 SIGNOR-260438 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT up-regulates activity phosphorylation Ser650 SVHERYSsPTAGSAK 9606 12006580 YES llicata Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.  0.806 SIGNOR-250763 sirolimus chemical CHEBI:9168 ChEBI LILRB1 protein Q8NHL6 UNIPROT down-regulates quantity by repression 9606 18652845 NO miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. 0.8 SIGNOR-255476 KIT protein P10721 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 15526160 YES miannu C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit 0.613 SIGNOR-254954 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000815 18570872 YES miannu  In this report, we show that cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. We demonstrate that AEG40730, a compound modeled on BIR-binding tetrapeptides, binds to cIAP1 and cIAP2, facilitates their autoubiquitination and proteosomal degradation, and causes a dramatic reduction in RIP1 ubiquitination. We show that cIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. 0.767 SIGNOR-272638 SGCA protein Q16586 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.543 SIGNOR-255985 AR protein P10275 UNIPROT ZBTB46 protein Q86UZ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 30962287 YES miannu Our study confirmed a novel positive association between ZBTB46 activity and LIF levels in prostate cancer tissues and cells. Under androgen regulation, low levels of ZBTB46 are an essential transcriptional factor for maintaining LIF-STAT3 signaling, while the loss of androgen signaling or inhibition of AR signaling causes LIF-enhanced therapeutic resistance and CRPC characteristics through the upregulation of ZBTB46. We also found that LIF activation drives malignant progression and NE-like reprogramming in prostate cancer by activating STAT3 signaling. 0.2 SIGNOR-277989 PRKCB protein P05771 UNIPROT EWSR1 protein Q01844 UNIPROT down-regulates activity phosphorylation Ser266 SSYGQQSsFRQDHPS 9606 9341188 YES miannu Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation. 0.276 SIGNOR-52854 FIG4 protein Q92562 UNIPROT PAS complex complex SIGNOR-C190 SIGNOR form complex binding 9606 BTO:0000007 17556371 YES miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. 0.931 SIGNOR-253528 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR SUV39H1 protein O43463 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23435416 NO lperfetto In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation. Although not shown directly, the authors speculated that KMT1A levels may be regulated by PAX3-FOXO1, as KMT1A expression was only increased on induction of differentiation in PAX3-FOXO1 positive cell lines 0.2 SIGNOR-249598 PGAM5 protein Q96HS1 UNIPROT FUNDC1 protein Q8IVP5 UNIPROT up-regulates activity dephosphorylation 9606 BTO:0000567 24746696 YES miannu Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation. 0.626 SIGNOR-273654 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 9606 29544897 YES miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. 0.446 SIGNOR-259022 HTR1D protein P28221 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257116 ARHGAP39 protein Q9C0H5 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.5 SIGNOR-260494 AURKB protein Q96GD4 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 YES miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). 0.862 SIGNOR-275426 MLL3 complex complex SIGNOR-C446 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 34156443 YES miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. 0.2 SIGNOR-268810 USP25 protein Q9UHP3 UNIPROT TRiC complex SIGNOR-C539 SIGNOR up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 25755282 YES miannu Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.  0.2 SIGNOR-273583 ARFGAP1 protein Q8N6T3 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity gtpase-activating protein -1 10102276 YES The ARFGAP molecule binds to switch 2 and helix α3 to orient ARF1 residues for catalysis, but it supplies neither arginine nor other amino acid side chains to the GTPase active site. 0.862 SIGNOR-261915 RAB1A protein P62820 UNIPROT GOLGA2 protein Q08379 UNIPROT up-regulates activity relocalization 10116 11285137 YES Giulio Here, we demonstrate that the cis ‐Golgi tethering protein GM130, complexed with GRASP65 and other proteins, forms a novel Rab1 effector complex that interacts with activated Rab1‐GTP in a p115‐independent manner and is required for coat protein II vesicle targeting/fusion with the cis ‐Golgi 0.717 SIGNOR-261285 STK11 protein Q15831 UNIPROT MARK4 protein Q96L34 UNIPROT up-regulates phosphorylation Thr214 TLGSKLDtFCGSPPY 9606 14976552 YES lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold 0.534 SIGNOR-122682 NSD3 protein Q9BZ95 UNIPROT MYC protein P01106 UNIPROT up-regulates activity binding 9606 BTO:0002181 28205554 YES irozzo Indeed, dose-dependent TR-FRET and affinity pull-down assay confirmed the interaction of NSD3-s with MYC. Supporting functional significance of the interaction, co-expression of NSD3-s, but not the MYC-binding defective fragment of NSD3-s (1–347), stabilized MYC protein and increased MYC transcriptional activity as revealed by a MYC-driven reporter assay. 0.2 SIGNOR-259200 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT down-regulates activity phosphorylation Ser178 TAHNKRIsTLTIEEG -1 9407077 YES miannu NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A 0.486 SIGNOR-250032 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity phosphorylation Ser139 DNETGTEsMVSHRRE 9606 16965538 YES lperfetto Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development. 0.636 SIGNOR-217845 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination Lys191 RNHIQLVkLQVEEVH 9606 BTO:0002552 31732561 YES lperfetto AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination. 0.378 SIGNOR-267672 CHRM5 protein P08912 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.45 SIGNOR-257217 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser282 NSLQRVPsYDSFDSE 9606 BTO:0000782 12475968 YES lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition 0.31 SIGNOR-96338 TFAP2B protein Q92481 UNIPROT PTGDS protein P41222 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002605 15743775 NO miannu Deletion and mutation of the AP-2 element at -98 in the L-PGDS gene promoter result in a drastic decrease in the reporter activity (Figs. 1 and 2). Results from the EMSA and ChIP assay demonstrated that AP-2β bound to the AP-2 element both in vitro and in TE671 cells 0.2 SIGNOR-255425 CDK6 protein Q00534 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates activity phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 16508017 YES gcesareni Here, we show that p21cip1 is associated with k cyclin both in overexpression models and in primary effusion lymphoma cells and is a substrate of the k cyclin/cdk6 complex, resulting in phosphorylation of p21cip1 on serine 130. This phosphoform of p21cip1 appeared unable to associate with cdk2 in vivo. 0.864 SIGNOR-144832 EDN3 protein P14138 UNIPROT EDNRB protein P24530 UNIPROT up-regulates binding 9606 BTO:0000975 8086489 YES gcesareni These results demonstrate that lys-161 of the receptor is important for high affinity binding with et-3 which, in part, confers the non-selective binding characteristics of the etb receptor for et isopeptides. 0.797 SIGNOR-36017 pazopanib chemical CHEBI:71219 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 YES Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. 0.8 SIGNOR-257737 SMARCC1 protein Q92922 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 YES miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.64 SIGNOR-269786 BIRC3 protein Q13489 UNIPROT RIPK2 protein O43353 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 YES miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. 0.786 SIGNOR-272715 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser14 RTADSSSsEDEEEYV 9606 21245376 YES gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. 0.367 SIGNOR-171707 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 20724475 YES lperfetto ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process. 0.2 SIGNOR-244591 FGF2 protein P09038 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-252279 FGFR1 protein P11362 UNIPROT Non-structural protein 2 protein P0C6X7-PRO_0000037310 UNIPROT down-regulates activity chemical inhibition 9606 18620382 YES Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. 0.2 SIGNOR-260150 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Tyr132 CVIAVDRyFAITSPF 10029 BTO:0000246 8557631 YES Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. 0.377 SIGNOR-251299 ANXA3 protein P12429 UNIPROT CASP3 protein P42574 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109;BTO:0000038 30998268 NO miannu ANXA3 depletion promoted cell apoptosis and upregulated c‐caspase 3 expression in HCT116/Ox and SW480/Ox cells with or without Ox, which is consistent with findings from a preliminary study by Yan et al 0.262 SIGNOR-262209 MAPK11 protein Q15759 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 YES llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro 0.2 SIGNOR-173405 FBXW11 protein Q9UKB1 UNIPROT IKBKB protein O14920 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10321728 YES miannu We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.  0.441 SIGNOR-272544 CDK2 protein P24941 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 16085715 YES gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. During the s and g2 phases, s123 (wee1) is phosphorylated by a cdk (possibly cdk2). 0.665 SIGNOR-139469 iloprost chemical CHEBI:63916 ChEBI PTGIR protein P43119 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257574 SKP2 protein Q13309 UNIPROT Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR up-regulates activity binding 9606 BTO:0003725 11439327 YES miannu We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line. 0.92 SIGNOR-272576 NR5A1 protein Q13285 UNIPROT CYP11B2 protein P19099 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002588 21169726 NO miannu Inhibitory SF-1 was found to decrease the sensitivity of CYP11B2 and aldosterone to Ang II stimulation, whereas a down-regulation of SF-1 enhanced basal CYP11B2 expression and aldosterone production in H295R cells. 0.48 SIGNOR-254867 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-259703 ziprasidone chemical CHEBI:10119 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 10116 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258502 TLN1 protein Q9Y490 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 YES miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. 0.489 SIGNOR-257623 USF1 protein P22415 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7862113 NO irozzo Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study. 0.317 SIGNOR-255702 TJP1 protein Q07157 UNIPROT ARVCF protein O00192 UNIPROT up-regulates activity binding 9615 BTO:0000837 15456900 YES Regulation of binding miannu We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. E-cadherin, ZO-1, and ARVCF are recruited to sites of initial cell-cell contact. Binding of the ZO-1 PDZ domains per se does not facilitate membrane recruitment of ARVCF, indicating a requirement for the intact ZO-1 and possibly its association with membrane proteins and/or the cytoskeleton for this process. 0.454 SIGNOR-252121 FZR1 protein Q9UM11 UNIPROT TK1 protein P04183 UNIPROT down-regulates quantity by destabilization binding -1 14701726 YES miannu We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif. 0.342 SIGNOR-272945 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 12411508 YES gcesareni Cell division cycle 25 a (cdc25a), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (cdks), such as cdk2, cdk4, and cdk6, and positively regulates the activities of cdks that lead to cell cycle progression. 0.829 SIGNOR-95252 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone chemical CHEBI:91372 ChEBI ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 15604286 YES gcesareni Through screening a small molecule compound library developed for the phosphatidylinositol 3'-kinase-like kinase family, we identified an atp-competitive inhibitor, 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (ku-55933), that inhibits atm with an ic(50) of 13 nmol/l and a ki of 2.2 nmol/l 0.8 SIGNOR-132441 TEAD1 protein P28347 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103;BTO:0001760 20153295 NO lperfetto We found that the expression of myf5 and cyclind1 remained significantly elevated upon induction of differentiation in cells that were overexpressing hyap1 s127a compared to cells transfected with wildtype hyap and empty vector;yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor. 0.272 SIGNOR-235849 LPAR1 protein Q92633 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.515 SIGNOR-256839 RXRB protein P28702 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 10976919 YES gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr 0.649 SIGNOR-81452 CHUK protein O15111 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization phosphorylation Thr559 TGDYIPGtETHMAPE 9606 BTO:0000776 20501937 YES lperfetto Upon activation by nik, ikkalfa phosphorylates nik, triggering its proteolysis. 0.698 SIGNOR-165622 TRAF6 protein Q9Y4K3 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity ubiquitination Lys180 SPAPSSTkPGPESSV 9606 18347055 YES K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B 0.913 SIGNOR-252252 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 22263797 YES gcesareni Cell division cycle 25 a (cdc25a), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (cdks), such as cdk2, cdk4, and cdk6, and positively regulates the activities of cdks that lead to cell cycle progression. 0.829 SIGNOR-195521 Inflammation phenotype SIGNOR-PH12 SIGNOR IL4 protein P05112 UNIPROT up-regulates 9606 BTO:0000399 11290754 NO apalma Our findings indicate that chemokines acting via CCR3-initiated signaling pathways can very rapidly mobilize preformed stores of IL-4 from within human eosinophils. The means of extracellular release was by noncytotoxic, vesicular transport 0.7 SIGNOR-255494 SIRT6 protein Q8N6T7 UNIPROT TNF protein P01375 UNIPROT up-regulates deacetylation Lys19 LAEEALPkKTGGPQG 9606 23552949 YES gcesareni Sirt6 regulates tnf-alfa secretion through hydrolysis of long-chain fatty acyl lysine 0.314 SIGNOR-201658 INSR protein P06213 UNIPROT FABP4 protein P15090 UNIPROT unknown phosphorylation Tyr20 SSENFDDyMKEVGVG -1 1648089 YES Adipocyte lipid-binding protein is phosphorylated on tyrosine 19 in an insulin-stimulated fashion by the insulin receptor 0.39 SIGNOR-251309 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 YES miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz 0.8 SIGNOR-258898 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.2 SIGNOR-269167 PPM1D protein O15297 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity dephosphorylation Ser140 PKTDPSDsQTGLAEQ 9606 31959038 YES miannu Increased expression of wildtype WIP1 reduces stability of p27 Kip1 while increased expression of similar amounts of phosphatase-dead WIP1 has no effect on p27 Kip1 protein stability.|We demonstrate that wildtype, but not phosphatase-dead WIP1, efficiently dephosphorylates p27 Kip1 Ser140 both in vitro and in cells and that this dephosphorylation is sensitive to the WIP1 specific inhibitor GSK 2830371. 0.26 SIGNOR-277109 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000150 10550055 YES gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. 0.497 SIGNOR-72087 CENPN protein Q96H22 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR up-regulates activity binding 9606 BTO:0000567 20566683 YES miannu CENP-C, like CENP-N, interacts directly and specifically with CENP-A nucleosomes. CENP-C and CENP-N bind to different sites on the same CENP-A nucleosomes. CENP-N also binds directly to CENP-A nucleosomes, thus providing additional CENP-A nucleosome contacts that reinforce the specificity of the centromere assembly process 0.904 SIGNOR-263705 RALBP1 protein Q15311 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.581 SIGNOR-260513 RDX protein P35241 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 BTO:0000132 35267019 NO miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway. 0.7 SIGNOR-268433 Oxotremorine chemical CHEBI:7851 ChEBI CHRM1 protein P11229 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 YES miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. 0.8 SIGNOR-258651 PP1 proteinfamily SIGNOR-PF54 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 YES lperfetto Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. 0.2 SIGNOR-264666 SYK protein P43405 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates phosphorylation Tyr378 EPEPENDyEDVEEMD 9606 9104825 YES llicata Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis. 0.666 SIGNOR-47338 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI Early macropinosomes phenotype SIGNOR-PH228 SIGNOR down-regulates 9606 33722976 YES miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis. These observations raised the possibility that PtdIns(4,5)P2 depletion is in fact required for the completion of macropinocytosis or to prevent macropinosome back-fusion with the plasmalemma. 0.7 SIGNOR-277774 NBEAL2 protein Q6ZNJ1 UNIPROT DOCK7 protein Q96N67 UNIPROT up-regulates activity binding 10090 BTO:0000132 29187380 YES lperfetto In summary, from 129 binding partners of Nbeal2 identified by mass spectrometry, we have confirmed the interaction of 3, Dock7, Sec16a, and Vac14, by different biochemical and cellular approaches|Given the significant reduction of Dock7 levels and its altered localization in Nbeal2−/− platelets, we postulated that this canonical signaling pathway may be disrupted and set out to test this using control and Nbeal2−/− platelets. 0.381 SIGNOR-261891 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser77 YEPEGSAsPTPPYLK 9606 17318175 YES The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated 0.27 SIGNOR-248495 HECTD3 protein Q5T447 UNIPROT STX8 protein Q9UNK0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18821010 YES miannu Our co-immunoprecipitation experiments show that Syntaxin 8 directly interacts with HECTd3 and that the overexpression of HECTd3 promotes the ubiquitination of Syntaxin 8.  Immunoprecipitates probed with the anti-ubiquitin (Santa Cruz) antibody could be recognized by the anti-ubiquin antibody (Fig. 3a), indicating that the shift of the His-syntaxin 8 protein bands were caused by polyubiquitin conjugations. Our data suggest that HECTd3 may function as an E3 ubiquitin-protein ligase to promote the ubiquitination and degradation of Syntaxin 8 through the proteasome pathway. 0.441 SIGNOR-271772 KLHL17 protein Q6TDP4 UNIPROT GRIK2 protein Q13002 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0000298 17062563 YES miannu Here, we report that actinfilin is able to bind to GluR6, a kainate-type glutamate receptor subunit, and target GluR6 for degradation. Like many members of its protein family, actinfilin acts as a substrate adaptor, binding Cullin 3 (Cul3) and linking GluR6 to the E3 ubiquitin-ligase complex. Together our data demonstrate that actinfilin acts as a scaffold, linking GluR6 to the Cul3 ubiquitin ligase to provide a novel mechanism for kainate receptor degradation. 0.496 SIGNOR-271612 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser282 RNLVYDQsPNRTGGP 9606 BTO:0000007 16682949 YES done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. 0.543 SIGNOR-274083 ITGAV protein P06756 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.835 SIGNOR-253289 lurasidone chemical CHEBI:70735 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10030 20404009 YES Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. 0.8 SIGNOR-259462 clomipramine chemical CHEBI:47780 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258876 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates relocalization 9606 14517246 YES gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin. 0.711 SIGNOR-103360 CRX protein O43186 UNIPROT RBP3 protein P10745 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10354480 NO miannu OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments. 0.38 SIGNOR-254890 MYOD1 protein P15172 UNIPROT DES protein P17661 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000222 25653159 YES lperfetto MyoD and HDAC2 repress myogenic late genes at early times of differentiation.A time course of Ckm, Des and Acta1 gene expression demonstrated that these genes were prematurely expressed when differentiation was driven by myogenin and Mef2D1b (Figure _(Figure6A).6A). Since MyoD is not expressed under these conditions, it cannot bind to these genes; ChIP assays demonstrated that HDAC2 also was not present on the Ckm, Des and Acta1 regulatory sequences under these conditions (Figure _(Figure6B).6B). Therefore the presence of MyoD and HDAC2 prior to gene expression functions to repress late gene expression at early times of differentiation. 0.24 SIGNOR-241762 MMP10 protein P09238 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 NO lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. 0.7 SIGNOR-272355 PPP3CC protein P48454 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18177723 NO lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy 0.2 SIGNOR-251735 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNT2 protein P45379 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 NO miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) 0.333 SIGNOR-136870 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 12000790 YES lperfetto We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms. 0.536 SIGNOR-227973 MECOM protein Q03112 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity binding 10090 17575132 YES irozzo The results that we present here support this model and show that EVI1 interacts with and inhibits RUNX1. As for GATA1, EVI1 seems to repress RUNX1 function by interacting specifically with its DNA-binding domain Runt, leading to destabilization and dissolution of the DNA-RUNX1 complex. 0.523 SIGNOR-255716 NTS protein P30990 UNIPROT NTSR2 protein O95665 UNIPROT down-regulates binding 9606 BTO:0000975 9851594 YES gcesareni Neurotensin binding to recombinant neurotensin nt2 receptor expressed in cho cells does not elicit a biological response as determined by second messenger measurements. 0.898 SIGNOR-62519 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 YES lperfetto Activation of wild type stat3: il-6 treatment causes stat3 recruitment to receptor tyrosine phosphopeptides (gp130) where it is phosphorylated on tyrosine 705 (y) by jak kinase 0.817 SIGNOR-236463 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT down-regulates activity phosphorylation Thr352 PSEPMMStPPPASEL 9606 BTO:0000567 26080397 YES miannu ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68. 0.2 SIGNOR-266378 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 17317136 YES lperfetto Recruitment of ww and hect domain e3-ubiquitin ligases smurf1 and 2 to induce type i receptor ubiquitination and subsequent receptor degradation; 0.709 SIGNOR-153423 CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser90 LPGSRPGsPEREVPA 9606 16103124 YES lperfetto Moreover, app stabilized tip60 through cdk-dependent phosphorylation 0.479 SIGNOR-139653 ROS stimulus SIGNOR-ST2 SIGNOR FOXL2 protein P58012 UNIPROT up-regulates quantity by expression 9606 19010791 NO miannu Transcriptional upregulation of foxl2 during oxidative and heat stress 0.7 SIGNOR-182303 SMARCD1 protein Q96GM5 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.747 SIGNOR-270722 JAK1 protein P23458 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity phosphorylation Tyr690 NLQERRKyLKHRLIV 9020188 YES STAT2 plays a pivotal role in IFN-a signaling. It is recruited to the activated receptor first and, after phosphorylation by JAK kinases on tyrosine 690, provides a docking site for the SH2 domain of STAT1. 0.767 SIGNOR-251344 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 17217339 YES lperfetto Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.These results strongly support the observation that irak-4 is a kinase for p47phox in vivo. We also detected the signature of phosphorylation at ser320 and ser345 0.38 SIGNOR-152015 RIPK1 protein Q13546 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT up-regulates activity phosphorylation Ser728 PSPARSSsYSEANEP 9913 17389591 YES We further show that RIP1 (the Ser/Thr protein kinase receptor-interacting protein) associates with the GAP domain of AIP1 and mediates TNF-induced AIP1 phosphorylation at Ser-604 and JNK/p38 activation as demonstrated by both overexpression and small interfering RNA knockdown of RIP1 in EC. 0.427 SIGNOR-259976 HK1 protein P19367 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. 0.8 SIGNOR-266445 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser163 SYRESSLsPSPASSI 9606 BTO:0000782 9374467 YES lperfetto Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation 0.711 SIGNOR-53364 PRKCA protein P17252 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity phosphorylation Ser165 CSMAALTsHLQNQSN 23195996 YES lperfetto Phosphorylation of MBD4 promotes 5-meC glycosylase activity Further evidence emerged to support the involvement of MBD4 in active demethylation. Protein-kinase C phosphorylation of MBD4 at two specific serine residues (165 and 262) following parathyroid hormone stimulation was shown to promote demethylation within the CYP27B1 gene promoter [12] 0.2 SIGNOR-275673 FBXW11 protein Q9UKB1 UNIPROT SKP1 protein P63208 UNIPROT up-regulates binding 9606 10023660 YES gcesareni The scf is composed of skp1, cdc53/cul1, and a specificity-conferring f-box protein. F-box proteins contain two domains, an f-box motif that binds skp1 and allows assembly into skp1/cdc53 complexes, and a second proteinprotein interaction domain that interacts specifically with one or more target proteins. Cdc53/cul1, in turn, interacts with both the e2 and the skp1/f-box protein complex. 0.801 SIGNOR-64505 2,5-dimethylcelecoxib chemical CHEBI:232608 ChEBI NFKB1 protein P19838 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000567 21983014 YES Marta Tosoni DMC inhibits EGR1 promoter activity by influencing NF-κB 0.8 SIGNOR-278101 ATF1 protein P18846 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8999965 NO miannu it was shown that both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments. 0.2 SIGNOR-253742 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 19620713 YES gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.642 SIGNOR-187190 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT up-regulates activity phosphorylation Ser343 TVSKTETsQVAPA -1 8617805 YES That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated. 0.923 SIGNOR-251191 SMDT1 protein Q9H4I9 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 SIGNOR form complex binding 9606 32315830 YES miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. 0.631 SIGNOR-270861 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.718 SIGNOR-219341 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr323 STVSFNPyEPELAPW 9606 BTO:0000776 9820500 YES lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 0.2 SIGNOR-246605 TGFBR1 protein P36897 UNIPROT SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28520219 NO miannu The transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways. 0.432 SIGNOR-260590 PTPN1 protein P18031 UNIPROT PITX1 protein P78337 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr160 LDLCKGGyVPQFSGL 9606 27752061 YES lperfetto PTP1B dephosphorylates PITX-1 at Y160, 175 and Y179.|Through directly dephosphorylating PITX-1 at Y160, Y175 and Y179, PTP1B promoted proteasomal degradation of PITX-1, thus leaded in downregulating p120RasGAP and CRC cell survival. 0.354 SIGNOR-276974 MAPK1 protein P28482 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 BTO:0001130 18511414 YES gcesareni Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126 0.512 SIGNOR-178718 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys144 GTGSFFPkGEDFYCV 9606 17509614 YES gcesareni Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1 0.256 SIGNOR-154801 estramustine chemical CHEBI:4868 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation 9606 14755680 YES miannu A variety of new estrogenic/anti‐estrogenic/selective estrogen receptor modulator (SERM)‐like compounds, including 2‐methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. 0.8 SIGNOR-259299 CIITA protein P33076 UNIPROT RFX5 protein P48382 UNIPROT up-regulates activity binding 9606 BTO:0000776 9177217 YES 2 miannu RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II major histocompatibility complex promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA. 0.759 SIGNOR-240980 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT up-regulates binding 9606 9641916 YES gcesareni Galpha13 bound tightly top115 rhogefand stimulated its capacity to catalyze nucleotide exchange onrho. 0.607 SIGNOR-58417 THOC1 protein Q96FV9 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 YES miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. 0.916 SIGNOR-268508 GLI2 protein P10070 UNIPROT HHIP protein Q96QV1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 NO lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. 0.581 SIGNOR-209635 SMURF1 protein Q9HCE7 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 11278251 YES miannu Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.  0.693 SIGNOR-272943 DCST1 protein Q5T197 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27782195 YES miannu DCST1 promotes ubiquitination of STAT2.|In our study, DCST1 was found to interact with and promote ubiquitination of STAT2, leading to reduced STAT2 expression and attenuated activation of the ISG induction pathway.|DCST1 promotes STAT2 degradation. 0.448 SIGNOR-278746 REST protein Q13127 UNIPROT PENK protein P01210 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21832040 NO miannu HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). 0.2 SIGNOR-255074 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0001538 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.718 SIGNOR-219332 iodide smallmolecule CHEBI:16382 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 16098474 YES scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 0.8 SIGNOR-266958 CRY2 protein Q49AN0 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 YES miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. 0.895 SIGNOR-267972 SEC24C protein P53992 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 YES lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat 0.693 SIGNOR-265294 PRMT5 protein O14744 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates activity methylation Arg140 KPEPLSArRGDCPTL 9606 BTO:0000007 22269951 YES lperfetto Hoxa9 methylation by prmt5 is essential for endothelial cell expression of leukocyte adhesion molecules. / prmt5 is a critical coactivator component in a newly defined, hoxa9-containing transcription complex./ Hoxa9 is methylated on arg140 by prmt5. 0.463 SIGNOR-195526 SPOP protein O43791 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0002181 16524876 YES Gianni These results suggest that SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis. 0.484 SIGNOR-268858 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates activity phosphorylation Tyr191 SRLLHSDyMNMTPRR 8992971 YES EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor. 0.689 SIGNOR-251336 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR1 protein Q92633 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-193558 XL765 chemical CHEBI:71958 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207872 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser1448 TSRQSPAsPPPLGGG 9606 BTO:0000007 20622900 YES miannu HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further. 0.2 SIGNOR-263064 AMPA proteinfamily SIGNOR-PF58 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 YES miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. 0.8 SIGNOR-264941 Mubritinib chemical CID:6444692 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-194581 tibolone chemical CHEBI:32223 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation 9606 19464167 YES Luana In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1). 0.8 SIGNOR-257821 SET protein Q01105 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates binding 9606 21806989 YES miannu Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac 0.532 SIGNOR-175719 TNFRSF13C protein Q96RJ3 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000776;BTO:0000785 20889926 YES lperfetto Activation of br3 induces recruitment and degradation of traf3. 0.757 SIGNOR-168199 PF-2545920 chemical CID:11581936 PUBCHEM PDE10A protein Q9Y233 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206001 PKM protein P14618 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 YES llicata Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3 0.443 SIGNOR-195766 ARHGAP28 protein Q9P2N2 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.502 SIGNOR-260483 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1665 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.542 SIGNOR-273041 trichostatin A chemical CHEBI:46024 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 17868033 YES Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. 0.8 SIGNOR-257937 FOXS1 protein O43638 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates quantity by repression transcriptional regulation 9913 BTO:0004577 18288644 YES Luana Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4. 0.2 SIGNOR-261611 PPP2R5B protein Q15173 UNIPROT BCL2 protein P10415 UNIPROT down-regulates dephosphorylation Ser70 RDPVARTsPLQTPAA 9606 18845789 YES gcesareni Pp2a directly interacts with the bh4 domain of bcl2 as a docking site to potentially bridge pp2a to bcl2's flexible loop domain containing the target serine 70 phosphorylation site. 0.322 SIGNOR-181559 JNK proteinfamily SIGNOR-PF15 SIGNOR YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr154 VVSGPAAtPTAQHLR 9606 BTO:0001938 21364637 YES miannu JNK phosphorylates YAP on multiple sites. The wild-type YAP (WT) and five mutant (T119A, S138A, T154A, S317A and T362A) Flag–YAP constructs were each transfected into U2OS cells 0.2 SIGNOR-277643 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0004055 9430688 YES lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. 0.765 SIGNOR-252743 MAPK1 protein P28482 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity phosphorylation Thr280 FSPTPGFtPTLGFSP -1 11606045 YES lperfetto Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a 0.501 SIGNOR-249453 HDAC1 protein Q13547 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 NO miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. 0.283 SIGNOR-254576 TGFB2 protein P61812 UNIPROT TGFB2 protein P61812 UNIPROT up-regulates binding 9606 16885528 YES gcesareni The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge 0.2 SIGNOR-148608 Ub:E2 complex SIGNOR-C497 SIGNOR RNF224 protein P0DH78 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271260 PLK1 protein P53350 UNIPROT ZMYM2 protein Q9UBW7 UNIPROT down-regulates quantity by destabilization phosphorylation Ser303 QKQPGVDsLSPVASL 25855382 YES lperfetto PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis|Similar analyses with ZNF198 identified two clusters of putative Plk1 phosphorylation sites in vitro. A cluster of serine residues at the N-terminus of ZNF198, S303, S305, and S309, and a cluster at the C-terminus, S1056 and S1064. The triple Ser to Ala mutant, S303A/S305A/S309A, consistently exhibited the lowest level of phosphorylation in vitro, in comparison to the double S1056A/S1064A mutant 0.376 SIGNOR-275559 EXOC2 protein Q96KP1 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 YES miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. 0.961 SIGNOR-270785 HDLBP protein Q00341 UNIPROT CTCF protein P49711 UNIPROT up-regulates activity binding 9606 BTO:0000599 24725430 YES miannu Vigilin interacts with CCCTC-binding factor (CTCF) and is involved in CTCF-dependent regulation of the imprinted genes Igf2 and H19. vigilin is present at several known CTCF target sites, such as the promoter regions of c-myc and BRCA1, the locus control region of β-globin, and several regions within the Igf2/H19 locus. These results reveal the functional relevance of vigilin and CTCF, and show that the CTCF-vigilin complex contributes to regulation of Igf2/H19. 0.481 SIGNOR-266693 KCNQ5 protein Q9NR82 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 YES miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. 0.8 SIGNOR-265983 NRF1 protein Q16656 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001363; BTO:0000142 11058604 NO miannu We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs. 0.289 SIGNOR-254881 INSR protein P06213 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr577 YMEDSTYyKASKGKL -1 9507031 YES P125(Fak) sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor. p125(Fak) phosphorylation by the receptor results in its activation. 0.354 SIGNOR-251324 FOXO1 protein Q12778 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 YES miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. 0.258 SIGNOR-260101 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser645 RPASVPPsPSLSRHS -1 6772446 YES Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. 0.685 SIGNOR-253006 PPP1CA protein P62136 UNIPROT PREX2 protein Q70Z35 UNIPROT up-regulates activity dephosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 YES miannu PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. 0.2 SIGNOR-277183 TLK1 protein Q9UKI8 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR -1 11314006 YES The effect has been demonstrated using Q9UKI8-2|Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto Purified tlk1b phosphorylated histone h3 at s(10) with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone h3 is a physiological substrate for tlk1b. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events. 0.2 SIGNOR-107037 DLL1 protein O00548 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding BTO:0001103 12361602 YES apalma When activated by its ligands (Delta and Jagged in vertebrates and Serrate in invertebrates), the intracellular portion of Notch is cleaved and translocates to the nucleus 0.64 SIGNOR-255368 PPP1CA protein P62136 UNIPROT PREX1 protein Q8TCU6 UNIPROT up-regulates activity dephosphorylation Ser834 LSLGPRLsLCEDSPM 9606 22242915 YES lperfetto MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation. 0.2 SIGNOR-277022 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 9727491 YES gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. 0.741 SIGNOR-256459 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 9606 SIGNOR-C110 12000790 YES gcesareni We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms. 0.554 SIGNOR-87433 TFEB protein P19484 UNIPROT GUSB protein P08236 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 YES lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants 0.249 SIGNOR-276553 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 18508628 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes. 0.2 SIGNOR-178704 NEXMIF protein Q5QGS0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0000938 27822498 NO miannu The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling. We found that KIDLIA is distributed exclusively in the nucleus 0.7 SIGNOR-269659 manganese(2+) chemical CHEBI:29035 ChEBI BRCA1-C complex complex SIGNOR-C299 SIGNOR form complex binding 25400280 YES lperfetto The BRCA1‚ÄìC complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2 0.8 SIGNOR-269476 MYC protein P01106 UNIPROT TYMS protein P04818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18677108 YES miannu Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. 0.338 SIGNOR-267374 CMTM6 protein Q9NX76 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization stabilization 9606 BTO:0002806 28813410 YES Barakat Furthermore, the observations that (i) CMTM6 affects PD-L1 protein stability at late time points after biosynthesis; (ii) CMTM6, CMTM4 and PD-L1 interact, as shown by co-immunoprecipitation; and that (iii) CMTM6 is largely located at the cell surface, collectively suggest a model in which CMTM6 interacts with PD-L1 at the tumour cell surface and thereby protects it from degradation 0.471 SIGNOR-274980 MRE11 protein P49959 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 21763684 YES gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. 0.2 SIGNOR-175006 MAX protein P61244 UNIPROT MXD4 protein Q14582 UNIPROT up-regulates activity binding 9606 7954804 YES 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. 0.483 SIGNOR-240224 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates activity phosphorylation Ser634 ISQCGYSsTIVHVPP 9534 BTO:0000298 11865049 YES llicata The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.  0.74 SIGNOR-250819 GRK2 protein P25098 UNIPROT OPRD1 protein P41143 UNIPROT down-regulates activity phosphorylation Thr358 ATARERVtACTPSDG 9606 BTO:0000007 11040053 YES GRK2 strongly enhanced agonist-stimulated phosphorylation of the wild-type DOR (WT), but Delta15 or mutant DOR (T358A/T361A/S363G) failed to show any detectable phosphorylation under these conditions. agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus. GRKs are important mediators in agonist-induced opioid receptor phosphorylation and desensitization. 0.2 SIGNOR-251457 PRKACA protein P17612 UNIPROT KDELR1 protein P24390 UNIPROT up-regulates phosphorylation Ser209 VLKGKKLsLPA 9606 14517323 YES llicata We conclude that pka phosphorylation of serine 209 is required for the retrograde transport of the kdel receptor from the golgi complex to the er from which the retrieval of proteins bearing the kdel signal depends. 0.31 SIGNOR-118257 KAT2B protein Q92831 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates acetylation 9606 22120716 YES gcesareni In earlier studies, we demonstrated that maml1 enhanced p300 acetyltransferase activity, which increased the acetylation of notch by p300.Acetylation controls notch stability and function in t-cell leukemia. 0.601 SIGNOR-254311 HK2 protein P52789 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates activity 10090 16892090 NO HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host 0.7 SIGNOR-259979 SNAI2 protein O43623 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 20509143 NO miannu SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. 0.408 SIGNOR-255153 MAPK1 protein P28482 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation 9606 23616010 YES lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. 0.79 SIGNOR-201943 KTN1 protein Q86UP2 UNIPROT KIF5B protein P33176 UNIPROT up-regulates binding 9606 15316074 YES miannu This study demonstrated the effect of kinectin-kinesin interaction on lysosome dynamics and observed that the kinesin-binding domain of kinectin can significantly enhance the mt-stimulated atpase activity of kinesin. 0.608 SIGNOR-128092 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000975 14572442 YES Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation gcesareni Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. 0.965 SIGNOR-118852 PPIF protein P30405 UNIPROT ATP5PO protein P48047 UNIPROT up-regulates activity binding 9606 BTO:0000007 32814770 YES lperfetto We here hypothesized that CypD phosphorylation on its residue S191 induces its translocation and binding to the OSCP to favor mPTP opening.  0.2 SIGNOR-264881 FGF1 protein P05230 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 10618369 YES lperfetto We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2. 0.909 SIGNOR-73811 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI L-tyrosine zwitterion smallmolecule CHEBI:58315 ChEBI up-regulates quantity precursor of 9606 28153798 YES scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. 0.8 SIGNOR-267035 SLBP protein Q14493 UNIPROT H2BC11 protein P06899 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 YES lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. 0.2 SIGNOR-265381 REST protein Q13127 UNIPROT CARTPT protein Q16568 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 18485095 NO miannu When expression of NRSF was down-regulated in HeLa cells using a RNA interfering technique, the transcriptional activity of the CART promoter or a NRSE reporter was significantly increased. Taken together, our data suggested that CART gene expression in neuroendocrine cells is strictly controlled by NRSF, via a mechanism dependent upon the CART NRSE. 0.2 SIGNOR-255073 GAMT protein Q14353 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates -1 26319512 NO Luana GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system 0.7 SIGNOR-265795 Ub:E2 complex SIGNOR-C497 SIGNOR RNF5 protein Q99942 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270998 PPP1CA protein P62136 UNIPROT CASP9 protein P55211 UNIPROT up-regulates dephosphorylation Thr125 PEVLRPEtPRPVDIG 9606 22311969 YES gcesareni Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis. 0.2 SIGNOR-195992 TPO protein P07202 UNIPROT 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI up-regulates quantity chemical modification 9606 16098474 YES scontino TPO plays a key role in thyroid hormone synthesis by catalyzing both the iodination of tyrosine residues to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues. The first step in the process of thyroid hormone synthesis is the binding of iodine to tyrosine residues in Tg, which yields MIT and DIT residues. 0.8 SIGNOR-266957 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000141 18179858 YES irozzo KIT mutations within the carboxy-terminal region of the cytoplasmic tyrosine kinase domain (TK2), such as KITD816V, stabilize the KIT activation loop conformation in its active form.Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT. Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models. 0.72 SIGNOR-256121 JNK proteinfamily SIGNOR-PF15 SIGNOR KIF5C protein O60282 UNIPROT up-regulates activity phosphorylation Ser176 CTERFVSsPEEVMDV 9606 BTO:0000142 27013971 YES miannu JNK phosphorylates KIF5C on S176 in the motor domain; a site that we show is phosphorylated in brain. In the peroxisome cargo-bound state, S176 phosphorylated KIF5C(1-560) transports to microtubule plus ends, whereas dephosphorylated KIF5C(1-560) is bound tightly to microtubules resulting in an immobile state. As a consequence, phosphorylation of S176 can facilitate plus-end cargo transport by KIF5C(1-560). 0.2 SIGNOR-264063 N-formyl-L-methionyl-L-leucyl-L-phenylalanine smallmolecule CHEBI:53490 ChEBI FPR1 protein P21462 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257492 regorafenib chemical CHEBI:68647 ChEBI EPHA2 protein P29317 UNIPROT down-regulates activity chemical inhibition 9606 24756792 YES miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. 0.8 SIGNOR-259210 EEF1A2 protein Q05639 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269531 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Ala657 MVGGVVIaTVIVITL -1 10605825 YES lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. 0.489 SIGNOR-261738 regorafenib chemical CHEBI:68647 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition 9606 26254357 YES miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF 0.8 SIGNOR-259180 ziprasidone chemical CHEBI:10119 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 BTO:0001311 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258501 ADSL protein P30566 UNIPROT 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI up-regulates quantity chemical modification 9606 22812634 YES miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case 0.8 SIGNOR-266608 NEDD4L protein Q96PU5 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 YES miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). 0.288 SIGNOR-253462 CUDC-101 chemical CID:24756910 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 20143778 YES miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. 0.8 SIGNOR-262255 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity precursor of 9606 15170386 YES Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure‚Äì function relationships in PFK-2 (6-phosphofructo-2-kinase)/ FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2 0.8 SIGNOR-267265 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr30 NQSSGYRyGTDPTPQ -1 9425276 YES Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. 0.2 SIGNOR-251165 F2R protein P25116 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 NO miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. 0.2 SIGNOR-254848 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 15568999 YES gcesareni In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. 0.584 SIGNOR-131379 SH3KBP1 protein Q96B97 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 24167568 YES gcesareni The cin85 sh3 domains interact with c-cbl, an e3 ubiquitin ligase, via an unconventional pxxxpr ligand sequence, with the highest affinity displayed by the sh3-b domain. Interaction with cin85 recruits c-cbl to the amap1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix. 0.746 SIGNOR-203139 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PFKP protein Q01813 UNIPROT down-regulates activity phosphorylation Ser679 MQQGGAPsPFDRNFG 9606 BTO:0000782 28607489 YES lperfetto Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3–CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.|Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity 0.2 SIGNOR-273033 CHUK protein O15111 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity phosphorylation 9606 19786094 YES miannu These data indicate that in context of MyD88 signaling pathway IKKalpha suppresses IRF-5 activation.|These data showed that the IKK\u03b1 phosphorylates IRF-5 and that IKK\u03b1 mediated phosphorylation stimulates formation of IRF-5 dimers. 0.475 SIGNOR-278293 ARID1A protein O14497 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Here, we show that BAF complexes are required for the self-renewal and pluripotency of mouse ES cells but not for the proliferation of fibroblasts or other cells. Proteomic studies reveal that ES cells express distinctive complexes (esBAF) defined by the presence of Brg (Brahma-related gene), BAF155, and BAF60A, and the absence of Brm (Brahma), BAF170, and BAF60C. 0.729 SIGNOR-270714 IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 YES lperfetto Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta. 0.819 SIGNOR-216365 hsa-miR-139-5p mirna URS000025D232_9606 RNAcentral CXCR4 protein P61073 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002392 21925125 YES MiR-139 acts as a tumor suppressor by directly targeting CXCR4, a key metastasis-promoting receptor, but HER2 and CD44 suppress miR-139 expression through epigenetic mechanisms. 0.4 SIGNOR-277932 CSK protein P41240 UNIPROT LYN protein P07948 UNIPROT down-regulates phosphorylation Tyr508 YTATEGQyQQQP 9606 BTO:0000776 15626731 YES gcesareni Lyn tyr507 kinase, csk, is recruited by pag, which targets lipid rafts by palmitoylation.Thus, our data suggest that il-6 treatment induces the translocation of cd45 to lipid rafts sequentially, followed by the association of cd45 with lyn and pag;dephosphorylation of lyn tyr507 and pag tyr314;lyn activation;and csk release from lipid rafts 0.536 SIGNOR-132912 NEK9 protein Q8TD19 UNIPROT NEK6 protein Q9HC98 UNIPROT up-regulates activity phosphorylation Ser206 SETTAAHsLVGTPYY 9606 BTO:0000007 12840024 YES lperfetto Nercc1/nek9 activates the nek6 and nek7 kinases. Nercc1 catalyzes the direct phosphorylation of prokaryotic recombinant nek6 at ser206 in vitro concomitant with 20-25-fold activation of nek6 activity. 0.689 SIGNOR-102996 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 10090 BTO:0001103 SIGNOR-C15 17609368 YES lperfetto AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter 0.574 SIGNOR-228654 PAK1 protein Q13153 UNIPROT SPEN protein Q96T58 UNIPROT down-regulates activity phosphorylation Ser3486 QPAPKQDsSPHLTSQ 9606 15824732 YES miannu Pak1 phosphorylation sites in SHARP were mapped to Ser3486 and Thr3568 within the SHARP repression domain. 0.2 SIGNOR-278968 CALM3 protein P0DP25 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 YES miannu To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines. we can conclude that TANC2 and liprin-α are enriched in dendritic spines and interact with various synaptic proteins. TANC2 and Liprin-α2 Act as Immobile Postsynaptic Posts Able to Recruit KIF1A in a Subset of Dendritic Spines 0.27 SIGNOR-266890 Tubulin proteinfamily SIGNOR-PF46 SIGNOR Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 NO miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation 0.7 SIGNOR-266827 SNTB2 protein Q13425 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 YES apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). 0.481 SIGNOR-255993 MAP3K8 protein P41279 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates phosphorylation 9606 22435554 YES gcesareni Furthermore, we found that immunoprecipitated tpl-2 could directly phosphorylate and activate both mek-1 and mkk4 (also known as sek-1) 0.558 SIGNOR-196744 KDM6A protein O15550 UNIPROT HOXA1 protein P49639 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 YES miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. 0.401 SIGNOR-260019 MYC protein P01106 UNIPROT VEGFA protein P15692 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12368264 NO These defects are intrinsic to c-Myc, and are in part associated with a requirement for c-Myc for the expression of vascular endothelial growth factor (VEGF), as VEGF can partially rescue these defects. 0.46 SIGNOR-259369 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Thr132 SSPPTPTtPGFQVQH 9606 BTO:0000938 BTO:0000142 17681692 YES llicata We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter. 0.395 SIGNOR-157171 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 NO brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) 0.7 SIGNOR-263779 AP3B1 protein O00203 UNIPROT KIF3A protein Q9Y496 UNIPROT up-regulates activity binding 10090 BTO:0002572 19934039 YES Giorgia Here, we show that the beta subunit of AP-3, a clathrin-associated protein complex required for HIV-1 release, is a target of IP(7)-mediated pyrophosphorylation. We have identified Kif3A, a motor protein of the kinesin superfamily, as an AP3B1-binding partner and demonstrate that Kif3A, like the AP-3 complex, is involved in an intracellular process required for HIV-1 Gag release. 0.372 SIGNOR-260398 EXT1/EXT2 complex SIGNOR-C51 SIGNOR heparan sulfate octasaccharide smallmolecule CHEBI:142519 ChEBI up-regulates quantity chemical modification 9606 20377530 YES miannu HS (heparan sulfate) is synthesized by HS co-polymerases encoded by the EXT1 and EXT2 genes (exostosin 1 and 2), which are known as causative genes for hereditary multiple exostoses, a dominantly inherited genetic disorder characterized by multiple cartilaginous tumours. 0.8 SIGNOR-264016 PHF5A protein Q7RTV0 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 YES lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. 0.769 SIGNOR-270670 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000938 9346240 NO lperfetto Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt 0.791 SIGNOR-252708 YARS1 protein P54577 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI down-regulates quantity chemical modification 9606 16429158 YES miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr 0.8 SIGNOR-270518 CHD1 protein O14646 UNIPROT SF3a complex SIGNOR-C345 SIGNOR up-regulates activity binding 9606 BTO:0000567 18042460 YES miannu CHD1 was found to bridge core spliceosomal components to H3K4me3 via specific interactions with the SF3a sub-complex of U2 snRNP. The recruitment of SF3a and the efficiency of pre-mRNA splicing were perturbed upon reduction of CHD1 and H3K4me3. 0.248 SIGNOR-263951 DUSP6 protein Q16828 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 YES inferred from 70% of family members gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). 0.2 SIGNOR-269905 IKBKG protein Q9Y6K9 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity binding 9606 SIGNOR-C14 SIGNOR-C14 12192055 YES lperfetto The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation 0.962 SIGNOR-91705 RNF2 protein Q99496 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 YES miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. 0.568 SIGNOR-255277 CHFR protein Q96EP1 UNIPROT CHFR protein Q96EP1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 17442268 YES miannu In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell.  USP7 mediates deubiquitination of Chfr. 0.2 SIGNOR-271461 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT up-regulates quantity by stabilization phosphorylation Ser830 QEHARHIsFGGNLIT 9606 BTO:0000007 15987997 YES miannu Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life. 0.75 SIGNOR-262652 GALR3 protein O60755 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.449 SIGNOR-256719 MEN1 protein O00255 UNIPROT HOXA9 protein P31269 UNIPROT up-regulates quantity by expression methylation 9606 BTO:0004730 16415155 YES irozzo Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus.  0.478 SIGNOR-255894 CREB5 protein Q02930 UNIPROT CREB5 protein Q02930 UNIPROT up-regulates activity binding 9534 BTO:0000318 8378084 YES miannu CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription 0.2 SIGNOR-219602 MRPL34 protein Q9BQ48 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.667 SIGNOR-262363 TTK protein P33981 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity phosphorylation 9606 18342609 YES miannu Strikingly, phosphorylation of Cenp-E C tail by wild-type (WT) MPS1 or CDK1-cyclin B completely reverses its inhibitory effect toward Cenp-E motor ATPase in solution. 0.43 SIGNOR-278999 TNPO1 protein Q92973 UNIPROT FUS protein P35637 UNIPROT up-regulates activity relocalization -1 23056579 YES lperfetto The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1). 0.643 SIGNOR-262101 MRPL42 protein Q9Y6G3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.695 SIGNOR-262354 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10710310 YES gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. 0.79 SIGNOR-75645 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser133 NAIRYIEsLQELLRE -1 9461343 YES llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  0.307 SIGNOR-251016 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT up-regulates activity phosphorylation Ser335 TKEGSEFsFSDGEVA -1 21880710 YES miannu Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. F urthermore, time-lapse imaging data show that overexpression of Rio2 but not Rio2 S3A results in a slowed metaphase-anaphase transition. Collectively, these findings strongly indicate that the Plk1-mediated phosphorylation of Rio2 regulates metaphase-anaphase transition during mitotic progression. 0.429 SIGNOR-262937 AMPD1 protein P23109 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI up-regulates quantity chemical modification 9606 BTO:0001103 1631143 YES miannu AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. 0.8 SIGNOR-269775 CELF4 protein Q9BZC1 UNIPROT TNNT2 protein P45379 UNIPROT up-regulates quantity post transcriptional regulation 9606 11158314 NO miannu We also demonstrated that CUG-binding protein (CUG-BP) binds a conserved CUG motif within a human cTNT MSE and positively regulates MSE-dependent exon inclusion. Alternative splicing of cardiac troponin T (cTNT) exon 5 undergoes a developmentally regulated switch such that exon inclusion predominates in embryonic, but not adult, striated muscle. 0.361 SIGNOR-264256 SUZ12/EZH2 complex SIGNOR-C77 SIGNOR YY1 protein P25490 UNIPROT up-regulates activity binding 10090 BTO:0000165;BTO:0002314 20887952 YES lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. 0.733 SIGNOR-235574 TCP1 protein P17987 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 YES miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). 0.754 SIGNOR-272863 CSNK2A1 protein P68400 UNIPROT ABCC1 protein P33527 UNIPROT up-regulates phosphorylation Thr249 WSLNKEDtSEQVVPV 9606 22695718 YES lperfetto Casein kinase 2_ regulates multidrug resistance-associated protein 1 function via phosphorylation of thr249. This study supports a model in which ck2_ potentiates mrp1 function via direct phosphorylation of thr249. 0.375 SIGNOR-197844 CSNK1A1 protein P48729 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates activity phosphorylation Thr232 LTLWTSDtQGDEAEA 9606 BTO:0000007 9360956 YES llicata This protein kinase has been identified as casein kinase Ialpha (CKIalpha) by peptide mapping analysis and sequencing. Among mammalian 14-3-3, only 14-3-3 tau possesses a phosphorylatable residue at the same position (Ser-233), and we show that this residue is also phosphorylated by CKI. In addition, we show that 14-3-3 zeta is exclusively phosphorylated on Thr-233 in human embryonic kidney 293 cells. The residue 233 is located within a region shown to be important for the association of 14-3-3 to target proteins. | We have now shown that in vivo phosphorylation of 14-3-3 zeta at the CKIalpha site (Thr-233) negatively regulates its binding to c-Raf, and may be important in Raf-mediated signal transduction. 0.578 SIGNOR-250796 PPP1CA protein P62136 UNIPROT MECOM protein Q03112 UNIPROT down-regulates activity dephosphorylation Ser1037 IGNSNHGsQSPRNVE 23858473 YES phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. 0.2 SIGNOR-273429 TMLHE protein Q9NVH6 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI down-regulates quantity chemical modification 9606 11431483 YES miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. 0.8 SIGNOR-269682 SP3 protein Q02447 UNIPROT SLC19A3 protein Q9BZV2 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 15217784 NO miannu In transiently transfected Drosophila SL2 cells, both SP1 and SP3 transactivated the SLC19A3 minimal promoter in a dose-dependent manner and in combination demonstrated an additive stimulatory effect. 0.295 SIGNOR-255214 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 YES lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity 0.2 SIGNOR-252764 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 YES JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity 0.2 SIGNOR-251356 A11/b1 integrin complex SIGNOR-C168 SIGNOR Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 10090 BTO:0000165 11518510 NO lperfetto In addition, alpha11beta1 mediated contraction of fibrillar collagen gels in a manner similar to alpha2beta1, and supported migration on collagen I in response to chemotactic stimuli. Our data support a role for alpha11beta1 as a receptor for interstitial collagens on mesenchymally derived cells and suggest a multifunctional role of alpha11beta1 in the recognition and organization of interstitial collagen matrices during development. 0.7 SIGNOR-253349 hsa-miR-125b-5p mirna URS0000209905_9606 RNAcentral SPHK1 protein Q9NYA1 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000599 26807182 YES Parnian Together, these data indicate that miR-125b directly interacts with SphK1 mRNA and suppresses SphK1 protein expression. 0.4 SIGNOR-278861 CCL5 protein P13501 UNIPROT hsa-miR-199a-5p mirna URS0000554A4F_9606 RNAcentral down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005168 25444917 YES Parnian These results suggest that CCL5 promotes VEGF-dependent angiogenesis and tumor growth by downregulating miR-199a in vivo. 0.4 SIGNOR-278863 MAPK14 protein Q16539 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates activity phosphorylation 9606 SIGNOR-C77 21902831 YES lperfetto P38 can phosphorylate the histone-lysine n-methyltransferase ezh2, the catalytic subunit of the polycomb repressive complex 2 (prc2), with phosphorylation of ezh2 necessary for prc2s association with the transcriptional repressor yy1 and subsequent chromatin remodelling. 0.372 SIGNOR-176548 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR PRDM1 protein O75626 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 YES SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). 0.363 SIGNOR-269255 ASH1L protein Q9NR48 UNIPROT NRXN1 protein Q9ULB1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000942 27229316 YES Gianni Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning. 0.259 SIGNOR-269056 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser525 YGMIERLsPGTRKIE 9606 BTO:0000007 33217317 YES miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. 0.2 SIGNOR-265952 SMARCE1 protein Q969G3 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 YES miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency 0.74 SIGNOR-270720 MAPK3 protein P27361 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 20230789 YES lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity 0.267 SIGNOR-164231 CD79A protein P11912 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000776 12324477 NO gcesareni Bcr ligation activated mitochondrial apoptotic pathways including down-regulation of bcl-x(l). 0.269 SIGNOR-93481 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.286 SIGNOR-129296 PRKDC protein P78527 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT unknown phosphorylation Ser245 PHTSNSAsLQGIDSQ 9606 18644470 YES lperfetto Here, we have identified two major in vitro dna-pk phosphorylation sites in the c-terminal region of xlf, serines 245 and 251. We show that these represent the major phosphorylation sites in xlf in vivo and that serine 245 is phosphorylated in vivo by dna-pk, while serine 251 is phosphorylated by ataxia-telangiectasia mutated (atm). 0.664 SIGNOR-179532 MAPK3 protein P27361 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 11904294 YES gcesareni We report here that the important proangiogenic stimulus hypoxia stimulates phosphorylation, ubiquitination, and proteasomal breakdown of tal1 in endothelial cells. A specific serine in the putative transactivation domain of the protein, ser122, is preferentially phosphorylated by mapk in vitro. 0.357 SIGNOR-116153 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 15350223 YES gcesareni Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp. 0.641 SIGNOR-128643 MKRN1 protein Q9UHC7 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys292 EEENLRKkGEPHHEL 9606 BTO:0002552 19536131 YES miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53 0.432 SIGNOR-271847 LYRM4 protein Q9HD34 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 YES lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. 0.689 SIGNOR-262126 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR2 protein O95136 UNIPROT up-regulates activity chemical activation 9606 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257578 FSTL3 protein O95633 UNIPROT MSTN protein O14793 UNIPROT down-regulates binding 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 YES gcesareni Fstl3 inhibits myostatin via its n-terminal domain. 0.676 SIGNOR-199063 DSCAML1 protein Q8TD84 UNIPROT AQP9 protein O43315 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 YES miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. 0.2 SIGNOR-264280 PAK2 protein Q13177 UNIPROT RPS6 protein P62753 UNIPROT unknown phosphorylation Ser235 IAKRRRLsSLRASTS -1 1985906 YES miannu The synthetic peptide AKRRRLSSLRASTSKSESSQK (S6-21) which corresponds to the carboxyl-terminal 21 amino acids of human ribosomal protein S6 was synthesized and tested as a substrate for S6/H4 kinase purified from human placenta. The principal phosphorylation sites were serines in the acidic carboxyl-terminal domain of the peptide. 0.31 SIGNOR-250231 MECOM protein Q03112 UNIPROT ANGPT1 protein Q15389 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15889140 YES Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  0.2 SIGNOR-266059 PPM1B protein O75688 UNIPROT TBK1 protein Q9UHD2 UNIPROT down-regulates activity dephosphorylation -1 22750291 YES lperfetto PPM1B dephosphorylates TBK1 in vivo and in vitro.|These results demonstrate that PPM1B inhibits TBK1 mediated antiviral signaling by directly dephosphorylating TBK1 at Ser172. 0.353 SIGNOR-276985 ATR protein Q13535 UNIPROT PI4K2A protein Q9BTU6 UNIPROT down-regulates 9606 18082599 NO gcesareni Plk1 itself is negatively regulated by the ddr in an atm/atr-dependent manner. 0.278 SIGNOR-159933 PPP1CA protein P62136 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 YES The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation 0.2 SIGNOR-248558 EFNA4 protein P52798 UNIPROT EPHA5 protein P54756 UNIPROT up-regulates binding 9606 9330863 YES tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor 0.81 SIGNOR-52430 TUBA1A protein Q71U36 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 NO miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. 0.7 SIGNOR-269725 MAPKAPK2 protein P49137 UNIPROT CEP131 protein Q9UPN4 UNIPROT down-regulates quantity phosphorylation Ser47 KPIVRSVsVVTGSEQ 9606 26616734 YES miannu We identify CEP131 as a major Centriolar satellites-associated substrate of p38-dependent, MK2-mediated phosphorylation on two defined residues and show that these modifications promote binding to 14-3-3 proteins, in turn leading to cytoplasmic sequestration of CEP131 and associated Centriolar satellites factors.|We therefore conclude that MK2 dependent phosphorylation of CEP131 at S47 and S78 and the ensuing binding of 14-3-3 proteins play an essential role in triggering stress induced remodelling of CS. 0.291 SIGNOR-278181 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation 9606 19620713 YES lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.642 SIGNOR-255265 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA1 protein Q9Y5H4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265686 TOMM40 protein O96008 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 YES lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. 0.745 SIGNOR-267681 HOXA10 protein P31260 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 NO miannu HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. 0.2 SIGNOR-254215 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr724 ANCTHDLyMIMRECW 9606 BTO:0000007 11294897 YES lperfetto Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation. 0.2 SIGNOR-106738 TNK2 protein Q07912 UNIPROT SNX9 protein Q9Y5X1 UNIPROT up-regulates phosphorylation 9606 16316319 YES gcesareni We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor. 0.506 SIGNOR-142569 FH protein P07954 UNIPROT fumarate(2-) smallmolecule CHEBI:29806 ChEBI down-regulates quantity chemical modification 9606 30761759 YES miannu Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. 0.8 SIGNOR-266279 MAP2K2 protein P36507 UNIPROT CASP9 protein P55211 UNIPROT down-regulates activity phosphorylation Thr125 PEVLRPEtPRPVDIG 12792650 YES lperfetto Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2 0.347 SIGNOR-249386 NBAS protein A2RRP1 UNIPROT NRZ complex complex SIGNOR-C358 SIGNOR form complex binding 25364732 YES lperfetto NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay. 0.798 SIGNOR-265024 NME1 protein P15531 UNIPROT L1CAM protein P32004 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17671192 NO miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 0.2 SIGNOR-255161 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270392 RPS21 protein P63220 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.858 SIGNOR-262429 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser33 DLRNPHPsSAFLNLI 22584576 YES lperfetto LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation. 0.2 SIGNOR-275527 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 YES lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. 0.2 SIGNOR-269160 SIRT1 protein Q96EB6 UNIPROT NCOR1 protein O75376 UNIPROT up-regulates 9606 22395773 YES FFerrentino In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription. 0.622 SIGNOR-253505 Complement C1 complex complex SIGNOR-C309 SIGNOR C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Gly1446 TPLQLFEgRRNRRRR -1 9087411 YES lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. 0.642 SIGNOR-263439 PRKACA protein P17612 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT up-regulates activity phosphorylation Ser686 LGRSIVSsPQGKSGP -1 29230552 YES miannu PKD2L1 channel activation by PKA phosphorylation. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of β2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation. 0.2 SIGNOR-273561 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR MTA1 protein Q13330 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24089055 YES lperfetto Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. | The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. 0.2 SIGNOR-253718 CDKN3 protein Q16667 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity dephosphorylation Thr160 GVPVRTYtHEVVTLW 9606 11463386 YES The CDK-interacting protein phosphatase KAP dephosphorylates phosphoThr-160 (pThr-160) of the CDK2 activation segment, the site of regulatory phosphorylation that is essential for kinase activity. 0.716 SIGNOR-248724 NLGN4X protein Q8N0W4 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 YES brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) 0.769 SIGNOR-264145 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM4 protein O15151 UNIPROT up-regulates activity phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 YES lperfetto We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2. 0.2 SIGNOR-178063 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 12408982 YES gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. 0.417 SIGNOR-95238 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1E protein P28566 UNIPROT up-regulates activity chemical activation 9534 8935801 YES miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. 0.8 SIGNOR-258568 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr74 QINMLYGtITEFCTE 9606 BTO:0000007 18362890 YES gcesareni These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1 0.85 SIGNOR-177977 CREB1 protein P16220 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 14614508 NO HES-1 is a direct CREB target in vivo. 0.249 SIGNOR-254742 PRKCA protein P17252 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates activity phosphorylation Ser415 QRKITRPsQRPKTPP -1 17911614 YES miannu Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of Ser(394) by protein kinase C slightly suppresses KIR3DL1 inhibitory function, and reduces receptor internalization and turnover.Both CKII and PKC phosphorylate KIR3DL1 in vitro. Ser364 can be phosphorylated after phosphorylation of Ser367 by CKII. 0.2 SIGNOR-276080 PRKG1 protein Q13976 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 YES miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The 1 IC-loop does not have consensus sequences for PKG, but we found that this enzyme phosphorylated the same sites as PKA: S422, S423 (Fig. 5A).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation 0.317 SIGNOR-262756 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1193 QPTSKAYsPRYSISD 9534 BTO:0004055 8816480 YES lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 0.713 SIGNOR-236440 PPP1CC protein P36873 UNIPROT CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Ser175 FGLARAFsLAKNSQP 9606 21533037 YES gcesareni Protein phosphatase-1 activates cdk9 by dephosphorylating ser175 0.2 SIGNOR-173450 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr465 GEEELSNyICMGGKG 10116 7651388 YES lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). 0.914 SIGNOR-236713 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 16670091 NO lperfetto  FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect.  0.2 SIGNOR-252910 Rigosertib sodium chemical CID:23696523 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-195028 PPP1R9B protein Q96SB3 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates activity binding 9606 BTO:0000938 10194355 YES miannu In the present study, the interaction between PP1 and spinophilin, a neuronal protein that targets PP1 to dendritic spines, has been characterized. . These studies support the notion that spinophilin functions in vivo as a neuronal PP1 targeting subunit by directing the enzyme to postsynaptic densities and regulating its activity toward physiological substrates. 0.773 SIGNOR-269178 HSP90AA1 protein P07900 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 15861399 YES miannu The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes. 0.762 SIGNOR-251536 RBM10 protein P98175 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30403180 NO irozzo These data indicated that RBM10 overexpression induced osteosarcoma cell apoptosis via promoting the production of TNF-α that appear to act as an autocrine factor regulating osteosarcoma programmed cell death. 0.2 SIGNOR-259153 NuA4 complex complex SIGNOR-C459 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation 9606 14966270 YES miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. 0.2 SIGNOR-269286 PI3K complex SIGNOR-C156 SIGNOR RAC1 protein P63000 UNIPROT up-regulates 9606 21779497 NO gcesareni Pi3k can also activate rac, and this activation is involved in cytoskeleton reorganization. 0.548 SIGNOR-252707 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr932 IRRESSVyDISEHRR -1 11024032 YES Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. 0.767 SIGNOR-251174 CDK1 protein P06493 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 YES gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop 0.511 SIGNOR-249653 NAE complex SIGNOR-C131 SIGNOR CUL9 protein Q8IWT3 UNIPROT up-regulates activity neddylation 9606 25504797 YES lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. 0.48 SIGNOR-243169 STK11 protein Q15831 UNIPROT SNRK protein Q9NRH2 UNIPROT up-regulates activity phosphorylation Thr173 QPGKKLTtSCGSLAY 9606 BTO:0000567 15733851 YES lperfetto we identify the sucrose non-fermenting protein (SNF1)-related kinase (SNRK), a largely unstudied AMPK subfamily member, as a novel substrate for LKB1. We demonstrate that LKB1 activates SNRK by phosphorylating the T-loop residue (Thr173), 0.368 SIGNOR-247493 OXSR1 protein O95747 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates phosphorylation Thr60 MRTFGYNtIDVVPTY 9606 BTO:0000007 BTO:0000671 18270262 YES miannu We demonstrate that the spak and osr1 kinases that are activated by wnk1 phosphorylate human ncc at three conserved residues (thr46, thr55 and thr60) / our results also indicate that phosphorylation of thr60 plays the most crucial role in triggering the activation of ncc in hek293 cells and its mutation also inhibits phosphorylation of the adjacent thr46 and thr55 sites. 0.388 SIGNOR-160833 NFATC1 protein O95644 UNIPROT IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8668213 YES lperfetto Recombinant NFAT1 can mediate transcription of the interleukin-2, interleukin-4, tumor necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor promoters in T cells, suggesting that NFAT1 contributes to the CsA-sensitive transcription of these genes during the immune response. 0.548 SIGNOR-254498 HDAC2 protein Q92769 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.797 SIGNOR-263850 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser107 SQPPSPPsPAPSSFS 9606 20305697 YES lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt 0.558 SIGNOR-164621 EEF1A1 protein P68104 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269509 CDK1 protein P06493 UNIPROT ATAD5 protein Q96QE3 UNIPROT down-regulates activity phosphorylation Ser653 TVPFDSEsPIRMKFT 9606 BTO:0000007 31875566 YES miannu To determine whether mitotic CDK phosphorylates ATAD5, a CDK1 inhibitor (RO3306) was applied to nocodazole-arrested cells (Figure S3F). CDK1 inhibition resulted in a loss of S653 phosphorylation (Figure S3F). These data meant that the S653 residue in the BET BD of ATAD5 is phosphorylated by mitotic CDK. This result suggested that the BRD4-ATAD5 interaction is inhibited during mitosis. 0.24 SIGNOR-266410 CSNK2A1 protein P68400 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 10617630 YES lperfetto In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes. 0.513 SIGNOR-73807 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp78 PNVVAARdVPEGMQN 9606 11741536 YES gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. 0.365 SIGNOR-112800 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 YES lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.726 SIGNOR-269347 PMS1 protein P54277 UNIPROT MLH1/PMS1 complex SIGNOR-C58 SIGNOR form complex binding 9606 10542278 YES miannu We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_. 0.694 SIGNOR-71774 FADS3 protein Q9Y5Q0 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 YES miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. 0.8 SIGNOR-267909 SGK1 protein O00141 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 YES gcesareni Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna. 0.469 SIGNOR-179117 EGFR protein P00533 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT up-regulates activity phosphorylation Tyr394 KKVSSTHyYLLPERP 10090 BTO:0000944 phosphorylation:Tyr395 KVSSTHYyLLPERPP 26280531 YES "here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src." 0.643 SIGNOR-252091 LARP4B protein Q92615 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 20573744 NO miannu Our data suggest LARP4B to act as a general stimulatory factor of translation, associated in poly(A)-mRNA-bound mRNP complexes. Under physiological conditions, LARP4B co-sedimented with polysomes in cellular extracts, suggesting a role in translation. In agreement with this notion, overexpression of LARP4B stimulated protein synthesis, whereas knockdown of the factor by RNA interference impaired translation of a large number of cellular mRNAs. 0.7 SIGNOR-260942 SRC protein P12931 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity phosphorylation Tyr328 EELPYSEyFEYFAPD -1 30317579 YES miannu C-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form).  0.386 SIGNOR-277485 SIRT1 protein Q96EB6 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates deacetylation 9606 15126506 YES gcesareni Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes. 0.743 SIGNOR-124714 (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide chemical CHEBI:91449 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-204490 PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 YES fspada Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42). 0.389 SIGNOR-252967 IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates transcriptional regulation 10090 26315890 NO svumbaca IL-1b was present in the sera of wild-type mice but was not detected in the sera of IRF5-/- mice 0.292 SIGNOR-255340 ANAPC10 protein Q9UM13 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 YES lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. 0.919 SIGNOR-252009 hsa-miR-338-3p mirna URS00000254A6_9606 RNAcentral SNAI1 protein O95863 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004169 29069716 NO Parnian MHCC-97H cells treated with the miR-338-3p mimic exhibited decreased Snail1 mRNA and protein expression 0.4 SIGNOR-277975 TPH1 protein P17752 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI down-regulates quantity chemical modification 9606 31024440 YES brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. 0.8 SIGNOR-264009 SNAI1 protein O95863 UNIPROT CTBP1 protein Q13363 UNIPROT up-regulates activity 9606 BTO:0001570 19277896 NO lperfetto We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling 0.469 SIGNOR-254103 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates relocalization 10090 BTO:0002572 18423396 YES lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation 0.91 SIGNOR-252837 EGLN3 protein Q9H6Z9 UNIPROT PKM protein P14618 UNIPROT up-regulates activity hydroxylation Pro403 EELRRLApITSDPTE 9606 BTO:0000567 21620138 YES Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. 0.436 SIGNOR-267476 DYRK1B protein Q9Y463 UNIPROT HNF1A protein P20823 UNIPROT up-regulates phosphorylation Ser249 IQRGVSPsQAQGLGS 9606 BTO:0000887;BTO:0001103 11980910 YES lperfetto Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk 0.503 SIGNOR-86728 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 9381178 YES Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. 0.2 SIGNOR-251469 doxepin chemical CHEBI:4710 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 YES miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. 0.8 SIGNOR-258879 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 BTO:0000938 11970864 YES gcesareni Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer. 0.593 SIGNOR-117344 MAPK1 protein P28482 UNIPROT LIN28A protein Q9H9Z2 UNIPROT down-regulates activity phosphorylation Ser200 EEEEEIHsPTLLPEA 9606 BTO:0000567 28179426 YES miannu Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200.  0.263 SIGNOR-277338 EEF1A1 protein P68104 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 ChEBI up-regulates relocalization 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. 0.8 SIGNOR-269510 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization phosphorylation Thr58 KKFELLPtPPLSPSR 9606 16023596 YES gcesareni Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation. 0.719 SIGNOR-138603 BRSK1 protein Q8TDC3 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser375 ARVLRSKsLCHDEIE 9606 BTO:0000567 15150265 YES lperfetto Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectively phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 0.507 SIGNOR-107404 GNG12 protein Q9UBI6 UNIPROT PRKACA protein P17612 UNIPROT down-regulates binding 9606 17251915 YES gcesareni As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp. 0.399 SIGNOR-152615 FAU protein P62861 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 YES lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. 0.842 SIGNOR-262443 CSNK1D protein P48730 UNIPROT PER3 protein P56645 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 YES miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. 0.718 SIGNOR-267998 WNT10A protein Q9GZT5 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 YES gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. 0.622 SIGNOR-131616 PPARA protein Q07869 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR up-regulates 9606 BTO:0001103;BTO:0000671 18836859 NO miannu PPAR-α is predominantly expressed in the liver and skeletal muscles, participating in fatty-acids catabolism. PPAR-α also activates fatty-acid oxidation in the kidney, skeletal muscles, and heart 0.7 SIGNOR-268027 GRSF1 protein Q12849 UNIPROT FASTKD5 protein Q7L8L6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25683715 NO miannu DHX30 siRNA treatment resulted in an increase of FASTKD2 levels, and FASTKD5 was increased in cells treated with siRNA for GRSF1. 0.369 SIGNOR-261224 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates activity phosphorylation Tyr591 SSDNEYFyVDFREYE 10090 BTO:0001516 16627759 YES lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated.|This finding suggests that the combination of tyrosine residues 589 and 591 is required for activation of STAT-5 signaling pathways. 0.2 SIGNOR-271921 PRKCB protein P05771 UNIPROT MAPT protein P10636-2 UNIPROT down-regulates activity phosphorylation Ser324 RHLSNVSsTGSIDMV -1 10090741 YES miannu We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs. 0.259 SIGNOR-275443 MAPK1 protein P28482 UNIPROT RXRA protein P19793 UNIPROT down-regulates activity phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 YES lperfetto In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE 0.533 SIGNOR-88658 NRG1 protein Q02297 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates binding 9606 14967450 YES inferred from 70% of family members gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. 0.906 SIGNOR-269870 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation Thr40 DAESYTFtVPRRHLE 23972993 YES For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP 0.409 SIGNOR-274052 PTPN13 protein Q12923 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 BTO:0000007 11106428 YES Identification of IkappaBalpha as a substrate of Fas-associated phosphatase-1|A full-length FAP-1 protein preferentially dephosphorylates Tyr-42 of IkBa|Moreover, other studies have shown that tyrosine phosphorylation of IkBa on Tyr-42 (which occurs with Fas ligand binging) protected against inducible degradation both in vitro [30] and in vivo [38] 0.443 SIGNOR-248712 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Thr850 EAKRMKLtFSEAIRN -1 10366608 YES lperfetto In addition, we identified threonine 830 as a potential PKC phosphorylation site. 0.568 SIGNOR-249017 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR CDH1 protein P12830 UNIPROT up-regulates 9606 24532814 NO milica Adherens junctions and the cadheriBeta-catenin complex have been found to activate the Hippo signaling pathway and inhibit cell growth. Cadherin-mediated stimulation of the Hippo signaling pathway requires cadherin ligation and the formation of a homophilic bond – consistent with a role in cell-cell contact – and works owing to phosphorylation of YAP by Lats and nuclear exclusion of YAP. 0.7 SIGNOR-230707 HTR2B protein P41595 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.25 SIGNOR-257022 mTORC2 complex SIGNOR-C2 SIGNOR FUS protein P35637 UNIPROT down-regulates activity 9606 BTO:0000007 33082139 NO When mTORC2 is inhibited, FUS is recruited to polyribosomes to promote translation inhibition and polyribosome stalling. Panel iv, ALS-FUS R521G and P525L mutants that localize more prominently to the cytoplasm also associate more abundantly with polyribosomes to inhibit translation and protein synthesis. 0.294 SIGNOR-262819 RET protein P07949 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser2056 VQSYSYSsQDPRPAT 9606 26065416 YES miannu Phosphorylation of DNA-PKcs at s2056 is elevated in RET expressing cells and can be reduced by RET inhibition. 0.27 SIGNOR-279275 MID1IP1 protein Q9NPA3 UNIPROT ACACB protein O00763 UNIPROT up-regulates activity binding 10029 20952656 YES miannu Recently, we reported the discovery that MIG12, a 183 amino acid protein, binds to ACC1 and ACC2, which induces polymerization and subsequently increases the enzymatic activity of the protein 0.28 SIGNOR-267112 NLK protein Q9UBE8 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR form complex binding 10090 21952300 YES FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43. 0.446 SIGNOR-253525 TWIST1 protein Q15672 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002590 17487558 NO miannu Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells 0.543 SIGNOR-255512 PHKA1 protein P46020 UNIPROT PHKG2 protein P15735 UNIPROT down-regulates activity binding 9606 10487978 YES Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. 0.852 SIGNOR-267407 PRKACA protein P17612 UNIPROT VTN protein P04004 UNIPROT unknown phosphorylation Ser397 NQNSRRPsRATWLSL -1 1706595 YES miannu Phosphorylation of vitronectin by protein kinase A is stoichiometric (approx. 1 mol/mol), that it is targeted to one site (Ser-378) at the C-terminal edge of the heparin-binding domain. gh the role of phosphorylation by PKA remains to be established, the identification of Ser-378 as the sole site for PKA action, and the proximity of the phosphorylation site to the point of cleavage that converts V75 into V65 10' focuses attention on a putative role for PKA in the modulation of this cleavage. 0.307 SIGNOR-250072 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity precursor of 9606 22718265 YES miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. 0.8 SIGNOR-267547 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CIC protein Q96RK0 UNIPROT down-regulates phosphorylation 9606 BTO:0000848 21087211 YES inferred from 70% family members gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3)[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3 0.2 SIGNOR-270090 Aldolase proteinfamily SIGNOR-PF75 SIGNOR D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 YES miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. 0.8 SIGNOR-266482 GALR1 protein P47211 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.47 SIGNOR-256687 CDC14B protein O60729 UNIPROT TAF1C protein Q15572 UNIPROT up-regulates activity dephosphorylation 9606 26023773 YES miannu Consistent with prior studies showing that the phosphatase hCdc14B regulates progression through mitosis by counteracting mitotic phosphorylation by Cdk1/cyclin B [ ], hCdc14B dephosphorylates TAFI110, thus promoting its reactivation as cells exit mitosis.|Here we show that hCdc14B, the phosphatase that regulates Cdk1/cyclin B activity and progression through mitosis, promotes reactivation of rDNA transcription by dephosphorylating TAFI110. 0.2 SIGNOR-277135 SSTR1 protein P30872 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.474 SIGNOR-256822 DAB2IP protein Q5VWQ8 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 27858941 YES miannu DAB2IP acts as a scaffold protein for PP2A to suppress DHT-elicited S81 phosphorylation of the AR, preventing its nuclear translocation and binding to androgen response elements. In addition, DAB2IP can compete with the AR for binding to c-Src, thus blocking the non-genomic AR pathway 0.328 SIGNOR-254758 GNAI2 protein P04899 UNIPROT Cell_invasion phenotype SIGNOR-PH226 SIGNOR down-regulates 9606 BTO:0001950 20054866 YES Marta Tosoni GNAI2 can significantly inhibit HCC cell migration and invasion 0.7 SIGNOR-278880 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000567 18079698 YES miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. 0.272 SIGNOR-276095 DYRK1A protein Q13627 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. 0.36 SIGNOR-183674 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR form complex binding 9606 1904542 YES irozzo The proteins encoded by the proto-oncogenes c-fos and c-jun (Fos and Jun, respectively) form a heterodimeric complex that regulates transcription by interacting with the DNA-regulatory element known as the activator protein 1 (AP-1) binding site. 0.952 SIGNOR-256364 DNMT3B protein Q9UBC3 UNIPROT DPP6 protein P42658 UNIPROT down-regulates quantity by repression transcriptional regulation 23409053 YES lperfetto Dnmt3b was responsible for transcriptional silencing of Dpp6 gene as depletion of Dnmt3b resulted in increased mRNA and protein expression of Dpp6. 0.327 SIGNOR-268963 CACNA1E protein Q15878 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 YES miannu CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. 0.8 SIGNOR-264322 FSTL1 protein Q12841 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0001176;BTO:0002320 18718903 NO miannu In this study, Fstl1 was shown to activate Akt signaling in cardiac myocytes and inhibit apoptosis. Thus, Fstl1 can function as a survival factor for both cardiac myocytes and endothelial cells via the activation of Akt signaling.  0.383 SIGNOR-266604 CEBPB protein P17676 UNIPROT CSRP1 protein P21291 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14522018 YES We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter 0.2 SIGNOR-254049 SIM1 protein P81133 UNIPROT ARNT protein P27540 UNIPROT down-regulates activity binding -1 SIGNOR-C125 9020169 YES 2 miannu SIM1 can inhibit AHR·ARNT binding to the XRE and can inhibit expression from an XRE-driven reporter gene indicates that SIM1 may act as negative regulator of transcription as well as a positive regulator. The above inhibitory effects may result from SIM1 competing with AHR for binding to ARNT, although we cannot exclude the possibility that SIM1 may also have other inhibitory effects of AHR·ARNT activity. In a similar fashion, SIM1 may act as a negative regulator of all ARNT-dependent genes. 0.532 SIGNOR-240756 CALM2 protein P0DP24 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 YES miannu To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines 0.261 SIGNOR-266889 MAPK11 protein Q15759 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 21757713 YES lperfetto Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation. 0.33 SIGNOR-217580 PRKD1 protein Q15139 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates activity phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 20940406 YES lperfetto Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba. 0.467 SIGNOR-168537 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PFKL protein P17858 UNIPROT down-regulates activity phosphorylation -1 28607489 YES miannu In vitro kinase reactions revealed that all three PFK1 isoforms (PFKP, PFKL, PFKM) and PKM2 were phosphorylated by cyclin D3-CDK6 (Extended Data Fig. 2a–d, Supplementary Table 4). 0.2 SIGNOR-276451 isoprenaline chemical CHEBI:64317 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8982677 YES miannu K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists. 0.8 SIGNOR-258577 FBXW5 protein Q969U6 UNIPROT SEC23B protein Q15437 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 30596474 YES lperfetto SCFFBXW5 interacts with SEC23B and targets it for ubiquitylation and proteasome-mediated degradation. 0.2 SIGNOR-265286 Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 25195934 NO miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.7 SIGNOR-270621 TKT protein P29401 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 24929114 YES miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. 0.8 SIGNOR-267088 dabrafenib chemical CHEBI:75045 ChEBI CDK16 protein Q00536 UNIPROT down-regulates activity chemical inhibition 9606 29112787 YES Monia We have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. We confirmed NEK9 to be a potent target of dabrafenib by in vitro kinase assays, with inhibition of NEK9 observed in the single-digit nanomolar range. 0.8 SIGNOR-261073 FZR1 protein Q9UM11 UNIPROT MOAP1 protein Q96BY2 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 22529100 YES miannu MOAP-1 is an APC/CCdh1 substrate. Here, we identify MOAP-1 as a novel APC/CCdh1 substrate. MOAP-1 is degraded during G1 by APC/CCdh1, and this degradation is inhibited by Trim39 acting on the APC/C. 0.299 SIGNOR-272913 EXOSC6 protein Q5RKV6 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.917 SIGNOR-261389 IL12A protein P29459 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 10653850 NO miannu IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement. 0.7 SIGNOR-260966 ZEB1 protein P37275 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 NO miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. 0.683 SIGNOR-255158 CDK2 protein P24941 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser624 KMFKDKVsPLQNLAS 33082307 YES lperfetto The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A. 0.296 SIGNOR-273426 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser172 LCLSPASsGSSASFI 9606 BTO:0000567 11030334 YES NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity 0.649 SIGNOR-252316 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.754 SIGNOR-273104 RALGDS protein Q12967 UNIPROT RIT1 protein Q92963 UNIPROT up-regulates activity binding 9606 10545207 YES miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. 0.535 SIGNOR-220859 STAT6 protein P42226 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15632317 NO miannu IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation. 0.2 SIGNOR-255249 Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 NO miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes 0.7 SIGNOR-270700 BCHE protein P06276 UNIPROT acetylcholine smallmolecule CHEBI:15355 ChEBI down-regulates quantity chemical modification 15841900 YES The other subgroup, butyrylcholinesterase (BuChE) (or acyl- choline acyl-hydrolase, EC 3.1.1.8) also known as plasma, serum, benzoyl, false, butyryl, nonspecific, or type II ChE. BuChE exists in plasma and has more than eleven isoenzy- me variants. BuChE is also present in liver, smooth muscle, intestines, pancreas, heart and white matter of brain |It hydrolyzes butyrylcholine 4 times more rapidly than acetylcholine. 0.8 SIGNOR-253982 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 BTO:0000782 8892604 YES lperfetto Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function 0.727 SIGNOR-44665 USP15 protein Q9Y4E8 UNIPROT BRAP protein Q7Z569 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 23105109 YES miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. 0.267 SIGNOR-272030 PLK1 protein P53350 UNIPROT CNTROB protein Q8N137 UNIPROT up-regulates activity phosphorylation 9606 23291182 YES miannu However, unlike NEK2, PLK1 phosphorylation enhances the microtubule stabilizing activity of centrobin [22].|PLK1 phosphorylation of centrobin is critical for bipolar spindle formation. 0.324 SIGNOR-279551 SPOP protein O43791 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001033 28089830 YES lperfetto Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells 0.348 SIGNOR-261996 MAPK1 protein P28482 UNIPROT NID1 protein P14543 UNIPROT unknown phosphorylation Ser333 YSVPSVLsPRRAATE 10090 BTO:0000944 22028470 YES miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) 0.251 SIGNOR-262771 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 YES lperfetto Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling 0.38 SIGNOR-205115 SMC1A protein Q14683 UNIPROT RAD21L Cohesin complex complex SIGNOR-C355 SIGNOR form complex binding 10090 BTO:0000534 21242291 YES miannu RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. 0.783 SIGNOR-264538 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 YES miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. 0.8 SIGNOR-264927 perfluorohexanesulfonic acid chemical CHEBI:132448 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 YES miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. 0.8 SIGNOR-268755 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser15 GLGGGAAsPPAASPF 9534 BTO:0000298 12756254 YES miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. 0.879 SIGNOR-250123 USP17L2 protein Q6R6M4 UNIPROT BHLHE40 protein O14503 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0002181 25202122 YES miannu Upon DNA damage, DEC1 is rapidly induced in an ATM/ATR-dependent manner. DEC1 induction results from protein stabilization via a mechanism that requires the USP17 ubiquitin protease. USP17 binds and deubiquitylates DEC1, markedly extending its half-life.  0.2 SIGNOR-276852 PRKCB protein P05771 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 YES lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. 0.328 SIGNOR-248974 CDK5 protein Q00535 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates activity phosphorylation Thr668 ENLDLKLtPYKVLAT 9606 BTO:0000007 20513426 YES miannu Phosphorylation of Vps34 on Thr159 inhibits its interaction with Beclin 1. two additional amino acids in Vps34, Thr159 and Thr668, were found to be phosphorylated only after co-transfection with Cdk5/p25 0.357 SIGNOR-259811 HES1 protein Q14469 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity transcriptional regulation 10090 BTO:0000165 10066785 YES gcesareni Notch signaling up-regulated HES1 mRNA expression within 1 h and subsequently reduced expression of MyoD mRNA 0.295 SIGNOR-243181 Caspase 3 complex complex SIGNOR-C221 SIGNOR STX5 protein Q13190 UNIPROT down-regulates activity cleavage 9606 14970262 YES miannu Giantin and syntaxin 5 are cleaved by caspase-3. Given that both giantin and syntaxin 5 are cleaved at an early stage during apoptosis, we anticipated that, at the very least, the delivery of ER-derived transport intermediates to the Golgi would be impaired in apoptotic cells. 0.2 SIGNOR-261236 PICK1 protein Q9NRD5 UNIPROT BNC1 protein Q01954 UNIPROT up-regulates activity relocalization 10116 BTO:0000938 11802773 YES miannu we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction 0.307 SIGNOR-223414 AKT1 protein P31749 UNIPROT SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 YES miannu We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh. 0.394 SIGNOR-252501 STK24 protein Q9Y6E0 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Thr442 DWVFLNYtYKRFEGL 9606 BTO:0000007 16314523 YES lperfetto Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity. 0.441 SIGNOR-142510 WNT10B protein O00744 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 NO fspada We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b 0.475 SIGNOR-176190 EPGN protein Q6UW88 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 YES gcesareni Areg (amphiregulin), btc (beta-cellulin), egf, epgn (epigen), ereg (epiregulin), hbegf, nrg1, nrg2, nrg3, nrg4 and tgfa (tgfalpha) constitute egf family ligands for erbb family receptors. 0.394 SIGNOR-147835 RUNX2 protein Q13950 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004473 19049325 NO miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. 0.338 SIGNOR-252192 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity relocalization 9606 BTO:0001545 26607380 YES miannu Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity. 0.283 SIGNOR-261514 PAK5 protein Q9P286 UNIPROT PAK5 protein Q9P286 UNIPROT up-regulates activity phosphorylation His22 SNFEHRVhTGFDPQE -1 12860998 YES miannu Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation. 0.2 SIGNOR-250249 PBK protein Q96KB5 UNIPROT GPSM2 protein P81274 UNIPROT up-regulates phosphorylation Thr457 LKGKKYKtNSSTKVL 9606 BTO:0000150 20589935 YES lperfetto We found that the 450th threonine (thr450) of lgn/gpsm2 was phosphorylated by the serine/threonine kinase pbk/topk during mitosis. Western blot analysis indicated the highest expression and the phosphorylated form of lgn/gpsm2 protein in g2/m phase. 0.27 SIGNOR-166461 NRXN2 protein Q9P2S2 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 22626544 YES miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites 0.828 SIGNOR-265454 AKT1 protein P31749 UNIPROT FANCA protein O15360 UNIPROT unknown phosphorylation Ser1149 CLRSRDPsLMVDFIL -1 11855836 YES FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time. 0.46 SIGNOR-252567 UCHL3 protein P15374 UNIPROT RPS27A protein P62979 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 YES miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. 0.802 SIGNOR-270828 GRK5 protein P34947 UNIPROT GRK5 protein P34947 UNIPROT up-regulates activity phosphorylation Thr485 LDIEQFStVKGVNLD -1 8144599 YES Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5. 0.2 SIGNOR-251202 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr999 YASSNPEyLSASDVF 10116 15738637 YES In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. 0.286 SIGNOR-248443 CHEK1 protein O14757 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates quantity by destabilization phosphorylation Ser20 QLKRWIGsETDLEPP 9606 BTO:0000567 29262732 YES miannu  MYPT1 is phosphorylated by CDK1, thus recruiting protein phosphatase 1β (PP1cβ) to dephosphorylate and inactivate Plk1. Here we identified that Chk1 directly interacts with MYPT1 and preferentially phosphorylates MYPT1 at Ser20, which is essential for MYPT1-PP1cβ interaction and subsequent Plk1 dephosphorylation. 0.2 SIGNOR-277870 DIS3L protein Q8TF46 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 YES miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). 0.911 SIGNOR-261391 LCK protein P06239 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr715 LVMLGASyWYRARLH 9606 BTO:0000661 11741929 YES lperfetto Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling. 0.35 SIGNOR-112931 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 9606 BTO:0000938 15381704 YES The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. 0.322 SIGNOR-129332 BAZ2B protein Q9UIF8 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 YES miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. 0.2 SIGNOR-266619 Naltrindole chemical CHEBI:81528 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258817 CDK16 protein Q00536 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates activity phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000567 25605337 YES lperfetto PCTK1 regulates spindle orientation in a kinase-dependent manner. Phosphoproteomic analysis together with an RNA interference screen revealed that PCTK1 regulates spindle orientation through phosphorylation of Ser83 on KAP0, a regulatory subunit of protein kinase A (PKA) 0.272 SIGNOR-273018 AKT1 protein P31749 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr72 TERPRPNtFIIRCLQ -1 16549426 YES miannu Autophosphorylation of Akt on Thr-72 and Ser-246 appeared to require prior phosphorylation of Akt on Thr-308 and Ser-473. Compared with wild-type Akt, Akt/T72A/S246A mutant exhibited markedly reduced basal Akt kinase activity and response to cellular stimulation by insulin-like growth factor-1, and also conferred less cellular resistance to doxorubicin-induced apoptosis. 0.2 SIGNOR-276054 CDH18 protein Q13634 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.575 SIGNOR-265857 MAPK3 protein P27361 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 YES lperfetto Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol 0.2 SIGNOR-137179 FUS protein P35637 UNIPROT HNRNPA2B1 protein P22626 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 28515487 NO This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease 0.511 SIGNOR-262802 PRKCD protein Q05655 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Ser139 EEWTRHGsFVNKPTR 9606 16963224 YES The effect has been demonstrated using P29353-2 gcesareni Pkc delta phosphorylates p52shca at ser29 to regulate erk activation in response to h2o2. 0.567 SIGNOR-149398 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10116 11416002 YES lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin re- ceptors Tyr(612) and Tyr(632) in human insulin receptor substrate-1 are important for full activation of insulin-stimulated phosphatidylinositol 3-kinase activity and translocation of GLUT4 in adipose cells 0.914 SIGNOR-236709 PTPRB protein P23467 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity dephosphorylation Tyr81 WEVGSITyDTLSAQA 9606 32653904 YES miannu VE-PTP inhibition enhances eNOS activity to improve endothelial function and decrease blood pressure indirectly, through the activation of Tie-2 and the CD31/VE, cadherin, and VEGFR2 complex, and directly by dephosphorylating eNOS Tyr81.|VE-PTP, on the other hand, formed a complex with eNOS in endothelial cells and directly dephosphorylated eNOS Tyr81 in vitro. 0.267 SIGNOR-277041 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270423 NME1 protein P15531 UNIPROT PTN protein P21246 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 NO miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. 0.2 SIGNOR-255167 PTPN2 protein P17706 UNIPROT GJA1 protein P17302 UNIPROT up-regulates dephosphorylation Tyr265 KDCGSQKyAYFNGCS 9606 BTO:0000671 24849651 YES lperfetto Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43. 0.324 SIGNOR-205101 uridine smallmolecule CHEBI:16704 ChEBI uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity precursor of 11306702 YES lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. 0.8 SIGNOR-275856 ACVR1B protein P36896 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by stabilization 9606 2920215 NO Regulation miannu Activin, also named FSH-releasing protein, was previously shown to induce hemoglobin accumulation in K562 cells and potentiate the proliferation and differentiation of CFU-E in human bone marrow cultures. 0.2 SIGNOR-251769 SYK protein P43405 UNIPROT EZR protein P15311 UNIPROT up-regulates activity phosphorylation 9606 23703860 YES miannu Phospho-SYK has also been shown to specifically activate ezrin upon CD81 engagement.|We found that the activated SYK led to a time dependent phosphorylation of ezrin (pY354 and pThr567) and radixin (pThr564) (XREF_FIG). 0.448 SIGNOR-279129 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.317 SIGNOR-120204 MCHR2 protein Q969V1 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. 0.25 SIGNOR-256795 NLK protein Q9UBE8 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 26588989 YES done miannu NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment.  0.328 SIGNOR-273908 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 11154281 YES lperfetto We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253. 0.794 SIGNOR-236607 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 17110930 YES Barakat Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK 0.723 SIGNOR-274147 ATR protein Q13535 UNIPROT RAD17 protein O75943 UNIPROT up-regulates activity phosphorylation Ser656 SASELPAsQPQPFSA 9606 11687627 YES lperfetto Here we demonstrate that atr but not atm phosphorylates the human rad17 (hrad17) checkpoint protein on ser(635) and ser(645) in vitro.The rfc-related checkpoint protein rad17, a phosphorylation substrate of atr, is critical for atr-mediated checkpoint signaling and cell survival. 0.858 SIGNOR-111252 PPP2CA protein P67775 UNIPROT KRT8 protein P05787 UNIPROT unknown dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000182 16554440 YES K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts. 0.2 SIGNOR-248623 SRSF3 protein P84103 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates binding 9606 18364396 YES miannu 9g8 and srp20 also enhance the tap rna-binding activity 0.679 SIGNOR-178111 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr980 LLPLDKDyYVVREPG 9606 9391116 YES gcesareni We found that jak3 is autophosphorylated on multiple sites including y980 and y981. Compared with the activity of wild-type (wt) jak3, mutant y980f demonstrated markedly decreased kinase activity, and optimal phosphorylation of jak3 on other sites was dependent on y980 phosphorylation. The mutant y980f also exhibited reduced phosphorylation of its substrates, gammac and stat5a. In contrast, mutant y981f had greatly increased kinase activity, whereas the double mutant, yy980/981ff, had intermediate activity. 0.2 SIGNOR-53590 AKT2 protein P31751 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates activity phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 26759241 YES miannu AKT2 phosphorylates Twist1 at S42 to enhance Twist1 mediated E-cadherin suppression. 0.399 SIGNOR-279137 CSNK2A1 protein P68400 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 YES llicata In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro. 0.437 SIGNOR-250941 STK10 protein O94804 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 19255442 YES llicata Evidence in jurkat cells that lok phosphorylates erm and that erm phosphorylation impedes migration. 0.386 SIGNOR-184433 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 9029153 YES lperfetto Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_ 0.363 SIGNOR-217320 PRKACB protein P22694 UNIPROT NGFR protein P08138 UNIPROT up-regulates phosphorylation Ser303 PEGEKLHsDSGISVD 9606 BTO:0000938 12682012 YES llicata Pka phosphorylates the p75 receptor and regulates its localization to lipid rafts. activation of camp?PKA Is required for translocation of p75ntr to lipid rafts, and for biochemical and biological activities of p75ntr, such as inactivation of rho and the neurite outgrowth. 0.624 SIGNOR-99755 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258291 hsa-miR-23b-3p mirna URS00004E57E7_9606 RNAcentral MAP3K1 protein Q13233 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001109 22109528 YES Parnian MiR-23b, which is downregulated in human colon cancer samples, potently mediates the multiple steps of metastasis, including tumour growth, invasion and angiogenesis in vivo . | Mutation of the putative miR-23b site(s) in the 3′-UTR of FZD7, MAP3K1 (MEKK1), PAK2, TGFβR2, RRAS2 or uPA resulted in an abrogated responsiveness to miR-23b. 0.4 SIGNOR-277960 CTDSPL2 protein Q05D32 UNIPROT STK35 protein Q8TDR2 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser385 KVADFGLsKVCAGLA 9606 BTO:0002181 35021089 YES miannu  We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D). 0.282 SIGNOR-273775 TCL1B protein O95988 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 YES gcesareni In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation. 0.671 SIGNOR-81713 LRRK2 protein Q5S007 UNIPROT AP2M1 protein Q96CW1 UNIPROT up-regulates activity phosphorylation Thr156 SQITSQVtGQIGWRR 9606 34315807 YES miannu These data confirmed that LRRK2 phosphorylates AP2M1 at Thr 156 in vitro. 0.26 SIGNOR-278183 BMP7 protein P18075 UNIPROT PRDM16 protein Q9HAZ2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18719589 NO fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways 0.404 SIGNOR-180317 EGFR protein P00533 UNIPROT CRK protein P46108 UNIPROT down-regulates activity phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 BTO:0000007 9642287 YES llicata To address these questions, we have developed an antibody that specifically recognizes the CrkII protein phosphorylated on Tyr221, and we found that the EGF receptor directly phosphorylates CrkII on Tyr221. Furthermore, we observed that the phosphorylation of Tyr221 of CrkII correlated with its dissociation from the EGF receptor, implicating the phosphorylation of Tyr221 in the negative feedback of binding to the EGF receptor. 0.739 SIGNOR-251091 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 YES In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator 0.737 SIGNOR-248743 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CIITA protein P33076 UNIPROT down-regulates phosphorylation 9606 18245089 YES inferred from 70% family members gcesareni In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. 0.2 SIGNOR-270173 AR protein P10275 UNIPROT BTG2 protein P78543 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 NO After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. 0.378 SIGNOR-253674 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 YES lperfetto The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling. 0.722 SIGNOR-32748 MTA1 protein Q13330 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR up-regulates activity binding 10090 24089055 YES lperfetto Here we provide genetic and biochemical evidence that metastasis-associated protein 1 (MTA1), a widely upregulated gene product in human cancers, is an integral component of the circadian molecular machinery. | The CLOCK-BMAL1 heterodimer activates MTA1 transcription through a conserved E-box element at its promoter. MTA1, in turn, interacts with and recruits CLOCK-BMAL1 at its own and CRY1 promoters and promotes their transcription. 0.2 SIGNOR-253723 REN protein P00797 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT up-regulates quantity cleavage 9606 32201502 YES miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). 0.2 SIGNOR-260225 LPCAT2 protein Q7L5N7 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI down-regulates quantity chemical modification 9606 21498505 YES miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  0.8 SIGNOR-272767 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 31995776 YES miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . 0.8 SIGNOR-268733 SEMA5A protein Q13591 UNIPROT PLXNB3 protein Q9ULL4 UNIPROT up-regulates activity binding 10090 BTO:0000944 15218527 YES miannu Plexin-B3 is a functional receptor for semaphorin 5A. Here we show that plexin-B3 is a high-affinity receptor specific for Sema5A. We further demonstrate that plexin-B3 activation by Sema5A mediates functional responses in plexin-B3-expressing cells (either fibroblasts, epithelial and primary endothelial cells). 0.622 SIGNOR-268373 MAP3K7 protein O43318 UNIPROT TAB1 protein Q15750 UNIPROT up-regulates activity phosphorylation Ser453 TNTHTQSsSSSSDGG 9606 BTO:0000007 22216226 YES miannu We identified amino acids (aa) 452/453 and 456/457 of TAB1 as novel sites phosphorylated by TAK1 as well as by p38 MAPK in intact cells as well as in vitro.  0.929 SIGNOR-276366 SOCS3 protein O14543 UNIPROT IRS1 protein P35568 UNIPROT down-regulates binding 9606 23115649 YES gcesareni Irs-1 is the major signaling protein that socs3 targets to inhibit insulin signaling 0.739 SIGNOR-199361 STRA6 protein Q9BX79 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI up-regulates quantity relocalization 9913 17255476 YES lperfetto We identified in bovine retinal pigment epithelium cells STRA6, a multitransmembrane domain protein, as a specific membrane receptor for RBP. STRA6 binds to RBP with high affinity and has robust vitamin A uptake activity from the vitamin A-RBP complex 0.8 SIGNOR-265107 SPI1 protein P17947 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16923394 NO miannu PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation 0.306 SIGNOR-256039 OXTR protein P30559 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.447 SIGNOR-257178 PBK protein Q96KB5 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 26745678 YES miannu TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.|These data confirm the phosphorylation of c-Jun by TOPK at serine 63 and 73 during the development of resistance to EGFR-targeted TKIs. 0.431 SIGNOR-278155 KRAS protein P01116 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 NO miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 0.425 SIGNOR-267361 POLR2H protein P52434 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 YES lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  0.912 SIGNOR-266149 PTGS2 protein P35354 UNIPROT prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity chemical modification -1 7592599 YES Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, 0.8 SIGNOR-269776 SMAD7 protein O15105 UNIPROT ACVRL1 protein P37023 UNIPROT down-regulates 9606 BTO:0000975 12023024 NO gcesareni Smad7, induced by alk1 activation, recruits pp1? To alk1 and thereby inhibits tgf-?/Alk1-induced smad1/5 phosphorylation in ecs. 0.57 SIGNOR-87673 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 YES miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. 0.8 SIGNOR-267884 GSK3B protein P49841 UNIPROT USF2 protein Q15853 UNIPROT up-regulates activity phosphorylation Thr230 PKIDGTRtPRDERRR 9606 25238393 YES miannu Although no study has yet correlated the activity of GSK3beta with the activity of USF2 in a certain tumor setting, the findings of the present study would favor the tumor promoting aspects of GSK3beta and USF2 since GSK3beta activated USF2 enhanced cell migration which may be important in terms of tumor cell metastasis.|Together, these data show that there are two residues within USF2, namely S155 and T230, which can be phosphorylated by GSK3beta. 0.284 SIGNOR-278158 KATNA1 protein O75449 UNIPROT KATNB1 protein Q9BVA0 UNIPROT up-regulates activity binding 9606 BTO:0000567 10751153 YES miannu In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer 0.755 SIGNOR-267174 PLK1 protein P53350 UNIPROT YBX1 protein P67809 UNIPROT up-regulates quantity phosphorylation Ser174 SGEKNEGsESAPEGQ 9606 36805592 YES miannu Here we identify that PLK1 inhibition can induce apoptosis and DNA damage of GSCs, we have also delineat the possible underlying molecular mechanisms: PLK1 interacts with YBX1 and directly phosphorylates serine 174 and serine 176 of YBX1.|Inhibition of PLK1 reduces the phosphorylation level of YBX1, and decreased phosphorylation of YBX1 prevents its nuclear translocation, thereby inducing apoptosis and DNA damage of GSCs. 0.253 SIGNOR-279254 TM9SF4 protein Q92544 UNIPROT ATP6V1H protein Q9UI12 UNIPROT up-regulates activity binding 9606 BTO:0001109;BTO:0000038 25659576 YES miannu Here, we demonstrate that TM9SF4 represents a novel V-ATPase-associated protein involved in V-ATPase activation. We have observed in HCT116 and SW480 colon cancer cell lines that TM9SF4 interacts with the ATP6V1H subunit of the V-ATPase V1 sector. Suppression of TM9SF4 with small interfering RNAs strongly reduces assembly of V-ATPase V0/V1 sectors, thus reversing tumor pH gradient with a decrease of cytosolic pH, alkalization of intracellular vesicles and a reduction of extracellular acidity. 0.271 SIGNOR-266885 CARM1 protein Q86X55 UNIPROT PAX7 protein P23759 UNIPROT up-regulates methylation 10090 BTO:0002314 BTO:0001103 29681515 YES apalma Carm1 specifically methylates Pax7 at multiple arginine residues in the N terminus of Pax7 0.421 SIGNOR-255898 GSK3B protein P49841 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity phosphorylation Ser683 NLFGHVGsTTASRGE 9606 27501329 YES miannu GSK3beta phosphorylates KDM1A serine 683 upon priming phosphorylation of KDM1A serine 687 by CK1alpha.|Together, these results support the notion that GSK3\u03b2 stabilizes KDM1A by decreasing its ubiquitination. 0.265 SIGNOR-278225 PRKCI protein P41743 UNIPROT LLGL1 protein Q15334 UNIPROT up-regulates activity phosphorylation Ser659 RVKSLKKsLRQSFRR 9615 12725730 YES miannu This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner. 0.633 SIGNOR-263179 TP53 protein P04637 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 NO P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts 0.7 SIGNOR-255669 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.522 SIGNOR-257372 NTRK2 protein Q16620 UNIPROT SHC3 protein Q92529-2 UNIPROT up-regulates activity phosphorylation Tyr218 GDGSDHPyYNSIPSK -1 11791173 YES done miannu We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo. 0.755 SIGNOR-273916 MTA2 protein O94776 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.819 SIGNOR-263841 SMARCD1 protein Q96GM5 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.812 SIGNOR-270615 GHSR protein Q92847 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.267 SIGNOR-256925 PRKACA protein P17612 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Ser455 PAPSRTAsFSESRAD -1 10653665 YES miannu Phosphorylation of Recombinant Human ATP:Citrate Lyase by cAMP-Dependent Protein Kinase Abolishes Homotropic Allosteric Regulation of the Enzyme by Citrate and Increases the Enzyme Activity. Ser 454, which is phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA) 0.31 SIGNOR-250328 DAPK2 protein Q9UIK4 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser721 TPRLRSVsSYGNIRA 9606 25361081 YES miannu DAPK2 phosphorylates raptor in vitro on Ser721. 0.355 SIGNOR-278243 AKT proteinfamily SIGNOR-PF24 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser939 SFRARSTsLNERPKS 10090 BTO:0000944 12150915 YES lperfetto We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. 0.2 SIGNOR-244369 BMPR1A protein P36894 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 19620713 YES gcesareni Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. 0.687 SIGNOR-187184 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A1 protein P68104 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 YES lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. 0.921 SIGNOR-269387 CHEK2 protein O96017 UNIPROT ELAVL1 protein Q15717 UNIPROT down-regulates activity phosphorylation Ser88 LNGLRLQsKTIKVSY 9606 21745814 YES miannu Given the fact that Chk2 phosphorylates HuR at residues S88, S100 and T118 and that each individual phosphorylation site by Chk2 plays a distinct role in regulating HuR- binding to different target mRNAs (22,42), we further tested HuR mutants with alanine substitutions at each of the Chk2 phosphorylation sites. 0.551 SIGNOR-278163 EEF1A1 protein P68104 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity binding 9606 BTO:0000608 37973952 YES Marta Tosoni Subsequently, the elevated expression of eEF1A1 resulted in its binding to SP1, which in turn drove the binding of SP1 to its target HGF gene promoter to increase its transcription 0.2 SIGNOR-278105 ULK1 protein O75385 UNIPROT HK1 protein P19367 UNIPROT up-regulates activity phosphorylation Ser124 NIVHGSGsQLFDHVA 9606 BTO:0000007 27153534 YES done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). 0.257 SIGNOR-274034 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser824 LVDKEHDsAEGSHTS 9606 BTO:0001109 28114302 YES miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. 0.328 SIGNOR-276516 POU2F1 protein P14859 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 YES lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation 0.2 SIGNOR-238757 ACE protein P12821 UNIPROT bradykinin smallmolecule CHEBI:3165 ChEBI down-regulates quantity by destabilization binding 9606 16219810 YES The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin. 0.8 SIGNOR-253341 JAK1 protein P23458 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 10825200 NO gcesareni Syk activation required jak3, probably indirectly via activation of jak1. 0.535 SIGNOR-77551 ITGA6 protein P23229 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR form complex binding 16988024 YES lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. 0.819 SIGNOR-253179 TAC1 protein P20366 UNIPROT TACR2 protein P21452 UNIPROT up-regulates binding 9606 8925404 YES gcesareni The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag). 0.874 SIGNOR-44773 PBXIP1 protein Q96AQ6 UNIPROT PBX1 protein P40424 UNIPROT down-regulates activity binding 9606 BTO:0000007 24488098 YES miannu This protein that we have termed hematopoietic PBX-interacting protein (HPIP) is mainly localized in the cytosol and in small amounts in the nucleus. The region of PBX that interacts with HPIP includes both the homeodomain and immediate N-terminal flanking sequences. Strikingly, electrophoretic mobility shift assays revealed that HPIP inhibits the ability of PBX-HOX heterodimers to bind to target sequences.  0.331 SIGNOR-273666 FASN protein P49327 UNIPROT Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 9356448 NO miannu Our model of the native fatty acid synthase (FAS) depicts it as a dimer of two identical multifunctional proteins (Mr approximately 272,000) arranged in an antiparallel configuration so that the active Cys-SH of the beta-ketoacyl synthase of one subunit (where the acyl group is attached) is juxtaposed within 2 A of the pantetheinyl-SH of the second subunit (where the malonyl group is bound). This arrangement generates two active centers for fatty acid synthesis and predicts that if we have two appropriate halves of the monomer, we should be able to reconstitute an active fatty acid-synthesizing site 0.7 SIGNOR-268159 ADRA2B protein P18089 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.461 SIGNOR-256714 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM10 protein Q9UDY6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270972 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Thr785 SINEMLStQALRLDE 9606 17396146 YES gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. 0.418 SIGNOR-154175 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser376 LKSKKGQsTSRHKKL 9606 9315650 YES llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro. serines 371, 376, 378, and 392 may be the potential sites for this kinase. 0.459 SIGNOR-51284 SCN8A protein Q9UQD0 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 NO miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. 0.7 SIGNOR-253452 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 1178183 YES lperfetto Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge. 0.512 SIGNOR-16043 POU3F2 protein P20265 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by expression transcriptional regulation 18628967 YES lperfetto We further demonstrate that BRN2 induces MITF transcription through a binding site located at ˆ’50/ˆ’36 of the MITF promoter 0.438 SIGNOR-249616 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1763 TPTSPSYsPTSPSYS -1 22137580 YES Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. 0.432 SIGNOR-248789 Class II MHC:Antigen complex SIGNOR-C429 SIGNOR CD4 protein P01730 UNIPROT up-regulates activity binding 9606 31001252 YES scontino Extracellular domain of¬†CD4, which is responsible for the recognition of its ligands, is composed of four globular Ig-like domains (D1-D4). The N-terminal D1 domain binds to a segment of the non-polymorphic Œ≤2 domain of MHC class II. CD4 is required for the recognition of most antigens in vivo. The presence of the CD4 coreceptor enhances T cell sensitivity to antigens 0.2 SIGNOR-267990 ITGB1BP1 protein O14713 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR down-regulates activity binding 9606 19118207 YES miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation 0.734 SIGNOR-257639 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 YES lperfetto AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬† 0.2 SIGNOR-244311 PAPOLB protein Q9NRJ5 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization chemical modification 9606 19224921 YES lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. 0.8 SIGNOR-268328 HBEGF protein Q99075 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 14967450 YES Heparin-binding EGF-like growth factor??is synthesized as a membrane-anchored mitogenic and chemotactic glycoprotein. gcesareni Ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4 0.767 SIGNOR-121977 MRPL38 protein Q96DV4 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.691 SIGNOR-262359 E2F1 protein Q01094 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12110166 NO fspada We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation 0.46 SIGNOR-90459 CDK1 protein P06493 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser589 NRHSPSWsPDGRRRQ 9606 20890132 YES miannu In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. the phosphorylation at the site Ser589 by Cdc2/cyclin B1 plays an important role in Nlp protein stability probably due to its effect on protein degradation. 0.421 SIGNOR-259831 SPOP protein O43791 UNIPROT GMNN protein O75496 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 34599168 YES miannu SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication. 0.2 SIGNOR-268926 PLCG1 protein P19174 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 21918248 YES gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. 0.8 SIGNOR-176609 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 YES lperfetto We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2. 0.791 SIGNOR-236014 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2366 MEQGHFAsPDQNSML 9606 17623675 YES lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. 0.2 SIGNOR-244537 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates quantity phosphorylation Thr267 KSNLKRVtLELGGKS 9606 28193222 YES miannu AURKA phosphorylates ALDH1A1 at T267, T442, and T493.|Our data revealed that AURKA increases ALDH1A1 levels by inhibiting its ubiquitylation; thus, we examined whether 3A-ALDH1A1 was impervious to AURKA mediated protein stability. 0.372 SIGNOR-278166 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates quantity phosphorylation Thr442 KDIDKAItISSALQA 9606 28193222 YES miannu AURKA phosphorylates ALDH1A1 at T267, T442, and T493.|Our data revealed that AURKA increases ALDH1A1 levels by inhibiting its ubiquitylation; thus, we examined whether 3A-ALDH1A1 was impervious to AURKA mediated protein stability. 0.372 SIGNOR-278167 NUP43 protein Q8NFH3 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 YES lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). 0.693 SIGNOR-262087 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 YES Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence 0.633 SIGNOR-273060 PHA-680632 chemical CID:11249084 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206103 CDK2 protein P24941 UNIPROT UBTF protein P17480 UNIPROT up-regulates activity phosphorylation Ser389 INKKQATsPASKKPA 10090 BTO:0000944 SIGNOR-C16 11698641 YES lperfetto Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity 0.372 SIGNOR-235419 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr327 NSKPKKSyIATQGCL 9534 BTO:0004055 8995399 YES lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 0.793 SIGNOR-236270 FGFR3 protein P22607 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 YES miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). 0.2 SIGNOR-276181 VTI1A protein Q96AJ9 UNIPROT LE-TGN SNARE complex SIGNOR-C157 SIGNOR form complex binding 9606 BTO:0000567 18195106 YES lperfetto We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport 0.81 SIGNOR-253081 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity phosphorylation Ser616 EGDDRPEsPEYSGGN 10116 BTO:0000601 11080179 YES miannu We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP. 0.367 SIGNOR-262934 CUL3 protein Q13618 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR form complex binding 9606 BTO:0000007 16547521 YES miannu  KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation. 0.878 SIGNOR-271560 CSNK1E protein P49674 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity phosphorylation Tyr446 SLYSQPFyTGYFGYK 9606 BTO:0002181 32779804 YES miannu We found that the interaction of CK1ε with TRAF3Y116F, TRAF3Y446F were markedly decreased compared with interactions with WT TRAF3 by Co‐IP (Figure 6C); as expected, TRAF3Y116F and TRAF3Y446F mutants exhibited reduced K63‐linked ubiquitination (Figure 6D). These data suggest that the phosphorylation of TRAF3 at Tyr 116 and Tyr 446 regulate CK1ε‐induced K63‐linked ubiquitination. 0.307 SIGNOR-277524 NBEAL2 protein Q6ZNJ1 UNIPROT Platelet_alpha_granule_formation phenotype SIGNOR-PH136 SIGNOR up-regulates 9606 BTO:0000132 28082341 NO lperfetto We compared platelet size and number of α-granules for two NBEAL2 and two GATA1-deficient patients and found reduced numbers of α-granules for all, with the defect being more pronounced for NBEAL2 deficiency.  0.7 SIGNOR-261883 TNKS protein O95271 UNIPROT BLZF1 protein Q9H2G9 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 21478859 YES lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. 0.351 SIGNOR-263385 MLF1 protein P58340 UNIPROT COP1 protein Q8NHY2 UNIPROT up-regulates 9606 15861129 NO miannu As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53 0.2 SIGNOR-135940 Parathyroid hormone-related peptide (1-36) smallmolecule CHEBI:80274 ChEBI PTH1R protein Q03431 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257575 EGR1 protein P18146 UNIPROT SLC9A3 protein P48764 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 16464174 NO Transcriptional stimulation of the human NHE3 promoter activity by PMA: PKC independence and involvement of the transcription factor EGR-1|Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity 0.246 SIGNOR-254269 LATS1 protein O95835 UNIPROT PRPS1 protein P60891 UNIPROT down-regulates quantity by destabilization phosphorylation Ser285 EDKMKHCsKIQVIDI -1 34465890 YES miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. 0.2 SIGNOR-276505 MUL1 protein Q969V5 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization ubiquitination Lys284 LENLMLDkDGHIKIT 9606 BTO:0000007 22410793 YES gcesareni The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability. 0.476 SIGNOR-252437 MC1R protein Q01726 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 YES lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins 0.479 SIGNOR-268697 ARRB2 protein P32121 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000971 12488444 YES miannu Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination. 0.434 SIGNOR-272592 DRD1 protein P21728 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.284 SIGNOR-257068 TP63 protein Q9H3D4 UNIPROT PERP protein Q96FX8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21965674 NO miannu SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding. 0.622 SIGNOR-255136 RNF5 protein Q99942 UNIPROT CFTR protein P13569 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21148293 YES miannu JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. 0.664 SIGNOR-271494 FZR1 protein Q9UM11 UNIPROT SKIL protein P12757 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 11741538 YES miannu  We demonstrate that the anaphase-promoting complex (APC) is a ubiquitin ligase required for the destruction of SnoN and that the APC pathway is regulated by TGF-beta. The destruction box of SnoN is required for its degradation in response to TGF-beta signaling. Furthermore, the APC activator CDH1 and Smad3 synergistically regulate SnoN degradation. Under these circumstances, CDH1 forms a quaternary complex with SnoN, Smad3, and APC.  0.386 SIGNOR-272621 CDK1 protein P06493 UNIPROT USP22 protein Q9UPT9 UNIPROT up-regulates activity phosphorylation 9606 27030811 YES miannu On the other hand, CDK1 enhances USP22 activity to stabilize CCNB1 during the G2/M phase.|Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1. 0.471 SIGNOR-278241 GATA1 protein P15976 UNIPROT MPL protein P40238 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15466856 NO miannu Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. 0.441 SIGNOR-254162 KCTD10 protein Q9H3F6 UNIPROT Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR up-regulates activity binding 9606 BTO:0004790 30404837 YES miannu Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation. we identified the cullin-3-RBX1-KCTD10 complex as the E3 ligase that mediates CEP97 degradation and removal from the mother centriole. 0.495 SIGNOR-272924 PRKD2 protein Q9BZL6 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates activity phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 YES lperfetto Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase 0.291 SIGNOR-275937 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser175 EEEEDLSsPPGLPEP 9606 14697653 YES lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. 0.268 SIGNOR-120467 SPRED1 protein Q7Z699 UNIPROT NF1 protein P21359 UNIPROT up-regulates quantity binding 9606 BTO:0000007 32697994 YES miannu Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS. 0.635 SIGNOR-273660 SRC protein P12931 UNIPROT AR protein P10275 UNIPROT up-regulates activity phosphorylation Tyr535 MDSYSGPyGDMRLET 9606 20383201 YES miannu In addition to the ability of Src to promotes castration resistant progression and AR activation, Src is involved in regulating prostate cancer cell migration, invasion, and metastasis and affects bone remodeling.|These data suggest that downstream of cell surface receptors, Ack1 mediates AR tyrosine phosphorylation at Tyr 267 and Src mediates AR tyrosine phosphorylation at Tyr 534. 0.76 SIGNOR-278168 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates phosphorylation 9606 26194464 YES MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). 0.722 SIGNOR-255032 MAP3K11 protein Q16584 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates phosphorylation Ser138 QKPFEDAsFALRTGE 9606 25519816 YES llicata Here we demonstrate that mixed-lineage kinase 3 (mlk3), a map3k family member, phosphorylates pin1 on a ser138 site to increase its catalytic activity and nuclear translocation. 0.263 SIGNOR-205586 SMAD1/4 complex SIGNOR-C85 SIGNOR PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18854943 NO fferrentino This Smad1/4 complex can directly interact with Shn-2 and C/EBP a on the PPAR g promoter thus, resulting in the transcriptional activation of PPAR g 0.285 SIGNOR-253551 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr973 RLGNGVLyASVNPEY -1 7493944 YES lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. 0.2 SIGNOR-246252 DERA protein Q9Y315 UNIPROT 2-deoxy-D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:62877 ChEBI down-regulates quantity chemical modification 9606 25229427 YES miannu Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase. 0.8 SIGNOR-267097 IRF3 protein Q14653 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22291912 NO miannu SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. 0.363 SIGNOR-254495 nilotinib chemical CHEBI:52172 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 YES Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. 0.8 SIGNOR-258259 atropine chemical CHEBI:16684 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 YES miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. 0.8 SIGNOR-258390 Immunoglobulin kappa light chain protein P0DOX7 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 20176268 YES scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. 0.2 SIGNOR-268194 MRGPRX2 protein Q96LB1 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.2 SIGNOR-257327 PBX1 protein P40424 UNIPROT HOXB1 protein P14653 UNIPROT up-regulates activity binding -1 10052460 YES 2 miannu Pbx1 and exd act as cofactors that enhance the DNA binding specificity of Hox proteins. The structure of the HoxB1–Pbx1–DNA ternary complex shows that HoxB1 and Pbx1 bind to overlapping binding sites located on opposite faces of the DNA. 0.807 SIGNOR-241219 Ub:E2 complex SIGNOR-C497 SIGNOR PML protein P29590 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-270992 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 19188143 YES gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity 0.507 SIGNOR-252905 GPR119 protein Q8TDV5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.278 SIGNOR-257040 MAP3K7 protein O43318 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity phosphorylation Ser355 TSAVPSTsTMSQEPE -1 37832545 YES miannu Activated TAK1 directly mediates STING phosphorylation on serine 355, which facilitates its interaction with STING ER exit protein (STEEP) and thereby promotes its oligomerization and translocation to the ERGIC for subsequent activation 0.2 SIGNOR-277887 CSNK2A2 protein P19784 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates activity phosphorylation Ser424 CDEEFSDsEDEGEGG 9606 BTO:0000567 12082111 YES llicata HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. | Since our data suggest that protein kinase CK2 is the major kinase responsible for HDAC2 phosphorylation, and because Ser422 and Ser424, but not Ser411, lie within CK2 recognition sequences, we believe that Ser394, Ser422, and Ser424 constitute the three phosphorylated residues in HDAC2. 0.39 SIGNOR-251003 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 20138985 YES lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. 0.729 SIGNOR-217586 MAPK3 protein P27361 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 9606 15262992 YES lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. 0.274 SIGNOR-126867 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 BTO:0001615 32238881 YES lperfetto Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. 0.2 SIGNOR-275584 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 21084559 YES miannu Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. 0.942 SIGNOR-256186 MAPK8 protein P45983 UNIPROT ARHGAP8 protein P85298 UNIPROT up-regulates activity phosphorylation Ser455 TKPTLPPsPLMAARR 28092672 YES lperfetto Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation. 0.327 SIGNOR-275550 SYNE1 protein Q8NF91 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR up-regulates activity binding 9606 BTO:0001950 24781983 YES miannu Nesprin-1 is involved in the DNA Damage Response network. The Nesprin-1 interaction with MSH2 and MSH6 (MutSα complex) is a constitutive cellular event required for proper DNA repair. 0.252 SIGNOR-261823 CDK1 protein P06493 UNIPROT SKA3 protein Q8IX90 UNIPROT up-regulates activity phosphorylation Thr360 ENLLRTPtPPEVTKI 9606 28479321 YES miannu Cdk1 treatment further enhanced the binding of Ska3 2D to Ndc80, suggesting that phosphorylation of other Cdk1 sites in Ska3 further contributes to the Ndc80C-Ska3 interaction, although this contribution is not apparent in our kinetochore localization assay.We next purified the GST-Ndc80C Bonsai construct that lacks the loop region of Ndc80 as well as the coiled coil regions of Ndc80C [17].|Thus, Ska3 can be phosphorylated by Cdk1 on T358 and T360 sites in vitro.We next tested whether Ska3 was required for Ska1 or Ska2 localization. 0.394 SIGNOR-278375 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 35318320 YES miannu Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. 0.755 SIGNOR-273843 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. 0.2 SIGNOR-70436 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Thr87 GVPAEGRtPPPFPGE 9606 22721717 YES lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation 0.341 SIGNOR-197936 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT unknown phosphorylation Ser34 PEVTGRSsVLRVSQK -1 26134678 YES lperfetto To address whether the phosphorylation state of TACC3 influenced Aurora-A binding and activation, we generated TACC3 variants in which all three Aurora-A phosphorylation sites (S34, S552 and S558)| The SA mutant had strongly reduced levels of phosphorylation compared to the individual mutations| 0.936 SIGNOR-263697 EPHA3 protein P29320 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 BTO:0000007 11870224 YES lperfetto Our results suggest that recruitment of crkii and activation of rho signalling are responsible for epha3-mediated cell rounding, blebbing and de-adhesion, and that ephrin-a5-mediated receptor clustering and epha3 tyrosine kinase activity are essential for this response 0.625 SIGNOR-115335 SH3GLB1 protein Q9Y371 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates binding 9606 21311563 YES gcesareni Bif-1 forms a complex with beclin1 through uvrag and promotes the activation of the class iii pi3 kinase, vps34, in mammalian cells. 0.543 SIGNOR-171899 FFAR2 protein O15552 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.402 SIGNOR-257276 Cullin 3-RBX1-Skp1 complex SIGNOR-C526 SIGNOR PIK3C3 protein Q8NEB9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 26687681 YES miannu Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. KLHL20 promotes ubiquitination of phagophore-residing VPS34 and Beclin-1 0.28 SIGNOR-272418 TGFBI protein Q15582 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates activity binding 26387839 YES lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers 0.359 SIGNOR-253271 STAT1 protein P42224 UNIPROT S100A10 protein P60903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0002923 12645529 NO miannu IFN-gamma induced a rapid tyrosine phosphorylation and nuclear translocation of STAT1 protein, which is involved in the binding to the GAS-2 site in the p11 promoter by EMSA analysis. These data suggest that IFN-gamma-induced p11 expression is mediated through the binding of STAT1 to GAS sites in the p11 promoter. 0.2 SIGNOR-255237 MAPK3 protein P27361 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser279 SSPTAPLsPMSPPGY 9606 9535909 YES lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. 0.636 SIGNOR-249466 GSK3A protein P49840 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser393 LTPEKGQsQGLIWDF 9606 BTO:0002181 31843895 YES miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. 0.263 SIGNOR-276762 CNR1 protein P21554 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.358 SIGNOR-257285 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity phosphorylation Ser126 PILVDTAsPSPMETS 9606 BTO:0000567 11242082 YES lperfetto Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation. 0.922 SIGNOR-105707 FLT3 protein P36888 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Tyr88 KGSLPEFyYRPPRPP 10090 BTO:0001516 28522571 YES lperfetto FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27 Kip1 in acute myeloid leukemia|P27Kip1 (p27) can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88. 0.29 SIGNOR-269208 RAC1 protein P63000 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR up-regulates activity binding 10090 BTO:0000142 8107774 YES gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. 0.789 SIGNOR-248256 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1280 QVILAKAsQEHHLSE 9606 BTO:0002181 11114888 YES llicata Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. 0.8 SIGNOR-250582 AKT proteinfamily SIGNOR-PF24 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 10559253 YES esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. 0.2 SIGNOR-72133 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 YES miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. 0.8 SIGNOR-268785 FBXL3 protein Q9UKT7 UNIPROT CRY2 protein Q49AN0 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 17463251 YES miannu  We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex. This regulation by SCF(Fbxl3) is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. HEK293T cells were transfected with Cry2, Skp1, Cul1, and Roc1 in the absence or presence of either FLAG-tagged Fbxl3 or a FLAG-tagged Fbxl3(ΔF-box) mutant. Fbxl3, but not an inactive Fbxl3(ΔF-box) mutant (4), induced the ubiquitination of Cry2 (Fig. 2D), which supports the notion that the effect of Fbxl3 on Cry2 is direct. 0.768 SIGNOR-271648 KNL1 protein Q8NG31 UNIPROT BUB1B protein O60566 UNIPROT up-regulates binding 9606 17981135 YES gcesareni Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions 0.2 SIGNOR-158894 tandutinib chemical CHEBI:90237 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-207209 TLR7 protein Q9NYK1 UNIPROT IFNA1 protein P01562 UNIPROT up-regulates quantity 9606 BTO:0004625 15661881 NO miannu TLR7 in pDC is functionally associated with the production of IFN-α- and IFN-regulated cytokines, similar to the role of TLR9. 0.404 SIGNOR-259248 PRKD2 protein Q9BZL6 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 9606 11062248 YES gcesareni The addition of phorbol 12,13-dibutyrate in the presence of dioleoylphosphatidylserine stimulated the autophosphorylation of pkd2 in a synergistic fashion.In addition, we could identify the c-terminal ser(876) residue as an in vivo phosphorylation site within pkd2. Phosphorylation of ser(876) of pkd2 correlated with the activation status of the kinase. 0.2 SIGNOR-83834 SEH1L protein Q96EE3 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 YES miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 0.838 SIGNOR-255304 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates chemical activation 9606 22863277 YES gcesareni Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors. 0.8 SIGNOR-198523 HTR1E protein P28566 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.446 SIGNOR-256705 TGFb proteinfamily SIGNOR-PF5 SIGNOR Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 NO inferred from 70% family members lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-Œ±, TGF-Œ≤, tumor necrosis factor (TNF)-Œ±, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor 0.7 SIGNOR-270216 PTPN6 protein P29350 UNIPROT TRAF3 protein Q13114 UNIPROT down-regulates activity dephosphorylation Tyr116 EILALQIyCRNESRG 9606 BTO:0002181 32779804 YES miannu We identified a direct interaction between SHP‐1 and TRAF3; the association between these two proteins resulted in diminished recruitment of CK1ε to TRAF3 and inhibited its K63‐linked ubiquitination; SHP‐1 inhibited K63‐linked ubiquitination of TRAF3 by promoting dephosphorylation at Tyr116 and Tyr446. 0.2 SIGNOR-277527 PRKACA protein P17612 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates phosphorylation Ser1105 LDRKRHNsISEAKMR 9606 10893237 YES llicata These data indicate that pkc and pka act similarly in that they inhibit galpha(q)-stimulated plcbeta(3) as a result of phosphorylation of ser(1105). 0.26 SIGNOR-79148 FYN protein P06241 UNIPROT NMT1 protein P30419 UNIPROT unknown phosphorylation Tyr180 YTLLNENyVEDDDNM -1 11594778 YES Human NMT was found to be phosphorylated by non-receptor tyrosine kinase family members of Lyn, Fyn and Lck. Tyr100 is the principle phosphorylation site on hNMT for Lyn and Fyn. The significance of a phosphorylation-dependent interaction between NMT and a tyrosine kinase is not known at present. 0.382 SIGNOR-251179 GSK3B protein P49841 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 NNTSTDGsLPSTPPP 10090 BTO:0003328 16543145 YES MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1. 0.501 SIGNOR-251242 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 10455013 YES lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity 0.2 SIGNOR-235782 TGM2 protein P21980 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 16407273 YES Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells. 0.2 SIGNOR-143642 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates activity chemical activation 9606 18790874 YES brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). 0.8 SIGNOR-263787 SDC3 protein O75056 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity binding 10090 BTO:0002314 20696709 YES gcesareni Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. 0.382 SIGNOR-254329 KIF19 protein Q2TAC6 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 NO In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. 0.7 SIGNOR-272532 NR3C1 protein P04150 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates quantity 10090 BTO:0000944 11742987 YES gcesareni Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity. 0.578 SIGNOR-253546 PPP2R2A protein P63151 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates activity binding 9606 19114990 YES lperfetto Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity 0.912 SIGNOR-217875 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity precursor of 9606 8755651 YES scontino Type II iodothyronine deiodinase (DII), which catalyzes deiodination of thyroxine (T4) exclusively on the outer ring (5‚Äô-position) to yield T3 0.8 SIGNOR-266948 EIF3D protein O15371 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 YES miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). 0.931 SIGNOR-266397 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 YES lperfetto We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735.These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by mapks may regulate the proteolytic function of membrane secretases. 0.2 SIGNOR-89614 PDIA6 protein Q15084 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity 10116 BTO:0003318 26487694 YES Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling. 0.2 SIGNOR-256537 PIP5K1C protein O60331 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates activity chemical modification 9606 9367159 YES miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities 0.8 SIGNOR-277285 HUWE1 protein Q7Z6Z7 UNIPROT KLF4 protein O43474 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 28084302 YES miannu K48 linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression.|Instead, we identified the transcription factor KLF4 as a novel Mule substrate that is ubiquitinated by this E3 ligase and thus undergoes proteasomal degradation in T cells.|Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase. 0.34 SIGNOR-278749 TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 10116 BTO:0003324 16407200 YES lperfetto In contrast to MKK3-induced p38 kinase downstream effects, TAB-1-induced p38 kinase activation does not induce expression of pro-inflammatory genes, cardiac marker gene expression, or changes in cellular morphology. Rather, TAB-1 binds to p38 and prevents p38 nuclear localization. 0.823 SIGNOR-143576 CDK1 protein P06493 UNIPROT TPX2 protein Q9ULW0 UNIPROT down-regulates activity phosphorylation Thr72 NLQQAIVtPLKPVDN -1 25688093 YES lperfetto In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle 0.636 SIGNOR-265096 RNF146 protein Q9NTX7 UNIPROT TNKS2 protein Q9H2K2 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 YES We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation. 0.612 SIGNOR-260005 LPAR2 protein Q9HBW0 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.482 SIGNOR-257431 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT up-regulates activity phosphorylation Tyr60 KTASSLSyDIHYWIG 9606 BTO:0000567 15342783 YES lperfetto These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton 0.364 SIGNOR-247437 ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT up-regulates activity phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 YES C-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. he functional significance of c-Abl-dependent phosphorylation of Rad52 is underscored by our findings that cells that express the phosphorylation-resistant Rad52 mutant, in which tyrosine 104 is replaced by phenylalanine, exhibit compromised nuclear foci formation in response to IR. 0.684 SIGNOR-251435 SCF-FBW7 complex SIGNOR-C135 SIGNOR GFI1 protein Q99684 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000498 31289136 YES miannu GSK3β-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. 0.2 SIGNOR-277467 CLK2 protein P49760 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates activity phosphorylation 9606 20074525 YES miannu Clk2 could also repress PGC-1alpha activation of Foxo1 on the IRS response element , as well as repress the Pepck promoter .|Clk2 phosphorylates and represses PGC-1\u03b1. 0.2 SIGNOR-278228 MARK3 protein P27448 UNIPROT TNK1 protein Q13470 UNIPROT down-regulates activity phosphorylation Ser502 RMKGISRsLESVLSL 9606 BTO:0000018 34504101 YES miannu We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.Phosphorylation of TNK1 at S502 within the proline rich domain is required for TNK1 binding to 14-3-3.MARKs mediate phosphorylation at S502 and 14-3-3 binding to TNK1, which restrains the movement of TNK1 into heavy membrane-associated clusters. 0.2 SIGNOR-273868 mTORC1 complex SIGNOR-C3 SIGNOR BTRC protein Q9Y297 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002572 33861966 YES miannu mTORC1 regulates the stability of CREB2. Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). 0.287 SIGNOR-267829 PROS1 protein P07225 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 7867073 YES gcesareni We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. 0.464 SIGNOR-34483 ACTL6A protein O96019 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 YES miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  0.812 SIGNOR-270620 TP53 protein P04637 UNIPROT FNTB protein P49356 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26469958 NO lperfetto In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs. 0.2 SIGNOR-242353 MRPL44 protein Q9H9J2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 YES lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules 0.702 SIGNOR-262352 BGLF5 protein P03217 UNIPROT TLR2 protein O60603 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002181 26428381 YES scontino The RNA degradation induced by EBV BGLF5 can affect immunologically relevant proteins, including TLR2. Alkaline exonuclease involved in host shutoff, downregulates TLR2. 0.2 SIGNOR-266741 S protein P59594 UNIPROT TLR2 protein O60603 UNIPROT up-regulates activity binding 9606 BTO:0001025 19185596 YES miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. 0.2 SIGNOR-260972 OGT protein O15294 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR down-regulates activity glycosylation 9606 BTO:0000007 22923583 YES lperfetto O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway| O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) to serine or threonine residues 0.346 SIGNOR-267586 HIRA protein P54198 UNIPROT HIRA complex 1 complex SIGNOR-C461 SIGNOR form complex binding 9606 30285846 YES miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. 0.697 SIGNOR-269434 SRC protein P12931 UNIPROT SOCS1 protein O15524 UNIPROT down-regulates activity phosphorylation Tyr80 LLDACGFyWGPLSVH -1 31101761 YES miannu SOCS1 is phosphorylated on Y80 by SRC family kinase members SRC and YES1. 0.45 SIGNOR-276857 CHD4 protein Q14839 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 YES miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. 0.835 SIGNOR-263856 GSK3B protein P49841 UNIPROT NACA protein E9PAV3 UNIPROT down-regulates phosphorylation Thr2022 NIQENTQtPTVQEES 9606 BTO:0000007 15005626 YES gcesareni Gsk3 beta-dependent phosphorylation of the alpha nac coactivator regulates its nuclear translocation and proteasome-mediated degradation. 0.2 SIGNOR-123262 PRKDC protein P78527 UNIPROT YBX1 protein P67809 UNIPROT up-regulates activity phosphorylation Thr89 EDVFVHQtAIKKNNP 9606 BTO:0000007 36475703 YES miannu The DNA-PK subunits and YB-1 phosphorylated at T89 were found colocalized suggesting their in vivo interaction.DNA-PK directly phosphorylates YB-1 and, this way, modulates YB-1 function. Point mutation of YB-1 at this residue abrogated the translocation of YB-1 into the nucleus. 0.338 SIGNOR-277611 ZSWIM2 protein Q8NEG5 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 16522193 NO miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  0.7 SIGNOR-271556 CDK9 protein P50750 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR form complex binding -1 34955012 YES lperfetto Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb).  0.964 SIGNOR-267740 ROCK1 protein Q13464 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 22944199 NO gcesareni Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements 0.7 SIGNOR-198840 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT up-regulates activity chemical activation 9606 19951971 YES lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. 0.8 SIGNOR-249628 CAP1 protein Q01518 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity 9606 BTO:0000567 30894654 NO lperfetto In HeLa and metastatic breast cancer cells, depletion of CAP1 leads to activation of FAK and enhanced cell adhesion 0.2 SIGNOR-264824 CDK5 protein Q00535 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity phosphorylation Ser203 DLEFSSGsPGKETNE 9606 17440046 YES llicata Cdk5 phosphorylated gr at multiple serines, including ser203 and ser211 of its n-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to dna.| the effect of CDK5 on GR-induced transcriptional activity is specific to gene promoter, and possibly, to tissue 0.48 SIGNOR-154401 MMP9 protein P14780 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Gly702 YEMHGPEgLRVGFYE -1 9344465 YES lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. 0.491 SIGNOR-261781 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 7566092 YES svumbaca Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. 0.95 SIGNOR-255363 PLK1 protein P53350 UNIPROT NCAPH2 protein Q6IBW4 UNIPROT up-regulates activity phosphorylation Ser288 ESRSPQQsAALPRRY 9606 28717250 YES miannu Plk1 phosphorylation of CAP-H2 at Ser288 is required for the accumulation of CAP-H2 and accurate chromosomal condensation during prophase. 0.442 SIGNOR-278419 CBL protein P22681 UNIPROT FRS2 protein Q8WU20 UNIPROT down-regulates ubiquitination 9606 11997436 YES lperfetto The experiments presented in this report illustrate that in response to fgf stimulation, cbl is recruited by grb2 binding to the frs2_ multiprotein complex, resulting in ubiquitination of frs2_ and fgfr. grb2 functions as a link between frs2_ and cbl;grb2 is bound to tyrosine-phosphorylated frs2_ by means of its sh2 domain and to a proline-rich region in the c terminus of cbl by means of its sh3 domains. 0.575 SIGNOR-87166 TAF10 protein Q12962 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 YES lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module 0.775 SIGNOR-269581 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 BTO:0000938 24614225 YES lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. 0.542 SIGNOR-204696 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 10454565 YES Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro 0.842 SIGNOR-248479 TNIP1 protein Q15025 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT up-regulates activity relocalization 21885437 YES lperfetto ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. 0.451 SIGNOR-275735 HACD2 protein Q6Y1H2 UNIPROT FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 YES Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, 0.2 SIGNOR-267761 CXCL8 protein P10145 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 NO miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection 0.7 SIGNOR-261030 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT up-regulates activity phosphorylation Tyr405 PTSLRAHyDTPRSLC 10090 20603078 YES miannu Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. 0.723 SIGNOR-273846 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 YES lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. 0.383 SIGNOR-161626 TP53 protein P04637 UNIPROT CCNG1 protein P51959 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 9688532 YES lperfetto Individual promoter and intron p53-binding motifs from the rat Cyclin G1 promoter region support transcriptional activation by p53 but do not show co-operative activation. 0.79 SIGNOR-268961 CTNND2 protein Q9UQB3 UNIPROT CDH5 protein P33151 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 YES miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. 0.316 SIGNOR-252132 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser693 ASITSMLsPSFTPTS 9606 22966201 YES llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. 0.322 SIGNOR-199000 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 YES miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. 0.8 SIGNOR-270415 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser73 SAVRLRSsVPGVRLL -1 11895474 YES miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.  0.307 SIGNOR-250243 STK3 protein Q13188 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates phosphorylation 9606 21808241 YES inferred from 70% of family members gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. 0.619 SIGNOR-269862 DCAF7 protein P61962 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates activity binding 9534 BTO:0000298 14593110 YES Giorgia Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions. 0.712 SIGNOR-260630 CORT protein O00230 UNIPROT SSTR4 protein P31391 UNIPROT up-regulates binding 9606 BTO:0000938 11011067 YES gcesareni Cortistatin is known to bind all five cloned somatostatin receptors and share many pharmacological and functional properties with somatostatin including the depression of neuronal activity. 0.649 SIGNOR-82493 POU5F1 protein Q01860 UNIPROT HLX protein Q14774 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 NO miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. 0.2 SIGNOR-254936 GNB/GNG complex SIGNOR-C202 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates 23994464 YES apalma Similar to PLCβ activation, PI3K-activation by neutrophil GPCRs also occurs primarily through Gβγ subunits, through the unique PI3Kγ isoform which is directly activated by Gβγ dimers 0.489 SIGNOR-255010 STAT6 protein P42226 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19567879 NO lperfetto We demonstrate that IL-4dependent Jmjd3 expression is mediated by STAT6, a major transcription factor of IL-4mediated signaling. After IL-4 stimulation, activated STAT6 is increased and binds to consensus sites at the Jmjd3 promoter. 0.433 SIGNOR-249539 SP1 protein P08047 UNIPROT CADM1 protein Q9BY67 UNIPROT up-regulates quantity by expression transcriptional regulation 18794147 NO lperfetto Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation. 0.252 SIGNOR-268958 GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 NO lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors 0.2 SIGNOR-268590 Ub:E2 complex SIGNOR-C497 SIGNOR RNF7 protein Q9UBF6 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271116 ARHGAP19 protein Q14CB8 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 YES Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). 0.567 SIGNOR-260471 NDUFA4 protein O00483 UNIPROT Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 YES lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits 0.539 SIGNOR-267752 VPS16 protein Q9H269 UNIPROT HOPS tethering complex complex SIGNOR-C549 SIGNOR form complex binding 9606 23351085 YES miannu The two Vps-C complexes CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) perform diverse biochemical functions in endocytosis: they tether membranes, interact with Rab GTPases, activate and proof-read SNARE assembly to drive membrane fusion, and possibly attach endosomes to the cytoskeleton. The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) The core subunits Vps11, Vps16 and Vps18 present the SNARE-interacting Vps33 subunit on one side and bind the Rab GTPase interaction module through Vps3/Vps8 (in CORVET) or Vps39/Vps41 (in HOPS) on the other side (Fig. 3A) 0.934 SIGNOR-273687 F2R protein P25116 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.566 SIGNOR-257353 SNX9 protein Q9Y5X1 UNIPROT DNM2 protein P50570 UNIPROT up-regulates binding 9606 BTO:0000567 15703209 YES miannu Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes. 0.811 SIGNOR-133976 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu72 CSYEEAFeALESSTA -1 10556651 YES lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. 0.668 SIGNOR-263683 CAMK2A protein Q9UQM7 UNIPROT SLN protein O00631 UNIPROT down-regulates activity phosphorylation Thr5 tRELFLNF 10116 23455424 YES lperfetto SLN is also phosphorylated by CaMKII at Thr 5, and a phosphorylation mimic (Thr5Glu mutation) abolishes the inhibitory function of ectopically expressed SLN in adult rat ventricular myocytes| Thr 5 interacts with SERCA Trp 932, and phosphorylation at this site would cause a steric clash that destabilizes binding 0.241 SIGNOR-264778 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1651 SPTSPSYsPTSPSYS -1 15125841 YES Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro 0.854 SIGNOR-248818 KLC1 protein Q07866 UNIPROT TOR1A protein O14656 UNIPROT up-regulates activity binding 10116 14970196 YES Monia We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wildtype torsinA and kinesin-I form a complex in vivo. These studies suggest that wild-type torsinA undergoes anterograde transport along microtubules mediated by kinesin and may act as a molecular chaperone regulating kinesin activity and/or cargo binding. 0.39 SIGNOR-261172 ATM protein Q13315 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT down-regulates phosphorylation Ser19 GTSKCPPsQRVPALT 9606 18536714 YES llicata Disruption of the hipk2-siah-1 complex is mediated by the atm/atr pathway and involves atm/atr-dependent phosphorylation of siah-1 at ser 19. 0.308 SIGNOR-177945 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR WIPI2 protein Q9Y4P8 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 30898011 YES miannu Here we show that WIPI2/ATG18B (WD repeat domain, phosphoinositide interacting 2), an autophagy-related (ATG) protein that plays a critical role in autophagosome biogenesis, is a direct substrate of CUL4-RING ubiquitin ligases (CRL4s) 0.2 SIGNOR-272302 PRKG1 protein Q13976 UNIPROT CRIP2 protein P52943 UNIPROT unknown phosphorylation Ser104 RAEERKAsGPPKGPS 9534 BTO:0000298 10681529 YES lperfetto  Cyclic GMP kinase I phosphorylated CRP2 at Ser-104, because the mutation to Ala completely prevented the in vivo phosphorylation. 0.451 SIGNOR-249038 MAP2K1 protein Q02750 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser304 LSSYGMDsRPPMAIF -1 8226933 YES MEK1 and MEK2 can also be activated by autophosphorylation. Tyrosine 304 may be a candidate for the autophosphorylation site in MEK1. 0.2 SIGNOR-251415 SPP1 protein P10451 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates binding 9606 10835423 YES gcesareni Among others, vitronectin (vn)1- (11, 13, 14) and osteopontin (opn)-coated (15-20) substrates have been shown to support cell adhesion via avb3. 0.619 SIGNOR-77910 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser341 GTMSRPAsVDGSPVS -1 12351658 YES IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. 0.654 SIGNOR-251294 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 9315650 YES llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. 0.436 SIGNOR-269324 D-thyroxine smallmolecule CHEBI:30659 ChEBI THRB protein P10828 UNIPROT up-regulates activity chemical activation 9606 BTO:0003736 6777394 YES miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. 0.8 SIGNOR-258401 Cullin 1-RBX1-Skp1 complex SIGNOR-C529 SIGNOR NLRP3 protein Q96P20 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys689 GFLHNMPkEEEEEEK 9606 BTO:0000018 26037928 YES miannu LPS exposure reduces the ubiquitin-mediated proteasomal processing of NALP3 by inducing levels of an E3 ligase component, FBXO3, which targets FBXL2. The latter is an endogenous mediator of NALP3 degradation. FBXL2 recognizes Trp-73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation.  0.2 SIGNOR-272434 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001853 24379783 YES lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites 0.263 SIGNOR-251618 RXRA protein P19793 UNIPROT PPARD protein Q03181 UNIPROT up-regulates binding 9606 11237216 YES lperfetto Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology 0.581 SIGNOR-105442 F2RL3 protein Q96RI0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22318735 YES gcesareni Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13). 0.483 SIGNOR-196012 HDAC3 protein O15379 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 23213415 YES gcesareni We show here that smad7 can form a complex with endogenous histone deacetylase proteins hdac-1 and hdac-3 in nih 3t3 mouse fibroblast cells 0.342 SIGNOR-199967 ATM protein Q13315 UNIPROT RNF40 protein O75150 UNIPROT up-regulates phosphorylation 9606 21763684 YES gcesareni E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm. 0.444 SIGNOR-175003 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates 9606 18481201 NO lperfetto Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. 0.635 SIGNOR-244877 DNER protein Q8NFT8 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000938 15965470 YES gcesareni Dner binds to notch1 at cell-cell contacts and activates notch signaling in vitro. 0.46 SIGNOR-138346 P-TEFb complex SIGNOR-C238 SIGNOR MLLT3 protein P42568 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000007 17135274 YES miannu Phosphorylation of Af9 and Enl by P-TEFb promotes their proteolysis 0.698 SIGNOR-266800 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 10090 BTO:0002572;BTO:0000801 21232017 YES miannu TRADD and RIP1 contain a C‐terminal death domain which mediates binding to the death domain of TNFR1. Upon association with ligated TNFR1, TRADD further recruits the adapter protein TRAF2 via its N‐terminal TRAF‐binding domain 0.805 SIGNOR-245029 CDC14B protein O60729 UNIPROT KMT5A protein Q9NQR1 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 YES The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis. 0.2 SIGNOR-248339 EIF6 protein P56537 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR down-regulates activity binding 9606 14654845 YES lperfetto The assembly of 80S ribosomes requires joining of the 40S and 60S subunits, which is triggered by the formation of an initiation complex on the 40S subunit. This event is rate-limiting for translation, and depends on external stimuli and the status of the cell. Here we show that 60S subunits are activated by release of eIF6 (also termed p27BBP). | Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. 0.493 SIGNOR-269150 ADSS2 protein P30520 UNIPROT N(6)-(1,2-dicarboxylatoethyl)-AMP(4-) smallmolecule CHEBI:57567 ChEBI up-regulates quantity chemical modification 9606 10496970 YES miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. 0.8 SIGNOR-267347 SP1 protein P08047 UNIPROT PCYT1A protein P49585 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 10744779 YES Luana Sp1 and Sp3 function as transcriptional activators of the Ctpct promoter 0.2 SIGNOR-266231 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 YES lperfetto We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1 0.493 SIGNOR-176887 PRKG1 protein Q13976 UNIPROT ENAH protein Q8N8S7 UNIPROT down-regulates activity phosphorylation 9606 15066263 YES miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts. PKG may preferentially phosphorylate sites of Ena/VASP proteins that reduce or inactivate these proteins. Inactivated Ena/VASP proteins dissociate from actin filaments, allowing capping proteins to bind and block monomer addition to plus ends, resulting in filament retraction. 0.303 SIGNOR-268288 RARG protein P13631 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 YES gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. 0.686 SIGNOR-16659 AFF2 protein P51816 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 17135274 YES miannu Here, we provide the first evidence for a direct role of AF4 in the regulation of transcriptional elongation by RNA polymerase II (Pol II). We demonstrate that mouse Af4 functions as a positive regulator of Pol II transcription elongation factor b (P-TEFb) kinase and, in complex with MLL fusion partners Af9, Enl and Af10, as a mediator of histone H3-K79 methylation by recruiting Dot1 to elongating Pol II. These pathways are interconnected and tightly regulated by the P-TEFb-dependent phosphorylation of Af4, Af9 and Enl which controls their transactivation activity and/or protein stability. 0.2 SIGNOR-266797 FLT3 protein P36888 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15003515 NO Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. 0.288 SIGNOR-261520 CSNK2A2 protein P19784 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates activity phosphorylation Ser421 IACEEEFsDSEEEGE 9606 BTO:0000661 11602581 YES llicata Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified. Loss of phosphorylation at Ser(421) and Ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of HDAC1. 0.399 SIGNOR-250999 KEAP1 protein Q14145 UNIPROT CUL3-RBX1-KEAP1 complex SIGNOR-C562 SIGNOR form complex binding 9606 24138990 YES miannu KEAP1/CUL3/RBX1 E3-ligase protein complex exert different functions under physiological and oxidative conditions. 0.841 SIGNOR-279841 hsa-mir-145-5p mirna URS0000527F89_9606 RNAcentral ADAM17 protein P78536 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005865 23076445 YES Tiberia Ectopic expression of miR-145 in U87 and U251n glioma cells caused decreased proliferation, migration and invasion with accompanying low protein expression of ADAM17. 0.4 SIGNOR-279885 CUL3 protein Q13618 UNIPROT CUL3-RBX1-KEAP1 complex SIGNOR-C562 SIGNOR form complex binding 9606 24138990 YES miannu KEAP1/CUL3/RBX1 E3-ligase protein complex exert different functions under physiological and oxidative conditions. 0.927 SIGNOR-279842 CHD8 protein Q9HCK8 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 BTO:0000567 19255092 YES miannu We also show that CHD8 associates with the elongating form of RNAPII, which is phosphorylated in its carboxy-terminal domain (CTD). Furthermore, CHD8-depleted cells are hypersensitive to drugs that inhibit RNAPII phosphorylation at serine 2, suggesting that CHD8 is required for an early step of the RNAPII transcription cycle. 0.277 SIGNOR-268806 hsa-miR-148a-3p mirna URS00003BBF48_9606 RNAcentral ADAM17 protein P78536 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001109 33356812 YES Tiberia Transfection of HCT116 with miR-148a inhibited ADAM17 expression and luciferase activity. MiR-148a directly suppresses ADAM17 in colonocytes and is downregulated in colon cancer. 0.4 SIGNOR-279886 hsa-mir-152-3p mirna URS00003AFD9B_9606 RNAcentral ADAM17 protein P78536 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001109 33356812 YES Tiberia Transfection of HCT116 with miR-152-3p inhibited ADAM17 expression and luciferase activity.MiR-152 directly suppresses ADAM17 in colonocytes and is downregulated in colon cancer. 0.4 SIGNOR-279887 hsa-miR-338-3p mirna URS00000254A6_9606 RNAcentral ADAM17 protein P78536 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002181 26617808 YES Tiberia MiR-338-3p is significantly reduced in gastric cancer and inhibits cell proliferation, migration and invasion through downregulation of ADAM17, therefore, miR-338-3p may represent a potential therapeutic target for gastric cancer intervention. 0.4 SIGNOR-279888 hsa-mir-708-3p mirna URS000049EEDF_9606 RNAcentral ADAM17 protein P78536 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001590 29869625 YES Tiberia MiR-708-3p directly regulates its target gene, a disintegrin and metalloproteinase 17 (ADAM17), through a binding site in the 3' untranslated region. MiR-708-3p blocked the expression of ADAM17 0.4 SIGNOR-279889 hsa-mir-224-5p  mirna URS0000D55DFB_9606 RNAcentral ADAM17 protein P78536 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005855 31207072 YES Tiberia Luciferase and Western blot assays revealed that ADAM17 protein was a downstream target of miR-224. MiR-224 inhibits the growth and invasion of OSCC cells by regulating the expression of ADAM17. 0.4 SIGNOR-279890 hsa-mir-146a-5p mirna URS000050B527_9606 RNAcentral FERMT1 protein Q9BQL6 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005170 28595995 YES Tiberia Transfection of miR-146a suppressed the luciferase activity of reporters containing 3' UTR regions of FERMT1. Transfection of miR-146a suppressed the expression of endogenous FERMT1 at the mRNA level and, to a lesser extent, at the protein level, when stimulated with TNF-α, IFN-γ, or IL-17A. 0.4 SIGNOR-279891 EGFL7 protein Q9UHF1 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 9606 20372059 NO miannu EGFL7 drives the formation of neurons from neural stem cells. In the embryonic and adult brain this process is essential for neurogenesis and homeostasis of the nervous system. In this review, we discuss the implications of our findings for adult neurogenesis and illustrate the potential of EGFL7 to serve as an agent to increase neurogenesis and the self-renewal potential of the brain 0.7 SIGNOR-266859 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001056 23409026 YES miannu Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. 0.8 SIGNOR-259269 hsa-miR-21-5p mirna URS000039ED8D_9606 RNAcentral TGFBR2 protein P37173 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0005198 19816956 YES Tiberia Overexpression of miR-21 reduced both protein and mRNA levels of TGFBR2. 0.4 SIGNOR-279892 hsamir7085p mirna URS000019D79B_9606 RNAcentral IKBKG protein Q9Y6K9 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004602 25623956 YES Tiberia Transfection of endothelial cells with pre-miR-708 reduced IKK-γ protein levels compared to control groups. 0.4 SIGNOR-279894 hsa-mir-98-5p mirna URS00004E0808_9606 RNAcentral CHUK protein O15111 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004602 25623956 YES Tiberia Transfection of endothelial cells with pre-miR-98 reduced CHUK levels, compared to control groups. 0.4 SIGNOR-279895 hsa-let7c-5p mirna URS000050DE77_9606 RNAcentral TGFBR1 protein P36897 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001950 19841744 YES Tiberia Let-7c was able to inhibit the expression of both HMGA2 (a known target of let-7c) and TGFBR1 mRNAs. At the protein level, TGFBR1 expression was significantly inhibited by let-7c and the nonspecific effect of the pre-miR negative control was not observed after 72 h. 0.4 SIGNOR-279897 CUL3-RBX1-KEAP1 complex SIGNOR-C562 SIGNOR NFE2L2 protein Q16236 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0003081 39534872 YES miannu NFE2L2 is primarily regulated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, which, under normal conditions, promotes the ubiquitination and proteasomal degradation of NFE2L2, keeping its cellular levels low. 0.582 SIGNOR-279844 bafilomycin A1 chemical CHEBI:22689 ChEBI ATP6V1A protein P38606 UNIPROT down-regulates activity chemical inhibition 9606 9572882 YES Simone Vumbaca The macrolide antibiotic bafilomycin A1 is a very potent and specific inhibitor of V-ATPases. 0.8 SIGNOR-261084 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 YES lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. 0.311 SIGNOR-120116 EGFR protein P00533 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr725 AGGGSATyMDQAPSP 9606 11751923 YES llicata Novel activation of stat5b in response to epidermal growth factor. novel activation of stat5b in response to epidermal growth factor. 0.829 SIGNOR-113393 Vincristine sulfate chemical CHEBI:79401 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000142 30599272 YES miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. 0.8 SIGNOR-259254 IL34 protein Q6ZMJ4 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000876 BTO:0001103 24890514 YES apalma The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34) 0.912 SIGNOR-255569 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7310 ADPKKSAsRPGSRAG 9606 BTO:0004905 21295697 YES lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. 0.436 SIGNOR-264430 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY 10090 BTO:0000944 8131746 YES lperfetto Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity. 0.66 SIGNOR-235564 CXCL11 protein O14625 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 YES miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. 0.776 SIGNOR-260971 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ETV6 protein P41212 UNIPROT down-regulates phosphorylation 10090 15060146 YES inferred from 70% family members miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. 0.2 SIGNOR-270120 Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 28347630 NO miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation 0.7 SIGNOR-266830 CDK1 protein P06493 UNIPROT CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser116 PQKLLGCsPALKRSH 9606 SIGNOR-C17 12411508 YES lperfetto Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover. 0.842 SIGNOR-95256 hsa-mir-186-5p mirna URS000040DCFF_9606 RNAcentral XIAP protein P98170 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0003324 30816481 YES Tiberia The dual luciferase reporter gene experiment found that miR-186-5p could directly combine with the 3'-UTR of XIAP mRNA and further inhibit XIAP expression directly. 0.4 SIGNOR-279902 hsa-mir-27a-3p mirna URS00003B95DA_9606 RNAcentral ICOS protein Q9Y6W8 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0000011 32212417 YES Tiberia The interaction between miR-27a-3p and ICOS was confirmed by dual-luciferase reporter assay. miR-27a-3p showed negative correlation with ICOS and suppressed its expression. 0.4 SIGNOR-279906 ATM protein Q13315 UNIPROT PAN2 protein Q504Q3 UNIPROT up-regulates activity phosphorylation Ser1003 TKSTIKPsQMSVARI 9606 BTO:0000007 33097710 YES miannu Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52.  0.2 SIGNOR-273508 NOTCH1 protein P46531 UNIPROT HEY1 protein Q9Y5J3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11486044 YES lperfetto These data establish that HERP2 is a novel primary target gene of Notch that, together with HES, may effect diverse biological activities of Notch 0.773 SIGNOR-235397 hsa-miR-106a-5p mirna URS00003FE4D4_9606 RNAcentral STAT3 protein P40763 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0006483 36157880 YES Tiberia Interestingly, MiR-106a has been reported to be a downregulated miRNA that suppresses Th17 differentiation and reduces the severity of autoimmune inflammatory response by targeting ROR γ t and STAT3 0.4 SIGNOR-279911 hsa-miR-20b-5p mirna URS00002B3783_9606 RNAcentral STAT3 protein P40763 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0006483 36157880 YES Tiberia MiR-20b is a downregulated miRNA that suppresses Th17 differentiation and reduces the severity of autoimmune inflammatory response by targeting ROR γ t and STAT3 0.4 SIGNOR-279912 hsa-miR-122-5p mirna URS00003380CC_9606 RNAcentral EGFR protein P00533 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000195 28641303 YES Tiberia MiR-122a could be a positive factor of zonulin by targeting EGFR, which increased the intestinal epithelial permeability in vivo and in vitro. 0.4 SIGNOR-279913 hsa-miR-138-5p mirna URS000040780F_9606 RNAcentral CTLA4 protein P16410 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0006483 26658052 YES Tiberia We observed only a partial downregulation of CTLA-4 expression by miR-138, which could be due to insufficient miRNA delivery with our current technique or to the involvement of other yet undefined epigenetic regulators. 0.4 SIGNOR-279914 hsa-miR-138-5p mirna URS000040780F_9606 RNAcentral PDCD1 protein Q15116 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0006483 26658052 YES Tiberia Partial downregulation of PD-1 expression by miR-138, which could be due to insufficient miRNA delivery with our current technique or to the involvement of other yet undefined epigenetic regulators. 0.4 SIGNOR-279915 hsa-mir-379-5p  mirna URS000060A1F4_9606 RNAcentral STAT1 protein P42224 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001950 35945406 YES Tiberia By combining mass spectrometry (MS) and luciferase assay, we identified miR-379-5p that suppresses STAT1 through transcriptional and translational regulation. 0.4 SIGNOR-279916 hsa-mir-483-3p mirna URS00000EA063_9606 RNAcentral STAT3 protein P40763 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001938 33546665 YES Tiberia Mechanistically, miR-483 specifically targeted the 3' untranslated region (3'UTR) of STAT3 and repressed its expression. 0.4 SIGNOR-279917 hsa-miR-155-5p mirna URS0000338542_9606 RNAcentral STAT1 protein P42224 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000182 28418858 YES Tiberia As expected, STAT1 expression was inhibited in CRC cells in response to miR-155 overexpression. 0.4 SIGNOR-279918 hsa-mir-132-3p mirna URS00006054DA_9606 RNAcentral SPRY1 protein O43609 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0001949 25945589 YES Tiberia We found that miR-132 can significantly suppress the luciferase activity of Spry1 -3'UTR at 25 nmol/L, compared with scramble control miRNAs. 0.4 SIGNOR-279922 hsa-mir-210-3p  mirna URS000055128B_9606 RNAcentral SPRED2 protein Q7Z698 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000182 26254226 YES Tiberia MiR-210 can directly inhibit the expression of sprouty-related domain 2 of EVH1 (SPRED2), and SPRED2 reduces cell migration through ERK/c-Fos/MMP pathways. 0.4 SIGNOR-279923 hsa-miR-31-5p mirna URS00005416E3_9606 RNAcentral SPRED1 protein Q7Z699 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000552 29605672 YES Tiberia Luciferase reporter assay showed that miR-31 mimics significantly repressed the luciferase activity of constructs containing Spred1 3'UTR elements 0.4 SIGNOR-279924 hsa-miR-31-5p mirna URS00005416E3_9606 RNAcentral SPRY4 protein Q9C004 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000552 29605672 YES Tiberia Luciferase reporter assay showed that miR-31 mimics significantly repressed the luciferase activity of constructs containing Spry4 3'UTR elements. 0.4 SIGNOR-279925 hsa-miR-31-5p mirna URS00005416E3_9606 RNAcentral RASA1 protein P20936 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000552 29605672 YES Tiberia The luciferase reporter assay showed that miR-31 mimics significantly repressed the luciferase activity of the constructs containing Rasa1 3'UTR elements. 0.4 SIGNOR-279926 CDK1 protein P06493 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr221 KDEILPTtPISEQKG 9606 21871177 YES gcesareni These results suggest that the phosphorylation of rps3 by cdk1 occurs at thr221 during g2/m phase and, moreover, that this event is important for nuclear accumulation of rps3. 0.363 SIGNOR-176131 hsa-miR-31-5p mirna URS00005416E3_9606 RNAcentral SPRED2 protein Q7Z698 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000552 29605672 YES Tiberia Luciferase reporter assay showed that miR-31 mimics significantly repressed the luciferase activity of constructs containing Spred2 3'UTR elements. 0.4 SIGNOR-279927 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral LRP6 protein O75581 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0003264 23811937 YES Tiberia To understand the role of LRP6 in miR-126-mediated Wnt/β-catenin signaling pathway, we examined the downstream gene expression after CVB3 infection. We confirmed that miR-126 mimetic suppressed LRP6 expression 0.4 SIGNOR-279928 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral RHOU protein Q7L0Q8 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0003264 23811937 YES Tiberia To understand the role of and RHOU in miR-126-mediated Wnt/β-catenin signaling pathway, we examined the downstream gene expression after CVB3 infection. We first confirmed that miR-126 mimetic suppressed RHOU expression, while miR-126 inhibitor increased WRCH1 expression. 0.4 SIGNOR-279929 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral VCAM1 protein E9PDD2 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002524 26968021 YES Tiberia The results suggest that miR-126a-3p could directly bind and inhibit the expression of VCAM-1. 0.4 SIGNOR-279930 has-mir-126-3p mirna URS00001F1DA8_9606 RNAcentral SPRED1 protein Q7Z699 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0002524 26968021 YES Tiberia The results suggest that miR-126a-3p could directly bind and inhibit the expression of SPRED1. 0.4 SIGNOR-279931 MTOR protein P42345 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser2481 TVPESIHsFIGDGLV 9606 BTO:0000782 SIGNOR-C2 SIGNOR-C2 10702316 YES lperfetto We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase). 0.2 SIGNOR-75394 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 YES lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. 0.708 SIGNOR-249644 MECP2 protein P51608 UNIPROT BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 18599437 NO MeCP2 is involved in gene silencing and known to affect the activity of brain-derived neurotrophic factor (BDNF) 0.471 SIGNOR-254023 sulindac chemical CHEBI:9352 ChEBI RXRA protein P19793 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001109 20541701 YES Luana NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling 0.8 SIGNOR-257847 REEP5 protein Q00765 UNIPROT CXCR1 protein P25024 UNIPROT up-regulates activity binding 9606 27966653 YES miannu In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses. 0.324 SIGNOR-261366 E protein P59637 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity 9534 BTO:0001444 22028656 NO miannu SARS-CoV E protein down-regulated the signaling pathway inositol-requiring enzyme 1 (IRE-1) of the unfolded protein response, but not the PKR-like ER kinase (PERK) or activating transcription factor 6 (ATF-6) pathways, and reduced cell apoptosis. 0.2 SIGNOR-260347 DSCAML1 protein Q8TD84 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000938 30745319 NO miannu Nuclear DSCAM and DSCAML1 impair neurite outgrowth. this demonstrates that enhanced nuclear translocation of the DSCAM and DSCAML1 ICDs profoundly impairs neurite outgrowth and development of primary cortical neurons 0.7 SIGNOR-264275 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser240 RLSSLRAsTSKSESS 9606 21233202 YES lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity 0.59 SIGNOR-171243 NCAPH2 protein Q6IBW4 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 YES miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. 0.903 SIGNOR-263910 CAPN1 protein P07384 UNIPROT CDK5R1 protein Q15078 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 YES lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain 0.57 SIGNOR-251583 leucine smallmolecule CHEBI:25017 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 22749528 NO Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 0.8 SIGNOR-268010 CSNK2A1 protein P68400 UNIPROT DTD1 protein Q8TEA8 UNIPROT up-regulates activity phosphorylation Ser182 AKGPSESsKERNTPR -1 25258324 YES done miannu  Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D). 0.285 SIGNOR-273978 MAPK14 protein Q16539 UNIPROT JUNB protein P17275 UNIPROT up-regulates phosphorylation Ser79 QGSDTGAsLKLASSE 9606 15308641 YES lperfetto These results clearly demonstrate that phosphorylation by p38 kinase is essential for the regulation of dmp1 transcription by junb and p300. phosphorylation of junb at ser-79 was found to be essential for its interaction with p300. 0.501 SIGNOR-127545 SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16829981 YES gcesareni In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation. 0.819 SIGNOR-147865 SH2B1 protein Q9NRF2 UNIPROT BLNK protein Q8WV28 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000776 32323266 YES scontino SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK. 0.2 SIGNOR-268446 TNF protein P01375 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 NO scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. 0.2 SIGNOR-267485 ATM protein Q13315 UNIPROT DCK protein P27707 UNIPROT up-regulates activity phosphorylation Ser74 EFEELTMsQKNGGNV 27879648 YES lperfetto Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. 0.4 SIGNOR-275798 RAP1GDS1 protein P52306 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 21242305 YES miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob 0.417 SIGNOR-171415 PRKAA2 protein P54646 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser505 GSVKRVTsGPSLGSL 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 20231899 YES gcesareni Ampk-wild type (wt) stimulates pld activity, while ampk-dominant negative (dn) inhibits it. Ampk regulates pld1 activity through phosphorylation of the ser-505 and this phosphorylation is increased by the presence of amp. 0.2 SIGNOR-164293 P4HA1 protein P13674 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity 31239153 NO miannu P4HA1 regulates HIF1a activity in pancreatic cancer. P4HA1 can also increase HIF1a protein level in PDAC cells indicative of a positive feedback loop between P4HA1 and HIF1a. 0.314 SIGNOR-279875 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 YES gcesareni Here we show that in vitro, atm phosphorylates the ser-gln/thr-gln (sq/tq) cluster domain (scd) on chk2, which contains seven sq/tq motifs, and thr68 is the major in vitro phosphorylation site by atm. Atm predominantly phosphorylates chk2 at thr68, promoting homodimerization and activation via intramolecular trans-autophosphorylation at thr383/387. 0.834 SIGNOR-81438 N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 17194761 YES miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. 0.8 SIGNOR-267525 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser639 YMPMSPKsVSAPQQI 10116 BTO:0000452 11287630 YES lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten 0.766 SIGNOR-106590 acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 9606 19524112 YES miannu The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA. 0.8 SIGNOR-267520 CASP7 protein P55210 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 YES lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. 0.319 SIGNOR-261751 ARID5B protein Q14865 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 NO miannu ARID5B transcriptionally activates the oncogene MYC in T-ALL cells 0.275 SIGNOR-256156 PPM1A protein P35813 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 YES Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. 0.337 SIGNOR-248493 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation Tyr420 RLIEDNEyTARQGAK 9606 22080863 YES lperfetto Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks 0.2 SIGNOR-177109 CCKBR protein P32239 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.265 SIGNOR-256908 MFN2 protein O95140 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 NO lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria 0.7 SIGNOR-272985 STK39 protein Q9UEW8 UNIPROT CFTR protein P13569 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000988 21317537 YES lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, 0.345 SIGNOR-264643 MAPK14 protein Q16539 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser396 TFDSLPSsPSSATPH -1 12171600 YES miannu Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%. 0.334 SIGNOR-249707 RSPO2 protein Q6UXX9 UNIPROT LGR5 protein O75473 UNIPROT up-regulates binding 9606 21693646 YES Furin domain gcesareni Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation 0.692 SIGNOR-174532 SALL4 protein Q9UJQ4 UNIPROT SALL1 protein Q9NSC2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19440552 NO miannu Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. 0.454 SIGNOR-255127 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser121 ESSDSGTsVSENRCH 9606 20708156 YES gcesareni Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase. 0.346 SIGNOR-167501 codeine chemical CHEBI:16714 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 YES miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. 0.8 SIGNOR-258933 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 12270934 YES inferred from 70% of family members lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. 0.2 SIGNOR-269913 Ub:E2 complex SIGNOR-C497 SIGNOR ZNF511 protein Q8NB15 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271278 INSR protein P06213 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr536 QKGQESEyGNITYPP 9606 7512963 YES llicata Insulin stimulates the phosphorylation of tyr538 and the catalytic activity of ptp1c, a protein tyrosine phosphatase with src homology-2 domains. these results suggest that ptp1c is a target protein for the insulin receptor tyrosine kinase 0.36 SIGNOR-26870 PRKN protein O60260 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000793 20871098 YES miannu Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2.  Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy. 0.2 SIGNOR-272779 AKT proteinfamily SIGNOR-PF24 SIGNOR CFLAR protein O15519 UNIPROT down-regulates quantity phosphorylation Ser273 LLRDTFTsLGYEVQK 9606 19339247 YES gcesareni TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling. 0.2 SIGNOR-245304 UBE3A protein Q05086 UNIPROT EEF1E1 protein O43324 UNIPROT down-regulates quantity ubiquitination 9606 30020076 YES miannu These results strongly suggest that Ube3a decreases p18 levels via ubiquitination followed by proteasomal degradation.|We demonstrate that Ube3a directly ubiquitinates p18 and targets it for proteasomal degradation, which normally limits mTORC1 signaling and activity dependent synaptic remodeling. 0.2 SIGNOR-278680 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA6 protein Q9Y5G7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 YES miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. 0.2 SIGNOR-265716 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR STK3 protein Q13188 UNIPROT up-regulates 9606 22683405 NO milica In response to growth inhibitory signal (e.g. cell–cell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127. 0.7 SIGNOR-230696 epitope chemical CHEBI:53000 ChEBI Class II MHC:Antigen complex SIGNOR-C429 SIGNOR form complex binding 9606 33374673 YES scontino The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR). 0.8 SIGNOR-269479 Cadherins proteinfamily SIGNOR-PF71 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 YES miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin 0.2 SIGNOR-265812 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT up-regulates activity phosphorylation Ser1465 PVDPQVQsAADETAV -1 22302995 YES miannu Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication. 0.7 SIGNOR-262908 NFE2L2 protein Q16236 UNIPROT FECH protein P22830 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 39534872 YES miannu NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.Two critical enzymes in this pathway, ATP binding cassette subfamily B member 6 (ABCB6) and ferrochelatase (FECH), are regulated by the transcription factor NFE2L2 and play significant roles in inhibiting ferroptosis when upregulated. 0.322 SIGNOR-279865 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr18 AIEWPGAyPKLMEID 9606 15952790 YES llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. 0.605 SIGNOR-138142 CSNK1A1 protein P48729 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser318 SRTNSNAsTVSGRLS 9606 20110348 YES lperfetto Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export 0.2 SIGNOR-163672 GATA4 protein P43694 UNIPROT CTNNA3 protein Q9UI47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 YES miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter 0.25 SIGNOR-265490 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates activity chemical activation 10116 10617617 YES We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation. 0.8 SIGNOR-261142 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr1179 GLENGLNyIDLDLVK 9606 7515062 YES gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. 0.897 SIGNOR-27024 AXIN2 protein Q9Y2T1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 BTO:0000149 11940574 NO gcesareni Although wnts act to stabilize _-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3_, and axin1 or its homolog axin2/axil/conductin promotes _-catenin phosphorylation and subsequent proteasomal degradation. 0.848 SIGNOR-116480 bis(2-ethylhexyl) phthalate chemical CHEBI:17747 ChEBI SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression 10116 16257484 NO miannu DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged. 0.8 SIGNOR-268744 PRKCA protein P17252 UNIPROT RALB protein P11234 UNIPROT unknown phosphorylation Ser198 KSSKNKKsFKERCCL 9606 20940393 YES llicata Here we test this hypothesis and show that ralb is phosphorylated at s198 by protein kinase c (pkc). this indicates phosphorylation of ralb is important for the development of lung metastasis in human bladder cancer cells. 0.29 SIGNOR-168532 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1A protein P48039 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257545 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 18728222 YES gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. 0.771 SIGNOR-180532 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1101 NAQNLMQsVKETVRE -1 11741957 YES lperfetto PKC Phosphorylates Serines 1033 and 1045 in Helix H5 0.391 SIGNOR-249128 PATJ protein Q8NI35 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR form complex binding 9606 24366813 YES lperfetto To gain a more detailed view on the organization of this cell polarity network linked to yap1 we included several proteins of the cell junction complex (amot, mpp5, lin7a), 0.2 SIGNOR-203488 PIM1 protein P11309 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization phosphorylation Ser62 S-->E 9606 29472550 YES miannu In addition, PIM1 exerts its tumorigenicity by regulating c-Myc 0.696 SIGNOR-279249 SRMS protein Q9H3Y6 UNIPROT MAP2K4 protein P45985 UNIPROT down-regulates activity phosphorylation Tyr269 RDAGCRPyMAPERID 9606 BTO:0002181 37020040 YES miannu SRMS directly phosphorylates MKK4 and inhibits MKK4-JNK-c-Jun activation upon platinum treatment. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation. 0.2 SIGNOR-277903 EGR1 protein P18146 UNIPROT FAP protein Q12884 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 20515787 NO Down-regulation of EGR1 resulted in a significant reduction in endogenous FAP mRNA expression. These findings identify the basal transcriptional requirements of FAP gene expression and show EGR1 is an important regulator of FAP expression. 0.2 SIGNOR-254248 TRIP11 protein Q15643 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 9256431 YES miannu Trip230 binds to rb independently of thyroid hormone while it forms a complex with tr in a thyroid hormone-dependent manner. Ectopic expression of the protein trip230 in cells, but not a mutant form that does not bind to tr, enhances specifically tr-dependent transcriptional activity. 0.388 SIGNOR-50348 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 YES lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A 0.535 SIGNOR-145311 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR FGB protein P02675 UNIPROT up-regulates activity binding 9606 BTO:0000132 16418530 YES lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. 0.498 SIGNOR-253361 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000567 11583623 YES Smac/DIABLO released from mitochondria amattioni Smac/diablo, an inhibitor of xiap, is released from mitochondria upon receiving apoptotic stimuli and binds to the bir2 and bir3 domains of xiap, thereby inhibiting its caspase-inhibitory activity 0.914 SIGNOR-110831 Odanacatib chemical CID:10152654 PUBCHEM CTSK protein P43235 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-195007 ACVR2A protein P27037 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 34003511 YES lperfetto In ACVR2A/B dKO parental cells, only ACVR2A , but not ACVR2A , could rescue both pSMAD2 and pSMAD1/5 (Fig\u00a04B).|In marked contrast, in ACVR2A/B dKO HOM1 cells, ACVR2A restored SMAD1/5 phosphorylation, but not SMAD2 phosphorylation (Fig\u00a04C). 0.709 SIGNOR-279786 PINK1 protein Q9BXM7 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 9606 29033320 YES miannu Our studies thus indicated that mitophagy\npositively regulated hepatic CSCs by suppressing p53, which otherwise would be activated by\nPINK1 to suppress the expression of NANOG and hepatic CSCs.|These results indicated that the phosphorylation of p53 at S392 by\nPINK1 likely took place on mitochondria. 0.321 SIGNOR-278418 ETF complex SIGNOR-C463 SIGNOR FADH2 smallmolecule CHEBI:17877 ChEBI up-regulates quantity chemical modification 9606 33450351 YES miannu ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a). 0.8 SIGNOR-269455 CCP110 protein O43303 UNIPROT CALM3 protein P0DP25 UNIPROT up-regulates activity binding 9606 16760425 YES miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. 0.329 SIGNOR-266348 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000047 20371771 YES lperfetto Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). 0.2 SIGNOR-268616 AKT proteinfamily SIGNOR-PF24 SIGNOR ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser346 LLCLRRSsLKAYGNG 9606 11809767 YES lperfetto Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation. 0.2 SIGNOR-114470 KPNA4 protein O00629 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 YES gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. 0.287 SIGNOR-254322 WNK4 protein Q96J92 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Ser335 KRASFAKsVIGTPEF -1 25542968 YES miannu  Elimination of the catalytic activity (D321A or D321K-K186D) or the autophosphorylation site (S335A) in mutant WNK4-L322F abrogated the positive effect on NCC.  0.2 SIGNOR-276871 HIF1A protein Q16665 UNIPROT KDM5A protein P29375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 YES SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. 0.273 SIGNOR-271565 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Tyr69 NESGLTEyRLVSINK -1 10978167 YES lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. 0.582 SIGNOR-263564 GTP smallmolecule CHEBI:15996 ChEBI GNAS protein P63092 UNIPROT up-regulates chemical activation 9606 17095603 YES gcesareni Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis. 0.8 SIGNOR-150552 PRIM1 protein P49642 UNIPROT DNA primase complex complex SIGNOR-C261 SIGNOR form complex binding -1 24043831 YES lperfetto Here, we describe the crystal structure of human primase in heterodimeric form consisting of full-length catalytic subunit and a C-terminally truncated large subunit. 0.99 SIGNOR-261339 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0002181 23279204 NO SARA G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs 0.7 SIGNOR-260984 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 9606 16600297 YES lperfetto Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin 0.698 SIGNOR-145837 SPI1 protein P17947 UNIPROT ACP5 protein P13686 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11481336 NO miannu The combination of MITF and PU.1 synergistically activated the TRAP promoter in transient assays. 0.347 SIGNOR-254585 ITCH protein Q96J02 UNIPROT GLI1 protein P08151 UNIPROT down-regulates ubiquitination 9606 20818436 YES gcesareni The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation 0.577 SIGNOR-167838 CSNK2A1 protein P68400 UNIPROT TNFAIP1 protein Q13829 UNIPROT up-regulates phosphorylation Ser280 SRSQASPsEDEETFE 9606 BTO:0000567 19851886 YES lperfetto It was demonstrated that ck2 could phosphorylate tnfaip1 in vitro and in vivo, which facilitated the distribution of tnfaip1 in nucleus and enhanced its interaction with pcna. It is suggested that the phosphorylation of tnfaip1 may be required for its functions. 0.2 SIGNOR-188849 UGP2 protein Q16851 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI down-regulates quantity chemical modification 9606 8631325 YES miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. 0.8 SIGNOR-267926 PRKACA protein P17612 UNIPROT ATP2B1 protein P20020 UNIPROT up-regulates activity phosphorylation Ser1178 APTKRNSsPPPSPNK -1 2548572 YES miannu The ATPase is phosphorylated only at this site by the cAMP-dependent protein kinase, and the phosphorylation is inhibited by calmodulin. The effect of the phosphorylation is to decrease the Km for Ca2+ of the purified ATPase from about 10 microM to about 1.4 microM and to increase the Vmax of ATP hydrolysis about 2-fold. 0.45 SIGNOR-262694 NOTCH1 protein P46531 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 18342499 NO flangone Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages 0.7 SIGNOR-241998 FUS protein P35637 UNIPROT VPS16 protein Q9H269 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 NO This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease 0.2 SIGNOR-262808 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr514 TTTPKGGtPAGSARG 9606 16611631 YES lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro 0.364 SIGNOR-145987 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 YES miannu PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2 0.346 SIGNOR-257601 TCF25 protein Q9BQ70 UNIPROT RQC complex complex SIGNOR-C559 SIGNOR form complex binding 28528489 YES lperfetto The ribosome-bound quality control (RQC) complex is a multi-protein complex conserved throughout eukaryotes and composed of the E3 ubiquitin ligase Ltn1/Listerin, the ATPase Cdc48/p97 with its co-factors Ufd1/UFD1L and Npl4/NPLOC4, as well as the factors Rqc1/TCF25 and Rqc2/NEMF (Fig. 1). 0.461 SIGNOR-277698 RIPK3 protein Q9Y572 UNIPROT OGDC complex SIGNOR-C397 SIGNOR up-regulates activity phosphorylation -1 29358703 YES miannu Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. 0.2 SIGNOR-268066 Myog/SWI/SNF complex complex SIGNOR-C94 SIGNOR MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 17194702 YES miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle 0.483 SIGNOR-151697 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 BTO:0000130 14499342 YES lperfetto Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils. 0.769 SIGNOR-118036 BCS1L protein Q9Y276 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 BTO:0000567 18628306 NO lperfetto We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains. 0.7 SIGNOR-262544 homocysteine smallmolecule CHEBI:17230 ChEBI methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity precursor of 9606 10520212 YES lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. 0.8 SIGNOR-253140 NFIB protein O00712 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 YES Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development 0.2 SIGNOR-268881 PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity chemical modification 9606 12040186 YES lperfetto The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. 0.8 SIGNOR-252713 SB 431542 chemical CHEBI:91108 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other YES Selleck gcesareni 0.8 SIGNOR-206706 ESRRB protein O95718 UNIPROT NR0B1 protein P51843 UNIPROT down-regulates 9606 12482977 NO lperfetto When dax-1 was cotransfected, it exerted efficient repression on transcription of the reporter gene activated by gal4-ad4bp-lbd, gal4-lrh-1-lbd, gal4-err2-lbd 0.343 SIGNOR-96533 CUL3 protein Q13618 UNIPROT TBCB protein Q99426 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000142 18680552 YES miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. 0.245 SIGNOR-268945 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14976552 YES gcesareni We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli 0.626 SIGNOR-122725 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ARRB1 protein P49407 UNIPROT down-regulates phosphorylation 9606 10347142 YES inferred from 70% family members gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation 0.2 SIGNOR-270094 CSNK2A1 protein P68400 UNIPROT GBF1 protein Q92538 UNIPROT down-regulates quantity by destabilization phosphorylation Ser292 VVSPSTDsGLEFSSQ 9606 BTO:0002181 29898406 YES miannu We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation. 0.2 SIGNOR-277397 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 18483407 YES gcesareni We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657. 0.309 SIGNOR-178648 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 34010649 YES lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 0.2 SIGNOR-275948 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 16782899 YES llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain 0.496 SIGNOR-147195 GSK1016790A chemical CID:23630211 PUBCHEM TRPV4 protein Q9HBA0 UNIPROT up-regulates activity binding 23021218 YES lperfetto We next examined whether chemical activation of TRPV4 would have the opposite impact on these pathways. When added to 3T3-F442A adipocytes, the TRPV4 agonist GSK1016790A repressed the expression of mRNAs encoding Pgc1a, Ucp1, and Cox8b in a TRPV4-dependent manner (Fig- ure 2I). Taken together, these data strongly suggest that TRPV4 functions as a negative regulator of PGC1a and oxidative metabolism in white adipocytes. 0.8 SIGNOR-253094 XAV939 chemical CHEBI:62878 ChEBI AXIN2 protein Q9Y2T1 UNIPROT up-regulates 9606 19759537 NO gcesareni Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2 0.8 SIGNOR-188048 TFAP2B protein Q92481 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 YES miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 0.2 SIGNOR-253637 PDPK1 protein O15530 UNIPROT PKN2 protein Q16513 UNIPROT up-regulates phosphorylation Thr816 GYGDRTStFCGTPEF 9606 10753910 YES miannu It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively) 0.704 SIGNOR-76710 KLF4 protein O43474 UNIPROT STAT6 protein P42226 UNIPROT up-regulates 9606 BTO:0000801 22378047 NO lperfetto KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPAR?) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-kappaB activation. 0.346 SIGNOR-249569 SP1 protein P08047 UNIPROT SLC9A3 protein P48764 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 16464174 NO Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity 0.2 SIGNOR-254270 EIF2AK3 protein Q9NZJ5 UNIPROT PPP3CA protein Q08209 UNIPROT down-regulates activity phosphorylation 9606 20700529 YES miannu CN becomes phosphorylated by PERK, decreasing its activity.|Finally, evidence is presented that PERK phosphorylates CN-A at low resting levels of Ca 2+. 0.2 SIGNOR-278933 CSNK2A1 protein P68400 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Ser154 FLWSPFEsLCEIGEK 9606 21209074 YES lperfetto We report here that phosphorylation of cdc27, a core subunit of apc, in response to tgf- signaling can facilitate the activation of apc.we have demonstrated that casein kinase ii (ckii) is involved in the phosphorylation of cdc27 in response to tgf- signaling. 0.379 SIGNOR-170872 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 YES miannu MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. 0.519 SIGNOR-250150 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 YES lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. 0.704 SIGNOR-251588 ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI O-phosphonatoethanaminium(1-) smallmolecule CHEBI:58190 ChEBI up-regulates quantity precursor of 29928787 YES lperfetto In this study, we investigated the roles of ethanolamine kinases (Etnk-1 and 2) and choline kinases (Chk-α and β) in contributing to increased PE in human breast and pancreatic cancer cells. 0.8 SIGNOR-275638 AURKA protein O14965 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 17563743 YES llicata Aurora-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest. 0.448 SIGNOR-155815 EGFR protein P00533 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation 9606 14967450 YES lperfetto The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation 0.737 SIGNOR-121962 PTGER1 protein P34995 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000586 17251915 YES gcesareni Ep1 is a galfaq-coupled receptor that promotes calcium mobilization and pkc activation, whereas ep2 and ep4, which have a more prominent role in colon cancer, are coupled to galfas and stimulate camp accumulation 0.448 SIGNOR-152802 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CKAP2 protein Q8WWK9 UNIPROT up-regulates phosphorylation Thr623 FKELKFLtPVRRSRR 9606 19369249 YES lperfetto Among these, thr-622 was specifically phosphorylated by cdk1-cyclin b1 both in vitro and in vivo. these findings suggest that cdk1-cyclin b1-mediated phosphorylation of tmap is important for and contributes to proper regulation of microtubule dynamics and establishment of functional bipolar spindles during mitosis. 0.295 SIGNOR-216829 GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 19703466 YES Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma) 0.596 SIGNOR-256499 PIM proteinfamily SIGNOR-PF34 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 18593906 YES gcesareni We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels. 0.2 SIGNOR-259425 GRB2 protein P62993 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates activity relocalization 10090 BTO:0000669 23452850 YES GRB2 associated guanine nucleotide exchange factor Sos activates Ras through the exchange of GDP for GTP lperfetto Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate. 0.912 SIGNOR-235773 ABL1 protein P00519 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Tyr266 TDSIRDEyAFLQKKY 9606 BTO:0000793 29022905 YES miannu In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo, which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation. 0.26 SIGNOR-277328 MARK2 protein Q7KZI7 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 16980613 YES lperfetto We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function 0.344 SIGNOR-149583 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr334 MQDNSGTyGKIWEGS 9534 BTO:0000298 11381116 YES The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2). 0.525 SIGNOR-251385 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000567 17868033 YES Simone Vumbaca Apicidin inhibited rhHDACs 2 and 3 in the nanomolar range. 0.8 SIGNOR-261127 EIF2S1 protein P05198 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity transcriptional regulation 9606 27629041 YES miannu ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap dependent translation while concomitantly initiates the preferential translation of ISR specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery 0.638 SIGNOR-260169 ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 YES gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. 0.8 SIGNOR-152546 PHF2 protein O75151 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000007 21532585 YES miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. 0.2 SIGNOR-264516 RAD23B protein P54727 UNIPROT RPA2 protein P15927 UNIPROT up-regulates activity binding 24086043 YES lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo 0.521 SIGNOR-275699 Cytochrome c oxidase-Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 NO lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). 0.7 SIGNOR-262140 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22703233 NO lperfetto Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products. 0.7 SIGNOR-249551 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates activity phosphorylation Ser495 KTMIRKRsFGNPFEG 9534 BTO:0000298 32913128 YES miannu  Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues.  0.2 SIGNOR-277238 CDC25A protein P30304 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates activity dephosphorylation 9606 16682204 YES miannu Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1  [4,5] . 0.855 SIGNOR-277137 FGFR1 protein P11362 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates 9606 12270934 NO lperfetto  Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors 0.31 SIGNOR-218010 CASP3 protein P42574 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity cleavage -1 10579725 YES lperfetto P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro 0.603 SIGNOR-252624 KLF11 protein O14901 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 10207080 NO Regulation miannu Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. 0.2 SIGNOR-251827 FGF11 protein Q92914 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 BTO:0001103 20679355 YES miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. 0.2 SIGNOR-253434 SOSTDC1 protein Q6X4U4 UNIPROT WNT1 protein P04628 UNIPROT down-regulates activity 10090 22829579 NO lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. 0.276 SIGNOR-242704 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000567 16825193 YES lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding 0.486 SIGNOR-236645 AKT1 protein P31749 UNIPROT MDM4 protein O15151 UNIPROT up-regulates quantity by stabilization phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 YES lperfetto We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2. 0.509 SIGNOR-252517 RPS6KA6 protein Q9UK32 UNIPROT EP300 protein Q09472 UNIPROT down-regulates activity phosphorylation Ser89 SELLRSGsSPNLNMG 34261798 YES lperfetto Figure 2G shows that Ser89 phosphorylation of p300, an event that inhibits p300’s acetyltransferase activity (13), was decreased in RSK4-silenced A549 and T24 cells. Consequently, RSK4 may regulate the activity of the NFκB pathway by direct phosphorylation of p300, as recombinant RSK4 phosphorylates p300 on Ser89 in vitro  0.253 SIGNOR-275796 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 25601544 YES Luana We show that mammalian NDR1/2 kinases phosphorylate YAP1 on S127 and thereby negatively regulate YAP1 activity in tissue-cultured cells. 0.383 SIGNOR-259855 CYSLTR2 protein Q9NS75 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.383 SIGNOR-257140 SMURF1 protein Q9HCE7 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity ubiquitination 9606 14701828 YES lperfetto Recently we have found that smurf1 mediates the protein degradation of the osteoblast-specific transcription factor runx2/cbfa1. 0.504 SIGNOR-95233 UBAP2L protein Q14157 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity binding 9606 BTO:0000007 25185265 YES Sara We identified UBAP2L as a novel BMI1-interacting protein. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex 0.513 SIGNOR-261315 PLK3 protein Q9H4B4 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 19889641 YES lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. 0.381 SIGNOR-189057 CDK7 protein P50613 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser403 PEEFISLsPPHEALD 9606 10428966 YES lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. 0.494 SIGNOR-69776 SIK2 protein Q9H0K1 UNIPROT EP300 protein Q09472 UNIPROT down-regulates activity phosphorylation Ser89 SELLRSGsSPNLNMG 9606 26983400 YES miannu Indeed, overexpression of SIK2 increased p300 phosphorylation at Ser89, while knockdown of SIK2 decreased it (Fig. 4B). 0.278 SIGNOR-278368 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 9606 21084559 YES gcesareni Phosphorylation of yap ser127 and of the corresponding sites in yki and taz generates a protein-binding motif for the 14-3-3 family proteins, which, upon binding by a 14-3-3 protein, leads to their cytoplasmic retention. One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. 0.2 SIGNOR-169719 FASN protein P49327 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 15507492 YES Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† 0.8 SIGNOR-267208 CSNK1A1 protein P48729 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 SIGNOR-C110 22083140 YES gcesareni In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] 0.577 SIGNOR-177233 Ub:E2 complex SIGNOR-C497 SIGNOR UNKL protein Q9H9P5 UNIPROT up-regulates activity ubiquitination 9606 34199813 YES miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t 0.2 SIGNOR-271227 GGCX protein P38435 UNIPROT GAS6 protein Q14393 UNIPROT up-regulates activity carboxylation 9606 31226734 YES lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. 0.523 SIGNOR-265923 SLC36A4 protein Q6YBV0 UNIPROT tryptophan smallmolecule CHEBI:27897 ChEBI up-regulates quantity relocalization 8355 21097500 YES lperfetto HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM). 0.8 SIGNOR-264735 PXN protein P49023 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 18650496 NO VEGF pathway Gianni Through the interactions of its multiple protein-protein binding modules, many of which are regulated by phosphorylation, paxillin serves as a platform for the recruitment of numerous regulatory and structural proteins that together control the dynamic changes in cell adhesion, cytoskeletal reorganization and gene expression that are necessary for cell migration and survival. 0.7 SIGNOR-261944 MAPK1 protein P28482 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL 9534 BTO:0004055 8386367 YES lperfetto Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62. 0.734 SIGNOR-235700 Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI up-regulates quantity chemical modification -1 27519411 YES lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]¬∑[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. 0.8 SIGNOR-262129 NTRK2 protein Q16620 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 12074588 YES gcesareni We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction. 0.336 SIGNOR-89764 DVL2 protein O14641 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 17529994 YES amattioni Dix domain of dvl2 mediates dynamic polymerization, which is essential for the signaling activity of dvl2. 0.2 SIGNOR-155224 CSNK2A1 protein P68400 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Ser45 LFRLSEHsSPEEEAS -1 2557337 YES llicata Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase 0.341 SIGNOR-250928 INSR protein P06213 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Tyr174 TIPSQRRyVYYYSYL -1 23995781 YES miannu Our results show that the kinase region of IRβ subunit physically binds to PTEN and phosphorylates on Y27 and Y174. In the current study, we discovered that IR also downregulates PTEN through tyrosine phosphorylation and suggest that Y27 and 174 are the two key tyrosines. 0.443 SIGNOR-276471 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 YES gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. 0.378 SIGNOR-75906 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14633987 YES lperfetto These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction. 0.936 SIGNOR-119370 MERTK protein Q12866 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr376 DRVKSTAyLSPQELE 9606 BTO:0000007 31230815 YES done miannu TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6). 0.2 SIGNOR-274118 PRKCZ protein Q05513 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr375 GRGARGGtRGGRGRI 9606 BTO:0004974 14699138 YES lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation 0.292 SIGNOR-249257 ATF1 protein P18846 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 10391889 YES lperfetto Phosphorylated CREB and ATF1 then bind to the CRE of the egr-1 promoter and cause a stress-dependent transcriptional activation of this gene. 0.275 SIGNOR-271686 IKBKG protein Q9Y6K9 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 14695475 YES Barakat Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquitinated inhibited Bcl10-induced NF-κB activation. 0.827 SIGNOR-274149 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Ser282 FFAKRKRsAPEKSSG 9606 BTO:0000150 23421998 YES lperfetto Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination 0.2 SIGNOR-201042 MTOR protein P42345 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity phosphorylation 9606 35697076 YES miannu Mechanistic target of rapamycin complex 1 (mTORC1) phosphorylates and inhibits eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). 0.801 SIGNOR-278963 SRC protein P12931 UNIPROT CTNND2 protein Q9UQB3 UNIPROT up-regulates activity phosphorylation Tyr1154 QEPSRKDyETYQPFQ 9606 24412473 YES miannu Furthermore, according to our data from immunoprecipitation to py20 antibody, c-Src can phosphorylate delta-catenin on Y1073, Y1176, Y1179 and Y1112, with the predominant sites being Y1073, Y1112 and Y1176.|Interestingly, we found that c-Src can increase the stability of delta-catenin in MEF cells. 0.329 SIGNOR-278326 PTGER1 protein P34995 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 YES GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.448 SIGNOR-257083 lysophosphatidylserine 14:0(1-) chemical CHEBI:72402 ChEBI GPR174 protein Q9BXC1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257503 Thrombin smallmolecule CHEBI:9574 ChEBI F2RL3 protein Q96RI0 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 YES Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. 0.8 SIGNOR-257487 MAP3K14 protein Q99558 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 9520446 YES lperfetto Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176.Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa. 0.724 SIGNOR-217433 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT unknown phosphorylation Tyr345 PERNEGVyTAIAVQE 10090 BTO:0004055 11163214 YES gcesareni These data suggest that Tyr-344 is a major c-Abl phosphorylation site, or that phosphorylation of Tyr-344 is required for subsequent phosphorylation at other tyrosine residues. 0.598 SIGNOR-246219 B-WICH complex complex SIGNOR-C447 SIGNOR RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity binding 9606 BTO:0000567 25883140 YES miannu The chromatin-remodelling complex B-WICH, comprised of William syndrome transcription factor, the ATPase SNF2h and nuclear myosin, specifically activates RNA polymerase III transcription of the 5S rRNA and 7SL genes. 0.2 SIGNOR-268841 PRKG2 protein Q13237 UNIPROT HCN2 protein Q9UL51 UNIPROT down-regulates activity phosphorylation Ser668 DRIGKKNsILLHKVQ 10090 BTO:0000142 21347269 YES miannu Here, we show for the first time that in the HCN2 channel cGMP can also exert an inhibitory effect on gating via cGMP-dependent protein kinase II (cGKII)-mediated phosphorylation.We identify the proximal C-terminus of HCN2 as binding region of cGKII and show that cGKII phosphorylates HCN2 at a specific serine residue (S641) in the C-terminal end of the CNBD. The cGKII shifts the voltage-dependence of HCN2 activation to 2-5 mV more negative voltages and, hence, counteracts the stimulatory effect of cGMP on gating. 0.2 SIGNOR-263185 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr323 GCHLLVAtPGRLVDM 9606 16280325 YES lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. 0.34 SIGNOR-216872 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 21993628 YES gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. 0.8 SIGNOR-176751 MAPK14 protein Q16539 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates phosphorylation Ser211 PGKETNEsPWRSDLL 9606 15817653 YES llicata We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis. 0.509 SIGNOR-135198 CHEK1 protein O14757 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity 9606 28138032 NO miannu Mechanistically, Ras-MEK signaling drives Chk1 expression and promotes cancer cell growth that produces genotoxic stress that requires Chk1 to mediate a response to the consequent DNA damage. Reciprocally, Chk1 engages a negative feedback loop to prevent hyperactivation of Ras-MEK signaling, thereby limiting DNA damage. Ras–MEK signaling transcriptionally activates Chk1, which appears to sustain cancer cell growth by maintaining DNA damage levels below a threshold that would otherwise drive apoptosis. 0.324 SIGNOR-263059 NEK6 protein Q9HC98 UNIPROT FOXJ2 protein Q9P0K8 UNIPROT up-regulates activity phosphorylation Thr23 PQLTLRAtIEKLGSA 9606 27899381 YES miannu Additionally, we found that NEK6 phosphorylated FOXJ2 at Thr23 and Ser254 (XREF_FIG, lanes 3 and 5), and NCOA5 at Ser21 and Ser151 (XREF_FIG, lanes 3 and 4). 0.2 SIGNOR-278964 SPOP protein O43791 UNIPROT GLYR1 protein Q49A26 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25278611 YES miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. 0.274 SIGNOR-272824 CHEK1 protein O14757 UNIPROT FANCE protein Q9HB96 UNIPROT up-regulates phosphorylation Ser374 LFLGRILsLTSSASR 9606 17296736 YES llicata Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway. 0.715 SIGNOR-153023 GRK5 protein P34947 UNIPROT GRK5 protein P34947 UNIPROT up-regulates activity phosphorylation Ser484 VLDIEQFsTVKGVNL -1 8144599 YES Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5. 0.2 SIGNOR-251201 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 15829969 YES lperfetto During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 . 0.954 SIGNOR-135381 PTPRJ protein Q12913 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr813 NSLFTPDyELLTEND 9606 28912580 YES miannu These results support PTPRJ preferentially dephosphorylating Y813 and Y868 in JAK2.|We revealed that PTPRJ negatively regulates leptin signaling by dephosphorylating specific tyrosine residues (Y813 and Y868) in JAK2, the simultaneous phosphorylation of which plays a pivotal role in JAK2 activation. 0.324 SIGNOR-277093 GSK3A protein P49840 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation 9606 phosphorylation:Ser1387 QPLSKSSsSPELQTL 20226003 YES gcesareni Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation. 0.362 SIGNOR-164098 PKM protein P14618 UNIPROT RBBP8 protein Q99708 UNIPROT up-regulates activity phosphorylation Thr126 ELMNERNtLQEENKK 9606 BTO:0002036 30297868 YES miannu Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair. In response to ionizing radiation and oxidative stress, ATM phosphorylates PKM2 at T328 resulting in its nuclear accumulation. 0.2 SIGNOR-277413 IKBKB protein O14920 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Ser201 KPPDEGPsEYQTIPL -1 31950832 YES lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. 0.331 SIGNOR-275518 ABL1 protein P00519 UNIPROT GPX1 protein P07203 UNIPROT up-regulates activity phosphorylation Tyr98 EILNSLKyVRPGGGF 9606 12893824 YES lperfetto GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress. 0.46 SIGNOR-104324 EID2 protein Q8N6I1 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 14612439 YES gcesareni In this study, we examined the effect of eid-2 on smad-mediated tgf- signaling. Here, we show that eid-2 inhibits tgf- /smad transcriptional responses. Eid-2 interacts constitutively with smad proteins, and most strongly with smad3. 0.397 SIGNOR-119171 PPP2CA protein P67775 UNIPROT DCK protein P27707 UNIPROT down-regulates activity dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 YES lperfetto Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation 0.2 SIGNOR-275803 LYN protein P07948 UNIPROT LPXN protein O60711 UNIPROT up-regulates activity phosphorylation Tyr72 NIQELNVySEAQEPK 9606 BTO:0000007 17640867 YES miannu Of a total of 11 tyrosine sites in LPXN, we mutated Tyr(22), Tyr(72), Tyr(198), and Tyr(257) to phenylalanine and demonstrated that LPXN was phosphorylated by Lyn only at Tyr(72) and that this tyrosine site is proximal to the LD3 domain. We further show that LPXN suppressed the secretion of interleukin-2 by BCR-activated A20 B cells and that this inhibition was abrogated in the Y72F LPXN mutant, indicating that the phosphorylation of Tyr(72) is critical for the biological function of LPXN. 0.376 SIGNOR-262892 SP1 protein P08047 UNIPROT PHGDH protein O43175 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18378410 NO miannu Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. 0.2 SIGNOR-255208 DDX5 protein P17844 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 17369852 YES miannu Wt p68 co-immunoprecipitates efficiently with hdac1, the k53r p68 does not / sumoylation is important for the interaction of p68 with hdac1 and for transcriptional repression by p68 0.394 SIGNOR-153715 PRKG1 protein Q13976 UNIPROT PTS protein Q03393 UNIPROT up-regulates phosphorylation Ser19 AQVSRRIsFSASHRL 9606 BTO:0000142 10531334 YES gcesareni Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps 0.257 SIGNOR-71680 EPB41 protein P11171 UNIPROT NUMA1 protein Q14980 UNIPROT up-regulates activity relocalization 9606 23870127 YES lperfetto These results indicate that 4.1 proteins recruit NuMA and dynein to the anaphase cell cortex through their conserved CTD (Figure 2I). 0.534 SIGNOR-266012 CEP68 protein Q76N32 UNIPROT PCNT protein O95613 UNIPROT up-regulates activity relocalization 25503564 YES lperfetto We also found that Cep68 forms a complex with Cep215 (also known as Cdk5Rap2) and PCNT (also known as pericentrin), two PCM (pericentriolar material) proteins involved in centriole engagement. |Cep68 stabilization increases the amount of PCNT at metaphase centrosomes, but does not affect its removal at the end of mitosis 0.341 SIGNOR-275623 6 protein P0DTC6 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity 9606 32529952 NO miannu Orf6 of both SARS-CoV and SARS-CoV-2 were able to inhibit type I (IFNα2 and IFNβ) and type III (IFNλ1 and IFNλ2/3) interferons secretion into cell culture supernatant upon Sendai virus infection (Figure 2(I–L)).Interferon beta luciferase assay showed that orf6 of both viruses were able to effectively inhibit RIG-I induced interferon production (Figure 2(B)). These altogether supported the notion that SARS-CoV-2 is a potent interferon antagonist. 0.2 SIGNOR-262516 6 protein P59634 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity 9606 32529952 NO miannu Orf6 of both SARS-CoV and SARS-CoV-2 were able to inhibit type I (IFNα2 and IFNβ) and type III (IFNλ1 and IFNλ2/3) interferons secretion into cell culture supernatant upon Sendai virus infection (Figure 2(I–L)).Interferon beta luciferase assay showed that orf6 of both viruses were able to effectively inhibit RIG-I induced interferon production (Figure 2(B)). These altogether supported the notion that SARS-CoV-2 is a potent interferon antagonist. 0.2 SIGNOR-262517